The antitumor effect of cardiotonic steroids (CTS) has stimulated the search for new methods to evaluate both kinetic and thermodynamic aspects of their binding to Na⁺/K⁺-ATPase (IUBMB Enzyme Nomenclature). We propose a real-time assay based on a chromogenic substrate for phosphatase activity (pNPPase activity), using only two concentrations with an inhibitory progression curve, to obtain the association rate (k_on), dissociation rate (k_off), and equilibrium (K_i) constants of CTS for the structure-kinetics relationship in drug screening. We show that changing conditions (from ATPase to pNPPase activity) resulted in an increase of K_i of the cardenolides digitoxigenin, essentially due to a reduction of k_on. In contrast, the K_i of the structurally related bufadienolide bufalin increased much less due to the reduction of its k_off partially compensating the decrease of its k_on. When evaluating the kinetics of 15 natural and semisynthetic CTS, we observed that both k_on and k_off correlated with K_i (Spearman test), suggesting that differences in potency depend on variations of both k_on and k_off. A rhamnose in C3 of the steroidal nucleus enhanced the inhibitory potency by a reduction of k_off rather than an increase of k_on. Raising the temperature did not alter the k_off of digitoxin, generating a H (k_off) of –10.4 ± 4.3 kJ/mol, suggesting a complex dissociation mechanism. Based on a simple and inexpensive methodology, we determined the values of k_on, k_off, and K_i of the CTS and provided original kinetics and thermodynamics differences between CTS that could help the design of new compounds.

Despite a significant decrease in the number of prescriptions for opioids, the opioid crisis continues, fueled in large part by the availability of the phenylpiperidine mu opioid receptor (MOR) agonist fentanyl. In contrast, the number of prescriptions for and the off-label use of gabapentinoids (gabapentin and pregabalin) has increased dramatically, with gabapentinoids commonly detected in opioid overdose victims. Although gabapentinoids can decrease the potency of the opioid receptor antagonist naloxone to reverse heroin-induced hypoventilation in male rats, the specificity and nature of interaction between gabapentinoids and MOR agonists and any potential sex difference in those interactions are not well characterized. Gabapentinoids were studied in female and male rats discriminating fentanyl (0.0032 mg/kg, i.p.) or cocaine (3.2 mg/kg, i.p.). Alone, neither gabapentin nor pregabalin significantly increased fentanyl- or cocaine-appropriate responding. In rats discriminating fentanyl, each gabapentinoid dose-dependently shifted the fentanyl and heroin discrimination dose-effect functions to the left, whereas naloxone dose-dependently shifted the fentanyl and heroin discrimination dose-effect functions to the right. Each gabapentinoid (100 mg/kg) significantly decreased the potency of naloxone to antagonize the discriminative stimulus effect of fentanyl or heroin. In contrast, each gabapentinoid dose-dependently shifted the cocaine and d-methamphetamine discrimination dose-effect functions to the right. There were no significant sex differences in this study. These results suggest that gabapentinoids impact the misuse of opioids, the co-use of opioids and stimulant drugs, and the increasing number of overdose deaths in individuals using opioids, stimulant drugs, and gabapentinoids in mixtures.

BACKGROUND AND PURPOSE:

Previous studies have reported metal accumulation and microstructure changes in deep gray nuclei (DGN) in Wilson disease (WD). However, there are limited studies that investigate whether there is metal accumulation and microstructure changes in DGN of patients with WD with normal-appearing routine MRI. This study aimed to evaluate multiparametric changes in DGN of WD and whether the findings correlate with clinical severity in patients with WD.

There is conflicting evidence regarding the use of steroids in severe community-acquired pneumonia (CAP), with previous randomised controlled trials limited by small sample sizes. ESCAPe and CAPE COD are two recently published large trials on steroids in severe CAP. ESCAPe assessed the initiation of methylprednisolone within 72–96 h of hospital admission, while CAPE COD studied the use of hydrocortisone within 24 h of the development of severe CAP. ESCAPe did not show any differences in all-cause 60-day mortality or any of its secondary outcomes. CAPE COD showed that hydrocortisone improved all-cause 28-day mortality and reduced the risk of intubation or vasopressor-dependent shock. Important differences between the trials included the steroid regimens used, timing of steroid administration and baseline characteristics, with more diabetic patients included in ESCAPe. The results of CAPE COD support the initiation of hydrocortisone within 24 h of developing severe CAP, but more research is needed to evaluate long-term outcomes and optimum dosing regimens for steroids in severe CAP.

