ul

Thioredoxin regulates human mercaptopyruvate sulfurtransferase at physiologically-relevant concentrations [Enzymology]

3-Mercaptopyruvate sulfur transferase (MPST) catalyzes the desulfuration of 3-mercaptopyruvate (3-MP) and transfers sulfane sulfur from an enzyme-bound persulfide intermediate to thiophilic acceptors such as thioredoxin and cysteine. Hydrogen sulfide (H2S), a signaling molecule implicated in many physiological processes, can be released from the persulfide product of the MPST reaction. Two splice variants of MPST, differing by 20 amino acids at the N terminus, give rise to the cytosolic MPST1 and mitochondrial MPST2 isoforms. Here, we characterized the poorly-studied MPST1 variant and demonstrated that substitutions in its Ser–His–Asp triad, proposed to serve a general acid–base role, minimally affect catalytic activity. We estimated the 3-MP concentration in murine liver, kidney, and brain tissues, finding that it ranges from 0.4 μmol·kg−1 in brain to 1.4 μmol·kg−1 in kidney. We also show that N-acetylcysteine, a widely-used antioxidant, is a poor substrate for MPST and is unlikely to function as a thiophilic acceptor. Thioredoxin exhibits substrate inhibition, increasing the KM for 3-MP ∼15-fold compared with other sulfur acceptors. Kinetic simulations at physiologically-relevant substrate concentrations predicted that the proportion of sulfur transfer to thioredoxin increases ∼3.5-fold as its concentration decreases from 10 to 1 μm, whereas the total MPST reaction rate increases ∼7-fold. The simulations also predicted that cysteine is a quantitatively-significant sulfane sulfur acceptor, revealing MPST's potential to generate low-molecular-weight persulfides. We conclude that the MPST1 and MPST2 isoforms are kinetically indistinguishable and that thioredoxin modulates the MPST-catalyzed reaction in a physiologically-relevant concentration range.




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A single amino acid substitution uncouples catalysis and allostery in an essential biosynthetic enzyme in Mycobacterium tuberculosis [Enzymology]

Allostery exploits the conformational dynamics of enzymes by triggering a shift in population ensembles toward functionally distinct conformational or dynamic states. Allostery extensively regulates the activities of key enzymes within biosynthetic pathways to meet metabolic demand for their end products. Here, we have examined a critical enzyme, 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase (DAH7PS), at the gateway to aromatic amino acid biosynthesis in Mycobacterium tuberculosis, which shows extremely complex dynamic allostery: three distinct aromatic amino acids jointly communicate occupancy to the active site via subtle changes in dynamics, enabling exquisite fine-tuning of delivery of these essential metabolites. Furthermore, this allosteric mechanism is co-opted by pathway branchpoint enzyme chorismate mutase upon complex formation. In this study, using statistical coupling analysis, site-directed mutagenesis, isothermal calorimetry, small-angle X-ray scattering, and X-ray crystallography analyses, we have pinpointed a critical node within the complex dynamic communication network responsible for this sophisticated allosteric machinery. Through a facile Gly to Pro substitution, we have altered backbone dynamics, completely severing the allosteric signal yet remarkably, generating a nonallosteric enzyme that retains full catalytic activity. We also identified a second residue of prime importance to the inter-enzyme communication with chorismate mutase. Our results reveal that highly complex dynamic allostery is surprisingly vulnerable and provide further insights into the intimate link between catalysis and allostery.




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Trump’s Threat to Target Iran’s Cultural Heritage Is Illegal and Wrong

7 January 2020

Héloïse Goodley

Army Chief of General Staff Research Fellow (2018–19), International Security
Targeting cultural property is rightly prohibited under the 1954 Hague Convention.

2020-01-07-Trump.jpg

Donald Trump at Mar-a-Lago in December. Photo: Getty Images

As tensions escalate in the Middle East, US President Donald Trump has threatened to strike targets in Iran should they seek to retaliate over the killing of Qassem Soleimani. According to the president’s tweet, these sites includes those that are ‘important to Iran and Iranian culture’.

Defense Secretary Mark Esper was quick on Monday to rule out any such action and acknowledged that the US would ‘follow the laws of armed conflict’. But Trump has not since commented further on the matter.

