Offsetting the North Korean strategic challenge 16 March 2023 — 9:30AM TO 10:30AM Anonymous (not verified) 8 March 2023 Online

This event explores what balance between pressure and dialogue is most likely to incentivise North Korea to limit its provocations.

With North Korea having steadily increased its nuclear and conventional security capabilities over the course of recent months, the speakers explore practical options for lowering tensions on the Korean peninsula.

They consider how best to re-engage diplomatically with North Korea, including the role of key actors such as the US, South Korea, Japan, and European states, in advancing a constructive resolution of current tensions.

The discussion explores finding a balance between pressure and dialogue which is most likely to incentivise North Korea to limit its provocations, assess the risks of a possible seventh nuclear test, and consider the viability of multilateral cooperation in enhancing regional security in north-east Asia.

This event forms part of the Korea Foundation Korea Fellowship, funded by the Korea Foundation and Taejae Academy.

Ivan Matic
Jan 1, 2008; 7:132-144
Research

M. Wang
Aug 1, 2012; 11:492-500
Technological Innovation and Resources

Amelia C. Peterson
Nov 1, 2012; 11:1475-1488
Technological Innovation and Resources

Jeffrey C. Silva
Jan 1, 2006; 5:144-156
Research

Yasushi Ishihama
Sep 1, 2005; 4:1265-1272
Research

G20's lack of progress highlights challenge for COP26 Expert comment NCapeling 1 November 2021

A positive outcome from the G20 summit was committing to end international financing for coal projects but, on other issues, the communique was ultimately weak.

Success at Glasgow depends on bridging fault lines

Renata Dwan

The G20 summit’s lack of progress on climate highlights the scale of the challenge – and the stakes – for COP26.  The countries responsible for 80 per cent of global emissions recognized but failed to agree concrete action to limit global warming to 1.5C.

The leaders’ gathering reveals multilateralism’s fault lines. One is the tension between domestic politics and international priorities, reflected in the lack of ambition to reduce coal dependency.  The second is the tension between industrialized and developing states over responsibility for delivering global goods.

The G20 failed to endorse the G7’s pledge to achieve net zero emissions by 2050 or to accelerate the mobilization of previously agreed climate financing. Success at Glasgow – and beyond – will depend on the extent to which these fault lines can be bridged.

Communique’s language was weak

Professor Tim Benton

A positive outcome on climate from the G20 summit was the commitment to end international financing for coal projects by the end of 2021. This is a win for the climate and for the G20-host, Italy.

The references to 1.5 degrees and the commitment to taking further action this decade were also important, and help lay the groundwork for COP26. On the downside, the communique’s language on phasing out fossil fuel subsidies and coal domestically was very weak.

The G20 summit should be regarded as the next step – it is crucial world leaders accelerate their efforts at COP26 in Glasgow to avert climate catastrophe and keep 1.5 degrees alive.

Platitudes and vague plans on pandemic preparedness

Robert Yates

As G20 leaders head to Glasgow to tackle the evolving climate crisis, they leave Rome having failed, yet again, to take serious action to end the ongoing COVID-19 crisis.

Despite the obvious urgency to achieve universal vaccine coverage, their communique contains little more than platitudes and vague plans to prepare better for future pandemics. It is not as if they had not been briefed. 

In the run up to the G20, the leaders of the WHO, WTO, IMF, World Bank, former world leaders, Nobel laureates and the Pope, all highlighted the costs of ongoing vaccine inequity: five million deaths next year and $5.3 trillion dollars in lost economic output by 2026.

The ask was also straightforward: launch a massive airlift of unneeded vaccines from rich countries through COVAX, ramp up financing of the multilateral response and accelerate technology transfers to developing countries.

But on all these issues the wording of the communique is weak, with no numbers on vaccines or funding, no hard timescales and no urgency. This does not augur well for the COP-26 summit.

