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HIGD2A is required for assembly of the COX3 module of human mitochondrial complex IV [Research]

Assembly factors play a critical role in the biogenesis of mitochondrial respiratory chain complexes I-IV where they assist in the membrane insertion of subunits, attachment of co-factors, and stabilization of assembly intermediates. The major fraction of complexes I, III and IV are present together in large molecular structures known as respiratory chain supercomplexes. A number of assembly factors have been proposed as required for supercomplex assembly, including the hypoxia inducible gene 1 domain family member HIGD2A. Using gene-edited human cell lines and extensive steady state, translation and affinity enrichment proteomics techniques we show that loss of HIGD2A leads to defects in the de novo biogenesis of mtDNA-encoded COX3, subsequent accumulation of complex IV intermediates and turnover of COX3 partner proteins. Deletion of HIGD2A also leads to defective complex IV activity. The impact of HIGD2A loss on complex IV was not altered by growth under hypoxic conditions, consistent with its role being in basal complex IV assembly. While in the absence of HIGD2A we show that mitochondria do contain an altered supercomplex assembly, we demonstrate it to harbor a crippled complex IV lacking COX3. Our results redefine HIGD2A as a classical assembly factor required for building the COX3 module of complex IV.




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Flow-induced reorganization of laminin-integrin networks within the endothelial basement membrane uncovered by proteomics [Research]

The vessel wall is continuously exposed to hemodynamic forces generated by blood flow. Endothelial mechanosensors perceive and translate mechanical signals via cellular signaling pathways into biological processes that control endothelial development, phenotype and function. To assess the hemodynamic effects on the endothelium on a system-wide level, we applied a quantitative mass spectrometry approach combined with cell surface chemical footprinting. SILAC-labeled endothelial cells were subjected to flow-induced shear stress for 0, 24 or 48 hours, followed by chemical labeling of surface proteins using a non-membrane permeable biotin label, and analysis of the whole proteome and the cell surface proteome by LC-MS/MS analysis. These studies revealed that of the >5000 quantified proteins 104 were altered, which were highly enriched for extracellular matrix proteins and proteins involved in cell-matrix adhesion. Cell surface proteomics indicated that LAMA4 was proteolytically processed upon flow-exposure, which corresponded to the decreased LAMA4 mass observed on immunoblot. Immunofluorescence microscopy studies highlighted that the endothelial basement membrane was drastically remodeled upon flow exposure. We observed a network-like pattern of LAMA4 and LAMA5, which corresponded to the localization of laminin-adhesion molecules ITGA6 and ITGB4. Furthermore, the adaptation to flow-exposure did not affect the inflammatory response to tumor necrosis factor α, indicating that inflammation and flow trigger fundamentally distinct endothelial signaling pathways with limited reciprocity and synergy. Taken together, this study uncovers the blood flow-induced remodeling of the basement membrane and stresses the importance of the subendothelial basement membrane in vascular homeostasis.




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Organellar maps through proteomic profiling - a conceptual guide [Review]

Protein subcellular localization is an essential and highly regulated determinant of protein function. Major advances in mass spectrometry and imaging have allowed the development of powerful spatial proteomics approaches for determining protein localization at the whole cell scale. Here, a brief overview of current methods is presented, followed by a detailed discussion of organellar mapping through proteomic profiling. This relatively simple yet flexible approach is rapidly gaining popularity, due to its ability to capture the localizations of thousands of proteins in a single experiment. It can be used to generate high-resolution cell maps, and as a tool for monitoring protein localization dynamics. This review highlights the strengths and limitations of the approach, and provides guidance to designing and interpreting profiling experiments. 




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The DNA sensor cGAS is decorated by acetylation and phosphorylation modifications in the context of immune signaling [Research]

The cyclic GMP-AMP synthase (cGAS) protein is a pattern-recognition receptor of the mammalian innate immune system that is recognized as a main cytosolic sensor of pathogenic or damaged DNA. cGAS DNA binding initiates catalytic production of the second messenger, cyclic GMP-AMP, which activates the STING-TBK1-IRF3 signaling axis to induce cytokine expression. Post-translational modification (PTM) has started to be recognized as a critical component of cGAS regulation, yet the extent of these modifications remains unclear. Here, we report the identification and functional analysis of cGAS phosphorylations and acetylations in several cell types under basal and immune-stimulated conditions. cGAS was enriched by immunoaffinity purification from human primary fibroblasts prior to and after infection with herpes simplex virus type 1 (HSV-1), as well as from immune-stimulated STING-HEK293T cells. Six phosphorylations and eight acetylations were detected, of which eight PTMs were not previously documented. PTMs were validated by parallel reaction monitoring (PRM) mass spectrometry in fibroblasts, HEK293T cells, and THP-1 macrophage-like cells. Primary sequence and structural analysis of cGAS highlighted a subset of PTM sites with elevated surface accessibility and high evolutionary sequence conservation. To assess the functional relevance of each PTM, we generated a series of single-point cGAS mutations. Stable cell lines were constructed to express cGAS with amino acid substitutions that prevented phosphorylation (Ser-to-Ala) and acetylation (Lys-to-Arg) or that mimicked the modification state (Ser-to-Asp and Lys-to-Gln). cGAS-dependent apoptotic and immune signaling activities were then assessed for each mutation. Our results show that acetyl-mimic mutations at Lys384 and Lys414 inhibit the ability of cGAS to induce apoptosis. In contrast, the Lys198 acetyl-mimic mutation increased cGAS-dependent interferon signaling when compared to the unmodified charge-mimic. Moreover, targeted PRM quantification showed that Lys198 acetylation is decreased upon infections with two herpesviruses—HSV-1 and human cytomegalovirus (HCMV), highlighting this residue as a regulatory point during virus infection.




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Immunopeptidomic analysis reveals that deamidated HLA-bound peptides arise predominantly from deglycosylated precursors [Technological Innovation and Resources]

The presentation of post-translationally modified (PTM) peptides by cell surface HLA molecules has the potential to increase the diversity of targets for surveilling T cells. Whilst immunopeptidomics studies routinely identify thousands of HLA-bound peptides from cell lines and tissue samples, in-depth analyses of the proportion and nature of peptides bearing one or more PTMs remains challenging. Here we have analyzed HLA-bound peptides from a variety of allotypes and assessed the distribution of mass spectrometry-detected PTMs, finding deamidation of asparagine or glutamine to be highly prevalent. Given that asparagine deamidation may arise either spontaneously or through enzymatic reaction, we assessed allele-specific and global motifs flanking the modified residues. Notably, we found that the N-linked glycosylation motif NX(S/T) was highly abundant across asparagine-deamidated HLA-bound peptides. This finding, demonstrated previously for a handful of deamidated T cell epitopes, implicates a more global role for the retrograde transport of nascently N-glycosylated polypeptides from the ER and their subsequent degradation within the cytosol to form HLA-ligand precursors. Chemical inhibition of Peptide:N-Glycanase (PNGase), the endoglycosidase responsible for the removal of glycans from misfolded and retrotranslocated glycoproteins, greatly reduced presentation of this subset of deamidated HLA-bound peptides. Importantly, there was no impact of PNGase inhibition on peptides not containing a consensus NX(S/T) motif. This indicates that a large proportion of HLA-I bound asparagine deamidated peptides are generated from formerly glycosylated proteins that have undergone deglycosylation via the ER-associated protein degradation (ERAD) pathway. The information herein will help train deamidation prediction models for HLA-peptide repertoires and aid in the design of novel T cell therapeutic targets derived from glycoprotein antigens.




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Perlecan knockdown significantly alters extracellular matrix composition and organization during cartilage development [Research]

Perlecan is a critical proteoglycan found in the extracellular matrix (ECM) of cartilage. In healthy cartilage, perlecan regulates cartilage biomechanics and we previously demonstrated perlecan deficiency leads to reduced cellular and ECM stiffness in vivo. This change in mechanics may lead to the early onset osteoarthritis seen in disorders resulting from perlecan knockdown such as Schwartz-Jampel syndrome (SJS). To identify how perlecan knockdown affects the material properties of developing cartilage, we used imaging and liquid chromatography–tandem mass spectrometry (LC-MS/MS) to study the ECM in a murine model of SJS, Hspg2C1532Y-Neo. Perlecan knockdown led to defective pericellular matrix formation, whereas the abundance of bulk ECM proteins, including many collagens, increased. Post-translational modifications and ultrastructure of collagens were not significantly different; however, LC-MS/MS analysis showed more protein was secreted by Hspg2C1532Y-Neo cartilage in vitro, suggesting that the incorporation of newly synthesized ECM was impaired. In addition, glycosaminoglycan deposition was atypical, which may explain the previously observed decrease in mechanics. Overall, these findings provide insight into the influence of perlecan on functional cartilage assembly and the progression of osteoarthritis in SJS.




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Promoting a Just Transition to an Inclusive Circular Economy

1 April 2020

Considerations of justice and social equity are as important for the circular economy transition as they are in the contexts of low-carbon transitions and digitalization of the economy. This paper sets out the just transition approach, and its relevance in climate change and energy transition debates.

Patrick Schröder

Senior Research Fellow, Energy, Environment and Resources Programme

2020-04-01-circular-economy.jpg

Residents of Mount Ijen take sulphur at Ijen Crater, Banyuwangi, East Java, on 2 July 2018. Photo: Getty Images.

