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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




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

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




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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




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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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Quantitation of atherosclerosis in murine models: correlation between lesions in the aortic origin and in the entire aorta, and differences in the extent of lesions between sexes in LDL receptor-deficient and apolipoprotein E-deficient mice

RK Tangirala
Nov 1, 1995; 36:2320-2328
Articles




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Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression

K Schoonjans
May 1, 1996; 37:907-925
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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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 amphipathic helix in the exchangeable apolipoproteins: a review of secondary structure and function

JP Segrest
Feb 1, 1992; 33:141-166
Reviews




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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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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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Molecular physiology of reverse cholesterol transport

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




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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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Harnessing the Potential of Cities

Corporate Members Event

13 December 2019 - 12:30pm to 2:00pm

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

Event participants

Penny Abeywardena, Commissioner for International Affairs, New York City

Chair: Dr Beyza Unal, Senior Research Fellow, International Security Department, Chatham House

Cities are strong engines of growth and job creation accounting for some 85 per cent of global GDP. By 2030, more than 60 per cent of people worldwide will live in cities and they will be on the front lines of managing issues transcending borders such as climate, migration and sustainability. International organizations like the United Nations are striving to meet these challenges but relying on traditional multilateral agreements is growing ever more unpredictable. If cities and local governments are key to global prosperity, how can their power and influence be harnessed to accelerate impact for their citizens?

Drawing on the pioneering work of New York City in the area of foreign policy leadership at a municipal level, Penny Abeywardena will discuss how the influence of subnational leadership and diplomacy is more important than ever as national governments are abdicating their responsibility at the multilateral level. How can the Sustainable Development Goals be localized among cities on policy issues that impact communities? And what can large cities, beyond the capital, do to remain influential and harness job growth?

 This event will be preceded by an informal sandwich reception from 12.30pm-1pm. The roundtable discussion to follow will take place from 1pm-2pm.

This event is corporate members only.  If you'd like to attend, please RSVP to Linda Bedford.

To enable as open a debate as possible, this event will be held under the Chatham House Rule.

Members Events Team




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Implications of AMLO and Bolsonaro for Mexican and Brazilian Foreign Policy

Invitation Only Research Event

26 February 2020 - 12:15pm to 1:15pm

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

Event participants

Ambassador Andrés Rozental, Senior Adviser, Chatham House; Founding President, Mexican Council on Foreign Relations
Dr Elena Lazarou, Associate Fellow, US and the Americas Programme, Chatham House
Chair: Dr Christopher Sabatini, Senior Research Fellow for Latin America, US and the Americas Programme, Chatham House

The end of 2018 was a monumental year for Latin America’s two biggest economies. In December 2018, Andrés Manuel López Obrador (AMLO) was inaugurated as Mexico’s 58th president. The following month saw another political shift further south, as Jair Bolsonaro became Brazil’s 38th president. While sitting on opposite ends of the political spectrum, both AMLO and Bolsonaro were considered to be political outsiders and have upended the status quo through their election to office. 

To what extent does the election of AMLO in Mexico and Bolsonaro in Brazil represent a shift in those countries’ definitions of national interest and foreign policy priorities? How will this affect these states’ policies regarding international commitments and cooperation on issues such as human rights, environment and climate change, migration, and trade? To what extent do possible shifts reflect changing domestic opinions?  Will any changes represent a long-term shift in state priorities and policies past these administrations?

US and Americas Programme




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US 2020: State of the Union and State of the Race

Corporate Members Event Nominees Breakfast Briefing Partners and Major Corporates

11 March 2020 - 8:00am to 9:15am

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

Event participants

Dr Lindsay Newman, Senior Research Fellow, US and the Americas Programme, Chatham House
Chair: Dr Leslie Vinjamuri, Dean, Queen Elizabeth II Academy for Leadership in International Affairs; Director, US and the Americas Programme, Chatham House

The US is eight months out from consequential presidential and congressional elections. Since his election in 2016, US President Donald Trump has presided over economic expansion and record unemployment rates following a 2017 tax overhaul and deregulation policies. Trump’s approval rating is at the highest level of his presidency, while on the Democratic side, the once-wide field is in a process of narrowing as intra-party ideological differences persist.
 
As we look ahead to the presidential elections in November 2020, Dr Lindsay Newman will reflect on Donald Trump’s presidency, the state of the 2020 election and preview the potential directions of travel ahead under a Trump 2.0 or a Democratic administration. How can we understand the health of Trump’s presidency post-impeachment and post-State of the Union address? What will Trump’s likely foreign policy priorities be ahead of his re-election bid including prospects for a US-UK or a US-Europe trade deal? And, across the aisle, how can we understand the Democratic primary so far and how are the Democrats positioned going into the general election? 
 

This event is only open to Major Corporate Member and Partner organizations of Chatham House. If you would like to register your interest, please RSVP to Linda Bedford. We will contact you to confirm your attendance.

