Six (nearly 46.2%) of the 13 countries that have at least ten million confirmed cases are in Europe, incl. France, Germany, South Korea, Italy, Japan, Turkey, Spain and Vietnam later joined the list of countries with at least ten million confirmed cases. Brazil, the United Kingdom and Russia joined the list of countries with at least ten million confirmed cases in 2021. The United States and India became first two countries with at least ten million confirmed cases in late 2020. Thailand was the only country to have at least one confirmed case outside China in January 2020. In December 2019 and January 2020, China was the only country to have at least one confirmed case. the United States, India, France, Brazil, Germany, the United Kingdom, South Korea, Italy, Russia, Japan, Turkey, Spain and Vietnam. As of August 2022, 13 countries have at least ten million confirmed cases, incl. In July 2022, Japan joined the list of countries with at least ten million confirmed cases. Later on, in April 2022, Vietnam joined the list of countries with at least ten million cases. In March 2022, South Korea joined the list of countries with at least ten million confirmed cases, days after overtaking Japan in terms of the number of confirmed cases. The United States was also the only country to have at least ten million confirmed cases in November and December 2020. At the beginning of February 2022, Germany and Spain joined the list of countries with at least ten million cases. Then, Italy joined the list of countries with at least ten million confirmed cases. More than a week later, Turkey joined the list of countries with at least ten million confirmed cases. ![]() At the beginning of 2022, France joined the list of countries with at least ten million confirmed cases. In December 2021, Russia became the fifth country to have at least ten million confirmed cases. In November 2021, the United Kingdom became the fourth country to have at least ten million confirmed cases. In February 2021, Brazil became the third country to have at least ten million confirmed cases. In December 2020, India became the second country to have at least ten million confirmed cases. In November 2020, the United States became the first country to have at least ten million confirmed cases. 2 Worldwide timelines by month and year.This entry is part two of a three-part series on the 10th Anniversary of the 9/11 Attacks - (see also Part 1: The Week Before and Part 3: The Decade Since). These attacks and the global reaction to them have profoundly shaped the world we live in, so it remains important to see the images and remember just what happened on that dark day. It was one of the most-covered media events of all time, and after a decade, the images are still difficult to view. More than 400 of the dead were first responders, including New York City firefighters, police officers, and EMTs. In a single day, these deliberate acts of mass murder killed nearly 3,000 human beings from 57 countries. ![]() Three of the planes struck their targets the fourth crashed into a field in Pennsylvania. ![]() The attackers simultaneously hijacked four large passenger aircraft with the intention of crashing them into major landmarks in the United States, inflicting as much death and destruction as possible. ![]() Ten years ago, 19 men trained by al-Qaeda carried out a coordinated terrorist attack on the United States that had been planned for years.
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Events and options in the game are largely determined by the type of person you are. Character Focused Gameplay: Every character you play or interact with has their own unique personality.The PS5’s Activities and Game Help also provide a platform to assist new players as they take their first steps in the world of Crusader Kings. The more stress a character has accrued, the more resistance will be applied to the DualSense controller’s Adaptive Triggers, for instance. PlayStation 5 users will experience the game’s stress mechanics themselves, as their DualSense controllers physically react to in-game events as they unfold. Players will be able to switch between gameplay and other applications, like YouTube, using Quick Resume, where they can consult a tutorial on how to quell a peasant revolt. The console edition also utilizes the key capabilities of the Xbox Series X|S and PlayStation 5, like super-fast load times for a seamless gameplay experience as well as Haptic and Adaptive Trigger controller feedback. The all-new control map lets players quickly and easily navigate the game’s menus via triggers, bumpers, and quick flicks of the analog stick. ![]() Few other games have as rich a tapestry of strategic options, with political marriages to bind noble houses, brutal wars to enforce quasi-legal claims, personal relationships to unite a fractured realm, and even subtle scheming to undermine or eliminate rivals.