v New UK bill can fight fresh wave of online racist abuse By www.chathamhouse.org Published On :: Wed, 21 Jul 2021 08:24:28 +0000 New UK bill can fight fresh wave of online racist abuse Expert comment NCapeling 21 July 2021 The Euros final and Grand Prix put online abuse once more in the spotlight. The UK’s Online Safety Bill provides a strong framework for tackling the problem. The ugly online abuse targeted at members of the England football team following the Euros final, and then at Lewis Hamilton after the British Grand Prix, was not only hateful to the individuals concerned, but divisive for the UK more broadly. More needs to be done to regulate online platforms to avoid the spread of such abuse at scale. Online platforms are making increasing efforts to ‘self-regulate’ in order to tackle online abuse. Over the past year, Facebook and Twitter have strengthened their policies on hateful speech and conduct, such as Facebook’s policy banning Holocaust denial. Both have become more vigilant at deplatforming those who violate their terms of service, such as Donald Trump, and at removing online abuse using a combination of machines and humans. Twitter announced in the 24 hours following the Euros final that it had removed more than 1,000 tweets, and permanently suspended several accounts, for violating its rules. But inevitably not all abusive posts are picked up given the scale of the issue and, once the post has been seen, arguably the damage is done. Platforms have also partnered with NGOs on initiatives to counter hate speech and have launched initiatives to tackle the rise in coordinated inauthentic behaviour and information operations that seek to sow distrust and division. But while these efforts are all laudable, they are not enough. The UK government’s Online Safety Bill, published in May 2021, aims to tackle harmful content online by placing a duty of care on online platforms The root of the problem is not the content but a business model in which platforms’ revenue from advertising is directly linked to engagement. This encourages the use of ‘recommender’ algorithms which amplify divisive content by microtargeting users based on previous behaviour, as seen not just with racist abuse but also other toxic content such as anti-vaccination campaigns. Abusers can also remain anonymous, giving them protection from consequences. Creating a legal duty of care The UK government’s Online Safety Bill, published in May 2021, aims to tackle harmful content online by placing a duty of care on online platforms to keep users safe and imposing obligations tailored to the size, functionality, and features of the service. Social media companies will be expected to comply with their duties by carrying out risk assessments for specified categories of harm, guided by codes of practice published by the independent regulator, OFCOM. The bill gives OFCOM the power to fine platforms up to £18 million or ten per cent of global turnover, whichever is higher, for failure to comply. Following the Euros final, the UK government spoke of referring some racist messages and conduct online to the police. But only a small proportion of it can be prosecuted given the scale of the abuse and the fact only a minority constitutes criminal activity. The majority is ‘lawful but harmful’ content – toxic and dangerous but not technically falling foul of any law. When addressing ‘lawful but harmful’ material, it is crucial that regulation negotiates the tension between tackling the abuse and preserving freedom of expression. The scale at which such expression can spread online is key here – freedom of speech should not automatically mean freedom of reach. But it is equally important that regulation does not have a chilling effect on free speech, as with the creeping digital authoritarianism in much of the world. When addressing ‘lawful but harmful’ material, it is crucial that regulation negotiates the tension between tackling the abuse and preserving freedom of expression The Online Safety Bill’s co-regulatory approach aims to address these tensions by requiring platforms within the scope of the bill to specify in their terms and conditions how they deal with content on their services that is legal but harmful to adults, and by giving the regulator powers to police how platforms enforce them. Platforms such as Facebook and Twitter may already have strong policies on hate speech – now there will be a regulator to hold them to account. Devil is in the detail How successful OFCOM is in doing so will depend on the precise powers bestowed on it in the bill, and how OFCOM chooses to use them. It’s still early days - the bill will be scrutinized this autumn by a committee of MPs before being introduced to parliament. This committee stage will provide an opportunity for consideration of how the bill may need to evolve to get to grips with online abuse. These latest two divisive and toxic episodes in UK sport are only likely to increase pressure from the public, parliament, and politicians for the bill to reserve robust powers for OFCOM in this area. If companies do not improve at dealing with online abuse, then OFCOM should have the power to force platforms to take more robust action, including by conducting an audit of platforms’ algorithms, enabling it to establish the extent to which their ‘recommender’ settings play a part in spreading hateful content. Currently, the bill’s definition of harm is confined to harm to individuals, and the government has stated it does not intend this bill to tackle harm to society more broadly. But if racist abuse of individuals provokes racist attacks more widely, as has happened, the regulator should be able to take that wider context into account in its investigation and response. Responses to the draft bill so far indicate challenges ahead. Some argue the bill does not go far enough to tackle online abuse, especially on the issue of users’ anonymity, while others fear the bill goes too far in stifling freedom of expression, labelling it a recipe for censorship. Parliamentary scrutiny will need to take into account issues of identity, trust, and authenticity in social networks. While some call for a ban on the cloak of anonymity behind which racist abusers can hide online, anonymity does have benefits for those in vulnerable groups trying to expose hate. Subscribe to our weekly newsletterOur flagship newsletter provides a weekly round-up of content, plus receive the latest on events and how to connect with the institute. Enter email address Subscribe An alternative approach gaining attention is each citizen being designated a secure digital identity, which would both provide users with greater control over what they can see online and enable social media platforms to verify specific accounts. Instituted with appropriate privacy and security safeguards, a secure digital ID would have benefits beyond social media, particularly in an online COVID-19 era. The online public square is global so countries other than the UK and international organizations must also take measures. It is encouraging to see synergies between the UK’s Online Safety Bill and the EU’s Digital Services Act, published in draft form in December 2020, which also adopts a risk-based, co-regulatory approach to tackling harmful online content. And the UK is using its G7 presidency to work with allies to forge a more coherent response to internet regulation at the international level, at least among democratic states. Addressing the scourge of online hate speech is challenging so the UK’s Online Safety Bill will not satisfy everyone. But it can give the public, parliament, and politicians a structure to debate these crucial issues and, ultimately, achieve more effective ways of tackling them. Full Article
v Counter-terrorism measures and sanctions: How to avoid negative consequences for humanitarian action? By www.chathamhouse.org Published On :: Wed, 21 Jul 2021 13:15:52 +0000 Counter-terrorism measures and sanctions: How to avoid negative consequences for humanitarian action? 9 September 2021 — 2:00PM TO 3:30PM Anonymous (not verified) 21 July 2021 Online Exploring current endeavours to address the tensions between counter-terrorism measures, sanctions and humanitarian action. Counter-terrorism measures address broad forms of support to terrorist acts. Their expansion, internationally and domestically, has given rise to new points of friction with international humanitarian law. Unless the measures include adequate safeguards, they can impede humanitarian action. Country-specific sanctions imposed for other objectives, such as ending conflicts or protecting civilians, raise similar challenges for humanitarian action. These problems are not new, but solutions at international and national level remain elusive. At this panel event, which marks the launch of a new Chatham House research paper, panellists explore current endeavours to address the tensions between counter-terrorism measures, sanctions and humanitarian action. What are the current dynamics and developments at Security Council level? What are the opportunities now that the UK is developing its independent sanctions strategy? What challenges do counter-terrorism requirements in funding agreements for humanitarian action pose? What is necessary to make progress? Full Article
