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Reimagining Trade Rules to Address Climate Change in a Post-Pandemic World

Webinar Research Event

5 May 2020 - 2:00pm to 3:00pm

Event participants

James Bacchus, Distinguished University Professor of Global Affairs and Director of the Center for Global Economic and Environmental Opportunity at the University of Central Florida; Member and Chair, WTO Appellate Body, 1995 - 2003
Chair: Creon Butler, Director, Global Economy and Finance Programme, Chatham House

This event is part of the Chatham House Global Trade Policy Forum and will take place virtually only.

International trade has a crucial role to play in tackling climate change. The production and transport of goods is a major contributor to green-house gas emissions, as is the delivery of certain cross-border services. At the same time, it looks inevitable that the COVID-19 pandemic will lead to a radical re-think of global supply chains as companies and governments seek to build in greater resilience while at the same time preserving as far as possible the efficiency gains and lower costs that global supply chains generate when operating normally.

Future international trade rules will have a crucial role to play in addressing both challenges; they represent both an opportunity and a risk. If designed well, they could play a very important role in re-enforcing moves towards a more sustainable use of resources, greater overall alignment of economies with the Paris Agreement, and greater economic resilience. But they could also, if poorly designed and implemented, or overly influenced by strategic political considerations, have significant unintended and negative implications. These include: reduced economic efficiency, increased poverty, unnecessary economic decoupling and reduced consensus on the broader mitigation and adaptation measures required to meet the challenge of climate change.

Against this background, a number of key questions arise: In what areas, if any, do we need to modify or adapt key principles underlying the system of global trade rules in order to respond to the twin challenges of responding to climate change and building greater economic resilience?  Which are the most promising/practical areas on which trade policy experts should focus now to re-launch/re-energize discussions on WTO reform, including, for example, dispute settlement? What national economic policies will be needed to complement the development of new/reformed trade disciplines in these areas? How might future political changes, such as a change in the US administration, affect the prospects for and political momentum behind such deliberations? What in any eventuality is the best way to build the required political momentum?
 
This roundtable is convened by the Global Economy and Finance Programme and the US and the Americas Programme and it is part of the Chatham House Global Trade Policy Forum. The event will take place virtually only.

We would like to take this opportunity to thank founding partner AIG and supporting partners Clifford Chance LLP, Diageo plc, and EY for their generous support of the Chatham House Global Trade Policy Forum.

Please note this event is taking place between 2pm to 3pm BST.




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Webinar: Make or Break: China and the Geopolitical Impacts of COVID-19

Research Event

28 April 2020 - 12:00pm to 12:45pm

Event participants

Yu Jie, Senior Research Fellow on China, Asia-Pacific Programme, Chatham House
Kerry Brown, Associate Fellow, Asia-Pacific Programme, Chatham House; Professor of Chinese Studies and Director of Lau China Institute, King’s College London

The COVID-19 crisis has accelerated geopolitical tensions that, in part, have arisen from US-China tensions. At a time when the world needs strong and collective leadership to fight the coronavirus, both countries have been locked in a battle of words characterized by escalating hostility, polarizing narratives, blame and misinformation. Caught in the crossfire, many people of Chinese descent across differing countries have reported an increase in xenophobic attacks.

Middle powers such as the UK and Australia have swerved between recognition of the global collaboration needed to solve this pandemic and calls for China to be held ‘accountable’ for its initial response. Others such, as France and Japan, have been trying to foster international cooperation. 

Against this context, speakers will discuss China’s response to the crisis, including the initial delay and Beijing’s later containment strategies. How do we best assess the delay amidst all the heated rhetoric? What was the response of people within China to the measures? Does COVID-19 mark a point of no return for US-China relations? How might this impact on relations between US allies and China? And what kind of China will emerge from this current crisis?

Lucy Ridout

Programme Administrator, Asia-Pacific Programme
+44 (0) 207 314 2761




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Webinar: Will COVID-19 Mark the Endgame for Iraq's Muhasasa Ta'ifia?

Research Event

30 April 2020 - 2:00pm to 3:00pm

Event participants

Ahmed Tabaqchali, Chief Investment Officer, Asia Frontier Capital Iraq Fund; Adjunct Assistant Professor, American University of Iraq Sulaimani
Moderator: Renad Mansour, Senior Research Fellow, Middle East and North Africa Programme, Chatham House

Control of oil rents underpins Iraq’s post-2003 political order. This political order, known as Muhasasa Ta’ifia (ethno-sectarian apportionment), features an elite bargain inclusive of all major ethnic and sect-based political groups. It has enabled the state's continuity and apparent stability through multiple crises, including the 2008 financial crisis, the 2014 oil crisis, and the war with ISIS.

