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Israel passes law to deport relatives of attackers, including citizens

Opponents say the legislation, which would apply to close family members, is unconstitutional.




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'Dick Dastardly' tactics - Hill criticises Verstappen

Red Bull's Max Verstappen is accused of acting like Wacky Races villain Dick Dastardly by former world champion Damon Hill.




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Music stars sing praises of team sweeping Ghana clean

Known as Buz Stop Boys, the group's leader says they want "a cleaner, healthier, and prouder Ghana".




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The Kung Fu classes helping kids with confidence

Shaolin Temple Cultural Centre has been able to expand classes thanks to BBC Children in Need.




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Track defect causes train delays and cancellations

Elizabeth line, Great Western Railway and Heathrow Express services are all being affected.




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Missing boy's dad praises train firm's focus on vulnerable

Doncaster teenager Andrew Gosden was last spotted on CCTV leaving Kings Cross in September 2007.




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Biden Refuses During Presidential Debate To Answer Court-Packing Question

Democratic nominee Joe Biden refused to answer the question during the first presidential debate Tuesday night as to whether he would support “packing” the Supreme Court if elected President and the Senate Republicans confirms President Trump’s nominee Amy Coney Barrett. “If Senate Republicans go ahead and confirm Justice Barrett there has been talk about ending the […]

The post Biden Refuses During Presidential Debate To Answer Court-Packing Question appeared first on Hispolitica.




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Children's charity loses everything in huge fire

The Magic Cottage was the epicentre of the blaze which broke out in Abergavenny on Sunday night.




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Van Gerwen exits Grand Slam but Littler progresses

Michael van Gerwen fails to make it through to the Grand Slam of Darts last 16 but Luke Littler breezes through to the knockout stage.




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Lionesses face Portugal in Nations League opener

England face Portugal in their opening game of the 2025 Nations League after Uefa announce the match schedule for the competition.







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Iran’s Currency Collapses as Soon as Trump Wins the Election

We have already gotten a major success in foreign policy with Donald Trump’s election. The minute Trump got elected Iran’s currency collapsed to an all-time low. Iranian Rial fell to an all-time low of 703,000 rials to the dollar. This decline comes as Donald Trump runs for U.S presidency again, exacerbating tensions due to his […]

The post Iran’s Currency Collapses as Soon as Trump Wins the Election appeared first on The Lid.




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Biden’s Nitwit Dept. of Defense Uses Photo of Chinese Jet in Veterans Day Message

Joe Biden’s stupid, corrupt regime can’t even get a simple Veterans Day message right. As the nation came together to celebrate those who served out country, Biden’s Department of Defense pushed out a social media message telling Americans “Veterans Day, honoring all who served.” While, that is a perfectly fine message, the DoD added a […]

The post Biden’s Nitwit Dept. of Defense Uses Photo of Chinese Jet in Veterans Day Message appeared first on The Lid.




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News24 | Donald Trump's 'very polarising brand' raises new conflicts of interest following US election win

Donald Trump's impending White House return poses questions once again about conflicts of interest related to his business empire, with new cryptocurrency and other ventures raising fresh concerns.




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Apple Releases New Mac Mini, Revamped iMac, & M4 MacBook Pro

Apple has spent the last few days trickling releases of new Mac hardware, debuting a revamped iMac with an M4 chip and new colors, a redesigned Mac Mini that is smaller in size and now has an M4 chip, and the MacBook Pro lineup has been revamped with M4 processors as well. Each of the ... Read More




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5 Helpful Uses for Apple Intelligence on Mac, iPhone, & iPad

Apple Intelligence is here on Mac, iPhone, and iPad, and while the system requirements are strict, the Apple devices that are new and powerful enough to use the AI tools now gain some really fantastic features. We’re going to show you six helpful Apple Intelligence features and uses that you’ll find beneficial to your workflow, ... Read More




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Teachers can assess young students’ literacy skills and knowledge by encouraging them to produce books based on animal facts.

A new children's book transforms a sad, scared and anxious little boy into a superhero. The book is called "Cape," in honor of the bright-red cape the little boy wears and finds comfort in following the death of his father. "Cape" is Kevin Johnson's debut picture book, and it's vividly illustrated by artist Kitt Thomas.




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I've been on 105-day cruises, but this 13-day one was the toughest. Its itinerary had a major flaw I'll avoid on future trips.

