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Procedure for determination of free and total cholesterol in micro- or nanogram amounts suitable for studies with cultured cells

W Gamble
Nov 1, 1978; 19:1068-1070
Articles




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Intracellular cholesterol transport

CJ Fielding
Aug 1, 1997; 38:1503-1521
Reviews




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The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism

Gijs den Besten
Sep 1, 2013; 54:2325-2340
Reviews




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Thematic review series: Brain Lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal

John M. Dietschy
Aug 1, 2004; 45:1375-1397
Thematic Reviews




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The human ATP-binding cassette (ABC) transporter superfamily

Michael Dean
Jul 1, 2001; 42:1007-1017
Thematic Reviews




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Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans

JM Dietschy
Oct 1, 1993; 34:1637-1659
Reviews




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Apolipoprotein-mediated removal of cellular cholesterol and phospholipids

JF Oram
Dec 1, 1996; 37:2473-2491
Reviews




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Lipid extraction by methyl-tert-butyl ether for high-throughput lipidomics

Vitali Matyash
May 1, 2008; 49:1137-1146
Methods




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Cell cholesterol efflux: integration of old and new observations provides new insights

George H. Rothblat
May 1, 1999; 40:781-796
Reviews




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Plasma cholesteryl ester transfer protein

AR Tall
Aug 1, 1993; 34:1255-1274
Reviews




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Use of cyclodextrins for manipulating cellular cholesterol content

AE Christian
Nov 1, 1997; 38:2264-2272
Articles




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Direct transesterification of all classes of lipids in a one-step reaction

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




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Bile salt biotransformations by human intestinal bacteria

Jason M. Ridlon
Feb 1, 2006; 47:241-259
Reviews




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Preparation of fatty acid methyl esters and dimethylacetals from lipids with boron fluoride--methanol

William R. Morrison
Oct 1, 1964; 5:600-608
Articles




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The plasma lecithin:cholesterol acyltransferase reaction

John A. Glomset
Mar 1, 1968; 9:155-167
Reviews




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Molecular physiology of reverse cholesterol transport

CJ Fielding
Feb 1, 1995; 36:211-228
Reviews




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The Implication of Greater Use of Investment Screening

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.




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The regional and international implications of restrictions to online freedom of expression in Asia

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.




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A seat at the table – why inclusivity matters in global governance

A seat at the table – why inclusivity matters in global governance 10 May 2021 — 1:30PM TO 3:00PM Anonymous (not verified) 22 April 2021 Online

Exploring the changing dynamics of global cooperation and the role inclusivity can play in building collaborative action.

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.

The scale of today’s global challenges demand collaborative and coordinated action. But deepening geopolitical competition is threatening multilateralism while growing inequality and social tensions continue to undermine public confidence in the ability of international institutions to deliver.

Into this challenging environment, add the complexity and sheer pace of many global challenges such as the climate crisis and the proliferation of new technologies – issues that cannot be addressed effectively by governments alone.

  • How do global institutions and mechanisms need to adapt to address the demands for a fairer distribution of power between states and to engage the diverse set of actors essential today for effective solutions?
  • What can be learnt from existing initiatives that bring together governments, civil society, private sector, cities, next generation leaders and other stakeholders?
  • And what are the political obstacles to greater inclusivity?

This event supports the launch of a synthesis paper from Chatham House’s Inclusive Governance Initiative.




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Influence of soft law grows in international governance

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.

States increasingly find soft law-making attractive because there are relatively fewer decision costs involved

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.

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

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.

Ultimately, the most effective domestic regimes are likely to be a mix of hard law standards supported by more flexible standards and guidance

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.




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Counter-terrorism measures and sanctions: How to avoid negative consequences for humanitarian action?

Counter-terrorism measures and sanctions: How to avoid negative consequences for humanitarian action? 9 September 2021 — 2:00PM TO 3:30PM Anonymous (not verified) 21 July 2021 Online

Exploring current endeavours to address the tensions between counter-terrorism measures, sanctions and humanitarian action.

Counter-terrorism measures  address broad forms of support to terrorist acts. Their expansion, internationally and domestically, has given rise to new points of friction with international humanitarian law. Unless the measures include adequate safeguards, they  can impede humanitarian action. Country-specific sanctions imposed for other objectives, such as ending conflicts or protecting civilians, raise similar challenges for humanitarian action. 

These problems are not new, but solutions at international and national level remain elusive. 

At this panel event, which marks the launch of a new Chatham House research paper, panellists explore current endeavours to address the tensions between counter-terrorism measures, sanctions and humanitarian action.

  • What are the current dynamics and developments at Security Council level?  
  • What are the opportunities now that the UK is developing its independent sanctions strategy? 
  • What challenges do counter-terrorism requirements in funding agreements for humanitarian action  pose? 
  • What is necessary to make progress?




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Protecting universal human rights: Imagine a better world

Protecting universal human rights: Imagine a better world Explainer Video NCapeling 19 November 2021

Short animation examining why protecting and defending human rights ensures an equitable response to humanitarian crises and addresses economic inequality.

Human rights are not policies that can be overturned, they are not granted by governments. They belong to everyone as human beings.

For the most part, states are meeting their commitments to defend and protect universal human rights. But increasingly some governments are beginning to shy away from their obligations, and some are even actively seeking to subvert human rights.

And the regional and international bodies created and charged with defending these rights are being challenged by the rise of new powers and political movements.

Chatham House is built on big ideas. Help us imagine a better world.

Our researchers develop positive solutions to global challenges, working with governments, charities, businesses and society to build a better future.

SNF CoLab is our project supported by the Stavros Niarchos Foundation (SNF) to share our ideas in experimental, collaborative ways – and to learn about designing a better future.




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Chatham House welcomes 2022 interns

Chatham House welcomes 2022 interns News release jon.wallace 11 May 2022

Internships provide learning opportunities about shaping policy, influencing debate and creating real change.

Chatham House is excited to welcome the second cohort to the Molchanov Sustainability Internship Programme.

Introduced in January 2021, the programme has been made possible following the gift of Pavel Molchanov, to support the next generation of leaders in sustainability.

The internships grant invaluable, practical learning opportunities about shaping policy, influencing debate and creating real change towards a sustainable future.

Alis Martin, Internships and Outreach Manager at Chatham House, said:

‘We are delighted to welcome the second cohort to the Molchanov Sustainability Internship Programme. This cohort brings a diversity of new and invaluable perspectives and ideas to the work of our programmes.

