Alterations in calcium signaling in pancreatic acinar cells can result in pancreatitis. Although pressure changes in the pancreas can elevate cytosolic calcium (Ca2+) levels, it is not known how transient pressure-activated elevations in calcium can cause prolonged calcium changes and consequent pancreatitis. In this issue of the JCI, Swain et al. describe roles for the mechanically activated plasma membrane calcium channels Piezo1 and transient receptor potential vanilloid subfamily 4 (TRPV4) in acinar cells. The authors used genetic deletion models and cell culture systems to investigate calcium signaling. Notably, activation of the Piezo1-dependent TRPV4 pathway was independent of the cholecystokinin (CCK) stimulation pathway. These results elegantly resolve an apparent discrepancy in calcium signaling and the pathogenesis of pancreatitis in pancreatic acinar cells.

Elevated pressure in the pancreatic gland is the central cause of pancreatitis following abdominal trauma, surgery, endoscopic retrograde cholangiopancreatography, and gallstones. In the pancreas, excessive intracellular calcium causes mitochondrial dysfunction, premature zymogen activation, and necrosis, ultimately leading to pancreatitis. Although stimulation of the mechanically activated, calcium-permeable ion channel Piezo1 in the pancreatic acinar cell is the initial step in pressure-induced pancreatitis, activation of Piezo1 produces only transient elevation in intracellular calcium that is insufficient to cause pancreatitis. Therefore, how pressure produces a prolonged calcium elevation necessary to induce pancreatitis is unknown. We demonstrate that Piezo1 activation in pancreatic acinar cells caused a prolonged elevation in intracellular calcium levels, mitochondrial depolarization, intracellular trypsin activation, and cell death. Notably, these effects were dependent on the degree and duration of force applied to the cell. Low or transient force was insufficient to activate these pathological changes, whereas higher and prolonged application of force triggered sustained elevation in intracellular calcium, leading to enzyme activation and cell death. All of these pathological events were rescued in acinar cells treated with a Piezo1 antagonist and in acinar cells from mice with genetic deletion of Piezo1. We discovered that Piezo1 stimulation triggered transient receptor potential vanilloid subfamily 4 (TRPV4) channel opening, which was responsible for the sustained elevation in intracellular calcium that caused intracellular organelle dysfunction. Moreover, TRPV4 gene–KO mice were protected from Piezo1 agonist– and pressure-induced pancreatitis. These studies unveil a calcium signaling pathway in which a Piezo1-induced TRPV4 channel opening causes pancreatitis.

Nerve growth factor (NGF) regulates many aspects of neuronal biology by retrogradely propagating signals along axons to the targets of those axons. How this occurs when axons contain a plethora of proteins that can silence those signals has long perplexed the neurotrophin field. In this issue of the JCI, Li et al. suggest an answer to this vexing problem, while exploring why the Elp1 gene that is mutated in familial dysautonomia (FD) causes peripheral neuropathy. They describe a distinctive function of Elp1 as a protein that is required to sustain NGF signaling by blocking the activity of its phosphatase that shuts off those signals. This finding helps explain the innervation deficits prominent in FD and reveals a unique role for Elp1 in the regulation of NGF-dependent TrkA activity.

An in-depth understanding of immune escape mechanisms in cancer is likely to lead to innovative advances in immunotherapeutic strategies. However, much remains unknown regarding these mechanisms and how they impact immunotherapy resistance. Using several preclinical tumor models as well as clinical specimens, we identified a mechanism whereby CD8+ T cell activation in response to programmed cell death 1 (PD-1) blockade induced a programmed death ligand 1/NOD-, LRR-, and pyrin domain–containing protein 3 (PD-L1/NLRP3) inflammasome signaling cascade that ultimately led to the recruitment of granulocytic myeloid-derived suppressor cells (PMN-MDSCs) into tumor tissues, thereby dampening the resulting antitumor immune response. The genetic and pharmacologic inhibition of NLRP3 suppressed PMN-MDSC tumor infiltration and significantly augmented the efficacy of anti–PD-1 antibody immunotherapy. This pathway therefore represents a tumor-intrinsic mechanism of adaptive resistance to anti–PD-1 checkpoint inhibitor immunotherapy and is a promising target for future translational research.

