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Episode 18 - The Internet of the EU (IoEU) Website crashes, Oculus games & WWDC

Host Matt Egan is joined this week by Henry Burrell, staff writer at Macworld UK to talk about the EU referendum website crashing Lewis Painter, staff writer at PC Advisor, jumps in to chat about Oculus Rift games and how immersive they are. Finally regular David Price comes on to talk about Apple's upcoming WWDC software developer conference and what we can (and cannot) expect.  


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Episode 90 - The Internet of Meaty Topics (IoMT) Digital afterlife, net neutrality and GDPR emails

Oh boy what a meaty session we have for you as Christina Mercer, Somrata Sarkar, David Price and Henry Burrell tackle three whopics (whopping topics) head on.


Somrata takes us into the sometimes scary thoughts of our own digital afterlives. Should we be worried that we'll end up as misrepresentative chat bots one day? Who will have the authority to police the companies that harvest our data?


Then Christina explains the knife edge America is on when it comes to net neutrality. Despite recent hope, there's still a chance the web across the pond will be ruthlessly metered and segmented.


Finally David asks us if we've checked our unused email accounts recently, as there might be a lot of desperate noodle companies in there begging you to stay on their mailing lists.


 

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Episode 107 - The Internet of Super Sleuthing (IoSS) Detective Pikachu and Facebook still sucks

We were all surprised this week with the weirdly excellent trailer for Detective Pikachu with Ryan Reynolds voicing the yellow pocket scamp. Dom Preston drops in to tell us how Nintendo is getting into film and we laugh about the Bob Hoskins Mario film. We also talk about the moving new Tetris game (yes, it's made people cry).


Scott Carey then lays out the latest Facebook expose and asks if Zuck and Sheryl Sandberg are ruling the company properly - should it be actively siding politically and morally against misuses of the platform? Or is it too big for them to even control?

 

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Comparative profiling and comprehensive quantification of stratum corneum ceramides in humans and mice by LC-MS/MS [Research Articles]

Ceramides are the predominant lipids in the stratum corneum (SC) and are crucial components for normal skin barrier function. Although the composition of various ceramide classes in the human SC has been reported, that in mice is still unknown, despite mice being widely used as animal models of skin barrier function. Here, we performed LC–MS/MS analyses using recently available ceramide class standards to measure 25 classes of free ceramides and 5 classes of protein-bound ceramides from the human and mouse SC. Phytosphingosine-type ceramides (P-ceramides) and 6-hydroxy sphingosine-type ceramides (H-ceramides), which both contain an additional hydroxyl group, were abundant in human SC (35% and 45% of total ceramides, respectively). In contrast, in mice, P-ceramides and H-ceramides were present at ~1% and undetectable levels, respectively, and sphingosine-type ceramides accounted for ~90%. In humans, ceramides containing α-hydroxy FA were abundant, whereas ceramides containing β-hydroxy FA (B-ceramides) or -hydroxy FA were abundant in mice. The hydroxylated β-carbon in B-ceramides was in the (R)-configuration. Genetic knockout of β-hydroxy acyl-CoA dehydratases in HAP1 cells increased B-ceramide levels, suggesting that β-hydroxy acyl-CoA, an FA-elongation cycle intermediate in the endoplasmic reticulum, is a substrate for B-ceramide synthesis. We anticipate that our methods and findings will help to elucidate the role of each ceramide class in skin barrier formation and in the pathogenesis of skin disorders.




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Coronavirus: Why The EU Needs to Unleash The ECB

18 March 2020

Pepijn Bergsen

Research Fellow, Europe Programme
COVID-19 presents the eurozone with an unprecedented economic challenge. So far, the response has been necessary, but not enough.

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EU President of Council Charles Michel chairs the coronavirus meeting with the leaders of EU member countries via teleconference on March 17, 2020. Photo by EU Council / Pool/Anadolu Agency via Getty Images.

The measures taken to limit the spread of the coronavirus - in particular social distancing -  come with significant economic costs, as the drop both in demand for goods and services and in supply due to workers being at home sick will create a short-term economic shock not seen in modern times.

Sectors that are usually less affected by regular economic swings such as transport and tourism are being confronted with an almost total collapse in demand. In the airline sector, companies are warning they might only be able to hold out for a few months more.

Building on the calls to provide income support to all citizens and shore up businesses, European leaders should now be giving explicit permission to the European Central Bank (ECB) to provide whatever financial support is needed.

Although political leaders have responded to the economic threat, the measures announced across the continent have mainly been to support businesses. The crisis is broader and deeper than the current response.

Support for weaker governments

The ECB already reacted to COVID-19 by announcing measures to support the banking system, which is important to guarantee the continuity of the European financial system and to ensure financially weaker European governments do not have to confront a failing banking system as well.

Although government-subsidised reduced working hours and sick pay are a solution for many businesses and workers, crucially they are not for those working on temporary contracts or the self-employed. They need direct income support.

