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Save $100 on the Apple Watch SE (2nd Gen) this Black Friday

Mashable - Tue, 11/26/2024 - 10:58

SAVE $100: The Apple Watch SE (2nd Gen) is down to $179 in the Amazon Black Friday sale. That’s 36% off its $279 list price.

Opens in a new window Credit: Apple Apple Watch SE (2nd Gen) $179.00 at Amazon
$279.00 Save $100.00 Get Deal

Black Friday is the ultimate time to snag tech deals, and this one is a standout: The Apple Watch SE (2nd Gen) is down to $179 at Amazon. That's a sweet $100 discount from its usual $279 price. This is your moment if you've been searching for an affordable yet powerful Apple Watch.

This sleek smartwatch combines all the essential features of an Apple Watch with a budget-friendly price tag. It runs on watchOS 11, delivering advanced metrics, seamless compatibility with your Apple devices, and smarter personalization. Apple Watch SE has you covered checking texts, taking calls, or tracking your workouts. It even offers Emergency SOS and Crash Detection, so safety is always within reach.

SEE ALSO: We track Apple deals year-round — Black Friday 2024 has the lowest prices we’ve ever seen

Fitness buffs will love the advanced workout metrics and three months of free Apple Fitness+. You'll also get notifications for irregular heart rhythms or unusual heart rates, making it a handy tool for monitoring your health. With 50-meter water resistance, the SE is perfect for swimmers or anyone who loves to accessorize with confidence, rain or shine.

This Black Friday deal features the midnight aluminum case with a midnight sport band, designed to look good in any setting. Its 44mm Retina display ensures everything is sharp and easy to read, and the battery easily lasts through your busiest days.

At $179, this Black Friday deal is one of the best prices we've seen for the Apple Watch SE. It's a perfect gift or personal upgrade that won't destroy your Apple Pay wallet. Grab yours before this deal disappears. Your wrist (and wallet) will thank you.

Categories: IT General, Technology

Grab the Google Pixel Watch 2 for under $150 this Black Friday

Mashable - Tue, 11/26/2024 - 10:55

SAVE OVER $100: As of Nov. 26, the Google Pixel Watch 2 is discounted to $145 in the Amazon Black Friday sale. That's a 42% drop from its original $249.99 price.

Opens in a new window Credit: Google Google Pixel Watch 2 $145.00 at Amazon
$249.99 Save $104.99 Get Deal

Looking to upgrade your wrist tech, this Black Friday deal on the Google Pixel Watch 2 might be the perfect excuse. The popular Android smartwatch is down to just $145 at Amazon, saving you $105 off its usual $249.99 price tag. With this stylish yet functional wearable, you'll be stepping up your fitness tracking, stress management, and safety monitoring at a wallet-friendly price.

The Google Pixel Watch 2 combines sleek design with cutting-edge tech. Made from 100% recycled aluminum, it's lightweight and comfortable for all-day wear. It also features Fitbit's most advanced heart rate sensor, powered by Google AI, to deliver precise fitness data. Whether you're working out, tracking your sleep, or monitoring your blood oxygen levels, this watch has you covered.

SEE ALSO: The new Google Pixel Buds Pro 2 are 22% off at Amazon — their first discount ever

But it's not just about fitness. The Pixel Watch 2 brings a range of safety features to your wrist. Emergency SOS and fall detection ensure you can get help when needed. At the same time, Safety Check lets you set a timer that alerts your contacts if you don't respond. Plus, the always-on display and improved 24-hour battery mean you'll always stay connected without constantly reaching for the charger.

The WiFi model is perfect for Android users and is available in a matte black aluminum case with an obsidian active band. This Black Friday deal is one of the best prices we've seen for this smartwatch, making it an excellent opportunity to snag premium tech for less.

At just $145, the Pixel Watch 2 is ready to make your life easier and your Black Friday holiday season more connected. Grab it while the deal lasts.

Categories: IT General, Technology

Score a pocket-sized thermal camera for under $180 this Black Friday

Mashable - Tue, 11/26/2024 - 10:52

SAVE $69: The P2 Thermal Camera for Android is down to $179.99 in the Amazon Black Friday sale. Usually priced at $249, this is the lowest price we've seen.

Opens in a new window Credit: P2 P2 Thermal Camera $179.99 at Amazon
$249.99 Save $70.00 Get Deal

If you've ever wished for superhero-like vision, this Black Friday deal might be the closest you'll get. The P2 Thermal Camera for Android is on sale for just $179.99 at Amazon — a $69 discount from its regular price of $249. And yes, this includes free returns, so you can test your infrared-detecting prowess without breaking the bank.

