tor AT#198 - Travel to the Yukon Territory in Canada (and nearby Alaska) By canada.amateurtraveler.com Published On :: Sat, 05 Sep 2009 14:00:00 +0000 The Amateur Traveler talks to Sarah from Whitehorse in the Yukon about that corner of Canada with long winters but dramatic scenery. She tells of of Winter festivals like the Yukon Sourdough Rendezvous as well as Summer festivals like Dawson City Music fest, Atlin Arts and Music Fest and the Kluane Mountain Bluegrass Festival. We talk about sporting events like the 24 Hours of Light and Kluane to Chilkat (Haines to Haines) bike races because Sarah says you have to like the outdoors to come to the Yukon. Sarah also gives us some itineraries for road warriors like the Top of the World Highway to Dawson (and the Dempster Highway for the bold among you) and the Golden Circle route into Alaska. We walk the Chilkoot Trail but without the requirement to bring 1,000 pounds of supplies like in the Yukon gold rush. It is the beauty of Kluane National Park that you will remember but strangely enough it was something else that Sarah was looking at when she decided to move to the Yukon. Full Article
tor AT#248 - Travel to Toronto, Ontario By canada.amateurtraveler.com Published On :: Sat, 18 Sep 2010 14:00:00 +0000 The Amateur Traveler talks to Corinne from Have Baby Will Travel who is a life-long Torontonian (that is to say that she lives in Toronto, Ontario). Corinne gives us an introduction to her city and its many parks, its great ethnic food, its iconic skyline punctuated by the CN Tower. Its neighborhoods includes two different Chinatowns, Greektown, the Irish-influenced Cabbagetown, Distillery District, Kensington Market, Harbourfront and St. Lawrence Market, She particularly suggests you visit during Thanksgiving (Canada's which is in October) or Toronto International Film Festival. Corinne also describes side trips from the city heading out towards Niagra and Ontario's wine country. The city houses both a working farm in Riverdale Farms and a warren of underground shops in the Toronto Underground PATH. Full Article
tor AT#371 - Travel to Victoria Falls (Zimbabwe, Zambia) By africa.amateurtraveler.com Published On :: Sat, 11 May 2013 12:30:00 +0000 Hear about travel to Victoria Falls as the Amateur Traveler talks to Nir Ben-Dov about his trip to this spectacular falls on the border of Zimbabwe and Zambia. This was Nir’s second trip and his wife’s first trip from their home in Israel to this famed set of falls in southern Africa. Full Article
tor AT#458 - Volunteer Travel with Peace Corp Director Carrie Hessler-Radelet By amateurtraveler.com Published On :: Sat, 07 Mar 2015 19:44:44 +0000 Hear about volunteer travel with the Peace Corps as the Amateur Traveler talks to Peace Corps Director Carrie Hessler-Radelet. Director Hessler-Radelet not only served in the Peace Corps herself in Western Samoa but 4 generations of her family have done so. Full Article
tor AT#573 - Travel to the Yukon Territory By canada.amateurtraveler.com Published On :: Sat, 02 Sep 2017 12:24:37 +0000 Hear about travel to the Yukon Territory in Canada as the Amateur Traveler talks to Stephen Reynolds from Tourism Yukon about a recent trip that I did to his home. Full Article
tor AT#670 - Africa Overland - Johannesburg to Victoria Falls By AmateurTraveler.com Published On :: Sat, 24 Aug 2019 14:00:00 +0000 In this special episode of Amateur Traveler, I get to introduce to you some of the wonderful people who joined me in Africa last May. We drove overland from Johannesburg, South Africa to Victoria Falls, Zimbabwe. Full Article
tor AT#573 - Travel to the Yukon Territory (Repeat) By amateurtraveler.com Published On :: Sat, 02 Nov 2019 14:00:00 +0000 Hear about travel to the Yukon Territory in Canada as the Amateur Traveler talks to Stephen Reynolds from Tourism Yukon about a recent trip that I did to his home. Full Article
tor Stories of CERB: Canadians share how they're using the emergency benefit By www.ctvnews.ca Published On :: Fri, 8 May 2020 20:03:00 -0400 CTVNews.ca asked Canadians to share how they were using their CERB payments and got a flood of responses. Most said they were covering the basics -- housing, groceries, transportation and medicine. Full Article
tor Attorney General Orders FanDuel, DraftKings, Out of New York By feedproxy.google.com Published On :: Tue, 10 Nov 2015 18:49:56 EST Attorney General Eric Schneiderman has issued a cease-and-desist order to the nation’s two largest daily fantasy sports companies, saying that the betting that takes place on their sites breaks New York's online gambling laws. Full Article
tor 10 of the best fitness trackers for monitoring heart rate By feedproxy.google.com Published On :: Sat, 27 Oct 2018 09:00:00 +0000 BEST FITNESS TRACKER DEALS: Fitbit - Charge 3 Activity Tracker + Heart Rate — $99.95 (save $30) Garmin - Forerunner 645 Music GPS Heart Rate Monitor Running Watch — $449.99 3Plus - HR Activity Tracker + Heart Rate — $49.99 Wellness is a buzzy word lately. Over the past few years, we’ve seen a surge in all things health, wellness, and spirituality. Juice bars are popping up, boutique studios are becoming more accessible, and essential oils are chilling us out. Self-care is becoming more of the norm too, but amidst all this hype, it can be challenging to find the right routine that promotes good exercise, sleep, vitals, and mindset. Read more...More about Apple Watch, Fitness Trackers, Smart Watch, Heart Rate Monitor, and Mashable Shopping IMAGE: Amazon BEST OVERALL Apple Watch Series 4 Take heart monitoring to the next level with the Apple Watch Series 4's amazing EKG feature and FDA-cleared precision. Warranty: 90 days with Apple Care+ Smartphone compatibility: Yes Battery life: 22 hours Weight: 1.06 oz What you'll get: A case, band, 1m magnetic charging cable, and 5W USB Power Adapter $236.98 from Amazon IMAGE: Amazon BEST BANG FOR YOUR BUCK Polar A370 Fitness Tracker Smartphone compatibility and a variety of wellness features makes Polar’s A370 Fitness Tracker our top choice for health management. Warranty: 2 years Smartphone Compatibility: Yes Battery life: 4 days Weight: 13.8 ounces What you’ll get: A Polar A370 Fitness Tracker, a band, a charging cable, and a manual $114.99 from Amazon IMAGE: Amazon EASIEST TO USE Fitbit Charge 3 Fitness Activity Tracker The new Charge 3 provides no-fuss wellness features to take your daily sleep, workouts, and vitals to the next level. Warranty: 45-day guarantee and 1 year warranty Smartphone compatibility: Yes Battery life: 7 days Weight: 4.8 ounces What you’ll get: A Fitbit Charge 3, classic wristbands (both small & large), and a charging cable $119.03 from Amazon IMAGE: Best Buy BEST FOR ATHLETES Garmin Forerunner 735XT Smartwatch With sport-specific settings, advanced training feedback, and a connected app, Garmin’s Forerunner 735XT Smartwatch is the perfect fitness companion for athletes. Warranty: 1 year Smartphone compatibility: Yes Battery life: 1 day Weight: 1.4 ounces What you’ll get: A Garmin Forerunner 735XT Smartwatch, a charging/data clip, and a manual $349.99 from Best Buy IMAGE: Amazon BEST FOR TECH ENTHUSIASTS Nokia Steel HR Hybrid Smartwatch Add some tech to your exercise regimen with the Nokia’s Steel HR Hybrid with Alexa integration and three different heart monitor modes. Warranty: 1 year Smartphone compatibility: Yes Battery life: 25 days Weight: 8.2 ounces What you’ll get: A Nokia Steel HR Hybrid Smartwatch and a CR2 battery $199.95 from Amazon IMAGE: Amazon BEST FOR WATER SPORTS Garmin vívoactive 3 Warranty: 1 year Smartphone compatibility: Yes Battery life: 10 days Weight: 1.44 ounces What you'll get: A vívoactive 3 Fitness Tracker, a charging/data cable, and manuals $319.99 from Amazon IMAGE: Amazon BEST FOR STYLE Motiv Ring Warranty: 45-day guarantee and 1-year warranty Smartphone compatibility: Yes Battery life: 3 days Weight: 1.6 ounces What you'll get: A Motiv Ring, sizing set, and two slim charging docks $199.99 from Amazon IMAGE: Amazon BUDGET PICK Microtella Fitness Tracker Microtella’s Fitness Tracker is affordable, monitors your heart rate, and comes with 14 different fitness settings for personalized workout stats. Warranty: None Smartphone Compatibility: Yes Battery life: 7 days Weight: 4 ounces What you’ll get: A Microtella Fitness Tracker, a band, and a USB charger $39.99 from Amazon IMAGE: Amazon BEST OF BOTH WORLDS Samsung Galaxy Fit The perfect midpoint between the Fitbit and Apple Watch, the Samsung Galaxy Fit is great for tracking your high-intensity activities and for managing your daily life. Warranty: 1 year Smartphone Compatibility: Yes Battery Life: 7 days Weight: 3.2 ounces What you'll get: Samsung Galaxy Fit, charging cable, manuals $79 from Amazon IMAGE: Amazon BEST ON-SCREEN WORKOUTS Fitbit Versa The Fitbit Versa is best for those who need some extra guidance in the gym, and thanks to its comprehensive array of on-screen workouts, you'll get exactly that. Warranty: 1 year Smartphone Compatibility: Yes Battery Life: 4 days Weight: 5.12 ounces What you'll get: Fitbit Versa, charging cable, manuals $199.95 from Amazon IMAGE: Amazon BEST BATTERY LIFE Wahoo TICKR Won't take up precious real estate on your wrists and will provide personalized heart rate training, as well as an unbeatable 12-month battery life. Warranty: 1 year Smartphone Compatibility: Yes Battery Life: 1 year Weight: 2.4 ounces What you'll get: Wahoo TICKR, battery, manuals $45.94 from Amazon Full Article Apple Watch Fitness Trackers Smart Watch Heart Rate Monitor Mashable Shopping
