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

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.

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.

Oxidative stress, fibrosis, and inflammasome activation from advanced glycation end product (AGE)–receptor of advanced glycation end product (RAGE) interaction contribute to diabetic cardiomyopathy (DCM) formation and progression. Our study revealed the impact of β-caryophyllene (BCP) on activating cannabinoid type 2 receptors (CB2Rs) against diabetic complication, mainly cardiomyopathy and investigated the underlying cell signaling pathways in mice. The murine model of DCM was developed by feeding a high-fat diet with streptozotocin injections. After the development of diabetes, the animals received a 12-week oral BCP treatment at a dose of 50 mg/kg/body weight. BCP treatment showed significant improvement in glucose tolerance and insulin resistance and enhanced serum insulin levels in diabetic animals. BCP treatment effectively reversed the heart remodeling and restored the phosphorylated troponin I and sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a expression. Ultrastructural examination showed reduced myocardial cell injury in DCM mice treated with BCP. The preserved myocytes were found to be associated with reduced expression of AGE/RAGE in DCM mice hearts. BCP treatment mitigated oxidative stress by inhibiting expression of NADPH oxidase 4 and activating phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/nuclear factor erythroid 2–related factor 2 (Nrf2) signaling. Also, BCP suppressed cardiac fibrosis and endothelial-to-mesenchymal transition in DCM mice by inhibiting transforming growth factor β (TGF-β)/suppressor of mothers against decapentaplegic (Smad) signaling. Further, BCP treatment suppressed nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (NLRP3) inflammasome activation in DCM mice and alleviated cellular injury to the pancreatic tissues evidenced by significant elevation of the number of insulin-positive cells. To demonstrate a CB2R-dependent mechanism of BCP, another group of DCM mice were pretreated with AM630, a CB2R antagonist. AM630 was observed to abrogate the beneficial effects of BCP in DCM mice. Taken together, BCP demonstrated the potential to protect the myocardium and pancreas of DCM mice mediating CB2R-dependent mechanisms.

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.

Chronic pain conditions affect nearly 20% of the population in the United States. Current medical interventions, such as opioid drugs, are effective at relieving pain but are accompanied by many undesirable side effects. This is one reason increased numbers of chronic pain patients have been turning to Cannabis for pain management. Cannabis contains many bioactive chemical compounds; however, current research looking into lesser-studied minor cannabinoids in Cannabis lacks uniformity between experimental groups and/or excludes female mice from investigation. This makes it challenging to draw conclusions between experiments done with different minor cannabinoid compounds between laboratories or parse out potential sex differences that could be present. We chose five minor cannabinoids found in lower quantities within Cannabis: cannabinol (CBN), cannabidivarin (CBDV), cannabigerol (CBG), 8-tetrahydrocannabinol (8-THC), and 9-tetrahydrocannabivarin (THCV). These compounds were then tested for their cannabimimetic and pain-relieving behaviors in a cannabinoid tetrad assay and a chemotherapy-induced peripheral neuropathy (CIPN) pain model in male and female CD-1 mice. We found that the minor cannabinoids we tested differed in the cannabimimetic behaviors evoked, as well as the extent. We found that CBN, CBG, and high-dose 8-THC evoked some tetrad behaviors in both sexes, while THCV and low-dose 8-THC exhibited cannabimimetic tetrad behaviors only in females. Only CBN efficaciously relieved CIPN pain, which contrasts with reports from other researchers. Together these findings provide further clarity to the pharmacology of minor cannabinoids and suggest further investigation into their mechanism and therapeutic potential.

