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BREAKING! Supreme Court Decision Used For Immediate Nationwide Block of Border Crisis Rule! (Video)

In this video, Armed Scholar expounds on the recent decision by the US Supreme Court concerning our border and the flooding of illegal immigrants, including the Biden administration, through the Department of Homeland Security, concerning programs set up that promised citizenship to illegal aliens. The decision was handed down following the 2024 elections, striking down …




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Open Source Project DeFlock Is Mapping License Plate Surveillance Cameras All Over the World

An anonymous reader quotes a report from 404 Media: Flock is one of the largest vendors of automated license plate readers (ALPRs) in the country. The company markets itself as having the goal to fully "eliminate crime" with the use of ALPRs and other connected surveillance cameras, a target experts say is impossible. [...] Flock and automated license plate reader cameras owned by other companies are now in thousands of neighborhoods around the country. Many of these systems talk to each other and plug into other surveillance systems, making it possible to track people all over the country. "It went from me seeing 10 license plate readers to probably seeing 50 or 60 in a few days of driving around," [said Alabama resident and developer Will Freeman]. "I wanted to make a record of these things. I thought, 'Can I make a database of these license plate readers?'" And so he made a map, and called it DeFlock. DeFlock runs on Open Street Map, an open source, editable mapping software. He began posting signs for DeFlock (PDF) to the posts holding up Huntsville's ALPR cameras, and made a post about the project to the Huntsville subreddit, which got good attention from people who lived there. People have been plotting not just Flock ALPRs, but all sorts of ALPRs, all over the world. [...] When I first talked to Freeman, DeFlock had a few dozen cameras mapped in Huntsville and a handful mapped in Southern California and in the Seattle suburbs. A week later, as I write this, DeFlock has crowdsourced the locations of thousands of cameras in dozens of cities across the United States and the world. He said so far more than 1,700 cameras have been reported in the United States and more than 5,600 have been reported around the world. He has also begun scraping parts of Flock's website to give people a better idea of where to look to map them. For example, Flock says that Colton, California, a city with just over 50,000 people outside of San Bernardino, has 677 cameras. People who submit cameras to DeFlock have the ability to note the direction that they are pointing in, which can help people understand how these cameras are being positioned and the strategies that companies and police departments are using when deploying them. For example, all of the cameras in downtown Huntsville are pointing away from the downtown core, meaning they are primarily focused on detecting cars that are entering downtown Huntsville from other areas.

Read more of this story at Slashdot.




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Biden’s Signature Climate ‘Boondoggle’ Might Be On Chopping Block After Trump Win

By David Blackmon In the wake of the election of President Donald Trump to serve a second term in office, along with presumptive Republican majorities in both houses of Congress, many are now asking about what the future will hold for the oddly named Inflation Reduction Act. Trump made it repeatedly clear on the campaign […]

The post Biden’s Signature Climate ‘Boondoggle’ Might Be On Chopping Block After Trump Win appeared first on Liberty Unyielding.




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Federal judge blocks Louisiana Ten Commandments law

The law requires public schools to display a poster of the Ten Commandments in every classroom.




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US says Israel hasn't breached its law against blocking aid in Gaza

Officials say Israel has taken some steps to meet a US demand for more supplies to enter Gaza, but aid agencies say conditions have actually worsened.




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velocityconf: Free webcast w/ @jon lives http://t.co/TxL60Oagos 'Michelin Starred Cooking with Chef at Etsy' starting NOW. #velocityconf #devops

velocityconf: Free webcast w/ @jon lives http://t.co/TxL60Oagos 'Michelin Starred Cooking with Chef at Etsy' starting NOW. #velocityconf #devops




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velocityconf: @rkustner Congrats, thank you, and good luck!

velocityconf: @rkustner Congrats, thank you, and good luck!