Any move to target Iranian cultural heritage could constitute a breach of the international laws protecting cultural property. Attacks on cultural sites are deemed unlawful under two United Nations conventions; the 1954 Hague Convention for the Protection of Cultural Property during Armed Conflict, and the 1972 UNESCO World Heritage Convention for the Protection of the World Cultural and Natural Heritage.

These have established deliberate attacks on cultural heritage (when not militarily necessary) as a war crime under the Rome Statute of the International Criminal Court in recognition of the irreparable damage that the loss of cultural heritage can have locally, regionally and globally.

These conventions were established in the aftermath of the Second World War, in reaction to the legacy of the massive destruction of cultural property that took place, including the intense bombing of cities, and systematic plunder of artworks across Europe. The conventions recognize that damage to the cultural property of any people means ‘damage to the cultural heritage of all mankind’. The intention of these is to establish a new norm whereby protecting culture and history – that includes cultural and historical property – is as important as safeguarding people.

Such historical sites are important not simply as a matter of buildings and statues, but rather for their symbolic significance in a people’s history and identity. Destroying cultural artefacts is a direct attack on the identity of the population that values them, erasing their memories and historical legacy. Following the heavy bombing of Dresden during the Second World War, one resident summed up the psychological impact of such destruction in observing that ‘you expect people to die, but you don’t expect the buildings to die’.

Targeting sites of cultural significance isn’t just an act of intimidation during conflict. It can also have a lasting effect far beyond the cessation of violence, hampering post-conflict reconciliation and reconstruction, where ruins or the absence of previously significant cultural monuments act as a lasting physical reminder of hostilities.

For example, during the Bosnian War in the 1990s, the Old Bridge in Mostar represented a symbol of centuries of shared cultural heritage and peaceful co-existence between the Serbian and Croat communities. The bridge’s destruction in 1993 at the height of the civil war and the temporary cable bridge which took its place acted as a lasting reminder of the bitter hostilities, prompting its reconstruction a decade later as a mark of the reunification of the ethnically divided town.

More recently, the destruction of cultural property has been a feature of terrorist organizations, such as the Taliban’s demolition of the 1,700-year-old Buddhas of Bamiyan in 2001, eliciting international condemnation. Similarly, in Iraq in 2014 following ISIS’s seizure of the city of Mosul, the terrorist group set about systematically destroying a number of cultural sites, including the Great Mosque of al-Nuri with its leaning minaret, which had stood since 1172. And in Syria, the ancient city of Palmyra was destroyed by ISIS in 2015, who attacked its archaeological sites with bulldozers and explosives.

Such violations go beyond destruction: they include the looting of archaeological sites and trafficking of cultural objects, which are used to finance terrorist activities, which are also prohibited under the 1954 Hague Convention.

As a war crime, the destruction of cultural property has been successfully prosecuted in the International Criminal Court, which sentenced Ahmad Al-Faqi Al-Mahdi to nine years in jail in 2016 for his part in the destruction of the Timbuktu mausoleums in Mali. Mahdi led members of Al-Qaeda in the Islamic Maghreb to destroy mausoleums and monuments of cultural and religious importance in Timbuktu, irreversibly erasing what the chief prosecutor described as ‘the embodiment of Malian history captured in tangible form from an era long gone’.

Targeting cultural property is prohibited under customary international humanitarian law, not only by the Hague Convention. But the Convention sets out detailed regulations for protection of such property, and it has taken some states a lot of time to provide for these.

Although the UK was an original signatory to the 1954 Hague Convention, it did not ratify it until 2017, introducing into law the Cultural Property (Armed Conflicts) Act 2017, and setting up the Cultural Protection Fund to safeguard heritage of international importance threatened by conflict in countries across the Middle East and North Africa.

Ostensibly, the UK’s delay in ratifying the convention lay in concerns over the definition of key terms and adequate criminal sanctions, which were addressed in the Second Protocol in 1999. However, changing social attitudes towards the plunder of antiquities, and an alarming increase in the use of cultural destruction as a weapon of war by extremist groups to eliminate cultures that do not align with their own ideology, eventually compelled the UK to act.

In the US, it is notoriously difficult to get the necessary majority for the approval of any treaty in the Senate; for the Hague Convention, approval was achieved in 2008, following which the US ratified the Convention in 2009.

