em

LDL subclass lipidomics in atherogenic dyslipidemia:Effect of statin therapy on bioactive lipids and dense LDL [Patient-Oriented and Epidemiological Research]

Atherogenic LDL particles are physicochemically and metabolically heterogeneous. Can bioactive lipid cargo differentiate LDL subclasses, and thus potential atherogenicity?  What is the effect of statin treatment? Obese, hypertriglyceridemic, hypercholesterolemic males (n=12; Lp(a) <10 mg/dL) received pitavastatin calcium (4mg/day) for 180 days in a single-phase, unblinded study. The lipidomic profiles (23 lipid classes) of five LDL subclasses fractionated from baseline and post-statin plasmas were determined by LC-MS. At baseline and on statin treatment, very small dense LDL (LDL5) was preferentially enriched (up to 3-fold) in specific lysophospholipids (lysophosphatidylcholine (LPC); lysophosphatidylinositol (LPI); lyso-platelet activating factor (LPC(O)); 9,0.2 and 0.14 mol/mol apoB respectively; all p<0.001 versus LDL1-4), suggesting  elevated inflammatory potential per particle. In contrast, lysophosphatidylethanolamine was uniformly distributed among LDL subclasses. Statin treatment markedly reduced absolute plasma concentrations of all LDL subclasses (up to 33.5%), including LPC, LPI and LPC(O) contents (up to -52%), consistent with reduction in cardiovascular risk. Despite such reductions, lipotoxic ceramide load per particle in LDL1-5 (1.5 - 3 mol/mol apoB; 3 - 7 mmol/mol phosphatidylcholine) was either conserved or elevated. Bioactive lipids may constitute biomarkers for the cardiometabolic risk associated with specific LDL subclasses in atherogenic dyslipidemia at baseline, and with residual risk on statin therapy.




em

Ebola virus matrix protein VP40 hijacks the host plasma membrane to form the virus envelope [Images in Lipid Research]




em

A simple method for sphingolipid analysis of tissues embedded in optimal cutting temperature compound [Methods]

Mass spectrometry (MS) assisted lipidomic tissue analysis is a valuable tool to assess sphingolipid metabolism dysfunction in disease. These analyses can reveal potential pharmacological targets or direct mechanistic studies to better understand the molecular underpinnings and influence of sphingolipid metabolism alterations on disease etiology. But procuring sufficient human tissues for adequately powered studies can be challenging. Therefore, biorepositories, which hold large collections of cryopreserved human tissues, are an ideal retrospective source of specimens. However, this resource has been vastly underutilized by lipid biologists, as the components of optimal cutting temperature compound (OCT) used in cryopreservation are incompatible with MS analyses. Here, we report results indicating that OCT also interferes with protein quantification assays, and that the presence of OCT impacts the quantification of extracted sphingolipids by LC–ESI–MS/MS. We developed and validated a simple and inexpensive method that removes OCT from OCT-embedded tissues. Our results indicate that removal of OCT from cryopreserved tissues does not significantly affect the accuracy of sphingolipid measurements with LC–ESI–MS/MS. We used the validated method to analyze sphingolipid alterations in tumors compared with normal adjacent uninvolved lung tissues from individuals with lung cancer, and to determine the long-term stability of sphingolipids in OCT-cryopreserved normal lung tissues. We show that lung cancer tumors have significantly altered sphingolipid profiles and that sphingolipids are stable for up to 16 years in OCT-cryopreserved normal lung tissues. This validated sphingolipidomic OCT-removal protocol should be a valuable addition to the lipid biologist’s toolbox.




em

Phosphatidylinositol Metabolism, Phospholipases, Lipidomics, and Cancer:In Memoriam of Michael J. O. Wakelam (1955-2020) [Tribute]




em

Sphingolipids distribution at mitochondria-associated membranes (MAM) upon induction of apoptosis. [Research Articles]

The levels and composition of sphingolipids and related metabolites are altered in aging and common disorders such as diabetes and cancers, as well as in neurodegenerative, cardiovascular, and respiratory diseases. Changes in sphingolipids have been implicated as being an essential step in mitochondria-driven cell death. However, little is known about the precise sphingolipid composition and modulation in mitochondria or related organelles. Here, we used LC–MS/MS to analyze the presence of key components of the ceramide metabolic pathway in vivo and in vitro in purified endoplasmic reticulum (ER), mitochondria-associated membranes (MAM), and mitochondria. Specifically, we analyzed the sphingolipids in the three pathways that generate ceramide: sphinganine in the de novo ceramide pathway, sphingomyelin in the breakdown pathway, and sphingosine in the salvage pathway. We observed sphingolipid profiles in mouse liver, mouse brain, and a human glioma cell line (U251). We analyzed the quantitative and qualitative changes of these sphingolipids during staurosporine (STS)-induced apoptosis in U251 cells. Ceramide, especially C16-ceramide, levels increased during early apoptosis possibly through a conversion from mitochondrial sphinganine and sphingomyelin, but sphingosine and lactosyl- and glucosyl-ceramide levels were unaffected. We also found that ceramide generation is enhanced in mitochondria when sphingomyelin levels are decreased in the MAM. This decrease was associated with an increase in acid sphingomyelinase (ASM) activity in MAM. We conclude that meaningful sphingolipid modifications occur in MAM, the mitochondria, and ER during the early phases of apoptosis.




em

Mass spectrometry imaging and LC-MS reveal decreased cerebellar phosphoinositides in Niemann-Pick type C1-null mice [Research Articles]

Niemann-Pick disease, type C1 (NPC1) is a lipid storage disorder in which cholesterol and glycosphingolipids accumulate in late endosomal/lysosomal compartments because of mutations in the NPC1 gene. A hallmark of NPC1 is progressive neurodegeneration of the cerebellum as well as visceral organ damage; however, the mechanisms driving this disease pathology are not fully understood. Phosphoinositides are phospholipids that play distinct roles in signal transduction and vesicle trafficking. Here, we utilized consensus spectra analysis of MS imaging datasets and orthogonal LC–MS analyses to evaluate the spatial distribution of phosphoinositides and quantify them in cerebellar tissue from Npc1-null mice. Our results suggest significant depletion of multiple phosphoinositide species, including phosphatidylinositol (PI), phosphatidylinositol monophosphate (PIP), and bisphosphate (PIP2), in the cerebellum of the Npc1-null mice in both whole-tissue lysates and myelin-enriched fractions. Additionally, we observed altered levels of the regulatory enzyme phosphatidylinositol 4-kinase type 2 α (PI4K2A) in Npc1-null mice. In contrast, the levels of related kinases, phosphatases, and transfer proteins were unaltered in the Npc1-null mouse model as observed by Western blot analysis. Our discovery of phosphoinositide lipid biomarkers for NPC1 opens new perspectives on the pathophysiology underlying this fatal neurodegenerative disease.




em

Bisretinoid phospholipid and vitamin A aldehyde: Shining a light [Thematic Reviews]

Vitamin A aldehyde covalently bound to opsin protein is embedded in a phospholipid-rich membrane that supports photon absorption and phototransduction in photoreceptor cell outer segments. Following absorption of a photon, the 11-cis-retinal chromophore of visual pigment in photoreceptor cells isomerizes to all-trans-retinal. To maintain photosensitivity 11-cis-retinal must be replaced. At the same time, however, all-trans-retinal has to be handled so as to prevent nonspecific aldehyde activity. Some molecules of retinaldehyde upon release from opsin are efficiently reduced to retinol. Other molecules are released into the lipid phase of the disc membrane where they form a conjugate (N-retinylidene-PE, NRPE) through a Schiff base linkage with phosphatidylethanolamine (PE). The reversible formation of NRPE serves as a transient sink for retinaldehyde that is intended to return retinaldehyde to the visual cycle. However, if instead of hydrolyzing to PE and retinaldehyde, NRPE reacts with a second molecule of retinaldehyde a synthetic pathway is initiated that leads to the formation of multiple species of unwanted bisretinoid fluorophores. We report on recently identified members of the bisretinoid family some of which differ with respect to the acyl chains associated with the glycerol backbone. We discuss processing of the lipid moieties of these fluorophores in lysosomes of retinal pigment epithelial (RPE) cells, their fluorescence characters and new findings related to light and iron-associated oxidation of bisretinoids.




em

To Advance Trade and Climate Goals, ‘Global Britain’ Must Link Them

19 March 2020

Carolyn Deere Birkbeck

Associate Fellow, Global Economy and Finance Programme, and Hoffmann Centre for Sustainable Resource Economy

Dr Emily Jones

Associate Professor, Blavatnik School of Government

Dr Thomas Hale

Associate Professor, Blavatnik School of Government
COVID-19 is a sharp reminder of why trade policy matters. As the UK works to forge new trade deals, it must align its trade policy agenda with its climate ambition.

2020-03-19-Boris-Johnson-COP26.jpg

Boris Johnson at the launch of the UK-hosted COP26 UN Climate Summit at the Science Museum, London on February 4, 2020. Photo by Jeremy Selwyn - WPA Pool/Getty Images.

COVID-19 is a sharp reminder of why trade and climate policy matters. How can governments maintain access to critical goods and services, and ensure global supply chains function in times of crisis?

The timing of many trade negotiations is now increasingly uncertain, as are the UK’s plans to host COP26 in November. Policy work continues, however, and the EU has released its draft negotiating text for the new UK-EU trade deal, which includes a sub-chapter specifically devoted to climate. 

This is a timely reminder both of the pressing need for the UK to integrate its trade and climate policymaking and to use the current crisis-induced breathing space in international negotiations - however limited - to catch up on both strategy and priorities on this critical policy intersection.

The UK government has moved fast to reset its external trade relations post-Brexit. In the past month it formally launched bilateral negotiations with the EU and took up a seat at the World Trade Organization (WTO) as an independent member. Until the COVID-19 crisis hit, negotiations were also poised to start with the US.

The UK is also in the climate spotlight as host of COP26, the most important international climate negotiation since Paris in 2015, which presents a vital opportunity for the government to show leadership by aligning its trade agenda with its climate and sustainability commitments in bold new ways.

Not just an empty aspiration

This would send a signal that ‘Global Britain’ is not just an empty aspiration, but a concrete commitment to lead.

Not only is concerted action on the climate crisis a central priority for UK citizens, a growing and increasingly vocal group of UK businesses committed to decarbonization are calling on the government to secure a more transparent and predictable international market place that supports climate action by business.

With COP26, the UK has a unique responsibility to push governments to ratchet up ambition in the national contributions to climate action – and to promote coherence between climate ambition and wider economic policymaking, including on trade. If Britain really wants to lead, here are some concrete actions it should take.

At the national level, the UK can pioneer new ways to put environmental sustainability – and climate action in particular - at the heart of its trade agenda. Achieving the government’s ambitious Clean Growth Strategy - which seeks to make the UK the global leader in a range of industries including electric cars and offshore wind – should be a central objective of UK trade policy.

