ai What you need to know about product management for AI By feedproxy.google.com Published On :: Tue, 31 Mar 2020 10:00:00 +0000 If you’re already a software product manager (PM), you have a head start on becoming a PM for artificial intelligence (AI) or machine learning (ML). You already know the game and how it is played: you’re the coordinator who ties everything together, from the developers and designers to the executives. You’re responsible for the design, […] Full Article AI & ML Deep Dive
ai Watch this Klingon perform "Somewhere Over the Rainbow" in her native tongue By feedproxy.google.com Published On :: Fri, 08 May 2020 08:20:32 PDT Jennifer Usellis-Mackay, aka the Klingon Pop Warrior, sings "Somewhere Over the Rainbow" in her native tongue. The performance took place in 2015 at Chicago's iO Theater. From the video description: Opening for Improvised Star Trek, I sang a new (old) song. Got some newly translated words the day of the performance... enjoy this little slice of nerdiness... or don't. Vocals - The Klingon Pop Warrior (Jennifer Usellis-Mackay) Guitar - The Red Shirt (Joe Mizzi) Translation - Admiral qurgh (Christopher Lipscombe) Video - Eric Scull (via r/ObscureMedia) Read the rest Full Article Video music star trek trekkers
ai Pence aide tests positive for coronavirus By feedproxy.google.com Published On :: Fri, 08 May 2020 09:33:05 PDT CNBC reports that an aide to Pence has tested positive for COVID-19. This follows yesterday's report that Trump's personal valet tested positive for the virus. A spokeswoman for Pence did not immediately respond to CNBC’s request for comment. Pence was scheduled to travel to Des Moines, Iowa, in the morning, but his departure from Andrews Air Force Base was delayed by nearly an hour as staff dealt with news of the diagnosis. Reporters traveling with Pence said several staffers disembarked from Air Force Two just before takeoff. Photo of Pence: Know Your Meme Read the rest Full Article Post coronavirus COVID-19 trump
ai Puppy training doesn’t have to descend your house into chaos thanks to these online classes By feedproxy.google.com Published On :: Fri, 08 May 2020 19:00:49 PDT One positive upside of the past two months is how sheltering at home has all but emptied area animal shelters. It’s tough to get solid numbers nationally, but shelters in cities and regions all across America are reporting massive surges in animal adoptions. Even the steep increase in Google searches for “adopt a pet,” up a whopping 335 percent in April, proves what we probably all knew anyway — that in times of stress, having a furry friend is a huge comfort for millions. Unfortunately, one of the downsides of the past two months is there are no trainers available to help whip some of these new family pets, particularly puppies, into shape. From barking and jumping to house training and scratching, The Complete Guide to Puppy and Dog Training Bundle is a full plan for getting the newest member of your family integrated into the house safely and sanely all by yourself. The collection includes eight courses all geared toward getting a new dog or puppy behaving the right way. And if you’ve ever had any thoughts about starting a dog training business of your own, this coursework is a perfect starting spot. Puppies: A-Z Guide to Puppy & Dog Training kicks off the learning, explaining the best way to train, teach and socialize your puppy so they grow into a joyful, well balanced, and well-behaved dog. Of course, most puppies each have their particular issues, so a handful of courses look more closely at some of the tactics for helping your puppy overcome certain challenging behaviors. Read the rest Full Article Post shop
ai 1 dead after train slams into pickup truck near Brooks, Alta. By calgary.ctvnews.ca Published On :: Fri, 8 May 2020 18:53:00 -0600 RCMP say a 50-year-old man died and a 60-year-old man is in hospital following a crash involving a CP Rail train Friday morning. Full Article
ai Sport24.co.za | Hard work paid off for former Springbok Bands By www.sport24.co.za Published On :: Sat, 09 May 2020 16:32:59 +0200 It isn’t surprising that former Springbok tighthead Richard Bands is remembered mainly for one bullocking run for the Springboks in Dunedin in 2003. Full Article
ai Sport24.co.za | Umtiti suffers calf knock in second Barca training session By www.sport24.co.za Published On :: Sat, 09 May 2020 17:11:45 +0200 France defender Samuel Umtiti has picked up a calf injury in just the second session since Barcelona returned to training from the cornonavirus quarantine. Full Article
ai Sport24.co.za | Haiti football federation boss probed for alleged rape of girls By www.sport24.co.za Published On :: Sat, 09 May 2020 18:12:58 +0200 Police in Haiti are investigating allegations that the president of the national football federation raped teenage girls. Full Article
ai Sport24.co.za | New Bulls chief Rathbone can't wait to learn from Jake By www.sport24.co.za Published On :: Sat, 09 May 2020 16:23:54 +0200 The genial young administrator with a burgeoning reputation chuckles when it's pointed out to him that he can't seem to shake off 'working' for some of South Africa's biggest businessmen. Full Article
ai Sport24.co.za | Jennings backs Markram as next Proteas Test captain By www.sport24.co.za Published On :: Sat, 09 May 2020 17:00:07 +0200 Former Proteas head coach Ray Jennings is adamant Aiden Markram should be chosen as Faf du Plessis' replacement as captain of the Test team. Full Article
ai Signs of Slowing Unemployment; U.S. Jobless Claims Decline for Four Weeks in a Row By feedproxy.google.com Published On :: Thu, 30 Apr 2020 16:58:19 +0000 Signs of Slowing Unemployment Although millions of people lost their jobs because of the coronavirus, a surge of companies is hiring additional employees due to increased demands. By: Nadia Evangelou Coronavirus Full Article
ai Signs of Slowing Unemployment; More Than Half of States Had Fewer Jobless Claims for Four Weeks in a Row By feedproxy.google.com Published On :: Thu, 07 May 2020 20:03:33 +0000 Signs of Slowing Unemployment Following an unprecedented surge in jobless claims in March due to the coronavirus, unemployment is continuously slowing in April in 26 states. By: Nadia Evangelou Full Article
ai Five of the Best B2B Content Marketing Trends That Are Proven Effective To Gain New Clients By feedproxy.google.com Published On :: Wed, 06 May 2020 16:30:12 +0000 Digital marketing is fast-paced with trends and new updates to existing systems continuously popping out. That’s why it is important to stay up-to-date with the latest strategies that can be beneficial in reaching new audiences. Keeping up to date with the marketing trends will also help a business stay ahead of their competition. The best […] The post Five of the Best B2B Content Marketing Trends That Are Proven Effective To Gain New Clients appeared first on Dumb Little Man. Full Article Business Entrepreneur
ai Article: Will Blockchain Blow Up Digital Advertising Paradigms? By www.emarketer.com Published On :: Wed, 20 Dec 2017 04:01:00 GMT Ian McKee, founder and CEO of Singapore-based Vuulr, explains the value of blockchain technology—and the threat it poses to the structure of traditional digital advertising. Full Article
ai Airhook Looks to Reinvent the Traditional Airplane Tray Table By feedproxy.google.com Published On :: Thu, 06 Jun 2019 14:17:52 +0000 A clever, versatile, well-made alternative to traditional airplane tray tables. The post Airhook Looks to Reinvent the Traditional Airplane Tray Table appeared first on Vagabondish. Full Article Gear Modern Vagabond Review airplane Tray Table
ai 6 Ultimate Inca Trail Highlights By feedproxy.google.com Published On :: Fri, 17 Apr 2015 05:13:13 +0000 One of the most popular hikes in South America, the Inca Trail is definitely the experience of a lifetime. A centuries-old trail, it begins in the ancient Incan capital of Cusco and winds some 88 kilometers to some of the world’s most iconic ruins: Machu Picchu. Of course, the entirety of Inca Trail is absolutely stunning, from stunning snowcapped Andean peaks to centuries-old ruins situated in bucolic river valleys. However, these 5 highlights are truly bound to make your jaw drop. Wayllabamba. The endpoint of the first day’s trek along the Inca Trail, Wayllabamba, which means “grassy plain” in Quechua, is the perfect spot to watch the sunset behind the dramatic Andean peaks. This grassy plain overlooks a stunning spot of Andean scenery, with centuries-old Incan terraces winding through the surrounding mountainsides. There is even a village nearby where travelers can mingle with local villagers. Image courtesy of flatfootedadventurer.com The Valley of Llulluchapampa. Trekkers will start off the first portion of day two of the journey hiking through the picturesque Valley of Llulluchapampa. As you gradually ascend in altitude, you will even be afforded perfect views of stunning snowcapped cliffs. Image courtesy of Panoramio.com Runkuracay: This unique oval structure, sometimes