Destroying the buildings and monuments which form the common heritage of humanity is to wipe out the physical record of who we are. People are people within a place, and they draw meaning about who they are from their surroundings. Religious buildings, historical sites, works of art, monuments and historic artefacts all tell the story of who we are and how we got here. We have a responsibility to protect them.




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Religious violence, gender and post-secular counterterrorism

4 March 2020 , Volume 96, Number 2

Katherine E. Brown

This article argues that despite the framing of religion in the discipline and practice of International Relations (IR) as a force for good, or a cause of evil in the world, IR fails to treat religion on its own terms (as sui generis). With a few exceptions, the discipline has pigeonholed religion as a variable of IR, one that can be discussed as one might GDP, HIV, or numbers of nuclear missiles: measurable, with causality and essential properties. IR has also tended to treat religion as equivalent to features of global politics that it already recognizes—as an institution or community or ideology, for example—but in doing so, it misses intrinsic (and arguably unique) elements of religion. Drawing on feminist insights about how gender works in IR, namely that gender is a construct, performative and structural, this article argues a similar case for religion. A reframing of religion is applied to the case of Daesh (so-called Islamic State of Iraq and Syria, ISIS) to show how our understanding of the organization changes when we view religion differently. The implications for counterterrorism policies if religion is viewed as more than a variable are explored in light of recent territorial and military losses for Daesh. The article therefore proposes a post-secular counterterrorism approach.




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It's a man's world: carnal spectatorship and dissonant masculinities in Islamic State videos

7 May 2020 , Volume 96, Number 3

Manni Crone

Islamic State videos have often been associated with savage violence and beheadings. An in-depth scrutiny however reveals another striking feature: that female bodies are absent, blurred or mute. Examining a few Islamic State videos in depth, the article suggests that the invisibility of women in tandem with the ostentatious visibility of male bodies enable gendered and embodied spectators to indulge in homoerotic as well as heterosexual imaginaries. In contrast to studies on visual security and online radicalization which assert that images affect an audience, this article focuses on the interaction between video and audience and argues that spectators are not only rational and emotional but embodied and gendered as well. Islamic State videos do not only attract western foreign fighters through religious–ideological rhetoric or emotional impact but also through gendered forms of pleasure and desire that enable carnal imagination and identification. The article probes the analytical purchase of carnal aesthetics and spectatorship.




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Webinar: Are the Gulf Standoffs Resolvable?

Research Event

21 April 2020 - 1:00pm to 2:00pm

Event participants

David Roberts, Assistant Professor and School of Security Studies Lead for Regional Security and Development, King's College London
Kristian Coates Ulrichsen, Associate Fellow, Middle East and North Africa Programme, Chatham House
Chair: Sanam Vakil, Deputy Director and Senior Research Fellow, Middle East and North Africa Programme, Chatham House

This webinar, part of the MENA Programme Webinar Series, will examine the trajectory of political and security dynamics in the Gulf in view of the ongoing rift within the Gulf Cooperation Council (GCC), the death of Sultan Qaboos in Oman, the escalation of tensions between Iran and the United States, and the COVID-19 crisis.

Speakers will explore the orientation of the GCC under a new Secretary-General and the prospects for mediation between Qatar and its neighbours, the future of Omani domestic and foreign policy under Sultan Haitham bin Tariq Al Said, eventual transitions to new leadership in Bahrain and Kuwait, and whether the impact of COVID-19 may help replace the confrontation within the GCC with closer coordination among its six member states.

The webinar will be livestreamed 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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Online Study Group: All Lukashenka’s Men: The Belarusian Ruling Elite and Why It Matters

Invitation Only Research Event

22 April 2020 - 2:30pm to 4:00pm

Event participants

Ryhor Astapenia, Robert Bosch Stiftung Academy Fellow, Russia and Eurasia Programme, Chatham House
Chair: James Nixey, Programme Director, Russia and Eurasia, Chatham House

Soon after assuming power in 1994, President Aliaksandr Lukashenka turned his back on democratic norms and overpowered the Belarusian political elite. However, the influence of the governing elite in Belarus is growing again. It seems likely that the current governing class could rule the country after Lukashenka leaves. It is thus important to study Belarusian elites not only to understand the current regime, but also to better forecast and navigate the political system that will one day replace it. 

