In Savings and Trust, historian Justene Hill Edwards tells the story of the Freedman's Bank. Created for formerly enslaved people following the Civil War, its collapse cost depositors millions.

Situated on the northwest coast of the picturesque island of Crete, Chania stands as a testament to a vibrant mix of cultures that have left their mark over the millennia Breathtaking, famous for rich historical fabrics and the warm hospitality of his people is not appropriate to the destination; It’s an experience waiting to be discovered. This blog post will be your gateway to why Chania, Greece is the paradise you have been searching for. What sets Chania apart? A mixture of histories The streets of Chania speak of the past, whispering stories of Venice, the Ottomans and the Egyptian conquerors, each of whom left behind them a piece of its culture, architecture and spirit and through this blend of influences no Chania becomes a living canvas with so much history and beauty. The Old Port of Venice, with its magnificent lighthouse, stands as a symbol of Chania’s enduring heritage, inviting visitors to walk and marvel at the texts carved into its ancient stones. Unsurpassed natural beauty From tranquil beaches with crystal-clear waters to majestic white mountains in the background, Chania offers natural landscapes as diverse as stunning with stunning white and pink sands like Balos The Lagoon and Elafonissi Beach are not heavenly. For adventure enthusiasts, the Samaria Gorge, one of the longest canyons in Europe, is both a challenge and a reward of unparalleled panoramic views Elegant Gastronomic Delights Chania’s cuisine is typical of Crete’s many dishes. With a culinary tradition that emphasizes innovation and local ingredients, Chania offers a quality and divine culinary experience. Olive oil, wild herbs, fresh herbs and catch of the day feature prominently, delivering authenticity. The heart of Chania: its people Perhaps, though, what really sets Chania apart is the kindness and hospitality of its people. Guests are welcomed with open arms and treated as part of the family, making every experience in Chania feel personal and authentic. Whether it’s through shared meals, guided tours or casual conversation, Chanias make sure you take a piece of their heart with you when you leave Why choose Chania for your next vacation Chania, a picturesque town on the northwest coast of Crete, Greece, captures the heart of every traveler with its breathtaking beauty, rich history and crystal clear beaches If you want to relax, you relax or go deeper into history, Chania has something special in store for you. Pristine Beaches Balos Lagoon and Elafonissi Beach Balos Lagoon: Nestled between the Gramvousa Peninsula and the coast of Crete, Balos Lagoon is famed for its wild natural beauty, exotic turquoise waters, and fine white sand. This beach is accessible by boat or a short hike, offering stunning views that are worth the journey. Elafonissi Beach: Known for its unique pink sand, Elafonissi Beach is located on the southwestern tip of Crete. The beach is a protected nature reserve, providing shallow crystal-clear waters perfect for families. The island opposite the beach is accessible by foot through shallow water, revealing rare plant species and an environment unspoiled by human activity. These beaches are not just places to sunbathe and swim; they are destinations where nature’s artistry is on full display, featuring: Crystal-clear blue waters Exotic landscapes Unique natural environments Rich History and Culture Chania is a city soaked in history, with its roots stretching back to ancient civilizations. Walking through Chania is akin to traversing through time, with each step uncovering a new layer of its past. Overview of Chania’s History From the Minoan civilization to Byzantine times, followed by Venetian, Ottoman, and Egyptian influence, Chania is a living museum showcasing the rich tapestry of human history. This diverse historical influence has shaped the city’s architecture, culture, and traditions, making it a fascinating place to explore. Historical Sites The Old Venetian Harbor: The heart of Chania, this harbor is lined with historic buildings, bustling cafes, and quaint shops. The striking lighthouse, built by the Venetians and reconstructed by the Egyptians, is one of the most iconic images of Chania. The Ancient Ruins of Aptera: Located a few kilometers outside of Chania, the ancient city of Aptera presents a captivating site with ruins dating back to the Minoan era. Visitors can explore ancient temples, Roman baths, and impressive fortifications that offer a glimpse