In a recent article, Ahmed Tabaqchali examines how the crash in oil rents, brought about by COVID-19’s disruption of the world economy, exposes the structural inconsistencies and inherent contradictions of the Muhasasa Tai’fia system. The article argues that the current Iraqi political elite is ill-equipped to resolve the multi-faceted challenge facing the country because of its increasing fragmentation and the erosion of its legitimacy, advanced institutional decay and fundamentally different oil dynamics.

In this webinar, part of the Chatham House project on the future of the state in the Middle East and North Africa, the article’s author will discuss the deficiencies of the Muhasasa Ta’ifia system and will offer his insight into the future of this governance model in the context of a worsening economic crisis resulting from the COVID-19 pandemic and existing demographic pressures.
 
You can express your interest in attending by following this link. You will receive a Zoom confirmation email should your registration be successful. Alternatively, you can watch the event live on the MENA Programme Facebook page.
 

Reni Zhelyazkova

Programme Coordinator, Middle East and North Africa Programme
+44 (0)20 7314 3624




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Webinar: International Humanitarian Law Amid Coronavirus

Members Event Webinar

15 May 2020 - 1:00pm to 2:00pm
Add to Calendar

Emanuela-Chiara Gillard, Associate Fellow, International Law Programme, Chatham House

Chair: Chanu Peiris, Programme Manager, International Law Programme, Chatham House

Further speakers to be announced.

In April 2020, UN Secretary General Antonio Guterres called for a global ceasefire in order for communities and states to focus efforts on responding to the coronavirus outbreak. The consequences of armed conflict – including displacement, detention, lack of access to health services and disrupted social infrastructures – mean that those in conflict-ridden areas are amongst the most vulnerable to the virus. Observing international humanitarian law (IHL) could be one way of safeguarding against, at least, the provision of vital medical supplies and personnel for vulnerable groups. Against the backdrop of a growing health and economic emergency that is otherwise dominating government agendas, how do we emphasise the importance of humanitarian action and guarantee - or improve - compliance?

The panellists will discuss the remit and limitations of international humanitarian law and how the pandemic might complicate compliance. What is the framework for humanitarian action under international humanitarian law? What are the challenges to delivering relief? And how has COVID-19 impacted humanitarian action in conflict-ridden areas?

This event is for Chatham House members only. Not a member? Find out more.




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Human Development as Positive Freedom: A World View Since 1870

Invitation Only

26 February 2014 - 8:15am to 9:30am

Chatham House, London

Event participants

Leandro Prados de la Escosura, Professor, Economic History, Universidad Carlos III de Madrid 

This meeting will see the launch of the Chatham House-CAGE briefing paper ‘Human Development as Positive Freedom: A World View since 1870’. The author of the paper will argue that while substantial gains in world human development have been achieved since 1870, the main period of improvement actually occurred between World War I and 1970. He will further argue that, despite initial successes in lifting human development, the socialist experiments of the 20th century failed to sustain momentum and then (with the exception of Cuba) stagnated and fell behind prior to the socialist model's ultimate demise. Finally, he will contend that since 1970, while most OECD countries have experienced a second (later life) health transition, all developing regions have fallen behind in this dimension.

The briefing paper is the 12th publication in the Chatham House-CAGE series, published in partnership with the Centre for Competitive Advantage in the Global Economy (CAGE) at the University of Warwick.

Attendance at this event is by invitation only.





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Human Development as Positive Freedom: A World View Since 1870

1 February 2014

Substantial gains in world human development have been achieved since 1870, but research shows that the main improvement actually occurred between the First World War and 1970.

Leandro Prados de la Escosura

20140200CAGEhumandevelopmentW.jpg

Photo by 1xpert /iStock.

Summary points:

  • Substantial gains in world human development have been achieved since 1870, but research shows that the main improvement actually occurred between the First World War and 1970.
     
  • Across-the-board advances took place in life expectancy and education between 1920 and 1950, a phase during which there was a major backlash against economic globalization. This is evidence of a development puzzle: economic growth and human development do not always go hand in hand.
     
  • Between 1913 and 1970 the absolute gap between most countries in the OECD and the rest of the world widened, with different regions experiencing mixed success in catching up. Since the 1970s the performance of developing regions has varied greatly.
     
  • Despite initial successes in lifting human development, the socialist experiments of the 20th century failed to sustain momentum and then (with the exception of Cuba) stagnated and fell behind prior to the socialist model’s ultimate demise.
     