colloquially know as the “Egg Hut,” is believed to have been a kind of rest stop for Incan travelers, called a tambo, providing them with a place to spend the night and rest their animals. It is the perfect place to enjoy a mid-hike break and marvel at the beauty of Incan architecture. Image courtesy of lenstherapy.wordpress.com Sayacmarca: First discovered by the famous Hiram Bingham when he wandered along a road extending from Machu Picchu, the dramatic Sayacmarca is situated at a fork in an old Incan road in a dense subtropical forest full of butterflies and hummingbirds. Quechua for “Dominant Town,” these unique ruins have an almost mystical air about them and are arguably the most impressive along the Inca Trail (except for Machu Picchu itself, of course!). It is believed that Sayacmarca was actually built by the Colla, a major enemy of the Incas, and that the Incas took over the site following their conquest of the group. Image courtesy of 4feet2mouths.com Phuyupatamarca: Dubbed “La Ciudad entre la Niebla” (“The City above the Clouds”), this major archeological site is situated a staggering 3,200 meters above sea level. Apropos to the nickname, Phuyupatamarca is very often surrounded by dense, white clouds. The ruins, dramatically constructed into a steep cliffside, contain five stone baths that fill up with freshwater during the rainy season. It is believed that these baths were used for religious ceremonies. Visitors can also check out the site’s elaborate hydraulic system, a true testament to impressive capabilities of Incan engineering. Of all of the Incan ruins in the region, Phuyupatamarca is arguably the most intact and therefore a truly spectacular site for trekkers passing through. "Phuyupatamarca (cloud-level town)" by D. Gordon E. Robertson - Own work. Licensed under CC BY-SA 3.0 via Wikimedia Commons. Huiñay Huayna (Wiñay Wayna): Huiñay Huayna (traditionally spelled Wiñay Wayna in Quechua, the language of the Incas) was constructed into a steep hillside overlooking the Urubamba River. In addition to the site’s ancient houses and temples, it also boasts an incredibly complex system of Incan terraces, formerly used for agriculture. The name of the site roughly translates to “Forever Young,” and many trekkers report that these ruins are the most beautiful found along the trail. Image courtesy of http://blog.teara.govt.nz These are just some of what you will see along the Inca Trail: Learn more about popular Inca Trail itineraries here Full Article Machu Picchu Inca Trail Places To See and Stay Inca Trail. Ancient Ruins Llulluchapampa Machu Picchu Moray Phuyupatamarca Runkuracay Sayacmarca Winay Wayna
ai 6 Tips and Tricks for Hiking the Inca Trail By feedproxy.google.com Published On :: Thu, 28 May 2015 23:23:31 +0000 My flight was booked! My dream of hiking the Inca Trail, and walking through the sun gate to Machu Picchu was finally becoming a reality. But then, the reality hit me. I have never done an overnight hike before! What do I pack? How do I get into shape? Is it safe? Do I go alone or with a group? As excited as I was, I realized I had a lot of planning ahead of me, but every moment of preparation (and sometimes extreme anxiety) was all worth it. Here are a few tips and tricks that helped me not only survive the Inca Trail, but have the trip of a lifetime! Find an Incredible Tour Group Before booking my trip, I was not sure how I felt about going with a tour group. I was worried that traveling with a group of strangers would take away from the trip. However, after plenty of research, I decided to go with Active Adventures on the Ultimate Peru Adventure. Our trip leader was not only full of helpful and interesting information, but became a friend who gave local tips, and made me feel comfortable and safe. I became close friends with my small tour group of 10 people, and still keep in touch with them. Picking a quality tour group like Active Adventures not only helped take the stress out of travelling logistics, but is truly what made my trip an enjoyable experience. (And for all the foodies out there, our Inca Trail chefs were incredible). Get Fit On the Inca Trail we had people of all ages, sizes, and fitness levels. However, I highly recommend preparing your body a little, and familiarizing yourself with how your body reacts to high altitude. But, don’t worry, you don’t need to an extreme amount of training. To prepare, I went on one to two hikes a week, and did plenty of dog walking. My hikes on average ranged from 3 to 7 miles. However, as fit as you are, everybody reacts differently to altitude. Try finding a hike in your area that has somewhat of a higher altitude. I only had the opportunity to do one higher altitude hike. It was not as high as the Inca Trail, but it still gave me an idea of how my body feels in high altitude. But don’t stress out too much! Your tour leader has helped many people hike the Inca Trail, and will be there to help you if you start to feel sick, or simply need a little extra motivation. Technology Tools I am a firm believer in digital detoxing when traveling, but when hiking in the wilderness, it is comforting to know that I have helpful resources at my fingertips if I ever need it. When hiking or traveling, there are always a few resources and apps I like to have on my phone or iTouch to stay safe. As a traveler, we are more vulnerable to security threats or identity theft on public computers and Wi-Fi. I choose to use a VPN when traveling for Wi-Fi security in hotels, to avoid computer viruses, and to gain access to content that is geo-blocked. For my Inca Trail trek I downloaded the MotionX GPS app. The app supports GPS navigation without the need for cell service. Thankfully our guides kept us on track, but it was comforting knowing that if anything happened, I could use my phone as a backup for navigation help. Make a Visit to Your Doctor When traveling anywhere, it is important to check in with your doctor. Different regions of the world may require various vaccinations, or medication. Before visiting your doctor, it is also helpful to do a little bit of your own research as to what medications or vaccinations are needed for travel. Your doctor may be familiar with vaccinations needed for Peru, but you are the only person who knows what your trip will consist of. Be sure to mention to your doctor if you are going to the Peruvian Amazon, or high altitude. For the Inca Trail I recommend packing the following medications: -Altitude sickness medication (Acetazolamide) -Imodium -Antibiotics (Ciprofloxacin) -Bug spray (not technically a medication, but important to bring as well) -Ibuprofen (always good to have) This list is most likely what your doctor will recommend as well, but be sure to do your own research as well. You may need malaria pills or certain vaccinations depending on where else your trip is going, or personal previous medical history. Pack Light The hardest part of my trip (aside from trekking up the stairs of the Inca Trail) was packing! There are several limitations on how much you pack on the Inca Trail in order to maintain that porters are being treated fairly and respectfully. Each porter is limited to carrying 20kg. This includes all blankets, clothes, and the porter’s personal belongings. Talk to your Active Adventure tour guide before leaving on your trip to find out up to date information on how much you are able to pack, and information on sleeping bags and pads. Aside from packing light, there are of course certain items you will want to pack, depending on the time of year your trek is. I used Her Packing List, along with the information provided by Active Adventures to help me in packing everything I need. Have the Time of Your Life Last, but not least, be ready to have incredible experiences and memories that will last a life time. When I first booked my trip to Peru and the Inca Trail I had certain expectations and ideas of what the trip would be like. I was looking forward to seeing Machu Picchu, but what I found was that the most memorable and exciting parts of my trip were not necessarily seeing the big tourist spots like Machu Picchu, but the journey getting there, and the unexpected surprises that came along the way. Peru and its people exceeded all expectations, and opened my mind in ways I did not know were possible. Hi, my name is Jess Signet. My parents were travelers since before I was born. Even in the womb, I was able to travel all over the place! Boy, did things NOT change as I grew older! Knowing there’s more to the world than the bubble I live in made me want to travel even further. Traveling is my drug and I’m addicted. (Please, no intervention!) Full Article Hiking and Trekking Tips and Things To Know
ai Why HEY had to wait By feedproxy.google.com Published On :: Tue, 31 Mar 2020 19:29:25 +0000 We had originally planned to release HEY, our new email service, in April. There was the final cycle to finish the features, there was a company meetup planned for the end of the month to celebrate together, we’d been capacity testing extensively, and the first step of a marketing campaign was already under way. But… keep reading Full Article Uncategorized