G20 communique is a launching pad

Dr Leslie Vinjamuri

The G20 might seem disappointing to some, but a lot will depend on expectations. If your starting point is a pandemic that has so far taken five million lives and driven a global economic crisis, and that both these crises are marked by deep inequality, then the measures adopted are bound to look insufficient. But if your starting point is 16 years of democracy in decline, rampant disinformation on issues of climate and public health, four years of failed international leadership during the Donald Trump presidency and, especially today, heightened tensions between the US and China, the world’s two greatest powers, then the fact that the G20 communique achieved as much as it has is remarkable.

Any written document that requires agreement between the US, UK, China, Russia, India, Saudi Arabia and the EU is necessarily going to be watered down.

But the principles are in the document, and mostly everyone turned up – if some by video. That is a good outcome for this kind of multilateralism in 2021. The G20 communique is a floor not a ceiling, and it’s a launching pad for activism and mobilisation by individual states, but also by corporates, civil society, and subnational actors. 

Now we need to hope that those on the right side of progress, whether on climate, health, or development, will use this language to drive forward concrete actions towards net zero, climate finance, vaccine distribution, and debt relief.

Specifics are for the most part missing

Creon Butler

This year’s G20 leaders’ summit marks a stark contrast with the past four years when much of the group’s energy was exhausted simply trying to maintain a consensus – in the face of opposition by a President Trump-led United States – on such issues as the importance of tackling climate change, the benefits of the rules-based multilateral trade system and the centrality of the International Monetary Fund (IMF) in the global financial safety net. 

By contrast, today’s G20 Rome Leaders’ declaration early on underlines ‘the crucial role of multilateralism in finding shared, effective solutions’. In two critical areas for the world economy – the global boost to liquidity from the general allocation of $650bn in Special Drawing Rights and the global tax deal focused on addressing challenges arising from digitalisation – this outlook has been translated into very substantial and concrete achievements announced earlier in the year.

Trump and his growing number of European allies threaten the European project Expert comment LToremark 8 November 2024

With Trump in the White House, a key challenge for Europe will be the growing transatlantic illiberal ties which risk undermining European unity.

As the US presidential election result became clear, European leaders followed a similar formula when congratulating President-elect Trump. They offered their congratulations, mentioned previous good working relations with the US (special points for a nod to long-standing relations), and – most importantly – emphasized the need for this to continue for the benefit of the citizens of both their country and the US.

The formula was a telling sign of the political bartering most European heads of state expect with Trump back in the White House. The exception, of course, were Trump’s European allies who were simply ecstatic.

Transatlantic illiberalism

Trump’s growing number of European allies and the increase of illiberalism and populism is perhaps the most worrying development for Europe. In 2016, some of Trump’s counterparts in Europe were Angela Merkel in Germany, Emmanuel Macron in France, Mark Rutte in the Netherlands, and Giuseppe Conte in Italy. Regardless of their record, they were moderates.

The picture looks very different today. Anti-war extremist parties Alternative for Germany and the Sahra Wagenknecht Alliance are on the rise in Germany. In France, pro-Russia Marine le Pen has been able to reduce support for Ukraine from €3 billion to €2 billion in the draft French budget. In the Netherlands, the far-right Freedom Party is the biggest coalition partner. In Italy, Prime Minister Georgia Meloni hails from a neo-fascist party. Hungarian Prime Minister Viktor Orbán’s populist and illiberal playbook is being replicated across Europe. 

Meanwhile in Poland, moderate prime minister, Donald Tusk, is experiencing the difficulties of reversing damage done by the previous populist government.

What European populist leaders have in common is a deep-seated scepticism of the EU and a desire to erode it from within. And many of these leaders also welcome the return of Trump.

It is no coincidence that Orbán scheduled the European Political Community Summit, hosted by Hungary, to take place just days after the US election. The Trump win was an added bonus. This meant European heads of state travelled to Budapest for the summit still reeling from – or rejoicing at – the election result. 

Orbán would like to position himself as Trump’s man in Europe. He has spent the past four years building ties with the president-elect and the MAGA wing of the Republican party. Trump even namechecked Orbán – a Eurosceptic Putin-supporter – during the presidential debate.