This single-center, single-arm, phase II trial (ChiCTR2100050057) investigated the ability of ¹⁸F-labeled fibroblast activation protein inhibitor ([¹⁸F]AlF-NOTA-FAPI-04, denoted as ¹⁸F-FAPI) PET/CT to predict the response to neoadjuvant camrelizumab plus chemotherapy (nCC) in locally advanced esophageal squamous cell carcinoma (LA-ESCC). Methods: This study included 32 newly diagnosed LA-ESCC participants who underwent ¹⁸F-FAPI PET/CT at baseline, of whom 23 also underwent scanning after 2 cycles of nCC. The participants underwent surgery after 2 cycles of nCC. Recorded PET parameters included maximum, peak, and mean SUVs and tumor-to-background ratios (TBRs), metabolic tumor volume, and total lesion FAP expression. PET parameters were compared between patient groups with good and poor pathologic responses, and the predictive performance for treatment response was analyzed. Results: The good and poor response groups each included 16 participants (16/32, 50.0%). On ¹⁸F-FAPI PET/CT, the posttreatment SUVs were significantly lower in good responders than in poor responders, whereas the changes in SUVs with treatment were significantly higher (all P < 0.05). SUV_max (area under the curve [AUC], 0.87; P = 0.0026), SUV_peak (AUC, 0.89; P = 0.0017), SUV_mean (AUC, 0.88; P = 0.0021), TBR_max (AUC, 0.86; P = 0.0031), and TBR_mean (AUC, 0.88; P = 0.0021) after nCC were significant predictors of pathologic response to nCC, with sensitivities of 63.64%–81.82% and specificities of 83.33%–100%. Changes in SUV_max (AUC, 0.81; P = 0.0116), SUV_peak (AUC, 0.82; P = 0.0097), SUV_mean (AUC, 0.81; P = 0.0116), and TBR_mean (AUC, 0.74; P = 0.0489) also were significant predictors of the pathologic response to nCC, with sensitivities and specificities in similar ranges. Conclusion: ¹⁸F-FAPI PET/CT parameters after treatment and their changes from baseline can predict the pathologic response to nCC in LA-ESCC participants.

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:

Periprocedural intracranial hemorrhage is one of common complications after stent placement for symptomatic intracranial atherosclerotic stenosis. This study was conducted to demonstrate predictors and long-term outcomes of periprocedural intracranial hemorrhage after stent placement for symptomatic intracranial atherosclerotic stenosis.

BACKGROUND AND PURPOSE:

Reocclusion after treatment is a concern in endovascular therapy for isolated intracranial atherothrombotic stroke-related large-vessel occlusion (AT-LVO). However, the optimal endovascular therapy technique for AT-LVO has not yet been investigated. This study evaluated the optimal endovascular therapy technique for AT-LVO in a real-world setting.

BACKGROUND AND PURPOSE:

Alterations of the basilar artery (BA) anatomy have been suggested as a possible MRA feature of Fabry disease (FD). Nonetheless, no information about their clinical or pathophysiologic correlates is available, limiting our comprehension of the real impact of vessel remodeling in FD.

SUMMARY:

The 2021 World Health Organization Classification of Tumors of the Central Nervous System (CNS5), introduced significant changes, impacting tumors ranging from glial to ependymal neoplasms. Ependymal tumors were previously classified and graded based on histopathology, which had limited clinical and prognostic utility. The updated CNS5 classification now divides ependymomas into 10 subgroups based on anatomic location (supratentorial, posterior fossa, and spinal compartment) and genomic markers. Supratentorial tumors are defined by zinc finger translocation associated (ZFTA) (formerly v-rel avian reticuloendotheliosis viral oncogene [RELA]), or yes-associated protein 1 (YAP1) fusion; posterior fossa tumors are classified into groups A (PFA) and B (PFB), spinal ependymomas are defined by MYCN amplification. Subependymomas are present across all these anatomic compartments. The new classification kept an open category of "not elsewhere classified" or "not otherwise specified" if no pathogenic gene fusion is identified or if the molecular diagnosis is not feasible. Although there is significant overlap in the imaging findings of these tumors, a neuroradiologist needs to be familiar with updated CNS5 classification to understand tumor behavior, for example, the higher tendency for tumor recurrence along the dural flap for ZFTA fusion-positive ependymomas. On imaging, supratentorial ZFTA-fused ependymomas are preferentially located in the cerebral cortex, carrying predominant cystic components. YAP1-MAMLD1-fused ependymomas are intra- or periventricular with prominent multinodular solid components and have significantly better prognosis than ZFTA-fused counterparts. PFA ependymomas are aggressive paramedian masses with frequent calcification, seen in young children, originating from the lateral part of the fourth ventricular roof. PFB ependymomas are usually midline, noncalcified solid-cystic masses seen in adolescents and young adults arising from the fourth ventricular floor. PFA has a poorer prognosis, higher recurrence, and higher metastatic rate than PFB. Myxopapillary spinal ependymomas are now considered grade II due to high recurrence rates. Spinal-MYCN ependymomas are aggressive tumors with frequent leptomeningeal spread, relapse, and poor prognosis. Subependymomas are noninvasive, intraventricular, slow-growing benign tumors with an excellent prognosis. Currently, the molecular classification does not enhance the clinicopathologic understanding of subependymoma and myxopapillary categories. However, given the molecular advancements, this will likely change in the future. This review provides an updated molecular classification of ependymoma, discusses the individual imaging characteristics, and briefly outlines the latest targeted molecular therapies.