into the past. Exquisite Cuisine Step into Chania, and you’ll be welcomed with a feast not just for the eyes, but for the palate too. Cretan cuisine is a journey of taste, freshness, and tradition. Local Specialties: Dakos: A rustic appetizer featuring barley rusk topped with crushed tomato, mizithra cheese, and a drizzle of olive oil. Moussaka: A rich casserole layered with potatoes, eggplant, minced meat, and a creamy béchamel sauce. Kalitsounia: Sweet or savory cheese pies unique to the region. Health Benefits of the Mediterranean Diet: Rich in olive oil, legumes, and fresh produce, the Cretan diet is renowned for its health-promoting qualities. Dishes like Greek Salad and Grilled Seafood provide nutrients and antioxidants linked to longevity. Where to Find Local Cuisine: Tavernas in the Old Harbor serve fresh, local dishes with scenic views. Street vendors and local bakeries offer quick, delicious bites. Breathtaking Landscapes Chania’s dramatic landscapes invite both awe and adventure. Mountains and Gorges: The White Mountains: A towering range that gives you hiking trails and caves to explore. Samaria Gorge: A 16 km trek through a World Biosphere Reserve. Outdoor Activities: Guided treks are available for all levels of hikers. Boat trips allow you to appreciate the coastline from the water. Local Hospitality and Authentic Experiences The warmth of Chania’s people makes every moment spent here feel genuinely welcoming. Warm Hospitality Offered by Locals: Visitors are often greeted with a heartfelt “Kalimera” (good morning) and a smile. Many locals are eager to share stories or help guide you to the best spots. Immersive Experiences: Traditional Cretan Nights: Enjoy vibrant folk music and dancing. Local Markets: Visit the Agora (central market) to buy local honey, cheeses, and herbs. Planning Your Trip to Chania Nestled on the northwest coast of Crete, Greece, Chania is a captivating blend of scenic beauty, rich history, and vibrant culture. Planning your trip requires thoughtful consideration of when to visit, where to stay, how to navigate the city, and what experiences you shouldn’t miss. Best Time to Visit Analyzing Chania’s Weather Patterns: Spring (April to June): The weather starts warming up, making it ideal for outdoor activities without the summer crowds. Summer (July to August): Peak season with sunny days perfect for beach outings, but expect higher prices and more tourists. Autumn (September to October): Warm and less crowded. The sea remains warm enough for swimming. Winter (November to March): Cooler temperatures and occasional rain, suitable for those seeking tranquility and interested in exploring Chania’s cultural sites. Accommodations Chania offers a breadth of accommodation options to suit every taste and budget. Overview of Accommodation Options: Luxury Resorts: Beachfront properties providing exclusive amenities and breathtaking views. Boutique Hotels: Nestled in the Old Town, offering unique charm and close proximity to historical sites. Budget-Friendly Stays: Hostels and guesthouses that don’t compromise on comfort and provide excellent value. Getting Around Navigating Chania and its surrounding areas can be both fun and convenient. Tips on Navigating Chania: Public Transport: City buses are reliable for local travel. For adventures beyond the city, consider the KTEL buses that connect Chania to other parts of Crete. Car Rental: Offers the freedom to explore remote beaches and mountain villages at your pace. International driving permits are usually required for visitors. Must-Have Experiences Chania brims with activities and sights that cater to all interests. Curated List of Not-to-Miss Experiences: Old Venetian Harbor: Stroll around and enjoy the sunset views. Samaria Gorge: A challenging but rewarding hike offering stunning natural landscapes. Beaches: Balos Lagoon and Falassarna Beach are must-visits for beach lovers. Cretan Cuisine Tasting: Explore local tavernas for an authentic taste of Crete. conclusion Chania, with its perfect blend of climate, accommodation options, easy navigation and unique experiences, promises a memorable getaway. Chania is not just another holiday destination; It’s a place where every corner holds a story, every meal a celebration, every moment like heaven. Whether you’re wandering its cobblestone streets, sunbathing on its pristine beaches, or exploring its rich cultural heritage, Chania invites you to immerse yourself in its beauty, history and warmth is not just a place to visit; There is a world to experience. Make Chania your next holiday destination and discover a paradise that captures your heart.