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velocityconf: New #velocityconf speaker interview w/ @sascha_d http://t.co/zg4tzDzIlH Config Management: It's Not About the Tool

velocityconf: New #velocityconf speaker interview w/ @sascha_d http://t.co/zg4tzDzIlH Config Management: It's Not About the Tool




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velocityconf: @tsantero @garethr No, there's just a lot that goes into producing #velocityconf. Plus the chairs are getting ready for Santa Clara + NY! :)

velocityconf: @tsantero @garethr No, there's just a lot that goes into producing #velocityconf. Plus the chairs are getting ready for Santa Clara + NY! :)




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velocityconf: Help your dev + ops teams be cross-functional and more successful. http://t.co/1mqGK3zh0U Free webcast 5/22 w/ @lnxchk

velocityconf: Help your dev + ops teams be cross-functional and more successful. http://t.co/1mqGK3zh0U Free webcast 5/22 w/ @lnxchk




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velocityconf: If you don't understand your ppl, you don't understand #Ops http://t.co/DQTBLJlWza New #velocityconf interview w/ @katemats

velocityconf: If you don't understand your ppl, you don't understand #Ops http://t.co/DQTBLJlWza New #velocityconf interview w/ @katemats




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velocityconf: Free webcast from our friends at @citrix 5/29 http://t.co/IOeY4U0wUP Learn to consolidate 40 load balancers and ADCs into single platform

velocityconf: Free webcast from our friends at @citrix 5/29 http://t.co/IOeY4U0wUP Learn to consolidate 40 load balancers and ADCs into single platform




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




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velocityconf: LAST DAY for #velocityconf EU call for speakers http://t.co/qShofQCDPl Share your best #WPO, #Ops, and #DevOps stories.

velocityconf: LAST DAY for #velocityconf EU call for speakers http://t.co/qShofQCDPl Share your best #WPO, #Ops, and #DevOps stories.




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velocityconf: New #velocityconf CA program preview is up: http://t.co/rKjf91RXdD @ariyahidayat on End-to-End JS Quality Analysis.

velocityconf: New #velocityconf CA program preview is up: http://t.co/rKjf91RXdD @ariyahidayat on End-to-End JS Quality Analysis.




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velocityconf: RT @oreillyanimals Vote Instant Wild's Digital Eyes & Ears for Wildlife Protection to win Google Global Impact Award http://t.co/Z0EetiQshZ

velocityconf: RT @oreillyanimals Vote Instant Wild's Digital Eyes & Ears for Wildlife Protection to win Google Global Impact Award http://t.co/Z0EetiQshZ




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velocityconf: @da3mon Sorry! We were just doing some followup with past Velocity attendees. Sorry to intrude. No harm intended. :-(

velocityconf: @da3mon Sorry! We were just doing some followup with past Velocity attendees. Sorry to intrude. No harm intended. :-(




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velocityconf: Who's up for a 5 minute lightning talk. Last day to get your #Ignite proposal in for #velocityconf CA. http://t.co/pzL0WJtQH5

velocityconf: Who's up for a 5 minute lightning talk. Last day to get your #Ignite proposal in for #velocityconf CA. http://t.co/pzL0WJtQH5




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velocityconf: Call for speakers and registration is open for @webperfdays in Silicon Valley http://t.co/cJKBmynkjI June 22, Google HQ (cc @sfwebperf)

velocityconf: Call for speakers and registration is open for @webperfdays in Silicon Valley http://t.co/cJKBmynkjI June 22, Google HQ (cc @sfwebperf)




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velocityconf: RT @allspaw: Operations and System Safety - always a student http://t.co/1VYBEZYrK8 #devops #velocityconf

velocityconf: RT @allspaw: Operations and System Safety - always a student http://t.co/1VYBEZYrK8 #devops #velocityconf




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velocityconf: What Is the Risk That Amazon Will Go Down (Again)? http://t.co/DgnfQynjcM Thank you @bergstrom_johan for the awesome #velocityconf post.

velocityconf: What Is the Risk That Amazon Will Go Down (Again)? http://t.co/DgnfQynjcM Thank you @bergstrom_johan for the awesome #velocityconf post.




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

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




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velocityconf: RT @OReillyAnimals Advice, please! Elephant Listening Project asks for ideas/solutions/help with 3 practical problems http://t.co/Y90YP3maoz

velocityconf: RT @OReillyAnimals Advice, please! Elephant Listening Project asks for ideas/solutions/help with 3 practical problems http://t.co/Y90YP3maoz




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velocityconf: RT @avleen: Ok folks, home stretch! We need 10 more people to record short #OpsSchool videos NEXT WEEK at @velocityconf. We can do it!...

velocityconf: RT @avleen: Ok folks, home stretch! We need 10 more people to record short #OpsSchool videos NEXT WEEK at @velocityconf. We can do it!...