‘Over the course of 12 weeks, interns will be working alongside internationally respected experts in Chatham House programmes, exploring issues of sustainability through the lenses of climate change, the circular economy, conflict prevention, emerging technology, global health, governance, human rights, security policy, sustainable cities and sustainable finance.

‘Fostering sustainable and equitable growth and engaging the next generation of policy leaders is central to Chatham House’s vision. We are committed to providing the best experience and opportunities to our interns who share an interest in pursuing a career in the field of sustainability.

‘It is crucial that we incorporate the views and knowledge of those who will be affected most in the future and I very much look forward to seeing the innovative and impactful ideas that will undoubtedly result from their work.’

Mr Molchanov said:

‘Recent headlines around the world underscore the importance of taking the broadest possible perspective on sustainability. Energy supply concerns, rising food prices, and continued pandemic pressure are all interconnected with climate issues. I look forward to hearing about the work in which this year’s internship participants engage.’

Jerome Puri, intern, Middle East and North Africa Programme, said:

‘I applied for this internship to gain a holistic insight into the coordination of a policy institute and to understand how Chatham House promotes international cooperation and accountable governance around the world.  Chatham House offers an unparalleled opportunity to contribute to projects on frontier issues facing the MENA region and develop a diverse range of skills ranging from project management and communications to policy-oriented research skills.’

Obioma Egemonye, intern, Africa Programme, said:

‘I was particularly interested in joining the Africa Programme at Chatham House after learning an immeasurable amount from their work on the Social Norms and Accountable Governance (SNAG) research for my undergraduate dissertation. I am most looking forward to attending the variety of events held by Chatham House and the Africa programme specifically.’

Valdone Sniukaite, intern, Europe Programme, said:

‘I am excited to be joining the Europe Programme team and getting exposure to the inner workings of a policy and research think tank. I’m mostly looking forward to building my organizational skill set by working on the Belvedere Forum and using the opportunity of being around experts in the field of international affairs to broaden my knowledge.’

Lucile de Laforcade, intern, Queen Elizabeth II Academy for Leadership in International Affairs, said:

‘As part of the Academy, I am able to work at the crossroads of research, leadership, international affairs and personal development. This makes the Academy a place of constant challenge to find innovative, sustainable solutions, and emulate new ideas. As an aspiring academic, this is particularly empowering! I am hoping to gain new skills, further develop independent thinking, and cultivate my own research interests in the vibrant environment of a leading policy institute.’

Katie McCann, intern, Communications and Publishing, said:

‘I’m really interested in youth engagement in international politics so I’m very excited to be working on the Common Futures Conversations platform which brings young people across Europe and Africa into the debate on the pressing global issues of our time. I hope my time at Chatham House will expose me to people of different backgrounds and beliefs which will encourage me to engage even more critically with international affairs.’

Rachael Mullally, intern, International Law Programme, said:

‘What I admire most about the International Law Programme here is its position as a dependable yet experimental source on global governance debates. I am especially excited to get working on the Human Rights Pathways Project, focusing on tangible ideas as to how the human rights framework can evolve to meet power shifts between states and non-state actors.’

Elia Duran-Smith, intern, International Security Programme, said:

‘I was particularly drawn to this internship because of the thematic focuses of the programme around nuclear security and emerging technologies in the sector, which are fundamental to understanding the future of the global security environment. I am looking forward to learning more about these topics while developing and expanding my research and writing skills, as well as gaining an understanding of project management and how Chatham House engages with stakeholders on policy.’

Rory Selvey, intern, Sustainability Accelerator, said:

‘For me, speeding up the transition towards a fairer, low-carbon society is one of most important global challenges. I’m really excited to be an intern at the Sustainability Accelerator, collaborating with different teams and exploring innovation solutions to this challenge. Chatham House will help me develop vital knowledge and skills, acting as a fantastic springboard for a potential career in sustainable finance, macroeconomics, or international development.’

Bruna Miguel, intern, Environment and Society Programme, said:

‘Being an intern in the Environment and Society Programme will give me the opportunity to further investigate how these issues relate and how we can achieve true sustainability. I look forward to learning from the experts in the area that I will meet (and hopefully find a dissertation topic!).’

Ritvij Singh, intern, Global Health Programme, said:

‘My view of healthcare delivery is from the frontlines as a medical doctor. I applied to this internship to widen my perspective and get an insight into the institutions that will help facilitate universal health. I will use this experience to pursue a career in global health.’

For more information about the internships, please contact Alis Martin.

 




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What are the priorities for the new UK prime minister?

What are the priorities for the new UK prime minister? Expert comment GBhardwaj 2 September 2022

Experts from across Chatham House examine the range of domestic and foreign policy issues facing Rishi Sunak as he prepares to lead the UK government.

Experts from across Chatham House’s research programmes give their insights on a range of issues facing Rishi Sunak as he becomes UK prime minister, covering energy prices, the climate change agenda, war in Ukraine, China and the Indo-Pacific, Africa, the US, global health, international law and security, science and technology, trade, and the global economic crisis.

Rising energy prices

Antony Froggatt, Senior Research Fellow and Deputy Director, Environment and Society Programme, Chatham House

The social and economic impact of high energy prices this winter may be greater than that of COVID-19. However, in contrast to the pandemic, there has been ample warning of the expected scale of this crisis.

The European Union (EU) gets much more of its energy from Russia than the UK does, but all are part of a largely informal European price zone which is why UK consumers are now facing, what would have been to many, unimaginable bills despite no longer importing energy from Russia.   

The cost of energy will continue to be a major concern for households and businesses and, given the cost of interventions, will significantly affect government finance.

The current policy of capping the unit price for six months increases affordability but will only offer some relief for this winter. The new government urgently needs to look at what happens to bills in the spring and next winter which, from a gas supply perspective, may be even worse than this one.

The EU has reacted with much greater purpose, proposing new legislative packages to diversify supply, accelerate the deployment of renewable energy, make adjustments to markets, and put in place energy saving measures. While these are unlikely to be enough they will make a difference and can become a benchmark for UK policy.

Support for new supply needs to be immediately given to new low-carbon technologies which can deliver both cheaply and rapidly

The role that government plays in assisting public and private sectors to save energy will be important. This is where past administrations have wasted the last eight months, where public information campaigns and small technology changes, such as refurbishing and resetting boilers and larger energy consuming products or insulating homes, would have made a difference.

Action needs to be taken across all levels, including co-ordination with the devolved administrations and local government.

Support for new supply needs to be immediately given to new low-carbon technologies which can deliver both cheaply and rapidly, primarily onshore wind and solar, which also help to decarbonize the sector.

