Binding of arbitrary information into distinct memory representations that can be used to guide behavior is a hallmark of relational memory. What is and is not bound into a memory representation and how those things influence the organization of that representation remain topics of interest. While some information is intentionally and effortfully bound—often the information that is consistent with task goals or expectations about what information may be required later—other information appears to be bound automatically. The present set of experiments sought to investigate whether spatial memory would be systematically influenced by the presence and absence of distinct categories of stimuli on a spatial reconstruction task. In this task, participants must learn multiple item-location bindings and place each item back in its studied location after a short delay. Across three experiments, participants made significantly more within-category errors (i.e., misassigning one item to the location of a different item from the same category) than between-category errors (i.e., misassigning one item to the location of an item from a different category) when categories were perceptually or semantically distinct. These data reveal that category information contributed to the organization of the memory representation and influenced spatial reconstruction performance. Together, these results suggest that categorical information can influence memory organization, and not always to the benefit of overall task performance.

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.

SIGNIFICANCE STATEMENT

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. This study reports that in rats gabapentinoids increase the potency of fentanyl and heroin to produce discriminative stimulus effects while decreasing the potency of naloxone to antagonize those effects of fentanyl and heroin. These results can help guide policies for regulating gabapentinoids and treating opioid misuse and overdose.

Cannabinoid and opioid receptor activities can be modulated by a variety of post-translational mechanisms including the formation of interacting complexes. This study examines the involvement of endogenous and exogenous chaperones in modulating the abundance and activity of cannabinoid CB₁ receptor (CB₁R), opioid receptor (DOR), and CB₁R-DOR interacting complexes. Focusing on endogenous protein chaperones, namely receptor transporter proteins (RTPs), we examined relative mRNA expression in the mouse spinal cord and found RTP4 to be expressed at higher levels compared with other RTPs. Next, we assessed the effect of RTP4 on receptor abundance by manipulating RTP4 expression in cell lines. Overexpression of RTP4 causes an increase and knock-down causes a decrease in the levels of CB₁R, DOR, and CB₁R-DOR interacting complexes; this is accompanied by parallel changes in signaling. The ability of small molecule lipophilic ligands to function as exogenous chaperones was examined using receptor-selective antagonists. Long-term treatment leads to increases in receptor abundance and activity with no changes in mRNA supporting a role as pharmacological chaperones. Finally, the effect of cannabidiol (CBD), a small molecule ligand and a major active component of cannabis, on receptor abundance and activity in mice was examined. We find that CBD administration leads to increases in receptor abundance and activity in mouse spinal cord. Together, these results highlight a role for chaperones (proteins and small molecules) in modulating levels and activity of CB₁R, DOR, and their interacting complexes potentially through mechanisms including receptor maturation and trafficking.

SIGNIFICANCE STATEMENT

This study highlights a role for chaperones (endogenous and small membrane-permeable molecules) in modulating levels of cannabinoid CB₁ receptor, delta opioid receptor, and their interacting complexes. These chaperones could be developed as therapeutics for pathologies involving these receptors.

There is a growing interest in the use of medicinal plants to treat a variety of diseases, and one of the most commonly used medicinal plants globally is Cannabis sativa. The two most abundant cannabinoids (⁹-tetrahydrocannabinol and cannabidiol) have been governmentally approved to treat selected medical conditions; however, the plant produces over 100 cannabinoids, including cannabichromene (CBC). Although the cannabinoids share a common precursor molecule, cannabigerol, they are structurally and pharmacologically unique. These differences may engender differing therapeutic potentials. In this review, we will examine what is currently known about CBC with regards to pharmacodynamics, pharmacokinetics, and receptor profile. We will also discuss the therapeutic areas that have been examined for this cannabinoid, notably antinociceptive, antibacterial, and anti-seizure activities. Finally, we will discuss areas where new research is needed and potential novel medicinal applications for CBC.

SIGNIFICANCE STATEMENT

Cannabichromene (CBC) has been suggested to have disparate therapeutic benefits such as anti-inflammatory, anticonvulsant, antibacterial, and antinociceptive effects. Most of the focus on the medical benefits of cannabinoids has been focused on ⁹-tetrahydrocannabinol and cannabidiol. The preliminary studies on CBC indicate that this phytocannabinoid may have unique therapeutic potential that warrants further investigation. Following easier access to hemp, CBC products are commercially available over-the-counter and are being widely utilized with little or no evidence of their safety or efficacy.

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.