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velocityconf: S Bay Area #WomeninTech (+ allies!) pls come to the #VelocityConf women's communities meetup on 6/19 http://t.co/xSY7jcyPXV

velocityconf: S Bay Area #WomeninTech (+ allies!) pls come to the #VelocityConf women's communities meetup on 6/19 http://t.co/xSY7jcyPXV




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Selling in Europe – How to Localize Your eCommerce Business for Local Markets

As a digital company, your business is not bound by conventional borders and has the freedom and opportunity to reach customers anywhere in the world. And just as you look outward for new markets, customers are also looking beyond their physical borders for their goods and services. As a study by KPMG shows, online buyers […]






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News24 Business | South African AI body calls for LinkedIn probe over alleged local user data violations

The South African Artificial Intelligence Association wants LinkedIn to be investigated, as it claims the social networking platforms new data use practice violates local personal information protection law.




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Beyond Skills: Unlocking the Full Potential of Data Scientists

Modern organizations regard data as a strategic asset that drives efficiency, enhances decision making, and creates new value for customers. Across the organization—product management, marketing, operations, finance, and more—teams are overflowing with ideas on how data can elevate the business. To bring these ideas to life, companies are eagerly hiring data scientists for their technical […]




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Visiting Locorotondo, Italy – A Guide to the Trulli Town

Have you heard of Locorotondo, Italy? Locorotondo is one of Southern Italy’s most beautiful villages, in my opinion, but it isn’t yet overwhelmed with tourist crowds. A true hidden gem, Locorotondo is just a 12-minute drive from busy Alberobello in the Puglia region, but feels like a world away. Planning your trip to Locorotondo last […]

The post Visiting Locorotondo, Italy – A Guide to the Trulli Town appeared first on Adventurous Kate.




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Obama-Appointed Federal Judge Temporarily Blocks Ten Commandments Law

A Louisiana law that sought to post the Ten Commandments in every schoolroom in the state has been shelved by a federal judge. U.S. District Court Judge John W. deGravelles, […]

The post Obama-Appointed Federal Judge Temporarily Blocks Ten Commandments Law appeared first on The Western Journal.




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Beijing briefing: China’s wish for 2023? An end to lockdown

Beijing briefing: China’s wish for 2023? An end to lockdown The World Today mhiggins.drupal 29 November 2022

Xi Jinping will try to beef up Global South relations in 2023, but weary Chinese and the business sector need pandemic restrictions to end, says Yu Jie.

This past year in Chinese politics was capped by a highly anticipated 20th Party Congress in Beijing in October which marked the beginning of General Secretary Xi Jinping’s unprecedented third term. Xi stacked the all-powerful Politburo with male loyalists and left the rest of the world to sift through the implications of his leadership reshuffle.

Meanwhile, Xi made headlines at the G20 summit in Indonesia, maintaining a largely positive tone with President Joe Biden and being caught on camera chiding Canada’s Justin Trudeau for leaks after their talks. So, what can we expect Xi to pull out of the hat in 2023, the Chinese Year of the Rabbit? 

In February and March, the conversations around Beijing dinner tables will focus on the composition of the new central government – the important seats within the Chinese State Council. This body must deliver Xi’s ‘security-oriented’ economic agenda as well as his much-promoted ‘Common Prosperity’ initiative.

The ‘Zero-Covid’ strategy has exacerbated youth unemployment and tested the patience of China’s upwardly mobile middle-class

Pundits will be paying particular attention to who is put in charge of economic planning, who the new foreign minister might be and who will govern the central bank. I will offer my reading of these tea leaves as the year unfolds.

In April and May, speculation may turn to whether China will finally open its borders to foreign visitors and those compatriots who want to be reunited with loved ones after enduring the pandemic lockdown. While some loosening of restrictions began in November 2022, China is still balancing its twin aims of containing the spread of Covid and re-engineering its economy along similar lines to Europe.

Beijing’s controversial ‘Zero-Covid’ strategy has intensified economic pressures, exacerbated rising levels of youth unemployment and tested the patience of China’s middle class, which has led to unprecedented civil disobedience. Those not employed by the state have been hit particularly hard. It is difficult to see how China’s economy can crank up again until Beijing reduces its internal restrictions and reconnects with the world.