To enable as open a debate as possible, this event will be held under the Chatham House Rule.


COVID-19
This event is proceeding as scheduled, as are other Chatham House events, in accordance with the advice from the UK Government, Foreign and Commonwealth Office and Public Health England. However, we are closely monitoring the spread of COVID-19 and will send updates to attendees as the situation warrants. 
In the meantime, in line with the official advice for returning travellers or visitors to the UK from specified countries and areas (see guidance here), we ask that:

  • If you have travelled from Category 1 countries/areas, you refrain from attending the event even if asymptomatic (i.e. even if you are showing no symptoms);
  • If you have travelled from Category 2 countries/areas, you refrain from attending the event should you develop symptoms.

If you fall under one of these affected categories and have any questions, please call +44 (0)207 314 3638 or email lbedford@chathamhouse.org

 

Event attributes

Chatham House Rule

Members Events Team




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Virtual Roundtable: Tectonic Plates of 2020 – Developments in the US Presidential Race

Invitation Only Research Event

18 March 2020 - 1:00pm to 1:45pm

Event participants

John Zogby, Founder and Senior Partner, John Zogby Strategies
Chair: Dr Lindsay Newman, Senior Research Fellow, US and Americas Programme, Chatham House

This event is part of the Inaugural Virtual Roundtable Series on the US, Americas and the State of the World and will take place virtually only. Participants should not come to Chatham House for these events.

US and Americas Programme




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Virtual Roundtable: The Economic Impact of Coronavirus

Invitation Only Research Event

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

Event participants

Megan Greene, Dame DeAnne Senior Academy Fellow in International Relations, Chatham House; Senior Fellow, Harvard Kennedy School
Lord Jim O'Neill, Chairman, Chatham House
Chair: Creon Butler, Director, Global Economy and Finance, Chatham House

This event is part of the Inaugural Virtual Roundtable Series on the US, Americas and the State of the World and will take place virtually only.  Participants should not come to Chatham House for these events.

Department/project

US and Americas Programme




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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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Virtual Roundtable: The Shock of Coronavirus – Hard Truths

Research Event

15 April 2020 - 3:00pm to 4:00pm

Event participants

Professor Adam Tooze, Kathryn and Shelby Cullom Davis Professor of History, Columbia University
Discussant: Megan Greene, Dame DeAnne Julius Senior Academy Fellow in International Economics, Chatham House; Senior Fellow, Harvard Kennedy School
Chair: Dr Leslie Vinjamuri, Director, US and the Americas Programme; Dean, Queen Elizabeth II Academy for Leadership in International Affairs, Chatham House

This event is part of the Inaugural Virtual Roundtable Series on the US, Americas and the State of the World and will take place virtually only.

Department/project

US and Americas Programme




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In Search of the American State

6 April 2020

Dr Leslie Vinjamuri

Dean, Queen Elizabeth II Academy for Leadership in International Affairs; Director, US and the Americas Programme
The urgent need for US leadership to drive forward a coordinated international response to coronavirus is developing rapidly alongside snowballing demands for Washington to step up its efforts at home.

2020-04-06-US-covid-washington

Exercising in front of a deserted Lincoln Memorial in Washington, DC. Photo by Win McNamee/Getty Images.

As the US surgeon general warns Americans to brace for ‘our Pearl Harbor moment’, the US faces a week in which it may see the worst of the global pandemic. The absence of US leadership at the global level has enabled the Security Council’s inaction. And at the G7, President Trump actively obstructed efforts to agree a joint statement.

US efforts to increase its support of international aid to the tune of $274million are minimal, not least in light of a 50% reduction in its support for the World Health Organization (WHO) and radically diminished support for other global health programmes as well. International coordination is essential to mitigate unregulated competition for critical medical supplies, manage border closures, and guarantee international economic stability.

True, it won’t be possible to control the epidemic at home if the global effort to defeat the pandemic fails. But the absence of leadership from Washington at home is palpable. And what happens at home sets a natural limit on America’s internationalism.

Both solution and problem

In response to the coronavirus crisis, the US state is proving to be a solution - and a problem. The dramatic response to the economic crisis is evident with the $2.3trillion stimulus package signed into law by President Trump boldly supported by both Democrats and Republicans in the most significant piece of bipartisan legislation passed in decades.

America’s political economy is unrecognisable, moving left and looking increasingly more European each week as Congress and the executive branch agree a series of stimulus packages designed to protect citizens and businesses. Some elements of this legislation were more familiar to Americans, notably $200bn in corporate tax breaks.

But Congress also agreed unemployment insurance, and cheques - one in April, one in May – to be sent directly to those Americans most directly hit by the economic impact of COVID-19. In effect, this is adopting a temporary universal basic income.

