ago Beyerdynamic Lagoon ANC Review By www.digit.in Published On :: 2023-09-22T13:09:00+05:30 Read the in depth Review of Beyerdynamic Lagoon ANC Audio Video. Know detailed info about Beyerdynamic Lagoon ANC configuration, design and performance quality along with pros & cons, Digit rating, verdict based on user opinions/feedback. Full Article Audio Video
ago HP Dragonfly G4 Notebook PC Review By www.digit.in Published On :: 2023-09-22T13:09:00+05:30 Read the in depth Review of HP Dragonfly G4 Notebook PC Laptops. Know detailed info about HP Dragonfly G4 Notebook PC configuration, design and performance quality along with pros & cons, Digit rating, verdict based on user opinions/feedback. Full Article Laptops
ago Indago stops everytime sees the UVM_ERROR By community.cadence.com Published On :: Sun, 08 Sep 2024 02:56:06 GMT I am running simulation in gui mode using Indago and every time there is UVM_ERROR occur simulation stops. I have to resume it manually. is there any way to disable this feature. Full Article
ago Lagos sees rebound in FDI By master-7rqtwti-2nwxk3tn3ebiq.eu-2.platformsh.site Published On :: Wed, 13 Nov 2019 10:21:21 +0000 The number of foreign companies investing in Lagos increased in 2018 after four years of decline. Full Article
ago G’day USA: Aussie private F&B labels star in Chicago By www.austrade.gov.au Published On :: Thu, 24 Nov 2022 05:04:00 GMT Australian food and beverages wowed the crowd at the 2022 Private Label Trade Show in Chicago. Full Article Latest from Austrade
ago Indian foodies lured by Australia’s Patagonian toothfish By www.austrade.gov.au Published On :: Thu, 22 Dec 2022 23:18:00 GMT Hobart-based fisheries company, Australian Longline, is now exporting Patagonian toothfish to India. Full Article Latest from Austrade
ago Scale New Heights With ‘Dragon Age: The Veilguard’ in the Cloud on GeForce NOW By blogs.nvidia.com Published On :: Thu, 31 Oct 2024 13:00:08 +0000 Even post-spooky season, GFN Thursday has some treats for GeForce NOW members: a new batch of 17 games joining the cloud in November. Catch the five games available to stream this week, including Dragon Age: The Veilguard, the highly anticipated next installment in BioWare’s beloved fantasy role-playing game series. Players who purchased the GeForce NOW Read Article Full Article Gaming Cloud Gaming GeForce NOW
ago Jack Teixeira, who leaked Pentagon documents, sentenced to 15 years in prison By www.voanews.com Published On :: Tue, 12 Nov 2024 20:39:02 -0500 boston — A federal judge on Tuesday sentenced a Massachusetts Air National Guard member to 15 years in prison after he pleaded guilty to leaking highly classified military documents about the war in Ukraine. Jack Teixeira pleaded guilty earlier this year to six counts of willful retention and transmission of national defense information under the Espionage Act following his arrest in the most consequential national security case in years. Brought into court wearing an orange jumpsuit, he showed no visible reaction as he was sentenced by U.S. District Judge Indira Talwani. Before being sentenced, he apologized for his actions. "I wanted to say I'm sorry for all the harm that I brought and caused," Texeira said, referencing the "maelstrom" he caused to friends, family, and anyone affected overseas. "I understand all the responsibility and consequences fall upon my shoulders alone and accept whatever that will bring," he said, standing as he addressed the judge. Afterward, Teixeira hugged one of his attorneys and looked toward his family and smiled before he was led out of court. The security breach raised alarm over America's ability to protect its most closely guarded secrets and forced the Biden administration to scramble to try to contain the diplomatic and military fallout. The leaks embarrassed the Pentagon, which tightened controls to safeguard classified information and disciplined members found to have intentionally failed to take required action about Teixeira's suspicious behavior. Earlier in Tuesday's hearing, Assistant U.S. Attorney Jared Dolan argued that 200 months — or a little more than 16 1/2 years — was appropriate given the "historic" damage caused by Teixeira's conduct that aided adversaries of the United States and hurt the country's allies. He also said that the recommendation by prosecutors would send a message to anyone in the military who might consider similar conduct. "It will be a cautionary tale for the men and women in the U.S. military," Dolan said. "They are going to be told this is what happens if you break your promise, if you betray your country. ... They will know the defendant's name. They will know the sentence the court imposes." But Teixeira's attorney Michael Bachrach told the judge in court Tuesday that 11 years was sufficient. "It is a significant, harsh and difficult sentence, one that will not be easy to serve," Bachrach said. "It will serve as an extreme deterrent to anyone, particularly young servicemen. That is enough to keep them deterred from committing serious conduct." 