v How can the investor community address the ‘S’ in ESG? – the role of social purpose values By www.chathamhouse.org Published On :: Mon, 18 Oct 2021 19:34:24 +0000 How can the investor community address the ‘S’ in ESG? – the role of social purpose values 16 November 2021 — 1:30PM TO 2:30PM Anonymous (not verified) 18 October 2021 Online This webinar highlights the crucial relationship between an open civic space and a profitable business environment. 2020 was a tipping point for investors to think and act more responsibly, galvanized by catalysts like the killing of George Floyd and the pandemic. There is increasing investor support for social and environmental causes. Younger investors are placing increasing emphasis on values and social issues in their investment decisions. The ‘S’ in the Environment Social and Governance (ESG) agenda is clearly gaining traction, but how far does it extend to civil and political liberties i.e. the right of citizens, NGOs and journalists to speak freely, assemble and associate which are increasingly shrinking around the world? While there is increasing focus on human rights issues such as modern slavery and supply chains, civil society space issues often fall between the cracks when investors consider ESG. This webinar also explores opportunities and challenges that arise for the investor community in terms of factoring civic space issues into their political risk and ESG analysis. To what extent are civic space issues being factored into ESG social purpose values, especially by younger investors? What is the best methodology for assessing these issues in order to ensure a common and coherent set of global standards in this area? And how can investors mitigate the risks of their activities to civic space in practice? Full Article
v Protecting universal human rights: Imagine a better world By www.chathamhouse.org Published On :: Fri, 19 Nov 2021 09:55:18 +0000 Protecting universal human rights: Imagine a better world Explainer Video NCapeling 19 November 2021 Short animation examining why protecting and defending human rights ensures an equitable response to humanitarian crises and addresses economic inequality. Human rights are not policies that can be overturned, they are not granted by governments. They belong to everyone as human beings. For the most part, states are meeting their commitments to defend and protect universal human rights. But increasingly some governments are beginning to shy away from their obligations, and some are even actively seeking to subvert human rights. And the regional and international bodies created and charged with defending these rights are being challenged by the rise of new powers and political movements. Chatham House is built on big ideas. Help us imagine a better world. Our researchers develop positive solutions to global challenges, working with governments, charities, businesses and society to build a better future. SNF CoLab is our project supported by the Stavros Niarchos Foundation (SNF) to share our ideas in experimental, collaborative ways – and to learn about designing a better future. Full Article
v Why the private sector should protect civic society By www.chathamhouse.org Published On :: Fri, 10 Dec 2021 15:57:39 +0000 Why the private sector should protect civic society Explainer Video NCapeling 10 December 2021 A short animation explaining the crucial role that the private sector can play in protecting and defending civic space. This video explainer introduces a synthesis paper which analyses how the private sector can support the protection of civic society space. The private sector is in a unique position to work with civil society organizations to uphold and defend civic freedoms and support sustainable and profitable business environments. Companies have the capacity, resources and expertise to enhance the protection of civic space. By doing so, this helps create a society in which fundamental rights and the rule of law are respected and exercised by governments, private citizens, and all organizations which, in turn, is critical to a sustainable and profitable business environment. For more information, download the report. Full Article
v Transatlantic Tech Talks: Cooperation or sovereignty? By www.chathamhouse.org Published On :: Wed, 15 Dec 2021 11:45:06 +0000 Transatlantic Tech Talks: Cooperation or sovereignty? Audio bhorton.drupal 15 December 2021 A new mini-series from Undercurrents explores international cooperation on regulating the tech sector. Transatlantic Tech Talks is a three part mini-series on the Undercurrents podcast feed, produced with the support of Microsoft, which explores the state of international cooperation on digital governance between the United States, the UK and Europe. As technological innovation accelerates, and new digital tools and business models arise, governments are working to develop a framework of regulations to safeguard the rights and interests of their citizens. Not all stakeholders agree, however, on the best way to achieve this. While some advocate a ‘digital cooperation’ approach based on transparency and data-sharing, others are more concerned with maintaining ‘digital sovereignty’. In the first episode of this series, Ben is joined by Casper Klynge, Harriet Moynihan and Marianne Schneider-Petsinger, who set out the broad context for these debates. They assess where the major government, private sector and civil society actors stand on the question of digital governance, and how they are approaching the international negotiations. Full Article
v Sanctions must not prevent humanitarian work in Ukraine By www.chathamhouse.org Published On :: Mon, 30 May 2022 09:18:16 +0000 Sanctions must not prevent humanitarian work in Ukraine Expert comment NCapeling 30 May 2022 Restrictions on supply of certain items and financial sanctions can impede vital relief unless adequate safeguards are put in place such as exceptions or general licences. Sanctions play a major role in the response to Russia’s invasion of Ukraine. The United Nations (UN) has not imposed sanctions, but an important number of states have done so. They have imposed a wide array of restrictions and the number of targeted – or ‘designated’ – persons is unprecedented. The public has been captivated by the freezing of oligarchs’ assets. There is ongoing discussion about seizing them to provide compensation for war damage. Debate continues about how far to ban oil and gas imports. One aspect of the sanctions has received far less attention, even though it can exacerbate the effect of the conflict on civilians. Some of the trade restrictions and financial sanctions pose immediate and concrete challenges to the capacity of humanitarian organizations to work in Ukraine and in neighbouring states. Trade sanctions imposed by the European Union (EU) and UK prohibit the export or supply of certain goods and technology in the transport, telecommunications, energy, and oil or mineral exploration sectors to non-government-controlled areas of the Donetsk or Luhansk oblasts, or for use there. Experience shows that the due diligence measures adopted by humanitarian organizations do not always allay concerns of risk-averse sectors such as banks Restricted items include technical equipment which is necessary for humanitarian operations, such as water pumps and refrigerating equipment, but also far more mundane items such as vehicles for transport of persons and goods, and office equipment that are necessary for humanitarian organizations trying to work in the region. Designations can reduce options for support Financial sanctions also raise problems. Some are immediately apparent. Significantly for humanitarian operations, the two de facto republics of Donetsk and Luhansk are designated by the EU, the UK, and the US. Consequently, it is prohibited to make funds or assets available to them directly or indirectly. This prohibition covers the payment of any taxes, licences, and other fees to these authorities, as well as the provision of assets to ministries under their control in the course of humanitarian operations, such as ministries of health and