This compact gadget, weighing just 10 grams, is perfect for professionals and adventurers alike. Whether you're a home inspector on the hunt for energy leaks, an HVAC technician solving heating mysteries or a camper looking to spot wildlife in the dark, the P2 delivers. Its portability (it's the second-smallest thermal camera in the world) and keychain-ready design make it a must-have tool for anyone tackling temperature-based tasks.

SEE ALSO: Road trips, midnight snacks, backyard raccoons — capture it all on this day/night camera

Now, let's get nerdy for a second. The P2 boasts a super-sharp 512×384 IR resolution, which is a big upgrade from the standard 256×192, thanks to advanced algorithms like Razor X. It's so precise it can detect temperature changes as tiny as 0.04°C, making it your ultimate secret weapon against hidden hazards such as drafty windows to an overheating appliance. It's also great for wildlife trails and spotting hidden animals.

Plus, with a range spanning -4°F to a scorching 1,112°F, this thermal camera literally covers you. Need a closer look? Its 15x zoom lets you swipe through thermal readings like a pro. It even lets you DIY the color bar and temperature ranges for targeted measurements.

This Black Friday deal also includes an exclusive $20 coupon, bringing the final price to $179.99 — an even better steal. The question isn't if you'll use it — it's how many thermal problems you'll solve.

Categories: IT General, Technology

The Apple Pencil just got a huge discount in Amazons Black Friday sale

Mashable - Tue, 11/26/2024 - 10:38

SAVE $40: As of Nov. 26, the Apple Pencil (1st Gen) is on sale for $59 in Amazon's Black Friday sale. That's a 40% discount on the list price.

Opens in a new window Credit: Apple Apple Pencil (1st Gen) $59.00 at Amazon
$99.00 Save $40.00 Get Deal

Amazon's Black Friday sale has kicked off and the deals are aplenty. With discounts across everything from TVs to robot vacuums, you can find a deal on pretty much anything you need.

And if a new iPad stylus is on your wishlist, now is the time to buy. As of Nov. 26, the Apple Pencil (1st Gen) is on sale for just $59. Not only are you saving $40, but this is the lowest it has ever been priced at Amazon — who can argue with that?

SEE ALSO: Apple AirPods Pro 2 just got their biggest-ever discount at Amazon

The Apple Pencil (1st Gen) is a smart stylus that does more than just take notes. It offers precision, pressure, and tilt sensitivity. These allow you to create fine details, adjust line thickness, and add shading, just like using a regular pencil. There's also little to no noticeable lag, so it is perfect for drawing, sketching, shading, and any task that requires precision.

It works with various iPads, including the 6th to 10th generations (the 10th generation requires a USB-C to Apple Pencil Adapter). The package includes the Apple Pencil, a Lightning adapter, an extra tip, and a USB-C to Apple Pencil Adapter for charging and pairing.

This is not the latest model in the Apple Pencil range, with the Pencil 2 and Pencil Pro both succeeding it. For a more advanced stylus, we recommend the Pro which boasts haptic feedback and magnetic charging.

Categories: IT General, Technology

Apple AirPods Pro 2 just got their biggest-ever discount at Amazon

Mashable - Tue, 11/26/2024 - 10:29

SAVE $95: As of Nov. 26, the Apple AirPods Pro 2 are on sale for $153.99 in the Amazon Black Friday sale. That's a 38% discount on list price, and the lowest they've ever been on Amazon.

Opens in a new window Credit: Apple Apple AirPods Pro 2 $153.99 at Amazon
$249.00 Save $95.01 Get Deal

A new pair of AirPods doesn't need to cost you a fortune, especially with early Black Friday deals already kicking off. And Apple products are at the forefront of the discounts this year, with incredible prices from Walmart, Best Buy, and Amazon. Like this latest deal on the AirPods Pro 2.

As of Nov. 26, you can find them on sale for just £123.99 at Amazon. A discount of $95 and the lowest they have ever been priced.

SEE ALSO: Black Friday deals Amazon vs. Walmart: Comparing the best sales

The AirPods Pro 2 offer fantastic quality with amazing features such as a scientifically validated hearing test and clinical-grade hearing protection, both to protect and give insight on improving your ear health. Different sound modes will allow you to remain aware of your surroundings, or block it all out. Choose Active Noise Cancellation to block out background noise completely, while Adaptive Audio and Transparency modes deliver a blend of background sounds.

The Conversation Awareness function also adjusts playback for nearby interactions, and the H2 chip provides a strong, immersive sound for both music and calls.

They boast an IP54 rating, so are robust against sweat, water, and dust. Touch controls and Siri make use and managing your music super easy, while the case includes Precision Finding, a built-in speaker, and multiple charging options. For battery life, enjoy up to six hours of listening per charge, rising to 30 hours with the charging case.