SIGNIFICANCE STATEMENT

Cannabis has been used by humans as an effective medicine for millennia, including for pain management. Recent evidence emphasizes the therapeutic potential of compounds that modulate endocannabinoid signaling. Specifically, cannabidiol and inhibitors of the enzyme ABHD6 represent promising strategies to achieve pain relief by modulating endocannabinoid signaling in pain pathways via distinct, nonintoxicating mechanisms of action.

Historically, the intestinal lymphatics were considered passive conduits for fluids, immune cells, dietary lipids, lipid soluble vitamins, and lipophilic drugs. Studies of intestinal lymphatic drug delivery in the late 20th century focused primarily on the drugs’ physicochemical properties, especially high lipophilicity, that resulted in intestinal lymphatic transport. More recent discoveries have changed our traditional view by demonstrating that the lymphatics are active, plastic, and tissue-specific players in a range of biological and pathological processes, including within the intestine. These findings have, in turn, inspired exploration of lymph-specific therapies for a range of diseases, as well as the development of more sophisticated strategies to actively deliver drugs or vaccines to the intestinal lymph, including a range of nanotechnologies, lipid prodrugs, and lipid-conjugated materials that "hitchhike" onto lymphatic transport pathways. With the increasing development of novel therapeutics such as biologics, there has been interest in whether these therapeutics are absorbed and transported through intestinal lymph after oral administration. Here we review the current state of understanding of the anatomy and physiology of the gastrointestinal lymphatic system in health and disease, with a focus on aspects relevant to drug delivery. We summarize the current state-of-the-art approaches to deliver drugs and quantify their uptake into the intestinal lymphatic system. Finally, and excitingly, we discuss recent examples of significant pharmacokinetic and therapeutic benefits achieved via intestinal lymphatic drug delivery. We also propose approaches to advance the development and clinical application of intestinal lymphatic delivery strategies in the future.

Significance Statement

This comprehensive review details the understanding of the anatomy and physiology of the intestinal lymphatic system in health and disease, with a focus on aspects relevant to drug delivery. It highlights current state-of-the-art approaches to deliver drugs to the intestinal lymphatics and the shift toward the use of these strategies to achieve pharmacokinetic and therapeutic benefits for patients.

Over 4 decades of research support the link between Alzheimer disease (AD) and somatostatin [somatotropin-releasing inhibitory factor (SRIF)]. SRIF and SRIF-expressing neurons play an essential role in brain function, modulating hippocampal activity and memory formation. Loss of SRIF and SRIF-expressing neurons in the brain rests at the center of a series of interdependent pathological events driven by amyloid-β peptide (Aβ), culminating in cognitive decline and dementia. The connection between the SRIF and AD further extends to the neuropsychiatric symptoms, seizure activity, and inflammation, whereas preclinical AD investigations show SRIF or SRIF receptor agonist administration capable of enhancing cognition. SRIF receptor subtype-4 activation in particular presents unique attributes, with the potential to mitigate learning and memory decline, reduce comorbid symptoms, and enhance enzymatic degradation of Aβ in the brain. Here, we review the links between SRIF and AD along with the therapeutic implications.

Significance Statement

Somatostatin and somatostatin-expressing neurons in the brain are extensively involved in cognition. Loss of somatostatin and somatostatin-expressing neurons in Alzheimer disease rests at the center of a series of interdependent pathological events contributing to cognitive decline and dementia. Targeting somatostatin-mediated processes has significant therapeutic potential for the treatment of Alzheimer disease.

α-Synuclein (α-Syn) aggregation in Lewy bodies and Lewy neurites has emerged as a key pathogenetic feature in Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Various factors, including posttranslational modifications (PTMs), can influence the propensity of α-Syn to misfold and aggregate. PTMs are biochemical modifications of a protein that occur during or after translation and are typically mediated by enzymes. PTMs modulate several characteristics of proteins including their structure, activity, localization, and stability. α-Syn undergoes various posttranslational modifications, including phosphorylation, ubiquitination, SUMOylation, acetylation, glycation, O-GlcNAcylation, nitration, oxidation, polyamination, arginylation, and truncation. Different PTMs of a protein can physically interact with one another or work together to influence a particular physiological or pathological feature in a process known as PTMs crosstalk. The development of detection techniques for the cooccurrence of PTMs in recent years has uncovered previously unappreciated mechanisms of their crosstalk. This has led to the emergence of evidence supporting an association between α-Syn PTMs crosstalk and synucleinopathies. In this review, we provide a comprehensive evaluation of α-Syn PTMs, their impact on misfolding and pathogenicity, the pharmacological means of targeting them, and their potential as biomarkers of disease. We also highlight the importance of the crosstalk between these PTMs in α-Syn function and aggregation. Insight into these PTMS and the complexities of their crosstalk can improve our understanding of the pathogenesis of synucleinopathies and identify novel targets of therapeutic potential.

