The Committee to Protect Journalists named winner of the Chatham House Prize 2018 News Release sysadmin 5 October 2018

The Committee to Protect Journalists (CPJ) has been voted the winner of this year’s Chatham House Prize.

Chatham House appoints Rob Yates as the new head of the Centre on Global Health Security News Release sysadmin 27 June 2019

Chatham House is pleased to announce that Rob Yates has been appointed as head of the Centre on Global Health Security.

Announcing Design Resonance in an Age of Crisis News Release sysadmin 1 June 2020

London Design Biennale and Chatham House announce Design Resonance in an Age of Crisis, which calls for action by designers around the world to create radical design solutions to critical problems across four key areas: Health, Environment, Society and Work.

Design In An Age of Crisis - Open Call News Release sysadmin 21 July 2020

Chatham House and London Design Biennale announce full details of 'Design In An Age of Crisis,' a global Open Call for radical design thinking.

Renata Dwan Joins as Deputy Director and Senior Executive Officer News Release sysadmin 19 August 2020

Renata Dwan has been appointed deputy director and senior executive officer of Chatham House.

Lord Hammond Joins Panel of Senior Advisers News Release NCapeling 10 December 2020

Chatham House is pleased to announce that Lord Hammond of Runnymede is joining our Panel of Senior Advisers.

Design in an Age of Crisis Launches News Release jon.wallace 13 January 2021

Design open call receives 500 submissions from over 50 countries across six continents.

Supporting Next Generation of Leaders in Sustainability News Release NCapeling 28 January 2021

A new programme offering paid internships for young people who are passionate about social, economic, and environmental sustainability has been launched.

Supporting Civic Space: The Role and Impact of the Private Sector 23 September 2020 — 2:00PM TO 4:15PM Anonymous (not verified) 23 December 2020 Online

The meeting provides an opportunity to explore the drivers of – and barriers to – corporate activism.

A healthy civic space is vital for an enabling business environment. In recognition of this, a growing number of private sector actors are challenging, publicly or otherwise, the deteriorating environment for civic freedoms.

However, this corporate activism is often limited and largely ad hoc. It remains confined to a small cluster of multinationals leaving potential routes for effective coordination and collaboration with other actors underexplored.

This roundtable brings together a diverse and international group of business actors, civil society actors and foreign policy experts to exchange perspectives and experiences on how the private sector can be involved in issues around civic space.

The meeting provides an opportunity to explore the drivers of – and barriers to – corporate activism, develop a better understanding of existing initiatives, identify good practice and discuss practical strategies for the business community.

This meeting is the first of a series of roundtables at Chatham House in support of initiatives to build broad alliances for the protection of civic space. 

Supporting Civic Space: The Role and Impact of the Tech Sector 13 October 2020 — 2:00PM TO 4:15PM Anonymous (not verified) 23 December 2020 Online

This event brings together a diverse and international group of stakeholders to exchange perspectives and experiences on the role that tech actors can play in supporting civic space.

In a deteriorating environment for civic freedoms, tech sector actors are increasingly engaging, publicly or otherwise, on issues of civic space.

In the US, for example, a number of tech companies have cancelled contracts with the Pentagon and stopped censoring search results in China as a result of protests by employees. The Asia Internet Coalition recently wrote to Pakistan’s Prime Minister expressing human rights concerns about new rules regulating social media.

While we have recently seen technology companies show support for the social movements, including through substantial pledges, in some cases these have elicited criticism of hypocrisy, and the interventions of social media platforms on freedom of expression and privacy issues have been closely linked to the preservation of their own business models.

The COVID-19 crisis has also posed new dilemmas for the tech sector with the pervasiveness of disinformation, as well as new tools for tracking individuals which raise privacy issues.

This roundtable provides an opportunity to explore the drivers of (and barriers to) corporate activism, develop a better understanding of existing initiatives, identify good practice and routes to effective collaboration with other actors, and discuss practical strategies that could be adopted by the tech community.

It is the second of a series of roundtables at Chatham House in support of initiatives to build broad alliances for the protection of civic space.

Implications of post-COVID-19 Restructuring of Supply Chains for Global Investment Governance 14 July 2020 — 9:00AM TO 10:30AM Anonymous (not verified) 9 February 2021 Online

As companies rethink and diversify their supply chains in order to enhance resilience, what will this mean for current and future global investment governance?

What are the risks of negative effects on inclusivity and transparency? Does this shift create an opportunity to advance good governance of cross-border investment practices?

This event is part of the Inclusive Governance Initiative, which is examining how to build more inclusive models and mechanisms of global governance fit for purpose in today’s world.

The Future of Investment Dispute Settlement Regimes 30 June 2020 — 2:00PM TO 3:30PM Anonymous (not verified) 9 February 2021 Online

This event is part of the Inclusive Governance Initiative, which is examining how to build more inclusive models and mechanisms of global governance fit for purpose in today’s world.

Is an ‘atomized’ approach to cross-border investment dispute resolution inevitable? Has the multiplicity of mechanisms helped or hindered inclusivity in and transparency in governance? Is there a need for, and scope to, increase the international coordination of dispute resolution mechanisms? If so, what form should it take? What could be the implications for international economic law?