  • Education has been the driving force behind the limited catching-up of developing regions in terms of long-term human development. In terms of life expectancy,these regions achieved significant gains only during the first (early-life) health transition. Since 1970, while most OECD countries have experienced a second (later-life) health transition, all developing regions have fallen behind.
Project: Shifting Competitive Advantage in the Global Economy 


Launch event

Human Development as Positive Freedom: A World View Since 1870
26 February 2014

 

 




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The First World War and the transformations of the state

13 March 2014 , Volume 90, Number 2

Pierre Purseigle




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Lesotho’s Domestic Priorities and Global Interests: Small Country Levers for International Influence

Research Event

7 April 2014 - 3:00pm to 4:00pm

Chatham House, London

Event participants

HE Dr Motsoahae Thomas Thabane, Prime Minister of Lesotho
Chair: Ian Lucas MP, Shadow Minister for Africa and the Middle East

The landlocked southern African nation of Lesotho faces a number of domestic challenges in 2014. Reducing reliance on the agricultural sector, containing the prevalence of HIV and improving service delivery are all important issues that must be addressed to ensure sustainable growth. However, social achievements including literacy rates and levels of gender parity among the highest in Africa, the country’s potential for electricity exports, and the booming relationship between its textile industry and the United States, could mean Lesotho is well-placed for future growth and development. 

HE Prime Minister Tom Thabane will discuss how his government seeks to address the Lesotho’s domestic issues and how the country seeks to exert its influence in the regional Southern African Development Community.




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Ebb and flow of Europe's human tide

1 August 2014 , Volume 70, Number 4

The map (click below to download the PDF) shows how the proportion of migrants living in countries of the European Union has changed since 1990.

Alan Philps

Editor, The World Today




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Make It Awesome — Three Tips for Impressing Your Readers

You’re a fantasy writer. You’ve created an amazing and original world, full of wondrous magic, mind-blowing monsters, and fascinating new cultures. You’ve got powerful heroes, menacing villains, and mysterious mentors. There’s just the right amount of romance.

In short, you’ve got all that good stuff you’d expect to find in a fantasy novel.

Only, somehow it’s still not coming out quite as awe-inspiring as you’d envisioned it.

Today, I’ve got three tips for you on how to make your awesome stuff seem more awesome.

Establish the Norm

“When everything is awesome, awesome becomes average.”

Every now and then, I come across a book that begins with the writer very obviously trying to impress me with how cool their main character is, and what an amazing world they have created, and how scary the villain is. All at once. In the first chapter.

It rarely works.

Let’s say there’s a ballroom full of ultra-rich and mega-powerful vampires, and then someone flies in on a golden unicorn and starts shooting fireballs the shape of grinning skulls.

That would probably look rather spectacular as an introduction to a movie, but does it work in a book?

Continue reading Make It Awesome — Three Tips for Impressing Your Readers at Mythic Scribes.



  • Writing Craft & Technique

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Thematic review series: Lipid Posttranslational Modifications. Protein palmitoylation by a family of DHHC protein S-acyltransferases

David A. Mitchell
Jun 1, 2006; 47:1118-1127
Thematic Reviews




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Marked reduction in bile acid synthesis in cholesterol 7{alpha}-hydroxylase-deficient mice does not lead to diminished tissue cholesterol turnover or to hypercholesterolemia

Margrit Schwarz
Sep 1, 1998; 39:1833-1843
Articles




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Thematic Review Series: Glycerolipids. DGAT enzymes and triacylglycerol biosynthesis

Chi-Liang Eric Yen
Nov 1, 2008; 49:2283-2301
Thematic Reviews




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Thematic review series: The Pathogenesis of Atherosclerosis The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and HDL

Mohamad Navab
Jun 1, 2004; 45:993-1007
Thematic Reviews




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Lipidomics reveals a remarkable diversity of lipids in human plasma

Oswald Quehenberger
Nov 1, 2010; 51:3299-3305
Research Articles




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Fish oils and plasma lipid and lipoprotein metabolism in humans: a critical review

WS Harris
Jun 1, 1989; 30:785-807
Reviews




ma

Normal high density lipoprotein inhibits three steps in the formation of mildly oxidized low density lipoprotein: steps 2 and 3

Mohamad Navab
Sep 1, 2000; 41:1495-1508
Articles




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Rapid method for the isolation of lipoproteins from human serum by precipitation with polyanions

M. Burstein
Nov 1, 1970; 11:583-595
Articles




ma

Normal high density lipoprotein inhibits three steps in the formation of mildly oxidized low density lipoprotein: step 1

Mohamad Navab
Sep 1, 2000; 41:1481-1494
Articles




ma

Microsomal triglyceride transfer protein and its role in apoB-lipoprotein assembly