Significance Statement

α-Synuclein is a key pathogenic protein in Parkinson’s disease and other synucleinopathies, making it a leading therapeutic target for disease modification. Multiple posttranslational modifications occur at various sites in α-Synuclein and alter its biophysical and pathological properties, some interacting with one another to add to the complexity of the pathogenicity of this protein. This review details these modifications, their implications in disease, and potential therapeutic opportunities.

Both preclinical and clinical studies implicate functional impairments of several neuroactive metabolites of the kynurenine pathway (KP), the major degradative cascade of the essential amino acid tryptophan in mammals, in the pathophysiology of neurologic and psychiatric diseases. A number of KP enzymes, such as tryptophan 2,3-dioxygenase (TDO2), indoleamine 2,3-dioxygenases (IDO1 and IDO2), kynurenine aminotransferases (KATs), kynurenine 3-monooxygenase (KMO), 3-hydroxyanthranilic acid oxygenase (3-HAO), and quinolinic acid phosphoribosyltransferase (QPRT), control brain KP metabolism in health and disease and are therefore increasingly considered to be promising targets for the treatment of disorders of the nervous system. Understanding the distribution, cellular expression, and regulation of KP enzymes and KP metabolites in the brain is therefore critical for the conceptualization and implementation of successful therapeutic strategies.

Significance Statement

Studies have implicated the kynurenine pathway of tryptophan in the pathophysiology of neurologic and psychiatric diseases. Key enzymes of the kynurenine pathway regulate brain metabolism in both health and disease, making them promising targets for treating these disorders. Therefore, understanding the distribution, cellular expression, and regulation of these enzymes and metabolites in the brain is critical for developing effective therapeutic strategies. This review endeavors to describe these processes in detail.:

A Dundee ice hockey player has been jailed after being found guilty of raping a teenage girl in his car.

Chris builds a house with a tiger in it. Ryan remembers that bush. And Robert has to fend off the fan boys trying to take his Nikke girls. One week till Extra Life, please help us heal kids and identify bicycles.

The post RPG Cast – Episode 697: “Paper Marliano” appeared first on RPGamer.

The Steam Deck is something of a talisman for gaming on Linux, its popularity and penguin-powered SteamOS having almost singlehandedly dragged it past MacOS as the second-most-used operating system among Steam users. Sadly, this also means the Valve handheld is the primary casualty when developers decide to stop bothering with Linux support, as Respawn Entertainment have decided to do for Apex Legends.

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It's official: I am once again the Sunday correspondent around here. That means it falls to me to round up (mostly) good (mostly) writing about (mostly) video games. I will otherwise be spending my Sunday continuing the fight against my dog's fleas, which rebound every three weeks no matter how much I spray, scrub or throw things away.

On, the independent video game magazine which I linked to last week, has run a series of brief interviews with each of the contributors to its launch issue. I recommend Christian Donlan's for the puzzle game recommendations and Margaret Robertson's which expands on her fascination with Japanese paper games.

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Nostalgia, when you think about it, is bollocks. There has never been a better time than right this second – averaged out, and despite repeated attempts to the contrary, humanity has never been healthier, freer, or more enlightened by knowledge. It’s true of games too. For every by-committee platter of passionless map markers, there are thousands of more personal, more creative, more interesting works, all adding to the decades' worth of great stuff we can still play today.

What isn’t bollocks is the emotional pull that nostalgia, for all its lack of cold, hard reason, still manages to wield inside our warm, squishy brains. Hence, the centrepiece of Apex Legends’ Season 23 update is a mode that recreates the battle royale FPS as it was back in 2019, defaulting back to the original map and weapon arsenal while cutting the 26-strong legend roster to the earliest ten. It’s a Fortnite-style rolling back of the clock, and a passably enjoyable one, but also a reminder that the good old days weren’t always that good.

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November 8th, 2005 was my first day as a full-time games journalist, which means I have now entered my 20th year of doing this. "This" has changed a lot over time: from producing CD and DVD coverdiscs, to writing for a magazine, to editing magazines and a website, to solely editing a website, to managing several websites. Sprinkle podcasts, videos, events and a lot of other things in there and "games journalist" doesn't really cover it.