The itinerary on my 13-day Norwegian cruise was too packed. Spending only two of the 13 days at sea left me exhausted, even as a seasoned cruiser.




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News24 | WATCH | SA closes Lebombo border port of entry as Mozambique violence escalates

South Africa has closed the Lebombo port of entry to and from Mozambique after 15 officials from the Ressano Garcia border fled to SA on Thursday morning for protection.




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Meme Coins Are Soaring as Pepe Unchained Layer 2 ICO Raises $27.5 Million

November has turned into a remarkable month for cryptocurrency, with Bitcoin and meme coins like Dogecoin, Shiba Inu, and Pepe… Continue reading Meme Coins Are Soaring as Pepe Unchained Layer 2 ICO Raises $27.5 Million

The post Meme Coins Are Soaring as Pepe Unchained Layer 2 ICO Raises $27.5 Million appeared first on ReadWrite.




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News24 Business | Facebook, Instagram group bets on normal-looking AR glasses, celeb AI voices

Meta launched AI chatbots voiced by Hollywood celebrities including Judi Dench and John Cena on Wednesday, betting its billions of users are eager to embrace artificial intelligence.




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NASA plans to grow mushroom houses on the moon

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.




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IVT Raises $5.5 Million for Webcasting Software

As the article appeared in TechCrunch...

IVT, a company that produces enterprise-friendly webcasting software, has raised $5.5 million in Series B funding from Syncom Venture Partners with Barshop Ventures, Monitor Ventures and Tudor Ventures participating in the investment round. IVT raised $3 million in Series A funding in 2006.
IVT’s SaaS offering not only helps power webcasts, but also converts multimedia files, such as slideshows, into viewable videos for the web. IVT also offers a YouTube-like hosting and social media site for companies to disseminate videos and webcasts. And the startup has a number of prominent companies that use its webcasting software including Oracle, Dow Chemical, IBM and NEC.




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Adobe Releases Flash Player 10.1

You can download the official release of Adobe Flash Player 10.1 on the Adobe site.

This is the first step in what will be an extremely eventful year for streaming media. Adobe will soon enter the enterprise market in a big way with a version of Flash Media Server that supports both IP and Application Multicasting.

Flash has long dominated the public internet, but its inability to multicast meant corporations had to stick with Windows Media. This new capability will give large enterprises the opportunity to migrate to the Flash format and benefit from its ability to run on any OS and any browser, ease of use, support for higher quality codecs, ability to change bit rates on the fly etc.




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Independent Consultant Chooses WebCaster

Jan Ozer is a streaming media consultant and frequent contributor to industry magazines and websites on streaming related topics and the author of Video Compression for Flash, Apple Devices and HTML5.  This year he reviewed both the MediaPlatform WebCaster platform and the Polycom Accordent Capture Station and Media management System for Streaming Media magazine.

Here is a link to the Accordent review, which appeared in the August, 2011 edition of Streaming media magazine: Accordent Capture Station and Media Management System: Review

Here is a link to the WebCaster review, which appeared in the June, 2011 edition of Streaming media magazine:  MediaPlatform WebCaster Review: A Strong Option for Webcasts

We think it is important to note that an independent consultant with recent and intimate knowledge of the two leading webcasting platforms is running his next webcast on the WebCaster platform.  You can register to watch his webcast, titled Introduction to Live Event Streaming, which will be broadcast live on Tuesday, October 4, 2:00 - 3:00 PM EST.


Here is Ozer’s description of the event: “This seminar will introduce attendees to live event streaming. It will start by discussing the technologies underlying live event streaming, like codecs and formats, and how most live event platforms can reach both a desktop player (usually Flash) and Apple and Android devices.”




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Cowardly Kamala Pulls A Hillary — Refuses To Concede As Trump Paints The Country Red

It's all over but the crying for a campaign that was supposed to be characterized by 'joy'. There will be no concession speech tonight. At little before 1 am, Kamala is running like a scared rabbit.

The post Cowardly Kamala Pulls A Hillary — Refuses To Concede As Trump Paints The Country Red appeared first on Clash Daily.




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Trump's New Chief of Staff Susie Wiles Discloses His Day One Plans: Report

President-elect Donald Trump will begin his second term by putting pieces of his first one back in place, according to incoming White House Chief of Staff Susie Wiles. Wiles made […]

The post Trump's New Chief of Staff Susie Wiles Discloses His Day One Plans: Report appeared first on The Western Journal.