tor Apple to begin reopening U.S. stores this month By feedproxy.google.com Published On :: Fri, 08 May 2020 23:46:02 +0000 Apple, dear reader, has been missing you — and it's banking on the fact that you've been missing the opportunity to touch its products before you buy them, too. In an effort to ease this assuredly mutual feeling of longing, the company confirmed on Friday plans to begin reopening some of its U.S. stores as early as MondayApple had been aiming for a May reopening for some time, but now it's official. So reports CNBC, which notes that the openings are, for now, limited to stores in four states: Idaho, South Carolina, Alabama, and Alaska. "We've missed our customers and look forward to offering our support," an Apple spokesperson told CNN Business. Read more...More about Apple, Coronavirus, Tech, and Big Tech Companies Full Article Apple Coronavirus Tech Big Tech Companies
tor Watch the 'Bon Appétit' cast meet the creators behind the Meme Appetit account By feedproxy.google.com Published On :: Sat, 09 May 2020 16:32:07 +0000 What happens when memers meet the subject of their memes? In the case of the BA Test Kitchen meeting the brains behind @meme_appetit, pure gold. Harry Kersh and Will Martin started the accounts when they discovered their shared love of BA videos, and the Instagram and Twitter accounts have since taken off. Now with almost 400,000 followers on Instagram, the account has a lot of fans — including some members of the test kitchen. In this video, the BA cooks explain why they love (or dislike) some of the account's memes, whether it's accurate, and whether they even "get it." Watch them react to various memes and Kersh and Martin attempt to explain their reasoning behind them. Read more...More about Memes, Viral Video, Bon Appetit, Culture, and Web Culture Full Article Memes Viral Video Bon Appetit Culture Web Culture
tor Penguin Classics cover generator By feedproxy.google.com Published On :: Fri, 08 May 2020 06:01:53 PDT Nicholas Love's Penguin Classics cover generator lets you upload an image and set type in humorous imitation of the label. It can also do the similar but inverted Oxford World Classics look. But sadly not the classic classics look. Many excellent designs in this twitter thread; embedded here is my contribution. Read the rest Full Article Post books generators
tor Legendary East Village corner store, Gem Spa, closes its doors By feedproxy.google.com Published On :: Fri, 08 May 2020 10:14:17 PDT The Gothamist is reporting the sad news that Gem Spa, the iconic NY corner store that has been a fixture at St. Marks Place and Second Avenue for around 100 years is being forced to shutter its doors and windows for the last time. The Spa has been struggling to keep up with increasing rent prices and COVID-19 has apparently proven to be the final nail in its coffin. "It’s where Robert Mapplethorpe bought Patti Smith an egg cream on the day they met. It’s on the back cover of the New York Dolls’ 1973 debut (and where, according to lore, Johnny Thunders and others went for post-heroin sugar fixes between sets at CBGB). Before that, it was where Abbie Hoffman gathered Yippies to rain money on the New York Stock Exchange. It’s where Allen Ginsberg, Ted Berrigan, and other neighborhood poets went to pick up the Sunday New York Times on Saturday nights (and which was inevitably commemorated in their poems)." Read the rest. Image: Alex Lozupone, CC BY-SA 4.0 Read the rest Full Article Post loss new york city sad endings
tor Most Realtors® Don’t Expect Steep Price Declines in Next 12 Months By feedproxy.google.com Published On :: Mon, 27 Apr 2020 17:33:19 +0000 Most Realtors® Don’t Expect Steep Price Declines in... Among the 4,063 respondents, 23% expect prices to remain stable, 38% expect prices to increase, and 40% expect prices to fall. By: Scholastica (Gay) Cororaton Full Article
tor Watch The Delivery Man Online | Season 1 Full Episodes Video Streaming & Torrent Search By www.webtvwire.com Published On :: Mon, 27 Apr 2015 04:38:08 +0000 The Delivery Man Synopsis The Delivery Man is a comedy television series produced by ITV that premiered in April of 2015. The Delivery Man follows the story of Matthew (played by Darren Boyd – Spy), a police officer who decides to switch careers in his mid-thirties and becomes a midwife. The Delivery Man is currently […] Full Article TV Shows
tor Watch Other Space Full Episodes Online | Season 1 Video Streaming & Torrent Search By www.webtvwire.com Published On :: Tue, 28 Apr 2015 04:22:04 +0000 Other Space Synopsis Other Space is a Science Fiction comedy television series produced by Yahoo that premiered in April of 2015. Created by Paul Feig (Freaks and Geeks) Other Space is set in the early 22nd century and follows the story of the inexperienced crew aboard UMP Cruiser on a routine space exploratory mission. In […] Full Article TV Shows
tor Watch Peter Kay’s Car Share Online | Season 1 Full Episodes Video Streaming & Torrent Search By www.webtvwire.com Published On :: Tue, 28 Apr 2015 04:29:17 +0000 Peter Kay’s Car Share Synopsis Peter Kay’s Car Share is a situation comedy television series produced by BBC One that premiered in April of 2015. Peter Kay’s Car Share follows the story of John (played by Peter Kay), an assistant manager in a supermarket and his co-worker and promotions rep Kayleigh (played by Sian Gibson). […] Full Article TV Shows
tor Watch Meet the Smiths Online | Season 1 Full Episodes Video Streaming & Torrent Search By www.webtvwire.com Published On :: Wed, 29 Apr 2015 04:40:17 +0000 Meet the Smiths Synopsis Meet the Smiths is a scripted reality television series produced by TBS that premiered in April of 2015. Meet the Smiths follows the daily lives of Kenny Smith, an NBA analyst for TNT and his wife Gwendolyn Osborne-Smith, a model for The Price is Right. The couple has five children together […] Full Article TV Shows
tor Watch Arranged Full Episodes Online | Season 1 Video Streaming & Torrent Search By www.webtvwire.com Published On :: Wed, 29 Apr 2015 04:47:26 +0000 Arranged Synopsis Arranged is a reality television series produced by the FYI Network that premiered in April of 2015. Arranged follows the story of the three American couples who all come from different backgrounds, but their cultural traditions allow for arranged marriages. The series chronicles their lives in the lead up to the wedding and […] Full Article TV Shows
tor Watch Wayward Pines Full Episodes Online | Season 1 Video Streaming & Torrent Search By www.webtvwire.com Published On :: Thu, 30 Apr 2015 06:02:00 +0000 Wayward Pines Synopsis Wayward Pines is a mystery thriller television series produced by Fox Network and set to premiere in May of 2015. Based on the book Pines written by Blake Crouch and produced by M. Night Shyamalan Wayward Pines follows the story of an FBI agent Ethan Bruke (played by Matt Dillon), who travels […] Full Article TV Shows
tor Watch Miles from Tomorrowland Online | Season 1 Full Episodes Video Streaming & Torrent Search By www.webtvwire.com Published On :: Thu, 30 Apr 2015 06:07:54 +0000 Miles from Tomorrowland Synopsis Miles from Tomorrowland is an animated television series produced by the Disney Channel that premiered in February of 2015. Miles from Tomorrowland is an American animated TV series about the adventures of an inquisitive, if somewhat reckless boy named Miles who travels the universe with his family. Miles from Tomorrowland is […] Full Article TV Shows
tor Watch The Protectors (1982) Online | Season 1 & 2 Full Episodes Video Streaming & Torrent Search By www.webtvwire.com Published On :: Fri, 01 May 2015 04:31:45 +0000 The Protectors (1972) Synopsis The Protectors (1972) was an action thriller television series produced by ITV that premiered in September of 1972. The Protectors (1972) was a British action thriller series created by Gerry Anderson (Thunderbirds) about an international group of rich troubleshooters. Contessa di Contini (played by Nyree Dawn Porter), Paul Buchet (played by […] Full Article TV Shows
tor Watch Wormwood Online | Season 1 Video Streaming & Torrent Search By www.webtvwire.com Published On :: Fri, 01 May 2015 04:37:16 +0000 Wormwood Synopsis Wormwood was a children’s television series produced by Network Ten and ABC1 that premiered in October of 2007. Made as a joint Canadian-Australian production, Wormwood was a TV series about a quirky town where a group of kids investigated strange events. The series was based on the stories written by Paul Jennings. Wormwood […] Full Article TV Shows
tor Watch A Sharp Intake Of Breath Online | Season 1, 2, 3 & 4 Video Streaming & Torrent Search By www.webtvwire.com Published On :: Fri, 01 May 2015 04:45:08 +0000 A Sharp Intake Of Breath Synopsis A Sharp Intake Of Breath was a situation comedy television series produced by ITV that premiered in February of 1978. Created by Ronnie Taylor A Sharp Intake Of Breath followed the story of Peter Barnes (played by David Jason – Only Fools And Horses), an ordinary man who made […] Full Article TV Shows