Italy’s Meloni, meanwhile, has so far worked with EU institutions and NATO rather than against them: she has supported EU and NATO resolutions for Ukraine and demonstrated opposition to Russia. But this may have been a strategic calculation. She likely looked at her country’s balance sheet and realized she needed the European Commission’s COVID-19 recovery funds. 

But with the fund coming to an end and given her history of Euroscepticism and pro-Russian views, the transatlantic illiberal ties mean she may now feel emboldened to revise her positions. She is already deploying the illiberal playbook domestically.

Policy implications for Europe of a second Trump term 

Despite some ideological similarities, Trump’s policies will not be good for his European allies. He has threatened to impose 10 to 20 per cent tariffs on all EU imports. For Italy and the Netherlands, the second and fifth largest EU exporters to the US, this would have direct negative impacts on their economies.

Increased tariffs on Chinese goods – Trump has threatened up to 60 per cent – would also have an impact on Europe’s economies. Rerouting of Chinese goods could see China dump overproduction in Europe, one of the few remaining relatively open markets, and make European products compete with cheaper Chinese goods in Europe and on the global market. 

Neither of these developments are positive for export-led European countries. In France, the EU’s fourth largest exporter to the US, Marine le Pen – previously a strong supporter of Trump – had a notably muted response to his victory due to concerns over a trade war.

Even European leaders who might have hoped for a different election outcome may seek to hedge their bets. There are two things that are clear about Trump: he is unpredictable and transactional. 

It is quite possible that some European states, in particular frontline states with genuine fears over Russia’s imperialist ambitions, will seek to buy Trump’s support through bilateral arms deals – despite their distaste for Trump’s position vis-à-vis Russia. These countries already have some of the highest defence spending in NATO, with Poland, Estonia and Latvia leading the way, so this will not irk Trump – arms deals would simply be an additional insurance premium.

Countries rushing to make bilateral deals with the US risks a similar uncoordinated race for American arms deals as during Trump’s first term. This would in turn undermine much-needed European defence industrial cooperation efforts. As the need to reduce dependencies on third countries – even for defence equipment from historically close allies – has become increasingly clear, this would be a problematic development.

The silver lining may be that it could galvanize the UK and the EU just enough to take action on UK-EU security and defence cooperation, of which the defence industrial piece is the most essential.

Europe disunited

The transatlantic link between populist, illiberal leaders should be a concern. Trump is no longer isolated in Europe, he is rapidly accumulating allies among European heads of state. These leaders agree on the perceived existential threat posed by migration, the need for so-called ‘traditional family values’ and ‘anti-wokeism’. But beyond that, they share and want to advance an illiberal view of the world, with ramifications from security and global trade to human rights – and directly threatening the European project.

M el-Saadani
Apr 1, 1989; 30:627-630
Articles

G Lepage
Jan 1, 1986; 27:114-120
Articles

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.

Digital governance must not marginalize smaller states Expert comment LToremark 19 May 2021

For effective and inclusive digital governance, multi-stakeholderism must raise its game.

Last month, the G7 announced it is to work towards a trusted, values-driven digital ecosystem. While this is commendable, the G7 must recognize that key international digital governance decisions should involve all states whose populations will be affected. Not doing so is to deny the legitimate interests of those populations and may cause a lack of trust in international digital governance that embeds longer-term instability.

While a multi-stakeholder approach to digital governance is important, it must be structured in a way that allows for meaningful representation of states’ interests and ensures their representatives have the opportunity and capacity to take part. As the internet becomes fundamental to life in every country of the world, international digital governance is increasingly important to all governments and excluding some states’ perspectives may engender wider risks to international security and governance.