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Analysis of {beta}-lactone formation by clinically observed carbapenemases informs on a novel antibiotic resistance mechanism [Enzymology]

An important mechanism of resistance to β-lactam antibiotics is via their β-lactamase–catalyzed hydrolysis. Recent work has shown that, in addition to the established hydrolysis products, the reaction of the class D nucleophilic serine β-lactamases (SBLs) with carbapenems also produces β-lactones. We report studies on the factors determining β-lactone formation by class D SBLs. We show that variations in hydrophobic residues at the active site of class D SBLs (i.e. Trp105, Val120, and Leu158, using OXA-48 numbering) impact on the relative levels of β-lactones and hydrolysis products formed. Some variants, i.e. the OXA-48 V120L and OXA-23 V128L variants, catalyze increased β-lactone formation compared with the WT enzymes. The results of kinetic and product studies reveal that variations of residues other than those directly involved in catalysis, including those arising from clinically observed mutations, can alter the reaction outcome of class D SBL catalysis. NMR studies show that some class D SBL variants catalyze formation of β-lactones from all clinically relevant carbapenems regardless of the presence or absence of a 1β-methyl substituent. Analysis of reported crystal structures for carbapenem-derived acyl-enzyme complexes reveals preferred conformations for hydrolysis and β-lactone formation. The observation of increased β-lactone formation by class D SBL variants, including the clinically observed carbapenemase OXA-48 V120L, supports the proposal that class D SBL-catalyzed rearrangement of β-lactams to β-lactones is important as a resistance mechanism.




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Business Briefing: Assessing the geopolitical implications of EU AI regulation

Business Briefing: Assessing the geopolitical implications of EU AI regulation 17 September 2024 — 4:00PM TO 5:00PM Anonymous (not verified) Chatham House

Join us for this critical discussion of how the EU AI Act will shape the world’s approach to the technology.

Join us for this critical discussion of how the EU AI Act will shape the world’s approach to the technology

Governments, technology companies and civil society groups across the world are now advocating firmer AI regulation. Machine learning algorithms have changed the way we interact with technology and powered much of our online lives for decades: why has this pendulum swung back so far toward greater control, and why now?

In 2023 the UK government seized the initiative with its Bletchley AI Safety Summit. The event attempted to address the so called ‘frontier risks’ associated with AI development. Global competition on AI is reflected in AI governance efforts in China, US, the Gulf and beyond. But to date, it is the EU that has led the West in passing AI legislation. The EU AI Act, has separated AI systems into graded risk categories carrying different regulatory requirements, and it remains to be seen whether global AI will feel the Brussels effect.

This conversation will cover the following questions:

  • Critics have painted regulation including the AI Act as anti-innovation. Is this a fair assessment?
  • What lessons can we learn from the successes and shortcomings of GDPR?
  • How do we tackle the challenge of low public trust in AI and low public trust in government technology projects, particularly in Western democracies?
  • Does the proliferation of safety institutes, and the AI office, point to the emergence of a new type of technical governance institution? What is its future?




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Director’s Briefing: Assessing foreign policy challenges for the next US president

Director’s Briefing: Assessing foreign policy challenges for the next US president 5 September 2024 — 2:00PM TO 3:00PM Anonymous (not verified) Chatham House and Online

This briefing will explore what challenges might await the winner of 2024 US presidential election.

As the 2024 US Presidential election draws closer, the future direction of American foreign policy seems ever more uncertain. Kamala Harris, the Democratic presidential candidate, appears to be embracing many of Biden’s policies, but she brings a different background, and most likely a different team, so change is likely.  Donald Trump has more well-known views on foreign policy, but the context for a second Trump administration would be very different than the first.

The next U.S. President will be confronted a world in need of leadership with two major wars, a more assertive and capable China, a climate crisis, ungoverned technological change, emerging powers that demand a seat at the table, and debt distress across much of the developing world.

Please join us for this critical conversation covering:

  • How will US-China strategic competition and the threat of conflict over Taiwan challenge US policy makers?
  • What are the risks and challenges posed by Russia’s illegal full-scale invasion of Ukraine?
  • How does war in the Middle East and the threat of regional escalation shape US foreign policy?