ai Video: Star-studded trailer By www.bbc.co.uk Published On :: 2008-02-27T12:00:00 Part of the Sport Relief promo for the BBC UK Homepage Full Article
ai My Faith in Nerds: Stronger Than Any Gelatinous Cube By feedproxy.google.com Published On :: Fri, 10 Sep 2010 20:01:57 +0000 dConstruct 2010: Merlin Mann - "Kerning, Orgasms & Those Goddamned Japanese Toothpicks" (NSFW) ME - Kerning, Orgasms And Those Goddamned Japanese Toothpicks on Huffduffer Download the audio | Huffduff it Let's be honest. I don't go...mmmm...places very often. I sit in this chair. I go to the Safeway with my daughter. Sometimes, I take the train downtown to get a haircut. I check the mail. But, by and large, like most nerds, I'm without question, a bit of a shut-in. Which makes it more than a little ironic that my first trip off the North American continent brought me all the way to Brighton, England's wonderful dConstruct Conference. Which wonderful conference placed me inside a very royal complex, alone on a very large stage, 90 seconds after being informed I'd better be entertaining, because I'd be conducting my oration on the same spot where, a scant 36 years earlier, ABBA had become international stars by singing an up-tempo number about giving up. So, y'know. No pressure. Commanded to this location by two of my web heroes, I was told I could speak about whatever I wanted. So, wow, to quote the ladies of ABBA, how could I ever refuse? Thus, I stood on that stage for over 35 minutes, rambling to 800 talented, creative people about Dungeons & Dragons, japanese toothpicks, torrenting Photoshop, as well as what I used to find myself doing after a long evening of shooting mutants in Stargate.1 But, mostly? Yes. Mostly, I stood on a stage thousands of miles from the chair from which I barely move, and I told a lot of really smart people that they were nerds. I also told them they should get out more. I swear: it made sense at the time. Some Serious Talent My talk about the challenges and opportunities of being a giant nerd seemed well received. Honestly, I'm very happy with how it turned out. But--oh, brother--was I ever up against some heavy hitters. Serious Lou Gehrig shit. I'll leave it to other, more eloquent folks to tell you what a wonderful day this was. But I will very much suggest you learn this for yourself by listening to the audio of the fantastic talks. Because every one of them is a corker. Additionally, like I said, Tom Coates put on one of the loveliest slide decks it's ever been my pleasure to see (56MB PDF). Great speakers, great hosts, wonderful attendees (who aren't above buying a yank a pint [thanks, everybody]). And, Thanks, dConstruct I have to admit, I'm kind of over conferences as a thing, which makes it even more crazy when I go to one, and it blows me out of the water with the care and quality of the event, the speakers, and the attendees. dConstruct was absolutely one of those blown-out-of-the-water events. (photo: happy.apple) As I learned over and over again--yes, like me--these folks are nerds. But, brother are they ever talented nerds who care and care. Which I just love so much. I'll take a nerdy bunch of fontdorks and cellists over a splashy mega-conference full of VC pitches and skanks pushing free Red Bull anytime. Anytime. dConstruct was simply a top-notch operation from end-to-end, and I'm insanely grateful that I was invited to participate. Thanks, Clearleft. And, you, the reader? If you get the chance next time, go. Heck, I might even leave this chair and go there, myself. Maybe. I suppose when Dr. Who's over, I could just let these 20-sided dice decide for me. Lemme see...what's my Armor Class and Hit Points...? Listen for Yourself2 dConstruct Podcast MARTY NEUMEIER - The Designful Company The Designful Company on Huffduffer Download the audio | Huffduff it BRENDAN DAWES - Boil, Simmer, Reduce Boil, Simmer, Reduce on Huffduffer Download the audio | Huffduff it DAVID MCCANDLESS - Information Is Beautiful Information Is Beautiful on Huffduffer Download the audio | Huffduff it SAMANTHA WARREN - The Power and Beauty of Typography The Power and Beauty of Typography on Huffduffer Download the audio | Huffduff it JOHN GRUBER - The Auteur Theory Of Design The Auteur Theory Of Design on Huffduffer Download the audio | Huffduff it HANNAH DONOVAN - Jam Session: What Improvisation Can Teach Us About Design Jam Session: What Improvisation Can Teach Us About Design on Huffduffer Download the audio | Huffduff it JAMES BRIDLE - The Value Of Ruins The Value Of Ruins on Huffduffer Download the audio | Huffduff it TOM COATES - Everything The Network Touches Everything The Network Touches on Huffduffer Download the audio | Huffduff it Kerning, Orgasms And Those Goddamned Japanese Toothpicks ME - Kerning, Orgasms And Those Goddamned Japanese Toothpicks on Huffduffer Download the audio | Huffduff it Hint: Number Three. ↩ Code for these was stolen wholesale from the dConstruct site. Jeremy, et al - don't hesitate to tell me if that's a problem.Srsly. ↩ ”My Faith in Nerds: Stronger Than Any Gelatinous Cube” was written by Merlin Mann for 43Folders.com and was originally posted on September 10, 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 dConstruct Geeks Knowledge Workers Nerds Speaking NSFW
ai Woman, 70, airlifted in serious condition after car collides with transport truck in Huntsville By barrie.ctvnews.ca Published On :: Thu, 7 May 2020 12:35:00 -0400 Full Article
ai Human remains found in Mulmur Township confirmed to be missing Caledon senior By barrie.ctvnews.ca Published On :: Fri, 8 May 2020 13:11:00 -0400 Human remains located in Mulmur Township in March have been confirmed to be those of an 88-year-old Caledon man who was reported missing seven months ago. Full Article
ai K9 unit discovers human remains in search for missing Meaford man By barrie.ctvnews.ca Published On :: Thu, 7 May 2020 20:32:00 -0400 Grey Bruce provincial police say the OPP canine unit found human remains in Meaford, and one person is under arrest. Full Article
ai Donald Trump Jr. Offers To Walk Bride-to-Be Down The Aisle After Liberal Parents Refuse To Attend Her Wedding Because Fiance Is A Conservative By 100percentfedup.com Published On :: Wed, 06 May 2020 02:26:06 +0000 The following article, Donald Trump Jr. Offers To Walk Bride-to-Be Down The Aisle After Liberal Parents Refuse To Attend Her Wedding Because Fiance Is A Conservative, was first published on 100PercentFedUp.com. TDS or Trump Derangement Syndrome brings out the worst in a lot of people. One young Texan girl’s story of her intolerant parents who refuse to attend her wedding because she’s marrying a conservative, however, is a new low. Lawyer and conservative civil rights activist, Rogan O’Handley tweeted a Tik Tok video of a Texan […] Continue reading: Donald Trump Jr. Offers To Walk Bride-to-Be Down The Aisle After Liberal Parents Refuse To Attend Her Wedding Because Fiance Is A Conservative ... Full Article Featured Political Correctness Politics
ai NY Shame: Workers Who Tested Positive For COVID-19 Were Allowed To Remain On The Job At Nursing Homes, As Death Toll For Nursing Home Patients Exceeds 3,000 By 100percentfedup.com Published On :: Wed, 06 May 2020 21:44:54 +0000 The following article, NY Shame: Workers Who Tested Positive For COVID-19 Were Allowed To Remain On The Job At Nursing Homes, As Death Toll For Nursing Home Patients Exceeds 3,000, was first published on 100PercentFedUp.com. The coronavirus crisis at New York’s nursing homes is even worse than previously thought. Monday night, the state Department of Health issued new data, adding more than 1,600 people who were presumed to have died of the virus in nursing homes, but did not have a confirmed diagnosis, to the official toll. As of May […] Continue reading: NY Shame: Workers Who Tested Positive For COVID-19 Were Allowed To Remain On The Job At Nursing Homes, As Death Toll For Nursing Home Patients Exceeds 3,000 ... Full Article Featured Politics
ai Breaking: Texas AG Calls for Immediate Release of Salon Owner Jailed for Opening…Texas Lt Gov Offers to Pay Salon Owner’s $7k Fine By 100percentfedup.com Published On :: Thu, 07 May 2020 00:28:50 +0000 The following article, Breaking: Texas AG Calls for Immediate Release of Salon Owner Jailed for Opening…Texas Lt Gov Offers to Pay Salon Owner’s $7k Fine, was first published on 100PercentFedUp.com. Salon A La Mode owner Shelley Luther opened her salon in defiance of the lockdown order for salons to stay closed during the coronavirus crisis. She boldly ripped. up the citation she was given by the police and refused to shut her doors. Luther hired a lawyer and went to court where an activist judge […] Continue reading: Breaking: Texas AG Calls for Immediate Release of Salon Owner Jailed for Opening…Texas Lt Gov Offers to Pay Salon Owner’s $7k Fine ... Full Article Breaking Crime Featured Government Politics