The diagnosis of maturity-onset diabetes of the young (MODY), a monogenic form of diabetes mellitus caused by a mutation in a single gene, is often uncertain until genetic testing is performed. We report a 13-yr-old Korean boy who was initially diagnosed with type 2 diabetes (T2DM). MODY was suspected because of his nonobese body habitus and family history of multiple affected members. Targeted panel sequencing of all MODY-related genes was performed using the NextSeq 550Dx platform (Illumina). Sanger sequencing was performed using blood samples from the parents, siblings, and other relatives. A frameshift variant in the 3' region of the last exon of PDX1 was detected in the patient and his family members with diabetes. PP1_Moderate criterion was applied and this variant was confirmed to be the genetic cause of diabetes in the family and classified as likely pathogenic. The study highlights the importance of genetic testing for nonobese, early-onset diabetic patients with multiple affected family members. Increased awareness and aggressive genetic testing for MODY are needed.

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

Here, we highlight the case of a 31-yr-old man who had clinical features of primary hypertrophic osteoarthropathy (PHOAR) and harbored a homozygous variant (c.38C > A, p.Ala13Glu) in the HPGD gene, as indicated by whole-exome sequencing (WES). This variant has been previously classified by our laboratory as a variant of uncertain significance (VUS). However, another patient with the same phenotype and the same homozygous variant in HPGD was subsequently reported. In reassessing the variant, the absence of this variant in the gnomAD population database, supporting computational predictions, observation in homozygosity in two probands, and specificity of the phenotype for HPGD, all provide sufficient evidence to reclassify the HPGD c.38C > A, p.Ala13Glu variant as likely pathogenic.

Indwelling pleural catheters (IPCs) have rapidly grown in popularity since their introduction for the management of recurrent pleural effusions. In malignant pleural effusions especially, there has been a shift away from measuring pleurodesis success and towards more patient-centred outcomes. Multiple randomised controlled trials have shown that despite lower rates of pleurodesis, symptom control and quality of life outcomes are comparable when compared to alternatives such as talc pleurodesis. IPCs have the added benefit of minimising inpatient hospital stays and reducing the need for recurrent pleural interventions, key priorities for patients with palliative disease. As a result, IPC treatment is associated with excellent patient satisfaction coupled with acceptably low complication rates. Furthermore, in patients with a short life expectancy they confer a cost benefit for the healthcare system.

Far from causing harm, IPCs are now recommended as first-line treatment by current clinical guidelines. In malignant pleural disease, guidance advocates IPCs should be offered as a first-line option with the focus on patient priorities and preferences. Ultimately IPCs provide a safe, effective, ambulatory option for managing recurrent pleural effusions.

Malignant pleural effusions (MPE) tend to recur and require definitive treatment with either chest drain and talc pleurodesis or indwelling pleural catheters (IPCs), which offer similar symptomatic benefits. In recent years, IPCs have become popular due to the presumed convenience of an outpatient procedure followed by home drainage leading to a misconception of IPCs being an ideal treatment for MPE. However, IPCs predispose the patient to multiple complications and have significant physical and psychological implications that are under-recognised. Patients require additional clinical reviews, hospital admissions and treatment for these complications related to IPCs. Additionally, there is a huge psychological impact of living with a home catheter that is a constant reminder of their cancer and this has been shown to affect quality of life negatively. Hence, IPCs should not be considered the "ideal" treatment for MPE management and clinicians should reflect the equipoise of the evidence for the benefits and accurately reflect the adverse effects of IPCs in their discussions with patients to facilitate informed decision making.