The UK should re-orient trade policy frameworks to incentivize the shift toward a more circular and net zero global economy. And all elements of UK trade policy could be assessed against environmental objectives - for example, their contribution to phasing out fossil fuels, helping to reverse overexploitation of natural resources, and support for sustainable agriculture and biodiversity.

In its bilateral and regional trade negotiations, the UK can and should advance its environment, climate and trade goals in tandem, and implementation of the Paris Agreement must be a core objective of the UK trade strategy.

A core issue for the UK is how to ensure that efforts to decarbonise the economy are not undercut by imports from high-carbon producers. Here, a ‘border carbon adjustment (BCA)’ - effectively a tax on the climate pollution of imports - would support UK climate goals. The EU draft negotiating text released yesterday put the issue of BCAs front and centre, making crystal clear that the intersection of climate, environment and trade policy goals will be a central issue for UK-EU trade negotiations.

Even with the United States, a trade deal can and should still be seized as a way to incentivize the shift toward a net zero and more circular economy. At the multilateral level, as a new independent WTO member, the UK has an opportunity to help build a forward-looking climate and trade agenda.

The UK could help foster dialogue, research and action on a cluster of ‘climate and trade’ issues that warrant more focused attention at the WTO. These include the design of carbon pricing policies at the border that are transparent, fair and support a just transition; proposals for a climate waiver for WTO rules; and identification of ways multilateral trade cooperation could promote a zero carbon and more circular global economy.  

To help nudge multilateral discussion along, the UK could also ask to join a critical ‘path finder’ effort by six governments, led by New Zealand, to pursue an agreement on climate change, trade and sustainability (ACCTS). This group aims to find ways forward on three central trade and climate issues: removing fossil fuel subsidies, climate-related labelling, and promoting trade in climate-friendly goods and services.

At present, the complex challenges at the intersection of climate, trade and development policy are too often used to defer or side-step issues deemed ‘too hard’ or ‘too sensitive’ to tackle. The UK could help here by working to ensure multilateral climate and trade initiatives share adjustment burdens, recognise the historical responsibility of developed countries, and do not unfairly disadvantage developing countries - especially the least developed.

Many developing countries are keen to promote climate-friendly exports as part of wider export diversification strategies  and want to reap greater returns from greener global value chains. Further, small island states and least-developed countries – many of which are Commonwealth members – that are especially vulnerable to the impacts of climate change and natural disasters, need support to adapt in the face of trade shocks and to build climate-resilient, trade-related infrastructure and export sectors.

As an immediate next step, the UK should actively support the growing number of WTO members in favour of a WTO Ministerial Statement on environmental sustainability and trade. It should work with its key trading partners in the Commonwealth and beyond to ensure the agenda is inclusive, supports achievement of the UN Sustainable Development Goals (SDGs) and helps developing countries benefit from a more environmentally sustainable global economy.

As the UK prepares to host COP26, negotiates deals with the EU and US, and prepares for its first WTO Ministerial meeting as an independent member, it must show it can lead the way nationally, bilaterally, and multilaterally. And to ensure the government acts, greater engagement from the UK’s business, civil society and research sectors is critical – we need all hands on deck to forge and promote concrete proposals for aligning UK trade policy with the climate ambition our world needs.




em

The G20’s Pandemic Moment

24 March 2020

Jim O'Neill

Chair, Chatham House
The planned emergency meeting of the G20 leaders could be the beginning of smart, thoughtful, collective steps to get beyond this challenging moment in history.

2020-03-24-COVID-Vaccine

A researcher works on a vaccine against coronavirus COVID-19 at the Copenhagen University research lab. Photo by THIBAULT SAVARY/AFP via Getty Images.

Having chaired the independent (and global) Antimicrobial Resistance (AMR) Review for David Cameron, I know a similar approach should have been taken quickly about COVID-19.

Similar not in precise nature but - in so far as incorporating infectious disease modelling, and using economic analysis to try to contain and solve it - it should be applied in parallel.

The AMR Review is well-known for highlighting the potential loss of life as well as the economic costs of an escalating growth of resistance to antimicrobials, and the inaction to prevent it.

In particular we showed that, by 2050, there could be around 10 million people each year dying from AMR, and an accumulated $100trn economic cost to the world from 2015 to 2050.

Horrendous outcomes

What is less focused on, as we showed in our final report, is that to prevent these horrendous outcomes, a 'mere' $42bn would need to be invested globally. This would give an investment return of something like 2,000%.

I shudder to think what policymakers could do if we don’t make these investments and we reach a situation - possibly accelerated itself by escalating the inappropriate use of antibiotics in this COVID-19 crisis - where we run out of useful antibiotics. It will be a much longer time period to find new vaccines to beat COVID-19.

In addition to this crisis, requiring G20 policymakers to back up their generous words about combatting AMR would mean they need to spend around $10bn instigating the generally agreed Market Incentive Awards to promote serious efforts by pharmaceutical companies.

In fact, given that the financial crisis we are also now in means companies are greatly dependent on our governments for their future survival, perhaps the pharma Industry will finally understand the real world concept of 'Pay or Play', where companies that don’t try to find new antibiotics are taxed to provide the pool of money for others that are bold enough to try. And realise there is a world coming of different risk-rewards for all, including them.

When applied to the COVID-19 challenge, it is useful to look at the required investment in accelerating as much as possible the efforts to find useful vaccines to beat it, but also to immediately introduce the therapeutics and diagnostics in countries that are so poorly prepared.

Those Asian countries affected early include a number that seem to have coped so far in keeping the crisis to a minimum because they had the appropriate therapeutics and diagnostics, despite not having vaccines. A sum of approximately $10 bn from the G20 would be sufficient to cover all these vital areas.

Now consider the economics of social distancing. As soon as it became apparent that our policymakers were heeding the Chinese method of trying to suppress COVID-19, it was immediately obvious that our economies would - at least for a short period - sustain the collapse of GDP that China self-imposed in February. From industrial production and other regular monthly data, the Chinese economy has declined by around 20%.

It is quite likely many other economies - probably each of the G7 countries - will experience something not too dissimilar in March. And, to stop our complex democracies from further immediate pressure including social disharmony, governments in many countries have needed to undertake dramatic unconventional steps.

Here in the UK, our new chancellor effectively had three budgets within less than a fortnight. And outside of the £330bn loan policy he has announced, at least £50bn worth of economic stimulus has been announced.

Many other G20 countries have undertaken their own versions of what I call 'People’s QE', many of them bigger packages - the US appears to be contemplating a stimulus as much as $2 trillion.

But, for the sake of illustration, if the UK package were the price for three months social distancing and this was repeated across the G20, then the total cost for all G20 countries - adjusted for relative size - would be in the vicinity of $1trillion.

If this isn’t accompanied by steps involving the best therapeutics and diagnostics, and we have to keep everyone isolated for one year, it would become at least $4trillion.

This may be 'back of the envelope' calculations which ignores the almost inevitable challenges for social cohesion in so many nations. But the G20 must spend something around $10bn immediately to put in absolute best standards all over the world, and another $10 bn to kickstart the market for new antibiotics.

This is a version of an article that first appeared in Project Syndicate.




em

Let's Emerge From COVID-19 with Stronger Health Systems

26 March 2020

Robert Yates

Director, Global Health Programme; Executive Director, Centre for Universal Health
Heads of state should grasp the opportunity to become universal health heroes to strengthen global health security

2020-03-26-Health-Protest

A "Big Insurance: Sick of It" rally in New York City. Photo by Mario Tama/Getty Images.

As the COVID-19 pandemic presents the greatest threat to human health in over a century, people turn to their states to resolve the crisis and protect their health, their livelihoods and their future well-being.

How leaders perform and respond to the pandemic is likely to define their premiership - and this therefore presents a tremendous opportunity to write themselves into the history books as a great leader, rescuing their people from a crisis. Just as Winston Churchill did in World War Two.

Following Churchill’s advice to “never let a good crisis go to waste”, if leaders take decisive action now, they may emerge from the COVID-19 crisis as a national hero. What leaders must do quickly is to mitigate the crisis in a way which has a demonstrable impact on people’s lives.

Given the massive shock caused by the pandemic to economies across the world, it is not surprising that heads of state and treasury ministers have implemented enormous economic stimulus packages to protect businesses and jobs – this was to be expected and has been welcome.

National heroes can be made

But, in essence, this remains primarily a health crisis. And one obvious area for leaders to act rapidly is strengthening their nation’s health system to stop the spread of the virus and successfully treat those who have fallen sick. It is perhaps here that leaders have the most to gain - or lose - and where national heroes can be made.

This is particularly the case in countries with weak and inequitable health systems, where the poor and vulnerable often fail to access the services they need. One major practical action that leaders can implement immediately is to launch truly universal, publicly-financed health reforms to cover their entire population – not only for COVID-19 services but for all services.

This would cost around 1-2% GDP in the short-term but is perfectly affordable in the current economic climate, given some of the massive fiscal stimuluses already being planned (for example, the UK is spending 15% GDP to tackle COVID-19).

Within one to two years, this financing would enable governments to implement radical supply side reforms including scaling up health workforces, increasing the supply of essential medicines, diagnostics and vaccines and building new infrastructure. It would also enable them to remove health service user fees which currently exclude hundreds of millions of people worldwide from essential healthcare. Worldwide these policies have proven to be effective, efficient, equitable and extremely popular.

And there is plenty of precedent for such a move. Universal health reform is exactly what political leaders did in the UK, France and Japan as post-conflict states emerging from World War Two. It is also the policy President Kagame launched in the aftermath of the genocide in Rwanda, as did Prime Minister Thaksin in Thailand after the Asian Financial Crisis in 2002, and the Chinese leadership did following the SARS crisis, also in 2003.

In China’s case, reform involved re-socialising the health financing system using around 2% GDP in tax financing to increase health insurance coverage from a low level of one-third right up to 96% of the population.

All these universal health coverage (UHC) reforms delivered massive health and economic benefits to the people - just what is needed now to tackle COVID-19 - and tremendous political benefits to the leaders that implemented them.

When considering the current COVID-19 crisis, this strategy would be particularly relevant for countries underperforming on health coverage and whose health systems are more likely to be overwhelmed if flooded with a surge of patients, such as India, Pakistan, Bangladesh, Myanmar, Indonesia and most of sub-Saharan Africa, where many governments spend less than 1% of their GDP on health and most people have to buy services over the counter.

But also the two OECD countries without a universal health system – the United States and Ireland – are seeing the threat of COVID-19 already fuelling the debate about the need to create national, publicly-financed health system. And the presidents of South Africa, Kenya and Indonesia have already committed their governments to eventually reach full population coverage anyway, and so may use this crisis to accelerate their own universal reforms. 

Although difficult to predict which leaders are likely to grasp the opportunity, if some of these countries now fast-track nationwide UHC, at least something good will be coming from the crisis, something which will benefit their people forever. And ensuring everyone accesses the services they need, including public health and preventive services, also provides the best protection against any future outbreaks becoming epidemics.