The UK will need to maintain, and more likely increase, its relationship with the EU on energy as it continues to trade gas and electricity which is likely to require the resolution of tricky issues such as the Northern Ireland Protocol.

However, the discussions at the European Political Community in early October on greater co-operation on North Sea grids, creating an important opportunity for the accelerated deployment of offshore wind, needs to be taken forward.

Other supply options and market restructuring will be needed and they all must balance affordability, security of supply, and environmental considerations.

The agenda on climate change

Professor Tim Benton, Director, Environment and Society Programme, Chatham House

The record temperatures this summer show how the changing climate is impacting the daily lives of UK citizens. Climate change remains the most important challenge of this century and one that the prime minister will rapidly need to get a grip of ahead of COP27.

Hosting COP26 in 2021, along with Italy, was seen as an important post-Brexit opportunity for the UK in the climate space and ensured the development of many new multilateral sectorial initiatives, such as on climate finance, the Global Methane Pledge and on electric vehicles, while further supporting other emerging initiatives, such as on loss and damage. It will be important for the new prime minister, and the UK’s credibility, to continue to deliver on these.

Concrete things that are needed are a fast roll-out of renewable energy rather than fast-tracking more fossil fuel production, driving ahead the net-zero agenda particularly around land use and food and considering how to restructure markets to better deliver the long-term goals.

Grasping the need to address the demand-side of consumption growth, and not just supply, is key. The UK has prided itself on being a global leader on the climate over the last 15 years but let’s hope that is now not in peril.

Russia and the war in Ukraine

James Nixey, Director, Russia and Eurasia Programme, Chatham House

Supporting Ukraine and confronting Russia are indisputable foreign policy priorities so it is highly likely the new prime minister will look to continue on this path and go with both popular and expert consensus in assisting Ukraine generously and standing up to Russia.

Supporting Ukraine and confronting Russia are indisputable foreign policy priorities so it is highly likely the new prime minister will look to continue on this path

The other question, though, is to what extent the UK’s position can continue to make a difference to the outcome of the war.

Bringing the waverers of western Europe more firmly on board is surely beyond any UK prime minister’s ability considering the UK’s post-Brexit behaviour where the UK still has its own questions to answer including over the failure to tackle the problems of Russian influence at home.

That said, Brexit may not always be relevant to shared hard security challenges. Other countries do see the difference training, money and weapons are making and, if these continue to bring success, it is possible even the waverers can be guilted into providing more aid and economic support.

However, supporting Ukraine is one thing. Truly understanding Russia and devising a coherent Russia strategy is another. What needs to be learned is that Russia, in its present incarnation, cannot be reasoned with whatever the state of the war.

Therefore, given the threat Russia poses to the UK and other democracies, Britain now needs to consider how it can assist with engendering change in Russia. This should not be confused with engineering ‘regime change’ as the Kremlin accuses the UK of doing already.

But it does suggest a more proactive, less defensive Russia policy is required, rather than waiting for the Russian people to instigate change from within. That will take a degree of leadership and political will rarely seen in UK politics.

China and the Indo-Pacific tilt

Ben Bland, Director, Asia-Pacific Programme, Chatham House

Both candidates in the last Conservative leadership contest argued during their campaigns that China was the biggest long-term threat to the UK’s national security. They both promised to call out China’s violations of human rights and international law and extend curbs on China’s access to sensitive technology.

However, to successfully respond to the scale of the challenge, the next prime minister will need to do much more than say what they do not want from Beijing. There needs to be a convincing, positive vision for how the UK can navigate a world where the centre of global economic and geopolitical gravity is moving eastwards.

The Indo-Pacific ‘tilt’ which Liz Truss oversaw as UK foreign secretary was a good start. But tilting isn’t a strategy. So what comes next?

There needs to be a convincing, positive vision for how the UK can navigate a world where the centre of global economic and geopolitical gravity is moving eastwards.

At a time when its in-tray is full of problems closer to home, the UK government needs to sustain enhanced levels of engagement in the Indo-Pacific, particularly in Southeast Asia, while investing at home in the UK’s Asia literacy.

That should include more support for research and education about China as well as the rest of this dynamic region. Labelling China a threat does not make it go away. The UK needs to learn how to live in a world where Chinese power and influence will continue to grow from Asia to Latin America and across the UN and other multilateral organizations.

Investing in the UK’s knowledge of, and relationships in, Asia will also support British businesses as they look for new opportunities in fast-growing but challenging emerging markets such as India, Indonesia, and Vietnam.

The UK’s Middle East policy

Dr Lina Khatib, Director, Middle East and North Africa Programme, Chatham House

The UK government must restore a distinct cabinet position for the Middle East and North Africa and reorient to give Iran’s regional role greater focus.

The Middle East portfolio remains hefty and complex and requires diplomatic engagement to match. No sooner had the UK merged the ministerial Middle East portfolio into the broader one of minister of state for Asia and the Middle East than the war on Ukraine began, directing Western attention to Gulf Arab countries as one potential energy source to offset the loss of Russian oil and gas. Yet Gulf Arab countries are hesitating to fully heed Western calls to increase energy production. 

The UK government must restore a distinct cabinet position for the Middle East and North Africa and reorient to give Iran’s regional role greater focus.

One key cause is Gulf Arab perceptions that the UK and other Western countries have overlooked their concerns of the threats that Iran poses to their security and political clout.

Despite the UK’s characterization of Iraq as ‘post-conflict’, and of the situation in Syria as a ‘crisis’, recent clashes in Baghdad’s Green Zone and American and Israeli bombing of Iran-linked targets in Syria, as well as recurring attacks by Iran-backed groups on targets in Gulf Cooperation Council (GCC) countries, underline Iran’s role in ongoing instability in the Middle East, which threatens the interests of the UK and its allies in the region.

Although the UK’s Foreign, Commonwealth and Development Office resources have been recently redistributed to further support response to the Russian invasion of Ukraine, the UK can, and must, use existing resources earmarked for the Middle East to engage more effectively.

The two are not wholly distinct: Russia is using Iranian drones to attack Ukraine and Iranian military personnel are active on the ground in Ukraine in aid of the Russian military. Iran and Russia’s ongoing military intervention in Syria paved the way for their cooperation in the invasion of Ukraine.

The UK must restore diplomatic cabinet distribution to give the Middle East the attention it requires, but also revising its approach, putting Iran’s regional and international interventions high on the agenda and in parallel to efforts on the Iran nuclear deal.

The UK sees GCC countries as a potential alternative source of energy to Russian oil and gas specifically and as important trade partners more broadly. UK foreign policy must not compartmentalize its approach to the Middle East.