BACKGROUND Since December 2019, an outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, and is now becoming a global threat. We aimed to delineate and compare the immunological features of severe and moderate COVID-19.METHODS In this retrospective study, the clinical and immunological characteristics of 21 patients (17 male and 4 female) with COVID-19 were analyzed. These patients were classified as severe (11 cases) and moderate (10 cases) according to the guidelines released by the National Health Commission of China.RESULTS The median age of severe and moderate cases was 61.0 and 52.0 years, respectively. Common clinical manifestations included fever, cough, and fatigue. Compared with moderate cases, severe cases more frequently had dyspnea, lymphopenia, and hypoalbuminemia, with higher levels of alanine aminotransferase, lactate dehydrogenase, C-reactive protein, ferritin, and D-dimer as well as markedly higher levels of IL-2R, IL-6, IL-10, and TNF-α. Absolute numbers of T lymphocytes, CD4+ T cells, and CD8+ T cells decreased in nearly all the patients, and were markedly lower in severe cases (294.0, 177.5, and 89.0 × 106/L, respectively) than moderate cases (640.5, 381.5, and 254.0 × 106/L, respectively). The expression of IFN-γ by CD4+ T cells tended to be lower in severe cases (14.1%) than in moderate cases (22.8%).CONCLUSION The SARS-CoV-2 infection may affect primarily T lymphocytes, particularly CD4+ and CD8+ T cells, resulting in a decrease in numbers as well as IFN-γ production by CD4+ T cells. These potential immunological markers may be of importance because of their correlation with disease severity in COVID-19.TRIAL REGISTRATION This is a retrospective observational study without a trial registration number.FUNDING This work is funded by grants from Tongji Hospital for the Pilot Scheme Project, and partly supported by the Chinese National Thirteenth Five Years Project in Science and Technology for Infectious Disease (2017ZX10202201).

Treating neuropathic pain is challenging and novel non–opioid-based medicines are needed. Using unbiased receptomics, transcriptomic analyses, immunofluorescence, and in situ hybridization, we found that the expression of the orphan GPCR Gpr160 and GPR160 increased in the rodent dorsal horn of the spinal cord following traumatic nerve injury. Genetic and immunopharmacological approaches demonstrated that GPR160 inhibition in the spinal cord prevented and reversed neuropathic pain in male and female rodents without altering normal pain response. GPR160 inhibition in the spinal cord attenuated sensory processing in the thalamus, a key relay in the sensory discriminative pathways of pain. We also identified cocaine- and amphetamine-regulated transcript peptide (CARTp) as a GPR160 ligand. Inhibiting endogenous CARTp signaling in spinal cord attenuated neuropathic pain, whereas exogenous intrathecal CARTp evoked painful hypersensitivity through GPR160-dependent ERK and cAMP response element–binding protein (CREB). Our findings de-orphanize GPR160, identify it as a determinant of neuropathic pain and potential therapeutic target, and provide insights into its signaling pathways. CARTp is involved in many diseases including depression and reward and addiction; de-orphanization of GPR160 is a major step forward understanding the role of CARTp signaling in health and disease.

Colitis caused by Clostridium difficile infection is a growing cause of human morbidity and mortality, especially after antibiotic use in health care settings. The natural immunity of newborn infants and protective host immune mediators against C. difficile infection are not fully understood, with data suggesting that inflammation can be either protective or pathogenic. Here, we show an essential role for IL-17A produced by γδ T cells in host defense against C. difficile infection. Fecal extracts from children with C. difficile infection showed increased IL-17A and T cell receptor γ chain expression, and IL-17 production by intestinal γδ T cells was efficiently induced after infection in mice. C. difficile–induced tissue inflammation and mortality were markedly increased in mice deficient in IL-17A or γδ T cells. Neonatal mice, with naturally expanded RORγt+ γδ T cells poised for IL-17 production were resistant to C. difficile infection, whereas elimination of γδ T cells or IL-17A each efficiently overturned neonatal resistance against infection. These results reveal an expanded role for IL-17–producing γδ T cells in neonatal host defense against infection and provide a mechanistic explanation for the clinically observed resistance of infants to C. difficile colitis.