ai 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
ai Chicago Inmate Switches Identities While Wearing Mask…Is Released from Jail By 100percentfedup.com Published On :: Thu, 07 May 2020 03:16:17 +0000 The following article, Chicago Inmate Switches Identities While Wearing Mask…Is Released from Jail, was first published on 100PercentFedUp.com. A Cook County, Chicago inmate, was able to switch identities with another inmate allowing the wrong inmate to be released. How did they carry that off without anyone catching them? The inmate was wearing a mask when he was released, so it wasn’t as easy to identify him. Last Saturday, Quintin Henderson (pictured below), 28, […] Continue reading: Chicago Inmate Switches Identities While Wearing Mask…Is Released from Jail ... Full Article Breaking Crime Featured
ai Video Scrubbed of Obama-Biden Ambassador To China Praising Their Response to Coronavirus: “I take my hat off to China” By 100percentfedup.com Published On :: Thu, 07 May 2020 16:55:44 +0000 The following article, Video Scrubbed of Obama-Biden Ambassador To China Praising Their Response to Coronavirus: “I take my hat off to China”, was first published on 100PercentFedUp.com. During a recent interview on CNN, Obama-Biden ambassador to China (2014-2017) Max Baucus compared standing up to China on the coronavirus to “Hitler in the ’30s.” Baucus has proven himself to be sympathetic to China in recent interviews, where he puts down America and praises the Chinese. The MSNBC video via The Washington Free Beacon […] Continue reading: Video Scrubbed of Obama-Biden Ambassador To China Praising Their Response to Coronavirus: “I take my hat off to China” ... Full Article Breaking Featured Government Politics
ai Video: Salon Owner Shelley Luther Released from Jail After Obama-Loyalist Judge Sentenced Her to 7 Days By 100percentfedup.com Published On :: Thu, 07 May 2020 19:37:43 +0000 The following article, Video: Salon Owner Shelley Luther Released from Jail After Obama-Loyalist Judge Sentenced Her to 7 Days, was first published on 100PercentFedUp.com. Salon A La Mode owner Shelley Luther was just released from jail today. The Texas Supreme Court and Texas Governor Greg Abbott both called for her release today (see below). When Luther left jail she was greeted by supporters who yelled “Shelley’s Free!” She thanked all of the new friends she’s made during this difficult […] Continue reading: Video: Salon Owner Shelley Luther Released from Jail After Obama-Loyalist Judge Sentenced Her to 7 Days ... Full Article Breaking Crime Featured Government Uncategorized
ai BREAKING: Michigan’s Radical Governor Extends Lockdown AGAIN…Only One Day After Church Leaders and MI Lawmakers File Suit Against Her By 100percentfedup.com Published On :: Thu, 07 May 2020 22:53:35 +0000 The following article, BREAKING: Michigan’s Radical Governor Extends Lockdown AGAIN…Only One Day After Church Leaders and MI Lawmakers File Suit Against Her, was first published on 100PercentFedUp.com. Michigan was the first state to see protests against draconian lockdown measures by an overreaching governor. On April 15, the Michigan Conservative Coalition organized an in-vehicle protest in Lansing, MI that drew an estimated 15,000 vehicles. Since that time, several protests by Michigan workers who are being devastated by the one-size-fits-all shut down of the […] Continue reading: BREAKING: Michigan’s Radical Governor Extends Lockdown AGAIN…Only One Day After Church Leaders and MI Lawmakers File Suit Against Her ... Full Article Featured Politics
ai Mother of the Year, Michelle Obama Explains How Having Kids Was A “Concession”… Had To Give Up Her “Aspirations and Dreams” [VIDEO] By 100percentfedup.com Published On :: Fri, 08 May 2020 00:05:56 +0000 The following article, Mother of the Year, Michelle Obama Explains How Having Kids Was A “Concession”… Had To Give Up Her “Aspirations and Dreams” [VIDEO], was first published on 100PercentFedUp.com. While campaigning for her community organizer turned presidential candidate husband, Barack, Michelle Obama told a crowd of his supporters in Milwaukee, Wisconsin that for the first time in her life, she was proud to be an American. Four years later, Michelle Obama was a keynote speaker at the DNC convention, where she told Democrats how […] Continue reading: Mother of the Year, Michelle Obama Explains How Having Kids Was A “Concession”… Had To Give Up Her “Aspirations and Dreams” [VIDEO] ... Full Article Featured Left News Politics
ai BREAKING: New Docs Prove Obama Knew Details Of Flynn Wiretapping…Newly Surfaced Video Shows Obama Explaining How He Stays Out Of FBI Investigations By 100percentfedup.com Published On :: Fri, 08 May 2020 16:25:07 +0000 The following article, BREAKING: New Docs Prove Obama Knew Details Of Flynn Wiretapping…Newly Surfaced Video Shows Obama Explaining How He Stays Out Of FBI Investigations, was first published on 100PercentFedUp.com. Barack Obama knew. Documents released yesterday that were used to exonerate President Trump’s new NSA General Flynn, prove that President Barack Obama was aware of the details of Michael Flynn’s intercepted phone calls on December 16 with then-Russian Ambassador Sergey Kislyak. On January 5, 2017, then-Deputy Attorney General, Sally Yates attended an Oval Office meeting […] Continue reading: BREAKING: New Docs Prove Obama Knew Details Of Flynn Wiretapping…Newly Surfaced Video Shows Obama Explaining How He Stays Out Of FBI Investigations ... Full Article Featured Left News Political Correctness
ai Greg Gutfeld Levels Ilhan Omar With Epic Response To Her Claim That “White Privilege” Is Reason Charges Were Dropped Against General Flynn By 100percentfedup.com Published On :: Fri, 08 May 2020 19:54:46 +0000 The following article, Greg Gutfeld Levels Ilhan Omar With Epic Response To Her Claim That “White Privilege” Is Reason Charges Were Dropped Against General Flynn, was first published on 100PercentFedUp.com. Yesterday, after 3 1/2 years of having his character and integrity called into question, President Trump's first NSA, General Michael Flynn was finally... Continue reading: Greg Gutfeld Levels Ilhan Omar With Epic Response To Her Claim That “White Privilege” Is Reason Charges Were Dropped Against General Flynn ... Full Article Featured Politics
ai 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
ai 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
ai 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
ai To Advance Trade and Climate Goals, ‘Global Britain’ Must Link Them By feedproxy.google.com Published On :: Thu, 19 Mar 2020 17:12:54 +0000 19 March 2020 Carolyn Deere Birkbeck Associate Fellow, Global Economy and Finance Programme, and Hoffmann Centre for Sustainable Resource Economy @carolyndeere LinkedIn Google Scholar Dr Emily Jones Associate Professor, Blavatnik School of Government Dr Thomas Hale Associate Professor, Blavatnik School of Government COVID-19 is a sharp reminder of why trade policy matters. As the UK works to forge new trade deals, it must align its trade policy agenda with its climate ambition. 2020-03-19-Boris-Johnson-COP26.jpg Boris Johnson at the launch of the UK-hosted COP26 UN Climate Summit at the Science Museum, London on February 4, 2020. Photo by Jeremy Selwyn - WPA Pool/Getty Images. COVID-19 is a sharp reminder of why trade and climate policy matters. How can governments maintain access to critical goods and services, and ensure global supply chains function in times of crisis?The timing of many trade negotiations is now increasingly uncertain, as are the UK’s plans to host COP26 in November. Policy work continues, however, and the EU has released its draft negotiating text for the new UK-EU trade deal, which includes a sub-chapter specifically devoted to climate. This is a timely reminder both of the pressing need for the UK to integrate its trade and climate policymaking and to use the current crisis-induced breathing space in international negotiations - however limited - to catch up on both strategy and priorities on this critical policy intersection.The UK government has moved fast to reset its external trade relations post-Brexit. In the past month it formally launched bilateral negotiations with the EU and took up a seat at the World Trade Organization (WTO) as an independent member. Until the COVID-19 crisis hit, negotiations were also poised to start with the US.The UK is also in the climate spotlight as host of COP26, the most important international climate negotiation since Paris in 2015, which presents a vital opportunity for the government to show leadership by aligning its trade agenda with its climate and sustainability commitments in bold new ways.Not just an empty aspirationThis would send a signal that ‘Global Britain’ is not just an empty aspiration, but a concrete commitment to lead.Not only is concerted action on the climate crisis a central priority for UK citizens, a growing and increasingly vocal group of UK businesses committed to decarbonization are calling on the government to secure