The stimulus plan also dedicated $367bn to keep small businesses afloat for as long as the economy is shuttered. Already the government is negotiating a fourth stimulus package, but the paradox is that without rigorous steps to halt the health crisis, no level of state intervention designed to solve the economic response will be sufficient.

The scale of the state’s economic intervention is unprecedented, but it stands in stark contrast to Washington’s failure to coordinate a national response to America’s health crisis. An unregulated market for personal protective equipment and ventilators is driving up competition between cities, states, and even the federal government.

In some cases, cities and states are reaching out directly beyond national borders to international organisations, foreign firms and even America’s geopolitical competitors as they search for suppliers. In late March, the city of New York secured a commitment from the United Nations to donate 250,000 protective face masks.

Now Governor Cuomo has announced New York has secured a shipment of 140 ventilators from the state of Oregon, and 1,000 ventilators from China. The Patriots even sent their team plane to China to pick up medical supplies for the state of Massachusetts. And following a phone call between President Putin and President Trump, Russia sent a plane with masks and medical equipment to JFK airport in New York.

Networks of Chinese-Americans in the United States are rapidly mobilising their networks to access supplies and send them to doctors and nurses in need. And innovative and decisive action by governors, corporates, universities and mayors drove America’s early response to coronavirus.

This was critical to slowing the spread of COVID-19 by implementing policies that rapidly drove social distancing. But the limits of decentralized and uncoordinated action are now coming into sharp focus. President Trump has so far refused to require stay-at-home orders across all states, leaving this authority to individual governors. Unregulated competition has driven up prices with the consequence that critical supplies are going to the highest bidder, not those most in need.

Governor Cuomo’s call for a nationwide buying consortium has so far gone unheeded and, although the Federal Emergency Management Agency has attempted to deliver supplies to states most in need, the Strategic National Stockpile is depleting fast. Without critical action, the federal government risks hindering the ability of cities and states to get the supplies they need.

But President Trump is reluctant to fully deploy his powers under the Defense Production Act (DPA). In March, he did invoke the DPA to require certain domestic manufacturers to produce ventilators. But calls for it to be used to require manufacturers to produce PPE (personal protective equipment), control costs, and manage allocations has so far gone unheeded by a president generally opposed to state interventions for managing the economy.

It is true that federalism and a deep belief in competition are critical to the fabric of US history and politics, and innovations made possible by market values of entrepreneurism and competition cannot be underestimated. In the search for a vaccine, this could still prove to be key.

But with current estimates that more Americans will die from coronavirus than were killed in the Korean and Vietnam wars combined, it is clear now is the time to reimagine and reinvent the role of the American state.

In the absence of a coordinated effort driven by the White House, governors are working together to identify the areas of greatest need. Whether this will lead to a recasting of the American state and greater demand for a deeper and more permanent social safety net is a key question in the months ahead.

In the short-term the need for coordinated state action at the national level is self-evident. US leadership globally, to manage the health crisis and its economic impacts, is also vital. But this is unlikely to be forthcoming until America gets its own house in order.




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Webinar: Does COVID-19 Spell the End of America's Interest in Globalization?

Research Event

19 May 2020 - 2:00pm to 3:00pm
Add to Calendar
Dr Anne-Marie Slaughter, CEO, New America
Professor Stephen Walt, Robert and Renee Belfer Professor of International Affairs, Harvard Kennedy School
Chair: Dr Leslie Vinjamuri, Director, US and Americas Programme, Chatham House
This  event is  part of the US and Americas Programme Inaugural Virtual Roundtable Series on the US and the State of the World and will take place virtually only.
 
Please note this event is taking place between 2pm to 3pm BST.

US and Americas Programme

Department/project




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A Transatlantic Partnership for WTO Reform in the Age of Coronavirus

Webinar Research Event

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

Event participants

Ignacio Garcia Bercero, Director, Directorate General for Trade of the European Commission; European Union Visiting Fellow, Oxford University
Jennifer Hillman, Senior Fellow for Trade and International Political Economy, Council on Foreign Relations; Member, WTO Appellate Body, 2007 - 11
Chair: Marianne Schneider-Petsinger, Senior Research Fellow, US and Americas Programme, Chatham House

Global trade and the WTO – which has been at the heart of the rules-based international trade system since its creation in 1995 – faced a critical moment even before COVID-19. The Appellate Body’s demise in December 2019 led to a renewed focus on the future of the WTO. But the challenges facing the WTO run deeper than that – the organization has lost relevance as a negotiation forum, resulting in the global trade rules not having kept pace with changes in technology and the rise of China. While the WTO provides a forum for international cooperation to address the trade fallout from COVID-19, what implications will the pandemic have for the long-term reform of the global trade system?