Ĭrusader Kings III on console features an adapted interface and control scheme specifically tailored to larger screens and console gamepads. Working closely with the team from Paradox, together we've adapted the dynamic and ever-changing gameplay of Crusader Kings III to a new environment, taking advantage of the unique characteristics of console play. We've partnered with Paradox Interactive to bring their celebrated strategy role-playing experience to console, giving an entirely new group of players a chance to build a legendary dynasty in the quintessential historical strategy game. The noble pageantry of medieval grand strategy is coming soon to Xbox Series X|S and PlayStation 5 consoles. ![]() ![]() Devslopes has given me the support I needed to truly learn how to code. Before I started Devslopes I was stuck in an endless cycle of starting tutorials and never finishing. The weekly meetups are a great way to get questions answered and encouraged. Subjects: Web Design & Development, WordPress. Spring Framework, Udemy Courses, Interview Questions, Web Development. Plus, hes also a really refreshing and engaging Udemy instructor. Devslopes December - BIG THINGS Learn To Code, Projects To Try, December, Talk. Beginner Full-stack Web development by Devslopes The Complete Python Programmer Bootcamp by Giles. Many of his students have praised his style. We are passionate about helping people reveal their hidden talents and guiding them into the exciting world of startups and programming. They have great instructors who genuinely care about their students. Ill recommend some of my favorite courses on Udemy. To determine whether Devslopes by Mark Prices Udemy course is a good fit for you or. We want our students to build projects that they are proud of, that look and operate just like apps they use in their everyday life. 95 off Kotlin for Android: Beginner to Advanced (Coupon & Review). We strive to teach students how to code through polished apps inspired by real world examples. Get promotions and make substantial career changes Launch (and even sell) their technology startups It was last updated on September 04, 2018. Get jobs as developers with amazing salaries This course is written by Udemys very popular author Mark Price and Devslopes by Mark Price. After completing each course, you will have a strong portfolio, coupled with the technical understanding to build your own custom applications.Įntrepreneurs who want to build their own technology startupĬurrent developers looking to either advance their careers or learn new technologies.īy taking our courses, our students have been able to: Devslopes transforms beginner students into paid professionals through curated project based videos, interactive quizzes, and exercises. ![]() Wear a well-fitting face covering made with multiple layers or a surgical face mask if you do leave home or in shared areas in your home, especially if you live with someone with a weakened immune system Ventilate rooms you have been in by opening windows and leaving them open for at least 10 minutes after you have left the room Keep your distance from the people you live with if you can If you've been asked to attend a medical or dental appointment in person, tell them about your symptoms or positive testĪsk friends, family or neighbours to get food and other essentials for you, if you wish Work from home if you can – if you can't, talk to your employer about your options You should avoid meeting people at higher risk of becoming seriously unwell from coronavirus, especially those whose immune system means that they are at higher risk of serious illness from coronavirus for 10 days after the day you took your test. If you have a high temperature or still feel unwell after the 5 days, you should follow this advice until you feel well enough to resume normal activities and you no longer have a high temperature (if you had one). ![]() If you've had a positive test result, and have