Andrey Bogut’s knee injury has potentially sidelined him for the NBA playoffs and casts doubt on his role for the Boomers.

The cast regulars (Anna Marie, Chris and Kelley) are joined by Robert and newcomer Corey to discuss this week's news. A heated debate about free-to-play mechanics breaks out as the crew is split on Genshin Impact and other mobile titles while Chris eats chocolate covered almonds. Three weeks to go until Extra Life!

The post RPG Cast – Episode 560: “Kmart Breath of the Wild” appeared first on RPGamer.

Sam wants two things, coke and nuggs. Robert hails the hypnobooty. Ryan has to go recruit more Ryans. And Chris commissions a new Sesame Street horror adventure. Guard your eyes.

The post RPG Cast – Episode 695: “Jason Statham Is the Best Dinosaur” appeared first on RPGamer.

Publisher indie.io and developer Maple Powered Games announced G.I. Joe: Wrath of Cobra will launch for PlayStation 5, Xbox Series X|S, and Nintendo Switch on November 21.

The game is currently available for PC Steam, Epic Games Store, and GOG.

View the console reveal date trailer below:

Read details on the game below:

Cobra rears its ugly head yet again and it’s up to G.I. Joe to save the world! Embracing the 1980s era of the iconic universe, Wrath of Cobra is a retro side-scrolling beat ’em up. Play as one of the legendary G.I. Joe characters, including Duke, Scarlett, Roadblock, Snake Eyes, and more. Defeat hordes of Cobra troopers, Vipers, Crimson Guards and more of Cobra’s malevolent machinations.

Bring Cobra down, striking back at the likes of Destro, Serpentor, Baroness, and Cobra Commander himself! Fight your own way: Rely on your fists and get up close and personal using each character’s unique combos and special moves or keep your foes at a distance with a variety of weapons!

Retro Gameplay in a Modern Era

Wrath of Cobra takes the classic arcade beat ’em up and brings it into the modern age: Easy to play, hard to master, and smoother than a ride in a H.I.S.S. Want to play with your friends? The game supports local multiplayer (eg. from your couch) and online co-op!

Play as Classic Heroes

Fight Cobra as your favorite G.I. Joe heroes, painstakingly recreated in beautiful pixel art. The differences between characters aren’t just cosmetic: Each hero has different movesets and unique abilities. From the fast and nimble Snake Eyes to the rough and tumble Roadblock, each character is true to form!

Battle Iconic Villains

Cobra isn’t just the Cobra Commander, it’s also its legions! Face hordes of troopers, armored Alley Vipers, artificial B.A.T.s, armed with some of the most iconic weapon systems in the franchise, including the H.I.S.S., C.L.A.W., and the notorious Trubble Bubble.

Retro-Infused Soundtrack

Foil the Commander’s plot to the beat of classic G.I. Joe themes, reimagined by industry veterans at Kid Katana Records, bringing a modern twist to classic arcade music!

Post-Launch Support

Like Destro’s plots, Wrath of Cobra will continue with extensive post-launch support, bringing more G.I. Joe heroes into the fray, adding new game modes, levels, and more to keep the G.I. Joe legacy alive!

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/463047/gi-joe-wrath-of-cobra-releases-november-21-for-ps5-xbox-series-xs-and-switch/

The Real Housewives of Salt Lake City is TV’s best soap opera, week after week offering twists more shocking than secret twins and characters returning from the dead. That’s because it’s all real, happening in the most haunted suburb in the continental United States.

Where else do two women connect over knowing the long-lost birth father of one’s child? Is there another city where women squabble over body positivity in a parking lot off the side of a snowy mountain? Surely, there’s no other place on Earth where Lisa Barlow could come across anywhere near a voice of reason.

But that all happens here in Salt Lake City. Five episodes in, Season 5 has continued to evolve into the most captivating season in modern Real Housewives history, carried by the ever-changing bonds between our OGs and a team of wonderfully bizarre newbies.

Read more at The Daily Beast.

A hotel worker called 911 to request urgent assistance before musician Liam Payne fell to his death from the third floor of the building in Buenos Aires on Wednesday.