a more transparent and predictable international market place that supports climate action by business.With COP26, the UK has a unique responsibility to push governments to ratchet up ambition in the national contributions to climate action – and to promote coherence between climate ambition and wider economic policymaking, including on trade. If Britain really wants to lead, here are some concrete actions it should take.At the national level, the UK can pioneer new ways to put environmental sustainability – and climate action in particular - at the heart of its trade agenda. Achieving the government’s ambitious Clean Growth Strategy - which seeks to make the UK the global leader in a range of industries including electric cars and offshore wind – should be a central objective of UK trade policy.The UK should re-orient trade policy frameworks to incentivize the shift toward a more circular and net zero global economy. And all elements of UK trade policy could be assessed against environmental objectives - for example, their contribution to phasing out fossil fuels, helping to reverse overexploitation of natural resources, and support for sustainable agriculture and biodiversity.In its bilateral and regional trade negotiations, the UK can and should advance its environment, climate and trade goals in tandem, and implementation of the Paris Agreement must be a core objective of the UK trade strategy.A core issue for the UK is how to ensure that efforts to decarbonise the economy are not undercut by imports from high-carbon producers. Here, a ‘border carbon adjustment (BCA)’ - effectively a tax on the climate pollution of imports - would support UK climate goals. The EU draft negotiating text released yesterday put the issue of BCAs front and centre, making crystal clear that the intersection of climate, environment and trade policy goals will be a central issue for UK-EU trade negotiations.Even with the United States, a trade deal can and should still be seized as a way to incentivize the shift toward a net zero and more circular economy. At the multilateral level, as a new independent WTO member, the UK has an opportunity to help build a forward-looking climate and trade agenda.The UK could help foster dialogue, research and action on a cluster of ‘climate and trade’ issues that warrant more focused attention at the WTO. These include the design of carbon pricing policies at the border that are transparent, fair and support a just transition; proposals for a climate waiver for WTO rules; and identification of ways multilateral trade cooperation could promote a zero carbon and more circular global economy. To help nudge multilateral discussion along, the UK could also ask to join a critical ‘path finder’ effort by six governments, led by New Zealand, to pursue an agreement on climate change, trade and sustainability (ACCTS). This group aims to find ways forward on three central trade and climate issues: removing fossil fuel subsidies, climate-related labelling, and promoting trade in climate-friendly goods and services.At present, the complex challenges at the intersection of climate, trade and development policy are too often used to defer or side-step issues deemed ‘too hard’ or ‘too sensitive’ to tackle. The UK could help here by working to ensure multilateral climate and trade initiatives share adjustment burdens, recognise the historical responsibility of developed countries, and do not unfairly disadvantage developing countries - especially the least developed.Many developing countries are keen to promote climate-friendly exports as part of wider export diversification strategies and want to reap greater returns from greener global value chains. Further, small island states and least-developed countries – many of which are Commonwealth members – that are especially vulnerable to the impacts of climate change and natural disasters, need support to adapt in the face of trade shocks and to build climate-resilient, trade-related infrastructure and export sectors.As an immediate next step, the UK should actively support the growing number of WTO members in favour of a WTO Ministerial Statement on environmental sustainability and trade. It should work with its key trading partners in the Commonwealth and beyond to ensure the agenda is inclusive, supports achievement of the UN Sustainable Development Goals (SDGs) and helps developing countries benefit from a more environmentally sustainable global economy.As the UK prepares to host COP26, negotiates deals with the EU and US, and prepares for its first WTO Ministerial meeting as an independent member, it must show it can lead the way nationally, bilaterally, and multilaterally. And to ensure the government acts, greater engagement from the UK’s business, civil society and research sectors is critical – we need all hands on deck to forge and promote concrete proposals for aligning UK trade policy with the climate ambition our world needs. Full Article
ai Coronavirus: Could a People’s Bailout Help? By feedproxy.google.com Published On :: Wed, 06 May 2020 12:42:49 +0000 7 May 2020 Jim O'Neill Chair, Chatham House Lyndsey Jefferson Digital Editor, Communications and Publishing Department @LyndseyLdn The coronavirus crisis has resulted in an unprecedented economic downturn. Conventional quantitative easing measures used after the 2008 financial crisis will not be enough this time. 2020-05-06-Coronavirus-Food-Bank-NYC.jpg Local residents line up outside a food pantry during the COVID-19 pandemic on 23 April 2020 in Brooklyn, New York. Due to increased levels of unemployment, the lines at the daily food pantry have been getting longer. Photo: Getty Images. What is quantitative easing? How was it used after the 2008 financial crisis?Quantitative easing (QE) has been in existence since the Japanese central bank introduced it at the turn of the millennium. The simplest way to think about it is this: when interest rates can't go down anymore and play their normal role of stimulating growth, central banks try to expand the money supply. So, they're expanding the quantitative amount of money they put into the system. Of course, after 2008 because of the scale of the financial and economic collapse, many Western countries resorted to QE. Some have never gotten rid of it. Others have started to, but as a result of this crisis, have gone straight back to that playbook.33 million Americans have now filed for unemployment and one in five American workers have lost their jobs due to COVID-19. These are levels not seen since the Great Depression. You recently called for G20 countries to provide income support for all citizens. Why is this so urgent to implement now?It is incredible to reflect back on the short time since I published that piece. I entitled it the need for a so-called people's QE, and in some ways a number of European countries, including the UK, have executed some aspects of what I was suggesting. The United States has not, even though the absolute amounts of money the US authorities have put through their fiscal system to try and support the economy is actually bigger as a percentage of GDP than many in Europe. What they haven't done is support ongoing employment through various schemes that many European countries have done, of which the UK has, to some degree, been one of the most ambitious.That’s partly why you see such enormous filing for unemployment claims in the US. There’s no direct support to encourage employers to keep their employees on, in complete contrast to what you see in many Scandinavian countries who were the first to do it in Europe, and something the UK has since done. On a practical level, what might a smart people’s QE look like? We are living in an extraordinary time. Like many others in my generation, it’s nothing that any of us have gone through. Perhaps economically, the only parallel one can find is from the 1920s and 1930s.It became obvious to me in early March that governments are going to have to essentially force as many of us as possible, if we weren't doing absolutely crucial necessities, to stop working or to work from home. It was pretty obvious that the consequences could be horrific. So, the idea of a people's QE that I suggested then, some would have regarded as quite audacious. The most dramatic thing that could be done was, to put it simply, governments effectively pay for every business and every employee to have a two month paid holiday. Obviously, this would cost a very large amount of money for governments, but it would be the least disruptive way of getting us all to stay home.And when the time is right to start letting us get back to anything vaguely like normality, there wouldn't be as much permanent disruption. I think about six weeks have passed since I wrote that piece. Actually, given the policies many governments have announced, I'm not sure undertaking the audacity in generosity of what I suggested would have cost any more. Over the long term, it might have actually turned out to be less. Of course, there are