bra Branch site recognition by the spliceosome [REVIEW] By rnajournal.cshlp.org Published On :: 2024-10-16T07:18:13-07:00 The spliceosome is a eukaryotic multimegadalton RNA–protein complex that removes introns from transcripts. The spliceosome ensures the selection of each exon-intron boundary through multiple recognition events. Initially, the 5' splice site (5' SS) and branch site (BS) are bound by the U1 small nuclear ribonucleoprotein (snRNP) and the U2 snRNP, respectively, while the 3' SS is mostly determined by proximity to the branch site. A large number of splicing factors recognize the splice sites and recruit the snRNPs before the stable binding of the snRNPs occurs by base-pairing the snRNA to the transcript. Fidelity of this process is crucial, as mutations in splicing factors and U2 snRNP components are associated with many diseases. In recent years, major advances have been made in understanding how splice sites are selected in Saccharomyces cerevisiae and humans. Here, I review and discuss the current understanding of the recognition of splice sites by the spliceosome with a focus on recognition and binding of the branch site by the U2 snRNP in humans. Full Article
bra Differential Tissue Abundance of Membrane-Bound Drug Metabolizing Enzymes and Transporter Proteins by Global Proteomics [Special Section on New and Emerging Areas and Technologies in Drug Metabolism and Disposition, Part II] By dmd.aspetjournals.org Published On :: 2024-10-16T09:02:03-07:00 Protein abundance data of drug-metabolizing enzymes and transporters (DMETs) are useful for scaling in vitro and animal data to humans for accurate prediction and interpretation of drug clearance and toxicity. Targeted DMET proteomics that relies on synthetic stable isotope-labeled surrogate peptides as calibrators is routinely used for the quantification of selected proteins; however, the technique is limited to the quantification of a small number of proteins. Although the global proteomics-based total protein approach (TPA) is emerging as a better alternative for large-scale protein quantification, the conventional TPA does not consider differential sequence coverage by identifying unique peptides across proteins. Here, we optimized the TPA approach by correcting protein abundance data by the sequence coverage, which was applied to quantify 54 DMETs for characterization of 1) differential tissue DMET abundance in the human liver, kidney, and intestine, and 2) interindividual variability of DMET proteins in individual intestinal samples (n = 13). Uridine diphosphate-glucuronosyltransferase 2B7 (UGT2B7), microsomal glutathione S-transferases (MGST1, MGST2, and MGST3) carboxylesterase 2 (CES2), and multidrug resistance-associated protein 2 (MRP2) were expressed in all three tissues, whereas, as expected, four cytochrome P450s (CYP3A4, CYP3A5, CYP2C9, and CYP4F2), UGT1A1, UGT2B17, CES1, flavin-containing monooxygenase 5, MRP3, and P-glycoprotein were present in the liver and intestine. The top three DMET proteins in individual tissues were: CES1>CYP2E1>UGT2B7 (liver), CES2>UGT2B17>CYP3A4 (intestine), and MGST1>UGT1A6>MGST2 (kidney). CYP3A4, CYP3A5, UGT2B17, CES2, and MGST2 showed high interindividual variability in the intestine. These data are relevant for enhancing in vitro to in vivo extrapolation of drug absorption and disposition and can be used to enhance the accuracy of physiologically based pharmacokinetic prediction of systemic and tissue concentration of drugs. SIGNIFICANCE STATEMENT This study quantified the abundance and compositions of drug-metabolizing enzymes and transporters in pooled human liver, intestine, and kidney microsomes as well as individual intestinal microsomes using an optimized global proteomics approach. The data revealed large intertissue differences in the abundance of these proteins and high intestinal interindividual variability in the levels of cytochrome P450s (e.g., CYP3A4 and CYP3A5), uridine diphosphate-glucuronosyltransferase 2B17, carboxylesterase 2, and microsomal glutathione S-transferase 2. These data are applicable for the prediction of first-pass metabolism and tissue-specific drug clearance. Full Article
bra 50th Anniversary Celebration Collection Special Section on New and Emerging Areas and Technologies in Drug Metabolism and Disposition, Part II--Editorial [Special Section on New and Emerging Areas and Technologies in Drug Metabolism and Disposition, Part By dmd.aspetjournals.org Published On :: 2024-10-16T09:02:03-07:00 Full Article
bra Association of Free-to-Total PSA Ratio and 18F-DCFPyL Prostate-Specific Membrane Antigen PET/CT Findings in Patients with Biochemical Recurrence After Radical Prostatectomy: A Prospective Single-Center Study By jnm.snmjournals.org Published On :: 2024-11-01T04:25:31-07:00 In Canada and across the globe, access to PSMA PET/CT is limited and expensive. For patients with biochemical recurrence (BCR) after treatment for prostate cancer, novel strategies are needed to better stratify patients who may or may not benefit from a PSMA PET scan. The role of the free-to-total prostate-specific antigen (PSA) ratio (FPSAR) in posttreatment prostate cancer, specifically in the PSMA PET/CT era, remains unknown. Our aim in this study was to determine the association of FPSAR in patients referred for 18F-DCFPyL PSMA PET/CT in the BCR setting and assess the correlation between FPSAR and 18F-DCFPyL PSMA PET/CT positivity (local recurrence or distant metastases). Methods: This prospective study included 137 patients who were referred for 18F-DCFPyL PSMA PET/CT and had BCR with a total PSA of less than 1 ng/mL after radical prostatectomy (RP) (including adjuvant or salvage radiotherapy). Blood samples were collected on the day of 18F-DCFPyL PSMA PET/CT. FPSAR was categorized as less than 0.10 or as 0.10 or more. A positive 18F-DCFPyL PSMA