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Calpain activation mediates microgravity-induced myocardial abnormalities in mice via p38 and ERK1/2 MAPK pathways [Molecular Bases of Disease]

The human cardiovascular system has adapted to function optimally in Earth's 1G gravity, and microgravity conditions cause myocardial abnormalities, including atrophy and dysfunction. However, the underlying mechanisms linking microgravity and cardiac anomalies are incompletely understood. In this study, we investigated whether and how calpain activation promotes myocardial abnormalities under simulated microgravity conditions. Simulated microgravity was induced by tail suspension in mice with cardiomyocyte-specific deletion of Capns1, which disrupts activity and stability of calpain-1 and calpain-2, and their WT littermates. Tail suspension time-dependently reduced cardiomyocyte size, heart weight, and myocardial function in WT mice, and these changes were accompanied by calpain activation, NADPH oxidase activation, and oxidative stress in heart tissues. The effects of tail suspension were attenuated by deletion of Capns1. Notably, the protective effects of Capns1 deletion were associated with the prevention of phosphorylation of Ser-345 on p47phox and attenuation of ERK1/2 and p38 activation in hearts of tail-suspended mice. Using a rotary cell culture system, we simulated microgravity in cultured neonatal mouse cardiomyocytes and observed decreased total protein/DNA ratio and induced calpain activation, phosphorylation of Ser-345 on p47phox, and activation of ERK1/2 and p38, all of which were prevented by calpain inhibitor-III. Furthermore, inhibition of ERK1/2 or p38 attenuated phosphorylation of Ser-345 on p47phox in cardiomyocytes under simulated microgravity. This study demonstrates for the first time that calpain promotes NADPH oxidase activation and myocardial abnormalities under microgravity by facilitating p47phox phosphorylation via ERK1/2 and p38 pathways. Thus, calpain inhibition may be an effective therapeutic approach to reduce microgravity-induced myocardial abnormalities.




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M8R tropomyosin mutation disrupts actin binding and filament regulation: The beginning affects the middle and end [Molecular Bases of Disease]

Dilated cardiomyopathy (DCM) is associated with mutations in cardiomyocyte sarcomeric proteins, including α-tropomyosin. In conjunction with troponin, tropomyosin shifts to regulate actomyosin interactions. Tropomyosin molecules overlap via tropomyosin–tropomyosin head-to-tail associations, forming a continuous strand along the thin filament. These associations are critical for propagation of tropomyosin's reconfiguration along the thin filament and key for the cooperative switching between heart muscle contraction and relaxation. Here, we tested perturbations in tropomyosin structure, biochemistry, and function caused by the DCM-linked mutation, M8R, which is located at the overlap junction. Localized and nonlocalized structural effects of the mutation were found in tropomyosin that ultimately perturb its thin filament regulatory function. Comparison of mutant and WT α-tropomyosin was carried out using in vitro motility assays, CD, actin co-sedimentation, and molecular dynamics simulations. Regulated thin filament velocity measurements showed that the presence of M8R tropomyosin decreased calcium sensitivity and thin filament cooperativity. The co-sedimentation of actin and tropomyosin showed weakening of actin-mutant tropomyosin binding. The binding of troponin T's N terminus to the actin-mutant tropomyosin complex was also weakened. CD and molecular dynamics indicate that the M8R mutation disrupts the four-helix bundle at the head-to-tail junction, leading to weaker tropomyosin–tropomyosin binding and weaker tropomyosin–actin binding. Molecular dynamics revealed that altered end-to-end bond formation has effects extending toward the central region of the tropomyosin molecule, which alter the azimuthal position of tropomyosin, likely disrupting the mutant thin filament response to calcium. These results demonstrate that mutation-induced alterations in tropomyosin–thin filament interactions underlie the altered regulatory phenotype and ultimately the pathogenesis of DCM.




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High affinity binding of SARS-CoV-2 spike protein enhances ACE2 carboxypeptidase activity [Molecular Bases of Disease]

The novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) has emerged to a pandemic and caused global public health crisis. Human angiotensin-converting enzyme 2(ACE2) was identified as the entry receptor for SARS-CoV-2. As a carboxypeptidase, ACE2 cleaves many biological substrates besides angiotensin II to control vasodilatation and vascular permeability. Given the nanomolar high affinity between ACE2 and SARS-CoV-2 spike protein, we investigated how this interaction would affect the enzymatic activity of ACE2. Surprisingly, SARS-CoV-2 trimeric spike protein increased ACE2 proteolytic activity ∼3-10 fold against model peptide substrates, such as caspase-1 substrate and Bradykinin-analog. The enhancement in ACE2 enzymatic function was mediated by the binding of SARS-CoV-2 spike RBD domain. These results highlighted the potential for SARS-CoV-2 infection to enhance ACE2 activity, which may be relevant to the cardiovascular symptoms associated with COVID-19.




