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.

BACKGROUND AND PURPOSE:

Angioplasty and stent placement have been described as a bailout technique in individuals with failed thrombectomy. We aimed to investigate Stent retriever AssIsted Lysis (SAIL) with tirofiban before angioplasty and stent placement.

Although the progressive histologic steps leading to endometrial cancer (EndoCA), the most common female reproductive tract malignancy, from endometrial hyperplasia are well-established, the molecular changes accompanying this malignant transformation in a single patient have never been described. We had the unique opportunity to investigate the paired histologic and molecular features associated with the 12-yr development of EndoCA in a postmenopausal female who could not undergo hysterectomy and instead underwent progesterone treatment. Using a specially designed 58-gene next-generation sequencing panel, we analyzed a total of 10 sequential biopsy samples collected over this time frame. A total of eight pathogenic/likely pathogenic mutations in seven genes, APC, ARID1A, CTNNB1, CDKN2A, KRAS, PTEN, and TP53, were identified. A PTEN nonsense mutation p.W111* was present in all samples analyzed except histologically normal endometrium. Apart from this PTEN mutation, the only other recurrent mutation was KRAS G12D, which was present in six biopsy samplings, including histologically normal tissue obtained at the patient's first visit but not detectable in the cancer. The PTEN p.W111* mutant allele fractions were lowest in benign, inactive endometrial glands (0.7%), highest in adenocarcinoma (36.9%), and, notably, were always markedly reduced following progesterone treatment. To our knowledge, this report provides the first molecular characterization of EndoCA development in a single patient. A single PTEN mutation was present throughout the 12 years of cancer development. Importantly, and with potential significance toward medical and nonsurgical management of EndoCA, progesterone treatments were consistently noted to markedly decrease PTEN mutant allele fractions to precancerous levels.

Electron transport chain (ETC) disorders are a group of rare, multisystem diseases caused by impaired oxidative phosphorylation and energy production. Deficiencies in complex III (CIII), also known as ubiquinol–cytochrome c reductase, are particularly rare in humans. Ubiquinol–cytochrome c reductase core protein 2 (UQCRC2) encodes a subunit of CIII that plays a crucial role in dimerization. Several pathogenic UQCRC2 variants have been identified in patients presenting with metabolic abnormalities that include lactic acidosis, hyperammonemia, hypoglycemia, and organic aciduria. Almost all previously reported UQCRC2-deficient patients exhibited neurodevelopmental involvement, including developmental delays and structural brain anomalies. Here, we describe a girl who presented at 3 yr of age with lactic acidosis, hyperammonemia, and hypoglycemia but has not shown any evidence of neurodevelopmental dysfunction by age 15. Whole-exome sequencing revealed compound heterozygosity for two novel variants in UQCRC2: c.1189G>A; p.Gly397Arg and c.437T>C; p.Phe146Ser. Here, we discuss the patient's clinical presentation and the likely pathogenicity of these two missense variants.

We identified a de novo heterozygous transient receptor potential cation channel subfamily M (melastatin) member 3 (TRPM3) missense variant, p.(Asn1126Asp), in a patient with developmental delay and manifestations of cerebral palsy (CP) using phenotype-driven prioritization analysis of whole-genome sequencing data with Exomiser. The variant is localized in the functionally important ion transport domain of the TRPM3 protein and predicted to impact the protein structure. Our report adds TRPM3 to the list of Mendelian disease–associated genes that can be associated with CP and provides further evidence for the pathogenicity of the variant p.(Asn1126Asp).

Over the past decades the zebrafish has emerged as an excellent model organism with which to study the biology of all glial cell types in nervous system development, plasticity, and regeneration. In this review, which builds on the earlier work by Lyons and Talbot in 2015, we will summarize how the relative ease to manipulate the zebrafish genome and its suitability for intravital imaging have helped understand principles of glial cell biology with a focus on oligodendrocytes, microglia, and astrocytes. We will highlight recent findings on the diverse properties and functions of these glial cell types in the central nervous system and discuss open questions and future directions of the field.

