Youngsters can enjoy the fun and excitement of gymnastics at an Open House event next month. The Open House is hosted by the Bermuda Gymnastics Association’s training centre in Southside, St David’s, on July 10. The free session, from 9 am to 11 am, is for children aged 1 to 5. Related Stories Results: International […]

[Written by Stephen Wright] A team of 13 gymnasts represented the island at the recent Presidential Classic at the ESPN Wide World of Sports Complex in Orlando, Florida. The team, accompanied by their coach Dariana Rojas, competed at compulsory and optional levels against more than 4,000 participants worldwide. On the opening day, Alyssa Andrews, competing at […]

The Bermuda International Gymnastics Challenge will be held at the Training Centre in St David’s in March next year. Organised by Bermuda Gymnastics, the competition is from March 16 to 17, with male and female athletes judged under USA Gymnastics rules, all Xcel levels and levels 1 to 10. The entry deadline for gymnasts is […]

[Written by Stephen Wright] When Sydney Mason retired from gymnastics aged 18, she did not expect it to take five years to discover a sport that excited and challenged her as much as her first sporting love. Mason was once the top gymnast on the island, representing Bermuda at the Pan American Games in Toronto […]

[Written by Stephen Wright] The Bermuda Gymnastics Association [BGA] has expanded its operation by opening a second training facility called The Loft on Marsh Lane in Devonshire. Anna Balada, the BGA head coach, believes the more centrally located facility will help attract youngsters to the sport who cannot travel as far as Southside, St David’s, […]

The Bermuda Gymnastics Association [BGA] will hold its February Break Camp at its new Loft facility on Marsh Lane, Devonshire. The camp runs from February 12 to 16 for 4 to 12-year-olds and will include an excursion to the BGA’s main training base in Southside, St David’s. The full camp, costing $320, runs from 9 […]

The Bermuda Gymnastics Association [BGA] will hold its Spring Break Camps at its new Loft facility on Marsh Lane, Devonshire. The first camp runs from March 25 to 28 and the second from April 1 and 5 and will include an excursion to the BGA’s main training base in Southside, St David’s. The full camp […]

Hamilton Princess & Beach Club was ranked sixth in the Atlantic Islands by Condé Nast Traveler’s 2024 Readers’ Choice Awards, highlighting its outstanding service and guest experiences. A spokesperson said, “Hamilton Princess & Beach Club is pleased to announce that it has been recognized in the top 20 in the World Resorts Category in the […]

A new three-year NASA field expedition gets underway this year to survey more of the world’s coral reefs, with Dr Eric Hochberg from the Bermuda Institute of Ocean Sciences set to be involved in the study. NASA said, “Coral reefs, sometimes called the rainforests of the sea, are home to a quarter of all ocean […]

Nascent Group Ltd. announced that it has signed an agreement to acquire Bermuda Compliance Consultants Ltd, and the acquisition is expected to close in the fourth quarter of 2023. A spokesperson said, “Founded and headquartered in Bermuda, Bermuda Compliance Consultants Ltd. [BCCL] provides compliance advisory services to the insurance and the fund markets. Alison Morrison, […]

Condé Nast Traveler announced the results of their annual Readers’ Choice Awards, with Bermuda earning the top spot as Best Island in the Caribbean and Atlantic. A BTA spokesperson said, “Bermuda has done it again! Condé Nast Traveler today announced the results of its prestigious annual Readers’ Choice Awards, with Bermuda taking the #1 spot […]

If passed, it would be the first standalone NASA authorization since 2017.

An analysis of the U.S. Senate's FY 2025 budget request for NASA.

A single 3.5 billion-year-old rock shows signs of all the conditions life needs to thrive.

With all the advances in private space exploration, why do taxpayers still pay for space science missions?

Weeks before the new fiscal year, Congress still hasn't finalized NASA's 2025 budget.