education. Designations of other entities may also be relevant, such as Russian ‘state enterprises’ which operate in these areas and are the sole providers of commodities necessary for humanitarian response, such as heating fuel. These are the designations which most obviously impact humanitarian response. However, more than 1,000 persons and entities have been designated and humanitarian organizations must avoid purchasing goods and services from them. Risk-averse commercial partners Commercial actors – such as banks, insurers, freight companies and commodity providers – whose services are required by humanitarian organizations must also comply with the sanctions. Experience shows that the due diligence measures adopted by humanitarian organizations do not always allay concerns of risk-averse sectors such as banks. Fears of violating the sanctions, coupled with the fact humanitarian organizations are rarely profitable clients, have led them to severely restrict the services they provide. This is not the first occasion the problem has arisen. What is different in relation to Ukraine is the number of designated persons and the ‘sanctions packages’ adopted in quick succession. As compliance officers struggle to keep abreast, their institutions become even more risk-averse. For UK banks, the situation is exacerbated by the adoption of the Economic Crime (Transparency and Enforcement) Act 2022. This amends existing rules by removing the requirement for the UK Treasury to prove knowledge or reasonable cause to suspect that a transaction violated sanctions, imposing strict liability for sanctions violations. Time for the UK to follow others The EU, the US, Switzerland, and other states which have imposed sanctions have sought to mitigate their adverse effects by including safeguards for humanitarian action. Although the UK has largely replicated the measures adopted by the EU in terms of restrictions and designations, it lags behind in including such safeguards. The UK trade restrictions and financial sanctions do not include exceptions for humanitarian action. While several general licences have been issued, none relate to humanitarian operations. If the UK is to show it is serious about responding to the immense needs caused by the invasion it must introduce appropriate safeguards in its sanctions Instead, the UK measures foresee only the possibility of applying for specific licences – from the Treasury in the case of financial sanctions and the Department of International Trade for trade restrictions. But obtaining specific licences is a time-consuming process which is simply not appropriate for emergency response. If the UK is to show it is serious about responding to the immense needs caused by the invasion it must introduce appropriate safeguards in its sanctions – either in the form of exceptions or general licences. What matters is they cover all key humanitarian organizations responding to the Ukraine crisis that are subject to UK sanctions – either because they are UK persons or because their funding agreements with the UK government require them to comply with UK measures. These include UN agencies, funds and programmes, components of the International Red Cross and Red Crescent Movement, and non-governmental organizations (NGOs) responding to the crisis in Ukraine and neighbouring states. The provision must also clearly extend to commercial entities which provide necessary services for humanitarian operations. Given the UK recently adopted an exception along similar lines in relation to the Afghanistan sanctions, there is a valuable precedent for Ukraine. Full Article
v Geopolitical corporate responsibility can drive change By www.chathamhouse.org Published On :: Tue, 26 Jul 2022 12:55:12 +0000 Geopolitical corporate responsibility can drive change Expert comment NCapeling 26 July 2022 Russia’s long invasion of Ukraine is testing the commitment of business, but this could see the emergence of a new pillar of support for the rules-based international order. The massive exit of more than 1,000 international companies from Russia has surpassed – by a factor of nearly ten in merely four months – the number which pulled out of apartheid-led South Africa over an entire decade. These company exits extend beyond those industries targeted for sanctions – oil and gas, banks and financial services, aerospace, and certain technology sectors – to include hundreds in consumer products ranging from Levi’s and H&M clothing to Coca-Cola and McDonalds. Many of these companies may wish to return to a post-conflict – or post-Putin – Russia, while a few have already sold their Russian operations, as McDonald’s has to an existing Siberian licensee. Both reputational and operational factors are driving the huge exodus: reputational as companies have chosen to disassociate themselves from Putin’s regime; operational as transportation routes and supply chains have been interrupted. Few of these companies have made explicit the principles at stake, while many still face ‘tricky legal, operational and ethical considerations’ and some have kept operations in place. But the collective impact of the exit in response to Russia’s affront to international law has sent shockwaves around the world. Current issues and future implications Minds now turn to whether this exodus sets a blueprint for the future, and how companies having to make complex and sensitive risk assessments and global business planning decisions can address both current issues as well as similar future challenges. The new Declaration from the Business for Ukraine Coalition – an international civil society initiative of organizations and individuals – encourages companies to reinforce ‘responsible exit’ from Russia ‘in response to its unprovoked, full-scale war on Ukraine’. The declaration’s objective is to ‘block access to the economic and financial resources enabling Russian aggression’ and it urgently calls on companies that have terminated or suspended their business operations and relationships to ‘stand by those commitments until the territorial sovereignty of Ukraine within internationally recognized borders is restored.’ Business has a fundamental stake in the international order as the framework for stability, prosperity, open societies, and markets It also states companies yet to terminate or suspend operations in Russia should do so unless they can demonstrate through due diligence that their provision of ‘essential’ services or products – such as medicines – meet critical humanitarian needs. The 2022 Edelman Trust Barometer Special Report: The Geopolitical Business suggests Ukraine represents an inflection point posing ‘a new test’ for business. According to an online survey of 14,000 respondents in 14 countries, including employees, NGOs, and other stakeholders, there is a ‘rising call’ for business to be more engaged in geopolitics, with CEOs ‘expected to shape policy’ on societal and geopolitical issues. Such expectations have been intensifying with the impetus of the combined stakeholder capitalism and corporate purpose agenda, even as a political backlash in the US against the environmental, social, and governance (ESG) movement linking institutional investors and multinational corporations gains momentum. The emergence of corporate activism is a further development – partly driven by employees and accelerated during the pandemic – on issues of economic inequality, racial injustice, and gender equality, as well as the climate crisis. When considering what broader purpose should drive this corporate geopolitical engagement, the Business for Ukraine Declaration offers an answer, calling Russia’s aggression ‘an attack on the rules-based international order which must be protected to ‘safeguard the international community and the global economy.’ This points to broader interests and values at stake in the Russian war on Ukraine because supporting the rules-based international order can become the basis of a new geopolitical corporate responsibility. Business, especially multinational corporations and institutional investors, fundamentally depend on and have enormously benefitted from this order. Economic development needs a stable rules-based international order Trade and investment, entrepreneurship, and innovation – the sinews of economic development – depend on predictable, rational behaviour by states at home and abroad. Individual companies and entire industries share a stake in upholding this order at a time when its stability and even legitimacy is undergoing a severe challenge. A new geopolitical corporate responsibility does not need to become a doctrine but can instead be an agenda to support the international rules-based order under stress The rules-based international order has evolved since the adoption of the UN Charter in 1945, the Universal Declaration of Human Rights in 1948, and the establishment of the standards, norms and institutions that reflect and reinforce these lodestars. It defines the international community, the rule of law, accountable governance, civic freedoms, and human rights within nations. It also supports national self-determination, sovereignty, and the disavowal of the use of force to alter borders among nations, and it provides accountability for genocide, crimes against humanity, and war crimes. Business has a fundamental stake in the international order as the framework for stability, prosperity, open societies, and markets. A new geopolitical corporate responsibility does not need to become a doctrine but can instead be an agenda to support the international rules-based order under stress. Such an agenda may help multinationals deal with expectations they already face, such as: Avoiding situations where they cause, contribute, or are directly linked to human rights abuses. This objective is enshrined in the UN Guiding Principles on Business and Human Rights and companies can be further informed by the new UN Guide to Heightened Human Rights Due Diligence for Business in Conflict-Affected Contexts. Committing to the ‘shared space’ of the rule of law, accountable governance, civic freedoms, and human rights. These are both the enablers of civil society and the underpinning of sustainable and profitable business and investment environments. The Chatham House synthesis paper The role of the private sector in protecting civic space sets forth the rationale for companies to defend these vital elements. Supporting peace, justice, and strong institutions both within nations and across the international community as set forth by UN Sustainable Development Goal 16. The SDG 16 Business Framework: Inspiring Transformational Governance shows how companies, as well as national governments and international institutions, can contribute to these building blocks of stability and prosperity. Demonstrating corporate responsibility at the national and geopolitical levels to enhance equity, transparency, and accountability. Multinationals are already challenged to accept minimum corporate taxation within and across jurisdictions, curb excessive executive compensation, endorse mandatory disclosure of environmental and human rights due diligence, and strengthen corporate governance of ESG risks and responsibilities, including with respect to human rights. Diminishing inequality by tackling poverty and ensuring sustainability by arresting the climate crisis. Alongside governments and international institutions, the business community already faces increasing pressure to improve its efforts in these areas. Full Article
v Cyberspace governance at the United Nations By www.chathamhouse.org Published On :: Wed, 30 Nov 2022 11:17:13 +0000 Cyberspace governance at the United Nations 18 January 2023 — 3:00PM TO 4:00PM Anonymous (not verified) 30 November 2022 Online How can member states achieve lasting, adaptable, and meaningful success in cyberspace governance at the United Nations? Now in its second iteration, the Open-ended Working Group on Information and Communications Technologies (OEWG) has been a space for United Nations member states to discuss the use, regulation and governance of cyberspace since 2019. The progress of this forum in shaping cyberspace and its governance is evidenced by two consensus reports including a framework for responsible state behaviour in cyberspace and, more recently, plans for a Programme of Action. However, the true impact of these UN processes in limiting the threats of ICTs to international peace and security is contingent upon operationalizing the consensus at the international level and reflecting it in national policies and practices. Pervasive challenges continue to hamper operationalization efforts, including differences in national capacities and capabilities, and divergences in national perspectives regarding the application of international law to cyberspace. So, how can member states overcome these challenges and set this vital forum up for lasting, adaptable and meaningful success? What role does ‘multi-stakeholderism’ play in realizing responsible state behaviour in cyberspace? With a dual focus on cyber capacity building and international law, this event considers how these two elements interact and intersect, how discussions on them could progress in the UN space and outside it and how the two contribute to a safer and more secure cyberspace for all. This event is organized jointly by the International Security and International Law Programmes at Chatham House to launch Phase 2 of the project ‘Cyberspace4All: Towards an inclusive approach to cyber governance’ which is funded by the Ministry of Foreign Affairs of the Netherlands. Full Article
v Seven ways Russia’s war on Ukraine has changed the world By www.chathamhouse.org Published On :: Fri, 17 Feb 2023 10:06:57 +0000 Seven ways Russia’s war on Ukraine has changed the world Feature jon.wallace 17 February 2023 Chatham House experts examine the shifts in geopolitical alliances, security, energy, and supply chains and whether these changes are likely to be long-lasting. President Vladimir Putin’s decision to launch a full-scale re-invasion of Ukraine one year ago was a global shock which ‘marked an abrupt end to 30 years of globalization and all the international co-operation that made that possible’ with serious implications for countries around the world, outlined Chatham House director Bronwen Maddox in her inaugural lecture. Not only has the war threatened the stability of Europe but it has also impacted food and energy security globally including in the Middle East and Africa, creating shock waves in a world barely recovering from the COVID-19 pandemic. Full Article
v The UK must not sleepwalk into leaving the ECHR By www.chathamhouse.org Published On :: Fri, 17 Mar 2023 18:57:59 +0000 The UK must not sleepwalk into leaving the ECHR Expert comment NCapeling 17 March 2023 Talk of the UK leaving the European Convention on Human Rights (ECHR) keeps rearing its head with little thought for the real impact. Withdrawal from the European Convention on Human Rights (ECHR) has not been firmly ruled out as a potential UK government policy option to allow easier implementation of its controversial new measures to deport asylum seekers to Rwanda. This, in the context of a UK general election looming and tackling the ‘small boats problem’ being one of the five priorities of UK prime minister Rishi Sunak. In recent months, ECHR withdrawal has come up in relation to the UK’s controversial draft Illegal Migration Bill, the (now shelved) bill of rights, and – perhaps most significantly – the Northern Ireland Protocol deal with implications for the Good Friday Agreement. But leaving the ECHR – and likely the Council of Europe – would be counterproductive for the UK’s global leadership. UK values and priorities will be undermined The only other countries in the region outside of the Council of Europe, Russia and Belarus, both had sanctions imposed on them by the UK for their human rights record. Russia was expelled from the Council of Europe in 2022 due to its aggression in Ukraine and, although the UK would be deciding to remove itself from Europe’s oldest and largest intergovernmental human rights body, the optics would not be good. This is especially true considering the UK’s vocal support for Ukraine in international forums, including its intervention in Ukraine’s case against Russia before the International Court of Justice and, potentially, in a separate case against Russia before the European Court of Human Rights itself. If the UK withdraws from the ECHR, the EU would be entitled to terminate important provisions concerning international law enforcement and judicial cooperation in criminal justice matters More significantly and closer to home, the ECHR is a fundamental part of the Good Friday Agreement. It is difficult to argue UK withdrawal would not breach the agreement. As well as risking damage to intercommunal relations, such a breach is likely to significantly harm strategic relations with the US – and President Biden is set to visit Northern Ireland and the Republic of Ireland to mark the 25th anniversary of the Good Friday Agreement. It would also damage relations with the UK’s closest neighbours, Ireland, and the European Union (EU), with whom the prime minister has only recently scored credits for securing the Northern Ireland Protocol deal. If the UK withdraws from the ECHR, the EU would be entitled to terminate important provisions concerning international