tor How Backup And Storage Led To Cybercrime By feedproxy.google.com Published On :: Mon, 04 May 2020 15:00:15 +0000 Technology has come a long way, and cyber protection is the most crucial factor in advancing the future of digital defense. Interestingly enough, cybersecurity was not always an issue in backup and storage; but as technology advances, so do the methods of hackers. Saying this, let’s take a walk down memory lane. The 1900s: Where […] The post How Backup And Storage Led To Cybercrime appeared first on Dumb Little Man. Full Article Security Technology RSA NAS SAN MSP AWS RAM
tor 45 Funny, Heartfelt, Unforgettable Travel Stories By feedproxy.google.com Published On :: Mon, 16 Mar 2020 10:00:00 +0000 I tell travel stories for a living. I do this because I can’t NOT tell travel stories — every experience I have is shaped in the moment and waits in anticipation to shoot out of my fingertips. And I live to share those stories with an audience. As humans, we’re hard-wired to be influenced by … 45 Funny, Heartfelt, Unforgettable Travel Stories Read More » The post 45 Funny, Heartfelt, Unforgettable Travel Stories appeared first on Adventurous Kate. Full Article Blog
tor I’m Telling Stories I’ve Never Told Before — on Patreon! By feedproxy.google.com Published On :: Wed, 01 Apr 2020 10:00:25 +0000 When I started this blog more than 10 years ago, I had one goal: to entertain as many people as possible with my travel stories. I got away from that goal in recent years, focusing on guides for travelers instead, realizing that it’s hard to earn a living when you tell stories like these. But … I’m Telling Stories I’ve Never Told Before — on Patreon! Read More » The post I’m Telling Stories I’ve Never Told Before — on Patreon! appeared first on Adventurous Kate. Full Article Blog
tor History of Machu Picchu By feedproxy.google.com Published On :: Thu, 16 Mar 2017 00:50:09 +0000 History of Machu Picchu Archaeological evidence uncovered around the site suggests that the area was first used for agricultural purposes back in 760 B.C. The war of Vilcambamba Pachacutec in 1440 established the first settlement at the site. It was called the Tahuantinsuyo Empire which was later followed by the formation of the government of Manco Capac. It is thought that Machu Picchu was first inhabited by 300-1000 inhabitants, who were of the highest Class or "llactas". The valleys around these areas were important for their agricultural contribution, however after death of the Emperor Pachacutec, it lost it's importance, with the establishment of new sites like Ollaytantambo and Vilcambamba. The building of these new sites by his successors, in more accessible terrain made Machu Picchu less appealing. From 1527 to 1532, two brothers Huáscar and Atahualpa fought against each other in a civil war over the Inca Empire. Their father, Inca Huayna Capac had given each brother a section of the empire to manage, one in Huáscar in Cuzco and Atahualpa in Quito. When Huayna Capac and his heir, Ninan Cuyuchi, died somewhere between 1525 and 1527, the two brothers Atahualpa and Huáscar went to war over who should rule. The population who had come to live in the Machu Picchu area from rural or remote locations left after the war ended to return to where they came from. Later another brother, Manco Inca was sent into exile in Vilcambamba, and Machu Picchu was deserted. Antonio Raimondi was an Italian geographer and scientist from Milan who visited Machu Picchu in 1851. In 1867 Augusto Berns arrived to mine the site. Hiram Bingham re-discovered the ruins in 1911. He documented and publicised his "discovery". Hiram Bingham Full Article Machu Picchu Inca Trail
tor “Distraction,” Simplicity, and Running Toward Shitstorms By feedproxy.google.com Published On :: Tue, 05 Oct 2010 23:49:56 +0000 It can scarcely be denied that the supreme goal of all theory is to make the irreducible basic elements as simple and as few as possible without having to surrender the adequate representation of a single datum of experience. —Albert Einstein, “On the Method of Theoretical Physics” (1934) Context: Last week, I pinched off one of my typically woolly emails in response to an acquaintance whom I admire. He’s a swell guy who makes things I love, and he'd written, in part, to express concern that my recent Swift impersonation had been directed explicitly at something he'd made. Which, of course, it hadn’t—but which, as I'll try to discuss here, strikes me as irrelevant. To paraphrase Bogie, I played it for him, so now I suppose I might as well play it for you. (n.b.: Excerpted, redacted, munged, and heavily expanded from my original email) There are at least a couple things that mean a lot to me that I'm still just not very good at. Make nuanced points in whatever way they need to be made; even if that ends up seeming “un-nuanced” Never explain yourself. I want to break both these self-imposed rules privately with you here. [Editor’s Note: Um.] Because, I hope to nuance the shit out of some fairly un-nuanced points. And, to do that, I'll also (reluctantly) need to explain myself. But, here goes. First [regarding my goofing on “distraction-free writing environments”] I think there are some GIANT distinctions at play here that a lot of folks may not find nearly as obvious as I do: Tool Mastery vs. Productivity Pr0n – Finding and learning the right tools for your work vs solely dicking around with the options for those tools is just so important, but also so different. And, admittedly, it’s almost impossible to contrast those differences in terms of hard & fast rules that could be true for all people in all situations. But, that doesn’t make the difference any less qualitatively special or real. Similarly… Self-Help Vs. “Self”–“Help” – Solving the problem that caused the problem that caused the problem that caused the symptom we eventually noticed. Huge. Arguably, peerless. Viz.: How many of us ignore the actual cause of our problem in favor of just reading dozens of blog posts about how to “turbocharge” its most superficial symptoms? Sick. Focus & Play – Yes, focusing on important work is, as Ford used to say, Job 1. But, that focus benefits when we maintain the durable and unapologetic sense of play that affords true creativity and fosters an emergence of context and connection that’s usually killed by stress. BUT. Again, what conceivable “rule” could ever serve to immutably declare that “THIS goofing-off is critical for hippocampal plasticity” vs. “THAT goofing-off is just dumb, distracting bullshit?” Impossible. Because drawing those kinds of distinctions is one of our most important day-to-day responsibilities. Decisions are hard, and there’s no app or alarm gadget that can change that. Although, they certainly can help mask the depth of the underlying problem that made them seem so—what’s the parlance?—“indispensable”. Think: Elmo Band-Aids for that unsightly pancreatic tumor. Reducing Distraction through Care (Rather than braces, armatures, and puppet strings). Removing interruptions and external distractions that harm your work or life? Great. Counting on your distraction-removal tool to supplement your non-existent motivation to do work that will never get done anyway? Pathetic. Frankly, this is a big reason I'm so galled when anyone touts their tool/product/service as being the poor, misunderstood artist’s new miracle medicine—rather than just admitting they've made a slightly different spoon. Because, let’s be honest: although most of us have plenty of perfectly serviceable spoons, everybody knows collecting cutlery is way more fun than using it to swallow yucky medicine. Using a System Vs. Becoming a System. Having a system or process for getting work done vs. making the iteration of that system or process a replacement for the work. This is just…wow…big. But, maybe most importantly to me… Embracing the Impossibles. Getting past these or any other intellectual koans by simply accepting life’s innumerable and unresolvable paradoxes, hypocrisies, and impossibilities as God-given gifts of creative constraint. Rather than, say, a mimeographed page of long division problems that must be solved for a whole number, n. I just can’t ever get away from this one. For me, it’s what everything inevitably comes back to. The very definition of our jobs is to solve the right problem at the right level for the right reason—based on a combination of the best info we have for now and a clear-eyed dedication to never pushing an unnecessary rock up an avoidable hill. YET, we keep force-feeding the monster that tells us to fiddle and fart and blame the Big Cruel World whenever we face work that might threaten our fragile personal mythology. “Sigh. I wish I could finally start writing My Novel….Ooooooh, if only I had a slightly nicer pen…and Zeus loved me more….” All that stuff? That there’s a complex set of ideas to talk about for many complex reasons—not least of which being how many people either despise or (try to) deny the unavoidable impact of ol' number six. But, here’s the thing: as much as saying so pisses anybody off, I think