The mechanisms by which prostate cancer shifts from an indolent castration-sensitive phenotype to lethal castration-resistant prostate cancer (CRPC) are poorly understood. Identification of clinically relevant genetic alterations leading to CRPC may reveal potential vulnerabilities for cancer therapy. Here we find that CUB domain-containing protein 1 (CDCP1), a transmembrane protein that acts as a substrate for SRC family kinases (SFKs), is overexpressed in a subset of CRPC. Notably, CDCP1 cooperates with the loss of the tumor suppressor gene PTEN to promote the emergence of metastatic prostate cancer. Mechanistically, we find that androgens suppress CDCP1 expression and that androgen deprivation in combination with loss of PTEN promotes the upregulation of CDCP1 and the subsequent activation of the SRC/MAPK pathway. Moreover, we demonstrate that anti-CDCP1 immunoliposomes (anti–CDCP1 ILs) loaded with chemotherapy suppress prostate cancer growth when administered in combination with enzalutamide. Thus, our study identifies CDCP1 as a powerful driver of prostate cancer progression and uncovers different potential therapeutic strategies for the treatment of metastatic prostate tumors.

The editors of JCI and JCI Insight are revisiting our editorial processes in light of the strain that the COVID-19 pandemic places on the worldwide scientific community. Here, we discuss adjustments to our decision framework in light of restrictions placed on laboratory working conditions for many of our authors.

BACKGROUND The live attenuated BPZE1 vaccine candidate induces protection against B. pertussis and prevents nasal colonization in animal models. Here we report on the responses in humans receiving a single intranasal administration of BPZE1.METHODS We performed multiple assays to dissect the immune responses induced in humans (n = 12) receiving BPZE1, with particular emphasis on the magnitude and characteristics of the antibody responses. Such responses were benchmarked to adolescents (n = 12) receiving the complete vaccination program of the currently used acellular pertussis vaccine (aPV). Using immunoproteomics analysis, potentially novel immunogenic B. pertussis antigens were identified.RESULTS All BPZE1 vaccinees showed robust B. pertussis–specific antibody responses with regard to significant increase in 1 or more of the following parameters: IgG, IgA, and memory B cells to B. pertussis antigens. BPZE1–specific T cells showed a Th1 phenotype, and the IgG exclusively consisted of IgG1 and IgG3. In contrast, all aPV vaccines showed a Th2-biased response. Immunoproteomics profiling revealed that BPZE1 elicited broader and different antibody specificities to B. pertussis antigens as compared with the aPV that primarily induced antibodies to the vaccine antigens. Moreover, BPZE1 was superior at inducing opsonizing antibodies that stimulated ROS production in neutrophils and enhanced bactericidal function, which was in line with the finding that antibodies against adenylate cyclase toxin were only elicited by BPZE1.CONCLUSION The breadth of the antibodies, the Th1-type cellular response, and killing mechanisms elicited by BPZE1 may hold prospects of improving vaccine efficacy and protection against B. pertussis transmission.TRIAL REGISTRATION ClinicalTrials.gov NCT02453048, NCT00870350.FUNDING ILiAD Biotechnologies, Swedish Research Council (Vetenskapsrådet), Swedish Heart-Lung Foundation.

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В этот день 5-го мая, два года назад «Локомотив» стал чемпионом России. Третье золото клуба, как и оба предыдущих, команда добыла под руководством Юрия Семина. Все решилось в матче 29-го тура на «РЖД Арене». На стадионе почти аншлаг, а у болельщиков изрядный повод для волнений. «Локомотив» лидировал с серьезным отрывом и финиш тревог не сулил. Как вдруг две нулевые ничьи подряд с «Ахматом» и «Уфой» (причем обе дома!) и гостевое поражение в Краснодаре (0:2), три встречи без единого забитого мяча и все становится серьезно.

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Дмитрий Лоськов — из той редкой и ценной категории футболистов, которые ассоциируются с одним клубом. Пусть на заре карьеры полузащитник поиграл за «Ростов» (тогда ещё «Ростсельмаш»), а в 2007-м вынужден был уйти в «Сатурн» в результате конфликта с главным тренером Анатолием Бышовцем, он всё-таки человек «Локомотива».