Diplomatic engagement on Iran’s regional role is a key factor in strengthening trust between the UK and its Middle Eastern allies, including in the GCC, which in turn supports the UK’s economic and security priorities. This means UK policy must approach Iran not just more comprehensively, and coherently, but also as a component of the broader strategy of dealing with the geopolitical and economic threats presented by Russia. 

Africa and the UK

Alex Vines, Director, Africa Programme, Chatham House

Senior UK politicians often claim that Africa is a priority but UK prime ministers and foreign secretaries rarely visit the continent. Boris Johnson attending the Commonwealth Heads of Government Summit in Kigali in August was his first as prime minister where he was accompanied by Liz Truss who was then his foreign secretary.

Despite saying she was an Africa enthusiast as secretary of state for international trade and president of the Board of Trade, Truss had never visited the continent. Her focus was consistently on other parts of the world except for defending the UK’s contested partnership with Rwanda to repatriate to Kigali informal migrants to the UK.

Viewing global politics through the lens of great power rivalry has cast African states as second tier players, disrespecting their agency and prided sovereignty and ignoring the preference of many states to remain non-aligned on issues pertaining to great power competition.

This is a mistake as 25 per cent of the UNGA is comprised of African member states and, of them, 21 are Commonwealth members with Gabon and Togo recently joining. The Russian invasion of Ukraine and intensifying competition with China is a reminder that in this era of sharper geopolitics, Africa increasingly matters for UK’s foreign policy objectives.

The new prime minister will need to review the 2021 Integrated Review, which downplayed much of Africa for UK strategy and advocated a pivot focus to East Africa. The war in Ukraine, coupled with democratic reversals in East Africa and worsening stability in West Africa requires a UK priority rethink. With limited resources to support an expanded UK footprint, sharper focus and defined ambition is important.

Continuity is important too. Since 1989, there have been 21 ministers for Africa, an average tenure of just over 18 months. This is not the time to change the UK’s minister responsible for Africa but it is the moment to make once again that post focused just on sub-Saharan Africa rather than also covering the Caribbean and Latin America too.

The UK-US relationship

Dr Leslie Vinjamuri, Director, US and Americas Programme, Chatham House

As the US approaches its midterm elections, the new prime minister should think carefully about the UK’s response to potential disruption or challenges to the legitimacy of electoral results.

The US faces a period of unpredictable politics with the possibility of significant disruption, upheaval, and the potential for violence. The UK should be careful to differentiate between being independent with respect to partisan politics, which is essential, from being neutral with respect to democracy and especially the integrity of elections.

It would be a mistake for the UK prime minister or the next foreign secretary to be neutral on the question of free and fair elections and the importance of democracy in the US. Boris Johnson’s administration, especially his foreign secretary, was poorly equipped to respond to questions about the outcome of the 2020 presidential elections and prevaricated more than once. 

The UK will be both more attractive, and less supplicant, to the US if it has a strong relationship with Europe.

On foreign policy, a shared interest in supporting Ukraine and strengthening NATO is the current anchor for this partnership, but its historical foundation is both deeper and wider.

The new UK prime minister should demonstrate to the US, and to the world, that Britain is serious about its existing international commitments, especially in the Euro-Atlantic and through NATO, but also with respect to Northern Ireland and Europe.

The UK should deepen its participation in the new European Political Community and seize any opportunity to strengthen mechanisms for security cooperation with Europe. It should aim to restore Britain’s reputation as a nation committed to international, regional and domestic multilateral and legal frameworks.

These measures strengthen Britain’s attractiveness to the US and so lend it greater influence in this essential partnership. Any move to undermine the Northern Ireland protocol should be carefully measured against its wider impacts, not only with Europe, but also with the US.

Continuing Boris Johnson’s policy of restraint, rather than demanding a US-UK trade deal, is wise given the persistence of anti-trade sentiment in the US Congress and the looming US midterm elections.

The prime minister should also do what they can to lend support and work effectively and pragmatically with this US administration. What comes next could be disruptive so now is the time to leverage US power and lock the US into durable commitments that enhance international stability and prosperity.

US president Joe Biden is determined and pragmatic. He will choose the partners that best enable him to deliver his foreign policy priorities. The UK will be both more attractive, and less supplicant, to the US if it has a strong relationship with Europe.

Global health priorities

Robert Yates, Director, Global Health Programme and Executive Director, Centre for Universal Health, Chatham House and Emma Ross, Senior Research Fellow, Global Health Programme. 

Global health has been one of the areas where the UK has historically been seen as punching above its weight due to the magnitude of its financing for global health programmes and its reputation as a leader in global health initiatives.

However, the UK’s standing has taken a significant hit since the start of the pandemic with it demonstrating a lack of solidarity in combatting COVID-19 when it hoarded vaccines and failed to lead the G7 in raising adequate funding for the COVAX facility and blocked attempts to share vaccine technologies with developing countries.

Slashing the international aid budget and deprioritizing global health within its aid strategy has further tarnished the UK’s reputation as a global health leader.

The UK’s standing has taken a significant hit since the start of the pandemic with it demonstrating a lack of solidarity in combatting COVID-19.

Rebuilding the UK’s hard-earned status as a leading force in global health by at least restoring the level of official development assistance (ODA) for health, if not enhancing it, should be one of the new prime minister’s top priorities.

This should include support for major initiatives such as the Financial Intermediary Fund for Pandemic Prevention, Preparedness and Response (FIF), the Hub for Pandemic and Epidemic Intelligence in Berlin and the vaccine technology transfer hub in Africa.

There is a risk that the ongoing pandemic treaty negotiations will result in a weak instrument of little value. The UK prime minister should prioritize the successful outcome of the negotiations by championing provisions that ensure the treaty makes a meaningful difference in enhancing global health security.

There is a need for workable mechanisms to ensure countries cooperate next time in preventing, preparing for and responding to a pandemic and supporting countries that need extra resources while, another related priority, should be to engage in efforts to reform the International Health Regulations in a way that strengthens global health security.

Championing international law

Rashmin Sagoo, Director, International Law Programme, Chatham House

Compliance with international law is in the best interests of the UK, and the new UK government needs to recognize this.  

The UK wants Russia to comply with the UN Charter and stop its aggressive war against Ukraine. It wants China to recognize the rights of its Uighur citizens, for women to be protected from violence in armed conflict, for compliance with nuclear non-proliferation treaties and  negotiate lucrative international trade agreements. 

These are all excellent aims and they should continue to be pursued. But exhortations to the rest of the world to support the international rules-based order ring hollow if they come from a government which itself does not itself adhere to those rules. 