the topics we're NOT talking about whenever we disappear into Talmudic scholarship about “full-screen mode” or “minimalist desks” or whatever constitutes a “zen habit”—those shunned topics are precisely the things that I believe are most mind-blowingly critical to our real-world happiness as humans. In fact, I believe that to such a degree that helping provide a voice for those unpopular topics that can be heard over the din is now (what passes for) my career. I really believe these deeper ideas are worth socializing on any number of levels and in many media. Even when it’s inconvenient and slightly disrespectful of someone’s business model. So, that’s what I try to do. I talk about these things. Seldom by careful design. Often poorly. But, always because they each mean an awful lot to me. […] But, no matter how I end up saying whatever the hell I say, I believe in saying it not simply to be liked or followed or revered as a “nice guy” who pushes out shit-tons of whatever to “help people.” Because, believe me, friend, a great many of those apparently “nice guys” swarming around the web “helping people” these days are ass-fucking their audience for nickels and calling it a complimentary colonoscopy. And, while I absolutely think that in itself is empirically wrong, I also think it’s just as important to say that it’s wrong. Sometimes, True Things need to be said. Which in this instance amounts to saying, a) selling people a prettier way to kinda almost but not really write is not, in the canonical sense, “nice”—but, far worse, b) leaving your starry-eyed customers with the nauseatingly misguided impression that their “distraction” originates from anyplace but their own busted-ass brain is really not “helping.” Not on any level. It is, literally, harmful. “Helping” a junkie become more efficient at keeping his syringe loaded is hardly “nice.” It’s the opposite of nice. And, it’s the opposite of helpful. These are my True Things. And, to me, saying your True Things also means not watering down the message you care about in order to render it incapable of even conceivably hurting someone’s feelings—or of even conceivably losing you even one teeny-tiny slice of that precious “market share.” Well, that’s the price, and I'm fine paying it—best money I've ever spent. But, it also means trusting your audience by letting each of them decide to add water only as they choose to—by never corrupting the actual concentrate in a way that might make it less useful to the smartest or most eager 5% of people who'd like to try using it undiluted. Because, at that point, you're not only abandoning the coolest people you have the honor of serving—you risk becoming a charlatan. And, that’s precisely what you become when you start to iteratively inbreed the kind of fucktard audience for whom daily buffets of weak swill and beige assurance are life’s most gratifying reward. Sure. Those poor bastards may never end up using any of that watery information to do anything more ambitious than turbocharging their most regrettable symptoms. But, who’s the last person in the universe who’s going to grab them by the ears and tell them to get back to work? Exactly—that same “nice guy” whose livelihood now depends on keeping infantalized strangers addicted to his “help.” Holy shit—no way could I ever live with that. It’s so wrong, it’s not even right. ESC, ESC, ESC! […] Okay. So anyhow, there’s a really long-winded, overly generous, and extremely pompous way of trying to say I don’t know how to do what I do except how I do it. But, I do genuinely feel awful when innocent people feel they have been publicly humiliated or berated simply because I'm some dick who hates people. Which has to be my favorite irony of all. When I was a kid, I thought my Mom was “mean” not to let me play in traffic on busy Galbraith Road. Today, I'm not simply grateful that she had the strength and resolve to be so “mean”—I actually can’t imagine how sad it would be to not have people in your life who care enough about your long-term welfare to tell you to stop fucking around in traffic. To where you eventually might start even seeking 12x-daily safety hacks from some of the very same drivers whose recklessness may eventually kill you. Wow. […] Admitting when life is complicated or things aren’t shiny and happy all the time strikes me as a wonderfully sane and adult way to conduct one’s life. That there are so many folks offended by even the existence of this anarchic idea is not a problem I can solve. No more than I can wish useless email away or pray hard enough that it never rains on anyone’s leaky roof. All out of scope. And, then, I jizzed on at length about how much I admire the recipient’s work. Which I do. Good work doesn’t need a cookie I may admire your work, too. Especially if you care a lot about that work and don’t overly sweat peoples' opinions of it. Most definitely including my own. For these purposes, it doesn’t really matter whether we're friends and, honestly, it doesn’t even matter whether I love, use, or agree with everything you do, say, or make in a given day. It doesn’t matter because good work doesn’t need me to love it. Like tornadoes and cold sores, good work happens with total disregard to whether I'm “into it.” But, conversely, let’s stipulate that the points-of-view undergirding our opinions—again, including mine—will and should survive either agreement or lack of agreement with equivalently effortless ease. Because, like really good work, a really good point-of-view doesn’t require another person’s benediction. Guess we'll have to disagree to agree Now, to be only vaguely clearer here, I'm not posting this circuitous ego dump in the service of altering your opinion of either me, my friend, his work, or practically anything else for that matter. But, I would love it if we could all be more okay with the fact that real life means that we do each have a different, sometimes incongruous, and often totally incompatible point-of-view. Yes. Even you have a point-of-view that someone despises. Ready to change it now? Jesus, I sure hope not. Then, to be only slightly more clear, I'm also not advocating for that fakey brand of web-based kum ba ya that gets trotted out alternately as “tolerance” or “inclusion” or some styrofoam miniature of “civility.” I'm absolutely not against all of those things when authentically practiced, but I'm also really skeptical of the well-branded peacemakers who are forever appointing themselves the Internet’s “Now-Now-Let’s-All-Pretend-We're-Just-Saying-the-Same-Useless-Thing-Here” den mothers. Because we're not all saying the same things. Not at all. And, it infantalizes some important conversations when we tacitly demand that any instance of honest disagreement be immediately horseshat into a photo opp where some thought leader gets to hoist everyone’s hands in the air like he’s fucking Jimmy Carter. Nope. Not saying that. Who will you really rely on? What I AM saying is that alllllll this seemingly unrelated stuff is absolutely related—that the pattern of not relying on other people for anything you really care about is arguably the great-grandaddy of every useful productivity, creativity, or self-help pattern. Where’s this matter? Pretty much everywhere you have any sort of stake: Don’t rely on other people to remove your totally fake “distractions.” Don’t rely on other people to pat your beret, re-tie your cravat, and make you a nice cocoa whenever that mean man on the internet points out that your “distractions” are totally fake. (Which they are) Don’t rely on other people to tell you when or whether you have enough information. Don’t rely on other people to define your job. Don’t rely on other people to “design your lifestyle.” Don’t rely on other people to decide when your opinions are acceptable. Don’t rely on other people to tell you when you're allowed to be awesome. Don’t rely on other people to make you care. Don’t even rely on other people to tell you what you should or shouldn’t rely on. Yes. I went there. Because that’s the point. These hypocrisies, paradoxes, and ambiguities that people get so wound up about—that many of us are constantly (impotently) trying to resolve—cannot be resolved. Because, yeah: all of these harrowingly unsolvable problems are immune to new notebooks and less-distracting applications and shinier systems and “nicer” self-“help” and pretty much anything else that is not, specifically, you walking straight into the angriest and least convenient shitstorm you can find and getting your ass kicked until the storm gets bored with kicking it. Then, you find an even angrier storm. Then, another. And, so on. “Get the fuck off of my obstacle, Private Pyle!” Doing that annoying hard stuff is how you grow, get better, and learn what real help looks like. Even if that’s not the answer you wanted to hear. You get better by getting your ass out of your RSS reader and fucking making things until they suck less. Not by buying apps. You don’t whine about distractions, or derail yourself over needing a nicer pencil sharpener, or aggravate your chronic creative diabetes by starting another desperate waddle to the self-help buffet. No. You work. And, for what it’s worth, just like you