M. Mahmood Hussain
Jan 1, 2003; 44:22-32
Reviews




ma

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




ma

Regulation of hepatic secretion of apolipoprotein B-containing lipoproteins: information obtained from cultured liver cells

JL Dixon
Feb 1, 1993; 34:167-179
Reviews




ma

The human ATP-binding cassette (ABC) transporter superfamily

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




ma

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




ma

Thematic review series: The Pathogenesis of Atherosclerosis. Effects of infection and inflammation on lipid and lipoprotein metabolism mechanisms and consequences to the host

Weerapan Khovidhunkit
Jul 1, 2004; 45:1169-1196
Thematic Reviews




ma

Identification of multiple subclasses of plasma low density lipoproteins in normal humans

Ronald M. Krauss
Jan 1, 1982; 23:97-104
Articles




ma

Thematic review series: Adipocyte Biology. The perilipin family of structural lipid droplet proteins: stabilization of lipid droplets and control of lipolysis

Dawn L. Brasaemle
Dec 1, 2007; 48:2547-2559
Thematic Reviews




ma

Plasma cholesteryl ester transfer protein

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




ma

Bile salt biotransformations by human intestinal bacteria

Jason M. Ridlon
Feb 1, 2006; 47:241-259
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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Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans

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




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The plasma lecithin:cholesterol acyltransferase reaction

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




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Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI

JE Hixson
Mar 1, 1990; 31:545-548
Articles




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The Morass of Central American Migration: Dynamics, Dilemmas and Policy Alternatives

Invitation Only Research Event

22 November 2019 - 8:15am to 9:30am

Chatham House | 10 St James's Square | London | SW1Y 4LE

Event participants

Anita Isaacs, Professor of Political Science, Haverford College; Co-Director, Migration Encounters Project
Juan Ricardo Ortega, Principal Advisor for Central America, Inter-American Development Bank
Chair: Amy Pope, Associate Fellow, Chatham House; US Deputy Homeland Security Adviser for the Obama Administration (2015-17)

2019 has seen a record number of people migrating from Central America’s Northern Triangle – an area that covers El Salvador, Guatemala and Honduras. Estimates from June 2019 have placed the number of migrants at nearly double of what they were in 2018 with the increase in numbers stemming from a lack of economic opportunity combined with a rise in crime and insecurity in the region. The impacts of migration can already be felt within the affected states as the exodus has played a significant role in weakening labour markets and contributing to a ‘brain drain’ in the region. It has also played an increasingly active role in the upcoming US presidential election with some calling for more security on the border to curb immigration while others argue that a more effective strategy is needed to address the sources of migration. 

What are the core causes of Central American migration and how have the US, Central American and now also Mexican governments facilitated and deterred migration from the region? Can institutions be strengthened to alleviate the causes of migration? And what possible policy alternatives and solutions are there that could alleviate the pressures individuals and communities feel to migrate?   

Anita Isaacs, professor of Political Science at Haverford College and co-director of the Migration Encounters Project, and Juan Ricard Ortega, principal advisor for Central America at the Inter-American Development Bank, will join us for a discussion on the core drivers of migration within and across Central America.

Attendance at this event is by invitation only. 

Event attributes

Chatham House Rule

Department/project

US and Americas Programme




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The UK, US and Mauritius: Decolonization, Security, Chagos and the ICJ

Invitation Only Research Event

30 January 2020 - 8:15am to 9:15am

Chatham House | 10 St James's Square | London | SW1Y 4LE

Event participants

Professor Philippe Sands QC, Professor of Law, UCL 
Richard Burt, Managing Partner, McLarty Associates
Chair: Dr Leslie Vinjamuri, Director, US and Americas Programme; Dean, Queen Elizabeth II Academy, Chatham House

The Chagos archipelago in the Indian Ocean has garnered media attention recently after the UK failed to abide by a UN deadline to return the islands to Mauritius. The US has landed in the middle of the dispute as a 1965 agreement with the UK has allowed the US to establish a military base on one of the islands, Diego Garcia, which has since become instrumental in US missions in the Asia-Pacific and the Middle East. 

In February 2019, an Advisory Opinion of the International Court of Justice (ICJ) found that the Chagos archipelago was unlawfully dismembered from Mauritius, in violation of the right to self-determination and that the United Kingdom is under an obligation to end its administration of the Chagos archipelago ‘as rapidly as possible’. The UN General Assembly subsequently voted overwhelmingly in favour of the UK leaving the islands by the end of November 2019 and the right of the former residents who were removed by the UK to return. The UK does not accept the ICJ and UN rulings and argues that the islands are needed to protect Britain from security threats while Mauritius has made clear the base can remain.