This study group aims to disentangle how the Belarusian political system works, outline the types of individuals that make up the Belarusian ruling elite, assess the interaction of the elite and institutions with the West, and suggest changes that Western political actors might make to their approach to the Belarusian ruling class.

Event attributes

Chatham House Rule

Department/project

Anna Morgan

Administrator, Ukraine Forum
+44 (0)20 7389 3274




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Webinar: Egypt and the Gulf: Allies and Rivals

Research Event

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

Event participants

Speaker: David Butter, Associate Fellow, Middle East and North Africa Programme, Chatham House
Moderator: Mohamed El Dahshan, Associate Fellow, Middle East and North Africa Programme, Chatham House

The webinar will be livestreamed on the MENA Programme Facebook page.

Egypt and the Gulf Arab region have long been important poles of political, military, economic and cultural power and influence in the Middle East. A recently published Chatham House paper examines the strategic and economic relationship between Egypt and the Gulf, focusing in particular on the period since Abdel-Fattah el-Sisi came to power in Egypt. Author David Butter offers a detailed evaluation of these economic relationships, in the broader context of a strategic alliance that, since 2013, has been informed by a common commitment between Egypt and the UAE in particular to keep in check the Muslim Brotherhood and its regional state supporters, primarily Turkey and Qatar.

In this webinar, the author will discuss the paper’s main argument, namely, that the degree of Egypt’s dependence on Gulf countries has fluctuated, and that by 2019, Egypt’s direct financial dependence on the Gulf was significantly reduced by comparison with the initial three years of the Sisi era, although other economic linkages such as investment, trade, remittances and tourism remained strong, with potential for growth. The speaker will also discuss the impact of the global crisis caused by the COVID-19 pandemic on Egypt’s and Gulf countries’ economies and will explore the implications for the relationship between Egypt and the Gulf.

This webinar is part of the Chatham House Middle East and North Africa Programme's Online Event Series. 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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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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Alain de Botton on how the news should aim to improve our lives

6 February 2014 , Volume 70, Number 1

The author of books on love, religion and Proust, explains why the news agenda should be more positive

Agnes Frimston

deBotton.jpg

Photo: Getty Images

Is the news our society’s religion today?

In the developed economies, the news now occupies a position of power at least equal to that formerly enjoyed by the faiths. Matins has been transubstantiated into the breakfast bulletin, vespers into the evening report. It also demands that we approach it with some of the same deferential expectations we would once have harboured for the faiths. Here, too, we hope to receive revelations, learn who is good and bad, fathom suffering and understand the unfolding logic of existence. And here too, if we refuse to take part in the rituals, there could be imputations of heresy.

What would you like the news to be?

It feels like there is always an infinite amount of news, so much is happening in the world every day. Yet after a while it becomes clear that the same kinds of event are recurring again and again. The details change, but all circle round the same archetypal story. Men in highly responsible positions are coming unstuck because their desires lead them to do things that, when made public, are shameful.

Identifying the underlying theme is more important in the long run than going through the details of every case. The news that matters is not so much that this MP or banker did what they did. What we need to address is why such things happen.

How do you keep the public interested in the news that does matter?

We cannot be collectively dragged into being more responsible through guilt. The Arctic ice is melting and this is going to have major, lasting implications for sea levels and weather around the world. A few people care a lot but, strangely, Taylor Swift’s legs are far more captivating. The starting point has to be indulgence towards the way our minds work. We are interested in Swift’s legs not because we are evil – but because we are wired in unhelpful ways. If we are going to be interested en masse in the defrosting poles, we need to take our fragilities on board and therefore get serious about trying to make important news not just ‘important’, but also beguiling. Then things stand a chance of changing.

You argue that we should set aside ‘neutral reporting’. Are you asking for more bias?

Many people imagine that what makes news organizations serious is their ability to provide us with information that is ‘unbiased’. But facts can only become meaningful and relevant to us when they slot into some picture of important or trivial, right or wrong. News organizations that vaunt their neutrality forget that neutrality is simply impossible. There is no risk-free, all-knowing sober set of answers to cling to. At heart, the word ‘bias’ simply alludes to the business of having a ‘take’ on existence. One may have a better or worse take, but one can’t make any sense of the flotsam of daily events in the news without having one. All of the figures we revere in history have been highly biased: each of them had a strong sense of what mattered and why, and their judgments were anything but perfectly balanced. They were just flavoured in the right way. We don’t need news stripped of bias, we need news presented to us with the best kinds of bias.