law enforcement and judicial cooperation in criminal justice matters under Article 692 of the UK-EU Trade and Cooperation Agreement, further isolating the UK from allies who share its legal and other values. Withdrawal would be in the name of sovereignty but with little thought to the practical implications on rights and few perceived gains from doing so. But the idea could easily gain traction by erroneously conflating the Strasbourg court and Council of Europe (of which the UK is a member) with the European Union (which the UK has left). This means leaving the ECHR could easily be confused as a post-Brexit ‘tidy up’ exercise of taking back control from the EU when the reality is the UK would be withdrawing from a completely different regional body. It would also be at odds with the UK’s Integrated Review Refresh which, reassuringly, contains references to the UK’s commitment to the rule of law, ‘respect for the fundamental principles of the UN Charter and international law’, and ‘universal human rights that underpins our democracy’. This would make the UK far less able to champion international law and influence states with long records of human rights violations, and run contrary to UK strategic priorities such as tackling aggression from Russia and China, its support for multilateralism, and its global legal leadership. There are many reasons beyond simply human rights concerns which are preventing migrants being deported to Rwanda All this loss would come for little gain. Before going down this path, there must be a clearer understanding about exactly what concerns there are about the ECHR, and whether they stand up to scrutiny. Are they about UK sovereignty, specific issues about the European Court of Human Rights, or about the rights and obligations contained in the Convention? The latter would raise a far bigger question on the UK’s commitment to other international treaties, such as the International Covenant on Civil and Political Rights and the UN Convention on Rights of the Child, as many ECHR obligations also exist elsewhere in both common law and international law. The need for cool heads and a long-term view The significant concerns surrounding proposals in the Illegal Migration bill have been well-documented, including in relation to obligations under the ECHR and UN Refugee Convention. There are many reasons beyond simply human rights concerns which are preventing migrants being deported to Rwanda, including the fact there are insufficient countries with which the UK has agreements to allow for deportation. Full Article
v The ICC response to Russia’s war gives hope for justice By www.chathamhouse.org Published On :: Sun, 19 Mar 2023 19:33:21 +0000 The ICC response to Russia’s war gives hope for justice Expert comment NCapeling 19 March 2023 The ICC’s arrest warrants against Putin and Lvova-Belova show the commission of international crimes is not without consequences. Warrants of arrest for Russian president Vladimir Putin and Maria Alekseyevna Lvova-Belova, commissioner for children’s rights in the president’s office, have been issued because the Pre-Trial Chamber II of the International Criminal Court (ICC) has reasonable grounds to believe they have committed war crimes. Following an independent investigation and evidence-gathering by the ICC prosecutor Karim Khan in his first new case since taking office, the pair are accused of committing two different war crimes – the unlawful deportation of children from Ukraine to Russia, and the unlawful transfer of children from occupied areas of Ukraine to the Russian Federation. The focus on those two war crimes is likely due to clear evidence that deportation and forcible transfer of thousands of Ukrainian children have occurred, as the Russian government was overt about its policy of taking Ukrainian children to Russia and placing them in camps or putting them up for adoption by Russian families. Furthermore, in line with the Office of the Prosecutor’s policy on children, crimes against children are prioritized given their particularly vulnerable status. Jurisdiction and enforcement The ICC does not have jurisdiction over crimes committed fully in Russia by Russian nationals, as Russia is not a party to the Rome Statute which created the ICC. However, it does have jurisdiction over war crimes, crimes against humanity, and genocide committed in Ukraine irrespective of who committed them, pursuant to two declarations lodged by Ukraine in 2014 accepting the Court’s jurisdiction over its territory from November 2013. Making the warrants public enables the ICC to reclaim itself as a key avenue for ensuring accountability for international crimes, following a wave of criticism and disenchantment about its work Although a prosecution has been initiated, it is ultimately for the judges of the ICC to decide on the accused’s fate. But the chances of Putin getting arrested or tried for these offences are slim. The ICC lacks enforcement or police powers and depends on state cooperation to execute arrest warrants. Also, because it cannot try individuals in their absence, a trial or conviction cannot occur without Putin and Lvova-Belova being in custody. But by issuing and unsealing these arrest warrants, the ICC is relying on the symbolic function of international criminal law – it is publicly naming and shaming Putin and Lvova-Belova for the commission of serious atrocities, and it is sending a message to other leaders and the international community that such actions are not without consequence. The arrest warrants also give victims some form of vindication or recognition for their suffering and hope for justice in the future. And making the warrants public enables the ICC to reclaim itself as a key avenue for ensuring accountability for international crimes, following a wave of criticism and disenchantment about its work in Africa and delays in advancing its investigation on Afghanistan. International courts gearing into action This ICC case is the latest in a series of ongoing cases related to Russia’s war in Ukraine before different international courts and tribunals. Others include at least four cases before the European Court of Human Rights for events that occurred before Russia was excluded from the Council of Europe, such as the MH17 flight case and the annexation of Crimea. They showcase an important feature of the global legal system and its judicial architecture that cannot be underestimated – the ability to quickly swing into action in response to violations of international law Two cases have also been brought by Ukraine against Russia before the International Court of Justice – in 2017 and 2022 – with hearings scheduled for June. An unprecedented number of states parties have sought to intervene in one or more of these cases. Each case must be considered on its own merits and the decisions cannot be prejudged. But they showcase an important feature of the global legal system and its judicial architecture that cannot be underestimated – the ability to quickly swing into action in response to violations of international law. In this case, the response was prompted by Russia’s aggression against Ukraine in breach of the United Nations Charter and fundamental principles of international law. A starting point for a bigger case The ICC prosecutor already has a broader investigation into other international crimes committed in Ukraine since 21 November 2013. So this is likely to be just the starting point of a much bigger case against Putin and other senior Russian officials for international crimes committed in the context of the war in Ukraine and within the ICC’s jurisdiction. These potentially include other war crimes such as the indiscriminate or disproportionate targeting of civilians, crimes against humanity, and genocide. Full Article
v Amyloid precursor protein is a restriction factor that protects against Zika virus infection in mammalian brains [Gene Regulation] By www.jbc.org Published On :: 2020-12-11T00:06:20-08:00 Zika virus (ZIKV) is a neurotropic flavivirus that causes several diseases including birth defects such as microcephaly. Intrinsic immunity is known to be a frontline defense against viruses through host anti-viral restriction factors. Limited knowledge is available on intrinsic immunity against ZIKV in brains. Amyloid precursor protein (APP) is predominantly expressed in brains and implicated in the pathogenesis of Alzheimer's diseases. We have found that ZIKV interacts with APP, and viral infection increases APP expression via enhancing protein stability. Moreover, we identified the viral peptide, HGSQHSGMIVNDTGHETDENRAKVEITPNSPRAEATLGGFGSLGL, which is capable of en-hancing APP expression. We observed that aging brain tissues with APP had protective effects on ZIKV infection by reducing the availability of the viruses. Also, knockdown of APP expression or blocking ZIKV-APP interactions enhanced ZIKV replication in human neural progenitor/stem cells. Finally, intracranial infection of ZIKV in APP-null neonatal mice resulted in higher mortality and viral yields. Taken together, these findings suggest that APP is a restriction factor that protects against ZIKV by serving as a decoy receptor, and plays a protective role in ZIKV-mediated brain injuries. Full Article