Both the US and EU have proposed various WTO reform strategies and taken steps towards collaboration, but is a transatlantic partnership for WTO reform feasible? Do the US and EU believe that a rules-based international trade system is in their interest – especially in light of COVID-19? What are the biggest issues dividing the US and EU on reforming the WTO, and is there a common assessment of the key problems? What steps can the US and EU take to address the dispute settlement function of the WTO and to modernize the trade rules? Are there broader issues, such as environmental and social sustainability, that should be included in a transatlantic agenda for WTO reform?

This event is  part of the Chatham House Global Trade Policy Forum and 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.




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Dopamine transporter trafficking and Rit2 GTPase: Mechanism of action and in vivo impact [Neurobiology]

Following its evoked release, dopamine (DA) signaling is rapidly terminated by presynaptic reuptake, mediated by the cocaine-sensitive DA transporter (DAT). DAT surface availability is dynamically regulated by endocytic trafficking, and direct protein kinase C (PKC) activation acutely diminishes DAT surface expression by accelerating DAT internalization. Previous cell line studies demonstrated that PKC-stimulated DAT endocytosis requires both Ack1 inactivation, which releases a DAT-specific endocytic brake, and the neuronal GTPase, Rit2, which binds DAT. However, it is unknown whether Rit2 is required for PKC-stimulated DAT endocytosis in DAergic terminals or whether there are region- and/or sex-dependent differences in PKC-stimulated DAT trafficking. Moreover, the mechanisms by which Rit2 controls PKC-stimulated DAT endocytosis are unknown. Here, we directly examined these important questions. Ex vivo studies revealed that PKC activation acutely decreased DAT surface expression selectively in ventral, but not dorsal, striatum. AAV-mediated, conditional Rit2 knockdown in DAergic neurons impacted baseline DAT surface:intracellular distribution in DAergic terminals from female ventral, but not dorsal, striatum. Further, Rit2 was required for PKC-stimulated DAT internalization in both male and female ventral striatum. FRET and surface pulldown studies in cell lines revealed that PKC activation drives DAT-Rit2 surface dissociation and that the DAT N terminus is required for both PKC-mediated DAT-Rit2 dissociation and DAT internalization. Finally, we found that Rit2 and Ack1 independently converge on DAT to facilitate PKC-stimulated DAT endocytosis. Together, our data provide greater insight into mechanisms that mediate PKC-regulated DAT internalization and reveal unexpected region-specific differences in PKC-stimulated DAT trafficking in bona fide DAergic terminals.




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Learning the ABCs of ATP release [Signal Transduction]

ATP plays important roles outside the cell, but the mechanism by which it is arrives in the extracellular environment is not clear. Dunn et al. now show that decreases in cellular cholesterol levels mediated by the ABCG1 transporter increase ATP release by volume-regulated anion channels under hypotonic conditions. Importantly, these results may imply that cells that handle cholesterol differently might experience differential extracellular ATP release during hypotonicity.




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S-Palmitoylation of the sodium channel Nav1.6 regulates its activity and neuronal excitability [Cell Biology]

S-Palmitoylation is a reversible post-translational lipid modification that dynamically regulates protein functions. Voltage-gated sodium channels are subjected to S-palmitoylation and exhibit altered functions in different S-palmitoylation states. Our aim was to investigate whether and how S-palmitoylation regulates Nav1.6 channel function and to identify S-palmitoylation sites that can potentially be pharmacologically targeted. Acyl-biotin exchange assay showed that Nav1.6 is modified by S-palmitoylation in the mouse brain and in a Nav1.6 stable HEK 293 cell line. Using whole-cell voltage clamp, we discovered that enhancing S-palmitoylation with palmitic acid increases Nav1.6 current, whereas blocking S-palmitoylation with 2-bromopalmitate reduces Nav1.6 current and shifts the steady-state inactivation in the hyperpolarizing direction. Three S-palmitoylation sites (Cys1169, Cys1170, and Cys1978) were identified. These sites differentially modulate distinct Nav1.6 properties. Interestingly, Cys1978 is exclusive to Nav1.6 among all Nav isoforms and is evolutionally conserved in Nav1.6 among most species. Cys1978 S-palmitoylation regulates current amplitude uniquely in Nav1.6. Furthermore, we showed that eliminating S-palmitoylation at specific sites alters Nav1.6-mediated excitability in dorsal root ganglion neurons. Therefore, our study reveals S-palmitoylation as a potential isoform-specific mechanism to modulate Nav activity and neuronal excitability in physiological and diseased conditions.




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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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Breaking the Cycle of Violence: Transitional Justice for the Victims of ISIS in Syria

28 April 2020

This paper aims to assist the region’s local authorities, and their key foreign backers, in understanding how transitional justice can provide alternative avenues for holding local ISIS members to account while contributing to the healing of communities.

