Pregnane X receptor (PXR) belongs to the nuclear receptor superfamily that plays a crucial role in hepatic physiologic and pathologic conditions. Phase separation is a process in which biomacromolecules aggregate and condense into a dense phase as liquid condensates and coexist with a dilute phase, contributing to various cellular and biologic functions. Until now, whether PXR could undergo phase separation remains unclear. This study aimed to investigate whether PXR undergoes phase separation. Analysis of the intrinsically disordered regions (IDRs) using algorithm tools indicated a low propensity of PXR to undergo phase separation. Experimental assays such as hyperosmotic stress, agonist treatment, and optoDroplets assay demonstrated the absence of phase separation for PXR. OptoDroplets assay revealed the inability of the fusion protein of Cry2 with PXR to form condensates upon blue light stimulation. Moreover, phase separation of PXR did not occur even though the mRNA and protein expression levels of PXR target, cytochrome P450 3A4, changed after sorbitol treatment. In conclusion, for the first time, these findings suggested that exogenous PXR does not undergo phase separation following activation or under hyperosmotic stress in nucleus of cells.

ABSTRACTThe private health care sector is an important source of service delivery in low- and middle-income countries (LMICs). Yet, the private sector remains fragmented, making it difficult for health system actors to support and ensure the availability of quality health care services. In global health programs, social franchising is one model used to engage and organize the private health care sector. Two social franchise networks, ProFam in West Africa and Tunza in East and Central Africa, provide health care through branded networks of facilities. However, these social franchise networks include a limited number of private health care facilities, and in fragile contexts, like Burundi and Mali, they have faced challenges in integrating with national health systems. The MOMENTUM Private Healthcare Delivery (MPHD) project in Burundi and Mali sought to expand the number of health facilities it engaged beyond the existing ProFam and Tunza networks. The expansion aimed to help improve service quality in more private facilities while advancing localization and reducing fragmentation for improved stewardship by health system actors. MPHD achieved this expansion by removing barriers for private health facilities to join inclusive, nonbranded networks and engaging local partners to build and maintain these networks. We share lessons learned regarding the growing role of local organizations as actors within mixed health systems and provide insights on strengthening stewardship of the increasingly heterogeneous private health care delivery sector in LMICs, particularly in fragile settings.

Although acute inflammation serves essential functions in maintaining tissue homeostasis, chronic inflammation is causally linked to many diseases. Macrophages are a major cell type that orchestrates inflammatory processes. During inflammation, macrophages undergo polarization and activation, thereby mobilizing pro-inflammatory and anti-inflammatory transcriptional programs that regulate ensuing macrophage functions. Fatty acid binding protein 5 (FABP5) is a lipid chaperone highly expressed in macrophages. FABP5 deletion is implicated in driving macrophages toward an anti-inflammatory phenotype, yet signaling pathways regulated by macrophage-FABP5 have not been systematically profiled. We leveraged proteomic and phosphoproteomic approaches to characterize pathways modulated by FABP5 in M1 and M2 polarized bone marrow-derived macrophages (BMDMs). Stable isotope labeling by amino acids-based analysis of M1 and M2 polarized wild-type and FABP5 knockout BMDMs revealed numerous differentially regulated proteins and phosphoproteins. FABP5 deletion impacted downstream pathways associated with inflammation, cytokine production, oxidative stress, and kinase activity. Toll-like receptor 2 (TLR2) emerged as a novel target of FABP5 and pharmacological FABP5 inhibition blunted TLR2-mediated activation of downstream pathways, ascribing a novel role for FABP5 in TLR2 signaling. This study represents a comprehensive characterization of the impact of FABP5 deletion on the proteomic and phosphoproteomic landscape of M1 and M2 polarized BMDMs. Loss of FABP5 altered pathways implicated in inflammatory responses, macrophage function, and TLR2 signaling. This work provides a foundation for future studies seeking to investigate the therapeutic potential of FABP5 inhibition in pathophysiological states resulting from dysregulated inflammatory signaling.