The Pokémon series is no stranger to mobile games, being responsible for one of the most successful ever (Pokémon Go), as well as many others with different takes on the massive franchise, but this time it’s a Pokémon card game - a tradition nearly as old as the original games - that has taken the spotlight in Pokémon TCG Pocket.

For the physical version of Pokémon TCG, the collecting has always been as big or bigger than the battling, and right off the bat we can see that TCG Pocket has made plenty of room for both these aspects in its design. In fact, the battling isn’t even available until you level up a few times, which, while a bit limiting, is a fine way for players to get their bearing and collect a few cards before they start competing. The game does suffer from just a tad bit too much forced tutorialization in the early stages, particularly when getting to the battles, but it’s still hardly the worst sinner among mobile titles in this regard.

The collecting all starts with the opening of packs, an infamously addictive part of any card game, and they’ve done a good job of making the process quite satisfying TCG Pocket. More importantly, the number of packs given for free is quite generous - at least two packs a day by default - meaning the game is perfectly playable without spending money, regardless of whether you’re in it for the collecting or battling aspect. Whenever you obtain new cards, they also get filled out in a sort of card Pokédex, which adds to the fun of collecting new ones.

A lot of what makes the collecting in TCG Pocket enjoyable, however, is quite simply the excellent card art. This is, of course, borrowed mostly from the game’s physical counterpart, and strengthened by little touches like being able to being able to zoom in and tilt the cards, with a slight holographic on the rarer ones. Whether they’re cute or cool, the Pokémon themselves are at the heart of this franchise and with the generally splendid art the game does a great job of bringing them to life, in some ways doing them more justice than recent mainline entries with low-detailed 3D models.

As for the other part of aesthetics, namely sound design, the game is also passable in this area but nothing special with slightly boring battle music. It's not the biggest issue perhaps, as most are likely to play mobile games with sound disabled, but with all the cosmetic unlockables (which we shall get to) it   seems like a wasted opportunity not to have unlockable battle themes when the Pokémon series has so many great ones to draw upon from its legacy.

Looking for a moment at the less positive side, while Pokémon TCG Pocket is fairly generous to free-to-play players, it does still suffer from some of the pitfalls that are typical of that type of mobile game; namely, the amount of noise that comes with too many currencies, constant quests and rewards, and perhaps a few more types of cosmetics than is necessary. Again, I wouldn't describe Pokémon TCG Pocket as the worst sinner of this type of issue, mostly just that it can be a bit overwhelming at first, and of course knowing that it’s intended to add to the addictiveness of the game can be a bit iffy, but ultimately it isn’t too hard to ignore aspects you don’t care about and simply enjoy the ones you do.

It might be high time to touch on the battles themselves, which to many players might be their first encounter ever with the actual rules of these pretty collectible cards. While it might not be simplest card game ever invented, I’m happy to say the TCG Pocket variant is still intuitive, fun, and quite strategic once you get the hang of it. To summarize it in very brief: you play and evolve Pokémon from your hand onto the field and charge them up with energy types to allow them to attack. Just like in the RPGs, only one Pokémon is active at a time and can use one move per turn, while you can assign others to your “bench”, where they await their turn in the spotlight. Unlike in the RPGs, switching Pokémon won’t cost you your turn (only some energy), meaning benched Pokémon can potentially step into action immediately - if you have the energy necessary. Rather than any form of life-points, you win the battle by defeating three of your opponents' Pokémon, which each award one point.

This bench system and charging up of your Pokémon before they can take action might in some regards make the game slower compared to other card games, but it also adds a strategic element, since you can generally see what moves you and your opponent have available in the immediate future and can only really be caught by surprise by item or support cards (which can be quite useful but rarely complete game changers). It’s not the type of game where you perform crazy one-turn game-winning combos, but it’s fun for the strategic aspect and of course the satisfaction that comes from evolving your Pokémon throughout the battle - and sometimes pulling off an impressive comeback.