completed 5 days of self-isolationĪlthough many people will no longer be infectious to others after 5 days, some people may be infectious to other people for up to 10 days from the start of their infection. Children and young people tend to be infectious for less time than adults. If a child or young person aged 18 or under has a positive coronavirus test result, they should stay at home and avoid contact with other people for 3 days after the day they took the test or from the day their symptoms started (whichever was earliest), if they can. You should count the day after you took the test as day 1. If you have a positive coronavirus test result, stay at home and avoid contact with other people for 5 days after the day you took your test, or from the day your symptoms started (whichever was earlier). Do this until you no longer have a high temperature (if you had one) or until you feel better. ![]() If you aren't eligible for testing and you have symptoms of a respiratory infection such as coronavirus and have a high temperature or do not feel well enough to go to work or carry out normal activities, stay at home and avoid contact with other people. ![]() There are things you can do to reduce the spread of infection if you have symptoms, have tested positive, or are a close contact. You do not need to have a negative test result to end self-isolation, follow the stay at home advice. If you have received a positive test result and have been self-isolating, you do not need to continue with any further testing unless you have been advised to do so by a health professional. If you're going into hospital, you should access testing through that service.Īnyone else who is eligible for testing can order tests online or by phoning 119. If you're a health and social care worker, you should access testing through your organisation. you're applying for the self-isolation support grantĪn unpaid carer is someone providing face-to-face care to someone due to a disability, long-term health condition or old age.you're visiting a hospital or care home.you're going into hospital for surgery or a procedure.you have a health condition which means you’re eligible for new coronavirus treatments.you work in NHS health or social care settings.Most people in Scotland no longer need to test for coronavirus. headache that's unusual or longer lasting than usual.not wanting to eat or not feeling hungry.muscle aches or pains that are not due to exercise.loss of, or change in, your normal sense of taste or smell.do not feel well enough to go to work or carry out normal activitiesĭo this until you no longer have a high temperature (if you had one) or until you feel better.Stay at home and avoid contact with other people if you have symptoms of a respiratory infection such as coronavirus and you: But there's still a chance you might catch coronavirus, or another respiratory infection, and pass it on to other people. Vaccinations are very effective at preventing serious illness from coronavirus. Testing is still available to specific groups.Ĭoronavirus, and other respiratory infections such as flu, can spread easily and cause serious illness in some people. Most people no longer need to take a coronavirus test. ![]() If you take an average house using 10,000 kWh per year that has a 100% energy offset for the year and has 40% self-consumption, then 6,000 kWh will be exported to the grid. We’ve estimated that a PV system which offsets 100% of the homeowner’s energy usage will still end up exporting 50-70% of those kWh to the grid during the day, and the house will buy that energy back during the off hours. The yellow export section used to be valued at 9.2 cents per kWh, and now it’s down to 5.9 cents in the summer, 5.6 in the winter.Ĭustomers who export energy will see less credits for that portion of power, and therefore reduced bill savings. ![]() The green section is energy that the solar system produces during the day and offsets any energy being consumed at that time. From this we can subtract the credits they receive for any excess energy their solar panels produce (yellow). First is the sum of all the charges they accrue (blue). The biggest change to the net metering tariff in Rocky Mountain Power territory is that excess solar energy exported to the grid – shown in yellow in the chart below – receives lower compensation than before.