The Implication of Greater Use of Investment Screening 26 June 2020 — 9:00AM TO 10:30AM Anonymous (not verified) 11 February 2021 Online

What is driving the trend towards greater use of investment screening by nation states and regional economic groupings?

• How is the COVID-19 crisis affecting this trend?
• What will the economic implications be?
• Will this help or hinder inclusivity and transparency in investment governance?
• Is there a role for international safeguards and/or international coordination of national/regional approaches to investment screening?

This event is part of the Inclusive Governance Initiative, which is examining how to build more inclusive models and mechanisms of global governance fit for purpose in today’s world.

The regional and international implications of restrictions to online freedom of expression in Asia 25 March 2021 — 12:30PM TO 1:30PM Anonymous (not verified) 12 March 2021 Online

Panellists discuss the latest developments affecting online freedom of expression in the Asia region.

Please note this is an online event. Please register using the link below to finalize your registration.

In recent years, state-led clampdowns on online freedom of expression have become widespread in several countries across Asia, further intensified by the COVID-19 crisis.

The reasons for this are complex and diverse – drawing upon history, culture and politics, in addition to external influences. Across the region, governments have been accused of silencing online criticism and failing to uphold rights to free speech.

Individuals have been arrested, fined or attacked for the alleged spread of ‘fake news’, raising concern among human rights organizations. In some countries, this has culminated in the imposition of new social media rules, which could require social media companies to censor posts and share decrypted messages.

In China, the government’s restrictive online regime has relied on a combination of legal, technical and manipulation tactics to manage control of the internet, and now includes attempts at censorship beyond its borders.

Panellists will discuss the latest regional developments affecting online freedom of expression in the Asia region, and will consider the broader regional and international implications for technology governance.

This webinar launches the publication Restrictions on online freedom of expression in China: The domestic, regional and international implications of China’s policies and practices.

Monitoring of trade deals needs a risk-based approach Expert comment NCapeling 24 May 2021

On human rights issues, trading partners must do more than trust to luck.

The recent row within the UK government about the treatment of agricultural products in a proposed new trade deal with Australia provides a reminder that changes to trading arrangements can have social and environmental costs, as well as benefits.

Although the UK government clearly feels political pressure to demonstrate its ‘Global Britain’ credentials with some speedily concluded new deals, rushing ahead without a full understanding of the social, environmental, and human rights implications risks storing up problems for later. In the meantime, calls for better evaluation and monitoring of trade agreements against sustainability-related commitments and goals – ideally with statutory backing – will only get stronger.

EU experiences with these kinds of processes are instructive. For more than 20 years the Directorate General for Trade of the European Commission (DG Trade) has been commissioning sustainability impact assessments (SIAs) from independent consultants in support of trade negotiations, and since 2012 these assessments have explicitly encompassed human rights impacts as a core part of the analysis.

These processes have since been augmented with a programme of periodic ‘ex post’ evaluations of trade agreements to ‘analyse the observed economic, social, human rights, and environmental impacts’ of live trade deals and to make recommendations about any mitigation action which may be needed.

For credibility and objectivity, the Commission outsources much of its sustainability assessment and ex post evaluation activities to independent consultants, who are encouraged to innovate and tailor their approaches subject to broad methodological parameters laid down by the Commission. Over time, experiences with specific assessment and monitoring assignments have enabled external SIA practitioners – and the Commission itself – to progressively strengthen these processes and underlying methodologies.

Yet despite the improvements there remains legitimate questions about whether the human rights aspects of these SIA processes – and subsequent evaluations – are having real policy impact. The difficulty of predicting human rights impacts of trade agreements in advance – as the COVID-19 crisis amply demonstrates – suggests a need for realism about the extent to which a ‘one off’ process, often carried out at a time when there is only ‘agreement in principle’ as to future trading terms, can produce a robust roadmap for heading off future human rights-related risks.

Human rights impact assessments have a potentially valuable role to play in laying down the substantive and structural foundations for future human rights monitoring as part of a broader, iterative, human rights risk management strategy. But the fragmented manner in which many trade agreements approach human rights issues, and the fact that outcomes are the product of negotiation rather than necessarily design, make it difficult to turn this vision into reality.

Controversies surrounding the SIA process for the EU-Mercosur agreement illustrate why striving for more coherence in the identification and subsequent management of human rights-related risks is important. In June 2019, the Commission decided to wrap up negotiations with the South America Mercosur bloc, even though the SIA process for the proposed agreement was still incomplete and the interim and final SIA reports yet to be delivered. Frustrated NGOs made their feelings clear in the form of a formal complaint – and a slap on the wrist from the EU Ombudsman duly followed.

However, when it eventually appeared in December 2020, the final SIA report for the EU-Mercosur deal did include a number of interesting recommendations for responding to specific areas of human rights-related risk identified through the pre-signing assessment process – such as flanking measures designed to address issues pertaining to health, equality, and protection of indigenous peoples, and stressing the need for ‘continuous monitoring’.