One of the only constants is that I read a lot of writing about video games.

Dapper gent Oli Welsh wrote for Polygon about the fan reboot of City Of Heroes. We briefly covered fans getting an official license earlier this year, but Oli went and spoke to the folks making it all work.

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Astronomers have been spotting strange banana-shaped galaxies and the evidence seems to indicate that filaments of dark matter make them take this shape

A new procedure turns an alloy of nickel and titanium into a material as strong as steel but 20 times stretchier – and one application could be building planes with shape-shifting wings

Treat yourself to a Becky Lynch book signing, games with the Dropout stars, Kevin Smith’s Dogma, and so much more!

Meta had huge success last year with its flagship Quest 3 VR headset and it is back with a significantly cheaper 3S device that compromises on visuals but still delivers a great experience

NASA has released the clearest view of Mars seen thus far, with a field of blue rocks seen on the Martian landscape on top of an ancient lake.

Most one-use vape batteries are actually rechargeable, and this guy has proof.

Shop now to sculpt your midsection comfortably with soft, breathable fabric.

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Shop stylish diaper bags that busy moms won't mind carrying.

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We spoke to Reverend Doctor Stephen Cherry, Dean of Chapel at King's College, Cambridge.

President-elect Donald Trump has made many selections to lead his administration as his transition gets underway, ranging from chief of staff to head of the Environmental Protection Agency (EPA). At the same time, a number of crucial positions have yet to be filled just one week removed from the landslide election.

The post Donald Trump’s Administration Takes Shape After 15 Official or Expected Picks appeared first on Breitbart.

1. Xi Jinping leaves for APEC meeting and state visit in Peru  CGTN
2. Peru and China to sign strengthened free-trade agreement in Xi's APEC visit  Hindustan Times
3. Amid unease over Trump 2.0, Xi Jinping heads to South America; Peru first stop  Firstpost
4. Moments in Motion | President Xi's memorable moments - Peru  Xinhua
5. Another Modi, Xi meet likely at G20 in Brazil  Deccan Chronicle

1. RG Kar rape case: Bengal governor seeks report from CM after Sanjay Roy made big allegation against ex-Kolkata top cop  Hindustan Times
2. RG Kar rape case: Bengal Guv seeks report from Mamata govt after accused Sanjay Roy claims ‘Vineet Goel is threatening…’  Mint
3. Video | RG Kar Case News | Kolkata Horror: Prime Accused Sanjay Roy's 'Shocking Revelation' On Camera  NDTV
4. RG Kar rape-murder victim’s dad deposes on day 1 of trial  The Times of India
5. RG Kar case: CM Mamata asked to submit report on prime accused's claim  CNBCTV18

THE reasons behind a decision to release a secret expletive-laden recording of former Chief Justice Tim Carmody are almost as juicy as the tape is expected to be.

TekniPlex Healthcare is set to unveil its strongest-ever reinforced paper for medical device packaging applications at Pack Expo 2024, 3-6 November in Chicago.

Olivia Friett, editor of Medical Plastics News takes a look at the current regulatory landscape.

Here on Drug Channels, we have long highlighted the boom in provider-administered biosimilars. In contrast to the pharmacy market, adoption of these biosimilars is growing, prices are dropping, and formulary barriers continue to fall.

Novel transparency information reveals that this good news doesn’t always translate into savings. Below, we rely on a unique data set from Turquoise Health to examine how much four national commercial health plans—Aetna, Anthem, Cigna, and UnitedHealthcare—paid hospitals for Avastin and its two most significant biosimilar competitors.

As we demonstrate, health plans pay hospitals far above acquisition costs for biosimilars. What’s more, plans can pay hospitals more for a biosimilar than for the higher-cost reference product. The U.S. drug channel system is warping hospitals’ incentives to adopt biosimilars, while simultaneously raising costs for commercial plans.

The namesake of my alma mater once said: “Sunlight is said to be the best of disinfectants.” What would happen if we disinfected the entire channel?
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The U.S. Food and Drug Administration posted a video:

Quizás sepa que la FDA es responsable de aprobar los medicamentos nuevos, como medicamentos de receta, genéricos, biosimilares y de venta libre, y de garantizar que esos medicamentos sean seguros, de alta calidad y funcionen como se supone que deben hacerlo. Pero nuestro trabajo no termina ahí. Continuamos monitoreando la seguridad y calidad de los medicamentos aprobados en los años venideros. Aprenda más sobre nuestro papel en la regulación de estos medicamentos.