Haid Haid

Senior Consulting Fellow, Middle East and North Africa Programme

2020-04-28-Syria-prison.jpg

A fighter with the Syrian Democratic Forces monitors prisoners accused of being affiliated with ISIS, at a prison in the northeastern Syrian city of Hassakeh on 25 October 2019. Photo: Getty Images.

Summary

  • Following the territorial defeat of Islamic State of Iraq and Syria (ISIS) in northeastern Syria, the Kurdish-led autonomous administration in the region is now grappling with the task of quickly dealing with thousands of the group’s detained members while bringing justice to their victims. To that end, local authorities are focusing on the use of counterterrorism laws and courts to charge captured ISIS members and determine their guilt accordingly.
  • The piecemeal approach to justice is deeply flawed, and raises particular concerns about due process. No precise instruments exist to determine the personal responsibility of ISIS individuals for specific crimes, or for their role in war crimes committed by the group. In any event, the scale of the crimes and the number of victims – as well as severe shortages of resources and workers – make dispensation of justice extremely difficult through the traditional legal system.
  • Not all detained ISIS members receive prison sentences. Individuals who did not hold senior roles in the group’s apparatus and are not accused of ‘major’ crimes (in practice, largely defined as fighting for ISIS and murder) are being released under limited reconciliation deals with tribal leaders. But the involvement of local community leaders in those efforts is not enough to ensure positive results. Many victims are upset at seeing ISIS members walk free without even admitting their guilt publicly or apologizing for the pain they caused.
  • To overcome the limitations of the current, counterterrorism-focused framework, a ‘transitional justice’ approach could provide judicial and non-judicial instruments to establish accountability for ISIS crimes and reduce community resistance to the reintegration of group members. A combination of non-judicial mechanisms such as truth commissions, missing persons’ committees, and reparations and victim-healing programmes could play a vital role in providing ISIS victims with a sense of justice while contributing to peacebuilding and stability.
  • Ignoring the urgency of developing a long-term plan to serve justice and contribute to community healing will almost certainly allow ISIS to continue to prevent the recovery and development of northeastern Syria. This, in turn, risks undermining the stability of the country and the region at large.




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Webinar: Weekly COVID-19 Pandemic Briefing – The Geopolitics of the Coronavirus

Members Event Webinar

6 May 2020 - 10:00am to 10:45am

Online

Event participants

Professor Ilona Kickbusch, Associate Fellow, Global Health Programme, Chatham House; Founding Director and Chair, Global Health Centre, Graduate Institute of International and Development Studies 
Professor David Heymann CBE, Distinguished Fellow, Global Health Programme, Chatham House; Executive Director, Communicable Diseases Cluster, World Health Organization (1998-03)
Chair: Emma Ross, Senior Consulting Fellow, Global Health Programme, Chatham House

The coronavirus pandemic continues to claim lives around the world. As countries grapple with how best to tackle the virus and the reverberations the pandemic is sending through their societies and economies, scientific understanding of how the coronavirus is behaving, and what measures might best combat it, continues to advance.

Join us for the seventh in a weekly series of interactive webinars on the coronavirus with Professor David Heymann and special guest Professor Ilona Kickbusch helping us to understand the facts and make sense of the latest developments in the global crisis.

What will the geopolitics of the pandemic mean for multilateralism? As the US retreats, what dynamics are emerging around other actors and what are the implications for the World Health Organization? Is the EU stepping up to play a bigger role in global health? Will the pandemic galvanize the global cooperation long called for?

Professor Heymann is a world-leading authority on infectious disease outbreaks. He led the World Health Organization’s response to SARS and has been advising the organization on its response to the coronavirus. 

Professor Kickbusch is one of the world’s leading experts in global health diplomacy and governance. She advises international organizations, national governments, NGOs and the private sector on new directions and innovations in global health, governance for health and health promotion.




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Lebanese Women and the Politics of Disruption

Research Event

6 May 2020 - 1:00pm to 2:00pm

Event participants

Carmen Geha, Assistant Professor of Public Administration, Leadership and Organisational Development, American University of Beirut
Moderator: Lina Khatib, Director, Middle East and North Africa Programme, Chatham House
Lebanese women have been at the forefront of the protest movement that has shaken Lebanon since October 2019. The active participation by women and their visibility in Lebanon's protest movement has challenged the gender norms prevalent in Lebanese society and politics. However, the COVID-19 pandemic and the nationwide lockdown that ensued has disrupted women's ability to organize, and is threatening the fragile progress towards female inclusion in the political process.
 
In a recent article, Carmen Geha discussed the politics of representation in the context of women's participation in public life in Lebanon and argued that the country's political system is maintained through tightly-knit informal power relations among sectarian politicians, making women's participation in politics virtually impossible. The article explained how the October 2019 revolution challenged that norm by creating inclusive spaces where women activists could confront politicians and thus, transform the way women participate in politics and public life.
 