What is the purpose of foreign reporting?

Foreign reporting implicitly defers to the priorities of the state and of business, occupying itself almost exclusively with whom and where we should fight, trade or sympathize. But it should instead offer us a means by which to humanize the Other who instinctively repels, bores or frightens us and with whom we can’t, without help, imagine having anything in common.

Foreign countries also furnish a scale against which our own nation and ways of living can be assessed; they may help us to see our national oddities, blind spots and strengths. Stories from them may lead us to a fresh appreciation of the imperfect freedoms and comparative abundance of our homelands, which otherwise would be treated only as matters for grumbling or blame. Alternatively, problems with which we are all too familiar may be revealed to have been solved better elsewhere.

You mention the importance of historical perspective in reporting, so that we can respond to issues with context.

Contrary to what the news usually suggests, hardly anything is ever totally new, few things are truly amazing and very little is absolutely terrible. The economic indices are grim, but we have weathered comparable drops many times over the past century and even the worst scenarios only predict that we will return to a standard of living we had a few decades ago. A bad avian flu may disrupt international travel and defeat known drugs for a while, but research will eventually understand and contain it. The floods look dramatic, but in the end, they will affect merely a fraction of the population and recede soon.

How can photography change the way we report news?

There are now more images than ever before in the coverage we consume, but the problem lies in the lack of ambition behind their production and display. We might usefully divide news photographs into two genres. The first are images of corroboration, which do little other than confirm something we have learnt about a person or an event through an accompanying article. The second is a rarer kind of image, the photograph of revelation, whose ambition is not simply to back up what the text tells us but to advance our level of knowledge to a new point. It sets out to challenge cliché. We have lost any sense of photography’s potential as an information-bearing medium, as a force to properly introduce us to a planet that we keep conceitedly assuming that we know rather well already.

Do you feel oppressed by the news?

The pressure of not missing out makes one feel one has to care about a given topic, even when one doesn’t want to. Take Mandela’s funeral. One was supposed to care a lot, and yet, you don’t. You know the reasons why it is important, but they don’t grip you because you are focused elsewhere on subjects that, while tiny in the grand scheme of things, matter a lot within your context. It would be dangerous if hardly anyone paid attention to what the Government was doing, or what was happening to the environment. But it is not right to go from this to the demand that everyone should be interested in every item whenever the news machine calls. We badly need people whose attention is not caught up in the trends of the moment and who are not looking in the same direction as everyone else. We need people scanning the less familiar parts of the horizon.

Do you think we get the news we deserve?

Much of what we now take for granted as news has its origins in the information needed by those people taking major decisions or who are at the centre of national affairs. Ease of communication and a generous democratic impulse means that selections from the knowledge base, originally designed for decision-makers, now gets routinely sent via the media to very large numbers of people. It is as if a dossier which might properly arrive upon the desk of a Minister has accidentally been delivered to the wrong address and ends up on the breakfast table of an electrician in Pitlochry. Every day the news gives us stuff that is both interesting for some people and irrelevant to you. No wonder we’re sometimes a bit bored. It’s not our fault.




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Britain is experiencing a little turbulence

31 July 2014 , Volume 70, Number 4

A long view of the problems of modern migration

Robert Winder is author of ‘Bloody Foreigners' and former literary editor of The Independent and deputy editor of Granta

Winder.jpg

Some of the first Afro-Caribbean immigrants arrive in East London from Jamaica. Photo: Popperfoto/Getty




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Promoting a Culture of Development and Investment: Lessons from the Post-War Era

Research Event

5 December 2014 - 1:00pm to 2:00pm

Chatham House, London

Event participants

Giovanni Farese, Assistant Professor of Economic History, European University of Rome
Chair: Dr Paola Subacchi, Research Director, International Economics, Chatham House

This event will discuss the rise of the culture of world development. It will examine the post-war reconstruction and development projects of the 1940s through to the 1960s, including those devised at Chatham House. The speaker will argue that these projects hold valuable lessons that still apply to the current economic environment. The speaker will also discuss the key role played by Eugene R Black (1898-1992), the third president of the International Bank for Reconstruction and Development (the World Bank), who was one of the main architects of post-war reconstruction and development projects and a promoter of a ‘culture of development’.