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Новое кино от Глеба Чернявского.

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Это был лучший матч в карьере вратаря.

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Директор по связям с общественностью ФК «Локомотив» Кирилл Брейдо подтвердил информацию о том, что у двух сотрудников клуба был выявлен коронавирус. Об этом 7 мая сообщил телеграм-канал «Мутко против».

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Серба Марко Николича называют претендентом на должность Юрия Семина

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Анализ ситуации в «Локомотиве» и причин возможной отставки Юрия Семина провел для «СЭ» Лев Гоберман — бывший советник президента красно-зеленых, работавший там в первый год Ильи Геркуса в качестве президента и знающий изнутри все нюансы сложной управленческой структуры клуба.

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«Локомотив» в 1936 году. Слева направо: Петр Теренков, Виталий Стрелков, Виктор Лавров, Алексей Соколов, Николай Ильин, Иван Андреев, Михаил Жуков, Александр Семенов, Илья Гвоздков, Николай Разумовский, Дмитрий Максимов.

Жуков и Гвоздков погибли на войне, Теренков вернулся живым, Лавров, Ильин, Андреев, Разумовский и Максимов трудились в тылу

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It’s no secret that I love Japan. I mean, I really, really love Japan. I felt more at home in Tokyo than I ever have anywhere else, and I think about going back all. the. time. I’m even thinking about it right now. You’re probably reading this right now because, at the very least, some tiny part of you is curious about whether you should do it. It might be the tiiiiiiiniest little part, but I’m sure it’s there. Maybe you don’t want to admit it because it seems pretty impossible, and yeah, I will admit that if you have a job that you don’t want to leave, strong family ties, kids, pets, or no money (among other things), it must seem like a distant what-if that will never happen. Here’s the thing. If you’re really, honestly interested, then make it happen. Because guess what? You freaking can make it happen, and don’t let anybody tell you no. If you’re coming up with a “But…” right now, I’ll stop you right there! “But I have kids/pets…” Figure out how to take them with you, because you can! “But I don’t want to leave my job…” Take a sabbatical for a year, look into transfers to a branch abroad, look for a better job in the same field in Japan, or look into whether this job is really worth giving up on this dream (maybe it isn’t). “But I can’t speak the language…” So? I moved to Japan and didn’t speak a word. Some people learn before they go, some people learn while they’re there (me), and some people never learn (I don’t recommend this). I could go on forever, but the whole world is at your fingers if you really want it! I seriously believe that. It’s not always easy, but if you want something badly enough, don’t you owe it to yourself to at least try? Anyways, let me give you the top reasons why I think that you should give living in Japan a try! 1. Living in a different culture opens your eyes. This especially is true if you immerse yourself in as much of the culture as you can. Make Japanese friends, learn about what people do on a daily basis and what they believe in. Try doing things in ways that are new to you. Try new foods! Mochi is the schiz, by the way! Once you’ve experienced doing new things, it will change how you do things even if you return back home. I will always have a no-shoes policy in my house (it’s so much cleaner!), I absolutely CRAVE a train system (if only!), and I have a newfound respect for walking and cycling. I never did this when I was little, but now, if I can, I walk! 2. You’ll have a fresh start. In your new home in Japan, you won’t have any of the drama that surrounded you in your old one. Thanks to the internet, we can still keep in touch with friends and family, but being a few thousand miles away from them will keep a lot of the drama to a minimum. Take a chance to stretch your wings and see what kind of person you are when you have the freedom to be you without their judgement. Trust me, it takes a weight off being in a new place where nobody knows who you used to be (or who they thought you used to be). Oh, and you know what? I bet that you will love yourself more than you ever did before. 3. Japan is a magical place! Seriously. Cherry blossoms, gorgeous temples and “castles” (I wouldn’t call them castles, but they’re called that nonetheless, and they’re really cool anyway), a rich history filled with Samurai and ninjas (who doesn’t love ninjas?), seasonal treats, and an entire culture that grew up reading manga. How does this not sound like an amazing place to live?!  