John Hugley IV recodrded a NASTY block to help Xavier hold on to 40-25 lead at halftime vs. Jackson State

With summer in full swing, the National Fire Protection Association (NFPA) and Electrical Safety Foundation International (ESFI) are joining forces to remind people about the potential electrical hazards in swimming pools, hot tubs and spas, on board boats and in the waters surrounding boats, marinas and launch ramps.

NASA astronaut Suni Williams says her weight is stable aboard the International Space Station, rebutting tabloid claims that her orbital stay has made her emaciated.

The Jet Propulsion Laboratory, NASA's chief center for planetary exploration, is conducting its second round of layoffs in 2024, reducing its workforce by another 5%.

In this emergency episode of the Arsenal Women Arsecast, Tim and Jamie run the rule over the resignation of Jonas Eidevall as the Head Coach of Arsenal Women. Tim talks a little bit about how Arseblog News became aware of and were able to (just about) break the story on Tuesday morning. Then Tim and Jamie analyse where things went wrong, how the situation took a serious turn in the last week, why it didn't quite click the way the club and Jonas wanted it to and looked ahead to how Arsenal might succession plan for his departure. Tim and Jamie then each share one high point from Eidevall's reign.

Get extra bonus content and help support Arseblog by becoming an Arseblog Member on Patreon: https://www.patreon.com/arseblog

Hosted on Acast. See acast.com/privacy for more information.

Taiwanese network-attached storage (NAS) appliance maker Synology has addressed a critical security flaw impacting DiskStation and BeePhotos that could lead to remote code execution. Tracked as CVE-2024-10443 and dubbed RISK:STATION by Midnight Blue, the zero-day flaw was demonstrated at the Pwn2Own Ireland 2024 hacking contest by security researcher Rick de Jager. RISK:STATION is an "

The post Pretty Motor Mechanic Nastya appeared first on English Russia.

Join the Program in Judaic Studies and the Department of Religion on Tuesday, November 19, for this talk delivered by Ilana Pardes. Lunch will be available before the event's start, between 11:30am–12:00pm only. The account of the rise of Israelite kingship in the Book of Samuel is one of the greatest narratives of antiquity that has been passed down to us. Far from being a dry chronicle, it offers both an unblinking perspective on political realities and a daring representation of the humanness, the nakedness, of royal figures. The talk will revolve around the encounter of King David and the wise woman of Tekoa (2 Samuel 14). Special attention will be given to the dramas behind the scenes, to the hidden links between the parabolic tale of the wise woman and the story of the House of David. All are welcome to attend, but space is limited – please RSVP to judaic@princeton.edu and note any dietary needs. More about Ilana Pardes Ilana Pardes is the Katharine Cornell Professor of Comparative Literature at the Hebrew University of Jerusalem. She is currently a Visiting Professor in the Program in Judaic Studies Program at Princeton University. Her work has focused on the nexus of Bible, literature, and culture as well as on questions of gender, aesthetics, and hermeneutics. She is the author of Countertraditions in the Bible: A Feminist Approach (Harvard University Press, 1992), The Biography of Ancient Israel: National Narratives in the Bible (University of California Press, 2000), Melville's Bibles (University of California, 2008), Agnon's Moonstruck Lovers: The Song of Songs in Israeli Culture (The Samuel and Althea Stroum Lectures in Jewish Studies, University of Washington Press, 2013), The Song of Songs: A Biography (Princeton University Press, Lives of Great Religious Books, 2019), and Ruth: A Migrant’s Tale (Yale University Press, Jewish Lives, 2022).

As the first-ever “full-scale planetary defense test” to deflect a space rock, the DART mission aims to show that protecting Earth from a hazardous asteroid is possible.

NASA scientists used a neural network called ExoMiner to examine data from Kepler, increasing the total tally of confirmed exoplanets in the universe.

NASA’s massive SLS rocket and Orion spacecraft kick off a series of missions to put humans back on the Moon.

The James Webb Space Telescope only captures infrared light, but imaging developers can convert the invisible into something both beautiful and scientifically accurate.

