Bero Roos
Theor. Probability and Math. Statist. 111 (), 137-151.
Abstract, references and article information

The glucagon receptor (GCGR) activated by the peptide hormone glucagon is a seven-transmembrane G protein–coupled receptor (GPCR) that regulates blood glucose levels. Ubiquitination influences trafficking and signaling of many GPCRs, but its characterization for the GCGR is lacking. Using endocytic colocalization and ubiquitination assays, we have identified a correlation between the ubiquitination profile and recycling of the GCGR. Our experiments revealed that GCGRs are constitutively ubiquitinated at the cell surface. Glucagon stimulation not only promoted GCGR endocytic trafficking through Rab5a early endosomes and Rab4a recycling endosomes, but also induced rapid deubiquitination of GCGRs. Inhibiting GCGR internalization or disrupting endocytic trafficking prevented agonist-induced deubiquitination of the GCGR. Furthermore, a Rab4a dominant negative (DN) that blocks trafficking at recycling endosomes enabled GCGR deubiquitination, whereas a Rab5a DN that blocks trafficking at early endosomes eliminated agonist-induced GCGR deubiquitination. By down-regulating candidate deubiquitinases that are either linked with GPCR trafficking or localized on endosomes, we identified signal-transducing adaptor molecule–binding protein (STAMBP) and ubiquitin-specific protease 33 (USP33) as cognate deubiquitinases for the GCGR. Our data suggest that USP33 constitutively deubiquitinates the GCGR, whereas both STAMBP and USP33 deubiquitinate agonist-activated GCGRs at early endosomes. A mutant GCGR with all five intracellular lysines altered to arginines remains deubiquitinated and shows augmented trafficking to Rab4a recycling endosomes compared with the WT, thus affirming the role of deubiquitination in GCGR recycling. We conclude that the GCGRs are rapidly deubiquitinated after agonist-activation to facilitate Rab4a-dependent recycling and that USP33 and STAMBP activities are critical for the endocytic recycling of the GCGR.

Genetic mutations related to ALS, a progressive neurological disease, have been discovered in the gene encoding σ-1 receptor (σ1R). We previously reported that σ1RE102Q elicits toxicity in cells. The σ1R forms oligomeric states that are regulated by ligands. Nevertheless, little is known about the effect of ALS-related mutations on oligomer formation. Here, we transfected NSC-34 cells, a motor neuronal cell line, and HEK293T cells with σ1R-mCherry (mCh), σ1RE102Q-mCh, or nontagged forms to investigate detergent solubility and subcellular distribution using immunocytochemistry and fluorescence recovery after photobleaching. The oligomeric state was determined using crosslinking procedure. σ1Rs were soluble to detergents, whereas the mutants accumulated in the insoluble fraction. Within the soluble fraction, peak distribution of mutants appeared in higher sucrose density fractions. Mutants formed intracellular aggregates that were co-stained with p62, ubiquitin, and phosphorylated pancreatic eukaryotic translation initiation factor-2-α kinase in NSC-34 cells but not in HEK293T cells. The aggregates had significantly lower recovery in fluorescence recovery after photobleaching. Acute treatment with σ1R agonist SA4503 failed to improve recovery, whereas prolonged treatment for 48 h significantly decreased σ1RE102Q-mCh insolubility and inhibited apoptosis. Whereas σ1R-mCh formed monomers and dimers, σ1RE102Q-mCh also formed trimers and tetramers. SA4503 reduced accumulation of the four types in the insoluble fraction and increased monomers in the soluble fraction. The σ1RE102Q insolubility was diminished by σ1R-mCh co-expression. These results suggest that the agonist and WT σ1R modify the detergent insolubility, toxicity, and oligomeric state of σ1RE102Q, which may lead to promising new treatments for σ1R-related ALS.