'His intent was to educate' Teixeira, of North Dighton, Massachusetts, had pleaded guilty in March to six counts of the willful retention and transmission of national defense information under the Espionage Act. That came nearly a year after he was arrested in the most consequential national security leak in years. The 22-year-old admitted that he illegally collected some of the nation's most sensitive secrets and shared them with other users on the social media platform Discord. When Teixeira pleaded guilty, prosecutors said they would seek a prison term at the high end of the sentencing range. But the defense wrote in their sentencing memorandum earlier that the 11 years is a "serious and adequate to account for deterrence considerations and would be essentially equal to half the life that Jack has lived thus far." His attorneys described Teixeira as an autistic, isolated individual who spent most of his time online, especially with his Discord community. They said his actions, though criminal, were never meant to "harm the United States." He also had no prior criminal record. "Instead, his intent was to educate his friends about world events to make certain they were not misled by misinformation," the attorneys wrote. "To Jack, the Ukraine war was his generation's World War II or Iraq, and he needed someone to share the experience with." Prosecutors, though, had countered that Teixeira does not suffer from an intellectual disability that prevents him from knowing right from wrong. They argued that Teixeira's post-arrest diagnosis as having "mild, high-functioning" autism "is of questionable relevance in these proceedings." Teixeira, who was part of the 102nd Intelligence Wing at Otis Air National Guard Base in Massachusetts, worked as a cyber transport systems specialist, which is essentially an information technology specialist responsible for military communications networks. He remains in the Air National Guard in an unpaid status, an Air Force official said. Authorities said he first typed out classified documents he accessed and then began sharing photographs of files that bore SECRET and TOP SECRET markings. Prosecutors also said he tried to cover his tracks before his arrest, and authorities found a smashed tablet, laptop and an Xbox gaming console in a dumpster at his house. The leak exposed to the world unvarnished secret assessments of Russia's war in Ukraine, including information about troop movements in Ukraine, and the provision of supplies and equipment to Ukrainian troops. Teixeira also admitted posting information about a U.S. adversary's plans to harm U.S. forces serving overseas. Full Article USA
ago Knights and Dragons share the spoils By www.iol.co.za Published On :: Sun, 10 Nov 2024 19:17:33 GMT Full Article
ago Dragonfly Foods reassures public over safety of its products amid health concerns By www.iol.co.za Published On :: Tue, 12 Nov 2024 08:49:58 GMT Full Article
ago 102 years ago, one of the all-time greatest archaeological discoveries was made By www.jpost.com Published On :: Tue, 05 Nov 2024 16:00:00 GMT A member of the team, a water boy, accidentally stumbled upon a stone that turned out to be the first step of an ancient staircase. Full Article history discovery research
ago Playing Nuclear Games: Tickling the Tail of the Promethean Nuclear Fire Dragon By www.ipsnews.net Published On :: Tue, 08 Oct 2024 12:15:18 +0000 In recent years, the rhetoric, strategy and practice of nuclear deterrence has grown riskier, more urgent, more dangerous, less stable, and increasingly in the hands of deficient leaders and policymakers. Playing Nuclear Games The ten States that have manufactured and test detonated nuclear weapons since 1945, each have received and/or provided assistance to other States […] Full Article Armed Conflicts Featured Global Headlines IPS UN: Inside the Glasshouse Nuclear Disarmament Nuclear Energy - Nuclear Weapons TerraViva United Nations IPS UN Bureau Nuclear Abolition 2024