The 31-year-old British singer and former member of the boy band One Direction died after he “jumped from the balcony of his room,” Buenos Aires Security Ministry Communications Director Pablo Policicchio told the Associated Press. He added that police had been called to the Casa Sur Hotel in the Argentine capital after receiving an emergency call shortly after 5 p.m. local time about an “aggressive man who could be under the influence of drugs or alcohol.”

A transcript of a 911 call published by the BBC shows a worker at the hotel telling the operator that they have “a guest who is high on drugs and who is trashing the room” and the staff therefore “need someone to come.”

Read more at The Daily Beast.

Stroll on down to Uncle Capcom's garage, girls and boys, because it's time to meddle with a cat's voicebox, ride a combat peacock and meticulously injure a vast, blubbery teddybear. By which I mean, the Monster Hunter Wilds beta is now live on Steam through to 4th November at 2.59am GMT. That's 2.59am sharp. If you're hurrying along at 3am on Monday absolutely desperate to polish the aesthetics of a small enslaved catperson, you can sod off and play Dragon Age: The Veilguard instead.

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Like a plague doctor delicately administering another handful of leeches, Ice Pick Lodge have shared a bit more about the recently announced Pathologic 3, explaining how their plans for the cult epidemic-battling series have progressed since the release of Pathologic 2.

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When I was a competitive long-distance runner at school, breath control was paramount. We were never really taught this, mind. It was an art you picked up through practice: how to breathe before the race, saturating your blood with O2 without dizzying yourself; when to permit the shorter, emergency breaths and when to apply restraint; when to deepen your inhales and charge yourself up for an attack on a hill.

And then, how to organise your body around your breath, straightening your posture to expand your lungs without tipping back too far and squandering muscle power; how to breath in time with your stride and the movement of your shoulders, so as to firm up your momentum and shave a miraculous-feeling minute off your finishing time. All this, plus various daft psychological war gambits of my own devising. When overtaking or being overtaken, I used to seal my lips shut on that side and breath through the other corner of my mouth, to make it look like I was hardly out of breath at all.

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In America, there’s a significant kind of public insistence that one’s “freedom” is fundamentally tied to one’s wealth.

Much of the country views America through an aspirational and transformative lens, a colorblind and bias-free utopia, wherein wealth conveys equality and acts as a panacea for social and racial ills. Once an individual achieves massive financial success, or so the message goes, he or she will “transcend” the scourge of economic and racial inequality, truly becoming “free.”

Working in parallel with this reverence for this colorblind version of the “American Dream” is the belief that economic privilege mandates patriotic gratitude. Across industries and disciplines, Americans are told to love their nation uncritically, be thankful that they are exceptional enough to live in a country that allows citizens the opportunity to reach astronomical heights of economic prosperity.

For the nation’s black citizens, there’s often an additional racialized presumption lurking under the surface of these concepts: the notion that black success and wealth demands public silence on systemic issues of inequality and oppression.

These are durable and fragile ideologies that prop up the concept of the American Dream – durable because they are encoded in the very fabric of American culture (most Americans, including African Americans, have readily embraced these ideologies as assumed facts); yet fragile because it’s all too easy to see that one’s economic privilege is a lousy barrier against both individual and systemic discrimination and oppression.

Consequently, black people have also been among the most vocal challengers of these ideologies, as we’ve seen most recently with the Colin Kaepernick and the NFL #TakeAKnee demonstrations. In a show of solidary with the free agent quarterback, professional football players – the vast majority of whom are black – have been kneeling during the National Anthem as a means of protesting racial injustice and police brutality.

WATCH: NFL players team up in defiance and solidarity

Over the past few weeks, the president of the United States has brought renewed attention to the inherent tensions that define the ideologies of the “American Dream” through his repeated public criticisms of these kneeling NFL players.

“If a player wants the privilege of making millions of dollars in the NFL, or other leagues,” Trump recently tweeted, he or she should not be allowed to kneel. Labeling the protestors actions “disrespectful” to the country, flag and anthem, President Donald Trump has called for players to be fired, encouraged a boycott of the NFL, insisted that the league pass a rule mandating that players stand for the anthem and derided the protestors as “sons of bitches.”