PET/CT scan was defined by a PROMISE classification lesion score of 2 or 3, irrespective of the site of increased tracer uptake (e.g., prostate, pelvic nodes, bone, or viscera). Results: Overall, 137 blood samples of patients with BCR after RP were analyzed to calculate FPSAR. The median age at 18F-DCFPyL PSMA PET/CT was 68.6 y (interquartile range, 63.0–72.4 y), and the median PSA at 18F-DCFPyL PSMA PET/CT was 0.3 ng/mL (interquartile range, 0.3–0.6 ng/mL). Eighty-six patients (62.8%) had an FPSAR of less than 0.10, whereas 51 patients (37.2%) had an FPSAR of 0.10 or more. An FPSAR of 0.10 or more was identified as an independent predictor of a positive 18F-DCFPyL PSMA PET/CT scan, with an odds ratio of 6.99 (95% CI, 2.96–16.51; P < 0.001). Conclusion: An FPSAR of 0.10 or more after RP independently correlated with increased odds of a positive 18F-DCFPyL PSMA PET/CT scan among BCR post-RP patients. These findings may offer an inexpensive method by which to triage access to 18F-DCFPyL PSMA PET/CT in jurisdictions where availability is not replete. Full Article
bra The 75-Year Anniversary of the Department of Physiology and Pharmacology at Karolinska Institutet--Examples of Recent Accomplishments and Future Perspectives [75th Anniversary Celebration Collection Special Section-Perspective] By pharmrev.aspetjournals.org Published On :: 2024-10-16T07:40:25-07:00 Karolinska Institutet is a medical university encompassing 21 departments distributed across three departmental or campus groups. Pharmacological research has a long and successful tradition at the institute with a multitude of seminal findings in the areas of neuronal control of vasodilatation, cardiovascular pharmacology, neuropsychopharmacology, receptor pharmacology, and pharmacogenomics that resulted in, among many other recognitions, two Nobel prizes in Physiology and Medicine, one in 1970 to Ulf von Euler for his discovery of the processes involved in storage, release, and inactivation of neurotransmitters and the other in 1982 to Sune Bergström and Bengt Samuelsson for their work on prostaglandins and the discovery of leukotrienes. Pharmacology at Karolinska Institutet has over the last decade been ranked globally among the top 10 according to the QS World University Ranking. With the Department of Physiology and Pharmacology now celebrating its 75-year anniversary, we wanted to take this as an opportunity to showcase recent research achievements and how they paved the way for current activities at the department. We emphasize examples from preclinical and clinical research where the dpartment's integrative environment and robust infrastructure have successfully facilitated the translation of findings into clinical applications and patient benefits. The close collaboration between preclinical scientists and clinical researchers across various disciplines, along with a strong network of partnerships within the department and beyond, positions us to continue leading world-class pharmacological research at the Department of Physiology and Pharmacology for decades to come. Significance Statement Pharmacological research at Karolinska Institutet has a long and successful history. Given the 75-year anniversary of the Department of Physiology and Pharmacology, this perspective provides an overview of recent departmental achievements and future trajectories. For these developments, interdisciplinary and intersectoral collaborations and a clear focus on result translation are key elements to continue its legacy of world-leading pharmacological research. Full Article
bra Pharmacological Approaches to Hearing Loss [75th Anniversary Celebration Collection Special Section] By pharmrev.aspetjournals.org Published On :: 2024-10-16T07:40:25-07:00 Hearing disorders pose significant challenges to individuals experiencing them and their overall quality of life, emphasizing the critical need for advanced pharmacological approaches to address these conditions. Current treatment options often focus on amplification devices, cochlear implants, or other rehabilitative therapies, leaving a substantial gap regarding effective pharmacological interventions. Advancements in our understanding of the molecular and cellular mechanisms involved in hearing disorders induced by noise, aging, and ototoxicity have opened new avenues for drug development, some of which have led to numerous clinical trials, with promising results. The development of optimal drug delivery solutions in animals and humans can also enhance the targeted delivery of medications to the ear. Moreover, large genome studies contributing to a genetic understanding of hearing loss in humans combined with advanced molecular technologies in animal studies have shown a great potential to increase our understanding of the etiologies of hearing loss. The auditory system exhibits circadian rhythms and temporal variations in its physiology, its vulnerability to auditory insults, and its responsiveness to drug treatments. The cochlear clock rhythms are under the control of the glucocorticoid system, and preclinical evidence suggests that the risk/benefit profile of hearing disorder treatments using chronopharmacological approaches would be beneficial. If translatable to the bedside, such approaches may improve the outcome of clinical trials. Ongoing research into the molecular and genetic basis of auditory disorders, coupled with advancements in drug formulation and delivery as well as optimized timing of drug administration, holds great promise of more effective treatments. Significance Statement Hearing disorders pose significant challenges to individuals and their overall quality of life, emphasizing the critical need for advanced pharmacological approaches to address these conditions. Ongoing research into the molecular and genetic basis of auditory disorders, coupled with advancements in drug delivery procedures and optimized timing of drug administration, holds the promise of more effective treatments. Full Article