Head to Amazon for this great deal before it runs out.

Categories: IT General, Technology

MrBeast unveils teaser for controversial Beast Games series

Mashable - Tue, 11/26/2024 - 10:01

MrBeast's upcoming Prime Video show Beast Games, which was mired in controversy after contestants accused production of creating unsafe filming conditions, has its first teaser.

The 48-second clip – which has comments turned off – has the feel of one of the YouTuber's typical videos, only even bigger: There are 1000 participants this time, clips that include giant monster trucks and people jumping from helicopters, and a prize pot of $5 million.

Beast Games is streaming on Prime Video from Dec. 19.

Categories: IT General, Technology

NYTs The Mini crossword answers, hints for November 26, 2024

Mashable - Tue, 11/26/2024 - 09:49

The Mini is a bite-sized version of The New York Times' revered daily crossword. While the crossword is a lengthier experience that requires both knowledge and patience to complete, The Mini is an entirely different vibe.

With only a handful of clues to answer, the daily puzzle doubles as a speed-running test for many who play it.

So, when a tricky clue disrupts a player's flow, it can be frustrating! If you find yourself stumped playing The Mini — much like with Wordle and Connections — we have you covered.

SEE ALSO: Mahjong, Sudoku, free crossword, and more: Play games on Mashable

Here are the clues and answers to NYT's The Mini for Tuesday, November 26, 2024:

AcrossJoint that can be "flicked"
  • The answer is Wrist.

Official state sport of South Dakota, Texas and Wyoming
  • The answer is Rodeo.

Phone pop-up
  • The answer is Alert.

First thing you typically get at a buffet
  • The answer is Plate.

Poetry event
  • The answer is Slam.

SEE ALSO: NYT Connections Sports Edition today: Hints and answers for November 26 DownSandwich alternative
  • The answer is Wrap.

Toilet paper units
  • The answer is Rolls.

Best-case
  • The answer is Ideal.

Big name in mattresses
  • The answer is Serta.

Ancestral emblem
  • The answer is Totem.

If you're looking for more puzzles, Mashable's got games now! Check out our games hub for Mahjong, Sudoku, free crossword, and more.

Featured Video For You The Wordle Strategy used by the New York Times' Head of Games

Are you also playing NYT Strands? See hints and answers for today's Strands.

Not the day you're after? Here's the solution to yesterday's Mini Crossword.

Categories: IT General, Technology

NYT Connections Sports Edition today: Hints and answers for November 26

Mashable - Tue, 11/26/2024 - 09:45

Connections: Sports Edition is a new version of the popular New York Times word game that seeks to test the knowledge of sports fans.

Like the original Connections, the game is all about finding the "common threads between words." And just like Wordle, Connections resets after midnight and each new set of words gets trickier and trickier—so we've served up some hints and tips to get you over the hurdle.

If you just want to be told today's puzzle, you can jump to the end of this article for the latest Connections solution. But if you'd rather solve it yourself, keep reading for some clues, tips, and strategies to assist you.

SEE ALSO: Mahjong, Sudoku, free crossword, and more: Play games on Mashable What is Connections Sports Edition?

The NYT's latest daily word game has launched in association with The Athletic, the New York Times property that provides the publication's sports coverage. Connections can be played on both web browsers and mobile devices and require players to group four words that share something in common.

Tweet may have been deleted

Each puzzle features 16 words and each grouping of words is split into four categories. These sets could comprise of anything from book titles, software, country names, etc. Even though multiple words will seem like they fit together, there's only one correct answer.

If a player gets all four words in a set correct, those words are removed from the board. Guess wrong and it counts as a mistake—players get up to four mistakes until the game ends.

Tweet may have been deleted

Players can also rearrange and shuffle the board to make spotting connections easier. Additionally, each group is color-coded with yellow being the easiest, followed by green, blue, and purple. Like Wordle, you can share the results with your friends on social media.

SEE ALSO: NYT's The Mini crossword answers for November 26 Here's a hint for today's Connections Sports Edition categories

Want a hint about the categories without being told the categories? Then give these a try:

  • Yellow - Tony Hawk knows all about these

  • Green - Northern competitors

  • Blue - Have yet to reach the mountaintop

  • Purple - Also known as

Featured Video For You Connections: How to play and how to win Here are today's Connections Sports Edition categories

Need a little extra help? Today's connections fall into the following categories:

  • Yellow - Parts of a skateboard

  • Green - Canadian teams

  • Blue - Teams to never win an NBA title

  • Purple - Famous NFL player nicknames

Looking for Wordle today? Here's the answer to today's Wordle.

Ready for the answers? This is your last chance to turn back and solve today's puzzle before we reveal the solutions.