Adding to this are the EX-cards, extra powerful cards that come with the added risk of rewarding the opponent two points if defeated rather than one. I’ve seen complaints that this risk is too big in a game when it only takes three points to win (unlike the physical version of the game where you need six points), but when the card is extra strong and you have the option of switching it out it seems justified, plus you still have that golden window of playing it when your opponent already has two points, at which point the extra risk is nullified.

Ultimately there is one distinct issue with the battle system, however, which is how type weaknesses are handled. Pokémon TCG, whether physical or digital, has condensed Pokémon down to nearly half as many types (a tad too few in my opinion, though all 18 would definitely have been overwhelming), while the weaknesses and resistances are reduced to one type per card, and in TCG Pocket resistances are removed so you only have the weaknesses. This, for example, means that (most) Water types are weak to Lightning   but not Grass, while Fire types are weak to Water but not Ground (which has been combined with Fighting). The issue however is not so much the differences from the RPGs as it is simply having these basic and pretty consistent weaknesses in a game that, unfortunately, strongly encourages mono-type   decks in its design (or one type + colorless), since you’ll be needing specific energy types to charge your Pokémon and receive them at random if your deck uses multiple types.

While there is something to be said for having to commit to certain types, it’s a bit unfortunate that it’s taken to the degree where dual-type decks can feel awkward and triple-type decks, while allowed, require very specific cards or a lot of luck to pull off. The result is that when most players play with only one type and all types have one weakness, online matches will often either play out without weaknesses playing any role or with one player having an advantage before the first card is even played. One can always hope that this is somehow redesigned a bit in the future, but for now it’s an unfortunate though not game-breaking issue, as the weaknesses are at least a bit milder here, adding only a flat amount of damage rather than a multiplier.

Lastly it wouldn't review this game without mentioning the nostalgic aspect, which to many a player might add an extra appeal to the experience. Even as someone who hasn't dabbled in Pokémon cards for nearly 20 years, I can still recognize many that I’ve owned myself at some point, and it’s also great to revisit the first generation, which has smartly put front and center for now (with a small mix from other generations on top). I consider it a good call to start off with a single set of a manageable size for now - one that doesn’t seem too daunting - while leaving plenty of room to grow in the future.

All in all, Creatures Inc. and Dena Co. have done a great job adapting the Pokémon card game to mobile in a way that can appeal to both old and new players, and to those who want to collect and those who want to battle. It brings Pokémon to life with great card art and, contrary to unfortunate trends, the game is also fairly generous to its free-to-play players (and certainly a cheaper alternative to collecting the physical cards). While it does suffer from a few design issues and some classic pitfalls, it’s overall one of the better mobile games out there at the moment and certainly worth checking out for those who have nostalgia for the Pokémon TCG or old school Pokémon in general.

Full Article - https://www.vgchartz.com/article/463039/pokemon-tcg-pocket-android/

Prior to his untimely death in Argentina on Wednesday, One Direction’s Liam Payne, 31, was in the middle of a legal spat with his ex-fiancée Maya Henry.

On Monday, The Sun reported that Henry, 23, had lawyered up in an attempt to stop Payne from constantly messaging her family and friends.

“Maya Henry issued a cease and desist last week to Liam Payne following the emergence of new and concerning information…She has retained attorneys Marco Crawford and Daniel Cerna to represent her. At this time, that is her only comment on the matter,” a spokesperson for Henry told the tabloid.

Read more at The Daily Beast.

Ganymede, the largest moon in the solar system, has signs of an enormous ancient impact that would have redistributed its mass, changing its orientation in relation to Jupiter

A newly spotted asteroid named 2024 RW1 burned up in the atmosphere over the South Pacific, creating a spectacular bright flash in the sky over the Philippines just hours after first being detected

News of the asteroid 2024 RW1 impacting near the Philippines may have come as a shock this week, but space agencies and astronomers around the world are keeping an eye out to protect us

Cracks running through samples of asteroid Ryugu were probably formed by the repeated thawing and freezing of water inside it, which could have helped asteroids like this carry the building blocks of life to early Earth

The European Space Agency is sending a probe to get a closer look at the asteroid Dimorphos, which had its orbit altered by NASA’s DART mission in 2022