And no offense to any other country, but Japanese trains come quickly, go almost everywhere, are extremely punctual, and pretty clean, which makes them (Tokyo especially) easily #1 in the world in public transportation. Now that sounds magical to me. 4. Universal Health Care. If you’re American like me, this will make a HUGE difference in your life. Trust me. If you come from pretty much any other 1st world nation, it probably won’t matter as much, though. But at least it’s good! 5. Japan is safer than where you came from. There’s no gun violence. There’s very low crime in general. You can walk in the dead of night in the seediest parts of town, as a woman, alone, and still feel perfectly safe from other people. From earthquakes is another matter, but you’ll get used to them really fast, and Japan is built to withstand all but the biggest. 6. Wa. There is a concept called wa in Japanese society, which essentially promotes practicing peace and harmony in your daily life. Wa is obvious in everything from traditional architecture and decor to the way that people act around each other– courteousness, quiet, and respect are what you expect most from your neighbors. You’re never going to wake up to your neighbors blaring music at 3am having a raucous party. Even drunken people wandering the street are more polite than not (although most of them just sort of stumble home or sit down where they are for the night– but remember, Japan is safe so they only thing they have to worry about is getting chilly). We could all use a little bit of harmony in our lives, and that’s something that Japan taught me to value. I’m surprised that yoga isn’t more popular, since they’re pretty in tune with each other. 7. All the new gadgets, and all of the old culture. Sure, Silicon Valley is where a lot of new apps are coming out, but if you want lots of little weird but useful gadgets to make your life easier (or more interesting), take a stroll through Akihabara. Plus, there are tons of cheap versions of what you’re used to, like large-capacity flash drives and SD cards. And I would be remiss in not mentioning the used electronics! Smartphones! Right next to small neighborhood temples, btw. It’s the only place to find Ayanami Rei in a kimono, wandering the street. The best of both worlds! 8. MANGA AND ANIME EVERYWHERE. This should be your main reason. This should be enough of a reason. Not only is it available everywhere, but events abound. If you wanted, you could go to an anime-related event every weekend of the year. Also, let’s not forget that it’s the only place to see all of the anime movies released in the theater, go to the official events (like Jump Festa, Comicket, World Cosplay Summit, and Anime Japan, among others), and see the musicals, seiyuu radio shows, and stage plays. If this isn’t reason enough, you’re probably in the wrong place. 9. It’s cheaper than you think. I lived in Tokyo, and then I moved back to the US, thinking that because I was living in a place often called “The Most Expensive City In The World,” it would be cheaper here. Nope.. Apartment rents, even in small cities, are at least the price that I was paying in Tokyo (~$600/mo). And try finding that in LA. So far I haven’t had any luck, and especially not in the areas that are actually sort-of-kind-of safe. Food is also about on-par with the US, especially domestic food. Considering that it’s an island, it’s actually really, really cheap. Food in Hawaii cost sometimes 3-4 times what I was able to get it for in Japan. Then, when you factor in healthcare, which is pretty cheap (what you pay for the insurance is based on your income, and then it covers 80% of all your bills — this is a simplification, but generally holds true), and transportation costs (you don’t need a car, therefore no gas, no insurance, no car maintenance fees), it’s downright cheap. Even living in Tokyo. 10. You will never run out of things to do. In nearly a decade, I never ran out of cool things to do. Can you say the same about the city that you live in now? Thought so. Ah man, I kinda feel ready to jump back on a plane and move across the ocean… three cats and all! Somebody hold me back… resistance is fading……………….  

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Another escape Wednesday is here! Very retro Ariyoshi's game is quite short but fun, with refreshing approach to the genre. TomoLaSiDo locked you in their room on the day with special calendar date and you need to gather several outlets... Tagged as: ariyoshi, blog, browser, escape, free, japanese, nicolet, pixelkobo, pointandclick, puzzle, rating-g, tomolasido, weekday-escape

Welcome, this week it's retro time again! Vitamin Hana wants you to escape from an unusual place - from an oceanarium. Then you get locked in Yomino Kagura's prettily decorated room, and then it's time for No1game 's short adventure... Tagged as: blog, browser, escape, escapemen, free, fuwayura, japanese, no1game, pointandclick, puzzle, rating-g, vitaminhana, weekday-escape, yominokagura

Hi! The week is over and the brand new Weekday Escape here! Amajeto helps you to enjoy your stay at home and suggests some activities like looking for lost remote controller in coded drawers and finding ways how to open... Tagged as: amajeto, blog, browser, escape, free, japanese, masa, pixelkobo, pointandclick, puzzle, rating-g, rinnogogo, weekday-escape

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Apple today announced that it will begin reopening its retail stores in Germany on May 11, nearly two months after they were closed due to the global health crisis.