Low-efficacy mu opioid receptor (MOR) agonists may serve as novel candidate analgesics with improved safety relative to high-efficacy opioids. This study used a recently validated assay of pain-depressed behavior in mice to evaluate a novel series of MOR-selective C9-substituted phenylmorphan opioids with graded MOR efficacies. Intraperitoneal injection of dilute lactic acid (IP acid) served as a noxious stimulus to depress locomotor activity by mice in an activity chamber composed of two compartments connected by an obstructed door. Behavioral measures included (1) crosses between compartments (vertical activity over the obstruction) and (2) movement counts quantified as photobeam breaks summed across compartments (horizontal activity). Each drug was tested alone and as a pretreatment to IP acid. A charcoal-meal test and whole-body-plethysmography assessment of breathing in 5% CO₂ were also used to assess gastrointestinal (GI) inhibition and respiratory depression, respectively. IP acid produced a concentration-dependent depression in crosses and movement that was optimally alleviated by intermediate- to low-efficacy phenylmorphans with sufficient efficacy to produce analgesia with minimal locomotor disruption. Follow-up studies with two low-efficacy phenylmorphans (JL-2-39 and DC-1-76.1) indicated that both drugs produced naltrexone-reversible antinociception with a rapid onset and a duration of ~1 h. Potency of both drugs increased when behavior was depressed by a lower IP-acid concentration, and neither drug alleviated behavioral depression by a non-pain stimulus (IP lithium chloride). Both drugs produced weaker GI inhibition and respiratory depression than fentanyl and attenuated fentanyl-induced GI inhibition and respiratory depression. Results support further consideration of selective, low-efficacy MOR agonists as candidate analgesics.

In Canada and across the globe, access to PSMA PET/CT is limited and expensive. For patients with biochemical recurrence (BCR) after treatment for prostate cancer, novel strategies are needed to better stratify patients who may or may not benefit from a PSMA PET scan. The role of the free-to-total prostate-specific antigen (PSA) ratio (FPSAR) in posttreatment prostate cancer, specifically in the PSMA PET/CT era, remains unknown. Our aim in this study was to determine the association of FPSAR in patients referred for ¹⁸F-DCFPyL PSMA PET/CT in the BCR setting and assess the correlation between FPSAR and ¹⁸F-DCFPyL PSMA PET/CT positivity (local recurrence or distant metastases). Methods: This prospective study included 137 patients who were referred for ¹⁸F-DCFPyL PSMA PET/CT and had BCR with a total PSA of less than 1 ng/mL after radical prostatectomy (RP) (including adjuvant or salvage radiotherapy). Blood samples were collected on the day of ¹⁸F-DCFPyL PSMA PET/CT. FPSAR was categorized as less than 0.10 or as 0.10 or more. A positive ¹⁸F-DCFPyL PSMA PET/CT scan was defined by a PROMISE classification lesion score of 2 or 3, irrespective of the site of increased tracer uptake (e.g., prostate, pelvic nodes, bone, or viscera). Results: Overall, 137 blood samples of patients with BCR after RP were analyzed to calculate FPSAR. The median age at ¹⁸F-DCFPyL PSMA PET/CT was 68.6 y (interquartile range, 63.0–72.4 y), and the median PSA at ¹⁸F-DCFPyL PSMA PET/CT was 0.3 ng/mL (interquartile range, 0.3–0.6 ng/mL). Eighty-six patients (62.8%) had an FPSAR of less than 0.10, whereas 51 patients (37.2%) had an FPSAR of 0.10 or more. An FPSAR of 0.10 or more was identified as an independent predictor of a positive ¹⁸F-DCFPyL PSMA PET/CT scan, with an odds ratio of 6.99 (95% CI, 2.96–16.51; P < 0.001). Conclusion: An FPSAR of 0.10 or more after RP independently correlated with increased odds of a positive ¹⁸F-DCFPyL PSMA PET/CT scan among BCR post-RP patients. These findings may offer an inexpensive method by which to triage access to ¹⁸F-DCFPyL PSMA PET/CT in jurisdictions where availability is not replete.

Understanding the differences between prognostic and predictive indices is imperative for medical research advances. We have developed a new prognostic measure that will identify the strengths, limitations, and potential applications in clinical practice.