Summary

  • Many social and political issues have so far been neglected in planning for the circular economy transition. This paper aims to redress this by considering how ‘just transition’ and social equity may be achieved through policy and practice.
  • The prevailing economic model is linear, in that resources are extracted, transformed into products, used, and finally discarded. In contrast, the circular economy recognizes that natural resources are finite, and aims to keep the materials in products in circulation for as long as possible: reusing, repairing, remanufacturing, sharing and recycling. While the concept of the circular economy is largely focused on developing new technologies and businesses to enable keeping materials in circulation, it also includes the notions of ‘designing out’ waste, substituting renewable materials for non-renewable ones, and restoring natural systems.
  • The UN 2030 Agenda demonstrates that environmental, social and economic sustainability objectives cannot be separated. As the links between the environmental issues of climate change, overconsumption of resources and waste generation, and social issues of inequality and the future of work become increasingly obvious, the urgency to connect environmental with social justice is gaining in significance. The language of ‘just transition’ – a transition that ensures environmental sustainability, decent work, social inclusion and poverty eradication – has started to penetrate debates and research on sustainability policy, particularly in the contexts of climate change and low-carbon energy transition.
  • A just transition framework for the circular economy can identify opportunities that reduce waste and stimulate product innovation, while at the same time contributing positively to sustainable human development. And a just transition is needed to reduce inequalities within and between countries, and to ensure that the commitment of the UN Sustainable Development Goals to leave no one behind is fulfilled.
  • It is important to identify the likely impacts on employment as a result of digitalization and industrial restructuring. Combining circular economy policies with social protection measures will be important in order to ensure that the burden of efforts to promote circularity will not fall on the poor through worsening working conditions and health impacts, reduced livelihoods, or job losses. Identifying potential winners and losers through participatory ‘roadmapping’ can help shape effective cooperation mechanisms and partnerships nationally and internationally.
  • Many low- and middle-income countries that rely heavily on ‘linear’ sectors such as mining, manufacturing of non-repairable fast-moving consumer goods, textiles and agriculture, and the export of these commodities to higher-income countries, are likely to be negatively affected by the shift to circularity. These countries will need support from the international community through targeted assistance programmes if international trade in established commodities and manufactures declines in the medium to long term. 
  • International cooperation to create effective and fair governance mechanisms, and policy coordination at regional, national and local levels will play an important role in shaping a just transition. Multilateral technical assistance programmes will need to be designed and implemented, in particular to support low- and middle-income countries.
  • Governments, international development finance institutions and banks are among the bodies beginning to establish circular economy investment funds and programmes. Just transition principles are yet to be applied to many of these new finance mechanisms, and will need to be integrated into development finance to support the circular economy transition.
  • New international cooperation programmes, and a global mechanism to mobilize dedicated support funds for countries in need, will be critical to successful implementation across global value chains. Transparent and accountable institutions will also be important in ensuring that just transition funds reach those affected as intended.




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G8 and Russian Foreign Policy: Overcoming Shortcomings

1 June 2008 , Number 6

Dmitri Medvedev’s appearance at the G8 Summit in Hokkaido will be his first step on the wide international stage that Vladimir Putin occupied with such a swagger. Expectations of change will be high, but they are likely to be unrealistic at such an early stage in Medvedev’s presidency. Putin’s foreign policy legacy is a heavy one and he has made it clear that Medvedev will be no soft touch, but will his approach ultimately be more productive?

John Lough

Associate Fellow, Russia and Eurasia Programme




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Moscow's Domestic Policy: Russian Roulette

1 October 2008 , Number 4

Russia’s military action in Georgia was driven by Moscow’s domestic agenda. Foreign policy has become a tool of collective control back home. While the ‘ruling tandem’ has gained popularity, the new consensus does not provide for modernisation. Will the predatory state reform or collapse?

Lilia Shevtsova

Senior Associate, Carnegie Moscow Centre




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International Arms Trade Treaty: Gun Control

1 October 2008 , Number 11

Nuclear, biological or chemical weapons and acts of terror may make the headlines, but it is conventional arms that take the lives in large numbers; maybe around a thousand a day. This month, a United Nations committee will try to find a way to limit the arms trade with a new treaty. For those facing the barrel of a gun, it cannot come a moment too soon.

Paul Cornish

Head, International Security Programme, Chatham House




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Economic Crisis and the Delayed Arrival of a New President: Transition Trauma

1 November 2008 , Number 1

The new American president will not be inaugurated until January 20. He will certainly face the most difficult economic conditions since Franklin Roosevelt entered the White House in March 1933. The politics of presidential transition – in this year, as seventy-six years ago – seem likely only to exacerbate the global crisis.

John Dumbrell

Professor of Government, Durham University




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Russia and the Economic Crisis: No Safe Haven

1 November 2008 , Number 4

Russia is caught in the global crisis and cannot escape its impact. The crucial question is how the Dmitri Medvedev-Vladimir Putin leadership will respond. Putin has presided over a steadily strengthening economy; he now appears ill-equipped to handle crisis and contraction. The signs are not encouraging. Trust and confidence, two essential ingredients vital to resolving any financial crisis, are in short supply. The public could pay a heavy price for the hubris and schadenfreude of their leaders, still ‘dizzy with success’ from years of economic revival and what they perceive as a successful reaffirmation of the country’s great power status.

Julian Cooper,

Professor, Centre for Russian and East European Studies, University of Birmingham




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Europe: Fifty Years On - Essay Competition

1 January 2007 ,

An ageing population in Europe makes the opinion of young people about their continent’s future even more important. Leading international figures, including the President of the United Nations General Assembly, have been expressing concern over the limited role of young people in shaping policy. With this in mind, The World Today and the National Association for Gifted and Talented Youth have given students the opportunity to share their vision through a competition on Europe: The Next Fifty Years. The three finalists have been invited to an International Economics Programme workshop at Chatham House next month.




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Book Review: Corruption: Led into Temptation

1 May 2007 , Number 8

Corruption and Misuse of Public Office,
Colin Nicholls Qc, Tim Daniel, Martin Polaine and John Hatchard, Oxford University Press.

David Bentley

Associate Fellow, International Law, Chatham House




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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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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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China and Russia in R2P debates at the UN Security Council

7 May 2020 , Volume 96, Number 3

Zheng Chen and Hang Yin

While China and Russia's general policies towards the Responsibility to Protect (R2P) are similar, the two reveal nuanced differences in addressing specific emergencies. Both express support for the first two pillars of R2P while resisting coercive intervention under its aegis, as they share anxieties of domestic political security and concerns about their international image. Nonetheless, addressing cases like the Syrian crisis, Russian statements are more assertive and even aggressive while Chinese ones are usually vague and reactive. This article highlights the two states’ different tones through computer-assisted text analyses. It argues that diplomatic styles reflect Russian and Chinese perceptions of their own place in the evolving international order. Experiences in past decades create divergent reference points and status prospects for them, which leads to their different strategies in signalling Great Power status. As Beijing is optimistic about its status-rising prospects, it exercises more self-restraint in order to avoid external containments and is reluctant to act as an independent ‘spoiler’. Meanwhile, Moscow interprets its Great Power status more from a frame of ‘loss’ and therefore is inclined to adopt a sterner approach to signal its status. Although their policies complement each other on many occasions, there is nothing akin to a Sino–Russian ‘bloc’.




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Corporate Raiding in Russia, Ukraine and Kazakhstan

Invitation Only Research Event

5 November 2019 - 9:00am to 1:00pm

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

Event participants

John Patton, Argentem Creek
Rachel Cook, Peters & Peters
Tom Mayne, University of Exeter
Olga Bischof, Brown Rudnick LLP
Isobel Koshiw, Global Witness
Anton Moiseienko, RUSI

The widespread practice of illicit acquisition of a business or part of a business in the former Soviet states, known as ‘reiderstvo’ or asset-grabbing, is a major risk that disincentivises investment in the region.

It is distinct from the way corporate raiding occurs in the West and enabled by factors such as corruption and weak protection of property rights.

This roundtable will assess the practice of corporate raiding in Russia, Ukraine and Kazakhstan: its evolution over time, knock-on effects and potential solutions. The speakers will also address the implications for the UK legal system and possible policy responses.

Event attributes

Chatham House Rule

Department/project

Anna Morgan

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




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Russian Economic Policy and the Russian Economic System: Stability Versus Growth

17 December 2019

How is it possible for the directors of the Russian economy to pursue an orthodox stabilization policy with a great measure of success and yet to have achieved so little to stem the growth slowdown? This paper examines the reasons for the divergence in economic management.

Professor Philip Hanson OBE

Former Associate Fellow, Russia and Eurasia Programme

GettyImages-1174485152.jpg

Bank of Russia Governor Elvira Nabiullina, Economic Development Minister Maxim Oreshkin, Deputy Prime Minister Vitaly Mutko, Labour and Social Safety Minister Maxim Topilin, Economy and Finance Department Head Valery Sidorenko, and Russian presidential aide Andrei Belousov (l–r) after a meeting on stimulating economic growth, at Gorki residence, Moscow, on 8 October 2019. Photo: Getty Images.

Summary

  • Russia’s economic management is currently praised for its achievement of macroeconomic stability. Inflation has been brought down; the budget is in surplus; national debt is low; and the reserves are ample. At the same time, there is much criticism of the failure at present to secure more than very slow economic growth.
  • The macro-stabilization of 2014–18 was of a conventional, ‘liberal’ kind. Public spending was cut, and a budget rule was introduced that (so far) has weakened the link between increases in oil prices and increases in budgetary expenditure. The austerity campaign was harsh. Pensioners, the military, regional budgets and business all lost out, but in reality put up little resistance. The austerity drive was facilitated by the autocratic nature of the regime.
  • The growth slowdown dates from 2012, and cannot simply be blamed on falls in the oil price and sanctions. Rapid growth in 1999–2008 consisted in large part of recovery from the deep recession of the 1990s and the initial development of a services sector. These sources of growth are no longer available; investment is low; and the labour force is declining. The Western world also has a slow growth problem, but at a higher level of per capita output. In Russia, private investment and competition are inhibited by an intrusive and corrupt state. If the rule of law were in place, the economy would perform better in the long run. That would require a profound reform of formal and informal institutions.
  • The leadership wants faster growth, but has powerful incentives not to embark on systemic reform. Even the pragmatic ministers of the ‘economic bloc’ of government, who understand the problem, share this interest in maintaining the status quo. Growth is thus being sought through a highly ambitious programme, in 2018–24, of ‘national projects’, state-led and largely state-financed. This is already running into difficulties.
  • The contrast between successful stabilization and a (so far) unsuccessful growth strategy illustrates the difference between policymaking within a given system and reform of that system. Systemic reform brings with it more potential unintended consequences than do changes in policy. In the case of Russia, movement towards a rule of law could destabilize the social and political system. It is therefore unlikely to be attempted.