v A novel stress-inducible CmtR-ESX3-Zn2+ regulatory pathway essential for survival of Mycobacterium bovis under oxidative stress [Microbiology] By www.jbc.org Published On :: 2020-12-11T00:06:20-08:00 Reactive oxygen species (ROS) are an unavoidable host environmental cue for intracellular pathogens such as Mycobacterium tuberculosis and Mycobacterium bovis; however, the signaling pathway in mycobacteria for sensing and responding to environmental stress remains largely unclear. Here, we characterize a novel CmtR-Zur-ESX3-Zn2+ regulatory pathway in M. bovis that aids mycobacterial survival under oxidative stress. We demonstrate that CmtR functions as a novel redox sensor and that its expression can be significantly induced under H2O2 stress. CmtR can physically interact with the negative regulator Zur and de-represses the expression of the esx-3 operon, which leads to Zn2+ accumulation and promotion of reactive oxygen species detoxication in mycobacterial cells. Zn2+ can also act as an effector molecule of the CmtR regulator, using which the latter can de-repress its own expression for further inducing bacterial antioxidant adaptation. Consistently, CmtR can induce the expression of EsxH, a component of esx-3 operon involved in Zn2+ transportation that has been reported earlier, and inhibit phagosome maturation in macrophages. Lastly, CmtR significantly contributes to bacterial survival in macrophages and in the lungs of infected mice. Our findings reveal the existence of an antioxidant regulatory pathway in mycobacteria and provide novel information on stress-triggered gene regulation and its association with host–pathogen interaction. Full Article
v Genetic evidence for partial redundancy between the arginine methyltransferases CARM1 and PRMT6 [Signal Transduction] By www.jbc.org Published On :: 2020-12-11T00:06:20-08:00 CARM1 is a protein arginine methyltransferase (PRMT) that acts as a coactivator in a number of transcriptional programs. CARM1 orchestrates this coactivator activity in part by depositing the H3R17me2a histone mark in the vicinity of gene promoters that it regulates. However, the gross levels of H3R17me2a in CARM1 KO mice did not significantly decrease, indicating that other PRMT(s) may compensate for this loss. We thus performed a screen of type I PRMTs, which revealed that PRMT6 can also deposit the H3R17me2a mark in vitro. CARM1 knockout mice are perinatally lethal and display a reduced fetal size, whereas PRMT6 null mice are viable, which permits the generation of double knockouts. Embryos that are null for both CARM1 and PRMT6 are noticeably smaller than CARM1 null embryos, providing in vivo evidence of redundancy. Mouse embryonic fibroblasts (MEFs) from the double knockout embryos display an absence of the H3R17me2a mark during mitosis and increased signs of DNA damage. Moreover, using the combination of CARM1 and PRMT6 inhibitors suppresses the cell proliferation of WT MEFs, suggesting a synergistic effect between CARM1 and PRMT6 inhibitions. These studies provide direct evidence that PRMT6 also deposits the H3R17me2a mark and acts redundantly with CARM1. Full Article
v MicroRNA-98 reduces nerve growth factor expression in nicotine-induced airway remodeling [Gene Regulation] By www.jbc.org Published On :: 2020-12-25T00:06:30-08:00 Evolving evidence suggests that nicotine may contribute to impaired asthma control by stimulating expression of nerve growth factor (NGF), a neurotrophin associated with airway remodeling and airway hyperresponsiveness. We explored the hypothesis that nicotine increases NGF by reducing lung fibroblast (LF) microRNA-98 (miR-98) and PPARγ levels, thus promoting airway remodeling. Levels of NGF, miR-98, PPARγ, fibronectin 1 (FN1), endothelin-1 (EDN1, herein referred to as ET-1), and collagen (COL1A1 and COL3A1) were measured in human LFs isolated from smoking donors, in mouse primary LFs exposed to nicotine (50 μg/ml), and in whole lung homogenates from mice chronically exposed to nicotine (100 μg/ml) in the drinking water. In selected studies, these pathways were manipulated in LFs with miR-98 inhibitor (anti-miR-98), miR-98 overexpression (miR-98 mimic), or the PPARγ agonist rosiglitazone. Compared with unexposed controls, nicotine increased NGF, FN1, ET-1, COL1A1, and COL3A1 expression in human and mouse LFs and mouse lung homogenates. In contrast, nicotine reduced miR-98 levels in LFs in vitro and in lung homogenates in vivo. Treatment with anti-miR-98 alone was sufficient to recapitulate increases in NGF, FN1, and ET-1, whereas treatment with a miR-98 mimic significantly suppressed luciferase expression in cells transfected with a luciferase reporter linked to the putative seed sequence in the NGF 3'UTR and also abrogated nicotine-induced increases in NGF, FN1, and ET-1 in LFs. Similarly, rosiglitazone increased miR-98 and reversed nicotine-induced increases in NGF, FN1, and ET-1. Taken together, these findings demonstrate that nicotine-induced increases in NGF and other markers of airway remodeling are negatively regulated by miR-98. Full Article
v Inhibition of the SUV4-20 H1 histone methyltransferase increases frataxin expression in Friedreich's ataxia patient cells [Gene Regulation] By www.jbc.org Published On :: 2020-12-25T00:06:30-08:00 The molecular mechanisms of reduced frataxin (FXN) expression in Friedreich's ataxia (FRDA) are linked to epigenetic modification of the FXN locus caused by the disease-associated GAA expansion. Here, we identify that SUV4-20 histone methyltransferases, specifically SUV4-20 H1, play an important role in the regulation of FXN expression and represent a novel therapeutic target. Using a human FXN–GAA–Luciferase repeat expansion genomic DNA reporter model of FRDA, we screened the Structural Genomics Consortium epigenetic probe collection. We found that pharmacological inhibition of the SUV4-20 methyltransferases by the tool compound A-196 increased the expression of FXN by ∼1.5-fold in the reporter cell line. In several FRDA cell lines and patient-derived primary peripheral blood mononuclear cells, A-196 increased FXN expression by up to 2-fold, an effect not seen in WT cells. SUV4-20 inhibition was accompanied by a reduction in H4K20me2 and H4K20me3 and an increase in H4K20me1, but only modest (1.4–7.8%) perturbation in genome-wide expression was observed. Finally, based on the structural activity relationship and crystal structure of A-196, novel small molecule A-196 analogs were synthesized and shown to give a 20-fold increase in potency for increasing FXN expression. Overall, our results suggest that histone methylation is important in the regulation of FXN expression and highlight SUV4-20 H1 as a potential novel therapeutic target for FRDA. Full Article
v Nato Leaders’ Summit 2019: Treaty organisation faces deep divisions at 70 By www.chathamhouse.org Published On :: Tue, 21 Jan 2020 14:33:46 +0000 Source The National URL https://www.thenational.ae/world/nato-leaders-summit-2019-treaty-organisation-fa... Release date 02 December 2019 Expert Dr Lindsay Newman In the news type Op-ed Hide date on homepage Full Article
v Competing visions of Europe are threatening to tear the union apart By www.chathamhouse.org Published On :: Mon, 10 Feb 2020 16:18:01 +0000 Source The Observer URL https://www.theguardian.com/commentisfree/2018/jul/01/three-competing-visions-of... Release date 01 July 2018 Expert Hans Kundnani In the news type Op-ed Hide date on homepage Full Article
v Centralisation is hobbling China’s response to the coronavirus By www.chathamhouse.org Published On :: Mon, 10 Feb 2020 16:26:40 +0000 URL https://www.ft.com/content/1a76cf0a-4695-11ea-aee2-9ddbdc86190d Release date 05 February 2020 Expert Dr Yu Jie In the news type Op-ed Hide date on homepage Full Article
v The Democrats have set themselves up to fail in November's election — and they don't seem to realize it By www.chathamhouse.org Published On :: Mon, 24 Feb 2020 14:52:24 +0000 Source The Independent URL https://www.independent.co.uk/voices/democrats-buttigieg-sanders-trump-biden-str... Release date 21 February 2020 Expert Dr Lindsay Newman In the news type Op-ed Hide date on homepage Full Article