Most childhood cancers possess distinct clinicopathological profiles from those seen in adulthood, reflecting their divergent mechanisms of carcinogenesis. Rather than depending on the decades-long, stepwise accumulation of changes within a mature cell that defines adult carcinomas, many pediatric malignancies emerge rapidly as the consequence of random errors during development. These errors—whether they be genetic, epigenetic, or microenvironmental—characteristically block maturation, resulting in phenotypically primitive neoplasms. Only an event that falls within a narrow set of spatiotemporal parameters will forge a malignant clone; if it occurs too soon then the event might be lethal, or negatively selected against, while if it is too late or in an incorrectly primed precursor cell then the necessary intracellular conditions for transformation will not be met. The precise characterization of these changes, through the study of normal tissues and tumors from patients and model systems, will be essential if we are to develop new strategies to diagnose, treat, and perhaps even prevent childhood cancer.

Vision is initiated by capturing photons in highly specialized sensory cilia known as the photoreceptor outer segment. Because of its lipid and protein composition, the outer segments are prone to photo-oxidation, requiring photoreceptors to have robust antioxidant defenses and high metabolic synthesis rates to regenerate the outer segments every 10 days. Both processes required high levels of glucose uptake and utilization. Retinitis pigmentosa is a prevalent form of inherited retinal degeneration characterized by initial loss of low-light vision caused by the death of rod photoreceptors. In this disease, rods die as a direct effect of an inherited mutation. Following the loss of rods, cones eventually degenerate, resulting in complete blindness. The progression of vision loss in retinitis pigmentosa suggested that rod photoreceptors were necessary to maintain healthy cones. We identified a protein secreted by rods that functions to promote cone survival, and we named it rod-derived cone viability factor (RdCVF). RdCVF is encoded by an alternative splice product of the nucleoredoxin-like 1 (NXNL1) gene, and RdCVF was found to accelerate the uptake of glucose by cones. Without RdCVF, cones eventually die because of compromised glucose uptake and utilization. The NXNL1 gene also encodes for the thioredoxin RdCVFL, which reduces cysteines in photoreceptor proteins that are oxidized, providing a defense against radical oxygen species. We will review here the main steps of discovering this novel intercellular signaling currently under translation as a broad-spectrum treatment for retinitis pigmentosa.

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.

Tim Miller hopes Amazon's anthology series will help viewers appreciate the "blood, sweat, and tears" Firewalk Studios put into the scrapped game.

The head of one of the world's largest oil companies has had it with government flip-flopping.

New research shows that bystander CPR can substantially improve a person's odds of surviving a cardiac arrest while avoiding major brain damage, especially if given immediately.

This is not a joke, the subscription to ExpressVPN is at an unprecedented price. We'll tell you everything you need to know so you don't miss out on its Black Friday offer.

The Scotch whisky distiller has announced a major change

Up to 650 houses could be built on land at the golf club

You can purchase Steven Camley's cartoons by calling 0141 302 7000 or visiting thepicturedesk.co.uk.

The technology will deliver enhanced day-to-day and major incident response capability

The site, on the shores of a famous Scottish loch, has been acquired for a luxury lodge development

Pascal surprises everyone. New challenger Robert appears. Josh makes a triumphant return. Anna Marie leaves to go do important kitten things. Kelley proves she's the best at the Mario's. And Chris still says it's not really an Ys game.

The post RPG Cast – Episode 558: “Never Get on a Boat With Dad” appeared first on RPGamer.

Anna Marie, Chris, and Kelley are joined by special guest Ryan Radcliff! Chris swears every time E3 fails, an angel gets its wings. Anna Marie refuses to play games she's in. Kelley wants to pet the cat cream roll. And Ryan is dragging around Paws's corpse as he spins all the wheels.

The post RPG Cast – Episode 589: “Chaos Never Sleeps” appeared first on RPGamer.

Chris says the quiet things out loud, and challenges Anna Marie to play a gacha game without spending money. Kelley gets distracted by a three-headed monkey, while Josh ponders why the ten rings sounds like Jarvis.

The post RPG Cast – Episode 600: “It’s a HIGH Seven” appeared first on RPGamer.