To be a credible global leader, the UK must put the rule of law, including international law, at the heart of both its foreign and domestic policy. 

How the UK conducts itself domestically is a mirror of how it conducts itself internationally. What elected UK officials say and do here matters elsewhere. How we treat the rule of law in this country impacts how others treat it – and us.  

The new prime minister has an opportunity to lead by example by ending the slow but dangerous habitualization of the British public becoming numb to government ‘intentions’ to break international law whether or not such threats are ultimately carried out.

There should also be a full public and parliamentary scrutiny of constitutionally significant proposals, such as the Northern Ireland Protocol bill and reform of the Human Rights Act, rather than fast-track them past a public distracted by the cost-of-living crisis. 

International law is founded upon principles of mutual trust, cooperation, good faith and reciprocity. To be a credible global leader, the UK must put the rule of law, including international law, at the heart of both its foreign and domestic policy. They cannot be disaggregated.   

Strengthening international security

Dr Patricia Lewis, Director, International Security Programme, Chatham House

Security and defence will be high on the agenda for the new UK prime minister. Russia’s war in Ukraine and the potential for sudden, wider escalation remains a serious concern.

Threats of nuclear weapons use, possible false flag ‘dirty bomb’ threats, the continuing attacks on the Zaporizhzhia nuclear power plant threats and veiled references to chemical or biological attacks has demonstrated the willingness of Russia to take enormous risks in regard to threatening Europe as a whole in order to achieve its aims.

If Ukraine’s counter-offensive continues to make gains, then NATO countries will likely be threatened again in this manner. These are not just threats to Ukraine but to NATO states. And, most likely, given the significant role it has played in supporting Ukraine militarily, aimed primarily at the UK.

In the longer term, the UK prime minister needs to review the 2021 Integrated Review of Security, Defence, Development and Foreign Policy. The review came following the decision to increase defence spending and the UK secretary of defence Ben Wallace – continuing in place –has been clear that he has no need to increase his budget further although that may change as the impact of inflation becomes clearer across the board.

The Integrated Review is all about serious investment in the science and technology needed for security and defence in the future. Without such investment the UK will not be able to contribute to international security even in the limited way it can now and certainly not in an ambitious way in decades hence.

The UK has long played an important diplomatic role in finding creative solutions for international security and the new prime minister would be well advised to lever that reputation.

There are many long-term security threats that the UK will need to grapple with in addition to Russia’s aggression in Europe, not least of which are China’s rising military capabilities and global ambitions.

In the Arctic and Antarctic, China along with several other major economies, has serious ambitions for exploiting natural resources in terms of minerals, energy, particularly as climate change drives fish stock to the polar seas.

The newly-established AUKUS arrangement which plans to produce a nuclear-powered submarine capability for Australia also provides a mechanism for joint investment by Australia, the UK and the US in science and technologies such as in artificial intelligence (AI) and quantum technology. There are discussions about extending this arrangement to other countries such as Japan and could also include the space sector.    

Meanwhile, at home, in the short-term, there will be increasing calls to end Russia’s war in Ukraine. The prime minister will need to be ahead of that game so that Ukraine is supported and European security is enhanced rather than further stressed.

This will require a new approach to international security – a need that was further highlighted at the end of August in New York with yet another collapse of agreement in the Treaty on the Non-Proliferation of Nuclear Weapons as a result of Russia’s veto.

The UK has long played an important diplomatic role in finding creative solutions for international security and the new prime minister would be well advised to lever that reputation.

Supporting science and technology

Marjorie Buchser, Executive Director, Digital Society Initiative, Chatham House, David Lawrence, Research Fellow, UK in the World Initiative Chatham House and Alex Krasodomski, Head of Innovation Partnerships, Chatham House

In science and technology, the UK currently finds itself in a balancing act between the US and the EU: ideologically attached to the light-touch approach of the US while dependent on the EU as an export market and for supply chains.

While Brexit in theory gives Britain more regulatory freedom, UK companies have often ended up abiding by EU regulations they are unable to shape. The new prime minister should explore forms of regulatory cooperation with the EU that prioritize market access while offering incentives to attract scientists and boost technical innovation.

Fostering coalitions with a broader group of like-minded democracies will be crucial to addressing global technology concerns.

Beyond transatlantic and European partnerships, it is essential for the UK to foster coalitions with a broader group of like-minded democracies which will be crucial to addressing global technology concerns and countering China’s digital model expansion.

Entrenching the UK as a science and technology ‘superpower’ will require a collaborative approach and involve identifying critical areas where the UK can drive international efforts. For example, the UK should build on its recent successes in the sensitive issues of data flows and digital technical standards as well as encourage investment in open-source security and infrastructure.

Finally, it is essential to unblock the skills and talent pipeline. It is difficult and expensive for high-skilled workers to move to the UK and a key source of labour supply has been lost since leaving the EU. The UK should consider introducing a Commonwealth visa scheme and radically reduce the cost for science and technology companies to offer those visas.

Strengthening infrastructure and housing, particularly in areas that need levelling up, will allow talent to move to areas with the most productive opportunities. 

Trade, climate and green supply chains

Bernice Lee, Research Director, Futures; Hoffmann Distinguished Fellow for Sustainability; Chair, Sustainability Accelerator Advisory Board 

The new prime minister will soon find the answers to the UK’s supply security challenges and soaring energy and food prices as well as future growth lie not at home but are global problems.

At a time of crisis, solutions can only come from countries working together. The UK is a perfectly sized state with plenty of heft but it is not so large as to be able to afford to ignore the needs of others.

It should lead the convening of a growing ‘coalition of the willing’ on trade, climate and green supply chains which could include Australia and Canada as well as developing nations with large extractive sectors in Africa and Asia that are pro-trade, pro-climate, pro-development and pro-growth.

Scaling low-carbon, resource-efficient, sustainable and deforestation-free supply chains could help fuel the next generation of growth in the UK and beyond.

Even though working together on trade and green supply chains can reduce unwanted dependencies, support climate action and help businesses unlock the $26 trillion in market opportunities, many governments have yet to take bold steps due to a fear of disguised protectionism.

Meanwhile, the European Union (EU) carbon border adjustment mechanism (CBAM) is fuelling bitter divides on competitiveness and development concerns.

Trade retaliation is likely and most probably will happen in parallel with legal processes at the WTO. These dynamics mean trade will be underused as an instrument but will create challenging dynamics for COP27. 