Communication between individuals via molecules, termed chemosignaling, is widespread among animal and plant species. However, we lack knowledge on the specific functions of the substances involved for most systems. The femoral gland is an organ that secretes a waxy substance involved in chemical communication in lizards. Although the lipids and volatile substances secreted by the femoral glands have been investigated in several biochemical studies, the protein composition and functions of secretions remain completely unknown. Applying a proteomic approach, we provide the first attempt to comprehensively characterize the protein composition of femoral gland secretions from the Galápagos marine iguana. Using samples from several organs, the marine iguana proteome was assembled by next-generation sequencing and MS, resulting in 7513 proteins. Of these, 4305 proteins were present in the femoral gland, including keratins, small serum proteins, and fatty acid-binding proteins. Surprisingly, no proteins with discernible roles in partner recognition or inter-species communication could be identified. However, we did find several proteins with direct associations to the innate immune system, including lysozyme C, antileukoproteinase (ALP), pulmonary surfactant protein (SFTPD), and galectin (LGALS1) suggesting that the femoral glands function as an important barrier to infection. Furthermore, we report several novel anti-microbial peptides from the femoral glands that show similar action against Escherichia coli and Bacillus subtilis such as oncocin, a peptide known for its effectiveness against Gram-negative pathogens. This proteomics data set is a valuable resource for future functional protein analysis and demonstrates that femoral gland secretions also perform functions of the innate immune system.

Natural compounds that can stimulate salivary secretion are of interest in developing treatments for xerostomia, the perception of a dry mouth, that affects between 10 and 30% of the adult and elderly population. Chemesthetic transient receptor potential (TRP) channels are expressed in the surface of the oral mucosa. The TRPV1 agonists capsaicin and piperine have been shown to increase salivary flow when introduced into the oral cavity but the sialogogic properties of other TRP channel agonists have not been investigated. In this study we have determined the influence of different TRP channel agonists on the flow and protein composition of saliva. Mouth rinsing with the TRPV1 agonist nonivamide or menthol, a TRPM8 agonist, increased whole mouth saliva (WMS) flow and total protein secretion compared with unstimulated saliva, the vehicle control mouth rinse or cinnamaldehyde, a TRPA1 agonist. Nonivamide also increased the flow of labial minor gland saliva but parotid saliva flow rate was not increased. The influence of TRP channel agonists on the composition and function of the salivary proteome was investigated using a multi-batch quantitative MS method novel to salivary proteomics. Inter-personal and inter-mouth rinse variation was observed in the secreted proteomes and, using a novel bioinformatics method, inter-day variation was identified with some of the mouth rinses. Significant changes in specific salivary proteins were identified after all mouth rinses. In the case of nonivamide, these changes were attributed to functional shifts in the WMS secreted, primarily the over representation of salivary and nonsalivary cystatins which was confirmed by immunoassay. This study provides new evidence of the impact of TRP channel agonists on the salivary proteome and the stimulation of salivary secretion by a TRPM8 channel agonist, which suggests that TRP channel agonists are potential candidates for developing treatments for sufferers of xerostomia.

Review: One-man bandwagons The World Today rsoppelsa.drupal 25 May 2022

The ills of strongman politics are diagnosed sharply in this accessible overview – but a cure is nowhere to be found, says Natasha Lindstaedt

The Age of the Strongman: How the Cult of the Leader Threatens Democracy around the World
Gideon Rachman, Bodley Head, £20.00

For anyone reading the headlines, it should come as no surprise that democracy has regressed to where it was in 1989. The profound geopolitical and technological changes in the post-Cold World era have led to chaos, polarization, nationalist backlash and nostalgia for strong leadership in democracies. 

Countries such as Russia and China have provided a new model for leadership that has become frighteningly infectious – the strongman. 

Gideon Rachman charts this new era, offering an accessible overview of 14 examples, including Britain’s Boris Johnson, Donald Trump of the United States, Narendra Modi of India, Jair Bolsonaro of Brazil, Viktor Orbán of Hungary, Xi Jinping of China and – the archetype – Vladmir Putin of Russia.