The ‘glitter ball’ of digital governance

International digital governance is playing catch-up with the digital sphere it needs to govern. Its starting point is a ‘glitter ball’ of governance initiatives: a large number of complex facets with overlapping impacts – and an almost impenetrable core. Governance initiatives (see infographic) include governance of the internet itself and its uses, international cybersecurity, international human rights, data management, as well as the impact of digital developments in areas such as armed conflict, trade and health.

Many of the bodies involved – such as the Internet Governance Forum, the Internet Corporation for Assigned Names and Numbers (ICANN) and technical standards bodies – include a wide range of stakeholders, yet there is no one accessible, central body. Furthermore, certain key issues, such as the role and responsibilities of tech platforms, are barely touched upon by international governance mechanisms. There is also currently only a limited role for traditional UN multilateral decision-making, a process which builds in a role for smaller states.

The sheer number of forums involved, each with a different set of working methods and rules on participation, makes it difficult to fully grasp what digital governance looks like as a whole. The UN secretary-general’s High-level Panel on Digital Cooperation recognized the complexity of digital cooperation arrangements and the barriers to inclusion facing small and developing countries as well as under-represented groups. In response, the June 2020 UN Roadmap on Digital Cooperation accepts the need to streamline digital governance while ensuring marginalized voices are heard.

The UN is considering potential models for future governance, each of which would – reassuringly – involve multi-stakeholder participation, dedicated funds to boost participation, consolidation of discussions currently split between different forums and a minor coordinating role for the UN.  

Building in roles for smaller states

As the UN designs new digital governance architecture, it is particularly important to build in roles for small and medium states. Core constituencies affected by decisions should be at the centre and governments – as guardians of public interest – should have a key say in the decision-making process. The distrust generated by built-in power imbalances needs to be addressed, as does the dominance of voices from the Global North in bodies such as ICANN.   

There has been some progress made to increase participation. For example, the Freedom Online Coalition includes a number of developing countries and the 2020 Internet Governance Forum included input from 175 states.

However, participation is not only a matter of having a seat at the table. As discussed at the March 2021 UN Open-ended Working Group on ICTs in the context of international security, capacity-building is vital. The group’s conclusions include the suggested development of a global cyber capacity-building agenda with information sharing and norms guidance under the auspices of the UN. Representatives of small and medium states need a roadmap to understand in which forums they can defend and pursue their interests, and the financial help to do so if necessary.

Managing multi-stakeholder participation

A multi-stakeholder approach has been fundamental to digital governance from the start and has played a vital role in helping to secure the openness and universality of the internet. This approach is rightly seen as essential to effective governance because it introduces diverse expertise, allows the interests of all impacted sectors to be taken into account and helps ensure decisions are accepted by those affected.

However, as identified in a Chatham House report on inclusive global governance, multi-stakeholderism needs to raise its game. One of its downsides is that in the cacophony some important voices may not be heard because they lack resource or capacity to speak up. There is a perennial risk of debate and decision-making being captured by the wealthiest companies or the most powerful states. At present, small and medium states are under-represented in multi-stakeholder forums and it is important that those managing such forums seek to identify and include previously excluded voices.

Multi-stakeholderism should not come at the expense of efficiency. While it does not have to mean huge, inefficient meetings or endless discussion, it should also not mean that smaller, less well-funded voices are not heard. Instead, such processes should enable representation of appropriate interest groups, complemented by wider meetings (such as regional meetings, or sector-specific meetings) as needed. While inclusivity and transparency are key, synergies between regional and global forums can work well –  for example, some countries have adopted national versions of the Internet Governance Forum –  and so too can hybrid models such as the Freedom Online Coalition, which meets both as government members and for regular multi-stakeholder dialogue.

A multi-stakeholder approach should also not lose sight of the key role of states – and where mandated, sub-state entities – in making public policy decisions.

An important role for the UN

For 75 years, the UN has acted as a bulwark of international security and shared values, and a promoter of economic and social development. If misused, technology has the potential to undermine this bulwark, to facilitate conflict, erode rights and undermine development. The UN must encourage the harnessing of technology for society’s benefit, while leading a collective effort to guard against the risks through the retention and growth of a universal, open internet – particularly in the face of growing digital authoritarianism exacerbated by COVID-19.