Drumroll, please!

The solution to today's Connections Sports Edition #64 is...

What is the answer to Connections Sports Edition today
  • Parts of a skateboard: DECK, GRIP, TRUCK, WHEELS

  • Canadian teams: CANUCKS, JETS, RAPTORS, WHITECAPS

  • Teams to never win an NBA title: CLIPPERS, GRIZZLIES, JAZZ, MAGIC

  • Famous NFL player nicknames: BUS, MEGATRON, REFRIGERATOR, SWEETNESS

Don't feel down if you didn't manage to guess it this time. There will be new Connections for you to stretch your brain with tomorrow, and we'll be back again to guide you with more helpful hints.

Are you also playing NYT Strands? See hints and answers for today's Strands.

If you're looking for more puzzles, Mashable's got games now! Check out our games hub for Mahjong, Sudoku, free crossword, and more.

Not the day you're after? Here's the solution to yesterday's Connections.

Categories: IT General, Technology

Lead with Dignity

Havard Management Tip of the Day - Tue, 11/26/2024 - 06:01

Undervaluing employees or treating them as replaceable—for example, by overworking them or disrespecting them due to their status and position in the company—violates their intrinsic human value. This leads to disengagement and broken trust. You can avoid these consequences by leading with dignity: recognizing and honoring the humanity of every team member to create an […]

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Categories: Management

Get 15-minute audio summaries of bestselling books with this app

Mashable - Tue, 11/26/2024 - 06:00

TL;DR: Get a lifetime subscription to Headway Premium — the app that delivers quick, powerful insights from popular nonfiction books — on sale for £47.85 (reg. £239.27).

Opens in a new window Credit: GTHW App Limited Headway Premium: Lifetime Subscription £47.85 at the Mashable Shop
£239.27 Save £191.42 Get Deal

For those of us with big goals but little time, Headway offers a clever shortcut to wisdom. Imagine getting the main takeaways from bestselling books in short summaries that fit into your day. It's learning on your schedule.

With a lifetime plan to Headway Premium for a one-time payment of £47.85, you can tackle new skills, boost your knowledge, and feel like a lifelong learner without diving into hours of reading.

Users can choose from a wide variety of topics, including health, nutrition, finances, real estate, self-help, and more. There are more than 1,500 different summaries to choose from, and up to 50 more are added monthly. A very helpful feature allows you to get personalised recommendations according to your goals and preferences.

While this won't replace reading the actual book, it can clarify some of the more important points and let you know if it's something you'd like to know more about. Plus, you can choose to learn by reading, listening, or watching, which can keep things interesting, and allows you to listen to Headway summaries while you drive to work.

Right now at the Mashable Shop, you can score a lifetime subscription to Headway Premium and start your self-growth journey right.

StackSocial prices subject to change.

Categories: IT General, Technology

Amazon Black Friday ad: The best deals you can buy online

Mashable - Tue, 11/26/2024 - 06:00

Black Friday has become some sort of unstoppable monster that grows larger every year. We get that for some people, Black Friday is an irritating event that floods their screens with ads for sales they don't want or need. But for others, it's the single best time of the year to shop.

You can find deals on just about everything from leading retailers like Best Buy, Walmart, Target, and Home Depot. You can expect some really impressive offers from these sales, but when it really comes down to it, Amazon is still tough to beat during major shopping events like Black Friday.

SEE ALSO: Best Buy is treating most of November like Black Friday

Amazon had been dropping decent discounts on products in main categories like robot vacuums, Apple products, and Fire TVs throughout November. But now that Amazon's Black Friday sale has officially started, we're expecting a wave of truly stunning deals.

To help you make the most out of Amazon's Black Friday sale, we've checked out all the best Black Friday deals from the Amazon Black Friday ad that you can already buy online.

Best Apple deals at AmazonBest Echo deals at AmazonBest fitness tracker deals at AmazonBest headphones deals at AmazonBest Kindle deals at AmazonBest kitchen deals at AmazonBest robot vacuum deals at AmazonBest TV deals at Amazon
Categories: IT General, Technology

Wordle today: Answer, hints for November 26

Mashable - Tue, 11/26/2024 - 04:00

Oh hey there! If you're here, it must be time for Wordle. As always, we're serving up our daily hints and tips to help you figure out today's answer.

If you just want to be told today's word, you can jump to the bottom of this article for today's Wordle solution revealed. But if you'd rather solve it yourself, keep reading for some clues, tips, and strategies to assist you.

SEE ALSO: Mahjong, Sudoku, free crossword, and more: Play games on Mashable SEE ALSO: NYT Connections today: Hints and answers for November 26 Where did Wordle come from?