The FEMA official who was just fired for telling workers to avoid homes impacted by the hurricanes in Florida if they had Trump signs says that it was not “isolated” and that FEMA workers were instructed to do it in the Carolinas too. (X) The American people must get justice. Indict and convict. So, apparently this …

1. NASA Alert: Massive 'God of Chaos' Asteroid Apophis Makes Closest Pass by Earth Yet  Bizz Buzz
2. NASA alert! 'God of Chaos' asteroid approaching Earth on November 13 sparks worldwide concern  The Times of India
3. Nasa Alert: Massive 'God of Chaos' asteroid Apophis nears earth in closest pass yet  CNBCTV18
4. Giant Meteorite To Hit Earth On November 13? What We Know  News18
5. 'Astonishingly close': A colossal space rock could wreak havoc on Earth in 2029  Business Today

velocityconf: RT @suzaxtell: #WomeninTech You're invited to a women's meetup on Tues May 28 in SF w/ @courtneynash @mjawili, more http://t.co/MsMZ0IK8L2

velocityconf: RT @courtneynash: Bill Scott's #fluentconf keynote theme also rings true re #velocityconf: tech change is really about people/culture change

With NASA's sights on moon bases, the question becomes how do you build shelters for tomorrow's lunar inhabitants? Carting up large amounts of raw materials from Earth is prohibitively expensive. And the only resources on the surface are regolith—lunar dust—and water. — Read the rest

The post NASA plans to grow mushroom houses on the moon appeared first on Boing Boing.

G protein–coupled receptors (GPCRs) initiate signaling cascades via G-proteins and beta-arrestins (βarr). βarr-dependent actions begin with recruitment of βarr to the phosphorylated receptor tail and are followed by engagement with the receptor core. βarrs are known to act as adaptor proteins binding receptors and various effectors, but it is unclear whether in addition to the scaffolding role βarrs can allosterically activate their downstream targets. Here we demonstrate the direct allosteric activation of proto-oncogene kinase Src by GPCR–βarr complexes in vitro and establish the conformational basis of the activation. Whereas free βarr1 had no effect on Src activity, βarr1 in complex with M2 muscarinic or β2-adrenergic receptors reconstituted in lipid nanodiscs activate Src by reducing the lag phase in Src autophosphorylation. Interestingly, receptor–βarr1 complexes formed with a βarr1 mutant, in which the finger-loop, required to interact with the receptor core, has been deleted, fully retain the ability to activate Src. Similarly, βarr1 in complex with only a phosphorylated C-terminal tail of the vasopressin 2 receptor activates Src as efficiently as GPCR–βarr complexes. In contrast, βarr1 and chimeric M2 receptor with nonphosphorylated C-terminal tail failed to activate Src. Taken together, these data demonstrate that the phosphorylated GPCR tail interaction with βarr1 is necessary and sufficient to empower it to allosterically activate Src. Our findings may have implications for understanding more broadly the mechanisms of allosteric activation of downstream targets by βarrs.

Ligand bias is the ability of ligands to differentially activate certain receptor signaling responses compared with others. It reflects differences in the responses of a receptor to specific ligands and has implications for the development of highly specific therapeutics. Whereas ligand bias has been studied primarily for G protein–coupled receptors (GPCRs), there are also reports of ligand bias for receptor tyrosine kinases (RTKs). However, the understanding of RTK ligand bias is lagging behind the knowledge of GPCR ligand bias. In this review, we highlight how protocols that were developed to study GPCR signaling can be used to identify and quantify RTK ligand bias. We also introduce an operational model that can provide insights into the biophysical basis of RTK activation and ligand bias. Finally, we discuss possible mechanisms underpinning RTK ligand bias. Thus, this review serves as a primer for researchers interested in investigating ligand bias in RTK signaling.