Although the Agreement on Climate Change, Trade, and Sustainability (ACCTS) was launched in 2019, the UK could fill a leadership gap since no major economies have positioned themselves as leaders at the intersection of trade, climate, and green supply chains.

British International Investment, the UK’s development institution, should support the establishment and scaling of low-carbon, resource-efficient, sustainable and deforestation-free supply chains which could help fuel the next generation of growth in the UK and beyond.

Improve regulation, give priority to trade relations with the EU, and maintain transparency

Creon Butler, Research Director, Trade, Investment and New Governance Models, and Director, Global Economy and Finance Programme

The UK’s new prime minister comes into office with the country facing the most serious set of economic challenges since 2008-09.

But, in contrast to the global financial crisis, the causes of today’s crisis are more multifaceted and to a degree more UK-specific: the Brexit trade shock; increased public spending pressures linked to the backlog in the NHS and potentially serious long-term effects of ‘long COVID’ and disrupted schooling; the unprecedented shock to energy prices following Russia’s invasion of Ukraine linked in part to the UK’s lack of gas storage capacity; and the shock to market confidence in the UK’s economic management resulting from the 44-day Liz Truss administration.

While the new prime minister should not delay addressing the UK’s long-term challenges, there are three critical questions which will help determine the success or failure of the government’s approach.

First, should the priority be less regulation or, in the context of the tech revolution and the need to accelerate the transformation of the economy to net zero, smarter regulation?




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

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




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A novel stress-inducible CmtR-ESX3-Zn2+ regulatory pathway essential for survival of Mycobacterium bovis under oxidative stress [Microbiology]

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.







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Molecular basis for histone H3 “K4me3-K9me3/2” methylation pattern readout by Spindlin1 [Gene Regulation]

Histone recognition by “reader” modules serves as a fundamental mechanism in epigenetic regulation. Previous studies have shown that Spindlin1 is a reader of histone H3K4me3 as well as “K4me3-R8me2a” and promotes transcription of rDNA or Wnt/TCF4 target genes. Here we show that Spindlin1 also acts as a potent reader of histone H3 “K4me3-K9me3/2” bivalent methylation pattern. Calorimetric titration revealed a binding affinity of 16 nm between Spindlin1 and H3 “K4me3-K9me3” peptide, which is one to three orders of magnitude stronger than most other histone readout events at peptide level. Structural studies revealed concurrent recognition of H3K4me3 and H3K9me3/2 by aromatic pockets 2 and 1 of Spindlin1, respectively. Epigenomic profiling studies showed that Spindlin1 colocalizes with both H3K4me3 and H3K9me3 peaks in a subset of genes enriched in biological processes of transcription and its regulation. Moreover, the distribution of Spindlin1 peaks is primarily associated with H3K4me3 but not H3K9me3, which suggests that Spindlin1 is a downstream effector of H3K4me3 generated in heterochromatic regions. Collectively, our work calls attention to an intriguing function of Spindlin1 as a potent H3 “K4me3-K9me3/2” bivalent mark reader, thereby balancing gene expression and silencing in H3K9me3/2-enriched regions.




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Coupled intra- and interdomain dynamics support domain cross-talk in Pin1 [Signal Transduction]

The functional mechanisms of multidomain proteins often exploit interdomain interactions, or “cross-talk.” An example is human Pin1, an essential mitotic regulator consisting of a Trp–Trp (WW) domain flexibly tethered to a peptidyl-prolyl isomerase (PPIase) domain, resulting in interdomain interactions important for Pin1 function. Substrate binding to the WW domain alters its transient contacts with the PPIase domain via means that are only partially understood. Accordingly, we have investigated Pin1 interdomain interactions using NMR paramagnetic relaxation enhancement (PRE) and molecular dynamics (MD) simulations. The PREs show that apo-Pin1 samples interdomain contacts beyond the range suggested by previous structural studies. They further show that substrate binding to the WW domain simultaneously alters interdomain separation and the internal conformation of the WW domain. A 4.5-μs all-atom MD simulation of apo-Pin1 suggests that the fluctuations of interdomain distances are correlated with fluctuations of WW domain interresidue contacts involved in substrate binding. Thus, the interdomain/WW domain conformations sampled by apo-Pin1 may already include a range of conformations appropriate for binding Pin1's numerous substrates. The proposed coupling between intra-/interdomain conformational fluctuations is a consequence of the dynamic modular architecture of Pin1. Such modular architecture is common among cell-cycle proteins; thus, the WW–PPIase domain cross-talk mechanisms of Pin1 may be relevant for their mechanisms as well.




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Functional and structural characterization of allosteric activation of phospholipase Cϵ by Rap1A [Molecular Biophysics]

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.




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Building better polymerases: Engineering the replication of expanded genetic alphabets [Molecular Biophysics]

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.




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Structural basis for allosteric regulation of pyruvate kinase M2 by phosphorylation and acetylation [Molecular Biophysics]

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.







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Taiwan Charts a New Course After Elections

Taiwan Charts a New Course After Elections Expert comment sysadmin 19 January 2016

The resounding victory for the opposition marks a decisive break with the past and could make life much more difficult for Beijing.

DPP supporters shine lights from their mobile devices as they celebrate election results during a rally in Taipei on 16 January 2016. Photo via Getty Images.

A victory for Taiwan’s Democratic Progressive Party (DPP) in Taiwan’s presidential election on Saturday had been widely predicted. But the margin of victory, and the crushing defeat suffered by the ruling Kuomintang (KMT) in the concurrent legislative elections, could mean a conclusive shift in both the country’s domestic politics and its important relationship with Beijing.

Why the DPP won

President elect Tsai Ing-wen’s victory was no close run thing nor was it a result of a split in the opposition vote as was claimed for her predecessor. The KMT ran a disastrously inept presidential campaign. The farcical way in which they first chose then unseated a totally unsuitable candidate simply underlined their lack of cohesion or purpose. This came on top of an unconvincing record in administration that showed the party to be increasingly tired, self-destructive and out of touch. Eric Chu, the eventual replacement choice, had neither the time nor the charisma to put things right.

Moreover, on the key issue of mainland policy, the KMT had come to be seen as serving more a party interest than a national one. It now appears that a majority in Taiwan believe that the DPP will more effectively champion and promote their interests in relation to China than the KMT. The coup de theatre of the meeting of the presidents of China and Taiwan in November had no discernible electoral impact. More widely, the view of the national identity as a Taiwanese one rather than a Chinese or hybrid Chinese/Taiwanese one has taken firm hold. The DPP responded more effectively to this new political climate.