This might come down to instituting something that looks like a universal basic income (UBI), and ensuring money keeps flowing through the economy as much as possible to help avoid a cascade of defaults and significant long-term damage.

But while this is likely to be the most effective remedy to limit the medium-term impact on the economy, it is particularly costly. Just as an indication, total compensation of employees was on average around €470bn per month in the eurozone last year.

Attempting to target payments using existing welfare payment channels would reduce costs, but is difficult to implement and runs the risk of many households and businesses in need missing out.

The increase in spending and lost revenue associated with these support measures dwarf the fiscal response to the 2008-09 financial crisis. The eurozone economy could contract by close to 10% this year and budget deficits are likely be in double digits throughout the bloc.

The European Commission has already stated member states are free to spend whatever is necessary to combat the crisis, which is not surprising given the Stability and Growth Pact - which includes the fiscal rules - allows for such eventualities.

Several eurozone countries do probably have the fiscal space to deal with this. Countries such as Germany and the Netherlands have run several years of balanced budgets recently and significantly decreased their debt levels. For countries such as Italy, and even France, it is a different story and the combination of much higher spending and a collapse in tax revenue is more likely to lead to questions in the market over the sustainability of their debt levels. In order to avoid this, the Covid-19 response must be financed collectively.

The Eurogroup could decide to use the European Stability Mechanism (ESM) to provide states with the funds, while suitably ditching the political conditionality that came with previous bailout. But the ESM currently has €410bn in remaining lending capacity, which is unlikely to be enough and difficult to rapidly increase.

So this leaves the ECB to pick up the tab of national governments’ increase in spending, as the only institution with effectively unlimited monetary firepower. But a collective EU response is complicated by the common currency, and particularly by the role of the ECB.

The ECB can’t just do whatever it likes and is limited more than other major central banks in its room for manoeuvre. It does have a programme to buy government bonds but this relies on countries agreeing to a rescue programme within the context of the ESM, with all the resulting political difficulties.

There are two main ways that the ECB could finance the response to the crisis. First, it could buy up more or all bonds issued by the member states. A first step in this direction would be to scrap the limits on the bonds it can buy. Through self-imposed rules, the ECB can only buy up to a third of every country’s outstanding public debt. There are good reasons for this in normal times, but these are not normal times. With the political blessing of the European Council, the Eurosystem of central banks could then start buying bonds issued by governments to finance whatever expenditure they deem necessary to combat the crisis.

Secondly, essentially give governments an overdraft with the ECB or the national central banks. Although a central bank lending directly to governments is outlawed by the European treaties, the COVID-19 crisis means these rules should be temporarily suspended by the European Council.

Back in 2012, the then president of the ECB, Mario Draghi, proclaimed the ECB would do whatever it takes, within its mandate, to save the euro, which was widely seen as a crucial step towards solving the eurozone crisis. The time is now right for eurozone political leaders to explicitly tell the ECB that together they can do whatever it takes to save the eurozone economy through direct support for businesses and households.




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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.

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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.




eu

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. 




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Europe and the Mediterranean: Eyeing Other Shores

1 July 2008 , Number 3

Ahead of the French holiday rush for relaxation in warm waters, President Nicolas Sarkozy has flung himself into the Mediterranean policy pool. Not content with existing arrangements, plans and processes for dealing with those on the other shore, the President has built his very own scheme, now adopted by the European Union. But the tides have not been altogether kind.

Claire Spencer

Head, Middle East Programme, Chatham House




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United States Presidency and Europe: Over to You, Europe

1 November 2008 , Number 1

The race is on to ensure that relations between the United States and its European allies are set on the right track from the outset of Barack Obama’s presidency. Although they may not like it, the main responsibility for ensuring that the transatlantic relationship does not stumble into a series of disappointed expectations in its first critical year lies more in European capitals than in Washington.

Robin Niblett

Director and Chief Executive, Chatham House




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Europe: Fifty Years On - Essay Competition

1 January 2007 ,

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




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Towards a Low-Carbon Future: China and the European Union

1 October 2007 , Number 7

Chinese goods seem to flood western markets: computers, light bulbs, sweaters, T-shirts and bras. The instinct is to try to protect home producers. A better plan would be to work with Beijing on producing products for the next industrial revolution – the creation of a low-carbon economy. But that would take real vision and political courage.

Bernice Lee OBE

Research Director; Executive Director, Hoffmann Centre for Sustainable Resource Economy

Nick Mabey

Founding director and Chief Executive, E3G




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The multilevel identity politics of the 2019 Eurovision Song Contest

7 May 2020 , Volume 96, Number 3

Galia Press-Barnathan and Naama Lutz

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




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What Putin's Constitutional Shakeup Means

16 January 2020

Professor Nikolai Petrov

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

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

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

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

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

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

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

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

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

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

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




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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.