bra Nitric Oxide Signaling and Regulation in the Cardiovascular System: Recent Advances [75th Anniversary Celebration Collection Special Section] By pharmrev.aspetjournals.org Published On :: 2024-10-16T07:40:25-07:00 Nitric oxide (NO) from endothelial NO synthase importantly contributes to vascular homeostasis. Reduced NO production or increased scavenging during disease conditions with oxidative stress contribute to endothelial dysfunction and NO deficiency. In addition to the classical enzymatic NO synthases (NOS) system, NO can also be generated via the nitrate-nitrite-NO pathway. Dietary and pharmacological approaches aimed at increasing NO bioactivity, especially in the cardiovascular system, have been the focus of much research since the discovery of this small gaseous signaling molecule. Despite wide appreciation of the biological role of NOS/NO signaling, questions still remain about the chemical nature of NOS-derived bioactivity. Recent studies show that NO-like bioactivity can be efficiently transduced by mobile NO-ferroheme species, which can transfer between proteins, partition into a hydrophobic phase, and directly activate the soluble guanylyl cyclase-cGMP-protein kinase G pathway without intermediacy of free NO. Moreover, interaction between red blood cells and the endothelium in the regulation of vascular NO homeostasis have gained much attention, especially in conditions with cardiometabolic disease. In this review we discuss both classical and nonclassical pathways for NO generation in the cardiovascular system and how these can be modulated for therapeutic purposes. Significance Statement After four decades of intensive research, questions persist about the transduction and control of nitric oxide (NO) synthase bioactivity. Here we discuss NO signaling in cardiovascular health and disease, highlighting new findings, such as the important role of red blood cells in cardiovascular NO homeostasis. Nonclassical signaling modes, like the nitrate-nitrite-NO pathway, and therapeutic opportunities related to the NO system are discussed. Existing and potential pharmacological treatments/strategies, as well as dietary components influencing NO generation and signaling are covered. Full Article
bra International Union of Basic and Clinical Pharmacology CXV: The Class F of G Protein-Coupled Receptors [75th Anniversary Celebration Collection Special Section] By pharmrev.aspetjournals.org Published On :: 2024-10-16T07:40:25-07:00 The class F of G protein-coupled receptors (GPCRs) consists of 10 Frizzleds (FZD1–10) and Smoothened (SMO). FZDs bind and are activated by secreted lipoglycoproteins of the Wingless/Int-1 (WNT) family, and SMO is indirectly activated by the Hedgehog (Hh) family of morphogens acting on the transmembrane protein Patched. The advance of our understanding of FZDs and SMO as dynamic transmembrane receptors and molecular machines, which emerged during the past 14 years since the first-class F GPCR IUPHAR nomenclature report, justifies an update. This article focuses on the advances in molecular pharmacology and structural biology providing new mechanistic insight into ligand recognition, receptor activation mechanisms, signal initiation, and signal specification. Furthermore, class F GPCRs continue to develop as drug targets, and novel technologies and tools such as genetically encoded biosensors and CRISP/Cas9 edited cell systems have contributed to refined functional analysis of these receptors. Also, advances in crystal structure analysis and cryogenic electron microscopy contribute to the rapid development of our knowledge about structure-function relationships, providing a great starting point for drug development. Despite the progress, questions and challenges remain to fully understand the complexity of the WNT/FZD and Hh/SMO signaling systems. Significance Statement The recent years of research have brought about substantial functional and structural insight into mechanisms of activation of Frizzleds and Smoothened. While the advance furthers our mechanistic understanding of ligand recognition, receptor activation, signal specification, and initiation, broader opportunities emerge that allow targeting class F GPCRs for therapy and regenerative medicine employing both biologics and small molecule compounds. Full Article
bra Neuroactive Kynurenines as Pharmacological Targets: New Experimental Tools and Exciting Therapeutic Opportunities [75th Anniversary Celebration Collection Special Section] By pharmrev.aspetjournals.org Published On :: 2024-10-16T07:40:25-07:00 Both preclinical and clinical studies implicate functional impairments of several neuroactive metabolites of the kynurenine pathway (KP), the major degradative cascade of the essential amino acid tryptophan in mammals, in the pathophysiology of neurologic and psychiatric diseases. A number of KP enzymes, such as tryptophan 2,3-dioxygenase (TDO2), indoleamine 2,3-dioxygenases (IDO1 and IDO2), kynurenine aminotransferases (KATs), kynurenine 3-monooxygenase (KMO), 3-hydroxyanthranilic acid oxygenase (3-HAO), and quinolinic acid phosphoribosyltransferase (QPRT), control brain KP metabolism in health and disease and are therefore increasingly considered to be promising targets for the treatment of disorders of the nervous system. Understanding the distribution, cellular expression, and regulation of KP enzymes and KP metabolites in the brain is therefore critical for the conceptualization and implementation of successful therapeutic strategies. Significance Statement Studies have implicated the kynurenine pathway of tryptophan in the pathophysiology of neurologic and psychiatric diseases. Key enzymes of the kynurenine pathway regulate brain metabolism in both health and disease, making them promising targets for treating these disorders. Therefore, understanding the distribution, cellular expression, and regulation of these enzymes and metabolites in the brain is critical for developing effective therapeutic strategies. This review endeavors to describe these processes in detail.: Full Article