Bacteria grown from carbon compounds in asteroids could be turned into a kind of nutritionally balanced milkshake

Meet NASA’s NEO Surveyor, the space telescope identifying hazardous asteroids and comets within 48 million kilometres of Earth’s orbit

Asteroids that regularly fly between Earth, Venus and Mars could provide radiation shielding for human missions to explore neighbouring planets

Averting an asteroid strike will need many of the same skills we must hone to tackle climate change and future pandemics

From nuclear strikes to giant spikes, discover the systems in place to prevent a collision and test your decision-making to see if you could avoid a catastrophic impact

In the 1960s and 1970s, NASA spent a lot of time thinking about whether toroidal (donut-shaped) fuel tanks were the way to go with its spacecraft. Toroidal tanks have a bunch of potential advantages over conventional spherical fuel tanks. For example, you can fit nearly 40% more volume within a toroidal tank than if you were using multiple spherical tanks within the same space. And perhaps most interestingly, you can shove stuff (like the back of an engine) through the middle of a toroidal tank, which could lead to some substantial efficiency gains if the tanks could also handle structural loads.

Because of their relatively complex shape, toroidal tanks are much more difficult to make than spherical tanks. Even though these tanks can perform better, NASA simply doesn’t have the expertise to manufacture them anymore, since each one has to be hand-built by highly skilled humans. But a company called Machina Labs thinks that they can do this with robots instead. And their vision is to completely change how we make things out of metal.

The fundamental problem that Machina Labs is trying to solve is that if you want to build parts out of metal efficiently at scale, it’s a slow process. Large metal parts need their own custom dies, which are very expensive one-offs that are about as inflexible as it’s possible to get, and then entire factories are built around these parts. It’s a huge investment, which means that it doesn’t matter if you find some new geometry or technique or material or market, because you have to justify that enormous up-front cost by making as much of the original thing as you possibly can, stifling the potential for rapid and flexible innovation.

On the other end of the spectrum you have the also very slow and expensive process of making metal parts one at a time by hand. A few hundred years ago, this was the only way of making metal parts: skilled metalworkers using hand tools for months to make things like armor and weapons. The nice thing about an expert metalworker is that they can use their skills and experience to make anything at all, which is where Machina Labs’ vision comes from, explains CEO Edward Mehr who co-founded Machina Labs after spending time at SpaceX followed by leading the 3D printing team at Relativity Space.

“Craftsmen can pick up different tools and apply them creatively to metal to do all kinds of different things. One day they can pick up a hammer and form a shield out of a sheet of metal,” says Mehr. “Next, they pick up the same hammer, and create a sword out of a metal rod. They’re very flexible.”

The technique that a human metalworker uses to shape metal is called forging, which preserves the grain flow of the metal as it’s worked. Casting, stamping, or milling metal (which are all ways of automating metal part production) are simply not as strong or as durable as parts that are forged, which can be an important differentiator for (say) things that have to go into space. But more on that in a bit.

The problem with human metalworkers is that the throughput is bad—humans are slow, and highly skilled humans in particular don’t scale well. For Mehr and Machina Labs, this is where the robots come in.

“We want to automate and scale using a platform called the ‘robotic craftsman.’ Our core enablers are robots that give us the kinematics of a human craftsman, and artificial intelligence that gives us control over the process,” Mehr says. “The concept is that we can do any process that a human craftsman can do, and actually some that humans can’t do because we can apply more force with better accuracy.”

This flexibility that robot metalworkers offer also enables the crafting of bespoke parts that would be impractical to make in any other way. These include toroidal (donut-shaped) fuel tanks that NASA has had its eye on for the last half century or so.

Machina Labs’ CEO Edward Mehr (on right) stands behind a 15 foot toroidal fuel tank.Machina Labs

“The main challenge of these tanks is that the geometry is complex,” Mehr says. “Sixty years ago, NASA was bump-forming them with very skilled craftspeople, but a lot of them aren’t around anymore.” Mehr explains that the only other way to get that geometry is with dies, but for NASA, getting a die made for a fuel tank that’s necessarily been customized for one single spacecraft would be pretty much impossible to justify. “So one of the main reasons we’re not using toroidal tanks is because it’s just hard to make them.”