Hopefully these recommendations will be proactively followed up, but there are reasons not to be overly optimistic about that. To the extent that these recommendations might have required, or benefitted from, some tweaks to the terms of the trade agreement itself, it was clearly too late. And while there may be opportunities for EU institutions to follow up the recommendations through unilateral ex post evaluation processes, current legal, policy, and institutional arrangements provide few guarantees this will take place.

The credibility of the EU SIA programme has clearly taken a knock because of the problems with the EU-Mercosur process, and stakeholders could be forgiven for questioning whether expending time and effort on engaging in these processes is actually worthwhile. As a first step towards rectifying this, the Commission should be transparent about how it plans to respond to the EU-Mercosur SIA recommendations regarding flanking measures and follow up – ideally consulting with stakeholders about the various human rights monitoring options available.

Looking further ahead, the Commission should be urging SIA practitioners to deal more expansively with the options for follow up human rights monitoring in future SIA reports, setting out recommendations not just on the need for ongoing monitoring of human rights-related issues but on the detail of how this might be done, and how progress towards human rights-related goals could be tracked. And creativity should be encouraged because, as detailed in a newly-published Chatham House research paper, there may be more opportunities for human rights monitoring than first appear.

The SIA process could also provide a forum for exploring complementary measures needed to make future monitoring efforts as effective as possible – jointly and unilaterally; politically, structurally, and resources-wise; both within the framework of the trading relationship and extraneously. The credibility of the process – and hence stakeholder trust – would be further enhanced by commitments from the Commission to be more transparent in future about how different human rights monitoring recommendations laid out in SIAs have been taken into account in subsequent negotiations, in the supervisory arrangements developed for specific trading relationships, and in the implementation of EU trade policy more generally.

Influence of soft law grows in international governance Expert comment NCapeling 17 June 2021

Soft law is increasingly being used by policymakers to enable greater cooperation and inclusivity, and its role is here to stay in creating effective regimes.

As the UK government’s recent Integrated Review points out, international law-making in a fragmented international order is becoming increasingly difficult.

Geopolitical tensions, and the length of time required to agree multilateral treaties – typically decades – make it challenging to reach binding agreements in complex and fast-evolving policy areas such as climate change and technology governance.

As a result, the regulation of international behaviour through soft law – meaning non-binding instruments such as principles, codes of conduct or declarations – is starting to assume greater significance. And states increasingly find soft law-making attractive because there are relatively fewer decision costs involved.

Soft law also lays the ground for the possibility of transforming into hard law if, over time, its principles become widely accepted and it is evident states are treating them as legal obligations. And the emergence of a hybrid of both soft and hard law components in treaties has started to develop in recent years, such as the Paris Agreement on Climate Change.

Opening access to global governance

A major attraction of soft law-making is that it provides for non-traditional, non-state actors to take part in the process of global governance. Non-governmental organizations (NGOs), social movements, corporate sector, and individuals are more easily drawn into soft law-making compared to treaties, to which only states can be party.

This holds out the promise for greater inclusiveness in global rulemaking and governance, but soft law processes also pose many challenges. Soft law provides an avenue for states to avoid legal obligations on important subjects and developing rules in such an informal manner can lead to fragmentation and a lack of coherence in the international system.

As noted in dialogues held under Chatham House’s Inclusive Governance Initiative, some areas of international interaction require hard law, such as economic competition, certain international security issues, and aspects of the global commons. In these areas, soft law is just not appropriate or enough.

Soft law measures such as codes of conduct may be useful in rapidly developing areas such as technology, as they are more flexible and adaptable than hard law. And they may be particularly effective if used in conjunction with binding regulation, and subject to monitoring and enforcement by a regulator, as in recent proposals by the European Union (EU) for a Digital Services Act.

The Chatham House Inclusive Governance Initiative report highlights that the proliferation of soft law does not necessarily have to compete with the existing system of hard law, so long as soft law solutions do not conflict with, or undermine, hard law such as existing treaty provisions.

Case study: Business and human rights

The UN Guiding Principles on Business and Human Rights (UNGPs) are an interesting example of both the promise of soft law-making, and its challenges. Officially adopted by the UN General Assembly in 2011, the UNGPs set out the global standard of what is expected of companies as regards human rights due diligence (HRDD) to prevent and address business-related human rights harms.

The sections on HRDD in the UNGPs have been constructed as a non-binding ‘social’ standard of conduct, though with the expectation that this would eventually be reinforced through a “smart mix” of both soft law and hard law initiatives. Arguments in favour of the predominantly soft law approach at the time – subsequently borne out in practice – were that this would encourage a higher level of participation, by states and businesses in particular, and better foster creativity and innovation in a still-developing field.

The UNGPs recognize and reinforce the importance of meaningful and inclusive stakeholder engagement for both the credibility and legitimacy of processes, and for the quality of substantive outcomes. The Ruggie process which led to the UNGPs, drew extensively from a wide range of stakeholder engagement processes covering many different jurisdictions and all UN regional groupings. The importance of deep and inclusive stakeholder engagement is also recognized in the mandate of the UN Working Group on Business and Human Rights.

The annual UN Forum on Business and Human Rights is one of the largest and most vibrant multi-stakeholder events in the UN calendar. Now in its tenth year, the forum provides an opportunity for an annual review by stakeholders – government, business and civil society – of past achievements in implementing the UNGPs and knowledge sharing on ways to address more persistent, underlying challenges.