bra Seventy-Five Years of Interactions: The Department of Physiology and Pharmacology at Karolinska Institutet and Pharmacological Reviews [75th Anniversary Celebration Collection Special Section-Editorial] By pharmrev.aspetjournals.org Published On :: 2024-10-16T07:40:25-07:00 Full Article
bra Summing Up Pharmacological Reviews 75th Anniversary Year and a Look to the Future [75th Anniversary Celebration Collection Special Section-Editorial] By pharmrev.aspetjournals.org Published On :: 2024-10-16T07:40:25-07:00 Full Article
bra Probabilistic Presurgical Language fMRI Atlas of Patients with Brain Tumors [CLINICAL PRACTICE] By www.ajnr.org Published On :: 2024-11-07T15:14:12-08:00 BACKGROUND AND PURPOSE: Patients with brain tumors have high intersubject variation in putative language regions, which may limit the utility of straightforward application of healthy subject brain atlases in clinical scenarios. The purpose of this study was to develop a probabilistic functional brain atlas that consolidates language functional activations of sentence completion and Silent Word Generation language paradigms using a large sample of patients with brain tumors. MATERIALS AND METHODS: The atlas was developed using retrospectively collected fMRI data from patients with brain tumors who underwent their first standard-of-care presurgical language fMRI scan at our institution between July 18, 2015, and May 13, 2022. Three hundred seventeen patients (861 fMRI scans) were used to develop the language functional atlas. An independent presurgical language fMRI data set of 39 patients with brain tumors from a previous study was used to evaluate our atlas. Family-wise error–corrected binary functional activation maps from sentence completion, letter fluency, and category fluency presurgical fMRI were used to create probability overlap maps and pooled probabilistic overlap maps in Montreal Neurological Institute standard space. The Wilcoxon signed-rank test was used to determine a significant difference in the maximum Dice coefficient for our atlas compared with a meta-analysis-based template with respect to expert-delineated primary language area activations. RESULTS: Probabilities of activating the left anterior primary language area and left posterior primary language area in the temporal lobe were 87.9% and 91.5%, respectively, for sentence completion, 88.5% and 74.2%, respectively, for letter fluency, and 83.6% and 67.6%, respectively, for category fluency. Maximum Dice coefficients for templates derived from our language atlas were significantly higher than the meta-analysis-based template in the left anterior primary language area (0.351 and 0.326, respectively, P < .05) and the left posterior primary language area in the temporal lobe (0.274 and 0.244, respectively, P < .005). CONCLUSIONS: Brain tumor patient- and paradigm-specific probabilistic language atlases were developed. These atlases had superior spatial agreement with fMRI activations in individual patients compared with the meta-analysis-based template. Full Article
bra Neuroimaging Correlates with Clinical Severity in Wilson Disease: A Multiparametric Quantitative Brain MRI [RESEARCH] By www.ajnr.org Published On :: 2024-11-07T15:14:12-08:00 BACKGROUND AND PURPOSE: Previous studies have reported metal accumulation and microstructure changes in deep gray nuclei (DGN) in Wilson disease (WD). However, there are limited studies that investigate whether there is metal accumulation and microstructure changes in DGN of patients with WD with normal-appearing routine MRI. This study aimed to evaluate multiparametric changes in DGN of WD and whether the findings correlate with clinical severity in patients with WD. MATERIALS AND METHODS: The study enrolled 28 patients with WD (19 with neurologic symptoms) and 25 controls. Fractional anisotropy (FA), mean diffusivity (MD), and magnetic susceptibility in globus pallidus, pontine tegmentum, dentate nucleus, red nucleus, head of caudate nucleus, putamen, substantia nigra, and thalamus were extracted. Correlations between imaging data and the Unified Wilson’s Disease Rating Scale (UWDRS) neurologic subitems were explored. RESULTS: FA, MD, and susceptibility values were higher in multiple DGN of patients with WD than controls (P < .05). Patients with WD without abnormal signals in DGN on routine MRI also had higher FA, MD, and susceptibility values than controls (P < .017). We found that UWDRS neurologic subscores correlated with FA and susceptibility values of DGN (P < .05). In addition, we also found that FA and susceptibility values in specific structures correlated with specific neurologic symptoms of WD (ie, tremor, parkinsonism, dysarthria, dystonia, and ataxia) (P < .05). CONCLUSIONS: Patients with WD have increased FA, MD, and susceptibility values even before the lesion is morphologically apparent on routine MRI. The increased FA and susceptibility values correlate with clinical severity of WD. Full Article
bra De novo TRPM3 missense variant associated with neurodevelopmental delay and manifestations of cerebral palsy [RESEARCH ARTICLE] By molecularcasestudies.cshlp.org Published On :: 2024-01-10T08:13:38-08:00 We identified a de novo heterozygous transient receptor potential cation channel subfamily M (melastatin) member 3 (TRPM3) missense variant, p.(Asn1126Asp), in a patient with developmental delay and manifestations of cerebral palsy (CP) using phenotype-driven prioritization analysis of whole-genome sequencing data with Exomiser. The variant is localized in the functionally important ion transport domain of the TRPM3 protein and predicted to impact the protein structure. Our report adds TRPM3 to the list of Mendelian disease–associated genes that can be associated with CP and provides further evidence for the pathogenicity of the variant p.(Asn1126Asp). Full Article