Para obtener más información sobre el papel de la FDA en la regulación y la aprobación de medicamentos, visite nuestro sitio web en www.fda.gov/drugs/information-consumers-and-patients-drug...

Vea esta serie de tres partes: www.youtube.com/playlist?list=PL0AE2C851E6968546

The U.S. Food and Drug Administration posted a video:

Quizás sepa que la FDA es responsable de aprobar los medicamentos nuevos, como medicamentos de receta, genéricos, biosimilares y de venta libre, y de garantizar que esos medicamentos sean seguros, de alta calidad y funcionen como se supone que deben hacerlo. Pero nuestro trabajo no termina ahí. Continuamos monitoreando la seguridad y calidad de los medicamentos aprobados en los años venideros. Aprenda más sobre nuestro papel en la regulación de estos medicamentos.

Para obtener más información sobre el papel de la FDA en la regulación y la aprobación de medicamentos, visite nuestro sitio web en www.fda.gov/drugs/information-consumers-and-patients-drug...

<p> <b>BIOSIMILAR RED TAPE ELIMINATION ACT (S2305):</b><br /> <b><i>Weakening FDA Regulatory Standards for Biosimilars, Undermining Physician Confidence and Jeopardizing Patient Health</i></b><br /><b>31 October 2024&nbsp;|&nbsp;</b><b><a href="https://youtu.be/X6-dYZ7fjhM" target="_blank">WATCH REPLAY</a></b></p>

Sudan's civil war has displaced 10 million citizens. Here are profiles of two young people from the most vulnerable groups: an unaccompanied minor caring for twin brothers, a woman who was raped.

You have just a few more days to submit your paper proposal for the 2017 SAS® Global Forum in Orlando on April 2–5. The call for papers ends and registration begins October 3.

Life can sometimes feel like a never-ending cycle of stress and decisions. That's usually my weekdays in a nutshell: chasing deadlines, making tough calls, and hopping between meetings. When your brain feels like it's on overdrive, it's time to hit pause. Engaging in some therapeutic activities can give your mind the breather it desperately needs. The good news? They don't have to be complicated or time-consuming. Here are some that can work wonders for your mental clarity and overall well-being. Step outside for a walk Walking is one of the simplest ways to clear your mind. It's amazing what a little fresh air at your nearby PCN can do. Just stepping outside and getting those legs moving can shift your perspective in a matter of minutes — and burn a few calories too! Disconnect from your phone and enjoy the sights and sounds of the great outdoors. I find that a 30-min walk and a change of environment works wonders for me, helping me rationally dissect my worries, such as my crushing feelings of inadequacy at work.

KOLKATA — A court in the eastern state of West Bengal began the trial on Monday (Nov 11) of a police volunteer accused of raping and murdering a doctor at a government hospital in August, a case that sparked outrage over the lack of safety for women in India. The woman's body was found in a classroom at the R.G. Kar Medical College and Hospital in the state capital Kolkata on Aug 9, the federal police said. They also said they had arrested a police volunteer, Sanjay Roy, for the crime.

Jul 17, 2023

Apekshya Prasai, a political science doctoral candidate at the Massachusetts Institute of Technology, was recently named a 2023 Harry Frank Guggenheim Foundation Emerging Scholar.   The Emerging Scholars (nine in all) are doctoral candidates who are in the final year of writing dissertations on the nature of and responses to violence around the world.

Virtual tour of 350 Fifth, a new 20-story office building in one of the top-ranked U.S. cities for sustainable buildings. Pt. 1 Pittsburgh-Gateway to the World & 350 Fifth Urban Genius.

The Asbury Park Waterfront

Praised as the most beautiful countryside in China, the unique view of shaiqiu can only be found in Huangling village where baskets of colorful harvest bask in the sunshine.

The 12th Annual MORE/FITNESS/SHAPE Women�s Half-Marathon on April 19, 2015 in New York�s Central Park

Official music video for Crazy. Song by illWIN and Theory

Behind the scenes with Natalie Morales and Erica Hill at the 12th Annual MORE/SHAPE Women�s Half-Marathon on April 19, 2015.

St. Jude Rock �n� Roll Nashville Marathon

Behind the scenes with Elizabeth Goodman Artis, Natalie Morales, Danielle Brooks, Padma Lakshmi and Sara Bareilles at the 2016 MORE/SHAPE Women�s Half-Marathon in Central Park on April 17.