Every night large audiences are tuning in to press briefings fronted by their heads of state hungry for the latest update on the crisis and to get reassurance that their government’s strategy will bring the salvation they desperately need. To truly improve health security for people across the world, becoming UHC heroes could be the best strategic decision political leaders ever make.




em

Coronavirus and the Future of Democracy in Europe

31 March 2020

Hans Kundnani

Senior Research Fellow, Europe Programme
The pandemic raises difficult questions about whether liberal democracies can adequately protect their citizens.

2020-03-31-Police-Poland

Police officers wearing protective face masks patrol during coronavirus lockdown enforcement in Wroclaw, Poland. Photo by Bartek Sadowski/Bloomberg via Getty Images.

It is less than a month since we published our research paper on the future of democracy in Europe. But it feels like we now live in a different world. The coronavirus has already killed thousands of people in Europe, led to an unprecedented economic crisis and transformed daily life – and in the process raised difficult new questions about democracy.

The essence of our argument in the paper was that democracy in Europe should be deepened. But now there is a much more basic question about whether democracies can protect their citizens from the pandemic.

There has already been much discussion about whether authoritarian states will emerge stronger from this crisis than democracies. In particular, although the virus originated in China and the government initially seemed to struggle to deal with it, it was able to largely contain the outbreak in Hubei and deploy vast resources from the rest of the country to deal with it.

Come through the worst

China may have come through the worst of the health crisis – though a second wave of infections as restrictions are lifted is possible – and there have already been three times as many deaths in Italy, and twice as many in Spain, as in China (although there is increasing doubt about the accuracy of China’s figures).

However, it is not only authoritarian states that seem so far to have coped relatively well with the virus. In fact, some East Asian democracies appear to have done even better than China. At the time of writing South Korea, with a population of 51.5 million, has had only 144 death rates so far. Taiwan, with a population of nearly 24 million, has had only two deaths.

So rather than thinking in terms of the relative performance of authoritarian states and democracies, perhaps instead we should be asking what we in Europe can learn from East Asian democracies.

It is not yet clear why East Asian democracies were able to respond so effectively, especially as they did not all follow exactly the same approach. Whereas some quickly imposed restrictions on travel (for example, Taiwan suspended flights from China and then prohibited the entry of people from China and other affected countries) and quarantines, others used extensive testing and contact tracing, often making use of personal data collected from citizens.

Whatever the exact strategy they used, though, they did all act quickly and decisively – and the collective memory of the SARS outbreak in 2003 and other recent epidemics seems to have played a role in this. For example, following the SARS outbreak, Taiwan created a central epidemic command center. Europe, meanwhile, was hardly affected by SARS – and we seem to have assumed the coronavirus would be the same (although that does not quite explain why we were still so slow to react in February even after it was clear that the virus had spread to Italy).

However, while the relative success of East Asian democracies may have something to do with this recent experience of epidemics, it may also have something to do with the kind of democracies they are. It may be a simple matter of competence – the bureaucracy in Taiwan and South Korea may function better, and in particular in a more coordinated way, than in many European countries.

But it may also be more than that. In particular, it could be that East Asian democracies have a kind of 'authoritarian residue' that has helped in the initial response to this crisis. South Korea and Taiwan are certainly vibrant democracies – but they are also relatively new democracies compared to many in Europe. As a result, citizens may have a different relationship with the state and be more willing to accept sudden restrictions of freedoms, in particular on movement, and the use of personal data – at least in a crisis.

In that sense, the pandemic may be a challenge not to democracy as such but to liberal democracy in particular – in other words, a system of popular sovereignty together with guaranteed basic rights, such as including freedom of association and expression and checks and balances on executive power. There may now be difficult trade-offs to be made between those basic rights and security – and, after the experience of coronavirus, many citizens may choose security.

This brings us back to the issues we discussed in our research paper. Even before the coronavirus hit, there was already much discussion of a crisis of liberal democracy. In particular, there has been a debate about whether liberalism and democracy, which had long been assumed to go together, were becoming decoupled.

In particular, ‘illiberal democracies’ seemed to be emerging in many places including Europe (although, as we discuss in the paper, some analysts argue that the term is incoherent). This model of ‘illiberal democracy’ – in other words, one in which elections continue to be held but some individual rights are curtailed – may emerge stronger from this new crisis.

It is striking that Singapore – also seen as responding successfully to coronavirus – was seen as a paradigmatic ‘illiberal democracy’ long before Hungarian Prime Minister Viktor Orbán embraced the idea. In particular, there is little real opposition to the People’s Action Party, which has been in power since 1959.

Since this new crisis began, Orbán has gone further in suspending rights in Hungary. On March 11, he declared a state of emergency – as many other European countries have also done. But he has now gone further by passing legislation that allows him to govern by decree indefinitely and make it illegal to spread misinformation that undermines the government’s response to the pandemic. Clearly, this is a further decisive step in the deconsolidation of liberal democracy in Hungary.

So far, though, much of the discussion, particularly in the foreign policy world, has focused mainly on how to change popular perceptions that liberal democracies are failing in this crisis. For example, High Representative Josep Borrell, the European Union’s foreign minister, wrote last week of a 'battle of narratives'.

But this misses the point. It is not a matter of spinning the European model, but of taking seriously the substantial questions raised by the coronavirus about the ability of liberal democracies to adequately protect their citizens.




em

Emerging Lessons From COVID-19

2 April 2020

Jim O'Neill

Chair, Chatham House
Exploring what lessons can be learned from the crisis to improve society and the functioning of our economic model going forward.

2020-04-02-COVID-Italy

A man with a protective mask by the Coliseum in Rome during the height of Italy's COVID-19 epidemic. Photo by ALBERTO PIZZOLI/AFP via Getty Images.

As tentative evidence emerges that Italy and Spain may have reached - or are close to - the peak of the curve, this could demonstrate that not only can Asian countries get to grips with COVID-19, but so can western democracies. And, if so, this offers a path for the rest of us.

The last few weeks does demonstrate there is a role for governments to intervene in society, whether it be health, finance or any walk of life, as they have had to implement social distancing. Some have been forced, and the interventions are almost definitely only temporary, but perhaps some others may be less so.

Governments of all kinds now realise there is a connection between our health system quality and our economic capability. On an index of global economic sustainability that I presided over creating when I was at Goldman Sachs, the top ten best performing countries on growth environment scores includes eight of the best performing ten countries - so far- in handling the crisis in terms of deaths relative to their population.

Health system quality

The top three on the index (last calculated in 2014) were Singapore, Hong Kong and South Korea, all of which are exemplary to the rest of us on how to deal with this mess. This suggests that once we are through this crisis, a number of larger populated countries - and their international advisors such as the IMF - might treat the quality of countries' health systems just as importantly as many of the other more standard indicators in assessing ability to deal with shocks.

Policymakers have also been given a rather stark warning about other looming health disasters, especially antimicrobial resistance, of which antibiotic resistance lies at the heart. An independent review I chaired recommended 29 interventions, requiring $42 bn worth of investment, essentially peanuts compared to the costs of no solution, and the current economic collapse from COVID-19. It would seem highly likely to me that policymakers are going to treat this more seriously now.

As a clear consequence of the - hopefully, temporary - global economic collapse, our environment suddenly seems to be cleaner and fresher and, in this regard, we have bought some time in the battle against climate change. Surely governments are going to be able to have a bigger influence on fossil fuel extractors and intense users as we emerge from this crisis?

For any industries requiring government support, the government can make it clear this is dependent on certain criteria. And surely the days of excessive use of share buy backs and extreme maximisation of profit at the expense of other goals, are over?

It seems to me an era of 'optimisation' of a number of business goals is likely to be the mantra, including profits but other things too such as national equality especially as it relates to income. Here in the UK, the government has offered its strongest fiscal support to the lower end of the income earning range group and, in a single swoop, has presided over its most dramatic step towards narrowing income inequality for a long time.

This comes on top of a period of strong initiatives to support higher levels of minimum earnings, meaning we will emerge later in 2020, into 2021, and beyond, with lower levels of income inequality.

The geographic issue of rural versus urban is also key. COVID-19 has spread more easily in more tightly packed cities such as London, New York and many others. More geographically remote places, by definition, are better protected. Perhaps now there will be some more thought given by policymakers to the quality and purpose of life outside our big metropolitan areas.

Lastly, will China emerge from this crisis by offering a mammoth genuine gesture to the rest of the world, and come up, with, unlike, in 2008, a fiscal stimulus to its own consumers, that is geared towards importing a lot of things from the rest of the world? Now that would be good way of bringing the world back together again.

This is a version of an article originally published in The Article




em

Beware Russian and Chinese Positioning for After the Pandemic

9 April 2020

Keir Giles

Senior Consulting Fellow, Russia and Eurasia Programme
Authoritarian regimes can use the COVID-19 crisis to improve their international standing, taking advantage of others’ distraction. Their aims are different, but their methods have much in common.

2020-04-09-Russia-Aid-Serbia

An airlifter of the Russian Aerospace Forces prepares to fly to Serbia carrying equipment and professionals during the COVID-19 crisis. Photo by Russian Defence MinistryTASS via Getty Images.

Both Russia and China have mounted combined charm offensives and disinformation campaigns on the back of the pandemic. Shipments of ‘aid’ – reportedly of questionable utility and quality - have gone hand in hand with a concerted effort to deflect any blame from China for the early spread, and an ongoing drive by Russia to undermine states’ confidence and have sanctions lifted.

These concurrent operations have very different objectives, as Russia seeks to subvert international order while China is continuing its bid to demonstrate global leadership - but in both cases, they are seeking long-term gains by exploiting the inattention and distraction of their targets.

Both seek to present themselves as globally responsible stakeholders, but for divergent reasons – especially China which needs the rest of the world to recover and return to stability to ensure its own economic recovery. But despite this, the two campaigns appear superficially similar.

Fertile ground for disinformation

One reason lies in the unique nature of the current crisis. Unlike political issues that are local or regional in nature, COVID-19 affects everybody worldwide. The perceived lack of reliable information about the virus provides fertile ground for information and disinformation campaigns, especially feeding on fear, uncertainty and doubt. But Russia in particular would not be succeeding in its objectives without mis-steps and inattention by Western governments.

Confused reporting on Russia sending medical supplies to the United States showed Moscow taking advantage of a US administration in apparent disarray. Claims Russia was sending ’humanitarian aid’ were only belatedly countered by the US State Department pointing out it had been paid for. Meanwhile the earlier arrival of Russian military equipment in Italy also scored a propaganda victory for Russia, facilitated by curious passivity by the Italian government.

In both cases Russia also achieved secondary objectives. With the United States, Russia scored bonus points by shipping equipment produced by a subsidiary of a company under US sanctions. In the case of Italy, Russian state media made good use of misleading or heavily edited video clips to give the impression of widespread Italian acclaim for Russian aid, combined with disdain for the efforts of the EU.