can’t get to the moon by eating cheese, you'll also never leave boot camp with your original scrote intact by telling your drill sergeant to try using more honey than vinegar. No. That sergeant’s job is to make you miserable. It’s his job to break down your callow conceits about what’s supposed to be easy and fair. It’s his job to emotionally pummel you into giving up and becoming a Marine. You? You're not there to give the sergeant notes; you're there to sleep two hours a night, then not mind getting beaten for 20 hours until a decent Marine starts to fall out. Who knows? He may even surprise you by introducing a surprisingly effective “distraction-free learning environment.” “Tee ell dee ahr, Professor Brainiac.” Like most humans, I like things I can understand. Like most readers, I love specificity. Like most thinkers, I love clarity. Like most students, I love relevance and practicality. And, like most busy people, believe it or not, I actually do really like it when someone gets straight to the point. But, here’s the problem. If my 2-year-old daughter asks me about time travel, and I blithely announce, “E=mc2”, I will have said something that is entirely specific, clear, relevant, practical, and/or straight-to-the-point. For somebody. But, not so much for my daughter. And, to be honest, not even to any useful degree for me. She'd probably either laugh derisively at me (which she’s great at), or she'd pause and ask, “Whuh dat?” (which she’s even better at). Thing is, her understanding that jumble of characters less than me—and my understanding it WAY less than Professor Al—has zero impact on the profundity, truth, beauty, or impact of the man’s theory. Sure. You could quite accurately fault me for being a smartass and a poseur, and you could even berate my toddler for her unaccountably shallow understanding of Modern Physics. But, in any case, you can’t really blame either Albert or his theory. You're turbocharging nothing Specifically, Albert can’t begin to tell us what he really knows if we don’t understand math. So, let’s say this theory you've been hearing about really interests you. And, let’s also pretend, just for the sake of the analogy, that you haven’t completed Calculus III (212) or Quantum Mechanics (403) or even something as elementary as, say, Advanced Astrophysics II (537). I know you have. Obviously. But, let’s pretend. Where do you start? Well, you could read some tips about learning math. You could find a list of 500 indispensable resources for indispensable math resources. You could buy a new “distraction-free math environment.” Heck, there’s actually nothing to stop you from just declaring yourself a “math expert.” Congratulations, Professor. Thing is: you still don’t know math. Which means you still can’t really understand the theory—no more than a pathetic Liberal Arts refugee like me or a dullard Physics ignoramus like my kid can really grok relativity. Difference is, you will have blown a lot of time hoping that actual expertise follows non-existent effort—while my daughter and I get to remain total novices without charge. Only, we don’t get all mad at the theory as a result; a staggering number of fake math experts do. I mean, be honest—after all that recreational non-work and make-believe dedication almost trying to kinda learn math sorta—you might actually get frustrated at how brazenly Al defies your fondness for shortcuts by continuing to rely on so many terms and proofs and blah-blah-blah that you still just don’t understand. So annoying. You may simply decide that Albert Einstein’s a huge dick for never saying things that can be completely understood solely by scanning a headline. EPIC EINSTEIN FAIL, amirite? You never really know what you didn’t know until you know it But, Al just told the truth. Problem is, Al’s truth not only requires fancy things in order to be truly understood—the more of those fancy things you take away from his truth, the less true it gets. And, by the time it’s been diluted to the point where you're comfortable that you understand it? You'd be understanding the wrong thing. Even I can understand that. But, not one bit of any of this is Al’s fault. Al doesn’t get to control who uses, abuses, gets, or doesn’t get what he said or why it matters. Especially since he’s been dead for over fifty years. All I know is, regardless of who has ears to hear it on a given day, it would be to Al’s credit never to mangle something important in order to get it into terms everybody’s ready to handle without actually trying. And God bless him for never agreeing that your “distractions” to learning math are his problem. So, yeah, if you only need to hand in a crappy 5-page paper, you could certainly Cliff’s Notes your way through Borges, Eliot, or Joyce in an afternoon, and feel like you haven’t missed a thing. Trouble is, if you did care even a little, it’s impossible to even say how much you're missing since you can’t be bothered to soldier through the source text. The text itself is the entire point. Even the wonderfully cogent and readable layman’s explanations Einstein himself provided don’t really get to the nut, the application, and the implications of his real theory. That all takes real math. That “single datum of experience” matters Sometimes, complex or difficult things stop being true when you try to make them too simple. Sometimes, you have to actually get laid to understand why people think sex is such a thing. Sometimes, you need to learn some Greek if you really want to understand The Gospel of John. And, yeah, sometimes, you're going to have to just work unbelievably hard at whatever you claim to care about before anyone can begin to help you get any better—or less “distracted”—at it. The part I really know is what doesn’t work. Reading Penthouse Forum won’t help you CLEP out of Vaginal Intercourse 101. Watching a Rankin-Bass cartoon about the Easter Bunny will teach you very little about the intricacies of transubstantiation. And, if you can’t be troubled to care so much about your work that you reflexively force distractions away, dicking around with yet another writing application will merely aggravate the problem. Ironic, huh? These quantum mechanics of personal productivity are rife with such frustrating “paradoxes.” These are True Things. Achieving expertise and doing creative work is all horribly complicated and difficult and paradoxical and frustrating and recursive and James Joyce-y—and any guide, blog, binary, guru, or “nice guy” that tries to suggest otherwise is probably giving you a complimentary colonoscopy. Do the math. Want a new syllabus? Sure: Run straight into your shitstorm, my friends. Reject the impulse to think about work, rather than finishing it. And, open your heart to the remote possibility that any mythology of personal failure that involves messiahs periodically arriving to make everything “easy” for you might not really be helping your work or your mental health or your long-standing addiction to using tools solely to ship new excuses. Learn your real math, and any slide rule will suffice. Try, make, and do until you quit noticing the tools, and if you still think you need new tools, go try, make, and do more. If you can pull off this deceptively simple and millennia-old pattern, you'll eventually find that—god by dying god—any partial truth that’s supported your treasured excuses for not working will be replaced by a no-faith-required knowledge that you're really, actually, finally getting better at something you care about. Which is just sublimely un-distracting. Dedication This article is dedicated to my friend, Greg Knauss. No, he’s not the app guy–he’s just a good man who does good work, who accidentally/unintentionally helped me write this rant. He also happens to be a fella who could teach anyone a thing or two about writing with distractions. Thanks, Greg. ”“Distraction,” Simplicity, and Running Toward Shitstorms” was written by Merlin Mann for 43Folders.com and was originally posted on October 05, 2010. Except as noted, it's ©2010 Merlin Mann and licensed for reuse under CC BY-NC-ND 3.0. "Why a footer?" Full Article Creative Work Distractions Features
tor VIDEO: GOP senator says China made ‘conscious decision’ to allow COVID-19 to spread beyond border By dennismichaellynch.com Published On :: Sat, 09 May 2020 16:53:12 +0000 The DML News App offers the best in news reporting. The post VIDEO: GOP senator says China made ‘conscious decision’ to allow COVID-19 to spread beyond border appeared first on Dennis Michael Lynch. Full Article News Feed Powered by DMLNewsApp.com
tor Police find 8-foot boa constrictor while investigating Oppenheimer Park fight By bc.ctvnews.ca Published On :: Fri, 8 May 2020 18:36:00 -0700 Police officers responding to a call about a man with a machete in Oppenheimer Park Friday afternoon found what they were looking for, and then some. Full Article
tor 'The horror stories get worse and worse': Some tenants taking advantage of eviction ban By bc.ctvnews.ca Published On :: Fri, 8 May 2020 18:29:00 -0700 Landlords who are missing thousands of dollars in rent or who find their properties damaged or strewn with garbage are concerned some tenants are taking advantage of the eviction ban put in place during the pandemic. Full Article