The post Why Chania, Greece Should Be Your Next Paradise Vacation Destination appeared first on Geeky Traveller.

Amsterdam is a city of contrasts, where historic charm meets vibrant modernity. A city break in Amsterdam offers a chance to explore picturesque canals, world-renowned museums, and eclectic neighbourhoods, all within a compact and walkable setting. In this guide, I’ll take you through an unforgettable three-day itinerary designed to capture the essence of Amsterdam. From strolling along cobblestone streets to indulging in Dutch delicacies, here’s how to make the most of your Amsterdam city break. Considering taking a cruise to Amsterdam? Arriving by sea is not only a unique way to start your adventure but also offers breathtaking views of the city from the water. Cruises often include extras like guided tours or exclusive shore excursions, making it a convenient option for those looking to experience Amsterdam’s maritime charm from the moment they arrive. Day 1: Uncovering Amsterdam’s Historic Canals and Culinary Scene Morning: Arrive and Settle In If you’re arriving by cruise, you’ll dock at the Port of Amsterdam, just a stone’s throw away from the city centre. Once you’ve disembarked and checked into your accommodation, it’s time to start exploring. Begin your visit with a leisurely walk through Amsterdam’s Canal Belt, a UNESCO World Heritage site that embodies the city’s rich history and iconic architecture. As you wander, you’ll find charming bridges, historic houseboats, and narrow townhouses adorned with ornate gables. Each canal has its own character, but Prinsengracht, Herengracht, and Keizersgracht are among the most famous. You’ll quickly see why these canals are one of Amsterdam’s most photographed attractions. Afternoon: Dive into Amsterdam’s Maritime History with a Canal Cruise One of the best ways to immerse yourself in the city’s history is to take a canal cruise. Various operators offer guided tours, ranging from hour-long excursions to multi-course dinner cruises. As you glide along the water, you’ll get a sense of how Amsterdam’s intricate canal system helped shape its trade and commerce over the centuries. Plus, you’ll enjoy views of iconic landmarks like the Anne Frank House, the Rijksmuseum, and Westerkerk from a unique vantage point. Evening: Sample Amsterdam’s Diverse Culinary Offerings Amsterdam’s food scene is as diverse as its population. For your first evening, treat yourself to a traditional Dutch dinner. Try local dishes like stamppot, a hearty blend of potatoes, vegetables, and sausage, or erwtensoep, a thick pea soup perfect for chilly evenings. If you’re in the mood for something sweet, don’t miss poffertjes—tiny pancakes dusted with powdered sugar. For a more eclectic dining experience, Amsterdam is home to countless international restaurants, reflecting its role as a global melting pot. You’ll find everything from Indonesian rijsttafel (a feast of small dishes) to Middle Eastern mezze. Many restaurants are located along the canals, offering atmospheric outdoor seating and views of the water. Day 2: Art, Parks, and Local Markets Morning: Explore the Treasures of the Rijksmuseum Amsterdam is a haven for art lovers, and the Rijksmuseum is a must-visit. Housing masterpieces from the Dutch Golden Age, including Rembrandt’s The Night Watch and Vermeer’s The Milkmaid, the museum offers a comprehensive journey through Dutch art and history. Set aside at least a couple of hours to explore the galleries, as the collection is extensive. For an insider’s tip, arrive early to avoid crowds, especially if you want to get a close-up view of Rembrandt’s renowned pieces. If you’re visiting during spring or summer, don’t miss the museum’s garden, which features beautiful sculptures and tranquil spots for a mid-morning break. Afternoon: Discover Van Gogh’s Vibrant World and Stroll Through Vondelpark Just a short walk from the Rijksmuseum is the Van Gogh Museum, dedicated to the life and work of one of the most iconic artists in history. With over 200 paintings, including famous works like Sunflowers and The Bedroom, this museum provides an intimate look at Van Gogh’s creative genius and turbulent life. After you’ve soaked in Van Gogh’s vivid colours and swirling brushstrokes, take a break in nearby Vondelpark. This sprawling green space is a favourite among locals and visitors alike, offering a peaceful escape from the city’s hustle and bustle. Pack a picnic or grab a coffee from one of the park’s cafés, and spend some time people-watching, cycling, or simply soaking up the scenery. Evening: Dinner in De Pijp and a Stroll Through the Albert Cuyp Market For dinner, head to De Pijp, a lively neighbourhood known for its multicultural vibe and delicious food scene. Here, you’ll find everything from trendy eateries to traditional eetcafés, where you can enjoy hearty Dutch fare in a casual setting. While you’re in De Pijp, be sure to explore the Albert Cuyp Market, the largest outdoor market in Europe. With over 250 stalls selling everything from fresh produce and cheese to clothing and souvenirs, it’s a fantastic place to soak up the local atmosphere. Grab a snack like a freshly made stroopwafel, or pick up some Dutch cheese to take home as a tasty souvenir. Day 3: History and Shopping in Amsterdam’s Iconic Neighbourhoods Morning: Reflect on History at the Anne Frank House Begin your day with a visit to the Anne Frank House, where the young diarist and her family hid during World War II. The museum offers a poignant glimpse into the hardships faced by Anne and her family, as well as the resilience of those who lived through the era. Due to its popularity, it’s best to book tickets in advance to avoid long wait times. If you’re interested in exploring more of Amsterdam’s wartime history, consider adding a visit to the Resistance Museum, which offers further insights into the city’s experiences during the German occupation. Afternoon: Shop and Dine in the Negen Straatjes (Nine Streets) Next, head to the Negen Straatjes, or Nine Streets, a charming area within the Canal Belt known for its quirky boutiques, vintage shops, and cosy cafés. This is the perfect place to indulge in some retail therapy, with stores selling everything from high-end fashion and handmade jewellery to unique home decor and antique books. Take your time browsing the shops, and be sure to stop for lunch at one of the many cafés lining the streets. The area is famous for its atmospheric coffee shops and bakeries, offering everything from freshly baked pastries to artisanal sandwiches. For a sweet treat, try a slice of Dutch apple pie, which pairs perfectly with a strong espresso. Evening: Wrap Up Your Trip at a Cosy Brown Café As your city break in Amsterdam comes to a close, spend your last evening unwinding at a traditional Dutch brown café. These cosy pubs are named for their dark wood interiors and smoky atmospheres, and they’re a staple of local culture. Café Hoppe and Café De Dokter are both great choices, offering a warm ambiance and a selection of Dutch beers to sample. Whether you’re sharing a drink with friends or simply savouring a quiet moment, the relaxed atmosphere of a brown café is the perfect way to end your Amsterdam adventure. Tips for an Unforgettable Amsterdam City Break When to Visit: Spring and autumn are the best times to visit Amsterdam, as the weather is mild, and there are fewer tourists. Spring is particularly beautiful due to the blooming tulips, while autumn offers colourful foliage along the canals. Getting Around: Amsterdam’s public transport system includes trams, buses, and ferries, making it easy to navigate the city. However, the city centre is highly walkable, and cycling is a popular way to get around. Many hotels offer bike rentals, or you can rent one from a local shop. Accommodations: Amsterdam offers a wide range of accommodation options, from boutique hotels and cosy bed-and-breakfasts to trendy hostels and luxurious canal-side apartments. Consider staying in a central area like the Jordaan or De Pijp for easy access to the city’s top attractions. Must-Try Foods: Beyond traditional Dutch dishes like stamppot and haring (raw herring), Amsterdam is known for its cheese, with varieties like gouda and edam readily available. Street foods like patat (thick-cut fries) served with mayo and bitterballen (fried meatballs) are also popular, especially at local markets and pubs. Cultural Etiquette: While Amsterdam is known for its liberal attitudes, it’s essential to respect local customs. Keep in mind that cycling is a primary mode of transportation, so be cautious when crossing bike lanes, and always look both ways.

The post Amsterdam City Break: Discovering the Heart of the Netherlands in Three Magical Days appeared first on Geeky Traveller.