Beijing’s external information campaigns have sought to deflect or defuse criticism of its early mishandling and misinformation on coronavirus and counter accusations of secrecy and falsifying data while also pursuing an opportunity to exercise soft power. For Moscow, current efforts boost a long-standing and intensive campaign to induce the lifting of sanctions, demonstrating if nothing else that sanctions are indeed an effective measure. Official and unofficial lobbying has intensified in numerous capital cities, and will inevitably find supporters.

But both the aid and the information campaigns are seriously flawed. While appropriate and useful aid for countries that are struggling should of course be welcomed, both Russian and Chinese equipment delivered to Europe has repeatedly been found to be inappropriate or defective

Russian photographs of cardboard boxes stacked loose and unsecured in a transport aircraft bound for the United States sparked alarm and disbelief among military and aviation experts - and there has still been no US statement on what exactly was purchased, and whether it was found to be fit for purpose when it arrived.

Reporting from Italy that the Russian equipment delivered there was ‘80% useless’ has not been contradicted by the Italian authorities. In fact, although the Italian sources criticizing Russia remain anonymous it is striking that - President Trump aside - no government has publicly endorsed materials and assistance received from Russia as actually being useful and helpful.

Even in Serbia, with its traditionally close ties with Russia, the only information forthcoming on the activities of the Russian Nuclear, Biological and Chemical Protection Troops and their equipment that arrived on April 3 was from Russian press releases.

Both countries’ strategic communications efforts are similarly fallible. China’s notoriously heavy-handed approach to its critics is of only limited use in the face of such a severe and immediate threat. One suggestion that the virus originated in the US – an early response to US criticism – has already been walked back by the Chinese diplomat who made it.

And Russia continues to be capable of spectacularly misjudging its targets. When investigative journalists looked more closely at the nature of the assistance to Italy, Russia’s official response was rage and personal threats, laying bare the real nature of the campaign and immediately alienating many of those whom Moscow had sought to win over.

Errors and deficiencies such as these provide opportunities to mitigate the worst side-effects of the campaigns. And actions by individuals can also mitigate much of the impact. The most effective disinformation plays on deeply emotional issues and triggers visceral rather than rational reactions.

Advocates of ’informational distancing’ as well as social distancing suggest a tactical pause to assess information calmly, instead of reacting or spreading it further unthinkingly. This approach would bolster not only calm dispassionate assessment of the real impact of Russian and Chinese actions, but also counter spreading of misinformation on the pandemic as a whole - especially when key sources of disinformation are national leaders seeking to politicize or profit from the crisis.

Limitations of Russian and Chinese altruism must be stated clearly and frankly to fill gaps in public understanding. Where help is genuine, it should of course be welcomed: but if it is the case that assistance received from Moscow or Beijing is not appropriate, not useful, or not fit for purpose, this should be acknowledged publicly.

Even without central direction or coordination with other Russian strategic communications efforts, the self-perpetuating Russian disinformation ecosystem continues to push narratives designed to undermine confidence in institutions and their ability to deal with the crisis. This too must continue to be monitored closely and countered where it matters.

In all cases, miscalculations by Russia or China that expose the true intent of their campaigns – no matter how different their objectives might be - should be watched for closely and highlighted where they occur.

Despite the enormity of the present emergency it is not a time for any government to relax its vigilance over longer-term threats. States must not lose sight of manoeuvres seeking to exploit weakness and distraction. If Russia and China emerge from the current crisis with enhanced authority and unjustifiably restored reputations, this will make it still harder to resist their respective challenges to the current rules-based international order in the future.




em

Privileging Local Food is Flawed Solution to Reduce Emissions

23 April 2020

Christophe Bellmann

Associate Fellow, Hoffmann Centre for Sustainable Resource Economy
The COVID-19 pandemic has brought food security and food imports to the forefront again. Some fear that the crisis could quickly strain global food supply chains as countries adopt new trade restrictions to avoid domestic food shortages.

2020-04-23-Trade-Food-Apples

Apples being picked before going into cold storage so they can be bought up until Christmas. Photo by Suzanne Kreiter/The Boston Globe via Getty Images.

The pressure of the coronavirus pandemic is adding to a widely held misconception that trade in food products is bad for the environment due to the associated ‘food miles’ – the carbon footprint of agricultural products transported over long distances.

This concept, developed by large retailers a decade ago, is often invoked as a rationale for restricting trade and choosing locally-produced food over imports. Consuming local food may seem sensible at first glance as it reduces the carbon footprint of goods and generates local employment. 

However, this assumption ignores the emissions produced during the production, processing or storage stages which often dwarf transport emissions. Other avenues to address the climate change impact of trade are more promising.

Demystifying food emissions

In the US, for example, food items travel more than 8,000 km on average before reaching the consumer. Yet transport only accounts for 11 per cent of total emissions with 83 per cent – mostly nitrous oxide (N2O) and methane (CH4) emissions – occurring at the production stage.

US Department of Agriculture data on energy use in the American food system echoes this finding, showing that processing, packaging, and selling of food represent ten times the energy used to transport food.

In practice, it may be preferable from an environmental perspective to consume lamb, onion or dairy products transported by sea because the lower emissions generated at the production stage offset those resulting from transport. Similarly, growing tomatoes under heated greenhouses in Sweden is often more emissions-intensive than importing open-grown ones from Southern Europe.

Seasonality also matters. British apples placed in storage for ten months leads to twice the level of emissions as that of South American apples sea-freighted to the UK. And the type of transport is also important as, overall, maritime transport generates 25 to 250 times less emissions than trucks, and air freight generates on average five times more emissions than road transport.

Therefore, air-freighted Kenyan beans have a much larger carbon footprint than those produced in the UK, but crossing Europe by truck to import Italian wine might generate more emissions than transatlantic shipments.

Finally, one should take into account the last leg of transport. A consumer driving more than 10 km to purchase 1 kg of fresh produce will generate proportionately more greenhouse gas (GHG) emissions than air-freighting 1 kg of produce from Kenya.

Shifting consumption towards local foods may reduce GHG emissions in sectors with relatively low emissions intensities but, when non-carbon dioxide emissions are taken into account, this is more often the exception than the rule.

Under these circumstances, preventing trade is an inefficient and expensive way of reducing GHG emissions. Bureau et al. for example, calculate that a global tariff maintaining the volume of trade at current levels until 2030 may reduce global carbon dioxide emissions by 3.5 per cent. However, this would be roughly seven times less than the full implementation of the Paris Agreement and cost equivalent to the current GDP of Brazil or 1.8 per cent of world GDP.

By preventing an efficient use of resources, such restrictions would also undermine the role of trade in offsetting possible climate-induced production shortfalls in some parts of the world and allowing people to access food when they can’t produce it themselves.

Reducing the climate footprint of trade

This is not to say that nothing should be done to tackle transport emissions. The OECD estimates that international trade-related freight accounted for over 5 per cent of total global fuel emissions with shipping representing roughly half of it, trucks 40 per cent, air 6 per cent and rail 2 per cent. With the projected tripling of freight transport by 2050, emissions from shipping are expected to rise between 50 and 250 per cent.

Furthermore, because of their international nature, these emissions are not covered by the Paris Agreement. Instead the two UN agencies regulating these sectors – the International Civil Aviation Organization and the International Maritime Organization – are responsible for reducing these emissions and, so far, significant progress has proven elusive.

Regional or bilateral free trade agreements to further stimulate trade could address this problem by exploiting comparative advantages. Impact assessments of those agreements often point towards increases in GHG emissions due to a boost in trade flows. In the future, such agreements could incorporate – or develop in parallel – initiatives to ensure carbon neutrality by connecting carbon markets among contracting parties or by taxing international maritime and air transport emissions.

Such initiatives could be combined with providing additional preferences in the form of enhanced market access to low-carbon food and healthier food. The EU, as one of the chief proponents of bilateral and regional trade agreements and a leader in promoting a transition to a low-carbon economy could champion such an approach.

This article is part of a series from the Chatham House Global Trade Policy Forum, designed to promote research and policy recommendations on the future of global trade. It is adapted from the research paper, Delivering Sustainable Food and Land Use Systems: The Role of International Trade, authored by Christophe Bellmann, Bernice Lee and Jonathan Hepburn.




em

Can Protest Movements in the MENA Region Turn COVID-19 Into an Opportunity for Change?

29 April 2020

Dr Georges Fahmi

Associate Fellow, Middle East and North Africa Programme
The COVID-19 pandemic will not in itself result in political change in the MENA region, that depends on the ability of both governments and protest movements to capitalize on this moment. After all, crises do not change the world - people do.

2020-04-28-covid-19-protest-movement-mena.jpg

An aerial view shows the Lebanese capital Beirut's Martyrs Square that was until recent months the gathering place of anti-government demonstrators, almost deserted during the novel coronavirus crisis, on 26 March 2020. Photo by -/AFP via Getty Images.

COVID-19 has offered regimes in the region the opportunity to end popular protest. The squares of Algiers, Baghdad, and Beirut – all packed with protesters over the past few months – are now empty due to the pandemic, and political gatherings have also been suspended. In Algeria, Iraq and Lebanon, COVID-19 has achieved what snipers, pro-regime propaganda, and even the economic crisis, could not.

Moreover, political regimes have taken advantage of the crisis to expand their control over the political sphere by arresting their opponents, such as in Algeria where the authorities have cracked down on a number of active voices of the Hirak movement. Similarly, in Lebanon, security forces have used the pandemic as an excuse to crush sit-ins held in Martyr’s Square in Beirut and Nour Square in Tripoli.

However, despite the challenges that the pandemic has brought, it also offers opportunities for protest movements in the region. While the crisis has put an end to popular mobilization in the streets, it has  created new forms of activism in the shape of solidarity initiatives to help those affected by its consequences.

In Iraq, for example, protest groups have directed their work towards awareness-raising and sharing essential food to help mitigate the problem of food shortages and rising prices across the country. In Algeria, Hirak activists have run online campaigns to raise awareness about the virus and have encouraged people to stay at home. Others have been cleaning and disinfecting public spaces. These initiatives increase the legitimacy of the protest movement, and if coupled with political messages, could offer these movements an important chance to expand their base of popular support.

Exposes economic vulnerability

Economic grievances, corruption and poor provision of public services have been among the main concerns of this recent wave of protests. This pandemic only further exposes the levels of economic vulnerability in the region. COVID-19 is laying bare the socio-economic inequalities in MENA countries; this is particularly evident in the numbers of people engaged in the informal economy with no access to social security, including health insurance and pensions.

Informal employment, approximately calculated by the share of the labour force not contributing to social security, is estimated to amount to 65.5% of total employment in Lebanon, 64.4% in Iraq, and 63.3% in Algeria. The crisis has underscored the vulnerability of this large percentage of the labour force who have been unable to afford the economic repercussions of following state orders to stay at home.