A pivot to the Global South

June and July will be prime season for Beijing’s diplomacy with the Global South. Xi recently announced that China would host the third Belt and Road Forum in 2023 – a meeting of heads of states from predominantly developing countries to discuss his flagship foreign affairs initiative. As seen in the Political Report of the 20th Party Congress, Xi has abandoned the ‘new type of great power relations’ language he previously used to describe relations with the US-led western world. 

In its place, Xi is stressing that China should develop its ties with the Global South through his Global Development and Global Security initiatives which were announced in 2021 and 2022 respectively. These aim to reshape the global governance agenda in multilateral forums and project Beijing’s influence on to the developing world.

Sport will dominate throughout August and September. While Beijing’s spending spree on football promotion might have failed to see the national side qualify for the World Cup, its table tennis team has proved invincible and continues to cheer up the nation. I will offer my own verdict on why there is such a stark contrast between the success of the two men’s teams and explain the meaning of sports in modern Chinese society.

In October and November, young graduates will begin their careers while new university students start to arrive on campus. Chinese students are constantly subjected to strenuous testing. And like their western peers, they face the inevitable pressures of finding a job, repaying the mortgage and other everyday facts of life.

The burnout of China’s Generation Z 

The term ‘involution’ – neijuan – has been adopted by China’s Generation Z to describe their feelings of burnout at the ever-increasing expectations associated with high performance. Equally, they have strong opinions about their own government as well as western liberal democracies. China’s leaders of the future will come from their ranks so it will be worthwhile spending some time trying to understand what makes them tick.

Billions will want a return to normal life without the fear of having the wrong colour – yellow or red – on their Covid health QR code

Whatever the Year of the Rabbit holds for China, billions of its people will want to have their life return to normal without the fear of having the wrong colour – yellow or red – on their Covid health QR code. Only a green code shows a person is healthy and free to move around. The Covid threat has hovered over people for three years and as borders reopen, they may be holding their breath. 

A slowing economy dimming consumer confidence and a precarious international environment make it look even harder for President Xi to pursue the agenda outlined in October 2022. As the Year of the Rabbit dawns, China doesn’t need a Mad Hatter or a March Hare, instead it urgently needs a sound path to economic recovery and a plan to reopen its borders that works for everyone. 




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Parts per Million Mass Accuracy on an Orbitrap Mass Spectrometer via Lock Mass Injection into a C-trap

Jesper V. Olsen
Dec 1, 2005; 4:2010-2021
Technology




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Development and validation of a high-throughput whole cell assay to investigate Staphylococcus aureus adhesion to host ligands [Microbiology]

Staphylococcus aureus adhesion to the host's skin and mucosae enables asymptomatic colonization and the establishment of infection. This process is facilitated by cell wall-anchored adhesins that bind to host ligands. Therapeutics targeting this process could provide significant clinical benefits; however, the development of anti-adhesives requires an in-depth knowledge of adhesion-associated factors and an assay amenable to high-throughput applications. Here, we describe the development of a sensitive and robust whole cell assay to enable the large-scale profiling of S. aureus adhesion to host ligands. To validate the assay, and to gain insight into cellular factors contributing to adhesion, we profiled a sequence-defined S. aureus transposon mutant library, identifying mutants with attenuated adhesion to human-derived fibronectin, keratin, and fibrinogen. Our screening approach was validated by the identification of known adhesion-related proteins, such as the housekeeping sortase responsible for covalently linking adhesins to the cell wall. In addition, we also identified genetic loci that could represent undescribed anti-adhesive targets. To compare and contrast the genetic requirements of adhesion to each host ligand, we generated a S. aureus Genetic Adhesion Network, which identified a core gene set involved in adhesion to all three host ligands, and unique genetic signatures. In summary, this assay will enable high-throughput chemical screens to identify anti-adhesives and our findings provide insight into the target space of such an approach.




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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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How to revive Europe’s economy and unlock its potential

How to revive Europe’s economy and unlock its potential 7 November 2024 — 6:00PM TO 7:00PM Anonymous (not verified) Chatham House and Online

Enrico Letta, former prime minister of Italy, and other experts discuss how the European Union’s economy must adapt to a challenging world.