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 how women's activism in Lebanon has been affected by the coronavirus-induced lockdown. The speaker will consider how, under current circumstances, women activists can speak up collectively and bring back a movement to contest gender norms in order to build an alternative political model that can better represent women's priorities.
 
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: Implications of the COVID-19 Pandemic for African Elections and Democracy

Research Event

6 May 2020 - 2:30pm to 3:30pm

Event participants

Dr Christopher Fomunyoh, Senior Associate and Regional Director for Central and West Africa, National Democratic Institute (NDI)
Chair: Elizabeth Donnelly, Deputy Director, Africa Programme, Chatham House
2020 was anticipated to be a year of landmark elections across Africa, including general elections scheduled in Somalia and Ethiopia – countries at critical junctures in their transitions to electoral democracy – as well as a re-run of annulled presidential elections in Malawi.
 
The COVID-19 pandemic has created new challenges for African countries seeking to hold elections or further democratization – including the practicalities of adapting containment measures to electoral processes in the context of strained financial and logistical resources. It may also be used as a pretext for the pursuit of repressive legislation and constitutional amendments to preclude elections or bolster authoritarianism, compounded by new constraints on accountability mechanisms such as election observation missions.
 
At this event, Dr Christopher Fomunyoh discusses the likely impact of the COVID-19 pandemic on elections and democracy in various African countries, as well as responses and measures to meet the multifaceted challenges posed.

Hanna Desta

Programme Assistant, Africa Programme




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Virtual Roundtable: Evaluating Outcomes in Fragile Contexts: Adapting Research Methods in the Time of COVID-19

Invitation Only Research Event

5 May 2020 - 12:00pm to 1:00pm

Event participants

Rebecca Wolfe, Lecturer, Harris School for Public Policy and Associate, Pearson Institute for the Study and Resolution of Global Conflicts, University of Chicago
Tom Gillhespy, Principal Consultant, Itad
Shodmon Hojibekov, Chief Executive Officer, Aga Khan Agency for Habitat (Afghanistan)
Chair: Champa Patel, Director, Asia-Pacific Programme, Chatham House

This virtual roundtable has been co-convened by Chatham House and the Aga Khan Foundation.  

While conducting research in fragile and conflict-affected contexts has always presented challenges, the outbreak of COVID-19 creates additional challenges including travel restrictions, ethical challenges, and disruptions to usual modes of working. This virtual roundtable will explore how organizations can adapt their research and monitoring and evaluation models in response to the coronavirus pandemic. This event aims to discuss the research methods being used to mitigate the impact of the COVID-19 crisis; the important role of technology; and ways to engage policy and decision-makers during this time.

 

Event attributes

Chatham House Rule

Lucy Ridout

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




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Burma: On the Brink of Implosion

1 November 2007 , Number 4

The world’s most populous democracy and its new economic engine are both busy modifying positions on Burma, their much smaller but troublesome neighbour. India and China have growing economic interests there, yet seem to have come to very different conclusions about how to protect them.

Dr Gareth Price

Senior Research Fellow, Asia-Pacific Programme

Professor Kerry Brown

Associate Fellow, Asia-Pacific Programme




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Webinar: Breaking the Cycle of Violence: Transitional Justice for the Victims of ISIS in Syria

Research Event

12 May 2020 - 2:00pm to 3:00pm
Add to Calendar

Haid Haid, Senior Consulting Fellow, Middle East and North Africa Programme, Chatham House
Sara Kayyali, Syria Researcher, Middle East and North Africa Division, Human Rights Watch
Moderator: Lina Khatib, Director, Middle East and North Africa Programme, Chatham House

You can register your interest here. Alternatively, you can watch the webinar live on the MENA Programme Facebook page.

Following the territorial defeat of Islamic State of Iraq and Syria (ISIS) in northeastern Syria, the Kurdish-led autonomous administration in the region is now grappling with the task of quickly dealing with thousands of the group’s detained members while bringing justice to their victims. To that end, local authorities are focusing on the use of counterterrorism laws and courts to charge captured ISIS members and determine their guilt accordingly.

In a recent research paper, author Haid Haid argues that this approach to justice is deeply flawed as it raises concerns about due process and lacks the precise instruments to determine the personal responsibility of ISIS individuals for specific crimes, or for their role in war crimes committed by the group. The paper proposes that a ‘transitional justice’ approach could provide judicial and non-judicial instruments to establish accountability for ISIS crimes and reduce community resistance to the reintegration of group members.

In this webinar, part of the MENA Programme’s Online Event Series, speakers will examine the benefits of such an approach to justice for overcoming the limitations of the current, counterterrorism-focused framework. Panelists will discuss the alternative mechanisms local authorities and their key foreign backers can use to hold local ISIS members to account while contributing to the healing of communities.
 
The event will be held on the record.