The situation has also called attention to the vital need for efficient public services and healthcare systems. According to the fifth wave of the Arab Barometer, 74.4% of people in Lebanon are dissatisfied with their country’s healthcare services, as are 67.8% of people in Algeria and 66.5% in Iraq.

Meanwhile, 66.2% of people in Lebanon believe it is necessary to pay a bribe in order to receive better healthcare, as do 56.2% of people in Iraq and 55.9% in Algeria. The COVID-19 crisis has highlighted the need for more government investment in public healthcare systems to render them more efficient and less corrupt, strengthening the protesters’ case for the need for radical socio-economic reforms.

On the geopolitical level, the crisis puts into question the stability-focused approach of Western powers towards the region. For years, Western powers have directed their aid towards security forces in the interests of combating terrorism but COVID-19 has proved itself to be a much more lethal challenge to both the region and the West.

Facing this new challenge requires international actors to reconsider their approach to include supporting health and education initiatives, as well as freedom of expression and transparency. As argued by Western policymakers themselves, it was China’s lack of transparency and slow response that enabled the proliferation of the virus, when it could have been contained in Wuhan back in December 2019.

This crisis therefore offers regional protest movements the opportunity to capitalize on this moment and push back against the policies of Western powers that have invested in regional stability only to the extent of combating Islamic jihad. 

But crises do not change the world, people do. The COVID-19 pandemic will not in itself result in political change in the MENA region. Rather, it brings opportunities and risks that, when exploited, will allow political actors to advance their own agendas. While the crisis has put an end to popular mobilization and allowed regimes to tighten their grip over the political sphere, behind these challenges lie real opportunities for protest movements.

The current situation represents a possibility for them to expand their popular base through solidarity initiatives and has exposed more widely the importance of addressing socio-economic inequalities. Finally, it offers the chance to challenge the stability-focused approach of Western powers towards the region which until now has predominantly focused on combating terrorism.




em

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

1 May 2020

Dr Charles Clift

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

2020-05-01-Tedros-WHO-COVID

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

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

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

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

Potentially more deadly

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

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

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

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

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

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

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

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

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

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

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

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

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

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




em

Bayesian Proteoform Modeling Improves Protein Quantification of Global Proteomic Measurements [Technology]

As the capability of mass spectrometry-based proteomics has matured, tens of thousands of peptides can be measured simultaneously, which has the benefit of offering a systems view of protein expression. However, a major challenge is that with an increase in throughput, protein quantification estimation from the native measured peptides has become a computational task. A limitation to existing computationally-driven protein quantification methods is that most ignore protein variation, such as alternate splicing of the RNA transcript and post-translational modifications or other possible proteoforms, which will affect a significant fraction of the proteome. The consequence of this assumption is that statistical inference at the protein level, and consequently downstream analyses, such as network and pathway modeling, have only limited power for biomarker discovery. Here, we describe a Bayesian model (BP-Quant) that uses statistically derived peptides signatures to identify peptides that are outside the dominant pattern, or the existence of multiple over-expressed patterns to improve relative protein abundance estimates. It is a research-driven approach that utilizes the objectives of the experiment, defined in the context of a standard statistical hypothesis, to identify a set of peptides exhibiting similar statistical behavior relating to a protein. This approach infers that changes in relative protein abundance can be used as a surrogate for changes in function, without necessarily taking into account the effect of differential post-translational modifications, processing, or splicing in altering protein function. We verify the approach using a dilution study from mouse plasma samples and demonstrate that BP-Quant achieves similar accuracy as the current state-of-the-art methods at proteoform identification with significantly better specificity. BP-Quant is available as a MatLab ® and R packages at https://github.com/PNNL-Comp-Mass-Spec/BP-Quant.




em

Quantitative proteomics of human heart samples collected in vivo reveal the remodeled protein landscape of dilated left atrium without atrial fibrillation [Research]

Genetic and genomic research has greatly advanced our understanding of heart disease. Yet, comprehensive, in-depth, quantitative maps of protein expression in hearts of living humans are still lacking. Using samples obtained during valve replacement surgery in patients with mitral valve prolapse (MVP), we set out to define inter-chamber differences, the intersect of proteomic data with genetic or genomic datasets, and the impact of left atrial dilation on the proteome of patients with no history of atrial fibrillation (AF).  We collected biopsies from right atria (RA), left atria (LA) and left ventricle (LV) of seven male patients with mitral valve regurgitation with dilated LA but no history of AF. Biopsy samples were analyzed by high-resolution mass spectrometry (MS), where peptides were pre-fractionated by reverse phase high-pressure liquid chromatography prior to MS measurement on a Q-Exactive-HF Orbitrap instrument. We identified 7,314 proteins based on 130,728 peptides. Results were confirmed in an independent set of biopsies collected from three additional individuals. Comparative analysis against data from post-mortem samples showed enhanced quantitative power and confidence level in samples collected from living hearts. Our analysis, combined with data from genome wide association studies suggested candidate gene associations to MVP, identified higher abundance in ventricle for proteins associated with cardiomyopathies and revealed the dilated LA proteome, demonstrating differential representation of molecules previously associated with AF, in non-AF hearts. This is the largest dataset of cardiac protein expression from human samples collected in vivo. It provides a comprehensive resource that allows insight into molecular fingerprints of MVP and facilitates novel inferences between genomic data and disease mechanisms. We propose that over-representation of proteins in ventricle is consequent not to redundancy but to functional need, and conclude that changes in abundance of proteins known to associate with AF are not sufficient for arrhythmogenesis.




em

Dysregulation of Exosome Cargo by Mutant Tau Expressed in Human-Induced Pluripotent Stem Cell (iPSC) Neurons Revealed by Proteomics Analyses [Research]

Accumulation and propagation of hyperphosphorylated tau (p-tau) is a common neuropathological hallmark associated with neurodegeneration of Alzheimer's disease (AD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), and related tauopathies. Extracellular vesicles, specifically exosomes, have recently been demonstrated to participate in mediating tau propagation in brain. Exosomes produced by human induced pluripotent stem cell (iPSC)-derived neurons expressing mutant Tau (mTau), containing the P301L and V337M Tau mutations of FTDP-17, possess the ability to propagate p-tau pathology after injection into mouse brain.  To gain an understanding of the mTau exosome cargo involved in tau pathogenesis, these pathogenic exosomes were analyzed by proteomics and bioinformatics. The data showed that mTau expression dysregulates the exosome proteome to result in (1) proteins uniquely present only in mTau, and not control exosomes, (2) the absence of proteins in mTau exosomes, uniquely present in control exosomes, and (3) shared proteins which were significantly up-regulated or down-regulated in mTau compared to control exosomes. Notably, mTau exosomes (not control exosomes) contain ANP32A (also known as I1PP2A), an endogenous inhibitor of the PP2A phosphatase which regulates the phosphorylation state of p-tau.  Several of the mTau exosome-specific proteins have been shown to participate in AD mechanisms involving lysosomes, inflammation, secretases, and related processes.  Furthermore, the mTau exosomes lacked a substantial portion of proteins present in control exosomes involved in pathways of localization, vesicle transport, and protein binding functions. The shared proteins present in both mTau and control exosomes represented exosome functions of vesicle-mediated transport, exocytosis, and secretion processes. These data illustrate mTau as a dynamic regulator of the biogenesis of exosomes to result in acquisition, deletion, and up- or down-regulation of protein cargo to result in pathogenic mTau exosomes capable of in vivo propagation of p-tau neuropathology in mouse brain. 




em

Seminal Plasma Proteome as an Indicator of Sperm Dysfunction and Low Sperm Motility [Research]

Molecular mechanisms underlying sperm motility have not been fully explained, particularly in chickens. The objective was to identify seminal plasma proteins associated with chicken sperm motility by comparing the seminal plasma proteomic profile of roosters with low sperm motility (LSM, n = 4) and high sperm motility (HSM, n = 4). Using a label-free MS-based method, a total of 522 seminal plasma proteins were identified, including 386 (~74%) previously reported and 136 novel ones. A total of 70 differentially abundant proteins were defined, including 48 more-abundant, 15 less-abundant, and seven proteins unique to the LSM group (specific proteins). Key secretory proteins like less-abundant ADGRG2 and more-abundant SPINK2 in the LSM suggested that the corresponding secretory tissues played a crucial role in maintaining sperm motility. Majority (80%) of the more-abundant and five specific proteins were annotated to the cytoplasmic domain which might be a result of higher plasma membrane damage and acrosome dysfunction in LSM. Additionally, more-abundant mitochondrial proteins were detected in LSM seminal plasma associated with lower spermatozoa mitochondrial membrane potential (m) and ATP concentrations. Further studies showed that the spermatozoa might be suffering from oxidative stress, as the amount of spermatozoa reactive oxygen species (ROS) were largely enhanced, seminal malondialdehyde (MDA) concentrations were increased, and the seminal plasma total antioxidant capacity (T-AOC) were decreased. Our study provides an additional catalog of chicken seminal plasma proteome and supports the idea that seminal plasma could be as an indicator of spermatozoa physiology. More-abundant of acrosome, mitochondria and sperm cytoskeleton proteins in the seminal plasma could be a marker of sperm dysfunction and loss of motility. The degeneration of spermatozoa caused the reduced seminal T-AOC and enhanced oxidative stress might be potential determinants of low sperm motility. These results could extend our understanding of sperm motility and sperm physiology regulation.




em

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.




em

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.




em

Chemical, Biological, Radiological and Nuclear Terrorism: Tomorrow's Threat

1 March 2007 , Number 11

In early November, the retiring head of Britain’s Security Service MI5, Dame Eliza Manningham-Buller, warned that the danger of a terror attack was ‘serious’ and ‘growing’, with as many as thirty plots underway. Traditional terrorism of the sort practised by the Irish Republican Army has given way to the possibility, if not the expectation, that groups such as Al Qaeda might make use of chemical, biological, radiological and nuclear weapons and materials in an attack in Britain. So what are the dangers?

GettyImages-200457787-001 copy.jpg

Syrian Special Forces in gas masks, Saudi Arabia 1990




em

Turkey: Emerging Identity

1 April 2007 , Number 10

Turkey is about to face both presidential and parliamentary elections. Many argue that the usual faultlines – the role of the military, secularism, Islam, nationalism and the Kurdish question – change incrementally at best. But mounting evidence is challenging this basic assumption.

Fadi Hakura

Consulting Fellow, Europe Programme

GettyImages-93326288.jpg

Seagulls fly near Suleymaniye mosque in Istanbul Turkey




em

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




em

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.




em

Crimea’s Occupation Exemplifies the Threat of Attacks on Cultural Heritage

4 February 2020

Kateryna Busol

Robert Bosch Stiftung Academy Fellow, Russia and Eurasia Programme
Societies, courts and policymakers should have a clearer awareness that assaults against cultural heritage constitute a creeping encroachment on a people’s identity, endangering its very survival.