Professor Philippe Sands QC, professor of law at University College London and lead counsel for Mauritius on the ICJ case on Legal Consequences of the Separation of the Chagos archipelago from Mauritius in 1965, will be joining Ambassador Richard Burt, US chief negotiator in the Strategic Arms Reduction Talks with the former Soviet Union for a discussion on the fate of the archipelago including the future of the military base and the right of return of former residents.  

Attendance at this event is by invitation only. 

Event attributes

Chatham House Rule

Department/project

US and Americas Programme




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Immature leadership: Donald Trump and the American presidency

4 March 2020 , Volume 96, Number 2

Daniel W. Drezner

There has been a renaissance in the study of how the backgrounds of individual leaders affect foreign policy outcomes. Donald Trump's presidency highlights the limits of this approach. Trump's psychology is so unique, and so akin to that of a small child, that studying his background alone is insufficient to explain his decision-making. The evidence for this characterization of Trump's leadership comes not from his political opponents, but his allies, staffers and subordinates. Trump's lack of impulse control, short attention span and frequent temper tantrums have all undercut his effectiveness as president as compared to his predecessors. Nonetheless, the 45th president helps to clarify ongoing debates in American politics about the relative strength of the presidency as an institution. In particular, the powers of the presidency have become so enhanced that even comparatively weak and inexperienced leaders can execute dramatic policy shifts. The formal checks on presidential power, from the legislative, judicial and executive branches have all eroded. Similarly, the informal checks on the presidency had also degraded before Trump's inauguration. This article uses Trump's presidency—and his severe limitations as a decision-maker—to highlight the ways in which even a weak leader can affect change by holding a powerful office.




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Virtual Roundtable: The End of Globalism? Remaining Interconnected While Under Increased Pressure to Isolate

Invitation Only Research Event

30 March 2020 - 1:00pm to 2:00pm

Zoom Audio Call

Event participants

Fred Hochberg, Chairman and President, Export-Import Bank of the United States, 2009 -17
Chair: Dr Leslie Vinjamuri, Director, US and the Americas Programme, Chatham House

This event is part of the Chatham House Global Trade Policy Forum. We would like to take this opportunity to to thank founding partner AIG and supporting partners Clifford Chance LLP, Diageo plc and EY for their generous support of the forum. 

US and Americas Programme




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Reimagining Trade Rules to Address Climate Change in a Post-Pandemic World

Webinar Research Event

5 May 2020 - 2:00pm to 3:00pm

Event participants

James Bacchus, Distinguished University Professor of Global Affairs and Director of the Center for Global Economic and Environmental Opportunity at the University of Central Florida; Member and Chair, WTO Appellate Body, 1995 - 2003
Chair: Creon Butler, Director, Global Economy and Finance Programme, Chatham House

This event is part of the Chatham House Global Trade Policy Forum and will take place virtually only.

International trade has a crucial role to play in tackling climate change. The production and transport of goods is a major contributor to green-house gas emissions, as is the delivery of certain cross-border services. At the same time, it looks inevitable that the COVID-19 pandemic will lead to a radical re-think of global supply chains as companies and governments seek to build in greater resilience while at the same time preserving as far as possible the efficiency gains and lower costs that global supply chains generate when operating normally.

Future international trade rules will have a crucial role to play in addressing both challenges; they represent both an opportunity and a risk. If designed well, they could play a very important role in re-enforcing moves towards a more sustainable use of resources, greater overall alignment of economies with the Paris Agreement, and greater economic resilience. But they could also, if poorly designed and implemented, or overly influenced by strategic political considerations, have significant unintended and negative implications. These include: reduced economic efficiency, increased poverty, unnecessary economic decoupling and reduced consensus on the broader mitigation and adaptation measures required to meet the challenge of climate change.

Against this background, a number of key questions arise: In what areas, if any, do we need to modify or adapt key principles underlying the system of global trade rules in order to respond to the twin challenges of responding to climate change and building greater economic resilience?  Which are the most promising/practical areas on which trade policy experts should focus now to re-launch/re-energize discussions on WTO reform, including, for example, dispute settlement? What national economic policies will be needed to complement the development of new/reformed trade disciplines in these areas? How might future political changes, such as a change in the US administration, affect the prospects for and political momentum behind such deliberations? What in any eventuality is the best way to build the required political momentum?
 
This roundtable is convened by the Global Economy and Finance Programme and the US and the Americas Programme and it is part of the Chatham House Global Trade Policy Forum. The event will take place virtually only.