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Secrets and Spies: UK Intelligence Accountability After Iraq and Snowden

20 January 2020

How can democratic governments hold intelligence and security agencies to account when what they do is largely secret? Jamie Gaskarth explores how intelligence professionals view accountability in the context of 21st century politics. 

Jamie Gaskarth

Senior Lecturer, University of Birmingham

Using the UK as a case study, this book provides the first systematic exploration of how accountability is understood inside the secret world. It is based on new interviews with current and former UK intelligence practitioners, as well as extensive research into the performance and scrutiny of the UK intelligence machinery.

The result is the first detailed analysis of how intelligence professionals view their role, what they feel keeps them honest, and how far external overseers impact on their work.

The UK gathers material that helps inform global decisions on such issues as nuclear proliferation, terrorism, transnational crime, and breaches of international humanitarian law. On the flip side, the UK was a major contributor to the intelligence failures leading to the Iraq war in 2003, and its agencies were complicit in the widely discredited U.S. practices of torture and 'rendition' of terrorism suspects. UK agencies have come under greater scrutiny since those actions, but it is clear that problems remain.

Secrets and Spies is the result of a British Academy funded project (SG151249) on intelligence accountability.

Open society is increasingly defended by secret means. For this reason, oversight has never been more important. This book offers a new exploration of the widening world of accountability for UK intelligence, encompassing informal as well as informal mechanisms. It substantiates its claims well, drawing on an impressive range of interviews with senior figures. This excellent book offers both new information and fresh interpretations. It will have a major impact.

Richard Aldrich, Professor of International Security, University of Warwick, UK

Gaskarth’s novel approach, interpreting interviews with senior figures from the intelligence world, brings fresh insight on a significant yet contested topic. He offers an impressively holistic account of intelligence accountability—both formal and informal—and, most interestingly of all, of how those involved understand it. This is essential reading for those wanting to know what accountability means and how it is enacted.

Rory Cormac, Professor of International Relations, University of Nottingham

About the author

Jamie Gaskarth is senior lecturer at the University of Birmingham, where he teaches strategy and decision-making. His research looks at the ethical dilemmas of leadership and accountability in intelligence, foreign policy, and defence. He is author/editor or co-editor of six books and served on the Academic Advisory panel for the 2015 UK National Security Strategy and Strategic Defence and Security Review.

Available now: Buying options

Insights: Critical Thinking on International Affairs

Department/project




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What Putin's Constitutional Shakeup Means

16 January 2020

Professor Nikolai Petrov

Senior Research Fellow, Russia and Eurasia Programme, Chatham House
Nikolai Petrov on the key takeaways from the Russian president's latest move.

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A live broadcast of Vladimir Putin's annual address to the Federal Assembly of the Russian Federation, seen on the Leader Tower screen in St Petersburg. Photo: Getty Images.

Vladimir Putin’s proposed constitutional reforms will transform Russia’s political regime and allow him to prolong his grip on power when his fourth presidential term expires in 2024.

The proposals suggest that he will not seek another term as president after 2024, but is preparing the ground for retaining power after he leaves the presidency. The changes will introduce checks and balances on his close associates and ensure the country’s judiciary, legislative and executive bodies remain passive.

The State Duma, the lower house of parliament, is unlikely to rock the boat with legislative elections approaching in 2021. Former prime minister Dmitry Medvedev’s cabinet has been replaced by an acting government headed by a new prime minister, Mikhail Mishustin. The highest courts will be weakened further by Putin’s proposal to give the president the power to dismiss judges.

Most of the proposed changes are vague. Notable specific proposals include the requirement that any presidential candidate must be resident in Russia for a minimum of 25 years prior to the elections, and that anyone who has held a residency permit abroad at any point in their life would not be eligible to run. This is clearly aimed at eliminating political opposition based abroad.

While Putin mentioned a popular vote on the constitutional changes (which is not required by law), it is important to note that he didn’t use the term ‘referendum’, which would have mandated that the results be acted upon. Regardless, it is clear that, with no easy foreign policy and military wins in the offing, Putin will seek to boost his legitimacy through a popular vote. The current federal electoral cycle starts next year and will end in 2024 with the presidential election.

The key question now is how Putin will maintain control over the siloviki, Russia’s political elite, though he has made this task easier for himself by replacing some of the strongest players with mid-level officers and weakening the authority of those who remain.

The proposals to consult with the Federation Council, the upper house of parliament, when appointing siloviki and to keep the president in charge of law enforcement are a smokescreen. Putin will consolidate his power through his leadership at the Security Council and by chairing the State Council. For this reason, Putin is seeking to enshrine the State Council, which was reshaped in 2018 to include senior government ministers, in the constitution. 

It is too early to be certain of the major beneficiaries of these sweeping reforms, though Sergey Sobyanin, the current mayor of Moscow, is likely to become Putin’s deputy at the State Council. The head of the audit chamber, Alexei Kudrin, and Deputy Chief of Staff Sergei Kiriyenko are also likely to benefit from the changes, after helping to develop Putin’s political and economic strategies prior to the 2018 presidential election.

Notably, the audit chamber, headed by Kudrin, will now have the power to check Rostekh, Rosneftegaz and Gazprom, organizations associated with major siloviki figures Sergey Chemezov and Igor Sechin. The role offered to Medvedev – deputy chair of the Security Council – will be newly created: the scope is unclear but it is unlikely that Putin will relinquish any of his influence over the siloviki.




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Ukraine Beyond Donbas: Is Social Cohesion at Risk?

Invitation Only Research Event

28 February 2020 - 9:30am to 1:00pm

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

Event participants

Iryna Brunova-Kalisetska, Independent Researcher, Trainer and Dialogue Facilitator
Maxim Ieligulashvili, Independent Researcher, Trainer and Dialogue Facilitator
Volodymyr Lupatsy, Co-founder, National Platform on Dialogue for Peace and Secure Reintegration; Board Member, Centre for Security and Development Research, Ukraine
Orysia Lutsevych, Research Fellow and Manager, Ukraine Forum, Chatham House

Six years after the annexation of Crimea and the start of the armed conflict in Donbas, the process of coalescing the Ukrainian society around a common civic identity remains complex. Ukraine comprises many ethno-linguistic identities, and various internal and external actors have been able to exploit old and new grievances to increase tensions at the regional and local level.

The panellists will discuss the conflict dynamics along parts of Ukraine’s international border and the line of contact with Crimea. The speakers will review the internal political, social and economic trends that cause friction and suggest ways to strengthen cohesion.

The event will build upon key findings from International Alert’s analysis of the south of Odesa, Kherson and Zakarpattia oblasts and on the reintegration of veterans in Ukraine.

This event is organized in partnership with International Alert, supported by UK aid from the UK government as part of the Peace Research Partnership programme.

 

Anna Morgan

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




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Could Zelenskyy’s Strategy for Donbas Lead Ukraine Into a Kremlin Trap?

14 February 2020

Kataryna Wolczuk

Associate Fellow, Russia and Eurasia Programme

Hanna Shelest

Member of the Board, Foreign Policy Council 'Ukrainian Prism'
In pursuit of peace in the war-torn region, the Ukrainian president’s short-term, tactical approach is vulnerable in the face of Russia’s long-term strategy.

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Volodymyr Zelenskyy attends a ceremony welcoming Ukrainians who were freed by pro-Russian rebels during a prisoner exchange. Photo: Getty Images.

One of the key messages at the heart of Volodymyr Zelenskyy’s presidential campaign in 2019 was a very simple one: peace in Donbas, the war-torn region of Ukraine where Russian-supported separatists continue to fight a war against the Kyiv government. Zelenskyy’s message was based on the assumption that if a ceasefire could be respected, and all Ukrainian prisoners-of-war could return home, then peace would have been achieved.

Nine months after Zelenskyy’s inauguration and two months after his first Normandy Four summit (which brings together Germany and France with Ukraine and Russia to discuss Donbas), it appears more likely that this approach will lead Ukraine into a Russian trap.

Zelenskyy’s very immediate objectives and the tactics used to achieve them contrast with those of the previous president, Petro Poroshenko. Zelenskyy has pointedly avoided naming Russia as an aggressor and has focused on humanitarian issues and seeking compromise wherever possible, including in legal cases that Russia has already lost in international courts.

In contrast, President Poroshenko prioritised the security agenda as a precondition for any political settlement, encapsulated in the notion of ‘no elections without security guarantees’. This focused on regaining control of the border and the demilitarization of the separatist-controlled territories. At the same time, Poroshenko sought remedial action for Russian aggression through international courts. 

Kyiv is testing the Kremlin’s real intentions with a series of small steps without clearly communicating its overarching objectives. This has triggered considerable social disquiet, manifested by demonstrations in Kyiv and other cities as part of the ’No capitulation’ campaign. This wave of criticism forced Zelenskyy’s team to name certain red lines, which he promised he would not cross (‘we don’t trade territories and people’) in pursuit of conflict resolution.

Other key issues, such as Ukraine’s relations with the EU, future NATO membership, language issues and any possible ‘special status’ for Donbas, have been left undefined.

Two months since the Normandy summit, the number of casualties has not declined. It is increasingly difficult for Zelenskyy to argue that disengagement by Ukraine’s army from the contact line in three locations, which was a precondition for the December Normandy Four meeting, is a way to achieve peace.

The separatists continue to significantly impede the OSCE’s special monitoring mission, a full ceasefire is not being observed and there are numerous reports of heavy weapons movements closer to the contact line in the areas outside Kyiv’s control. These issues are particularly problematic as control over the border with Russia is essential for the demilitarization of the ‘people’s republics’, which is a prerequisite for the safe reintegration of these areas.

Conducting local elections in autumn 2020 is a top priority for the new team, but it is clear that even if Ukraine regains control of its border, the presence of Russian military personnel and weaponry in Donbas threatens the prospect of free and fair elections (which themselves raise the further issue of how to ensure the integrity of the votes).