2020-02-04-Bakhchysarai.jpg

'The destructive reconstruction of the 16th-century Bakhchysarai Palace is being conducted by a team with no experience of cultural sites, in a manner that erodes its authenticity and historical value.' Photo: Getty Images.

Violations against cultural property – such as archaeological treasures, artworks, museums or historical sites – can be no less detrimental to the survival of a nation than the physical persecution of its people. These assaults on heritage ensure the hegemony of some nations and distort the imprint of other nations in world history, sometimes to the point of eradication.

As contemporary armed conflicts in Syria, Ukraine and Yemen demonstrate, cultural property violations are not only a matter of the colonial past; they continue to be perpetrated, often in new, intricate ways.

Understandably, from a moral perspective, it is more often the suffering of persons, rather than any kind of ‘cultural’ destruction, that receives the most attention from humanitarian aid providers, the media or the courts. Indeed, the extent of the damage caused by an assault on cultural property is not always immediately evident, but the result can be a threat to the survival of a people. This is strikingly exemplified by what is currently happening in Crimea.

Ukraine’s Crimean peninsula has been occupied by Russia since February 2014, meaning that, under international law, the two states have been involved in an international armed conflict for the last six years.

While much attention has been paid to the alleged war crimes perpetrated by the occupying power, reports by international organizations and the International Criminal Court (ICC) have been less vocal on the issue of cultural property in Crimea. Where they do raise it, they tend to confine their findings to the issue of misappropriation.

However, as part of its larger policy of the annexation and Russification of the peninsula and its history, Russia has gone far beyond misappropriation.

Crimean artefacts have been transferred to Russia – without security justification or Ukrainian authorization as required by the international law of occupation – to be showcased at exhibitions celebrating Russia’s own cultural heritage. In 2016, the Tretyakov Gallery in Moscow staged its record-breaking Aivazovsky exhibition, which included 38 artworks from the Aivazovsky Museum in the Crimean town of Feodosia.

Other ‘cultural’ violations in the region include numerous unsanctioned archaeological excavations, whose findings are often unlawfully exported to Russia or end up on the black market.

There is also the example of Russia’s plan to establish a museum of Christianity in Ukraine’s UNESCO World Heritage site, the Ancient City of Tauric Chersonese. This is an indication of Russia’s policy of asserting itself as a bastion of Orthodox Christianity and culture in the Slavic world, with Crimea as one of the centres.

The harmful effects of Russia’s destructive cultural property policy can be seen in the situation of the Crimean Tatars, Ukraine’s indigenous Muslim people. Already depleted by a Stalin-ordered deportation in 1944 and previously repressed by the Russian Empire, the Crimean Tatars are now facing the destruction of much of the remainder of their heritage.

For example, Muslim burial grounds have been demolished to build the Tavrida Highway, which leads to the newly built Kerch Bridge connecting the peninsula to Russia.

The destructive reconstruction of the 16th-century Bakhchysarai Palace – the only remaining complete architectural ensemble of the indigenous people, included in the UNESCO World Heritage Tentative List – is another example of how the very identity of the Crimean Tatars is being threatened. This reconstruction is being conducted by a team with no experience of cultural sites, in a manner that erodes its authenticity and historical value – which is precisely as Russia intends.

There is a solid body of international and domestic law covering Russia’s treatment of Crimea’s cultural property.

Under the 1954 Hague Convention for the Protection of Cultural Property in the Event of Armed Conflict – ratified by both Ukraine and Russia – the occupying power must facilitate the safeguarding efforts of the national authorities in occupied territories. States parties must prevent any vandalism or misappropriation of cultural property, and, according to the first protocol of the convention, the occupying power is required to prevent any export of artefacts from the occupied territory.

The 1907 Hague Regulations and the 1949 Fourth Geneva Convention confirm that the authentic domestic legislation continues to apply in occupied territories. This leaves Russia with no excuse for non-compliance with Ukraine’s cultural property laws and imposing its own rules unless absolutely necessary.

Besides, both Ukrainian and Russian criminal codes penalise pillage in occupied territory, as well as unsanctioned archaeological excavations. As an occupying power, Russia must not just abstain from such wrongdoings in Crimea, but also duly investigate and prosecute the alleged misconduct.

The clarity of the international legal situation demonstrates that no exhibitions in continental Russia and no archaeological excavations which are not sanctioned by Ukraine can be justified. Likewise, any renovation or use of cultural sites, especially those on permanent or tentative UNESCO lists, must only be conducted pursuant to consultancy with and approval of the Ukrainian authorities.

But the resonance of the Crimean case goes beyond law and touches on issues of the very survival of a people. The Soviet deportation of the Crimean Tatars in 1944 did not only result in the deaths of individuals. Their footprints in Crimea have been gradually erased by baseless treason charges, the long exile of the indigenous community from their native lands and ongoing persecution.

First the Soviet Union and now Russia have targeted the Crimean Tatars’ cultural heritage to undermine their significance in the general historical narrative, making attempts to preserve or celebrate this culture seem futile. Russia is thus imposing its own historical and political hegemony at the expense of the Crimean Tatar and Ukrainian layers of Crimean history.

As exemplified by occupied Crimea, the manipulation and exploitation of cultural heritage can serve an occupying power’s wider policies of appropriating history and asserting its own dominance. Domestic cultural property proceedings are challenging due to the lack of access to the occupied territory, but they should still be pursued.

More effort is needed in the following areas: case prioritization; informing the documenters of alleged violations about the spectrum of cultural property crimes; developing domestic investigative and prosecutorial capacity, including by involving foreign expert consultancy; more proactively seeking bilateral and multilateral cooperation in art crime cases; liaising with auction houses (to track down objects originating from war-affected areas) and museums (to prevent the exhibition of the artefacts from occupied territories).

When possible, cultural property crimes should also be reported to the ICC.

Additionally, more international – public, policy, media and jurisprudential – attention to such violations is needed. Societies, courts and policymakers should have a clearer awareness that assaults against cultural heritage constitute a creeping encroachment on a people’s identity, endangering its very survival.




em

Putin or the System?

Invitation Only Research Event

20 February 2020 - 11:30am to 1:00pm

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

Event participants

Brian Taylor, Professor of Political Science and Chair, Maxwell School at Syracuse University; author of The Code of Putinism
Chair: Keir Giles, Senior Consulting Fellow, Russia and Eurasia Programme, Chatham House; author of Moscow Rules: What Drives Russia to Confront the West

 

To what extent are Russia's actions the product of one man's worldview? What events, ideas, psychologies and emotions have shaped Vladimir Putin and his inner circle over the past two decades? Is Russia headed for more of the same in the decades to come or is meaningful change possible? This event will examine Russia's, the Kremlin's and Putin's visions of the world and ask if they are indeed one and the same.

Anna Morgan

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




em

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.

2020-02-14-Zelenskyy.jpg

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.




em

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




em

Beware Russian and Chinese Positioning for After the Pandemic

9 April 2020

Keir Giles

Senior Consulting Fellow, Russia and Eurasia Programme
Authoritarian regimes can use the COVID-19 crisis to improve their international standing, taking advantage of others’ distraction. Their aims are different, but their methods have much in common.

2020-04-09-Russia-Aid-Serbia

An airlifter of the Russian Aerospace Forces prepares to fly to Serbia carrying equipment and professionals during the COVID-19 crisis. Photo by Russian Defence MinistryTASS via Getty Images.

Both Russia and China have mounted combined charm offensives and disinformation campaigns on the back of the pandemic. Shipments of ‘aid’ – reportedly of questionable utility and quality - have gone hand in hand with a concerted effort to deflect any blame from China for the early spread, and an ongoing drive by Russia to undermine states’ confidence and have sanctions lifted.

These concurrent operations have very different objectives, as Russia seeks to subvert international order while China is continuing its bid to demonstrate global leadership - but in both cases, they are seeking long-term gains by exploiting the inattention and distraction of their targets.

Both seek to present themselves as globally responsible stakeholders, but for divergent reasons – especially China which needs the rest of the world to recover and return to stability to ensure its own economic recovery. But despite this, the two campaigns appear superficially similar.

Fertile ground for disinformation

One reason lies in the unique nature of the current crisis. Unlike political issues that are local or regional in nature, COVID-19 affects everybody worldwide. The perceived lack of reliable information about the virus provides fertile ground for information and disinformation campaigns, especially feeding on fear, uncertainty and doubt. But Russia in particular would not be succeeding in its objectives without mis-steps and inattention by Western governments.

Confused reporting on Russia sending medical supplies to the United States showed Moscow taking advantage of a US administration in apparent disarray. Claims Russia was sending ’humanitarian aid’ were only belatedly countered by the US State Department pointing out it had been paid for. Meanwhile the earlier arrival of Russian military equipment in Italy also scored a propaganda victory for Russia, facilitated by curious passivity by the Italian government.

In both cases Russia also achieved secondary objectives. With the United States, Russia scored bonus points by shipping equipment produced by a subsidiary of a company under US sanctions. In the case of Italy, Russian state media made good use of misleading or heavily edited video clips to give the impression of widespread Italian acclaim for Russian aid, combined with disdain for the efforts of the EU.

Beijing’s external information campaigns have sought to deflect or defuse criticism of its early mishandling and misinformation on coronavirus and counter accusations of secrecy and falsifying data while also pursuing an opportunity to exercise soft power. For Moscow, current efforts boost a long-standing and intensive campaign to induce the lifting of sanctions, demonstrating if nothing else that sanctions are indeed an effective measure. Official and unofficial lobbying has intensified in numerous capital cities, and will inevitably find supporters.

But both the aid and the information campaigns are seriously flawed. While appropriate and useful aid for countries that are struggling should of course be welcomed, both Russian and Chinese equipment delivered to Europe has repeatedly been found to be inappropriate or defective

Russian photographs of cardboard boxes stacked loose and unsecured in a transport aircraft bound for the United States sparked alarm and disbelief among military and aviation experts - and there has still been no US statement on what exactly was purchased, and whether it was found to be fit for purpose when it arrived.

Reporting from Italy that the Russian equipment delivered there was ‘80% useless’ has not been contradicted by the Italian authorities. In fact, although the Italian sources criticizing Russia remain anonymous it is striking that - President Trump aside - no government has publicly endorsed materials and assistance received from Russia as actually being useful and helpful.

Even in Serbia, with its traditionally close ties with Russia, the only information forthcoming on the activities of the Russian Nuclear, Biological and Chemical Protection Troops and their equipment that arrived on April 3 was from Russian press releases.

Both countries’ strategic communications efforts are similarly fallible. China’s notoriously heavy-handed approach to its critics is of only limited use in the face of such a severe and immediate threat. One suggestion that the virus originated in the US – an early response to US criticism – has already been walked back by the Chinese diplomat who made it.