We would like to take this opportunity to thank founding partner AIG and supporting partners Clifford Chance LLP, Diageo plc, and EY for their generous support of the Chatham House Global Trade Policy Forum.

Please note this event is taking place between 2pm to 3pm BST.




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Roles of the DOCK-D family proteins in a mouse model of neuroinflammation [Neurobiology]

The DOCK-D (dedicator of cytokinesis D) family proteins are atypical guanine nucleotide exchange factors that regulate Rho GTPase activity. The family consists of Zizimin1 (DOCK9), Zizimin2 (DOCK11), and Zizimin3 (DOCK10). Functions of the DOCK-D family proteins are presently not well-explored, and the role of the DOCK-D family in neuroinflammation is unknown. In this study, we generated three mouse lines in which DOCK9 (DOCK9−/−), DOCK10 (DOCK10−/−), or DOCK11 (DOCK11−/−) had been deleted and examined the phenotypic effects of these gene deletions in MOG35–55 peptide-induced experimental autoimmune encephalomyelitis, an animal model of the neuroinflammatory disorder multiple sclerosis. We found that all the gene knockout lines were healthy and viable. The only phenotype observed under normal conditions was a slightly smaller proportion of B cells in splenocytes in DOCK10−/− mice than in the other mouse lines. We also found that the migration ability of macrophages is impaired in DOCK10−/− and DOCK11−/− mice and that the severity of experimental autoimmune encephalomyelitis was ameliorated only in DOCK10−/− mice. No apparent phenotype was observed for DOCK9−/− mice. Further investigations indicated that lipopolysaccharide stimulation up-regulates DOCK10 expression in microglia and that microglial migration is decreased in DOCK10−/− mice. Up-regulation of C–C motif chemokine ligand 2 (CCL2) expression induced by activation of Toll-like receptor 4 or 9 signaling was reduced in DOCK10−/− astrocytes compared with WT astrocytes. Taken together, our findings suggest that DOCK10 plays a role in innate immunity and neuroinflammation and might represent a potential therapeutic target for managing multiple sclerosis.




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{alpha}-Synuclein filaments from transgenic mouse and human synucleinopathy-containing brains are maȷor seed-competent species [Molecular Bases of Disease]

Assembled α-synuclein in nerve cells and glial cells is the defining pathological feature of neurodegenerative diseases called synucleinopathies. Seeds of α-synuclein can induce the assembly of monomeric protein. Here, we used sucrose gradient centrifugation and transiently transfected HEK 293T cells to identify the species of α-synuclein from the brains of homozygous, symptomatic mice transgenic for human mutant A53T α-synuclein (line M83) that seed aggregation. The most potent fractions contained Sarkosyl-insoluble assemblies enriched in filaments. We also analyzed six cases of idiopathic Parkinson's disease (PD), one case of familial PD, and six cases of multiple system atrophy (MSA) for their ability to induce α-synuclein aggregation. The MSA samples were more potent than those of idiopathic PD in seeding aggregation. We found that following sucrose gradient centrifugation, the most seed-competent fractions from PD and MSA brains are those that contain Sarkosyl-insoluble α-synuclein. The fractions differed between PD and MSA, consistent with the presence of distinct conformers of assembled α-synuclein in these different samples. We conclude that α-synuclein filaments are the main driving force for amplification and propagation of pathology in synucleinopathies.




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Small-molecule agonists of the RET receptor tyrosine kinase activate biased trophic signals that are influenced by the presence of GFRa1 co-receptors [Neurobiology]

Glial cell line–derived neurotrophic factor (GDNF) is a growth factor that regulates the health and function of neurons and other cells. GDNF binds to GDNF family receptor α1 (GFRa1), and the resulting complex activates the RET receptor tyrosine kinase and subsequent downstream signals. This feature restricts GDNF activity to systems in which GFRa1 and RET are both present, a scenario that may constrain GDNF breadth of action. Furthermore, this co-dependence precludes the use of GDNF as a tool to study a putative functional cross-talk between GFRa1 and RET. Here, using biochemical techniques, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, and immunohistochemistry in murine cells, tissues, or retinal organotypic cultures, we report that a naphthoquinone/quinolinedione family of small molecules (Q compounds) acts as RET agonists. We found that, like GDNF, signaling through the parental compound Q121 is GFRa1-dependent. Structural modifications of Q121 generated analogs that activated RET irrespective of GFRa1 expression. We used these analogs to examine RET–GFRa1 interactions and show that GFRa1 can influence RET-mediated signaling and enhance or diminish AKT Ser/Thr kinase or extracellular signal-regulated kinase signaling in a biased manner. In a genetic mutant model of retinitis pigmentosa, a lead compound, Q525, afforded sustained RET activation and prevented photoreceptor neuron loss in the retina. This work uncovers key components of the dynamic relationships between RET and its GFRa co-receptor and provides RET agonist scaffolds for drug development.