ago US warships repelled attack from Yemen's Houthis, Pentagon says By www.jpost.com Published On :: Tue, 12 Nov 2024 16:57:15 GMT Houthi spokesperson Yahya Sarea had earlier said the first operation targeted a US aircraft carrier in the Arabian sea with a number of missiles and drones. Full Article Yemen Houthi US Army Pentagon
ago Fifteen-year-old in serious accident in Xylophagou By cyprus-mail.com Published On :: 2024-11-13T08:09:51+02:00 A 15-year-old was seriously injured while riding a moped overnight in the Famagusta district. According to the police, the accident happened around 9pm on Tuesday in Xylophagou, when a 35-year-old woman driving on Anastassi Manoli Street, under circumstances that are being investigated, ran over and injured the 15-year-old boy. The 15-year-old was initially taken by […] Full Article Main minor moped serious accident xylophagou
ago Fanga'uta Lagoon Bridge Project By www.adb.org Published On :: 2025 The proposed project will build a bridge across the Fanga'uta Lagoon in Nuku'alofa, the capital of the Kingdom of Tonga (Tonga). The crossing will consist of an approximately 720 m long bridge and 4.96 km of approach roads from Nuku'alofa to Vaini, southern Tongatapu. Full Article
ago Sea level may have been higher than it is now just 6000 years ago By www.newscientist.com Published On :: Tue, 25 Jul 2023 16:00:45 +0100 Climate researchers thought that current global average sea levels were the highest in more than 100,000 years, but new models suggest oceans just 6000 years ago may have been higher than at the beginning of the industrial revolution, and possibly even higher than today Full Article
ago Huge earthquake shook Seattle 1100 years ago and it could happen again By www.newscientist.com Published On :: Wed, 27 Sep 2023 20:00:56 +0100 Analysis of tree rings shows that two faults near Seattle, Washington ruptured at the same time or soon after each other more than 1000 years ago – a repeat today would cause a major disaster in the region Full Article
ago Largest volcanic eruption in recorded history happened 7300 years ago By www.newscientist.com Published On :: Wed, 21 Feb 2024 13:58:06 +0000 The Kikai-Akahoya eruption of an underwater volcano off the coast of Japan ejected enough material to fill Lake Tahoe twice, three times as much as the eruption of Mount Tambora in 1815 Full Article
ago Huge crater in India hints at major meteorite impact 4000 years ago By www.newscientist.com Published On :: Tue, 26 Mar 2024 08:00:18 +0000 The Luna structure, a 1.8-kilometre-wide depression in north-west India, may have been caused by the largest meteorite to strike Earth in the past 50,000 years Full Article
ago Folklore uncovers a tsunami that rocked Hawaii hundreds of years ago By www.newscientist.com Published On :: Fri, 18 Oct 2024 18:00:44 +0100 A story passed down in folklore led scientists to evidence of an 8-metre tsunami that hit an island in Hawaii hundreds of years ago Full Article
ago Some wildfires are growing twice as fast as they did two decades ago By www.newscientist.com Published On :: Thu, 24 Oct 2024 20:00:06 +0100 In the western US, the average maximum growth rate of fires has more than doubled over the past two decades Full Article
ago Modern humans were already in northern Europe 45,000 years ago By www.newscientist.com Published On :: Wed, 31 Jan 2024 16:00:07 +0000 DNA from bones found in a cave in Germany has been identified as from Homo sapiens, showing that our species endured frigid conditions there as they expanded across the continent Full Article
ago Mammoth tusk tool may have been used to make ropes 37,000 years ago By www.newscientist.com Published On :: Wed, 31 Jan 2024 19:00:30 +0000 Experiments with a replica suggest that a piece of mammoth ivory with carved holes found in a cave in Germany was used by ancient humans to make ropes Full Article
ago Ancient canoes hint at bustling trade in Mediterranean 7000 years ago By www.newscientist.com Published On :: Wed, 20 Mar 2024 18:00:12 +0000 Italian canoes capable of transporting people and goods have been dated to the Neolithic period, suggesting there was a bustling trade across the Mediterranean Sea Full Article
ago Australia’s Indigenous people were making pottery over 2000 years ago By www.newscientist.com Published On :: Tue, 09 Apr 2024 22:00:58 +0100 An excavation on an island in the Coral Sea shows that Indigenous Australians were producing ceramics long before the arrival of Europeans Full Article