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Reply to Sysel et al.: Comment on the importance of using nitric oxide gas in the synthesis of nitrosylcobalamin and ICH-validated methods to assess purity and stability [Letters to the Editor]

In their comment (1) on our publication (2), the authors make two points: (i) they raise concerns about the possible effect of residual NONOate in our study, and (ii) they promote nitrosylcobalamin (NOCbl) supplied by their own company. Both points lack merit for the following reasons. The authors make the astonishing claim that the spectra of nitric oxide (NO•) and cobalamins overlap. Unlike NO•, cobalamin absorbs in the visible region, permitting unequivocal spectral assignment of NOCbl as reported (3). We demonstrated that whereas NOCbl is highly unstable in solution, it is stabilized by the B12 trafficking protein CblC. So even if present, residual NONOate (which is unstable at neutral pH and is removed during the work-up (3)) could not account for the observed difference.The authors then misrepresent our synthetic method, claiming that anaerobic conditions were used to generate nitrocobalamin (NO2Cbl), which results in the transient formation of NOCbl. We synthesized NO2Cbl aerobically using nitrite as described (4); NOCbl is not an intermediate in this ligand exchange reaction. The aerobic instability of NOCbl has been rigorously described by inorganic chemists (3, 5) and raises obvious questions about its purported biological effects as exemplified by the authors' own 2003 JBC publication, which was later withdrawn.As to promoting NOCbl from their company, the authors refer to a synthetic route from a mixture of NO• gas and aquocobalamin. The authors' method (6) has been described as “dubious” by chemists (5). Whereas DEAE NONOate used in our method is widely known as an NO• donor,...




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Comment on the importance of using nitric oxide gas in the synthesis of nitrosylcobalamin and ICH-validated methods to assess purity and stability [Letters to the Editor]

After a thorough read of this paper (1), we wish to clarify that the authors' anaerobic method of synthesis for the production of nitrocobalamin results in the transient formation of nitrosylcobalamin, an unstable intermediate upon exposure to air. We concur that the authors' method results in the production of nitrocobalamin based on the UV-visible data as shown. The authors' adapted anaerobic method consists of mixing hydroxocobalamin hydrochloride with diethylamine NONOate diethylammonium salt in aqueous solution. Of concern, the UV spectrum of nitric oxide overlaps that of all cobalamin species under anaerobic conditions, making any assignments of the binding of nitric oxide to hydroxocobalamin suspect (2). Additionally, the use of acetone to precipitate the authors' product causes precipitation of diethylamine NONOate, resulting in an impure product. As a result, its utility for drawing experimental conclusions is faulty.The product from the authors' anaerobic synthetic method has not been assessed for purity, and the synthetic method itself has not been validated using a stability-indicating method as required by the International Conference on Harmonization (ICH) (ICH Q2B, Validation of Analytical Procedures) methodology, which is a hallmark for analytical characterization. Our nitrosylcobalamin synthesis involves reacting nitric oxide gas with hydroxocobalamin acetate as a heterogeneous mixture in a non-electron-donating solvent followed by rotary evaporation. Our nitrosylcobalamin product is stable in air, releases nitric oxide gas in situ (3), and meets ICH stability guidelines (4). Additionally, our nitrosylcobalamin product demonstrates biological activity, which has not been observed for nitrocobalamin (3, 5).