Russia’s strategy

So despite Zelenskyy’s pacifist rhetoric, hopes and ambitions, his plans are far from being realized or, in fact, realizable. This is because these plans are at odds with Russia’s strategic objective, which is for Donbas to be conferred a status whereby it is de jure within Ukraine but de facto under Russian control and influence.

Zelenskyy’s media-friendly appearance in Paris in December 2019 could not mask the fact that the Normandy Four talks exposed the weakness of Ukraine’s position and the growing influence of Russia’s approach, particularly in the context of a disengaged UK and US, a Germany increasingly tired of this conflict, and a French president who is looking to accommodate Russian preferences.

Indeed, Vladimir Putin was able to exploit the opportunity to apply his favoured formula for conducting foreign policy: highly personalized informal interactions, which seek specific political concessions from a cornered partner and which are short on transparent, stable and law-based solutions. The Paris meeting of the Normandy Four in December 2019 clearly demonstrated that simply sitting down and talking to Putin is not a magic pill to end the conflict, an idea frequently expressed by Zelenskyy.

In 2020, the strongest clue as to what Putin’s plans for Ukraine might be is the appointment of Dmitry Kozak as the main curator of the ‘Ukraine file’ (meaning Donbas and Crimea), replacing Vladislav Surkov, his long-time competitor for the role. The next Normandy meeting is expected in April 2020, and Kyiv should be aware of the possible pitfalls.

While Kozak is perceived by some as a more pragmatic and less aggressive counterpart, his past tells a different story. In fact, he was the architect of the long-term strategy for Moldova, which centred on the federalization of Moldova and the reincorporation of the separatist region of Transnistria into Moldova.

The presence of Russian military forces stationed on the ground there amounts to ‘armed suasion’ – using a military presence to demand political concessions from Moldova. The so-called ‘Kozak memorandum’ – which de facto re-writes the constitution of Moldova – contains a detailed explanation of that strategy.

Kozak could try to deliver a similar situation for Ukraine. Less emphasis is being put on specific terms (federalization vs. special status) but the overarching aims are unchanged since 2014, in the same way they have been in Moldova since 2003. Kozak is a man who can play the long game, while the team of the Ukrainian president chases quick successes without calculating long-term risks. This could be a dangerous combination.

The ‘human-centric approach’ to resolving the conflict followed by President Zelenskyy is a double-edged sword. The focuses on humanitarian issues and readiness for big compromises are clear positive signals to Western partners and supporters of Zelenskyy’s Servant of the People party. But prioritizing humanitarian issues over national security considerations could easily lead Ukraine into a Russian trap, which does not so much rely on a massive military assault but envisages creeping control over Ukraine’s future as its ultimate goal.




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Lukashenka’s Commitment to Belarusian Sovereignty Is Overstated

18 February 2020

Ryhor Astapenia

Robert Bosch Stiftung Academy Fellow, Russia and Eurasia Programme
Although President Lukashenka has recently shown assertiveness in relations with Russia, overall he has done very little to ensure his country’s freedom of action.

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Putin and Lukashenka play ice hockey in Sochi after a day of talks in February. Photo: Getty Images.

Earlier this month, US Secretary of State Mike Pompeo became the highest-ranking US official to visit Belarus since Bill Clinton in 1994. After meetings with Belarusian President Alexander Lukashenka – who Condoleezza Rice once memorably described as ‘Europe’s last dictator’ – Pompeo said he was ‘optimistic about our strengthened relationship’. 

The EU and its member states have also changed their tune, at least a little. Previously, prosecutions of democratic activists led to sanctions against the Lukashenka regime. But his less-than-liberal manner of governance did not prevent him from visiting Austria last November or from receiving invitations to Brussels. 

Eight years ago, most EU contacts with Belarusian officials were frozen. Now, Western diplomats regularly meet with Belarusian officials again. This year, a US ambassador to Belarus will be appointed after a 12-year break.

The West is also more willing to support Belarus financially. The European Bank for Reconstruction and Development invested a record-breaking $433 million in the country in 2019. The European Investment Bank only began working with the country in 2017 but already has a portfolio of $600 million.

Certain policymakers in the EU and US now, at least publicly, appear to regard Lukashenka as one of the sources of regional security and a defender of Belarusian sovereignty against Russia.

There is some truth in this. He has taken a neutral position in Russia’s conflict with Ukraine, and he has consistently resisted pressure from the Kremlin to establish a military base in Belarus.

Now, amid Moscow’s demands for deeper integration in exchange for the continuation of Russian energy subsidies, Lukashenka has shown reluctance to sell his autonomy. In a token attempt to portray sovereignty Belarus even started buying oil from Norway, although this makes no economic sense.

But Lukashenka’s long-term record shows he has done little to ensure the country’s sovereignty. Lukashenka has resisted reforms that would have strengthened the economy (because they would have weakened his own position). The political system is also dependent on Russia because Lukashenka has been unwilling to build better relations with the West. Belarusians are still strongly influenced by Russian culture and media because the authorities marginalize their own national identity.

Since the conflict in Ukraine in 2014, Lukashenka’s primary goal has not been to strengthen the sovereignty of Belarus, but to preserve his absolute control over the country.

For example, when in 2018 Russia started pressing Belarus to deepen its integration in order to retain economic support, Minsk did not reject this approach outright; instead, it discussed no less than 31 ‘road maps’ for deepening integration for more than a year, hoping to receive more benefits. For Lukashenka, greater dependency on Russia is a matter of price and conditions, not principle. 

None of this is to say Belarus has illusions about Russia. It is just that Lukashenka does not take long-term steps to protect the country’s sovereignty or to strengthen relations with the West.

Belarus needs to start economic reform with the support of the International Monetary Fund, but this cannot happen without Lukashenka’s genuine commitment to transform the economy. Absence of cross-sectoral reform has led to the deterioration of the education system as well as unprecedented emigration. Few Belarusian experts are optimistic about their country’s future. Lukashenka knows all this, but does not change his system, fearing it would damage the stability of his regime.  

The West should therefore adopt a broader policy. Lukashenka is unlikely to still be president in 10–15 years, so policymakers should develop relations with the broader ruling elite, which will remain after he leaves, and try to be present in Belarus as much as possible helping it to improve public governance and develop private businesses.

The West should also support the country’s civil society and independent media, for whom Belarusian independence is a matter of principle rather than something to be bargained away.

Lukashenka may be a strong leader, but the state he has built is weak.




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In a COVID-19 World, Russia Sticks to International Distancing

29 March 2020

Mathieu Boulègue

Research Fellow, Russia and Eurasia Programme
While a global response is needed against the coronavirus crisis, Russia does not see it as in its interests to contribute – and in fact the Kremlin is using the crisis to further destabilise the world.

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Young woman wearing a face mask in front of St. Basil's Cathedral, Moscow. Photo by ALEXANDER NEMENOV/AFP via Getty Images.

Persistent internet rumours claiming the coronavirus outbreak originated from a secret American pharmaceutical company with the aim of destroying China from within were quickly discredited. Pop culture fans recognised the supposed activities of the Umbrella Corporation as being from the famous Japanese video games series Resident Evil.

However, although fake news, it can likely be attributed to Russian trolls conducting this and other similar activities online, especially when considered within the wider context of how the Russian regime is using this worldwide crisis to further destabilize the West and test its resolve.

Russian trolls never sleep

Russia’s COVID-19 related actions first and foremost take the form of a vast information warfare campaign, with media outlets simultaneously downplaying the threat of the pandemic - ‘it is less dangerous than seasonal flu’ - while stoking fear about what is happening elsewhere in Europe.

For the domestic audience in Russia, some media are reporting the pandemic marks the collapse of the Western world and liberalism altogether, calling it a form of collective punishment. Other point out how fast liberal democracies have curbed individual and entrepreneurial freedoms in order to slow down the viral outbreak, and seek to diminish the credibility of the Western response to the crisis.

Exploiting the coronavirus crisis in this way is a new low in Russia’s wider political warfare campaign to undermine global governance overall, as these activities are detrimental to people's very safety. For example, in Ukraine, it is thought a Russian-engineered disinformation operation may have caused the outburst of violence in the city of Novi Sanzhary following the arrival of evacuees from China.

In the military realm, fake news has been targeting the US-led multinational exercise DEFENDER-Europe 2020. The Russian leadership criticized the exercise as an offensive ‘anti-Russian scenario’ but then used accompanying propaganda that it could actively facilitate the spread of COVID-19 across Europe because of the arrival and movement of large numbers of troops.

The large-scale drills were planned to involve 18 participating nations and should have taken place across ten European countries from April to May 2020. But the exercise has now been scaled down – as has the Russian disinformation targeting it.

And while the world is pre-occupied with managing COVID-19, Moscow is able to grow bolder in its provocations. Recent air incursions were reported into Irish controlled airspace as well as over the North Sea. Although this practice is - unfortunately - routine as part of Russian constant military sabre-rattling, it does increase the risk of tactical errors and miscalculation.

Self-isolation, Kremlin style

Meanwhile, just when a global response is needed to fight the pandemic, Moscow’s response has been, at best, self-serving. On March 22, Russian military reportedly started sending medical equipment and supplies to Italy. While the nature and the scope of this assistance can be doubted, it still represents a charm offensive for Russia to be brought back in from the cold in Europe - since successive Italian leaderships have been accommodating to the Kremlin. And sending virologists to Italy might also be a useful learning curve for Russia’s regime.

But within Russia itself, Vladimir Putin does have to face the problem that, on top of all the projected social and healthcare costs, the coronavirus is also having negative political consequences. On March 25, the ‘popular vote’ - a mock referendum designed to rubber-stamp Putin’s recent constitutional changes - was pushed back. And the Ministry of Communications has been forced to postpone a major exercise aimed at ensuring the ‘stable and safe operation of Runet’ - namely eliminating vulnerabilities in the Russian ‘sovereign’ internet to potential external threats.