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Reactive dicarbonyl compounds cause Calcitonin Gene-Related Peptide release and synergize with inflammatory conditions in mouse skin and peritoneum [Molecular Bases of Disease]

The plasmas of diabetic or uremic patients and of those receiving peritoneal dialysis treatment have increased levels of the glucose-derived dicarbonyl metabolites like methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG). The elevated dicarbonyl levels can contribute to the development of painful neuropathies. Here, we used stimulated immunoreactive Calcitonin Gene–Related Peptide (iCGRP) release as a measure of nociceptor activation, and we found that each dicarbonyl metabolite induces a concentration-, TRPA1-, and Ca2+-dependent iCGRP release. MGO, GO, and 3-DG were about equally potent in the millimolar range. We hypothesized that another dicarbonyl, 3,4-dideoxyglucosone-3-ene (3,4-DGE), which is present in peritoneal dialysis (PD) solutions after heat sterilization, activates nociceptors. We also showed that at body temperatures 3,4-DGE is formed from 3-DG and that concentrations of 3,4-DGE in the micromolar range effectively induced iCGRP release from isolated murine skin. In a novel preparation of the isolated parietal peritoneum PD fluid or 3,4-DGE alone, at concentrations found in PD solutions, stimulated iCGRP release. We also tested whether inflammatory tissue conditions synergize with dicarbonyls to induce iCGRP release from isolated skin. Application of MGO together with bradykinin or prostaglandin E2 resulted in an overadditive effect on iCGRP release, whereas MGO applied at a pH of 5.2 resulted in reduced release, probably due to an MGO-mediated inhibition of transient receptor potential (TRP) V1 receptors. These results indicate that several reactive dicarbonyls activate nociceptors and potentiate inflammatory mediators. Our findings underline the roles of dicarbonyls and TRPA1 receptors in causing pain during diabetes or renal disease.




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Brain manganese and the balance between essential roles and neurotoxicity [Molecular Bases of Disease]

Manganese (Mn) is an essential micronutrient required for the normal development of many organs, including the brain. Although its roles as a cofactor in several enzymes and in maintaining optimal physiology are well-known, the overall biological functions of Mn are rather poorly understood. Alterations in body Mn status are associated with altered neuronal physiology and cognition in humans, and either overexposure or (more rarely) insufficiency can cause neurological dysfunction. The resultant balancing act can be viewed as a hormetic U-shaped relationship for biological Mn status and optimal brain health, with changes in the brain leading to physiological effects throughout the body and vice versa. This review discusses Mn homeostasis, biomarkers, molecular mechanisms of cellular transport, and neuropathological changes associated with disruptions of Mn homeostasis, especially in its excess, and identifies gaps in our understanding of the molecular and biochemical mechanisms underlying Mn homeostasis and neurotoxicity.




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Coronavirus: Public Health Emergency or Pandemic – Does Timing Matter?

1 May 2020

Dr Charles Clift

Senior Consulting Fellow, Global Health Programme
The World Health Organization (WHO) has been criticized for delaying its announcements of a public health emergency and a pandemic for COVID-19. But could earlier action have influenced the course of events?

2020-05-01-Tedros-WHO-COVID

WHO director-general Dr Tedros Adhanom Ghebreyesus at the COVID-19 press briefing on March 11, 2020, the day the coronavirus outbreak was classed as a pandemic. Photo by FABRICE COFFRINI/AFP via Getty Images.

The World Health Organization (WHO) declared the spread of COVID-19 to be a Public Health Emergency of International Concern (PHEIC) on January 30 this year and then characterized it as a pandemic on March 11.

Declaring a PHEIC is the highest level of alert that WHO is obliged to declare, and is meant to send a powerful signal to countries of the need for urgent action to combat the spread of the disease, mobilize resources to help low- and middle-income countries in this effort and fund research and development on needed treatments, vaccines and diagnostics. It also obligates countries to share information with WHO.

Once the PHEIC was declared, the virus continued to spread globally, and WHO began to be asked why it had not yet declared the disease a pandemic. But there is no widely accepted definition of a pandemic, generally it is just considered an epidemic which affects many countries globally.

Potentially more deadly

The term has hitherto been applied almost exclusively to new forms of flu, such as H1N1 in 2009 or Spanish flu in 1918, where the lack of population immunity and absence of a vaccine or effective treatments makes the outbreak potentially much more deadly than seasonal flu (which, although global, is not considered a pandemic).