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Naturally occurring hotspot cancer mutations in G{alpha}13 promote oncogenic signaling [Molecular Bases of Disease]

Heterotrimeric G-proteins are signaling switches broadly divided into four families based on the sequence and functional similarity of their Gα subunits: Gs, Gi/o, Gq/11, and G12/13. Artificial mutations that activate Gα subunits of each of these families have long been known to induce oncogenic transformation in experimental systems. With the advent of next-generation sequencing, activating hotspot mutations in Gs, Gi/o, or Gq/11 proteins have also been identified in patient tumor samples. In contrast, patient tumor-associated G12/13 mutations characterized to date lead to inactivation rather than activation. By using bioinformatic pathway analysis and signaling assays, here we identified cancer-associated hotspot mutations in Arg-200 of Gα13 (encoded by GNA13) as potent activators of oncogenic signaling. First, we found that components of a G12/13-dependent signaling cascade that culminates in activation of the Hippo pathway effectors YAP and TAZ is frequently altered in bladder cancer. Up-regulation of this signaling cascade correlates with increased YAP/TAZ activation transcriptional signatures in this cancer type. Among the G12/13 pathway alterations were mutations in Arg-200 of Gα13, which we validated to promote YAP/TAZ-dependent (TEAD) and MRTF-A/B-dependent (SRE.L) transcriptional activity. We further showed that this mechanism relies on the same RhoGEF-RhoGTPase cascade components that are up-regulated in bladder cancers. Moreover, Gα13 Arg-200 mutants induced oncogenic transformation in vitro as determined by focus formation assays. In summary, our findings on Gα13 mutants establish that naturally occurring hotspot mutations in Gα subunits of any of the four families of heterotrimeric G-proteins are putative cancer drivers.




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Disease-associated mutations in inositol 1,4,5-trisphosphate receptor subunits impair channel function [Molecular Bases of Disease]

The inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs), which form tetrameric channels, play pivotal roles in regulating the spatiotemporal patterns of intracellular calcium signals. Mutations in IP3Rs have been increasingly associated with many debilitating human diseases such as ataxia, Gillespie syndrome, and generalized anhidrosis. However, how these mutations affect IP3R function, and how the perturbation of as-sociated calcium signals contribute to the pathogenesis and severity of these diseases remains largely uncharacterized. Moreover, many of these diseases occur as the result of autosomal dominant inheritance, suggesting that WT and mutant subunits associate in heterotetrameric channels. How the in-corporation of different numbers of mutant subunits within the tetrameric channels affects its activities and results in different disease phenotypes is also unclear. In this report, we investigated representative disease-associated missense mutations to determine their effects on IP3R channel activity. Additionally, we designed concatenated IP3R constructs to create tetrameric channels with a predefined subunit composition to explore the functionality of heteromeric channels. Using calcium imaging techniques to assess IP3R channel function, we observed that all the mutations studied resulted in severely attenuated Ca2+ release when expressed as homotetramers. However, some heterotetramers retained varied degrees of function dependent on the composition of the tetramer. Our findings suggest that the effect of mutations depends on the location of the mutation in the IP3R structure, as well as on the stoichiometry of mutant subunits assembled within the tetrameric channel. These studies provide insight into the pathogenesis and penetrance of these devastating human diseases.




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Integrated Genomic and Proteomic Analyses of Gene Expression in Mammalian Cells

Qiang Tian
Oct 1, 2004; 3:960-969
Research




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The Paragon Algorithm, a Next Generation Search Engine That Uses Sequence Temperature Values and Feature Probabilities to Identify Peptides from Tandem Mass Spectra

Ignat V. Shilov
Sep 1, 2007; 6:1638-1655
Technology




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Identification of a domain critical for Staphylococcus aureus LukED receptor targeting and lysis of erythrocytes [Molecular Bases of Disease]

Leukocidin ED (LukED) is a pore-forming toxin produced by Staphylococcus aureus, which lyses host cells and promotes virulence of the bacteria. LukED enables S. aureus to acquire iron by lysing erythrocytes, which depends on targeting the host receptor Duffy antigen receptor for chemokines (DARC). The toxin also targets DARC on the endothelium, contributing to the lethality observed during bloodstream infection in mice. LukED is comprised of two monomers: LukE and LukD. LukE binds to DARC and facilitates hemolysis, but the closely related Panton–Valentine leukocidin S (LukS-PV) does not bind to DARC and is not hemolytic. The interaction of LukE with DARC and the role this plays in hemolysis are incompletely characterized. To determine the domain(s) of LukE that are critical for DARC binding, we studied the hemolytic function of LukE–LukS-PV chimeras, in which areas of sequence divergence (divergence regions, or DRs) were swapped between the toxins. We found that two regions of LukE's rim domain contribute to hemolysis, namely residues 57–75 (DR1) and residues 182–196 (DR4). Interestingly, LukE DR1 is sufficient to render LukS-PV capable of DARC binding and hemolysis. Further, LukE, by binding DARC through DR1, promotes the recruitment of LukD to erythrocytes, likely by facilitating LukED oligomer formation. Finally, we show that LukE targets murine Darc through DR1 in vivo to cause host lethality. These findings expand our biochemical understanding of the LukE–DARC interaction and the role that this toxin-receptor pair plays in S. aureus pathophysiology.