Originally created by engineer Josh Wardle as a gift for his partner, Wordle rapidly spread to become an international phenomenon, with thousands of people around the globe playing every day. Alternate Wordle versions created by fans also sprang up, including battle royale Squabble, music identification game Heardle, and variations like Dordle and Quordle that make you guess multiple words at once

Wordle eventually became so popular that it was purchased by the New York Times, and TikTok creators even livestream themselves playing.

What's the best Wordle starting word?

The best Wordle starting word is the one that speaks to you. But if you prefer to be strategic in your approach, we have a few ideas to help you pick a word that might help you find the solution faster. One tip is to select a word that includes at least two different vowels, plus some common consonants like S, T, R, or N.

What happened to the Wordle archive?

The entire archive of past Wordle puzzles was originally available for anyone to enjoy whenever they felt like it, but it was later taken down, with the website's creator stating it was done at the request of the New York Times. However, the New York Times then rolled out its own Wordle Archive, available only to NYT Games subscribers.

Is Wordle getting harder?

It might feel like Wordle is getting harder, but it actually isn't any more difficult than when it first began. You can turn on Wordle's Hard Mode if you're after more of a challenge, though.

SEE ALSO: NYT's The Mini crossword answers for November 26 Here's a subtle hint for today's Wordle answer:

Wicked.

Does today's Wordle answer have a double letter?

There are no reoccurring letters.

Today's Wordle is a 5-letter word that starts with...

Today's Wordle starts with the letter W.

SEE ALSO: Wordle-obsessed? These are the best word games to play IRL. The Wordle answer today is...

Get your last guesses in now, because it's your final chance to solve today's Wordle before we reveal the solution.

Drumroll please!

The solution to today's Wordle is...

WITCH.

Don't feel down if you didn't manage to guess it this time. There will be a new Wordle for you to stretch your brain with tomorrow, and we'll be back again to guide you with more helpful hints.

Are you also playing NYT Strands? See hints and answers for today's Strands.

SEE ALSO: NYT Connections Sports Edition today: Hints and answers for November 26

Reporting by Chance Townsend, Caitlin Welsh, Sam Haysom, Amanda Yeo, Shannon Connellan, Cecily Mauran, Mike Pearl, and Adam Rosenberg contributed to this article.

If you're looking for more puzzles, Mashable's got games now! Check out our games hub for Mahjong, Sudoku, free crossword, and more.

Not the day you're after? Here's the solution to yesterday's Wordle.

Categories: IT General, Technology

Black Friday Is Rife With Phishing: How to Avoid Being Scammed

How-To Geek - Tue, 11/26/2024 - 00:00

Every year, vast schools of shoppers swarm around Black Friday deals in a proverbial feeding frenzy, but the chaos can also attract scammers that only need one slip up to strike.

Categories: IT General, Technology

How to Add and Manage Additional Accounts in New Outlook

How-To Geek - Mon, 11/25/2024 - 23:15

The new Outlook app lets you add various email accounts from different email providers, which you can use to send or reply to emails. However, some traps along the way might catch you out. With this in mind, this guide covers all bases to help you make the most of this handy capability.

Categories: IT General, Technology

Black Friday headphone and speaker deals bring AirPods Pro and Bose headphones to record-low prices

Mashable - Mon, 11/25/2024 - 22:30

UPDATE: Nov. 25, 2024, 4:30 p.m. EST This post has been updated with the latest headphones and earbuds deals in the days leading up to Black Friday.

Best headphone and speaker deals ahead of Black Friday Best headphone deal Sony WH-1000XM4 $199.99 at Best Buy (Save $148.01) Get Deal Best earbuds deal Apple AirPods Pro (2nd gen) $154 at Amazon (Save $95) Get Deal Best Bluetooth speaker deal Ultimate Ears Wonderboom 4 $78.96 at Amazon (Save $21.03) Get Deal

Black Friday is just around the corner, but retailers aren't waiting to bring headphones down to record-low prices.

The start of Best Buy's Black Friday sale has brought the Sony WH-1000XM4 headphones down to one of the lowest prices we've ever seen them at $199.99, while Walmart's sale brought the Apple AirPods Pro to record-low price at Walmart and Amazon (they love to stay competitive). Essentially, every major audio brand, including Bose, JBL, Sennheiser, and Beats has headphones and earbuds down at record-low prices.

