Mitochondrial dysfunction is a hallmark of many genetic neurodegenerative diseases, but therapeutic options to reverse mitochondrial dysfunction are limited. While recent studies support the possibility of improving mitochondrial fusion/fission dynamics and motility to correct mitochondrial dysfunction and resulting neurodegeneration in Charcot-Marie-Tooth disease (CMT) and other neuropathies, the clinical utility of reported compounds and relevance of preclinical models are uncertain. Here, we describe motor and sensory neuron dysfunction characteristic of clinical CMT type 2 A in a CRISPR/Casp-engineered Mfn2 Thr105Met (T105M) mutant knock-in mouse. We further demonstrate that daily oral treatment with a novel mitofusin activator derived from the natural product piperine can reverse these neurologic phenotypes. Piperine derivative 8015 promoted mitochondrial fusion and motility in Mfn2-deficient cells in a mitofusin-dependent manner and reversed mitochondrial dysfunction in cultured fibroblasts and reprogrammed motor neurons from a human CMT2A patient carrying the MFN2 T105M mutation. Like previous mitofusin activators, 8015 exhibited stereospecific functionality, but the more active stereoisomer, 8015-P2, is unique in that it has subnanomolar potency and undergoes entero-hepatic recirculation which extends its in vivo half-life. Daily administration of 8015-P2 to Mfn2 T105M knock-in mice for 6 weeks normalized neuromuscular and sensory dysfunction and corrected histological/ultrastructural neurodegeneration and neurogenic myoatrophy. These studies describe a more clinically relevant mouse model of CMT2A and an improved mitofusin activator derived from piperine. We posit that 8015-P2 and other piperine derivatives may benefit CMT2A or other neurodegenerative conditions wherein mitochondrial dysdynamism plays a contributory role.

Neuropathic pain is a form of chronic pain that develops because of damage to the nervous system. Treatment of neuropathic pain is often incompletely effective, and most available therapeutics have only moderate efficacy and present side effects that limit their use. Opioids are commonly prescribed for the management of neuropathic pain despite equivocal results in clinical studies and significant abuse potential. Thus, neuropathic pain represents an area of critical unmet medical need, and novel classes of therapeutics with improved efficacy and safety profiles are urgently needed. The cannabidiol structural analog and novel antagonist of GPR55, KLS-13019, was screened in rat models of neuropathic pain. Tactile sensitivity associated with chemotherapy exposure was induced in rats with once-daily 1-mg/kg paclitaxel injections for 4 days or 5 mg/kg oxaliplatin every third day for 1 week. Rats were then administered KLS-13019 or comparator drugs on day 7 in an acute dosing paradigm or days 7–10 in a chronic dosing paradigm, and mechanical or cold allodynia was assessed. Allodynia was reversed in a dose-dependent manner in the rats treated with KLS-13019, with the highest dose reverting the response to prepaclitaxel injection baseline levels with both intraperitoneal and oral administration after acute dosing. In the chronic dosing paradigm, four consecutive doses of KLS-13019 completely reversed allodynia for the duration of the phenotype in control animals. Additionally, coadministration of KLS-13019 with paclitaxel prevented the allodynic phenotype from developing. Together, these data suggest that KLS-13019 represents a potential new drug for the treatment of neuropathic pain.

Targeting the endocannabinoid (eCB) signaling system for pain relief is an important treatment option that is only now beginning to be mechanistically explored. In this review, we focus on two recently appreciated cannabinoid-based targeting strategies, treatments with cannabidiol (CBD) and α/β-hydrolase domain containing 6 (ABHD6) inhibitors, which have the exciting potential to produce pain relief through distinct mechanisms of action and without intoxication. We review evidence on plant-derived cannabinoids for pain, with an emphasis on CBD and its multiple molecular targets expressed in pain pathways. We also discuss the function of eCB signaling in regulating pain responses and the therapeutic promises of inhibitors targeting ABHD6, a 2-arachidonoylglycerol (2-AG)-hydrolyzing enzyme. Finally, we discuss how the novel cannabinoid biosensor GRAB_eCB2.0 may be leveraged to enable the discovery of targets modulated by cannabinoids at a circuit-specific level.