The UN can also help protect against a commercial culture that threatens to trample fundamental freedoms of privacy and autonomy in its pursuit of wealth and to widen economic and social gulfs by leaving large swathes of the world behind. If the UN is to play this role effectively – and for the benefit of all its members ­– it requires the active participation of all states, large and small.

Geopolitical shifts and evolving social challenges – what role for human rights? 29 June 2021 — 3:00PM TO 4:30PM Anonymous (not verified) 10 June 2021 Online

Speakers reflect on some of the key themes that will influence the future of human rights.

Please click on the below link to confirm your participation and receive your individual joining details from Zoom for this event. You will receive a confirmation email from Zoom, which contains the option to add the event to your calendar if you so wish.

Shifts in geopolitical power and the rise of authoritarianism are disrupting the dynamics for making progress on human rights globally.

At the same time, the relevance of the global human rights framework is being called into question by some of our most acute social challenges – rapidly evolving technology, deepening inequality and the climate crisis.

Chatham House’s Human Rights Pathways project is exploring how alliances, strategies and institutions are adapting, and will need to evolve, to strengthen human rights protection in this increasingly contested and complex global environment.

At this panel event speakers reflect on some of the key themes that will influence the future of human rights, including the long-term impacts of the pandemic, the place of human rights diplomacy in the new geopolitics, the relevance of human rights to social movements, and the potential of human rights law to galvanise efforts on urgent challenges such as the climate crisis.

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.

Expert

Expert

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.

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.

N. R. Ikonomov and S. P. Suetin
Trans. Moscow Math. Soc. 83 (), 33-54.
Abstract, references and article information

We are extremely excited to announce on behalf of the American Society for Biochemistry and Molecular Biology (ASBMB) that the Journal of Biological Chemistry (JBC), Molecular & Cellular Proteomics (MCP), and the Journal of Lipid Research (JLR) will be published as fully open-access journals beginning in January 2021. This is a landmark decision that will have huge impact for readers and authors. As many of you know, many researchers have called for journals to become open access to facilitate scientific progress, and many funding agencies across the globe are either already requiring or considering a requirement that all scientific publications based on research they support be published in open-access journals. The ASBMB journals have long supported open access, making the accepted author versions of manuscripts immediately and permanently available, allowing authors to opt in to the immediate open publication of the final version of their paper, and endorsing the goals of the larger open-access movement (1). However, we are no longer satisfied with these measures. To live up to our goals as a scientific society, we want to freely distribute the scientific advances published in JBC, MCP, and JLR as widely and quickly as possible to support the scientific community. How better can we facilitate the dissemination of new information than to make our scientific content freely open to all?For ASBMB journals and others who have contemplated or made the transition to publishing all content open access, achieving this milestone generally requires new financial mechanisms. In the case of the...

Otto Overkamp
Trans. Amer. Math. Soc. 377 (), 5863-5903.
Abstract, references and article information

Ahmed Elshafei, Ana Cristina Ferreira, Miguel Sánchez and Abdelghani Zeghib
Trans. Amer. Math. Soc. 377 (), 5837-5862.
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Olha Prykhodko and Kostiantyn Ralchenko
Theor. Probability and Math. Statist. 111 (), 123-135.
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Lasse L. Wolf and Hong-Wei Zhang
Proc. Amer. Math. Soc. 152 (), 5445-5453.
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Shengyu Tang
Proc. Amer. Math. Soc. 152 (), 5381-5394.
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Giovanni Catino and Alberto Roncoroni
Proc. Amer. Math. Soc. 152 (), 5339-5354.
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Xiaoshang Jin
Proc. Amer. Math. Soc. 152 (), 5327-5337.
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Yong Suk Moon
Proc. Amer. Math. Soc. 152 (), 5095-5103.
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N. Lebedeva and A. Petrunin
St. Petersburg Math. J. 35 (), 473-476.
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