bra The importance of escalating molecular diagnostics in patients with low-grade pediatric brain cancer [PRECISION MEDICINE IN PRACTICE] By molecularcasestudies.cshlp.org Published On :: 2024-01-10T08:13:38-08:00 Pilocytic astrocytomas are the most common pediatric brain tumors, typically presenting as low-grade neoplasms. We report two cases of pilocytic astrocytoma with atypical tumor progression. Case 1 involves a 12-yr-old boy with an unresectable suprasellar tumor, negative for BRAF rearrangement but harboring a BRAF p.V600E mutation. He experienced tumor size reduction and stable disease following dabrafenib treatment. Case 2 describes a 6-yr-old boy with a thalamic tumor that underwent multiple resections, with no actionable driver detected using targeted next-generation sequencing. Whole-genome and RNA-seq analysis identified an internal tandem duplication in FGFR1 and RAS pathway activation. Future management options include FGFR1 inhibitors. These cases demonstrate the importance of escalating molecular diagnostics for pediatric brain cancer, advocating for early reflexing to integrative whole-genome sequencing and transcriptomic profiling when targeted panels are uninformative. Identifying molecular drivers can significantly impact treatment decisions and improve patient outcomes. Full Article
bra Cloning of Affibody Libraries for Display Methods By cshprotocols.cshlp.org Published On :: 2024-11-01T06:46:10-07:00 Affibody molecules are small (6-kDa) affinity proteins folded in a three-helical bundle and generated by directed evolution for specific binding to various target molecules. The most advanced affibody molecules are currently tested in the clinic, and data from more than 300 subjects show excellent activity and safety profiles. The generation of affibody molecules against a particular target starts with the generation of an affibody library, which can then be used for panning using multiple methods and selection systems. This protocol describes the molecular cloning of DNA-encoded affibody libraries to a display vector of choice, for either phage, Escherichia coli, or Staphylococcus carnosus display. The DNA library can come from different sources, such as error-prone polymerase chain reaction (PCR), molecular shuffling of mutations from previous selections, or, more commonly, from DNA synthesis using various methods. Restriction enzyme-based subcloning is the most common strategy for affibody libraries of higher diversity (e.g., >107 variants) and is described here. Full Article
bra [Developmental Biology] Glial Cell Development and Function in the Zebrafish Central Nervous System By cshperspectives.cshlp.org Published On :: 2024-11-01T06:50:52-07:00 Over the past decades the zebrafish has emerged as an excellent model organism with which to study the biology of all glial cell types in nervous system development, plasticity, and regeneration. In this review, which builds on the earlier work by Lyons and Talbot in 2015, we will summarize how the relative ease to manipulate the zebrafish genome and its suitability for intravital imaging have helped understand principles of glial cell biology with a focus on oligodendrocytes, microglia, and astrocytes. We will highlight recent findings on the diverse properties and functions of these glial cell types in the central nervous system and discuss open questions and future directions of the field. Full Article
bra Xi Jinping celebrates China’s rising power — and his own By www.pbs.org Published On :: Wed, 18 Oct 2017 22:35:21 +0000 Watch Video | Listen to the AudioHARI SREENIVASAN: President Xi Jinping opened China’s twice-per-decade Communist Party Congress today with a lengthy list of his achievements during his first five-year term, and his vision of where he hopes to take his nation. But beyond the words, Xi is asserting power like no Chinese leader in decades. William Brangham reports. WILLIAM BRANGHAM: The applause, the music, it was a reception befitting the commanding role that Xi Jinping has taken since being named party leader five years ago. He opened today’s proceedings by hailing reforms he’s put in place, and proclaiming a — quote — “new era for China.” PRESIDENT XI JINPING, China (through interpreter): The Chinese nation has realized a great leap, from declining in modern history to twisting its fate fundamentally and continuously moving to prosperity. WILLIAM BRANGHAM: Over 3.5 hours, Xi laid out his vision to shape the nation of 1.4 billion people into what he called a — quote — “great modern socialist country” over the next three decades. PRESIDENT XI JINPING (through interpreter): Achieving the great rejuvenation of the Chinese nation will be no walk in the park, and it will take more than drumbeating and gong-clanging to get there. The whole party must be prepared to make more arduous, strenuous efforts. WILLIAM BRANGHAM: Susan Shirk is chair of the 21st Century China Center at the University of California, San Diego. SUSAN SHIRK, University of California, San Diego: Xi Jinping has a vision of China’s role in the world that is much more ambitious than anything we have seen before, talking about China kind of moving toward the center of the world and having a lot more influence than it did before. WILLIAM BRANGHAM: In his address, Xi largely ignored the question of political reforms in China, and he didn’t mention President Trump or North Korea’s nuclear weapons program. But in a rare move, he did acknowledge that with global demand