In a statement shared with German website Macerkopf, Apple said the stores will initially be focusing on Genius Bar service and support. Enhanced health and safety measures will be implemented, such as body temperature checks prior to entry, limits on how many customers can be in the store at once, social distancing, and reduced hours of operation.

Apple operates 15 retail stores in Germany and will be posting specific hours of operation for each location on its website.

Apple closed all of its retail stores outside of the Greater China region in mid-March. The company has since started to reopen some locations, including in South Korea, Austria, and Australia. All locations in the United States remain closed.

This article, "Apple Stores in Germany to Begin Reopening May 11 With Enhanced Health and Safety Measures" first appeared on MacRumors.com

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Amazon is taking up to $100 off the Apple Watch Series 5 this week, with prices starting at $299.99 for the 40mm GPS models. Only the Gold Aluminum Case with Pink Sport Band is available at this price. If you order today, the Apple Watch should arrive sometime next week.

Note: MacRumors is an affiliate partner with Amazon. When you click a link and make a purchase, we may receive a small payment, which helps us keep the site running.

The Apple Watch Series 5 was released in September 2019 with a new OLED screen that supports an always-on feature, which represents the biggest change to the Series 5 models. The newest Apple Watch is available in 40mm and 44mm sizes, and it has the overall same design as the Series 4 models.

$100 OFF

Apple Watch S5 (40mm, GPS) for $299.99

If you're shopping for a cellular model, there are also a few solid discounts on Amazon for these devices. You can get the Gold Aluminum Case with Pink Sport Band (40mm) for $399.00, down from $499.00. Likewise, the Silver Aluminum Case with White Sport Band (40mm) is $399.00 right now.

For the 44mm cellular models, a solid deal is the Space Gray Aluminum Case with Black Sport Band at $429.00, down from $529.00. You'll find the same price on the Silver Aluminum Case with White Sport Band and the Gold Aluminum Case with Pink Sport Band.

Across the board, these sales are either new low prices on the Apple Watch Series 5, or they're matching previous low prices seen on these models on Amazon. There are a few other deals going on for different Series 5 models as well, including numerous 44mm cellular devices that are about $50 off Apple's original prices. Be sure to head to Amazon to check out the full sale before these prices expire, or the retailer runs out of stock.

Keep up with all of this week's best discounts on Apple products and related accessories in our dedicated Apple Deals roundup.
This article, "Deals: Apple Watch Series 5 Models Discounted by Up to $100 on Amazon" first appeared on MacRumors.com

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Woot is ending the week with a refurbished sale on the 15-inch MacBook Pro, available in multiple storage sizes and colors. The sale starts with the 256GB SSD model (16GB RAM, Intel Core i7) for $1,579.99.

Note: MacRumors is an affiliate partner with Woot. When you click a link and make a purchase, we may receive a small payment, which helps us keep the site running.

For more storage, the 512GB SSD model (16GB RAM, Intel Core i9) is on sale for $1,849.99. Woot's refurbished sales are offering more than $800 in savings when compared to the original prices of these notebooks, which began at $2,399.00 when they launched in May 2019.

Similar to previous Woot sales, each MacBook Pro comes with a One Year Limited Woot Warranty. Each device has been refurbished and is ensured to be in full working condition. When shipped, they are packaged in a generic white box.

You can find even more discounts on new MacBooks by visiting our Best Deals guide for MacBook Pro and MacBook Air. In this guide we track the steepest discounts for the newest MacBook models every week, so be sure to bookmark it and check back often if you're shopping for a new Apple notebook.

This article, "Deals: Refurbished 15-Inch MacBook Pro Notebooks on Sale at Woot From $1,580 ($800+ Off)" first appeared on MacRumors.com

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