What it means for relations with Beijing

Relations between Taiwan and the mainland can only become more difficult now, but quite how that works out in practical terms remains to be seen. It seems unlikely that China will choose, initially at least, to row back from the agreements reached with the outgoing administration, but further progress will be problematic. A new basis needs to be worked out for political negotiations, and neither side will wish to compromise its position. It is likely that there will be increasingly hard line and even bellicose rhetoric emanating from some quarters in China, but it will remain more measured on the official side. The reality of China’s military and economic power remains there for all to see.

The last DPP administration saw heightened tensions in US/China/Taiwan relations. The US will no doubt be arguing for calm and caution with both sides. All the official pronouncements so far from the DPP have been moderate. There is no desire for a confrontational policy from Taiwan, but equally Tsai made it clear that she was determined that ‘our democratic system, national identity, and international space must be respected. Any form of suppression will harm the stability of cross strait relations.’

A new era

President elect Tsai will be able to form and run an administration free from the shackles of a hostile legislature that made life so difficult for the first DPP administration under Chen Shui-bian, and her party can now claim a convincing popular mandate. She won by a margin of twelve percentage points over her rivals.

But the new administration faces real challenges, even beyond mainland policy. Taiwan’s economy has been relatively stagnant. There are increasing demands for new style politics. In her victory speech Tsai spoke of her wish to respond to the desire of the people for a government that is more willing to listen and one that is more transparent and accountable. She will want to escape from the shadow of the corruption that blighted the last DPP administration.

The DPP now has full control of Taiwan’s political processes for the first time ever, but equally significantly the pretensions of the KMT to be the natural ruling party in Taiwan have been dealt a devastating blow. Taiwan’s democracy has moved into a new era.

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Duterte’s Victory Is Cry for Help From Those Left Behind in Philippines

Duterte’s Victory Is Cry for Help From Those Left Behind in Philippines Expert comment sysadmin 12 May 2016

But large support for mainstream parties and a mature democratic system should keep the country from slipping back towards authoritarianism.

Rodrigo Duterte prepares to vote inside a polling precinct on 9 May 2016 in Davao. Photo by Getty Images.

The victory of political outsider Rodrigo Duterte in the 2016 Philippines’ elections is proof that a significant minority of the country’s population feels left behind by its recent economic success and estranged from its political elite. However the results of the elections as a whole suggest that most voters opted for a continuation of the current government’s policies.

Duterte looks almost certain to be inaugurated as the next president of the Philippines on 30 June. The country’s presidential voting system – a single round, first-past-the-post election – delivered victory to a populist outsider with 39 per cent support. Two candidates advocating a continuation of the current government’s policies − the Liberal Party’s Mar Roxas and independent Grace Poe − polled a combined 45 per cent. The long-standing factionalism within Philippines elite politics split the ‘anti-Duterte’ vote.

Changing the conversation

The contrast between Duterte and Roxas could hardly be greater. Mar Roxas is the grandson of the first president of an independent Philippines, a graduate of Wharton Business School and a former investment banker in the US. Rodrigo Duterte is a political outsider with an electoral base geographically almost as far from Manila as is possible to get in the Philippines: the city of Davao on the island of Mindanao.

The story of Duterte’s victory is the story of how ‘Duterte managed to change the national conversation from poverty towards crime and corruption,’ says Marites Vitug, editor-at-large of one of the Philippines’ most popular online news sites, Rappler. In January, Duterte was running fourth in opinion polls but a strategy that positioned him as the only opponent to the Manila elite gave him victory. This is the first time a provincial official has made it to the top job.

The headline figures tell us that the Philippines’ economy has done very well under President Benigno Aquino. Between 2010 and 2014, growth averaged 6.3 per cent per year. That fell to a still-impressive 5.8 per cent last year but is expected to pick up this year and next, according to the Asian Development Bank. Growth in agriculture, however, is significantly slower and rural areas feel left behind. While economic growth is benefiting the majority, inequality is worsening and resentment rising in poor villages. The contrast between the metropolitan sophistication of the Makati district in Manila and life in faraway provinces such as Duterte’s Mindanao is widening.

Ironically the Philippines’ economic success is a part of the explanation for the defeat of the ‘mainstream’ presidential candidates. Crime and corruption may have become more important issues simply because more voters have become better off and therefore more likely to be concerned about crime and corruption than before. It’s also undeniable that Duterte has a record for getting things done. Human rights groups rightly criticize his (at best) tolerance of the extra-judicial killing of alleged criminals but his repeated re-election as mayor demonstrates that many citizens are prepared to accept that in exchange for improved personal security. A surprising number of Manila residents have actually moved to Davao because of its better quality of life.

Traditional power bases

However, the results as a whole suggest a narrow majority in favour of current policies. In the vice-presidential race, the Liberal Party candidate Leni Robredo is narrowly ahead of Ferdinand ‘Bongbong’ Marcos, the son of the eponymous former president. Like Duterte she is regarded as a successful mayor of a well-run city, Albay. Duterte’s running mate Alan Cayetano received just 14 per cent of the vote.

In the senate election, Liberals won five of the 12 seats being contested, with a party- backed independent winning a sixth. The opposition, even with boxing champion and national idol Manny Pacquiao running for the United Nationalist Alliance, won four.

Taken as a whole, the results show the enduring nature of traditional Philippines power bases. The country’s many islands and distinct linguistic and cultural regions are virtual fiefs in which families and big bosses can wield almost total power through control of local authorities, businesses, the courts and security forces.

Threat to democracy?

It’s easy to forget that the election of Ferdinand Marcos in 1965 was originally welcomed as a challenge to the traditional elites of Philippine politics. The same accolades are currently greeting Duterte. Could they presage a return to the Philippines’ bad old days?

This seems less likely. Philippine democracy has matured considerably since Marcos declared martial law in 1972. There is a substantial, and vocal, middle class with experience of mobilizing against ‘bad’ presidents. There will also be pressures from international investors and the Philippines’ treaty ally, the United States, for better governance.

The Philippines will chair the Association of Southeast Asian Nations next year. That will put Duterte in the international spotlight as host of several international meetings – including the East Asia Summit attended by, among others, the presidents of China, Russia and the US. Since his victory Duterte has promised to act with decorum in office and declared that his election campaign antics were just a ploy to attract attention. Some leaders in Southeast Asia will use his victory to buttress their arguments against allowing their people to freely vote. It’s up to Duterte to decide whether he wants to be an advertisement for – or an argument against – democracy.