Its relatively informal approach to agenda setting has, year on year, enabled an increasingly diverse array of stakeholder-organized sessions, supporting a ‘bottom up’ approach which raises awareness of under-reported issues and undervalued solutions.

In addition, while the UNGPs provide the substantive framework for discussion, flexible governance arrangements allow for rapid reorientation to respond to present and emerging crises, such as COVID-19 pandemic and climate change.

However, the sluggish responses of many companies, coupled with revulsion at reports of serious abuses in the value chains of many well-known brands, have prompted some governments to seek ways of translating some aspects of HRDD methodologies into binding legal standards. France passed a Corporate Duty of Vigilance Law in 2017 and Germany adopted a new law on supply chain due diligence in June 2021 which is to enter into effect on 1 January 2023. The European Commission is also working up proposals for an EU-wide regime to be unveiled in mid-2021.

Soft law versus hard law

At the international level, there are signs of divergence between those states which see value in persevering with the soft law route towards better regulation and corporate standards, and those which want to move as rapidly as possible to a hard law framework for business and human rights, enshrined in treaty, to improve domestic-level regulation and access to effective remedies.

Those supporting the hard law route – largely less industrialized states – received a boost in 2016 when the UN Human Rights Council mandated an Intergovernmental Working Group to explore options for a new treaty on business and human rights.

This initiative, known as the ‘treaty process’, has completed six rounds of negotiations. Despite the necessarily greater formality, these treaty negotiation sessions continue to emphasize the importance of stakeholder consultation. NGOs with ECOSOC status are invited to contribute views on the framing and content of draft treaty provisions immediately following the interventions by states, intergovernmental organizations and national human rights institutions, in that order.

The key question is whether this dynamism and inclusivity can be preserved as the transition is made from soft law to more binding approaches. Translating soft law standards into binding regimes inevitably means making hard choices, and different stakeholder groups have different views as to where legal lines should be drawn, how key concepts should be defined, and where the balance between legal certainty and flexibility should be struck.

The negotiations needed to strike an effective balance between competing objectives and needs can be challenging and time-consuming, as experiences with the treaty process have shown. But stakeholder demand for inclusive processes to help shape the law remains strong. Stakeholder groups clearly want a say in how the new EU-wide regime for ‘mandatory human rights due diligence’ will work in practice. A recent online ‘stakeholder survey’ garnered more than 400,000 responses.

Ultimately, the most effective domestic regimes are likely to be a mix of hard law standards supported by more flexible standards and guidance. Civil society organizations and trade unions will continue to have a multi-faceted role to play. Not only are they vital sources of expertise on human rights challenges connected to business activities, at home and abroad, they can also act as private enforcers of standards and advocates for affected people and communities.

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 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.

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.

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.

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?

The trickle-up effect of rights-based climate litigation Expert comment NCapeling 16 November 2021

With governments failing in their pledges and companies accused of ‘green-washing’, human rights-based litigation is increasingly important for accountability.

Tuvalu’s foreign minister addressing COP26 while standing knee-deep in seawater was a stark illustration of how the climate emergency directly and imminently threatens the most basic human rights protected under international law – including to the right to life, self-determination and cultural rights.

Human rights are now a fundamental component of more than 90 per cent of the climate litigation currently taking place outside the US, highlighting the international reach of human rights law and how its emphasis on protecting the most vulnerable helps diverse communities find common arguments for shared goals.

Cases are set to continue and to evolve but three types of claim are emerging, each of which is examined in a new Chatham House briefing paper.

1. Enforcing commitments

One category of cases seeks to hold states accountable for pledges they have made on climate change, such as emission reduction targets made under the framework of the 2015 Paris Agreement. Drawing on human rights obligations, governments can be charged with not taking sufficient steps to implement these pledges.

The case of Leghari v Pakistan (2015) concerned the government’s failure to carry out the National Climate Change Policy of 2012 and the Framework for Implementation of Climate Change Policy (2014-2030). The Lahore High Court held that several of the human rights enshrined in Pakistan’s constitution cover climate change and ‘provide the necessary judicial toolkit to address the government’s response to climate change’.

The court ordered the government to carry out measures such as publishing an adaptation action plan realizable within a few months of the order and establishing a Climate Change Commission to monitor progress.

2. Positive duties to mitigate risks

Many rights-based climate cases are being brought to clarify the scope of states’ positive duties under human rights law to take meaningful steps to protect their citizens against foreseeable risks to life and other rights.

This ‘trickle-up’ effect of human rights was prominent in the case of State of the Netherlands vs the Urgenda Foundation (2019) where the Dutch Supreme Court held that reducing emissions with the highest possible level of ambition amounts to a ‘due diligence standard’ for states to comply with their positive duties to adopt adequate measures to address climate change. Human rights law was also used by the court to fill in the content of the due diligence standards.

There is also a growing trend for rights-based actions to be brought against corporations, such as a recent case which drew on the UN Guiding Principles on Business and Human Rights to define the parameters of Shell’s duty of care and due diligence obligations in relation to carbon emissions under Dutch law. The court ordered Shell to reduce emissions by a net rate of 45 per cent by the end of 2030 – relative to 2019 figures – through its group corporate policy.