Certainly it would be naive to believe Moscow will put self-interest to one side during this pandemic. ‘International distancing’ is not new for the Kremlin, and Russia has been practising self-isolation since at least 2008 through its own actions, most notably in Georgia and Ukraine.

Its self-perception as a ‘besieged fortress’ is being reinforced by this crisis and Russia will, at the very least, likely come out of the crisis feeling vindicated in its view that internationalism is dying or already dead.

With the health systems of many countries under massive strain, and societal resilience being tested by social distancing, the Kremlin continues to probe for weaknesses, and is also carefully watching other countries’ responses to the crisis in terms of adaptation and mobilization of resources.

COVID-19 provides a major intelligence-gathering opportunity for Moscow to learn how well others can implement wartime-like planning in peacetime. In a rapidly changing world, Russia is still Russia.




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Virtual Roundtable: Russia in Light of the COVID-19 Pandemic

Invitation Only Research Event

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

Event participants

Mathieu Boulegue, Research Fellow, Russia and Eurasia Programme, Chatham House
Nikolai Petrov, Senior Research Fellow, Russia and Eurasia Programme, Chatham House
Ekaterina Schulmann, Associate Fellow, Russia and Eurasia Programme, Chatham House
Chair: James Nixey, Programme Director, Russia and Eurasia, Chatham House

Politically speaking, Russia has been isolating itself from the West for some years now, feeding its citizens a ‘besieged fortress’ mentality. Its uniqueness, however, means its approach to - and outcome from - the COVID-19 pandemic will also be distinctive. 

This webinar will explore how Russia is adapting its internal politics and its international relations to the ‘new normal’ of today. 

Department/project

Anna Morgan

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




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Can Ukraine’s Appeal to the International Courts Work?

3 April 2020

Kateryna Busol

Robert Bosch Stiftung Academy Fellow, Russia and Eurasia Programme
First in a two-part series analysing why Ukraine’s attempts at international justice are worth taking - and outlining how the impact goes far beyond just the Russia-Ukraine conflict. Part one examines the response of the International Court of Justice (ICJ) to the possibility of holding Russia accountable as a state.

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Rally in support of keeping Crimea as part of Ukraine. Photo by Spencer Platt/Getty Images.

Russia’s ongoing occupation of Ukraine’s Crimean peninsula and support of separatist hostilities in the eastern provinces of Donbas have resulted in 1.5 million internally displaced persons, 3,000 civilians killed, and a growing list of alleged violations of international law and socio-economic hardship.

But Ukraine is struggling in its efforts to hold Russia accountable – either as a state or through individual criminal responsibility - as it cannot unilaterally ask any international court to give an overall judgment on the conflict.

So it focuses on narrower issues, referring them to authorised adjudication and arbitration platforms such as the International Court of Justice (ICJ), European Court of Human Rights, UNCLOS arbitration, and the International Criminal Court (ICC). These options are limited, but still worth taking - and their relevance is proving to be far wider than the Russia-Ukraine conflict.

Policy of cultural eradication

In 2017, Ukraine initiated proceedings against Russia at the ICJ on the basis of two international treaties: the International Convention on the Elimination of All Forms of Racial Discrimination (CERD), with regard to Crimea; and the International Convention for the Suppression of the Financing of Terrorism (ICSFT), with regard to Donbas.

Under the CERD, Ukraine alleges Russia has carried out a policy of cultural eradication of ethnic Ukrainians and Crimean Tatars in Crimea, including enforced disappearances, no education in the Ukrainian and Crimean Tatar languages, and the ban of the Mejlis, the main representative body of the Crimean Tatars.

Under the ICSFT, Ukraine alleges Russia has supported terrorism by providing funds, weapons and training to illegal armed groups in eastern Ukraine. In particular Ukraine alleges Russian state responsibility - through its proxies - for downing the infamous MH17 flight.

Both these treaties are binding upon Ukraine and Russia and entitle an individual state party to refer a dispute concerning them to the ICJ, but certain procedural pre-conditions must first be exhausted. These include a failed attempt to settle a dispute either through negotiations or the CERD Committee (for the CERD) or unsuccessful negotiations and arbitration (for the ICSFT).

Russia challenged Ukraine’s compliance with the pre-conditions, but the ICJ disagreed with Russia’s submission that Ukraine had to resort both to negotiations and to the CERD Committee. For the first time, the court clarified these procedures under the CERD were two means to reach the same aim, and therefore alternative and not cumulative.

Requiring states to avail of both procedures before going to the ICJ would undermine the very purpose of the CERD to eliminate racial discrimination promptly, and ensure the availability of effective domestic protection and remedies.

The relevance of this clarification transcends the Ukraine-Russia dispute. With the rise of discriminatory practices, from populist hate-filled rhetoric endangering vulnerable communities to large-scale persecution such as that of the Rohingyas, the UN’s principal judicial body is sending a clear larger message to the world: such practices are unacceptable and must be dealt with expeditiously and efficiently. If states fail to do so, there are now fewer procedural impediments to do it internationally.

The ICJ also confirmed Ukraine had complied with both procedural preconditions under the ICSFT and that it would give judgement on the alleged failure of Russia to take measures to prevent the financing of terrorism. The outcome of this will be of great importance to the international community, given the general lack of international jurisprudence on issues of terrorism.

The court’s interpretation of knowledge and intent in terrorism financing, as well as clarification of the term ‘funds’, is particularly relevant both for the Ukraine-Russia case and for international law.

As the final judgement may take several years, the ICJ granted some provisional measures requested by Ukraine in April 2017. The court obliged Russia to ensure the availability of education in Ukrainian and enable the functioning of the Crimean Tatar representative institutions, including the Mejlis.

When Russia contested Ukraine’s references to the alleged Stalin-ordered deportation of the Crimean Tatars and the rule of law in the Soviet Union being hypocritical, by arguing that history did not matter, the court disagreed.

In fact, Judge James Crawford emphasised the relevance of the ‘historical persecution’ of Crimean Tatars and the role of Mejlis in advancing and protecting their rights in Crimea ‘at the time of disruption and change’.

These conclusions are important reminders that the historical inheritance of injustices inflicted on vulnerable groups should be taken into account when nations address their imperial legacies.

The court’s provisional measures and Judge Crawford’s position are particularly relevant in light of Russia’s policy of the total - territorial, historical, cultural – ‘russification’ of Crimea, as they highlight the role of the historical background for assessing the alleged discriminatory and prosecutorial policy of Russia’s occupying authorities against the Crimean Tatars.

The ICJ’s judgement on the merits of this as well as other human rights, and terrorism issues of Crimea and Donbas will be an important consideration for the international community in its view of the Russia-Ukraine armed conflict and the sanctions policy against Russia.

The development of this case also has a mutually catalysing impact on Ukraine’s efforts to establish those individually criminally responsible for atrocities in Crimea and Donbas, through domestic proceedings and through the International Criminal Court.

Ukraine’s attempts to seek individual criminal responsibility for gross abuses in Donbas and Crimea at the International Criminal Court (ICC) are assessed in part two of this series, coming soon.




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Virtual Roundtable: The Impact of COVID-19 on the Wider FSU Region

Invitation Only Research Event

21 April 2020 - 10:00am to 11:30am

Event participants

Christopher Davis, Professorial Fellow, Institute of Population Ageing, University of Oxford
Nino Evgenidze, Executive Director, EPRC
Katya Gorchinskaya, Journalist, former CEO of Hromadske.ua
Konstantin Sokulskiy, Head of Governance, UNDP, Kazakhstan
Chair: James Nixey, Programme Director, Russia and Eurasia, Chatham House

COVID-19 has put a serious strain on healthcare and economic systems around the world. This virtual roundtable will explore its impact on Russia, Ukraine, Georgia and Kazakhstan. Through a comparative examination of government and society responses, this event will show how COVID-19 has laid bare the region’s broader social, economic and political challenges.

Department/project

Anna Morgan

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




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Belarusians Left Facing COVID-19 Alone

16 April 2020

Ryhor Astapenia

Robert Bosch Stiftung Academy Fellow, Russia and Eurasia Programme

Anaïs Marin

Associate Fellow, Russia and Eurasia Programme
The way the epidemic is being mismanaged creates a risk of political destabilisation and leaves the country exposed to external influence.

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Playing accordion in front of dummy football fans in Brest, Belarus as the country's championship continues despite the COVID-19 outbreak. Photo by SERGEI GAPON/AFP via Getty Images.

Since the World Health Organisation (WHO) declared COVID-19 a pandemic, few countries have chosen to ignore social distancing recommendations. But, even among those states which have, the Belarusian official response to its epidemic remains unique.

President Aliaksandr Lukashenka’s statements that vodka, sauna and tractors are protecting Belarusians from coronavirus attracted amused attention in international media. Lukashenka also described other societies’ response to COVID-19 as ‘a massive psychosis’.

Although Lukashenka is notorious for his awkward style of public communication, the fact that Belarus is refusing to impose comprehensive confinement measures is of concern. Belarusians continue to work, play football and socialise.

Lukashenka, himself playing ice hockey in front of state cameras, claims it is the best way to stay healthy. Belarusian authorities clearly appear to be in denial – and this could have dire humanitarian consequences.

From denial to half measures

Belarus actually has one of the largest numbers of hospital beds in the world per 1,000 of the population. But in the absence of quarantine measures its health system, already crippled by corruption and embezzlement, is likely to be overwhelmed.

Patients being treated for pneumonia in hospitals have suggested medical staff are uninformed and inadequately equipped. It is claimed doctors are not reporting COVID-19 as the suspected cause of death, either through a lack of testing or for fear of reprisals.

Observers believe the real mortality rate is already well above official figures (40 deaths as of 16 April). Based on an Imperial College London model, between 15,000 and 32,000 people could die under the current mild confinement regime – and such a high death toll would hugely impact the country’s political stability. Citing personal data protection, the Ministry of Health has imposed a total news blackout; the only cluster officially acknowledged so far is the city of Vitsebsk.

Although specific Belarusian cities and some individuals started changing their approach – by extending school vacations or cancelling weddings – such measures remain half-hearted.