Effie Theodoridou

+44 (0)20 7314 2760




ul

Regulation of stearoyl-CoA desaturase by polyunsaturated fatty acids and cholesterol

James M. Ntambi
Sep 1, 1999; 40:1549-1558
Reviews




ul

Cytochrome P450 and arachidonic acid bioactivation: molecular and functional properties of the arachidonate monooxygenase

Jorge H. Capdevila
Feb 1, 2000; 41:163-181
Reviews




ul

Disruption of endoplasmic reticulum structure and integrity in lipotoxic cell death

Nica M. Borradaile
Dec 1, 2006; 47:2726-2737
Research Articles




ul

Multivalent feedback regulation of HMG CoA reductase, a control mechanism coordinating isoprenoid synthesis and cell growth

MS Brown
Jul 1, 1980; 21:505-517
Reviews




ul

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

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




ul

Gene expression regulation by retinoic acid

James E. Balmer
Nov 1, 2002; 43:1773-1808
Reviews




ul

Intracellular cholesterol transport

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




ul

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

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




ul

Perilipin is located on the surface layer of intracellular lipid droplets in adipocytes

EJ Blanchette-Mackie
Jun 1, 1995; 36:1211-1226
Articles




ul

Apolipoprotein-mediated removal of cellular cholesterol and phospholipids

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




ul

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

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




ul

Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E

Robert W. Mahley
Jan 1, 1999; 40:1-16
Reviews




ul

Use of cyclodextrins for manipulating cellular cholesterol content

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




ul

Molecular physiology of reverse cholesterol transport

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




ul

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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ABC transporters control ATP release through cholesterol-dependent volume-regulated anion channel activity [Signal Transduction]

Purinergic signaling by extracellular ATP regulates a variety of cellular events and is implicated in both normal physiology and pathophysiology. Several molecules have been associated with the release of ATP and other small molecules, but their precise contributions have been difficult to assess because of their complexity and heterogeneity. Here, we report on the results of a gain-of-function screen for modulators of hypotonicity-induced ATP release using HEK-293 cells and murine cerebellar granule neurons, along with bioluminescence, calcium FLIPR, and short hairpin RNA–based gene-silencing assays. This screen utilized the most extensive genome-wide ORF collection to date, covering 90% of human, nonredundant, protein-encoding genes. We identified two ABCG1 (ABC subfamily G member 1) variants, which regulate cellular cholesterol, as modulators of hypotonicity-induced ATP release. We found that cholesterol levels control volume-regulated anion channel–dependent ATP release. These findings reveal novel mechanisms for the regulation of ATP release and volume-regulated anion channel activity and provide critical links among cellular status, cholesterol, and purinergic signaling.




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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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{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: Could a People’s Bailout Help?

7 May 2020

Jim O'Neill

Chair, Chatham House

Lyndsey Jefferson

Digital Editor, Communications and Publishing Department
The coronavirus crisis has resulted in an unprecedented economic downturn. Conventional quantitative easing measures used after the 2008 financial crisis will not be enough this time.

2020-05-06-Coronavirus-Food-Bank-NYC.jpg

Local residents line up outside a food pantry during the COVID-19 pandemic on 23 April 2020 in Brooklyn, New York. Due to increased levels of unemployment, the lines at the daily food pantry have been getting longer. Photo: Getty Images.

What is quantitative easing? How was it used after the 2008 financial crisis?

Quantitative easing (QE) has been in existence since the Japanese central bank introduced it at the turn of the millennium. The simplest way to think about it is this: when interest rates can't go down anymore and play their normal role of stimulating growth, central banks try to expand the money supply. So, they're expanding the quantitative amount of money they put into the system. 

Of course, after 2008 because of the scale of the financial and economic collapse, many Western countries resorted to QE. Some have never gotten rid of it. Others have started to, but as a result of this crisis, have gone straight back to that playbook.

33 million Americans have now filed for unemployment and one in five American workers have lost their jobs due to COVID-19. These are levels not seen since the Great Depression. You recently called for G20 countries to provide income support for all citizens. Why is this so urgent to implement now?