3. Avoiding harm in climate action

The global human rights regime is also increasingly invoked in litigation concerning states’ negative obligations to ensure that their climate mitigation and adaptation activities do not themselves contribute to human rights violations (including discrimination) and that states prioritize adaptation measures for those most at risk in a just and equitable way.

As Chatham House’s paper makes clear, this kind of litigation ‘puts pressure on governments to expand their approach to tackling climate change beyond purely a regulatory one to a more holistic strategy’.

Closing the climate justice gap

Climate and environmental litigation grounded in human rights is set to continue given the overwhelming scientific evidence of risks associated with human-induced climate change and the limited confidence in pledges made by states and corporations alike – including those made recently at COP26.

A growing collaboration between civil society organizations and vulnerable communities in relation to both the protection of nature and the enjoyment of their land and cultural rights was evident at COP26, and this alliance will add further momentum to the trend for rights-based climate litigation based on the rights of indigenous and other vulnerable communities, especially on issues such as deforestation.

But more challenges are coming. International human rights law recognizes a duty of international cooperation but there remain significant hurdles for climate-vulnerable communities in developing countries to compel action by richer nations despite the vast debts of ‘carbon colonialism.’

One big issue is the problem of extraterritoriality, as the extent to which states owe obligations to individuals outside their territory is contested. Courts in both Germany and the Netherlands have rejected claimants from developing countries in domestic class actions on this basis. But a recent decision of the UN Committee on the Rights of the Child on a complaint brought by Greta Thunberg and other youth activists against five countries opens the door for further litigation.

One of a number of cases being brought by youth claimants across the world, the committee concluded that a state’s human rights duties can – in some instances – extend to children in other countries. This includes any activities on the territory that host states have the power to prevent from causing ‘transboundary harm’ – such as emissions from the territory – where these activities ‘significantly’ impact the enjoyment of human rights of persons outside the territory.

To date, high-profile rights-based cases have argued for policy change and stronger targets underpinned by binding legislation responsive to the science. Claims are set to become more complex and contested. Building on scientific developments in climate attribution, rights-based litigation is now tackling other difficult questions such as apportioning responsibility and remedial action.

These cases examine both historically high emitters and the public and private actors who either continue specific activities or refrains from action in the face of the overwhelming science linking human activities such as extraction and burning of fossil fuels to deforestation and climatic consequences.

Courts are also likely to explore the duties that states and corporations owe to deliver a ‘just transition’ away from carbon-intensive industries, given the benefits of growth and climate action are already unevenly distributed.

A holistic human-rights based approach

Several states together with civil society are leading the charge for global recognition of the right to a healthy, clean, and sustainable environment in the United Nations (UN) Human Rights Council, and multi-stakeholder processes are defining what effective corporate due diligence looks like.

In addition, UN-appointed special rapporteurs are delivering practical guidance on how to devise solutions which are fair, non-discriminatory, participatory, and climate-resilient without exacerbating inequality – including difficult issues of planned relocation – and UN Human Rights Treaty Bodies are unpacking the duty of international cooperation to act in good faith to address loss and damage.

Recently the Committee on the Elimination of Discrimination Against Women recommended the Marshall Islands, in order to meet its duty to its citizens, should actively seek international cooperation and assistance – including climate change financing – from other countries but in particular the US, whose ‘extraterritorial nuclear testing activities have exacerbated the adverse effects of climate change and natural disasters’ in the islands.

Challenges of AI Explainer jon.wallace 22 March 2022

What are the practical, legal and ethical implications of artificial intelligence (AI) and how can regulation help meet these challenges?

This article explains the challenges associated with the funding, development, supply and regulation of artificial intelligence (AI). It deals with narrow AI, that is systems and applications that are task-specific.

The article is not concerned with the concept of artificial general intelligence, or AGI, that is an AI which could meet and exceed the full capabilities of the human mind in the future.

Definition of AI

There is no universally accepted definition of AI, but in the UK’s Industrial Strategy White Paper, AI is defined as ‘technologies with the ability to perform tasks that would otherwise require human intelligence’. 

AI makes decisions using algorithms that either follow rules or, in the case of machine learning, review large quantities of data to identify and follow patterns. Because machine learning consists of multiple layers, and machines develop their own learning and patterns, it is opaque compared to traditional rule-following computing.

Today AI applications are common in many economic activities including online shopping and advertising, web search, digital personal assistants, language translation, smart homes and infrastructure, health, transport and manufacturing. 

Risks and benefits of AI

AI has the potential to bring huge advantages, for example in medical science, education, food and aid distribution, more efficient public transport and in tackling climate change. 

Used well, it could help humanity meet the UN’s 2030 Sustainable Development Goals and make many processes swifter, fairer and more efficient. It is a technology which is likely to be as transformative to human history as was the Industrial Revolution.

However, there are serious ethical, safety and societal risks associated with the rapid growth of AI technologies. 

Will AI be a tool that makes rich people richer? Will it exaggerate bias and discrimination? Will AI decision-making create a less compassionate society? Should there be limits to what decisions an AI system can take autonomously, from overtaking a car on the motorway to firing a weapon?