Cate Blanchett intepreta Catherine Ravenscroft, uma famosa jornalista investigativa que recebe anonimamente um romance no qual ela é, indiscutivelmente, a personagem central

The United Kingdom is doubling down on its censorship and those who dissent from the official narrative. Proving it doesn’t value free speech, the UK has fined a “conspiracy theorist” $58,000 for the crime of speculating that the Manchester Arena bombing was staged. Two survivors of the 2017 Manchester Arena bombing were awarded £45,000 ($58,000) …

The genetic testing company 23andMe announced it will cut 40% of its workforce, or 200 jobs, and halt the work on therapies it was developing. As the BBC notes, the company is fighting for survival after hackers gained access to personal information of millions of its users, causing the stock to crater by more than 70%. All seven of its independent directors also resigned in September, following a protracted negotiation with founder and Chief Executive Anne Wojcicki over her plan to take the company private. The BBC reports: On Tuesday, the company warned investors of "substantial doubt" about its ability to continue operating, as it reported that revenue had fallen to $44 million between July and September compared to $50 million in the same period last year. Losses fell to $59 million from $75 million. The job cuts are expected to lead to one-off costs of $12 million, including severance pay, for the plan that will result in savings of $35 million. "We are taking these difficult but necessary actions as we restructure 23andMe and focus on the long-term success of our core consumer business and research partnerships," Ms Wojcicki said. The company also said it is considering what to do with the therapies it had in development, including licensing or selling them. 23andMe is a giant of the growing ancestor-tracing industry. It offers genetic testing from DNA, with ancestry breakdown and personalised health insights. Its customers include famous names, from rapper Snoop Dogg to multi-billionaire investor Warren Buffett. The company was valued at roughly $3.5 billion when it listed on the Nasdaq stock exchange in 2021 and its share price peaked at $17.65. But they have since tumbled and are currently trading at less than $5.

Read more of this story at Slashdot.

An anonymous reader quotes a report from NBC News: Former Massachusetts Air National Guard member Jack Teixeira was sentenced Tuesday to 15 years for stealing classified information from the Pentagon and sharing it online, the U.S. Attorney for Massachusetts announced. Teixeira received the sentence before Judge Indira Talwani in U.S. District Court for the District of Massachusetts. In March, the national guardsman pleaded guilty to six counts of willful retention and transmission of national defense information under the Espionage Act. He was arrested by the FBI in North Dighton, Massachusetts, in April 2023 and has been in federal custody since mid-May 2023. According to court documents, Teixeira transcribed classified documents that he then shared on Discord, a social media platform mostly used by online gamers. He began sharing the documents in or around 2022. A document he was accused of leaking included information about providing equipment to Ukraine, while another included discussions about a foreign adversary's plot to target American forces abroad, prosecutors said. [...] While the documents were discovered online in March 2023, Teixeira had been sharing them online since January of that year, according to prosecutors.

Read more of this story at Slashdot.

Even Democrats can get sick of the crime that results from left-wing policies. So the voters in California’s Alameda County — which voted lopsidedly for the Democrats in every statewide and national election — have voted to remove a soft-on-crime mayor and district attorney. A San Francisco news source reports: Voters in the East Bay […]

The post Voters in progressive county recall far-left mayor and district attorney appeared first on Liberty Unyielding.

A court challenge means the government will look again at the cap on the Disabled Facilities Grant.

A public hearing is set to examine the events surrounding the catastrophic failure of Oceangate’s submersible.

Climate change and sea ice loss leaves polar bears exposed to more diseases, research suggests.

England head coach Jon Lewis rejects accusations some of his players are not fit enough.

Arsenal boss Mikel Arteta praises his side's performance against Chelsea in the Premier League, but says that getting results is "what is missing" at the moment.

Tottenham boss Ange Postecoglou accepts responsibility for his side's 2-1 Premier League defeat at home by a previously winless Ipswich.

A “teacher” at Chino Valley School District launched into an unhinged rant after a student entered his classroom wearing a Trump hat. His name is Clyde J Colinco, who is also the girls golf course, and unfortunately, he still appears to be employed at Chino High School. “Trump Derangement Syndrome is a real thing. If […]

The post Teacher at Chino Valley School District Goes Off the Rails over a Student With a Trump Hat appeared first on The Lid.

United Nations Secretary-General Antonio Guterres told world leaders at the COP29 summit on Tuesday to "pay up" to prevent climate-led humanitarian disasters, and said time was running out to limit a destructive rise in global tempera

Amazon has been scrutinized in the past over workplace safety. An Amazon spokesperson said the accident will be investigated.

Over the past decade, parent advocacy groups led a grassroots movement resulting in most states adopting dyslexia-specific legislation, with many states mandating the use of the Orton-Gillingham (OG) approach to reading instruction. Orton-Gillingham is a direct, explicit, multisensory, structured, sequential, diagnostic, and prescriptive approach to reading for students with or at risk for word-level reading disabilities (WLRD). Evidence from a prior synthesis and What Works Clearinghouse reports yielded findings lacking support for the effectiveness of OG interventions.

LG’s latest prototype screen is stretchy. Shown off at LG’s Science Park in Seoul, the company demonstrated the new type… Continue reading LG gives glimpse into the future with stretchy display

The post LG gives glimpse into the future with stretchy display appeared first on ReadWrite.

News24 brings you the top stories of the day, summarised into neat little packages. Read through quickly or listen to the articles via our customised text-to-speech feature.

Scientific tests confirm rivers and dams have been poisoned by the raw sewage dumped by the municipality in the Bloubankspruit and Crocodile Rivers, killing aquatic life and destroying businesses and livelihoods.