ago Early humans spread as far north as Siberia 400,000 years ago By www.newscientist.com Published On :: Fri, 19 Apr 2024 13:00:49 +0100 A site in Siberia has evidence of human presence 417,000 years ago, raising the possibility that hominins could have reached North America much earlier than we thought Full Article
ago The plague may have wiped out most northern Europeans 5000 years ago By www.newscientist.com Published On :: Wed, 10 Jul 2024 17:00:21 +0100 DNA evidence from tombs in Sweden and Denmark suggests major plague outbreaks were responsible for the Neolithic decline in northern Europe Full Article
ago Butchered bones hint humans were in South America 21,000 years ago By www.newscientist.com Published On :: Wed, 17 Jul 2024 20:00:52 +0100 Prehistoric mammal bones found at a construction site in Argentina appear to have been cut with stone tools, suggesting that humans lived in the region much earlier than previously thought Full Article
ago Ancient DNA tells story of toddler who lived in Italy 17,000 years ago By www.newscientist.com Published On :: Wed, 02 Oct 2024 19:00:12 +0100 A young boy who lived towards the end of the last glacial period had dark skin, blue eyes and a congenital heart condition, a study of his genome reveals Full Article
ago Pentagon to Make COVID Vaccination Mandatory for Military By www.medicinenet.com Published On :: Mon, 29 Aug 2022 00:00:00 PDT Title: Pentagon to Make COVID Vaccination Mandatory for MilitaryCategory: Health NewsCreated: 8/23/2021 12:00:00 AMLast Editorial Review: 8/24/2021 12:00:00 AM Full Article
ago Pentagon Says Troops Must Start Lining Up Now for COVID Shots By www.medicinenet.com Published On :: Mon, 29 Aug 2022 00:00:00 PDT Title: Pentagon Says Troops Must Start Lining Up Now for COVID ShotsCategory: Health NewsCreated: 8/25/2021 12:00:00 AMLast Editorial Review: 8/26/2021 12:00:00 AM Full Article
ago Characterizing the Distribution of a Stimulator of Interferon Genes Agonist and Its Metabolites in Mouse Liver by Matrix-Assisted Laser Desorption/Ionization Imaging Mass Spectrometry [Special Section on New and Emerging Areas and Technologies in Drug Met By dmd.aspetjournals.org Published On :: 2024-10-16T09:02:03-07:00 A STING (stimulator of interferon genes) agonist GSK3996915 under investigation in early discovery for hepatitis B was orally dosed to a mouse model for understanding the parent drug distribution in liver, the target organ. Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) was used to quantify the distribution of GSK3996915 in liver collected from mice administered a single oral dose at 90 mg/kg. GSK3996915 was detected with a zonal distribution localized in the portal triad and highly concentrated in the main bile ducts, indicating clearance through biliary excretion. High spatial resolution imaging showed the distribution of the parent drug localized to the cellular populations in the sinusoids, including the Kupffer cells. Additionally, a series of drug-related metabolites were observed to be localized in the central zones of the liver. These results exemplify the potential of utilizing MALDI IMS for measuring not only quantitative drug distribution and target exposure but also drug metabolism and elimination in a single suite of experiments. SIGNIFICANCE STATEMENT An integrated imaging approach utilizing matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) complemented with immunohistochemistry (IHC) and histology was used to address the question of target exposure at the cellular level. Localized quantification of the parent drug in the target organ and identification of potential metabolites in the context of tissue histology were also achieved in one experimental suite to support characterization of pharmacokinetic properties of the drug in the early discovery stage.: Full Article
ago A Cosmopolitan Argument for Temporary “Diagonal” Short-Term Surgical Missions as a Component of Surgical Systems Strengthening By ghspjournal.org Published On :: 2024-10-29T12:28:39-07:00 Full Article
ago Gabapentinoids Increase the Potency of Fentanyl and Heroin and Decrease the Potency of Naloxone to Antagonize Fentanyl and Heroin in Rats Discriminating Fentanyl [Behavioral Pharmacology] By jpet.aspetjournals.org Published On :: 2024-10-18T07:04:15-07:00 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. Full Article