And if AI goes wrong – for example if a self-driving car has an accident – who should be liable? 

To ensure AI is used safely and fairly, up-to-date and rigorous regulation is needed. 

Regulation of AI

AI creates serious regulatory challenges due to the way it is funded, researched and developed.  

The private sector drives progress in AI, and governments mostly rely on big tech companies to build their AI software, furnish their AI talent, and achieve AI breakthroughs. In many respects this is a reflection of the world we live in, as big tech firms have the resources and expertise required.

However, without government oversight the future application of AI’s extraordinary potential will be effectively outsourced to commercial interests. That outcome provides little incentive to use AI to address the world’s greatest challenges, from poverty and hunger to climate change.

Government policy on AI

Currently governments are playing catch-up as AI applications are developed and rolled out. Despite the transnational nature of this technology, there is no unified policy approach to AI regulation, or to the use of data. 

It is vital that governments provide ‘guardrails’ for private sector development through effective regulation. But this is not yet in place, either in the US (where the largest amount of development is taking place) or in most other parts of the world. This regulation ‘vacuum’ has significant ethical and safety implications for AI. 

Some governments fear that imposing stringent regulations will discourage investment and innovation in their countries and lose them a competitive advantage. This attitude risks a ‘race to the bottom’, where countries compete to minimize regulation in order to lure big tech investment. 

The EU and UK governments are beginning to discuss regulation but plans are still at an early stage. Probably the most promising approach to government policy on AI is the EU’s proposed risk-based approach. It would ban the most problematic uses of AI, such as AI that distorts human behaviour or manipulates citizens through subliminal techniques. 

And it would require risk management and human oversight of AI that poses high risk to safety or human rights, such as AI used in critical infrastructure, credit checks, recruitment, criminal justice, and asylum applications.

Meanwhile, the UK is keen to see the establishment of an AI assurance industry that would provide kitemarks (or the equivalent) for AI that meets safety and ethical standards.

Despite these policy developments, there remain fundamental questions about how to categorize and apply risk assessments, what an AI rights-based approach could look like, and the lack of inclusivity and diversity in AI.

AI ethical issues

AI has serious ethical implications. Because AI develops its own learning, those implications may not be evident until it is deployed. The story of AI is littered with ethical failings: with privacy breaches, with bias, and with AI decision-making that could not be challenged.

It’s therefore important to identify and mitigate ethical risks while AI is being designed and developed, and on an ongoing basis once it is in use. 

But many AI designers work in a competitive, profit-driven context where speed and efficiency are prized and delay (of the kind implied by regulation and ethical review) is viewed as costly and therefore undesirable. 

Designers may also not have the training, tools or capacity to identify and mitigate ethical issues. The majority are from an engineering or computing background, and do not reflect the diversity in society.

Shareholders and senior management will also naturally be hostile to criticism which could affect profits.

Once an AI application has been designed, it is often sold to companies to fulfil a task (for example, sifting employment applicants) without the buyer being able to understand how it works or what risks may come with it.

Ethical frameworks for AI

Some international bodies have made efforts to create an ethical framework for AI development, including UNESCO’s Recommendation on the Ethics of Artificial Intelligence, and the IEEE’s Global Initiative on Ethics of Autonomous and Intelligent Systems. And some companies have developed their own ethical initiatives.

But each of these proposals naturally overlaps, is slightly different and is voluntary. They set out principles for creating ethical AI, but provide no accountability in the event that an AI goes wrong.

Ethical roles in the AI industry are a potentially important new profession, but the field is underfunded and under resourced. There is widespread agreement that ethics is important, but a lack of consensus on how it should be enforced.

Government use of AI

It’s equally important that the way governments use AI is understood, consensual and ethical, complying with human rights obligations. Opaque practices by governments may feed the perception of AI as a tool of oppression. 

China has some of the clearest regulation of AI private industry in the world, but the way the government has deployed AI tools in the surveillance of its citizens has serious civil liberties implications.

China’s exports of AI to other countries are increasing the prevalence of government surveillance internationally.

Privacy and AI

Probably the greatest challenge facing the AI industry is the need to reconcile AI’s need for large amounts of structured or standardized data with the human right to privacy. 

AI’s ‘hunger’ for large data sets is in direct tension with current privacy legislation and culture. Current law, in the UK and Europe limits both the potential for sharing data sets and the scope of automated decision-making. These restrictions are limiting the capacity of AI. 

During the COVID-19 pandemic, there were concerns that it would not be possible to use AI to determine priority allocation of vaccines. (These concerns were allayed on the basis that GPs provided oversight on the decision-making process.)

More broadly, some AI designers said they were unable to contribute to the COVID-19 response due to regulations that barred them from accessing large health data sets. It is at least feasible that such data could have allowed AI to offer more informed decisions about the use of control measures like lockdowns and the most effective global distribution of vaccines.

Better data access and sharing are compatible with privacy, but require changes to our regulation. The EU and UK are considering what adjustments to their data protection laws are needed to facilitate AI while protecting privacy.

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.

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.