In a dramatic ploy more befitting of a scripted reality television show, the president gloated that he had instructed Vice President Mike Pence to walk out of an Indianapolis Colts game the moment any player kneeled. This was an orchestrated show of power and outrage, designed to send a flamboyant political message given that Trump and Pence knew in advance that on that particular day, the Colts were playing the San Francisco 49ers – the team that currently has the most protestors. The NFL’s announcement this week that the league has no plans to penalize protesting players is the most recent event to provoke the president’s fury; taking to social media during the early morning, he once again equated kneeling with “total disrespect” for our country.

As many have pointed out, the president’s moralizing outrage toward the NFL players is selective and deeply flawed – his apparent patriotic loyalty hasn’t stopped the billionaire politician from criticizing the removal of Confederate statues, or attacking a Gold Star family, or mocking Sen. John McCain’s military service.

The NFL players and their defenders have repeatedly stated that the protests are intended to highlight racial inequality and oppression. They’ve also explained that their decision to kneel emerged from a desire to protest peacefully and respectfully after a sustained conversation with military veterans.

Trump has chosen to ignore these rationales and the structural issues of inequality that motivate the protests and instead, advance a narrative exclusively concerned with overt displays of American patriotism and the “privilege” of the NFL players. As one of president’s advisors explained, by aggressively targeting the NFL players, Trump believes that he is “winning the cultural war,” having made black “millionaire sport athletes his new [Hillary Clinton].”

READ MORE: As ‘America’s sport,’ the NFL cannot escape politics

It’s a cynical statement, revealing the president’s perception of the jingoism of his base of supporters who envision him as a crusader for American values and symbols.

In casting the black protestors as the antithesis of all of this, Trump has marked the players as unpatriotic elites and enemies of the nation. For a president who has consistently fumbled his way through domestic and foreign policy since he was elected, a culture war between “hard-working” and “virtuous” working-class and middle-class white Americans and rich, ungrateful black football players is a welcome public distraction.

Trump’s attacks on the NFL protestors are rooted in those competing tensions inherent to the American Dream: that wealth equals freedom; that economic privilege demands patriotic gratitude; and most importantly, that black people’s individual economic prosperity invalidates their concerns about systemic injustice and requires their silence on racial oppression.

Among the protestors’ detractors, this has become a common line of attack, a means of disparaging the black NFL players’ activism by pointing to their apparent wealth. The fact that systemic racism is demonstrably real and that individual prosperity does not make one immune to racial discrimination appears to be lost on the protestors’ critics.

Theirs is a grievance that suggests that black athletes should be grateful to live in this country; that racism can’t exist in America since black professional athletes are allowed to play and sign contracts for considerable sums of money; that black players owe the nation their silence since America “gave” them opportunity and access; that black athletes have no moral authority on issues of race and inequality because of their individual success; and that black athletes’ success was never theirs to earn, but instead, was given to them and can just as easily be taken away.

This culture war being waged over black athletes is not new. Black athletes – and entertainers – have long been hyper-aware of their peculiar place in American society as individuals beloved for their athletic and artistic talents, yet reviled the moment they use their public platform to protest systemic racial inequality. The parallels between the #TakeAKnee protests and the protests of Muhammad Ali or John Carlos and Tommie Smith are readily apparent; so too are there important similarities to the case of Paul Robeson.

An outspoken civil rights activist, collegiate and professional football player, lawyer, opera singer and actor, Robeson had his passport revoked in 1950 because of his political activism and speech – actions that all but destroyed his career. The star athlete and entertainer, “who had exemplified American upward mobility” quickly “became public enemy number one” as institutions cancelled his concerts, the public called for his death and anti-Robeson mobs burned effigies of him.

During a 1956 congressional hearing, the chairman of the House Committee on Un-American Activities beat a familiar refrain with Robeson, challenging the entertainer’s accusations of American racism and racial oppression. He saw no sign of prejudice, he argued, since Robeson was privileged, having gone to elite universities and playing collegiate and professional football.