To comment on this article, please contact Chatham House Feedback




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China Paves Its Way in New Areas of International Law

China Paves Its Way in New Areas of International Law Expert comment sysadmin 31 March 2017

China is looking to increase its capacity and influence in international legal matters – and it is particularly in frontier areas of the law that China is likely to take a proactive stance.

Xi Jinping at the UN European headquarters in Geneva. Photo: Getty Images.

Foreign Minister Wang Yi called China a staunch defender and builder of the international rule of law in his speech to the UN General Assembly in October 2014. He promised that as China grew stronger, it would make a greater contribution to the maintenance and promotion of international rule of law, and would work with other countries to build a fairer and more reasonable international political and economic order.

For many in China, that time has now come: there is a sense that China deserves a much stronger and more respected voice in discussions surrounding the future of the international system. The recent speeches of Xi Jinping in Davos and Geneva in January 2017 suggest that China is now seizing the initiative and fighting for a voice and influence commensurate with its status and power as the number two economy in the world.

But there is an interesting divide in the areas in which China chooses to assert itself. In traditional areas of international law – such as the law of the sea and international human rights law – China continues to harbour reservations about the fairness of the existing international order. Its misgivings are fuelled by a perception that it did not play a significant part in the creation of the post-Second World War international order, and that those rules operate mainly in the interests of Western powers.

There is also a sense that traditional areas of international law do not offer a level playing field for China, since Western states have far more experience at operating in those. We know from Chinese experts that in the South China Sea case, one background issue that played into China’s refusal to engage in litigation with the Philippines and other interested states (which were represented by leading Western international lawyers) was a lack of experience before international courts and tribunals.

Contrast this with newer areas of international law– such as the regimes governing cyber, space, climate change and deep sea mining issues. In these areas, the rules are still in the process of being developed and tested, and the influence of the existing powers is not so firmly established or accepted, so there is more opportunity for China’s voice to be heard and heeded.

On climate change, China has become a champion of the Paris Agreement, which it worked hard with the Obama administration to secure. China is also active in some of the processes related to cyber rule-making, both as a member of the UN Group of Governmental Experts on cyber issues and through bilateral dialogues with a number of states. China has taken a keen interest in the regime applicable to the mining of the international seabed, making submissions to the International Tribunal on the Law of the Sea about the procedure for settling disputes. In international economic law, another relatively new area, China has been assiduously cultivating expertise, and is a major player in the negotiation of the ‘mega regional’ trade deal, the Regional Comprehensive Economic Partnership.

In time, the development of China’s much heralded Belt and Road Initiative may provide an opportunity for China to be further involved in international norm-setting, through the creation of a system of economic and political interaction that is built and run more along Chinese determined lines. The emergence of the Asian Infrastructure Investment Bank may offer an early indicator of China’s attempts to shape global governance, although in this context China has so far scrupulously observed international standards and has made no open attempt to challenge them.

So far, China’s practical input to international norm-setting has been limited. While China is prone to making wide-ranging statements of principle, it finds it more challenging to engage in the nitty gritty of specific rule making. But as is clear from its membership of the WTO, China can adapt quickly. While initially it was a reluctant adherent to the WTO dispute settlement mechanism, China is now adept at making active and effective use of its rules to promote China’s interests, including launching a legal challenge regarding the contested issue of its non-market economy status. Overall, there is strong leadership backing for a more activist approach to its engagement with the international legal system.

China sees international law as an important instrument in the “toolbox” of international diplomacy. It will increasingly be seeking to leverage international law to promote its own interests, particularly in newer areas, as it seeks to strengthen its wider soft power and influence.




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Twenty Years After Hong Kong Handover, Does ‘One Country, Two Systems’ Still Work?

Twenty Years After Hong Kong Handover, Does ‘One Country, Two Systems’ Still Work? Expert comment sysadmin 28 June 2017

This unique constitutional framework can endure – if Hong Kong society can reconcile its different visions of the future.

Golden Bauhinia Square prepares for the anniversary commemorations. Photo: Getty Images.

Twenty years after the handover of Hong Kong from British to Chinese sovereignty, the ‘one country, two systems’ arrangement – the main aim of which was to guarantee the continuity of Hong Kong’s open society and way of life – can be said to have worked well. Street protests remain a regular feature of Hong Kong’s political culture. Freedom of information and expression are alive and well. Hong Kong retains its ‘capitalist way of life’, its legal system based on common law and independent judiciary, and its status as an international financial centre. As a result the city remains one of the most open economies across Asia, with robust institutions and transparency which are hard to find anywhere else in the region.

Yet the 79-day ‘occupy’ protests of autumn 2014 showed that something is not quite right in the city of Hong Kong.

The protests themselves had a number of causes. Partly they reflected socioeconomic concerns, especially the rise in income inequality and lack of affordable housing. These might have been dealt with to some extent by better governance over the years, but they are also a feature of many societies in the current phase of globalization – a case, perhaps, of too much ‘capitalist way of life’.

Politically, the desire expressed by many in 2014 was for a form of ‘genuine universal suffrage’ for the selection of Hong Kong’s chief executive which went beyond a provision of Hong Kong’s mini constitution, the Basic Law, that candidates should be put forward by a ‘nominating committee’. It was on this point that the possibility of constitutional reform foundered in 2015, leaving Hong Kong no further ahead in its ‘gradual progress’ towards democracy.

But this episode also brought to the surface the tension between different visions for Hong Kong’s future. In particular, many in Hong Kong are still uncomfortable with the ‘one country’ part of the deal, rejected by some (especially young people) in the ways that they conceptualize Hong Kong identity – according to one recent survey, as little as 3.1% of Hong Kong youths identify themselves as ‘Chinese’. These issues are likely to constrain political development for some time to come.

At their sharpest, some of these visions are for some form of self-determination, or even independence, for Hong Kong. This is not just anathema to the national authorities in Beijing, but contradicts a basic tenet of Hong Kong’s handover in 1997, the return to Chinese sovereignty. This is not just something on which Beijing will never compromise, but will seek to challenge.

It is this which explains the sense in Hong Kong that the central government has been looking to become politically more involved since 2014. But the challenge of influencing Hong Kong society is great, and other than strengthening relations with the establishment camp, Beijing has not been able to tighten its grip. If anything, the centre of gravity of Hong Kong politics has continued to drift away from Beijing, not towards it.

How this will play out remains to be seen. Some amelioration of social tensions could help. But the fundamental divergence in visions of Hong Kong’s future will not be resolved so easily.

Looking forward therefore, the key to the continued success of ‘one country, two systems’ lies in Hong Kong society. If mainstream acceptance of the compromises involved can return, then this unique constitutional framework can still work for years to come.





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