ethics issues around whether the system could be gamed or not, amongst other issues. But six weeks later, I still believe that would have been the smartest thing to do. It certainly would have been much better than trying to encourage many businesses, particularly smaller ones, to take out loans.A couple of countries got close to what I was suggesting – Germany and Switzerland were very quick to give 100% government guarantees to business, as well as generous wage support systems. But a number of other countries haven't, like the US, even though they wrote a $1200 check for each citizen. Should a people’s QE involve the purchase and write off of consumer debt and student debt by a central bank? I think these things might have to be considered. I remember being on a conference call to Chatham House members where we discussed what would be the likely economic consequences and what policymakers should do. One person on the call was talking about quite conventional forms of policy just through various forms of standard QE. During the Q&A, someone asked whether we thought the US Federal Reserve might end up buying equities. And I said, well, why not? Eventually, it might come to that. Actually, before that discussion was over, the Fed coincidentally announced they were going to buy high-yield corporate bonds, or very risky company debt. This is something that would have been unheard of even by the playbook of 2008. So, I don't think ideas like a kind of provision to help student debtors is entirely crazy. These are things that our policymakers are going to have to think about as we go forward in the challenging and unpredictable days and weeks ahead. Poorer countries like El Salvador have gone as far as cancelling rent and major utility bills for its citizens. Do you think countries like the US and UK have gone far enough to help people during the crisis?Going one step further than a people’s QE and postponing major payments is a pretty interesting concept. I think in reality, it would be very disruptive to the medium to long-term mechanism of our societies. It could be very, very complicated. But, of course, some parts of the G20 nations, including the UK, have moved significantly in these areas as it relates to rent payments or mortgage payments. There have been significant mortgage holidays being introduced for many sectors of our community. I think the British government has been quite thoughtful about it without doing the whole hog of potentially getting rid of our transaction system for two months or beyond.You know, this may well be something that has to be considered if, God forbid, there is a second peak of the virus. If countries come out of a lockdown and all that results in is a dramatic rise in infections and then death again, we're going to end up right back where we are. Policymakers may have to implement more generous versions of what we've done already, despite what the long term debt consequences could be.The Coronavirus Aid, Relief, and Economic Security (CARES) Act in the US has been criticized as a corporate bailout while offering little to the American people. It was recently reported that hedge fund managers are applying for bailouts as ‘small businesses.’ Do you think more oversight is needed in how the stimulus funds are allocated? The speed at which many countries have responded and introduced policies means that there's going to be some gaping holes which allow people to unfairly benefit from the system. And if indeed, that were to be the case, I cannot see why a hedge fund should benefit from government generosity.A true hedge fund is supposed to be a form of investment manager that thrives in times of great volatility, and knows how to better navigate such financial markets than more conventional funds. So this shouldn’t be an environment where hedge funds seek the same kind of help as small businesses. That is certainly something the government should be very careful about.Some economists argue that central banks are not independent as they finance fiscal spending through purchase of government bonds. Do the strong measures taken by central banks in response to the crisis undermine the argument for central bank independence? In my view, an effective central bank has to do whatever is necessary, including doing very unconventional things, when the society in which that central bank operates needs it. Most of the time, central banks are pretty boring places, but they really become crucial organizations when we go through times like the 1920s, 1930s, 2008, and of course, this current crisis. If they want to maintain their legitimacy, whatever the true parliamentary or congressional legal standing is, they have to do things quickly and as we've seen in this case, differently than the convention in order to do what our societies need. Somebody was asking me just last week whether the Fed buying high grade debt was legal or not. I think that’s a pretty irrelevant conversation because if it’s not legal now, it will be made legal tomorrow. So, I think central banks have to keep their legitimacy and they have to do what is necessary when the time requires it. In that sense, I think most central banks have handled this crisis so far pretty well. Full Article
ai The FKH domain in FOXP3 mRNA frequently contains mutations in hepatocellular carcinoma that influence the subcellular localization and functions of FOXP3 [Molecular Bases of Disease] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 The transcription factor forkhead box P3 (FOXP3) is a biomarker for regulatory T cells and can also be expressed in cancer cells, but its function in cancer appears to be divergent. The role of hepatocyte-expressed FOXP3 in hepatocellular carcinoma (HCC) is unknown. Here, we collected tumor samples and clinical information from 115 HCC patients and used five human cancer cell lines. We examined FOXP3 mRNA sequences for mutations, used a luciferase assay to assess promoter activities of FOXP3's target genes, and employed mouse tumor models to confirm in vitro results. We detected mutations in the FKH domain of FOXP3 mRNAs in 33% of the HCC tumor tissues, but in none of the adjacent nontumor tissues. None of the mutations occurred at high frequency, indicating that they occurred randomly. Notably, the mutations were not detected in the corresponding regions of FOXP3 genomic DNA, and many of them resulted in amino acid substitutions in the FKH region, altering FOXP3's subcellular localization. FOXP3 delocalization from the nucleus to the cytoplasm caused loss of transcriptional regulation of its target genes, inactivated its tumor-inhibitory capability, and changed cellular responses to histone deacetylase (HDAC) inhibitors. More complex FKH mutations appeared to be associated with worse prognosis in HCC patients. We conclude that mutations in the FKH domain of FOXP3 mRNA frequently occur in HCC and that these mutations are caused by errors in transcription and are not derived from genomic DNA mutations. Our results suggest that transcriptional mutagenesis of FOXP3 plays a role in HCC. Full Article
ai 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
ai Mechanistic insights explain the transforming potential of the T507K substitution in the protein-tyrosine phosphatase SHP2 [Signal Transduction] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 The protein-tyrosine phosphatase SHP2 is an allosteric enzyme critical for cellular events downstream of growth factor receptors. Mutations in the SHP2 gene have been linked to many different types of human diseases, including developmental disorders, leukemia, and solid tumors. Unlike most SHP2-activating mutations, the T507K substitution in SHP2 is unique in that it exhibits oncogenic Ras-like transforming activity. However, the biochemical basis of how the SHP2/T507K variant elicits transformation remains unclear. By combining kinetic and biophysical methods, X-ray crystallography, and molecular modeling, as well as using cell biology approaches, here we uncovered that the T507K substitution alters both SHP2 substrate specificity and its allosteric regulatory mechanism. We found that although SHP2/T507K exists in the closed, autoinhibited conformation similar to the WT enzyme, the interactions between its N-SH2 and protein-tyrosine phosphatase domains are weakened such that SHP2/T507K possesses a higher affinity for the scaffolding protein Grb2-associated binding protein 1 (Gab1). We also discovered that the T507K substitution alters the structure of the SHP2 active site, resulting in a change in SHP2 substrate preference for Sprouty1, a known negative regulator of Ras signaling and a potential tumor suppressor. Our results suggest that SHP2/T507K's shift in substrate specificity coupled with its preferential association of SHP2/T507K with Gab1 enable the mutant SHP2 to more efficiently dephosphorylate Sprouty1 at pTyr-53. This dephosphorylation hyperactivates Ras signaling, which is likely responsible for SHP2/T507K's Ras-like transforming activity. Full Article