The idea that we are living in the age of strongman politics is not particularly novel. Scholars of authoritarian politics have noted for years that there has been a steady rise in ‘personalist’ dictatorship and personalism in democracy in general. Nearly 40 per cent of all dictatorships are personalist, meaning domination by a single person, compared with 23 per cent in 1988. Autocracies have become increasingly aggressive, using sharp power to undermine democracy, which signals a shift. 

Autocracies used to focus on their own stability and didn’t interfere with democracies.

Rachman focuses on this threat that the strongman poses to democracy while macho one-man rule spreads across the globe. He provides a well-written, clear overview of why each leader fits the strongman label, what explains their appeal and what informs their worldview. 

Where Rachman is effective is in weaving together the commonalities of these strongmen – and they are all men – and their relationship to each other. Despite their ultra-nationalism, they have created an unofficial, multilateral network of mutual support. This includes leaders whose religious convictions may appear to be in conflict – such as Benjamin Netanyahu of Israel and Muhammed bin Salman of Saudi Arabia. 

This is not just a network of dictators – autocratic-style leaders of democratic countries have been welcomed to the club. In this system, strongmen openly admire each other, revel in their disdain for liberalism and human rights, and share advice and inspiration. 

This contrasts with western European leaders who fail to build such iron-clad bonds.

Each chapter is peppered with anecdotes about Rachman’s first-hand impressions of some of these leaders and other notables in positions of power gained from his decades as a foreign correspondent and analyst. His colourful commentary complements his understanding of how they operate. 

A common theme throughout is that the strongman’s appeal appears as a breath of fresh air for democracy, liberalism or peace. They are often labelled as anti-elitist and men of the people. This honeymoon period ends when each leader shows their true colours: attacking political opponents, sometimes in ruthless purges, disregarding the rule of law, weakening the courts and vilifying or controlling the media. 

A well-placed quote from Recep Erdogan sums this up: ‘Democracy is like a tram you ride until you arrive at your destination.’

Genuine public support exists for these manoeuvres. Dislocation from unmanaged globalization and economic crises has created an audience for political entrepreneurs. Strongman leaders have earned the distinction of being relatable and telling it like it is, despite many being considered to be liars and often filthy rich. 

Their ability to tap into people’s fears of the West, crime, immigrants or other ethnic and religious groups has helped gain them a fiercely loyal following. According to Rachman, strongman politics is linked to fear that a majority group that was once dominant is being threatened – something leaders such as Donald Trump have astutely tapped into.

Unlike some of the kleptocratic regimes of the 1970s and 1980s that were the embodiment of venal opportunists – think of Ferdinand Marcos of the Philippines, Mobutu of the Democratic Republic of the Congo and Jean-Claude Duvalier of Haiti – the strongmen of today have been inspired by the ideology of hyper-nationalism and anti-liberalism. 

Rachman links strongmen to the work of Carl Schmitt, a Nazi Party member, who was a vociferous critic of parliamentary democracy and cosmopolitanism, while touting the importance of illiberal norms to exercise power. Rachman argues that we are in a war of ideas, with liberalism under attack. He hones in on the perennial target George Soros, and how his support for liberal democracy has garnered the unwanted attention from the world’s right-wing ideologues and strongmen.

Social media has been usurped by these leaders and their regimes to forge closer, direct relationships with their supporters, to churn out fake news and create dangerous echo chambers. They are snake oil salesmen, making huge promises but offering very little in practice. They are never as they initially appear, and their images are carefully crafted.

Another theme emerges on the career pathway. Many served as a mayor of a cosmopolitan city. An interesting chapter on Johnson explains how he comes across like a relatable ‘good chap’, being able to handle embarrassing photo-ops. He was also a devoted Europhile, attended Eton and Oxford, and championed multi-culturalism as Mayor of London. Always the opportunist, Johnson had few qualms about campaigning for Brexit, and then later breaking the law to make it happen.

Yet there are some gaps in Rachman’s analysis.

It is never made clear why leaders such as Abdel Fattah el-Sisi of Egypt, Nicolás Maduro of Venezuela and Kim Jong-un of North Korea are largely missing, or a number of other strongman dictators in sub-Saharan Africa. 