It is incredible to reflect back on the short time since I published that piece. I entitled it the need for a so-called people's QE, and in some ways a number of European countries, including the UK, have executed some aspects of what I was suggesting. 

The United States has not, even though the absolute amounts of money the US authorities have put through their fiscal system to try and support the economy is actually bigger as a percentage of GDP than many in Europe. 

What they haven't done is support ongoing employment through various schemes that many European countries have done, of which the UK has, to some degree, been one of the most ambitious.

That’s partly why you see such enormous filing for unemployment claims in the US. There’s no direct support to encourage employers to keep their employees on, in complete contrast to what you see in many Scandinavian countries who were the first to do it in Europe, and something the UK has since done. 

On a practical level, what might a smart people’s QE look like? 

We are living in an extraordinary time. Like many others in my generation, it’s nothing that any of us have gone through. Perhaps economically, the only parallel one can find is from the 1920s and 1930s.

It became obvious to me in early March that governments are going to have to essentially force as many of us as possible, if we weren't doing absolutely crucial necessities, to stop working or to work from home. It was pretty obvious that the consequences could be horrific. 

So, the idea of a people's QE that I suggested then, some would have regarded as quite audacious. The most dramatic thing that could be done was, to put it simply, governments effectively pay for every business and every employee to have a two month paid holiday. Obviously, this would cost a very large amount of money for governments, but it would be the least disruptive way of getting us all to stay home.

And when the time is right to start letting us get back to anything vaguely like normality, there wouldn't be as much permanent disruption. I think about six weeks have passed since I wrote that piece. Actually, given the policies many governments have announced, I'm not sure undertaking the audacity in generosity of what I suggested would have cost any more. Over the long term, it might have actually turned out to be less. 

Of course, there are ethics issues around whether the system could be gamed or not, amongst other issues. But six weeks later, I still believe that would have been the smartest thing to do. It certainly would have been much better than trying to encourage many businesses, particularly smaller ones, to take out loans.

A couple of countries got close to what I was suggesting – Germany and Switzerland were very quick to give 100% government guarantees to business, as well as generous wage support systems. But a number of other countries haven't, like the US, even though they wrote a $1200 check for each citizen. 

Should a people’s QE involve the purchase and write off of consumer debt and student debt by a central bank? 

I think these things might have to be considered. I remember being on a conference call to Chatham House members where we discussed what would be the likely economic consequences and what policymakers should do. One person on the call was talking about quite conventional forms of policy just through various forms of standard QE. 

During the Q&A, someone asked whether we thought the US Federal Reserve might end up buying equities. And I said, well, why not? Eventually, it might come to that. 

Actually, before that discussion was over, the Fed coincidentally announced they were going to buy high-yield corporate bonds, or very risky company debt. This is something that would have been unheard of even by the playbook of 2008. 

So, I don't think ideas like a kind of provision to help student debtors is entirely crazy. These are things that our policymakers are going to have to think about as we go forward in the challenging and unpredictable days and weeks ahead. 

Poorer countries like El Salvador have gone as far as cancelling rent and major utility bills for its citizens. Do you think countries like the US and UK have gone far enough to help people during the crisis?

Going one step further than a people’s QE and postponing major payments is a pretty interesting concept. I think in reality, it would be very disruptive to the medium to long-term mechanism of our societies. It could be very, very complicated. 

But, of course, some parts of the G20 nations, including the UK, have moved significantly in these areas as it relates to rent payments or mortgage payments. There have been significant mortgage holidays being introduced for many sectors of our community. I think the British government has been quite thoughtful about it without doing the whole hog of potentially getting rid of our transaction system for two months or beyond.

You know, this may well be something that has to be considered if, God forbid, there is a second peak of the virus. If countries come out of a lockdown and all that results in is a dramatic rise in infections and then death again, we're going to end up right back where we are. Policymakers may have to implement more generous versions of what we've done already, despite what the long term debt consequences could be.

The Coronavirus Aid, Relief, and Economic Security (CARES) Act in the US has been criticized as a corporate bailout while offering little to the American people. It was recently reported that hedge fund managers are applying for bailouts as ‘small businesses.’ Do you think more oversight is needed in how the stimulus funds are allocated? 