Clearly a major reason for such an apparently irresponsible reaction is that Belarus cannot afford a massive lockdown that would freeze its already underdeveloped economy and drive it deeper into recession. Unlike many other nations, Belarus lacks budgetary resources for a sizable stimulus package. But a delayed response might backfire on the economy.

Economic recession has been forecast to amount to at least 10% of GDP. For Lukashenka, who openly challenged conventional wisdom regarding the need for quarantine and isolation, such an economic downturn would harm his confidence rating in the eyes of Belarusian voters, mindful of the state’s mismanagement of the crisis. And it could create doubt within the ruling elite itself, with Lukashenka seeking re-election for a sixth mandate in late August.

Against this backdrop, a radicalization of the opposition-minded part of society is also to be expected, with greater reliance on social networks in the face of official secrecy and disinformation. The expected response of the regime is then likely to be pre-emptive repression. Evidence is emerging that law enforcement agencies have already stepped up judicial and paralegal harassment of dissenters, notably independent journalists and bloggers.

Russia’s initial reluctance to address the coronavirus crisis may also have influenced Belarus. Lukashenka and his administration often react to public health challenges by the Soviet rulebook, reminiscent of the Soviet authorities’ mismanagement of the Chernobyl disaster in 1986.

Russia has unilaterally closed its borders with Belarus and, as bilateral relations continue to deteriorate, this casts further doubt on the viability of the Union State of Belarus and Russia. Pro-Russian media forecast Moscow will be unwilling to alleviate the expected socio-economic crisis, as it continues to reject Minsk’s demands regarding subsidised oil deliveries. Yet the Kremlin might use the crisis as an opportunity to resume its integrationist pressure on Belarus.

China, with which Belarus engaged in a seemingly privileged strategic partnership in the 2010s, was actually the first country to dispatch humanitarian aid to beef up Belarusian capacity to fight the virus.

But Minsk should not expect Beijing to rescue its economy and, unless it commits to more internal reforms, Belarus is not likely to receive much from the EU either. The regime has already applied to the IMF for emergency financial support, but conditions are attached and, even if successful, the funds would amount to no more than $900m.

The government’s decision to take only half measures so far is rooted in the hope COVID-19 is not as bad as foreign experts fear. But, unless the leadership acknowledges the public health crisis and mitigates its economic impact, COVID-19 will accelerate Belarus’s slide back into international self-isolation. If combined with a humanitarian crisis, this will put the Belarusian regime under considerable stress.

This crisis does risk a new ‘Chernobyl moment’ for the authorities, but the population could react more vocally this time. As volunteers self-organise to fight the epidemic, it might become more difficult for the authorities to say that it is efficient in running the country. But the bottom line is Belarus desperately needs money. Whoever steps up to support Belarus financially will also be able to heavily influence its politics.




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Webinar: Russian Disinformation's Golden Moment: Challenges and Responses in the COVID-19 Era

Invitation Only Research Event

7 May 2020 - 3:00pm to 4:30pm

Event participants

Anneli Ahonen, Head, StratCom East Task Force, European External Action Service
Keir Giles, Senior Consulting Fellow, Russia and Eurasia Programme, Chatham House
Thomas Kent, Adjunct Associate Professor, Harriman Institute, Columbia University; Senior Fellow, the Jamestown Foundation
Chairs:
James Nixey, Programme Director, Russia and Eurasia, Chatham House
Glen Howard, President, The Jamestown Foundation
The COVID-19 pandemic provides the ideal environment for malign influence to thrive as it feeds on fear and a vacuum of authoritative information. What are the current challenges posed by Russian disinformation, and how should Western nations be responding?
 
In this discussion, jointly hosted by the Jamestown Foundation and the Chatham House Russia and Eurasia Programme, the speakers will consider what best practice looks like in safeguarding Western societies against the pernicious effects of disinformation. 
 
This event will be held on the record.

Anna Morgan

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




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Fighting COVID-19 the Ukrainian Way

28 April 2020

Orysia Lutsevych

Research Fellow and Manager, Ukraine Forum, Russia and Eurasia Programme
Coronavirus has exposed vulnerabilities in Ukraine but also activated private sector and citizen engagement in delivering help. This could accelerate social change if a smart response is adopted and political reforms follow.

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Girls wearing face masks at the monument to Chernobyl victims in Slavutich during a memorial ceremony amid the COVID-19 pandemic. Photo by SERGEI SUPINSKY/AFP via Getty Images.

Ukrainians are accustomed to crisis. As COVID-19 spread, forest fires were raging in the Chernobyl exclusion zone, turning Kyiv into the most polluted city in the world. The fighting in Donbas continued, claiming the lives of more Ukrainian soldiers, bringing the total to more than 4,000 — and, on top of that, President Zelenskyy overhauled his government. So Ukraine is fighting three battles at the same time — war with Russia, the struggle against its own ineffective system, and now COVID-19.

Every crisis is a reality check — the coronavirus provoked and exposed the strategic vulnerabilities and deep-rooted features of Ukraine’s system of governance. Three trends have come to the fore. First, the inefficiency and paralysis of many state agencies, particularly the lack of coordination between them and the prevalence of vested interests. Second, the reliance of the country’s leaders on large financial-industrial groups (FIGs) to compensate for weak institutional capacity. Third, a strong societal and private sector mobilization to fill the gaps in the dilapidated public health system.

State agencies are rigid and ineffective. Despite the modern Prozorro digital public procurement system, and the government’s allocation of $2.5 million from the early days of the epidemic, the Ministry of Health blocked COVID-related purchases for over a month. This was a tactic by — now ex-minister — Yemets to pressure the state medical procurement agency into appointing a protégé of his as one of its deputy heads.

Lowest testing rate in Europe

Similarly, in some regions, notably Odesa, procurement stalled and orders went to politically connected businesses at higher-than-market prices. Lack of tests and laboratory equipment means Ukraine has administered only 72,000 tests within a population of 42 million to date — the lowest rate in Europe.

Doctors were given orders to ensure they only test patients in hospitals with COVID-19 symptoms and only those arriving from Asia, while ignoring the fact that millions of Ukrainian labour migrants were in Europe. Indeed, the first confirmed case was imported from Italy.

Ukrainian government and public health officials lack information to take informed decisions. There is no accurate electronic database of registered deaths and reporting is lagging behind events. Information on testing availability in the regions is missing.

Thirteen days after the first case of the virus was recorded, Zelenskyy exhorted business tycoons to come to the rescue. Taking a populist tone, Zelenskyy said ‘Ukraine has been feeding you for a long time and it is time that you helped the country’. The tycoons divided the regions among themselves to deliver relief efforts according to the location of their enterprises.

It is believed FIGs have donated around $25 million to procure testing kits, ventilators, personal protective equipment (PPE) and disinfectants. This may sound impressive, but many of those same tycoons actually owe millions to the state, some even billions, and cause serious problems by perpetuating the current rent-seeking system, where public resources benefit those groups resulting in serious social losses.

Reliance on these groups makes Zelenskyy a hostage to their favour in any potential reform efforts. It is a dangerous solution, as these tycoons often obstruct Ukraine’s economic development.

An alternative — and more transformative — trend of public-private partnerships is emerging in some regions. Across Ukraine, hundreds of small- and medium-sized enterprises (SMEs) have led efforts to deliver PPE, support the vulnerable with food supplies, and to procure ventilators for key hospitals.

They have mobilised hundreds of volunteers to deliver assistance and partnered with local non-profits. Fundraising initiatives have begun in Lviv, Odesa, Kyiv and Poltava with donations and expenditure has been posted online for transparency. Companies have repurposed to produce PPE kits and medical equipment. The efforts unfolded quickly and, in some cases, in smooth collaboration with municipal and regional authorities.

Ukraine cannot afford to ‘waste’ this crisis, which could help accelerate healthcare reform, decentralization, modernize governance, and boost citizen empowerment. But for this to happen, the country has to deploy a ‘smart response’.

Such ‘smart response’ means applying a resilience framework that nurtures the agility of the system of governance, ensures a diversity of actors in decision-making, supporting both self-regulation and better coordination. Rather than reaching out to tycoons, Zelenskyy should enter a coalition with true agents of change — SME leaders, volunteers, and mayors who have mobilized effective grassroots action. These actors demand a level playing field with accountable governance and effective state institutions.

Civic COVID-19 response hubs and local authorities should be joined in a network that spans the regions, and connected with the national agencies designing pandemic responses. For a national strategy to be effective, central headquarters should draw information from local communities and manage a ‘team of teams’ in a decentralised fashion.

Ensuring effective public service delivery without compromising integrity and keeping the risk of corruption low should also be a priority of political reform, with volunteers and the private sector ensuring civic oversight of both regional and national funding.

Civic engagement such as this can be transformative as it defies the Soviet legacy of paternalism and expands the belief among citizens that society can work for them. By assisting the relief effort, citizens are gaining valuable insights into quality of public services and participate in holding them to account.

Citizens are also developing a better understanding of the purpose of having effective armed forces, police, border guards and modern hospitals. They are coming to understand the value of taxpayer money and witnessing how corruption erodes institutions.

This survival mobilization — if properly harnessed by the state — could drive transformative change and make Ukraine more resilient, not just against present crises, but future ones too.