Stop codon read-through (SCR) is a process of continuation of translation beyond a stop codon. This phenomenon, which occurs only in certain mRNAs under specific conditions, leads to a longer isoform with properties different from that of the canonical isoform. MTCH2, which encodes a mitochondrial protein that regulates mitochondrial metabolism, was selected as a potential read-through candidate based on evolutionary conservation observed in the proximal region of its 3' UTR. Here, we demonstrate translational read-through across two evolutionarily conserved, in-frame stop codons of MTCH2 using luminescence- and fluorescence-based assays, and by analyzing ribosome-profiling and mass spectrometry (MS) data. This phenomenon generates two isoforms, MTCH2x and MTCH2xx (single- and double-SCR products, respectively), in addition to the canonical isoform MTCH2, from the same mRNA. Our experiments revealed that a cis-acting 12-nucleotide sequence in the proximal 3' UTR of MTCH2 is the necessary signal for SCR. Functional characterization showed that MTCH2 and MTCH2x were localized to mitochondria with a long t1/2 (>36 h). However, MTCH2xx was found predominantly in the cytoplasm. This mislocalization and its unique C terminus led to increased degradation, as shown by greatly reduced t1/2 (<1 h). MTCH2 read-through–deficient cells, generated using CRISPR-Cas9, showed increased MTCH2 expression and, consistent with this, decreased mitochondrial membrane potential. Thus, double-SCR of MTCH2 regulates its own expression levels contributing toward the maintenance of normal mitochondrial membrane potential.

Hepatocyte nuclear factor-1β (HNF-1β) is a tissue-specific transcription factor that is required for normal kidney development and renal epithelial differentiation. Mutations of HNF-1β produce congenital kidney abnormalities and inherited renal tubulopathies. Here, we show that ablation of HNF-1β in mIMCD3 renal epithelial cells results in activation of β-catenin and increased expression of lymphoid enhancer–binding factor 1 (LEF1), a downstream effector in the canonical Wnt signaling pathway. Increased expression and nuclear localization of LEF1 are also observed in cystic kidneys from Hnf1b mutant mice. Expression of dominant-negative mutant HNF-1β in mIMCD3 cells produces hyperresponsiveness to exogenous Wnt ligands, which is inhibited by siRNA-mediated knockdown of Lef1. WT HNF-1β binds to two evolutionarily conserved sites located 94 and 30 kb from the mouse Lef1 promoter. Ablation of HNF-1β decreases H3K27 trimethylation repressive marks and increases β-catenin occupancy at a site 4 kb upstream to Lef1. Mechanistically, WT HNF-1β recruits the polycomb-repressive complex 2 that catalyzes H3K27 trimethylation. Deletion of the β-catenin–binding domain of LEF1 in HNF-1β–deficient cells abolishes the increase in Lef1 transcription and decreases the expression of downstream Wnt target genes. The canonical Wnt target gene, Axin2, is also a direct transcriptional target of HNF-1β through binding to negative regulatory elements in the gene promoter. These findings demonstrate that HNF-1β regulates canonical Wnt target genes through long-range effects on histone methylation at Wnt enhancers and reveal a new mode of active transcriptional repression by HNF-1β.

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.

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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.

In animals, the response to chronic hypoxia is mediated by prolyl hydroxylases (PHDs) that regulate the levels of hypoxia-inducible transcription factor α (HIFα). PHD homologues exist in other types of eukaryotes and prokaryotes where they act on non HIF substrates. To gain insight into the factors underlying different PHD substrates and properties, we carried out biochemical and biophysical studies on PHD homologues from the cellular slime mold, Dictyostelium discoideum, and the protozoan parasite, Toxoplasma gondii, both lacking HIF. The respective prolyl-hydroxylases (DdPhyA and TgPhyA) catalyze prolyl-hydroxylation of S-phase kinase-associated protein 1 (Skp1), a reaction enabling adaptation to different dioxygen availability. Assays with full-length Skp1 substrates reveal substantial differences in the kinetic properties of DdPhyA and TgPhyA, both with respect to each other and compared with human PHD2; consistent with cellular studies, TgPhyA is more active at low dioxygen concentrations than DdPhyA. TgSkp1 is a DdPhyA substrate and DdSkp1 is a TgPhyA substrate. No cross-reactivity was detected between DdPhyA/TgPhyA substrates and human PHD2. The human Skp1 E147P variant is a DdPhyA and TgPhyA substrate, suggesting some retention of ancestral interactions. Crystallographic analysis of DdPhyA enables comparisons with homologues from humans, Trichoplax adhaerens, and prokaryotes, informing on differences in mobile elements involved in substrate binding and catalysis. In DdPhyA, two mobile loops that enclose substrates in the PHDs are conserved, but the C-terminal helix of the PHDs is strikingly absent. The combined results support the proposal that PHD homologues have evolved kinetic and structural features suited to their specific sensing roles.