Amid a fractured geopolitical environment, global trade volatility and hardening protectionist policies in many countries, the European economy must adapt fast. The single market is a key driver of European integration, but it was designed in a very different global economic context.

Launched in April, Enrico Letta’s Much more than a market report set out how the European Union should adapt the arrangements of the single market to ensure it delivers prosperity and economic security for EU citizens in the 21st century. The report resonates with ongoing debates over the future of European competitiveness, industrial strategy and how to respond to an apparently deglobalizing world. In this event, Letta and other experts on the European economy and integration will discuss the prospect of meaningful reform of the single market, and what the incoming Commission can do to ensure the EU unlocks the potential of its economy for all its citizens.

Key questions will include:

  • What dynamics are shaping the Europe’s economic landscape?
  • What opportunities are there to enhance the strength and competitiveness of the single market
  • How can the EU’s leaders ensure the single market is aligned with other strategic objectives such as security and enlargement?
  • What political hurdles may prevent progress on single market reform? And how can these be overcome?

The institute occupies a position of respect and trust, and is committed to fostering inclusive dialogue at all events. Event attendees are expected to uphold this by adhering to our code of conduct.




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The Challenge of Ambition? Unlocking Climate Action and the Outcomes of COP24




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Perilipin is located on the surface layer of intracellular lipid droplets in adipocytes

EJ Blanchette-Mackie
Jun 1, 1995; 36:1211-1226
Articles




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Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans

Saverio Cinti
Nov 1, 2005; 46:2347-2355
Research Articles




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The Arg-293 of Cryptochrome1 is responsible for the allosteric regulation of CLOCK-CRY1 binding in circadian rhythm [Computational Biology]

Mammalian circadian clocks are driven by transcription/translation feedback loops composed of positive transcriptional activators (BMAL1 and CLOCK) and negative repressors (CRYPTOCHROMEs (CRYs) and PERIODs (PERs)). CRYs, in complex with PERs, bind to the BMAL1/CLOCK complex and repress E-box–driven transcription of clock-associated genes. There are two individual CRYs, with CRY1 exhibiting higher affinity to the BMAL1/CLOCK complex than CRY2. It is known that this differential binding is regulated by a dynamic serine-rich loop adjacent to the secondary pocket of both CRYs, but the underlying features controlling loop dynamics are not known. Here we report that allosteric regulation of the serine-rich loop is mediated by Arg-293 of CRY1, identified as a rare CRY1 SNP in the Ensembl and 1000 Genomes databases. The p.Arg293His CRY1 variant caused a shortened circadian period in a Cry1−/−Cry2−/− double knockout mouse embryonic fibroblast cell line. Moreover, the variant displayed reduced repressor activity on BMAL1/CLOCK driven transcription, which is explained by reduced affinity to BMAL1/CLOCK in the absence of PER2 compared with CRY1. Molecular dynamics simulations revealed that the p.Arg293His CRY1 variant altered a communication pathway between Arg-293 and the serine loop by reducing its dynamicity. Collectively, this study provides direct evidence that allosterism in CRY1 is critical for the regulation of circadian rhythm.




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From local to global: A roadmap for US climate action

From local to global: A roadmap for US climate action 14 April 2021 — 6:30PM TO 8:00PM Anonymous (not verified) 28 March 2021 Online

Ahead of Biden’s Earth Day Summit, panellists discuss a range of climate issues, from city-level climate management to the international security implications of climate deals.

On their first day in office, the Biden-Harris administration sent a strong message to Americans and allies by rejoining the Paris Agreement. Experienced climate and environmental leaders were appointed to senior leadership roles as part of a ‘whole of government approach’ to climate action.

Although decisive action is welcomed by many Americans and international partners, the divided domestic perspectives on climate and a changed international landscape pose significant challenges.

Ahead of the Earth Day Summit on April 22, an event hosted by Joe Biden to mark America’s formal return to global climate talks, panellists discuss a range of climate issues, from city-level climate management to the international security implications of climate deals.

  • How will post-COVID domestic priorities and policy influence the international approach of the US to climate action?
  • How will US policy, both foreign and domestic, need to respond to the security and geopolitical elements posed by climate change?
  • What actions are needed during the upcoming Earth Day Summit for the US to establish credibility as a climate leader?
  • What shape are key debates taking on US-China climate relations ahead of COP 26, and how might climate issues be approached in relation to wider geopolitical tensions?