ago Alternative Reinforcers Enhance the Effects of Opioid Antagonists, but Not Agonists, on Oxycodone Choice Self-Administration in Nonhuman Primates [Behavioral Pharmacology] By jpet.aspetjournals.org Published On :: 2024-10-18T07:04:15-07:00 Clinical reports suggest that the most effective strategies for managing opioid use disorder comprise a comprehensive treatment program of both pharmacological and nonpharmacological approaches. However, the conditions under which these combinations are most effective are not well characterized. This study examined whether the presence of an alternative reinforcer could alter the efficacy of Food and Drug Administration–approved opioid antagonist or agonist medications, as well as the nonopioid flumazenil, in decreasing oxycodone choice self-administration in nonhuman primates. Adult squirrel monkeys (n = 7; four females) responded under concurrent second-order fixed-ratio (FR)-3(FR5:S);TO45s schedules of reinforcement for intravenous oxycodone (0.1 mg/kg) or saline on one lever and 30% sweetened condensed milk or water on the other. Doses of naltrexone (0.00032–1.0 mg/kg), nalbuphine (0.32–10 mg/kg), buprenorphine (0.0032–0.032 mg/kg), methadone (0.32–1.0 mg/kg), or flumazenil (1–3.2 mg/kg) were administered intramuscularly prior to oxycodone self-administration sessions that occurred with either milk or water as the alternative. Naltrexone, a μ-opioid receptor antagonist, was >30-fold more potent when milk was available compared with water and abolished oxycodone intake (injections/session) while concomitantly increasing milk deliveries at the highest dose tested. Pretreatment with the low-efficacy μ-agonist nalbuphine was most effective in the presence of milk compared with water, decreasing oxycodone preference to <50% of control values. The higher efficacy μ-agonists, methadone and buprenorphine, and the benzodiazepine antagonist flumazenil did not appreciably alter the reinforcing potency of oxycodone under either condition. These results suggest that antagonist medications used in combination with alternative reinforcers may be an effective strategy to curtail opioid abuse–related behaviors. SIGNIFICANCE STATEMENT Clinical treatment programs for opioid use disorder use a combination of pharmacological and nonpharmacological approaches. However, the conditions under which these combinations are most effective have not been fully characterized. This study examined whether the effectiveness of μ-opioid medications to decrease oxycodone self-administration is altered in the presence of an alternative reinforcer. The results suggest that alternative reinforcers enhance the effects of antagonist or low-efficacy partial agonists, suggesting they may be a more effective strategy to curtail opioid use. Full Article
ago Evaluating the Abuse Potential of Lenabasum, a Selective Cannabinoid Receptor 2 Agonist [Special Section: Cannabinoid Signaling in Human Health and Disease] By jpet.aspetjournals.org Published On :: 2024-10-18T07:04:15-07:00 Endocannabinoids, which are present throughout the central nervous system (CNS), can activate cannabinoid receptors 1 and 2 (CB1 and CB2). CB1 and CB2 agonists exhibit broad anti-inflammatory properties, suggesting their potential to treat inflammatory diseases. However, careful evaluation of abuse potential is necessary. This study evaluated the abuse potential of lenabasum, a selective CB2 receptor agonist in participants (n = 56) endorsing recreational cannabis use. Three doses of lenabasum (20, 60, and 120 mg) were compared with placebo and nabilone (3 and 6 mg). The primary endpoint was the peak effect (Emax) on a bipolar Drug Liking visual analog scale (VAS). Secondary VAS and pharmacokinetic (PK) endpoints and adverse events were assessed. Lenabasum was safe and well tolerated. Compared with placebo, a 20-mg dose of lenabasum did not increase ratings of Drug Liking and had no distinguishable effect on other VAS endpoints. Dose-dependent increases in ratings of Drug Liking were observed with 60 and 120 mg lenabasum. Drug Liking and all other VAS outcomes were greatest for nabilone 3 mg and 6 mg, a medication currently approved by the US Food and Drug Administration (FDA). At a target therapeutic dose (20 mg), lenabasum did not elicit subjective ratings of Drug Liking. However, supratherapeutic doses of lenabasum (60 and 120 mg) did elicit subjective ratings of Drug Liking compared with placebo. Although both doses of lenabasum were associated with lower ratings of Drug Liking compared with 3 mg and 6 mg nabilone, lenabasum does have abuse potential and should be used cautiously in clinical settings. SIGNIFICANCE STATEMENT This work provides evidence that in people with a history of recreational cannabis use, lenabasum was safe and well tolerated, although it did demonstrate abuse potential. This work supports further development of lenabasum for potential therapeutic indications. Full Article