Our knowledge of the roles of individual cytochrome P450 (P450) enzymes in drug metabolism has developed considerably in the past 30 years, and this base has been of considerable use in avoiding serious issues with drug interactions and issues due to variations. Some newer approaches are being considered for "phenotyping" metabolism reactions with new drug candidates. Endogenous biomarkers are being used for noninvasive estimation of levels of individual P450 enzymes. There is also the matter of some remaining "orphan" P450s, which have yet to be assigned reactions. Practical problems that continue in drug development include predicting drug-drug interactions, predicting the effects of polymorphic and other P450 variations, and evaluating interspecies differences in drug metabolism, particularly in the context of "metabolism in safety testing" regulatory issues ["disproportionate (human) metabolites"].

BACKGROUND AND PURPOSE:

A cleftlike nonenhancing hypointensity was observed repeatedly in the pituitary gland at the adenohypophysis/neurohypophysis border on contrast-enhanced 3D fat-saturated T1-MPRAGE using clinical 7T MRI. Our primary goal was to assess the prevalence of this finding. The secondary goals were to evaluate the frequency of other incidental pituitary lesions, MRI artifacts, and their effect on pituitary imaging on the contrast-enhanced 3D fat-saturated T1 MPRAGE at 7T.

BACKGROUND AND PURPOSE:

Incidental findings on brain MRI and variations of the circle of Willis (CoW) are relatively common among the general population. Ethnic differences have been described before, but few studies have explored the prevalence of incidental intracranial cerebrovascular findings and CoW variants in the setting of a single multiethnic cohort. The purpose of this investigation was to describe both incidental cerebrovascular findings and the morphology of the CoW on high-resolution 3T TOF-MRA in a UK tri-ethnic population-based cohort and to present updated prevalence estimates and morphologic reference values.

Imaging methods are fundamental tools to detect and diagnose lung diseases, monitor their treatment and detect possible complications. Each modality, starting from classical chest radiographs and computed tomography, as well as the ever more popular and easily available thoracic ultrasound, magnetic resonance imaging and nuclear medicine methods, and new techniques such as photon counting computed tomography, radiomics and application of artificial intelligence, has its strong and weak points, which we should be familiar with to properly choose between the methods and interpret their results. In this review, we present the indications, strengths and main limitations of methods for chest imaging.

Writer-director partners Scott Beck and Bryan Woods dive into the biggest spoilers of their new Hugh Grant thriller.

The Herald understands that former first minister Nicola Sturgeon has made no decisions on whether she will stand for election in 2026.

"I hear journalists are wondering if I’ve put my name in for the Scottish Parliament. Big news re 2026 coming in the next hour…watch this space."

Josh has a decently sized angry cat burrito. Kelley butters the wolf in Rune Factory. Chris wonders if people have phones. But we all agree the new trend in game graphics should be soulshading.

The post RPG Cast – Episode 628: “Air Conditioning for Your Feet” appeared first on RPGamer.

Jason and Robert have a weeb-off. Kelley dies for two days and wakes up in her own sweat. Chris goes to a store that's half comics, half anime, and half body pillows. Bullseye!

The post RPG Cast – Episode 674: “Stop Sending Dragons, I Have Things to Do” appeared first on RPGamer.

Sam brings the sexy back to RPG Cast. Chris goes down the rabbit hole of Skyrim Mods. Kelley's cannon stuffs kids into itself. And Josh collects a series of progressively larger vegetables.

The post RPG Cast – Episode 676: “Sending All Our Love to the Korok Down the Well” appeared first on RPGamer.

Josh learns that despite Bethesda's best efforts, Starfield is not Fallout 76. Robert learns the taste of Amiibo blood. Chris is just here to ask, "kink-why?" And Kelley is obsessed with Red XIII on a chocobo.

The post RPG Cast – Episode 692: “Vending Machine Isekai” appeared first on RPGamer.

Chris requires pirate games to be on the ocean. Kelley's over capybaras. Josh is betrayed by his potato peeler's safety guard. Also, everybody hates Wakka.

The post RPG Cast – Episode 737: “India’s Best Divorce Lawyer” appeared first on RPGamer.