Kelley puts a price on a good nap. Josh complains about Pokémon (someone has to). And Chris's true Dark Souls adventure begins with his dryer.

The post RPG Cast – Episode 621: “My Elden Ring Fever Dreams” appeared first on RPGamer.

Kelley is creeped out by grown men in diapers. Josh can't name a kaiju that isn't Godzilla or Mothra. And Chris gets an Elden Pacifier since he's never happy.

The post RPG Cast – Episode 647: “Stellar Eve for When You Don’t Feel Fresh” appeared first on RPGamer.

Chris launches his new brand, Elsa coffee. Kelley's Pokémon demand she finds a caramel apple and a teacup. Ryan apparently got left in Seattle and is still at PAX West.

The post RPG Cast – Episode 693: “The Brew Never Bothered Me Anyways” appeared first on RPGamer.

Kelley gets bored and cleans her bathroom. Memories of the Virtual Boy make Josh's eyes hurt. Robert can't stop singing about Albuquerque. Chris, meanwhile, decides to make his own farming sim with coffee shops and old people.

The post RPG Cast – Episode 719: “Good morning, everybody. Hairball!” appeared first on RPGamer.

Ryan slip 'n slides his health away. Robert lives on the side of danger and poor choices in video games. Meanwhile, Chris makes his own bathtub Geralt.

The post RPG Cast – Episode 725: “Not Every Idea in the Factory Is a Good One” appeared first on RPGamer.

Kelley tells us about her new clawed abomination: the cat-raptor. Chris tries to figure out who cross Ross is and why he's so angry. Robert is "surprised" to find horse girls show up on the sheet. Josh is definitely here for the icons.

The post RPG Cast – Episode 730: “Never Played a JRPG” appeared first on RPGamer.

Reverb features new works by Es Devlin and Theaster Gates, plus Devon Turnbull's Listening Room.

The post The Vinyl Factory: Reverb exhibition extended until 22 December appeared first on Fact Magazine.

Up to 700 international competitors and crew will flock to Benalla as the event returns to Australia after 30 years.

A 10-year analysis of air accidents reveals good news for most passengers but worrying trends in training and drones.

Sega has sold Humankind and Endless developer Amplitude Studios to members of its internal team, announced the developer in a community post. This means the studio is now independent.

"Our studio is backed by strong and meaningful franchises and our team is committed to creating the best games possible," said Amplitude Studios founder Romain de Waubert de Genlis.

"With our extensive experiences in strategy game development and two exciting titles currently in progress, we are confident in our ability to deliver outstanding experience to players. This decision allows us to be more agile in our approach while continuing to shape the vision that has been ours from the very beginning, empowering us to push boundaries and be closer as ever of our community."

Sega in its own statement said: "Sega Europe has today announced the sale of Amplitude Studios following a management buyout from senior leaders and employees at the Parisian studio. The move will see Amplitude go back to its roots as an independent organisation and concludes the structural reforms that have been taking place in Sega’s European business.  

"The decision to part ways follows a period of close consultation between Sega Europe and Amplitude. As an independent studio once more, Amplitude will focus on its in-development projects and growing its own franchises, while Sega will continue to advance its strong and diverse stable of Japanese and Western IP. 

“Sega Europe acquired Amplitude in 2016, and together have released epic strategy titles like Endless Space 2 and Humankind, along with Endless Dungeon, the successor to 2014’s indie hit, Dungeon of the Endless.

"While Amplitude is no longer a part of the Sega family of studios, the two entities will continue to work together on the smooth transition of services and operations, ensuring minimum disruption for Amplitude employees and continuity of service for players of Amplitude games."

A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012 and taking over the hardware estimates in 2017. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel. You can contact the author on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/463024/sega-sells-humankind-developer-amplitude-studios/

Neowiz announced it has signed a global publishing rights partnership with Warsaw, Poland-based developer Zakazane to publish the first title from the studio. The game from Zakazane is a single-player noir western RPG.

Zakazane is led by Jan Bartkowicz, Piotr Chomiak, Radosław Gwarek, and Marta Sobek, and features developers who previously worked at central European game companies, including  CD Projekt RED and 11 bit studios.