Though there is a chapter devoted to Abiy Ahmed of Ethiopia, along with a few paragraphs devoted to Paul Kagame of Rwanda, Meles Zenawi also of Ethiopia, Emmerson Mnangagwa of Zimbabwe and Jacob Zuma of South Africa, the chapter on African strongmen does not acknowledge that this is the only continent where the regional trend is not as depressing. 

Rachman only occasionally engages with data on dictatorships to verify some of the patterns that he explores in the book. And his work would benefit from an examination of the institutional factors that may explain the rise of strongman politics, such as the pre-existing weakness of parties, parliaments and courts. 

Nor does he go in depth into how strongmen interact with their institutions and what the implications of this brand of politics are for conflict and development. The failures of strongmen to address Covid-19 are mentioned, but it is never explained why they may be so poorly equipped to govern. 

So, is democracy dead? Though Rachman is largely pessimistic, he acknowledges that politics tends to go in waves. There is little advice about how the West can expedite the end of this particular wave. 

The one positive Rachman offers is that strongman rule cannot deal with succession. This is largely true, though handovers have taken place, such as with the Kim dynasty. 

But there are definitely more questions raised than answers provided. What is left after strongmen are no longer in power? What must democracies do to undermine strongmen or prevent their rise? Where will the next strongman appear? 

Rachman’s book doesn’t provide these answers, but he does offer an interesting overview of the leaders dominating the headlines.
 

The peptide hormone ghrelin is produced in cardiomyocytes and acts through the myocardial growth hormone secretagogue receptor (GHSR) to promote cardiomyocyte survival. Administration of ghrelin may have therapeutic effects on post–myocardial infarction (MI) outcomes. Therefore, there is a need to develop molecular imaging probes that can track the dynamics of GHSR in health and disease to better predict the effectiveness of ghrelin-based therapeutics. We designed a high-affinity GHSR ligand labeled with ¹⁸F for imaging by PET and characterized its in vivo properties in a canine model of MI. Methods: We rationally designed and radiolabeled with ¹⁸F a quinazolinone derivative ([¹⁸F]LCE470) with subnanomolar binding affinity to GHSR. We determined the sensitivity and in vivo and ex vivo specificity of [¹⁸F]LCE470 in a canine model of surgically induced MI using PET/MRI, which allowed for anatomic localization of tracer uptake and simultaneous determination of global cardiac function. Uptake of [¹⁸F]LCE470 was determined by time–activity curve and SUV analysis in 3 regions of the left ventricle—area of infarct, territory served by the left circumflex coronary artery, and remote myocardium—over a period of 1.5 y. Changes in cardiac perfusion were tracked by [¹³N]NH₃ PET. Results: The receptor binding affinity of LCE470 was measured at 0.33 nM, the highest known receptor binding affinity for a radiolabeled GHSR ligand. In vivo blocking studies in healthy hounds and ex vivo blocking studies in myocardial tissue showed the specificity of [¹⁸F]LCE470, and sensitivity was demonstrated by a positive correlation between tracer uptake and GHSR abundance. Post-MI changes in [¹⁸F]LCE470 uptake occurred independently of perfusion tracer distributions and changes in global cardiac function. We found that the regional distribution of [¹⁸F]LCE470 within the left ventricle diverged significantly within 1 d after MI and remained that way throughout the 1.5-y duration of the study. Conclusion: [¹⁸F]LCE470 is a high-affinity PET tracer that can detect changes in the regional distribution of myocardial GHSR after MI. In vivo PET molecular imaging of the global dynamics of GHSR may lead to improved GHSR-based therapeutics in the treatment of post-MI remodeling.

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The post Building the Quantum Economy — Chicago Style appeared first on HPCwire.

President-elect Donald Trump on Tuesday night announced his nomination of Fox News host and Army veteran Pete Hegseth to head the Department of Defense.