tor BREAKING: 43-Yr-Old Father Of 9, Dollar Store Sec Guard, Shot DEAD While Allegedly Trying To Enforce MI Gov Whitmer’s Face Covering Exec Order By 100percentfedup.com Published On :: Wed, 06 May 2020 18:27:38 +0000 The following article, BREAKING: 43-Yr-Old Father Of 9, Dollar Store Sec Guard, Shot DEAD While Allegedly Trying To Enforce MI Gov Whitmer’s Face Covering Exec Order, was first published on 100PercentFedUp.com. Will the mainstream media report about the senseless death of a 43-year-old father of nine, who would have been alive today if it were not for VP wannabe, Gretchen Whitmer's executive order that forced him to respond to a customer not wearing a face mask? Continue reading: BREAKING: 43-Yr-Old Father Of 9, Dollar Store Sec Guard, Shot DEAD While Allegedly Trying To Enforce MI Gov Whitmer’s Face Covering Exec Order ... Full Article Featured Left News Politics
tor Attorney for Jailed Dallas Salon Owner Shelley Luther Slams Obama Loyalist Judge as a “Tiny Tyrant” By 100percentfedup.com Published On :: Thu, 07 May 2020 02:33:27 +0000 The following article, Attorney for Jailed Dallas Salon Owner Shelley Luther Slams Obama Loyalist Judge as a “Tiny Tyrant”, was first published on 100PercentFedUp.com. Warren Norred, attorney for Shelley Luther, joined Tucker Carlson to discuss the decision by an Obama loyalist Texas judge to jail his client for reopening her salon during the COVID-19 pandemic. Norred said the judge has exposed himself for the “tiny tyrant” that he is. The judge jailed Luther and even fined her $7,000. Texas […] Continue reading: Attorney for Jailed Dallas Salon Owner Shelley Luther Slams Obama Loyalist Judge as a “Tiny Tyrant” ... Full Article Featured Government Politics
tor Video: Dallas Salon Owner Shelley Luther Gets Surprise Visit from Sen Ted Cruz for a Celebratory Haircut By 100percentfedup.com Published On :: Sat, 09 May 2020 13:19:16 +0000 The following article, Video: Dallas Salon Owner Shelley Luther Gets Surprise Visit from Sen Ted Cruz for a Celebratory Haircut, was first published on 100PercentFedUp.com. When Dallas, Texas salon owner Shelley Luther opened her salon in defiance of the lockdown order in Texas, she was visited numerous times by the local police and then sentenced to 7 days in jail with a fine of $7,000. After public outrage at her punishment, the Texas Supreme Court stepped in to demand her […] Continue reading: Video: Dallas Salon Owner Shelley Luther Gets Surprise Visit from Sen Ted Cruz for a Celebratory Haircut ... Full Article Breaking Featured Government News Politics
tor Council votes against proposed cannabis store location in Lakeshore By windsor.ctvnews.ca Published On :: Fri, 8 May 2020 16:54:00 -0400 In Lakeshore, it may be a little while longer before a retail cannabis store opens. Full Article
tor Owners of new retail cannabis store hoping to open soon in Pillette Village By windsor.ctvnews.ca Published On :: Fri, 8 May 2020 16:51:00 -0400 At a time when store front vacancies are growing thanks to COVID-19, a new retail cannabis store in Pillette Village is hoping to open soon. Full Article
tor May snowstorm buries southwest Manitobans By winnipeg.ctvnews.ca Published On :: Sat, 9 May 2020 10:46:00 -0600 Instead of May flowers, Manitobans in the southwest part of the province received a blanketing of snow for Mother's Day weekend. Full Article
tor The EU Cannot Build a Foreign Policy on Regulatory Power Alone By feedproxy.google.com Published On :: Tue, 11 Feb 2020 16:33:26 +0000 11 February 2020 Alan Beattie Associate Fellow, Global Economy and Finance Programme and Europe Programme @alanbeattie LinkedIn Brussels will find its much-vaunted heft in setting standards cannot help it advance its geopolitical interests. 2020-02-11-Leyen.jpg EU Commission President Ursula von der Leyen speaks at the European Parliament in Strasbourg in February. Photo: Getty Images. There are two well-established ideas in trade. Individually, they are correct. Combined, they can lead to a conclusion that is unfortunately wrong.The first idea is that, across a range of economic sectors, the EU and the US have been engaged in a battle to have their model of regulation accepted as the global one, and that the EU is generally winning.The second is that governments can use their regulatory power to extend strategic and foreign policy influence.The conclusion would seem to be that the EU, which has for decades tried to develop a foreign policy, should be able to use its superpower status in regulation and trade to project its interests and its values abroad.That’s the theory. It’s a proposition much welcomed by EU policymakers, who know they are highly unlikely any time soon to acquire any of the tools usually required to run an effective foreign policy.The EU doesn’t have an army it can send into a shooting war, enough military or political aid to prop up or dispense of governments abroad, or a centralized intelligence service. Commission President Ursula von der Leyen has declared her outfit to be a ‘geopolitical commission’, and is casting about for any means of making that real.Through the ‘Brussels effect’ whereby European rules and standards are exported via both companies and governments, the EU has indeed won many regulatory battles with the US.Its cars, chemicals and product safety regulations are more widely adopted round the world than their American counterparts. In the absence of any coherent US offering, bar some varied state-level systems, the General Data Protection Regulation (GDPR) is the closest thing the world has to a single model for data privacy, and variants of it are being adopted by dozens of countries.The problem is this. Those parts of global economic governance where the US is dominant – particularly the dollar payments system – are highly conducive to projecting US power abroad. The extraterritorial reach of secondary sanctions, plus the widespread reliance of banks and companies worldwide on dollar funding – and hence the American financial system – means that the US can precisely target its influence.The EU can enforce trade sanctions, but not in such a powerful and discriminatory way, and it will always be outgunned by the US. Donald Trump could in effect force European companies to join in his sanctions on Iran when he pulled out of the nuclear deal, despite EU legislation designed to prevent their businesses being bullied. He can go after the chief financial officer of Huawei for allegedly breaching those sanctions.By contrast, the widespread adoption of GDPR or data protection regimes inspired by it may give the EU a warm glow of satisfaction, but it cannot be turned into a geopolitical tool in the same way.Nor, necessarily, does it particularly benefit the EU economy. Europe’s undersized tech sector seems unlikely to unduly benefit from the fact that data protection rules were written in the EU. Indeed, one common criticism of the regulations is that they entrench the power of incumbent tech giants like Google.There is a similar pattern at work in the adoption of new technologies such as artificial intelligence and the Internet of Things. In that field, the EU and its member states are also facing determined competition from China, which has been pushing its technologies and standards through forums such as the International Telecommunication Union.The EU has been attempting to write international rules for the use of AI which it hopes to be widely adopted. But again, these are a constraint on the use of new technologies largely developed by others, not the control of innovation.By contrast, China has created a vast domestic market in technologies like facial recognition and unleashed its own companies on it. The resulting surveillance kit can then be marketed to emerging market governments as part of China’s enduring foreign policy campaign to build up supporters in the developing world.If it genuinely wants to turn its economic power into geopolitical influence – and it’s not entirely clear what it would do with it if it did – the EU needs to recognize that not all forms of regulatory and trading dominance are the same.Providing public goods to the world economy is all very well. But unless they are so particular in nature that they project uniquely European values and interests, that makes the EU a supplier of useful plumbing but not a global architect of power.On the other hand, it could content itself with its position for the moment. It could recognize that not until enough hard power – guns, intelligence, money – is transferred from the member states to the centre, or until the member states start acting collectively, will the EU genuinely become a geopolitical force. Speaking loudly and carrying a stick of foam rubber is rarely a way to gain credibility in international relations.This article is part of a series of publications and roundtable discussions in the Chatham House Global Trade Policy Forum. Full Article