SEE ALSO: Walmart's first wave of Black Friday TV deals goes extremely hard

Check out our top picks below for the best headphone and speaker deals below:

Best headphones deal ahead of Black Friday Opens in a new window Credit: Sony Sony WH-1000XM4 $199.99 at Best Buy
$348.00 Save $148.01 Get Deal Why we like it

While these headphones hit the market back in 2020, they're still a decent option to pick up, especially if you're looking to spend no more than $200. While they do go on sale throughout the year, they typically drop about $100, making this nearly $150 especially good. Because they're older, they no longer have top of the line noise-cancelling or sound quality, but they still more than get the job done. Plus, unlike the newer Sony WH-1000XM5 headphones, the XM4 ear cups fold in, potentially making them a better option for folks who travel frequently.

More headphone dealsBest earbuds deal ahead of Black Friday Opens in a new window Credit: Apple Apple AirPods Pro (2nd gen) $154.00 at Amazon
$249.00 Save $95.00 Get Deal Why we like it

This is not a drill: The AirPods Pro are down to a brand-new record-low price days ahead of Black Friday. In October, Prime Day brought the popular Apple earbuds down to a record-low of $168.99, which dropped lower to $159 last week. With Walmart's second Black Friday kicking off on Nov. 25, the retailer dropped the price of these earbuds down to another new record-low of $154, which Amazon had to match. In other words, if you've been waiting to buy the AirPods Pro, this is a really good time to buy them. While we can't say for sure whether they'll drop even more come Friday (retailers have often reserved their best prices for the day), $154 is the kind of price we would've expected to see then.

More earbuds dealsBest speaker deal ahead of Black Friday Opens in a new window Credit: Ultimate Ears Ultimate Ears Wonderboom 4 $78.96 at Amazon
$99.99 Save $21.03 Get Deal Why we picked this

The Ultimate Ears Wonderboom 4 is our favorite speaker under $100 at full price, so we think this deal is especially worth it. Despite its relatively compact size, this speaker reaches impressive volumes, can be taken pretty much anywhere you want to go thanks to its IP67 waterproof rating, and has 14 hours of battery life. That said, this isn't the first time we've seen this speaker drop down in price. Even shortly after its release this past June, it dropped down to $79.99 — but a few days ahead of Black Friday, you can get it for ever so slightly cheaper.

More speaker deals
Categories: IT General, Technology

How to Mirror Your Android Screen to Your PC Using Windows Phone Link

How-To Geek - Mon, 11/25/2024 - 22:30

Windows 10 and Windows 11 offer a "phone link" application that lets you control your smartphone from the Windows desktop, and even mirror your phone's screen. It's a little tricky to set up, but if you follow the steps below you'll have it working in no time.

Categories: IT General, Technology

Accelerating drug discovery with TamGen: A generative AI approach to target-aware molecule generation

Microsoft Research - Mon, 11/25/2024 - 22:02

The Global Health Drug Discovery Institute (opens in new tab) (GHDDI) and Microsoft Research have reached a milestone in tuberculosis (TB) drug research with TamGen (opens in new tab), an open-source (opens in new tab), transformer-based chemical language model for developing target-specific drug compounds. Working in collaboration, the joint team successfully identified several promising inhibitors for a TB protease, with the most effective compound showing significant bioactivity. Research shows that TamGen can also optimize existing molecules by designing target-aware molecule fragments, potentially enabling the discovery of novel compounds that build on a known molecular core structure.  

Generative AI helps overcome limitations in drug discovery

Generative AI is opening new avenues for scientific exploration by allowing computers to autonomously learn and produce original content. TamGen offers a new approach to drug discovery by applying the principles of generative AI to molecular design. Unlike traditional methods, which depend on systematically screening known compounds—a process that is long, complex, and costly due to its reliance on empirical knowledge and the time-consuming task of exploring a vast chemical library—generative AI provides opportunities for designing entirely new chemical structures.  

TamGen goes beyond analyzing existing data by generating chemically diverse compounds that conventional approaches might miss. Figure 1 shows that generative AI expands chemical exploration, allowing for a deeper and more comprehensive search for therapeutic solutions compared to traditional methods.

Figure 1. Compared with the traditional screening-based approach to drug discovery, a generative AI-based approach enables the discovery of novel compounds.  TamGen workflow 

TamGen’s workflow uses generative AI to design target-specific chemical compounds. Building on the success of large language models (LLMs), we adapted a similar approach for molecular generation, using a training method like that of GPT models, which involves next-token prediction. Molecules were first converted into a simplified molecular input line entry system (SMILES)—a notation representing molecular structures as symbol sequences, similar to text. We then developed a protein encoder to process information about proteins, including their 3D structure.  

A contextual encoder combines insights from medical professionals with data on the protein target and existing compounds that have proven to be effective or promising. Using expert knowledge and computational analysis, this encoder guides the compound generator to produce new molecules that are more likely to bind to a given protein. This workflow is illustrated in Figure 2. 