The MK Party continued its campaign against accountability for corruption, with its deputy leader, John Hlophe, suggesting National Director of Public Prosecutions Shamila Batohi was "misleading the nation" about the Guptas' extradition.

Nintendo is cracking down on emulators of its hardware and media depicting their use. First Yuzu was taken down with a lawsuit, and now departs Ryujinx, a similar project that had sought to avoid the legal landmines Yuzu stepped on. — Read the rest

The post Another emulation project disappears amid Nintendo crackdown appeared first on Boing Boing.

The following article, Teacher at Chino Valley School District Goes Off the Rails over a Student With a Trump Hat, was first published on Conservative Firing Line.

A “teacher” at Chino Valley School District launched into an unhinged rant after a student entered his classroom wearing a Trump hat. His name is Clyde J Colinco, who is also the girls golf course, and unfortunately, he still appears to be employed at Chino High School. “Trump Derangement Syndrome is a real thing. If …

Continue reading Teacher at Chino Valley School District Goes Off the Rails over a Student With a Trump Hat ...

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:

1. 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…

2. 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.

3. 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.

4. 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.

5. 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…

6. 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.

President-elect Donald Trump will begin his second term by putting pieces of his first one back in place, according to incoming White House Chief of Staff Susie Wiles. Wiles made […]

The post Trump's New Chief of Staff Susie Wiles Discloses His Day One Plans: Report appeared first on The Western Journal.

Just because you’re paranoid, it doesn’t mean you’re wrong. And for any supporters of President-elect Donald Trump who feel that they’ve been unfairly targeted by the government, but were summarily […]

The post Fired FEMA Worker Reveals Discrimination Against Trump Supporters Was Even Worse Than First Reported appeared first on The Western Journal.

In his latest Rucking with Rob newsletter, Rob Houwing argues that for England to have any hopes of beating the Springboks, they'll have to be on the ball in the final stages.

Evidence Makgopa wore a sheepish smile when Bafana Bafana coach Hugo Broos showered him with praise before literally patting the forward on the back, making him blush at Dobsonville Stadium.

Originally published in Gatestone Institute on Nov. 25, 2022 By Cynthia Farahat Bahgat Saber, a member of the Muslim Brotherhood, operates from his New York apartment and often streams live videos from Times Square. During his multi-hour videos, Saber routinely incites terrorism, assassinations, kidnapping and torture in an extremely graphic manner. The calls for violence […]

Toni Annala, Marc Hoyois and Ryomei Iwasa
J. Amer. Math. Soc. 38 (), 243-289.
Abstract, references and article information

Alexander Kupers and Oscar Randal-Williams
J. Amer. Math. Soc. 38 (), 63-178.
Abstract, references and article information

The human cardiovascular system has adapted to function optimally in Earth's 1G gravity, and microgravity conditions cause myocardial abnormalities, including atrophy and dysfunction. However, the underlying mechanisms linking microgravity and cardiac anomalies are incompletely understood. In this study, we investigated whether and how calpain activation promotes myocardial abnormalities under simulated microgravity conditions. Simulated microgravity was induced by tail suspension in mice with cardiomyocyte-specific deletion of Capns1, which disrupts activity and stability of calpain-1 and calpain-2, and their WT littermates. Tail suspension time-dependently reduced cardiomyocyte size, heart weight, and myocardial function in WT mice, and these changes were accompanied by calpain activation, NADPH oxidase activation, and oxidative stress in heart tissues. The effects of tail suspension were attenuated by deletion of Capns1. Notably, the protective effects of Capns1 deletion were associated with the prevention of phosphorylation of Ser-345 on p47phox and attenuation of ERK1/2 and p38 activation in hearts of tail-suspended mice. Using a rotary cell culture system, we simulated microgravity in cultured neonatal mouse cardiomyocytes and observed decreased total protein/DNA ratio and induced calpain activation, phosphorylation of Ser-345 on p47phox, and activation of ERK1/2 and p38, all of which were prevented by calpain inhibitor-III. Furthermore, inhibition of ERK1/2 or p38 attenuated phosphorylation of Ser-345 on p47phox in cardiomyocytes under simulated microgravity. This study demonstrates for the first time that calpain promotes NADPH oxidase activation and myocardial abnormalities under microgravity by facilitating p47phox phosphorylation via ERK1/2 and p38 pathways. Thus, calpain inhibition may be an effective therapeutic approach to reduce microgravity-induced myocardial abnormalities.

Dilated cardiomyopathy (DCM) is associated with mutations in cardiomyocyte sarcomeric proteins, including α-tropomyosin. In conjunction with troponin, tropomyosin shifts to regulate actomyosin interactions. Tropomyosin molecules overlap via tropomyosin–tropomyosin head-to-tail associations, forming a continuous strand along the thin filament. These associations are critical for propagation of tropomyosin's reconfiguration along the thin filament and key for the cooperative switching between heart muscle contraction and relaxation. Here, we tested perturbations in tropomyosin structure, biochemistry, and function caused by the DCM-linked mutation, M8R, which is located at the overlap junction. Localized and nonlocalized structural effects of the mutation were found in tropomyosin that ultimately perturb its thin filament regulatory function. Comparison of mutant and WT α-tropomyosin was carried out using in vitro motility assays, CD, actin co-sedimentation, and molecular dynamics simulations. Regulated thin filament velocity measurements showed that the presence of M8R tropomyosin decreased calcium sensitivity and thin filament cooperativity. The co-sedimentation of actin and tropomyosin showed weakening of actin-mutant tropomyosin binding. The binding of troponin T's N terminus to the actin-mutant tropomyosin complex was also weakened. CD and molecular dynamics indicate that the M8R mutation disrupts the four-helix bundle at the head-to-tail junction, leading to weaker tropomyosin–tropomyosin binding and weaker tropomyosin–actin binding. Molecular dynamics revealed that altered end-to-end bond formation has effects extending toward the central region of the tropomyosin molecule, which alter the azimuthal position of tropomyosin, likely disrupting the mutant thin filament response to calcium. These results demonstrate that mutation-induced alterations in tropomyosin–thin filament interactions underlie the altered regulatory phenotype and ultimately the pathogenesis of DCM.

The novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) has emerged to a pandemic and caused global public health crisis. Human angiotensin-converting enzyme 2(ACE2) was identified as the entry receptor for SARS-CoV-2. As a carboxypeptidase, ACE2 cleaves many biological substrates besides angiotensin II to control vasodilatation and vascular permeability. Given the nanomolar high affinity between ACE2 and SARS-CoV-2 spike protein, we investigated how this interaction would affect the enzymatic activity of ACE2. Surprisingly, SARS-CoV-2 trimeric spike protein increased ACE2 proteolytic activity ∼3-10 fold against model peptide substrates, such as caspase-1 substrate and Bradykinin-analog. The enhancement in ACE2 enzymatic function was mediated by the binding of SARS-CoV-2 spike RBD domain. These results highlighted the potential for SARS-CoV-2 infection to enhance ACE2 activity, which may be relevant to the cardiovascular symptoms associated with COVID-19.

Heterotrimeric G-proteins are signaling switches broadly divided into four families based on the sequence and functional similarity of their Gα subunits: Gs, Gi/o, Gq/11, and G12/13. Artificial mutations that activate Gα subunits of each of these families have long been known to induce oncogenic transformation in experimental systems. With the advent of next-generation sequencing, activating hotspot mutations in Gs, Gi/o, or Gq/11 proteins have also been identified in patient tumor samples. In contrast, patient tumor-associated G12/13 mutations characterized to date lead to inactivation rather than activation. By using bioinformatic pathway analysis and signaling assays, here we identified cancer-associated hotspot mutations in Arg-200 of Gα13 (encoded by GNA13) as potent activators of oncogenic signaling. First, we found that components of a G12/13-dependent signaling cascade that culminates in activation of the Hippo pathway effectors YAP and TAZ is frequently altered in bladder cancer. Up-regulation of this signaling cascade correlates with increased YAP/TAZ activation transcriptional signatures in this cancer type. Among the G12/13 pathway alterations were mutations in Arg-200 of Gα13, which we validated to promote YAP/TAZ-dependent (TEAD) and MRTF-A/B-dependent (SRE.L) transcriptional activity. We further showed that this mechanism relies on the same RhoGEF-RhoGTPase cascade components that are up-regulated in bladder cancers. Moreover, Gα13 Arg-200 mutants induced oncogenic transformation in vitro as determined by focus formation assays. In summary, our findings on Gα13 mutants establish that naturally occurring hotspot mutations in Gα subunits of any of the four families of heterotrimeric G-proteins are putative cancer drivers.

The inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs), which form tetrameric channels, play pivotal roles in regulating the spatiotemporal patterns of intracellular calcium signals. Mutations in IP3Rs have been increasingly associated with many debilitating human diseases such as ataxia, Gillespie syndrome, and generalized anhidrosis. However, how these mutations affect IP3R function, and how the perturbation of as-sociated calcium signals contribute to the pathogenesis and severity of these diseases remains largely uncharacterized. Moreover, many of these diseases occur as the result of autosomal dominant inheritance, suggesting that WT and mutant subunits associate in heterotetrameric channels. How the in-corporation of different numbers of mutant subunits within the tetrameric channels affects its activities and results in different disease phenotypes is also unclear. In this report, we investigated representative disease-associated missense mutations to determine their effects on IP3R channel activity. Additionally, we designed concatenated IP3R constructs to create tetrameric channels with a predefined subunit composition to explore the functionality of heteromeric channels. Using calcium imaging techniques to assess IP3R channel function, we observed that all the mutations studied resulted in severely attenuated Ca2+ release when expressed as homotetramers. However, some heterotetramers retained varied degrees of function dependent on the composition of the tetramer. Our findings suggest that the effect of mutations depends on the location of the mutation in the IP3R structure, as well as on the stoichiometry of mutant subunits assembled within the tetrameric channel. These studies provide insight into the pathogenesis and penetrance of these devastating human diseases.