tor Repression of sphingosine kinase (SK)-interacting protein (SKIP) in acute myeloid leukemia diminishes SK activity and its re-expression restores SK function [Molecular Bases of Disease] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 Previous studies have shown that sphingosine kinase interacting protein (SKIP) inhibits sphingosine kinase (SK) function in fibroblasts. SK phosphorylates sphingosine producing the potent signaling molecule sphingosine-1-phosphate (S1P). SKIP gene (SPHKAP) expression is silenced by hypermethylation of its promoter in acute myeloid leukemia (AML). However, why SKIP activity is silenced in primary AML cells is unclear. Here, we investigated the consequences of SKIP down-regulation in AML primary cells and the effects of SKIP re-expression in leukemic cell lines. Using targeted ultra-HPLC-tandem MS (UPLC-MS/MS), we measured sphingolipids (including S1P and ceramides) in AML and control cells. Primary AML cells had significantly lower SK activity and intracellular S1P concentrations than control cells, and SKIP-transfected leukemia cell lines exhibited increased SK activity. These findings show that SKIP re-expression enhances SK activity in leukemia cells. Furthermore, other bioactive sphingolipids such as ceramide were also down-regulated in primary AML cells. Of note, SKIP re-expression in leukemia cells increased ceramide levels 2-fold, inactivated the key signaling protein extracellular signal-regulated kinase, and increased apoptosis following serum deprivation or chemotherapy. These results indicate that SKIP down-regulation in AML reduces SK activity and ceramide levels, an effect that ultimately inhibits apoptosis in leukemia cells. The findings of our study contrast with previous results indicating that SKIP inhibits SK function in fibroblasts and therefore challenge the notion that SKIP always inhibits SK activity. Full Article
tor Inhibition of the erythropoietin-producing receptor EPHB4 antagonizes androgen receptor overexpression and reduces enzalutamide resistance [Molecular Bases of Disease] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 Prostate cancer (PCa) cells heavily rely on an active androgen receptor (AR) pathway for their survival. Enzalutamide (MDV3100) is a second-generation antiandrogenic drug that was approved by the Food and Drug Administration in 2012 to treat patients with castration-resistant prostate cancer (CRPC). However, emergence of resistance against this drug is inevitable, and it has been a major challenge to develop interventions that help manage enzalutamide-resistant CRPC. Erythropoietin-producing human hepatocellular (Eph) receptors are targeted by ephrin protein ligands and have a broad range of functions. Increasing evidence indicates that this signaling pathway plays an important role in tumorigenesis. Overexpression of EPH receptor B4 (EPHB4) has been observed in multiple types of cancer, being closely associated with proliferation, invasion, and metastasis of tumors. Here, using RNA-Seq analyses of clinical and preclinical samples, along with several biochemical and molecular methods, we report that enzalutamide-resistant PCa requires an active EPHB4 pathway that supports drug resistance of this tumor type. Using a small kinase inhibitor and RNAi-based gene silencing to disrupt EPHB4 activity, we found that these disruptions re-sensitize enzalutamide-resistant PCa to the drug both in vitro and in vivo. Mechanistically, we found that EPHB4 stimulates the AR by inducing proto-oncogene c-Myc (c-Myc) expression. Taken together, these results provide critical insight into the mechanism of enzalutamide resistance in PCa, potentially offering a therapeutic avenue for enhancing the efficacy of enzalutamide to better manage this common malignancy. Full Article
tor A peroxisome deficiency-induced reductive cytosol state up-regulates the brain-derived neurotrophic factor pathway [Metabolism] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 The peroxisome is a subcellular organelle that functions in essential metabolic pathways, including biosynthesis of plasmalogens, fatty acid β-oxidation of very-long-chain fatty acids, and degradation of hydrogen peroxide. Peroxisome biogenesis disorders (PBDs) manifest as severe dysfunction in multiple organs, including the central nervous system (CNS), but the pathogenic mechanisms in PBDs are largely unknown. Because CNS integrity is coordinately established and maintained by neural cell interactions, we here investigated whether cell-cell communication is impaired and responsible for the neurological defects associated with PBDs. Results from a noncontact co-culture system consisting of primary hippocampal neurons with glial cells revealed that a peroxisome-deficient astrocytic cell line secretes increased levels of brain-derived neurotrophic factor (BDNF), resulting in axonal branching of the neurons. Of note, the BDNF expression in astrocytes was not affected by defects in plasmalogen biosynthesis and peroxisomal fatty acid β-oxidation in the astrocytes. Instead, we found that cytosolic reductive states caused by a mislocalized catalase in the peroxisome-deficient cells induce the elevation in BDNF secretion. Our results suggest that peroxisome deficiency dysregulates neuronal axogenesis by causing a cytosolic reductive state in astrocytes. We conclude that astrocytic peroxisomes regulate BDNF expression and thereby support neuronal integrity and function. Full Article
tor N{alpha}-Acetylation of the virulence factor EsxA is required for mycobacterial cytosolic translocation and virulence [Molecular Bases of Disease] By feedproxy.google.com Published On :: 2020-04-24T06:08:45-07:00 The Mycobacterium tuberculosis virulence factor EsxA and its chaperone EsxB are secreted as a heterodimer (EsxA:B) and are crucial for mycobacterial escape from phagosomes and cytosolic translocation. Current findings support the idea that for EsxA to interact with host membranes, EsxA must dissociate from EsxB at low pH. However, the molecular mechanism by which the EsxA:B heterodimer separates is not clear. In the present study, using liposome-leakage and cytotoxicity assays, LC-MS/MS–based proteomics, and CCF-4 FRET analysis, we obtained evidence that the Nα-acetylation of the Thr-2 residue on EsxA, a post-translational modification that is present in mycobacteria but absent in Escherichia coli, is required for the EsxA:B separation. Substitutions at Thr-2 that precluded Nα-acetylation inhibited the heterodimer separation and hence prevented EsxA from interacting with the host membrane, resulting in attenuated mycobacterial cytosolic translocation and virulence. Molecular dynamics simulations revealed that at low pH, the Nα-acetylated Thr-2 makes direct and frequent “bind-and-release” contacts with EsxB, which generates a force that pulls EsxB away from EsxA. In summary, our findings provide evidence that the Nα-acetylation at Thr-2 of EsxA facilitates dissociation of the EsxA:B heterodimer required for EsxA membrane permeabilization and mycobacterial cytosolic translocation and virulence. Full Article
tor ER stress increases store-operated Ca2+ entry (SOCE) and augments basal insulin secretion in pancreatic beta cells [Molecular Bases of Disease] By feedproxy.google.com Published On :: 2020-04-24T06:08:45-07:00 Type 2 diabetes mellitus (T2DM) is characterized by impaired glucose-stimulated insulin secretion and increased peripheral insulin resistance. Unremitting endoplasmic reticulum (ER) stress can lead to beta-cell apoptosis and has been linked to type 2 diabetes. Although many studies have attempted to link ER stress and T2DM, the specific effects of ER stress on beta-cell function remain incompletely understood. To determine the interrelationship between ER stress and beta-cell function, here we treated insulin-secreting INS-1(832/13) cells or isolated mouse islets with the ER stress–inducer tunicamycin (TM). TM induced ER stress as expected, as evidenced by activation of the unfolded protein response. Beta cells treated with TM also exhibited concomitant alterations in their electrical activity and cytosolic free Ca2+ oscillations. As ER stress is known to reduce ER Ca2+ levels, we tested the hypothesis that the observed increase in Ca2+ oscillations occurred because of reduced ER Ca2+ levels and, in turn, increased store-operated Ca2+ entry. TM-induced cytosolic Ca2+ and membrane electrical oscillations were acutely inhibited by YM58483, which blocks store-operated Ca2+ channels. Significantly, TM-treated cells secreted increased insulin under conditions normally associated with only minimal release, e.g. 5 mm glucose, and YM58483 blocked this secretion. Taken together, these results support a critical role for ER Ca2+ depletion–activated Ca2+ current in mediating Ca2+-induced insulin secretion in response to ER stress. Full Article