v Coronavirus: Why are we catching more diseases from animals? By www.chathamhouse.org Published On :: Fri, 06 Mar 2020 16:27:22 +0000 Source BBC URL https://www.bbc.co.uk/news/health-51237225 Release date 28 January 2020 Expert Professor Tim Benton In the news type Op-ed Hide date on homepage Full Article
v For China’s coronavirus diplomacy to succeed, Beijing must dial up generosity and downplay ideology By www.chathamhouse.org Published On :: Wed, 06 May 2020 17:31:39 +0000 Source South China Morning Post URL https://www.scmp.com/comment/opinion/article/3079971/chinas-coronavirus-diplomac... Release date 16 April 2020 Expert Dr Yu Jie In the news type Op-ed Hide date on homepage Full Article
v Is COVID-19 an opportunity for more equitable health systems in the Middle East? By www.chathamhouse.org Published On :: Wed, 06 May 2020 17:33:00 +0000 Source Euronews URL https://www.euronews.com/2020/04/03/covid-19-pandemic-and-health-systems-in-the-... Release date 03 April 2020 Expert Dr Osman Dar In the news type Op-ed Hide date on homepage Full Article
v Iraq is trying yet again to form a government. Why is it so hard? By www.chathamhouse.org Published On :: Wed, 06 May 2020 17:33:52 +0000 Source The Washington Post URL https://www.washingtonpost.com/politics/2020/04/15/iraq-is-trying-yet-again-form... Release date 15 April 2020 Expert Dr Renad Mansour In the news type Op-ed Hide date on homepage Full Article
v To Save the Amazon, Treat It Like a UNESCO World Heritage Site By www.chathamhouse.org Published On :: Wed, 06 May 2020 17:35:30 +0000 Source World Politics Review URL https://www.worldpoliticsreview.com/articles/28620/the-solution-to-amazon-defore... Release date 23 March 2020 Expert Dr Christopher Sabatini In the news type Op-ed Hide date on homepage Full Article
v There are valid questions about how China handled coronavirus but advocating hostility won't help By www.chathamhouse.org Published On :: Wed, 06 May 2020 17:36:29 +0000 Source The Independent URL https://www.independent.co.uk/independentpremium/voices/coronavirus-china-cases-... Release date 10 April 2020 Expert Dr Tim Summers In the news type Op-ed Hide date on homepage Full Article
v China hawks are calling coronavirus their smoking gun. Don't buy it By www.chathamhouse.org Published On :: Wed, 06 May 2020 17:37:27 +0000 Source Newsweek URL https://www.newsweek.com/china-hawks-are-calling-coronavirus-their-smoking-gun-d... Release date 14 April 2020 Expert Professor Kerry Brown In the news type Op-ed Hide date on homepage Full Article
v Fighting escalates in Yemen despite coronavirus 'ceasefire' By www.chathamhouse.org Published On :: Wed, 06 May 2020 17:38:30 +0000 Source The Guardian URL https://www.theguardian.com/world/2020/apr/14/fighting-escalates-in-yemen-despit... Release date 14 April 2020 Expert Farea Al-Muslimi In the news type Op-ed Hide date on homepage Full Article
v As world leaders go into coronavirus isolation, how would quarantine affect Trump's presidency? By www.chathamhouse.org Published On :: Wed, 06 May 2020 17:40:21 +0000 Source Newsweek URL https://www.newsweek.com/world-leaders-go-coronavirus-isolation-how-would-quaran... Release date 30 March 2020 Expert Dr Leslie Vinjamuri In the news type Op-ed Hide date on homepage Full Article
v From Russia With Love’: A Coronavirus Geopolitical Game By www.chathamhouse.org Published On :: Wed, 13 May 2020 15:36:35 +0000 Source The Moscow Times URL https://www.themoscowtimes.com/2020/04/07/from-russia-with-love-a-coronavirus-ge... Release date 07 April 2020 Expert Mathieu Boulègue In the news type Op-ed Hide date on homepage Full Article
v A Deep-Diving Sub. A Deadly Fire. And Russia’s Secret Undersea Agenda By www.chathamhouse.org Published On :: Wed, 13 May 2020 15:37:45 +0000 Source New York Times URL https://www.nytimes.com/2020/04/20/world/europe/russian-submarine-fire-losharik.... Release date 20 April 2020 Expert Mathieu Boulègue In the news type Op-ed Hide date on homepage Full Article
v EU recovery fund is a chance to accelerate the circular economy By www.chathamhouse.org Published On :: Wed, 27 May 2020 11:55:52 +0000 Source EURACTIV URL https://www.euractiv.com/section/circular-economy/opinion/eu-recovery-fund-is-a-... Release date 27 May 2020 Expert Patrick Schröder In the news type Op-ed Hide date on homepage Full Article
v Digital contact-tracing: The Trojan horse in the battle over data By www.chathamhouse.org Published On :: Wed, 27 May 2020 11:57:45 +0000 Source The Hill URL https://thehill.com/opinion/cybersecurity/499113-digital-contact-tracing-the-tro... Release date 22 May 2020 Expert Sophia Ignatidou In the news type Op-ed Hide date on homepage Full Article
v Why democracies do better at surviving pandemics By www.chathamhouse.org Published On :: Wed, 27 May 2020 11:59:28 +0000 Source Los Angeles Times URL https://www.latimes.com/opinion/story/2020-05-26/democracies-autocracies-coronav... Release date 26 May 2020 Expert Robin Niblett Dr Leslie Vinjamuri In the news type Op-ed Hide date on homepage Full Article
v Israeli law encourages corruption at the very top By www.chathamhouse.org Published On :: Wed, 27 May 2020 12:05:28 +0000 Source Arab News URL https://www.arabnews.com/node/1673596 Release date 12 May 2020 Expert Professor Yossi Mekelberg In the news type Op-ed Hide date on homepage Full Article
v Coronavirus and trade war pushing China to focus on fixing economy rather than leading world order By www.chathamhouse.org Published On :: Wed, 10 Jun 2020 08:49:06 +0000 Source The South China Morning Post URL https://www.scmp.com/comment/opinion/article/3087713/coronavirus-and-trade-war-p... Release date 08 June 2020 Expert Dr Yu Jie In the news type Op-ed Hide date on homepage Full Article
v When Donald Trump spoke, a sense of delusion hovered over the White House By www.chathamhouse.org Published On :: Thu, 03 Sep 2020 09:08:27 +0000 Source The Telegraph URL https://www.telegraph.co.uk/news/2020/08/28/donald-trump-spoke-sense-delusion-ho... Release date 28 August 2020 Expert Dr Leslie Vinjamuri In the news type Op-ed Hide date on homepage Full Article
v China's Climate Commitments and Energy Ambitions Beyond COVID-19 By www.chathamhouse.org Published On :: Thu, 17 Sep 2020 15:32:51 +0000 Source Oxford Energy Forum URL https://www.oxfordenergy.org/wpcms/wp-content/uploads/2020/07/OEF123.pdf Release date 01 July 2020 Expert Dr Sam Geall In the news type Op-ed Hide date on homepage Full Article
v Raging at China over coronavirus won't help – scrutinising our own governments might By www.chathamhouse.org Published On :: Thu, 17 Sep 2020 15:33:47 +0000 Source The Guardian URL https://www.theguardian.com/commentisfree/2020/may/06/china-investigated-coronav... Release date 06 May 2020 Expert Dr Sam Geall In the news type Op-ed Hide date on homepage Full Article
v Functional and structural characterization of allosteric activation of phospholipase Cϵ by Rap1A [Molecular Biophysics] By www.jbc.org Published On :: 2020-12-04T00:06:05-08:00 Phospholipase Cε (PLCε) is activated downstream of G protein–coupled receptors and receptor tyrosine kinases through direct interactions with small GTPases, including Rap1A and Ras. Although Ras has been reported to allosterically activate the lipase, it is not known whether Rap1A has the same ability or what its molecular mechanism might be. Rap1A activates PLCε in response to the stimulation of β-adrenergic receptors, translocating the complex to the perinuclear membrane. Because the C-terminal Ras association (RA2) domain of PLCε was proposed to the primary binding site for Rap1A, we first confirmed using purified proteins that the RA2 domain is indeed essential for activation by Rap1A. However, we also showed that the PLCε pleckstrin homology (PH) domain and first two EF hands (EF1/2) are required for Rap1A activation and identified hydrophobic residues on the surface of the RA2 domain that are also necessary. Small-angle X-ray scattering showed that Rap1A binding induces and stabilizes discrete conformational states in PLCε variants that can be activated by the GTPase. These data, together with the recent structure of a catalytically active fragment of PLCε, provide the first evidence that Rap1A, and by extension Ras, allosterically activate the lipase by promoting and stabilizing interactions between the RA2 domain and the PLCε core. Full Article