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In 1918, Lulu Hunt Peters—one of the first women in America to earn a medical doctorate—published the best seller Diet and Health With Key to the Calories, making a name for herself as an apostle for weight reduction in an era when malnutrition was a far greater public health threat than obesity. She pioneered the idea of measuring food intake via the calorie, which at the time was an obscure unit of measurement familiar only to chemists.  A century later, the Centers for Disease Control and Prevention reports (https://www.cdc.gov/nchs/products/databriefs/db360.htm) that 42 percent of American adults are clinically obese and that Type 2 diabetes is on the rise (https://www.cdc.gov/media/releases/2022/p1229-future-diabetes-surge.html) . With those who can afford it now turning to pharmaceuticals to help them lose weight, we’ll examine why and how calorie counting has failed to help Americans maintain a “healthy” weight.  In this episode of “There’s More to That,” we hear from food historian Michelle Stacey about Peters’ legacy—and from Ronald Young Jr., creator and host of the critically acclaimed podcast “Weight For It (https://www.radiotopia.fm/podcasts/weight-for-it) ,” about how American society continues to stigmatize what he calls “fat folks” for reasons that have nothing to do with public, or even individual, health. A transcript is below. To subscribe to “There’s More to That,” and to listen to past episodes on the complex legacy of Sojourner Truth (https://www.smithsonianmag.com/history/how-to-separate-fact-from-myth-in-the-extraordinary-story-of-sojourner-truth-180983820/) , how Joan Baez opened the door for Taylor Swift (https://www.smithsonianmag.com/arts-culture/before-beyonce-taylor-swift-ran-world-joan-baez-180983893/) , how machine learning is helping archeologists to read scrolls (https://www.smithsonianmag.com/history/how-artificial-intelligence-is-making-2000-year-old-scrolls-readable-again-180984264/) buried by the eruption of Mount Vesuvius nearly 2,000 years ago and more, find us on Apple Podcasts (https://podcasts.apple.com/us/podcast/theres-more-to-that/id1694965155?ign-itscg=30200&ign-itsct=podcast_box_player) , Spotify (https://open.spotify.com/show/4NYRCRxkYJTLjW71sqYOFv?si=08fa62c3e59d450f&nd=1) or wherever you get your podcasts. Read Michelle Stacey's story about Dr. Lulu Hunt Peters in the June 2024 issue of Smithsonian here (https://www.smithsonianmag.com/science-nature/doctor-pioneered-counting-calories-century-ago-were-still-dealing-with-consequences-180984282/) . Listen to Ronald Young, Jr.'s podcast "Weight For It" here (https://www.radiotopia.fm/podcasts/weight-for-it) . Find prior episodes of our show here (https://www.smithsonianmag.com/podcast/) . There’s More to That is a production of Smithsonian magazine and PRX Productions. From the magazine, our team is Chris Klimek, Debra Rosenberg and Brian Wolly. From PRX, our team is Jessica Miller, Adriana Rosas Rivera, Genevieve Sponsler, Rye Dorsey, and Edwin Ochoa. The Executive Producer of PRX Productions is Jocelyn Gonzales. Fact-checking by Stephanie Abramson. Episode artwork by Emily Lankiewicz. Music by APM Music.

A ring could explain a mysterious arrangement of impact craters near the equator and might even have caused an ice age, according to a new study

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A team at the Paul Scherrer Institute (PSI) has achieved a breakthrough with the Kagome superconductor RbV3Sb5, demonstrating time-reversal symmetry (TRS) breaking at 175 Kelvin. This discovery at higher temperatures than typically possible could pave the way for more energy-efficient and practical quantum systems, crucial for quantum computing and storage. The TRS-breaking properties are tunable, offering potential for further advancements in quantum technology, with implications for applications beyond laboratory settings.

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NEW CASTLE (24 de Agosto de 2022) – La División de Servicios Sociales de Delaware emitirá beneficios de emergencia para Agosto a los hogares elegibles como parte de la respuesta continua del Estado a la crisis de salud pública de COVID-19. Los beneficios se emitirán como parte del Programa de Asistencia Nutricional Suplementaria (SNAP) y […]