Yu Xue
Sep 1, 2008; 7:1598-1608
Research

Accumulation of the microtubule-associated protein tau is associated with Alzheimer's disease (AD). In AD brain, tau is abnormally phosphorylated at many sites, and phosphorylation at Ser-262 and Ser-356 plays critical roles in tau accumulation and toxicity. Microtubule affinity–regulating kinase 4 (MARK4) phosphorylates tau at those sites, and a double de novo mutation in the linker region of MARK4, ΔG316E317D, is associated with an elevated risk of AD. However, it remains unclear how this mutation affects phosphorylation, aggregation, and accumulation of tau and tau-induced neurodegeneration. Here, we report that MARK4ΔG316E317D increases the abundance of highly phosphorylated, insoluble tau species and exacerbates neurodegeneration via Ser-262/356–dependent and –independent mechanisms. Using transgenic Drosophila expressing human MARK4 (MARK4wt) or a mutant version of MARK4 (MARK4ΔG316E317D), we found that coexpression of MARK4wt and MARK4ΔG316E317D increased total tau levels and enhanced tau-induced neurodegeneration and that MARK4ΔG316E317D had more potent effects than MARK4wt. Interestingly, the in vitro kinase activities of MARK4wt and MARK4ΔG316E317D were similar. When tau phosphorylation at Ser-262 and Ser-356 was blocked by alanine substitutions, MARK4wt did not promote tau accumulation or exacerbate neurodegeneration, whereas coexpression of MARK4ΔG316E317D did. Both MARK4wt and MARK4ΔG316E317D increased the levels of oligomeric forms of tau; however, only MARK4ΔG316E317D further increased the detergent insolubility of tau in vivo. Together, these findings suggest that MARK4ΔG316E317D increases tau levels and exacerbates tau toxicity via a novel gain-of-function mechanism and that modification in this region of MARK4 may affect disease pathogenesis.

Jorge H. Capdevila
Feb 1, 2000; 41:163-181
Reviews

Pyruvate kinase muscle isoform 2 (PKM2) is a key glycolytic enzyme and transcriptional coactivator and is critical for tumor metabolism. In cancer cells, native tetrameric PKM2 is phosphorylated or acetylated, which initiates a switch to a dimeric/monomeric form that translocates into the nucleus, causing oncogene transcription. However, it is not known how these post-translational modifications (PTMs) disrupt the oligomeric state of PKM2. We explored this question via crystallographic and biophysical analyses of PKM2 mutants containing residues that mimic phosphorylation and acetylation. We find that the PTMs elicit major structural reorganization of the fructose 1,6-bisphosphate (FBP), an allosteric activator, binding site, impacting the interaction with FBP and causing a disruption in oligomerization. To gain insight into how these modifications might cause unique outcomes in cancer cells, we examined the impact of increasing the intracellular pH (pHi) from ∼7.1 (in normal cells) to ∼7.5 (in cancer cells). Biochemical studies of WT PKM2 (wtPKM2) and the two mimetic variants demonstrated that the activity decreases as the pH is increased from 7.0 to 8.0, and wtPKM2 is optimally active and amenable to FBP-mediated allosteric regulation at pHi 7.5. However, the PTM mimetics exist as a mixture of tetramer and dimer, indicating that physiologically dimeric fraction is important and might be necessary for the modified PKM2 to translocate into the nucleus. Thus, our findings provide insight into how PTMs and pH regulate PKM2 and offer a broader understanding of its intricate allosteric regulation mechanism by phosphorylation or acetylation.

RNase J enzymes are metallohydrolases that are involved in RNA maturation and RNA recycling, govern gene expression in bacteria, and catalyze both exonuclease and endonuclease activity. The catalytic activity of RNase J is regulated by multiple mechanisms which include oligomerization, conformational changes to aid substrate recognition, and the metal cofactor at the active site. However, little is known of how RNase J paralogs differ in expression and activity. Here we describe structural and biochemical features of two Staphylococcus epidermidis RNase J paralogs, RNase J1 and RNase J2. RNase J1 is a homodimer with exonuclease activity aided by two metal cofactors at the active site. RNase J2, on the other hand, has endonuclease activity and one metal ion at the active site and is predominantly a monomer. We note that the expression levels of these enzymes vary across Staphylococcal strains. Together, these observations suggest that multiple interacting RNase J paralogs could provide a strategy for functional improvisation utilizing differences in intracellular concentration, quaternary structure, and distinct active site architecture despite overall structural similarity.