"Neowiz is committed to delivering remarkable, story-driven games that resonate with gamers worldwide, and we’re actively searching for talented developers with a passion for well-crafted narratives,” said Neowiz co-CEO Seung-Cheol Kim.

"When we first met Zakazane, we felt an immediate kinship around their passion for developing projects that profoundly captivate audiences. Their upcoming neo-western RPG will be a key addition to our portfolio and reflects our ambition to build lasting franchises across PC and consoles. Together, we will create a brand that unites quality and storytelling for gamers to cherish for years to come."

Zakazane CEO and co-founder Jan Barkowicz, "We found a great understanding of our vision with Neowiz, who got excited about our debut title the minute we showed them the demo. In conversations that followed, they never tried to steer us away from our principles but rather to make sure we stick to our guns. It’s clear both sides understand that games can become important to people on a personal level, making them both valuable works of culture and good business."

A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012 and taking over the hardware estimates in 2017. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel. You can contact the author on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/463035/neowiz-to-publish-western-rpg-by-poland-based-developer-zakazane/

Tencent Games subsidiary LightSpeed Studios has announced Hideaki Itsuno, who recently left Capcom after 30 years working for the company, will be leading a new video game studio called LightSpeed Japan Studio.

LightSpeed Japan Studio will have two locations in Tokyo and Osaka and is focused on developing original AAA games.

"Joining LightSpeed Studios is an exciting new chapter for me," said Hideaki Itsuno. "With LightSpeed’s strong development capability and global network, I look forward to creating original AAA action game titles together with the amazing team and building aesthetic and innovative experiences for the global player community. We welcome all talented and passionate game creators from the world over to join our vision."

LightSpeed Studios president Jerry Chen added, "It is our great honor to have Hideaki Itsuno join LightSpeed Studios. The establishment of LightSpeed Japan Studio is a significant step in LightSpeed Studios’ expansion and demonstrates our commitment to bringing the best possible games to our players."

Itsuno directed entries in the Rival Schools, Power Stone, Capcom VS. SNK, Devil May Cry, and Dragon’s Dogma franchises.

A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012 and taking over the hardware estimates in 2017. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel. You can contact the author on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/463041/hideaki-itsuno-to-lead-new-aaa-developer-lightspeed-japan-studio/

Nintendo has announced its Black Friday 2024 deals. 

Dozens of games will be discounted including The Legend of Zelda: Tears of the Kingdom, Super Mario Maker 2, Animal Crossing: New Horizons, Pikmin 4, Nintendo Switch Sports, Kirby and the Forgotten Land, Super Mario Odyssey, Pikmin 1 + 2, and more.

The Neon Red and Neon Blue Joy-Con controllers and the Nintendo Switch Pro Controller will be discounted by $20, while the Nintendo Switch Carrying Case & Screen Protector - The Legend of Zelda: Tears of the Kingdom Edition will be discounted by $10.

The Nintendo Switch: Mario Kart 8 Deluxe Bundle will once again return for $299.99, while the new Nintendo Switch – OLED Model: Mario Kart 8 Deluxe Bundle will be available for $349.99. Both bundles include a digital download of Mario Kart 8 Deluxe and a 12-month Nintendo Switch Online Individual Membership.

The Nintendo Switch Lite: Hyrule Edition with Bonus Nintendo Switch Online + Expansion Pack will be available for $209.99. The bundle includes a 12-month Nintendo Switch Online + Expansion Pack Individual Membership.

A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012 and taking over the hardware estimates in 2017. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel. You can contact the author on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/463045/nintendos-black-friday-2024-deals-revealed/

Relatives of Lyle and Erik Menendez spoke in an interview Wednesday about their long-running fears that the brothers had been abused for years before they killed their parents.

After a press conference in which they’d called for the imprisoned siblings’ freedom, the family members told Chris Cuomo on NewsNation about how their suspicions only deepened as time passed.