And Russia continues to be capable of spectacularly misjudging its targets. When investigative journalists looked more closely at the nature of the assistance to Italy, Russia’s official response was rage and personal threats, laying bare the real nature of the campaign and immediately alienating many of those whom Moscow had sought to win over.

Errors and deficiencies such as these provide opportunities to mitigate the worst side-effects of the campaigns. And actions by individuals can also mitigate much of the impact. The most effective disinformation plays on deeply emotional issues and triggers visceral rather than rational reactions.

Advocates of ’informational distancing’ as well as social distancing suggest a tactical pause to assess information calmly, instead of reacting or spreading it further unthinkingly. This approach would bolster not only calm dispassionate assessment of the real impact of Russian and Chinese actions, but also counter spreading of misinformation on the pandemic as a whole - especially when key sources of disinformation are national leaders seeking to politicize or profit from the crisis.

Limitations of Russian and Chinese altruism must be stated clearly and frankly to fill gaps in public understanding. Where help is genuine, it should of course be welcomed: but if it is the case that assistance received from Moscow or Beijing is not appropriate, not useful, or not fit for purpose, this should be acknowledged publicly.

Even without central direction or coordination with other Russian strategic communications efforts, the self-perpetuating Russian disinformation ecosystem continues to push narratives designed to undermine confidence in institutions and their ability to deal with the crisis. This too must continue to be monitored closely and countered where it matters.

In all cases, miscalculations by Russia or China that expose the true intent of their campaigns – no matter how different their objectives might be - should be watched for closely and highlighted where they occur.

Despite the enormity of the present emergency it is not a time for any government to relax its vigilance over longer-term threats. States must not lose sight of manoeuvres seeking to exploit weakness and distraction. If Russia and China emerge from the current crisis with enhanced authority and unjustifiably restored reputations, this will make it still harder to resist their respective challenges to the current rules-based international order in the future.




em

Victory and Memory: WW2 Narratives in Modern Day Russia and Ukraine

Invitation Only Research Event

11 May 2020 - 4:00pm to 5:30pm
Add to Calendar
Nina Tumarkin, Kathryn Wasserman Davis Professor of Slavic Studies; Professor of History; Director, Russian Area Studies Program, Wellesley College
Georgiy Kasianov, Head, Department of Contemporary History and Politics, Institute of History of Ukraine, National Academy of Sciences of Ukraine
Chair: Robert Brinkley, Chairman, Steering Committee, Ukraine Forum, Chatham House
In 2020 the world commemorates the 75th anniversary of the end of World War II. The Russian government has organized a wide range of activities to mark the USSR’s victory, aiming to raise the already prominent role of the USSR to a new level. Moscow also uses its narrative about the war as a propaganda tool. Ukraine, which suffered disproportionally huge human losses and material destruction during WWII, is departing from its Soviet legacy by focusing commemorative efforts on honouring the victims of WWII rather than on glorifying victory. 
 
This event will analyze the evolution of the WWII narratives in Russia and Ukraine in recent years. The panellists will discuss the role of those narratives in shaping national discourses and their implications for the countries' respective futures.
 
This event will be held on the record.

Anna Morgan

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

Department/project




em

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.




em

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.




em

A nematode sterol C4{alpha}-methyltransferase catalyzes a new methylation reaction responsible for sterol diversity [Research Articles]

Primitive sterol evolution plays an important role in fossil record interpretation and offers potential therapeutic avenues for human disease resulting from nematode infections. Recognizing that C4-methyl stenol products [8(14)-lophenol] can be synthesized in bacteria while C4-methyl stanol products (dinosterol) can be synthesized in dinoflagellates and preserved as sterane biomarkers in ancient sedimentary rock is key to eukaryotic sterol evolution. In this regard, nematodes have been proposed to convert dietary cholesterol to 8(14)-lophenol by a secondary metabolism pathway that could involve sterol C4 methylation analogous to the C2 methylation of hopanoids (radicle-type mechanism) or C24 methylation of sterols (carbocation-type mechanism). Here, we characterized dichotomous cholesterol metabolic pathways in Caenorhabditis elegans that generate 3-oxo sterol intermediates in separate paths to lophanol (4-methyl stanol) and 8(14)-lophenol (4-methyl stenol). We uncovered alternate C3-sterol oxidation and 7 desaturation steps that regulate sterol flux from which branching metabolite networks arise, while lophanol/8(14)-lophenol formation is shown to be dependent on a sterol C4α-methyltransferse (4-SMT) that requires 3-oxo sterol substrates and catalyzes a newly discovered 3-keto-enol tautomerism mechanism linked to S-adenosyl-l-methionine-dependent methylation. Alignment-specific substrate-binding domains similarly conserved in 4-SMT and 24-SMT enzymes, despite minimal amino acid sequence identity, suggests divergence from a common, primordial ancestor in the evolution of methyl sterols. The combination of these results provides evolutionary leads to sterol diversity and points to cryptic C4-methyl steroidogenic pathways of targeted convergence that mediate lineage-specific adaptations.­­




em

High density lipoprotein and its apolipoprotein-defined subspecies and risk of dementia [Patient-Oriented and Epidemiological Research]

Whether HDL is associated with dementia risk is unclear. In addition to apoA1, other apolipoproteins are found in HDL, creating subspecies of HDL that may have distinct metabolic properties. We measured apoA1, apoC3, and apoJ levels in plasma and apoA1 levels in HDL that contains or lacks apoE, apoJ, or apoC3 using a modified sandwich ELISA in a case-cohort study nested within the Ginkgo Evaluation of Memory Study. We included 995 randomly selected participants and 521 participants who developed dementia during a mean of 5.1 years of follow-up. The level of total apoA1 was not significantly related to dementia risk, regardless of the coexistence of apoC3, apoJ, or apoE. Higher levels of total plasma apoC3 were associated with better cognitive function at baseline (difference in Modified Mini-Mental State Examination scores tertile 3 vs. tertile 1: 0.60; 95% CI: 0.23, 0.98) and a lower dementia risk (adjusted hazard ratio tertile 3 vs. tertile 1: 0.73; 95% CI: 0.55, 0.96). Plasma concentrations of apoA1 in HDL and its apolipoprotein-defined subspecies were not associated with cognitive function at baseline or with the risk of dementia during follow-up. Similar studies in other populations are required to better understand the association between apoC3 and Alzheimer’s disease pathology.




em

Nonsynonymous SNPs in LPA homologous to plasminogen deficiency mutants represent novel null apo(a) alleles [Patient-Oriented and Epidemiological Research]

Plasma lipoprotein (a) [Lp(a)] levels are largely determined by variation in the LPA gene, which codes for apo(a). Genome-wide association studies (GWASs) have identified nonsynonymous variants in LPA that associate with low Lp(a) levels, although their effect on apo(a) function is unknown. We investigated two such variants, R990Q and R1771C, which were present in four null Lp(a) individuals, for structural and functional effects. Sequence alignments showed the R990 and R1771 residues to be highly conserved and homologous to each other and to residues associated with plasminogen deficiency. Structural modeling showed both residues to make several polar contacts with neighboring residues that would be ablated on substitution. Recombinant expression of the WT and R1771C apo(a) in liver and kidney cells showed an abundance of an immature form for both apo(a) proteins. A mature form of apo(a) was only seen with the WT protein. Imaging of the recombinant apo(a) proteins in conjunction with markers of the secretory pathway indicated a poor transit of R1771C into the Golgi. Furthermore, the R1771C mutant displayed a glycosylation pattern consistent with ER, but not Golgi, glycosylation. We conclude that R1771 and the equivalent R990 residue facilitate correct folding of the apo(a) kringle structure and mutations at these positions prevent the proper folding required for full maturation and secretion. To our knowledge, this is the first example of nonsynonymous variants in LPA being causative of a null Lp(a) phenotype.




em

Monitoring the itinerary of lysosomal cholesterol in Niemann-Pick Type C1-deficient cells after cyclodextrin treatment [Research Articles]

Niemann-Pick disease type C (NPC) disease is a lipid-storage disorder that is caused by mutations in the genes encoding NPC proteins and results in lysosomal cholesterol accumulation. 2-Hydroxypropyl-β-cyclodextrin (CD) has been shown to reduce lysosomal cholesterol levels and enhance sterol homeostatic responses, but CD’s mechanism of action remains unknown. Recent work provides evidence that CD stimulates lysosomal exocytosis, raising the possibility that lysosomal cholesterol is released in exosomes. However, therapeutic concentrations of CD do not alter total cellular cholesterol, and cholesterol homeostatic responses at the ER are most consistent with increased ER membrane cholesterol. To address these disparate findings, here we used stable isotope labeling to track the movement of lipoprotein cholesterol cargo in response to CD in NPC1-deficient U2OS cells. Although released cholesterol was detectable, it was not associated with extracellular vesicles. Rather, we demonstrate that lysosomal cholesterol trafficks to the plasma membrane (PM), where it exchanges with lipoprotein-bound cholesterol in a CD-dependent manner. We found that in the absence of suitable extracellular cholesterol acceptors, cholesterol exchange is abrogated, cholesterol accumulates in the PM, and reesterification at the ER is increased. These results support a model in which CD promotes intracellular redistribution of lysosomal cholesterol, but not cholesterol exocytosis or efflux, during the restoration of cholesterol homeostatic responses.




em

Role of angiopoietin-like protein 3 in sugar-induced dyslipidemia in rhesus macaques: suppression by fish oil or RNAi [Research Articles]

Angiopoietin-like protein 3 (ANGPTL3) inhibits lipid clearance and is a promising target for managing cardiovascular disease. Here we investigated the effects of a high-sugar (high-fructose) diet on circulating ANGPTL3 concentrations in rhesus macaques. Plasma ANGPTL3 concentrations increased ~30% to 40% after 1 and 3 months of a high-fructose diet (both P < 0.001 vs. baseline). During fructose-induced metabolic dysregulation, plasma ANGPTL3 concentrations were positively correlated with circulating indices of insulin resistance [assessed with fasting insulin and the homeostatic model assessment of insulin resistance (HOMA-IR)], hypertriglyceridemia, adiposity (assessed as leptin), and systemic inflammation [C-reactive peptide (CRP)] and negatively correlated with plasma levels of the insulin-sensitizing hormone adropin. Multiple regression analyses identified a strong association between circulating APOC3 and ANGPTL3 concentrations. Higher baseline plasma levels of both ANGPTL3 and APOC3 were associated with an increased risk for fructose-induced insulin resistance. Fish oil previously shown to prevent insulin resistance and hypertriglyceridemia in this model prevented increases of ANGPTL3 without affecting systemic inflammation (increased plasma CRP and interleukin-6 concentrations). ANGPTL3 RNAi lowered plasma concentrations of ANGPTL3, triglycerides (TGs), VLDL-C, APOC3, and APOE. These decreases were consistent with a reduced risk of atherosclerosis. In summary, dietary sugar-induced increases of circulating ANGPTL3 concentrations after metabolic dysregulation correlated positively with leptin levels, HOMA-IR, and dyslipidemia. Targeting ANGPTL3 expression with RNAi inhibited dyslipidemia by lowering plasma TGs, VLDL-C, APOC3, and APOE levels in rhesus macaques.