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Differential compartmental processing and phosphorylation of pathogenic human tau and native mouse tau in the line 66 model of frontotemporal dementia [Molecular Bases of Disease]

Synapse loss is associated with motor and cognitive decline in multiple neurodegenerative disorders, and the cellular redistribution of tau is related to synaptic impairment in tauopathies, such as Alzheimer's disease and frontotemporal dementia. Here, we examined the cellular distribution of tau protein species in human tau overexpressing line 66 mice, a transgenic mouse model akin to genetic variants of frontotemporal dementia. Line 66 mice express intracellular tau aggregates in multiple brain regions and exhibit sensorimotor and motor learning deficiencies. Using a series of anti-tau antibodies, we observed, histologically, that nonphosphorylated transgenic human tau is enriched in synapses, whereas phosphorylated tau accumulates predominantly in cell bodies and axons. Subcellular fractionation confirmed that human tau is highly enriched in insoluble cytosolic and synaptosomal fractions, whereas endogenous mouse tau is virtually absent from synapses. Cytosolic tau was resistant to solubilization with urea and Triton X-100, indicating the formation of larger tau aggregates. By contrast, synaptic tau was partially soluble after Triton X-100 treatment and most likely represents aggregates of smaller size. MS corroborated that synaptosomal tau is nonphosphorylated. Tau enriched in the synapse of line 66 mice, therefore, appears to be in an oligomeric and nonphosphorylated state, and one that could have a direct impact on cognitive function.




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Assessing the trajectory of the Middle East conflict

Assessing the trajectory of the Middle East conflict 4 November 2024 — 4:00PM TO 5:00PM Anonymous (not verified) Online

Experts examine how the conflict may develop and what we can expect from regional and international actors.

A year on, the war in Gaza has spilled beyond Israel and Palestine with escalation across the region intensifying.

Recent weeks have seen Israel deepening its military offensive on Lebanon and keeping the north of the Gaza strip under siege, while leaders of Hezbollah and Hamas have been successfully targeted by its forces. Israel also launched an unprecedented assault against Iran in response to Tehran’s missile attacks on Israeli territory earlier in October.

Against this backdrop, regional states, particularly in the Gulf, in line with their overall approach to the conflict, are prioritizing diplomacy over escalation. They maintain their neutrality on the hostility between Israel and Iran and its aligned groups from the axis of resistance.

The strength of old alliances is being tested while new alignments are uncovered that may reshape the geopolitical landscape of the region, particularly following the US presidential election.

In this webinar, experts will examine:

  • What are Israel’s calculations at this stage and how have the domestic political dynamics changed over recent weeks?
  • What are the impacts of the war on Iran and its aligned actors and what can we expect from Tehran and groups from the axis of resistance?
  • How are the wars in Gaza and Lebanon connected and would ending one stop the other?
  • What is the response from regional states, particularly in the Gulf, and what role can they play?
  • What are the possible scenarios for a post-election US policy on Israel and the Middle East?




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America chooses a new role in the world

America chooses a new role in the world Expert comment jon.wallace

Donald Trump’s election victory will bring immediate costs for US allies, says Bronwen Maddox, and will remake the map of American partnership.

As a second Trump presidency became a certainty, countries around the world were racing to forge relationships with him and calculate the likely impacts – which could come within weeks of his inauguration. 

One Japanese official spoke for the mood in many capitals in saying ‘we have learned to respond to new American presidents as we would to a Christmas present – you open it, and whatever is inside, you say “That is exactly what I wanted!”’

In the case of Trump, that sentiment is most straightforward in Moscow, where President Vladimir Putin’s supporters were exultant. In Europe, especially the UK, and among the US’s Indo-Pacific allies, the calculation is more complicated. They are trying to work out their response based on remarks Trump has made, knowing that unpredictability and inconsistency were the hallmarks of his first presidency and may be of his second. 