Reni Zhelyazkova

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




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Meeting the Promise of the 2010 Constitution: Devolution, Gender and Equality in Kenya

Research Event

12 May 2020 - 1:00pm to 2:00pm
Add to Calendar
Natasha Kimani, Academy Associate, Chatham House; Head of Partnerships and Programmes, Shujaaz Inc.
Chair: Tighisti Amare, Assistant Director, Africa Programme, Chatham House
While gender equality was enshrined in Kenyan law under the 2010 constitution, gender-based marginalization remains a significant issue across all levels of society. The advent of devolution in 2013 raised hopes of enhanced gender awareness in policymaking and budgeting, with the 47 newly instituted county governments expected to tackle the dynamics of inequality close to home, but implementation has so far failed to match this initial promise. As Kenya approaches the tenth anniversary of the constitution, and with the COVID-19 pandemic throwing the challenges of gender inequality into sharper relief, it is critical to ensure that constitutional pathways are followed with the requisite level of urgency, commitment and investment to address entrenched gender issues.
 
This event, which will launch the report, Meeting the Promise of the 2010 Constitution: Devolution, Gender and Equality in Kenya, will assess the current status of efforts to devolve and adopt gender-responsive budgeting and decision-making in Kenya, and the priorities and potential future avenues to tackle the implementation gap.
 
This event will be held on the record.

To express your interest in attending, please follow this link. You will receive a Zoom confirmation email should your registration be successful.

Hanna Desta

Programme Assistant, Africa Programme




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Politics, policy-making and the presence of images of suffering children

7 May 2020 , Volume 96, Number 3

Helen Berents

In 2017 Trump expressed pity for the ‘beautiful babies’ killed in a gas attack on Khan Shaykhun in Syria before launching airstrikes against President Assad's regime. Images of suffering children in world politics are often used as a synecdoche for a broader conflict or disaster. Injured, suffering, or dead; the ways in which images of children circulate in global public discourse must be critically examined to uncover the assumptions that operate in these environments. This article explores reactions to images of children by representatives and leaders of states to trace the interconnected affective and political dimensions of these images. In contrast to attending to the expected empathetic responses prompted by images of children, this article particularly focuses on when such images prompt bellicose foreign policy decision-making. In doing this, the article forwards a way of thinking about images as contentious affective objects in international relations. The ways in which images of children's bodies and suffering are strategically deployed by politicians deserves closer scrutiny to uncover the visual politics of childhood inherent in these moments of international politics and policy-making.




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Social media and the visibility of horrific violence

7 May 2020 , Volume 96, Number 3

Constance Duncombe

Images are central to social media communication. Billions of images are shared across different social media platforms every day: photos, cartoons, GIFs and short video clips are exchanged by users, facilitating or framing discourse on participatory sites such as Twitter, Facebook and Instagram. Many of these images depict events of extreme violence, which circulate uninhibited by the conventional constraints associated with traditional news media censorship. A question arises here as to how such images mobilize public and policy-making responses to atrocities. This article examines the political dynamics of violent social media images. I argue that the particular qualities of social media can play an important role in how the digital visibility of horrific violence influences policy-making as a response to such atrocities. There is an important connection between the properties of social media platforms that allow user images to reach a global audience in real time and the emotional responses that this level of circulation generates. In turn, the pressure created by events made globally visible through the circulation of violent images and the audience responses to those images puts governments in a position where they are forced to act, which has significant implications for policy-making.




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Soundscapes of war: the audio-visual performance of war by Shi'a militias in Iraq and Syria

7 May 2020 , Volume 96, Number 3

Helle Malmvig

This article sets out to bring sound and music to the field of visual studies in International Relations. It argues that IR largely has approached the visual field as if it was without sound; neglecting how audial landscapes frame and direct our interpretation of moving imagery. Sound and music contribute to making imagery intelligible to us, we ‘hear the pictures’ often without noticing. The audial can for instance articulate a visual absence, or blast visual signs, bring out certain emotional stages or subjects’ inner life. Audial frames steer us in distinct directions, they can mute the cries of the wounded in war, or amplify the sounds of joy of soldiers shooting in the air. To bring the audial and the visual analytically and empirically together, the article therefore proposes four key analytical themes: 1) the audial–visual frame, 2) point of view/point of audition, 3) modes of audio-visual synchronization and 4) aesthetics moods. These are applied to a study of ‘war music videos’ in Iraq and Syria made and circulated by Shi'a militias currently fighting there. Such war music videos, it is suggested, are not just artefacts of popular culture, but have become integral parts of how warfare is practiced today, and one that is shared by soldiers in the US and Europe. War music videos are performing war, just as they shape how war is known by spectators and participants alike.