Figure 2. TamGen’s workflow  Evaluating TamGen computationally 

To evaluate TamGen’s performance, we compared it to five other common methods used to create 3D shapes of molecules intended to bind to certain proteins. We evaluated these methods using the CrossDocked benchmark, a dataset used in AI research to assess the quality of molecule generation conditioned on a target protein.

Evaluation metrics: 

  • Docking score: Measures how well a molecule binds to a target protein. 
  • Quantitative estimate of drug-likeness (QED): Assesses how good a candidate a molecule is for a drug. 
  • Synthesis accessibility score (SAS): Measures how easy or difficult it is to synthesize a particular chemical compound in a lab. 
  • Ro5 (Lipinski’s rule of five): Determines how likely a compound can be developed into an oral drug.  
  • LogP: Tests a compound’s ability to move between water and fats. 
  • Diversity: Measures the range of different molecular structures and properties in a collection of compounds.  

The findings, illustrated in Figure 3, show TamGen’s overall performance. While other methods may produce compounds that bind more strongly, they often include multiple interconnected ring structures. Research indicates that more of these structures can lower synthesis accessibility (SAS) and increase cellular toxicity, making these compounds harder to develop. We believe that molecular pretraining of the model contributed to the overall effectiveness of the compounds TamGen generated.

Figure 3. Results from TamGen’s computational performance verification Experimental lab verification 

To ensure real-world applicability, we also validated our findings in a hands-on lab environment. Here, we focused on the ClpP protease in Mycobacterium tuberculosis as the target because it plays a significant role in the bacterium’s survival under stress conditions. We proposed the Design-Refine-Test pipeline to effectively identify molecular compounds for TB drug discovery.

Design stage: We began by using TamGen to analyze the binding pocket of the protease, where molecules can attach and influence its function. TamGen generated about 2,600 potential compounds that could fit into this pocket. We assessed these compounds based on how well they could attach to the protease and their predicted biological effects, narrowing it down to four promising candidates. 

Refine stage: Next, we entered the four compounds into TamGen, along with three molecular fragments that had been validated in previous lab experiments. This generated a total of 8,600 new compounds, which we screened again using the same criteria, eventually narrowing the selection to 296 compounds.

Test stage: Because synthesizing all 296 compounds wasn’t feasible, we identified similar compounds available in commercial libraries and tested their initial activity against TB. Five compounds showed promising results. We then synthesized one of the originals and two variants of another. Additionally, we categorized the generated compounds into clusters, selected the top 10% from each cluster based on docking scores, and after manual review, synthesized eight more compounds. 

The team from Microsoft Research generated the compounds by TamGen, and the GHDDI team conducted binding analysis, structure–activity relationship studies, and lab experiments to verify the compounds’ inhibitory effect on the ClpP protease, measuring their capacity to interfere with or reduce its activity. Lower IC50 values signify greater potency. Out of the 16 compounds tested, 14 showed strong inhibitory activity measuring under 40 µM, indicating high potential. The most effective compound had a measured IC50 value of 1.88 µM.

Figure 4. The hands-on lab verification process   From molecule to fragment generation 

In addition to generating new molecules, TamGen can optimize existing ones by designing smaller molecular fragments. In this fragment generation process, TamGen builds on a given protein target and a molecular core structure to design new compounds around that core. By incorporating information about the target protein, it generates fragments that are highly specific to the target. This approach moves beyond traditional methods that rely on pre-existing databases, which often limit both novelty and effectiveness of molecular fragments.

For fragment generation, we adjusted the input to TamGen’s compound generator. We modified the SMILES string to ensure it ended at the desired growth site. This was done by specifying the fragment we wanted to retain and its connection point for further growth. The tailored SMILES string was then fed into the compound generator to extend the molecule. 

We evaluated this method by targeting the ClpP protease for TB, achieving a more than tenfold improvement in the binding affinity of the generated compound compared to the original. Some compounds also demonstrated slow binding, indicating potential for prolonged action and improved selectivity for the target protein.

AI’s potential in drug discovery 

TamGen showcases the transformative potential of generative AI in drug design, combining advanced molecular modeling with researcher-AI collaboration. Tasks that once took years can now be accomplished in a fraction of the time. This research underscores AI’s expanding role in drug discovery and its promise for developing effective treatments against persistent infectious diseases like TB. 

Looking ahead, we plan to integrate advanced techniques into TamGen, including diffusion models for generating 3D structures, reinforcement learning to apply physical constraints, and molecular dynamics simulations to capture proteins’ shifting shapes. These enhancements aim to improve how well generated compounds bind to target proteins, increase their ability to be synthesized, and strengthen other critical drug properties.

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The post Accelerating drug discovery with TamGen: A generative AI approach to target-aware molecule generation appeared first on Microsoft Research.