READ MORE: Poll: Americans divided on NFL protests

Black athletes, even the silent ones, largely understand that their economic privilege doesn’t insulate them from the realities of racial discrimination. They also understand that their wealth and success is precarious and is often dependent not only upon their athletic performance, but also upon them remaining silent on issues of racial injustice, especially those that appear to question the “American Dream” or implicate the American public by association.

It should come as no surprise then that Colin Kaepernick, whose protests turned him into a national pariah despite his on-the-field talents, has filed a grievance against the NFL, accusing the league and its teams of blackballing him because of his political beliefs. “Principled and peaceful political protest,” Kaepernick’s lawyers argued in a statement, “should not be punished and athletes should not be denied employment based on partisan political provocation by the Executive Branch of our government.” Whether the ostracized Kaepernick will win his grievance is unknown, but it is certainly telling that he and his lawyers have rooted their claims in contested definitions of freedom and the precarious economic privilege of outspoken NFL players.

For the loudest and most vocal critics of black protestors, in particular, outspokenness is tantamount to treason, grounds for the harshest of punishments. Perhaps they would benefit from a close reading of James Baldwin, who once argued: “I love America more than any other country in this world, and, exactly for this reason, I insist on the right to criticize her perpetually.”

The post Column: For black athletes, wealth doesn’t equal freedom appeared first on PBS NewsHour.

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HARI SREENIVASAN: Let’s turn to the continuing fallout and reaction to the Harvey Weinstein story.

Yesterday, Weinstein resigned from the board of his production company following numerous revelations of sexual harassment and several allegations of assault.

More than three dozen women have said Weinstein harassed them. While Weinstein has admitted to behaving inappropriately, he has said he didn’t physically assault anyone.

One of those women is Katherine Kendall. She was a 23-year-old actress who met Weinstein in 1993. She alleges that he invited her to his apartment in New York, where, she says, he took off his clothes and asked for a massage.

As other actresses began coming forward about their painful experiences, she also went public with her own story.

She joins me now from Los Angeles.

First, thanks for joining us.

And I don’t want to relive something that’s painful for you, but you are taking a public stance on it.

For people who don’t know your story, what happened?

KATHERINE KENDALL, Actress/ Photographer: Well, I was you know, a young actress, and I had had a formal meeting at the Miramax office earlier that day.

And then, at the end of the meeting, which I thought went really well, he invited me to come to screenings. He said: “Welcome to the Miramax family. You know, come to premieres, screenings, et cetera. In fact, there’s one this afternoon. Would you like to come?”

And I said, “Sure.”

And I ended up going to see a movie with him. It ended up just being a movie, not a screening, but the film “Red Rock West.” And, you know, that’s right when I had this sort of sinking feeling that something wasn’t going right.

And then, after the movie, we walked for a few blocks. And he said he needed to go up to his apartment to get something, and would I just come with him real quick? And I sort of said no, and we went back and forth on that for a minute. It was sort of a negotiation with him always, trying to sort of stand my ground, but then be convinced it was OK.

I did go into his apartment. Once there, we talked for a long time about art and movies. And I felt like he was treating me like an intellect.

And I felt like the meeting was going really well, and sort of continued. I didn’t feel unsafe once I was in there. And, at one point, then, he got up to go to the bathroom. And he came back in a robe and asked me to give him a massage.

And I was extremely uncomfortable. And I was like, oh, God, no, I’m not comfortable with that. And we went back and forth on that.

And then he went back to the bathroom again, and came back this time completely naked. And, you know, that changed it entirely for me, too. It just took it to the next place. It was completely disorienting. And I was scared, you know? I was really scared.

And then it became sort of a cat-and-mouse game of, like, how am I going to get out of there?

And I’m — it’s hard to make sense of what someone is trying to do to you when they’re fully naked, and they’re…

HARI SREENIVASAN: Yes.

KATHERINE KENDALL: You know, I’m 105 pounds. He’s a large man standing between me and the door.

And, I mean, I felt very resolute, like, I will definitely get out of here somehow. But I’m not — I’m not sure — I’m not sure what’s going to happen here. You know, a lot was going through my head.

And he said, well, if you won’t give me a massage, will you at least show me your breasts? And it was just — you know, it was, all in all, an extremely humiliating experience for me.

And even though I got away, I felt like something had still — like something horrible had just happened to me.