weakening, there were challenges facing China’s export-driven economy. PRESIDENT XI JINPING (through interpreter): While China’s overall productive forces have significantly improved and in many areas our production capacity leads the world, the more prominent problem is that our development is unbalanced and inadequate. WILLIAM BRANGHAM: Xi was one of the first foreign leaders to meet with President Trump. PRESIDENT DONALD TRUMP: The relationship developed by President Xi and myself, I think, is outstanding. WILLIAM BRANGHAM: That was decidedly warmer than Mr. Trump’s past criticism of China and its economic and trade policies. But other U.S. officials are more critical of Beijing’s actions. REX TILLERSON, Secretary of State: China, while rising alongside India, has done so less responsibly. WILLIAM BRANGHAM: Secretary of State Rex Tillerson today criticized China’s aggressive displays of economic and military power, particularly its expansion on man-made islands in the South China Sea. REX TILLERSON: We will not shrink from China’s challenges to the rules-based order, and where China subverts the sovereignty of neighboring countries and disadvantages the U.S. and our friends. SUSAN SHIRK: I think there are things to worry about in Chinese foreign policy that are mostly related to these maritime sovereignty issues and to a kind of bullying in Asia, but the global ambition could turn out to be positive. WILLIAM BRANGHAM: Susan Shirk says China has filled a vacuum left by the United States’ withdrawal from global agreements like the Trans-Pacific Partnership and the Paris climate accords. Perhaps the most important thing to watch for in the next few days is who Xi establishes as his likely successor. SUSAN SHIRK: That is why there is a lot of speculation now that he may be trying, much like Putin, to stay on beyond his normal term or to rule behind the scenes even after he retires. WILLIAM BRANGHAM: President Trump will be traveling to Beijing to meet Xi next month. For the PBS NewsHour, I’m William Brangham. The post Xi Jinping celebrates China’s rising power — and his own appeared first on PBS NewsHour. Full Article china Communist Party of China Xi Jinping
bra Scotch whisky distiller with famous brands reveals key change By www.heraldscotland.com Published On :: Mon, 11 Nov 2024 11:11:18 +0000 The Scotch whisky distiller has announced a major change Full Article
bra Libraries recognised for community contributions in annual award ceremony By www.heraldscotland.com Published On :: Tue, 12 Nov 2024 16:00:00 +0000 Shetland Library and the National Library of Scotland have been praised for "providing optimist for the future." Full Article
bra The Vinyl Factory celebrates art and sound with immersive exhibition at 180 Studios By www.factmag.com Published On :: Thu, 11 Apr 2024 10:32:56 +0000 REVERB features 17 audiovisual installations including new works by Es Devlin and Theaster Gates, plus Devon Turnbull's Listening Room. The post The Vinyl Factory celebrates art and sound with immersive exhibition at 180 Studios appeared first on Fact Magazine. Full Article Exhibitions
bra G.I. Joe: Wrath of Cobra Releases November 21 for PS5, Xbox Series X|S, and Switch By www.vgchartz.com Published On :: Tue, 12 Nov 2024 17:01:08 GMT 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/ Full Article Analysis Charts Industry
bra Moida Mansion is the new free game from Return Of The Obra Dinn’s Lucas Pope, and it's out now By www.rockpapershotgun.com Published On :: Fri, 01 Nov 2024 09:37:13 +0000 You remember Lucas Pope, right? He who casually dropped two of the most influential puzzle games ever then got distracted by yellow cranks for six years, occasionally popping up to drop a demake of Papers Please? Well, Pope has ceased hogging that crank, for now at least, and just released Haloween-y adventure game Moida Mansion. It’s on Itch here, and it’s completely free to play in your browser. Read more Full Article Puzzle Moida Mansion Free games Indiescovery Lucas Pope
bra The Binding Of Isaac: Rebirth celebrates 10 year anniversary with online co-op announcement and sale By www.rockpapershotgun.com Published On :: Tue, 05 Nov 2024 10:06:38 +0000 Beloved roguelike traumatic-childhood-em-up The Binding Of Issac: Rebirth turned 10 yesterday, and it’s half off on Steam to celebrate. What’s more, maker Edmund McMillen has announced that the foretold online co-op update is due on the 18th of this month, alongside a “considerable” balance update. Consider me considering the considerability of said considerable update! Read more Full Article Indie Action Adventure Single Player Arcade Xbox One PS4 PlayStation Vita Edmund McMillen Nicalis Multiplayer Competitive Multiplayer Cooperative PC Nintendo 3DS Bird view / Isometric Mac RPG Shooter Nintendo Wii U The Binding of Isaac: Rebirth
bra Spies can eavesdrop on phone calls by sensing vibrations with radar By www.newscientist.com Published On :: Thu, 31 Oct 2024 13:52:43 +0000 An off-the-shelf millimetre wave sensor can pick out the tiny vibrations made by a smartphone's speaker, enabling an AI model to transcribe the conversation, even at a distance in a noisy room Full Article