The diagnostic work-up of patients with fever of unknown origin (FUO) begins with a thorough history and physical examination, complete blood count with differential, chest x-ray, urinalysis and culture, electrolyte panel, liver enzymes, erythrocyte sedimentation rate, and C-reactive protein level. Additional imaging procedures, including nuclear medicine tests, are generally used as second-line procedures, with ¹⁸F-FDG PET and PET/CT assuming increasingly important roles in the diagnostic work-up. The Society of Nuclear Medicine and Molecular Imaging, the Infectious Diseases Society of America, and the American College of Nuclear Medicine convened an autonomous expert work group to comprehensively review the published literature for nuclear imaging in adults and children with FUO and establish appropriate use criteria (AUC). This process was performed in accordance with the Protecting Access to Medicare Act of 2014, which requires that all referring physicians consult AUC by using a clinical decision support mechanism before ordering advanced diagnostic imaging services. The complete findings and discussions of the work group were published on January 8, 2023, and are available at https://www.snmmi.org/ClinicalPractice/content.aspx?ItemNumber=15666. The AUC in the final document are intended to assist referring health care providers in appropriate use of nuclear medicine imaging procedures in patients with FUO. The work group noted limitations in the current literature on nuclear medicine imaging for FUO, with the need for well-designed prospective multicenter investigations. Consensus findings from published data and expert opinions were used to create recommendations in common clinical scenarios for adults and children. Included in the complete document is a discussion of inflammation of unknown origin (IUO), a recently described entity. In view of the fact that the criteria for FUO and IUO are similar (except for fever > 38.3°C [100.9°F]) and that the most common etiologies of these 2 entities are similar, it is the expert opinion of the work group that the recommendations for nuclear medicine imaging of FUO are also applicable to IUO. These recommendations are included in the full guidance document. This summary reviews rationale, methodology, and main findings and refers the reader to the complete AUC document.

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.

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.

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.

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.

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.

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.

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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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.

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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

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

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

It is thought that humans can only maintain relationships with around 150 people, a figure known as Dunbar's number, but it seems that AI models can outstrip this and reach consensus in far bigger groups

Donald Trump will embrace the truth Joe Biden has refused to countenance: Israel's enemies are America's enemies. And when Israel defeats its enemies, America wins.

The Biden administration passed $3 trillion of legislation aimed at revitalizing the American economy and fostering green, equitable, "middle-out" growth.

From Goats to airplanes, Xbox Game Pass has another bumper month in store for subscribers. Here's everything you need to know about what is heading to PC and console this November 2024

Black Ops 6 is here, and fans have been itching to know what's included in Season 1 - and now we have an answer. Here's what's included, and when you can play

PS5 owners can play some great games this month, including a Bethesda hit and more. Here's what's free for PS Plus subscribers for November, with more to be announced.

Hackers are exploiting EA FC 25 to nab millions of coins and snipe the world's best football players and EA seems unable to stop it - and this is how it happens

Cement is ubiquitous, but the process of making it emits carbon into the atmosphere. The industry says there's no easy way to avoid that, which is why it's turning to carbon capture and storage technology as a way to decarbonize.

It’s become a joke to talk about Cave Story and Dark Souls when describing other games, but in the case of Momodora: Reverie Under the Moonlight, I’d be remiss not to: the series has never been shy about its influences. In Reverie, the fourth game of the Momodora series, rdein has done a fantastic job […]

The sun blasted a coronal mass at Earth earlier this week, and after back-to-back major hurricanes, some are concerned it could impact the power grid.

The identification of a new hominin group called Denisovans was one of the most exciting discoveries in human evolution in the last decade.

The post Several Denisovan Populations Introgressed into Modern Humans Multiple Times: Study appeared first on Sci.News: Breaking Science News.

The World Health Organization has declared mpox a public health emergency of international concern – a new variant of the virus has caused an outbreak in Central and West Africa and spread to Sweden

I am one of millions of vapers in the UK, but growing evidence of the impact these e-cigarettes have on the environment means it may be time to quit, says Graham Lawton

Male pattern baldness could soon be a thing of the past, with new hair loss treatments beginning to show tantalising results

Health officials in Saskatchewan Canada are urging customers of Domino’s Pizza in Martensville to watch for symptoms of typhoid fever. The restaurant’s customers may have been exposed to Salmonella typhi, also known as typhoid fever. Anyone who consumed food or drink from the Domino’s store at 717 Centennial Drive South... Continue Reading

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First Mac mini redesign in almost 15 years highlights how good the insides are.

Yes, you can nail your own pedicure! But you'll need more than just nail varnish and toenail clippers.

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We spoke to Dr Ian Paul, who is a reverend and member of General Synod and the Archbishops’ Council.