Machina Labs is now making toroidal tanks for NASA. For the moment, the robots are just doing the shaping, which is the tough part. Humans then weld the pieces together. But there’s no reason why the robots couldn’t do the entire process end-to-end and even more efficiently. Currently, they’re doing it the “human” way based on existing plans from NASA. “In the future,” Mehr tells us, “we can actually form these tanks in one or two pieces. That’s the next area that we’re exploring with NASA—how can we do things differently now that we don’t need to design around human ergonomics?”

Machina Labs’ ‘robotic craftsmen’ work in pairs to shape sheet metal, with one robot on each side of the sheet. The robots align their tools slightly offset from each other with the metal between them such that as the robots move across the sheet, it bends between the tools. Machina Labs

The video above shows Machina’s robots working on a tank that’s 4.572 m (15 feet) in diameter, likely destined for the Moon. “The main application is for lunar landers,” says Mehr. “The toroidal tanks bring the center of gravity of the vehicle lower than what you would have with spherical or pill-shaped tanks.”

Training these robots to work metal like this is done primarily through physics-based simulations that Machina developed in house (existing software being too slow), followed by human-guided iterations based on the resulting real-world data. The way that metal moves under pressure can be simulated pretty well, and although there’s certainly still a sim-to-real gap (simulating how the robot’s tool adheres to the surface of the material is particularly tricky), the robots are collecting so much empirical data that Machina is making substantial progress towards full autonomy, and even finding ways to improve the process.

An example of the kind of complex metal parts that Machina’s robots are able to make.Machina Labs

Ultimately, Machina wants to use robots to produce all kinds of metal parts. On the commercial side, they’re exploring things like car body panels, offering the option to change how your car looks in geometry rather than just color. The requirement for a couple of beefy robots to make this work means that roboforming is unlikely to become as pervasive as 3D printing, but the broader concept is the same: making physical objects a software problem rather than a hardware problem to enable customization at scale.

An updated Android trojan called FakeCall hijacks bank calls. Tech expert Kurt “CyberGuy" Knutsson says Android phone manufacturers and Google need to step up their game on security.

The asteroid that wiped out dinosaurs after slamming into the Earth 66 million years ago is believed to have come from beyond Jupiter, a new study says.

A stadium-sized asteroid is passing relatively close to Earth on Tuesday, NASA announced. Its distance from Earth and its massive size makes it a "potentially hazardous object."

Scientists in New Mexico conducted several experiments and learned that asteroids can be deflected from Earth using explosions of nuclear warheads above the space rock's surface.

Samples from the asteroid Ryugu contain key ingredients in the biological cookbook.

Earlier this year, Feral Interactive’s superb iOS version of Alien: Isolation (Free) was updated to change the game’s business model …

Continue reading "‘Alien: Isolation’ for Android Is Now a Free To Start Release Just Like iOS Letting Everyone Try Two Missions for Free"

Back in October last year, Feral Interactive announced that cross platform multiplayer was in the works for Company of Heroes …

Continue reading "‘Company of Heroes’ Mobile Multiplayer Beta Announced for Next Week on Android, Full Update Coming to iOS and Switch As Well"

Netflix recently announced more games coming to its service in the coming months, but an unannounced (as far as I’m …

Continue reading "‘SpongeBob: Bubble Pop’ Is a New Bust-a-Move-Like Coming to iOS and Android Through Tic Toc Games, Nickelodeon, and Netflix"

When Square Enix released the monster collecting RPG Dragon Quest Monsters: The Dark Prince on Switch last year, I loved …

Continue reading "‘Dragon Quest Monsters: The Dark Prince’ Is Coming to iOS, Android, and Steam on September 11th With All DLC Included From the Switch Release"

Following pre-installation going live earlier in the week, HoYoverse has just released the major Genshin Impact (Free) version 5.0 “Flowers …

Continue reading "‘Genshin Impact’ Version 5.0 Update Is Now Available Worldwide on iOS, Android, PC, PS5, and More"

It looks like SNK is celebrating the 30th anniversary of the superb The King of Fighters series with a big …

Continue reading "All of SNK’s The King of Fighters ACA NeoGeo Games Are Discounted on iOS and Android, Switch Later Today"