“Over the years we really did know that there was abuse at gut-level. But as time goes on and we all talked to each other more and more, it validates the fears and the gut-level reactions that we had,” the brothers’ cousin Karen VanderMolen-Copley told Cuomo. “That solidified the knowledge that the sexual abuse actually did occur, because that’s not something you want to believe, and then once you talk to each other it becomes more and more obvious.”

Read more at The Daily Beast.

Stationeers and Icarus developers RocketWerkz are making a spiritual successor to beloved space sim Kerbal Space Program, which is currently titled "Kitten Space Agency" in a flagrant display of adherence to wholesome internet trends. It's based on an actual Kerbal Space Program 2 pitch the studio threw at Take-Two subsidiary Private Division back in the day. RocketWerkz CEO and original DayZ creator Dean Hall has hired several former KSP and KSP2 developers to work on the game, and is describing it on social media as a "KSP killer".

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I didn't sleep last night for entirely self-inflicted reasons and my brain feels like that one accursed hoover bag you refuse to empty, because there is no way of doing so that won't turn the neighbourhood into Silent Hill. I need to avoid any complicated write-ups, or my brain will detonate similarly and paint north London grey.

Ah, a minigolf game! I think I can just about hack the concept of minigolf, on this most desperate of Mondays. It is golf but mini. Bonzai golf. Digestible! Intuitive! Why, I've managed to write 100 words without even looking at the Steam page. Let's do so now. Wait a minute, this isn't minigolf. It's Mini Mini Golf Golf. What is Mini Mini Golf Golf? "Destabilize the present and plunge into a neon psychohistory of a bizarre entity in distress," the Steam page explains. "This is not a game about minigolf." It is too late to flee.

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When nightmarish sci-fi extraction shooter The Forever Winter launched into early access in September it was somewhat messy. Bugs and maddening enemy spawns diminished the tension of being a fleshy human scavenger in a mech battlefield. But one feature annoyed some players much more - fresh water. See, you need to keep your headquarters stocked with water, as it gets steadily used by your settlement's inhabitants. The catch being that this water diminishes even while you're not playing the game. If it runs out completely, then everything you've collected gets wiped. The developers have listened to complaints about this most Farmville of mechanics, and they've answered in an interesting way. Water thieves! Now, on top of the usual downward trickle, burglars will come to steal your H2O as well.

It's not as bad as it sounds.

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Putting aside my natural annoyance at Metal Gear Solid Delta: Snake Eater for almost beating out the Twarhammer series in the headline real estate wars, I am more than a little excited to play. Some days, you simply must feast on a tree frog, and while we still don’t have a solid release date, that day doesn’t feel too far away. Good news for stealth fans, and perhaps gooder news for a dozen strapline writers sweating profusely, soiling themselves in anticipation of using “kept you waiting, huh?”.

Until then, I at least have a steady drip feed of new information to keep me sated, the latest of which is the substantial hint that there'll be some new dialogue in the game, as per the video below. Alongside that, the previously pseudonymous Suzetta Miñet - who was credited with voicing EVA in MGS3 and Peace Walker - has revealed herself to be Jodi Benson, the voice of Ariel in Disney’s The Little Mermaid. Cheers for the spot, Automaton West.

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Update:

The RPS 100 is our list of the best games to play on PC. It encompasses the full breadth and width of PC gaming stretching back to 1873, but focuses solely on those games that remain great to play today. It's updated yearly by our crack team of writers, and the first half of the 2024 edition is live now.

Read more

A DWP employee who has been working in the welfare system for 42 years has shared some key advice for new claims for the likes of PIP and Attendance Allowance

The failure of Boeing's Starliner capsule has left two astronauts stuck in space for months – but also proved how private spaceflight can go right

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

Using images captured by the European Space Agency’s Mars Express spacecraft, researchers have created a cloud atlas of Mars, to better understand the climate of the Red Planet

The second-closest planet to the sun is more geologically active than we thought and could have more than 17,000 venusquakes a year

A distant planet should have been consumed when its star expanded to become a red giant, perhaps offering insights into planetary migration

The first “failed star” ever discovered has been a weird outlier since it was found nearly 30 years ago. New observations show that it is unusually massive because it isn’t a single star after all