v The HRDC domain oppositely modulates the unwinding activity of E. coli RecQ helicase on duplex DNA and G-quadruplex [Enzymology] By www.jbc.org Published On :: 2020-12-18T00:06:18-08:00 RecQ family helicases are highly conserved from bacteria to humans and have essential roles in maintaining genome stability. Mutations in three human RecQ helicases cause severe diseases with the main features of premature aging and cancer predisposition. Most RecQ helicases shared a conserved domain arrangement which comprises a helicase core, an RecQ C-terminal domain, and an auxiliary element helicase and RNaseD C-terminal (HRDC) domain, the functions of which are poorly understood. In this study, we systematically characterized the roles of the HRDC domain in E. coli RecQ in various DNA transactions by single-molecule FRET. We found that RecQ repetitively unwinds the 3'-partial duplex and fork DNA with a moderate processivity and periodically patrols on the ssDNA in the 5'-partial duplex by translocation. The HRDC domain significantly suppresses RecQ activities in the above transactions. In sharp contrast, the HRDC domain is essential for the deep and long-time unfolding of the G4 DNA structure by RecQ. Based on the observations that the HRDC domain dynamically switches between RecA core- and ssDNA-binding modes after RecQ association with DNA, we proposed a model to explain the modulation mechanism of the HRDC domain. Our findings not only provide new insights into the activities of RecQ on different substrates but also highlight the novel functions of the HRDC domain in DNA metabolisms. Full Article
v Novel fluorescent GPCR biosensor detects retinal equilibrium binding to opsin and active G protein and arrestin signaling conformations [Molecular Biophysics] By www.jbc.org Published On :: 2020-12-18T00:06:18-08:00 Rhodopsin is a canonical class A photosensitive G protein–coupled receptor (GPCR), yet relatively few pharmaceutical agents targeting this visual receptor have been identified, in part due to the unique characteristics of its light-sensitive, covalently bound retinal ligands. Rhodopsin becomes activated when light isomerizes 11-cis-retinal into an agonist, all-trans-retinal (ATR), which enables the receptor to activate its G protein. We have previously demonstrated that, despite being covalently bound, ATR can display properties of equilibrium binding, yet how this is accomplished is unknown. Here, we describe a new approach for both identifying compounds that can activate and attenuate rhodopsin and testing the hypothesis that opsin binds retinal in equilibrium. Our method uses opsin-based fluorescent sensors, which directly report the formation of active receptor conformations by detecting the binding of G protein or arrestin fragments that have been fused onto the receptor's C terminus. We show that these biosensors can be used to monitor equilibrium binding of the agonist, ATR, as well as the noncovalent binding of β-ionone, an antagonist for G protein activation. Finally, we use these novel biosensors to observe ATR release from an activated, unlabeled receptor and its subsequent transfer to the sensor in real time. Taken together, these data support the retinal equilibrium binding hypothesis. The approach we describe should prove directly translatable to other GPCRs, providing a new tool for ligand discovery and mutant characterization. Full Article
v Structural basis for allosteric regulation of pyruvate kinase M2 by phosphorylation and acetylation [Molecular Biophysics] By www.jbc.org Published On :: 2020-12-18T00:06:18-08:00 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. Full Article
v Mapping invisible epitopes by NMR spectroscopy [Molecular Biophysics] By www.jbc.org Published On :: 2020-12-18T00:06:18-08:00 Defining discontinuous antigenic epitopes remains a substantial challenge, as exemplified by the case of lipid transfer polyproteins, which are common pollen allergens. Hydrogen/deuterium exchange monitored by NMR can be used to map epitopes onto folded protein surfaces, but only if the complex rapidly dissociates. Modifying the standard NMR-exchange measurement to detect substoichiometric complexes overcomes this time scale limitation and provides new insights into recognition of lipid transfer polyprotein by antibodies. In the future, this new and exciting development should see broad application to a range of tight macromolecular interactions. Full Article
v FRET and optical trapping reveal mechanisms of actin activation of the power stroke and phosphate release in myosin V [Enzymology] By www.jbc.org Published On :: 2020-12-18T00:06:18-08:00 Myosins generate force and motion by precisely coordinating their mechanical and chemical cycles, but the nature and timing of this coordination remains controversial. We utilized a FRET approach to examine the kinetics of structural changes in the force-generating lever arm in myosin V. We directly compared the FRET results with single-molecule mechanical events examined by optical trapping. We introduced a mutation (S217A) in the conserved switch I region of the active site to examine how myosin couples structural changes in the actin- and nucleotide-binding regions with force generation. Specifically, S217A enhanced the maximum rate of lever arm priming (recovery stroke) while slowing ATP hydrolysis, demonstrating that it uncouples these two steps. We determined that the mutation dramatically slows both actin-induced rotation of the lever arm (power stroke) and phosphate release (≥10-fold), whereas our simulations suggest that the maximum rate of both steps is unchanged by the mutation. Time-resolved FRET revealed that the structure of the pre– and post–power stroke conformations and mole fractions of these conformations were not altered by the mutation. Optical trapping results demonstrated that S217A does not dramatically alter unitary displacements or slow the working stroke rate constant, consistent with the mutation disrupting an actin-induced conformational change prior to the power stroke. We propose that communication between the actin- and nucleotide-binding regions of myosin assures a proper actin-binding interface and active site have formed before producing a power stroke. Variability in this coupling is likely crucial for mediating motor-based functions such as muscle contraction and intracellular transport. Full Article
v Co-crystal structures of HIV TAR RNA bound to lab-evolved proteins show key roles for arginine relevant to the design of cyclic peptide TAR inhibitors [Molecular Biophysics] By www.jbc.org Published On :: 2020-12-04T00:06:05-08:00 RNA-protein interfaces control key replication events during the HIV-1 life cycle. The viral trans-activator of transcription (Tat) protein uses an archetypal arginine-rich motif (ARM) to recruit the host positive transcription elongation factor b (pTEFb) complex onto the viral trans-activation response (TAR) RNA, leading to activation of HIV transcription. Efforts to block this interaction have stimulated production of biologics designed to disrupt this essential RNA-protein interface. Here, we present four co-crystal structures of lab-evolved TAR-binding proteins (TBPs) in complex with HIV-1 TAR. Our results reveal that high-affinity binding requires a distinct sequence and spacing of arginines within a specific β2-β3 hairpin loop that arose during selection. Although loops with as many as five arginines were analyzed, only three arginines could bind simultaneously with major-groove guanines. Amino acids that promote backbone interactions within the β2-β3 loop were also observed to be important for high-affinity interactions. Based on structural and affinity analyses, we designed two cyclic peptide mimics of the TAR-binding β2-β3 loop sequences present in two high-affinity TBPs (KD values of 4.2 ± 0.3 and 3.0 ± 0.3 nm). Our efforts yielded low-molecular weight compounds that bind TAR with low micromolar affinity (KD values ranging from 3.6 to 22 μm). Significantly, one cyclic compound within this series blocked binding of the Tat-ARM peptide to TAR in solution assays, whereas its linear counterpart did not. Overall, this work provides insight into protein-mediated TAR recognition and lays the ground for the development of cyclic peptide inhibitors of a vital HIV-1 RNA-protein interaction. Full Article
v Multilevel interpolations for the generalized Nikishin system on a tree graph By www.ams.org Published On :: Tue, 01 Oct 2024 14:21 EDT V. G. Lysov Trans. Moscow Math. Soc. 83 (), 291-304. Abstract, references and article information Full Article
v Chebyshev–Padé approximants for multivalued functions By www.ams.org Published On :: Tue, 01 Oct 2024 14:21 EDT E. A. Rakhmanov and S. P. Suetin Trans. Moscow Math. Soc. 83 (), 269-290. Abstract, references and article information Full Article
v The Gonchar–Chudnovskies conjecture and a functional analogue of the Thue–Siegel–Roth theorem By www.ams.org Published On :: Tue, 01 Oct 2024 14:21 EDT A. I. Aptekarev and M. L. Yattselev Trans. Moscow Math. Soc. 83 (), 251-268. Abstract, references and article information Full Article