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Accountability, denial and the future-proofing of British torture

7 May 2020 , Volume 96, Number 3

Ruth Blakeley and Sam Raphael

When powerful liberal democratic states are found to be complicit in extreme violations of human rights, how do they respond and why do they respond as they do? Drawing on the example of the United Kingdom's complicity in torture since 9/11, this article demonstrates how reluctant the UK has been to permit a full reckoning with its torturous past. We demonstrate that successive UK governments engaged in various forms of denial, obfuscation and attempts to obstruct investigation and avoid accountability. The net effect of their responses has been to deny the victims redress, through adequate judicial processes, and to deny the public adequate state accountability. These responses are not simply aimed at shielding from prosecution the perpetrators and those who have oversight of them, nor preventing political embarrassment. The various forms of denial and obstruction are also designed to ensure that collusion can continue uninterrupted. A core concern of intelligence officials and ministers has been to prevent any process that would lead to a comprehensive prohibition on involvement in operations where torture and cruel, inhuman and degrading treatment are a real possibility. The door remains wide open, and deliberately so, for British involvement in torture.




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The multilevel identity politics of the 2019 Eurovision Song Contest

7 May 2020 , Volume 96, Number 3

Galia Press-Barnathan and Naama Lutz

This article uses the 2019 Eurovision Song Contest (ESC) that took place in Tel Aviv to explore how cultural mega-events serve both as political arenas and as tools for identity construction, negotiation and contestation. These processes of identity politics are all conducted across national–subnational–international–transnational levels. The hosting of mega-events fleshes out these multiple processes in a very strong manner. We first discuss the politics of hosting mega-events in general. We then examine the identity politics associated more specifically with the Eurovision Song Contest, before examining in depth the complex forms of identity politics emerging around the competition following the 2018 Israeli victory. We suggest that it is important to study together the multiple processes—domestic, international and transnational—of identity politics that take place around the competition, as they interact with each other. Consequently, we follow the various stakeholders involved at these different levels and their interactions. We examine the internal identity negotiation process in Israel surrounding the event, the critical actors debating how to use the stage to challenge the liberal, western, ‘normal’ identity Israel hoped to project in the contest and how other stakeholders (participating states, national broadcasting agencies, participating artists) reacted to them, and finally we examine the behaviour of the institution in charge, the European Broadcasting Union, and national governments. We contribute to the study of mega-events as fields of contestation, to the understanding of the complex, multilevel nature of national identity construction, negotiation and contestation in the current era, and more broadly to the role that popular culture plays in this context.




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Let's talk about the interregnum: Gramsci and the crisis of the liberal world order

7 May 2020 , Volume 96, Number 3

Milan Babic

The liberal international order (LIO) is in crisis. Numerous publications, debates and events have time and again made it clear that we are in the midst of a grand transformation of world order. While most contributions focus on either what is slowly dying (the LIO) or what might come next (China, multipolarity, chaos?), there is less analytical engagement with what lies in between those two phases of world order. Under the assumption that this period could last years or even decades, a set of analytical tools to understand this interregnum is urgently needed. This article proposes an analytical framework that builds on Gramscian concepts of crisis that will help us understand the current crisis of the LIO in a more systematic way. It addresses a gap in the literature on changing world order by elaborating three Gramsci-inspired crisis characteristics—processuality, organicity and morbidity—that sketch the current crisis landscape in a systematic way. Building on this framework, the article suggests different empirical entry points to the study of the crisis of the LIO and calls for a research agenda that takes this crisis seriously as a distinct period of changing world orders.




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Webinar: Director's Briefing – National Leadership in Times of Crisis

Corporate Members Event Webinar Partners and Major Corporates

14 May 2020 - 6:00pm to 7:00pm
Add to Calendar

Online

Janet Napolitano, President, University of California; US Secretary of Homeland Security (2009-13)

Chair: Dr Robin Niblett, Director and Chief Executive, Chatham House

Across the globe, leaders on the local, national and international levels are grappling with the impacts of COVID-19 on their communities and the economy. But the coronavirus pandemic is just one of several existential crises the world is currently facing. Climate change, political instability and growing tensions with China and Russia, along with a lack of strong global leadership, has made it more difficult for individual nations to respond and coalesce in times of crisis.

This discussion will explore how leaders at all levels can best negotiate both the practical issues and the larger questions associated with these ‘grand challenges’. How is current US foreign policy affecting our collective ability to respond to issues such as pandemics or climate change? Has the COVID-19 crisis cemented the US retreat from global leadership and if so, who might step into the breach? How do we maintain momentum on other issues in the midst of a public health disaster of this magnitude? And what is the role of the business community, higher education institutions and other sectors in responding to these crises and shaping future public policy?

This event is only open to Major Corporate Member and Partner organizations and selected giving circles of Chatham House. If you'd like to attend, please RSVP to lbedford@chathamhouse.org.




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The Rise of the Far Right Across Europe




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Crimean Reality Check: Four Years of Annexation




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Growth in a Multilateral World: The Role of Inclusive Trade and Quality Investment