For COVID-19, WHO seemed reluctant to declare a pandemic despite the evidence of global spread. Partly this was because of its influenza origins — WHO’s emergency programme executive director said on March 9 that ‘if this was influenza, we would have called a pandemic ages ago’.

He also expressed concern that the word traditionally meant moving — once there was widespread transmission — from trying to contain the disease by testing, isolating the sick and tracing and quarantining their contacts, to a mitigation approach, implying ‘the disease will spread uncontrolled’.

WHO’s worry was that the world’s reaction to the word pandemic might be there was now nothing to be done to stop its spread, and so countries would effectively give up trying. WHO wanted to send the message that, unlike flu, it could still be pushed back and the spread slowed down.

In announcing the pandemic two days later, WHO’s director-general Dr Tedros Adhanom Ghebreyesus reemphasised this point: ‘We cannot say this loudly enough, or clearly enough, or often enough: all countries can still change the course of this pandemic’ and that WHO was deeply concerned ‘by the alarming levels of inaction’.

The evidence suggests that the correct message did in fact get through. On March 13, US president Donald Trump declared a national emergency, referring in passing to WHO’s announcement. On March 12, the UK launched its own strategy to combat the disease. And in the week following WHO’s announcements, at least 16 other countries announced lockdowns of varying rigour including Austria, Belgium, Canada, Czech Republic, Denmark, Finland, France, Germany, Hungary, Netherlands, Norway, Poland, Portugal, Serbia, Spain and Switzerland. Italy and Greece had both already instituted lockdowns prior to the WHO pandemic announcement.

It is not possible to say for sure that WHO’s announcement precipitated these measures because, by then, the evidence of the rapid spread was all around for governments to see. It may be that Italy’s dramatic nationwide lockdown on March 9 reverberated around European capitals and elsewhere.

But it is difficult to believe the announcement did not have an effect in stimulating government actions, as was intended by Dr Tedros. Considering the speed with which the virus was spreading from late February, might an earlier pandemic announcement by WHO have stimulated earlier aggressive actions by governments?

Declaring a global health emergency — when appropriate — is a key part of WHO’s role in administering the International Health Regulations (IHR). Significantly, negotiations on revisions to the IHR, which had been ongoing in a desultory fashion in WHO since 1995, were accelerated by the experience of the first serious coronavirus outbreak — SARS — in 2002-2003, leading to their final agreement in 2005.

Under the IHR, WHO’s director-general decides whether to declare an emergency based on a set of criteria and on the advice of an emergency committee. IHR defines an emergency as an ‘extraordinary event that constitutes a public health risk through the international spread of disease and potentially requires a coordinated international response’.

In the case of COVID-19, the committee first met on January 22-23 but were unable to reach consensus on a declaration. Following the director-general’s trip to meet President Xi Jinping in Beijing, the committee reconvened on January 30 and this time advised declaring a PHEIC.

But admittedly, public recognition of what a PHEIC means is extremely low. Only six have ever been declared, with the first being the H1N1 flu outbreak which fizzled out quickly, despite possibly causing 280,000 deaths globally. During the H1N1 outbreak, WHO declared a PHEIC in April 2009 and then a pandemic in June, only to rescind both in August as the outbreak was judged to have transitioned to behave like a seasonal flu.

WHO was criticized afterwards for prematurely declaring a PHEIC and overreacting. This then may have impacted the delay in declaring the Ebola outbreak in West Africa as a PHEIC in 2014, long after it became a major crisis. WHO’s former legal counsel has suggested the PHEIC — and other aspects of the IHR framework — may not be effective in stimulating appropriate actions by governments and needs to be reconsidered.

When the time is right to evaluate lessons about the response, it might be appropriate to consider the relative effectiveness of the PHEIC and pandemic announcements and their optimal timing in stimulating appropriate action by governments. The effectiveness of lockdowns in reducing the overall death toll also needs investigation.




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Basem Mahmoud

Project Manager, Middle East and North Africa Programme

Biography

Basem Mahmoud is a project manager with the Middle East and North Africa Programme at Chatham House.

Basem joined Chatham House in 2019 and has contributed to the projects Future of Statehood in the MENA Region, Transformative Policies towards Syria, and Post-Conflict State Dynamics in Syria.

Prior to joining Chatham House, Basem worked in managing wide range of projects and programmes with the Anna Lindh Euro-Mediterranean Foundation, Freedom House, and Friedrich Naumann Foundation.

Basem has an MA in conflict, security, and development from the University of Bradford.

+44 (0) 20 7314 3658




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