Ī homeowner’s bill can be divided into three parts. What has Changed after the Rocky Mountain Power Credit Cut? Understanding your customer’s actual load profile and increasing self-consumption will give better outcomes. The low export rate makes selling excess PV energy less beneficial to the financial bottom line.This isn’t great for company bottom lines The best customer value may no longer be at 100% energy offset, but closer to 60%.Residential solar is still viable in Utah, but the value has been substantially reduced.In this blog post, we crunch the numbers to see if solar is still feasible in the beehive state. This change is applied to new customers going forward – those with existing systems will still continue to enjoy a fair export rate. This was a fair deal for a while as it was pretty close to the retail rate.Īt the end of October 2020, Utah’s Public Service Commission (PSC) granted a Rocky Mountain Power request to reduce that export credit from 9.2 cents per kWh down to 5.6-5.9 cents per kWh, seasonally adjusted. Rather than compensating solar production at the full retail rate (typically 8.8 – 11 cents per kWh for residential customers), owners would get paid a flat 9.2 cents per kWh for their exports. Rocky Mountain Power in Utah is one of the utilities that offers a NEM alternative in their transitional tariff. Recently, however, some utilities have begun removing or changing NEM policies, either by modifying the credits provided or by trying to remove net metering altogether. Net metering (NEM) policies, which provide customers with credits for excess electricity produced from their home’s solar panels, have been important in spurring the adoption of PV systems. Filmy oraz zdjęcia, a co najważniejsze, wspomnienia z takiego wydarzenia będą budziły zachwyt wszystkich rozmówców przez długie lata, a ludzie w nich uczestniczący jeszcze długo będą opowiadali związane z taką przejażdżką ciekawe anegdotki. ![]() Zazwyczaj wywołuje to sporo szumu w całym mieście i przyciąga to wzrok wszystkich mieszkańców, co jest bardzo ważne dla osób, które chcą całemu światu ogłosić, jak bardzo się kochają. Młode pary, które chcą zrobić wrażenie na swoich gościach, bardzo często odzywają się do nas z prośbą o zorganizowanie dla nich niezapomnianego przejazdu, na przykład, spod kościoła do domu weselnego. W ostatnich latach zauważyliśmy również zdecydowany wzrost zainteresowania, jeżeli chodzi o przejażdżki ślubne i weselne. Oprócz tego, że nasi kierowcy doskonale znają otaczające nas tereny, trzeba również nadmienić, że dokładnie znają budowę pojazdów, ich możliwości oraz posiadają dogłębną wiedzę na temat tego, w jaki sposób uczynić przejażdżkę interesującą i pełną emocji, a zarazem bezpieczną. ![]() Nasi kierowcy znają te tereny jak własną kieszeń i nie omieszkają zaprezentować wdzięków tej sielskiej krainy gościom, którzy zdecydują się na wzięcie udziału w przejażdżce. Teren, na którym odbywają się nasze przejażdżki pojazdami wojskowymi, to zachwycające okolice położone jedynie rzut beretem od parku krajobrazowego „ Ujście Warty”, a już samo przebywanie na tym terenie jest atrakcyjne samo w sobie i karmi zmysły spragnionych wrażeń wizualnych i nieskalanej przez człowieka natury gościom. 20-minutowa przejażdżka czołgiem po malowniczych terenach zalewowych rzeki Warty, z jednym z naszych kierowców za kierownicą, sprawia, że absolutnie każdy zmienia zdanie i już nie może doczekać się kolejnego razu. Uważają, że przejażdżki pojazdami wojskowym nie są w stanie zapewnić im odpowiedniej rozrywki, ale to tylko pozory. U ludzi, którzy nigdy nie mieli okazji doświadczyć tego typu aktywności, często występuje raczej sceptyczne podejście. ![]() Może się wydawać, że tego typu rozrywka zainteresuje jedynie mężczyzn, których hobby jest w jakiś sposób związane z militariami – jednakże jest to dosyć krzywdzący stereotyp, ponieważ, po pierwsze zainteresowania nie mają żadnego wpływy na frajdę płynącą z jazdy, a po drugie, przejażdżki pojazdami militarnymi wywołują tak somo duże emocje i wszystkich niezależnie od wieku czy płci. Przejażdżki pojazdami militarnymi to coś, co zawsze rozbudza wyobraźnie. ![]() The shrines added with The Champions' Ballad DLC appear in green on each map. ![]() Each tower unlocks a portion of Breath of the Wild’s map, and the shrines that appear in those regions appear beneath the region names below. We’ve organized our shrines guide based on geographic locations. The shrine maps below show the shrine locations of all 120 shrines across