Chris eats around dirty grapes. Kelley plays the goose class of Monster Hunter. Ryan runs out of disc space until he deletes a Rogue Trader save file. Don't get distracted by salsa.

The post RPG Cast – Episode 745: “The Shipwreck Ending” appeared first on RPGamer.

ublisher Bethesda Softworks and developer MachineGames have released a gameplay deep dive video for Indiana Jones and the Great Circle that is nearly 15 minutes in length.

"From locations and puzzles to gear and combat, MachineGames Audio Director, Pete Ward, takes us on a whirlwind journey through the world of The Great Circle," reads the description to the video. "Get ready for launch with this look at Indy’s grand adventure."

View the gameplay deep dive below:

Indiana Jones and the Great Circle will launch for the Xbox Series X|S, PC via Steam and Microsoft Store, and Xbox Game Pass on December 9.

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/463033/indiana-jones-and-the-great-circle-gets-gameplay-deep-dive/

Beloved roguelike traumatic-childhood-em-up The Binding Of Issac: Rebirth turned 10 yesterday, and it’s half off on Steam to celebrate. What’s more, maker Edmund McMillen has announced that the foretold online co-op update is due on the 18th of this month, alongside a “considerable” balance update. Consider me considering the considerability of said considerable update!

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Here’s a Steam quote for you: ‘The Rise Of The Golden Idol is the best game I’ve ever played where I spent most of my time staring at the screen going “well what chuffing well is it, then?!” Fiendish but fair, this detective puzzler demands a heady mix of observation, deduction, and logic, but rewards you with a progressively engaging story, and steadily more infuriatingly brilliant puzzles. Despite teaching you everything you need to know in the tutorial, it still manages to introduce new wrinkles and twists on the formula with each fresh chapter. My verdict? Imagine me lying my floor, massaging my temple with one hand and giving a fat thumbs up with the other.

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A grand jury has formally charged a 22-year-old man with capital murder and rape in the death of Nabra Hassanen, who was killed on her walk back to a Virginia mosque.

The Fairfax County Circuit Court indicted Darwin Martinez-Torres of Sterling, Virginia, on Monday on four counts of capital murder for killing Nabra, who was with friends while they had a meal before Ramadan services. Dozens of people had gathered outside the courthouse today, chanting “Justice for Nabra.”

Virginia law has specific conditions for pursuing the death penalty, but the Associated Press reported that the grand jury’s indictment described in graphic detail how Nabra’s killing was grounds for a death penalty against Martinez-Torres. The indictment appears to acknowledge for the first time that the 17-year-old Muslim teen was raped. Under state law, the combination of a rape charge with a premeditated murder charge means the death penalty can be pursued.

Police have said that Martinez-Torres, who is an undocumented immigrant, got into a confrontation on June 18 with a group of teens walking back to the All Dulles Area Muslim Society after grabbing a late meal. He is accused of returning later and beating Nabra with a baseball bat. Police said Nabra’s body was later discovered in a pond. A search warrant affidavit revealed that Martinez-Torres admitted to killing Nabra and had led authorities to where he dumped her body, AP reported.

Nabra’s parents and Muslim advocates have said that Nabra’s death was motivated by hate, but police has said that they will not treat the killing as a hate crime. Instead, police have said it was a road rage incident.

“The reason this guy he hit my daughter is because she’s Muslim,” Nabra’s father Mahmoud Hassanen told WAMU. “Why [didn’t he] hit the boy who bothered him?”

Nabra’s father added that he hoped for the death penalty, while her mother said she wanted Martinez-Torres to serve life in prison.

“I just want people to remember her, and don’t forget her,” Mahmoud told WAMU. “I think nobody can forget her too, for what she did in her life.”

A preliminary hearing for Martinez-Torres reportedly turned emotional on Friday, with Nabra’s parents both shouting at the suspect in court. Nabra’s mother Sawsan Gazzar apparently threw a shoe at Martinez-Torres during the proceedings.

READ MORE: D.C. memorial for slain Muslim teen was set on fire, officials say

The post Man accused of killing Muslim teen indicted on capital murder charges appeared first on PBS NewsHour.