ago Chronic Administration of Cannabinoid Agonists ACEA, AM1241, and CP55,940 Induce Sex-Specific Differences in Tolerance and Sex Hormone Changes in a Chemotherapy-Induced Peripheral Neuropathy [Special Section: Cannabinoid Signaling in Human Health and Dise By jpet.aspetjournals.org Published On :: 2024-10-18T07:04:15-07:00 Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of chemotherapy treatment, routinely manifesting as increased pain sensitivity (allodynia) in distal extremities. Despite its prevalence, effective treatment options are limited. Cannabinoids are increasingly being evaluated for their ability to treat chronic pain conditions, including CIPN. While previous studies have revealed sex differences in cannabinoid-mediated antinociception in acute and chronic pain models, there is a paucity of studies addressing potential sex differences in the response of CIPN to cannabinoid treatment. Therefore, we evaluated the long-term antiallodynic efficacy of cannabinoid receptor type 1 (CB1)-selective, cannabinoid receptor type 2 (CB2)-selective, and CB1/CB2 mixed agonists in the cisplatin CIPN model, using both male and female mice. CB1 selective agonism was observed to have sex differences in the development of tolerance to antiallodynic effects, with females developing tolerance more rapidly than males, while the antiallodynic effects of selective CB2 agonism lacked tolerance development. Compound-specific changes to the female estrous cycle and female plasma estradiol levels were noted, with CB1 selective agonism decreasing plasma estradiol while CB2 selective agonism increased plasma estradiol. Chronic administration of a mixed CB1/CB2 agonist resulted in increased mRNA expression of proinflammatory cytokines and endocannabinoid regulatory enzymes in female spinal cord tissue. Ovarian tissue was noted to have proinflammatory cytokine mRNA expression following administration of a CB2 acting compound while selective CB1 agonism resulted in decreased proinflammatory cytokines and endocannabinoid regulatory enzymes in testes. These results support the need for further investigation into the role of sex and sex hormones signaling in pain and cannabinoid-mediated antinociceptive effects. SIGNIFICANCE STATEMENT CIPN is a common side effect of chemotherapy. We have found that both CB1 and CB2 receptor agonism produce antinociceptive effects in a cisplatin CIPN model. We observed that tolerance to CB1-mediated antinociception developed faster in females and did not develop for CB2-mediated antinociception. Additionally, we found contrasting roles for CB1/CB2 receptors in the regulation of plasma estradiol in females, with CB1 agonism attenuating estradiol and CB2 agonism enhancing estradiol. These findings support the exploration of cannabinoid agonists for CIPN. Full Article
ago KLS-13019, a Novel Structural Analogue of Cannabidiol and GPR55 Receptor Antagonist, Prevents and Reverses Chemotherapy-Induced Peripheral Neuropathy in Rats [Special Section: Cannabinoid Signaling in Human Health and Disease] By jpet.aspetjournals.org Published On :: 2024-10-18T07:04:15-07:00 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. SIGNIFICANCE STATEMENT Chemotherapy-induced peripheral neuropathy (CIPN) is a common, debilitating side effect of cancer treatment with no known cure. The GPR55 antagonist KLS-13019 represents a novel class of drug for this condition that is a potent, durable inhibitor of allodynia associated with CIPN in rats in both prevention and reversal-dosing paradigms. This novel therapeutic approach addresses a critical area of unmet medical need. Full Article
ago Low-Efficacy Mu Opioid Agonists as Candidate Analgesics: Effects of Novel C-9 Substituted Phenylmorphans on Pain-Depressed Behavior in Mice [Behavioral Pharmacology] By jpet.aspetjournals.org Published On :: 2024-10-18T07:04:15-07:00 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. SIGNIFICANCE STATEMENT This study used a novel set of mu opioid receptor (MOR)-selective opioids with graded MOR efficacies to examine the lower boundary of MOR efficacy sufficient to relieve pain-related behavioral depression in mice. Two novel low-efficacy opioids (JL-2-39, DC-1-76.1) produced effective antinociception with improved safety relative to higher- or lower-efficacy opioids, and results support further consideration of these and other low-efficacy opioids as candidate analgesics. Full Article