HARI SREENIVASAN: You know, in the immediate aftermath, did you tell someone about it? Because you have said before that you felt ashamed…

KATHERINE KENDALL: I did.

HARI SREENIVASAN: … even though you were the victim.

KATHERINE KENDALL: I did.

It’s really interesting how that happens. And I think — you know, I’m older now, and I have done some work on myself. And I have learned that a lot of people feel that way.

It’s — it’s not — it wasn’t just me. But the just me feeling that this is my fault, this must have only happened to me, there’s something wrong with me, is so common when someone perpetrates against you.

HARI SREENIVASAN: What were the…

KATHERINE KENDALL: And I did. I told my mom.

And I told some good friends. But, you know, one of the things that happened was, I didn’t want them to tell anybody. You know, people wanted to help me, but they didn’t know how, and I didn’t want them to try too hard, because I didn’t want it to backlash.

I was scared. And I think that it’s important to remember that we don’t really come from a culture that supports women in talking about sexual harassment, in my — in my experience, that is. And, you know, I just haven’t felt like it was something I was going to get support on…

HARI SREENIVASAN: You know, how long…

KATHERINE KENDALL: … in the bigger picture.

HARI SREENIVASAN: Yes.

How long did this feeling last? Or, I guess, what are the longer-term ripple effects here? Did it shake your confidence in your abilities?

KATHERINE KENDALL: I think it did. I think it did. I think it did.

I think it made me feel like, wow, you know, that was a wash. He wasn’t interested at all in what I had to say, or, you know, he didn’t see any talent there or intellect there. He was assessing the situation the whole time for something else.

And I think that — that did hurt. You know, I wish it didn’t.

HARI SREENIVASAN: Yes.

KATHERINE KENDALL: But he had produced so many movies that I thought were wonderful. And it was — it’s hard when someone has made art that you love, and how do you stay attached to liking their art, but feeling conflicted about them?

And, yes, I think it does have long-term effects. I think you tuck it away. And then, for me, also, I realized that it came back when I would see his name or see him in person. I would start to sort of tremble all over again.

I mean, I wouldn’t think about him on a daily basis or anything for years, and then I would see him, and I would think, oh, I don’t feel well. I got to get out of here.

HARI SREENIVASAN: Right.

KATHERINE KENDALL: You know, it would bring up so much emotion.

And the most recent one was the woman in New York, the Italian model. I felt so, so enraged when I saw what happened there, and that they sort of — the police had him, and that then he got away. And then she was being dragged through the press as somebody who just, you know, wanted a payout, et cetera.

HARI SREENIVASAN: You know, in the wake of that, there was — a friend of yours had tweeted, “At some point, all the women who have been afraid to speak out about Harvey Weinstein are going to have to hold hands and jump.” This was back in 2015.

And from your Twitter account, you said, “Agreed.”

It seemed like you almost had the opportunity to come forward.

What made you want to come forward now? Has this become a turning point in the industry?

KATHERINE KENDALL: This is a turning point. It’s a turning point.

There are so many times when I thought about it, and then felt like — there were times when I thought about it and said, well, I have nothing to lose, I will just do it. And then I thought, I — I just didn’t have the strength or the courage yet.

And I think somebody like Jodi Kantor doing the story for The New York Times, the fact that she thought it was a story at all was startling to me and made me feel like, wow, something is going to be done.

And I knew she had told me — I mean, they were looking for women that this had happened to, because they’d been hearing rumors for so long that it happened to so many people. And she had told me other people were coming out.

And I thought, I can’t — when I watched Rose McGowan or any of the other actresses come forward, I just — or Ashley Judd — I just thought, they look strong to me, and I don’t want to be the one that stays silent.

HARI SREENIVASAN: Well, Katherine Kendall…

KATHERINE KENDALL: I want to stand beside them.

HARI SREENIVASAN: Katherine Kendall, thank you very much for speaking with us.

And, hopefully, there are other people that are empowered by you coming forward.

KATHERINE KENDALL: I hope so. Thank you.

The post Escaping Harvey Weinstein was a ‘cat-and-mouse game,’ says Katherine Kendall appeared first on PBS NewsHour.

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