bra ICRA@40 Conference Celebrates 40 Years of IEEE Robotics By spectrum.ieee.org Published On :: Wed, 18 Sep 2024 11:30:03 +0000 Four decades after the first IEEE International Conference on Robotics and Automation (ICRA) in Atlanta, robotics is bigger than ever. Next week in Rotterdam is the IEEE ICRA@40 conference, “a celebration of 40 years of pioneering research and technological advancements in robotics and automation.” There’s an ICRA every year, of course. Arguably the largest robotics research conference in the world, the 2024 edition was held in Yokohama, Japan back in May.ICRA@40 is not just a second ICRA conference in 2024. Next week’s conference is a single track that promises “a journey through the evolution of robotics and automation,” through four days of short keynotes from prominent roboticists from across the entire field. You can see for yourself, the speaker list is nuts. There are also debates and panels tackling big ideas, like: “What progress has been made in different areas of robotics and automation over the past decades, and what key challenges remain?” Personally, I’d say “lots” and “most of them,” but that’s probably why I’m not going to be up on stage.There will also be interactive research presentations, live demos, an expo, and more—the conference schedule is online now, and the abstracts are online as well. I’ll be there to cover it all, but if you can make it in person, it’ll be worth it.Forty years ago is a long time, but it’s not that long, so just for fun, I had a look at the proceedings of ICRA 1984 which are available on IEEE Xplore, if you’re curious. Here’s an excerpt of the forward from the organizers, which included folks from International Business Machines and Bell Labs:The proceedings of the first IEEE Computer Society International Conference on Robotics contains papers covering practically all aspects of robotics. The response to our call for papers has been overwhelming, and the number of papers submitted by authors outside the United States indicates the strong international interest in robotics.The Conference program includes papers on: computer vision; touch and other local sensing; manipulator kinematics, dynamics, control and simulation; robot programming languages, operating systems, representation, planning, man-machine interfaces; multiple and mobile robot systems.The technical level of the Conference is high with papers being presented by leading researchers in robotics. We believe that this conference, the first of a series to be sponsored by the IEEE, will provide a forum for the dissemination of fundamental research results in this fast developing field.Technically, this was “ICR,” not “ICRA,” and it was put on by the IEEE Computer Society’s Technical Committee on Robotics, since there was no IEEE Robotics and Automation Society at that time; RAS didn’t get off the ground until 1987.1984 ICR(A) had two tracks, and featured about 75 papers presented over three days. Looking through the proceedings, you’ll find lots of familiar names: Harry Asada, Ruzena Bajcsy, Ken Salisbury, Paolo Dario, Matt Mason, Toshio Fukuda, Ron Fearing, and Marc Raibert. Many of these folks will be at ICRA@40, so if you see them, make sure and thank them for helping to start it all, because 40 years of robotics is definitely something to celebrate. Full Article Icra Icra 2024 Conferences Robotics
bra Heroes among us: Celebrating American bravery on Veterans Day By www.foxnews.com Published On :: Mon, 11 Nov 2024 08:00:49 -0500 Tech expert Kurt “CyberGuy" Knutsson helps you honor our heroes with these powerful podcasts, audiobooks and documentaries this Veterans Day. Full Article 52424efb-aa6e-5eb5-9392-dc4ee09364ad fnc Fox News fox-news/tech fox-news/us/military/veterans fox-news/us/military fox-news/entertainment/genres/documentary fox-news/tech article
bra Man Utd fans DESPERATE for Alexis Sanchez to CELEBRATE if he scores against Arsenal By www.sport.co.uk Published On :: Fri, 25 Jan 2019 17:25:00 +0000 ALEXIS SANCHEZ returns to former club Arsenal tonight - and Manchester United fans are desperate to see him celebrate if he scores at the Emirates.. Full Article
bra Alarming study shows quarter of elite rugby players have 'brain abnormalities' By www.telegraph.co.uk Published On :: Thu, 22 Jul 2021 06:00:00 GMT Full Article topics:things/dementia structure:sport structure:football structure:rugby-union storytype:standard
bra 'More than 100' Post Office branches and 'hundreds of jobs at risk' after strategic review By www.express.co.uk Published On :: Tue, 12 Nov 2024 20:15:00 +0000 As many as 115 Post Office Branches and hundreds of jobs could be at risk following a strategic review held by Post Office Chairman Nigel Railton. Full Article UK
bra Alienware celebrates 25 years with revamped Aurora desktop PC By www.bit-tech.net Published On :: Fri, 15 Oct 2021 10:00:00 +0000 Alienware was born in a garage near Miami in 1996. The first Aurora arrived in 2004. Full Article
bra Your brain may be mutating in a way that was thought to be very rare By www.newscientist.com Published On :: Thu, 22 Aug 2024 20:00:04 +0100 DNA from mitochondria, the energy powerhouses inside cells, sometimes gets added to our genome – and the number of these mutations in the brain could be linked to ageing Full Article
bra The surprising mental health and brain benefits of weight-loss drugs By www.newscientist.com Published On :: Wed, 12 Jun 2024 17:00:00 +0100 Drugs like Ozempic and Wegovy have unexpected effects on the brain, opening up potential new ways to treat depression, anxiety, addiction and Alzheimer’s Full Article
bra Does the structure of your brain affect your risk of depression? By www.newscientist.com Published On :: Wed, 04 Sep 2024 17:00:55 +0100 A network of neurons in the brain seems to be larger in people with depression, which could change how we think about the condition's causes Full Article
bra Microglia: How the brain’s immune cells may be causing dementia By www.newscientist.com Published On :: Tue, 03 Sep 2024 17:00:00 +0100 They fight invaders, clear debris and tend neural connections, but sometimes microglia go rogue. Preventing this malfunction may offer new treatments for brain conditions including Alzheimer's Full Article
bra Evidence grows for dramatic brain remodelling during pregnancy By www.newscientist.com Published On :: Mon, 16 Sep 2024 17:00:58 +0100 A woman's brain was scanned throughout her pregnancy, adding to the growing body of evidence that dramatic remodelling takes place in preparation for motherhood Full Article