ai Modification of a PE/PPE substrate pair reroutes an Esx substrate pair from the mycobacterial ESX-1 type VII secretion system to the ESX-5 system [Molecular Bases of Disease] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 Bacterial type VII secretion systems secrete a wide range of extracellular proteins that play important roles in bacterial viability and in interactions of pathogenic mycobacteria with their hosts. Mycobacterial type VII secretion systems consist of five subtypes, ESX-1–5, and have four substrate classes, namely, Esx, PE, PPE, and Esp proteins. At least some of these substrates are secreted as heterodimers. Each ESX system mediates the secretion of a specific set of Esx, PE, and PPE proteins, raising the question of how these substrates are recognized in a system-specific fashion. For the PE/PPE heterodimers, it has been shown that they interact with their cognate EspG chaperone and that this chaperone determines the designated secretion pathway. However, both structural and pulldown analyses have suggested that EspG cannot interact with the Esx proteins. Therefore, the determining factor for system specificity of the Esx proteins remains unknown. Here, we investigated the secretion specificity of the ESX-1 substrate pair EsxB_1/EsxA_1 in Mycobacterium marinum. Although this substrate pair was hardly secreted when homologously expressed, it was secreted when co-expressed together with the PE35/PPE68_1 pair, indicating that this pair could stimulate secretion of the EsxB_1/EsxA_1 pair. Surprisingly, co-expression of EsxB_1/EsxA_1 with a modified PE35/PPE68_1 version that carried the EspG5 chaperone-binding domain, previously shown to redirect this substrate pair to the ESX-5 system, also resulted in redirection and co-secretion of the Esx pair via ESX-5. Our results suggest a secretion model in which PE35/PPE68_1 determines the system-specific secretion of EsxB_1/EsxA_1. Full Article
ai {alpha}-Synuclein filaments from transgenic mouse and human synucleinopathy-containing brains are maȷor seed-competent species [Molecular Bases of Disease] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Assembled α-synuclein in nerve cells and glial cells is the defining pathological feature of neurodegenerative diseases called synucleinopathies. Seeds of α-synuclein can induce the assembly of monomeric protein. Here, we used sucrose gradient centrifugation and transiently transfected HEK 293T cells to identify the species of α-synuclein from the brains of homozygous, symptomatic mice transgenic for human mutant A53T α-synuclein (line M83) that seed aggregation. The most potent fractions contained Sarkosyl-insoluble assemblies enriched in filaments. We also analyzed six cases of idiopathic Parkinson's disease (PD), one case of familial PD, and six cases of multiple system atrophy (MSA) for their ability to induce α-synuclein aggregation. The MSA samples were more potent than those of idiopathic PD in seeding aggregation. We found that following sucrose gradient centrifugation, the most seed-competent fractions from PD and MSA brains are those that contain Sarkosyl-insoluble α-synuclein. The fractions differed between PD and MSA, consistent with the presence of distinct conformers of assembled α-synuclein in these different samples. We conclude that α-synuclein filaments are the main driving force for amplification and propagation of pathology in synucleinopathies. Full Article
ai Brain manganese and the balance between essential roles and neurotoxicity [Molecular Bases of Disease] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Manganese (Mn) is an essential micronutrient required for the normal development of many organs, including the brain. Although its roles as a cofactor in several enzymes and in maintaining optimal physiology are well-known, the overall biological functions of Mn are rather poorly understood. Alterations in body Mn status are associated with altered neuronal physiology and cognition in humans, and either overexposure or (more rarely) insufficiency can cause neurological dysfunction. The resultant balancing act can be viewed as a hormetic U-shaped relationship for biological Mn status and optimal brain health, with changes in the brain leading to physiological effects throughout the body and vice versa. This review discusses Mn homeostasis, biomarkers, molecular mechanisms of cellular transport, and neuropathological changes associated with disruptions of Mn homeostasis, especially in its excess, and identifies gaps in our understanding of the molecular and biochemical mechanisms underlying Mn homeostasis and neurotoxicity. Full Article
ai Virtual Roundtable: Iraq in Uncertain Times By feedproxy.google.com Published On :: Thu, 26 Mar 2020 10:40:01 +0000 Invitation Only Research Event 30 March 2020 - 2:00pm to 3:30pm Event participants Toby Dodge, Associate Fellow, MENA Programme, Chatham HouseMac Skelton, Director, IRIS, American University of Iraq-SulaimaniAhmed Tabaqchali, Chief Investment Officer, AFC Iraq FundHanaa Edwar, Co-founder and Chairperson, Iraqi Al-Amal AssociationChair: Renad Mansour, Senior Research Fellow, MENA Programme, Chatham House The first months of 2020 have proven tumultuous for Iraq. The US killing of Iranian General Qassem Soleimani in January threatened to engulf the region in war and led to continued tit-for-tat violence between the US and Iran that has become almost a daily reality in Baghdad.Amid the ongoing protests that since last October have challenged the social contract and led to a violent response claiming 600 deaths and injuring tens of thousands, the government is still without a prime minister after Adil abd al-Mehdi's resignation in November 2019, leaving the country directionless.Most recently, the spread of COVID-19 threatens to expose a mismanaged healthcare system. At the same time, the rapid fall in the price of oil has impacted the government's ability to respond to or cope with these crises.At this virtual roundtable, part of the Chatham House Iraq Initiative, experts explore these developments and try to unpack the implications for Iraq’s fragile peace and stability. Department/project Middle East and North Africa Programme, Iraq Initiative 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
ai Modification of a PE/PPE substrate pair reroutes an Esx substrate pair from the mycobacterial ESX-1 type VII secretion system to the ESX-5 system [Molecular Bases of Disease] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 Bacterial type VII secretion systems secrete a wide range of extracellular proteins that play important roles in bacterial viability and in interactions of pathogenic mycobacteria with their hosts. Mycobacterial type VII secretion systems consist of five subtypes, ESX-1–5, and have four substrate classes, namely, Esx, PE, PPE, and Esp proteins. At least some of these substrates are secreted as heterodimers. Each ESX system mediates the secretion of a specific set of Esx, PE, and PPE proteins, raising the question of how these substrates are recognized in a system-specific fashion. For the PE/PPE heterodimers, it has been shown that they interact with their cognate EspG chaperone and that this chaperone determines the designated secretion pathway. However, both structural and pulldown analyses have suggested that EspG cannot interact with the Esx proteins. Therefore, the determining factor for system specificity of the Esx proteins remains unknown. Here, we investigated the secretion specificity of the ESX-1 substrate pair EsxB_1/EsxA_1 in Mycobacterium marinum. Although this substrate pair was hardly secreted when homologously expressed, it was secreted when co-expressed together with the PE35/PPE68_1 pair, indicating that this pair could stimulate secretion of the EsxB_1/EsxA_1 pair. Surprisingly, co-expression of EsxB_1/EsxA_1 with a modified PE35/PPE68_1 version that carried the EspG5 chaperone-binding domain, previously shown to redirect this substrate pair to the ESX-5 system, also resulted in redirection and co-secretion of the Esx pair via ESX-5. Our results suggest a secretion model in which PE35/PPE68_1 determines the system-specific secretion of EsxB_1/EsxA_1. Full Article