Alfred C. O. Vertegaal
Dec 1, 2006; 5:2298-2310
Research

Guoan Chen
Apr 1, 2002; 1:304-313
Research

Leukocidin ED (LukED) is a pore-forming toxin produced by Staphylococcus aureus, which lyses host cells and promotes virulence of the bacteria. LukED enables S. aureus to acquire iron by lysing erythrocytes, which depends on targeting the host receptor Duffy antigen receptor for chemokines (DARC). The toxin also targets DARC on the endothelium, contributing to the lethality observed during bloodstream infection in mice. LukED is comprised of two monomers: LukE and LukD. LukE binds to DARC and facilitates hemolysis, but the closely related Panton–Valentine leukocidin S (LukS-PV) does not bind to DARC and is not hemolytic. The interaction of LukE with DARC and the role this plays in hemolysis are incompletely characterized. To determine the domain(s) of LukE that are critical for DARC binding, we studied the hemolytic function of LukE–LukS-PV chimeras, in which areas of sequence divergence (divergence regions, or DRs) were swapped between the toxins. We found that two regions of LukE's rim domain contribute to hemolysis, namely residues 57–75 (DR1) and residues 182–196 (DR4). Interestingly, LukE DR1 is sufficient to render LukS-PV capable of DARC binding and hemolysis. Further, LukE, by binding DARC through DR1, promotes the recruitment of LukD to erythrocytes, likely by facilitating LukED oligomer formation. Finally, we show that LukE targets murine Darc through DR1 in vivo to cause host lethality. These findings expand our biochemical understanding of the LukE–DARC interaction and the role that this toxin-receptor pair plays in S. aureus pathophysiology.

Independent Thinking: Humanitarian disaster in Syria and Turkey Audio NCapeling 16 February 2023

Episode 15 of our weekly podcast examines the far-reaching consequences of the earthquakes which struck Turkey and Syria on the region’s fragile geopolitics.

With thousands killed and international aid flooding in, what hope is there for the many thousands of people in Syria and Turkey caught between the groups and governments involved in conflict for more than a decade.

The panel aslo discusses the political impact within Turkey, as fears grow that President Recep Tyap Erdogan may postpone the upcoming election amid outcries over corruption and the devastating loss of life.

Joining Bronwen this week is Lina Sinjab, Syrian filmmaker and BBC journalist covering the Middle East, Charles Lister, senior fellow and director of the Syria programme at the Middle East Institute, and Ziya Meral, senior associate fellow on Turkey at the Royal United Services Institute (RUSI).

About Independent Thinking

A weekly podcast hosted by Chatham House director Bronwen Maddox, in conversation with leading policymakers, journalists, and Chatham House experts providing insight on the latest international issues.

Accumulation of the microtubule-associated protein tau is associated with Alzheimer's disease (AD). In AD brain, tau is abnormally phosphorylated at many sites, and phosphorylation at Ser-262 and Ser-356 plays critical roles in tau accumulation and toxicity. Microtubule affinity–regulating kinase 4 (MARK4) phosphorylates tau at those sites, and a double de novo mutation in the linker region of MARK4, ΔG316E317D, is associated with an elevated risk of AD. However, it remains unclear how this mutation affects phosphorylation, aggregation, and accumulation of tau and tau-induced neurodegeneration. Here, we report that MARK4ΔG316E317D increases the abundance of highly phosphorylated, insoluble tau species and exacerbates neurodegeneration via Ser-262/356–dependent and –independent mechanisms. Using transgenic Drosophila expressing human MARK4 (MARK4wt) or a mutant version of MARK4 (MARK4ΔG316E317D), we found that coexpression of MARK4wt and MARK4ΔG316E317D increased total tau levels and enhanced tau-induced neurodegeneration and that MARK4ΔG316E317D had more potent effects than MARK4wt. Interestingly, the in vitro kinase activities of MARK4wt and MARK4ΔG316E317D were similar. When tau phosphorylation at Ser-262 and Ser-356 was blocked by alanine substitutions, MARK4wt did not promote tau accumulation or exacerbate neurodegeneration, whereas coexpression of MARK4ΔG316E317D did. Both MARK4wt and MARK4ΔG316E317D increased the levels of oligomeric forms of tau; however, only MARK4ΔG316E317D further increased the detergent insolubility of tau in vivo. Together, these findings suggest that MARK4ΔG316E317D increases tau levels and exacerbates tau toxicity via a novel gain-of-function mechanism and that modification in this region of MARK4 may affect disease pathogenesis.

Synapse loss is associated with motor and cognitive decline in multiple neurodegenerative disorders, and the cellular redistribution of tau is related to synaptic impairment in tauopathies, such as Alzheimer's disease and frontotemporal dementia. Here, we examined the cellular distribution of tau protein species in human tau overexpressing line 66 mice, a transgenic mouse model akin to genetic variants of frontotemporal dementia. Line 66 mice express intracellular tau aggregates in multiple brain regions and exhibit sensorimotor and motor learning deficiencies. Using a series of anti-tau antibodies, we observed, histologically, that nonphosphorylated transgenic human tau is enriched in synapses, whereas phosphorylated tau accumulates predominantly in cell bodies and axons. Subcellular fractionation confirmed that human tau is highly enriched in insoluble cytosolic and synaptosomal fractions, whereas endogenous mouse tau is virtually absent from synapses. Cytosolic tau was resistant to solubilization with urea and Triton X-100, indicating the formation of larger tau aggregates. By contrast, synaptic tau was partially soluble after Triton X-100 treatment and most likely represents aggregates of smaller size. MS corroborated that synaptosomal tau is nonphosphorylated. Tau enriched in the synapse of line 66 mice, therefore, appears to be in an oligomeric and nonphosphorylated state, and one that could have a direct impact on cognitive function.

Addressing Russia’s use of forced displacement in Ukraine 7 November 2024 — 12:30PM TO 2:00PM Anonymous (not verified) 17 October 2024 Chatham House and Online

Experts consider the role international law could play in responding to Russia’s forcible movement of people during its war against Ukraine.

In the two and a half years since its full-scale invasion of Ukraine, evidence has emerged of Russia’s use of forced deportation and forcible transfer. Russia has also employed arbitrary detention as a tool of war and occupation.