ago RPG Cast – Episode 652: “Because Dragons” By rpgamer.com Published On :: Sat, 22 Oct 2022 21:52:29 +0000 Josh is bringing Rabbids back. Also, RIP Kelley as her kitty goes on a rampage. Chris is a human in real life, but still has MMO sickness. The post RPG Cast – Episode 652: “Because Dragons” appeared first on RPGamer. Full Article News Podcasts RPG Cast Mario + Rabbids: Sparks of Hope Shining Force III The Legend of Heroes: Trails in the Sky The Legend of Heroes: Trails to Azure World of Warcraft: Shadowlands
ago RPG Cast – Episode 674: “Stop Sending Dragons, I Have Things to Do” By rpgamer.com Published On :: Sat, 29 Apr 2023 20:02:26 +0000 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. Full Article News Podcasts RPG Cast Final Fantasy Pixel Remaster Skyrim Yakuza Zero
ago RPG Cast – Episode 678: “Dagon Qest Incasition” By rpgamer.com Published On :: Sat, 27 May 2023 20:33:42 +0000 Chris learns that Star Wars has all the nudie mods and bans it from his mod manager. Kelley is an apologist for Big the Cat. Jason draws stick sticks with his feet. The post RPG Cast – Episode 678: “Dagon Qest Incasition” appeared first on RPGamer. Full Article News Podcasts RPG Cast Fallout: New Vegas Skyrim The Legend of Heroes: Trails in the Sky The Legend of Zelda: Tears of the Kingdom
ago RPG Cast – Episode 731: “Dragon Quest: Start Your Own Taco Adventure” By rpgamer.com Published On :: Sat, 13 Jul 2024 21:04:23 +0000 Kelley uses familiars to click her buttons. Josh scribbles in comic sans over your collector's edition with a sharpie. Which is good because Chris can't handle yet another collector's edition. They're all doing better than Ryan, though, who is suffering from Wizardry PTSD. The post RPG Cast – Episode 731: “Dragon Quest: Start Your Own Taco Adventure” appeared first on RPGamer. Full Article News Podcasts RPG Cast Fate Seeker II Final Fantasy XIV: Dawntrail Hades II The Legend of Heroes: Trails through Daybreak The Legend of Zelda: Tears of the Kingdom Undernauts: Labyrinth of Yomi World of Warcraft: Dragonflight
ago RPG Cast – Episode 735: “Dodge Dragonero” By rpgamer.com Published On :: Sat, 10 Aug 2024 20:19:36 +0000 Chris proclaims that WoW isn't a battery drainer, it's the Warlord of Draenor. Kelley has a soda-fresh Steamdeck. Josh discovers the fifth horseman of the apocalypse: politics. Robert wraps himself in a towel and puts himself in the oven. The post RPG Cast – Episode 735: “Dodge Dragonero” appeared first on RPGamer. Full Article News Podcasts RPG Cast Final Fantasy XIV: Dawntrail Path of Exile That Time I Got Reincarnated as a Slime ISEKAI Chronicles The Legend of Heroes: Trails through Daybreak World of Warcraft: Mists of Pandaria
ago Final Fantasy Series Sales Top 195M, Dragon Quest Series Tops 91M By www.vgchartz.com Published On :: Fri, 08 Nov 2024 15:57:56 GMT Square Enix has revealed the lifetime sales for two of its biggest franchises Final Fantasy and Dragon Quest. The Final Fantasy series has now sold over 195 million units worldwide and the Dragon Quest series has sold over 91 million units worldwide. "The Square Enix Group also boasts a valuable portfolio of intellectual property including: Final Fantasy, which has sold over 195 million units worldwide; Dragon Quest, which has sold over 91 million units worldwide; and the legendary Space Invaders," said Square Enix. 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/463021/final-fantasy-series-sales-top-195m-dragon-quest-series-tops-91m/ Full Article Analysis Charts Industry
ago Dragon Age: The Veilguard Debuts in 2nd on the Australian Charts By www.vgchartz.com Published On :: Fri, 08 Nov 2024 22:38:09 GMT Call of Duty: Black Ops 6 has remained in first place on the Australian charts, according to IGEA for the week ending November 3, 2024. There were three new releases in the top 10 this week with Dragon Age: The Veilguard debuting in second place, Horizon Zero Dawn Remastered in fourth place, and Life Is Strange: Double Exposure in ninth place. Hogwarts Legacy is up one spot to third place, EA Sports FC 25 remained in fifth place, and Super Mario Party Jamboree dropped from second to sixth place. Red Dead Redemption is in seventh place, NBA 2K25 is in eight place, and Battlefield 2042 rounds out the top 10. Here are the top 10 best-selling titles in Australia for the week: Call of Duty: Black Ops 6 Dragon Age: The Veilguard - NEW Hogwarts Legacy Horizon Zero Dawn Remastered - NEW EA Sports FC 25 Super Mario Party Jamboree Red Dead Redemption NBA 2K25 Life Is Strange: Double Exposure - NEW Battlefield 2042 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/463028/dragon-age-the-veilguard-debuts-in-2nd-on-the-australian-charts/ Full Article Analysis Charts Industry