Heme oxygenase-2 (HO2) and -1 (HO1) catalyze heme degradation to biliverdin, CO, and iron, forming an essential link in the heme metabolism network. Tight regulation of the cellular levels and catalytic activities of HO1 and HO2 is important for maintaining heme homeostasis. HO1 expression is transcriptionally regulated; however, HO2 expression is constitutive. How the cellular levels and activity of HO2 are regulated remains unclear. Here, we elucidate the mechanism of post-translational regulation of cellular HO2 levels by heme. We find that, under heme-deficient conditions, HO2 is destabilized and targeted for degradation, suggesting that heme plays a direct role in HO2 regulation. HO2 has three heme binding sites: one at its catalytic site and the others at its two heme regulatory motifs (HRMs). We report that, in contrast to other HRM-containing proteins, the cellular protein level and degradation rate of HO2 are independent of heme binding to the HRMs. Rather, under heme deficiency, loss of heme binding to the catalytic site destabilizes HO2. Consistently, an HO2 catalytic site variant that is unable to bind heme exhibits a constant low protein level and an enhanced protein degradation rate compared with the WT HO2. Finally, HO2 is degraded by the lysosome through chaperone-mediated autophagy, distinct from other HRM-containing proteins and HO1, which are degraded by the proteasome. These results reveal a novel aspect of HO2 regulation and deepen our understanding of HO2's role in maintaining heme homeostasis, paving the way for future investigation into HO2's pathophysiological role in heme deficiency response.

Broad-specificity glycoside hydrolases (GHs) contribute to plant biomass hydrolysis by degrading a diverse range of polysaccharides, making them useful catalysts for renewable energy and biocommodity production. Discovery of new GHs with improved kinetic parameters or more tolerant substrate-binding sites could increase the efficiency of renewable bioenergy production even further. GH5 has over 50 subfamilies exhibiting selectivities for reaction with β-(1,4)–linked oligo- and polysaccharides. Among these, subfamily 4 (GH5_4) contains numerous broad-selectivity endoglucanases that hydrolyze cellulose, xyloglucan, and mixed-linkage glucans. We previously surveyed the whole subfamily and found over 100 new broad-specificity endoglucanases, although the structural origins of broad specificity remained unclear. A mechanistic understanding of GH5_4 substrate specificity would help inform the best protein design strategies and the most appropriate industrial application of broad-specificity endoglucanases. Here we report structures of 10 new GH5_4 enzymes from cellulolytic microbes and characterize their substrate selectivity using normalized reducing sugar assays and MS. We found that GH5_4 enzymes have the highest catalytic efficiency for hydrolysis of xyloglucan, glucomannan, and soluble β-glucans, with opportunistic secondary reactions on cellulose, mannan, and xylan. The positions of key aromatic residues determine the overall reaction rate and breadth of substrate tolerance, and they contribute to differences in oligosaccharide cleavage patterns. Our new composite model identifies several critical structural features that confer broad specificity and may be readily engineered into existing industrial enzymes. We demonstrate that GH5_4 endoglucanases can have broad specificity without sacrificing high activity, making them a valuable addition to the biomass deconstruction toolset.