the world of Breath of the Wild - plus those added with The Champions' Ballad DLC, which appear in green on each map. Your sheikah sensor will help, but a lot of the shrines will remain elusive. It won’t take long, though, before finding them and the precious spirit orbs inside becomes a lot of work. The Little Mermaid, directed by Rob Marshall, opens in theaters nationwide on May 26, 2023.How many shrines are in The Legend of Zelda: Breath of the Wild? When you first start playing, shrines feel plentiful and easy-to-find. She makes a deal with the evil sea witch, Ursula, which gives her a chance to experience life on land, but ultimately places her life – and her father’s crown – in jeopardy. ![]() While mermaids are forbidden to interact with humans, Ariel must follow her heart. The youngest of King Triton’s daughters, and the most defiant, Ariel longs to find out more about the world beyond the sea, and while visiting the surface, falls for the dashing Prince Eric. The Little Mermaid is the beloved story of Ariel, a beautiful and spirited young mermaid with a thirst for adventure. The film stars Halle Bailey as Ariel, Daveed Diggs as the voice of Sebastian, Jacob Tremblay as the voice of Flounder, Awkwafina as the voice of Scuttle, Jonah Hauer-King as Prince Eric, Art Malik as Sir Grimsby, Noma Dumezweni as Queen Selina, Javier Bardem as King Triton, and Melissa McCarthy as Ursula. In our Roller Champions first impressions, we said, “Though it’s a solid start to what could be my next team-based competitive addiction, it also feels in danger of becoming repetitive rather quickly.”Ĭheck out the teaser trailer for The Little Mermaid, the upcoming live-action reimagining of the animated musical classic. Roller Champions is a free-to-play game that launched on May 25, 2022, for PC, PS4, Nintendo Switch, and Xbox One. “We strongly believe, however, that before we release new content, we’ve got to do right by our players, hence why we are taking the time needed before we do.” “As far as content is concerned, we can tell you that we’ve got exciting stuff planned for the net seasons,” explains the development team. You can rest assured we’ll keep you updated as we roll forward. Hello Champions! Let’s clear it out of the way first, Roller Champions isn’t getting cancelled, and Ubisoft fully supports it. Ubisoft’s statement is seemingly a response to rumors that began circulating saying that Roller Champions would be canceled after its third season. Additionally, the team is trying to fix issues and address player feedback before moving on to the game’s next season. The game's first and current season, Disco Fever, will be extended and an upcoming patch will include cross-invites, which allows players to bring in friends who play Roller Champions on other platforms. What the Roller Champions dev team is doing is making sure we focus on what our players have told us needs improvements, and that supersedes all other priorities," Ubisoft said in a statement on Twitter. "Let's clear it out of the way first, Roller Champions isn't getting canceled, and Ubisoft fully supports it. ![]() Jumbo Breakfast Platter, 540 Calories (Bacon) or 621 Calories (Sausage) The Sausage, Egg & Cheese Biscuit has 534 calories, 18g protein and 27g carbs. The chain has 15 items on the breakfast menu, but most are tied to at least one other item. These last five sandwiches are all the same except for meat and bread. ![]() See, part of how Jack in the Box simplifies its breakfast menu is by replication. Sausage, Egg & Cheese Biscuit, 534 Calories Those 520 calories come with 31g protein and 30g carbs. Joseph, Missouri, in August to see the solar eclipse, so we can run over to Kansas City and try out the chain while also rekindling our relationship with Arthur Bryant’s BBQ and Stroud’s Chicken.īut back to this magnificent sandwich: Two fried fresh eggs, two slices of ham, two strips of bacon, two slices of American cheese, all on a buttered bakery bun. The Ultimate Breakfast Sandwich, like some other menu items, is tempting, but since I live in Minnesota, I’m nowhere near a Jack in the Box. Ultimate Breakfast Sandwich, 520 Calories The calorie count rises to 487, with protein at 19g and carbs at 29g. Putting sausage instead of ham on the Breakfast Jack makes it a Sausage Breakfast Jack. OK, you can mess with simple goodness as long as it involves sausage. At 448 calories, you’ll have 19g protein and 32g carbs. On the Jack in the Box Supreme Croissant, you’ll enjoy grilled bacon, ham, a fried egg and American cheese. Some may love their buttermilk biscuits, but I’m partial to the soft cushion of a lovely croissant. Calories rise slightly to 410, with 16g protein and 26g carbs. With the Bacon, Egg & Cheese Biscuit, we move from a plain bun to a flaky buttermilk biscuit, which holds the same fresh fried egg, crisp bacon strips and slice of American cheese we found on the Breakfast Jack. Or substitute bacon for 380 calories, 17g protein and 30g carbs.