Much attention has been on the International Criminal Court’s arrest warrants against Russian President Vladimir Putin and his children’s commissioner Maria Alekseyevna Lvova-Belova. These warrants were issued in relation to the alleged war crimes concerning the unlawful deportation of children from Ukraine to Russia and the unlawful transfer of thousands of children from occupied areas of Ukraine.

Meanwhile, Ukrainian citizens are being arrested and sent to Russia to serve prison sentences. They are often detained without charge and conviction.

This panel discussion explores:

• What evidence is emerging of Russia using unlawful deportation and transfer of children, and the arbitrary detention of civilians?
• What is the role and significance of international law on these issues?
• What challenges might these practices create for later peace negotiations, as well as the securing of justice?
• What is the process of releasing illegally detained Ukrainians, and Ukrainian children in particular, and reuniting them with their families? How do Russian volunteers inside Russia cooperate with Ukrainian NGOs to facilitate family reunification?

The event includes a screening of part of the documentary After the Rain: Putin’s Stolen Children. 

The institute occupies a position of respect and trust, and is committed to fostering inclusive dialogue at all events. Event attendees are expected to uphold this by adhering to our code of conduct.

As the ruling party claims victory in Georgia’s disputed election, Western condemnation is no longer enough Expert comment LToremark 29 October 2024

As tens of thousands take to the streets to protest the election results, Georgia faces a familiar crisis – with a few key differences.

As the people of Georgia went to the polls on 26 October, many were hoping not only for a democratic change of government but also for an end to one-party dominance and a return to the path of European integration. The previously weak and divided opposition had grouped itself into four major electoral centres, promising a coalition government and framing these elections as a choice between Europe and Russia. 

Ahead of the election, President Salome Zourabishvili had put forward the Georgian Charter, a blueprint for a stable and democratic transition to a new style of governance and for initiating reforms to fulfil conditions for EU accession. It was signed by all pro-European and pro-Western opposition parties. 

The official election results gave the ruling Georgian Dream party a 54 per cent majority in contrast with exit polls that gave the opposition a 10 per cent lead. President Zourabishvili and the opposition parties refuse to recognize the results, beginning a long process of contestation with allegations of fraud and street protests. As the disappointment sets in and the streets once again replace the ballot box as a conduit for democratic change, there is a sense of déja vu.

Georgia has seen this before. A party sweeps to power on the tide of popular protest, initiates reforms to meet public expectations but, by the end of its second term, it takes an authoritarian turn. As it overstays its welcome, it starts manipulating elections to cling to power. People once again take to the streets and a new party wins by a landslide only to repeat the same cycle. But with each turn, the grip the ruling elites have on power gets stronger and the methods they use become more sophisticated. State security becomes equated with regime stability, leaving no space for normal democratic contestation or expressions of dissent. 

Although what is happening in Georgia fits this familiar pattern, there are some consequential differences. 

First, these were the first fully proportional elections. Previously, a mixed system of representation meant that the incumbency always had an advantage by dominating majoritarian districts. A new electoral system had created a not unreasonable expectation that these elections, if held freely, would result in a coalition government. The hope was this could help break the vicious cycle of Georgian politics, sustained by an extreme form of majoritarianism and a winner-takes-all political culture.

The Georgian Dream party was contesting its fourth consecutive term against a backdrop of falling popularity and growing societal mobilization in opposition to its authoritarian inclinations. Despite all this, it secured – some would insist manufactured – an absolute majority in elections that international observers say were marred by serious irregularities and fell short of democratic standards. 

The second important difference is that these elections were not only about saving Georgia’s democracy but also about rescuing its European perspective. Since Georgia was granted EU candidate status in December 2023, its parliament has adopted Russian-style laws on foreign agents and combating LGBTIQ+ ‘propaganda’. 

It has also adopted a strongly Eurosceptic political discourse, pushing back on international criticism and accusing EU and US officials of interference in domestic affairs and disregard for Georgia’s sovereignty. In response, the EU has suspended accession talks with Georgia indefinitely while the US has imposed targeted sanctions on high-ranking Georgian officials and judges. 

Georgia’s democratic backsliding at home and its pivot away from the West are both simultaneous and interrelated. It was widely hoped these elections would be a course correction and return Georgia to the path of European and Euro-Atlantic integration. The election results, if they stick, will prevent this from happening. A Georgian Dream government will not work to fulfil conditions for EU accession, viewed as a challenge to its hold on power. 

The third and final difference is that these elections took place in the context of heightened geopolitical confrontation. The Georgian Dream ‘victory’ is a win for anti-liberal, conservative forces around the world championed, among others, by Hungary’s Viktor Orbán. He was the first to congratulate Georgian Dream for its declared success and even visited Tbilisi in a show of solidarity and ideological alignment. 

The election result is also a win for Russia. It strengthens Moscow’s influence in the South Caucasus, which has waned as a result of the war in Ukraine and the fall of Nagorny-Karabakh. Russian officials and propagandist were quick to congratulate Georgian Dream, wishing them success in standing up to Western pressures and offering help in case things got tough. 

From Moscow’s perspective, Georgia’s elections are part of a global hybrid war. They represent a local battle in the ongoing geopolitical contest between Russia and the West, between the rules-based global order and competitive multipolarity. 

As Georgia repeats a familiar pattern, what do the election results mean for its future? While clear predictions are difficult at this stage, it is worth bearing in mind that as the democratic resilience of the Georgian society has strengthened over time, so too has the state capacity to supress and control.