Tariffs

The most immediate global impact is likely to come through the tariffs which Trump has vowed to impose on goods from China – and other countries too. Tariffs will not decouple the US and Chinese economies but could sharply check trade in electric vehicles and other imports. 

They could also undermine global economic growth: economists have warned – with no apparent effect on the Trump campaign – of the inflationary effect tariffs will have and the consequent upwards pressure on interest rates and the dollar.

A similar effect would apply to European countries. This will depend on the tariffs chosen and whether a Trump administration seeks actively to discourage Europe’s still relatively open economy from trade with China. 

Given that many European governments are struggling to get economic growth at all, this would be a significant new blow. 

Ukraine

In his victory speech Trump repeated a point of which he is immensely proud: that in his terms, there were ‘no new wars’ during his first administration.

He also said that while he wanted strong US armed forces, he preferred not to use them. He has publicly made much of his desire to end conflicts in Ukraine and in the Middle East and has boasted of his ability to strike ‘deals’ to that end. 

If Trump seeks to freeze the conflict along the current frontline, there will be little to protect Ukraine – or Europe – from further Russian aggression.

The key question is if and how Trump will push for a cessation of fighting in Ukraine. If he seeks to freeze the conflict along the current frontline, there will be little to protect Ukraine – or Europe – from further Russian aggression in the future unless the US pledges to block that. The US could offer Kyiv explicit security guarantees, although NATO membership remains a distant prospect.

A direct security pledge from Washington is more realistic, but it remains to be seen whether that would be sufficient to convince Ukraine to stop fighting. Ukrainian leadership and people regard the war as existential and any surrender of territory to Russian control, even if it were not formalized, may yet prove an impossible barrier in negotiations.

Nor is it obvious how Trump could secure an agreement with Putin worth the name. He has prided himself on his relationship with the Russian leader, and Russian disinformation campaigns appeared to weigh in on his side. But Russia has broken agreements before. 

It would be a more plausible deal if backed by China – but that would require Trump to deal with a regime he appears to regard as the US’s primary threat. 

Middle East

Trump could make the conflict in the region much worse – or just possibly, open a route to stability. He has consistently sided with Israel, but his relationship with Israeli Prime Minister Benjamin Netanyahu has been mixed. 

There is no doubt that Netanyahu hoped for a Trump victory. Were Trump to clearly side with the prime minister and those in his cabinet who have no intention of granting a state to the Palestinians, it would represent an inflammatory step. 

Elements of Israeli society would see this as the opportunity to annex the West Bank and seek control or partial reoccupation of Gaza, hoping to give Palestinians every incentive to leave those areas for neighbouring countries. Netanyahu may also be encouraged to strike further at Iran.

On the other hand, Trump appears to mean what he says about shutting down conflicts, even if only out of concern for US interests. Netanyahu may come under pressure to stop bombing southern Lebanon and to reach some deal in Gaza with Hamas, including the release of the hostages. 

A more hopeful route lies in Trump’s pride in the Abraham Accords, a signature achievement of his first term that normalized relations between Israel and the United Arab Emirates, Bahrain and Morocco. 

The great prize still dangling in front of Israel is the possibility of normalization with Saudi Arabia. That would allow Trump to claim he had brought peace to the Middle East. But that will remain impossible for Riyadh without Israeli commitment to a Palestinian state. 

The UK

There are no grounds to believe this will be an easy relationship for the UK to manage.

Foreign Secretary David Lammy has put in the air miles getting to know the Republicans around Trump.

Sir Keir Starmer was quick to congratulate Trump, pointedly including the phrase ‘special relationship’ and referring to cooperation on technology and security. But his new UK government, which has prioritized growth, will be acutely aware of the tariff threat. 

Foreign Secretary David Lammy has put in the air miles getting to know the Republicans around Trump, but his comments denouncing the president elect before Labour’s own election victory may well sour the mood. So too will reports of Labour supporters organizing to support Democrat campaigning.  

Chancellor Rachel Reeves is expected to visit China early in the new year. She will have to decide by then the UK’s position on whether to import cheap Chinese solar panels and electric vehicles. Trump’s victory will not make this decision easier.

Climate

Trump and Harris offered starkly different environmental visions. Trump’s commitment to pursue cheap US oil and gas is fashioned with voters at home in mind, and will remove the US further from global climate talks. 




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