ai The streptococcal multidomain fibrillar adhesin CshA has an elongated polymeric architecture [Microbiology] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 The cell surfaces of many bacteria carry filamentous polypeptides termed adhesins that enable binding to both biotic and abiotic surfaces. Surface adherence is facilitated by the exquisite selectivity of the adhesins for their cognate ligands or receptors and is a key step in niche or host colonization and pathogenicity. Streptococcus gordonii is a primary colonizer of the human oral cavity and an opportunistic pathogen, as well as a leading cause of infective endocarditis in humans. The fibrillar adhesin CshA is an important determinant of S. gordonii adherence, forming peritrichous fibrils on its surface that bind host cells and other microorganisms. CshA possesses a distinctive multidomain architecture comprising an N-terminal target-binding region fused to 17 repeat domains (RDs) that are each ∼100 amino acids long. Here, using structural and biophysical methods, we demonstrate that the intact CshA repeat region (CshA_RD1–17, domains 1–17) forms an extended polymeric monomer in solution. We recombinantly produced a subset of CshA RDs and found that they differ in stability and unfolding behavior. The NMR structure of CshA_RD13 revealed a hitherto unreported all β-fold, flanked by disordered interdomain linkers. These findings, in tandem with complementary hydrodynamic studies of CshA_RD1–17, indicate that this polypeptide possesses a highly unusual dynamic transitory structure characterized by alternating regions of order and disorder. This architecture provides flexibility for the adhesive tip of the CshA fibril to maintain bacterial attachment that withstands shear forces within the human host. It may also help mitigate deleterious folding events between neighboring RDs that share significant structural identity without compromising mechanical stability. Full Article
ai Corruption and poor governance impede progress in the fight against illegal logging in Cameroon and Malaysia By feedproxy.google.com Published On :: Mon, 02 Feb 2015 10:12:52 +0000 21 January 2015 20150120LoggingCameroon.jpg Pallisco logging company's FSC timber operations in Mindourou, Cameroon. Photo by Getty Images. Neither Cameroon nor Malaysia has made progress in tackling illegal logging since 2010, according to new reports from Chatham House. Corruption, lack of political will and a lack of transparency pose problems in both countries. Illegal logging is much more widespread in Cameroon, where entrenched corruption, weak institutions and unclear and inappropriate laws are all impeding reform. Although Malaysia does not have such high levels of illegality, problems remain, particularly in the state of Sarawak.Alison Hoare, Senior Research Fellow at Chatham House, said: 'Illegal logging has a devastating impact on some of the world’s most valuable remaining forests and on the people who live in them and rely on the resources they provide.' 'It is disappointing how little progress Cameroon and Malaysia have made in tackling illegal logging, which exacerbates deforestation, climate change, and poverty. In both countries corruption is a major issue, and the governments need to do much more to address the problem and its underlying drivers.' In Cameroon, the principle of transparency has not been accepted within the government, enforcement is weak and information management systems are inadequate. The misuse of small permits, often granted to allow clearance of forests for infrastructure projects or agricultural expansion, is particularly problematic and could be increasing. Meanwhile, a huge amount of illegal production takes place in the informal artisanal sector – accounting for around half of all timber produced in the country. Artisanal loggers mainly supply the domestic market, but their timber is also exported. In Malaysia, governance varies significantly from region to region but there are high levels of deforestation across the country. Expansion of timber, pulp and agricultural plantations is the primary cause of forest loss, with the area of plantations expected to double by 2020. Adequate recognition of indigenous peoples’ land rights is also a serious challenge in Malaysia and has held up the negotiation of a Voluntary Partnership Agreement with the European Union. Recent enhanced efforts to tackle corruption, including in Sarawak, could mark a turning point. Alison Hoare: 'In both countries, more concerted efforts are needed to tackle corruption, increase consultation, and improve transparency and availability of information. The Cameroonian government also needs to pay more attention to the informal sector and the domestic market.' Editor's notes Read the reports:Trade in Illegal Timber: The Response in the Cameroon by Alison HoareTrade in Illegal Timber: The Response in Malaysia by Alison HoareFor more information please contact Alison Hoare or visit the Illegal Logging portal.These findings are part of Chatham House’s 'Indicators of Illegal Logging and Related Trade’ project, which looks at consumer, producer and processing countries. A Synthesis Report will be published in early 2015. Full Article
ai Britain should treat Europe as its ‘inner circle’ or risk losing international influence By feedproxy.google.com Published On :: Mon, 19 Oct 2015 09:05:23 +0000 13 October 2015 20151019BritanEuropeWorld.jpg British Prime Minister David Cameron sits with other world leaders at the G20 summit in Brisbane, Australia on 15 November 2014. Photo by Getty Images. Given the international context, it is in Britain’s best interests to treat Europe as the ‘inner circle’ of its foreign, security and international economic policy, argues Dr Robin Niblett, director of Chatham House, in a new paper.The British government’s approach since 2010 of seeking to enhance the UK's relations with the world’s emerging powers while balancing these with relationships with the United States and Europe has had only limited success. With constrained resources, and in the face of intense global economic competition, mounting security challenges and decaying international institutions, trying to commit the UK equally on all three fronts will not succeed in the future.Britain, Europe and the World: Rethinking the UK’s Circles of Influence calls for a different mindset and strategy towards the UK’s place in the world – one in which Britain is surrounded by three concentric circles of influence:The first or ‘inner circle’ is the EU, the region with which the UK’s relationships need to be strongest and most active.The ‘second circle’ consists of the protective and enabling set of economic and security relationships with the US.Finally, an ‘outer circle’ comprises the UK’s other key bilateral and institutional relationships.Should the UK vote to remain in the EU, policy-makers should commit to placing the EU at the centre of Britain's foreign policy, using the country’s economic weight, diplomatic skills and networks to play a leading role in leveraging more effective EU-wide policies. Should the country vote to leave, the UK and the EU would enter an extended period of dislocation before arriving at a new, mutually diminished settlement. British policy-makers would be forced to deal and negotiate with the EU on critical policy issues from the outside. It is hard to see, argues Dr Niblett, how that could lead to EU policies or an international context more in line with British interests. Despite its structural flaws and competing national interests, the EU offers the best prospects for managing the rapidly changing global context, for three main reasons:First, it allows the UK to leverage the EU’s global economic weight to enhance the UK’s economic interests internationally, including securing beneficial trade agreements and contributing to EU and global standard-setting and rule-writing. Conversely, leaving would require the UK to renegotiate over 100 trade agreements, and would disadvantage UK interests in EU markets, including making EU governments less likely to liberalize services. Second, it gives the UK a say in designing new EU initiatives to strengthen both British and European security in the face of diverse threats, whether managing the flow of refugees and other emigrants; combatting terrorism; or managing a more assertive Russia and the fallout from a disintegrating Middle East. Third, cooperating with other EU members offers a way of maximizing opportunities to find joint solutions to shared problems, whether in terms of responding to climate change; managing growing cyber insecurity; reversing the decay of governance in failing states; or combating the rise of dangerous non-state actors.Dr Robin Niblett said:‘Britain is likely to be richer, safer and more influential in the coming decades if it treats Europe as the ‘inner circle’ of its foreign policy. For a mid-sized country like the UK, being a major player in a strong regional institution can offer a critical lever for international influence. In the UK’s case, this means choosing to be a leading player in the world’s principal civilian power, the European Union.’ Editor's notes Read Britain, Europe and the World: Rethinking the UK's Circles of InfluenceChatham House will host a press briefing with Dr Robin Niblett on Monday 19 October at 11:00-11:45 BST. To register, or for interview requests, please contact the press office.The views expressed in this paper are those of the author. Chatham House experts will publish a series of papers and commentaries in the run up to the UK’s referendum on its membership of the EU. The institute will also offer a platform for debate on the referendum and Britain’s role in Europe via a series of events and meetings.Read more about the EU referendum. Contacts Press Office +44 (0)20 7957 5739 Email Full Article