bra The brain has its own microbiome. Here's what it means for your health By www.newscientist.com Published On :: Wed, 25 Sep 2024 17:00:00 +0100 Neuroscientists have been surprised to discover that the human brain is teeming with microbes, and we are beginning to suspect they could play a role in neurodegenerative disorders like Alzheimer's Full Article
bra Boosting brainwaves in sleep improves rats’ memory By www.newscientist.com Published On :: Fri, 18 Oct 2024 19:00:59 +0100 Rats perform better on memory tests when certain brainwave-producing neurons are stimulated while they sleep. If we can boost these brainwaves in people, it could help treat memory impairments in those with dementia Full Article
bra Neuroscientist finds her brain shrinks while taking birth control By www.newscientist.com Published On :: Tue, 22 Oct 2024 20:52:51 +0100 A researcher who underwent dozens of brain scans discovered that the volume of her cerebral cortex was 1 per cent lower when she took hormonal contraceptives Full Article
bra EU groups raise concerns after Brazil audit findings By www.foodsafetynews.com Published On :: Tue, 12 Nov 2024 05:01:00 +0000 Several trade associations have called on European policymakers to reconsider the EU-Mercosur trade deal following findings from an audit in Brazil. The EU-Mercosur deal is an agreement between the European Union and Argentina, Brazil, Paraguay and Uruguay. A recently published audit report by DG Sante revealed Brazil’s issues in meeting European food... Continue Reading Full Article Food Politics audit Brazil Copa and Cogeca dg sante European Commission hormone-treated beef official controls trade agreement
bra Georgia on outside of College Football Playoff bracket as wild week brings rankings shakeup By www.foxnews.com Published On :: Tue, 12 Nov 2024 21:52:18 -0500 Georgia's loss to Ole Miss Saturday brought a wild shakeup to the college football rankings, and the Bulldogs find themselves out of the playoff picture. Full Article be1a5b1e-e9fd-515d-8deb-af99e8d76913 fnc Fox News fox-news/sports/ncaa-fb fox-news/sports/ncaa fox-news/sports fox-news/sports/ncaa/georgia-bulldogs fox-news/sports/ncaa/oregon-ducks fox-news/sports article
bra In Photos: Celebrating Hawaii’s Wonder a Year After the Maui Wildfires By time.com Published On :: Fri, 11 Oct 2024 11:00:00 +0000 In his latest book, The Blue on Fire: Hawaii, photographer Enzo Barracco hopes to inspire the world to protect the ocean. Full Article Uncategorized climate change healthscienceclimate
bra Comment on Keep Your Heart Safe This Chhath Puja: Expert Fasting Tips For A Healthy Celebration by Blue Techker By www.thehealthsite.com Published On :: Thu, 07 Nov 2024 23:49:34 +0000 <a href="https://bluetechker.com/" rel="nofollow ugc">Blue Techker</a> naturally like your web site however you need to take a look at the spelling on several of your posts. A number of them are rife with spelling problems and I find it very bothersome to tell the truth on the other hand I will surely come again again. Full Article
bra Remembrance Sunday commemorations at Cenotaph By www.channel4.com Published On :: King Charles has led Remembrance Sunday commemorations at the Cenotaph. Full Article
bra A Comprehensive Guide on How to Find Telegram Groups to Promote Your Brand By www.chartsattack.com Published On :: Fri, 27 Sep 2024 06:32:11 +0000 Telegram has established itself as a unique messaging platform with a strong emphasis on privacy, encryption, and an intuitive API. What sets it apart is its ability to support large group chats, with a capacity of up to 200,000 participants, which is far greater than what competitors like WhatsApp and Signal offer. This feature makes […] The post A Comprehensive Guide on How to Find Telegram Groups to Promote Your Brand appeared first on Chart Attack. Full Article Business Channels Promote Brand Telegram Groups
bra Ottawa principal apologizes for playing Arabic song during Remembrance Day ceremony By www.cbc.ca Published On :: Tue, 12 Nov 2024 20:20:11 EST An Ottawa high school principal has apologized for playing an Arabic song about peace during a Remembrance Day ceremony after facing swift backlash from critics calling it inappropriate and hurtful to members of the Jewish community. Full Article News/Canada/Ottawa
bra PM Narendra Modi to visit Nigeria, Brazil, Guyana from November 16 - The Hindu By news.google.com Published On :: Wed, 13 Nov 2024 01:44:00 GMT PM Narendra Modi to visit Nigeria, Brazil, Guyana from November 16 The HinduPM Modi to attend G20 Summit in Brazil, visit Nigeria and Guyana from November 16-20: Full schedule The Times of IndiaPM Modi to embark on three nation visit to Nigeria, Brazil and Guyana from 16th nov News On AIRPM Modi's Africa-Latin America trip begins Sunday The Economic TimesPM Modi to embark on 3-nation tour, attend G20 Leaders Summit in Brazil next week The Indian Express Full Article
bra Video game libraries lose legal appeal to emulate physical game collections online By arstechnica.com Published On :: Fri, 25 Oct 2024 19:25:44 +0000 Register of Copyrights sides with industry's "market harm" argument for rereleased games. Full Article Gaming Policy
bra Martin Garrix set to perform in ‘world’s biggest Holi celebration’ in India By www.thehindu.com Published On :: Fri, 08 Nov 2024 15:15:55 +0530 Tickets for the event will go on sale on November 10, 2024, via BookMyShow Full Article Entertainment
bra ‘Captain America: Brave New World’ trailer: Anthony Mackie faces off against Harrison Ford’s hulking red president By www.thehindu.com Published On :: Sun, 10 Nov 2024 15:13:17 +0530 Directed by Julius Onah, the upcoming film sees Ford as President Thaddeus “Thunderbolt” Ross, who offers Wilson an official role within the military, hoping to make Captain America a government ally Full Article Movies