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Erratum: FTY720/fingolimod decreases hepatic steatosis and expression of fatty acid synthase in diet-induced nonalcoholic fatty liver disease in mice [Errata]




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Plasma membrane asymmetry of lipid organization: fluorescence lifetime microscopy and correlation spectroscopy analysis [Methods]

A fundamental feature of the eukaryotic cell membrane is the asymmetric arrangement of lipids in its two leaflets. A cell invests significant energy to maintain this asymmetry and uses it to regulate important biological processes, such as apoptosis and vesiculation. The dynamic coupling of the inner or cytoplasmic and outer or exofacial leaflets is a challenging open question in membrane biology. Here, we combined fluorescence lifetime imaging microscopy (FLIM) with imaging total internal reflection fluorescence correlation spectroscopy (ITIR-FCS) to differentiate the dynamics and organization of the two leaflets of live mammalian cells. We characterized the biophysical properties of fluorescent analogs of phosphatidylcholine, sphingomyelin, and phosphatidylserine in the plasma membrane of two mammalian cell lines (CHO-K1 and RBL-2H3). Because of their specific transverse membrane distribution, these probes allowed leaflet-specific investigation of the plasma membrane. We compared the results of the two methods having different temporal and spatial resolution. Fluorescence lifetimes of fluorescent lipid analogs were in ranges characteristic for the liquid ordered phase in the outer leaflet and for the liquid disordered phase in the inner leaflet. The observation of a more fluid inner leaflet was supported by free diffusion in the inner leaflet, with high average diffusion coefficients. The liquid ordered phase in the outer leaflet was accompanied by slower diffusion and diffusion with intermittent transient trapping. Our results show that the combination of FLIM and ITIR-FCS with specific fluorescent lipid analogs is a powerful tool for investigating lateral and transbilayer characteristics of plasma membrane in live cell lines.




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Functional recombinant apolipoprotein A5 that is stable at high concentrations at physiological pH [Methods]

APOA5 is a low-abundance exchangeable apolipoprotein that plays critical roles in human triglyceride (TG) metabolism. Indeed, aberrations in the plasma concentration or structure of APOA5 are linked to hypertriglyceridemia, hyperchylomicronemia, myocardial infarction risk, obesity, and coronary artery disease. While it has been successfully produced at low yield in bacteria, the resulting protein had limitations for structure-function studies due to its low solubility under physiological buffer conditions. We hypothesized that the yield and solubility of recombinant APOA5 could be increased by: i) engineering a fusion protein construct in a codon optimized expression vector, ii) optimizing an efficient refolding protocol, and iii) screening buffer systems at physiological pH. The result was a high-yield (25 mg/l) bacterial expression system that produces lipid-free APOA5 soluble at concentrations of up to 10 mg/ml at a pH of 7.8 in bicarbonate buffers. Physical characterization of lipid-free APOA5 indicated that it exists as an array of multimers in solution, and far UV circular dichroism analyses show differences in total α-helicity between acidic and neutral pH buffering conditions. The protein was functional in that it bound and emulsified multilamellar dimyristoyl-phosphatidylcholine vesicles and could inhibit postprandial plasma TG accumulation when injected into C57BL/6J mice orally gavaged with Intralipid.




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Effects of omega-O-acylceramide structures and concentrations in healthy and diseased skin barrier lipid membrane models [Research Articles]

Ceramides (Cers) with ultralong (~32-carbon) chains and -esterified linoleic acid, composing a subclass called omega-O-acylceramides (acylCers), are indispensable components of the skin barrier. Normal barriers typically contain acylCer concentrations of ~10 mol%; diminished concentrations, along with altered or missing long periodicity lamellar phase (LPP), and increased permeability accompany an array of skin disorders, including atopic dermatitis, psoriasis, and ichthyoses. We developed model membranes to investigate the effects of the acylCer structure and concentration on skin lipid organization and permeability. The model membrane systems contained six to nine Cer subclasses as well as fatty acids, cholesterol, and cholesterol sulfate; acylCer content—namely, acylCers containing sphingosine (Cer EOS), dihydrosphingosine (Cer EOdS), and phytosphingosine (Cer EOP) ranged from zero to 30 mol%. Systems with normal physiologic concentrations of acylCer mixture mimicked the permeability and nanostructure of human skin lipids (with regard to LPP, chain order, and lateral packing). The models also showed that the sphingoid base in acylCer significantly affects the membrane architecture and permeability and that Cer EOP, notably, is a weaker barrier component than Cer EOS and Cer EOdS. Membranes with diminished or missing acylCers displayed some of the hallmarks of diseased skin lipid barriers (i.e., lack of LPP, less ordered lipids, less orthorhombic chain packing, and increased permeability). These results could inform the rational design of new and improved strategies for the barrier-targeted treatment of skin diseases.




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Quantification of bile acids: a mass spectrometry platform for studying gut microbe connection to metabolic diseases [Research Articles]

Bile acids (BAs) serve multiple biological functions, ranging from the absorption of lipids and fat-soluble vitamins to serving as signaling molecules through the direct activation of dedicated cellular receptors. Synthesized by both host and microbial pathways, BAs are increasingly understood as participating in the regulation of numerous pathways relevant to metabolic diseases, including lipid and glucose metabolism, energy expenditure, and inflammation. Quantitative analyses of BAs in biological matrices can be problematic due to their unusual and diverse physicochemical properties, making optimization of a method that shows good accuracy, precision, efficiency of extraction, and minimized matrix effects across structurally distinct human and murine BAs challenging. Herein we develop and clinically validate a stable-isotope-dilution LC/MS/MS method for the quantitative analysis of numerous primary and secondary BAs in both human and mouse biological matrices. We also utilize this tool to investigate gut microbiota participation in the generation of structurally specific BAs in both humans and mice. We examine circulating levels of specific BAs and in a clinical case-control study of age- and gender-matched type 2 diabetes mellitus (T2DM) versus nondiabetics. BAs whose circulating levels are associated with T2DM include numerous 12α-hydroxyl BAs (taurocholic acid, taurodeoxycholic acid, glycodeoxycholic acid, deoxycholic acid, and 3-ketodeoxycholic acid), while taurohyodeoxycholic acid was negatively associated with diabetes. The LC/MS/MS-based platform described should serve as a robust, high-throughput investigative tool for studying the potential involvement of structurally specific BAs and the gut microbiome on both physiological and disease processes.




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Worming our way toward multiple evolutionary origins of convergent sterol pathways [Commentary]




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The citrus flavonoid nobiletin confers protection from metabolic dysregulation in high-fat-fed mice independent of AMPK [Research Articles]

Obesity, dyslipidemia, and insulin resistance, the increasingly common metabolic syndrome, are risk factors for CVD and type 2 diabetes that warrant novel therapeutic interventions. The flavonoid nobiletin displays potent lipid-lowering and insulin-sensitizing properties in mice with metabolic dysfunction. However, the mechanisms by which nobiletin mediates metabolic protection are not clearly established. The central role of AMP-activated protein kinase (AMPK) as an energy sensor suggests that AMPK is a target of nobiletin. We tested the hypothesis that metabolic protection by nobiletin required phosphorylation of AMPK and acetyl-CoA carboxylase (ACC) in mouse hepatocytes, in mice deficient in hepatic AMPK (Ampkβ1–/–), in mice incapable of inhibitory phosphorylation of ACC (AccDKI), and in mice with adipocyte-specific AMPK deficiency (iβ1β2AKO). We fed mice a high-fat/high-cholesterol diet with or without nobiletin. Nobiletin increased phosphorylation of AMPK and ACC in primary mouse hepatocytes, which was associated with increased FA oxidation and attenuated FA synthesis. Despite loss of ACC phosphorylation in Ampkβ1–/– hepatocytes, nobiletin suppressed FA synthesis and enhanced FA oxidation. Acute injection of nobiletin into mice did not increase phosphorylation of either AMPK or ACC in liver. In mice fed a high-fat diet, nobiletin robustly prevented obesity, hepatic steatosis, dyslipidemia, and insulin resistance, and it improved energy expenditure in Ampkβ1–/–, AccDKI, and iβ1β2AKO mice to the same extent as in WT controls. Thus, the beneficial metabolic effects of nobiletin in vivo are conferred independently of hepatic or adipocyte AMPK activation. These studies further underscore the therapeutic potential of nobiletin and begin to clarify possible mechanisms.




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Alirocumab, evinacumab, and atorvastatin triple therapy regresses plaque lesions and improves lesion composition in mice [Research Articles]

Atherosclerosis-related CVD causes nearly 20 million deaths annually. Most patients are treated after plaques develop, so therapies must regress existing lesions. Current therapies reduce plaque volume, but targeting all apoB-containing lipoproteins with intensive combinations that include alirocumab or evinacumab, monoclonal antibodies against cholesterol-regulating proprotein convertase subtilisin/kexin type 9 and angiopoietin-like protein 3, may provide more benefit. We investigated the effect of such lipid-lowering interventions on atherosclerosis in APOE*3-Leiden.CETP mice, a well-established model for hyperlipidemia. Mice were fed a Western-type diet for 13 weeks and thereafter matched into a baseline group (euthanized at 13 weeks) and five groups that received diet alone (control) or with treatment [atorvastatin; atorvastatin and alirocumab; atorvastatin and evinacumab; or atorvastatin, alirocumab, and evinacumab (triple therapy)] for 25 weeks. We measured effects on cholesterol levels, plaque composition and morphology, monocyte adherence, and macrophage proliferation. All interventions reduced plasma total cholesterol (37% with atorvastatin to 80% with triple treatment; all P < 0.001). Triple treatment decreased non-HDL-C to 1.0 mmol/l (91% difference from control; P < 0.001). Atorvastatin reduced atherosclerosis progression by 28% versus control (P < 0.001); double treatment completely blocked progression and diminished lesion severity. Triple treatment regressed lesion size versus baseline in the thoracic aorta by 50% and the aortic root by 36% (both P < 0.05 vs. baseline), decreased macrophage accumulation through reduced proliferation, and abated lesion severity. Thus, high-intensive cholesterol-lowering triple treatment targeting all apoB-containing lipoproteins regresses atherosclerotic lesion area and improves lesion composition in mice, making it a promising potential approach for treating atherosclerosis.