īacon, Egg & Cheese Biscuit, 410 Calories For 350 calories, you’ll get 16g protein and 30g carbs. The Breakfast Jack places a freshly fried egg, a slice of ham and American cheese on a bun. It’s still simple, but it has a ring to it. Jack in the Box keeps breakfast pretty simple, including the names of the menu items, so the Breakfast Jack is about the snazziest of the titles. Potatoes are an excellent source of potassium.īreakfast Jack, 350 Calories (Ham), 380 Calories (Bacon) If you’re looking to boost your potassium intake, you’ll pull in 231g, which is pretty good for the calorie count. Don’t forget to count the butter (and you know you want it with butter). These hash browns come in a nice crispy patty. □Find GOOD Franchises in Your Target Industries That Are STILL Available in Your Area (Free Tool)Īnother low-cal choice that could be a side, a snack or a mini-meal, the Jack in the Box Hash Browns have only 187 calories with 2g protein and 17g carbs. Grilled Chicken Salad (dressing nutrition listed separately) (1 ea.□How Much Franchise Can You Afford? Use Our Free Financial Calculator Lemon Pepper Grilled Whitefish Dinner (1 ea.)Ĭhef Salad (dressing nutrition listed separately) (1 ea.) ![]() Southern Breaded Whitefish Dinner (1 ea.)īlackened Grilled Whitefish Dinner (1 ea.) Southwest Buttermilk Chicken Sandwich (1 ea.) Any time a choice is given for a side, information for those choices are listed separately under "sides". Nutritional values for each meal include those items which automatically come with that meal. Not all menu items are available at each restaurant. Menu items may vary on a daily basis by restaurant. We’re always innovating our menu, so check the nutrition facts often.Ģ,000 calories a day is used for general nutrition advice, but calorie needs may vary. We’re committed to providing a wide range of delicious options so you can enjoy the meal that’s right for you. View Iron Skillet Nutrition Information | TravelCenters of America. Halik lolo raw ang unang kiss sa kanya ni Kiko kaya humirit pa si Shawie ng mas masarap na halik mula sa kanyang esposo. Sa Abril 28 ay 10th wedding anniversary nina Sharon at Kiko. Kiko Pangilinan (na nakaupo sa front row kasama ang cute na cute na sina Frankie at Miel, at ang lola nilang si Mommy Elaine) at nagsayaw ng sweet ang mega-couple habang inaawit ni Martin ang theme song nila na The Promise. at okrayin si Louie Ocampo na ipinagpalit na raw siya kay Piolo Pascual. Nandiyang paglaruan niya ang gown ni Mega (na si Kuh ang nag-design), gayahin si Gary V. Sobrang harot ni Martin bago sila kumanta ni Shawie. Hindi nawalan ng poise si Kuh kahit namatay ang mikropono niya sa duet nila ni Sharon ng Wind Beneath My Wings.Īliw yung portion na nagsukbit ng electric guitar si Mega at kiyemeng tumugtog ng gitara sabay banat ng Wag na Wag Mong Sasabihin ni Kitchie Nadal at Hari ng Sablay ng Sugarfree. Guests niya sina Boyet de Leon, Kuh Ledesma at Christian Bautista, na nadagdagan ni Martin Nievera na nagpresintang mag-guest ni Mega kahit libre. Kahit sa gitna ng kanyang song numbers ay bigla siyang humihirit ng jokes kaya panay ang tawa ng crowd. Dati raw ay mukha siyang drum pero ngayon ay sumeseksi na siya. Sa katunayan ay nagsiluwag daw ang mga damit niya, lalo na ang mga pantalon niya na gawa ni Paul Cabral.Īliw na aliw ang mga tao kapag ginagawang katatawanan ni Shawie ang katawan niya. Aminado si Sharon na mataba pa rin siya pero malaki na raw ang ipinayat niya kumpara noon. Syempre pa ay mas applauded kapag sariling hit songs ni Mega ang kinakanta niya. Kahit pam-Valentines ang repertoire ni Sharon ay na-appreciate pa rin ito ng audience lalo na ang medley niya ng mga awitin nina Barbra Streisand, Karen Carpenter, Barry Manilow, Ogie Alcasid, atbp. Nasa Hong Kong kami nung unang My Mega Valentine concert ni Sharon Cuneta sa Araneta Coliseum, buti na lang at nagkaroon ito ng repeat nung Biyernes nang gabi kaya napanood namin ito. i'm sure, magugustuhan n'yo rin ang You're the One! it has a To Love Again feel to it! ![]() ![]() trust me! my fave among the songs in it are You're the One and Through the Night. na lang ang bilhin n'yo! it is one of her best underrated albums! very pop-ish and her vocals sounded so good in it. Sino ba gustong magka-CD ng mga 'yun? kalampagin kaya natin ng viva?