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Error analysis of second-order local time integration methods for discontinuous Galerkin discretizations of linear wave equations

Constantin Carle and Marlis Hochbruck
Math. Comp. 93 (), 2611-2641.
Abstract, references and article information




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Strong blocking sets and minimal codes from expander graphs

Noga Alon, Anurag Bishnoi, Shagnik Das and Alessandro Neri
Trans. Amer. Math. Soc. 377 (), 5389-5410.
Abstract, references and article information




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????²-spectrum, growth indicator function and critical exponent on locally symmetric spaces

Lasse L. Wolf and Hong-Wei Zhang
Proc. Amer. Math. Soc. 152 (), 5445-5453.
Abstract, references and article information





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If You Think Blocking People Over Political Views Is Petty, Just Wait Until You See The Other Reasons People Shared




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Structural and biochemical characteristics of two Staphylococcus epidermidis RNase J paralogs RNase J1 and RNase J2 [Protein Structure and Folding]

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.




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A highly potent CD73 biparatopic antibody blocks organization of the enzyme active site through dual mechanisms [Methods and Resources]

The dimeric ectonucleotidase CD73 catalyzes the hydrolysis of AMP at the cell surface to form adenosine, a potent suppressor of the immune response. Blocking CD73 activity in the tumor microenvironment can have a beneficial effect on tumor eradication and is a promising approach for cancer therapy. Biparatopic antibodies binding different regions of CD73 may be a means to antagonize its enzymatic activity. A panel of biparatopic antibodies representing the pairwise combination of 11 parental monoclonal antibodies against CD73 was generated by Fab-arm exchange. Nine variants vastly exceeded the potency of their parental antibodies with ≥90% inhibition of activity and subnanomolar EC50 values. Pairing the Fabs of parents with nonoverlapping epitopes was both sufficient and necessary whereas monovalent antibodies were poor inhibitors. Some parental antibodies yielded potent biparatopics with multiple partners, one of which (TB19) producing the most potent. The structure of the TB19 Fab with CD73 reveals that it blocks alignment of the N- and C-terminal CD73 domains necessary for catalysis. A separate structure of CD73 with a Fab (TB38) which complements TB19 in a particularly potent biparatopic shows its binding to a nonoverlapping site on the CD73 N-terminal domain. Structural modeling demonstrates a TB19/TB38 biparatopic antibody would be unable to bind the CD73 dimer in a bivalent manner, implicating crosslinking of separate CD73 dimers in its mechanism of action. This ability of a biparatopic antibody to both crosslink CD73 dimers and fix them in an inactive conformation thus represents a highly effective mechanism for the inhibition of CD73 activity.




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Economy Must Not Get Stuck Between Lockdown and Recovery

2 July 2020

Creon Butler

Research Director, Trade, Investment & New Governance Models: Director, Global Economy and Finance Programme
Despite recent outbreaks in several countries which had appeared to be close to excluding the virus, focusing on suppression and elimination is the best economic as well as health strategy.

2020-07-02-Plane-Virus-Business

An almost empty British Airways passenger plane flies from Milan to London. Photo by Laurel Chor/Getty Images.

Lockdowns are being eased in many countries, but from different starting points in terms of prevalence of the virus, and with different near-term trade-offs between protecting life and easing constraints on economic activity.

The pressure to ease is understandable. The IMF estimates $10tn has been spent so far on official support measures worldwide, and forecasts global GDP will contract by an unprecedented 4.9% in 2020.

However, the WHO director general, Dr Tedros Adhanom Ghebreyesus, recently insisted that there is an ‘urgent responsibility to do everything we can with the tools we have now to suppress transmission and save lives’, even as research into vaccines and therapeutics continues.

Focusing on suppressing and eliminating the virus as quickly as possible is not just the best strategy for saving life, it also makes most sense in terms of minimising the long-term economic damage from the pandemic.

The alternatives remain uncertain

Neither a vaccine nor improved treatment are currently sufficiently certain to be the focal point for an economic recovery strategy. Despite optimism about vaccine development, there is no certainty of a decisive outcome by a given date. And, even if a vaccine proved effective, manufacturing and distributing it to 8bn people will present an unprecedented set of logistical and economic challenges and take many months, if not years.