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Serum amyloid A is not incorporated into HDL during HDL biogenesis [Research Articles]

Liver-derived serum amyloid A (SAA) is present in plasma where it is mainly associated with HDL and from which it is cleared more rapidly than are the other major HDL-associated apolipoproteins. Although evidence suggests that lipid-free and HDL-associated forms of SAA have different activities, the pathways by which SAA associates and disassociates with HDL are poorly understood. In this study, we investigated SAA lipidation by hepatocytes and how this lipidation relates to the formation of nascent HDL particles. We also examined hepatocyte-mediated clearance of lipid-free and HDL-associated SAA. We prepared hepatocytes from mice injected with lipopolysaccharide or an SAA-expressing adenoviral vector. Alternatively, we incubated primary hepatocytes from SAA-deficient mice with purified SAA. We analyzed conditioned media to determine the lipidation status of endogenously produced and exogenously added SAA. Examining the migration of lipidated species, we found that SAA is lipidated and forms nascent particles that are distinct from apoA-I-containing particles and that apoA-I lipidation is unaltered when SAA is overexpressed or added to the cells, indicating that SAA is not incorporated into apoA-I-containing HDL during HDL biogenesis. Like apoA-I formation, generation of SAA-containing particles was dependent on ABCA1, but not on scavenger receptor class B type I. Hepatocytes degraded significantly more SAA than apoA-I. Taken together, our results indicate that SAA’s lipidation and metabolism by the liver is independent of apoA-I and that SAA is not incorporated into HDL during HDL biogenesis.




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Composition-function analysis of HDL subpopulations: influence of lipid composition on particle functionality [Research Articles]

The composition-function relationship of HDL particles and its effects on the mechanisms driving coronary heart disease (CHD) is poorly understood. We tested the hypothesis that the functionality of HDL particles is significantly influenced by their lipid composition. Using a novel 3D-separation method, we isolated five different-sized HDL subpopulations from CHD patients who had low preβ-1 functionality (low-F) (ABCA1-dependent cholesterol-efflux normalized for preβ-1 concentration) and controls who had either low-F or high preβ-1 functionality (high-F). Molecular numbers of apoA-I, apoA-II, and eight major lipid classes were determined in each subpopulation by LC-MS. The average number of lipid molecules decreased from 422 in the large spherical α-1 particles to 57 in the small discoid preβ-1 particles. With decreasing particle size, the relative concentration of free cholesterol (FC) decreased in α-mobility but not in preβ-1 particles. Preβ-1 particles contained more lipids than predicted; 30% of which were neutral lipids (cholesteryl ester and triglyceride), indicating that these particles were mainly remodeled from larger particles not newly synthesized. There were significant correlations between HDL-particle functionality and the concentrations of several lipids. Unexpectedly, the phospholipid:FC ratio was significantly correlated with large-HDL-particle functionality but not with preβ-1 functionality. There was significant positive correlation between particle functionality and total lipids in high-F controls, indicating that the lipid-binding capacity of apoA-I plays a major role in the cholesterol efflux capacity of HDL particles. Functionality and lipid composition of HDL particles are significantly correlated and probably both are influenced by the lipid-binding capacity of apoA-I.




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ANGPTL3, PCSK9, and statin therapy drive remarkable reductions in hyperlipidemia and atherosclerosis in a mouse model [Commentary]




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Is CYP2C70 the key to new mouse models to understand bile acids in humans? [Commentary]




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Lithium ion adduction enables UPLC-MS/MS-based analysis of multi-class 3-hydroxyl group-containing keto-steroids [Methods]

Steroids that contain a 3-hydroxyl group (3-OH steroids) are widely distributed in nature. During analysis with ESI-MS, they easily become dehydrated while in the protonated form, resulting in the production of several precursor ions and leading to low sensitivity of detection. To address this analytical challenge, here, we developed a method for the quantitation of 3-OH steroids by LC-MS/MS coupled with post-column addition of lithium (Li) ions to the mobile phase. The Li ion has a high affinity for the keto group of steroids, stabilizing their structures during ionization and permitting detection of analytes exclusively as the lithiated form. This not only improved the intensities of the precursor ions, but also promoted the formation of typical lithiated fragment ions. This improvement made the quantitation by multiple reaction monitoring more sensitive and reliable, as evidenced by 1.53–188 times enhanced detection sensitivity of 13 steroids that contained at least one keto and two hydroxyl groups or one keto and one 5-olefinic double bond, among 16 different 3-OH steroids. We deployed our newly developed method for profiling steroids in mouse brain tissue and identified six steroids in one tissue sample. Among these, 16-hydroxyestrone, tetrahydrocorticosterone, and 17α-hydroxypregnenolone were detected for the first time in the mouse brain. In summary, the method described here enables the detection of lithiated steroids by LC-MS/MS, including three 3-OH steroids not previously reported in the mouse brain. We anticipate that this new method may allow the determination of 3-OH steroids in different brain regions.




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Heritability of 596 lipid species and genetic correlation with cardiovascular traits in the Busselton Family Heart Study [Patient-Oriented and Epidemiological Research]

CVD is the leading cause of death worldwide, and genetic investigations into the human lipidome may provide insight into CVD risk. The aim of this study was to estimate the heritability of circulating lipid species and their genetic correlation with CVD traits. Targeted lipidomic profiling was performed on 4,492 participants from the Busselton Family Heart Study to quantify the major fatty acids of 596 lipid species from 33 classes. We estimated narrow-sense heritabilities of lipid species/classes and their genetic correlations with eight CVD traits: BMI, HDL-C, LDL-C, triglycerides, total cholesterol, waist-hip ratio, systolic blood pressure, and diastolic blood pressure. We report heritabilities and genetic correlations of new lipid species/subclasses, including acylcarnitine (AC), ubiquinone, sulfatide, and oxidized cholesteryl esters. Over 99% of lipid species were significantly heritable (h2: 0.06–0.50) and all lipid classes were significantly heritable (h2: 0.14–0.50). The monohexosylceramide and AC classes had the highest median heritabilities (h2 = 0.43). The largest genetic correlation was between clinical triglycerides and total diacylglycerol (rg = 0.88). We observed novel positive genetic correlations between clinical triglycerides and phosphatidylglycerol species (rg: 0.64–0.82), and HDL-C and alkenylphosphatidylcholine species (rg: 0.45–0.74). Overall, 51% of the 4,768 lipid species-CVD trait genetic correlations were statistically significant after correction for multiple comparisons. This is the largest lipidomic study to address the heritability of lipids and their genetic correlation with CVD traits. Future work includes identifying putative causal genetic variants for lipid species and CVD using genome-wide SNP and whole-genome sequencing data.




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Hexacosenoyl-CoA is the most abundant very long-chain acyl-CoA in ATP binding cassette transporter D1-deficient cells [Patient-Oriented and Epidemiological Research]

X-linked adrenoleukodystrophy (X-ALD) is an inherited disorder caused by deleterious mutations in the ABCD1 gene. The ABCD1 protein transports very long-chain FAs (VLCFAs) from the cytosol into the peroxisome where the VLCFAs are degraded through β-oxidation. ABCD1 dysfunction leads to VLCFA accumulation in individuals with X-ALD. FAs are activated by esterification to CoA before metabolic utilization. However, the intracellular pools and metabolic profiles of individual acyl-CoA esters have not been fully analyzed. In this study, we profiled the acyl-CoA species in fibroblasts from X-ALD patients and in ABCD1-deficient HeLa cells. We found that hexacosenoyl (26:1)-CoA, but not hexacosanoyl (26:0)-CoA, was the most abundantly concentrated among the VLCFA-CoA species in these cells. We also show that 26:1-CoA is mainly synthesized from oleoyl-CoA, and the metabolic turnover rate of 26:1-CoA was almost identical to that of oleoyl-CoA in both WT and ABCD1-deficient HeLa cells. The findings of our study provide precise quantitative and metabolic information of each acyl-CoA species in living cells. Our results suggest that VLCFA is endogenously synthesized as VLCFA-CoA through a FA elongation pathway and is then efficiently converted to other metabolites, such as phospholipids, in the absence of ABCD1.




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Dynamics of sphingolipids and the serine palmitoyltransferase complex in rat oligodendrocytes during myelination [Research Articles]

Myelin is a unique lipid-rich membrane structure that accelerates neurotransmission and supports neuronal function. Sphingolipids are critical myelin components. Yet sphingolipid content and synthesis have not been well characterized in oligodendrocytes, the myelin-producing cells of the CNS. Here, using quantitative real-time PCR, LC-MS/MS-based lipid analysis, and biochemical assays, we examined sphingolipid synthesis during the peak period of myelination in the postnatal rat brain. Importantly, we characterized sphingolipid production in isolated oligodendrocytes. We analyzed sphingolipid distribution and levels of critical enzymes and regulators in the sphingolipid biosynthetic pathway, with focus on the serine palmitoyltransferase (SPT) complex, the rate-limiting step in this pathway. During myelination, levels of the major SPT subunits increased and oligodendrocyte maturation was accompanied by extensive alterations in the composition of the SPT complex. These included changes in the relative levels of two alternative catalytic subunits, SPTLC2 and -3, in the relative levels of isoforms of the small subunits, ssSPTa and -b, and in the isoform distribution of the SPT regulators, the ORMDLs. Myelination progression was accompanied by distinct changes in both the nature of the sphingoid backbone and the N-acyl chains incorporated into sphingolipids. We conclude that the distribution of these changes among sphingolipid family members is indicative of a selective channeling of the ceramide backbone toward specific downstream metabolic pathways during myelination. Our findings provide insights into myelin production in oligodendrocytes and suggest how dysregulation of the biosynthesis of this highly specialized membrane could contribute to demyelinating diseases.




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Alcohol effects on hepatic lipid metabolism [Reviews]

Alcoholic liver disease (ALD) is the most prevalent type of chronic liver disease with significant morbidity and mortality worldwide. ALD begins with simple hepatic steatosis and progresses to alcoholic steatohepatitis, fibrosis, and cirrhosis. The severity of hepatic steatosis is highly associated with the development of later stages of ALD. This review explores the disturbances of alcohol-induced hepatic lipid metabolism through altered hepatic lipid uptake, de novo lipid synthesis, fatty acid oxidation, hepatic lipid export, and lipid droplet formation and catabolism. In addition, we review emerging data on the contributions of genetics and bioactive lipid metabolism in alcohol-induced hepatic lipid accumulation.




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HDL and pancreatic {beta} cells: a SMO-king gun? [Commentary]