Īnyway, suggestion lang sa mga wala pang sharon vicor series, if you can't afford to buy them all, SSHHH. mukhang out of stock na rin kasi till now, di pa nila dini-deliver 'yung pinaorder ko sa friend ng friend ko. online, regal films in california na lang siya available. i called viva records and they told me that they were out of stock. they were released on CDs before pero di na nasundan pa. sobrang na-enjoy ko talaga 'yun! ngayon, medyo kumpleto na 'yung collection except the two albums you mentioned. Hello, sun_god! last month, i went sharon album shopping! see my post >. Available ba ito in Cd format ? Sana irerelease ng VIVa i2 ![]() Included dun ung mga movie themes recorded by Sharon when she was in VIVA na lyk Oras Oras Araw Araw, Walng Karugtong ang Nakasraan, 3 mukha ng Pagibig etc. ![]() Speaking of movie themes, i used to have a tape nung SHARON MOVIE THEMESONGS at For Broken Hearts Only. It includes songs na di kasama sa 25th Anniversary Album gaya ng Nakgapos na Puso, Hanggang Saan Hangang Kailan, Pati ba Pintig ng Puso, and others. To my surprise, i saw the two disc Sharon Cuneta Album ( one of Vicor's 40th Anniversary releases). So the salesclerk suggested other Sha's albums. Last nyt, i visited Oddyseys branch at Gateway Mall with a plan to purchase Sharon's latest CD release (Isnt it Romantic?) unfortunately di pa sya available. ![]() In most PNH patients, GPI-anchor deficiency is caused by somatic mutations in phosphatidylinositol glycan anchor biosynthesis class A ( PIGA), an X-linked gene required for GPI anchor biosynthesis ( 4– 6) ( Figure 1). Paul Strübing, it was over a century later when the cause of PNH was identified as an absence of a group of membrane proteins attached to the cell surface by glycosylphosphatidylinositol (GPI) anchors ( 1– 3). Although PNH was recognized in the clinic as early as 1882 by Dr. Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare, life-threatening blood disease characterized by hemolysis, propensity for blood clotting, and bone marrow failure ( 1). Here, we critically review published data on PNH cell biology and clonal expansion and highlight limitations and opportunities to further our understanding of the emergence of PNH clones. Recent advancements in disease models and immunologic technologies, together with the growing understanding of autoimmune marrow failure, offer new opportunities to evaluate the mechanisms of clonal expansion in PNH. However, to what extent these contribute to PNH cell selection in patients continues to be a matter of active debate. Landmark studies identified several potential mechanisms which can promote PNH clonal expansion. Historical models of PNH in mice and the more recent PNH model in rhesus macaques showed that GPI (-) cells reconstitute near-normal hematopoiesis but have no intrinsic growth advantage and do not clonally expand over time. In PNH patients, PIGA-mutant, GPI (-) hematopoietic cells clonally expand to make up a large portion of patients’ blood production, yet mechanisms leading to clonal expansion of GPI (-) cells remain enigmatic. The loss of two GPI-anchored surface proteins, CD55 and CD59, from red blood cells causes unregulated complement activation and hemolysis in classical PNH disease. Ubiquitous in eukaryotes, GPI anchors are a group of conserved glycolipid molecules responsible for attaching nearly 150 distinct proteins to the surface of cell membranes. PNH patients develop somatic loss-of-function mutations in phosphatidylinositol N-acetylglucosaminyltransferase subunit A gene ( PIGA), required for the biosynthesis of glycosylphosphatidylinositol (GPI) anchors. Paroxysmal Nocturnal Hemoglobinuria (PNH) is a disease as simple as it is complex. 2Comprehensive Bone Marrow Failure Center, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, United States. ![]() 1Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, United States.Colden 1,2, Sushant Kumar 1,2, Bolormaa Munkhbileg 1,2 and Daria V. |
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