Categories: Microsoft

Offline Mode in PC Game Pass Is Perfect for Windows Laptops and Handhelds

How-To Geek - Mon, 11/25/2024 - 22:00

Having a Windows handheld PC or gaming laptop means getting access to PC Game Pass and its huge catalog of titles, but if you can't take these portables to where there's no internet, what's the point? Luckily, Microsoft has thought of that.

Categories: IT General, Technology

Microsoft Outlook outage: What happened?

Mashable - Mon, 11/25/2024 - 21:37

A Microsoft outage on Monday has affected Outlook and Teams users. Microsoft is aware of the issue and working on a fix, but said it's "facing delays in our recovery efforts."

Reports of issues began around 8 a.m. ET and spiked around 12:30 p.m. ET, according to DownDetector (which shares a parent company with Mashable). Reported outages have since tapered off, suggesting the issue might be resolved soon.

The Microsoft 365 account on X said, "We’ve identified a recent change which we believe has resulted in impact." It's unclear what specifically caused the outage besides mention of a recent change. But Microsoft's controversial AI-powered Recall feature was launched today for Windows Insiders in preview mode. Big deployments like Recall, which takes incremental snapshots of a user's screen, are sometimes the culprit for causing mass outages.

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Users took to X to express their frustration at not being able to access basic tools like Outlook for sending emails and Teams for video calls.

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Others didn't seem to mind the multi-hour outage on the Monday before Thanksgiving when they would otherwise be working.

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The outage seems to be on its way to resolution, but we will share updates if that's not the case.

Categories: IT General, Technology

Amazon workers plan global protests and strikes on Black Friday

Mashable - Mon, 11/25/2024 - 21:23

Amazon employees around the world are preparing for protests and strikes on Black Friday.

The global effort has been organized by UNI Global Union, which represents service industry workers, and activist group Progressive International. 

Amazon workers in more than 20 countries plan to strike and take part in protests starting on Black Friday, one of the biggest annual shopping days for retailers. The protest efforts will go on into Cyber Monday, one of the biggest online shopping days of the year.

Organizers say strikes will be taking place in major cities in countries such as the United States, Germany, the United Kingdom, Japan and Brazil. Specific protests include thousands of warehouse workers across Germany going on strike, garment workers in Bangladesh striking, and workers in New Delhi will rally to demand fair treatment after heatwave-related issues from this past summer. 

Protesters want to 'Make Amazon Pay'

The protest campaign is being organized under the banner of "Make Amazon Pay." The effort will put a spotlight on what organizers say is Amazon's "anti-worker and anti-democratic" practices.

Workers will focus on highlighting Amazon's "labor abuses, environmental degradation and threats to democracy" such as the company's role in corporate power.

“Amazon’s relentless pursuit of profit comes at a cost to workers, the environment and democracy,” said General Secretary of UNI Global Union Christy Hoffman. “Bezos’s company has spent untold millions to stop workers from organizing, but the strikes and protests happening around the world show that workers’ desire for justice – for union representation – can’t be stopped." 

"We stand united in demanding that Amazon treat its workers fairly, respect fundamental rights, and stop undermining the systems meant to protect us all," Hoffman continued. "‘Make Amazon Pay Day’ is becoming a global act of resistance against Amazon’s abuse of power.”

According to organizers, Make Amazon Pay will include participants from more than 80 unions, environmental groups, and activist organizations such as Greenpeace, 350.org, and Amazon Workers International. 

During the protests, workers will demand that Amazon pay fair wages to employees and commit to environmental sustainability efforts. Workers will also call on the company to pay their fair share of taxes as well as respect employees' rights to unionize. 

An Amazon spokesperson released a statement regarding the coming Black Friday protest events saying, "these groups represent a variety of interests, and while we're always listening and looking at ways to improve, we remain proud of the competitive pay, comprehensive benefits, and engaging, safe work experience we provide our teams."

In 2022, Amazon warehouse workers in Staten Island became the first and, so far, only company unit to vote to form a union. Amazon spent millions of dollars in union busting campaigns to fight the efforts from workers to unionize. A documentary on the Amazon Labor Union campaign was released this year. The filmmakers had to self-distribute the film as they had difficulty finding a distributor due to Amazon and its Prime Video streaming service's growing influence in Hollywood. 

Make Amazon Pay's upcoming protests will be the fifth year that Amazon workers have gone on strike on Black Friday.

“By uniting our movements across borders, we can not only force Amazon to change its ways but lay the foundations of a world that prioritizes human dignity, not Jeff Bezos’ bank balance.” said Progressive International’s Co-General Coordinator Varsha Gandikota-Nellutla. "Amazon is everywhere, but so are we."

Categories: IT General, Technology
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