Arabinogalactan proteins (AGPs) are plant proteoglycans with functions in growth and development. However, these functions are largely unexplored, mainly because of the complexity of the sugar moieties. These carbohydrate sequences are generally analyzed with the aid of glycoside hydrolases. The exo-β-1,3-galactanase is a glycoside hydrolase from the basidiomycete Phanerochaete chrysosporium (Pc1,3Gal43A), which specifically cleaves AGPs. However, its structure is not known in relation to its mechanism bypassing side chains. In this study, we solved the apo and liganded structures of Pc1,3Gal43A, which reveal a glycoside hydrolase family 43 subfamily 24 (GH43_sub24) catalytic domain together with a carbohydrate-binding module family 35 (CBM35) binding domain. GH43_sub24 is known to lack the catalytic base Asp conserved among other GH43 subfamilies. Our structure in combination with kinetic analyses reveals that the tautomerized imidic acid group of Gln263 serves as the catalytic base residue instead. Pc1,3Gal43A has three subsites that continue from the bottom of the catalytic pocket to the solvent. Subsite −1 contains a space that can accommodate the C-6 methylol of Gal, enabling the enzyme to bypass the β-1,6–linked galactan side chains of AGPs. Furthermore, the galactan-binding domain in CBM35 has a different ligand interaction mechanism from other sugar-binding CBM35s, including those that bind galactomannan. Specifically, we noted a Gly → Trp substitution, which affects pyranose stacking, and an Asp → Asn substitution in the binding pocket, which recognizes β-linked rather than α-linked Gal residues. These findings should facilitate further structural analysis of AGPs and may also be helpful in engineering designer enzymes for efficient biomass utilization.

Diana Samodova
Dec 1, 2020; 19:2139-2156
Technological Innovation and Resources

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.

Kinases are critical components of intracellular signaling pathways and have been extensively investigated with regard to their roles in cancer. p21-activated kinase-1 (PAK1) is a serine/threonine kinase that has been previously implicated in numerous biological processes, such as cell migration, cell cycle progression, cell motility, invasion, and angiogenesis, in glioma and other cancers. However, the signaling network linked to PAK1 is not fully defined. We previously reported a large-scale yeast genetic interaction screen using toxicity as a readout to identify candidate PAK1 genetic interactions. En masse transformation of the PAK1 gene into 4,653 homozygous diploid Saccharomyces cerevisiae yeast deletion mutants identified ∼400 candidates that suppressed yeast toxicity. Here we selected 19 candidate PAK1 genetic interactions that had human orthologs and were expressed in glioma for further examination in mammalian cells, brain slice cultures, and orthotopic glioma models. RNAi and pharmacological inhibition of potential PAK1 interactors confirmed that DPP4, KIF11, mTOR, PKM2, SGPP1, TTK, and YWHAE regulate PAK1-induced cell migration and revealed the importance of genes related to the mitotic spindle, proteolysis, autophagy, and metabolism in PAK1-mediated glioma cell migration, drug resistance, and proliferation. AKT1 was further identified as a downstream mediator of the PAK1-TTK genetic interaction. Taken together, these data provide a global view of PAK1-mediated signal transduction pathways and point to potential new drug targets for glioma therapy.

The tenovins are a frequently studied class of compounds capable of inhibiting sirtuin activity, which is thought to result in increased acetylation and protection of the tumor suppressor p53 from degradation. However, as we and other laboratories have shown previously, certain tenovins are also capable of inhibiting autophagic flux, demonstrating the ability of these compounds to engage with more than one target. In this study, we present two additional mechanisms by which tenovins are able to activate p53 and kill tumor cells in culture. These mechanisms are the inhibition of a key enzyme of the de novo pyrimidine synthesis pathway, dihydroorotate dehydrogenase (DHODH), and the blockage of uridine transport into cells. These findings hold a 3-fold significance: first, we demonstrate that tenovins, and perhaps other compounds that activate p53, may activate p53 by more than one mechanism; second, that work previously conducted with certain tenovins as SirT1 inhibitors should additionally be viewed through the lens of DHODH inhibition as this is a major contributor to the mechanism of action of the most widely used tenovins; and finally, that small changes in the structure of a small molecule can lead to a dramatic change in the target profile of the molecule even when the phenotypic readout remains static.

Frank C. Nichols
Dec 1, 2020; 61:1645-1657
Research Articles

Genta Kakiyama
Dec 1, 2020; 61:1629-1644
Research Articles