Yesterday during the Nintendo Indie World Partner Direct whatever it is called for the double feature, Red Nexus Games’ pachinko …

Continue reading "The Huge ‘Peglin’ 1.0 Update Is Now Live on iOS, Android, and Steam Following Switch Launch Yesterday"

Last month, GungHo announced a new casual RPG for mobile in the form of Disney Pixel RPG (Free), due later …

Continue reading "Casual RPG ‘Disney Pixel RPG’ From GungHo for iOS and Android Gets New Gameplay Trailer, Listed for October 7th"

Following developer TRAGsoft bringing monster collecting game Coromon to mobile after it debuted on PC and Switch, we are getting …

Continue reading "Roguelite ‘Coromon: Rogue Planet’ in Development for Release on iOS, Android, Switch, and Steam in 2025"

Feral Interactive’s tease seemingly was about Total War: Empire from Creative Assembly and SEGA because the developer just announced that …

Continue reading "‘Total War: Empire’ Is Coming to iOS and Android This Fall From Feral Interactive"

Florence et Marianne seront finalement au concert de leur idole, vendredi, à Toronto, mais elles ont eu toute une frousse.

La majorité des billets encore offerts en ligne pour aller voir Taylor Swift à Toronto sont des arnaques, constate un expert en cybersécurité.

Algiz-RT7 rugged tablet product presentation

Video 1 Preview Image Caption

Northwestern Mutual Honors Moms of Childhood Cancer Patients this Mother�s Day

Amazon's Children's Day Store is now open, featuring an array of products specially discounted for the occasion, including top-selling Android tablets ideal for e-learning. With price reductions of up to 75% on select items such as headphones, tablets, and kids' smartwatches,

Iconic Polaroid Onestep SX-70 now by LEGO bricks...

Asteroids that regularly fly between Earth, Venus and Mars could provide radiation shielding for human missions to explore neighbouring planets

This HaBO is from Krysty, who wants to find this romance: Hi, I stumbled upon your website yesterday hoping someone will help me find this book. It’s been in my head for over 10 years and I’m beginning to forget. So the book is about a heroine – Marianne or Mary – can’t quite remember, falls in love with a brooding, standoffish hero with a scarred face who stays in the dark in a big … Continue reading HaBO: Yet Another Scarred Hero, Virgin Heroine →

Women diagnosed with medlinksubclinical hypothyroidism/medlink before 21 weeks of pregnancy are four times more likely to develop full-blown medlinkthyroid

Doctors at King George's Medical University (KGMU) have successfully removed a massive four-kg fibroid (!--ref1--) tumor from the uterus of a 30-year-old woman.

Routine use of medlinkthyroid hormones/medlink in deceased organ donors, aimed at preserving organ function for transplantation, may be ineffective

Learn how systemic glucocorticoids, used for treating inflammatory conditions, are linked to a significantly higher risk of new-onset diabetes.

Grosvenor and EIH London Investments Ltd have today announced that South Molton, in London’s prestigious Mayfair, will be home to the Indian luxury hospitality group’s first Oberoi Hotel in the UK. Located on a prominent corner at 40-46 Brook Street, the hotel is poised to become Mayfair’s premier luxury boutique hotel, showcasing Oberoi’s iconic design, world-class service, and attention to detail. Grosvenor secured planning permission for the restoration of the 33,000 sq. ft Listed Building in 2022, as part of its wider South Molton development. This landmark project, currently the West End’s largest mixed-use development, will include the hotel, new office space, housing, cafes, shops, restaurants, community, and leisure spaces, all set within a rejuvenated public realm. At the heart of the project is a 267,000 sq. ft joint venture between Grosvenor and Mitsui Fudosan UK, set to deliver two best-in-class office buildings on Brook Street and Davies Street, offering corporate headqua...

Threat type: Backdoor

Aliases:

Platforms: Android

Overall Risk Rating: High

Damage Potential: Low

Distribution Potential: Low

Reported Infection: Low

Information Exposure: High

Overview:

As Samsung unveiled its new Galaxy S24 line today, Google announced a series of new AI features that are launching for Android Auto, which is the secondary interface that brings the look and functions of a smartphone, like navigation and messaging, to your vehicle’s infotainment screen. Google says that with the help of AI, Android […]

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