New research has revealed a growing mental phenomena sweeping the UK, which may only affect those with a certain income

Researchers recently found a possible reservoir of liquid water more than 11 kilometres below Mars's surface – the latest in a long series of potential water discoveries on the Red Planet, hinting at its temperate past

Planets that orbit close to their parent stars are blasted with radiation and contorted by gravity – and the exoplanet TOI-6255b might be the most extreme example yet

Past observations have indicated that the icy moon of Jupiter has a vast subsurface ocean. Launching in October, NASA’s Europa Clipper will go there in search of evidence that it could support life

Space missions are extremely hard. Things going wrong should be expected, so having a sensible plan B is crucial

“It might feel like 2064 on the surface, but in its nostalgic, rechargeable heart, the show parties like it’s 1999.”

A new report by OpenTheBooks reveals that the Health and Human Services Department (HHS) employs 294 people in diversity-focused positions, with 182 of them earning six-figure salaries.

… Junior Asia/ Oceania Davis Cup and Fed Cup final qualifying event. The … players selected for the Junior Davis Cup include Dev V. Javia, Sandeep … Gogoi (reserve). The Junior Fed Cup team includes Anisha Kashyap, Bhakti … Junior Asia/ Oceania Junior Davis Cup will begin in Kuching, Malaysia ….

If rumours are true and this one should be, I started it, we have a special edition of the Weekend show where we talk about the evolution of the role of the CIO with two incredible CIOs as the CIO Association of Canada turns 20. Don’t miss it.  MUSIC UP Can HP make you love […]

In Canada, your IP address has the right to remain silent. Elon Musk is suing OpenAI for not being Open. Apple faces a class action not allowing competitive access to backup services and the World Server Throwing Competition in March 2024 is accused of being too violent towards servers.   All this and more on the […]

Apple Music gives a whole new meaning to the phrase the hits just keep on coming.  It’s not the opposing candidates, it’s public AI systems that are spreading election disinformation, and LockBit, the cybercriminal gang may be back from the dead and saying so long to the ChatGPT plugins, which went from innovation to legacy […]

Imagine a world without Facebook. For just half an hour. A group of AI leaders get together but don’t seem to invite Elon Musk. Amazon takes data centres nuclear. A new competitor for ChatGPT and Google. And public trust in AI is declining.  All this and more on the “just breath, Facebook will be back” […]

A massive NASA spacecraft is ready to set sail for Jupiter and its moon Europa. The craft, named Europa Clipper, will determine if conditions there could support life.

Loneliness was long thought to cause health conditions ranging from diabetes to cardiovascular disease, but new research paints a more nuanced picture

New research into the moments between wakefulness and sleep could bring hope for insomniacs and even make us more creative problem-solvers

A new study by the Centers for Disease Control and Prevention found that some dairy farm employees showed signs of infection, even when they didn’t report feeling sick. The CDC concluded that more bird flu testing of dairy farm employees is required. According to Dr. Nirav Shah, the CDC’s principal... Continue Reading

Several trade associations have called on European policymakers to reconsider the EU-Mercosur trade deal following findings from an audit in Brazil. The EU-Mercosur deal is an agreement between the European Union and Argentina, Brazil, Paraguay and Uruguay. A recently published audit report by DG Sante revealed Brazil’s issues in meeting European food... Continue Reading

The Dallas Cowboys quarterback got another opinion on his hamstring and decided that surgery would be the best way to address the injury.

Senate Republicans met on Tuesday night to hear from the three candidates to succeed Mitch McConnell, and Rick Scott left with two new endorsements.

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Read on for everything you should know about the history-making politician.

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Officials in New York City have quietly told hundreds of migrants that the city will stop funding hotels in upstate Albany in December.

The post NYC Warns Migrants Funding for Upstate Hotel Rooms Is Ending appeared first on Breitbart.

Republican Senators huddled for over two hours Tuesday night for a family meeting over who will take the reins from Sen. Mitch McConnell (R-KY).

The post Republican Senators Hold Leader Candidate Forum Hours Before Consequential Vote appeared first on Breitbart.