em

Model systems for studying the assembly, trafficking, and secretion of apoB lipoproteins using fluorescent fusion proteins [Research Articles]

apoB exists as apoB100 and apoB48, which are mainly found in hepatic VLDLs and intestinal chylomicrons, respectively. Elevated plasma levels of apoB-containing lipoproteins (Blps) contribute to coronary artery disease, diabetes, and other cardiometabolic conditions. Studying the mechanisms that drive the assembly, intracellular trafficking, secretion, and function of Blps remains challenging. Our understanding of the intracellular and intraorganism trafficking of Blps can be greatly enhanced, however, with the availability of fusion proteins that can help visualize Blp transport within cells and between tissues. We designed three plasmids expressing human apoB fluorescent fusion proteins: apoB48-GFP, apoB100-GFP, and apoB48-mCherry. In Cos-7 cells, transiently expressed fluorescent apoB proteins colocalized with calnexin and were only secreted if cells were cotransfected with microsomal triglyceride transfer protein. The secreted apoB-fusion proteins retained the fluorescent protein and were secreted as lipoproteins with flotation densities similar to plasma HDL and LDL. In a rat hepatoma McA-RH7777 cell line, the human apoB100 fusion protein was secreted as VLDL- and LDL-sized particles, and the apoB48 fusion proteins were secreted as LDL- and HDL-sized particles. To monitor lipoprotein trafficking in vivo, the apoB48-mCherry construct was transiently expressed in zebrafish larvae and was detected throughout the liver. These experiments show that the addition of fluorescent proteins to the C terminus of apoB does not disrupt their assembly, localization, secretion, or endocytosis. The availability of fluorescently labeled apoB proteins will facilitate the exploration of the assembly, degradation, and transport of Blps and help to identify novel compounds that interfere with these processes via high-throughput screening.




em

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




em

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.




em

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.




em

In Memoriam: Lina M. Obeid (1957-2019) [Tribute]




em

SSO and other putative inhibitors of FA transport across membranes by CD36 disrupt intracellular metabolism, but do not affect FA translocation [Research Articles]

Membrane-bound proteins have been proposed to mediate the transport of long-chain FA (LCFA) transport through the plasma membrane (PM). These proposals are based largely on reports that PM transport of LCFAs can be blocked by a number of enzymes and purported inhibitors of LCFA transport. Here, using the ratiometric pH indicator (2',7'-bis-(2-carboxyethyl)-5-(and-6-)-carboxyfluorescein and acrylodated intestinal FA-binding protein-based dual fluorescence assays, we investigated the effects of nine inhibitors of the putative FA transporter protein CD36 on the binding and transmembrane movement of LCFAs. We particularly focused on sulfosuccinimidyl oleate (SSO), reported to be a competitive inhibitor of CD36-mediated LCFA transport. Using these assays in adipocytes and inhibitor-treated protein-free lipid vesicles, we demonstrate that rapid LCFA transport across model and biological membranes remains unchanged in the presence of these purported inhibitors. We have previously shown in live cells that CD36 does not accelerate the transport of unesterified LCFAs across the PM. Our present experiments indicated disruption of LCFA metabolism inside the cell within minutes upon treatment with many of the "inhibitors" previously assumed to inhibit LCFA transport across the PM. Furthermore, using confocal microscopy and a specific anti-SSO antibody, we found that numerous intracellular and PM-bound proteins are SSO-modified in addition to CD36. Our results support the hypothesis that LCFAs diffuse rapidly across biological membranes and do not require an active protein transporter for their transmembrane movement.




em

A novel GPER antagonist protects against the formation of estrogen-induced cholesterol gallstones in female mice [Research Articles]

Many clinical studies and epidemiological investigations have clearly demonstrated that women are twice as likely to develop cholesterol gallstones as men, and oral contraceptives and other estrogen therapies dramatically increase that risk. Further, animal studies have revealed that estrogen promotes cholesterol gallstone formation through the estrogen receptor (ER) α, but not ERβ, pathway. More importantly, some genetic and pathophysiological studies have found that G protein-coupled estrogen receptor (GPER) 1 is a new gallstone gene, Lith18, on chromosome 5 in mice and produces additional lithogenic actions, working independently of ERα, to markedly increase cholelithogenesis in female mice. Based on computational modeling of GPER, a novel series of GPER-selective antagonists were designed, synthesized, and subsequently assessed for their therapeutic effects via calcium mobilization, cAMP, and ERα and ERβ fluorescence polarization binding assays. From this series of compounds, one new compound, 2-cyclohexyl-4-isopropyl-N-(4-methoxybenzyl)aniline (CIMBA), exhibits superior antagonism and selectivity exclusively for GPER. Furthermore, CIMBA reduces the formation of 17β-estradiol-induced gallstones in a dose-dependent manner in ovariectomized mice fed a lithogenic diet for 8 weeks. At 32 μg/day/kg CIMBA, no gallstones are found, even in ovariectomized ERα (–/–) mice treated with 6 μg/day 17β-estradiol and fed the lithogenic diet for 8 weeks. In conclusion, CIMBA treatment protects against the formation of estrogen-induced cholesterol gallstones by inhibiting the GPER signaling pathway in female mice. CIMBA may thus be a new agent for effectively treating cholesterol gallstone disease in women.­




em

Nanodomains can persist at physiologic temperature in plasma membrane vesicles and be modulated by altering cell lipids [Research Articles]

The formation and properties of liquid-ordered (Lo) lipid domains (rafts) in the plasma membrane are still poorly understood. This limits our ability to manipulate ordered lipid domain-dependent biological functions. Giant plasma membrane vesicles (GPMVs) undergo large-scale phase separations into coexisting Lo and liquid-disordered lipid domains. However, large-scale phase separation in GPMVs detected by light microscopy is observed only at low temperatures. Comparing Förster resonance energy transfer-detected versus light microscopy-detected domain formation, we found that nanodomains, domains of nanometer size, persist at temperatures up to 20°C higher than large-scale phases, up to physiologic temperature. The persistence of nanodomains at higher temperatures is consistent with previously reported theoretical calculations. To investigate the sensitivity of nanodomains to lipid composition, GPMVs were prepared from mammalian cells in which sterol, phospholipid, or sphingolipid composition in the plasma membrane outer leaflet had been altered by cyclodextrin-catalyzed lipid exchange. Lipid substitutions that stabilize or destabilize ordered domain formation in artificial lipid vesicles had a similar effect on the thermal stability of nanodomains and large-scale phase separation in GPMVs, with nanodomains persisting at higher temperatures than large-scale phases for a wide range of lipid compositions. This indicates that it is likely that plasma membrane nanodomains can form under physiologic conditions more readily than large-scale phase separation. We also conclude that membrane lipid substitutions carried out in intact cells are able to modulate the propensity of plasma membranes to form ordered domains. This implies lipid substitutions can be used to alter biological processes dependent upon ordered domains.




em

Lipid rafts as a therapeutic target [Thematic Reviews]

Lipid rafts regulate the initiation of cellular metabolic and signaling pathways by organizing the pathway components in ordered microdomains on the cell surface. Cellular responses regulated by lipid rafts range from physiological to pathological, and the success of a therapeutic approach targeting "pathological" lipid rafts depends on the ability of a remedial agent to recognize them and disrupt pathological lipid rafts without affecting normal raft-dependent cellular functions. In this article, concluding the Thematic Review Series on Biology of Lipid Rafts, we review current experimental therapies targeting pathological lipid rafts, including examples of inflammarafts and clusters of apoptotic signaling molecule-enriched rafts. The corrective approaches include regulation of cholesterol and sphingolipid metabolism and membrane trafficking by using HDL and its mimetics, LXR agonists, ABCA1 overexpression, and cyclodextrins, as well as a more targeted intervention with apoA-I binding protein. Among others, we highlight the design of antagonists that target inflammatory receptors only in their activated form of homo- or heterodimers, when receptor dimerization occurs in pathological lipid rafts. Other therapies aim to promote raft-dependent physiological functions, such as augmenting caveolae-dependent tissue repair. The overview of this highly dynamic field will provide readers with a view on the emerging concept of targeting lipid rafts as a therapeutic strategy.




em

The ins and outs of lipid rafts: functions in intracellular cholesterol homeostasis, microparticles, and cell membranes [Thematic Reviews]

Cellular membranes are not homogenous mixtures of proteins; rather, they are segregated into microdomains on the basis of preferential association between specific lipids and proteins. These microdomains, called lipid rafts, are well known for their role in receptor signaling on the plasma membrane (PM) and are essential to such cellular functions as signal transduction and spatial organization of the PM. A number of disease states, including atherosclerosis and other cardiovascular disorders, may be caused by dysfunctional maintenance of lipid rafts. Lipid rafts do not occur only in the PM but also have been found in intracellular membranes and extracellular vesicles (EVs). Here, we focus on discussing newly discovered functions of lipid rafts and microdomains in intracellular membranes, including lipid and protein trafficking from the ER, Golgi bodies, and endosomes to the PM, and we examine lipid raft involvement in the production and composition of EVs. Because lipid rafts are small and transient, visualization remains challenging. Future work with advanced techniques will continue to expand our knowledge about the roles of lipid rafts in cellular functioning.




em

Hematopoiesis is regulated by cholesterol efflux pathways and lipid rafts: connections with cardiovascular diseases [Thematic Reviews]

Lipid rafts are highly ordered regions of the plasma membrane that are enriched in cholesterol and sphingolipids and play important roles in many cells. In hematopoietic stem and progenitor cells (HSPCs), lipid rafts house receptors critical for normal hematopoiesis. Lipid rafts also can bind and sequester kinases that induce negative feedback pathways to limit proliferative cytokine receptor cycling back to the cell membrane. Modulation of lipid rafts occurs through an array of mechanisms, with optimal cholesterol efflux one of the major regulators. As such, cholesterol homeostasis also regulates hematopoiesis. Increased lipid raft content, which occurs in response to changes in cholesterol efflux in the membrane, can result in prolonged receptor occupancy in the cell membrane and enhanced signaling. In addition, certain diseases, like diabetes, may contribute to lipid raft formation and affect cholesterol retention in rafts. In this review, we explore the role of lipid raft-related mechanisms in hematopoiesis and CVD (specifically, atherosclerosis) and discuss how defective cholesterol efflux pathways in HSPCs contribute to expansion of lipid rafts, thereby promoting myelopoiesis and thrombopoiesis. We also discuss the utility of cholesterol acceptors in contributing to lipid raft regulation and disruption, and highlight the potential to manipulate these pathways for therapeutic gain in CVD as well as other disorders with aberrant hematopoiesis.