The speed at which many countries have responded and introduced policies means that there's going to be some gaping holes which allow people to unfairly benefit from the system. And if indeed, that were to be the case, I cannot see why a hedge fund should benefit from government generosity.

A true hedge fund is supposed to be a form of investment manager that thrives in times of great volatility, and knows how to better navigate such financial markets than more conventional funds. So this shouldn’t be an environment where hedge funds seek the same kind of help as small businesses. That is certainly something the government should be very careful about.

Some economists argue that central banks are not independent as they finance fiscal spending through purchase of government bonds. Do the strong measures taken by central banks in response to the crisis undermine the argument for central bank independence? 

In my view, an effective central bank has to do whatever is necessary, including doing very unconventional things, when the society in which that central bank operates needs it. 

Most of the time, central banks are pretty boring places, but they really become crucial organizations when we go through times like the 1920s, 1930s, 2008, and of course, this current crisis. If they want to maintain their legitimacy, whatever the true parliamentary or congressional legal standing is, they have to do things quickly and as we've seen in this case, differently than the convention in order to do what our societies need. 

Somebody was asking me just last week whether the Fed buying high grade debt was legal or not. I think that’s a pretty irrelevant conversation because if it’s not legal now, it will be made legal tomorrow. So, I think central banks have to keep their legitimacy and they have to do what is necessary when the time requires it. In that sense, I think most central banks have handled this crisis so far pretty well.




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It's a man's world: carnal spectatorship and dissonant masculinities in Islamic State videos

7 May 2020 , Volume 96, Number 3

Manni Crone

Islamic State videos have often been associated with savage violence and beheadings. An in-depth scrutiny however reveals another striking feature: that female bodies are absent, blurred or mute. Examining a few Islamic State videos in depth, the article suggests that the invisibility of women in tandem with the ostentatious visibility of male bodies enable gendered and embodied spectators to indulge in homoerotic as well as heterosexual imaginaries. In contrast to studies on visual security and online radicalization which assert that images affect an audience, this article focuses on the interaction between video and audience and argues that spectators are not only rational and emotional but embodied and gendered as well. Islamic State videos do not only attract western foreign fighters through religious–ideological rhetoric or emotional impact but also through gendered forms of pleasure and desire that enable carnal imagination and identification. The article probes the analytical purchase of carnal aesthetics and spectatorship.




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Rethinking youth bulge theory in policy and scholarship: incorporating critical gender analysis

7 May 2020 , Volume 96, Number 3

Lesley Pruitt

For decades ‘youth bulge’ theory has dominated understandings of youth in mainstream International Relations. Youth bulge theory has also become part of some public media analyses, mainstream political rhetoric, and even officially enshrined in the foreign policy of some states. Through the ‘youth bulge’ lens, youth—especially males—have been presented as current or future perpetrators of violence. However, this article argues that the youth bulge thesis postulated in mainstream IR is based on flawed theoretical assumptions. In particular, supporters of youth bulge theory fail to engage with existing research by feminist IR scholars and thus take on a biological essentialist approach. This has led to theoretical and practical misunderstandings of the roles youth play in relation to conflict, peace and security. These partial and biased understandings have also resulted in less effective policy-making. In critically reflecting on the ‘youth bulge’ thesis, this article argues that applying gender analysis is crucial to understanding the involvement of young people in general—and young men in particular—in conflict. Doing so will contribute to advancing more accurate analysis in scholarship and policy-making.




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




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Should the Super-Rich Pay for a Universal Basic Income?




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Should Debt in the Developing World be Cancelled?




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Unfulfilled Ambitions: the State of Democracy in Africa




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The Reconstruction of Iraq: Lessons from Mosul




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Unelected Power: Finding Legitimacy in Central Banking and the Regulatory State




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A Decade on from the Financial Crisis: the Legacy and Lessons of 2008 - The Rt Hon Lord Darling of Roulanish




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Can and Should Brexit Be Stopped?




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Evan Davis In Conversation With Christian Ulbrich, CEO, JLL




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Leadership in an Era of Geopolitical Turbulence




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Chatham House Primer: National Populism




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Can Multilateralism Survive?




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Undercurrents: Episode 22 - China's Belt and Road Initiative, and the Rise of National Populism