ago Dragon Age: The Veilguard Debuts in 2nd on the New Zealand Charts By www.vgchartz.com Published On :: Fri, 08 Nov 2024 22:45:49 GMT Call of Duty: Black Ops 6 has remained in first place on the New Zealand charts, according to IGEA for the week ending November 3, 2024. There were two new releases in the top 10 this week with Dragon Age: The Veilguard debuting in second place and Horizon Zero Dawn Remastered in fourth place. Hogwarts Legacy is down one spot to third place, Grand Theft Auto V is up three spots to fifth place, and NBA 2K25 climbed from ninth to sixth place. Red Dead Redemption is in seventh place, Borderlands 3 is in eight place, Battlefield 2042 is in ninth place, and EA Sports FC 25 rounds out the top 10. Here are the top 10 best-selling titles in New Zealand for the week: Call of Duty: Black Ops 6 Dragon Age: The Veilguard - NEW Hogwarts Legacy Horizon Zero Dawn Remastered - NEW Grand Theft Auto V NBA 2K25 Red Dead Redemption Borderlands 3 Battlefield 2042 EA Sports FC 25 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/463029/dragon-age-the-veilguard-debuts-in-2nd-on-the-new-zealand-charts/ Full Article Analysis Charts Industry
ago The trick to Dragon Age's lore is that the lore is lying, says original "uber-plot" writer David Gaider By www.rockpapershotgun.com Published On :: Thu, 31 Oct 2024 16:48:59 +0000 Part of the fun of Dragon Age's fantasy is that it's inconsistent - or at least, inconsistent by the standards of fantasy RPGs, which often break down into a million neatly organised and interlocking codex entries. It all rides on who you speak to. The humans believe one thing about the origins and workings of Thedas, the elves another, the qunari something else entirely. These differences are the basis for many factional disagreements and thus, many core series plot developments. According to former lead writer David Gaider, however, there's an "uber-plot" behind it all that may one day be resolved and bring the series to a close, assuming BioWare continue to refer to his original (and closely guarded) narrative documents. Read more Full Article Strategy Electronic Arts RPG Dragon Age: The Veilguard Action Adventure Single Player Bioware
ago I am deeply enamoured by Dragon Age: The Veilguard's intricate and ridiculous fashion design By www.rockpapershotgun.com Published On :: Fri, 01 Nov 2024 11:53:53 +0000 Some extremely fresh vintage workwear that I bought for entirely practical reasons aside, I’m not exactly a fashion person. I have nobody to impress most days but my cat, and the only item of clothing she appears to have an opinion on is my Oodie, which is very comfortable for both of us and also smells like a chicken shop, which I imagine is more pleasant for her than me. This aside, I found myself taking a whole bunch of Dragon Age: The Veilguard screenshots as I played just to capture the RPG’s various outfits. They are ridiculous. Incredibly intricate and detailed, as well as being obscenely impractical for the most part. I do not like any of them in the sense I would wear them, but I like all of them in the sense that they display artists allowed to run free like caffeinated weasels and indulge their every whim. Read more Full Article Strategy Electronic Arts RPG Dragon Age: The Veilguard Action Adventure Single Player Bioware
ago Dragon Age: The Veilguard on PC is the surprise AAA tech success of 2024 By www.rockpapershotgun.com Published On :: Fri, 01 Nov 2024 17:02:04 +0000 There’s plenty that you could justifiably expect from a Bioware RPG: chats with mates, opportunities to get those mates horribly killed, surviving mates turning to the side then walking offscreen. But I don’t think anyone expected Dragon Age: The Veilguard to be, at least on a purely technical level, one of the smoothest-performing, settings-rich AAA PC releases of the year so far. Read more Full Article Strategy Single Player FSR Hardware DLSS 3 Electronic Arts Dragon Age: The Veilguard Action Adventure RPG DLSS Bioware