tor Structure-based discovery of a small-molecule inhibitor of methicillin-resistant Staphylococcus aureus virulence [Molecular Biophysics] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 The rapid emergence and dissemination of methicillin-resistant Staphylococcus aureus (MRSA) strains poses a major threat to public health. MRSA possesses an arsenal of secreted host-damaging virulence factors that mediate pathogenicity and blunt immune defenses. Panton–Valentine leukocidin (PVL) and α-toxin are exotoxins that create lytic pores in the host cell membrane. They are recognized as being important for the development of invasive MRSA infections and are thus potential targets for antivirulence therapies. Here, we report the high-resolution X-ray crystal structures of both PVL and α-toxin in their soluble, monomeric, and oligomeric membrane-inserted pore states in complex with n-tetradecylphosphocholine (C14PC). The structures revealed two evolutionarily conserved phosphatidylcholine-binding mechanisms and their roles in modulating host cell attachment, oligomer assembly, and membrane perforation. Moreover, we demonstrate that the soluble C14PC compound protects primary human immune cells in vitro against cytolysis by PVL and α-toxin and hence may serve as the basis for the development of an antivirulence agent for managing MRSA infections. Full Article
tor Non-photopic and photopic visual cycles differentially regulate immediate, early, and late phases of cone photoreceptor-mediated vision [Molecular Bases of Disease] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Cone photoreceptors in the retina enable vision over a wide range of light intensities. However, the processes enabling cone vision in bright light (i.e. photopic vision) are not adequately understood. Chromophore regeneration of cone photopigments may require the retinal pigment epithelium (RPE) and/or retinal Müller glia. In the RPE, isomerization of all-trans-retinyl esters to 11-cis-retinol is mediated by the retinoid isomerohydrolase Rpe65. A putative alternative retinoid isomerase, dihydroceramide desaturase-1 (DES1), is expressed in RPE and Müller cells. The retinol-isomerase activities of Rpe65 and Des1 are inhibited by emixustat and fenretinide, respectively. Here, we tested the effects of these visual cycle inhibitors on immediate, early, and late phases of cone photopic vision. In zebrafish larvae raised under cyclic light conditions, fenretinide impaired late cone photopic vision, while the emixustat-treated zebrafish unexpectedly had normal vision. In contrast, emixustat-treated larvae raised under extensive dark-adaptation displayed significantly attenuated immediate photopic vision concomitant with significantly reduced 11-cis-retinaldehyde (11cRAL). Following 30 min of light, early photopic vision was recovered, despite 11cRAL levels remaining significantly reduced. Defects in immediate cone photopic vision were rescued in emixustat- or fenretinide-treated larvae following exogenous 9-cis-retinaldehyde supplementation. Genetic knockout of Des1 (degs1) or retinaldehyde-binding protein 1b (rlbp1b) did not eliminate photopic vision in zebrafish. Our findings define molecular and temporal requirements of the nonphotopic or photopic visual cycles for mediating vision in bright light. Full Article
tor Reactive dicarbonyl compounds cause Calcitonin Gene-Related Peptide release and synergize with inflammatory conditions in mouse skin and peritoneum [Molecular Bases of Disease] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 The plasmas of diabetic or uremic patients and of those receiving peritoneal dialysis treatment have increased levels of the glucose-derived dicarbonyl metabolites like methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG). The elevated dicarbonyl levels can contribute to the development of painful neuropathies. Here, we used stimulated immunoreactive Calcitonin Gene–Related Peptide (iCGRP) release as a measure of nociceptor activation, and we found that each dicarbonyl metabolite induces a concentration-, TRPA1-, and Ca2+-dependent iCGRP release. MGO, GO, and 3-DG were about equally potent in the millimolar range. We hypothesized that another dicarbonyl, 3,4-dideoxyglucosone-3-ene (3,4-DGE), which is present in peritoneal dialysis (PD) solutions after heat sterilization, activates nociceptors. We also showed that at body temperatures 3,4-DGE is formed from 3-DG and that concentrations of 3,4-DGE in the micromolar range effectively induced iCGRP release from isolated murine skin. In a novel preparation of the isolated parietal peritoneum PD fluid or 3,4-DGE alone, at concentrations found in PD solutions, stimulated iCGRP release. We also tested whether inflammatory tissue conditions synergize with dicarbonyls to induce iCGRP release from isolated skin. Application of MGO together with bradykinin or prostaglandin E2 resulted in an overadditive effect on iCGRP release, whereas MGO applied at a pH of 5.2 resulted in reduced release, probably due to an MGO-mediated inhibition of transient receptor potential (TRP) V1 receptors. These results indicate that several reactive dicarbonyls activate nociceptors and potentiate inflammatory mediators. Our findings underline the roles of dicarbonyls and TRPA1 receptors in causing pain during diabetes or renal disease. Full Article
tor Webinar: Reimagining the Role of State and Non-State Actors in (Re)building National Health Systems in the Arab World By feedproxy.google.com Published On :: Wed, 15 Apr 2020 14:15:01 +0000 Research Event 22 April 2020 - 1:00pm to 2:00pm Event participants Fadi El-Jardali, Professor of Health Policy and Systems, American University of BeirutModerator: Nadim Houry, Executive Director, Arab Reform Initiative As new cases of COVID-19 continue to surge, countries around the world struggle to mitigate the public health and economic effects of the virus. It is becoming increasingly clear that an effective pandemic response requires a whole-of-government, whole-of-society approach. In the Arab world, where health systems are already strained by armed conflicts and displaced populations, a whole-of-society response to the pandemic is particularly critical as countries have become increasingly dependent on non-state actors, notably the private sector, for healthcare provision and any response that includes the state alone may not be sufficient to address the pandemic.In a recent article, Fadi El-Jardali, argued that while the pandemic will have grave health and economic consequences for years to come, it brings with it a valuable opportunity to re-envision the role of state and non-state actors in strengthening health systems. The article addressed the need for increased collaboration between state and non-state actors, and the rethinking of existing cooperation models to provide quality healthcare services for all. In this webinar, part of the Chatham House project on the future of the state in the Middle East and North Africa, Dr El-Jardali will discuss how state and non-state actors can collaborate more effectively to address the shortcomings of national health care systems amidst the pandemic and beyond. The article’s author will share insights on the different capacities available in Arab societies that governments can draw upon to ensure that Universal Health Coverage, equity considerations and social justice are at the core of health systems.You can express your interest in attending by following this link. You will receive a Zoom confirmation email should your registration be successful. Alternatively, you can watch the event live on the MENA Programme Facebook page. Department/project Middle East and North Africa Programme, The Future of the State in the Middle East Reni Zhelyazkova Programme Coordinator, Middle East and North Africa Programme +44 (0)20 7314 3624 Email Full Article
Reni Zhelyazkova Programme Coordinator, Middle East and North Africa Programme +44 (0)20 7314 3624 Email
tor The transcriptional regulator IscR integrates host-derived nitrosative stress and iron starvation in activation of the vvhBA operon in Vibrio vulnificus [Gene Regulation] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 For successful infection of their hosts, pathogenic bacteria recognize host-derived signals that induce the expression of virulence factors in a spatiotemporal manner. The fulminating food-borne pathogen Vibrio vulnificus produces a cytolysin/hemolysin protein encoded by the vvhBA operon, which is a virulence factor preferentially expressed upon exposure to murine blood and macrophages. The Fe-S cluster containing transcriptional regulator IscR activates the vvhBA operon in response to nitrosative stress and iron starvation, during which the cellular IscR protein level increases. Here, electrophoretic mobility shift and DNase I protection assays revealed that IscR directly binds downstream of the vvhBA promoter PvvhBA, which is unusual for a positive regulator. We found that in addition to IscR, the transcriptional regulator HlyU activates vvhBA transcription by directly binding upstream of PvvhBA, whereas the histone-like nucleoid-structuring protein (H-NS) represses vvhBA by extensively binding to both downstream and upstream regions of its promoter. Of note, the binding sites of IscR and HlyU overlapped with those of H-NS. We further substantiated that IscR and HlyU outcompete H-NS for binding to the PvvhBA regulatory region, resulting in the release of H-NS repression and vvhBA induction. We conclude that concurrent antirepression by IscR and HlyU at regions both downstream and upstream of PvvhBA provides V. vulnificus with the means of integrating host-derived signal(s) such as nitrosative stress and iron starvation for precise regulation of vvhBA transcription, thereby enabling successful host infection. Full Article