In the meantime, although substantial progress has been made in reducing loss of life among those made seriously ill by the virus - and who have access to advanced medical facilities - it remains highly dangerous for a significant proportion of the population - around 20% in advanced economies.

An alternative containment strategy based on gradually reducing the prevalence of the virus in the population by maintaining an “R” number (replication coefficient) just below one will be both economically costly and highly risky when compared with a decisive push to eliminate the virus quickly.

With an R number just below one it is true the virus may eventually disappear, but only over a lengthy period, during which economically damaging social distancing measures will have to stay in place, dragging out the impact on both demand and supply.

Wage support measures to limit ‘economic scarring’ will have to be maintained, and kickstarting the economy with a conventional fiscal stimulus will be difficult, if not impossible, especially when the ability - or willingness - of consumers to spend is still heavily constrained either by social distancing measures or a lack of confidence.

There is also a major risk when the R number is close to one that the virus could suddenly take off again, leading to a complete failure of the strategy.

Benefits of suppress and eliminate

A successful policy focused on suppressing and eliminating the virus offers much better prospects. First, the government can then protect the vast bulk of the economy within its territory, even if it means continuing travel restrictions for some time vis-a-vis countries that are less committed to or less successful in eliminating the virus.

Some sectors - particularly long-haul air transport - will be hard hit, but other critical high value or employment intensive sectors - such as domestic hospitality, leisure and the arts - will be able to make a substantial recovery. To put it bluntly, the authorities may have to hold back some sectors to save others. Such a strategy would also ensure an economy can participate sustainably in free travel zones with other countries.

Second, a drive to suppress and eliminate the virus in the shortest possible timeframe, and then maintain that status, will help authorities communicate clearly to the public the overarching framework guiding the application of social distancing measures, and the nature of the ‘new normal’ economy that can be expected to emerge over the medium to long-term.

Achieving such clarity will enhance the public’s trust in the government’s strategy and hence responsiveness to government instructions. It will also minimise unnecessary and costly adaptations by business and increase its ability to target new opportunities arising from the genuine long-term changes brought about by the crisis.

In addition, a suppress and eliminate strategy is the only sure way to address the disproportionate impact of the virus on ethnic minorities and the poor, and to put an end to the isolation of the millions who currently have to shield themselves.

We know that suppressing the virus almost completely within a given territory is possible because some countries have already done it - notably New Zealand, South Korea, and Taiwan. Some which started with a serious epidemic, such as China, Spain and Italy, have also managed to reach a point where almost complete elimination within their territory can be envisaged.

Renewed outbreaks are likely to happen, particularly while the virus remains in active circulation globally. But this does not invalidate the underlying suppress and eliminate strategy.

Key policies to suppress and eliminate the virus include: a rapid and decisive national lockdown to reduce the disease to levels low enough for test, trace and quarantine systems to identify and suppress local outbreaks; social distancing measures for a limited period or in a specific locality to limit spread while, as far as possible, minimising economic impact; and effective quarantine and track systems applied at borders to prevent the disease from being re-introduced by non-essential travellers and returning nationals.

The precise form of these policies is evolving rapidly as we learn more about the virus. For example, if there is a need today to stop a rapidly escalating epidemic in a given territory, it won’t necessarily mean adopting exactly the same package of lock down measures across the board as were applied three months ago. Several activities had to cease then simply because the virus was spreading so fast there was no time to put in place effective mitigation measures. This does not have to be repeated.

In addition, the benefits of the widespread use of face masks are now much better understood. As is the value of deploying a battery of measures, each one only partially effective on its own but, in combination, with a decisive impact. Financial support measures may need to be adjusted or extended to underpin local lockdowns and, at any given point, the authorities will need to work within an overall budget for relaxation measures and prioritise - getting pupils back in school may mean holding back easing of restrictions elsewhere.

Choosing an effective strategy inevitably means making tough choices. Delaying short-term recovery measures, even by a matter of weeks in whole economies or specific localities, can make a decisive difference to delivering a long-term sustainable economic outcome. The authorities may also be forced to hold back some economic sectors, possibly even leading to permanent damage, as the price of a general recovery. But if we are not ready to make these choices, the economy may become permanently stuck in a halfway house between lockdown and recovery.