DNA polymerases are today used throughout scientific research, biotechnology, and medicine, in part for their ability to interact with unnatural forms of DNA created by synthetic biologists. Here especially, natural DNA polymerases often do not have the “performance specifications” needed for transformative technologies. This creates a need for science-guided rational (or semi-rational) engineering to identify variants that replicate unnatural base pairs (UBPs), unnatural backbones, tags, or other evolutionarily novel features of unnatural DNA. In this review, we provide a brief overview of the chemistry and properties of replicative DNA polymerases and their evolved variants, focusing on the Klenow fragment of Taq DNA polymerase (Klentaq). We describe comparative structural, enzymatic, and molecular dynamics studies of WT and Klentaq variants, complexed with natural or noncanonical substrates. Combining these methods provides insight into how specific amino acid substitutions distant from the active site in a Klentaq DNA polymerase variant (ZP Klentaq) contribute to its ability to replicate UBPs with improved efficiency compared with Klentaq. This approach can therefore serve to guide any future rational engineering of replicative DNA polymerases.

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.

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.

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.

Centrioles are key eukaryotic organelles that are responsible for the formation of cilia and flagella, and for organizing the microtubule network and the mitotic spindle in animals. Centriole assembly requires oligomerization of the essential protein spindle assembly abnormal 6 (SAS-6), which forms a structural scaffold templating the organization of further organelle components. A dimerization interaction between SAS-6 N-terminal “head” domains was previously shown to be essential for protein oligomerization in vitro and for function in centriole assembly. Here, we developed a pharmacophore model allowing us to assemble a library of low-molecular-weight ligands predicted to bind the SAS-6 head domain and inhibit protein oligomerization. We demonstrate using NMR spectroscopy that a ligand from this family binds at the head domain dimerization site of algae, nematode, and human SAS-6 variants, but also that another ligand specifically recognizes human SAS-6. Atomistic molecular dynamics simulations starting from SAS-6 head domain crystallographic structures, including that of the human head domain which we now resolve, suggest that ligand specificity derives from favorable Van der Waals interactions with a hydrophobic cavity at the dimerization site.

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.

Erythromycin-resistance methyltransferases are SAM dependent Rossmann fold methyltransferases that convert A2058 of 23S rRNA to m6 2A2058. This modification sterically blocks binding of several classes of antibiotics to 23S rRNA, resulting in a multidrug-resistant phenotype in bacteria expressing the enzyme. ErmC is an erythromycin resistance methyltransferase found in many Gram-positive pathogens, whereas ErmE is found in the soil bacterium that biosynthesizes erythromycin. Whether ErmC and ErmE, which possess only 24% sequence identity, use similar structural elements for rRNA substrate recognition and positioning is not known. To investigate this question, we used structural data from related proteins to guide site-saturation mutagenesis of key residues and characterized selected variants by antibiotic susceptibility testing, single turnover kinetics, and RNA affinity–binding assays. We demonstrate that residues in α4, α5, and the α5-α6 linker are essential for methyltransferase function, including an aromatic residue on α4 that likely forms stacking interactions with the substrate adenosine and basic residues in α5 and the α5-α6 linker that likely mediate conformational rearrangements in the protein and cognate rRNA upon interaction. The functional studies led us to a new structural model for the ErmC or ErmE-rRNA complex.

A. I. Aptekarev and M. L. Yattselev
Trans. Moscow Math. Soc. 83 (), 251-268.
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L. Oeding
Trans. Moscow Math. Soc. 83 (), 227-250.
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A. V. Domrina
Trans. Moscow Math. Soc. 83 (), 201-215.
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A. Kh. Khachatryan, Kh. A. Khachatryan and A. Zh. Narimanyan
Trans. Moscow Math. Soc. 83 (), 183-200.
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H. G. Kazaryan and V. N. Margaryan
Trans. Moscow Math. Soc. 83 (), 151-181.
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Z. A. Kasumov and N. R. Akhmedzade
Trans. Moscow Math. Soc. 83 (), 67-74.
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A. G. Sergeev, A. Kh. Khachatryan and Kh. A. Khachatryan
Trans. Moscow Math. Soc. 83 (), 55-65.
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N. R. Ikonomov and S. P. Suetin
Trans. Moscow Math. Soc. 83 (), 33-54.
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A. P. Starovoitov and N. V. Ryabchenko
Trans. Moscow Math. Soc. 83 (), 15-31.
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M. A. Stepanova
Trans. Moscow Math. Soc. 83 (), 1-13.
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Visualizing the Data: The Evolution of Trade Tensions in Metals and Minerals Markets 18 January 2018 — 4:30PM TO 6:00PM Anonymous (not verified) 19 December 2017 Chatham House, London

Over the past decade, producer countries such as South Africa, Zambia, Indonesia, the DRC and, most recently, Tanzania have restricted exports of unprocessed precious metals, copper, nickel, cobalt and other minerals in an attempt to support, or create, downstream processing industries and jobs or increase revenues. These moves have invariably created tensions with trading partners. Research suggests that export restrictions are not the best way to achieve such policy objectives and can instead harm the producer country’s economy and undermine the functioning of international metals and minerals.

Drawing on OECD and Chatham House research on resource trade, the speaker will present analysis and data visualizations exploring the drivers of past export restrictions and their political and economic impacts. They will also consider how the drivers of ‘resource nationalist measures’ are changing, whether and where export restrictions might present strategic and economic risks in the current context, and the extent to which producer and consumer governments and international governance mechanisms are prepared to address them.

Attendance at this event is by invitation only.