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Lipid rafts in glial cells: role in neuroinflammation and pain processing [Thematic Reviews]

Activation of microglia and astrocytes secondary to inflammatory processes contributes to the development and perpetuation of pain with a neuropathic phenotype. This pain state presents as a chronic debilitating condition and affects a large population of patients with conditions like rheumatoid arthritis and diabetes, or after surgery, trauma, or chemotherapy. Here, we review the regulation of lipid rafts in glial cells and the role they play as a key component of neuroinflammatory sensitization of central pain signaling pathways. In this context, we introduce the concept of an inflammaraft (i-raft), enlarged lipid rafts harboring activated receptors and adaptor molecules and serving as an organizing platform to initiate inflammatory signaling and the cellular response. Characteristics of the inflammaraft include increased relative abundance of lipid rafts in inflammatory cells, increased content of cholesterol per raft, and increased levels of inflammatory receptors, such as toll-like receptor (TLR)4, adaptor molecules, ion channels, and enzymes in lipid rafts. This inflammaraft motif serves an important role in the membrane assembly of protein complexes, for example, TLR4 dimerization. Operating within this framework, we demonstrate the involvement of inflammatory receptors, redox molecules, and ion channels in the inflammaraft formation and the regulation of cholesterol and sphingolipid metabolism in the inflammaraft maintenance and disruption. Strategies for targeting inflammarafts, without affecting the integrity of lipid rafts in noninflammatory cells, may lead to developing novel therapies for neuropathic pain states and other neuroinflammatory conditions.




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Lipid rafts and neurodegeneration: structural and functional roles in physiologic aging and neurodegenerative diseases [Thematic Reviews]

Lipid rafts are small, dynamic membrane areas characterized by the clustering of selected membrane lipids as the result of the spontaneous separation of glycolipids, sphingolipids, and cholesterol in a liquid-ordered phase. The exact dynamics underlying phase separation of membrane lipids in the complex biological membranes are still not fully understood. Nevertheless, alterations in the membrane lipid composition affect the lateral organization of molecules belonging to lipid rafts. Neural lipid rafts are found in brain cells, including neurons, astrocytes, and microglia, and are characterized by a high enrichment of specific lipids depending on the cell type. These lipid rafts seem to organize and determine the function of multiprotein complexes involved in several aspects of signal transduction, thus regulating the homeostasis of the brain. The progressive decline of brain performance along with physiological aging is at least in part associated with alterations in the composition and structure of neural lipid rafts. In addition, neurodegenerative conditions, such as lysosomal storage disorders, multiple sclerosis, and Parkinson’s, Huntington’s, and Alzheimer’s diseases, are frequently characterized by dysregulated lipid metabolism, which in turn affects the structure of lipid rafts. Several events underlying the pathogenesis of these diseases appear to depend on the altered composition of lipid rafts. Thus, the structure and function of lipid rafts play a central role in the pathogenesis of many common neurodegenerative diseases.




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Does general anesthesia affect neurodevelopment in infants and children?




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Noncatalytic Bruton's tyrosine kinase activates PLC{gamma}2 variants mediating ibrutinib resistance in human chronic lymphocytic leukemia cells [Membrane Biology]

Treatment of patients with chronic lymphocytic leukemia (CLL) with inhibitors of Bruton's tyrosine kinase (BTK), such as ibrutinib, is limited by primary or secondary resistance to this drug. Examinations of CLL patients with late relapses while on ibrutinib, which inhibits BTK's catalytic activity, revealed several mutations in BTK, most frequently resulting in the C481S substitution, and disclosed many mutations in PLCG2, encoding phospholipase C-γ2 (PLCγ2). The PLCγ2 variants typically do not exhibit constitutive activity in cell-free systems, leading to the suggestion that in intact cells they are hypersensitive to Rac family small GTPases or to the upstream kinases spleen-associated tyrosine kinase (SYK) and Lck/Yes-related novel tyrosine kinase (LYN). The sensitivity of the PLCγ2 variants to BTK itself has remained unknown. Here, using genetically-modified DT40 B lymphocytes, along with various biochemical assays, including analysis of PLCγ2-mediated inositol phosphate formation, inositol phospholipid assessments, fluorescence recovery after photobleaching (FRAP) static laser microscopy, and determination of intracellular calcium ([Ca2+]i), we show that various CLL-specific PLCγ2 variants such as PLCγ2S707Y are hyper-responsive to activated BTK, even in the absence of BTK's catalytic activity and independently of enhanced PLCγ2 phospholipid substrate supply. At high levels of B-cell receptor (BCR) activation, which may occur in individual CLL patients, catalytically-inactive BTK restored the ability of the BCR to mediate increases in [Ca2+]i. Because catalytically-inactive BTK is insensitive to active-site BTK inhibitors, the mechanism involving the noncatalytic BTK uncovered here may contribute to preexisting reduced sensitivity or even primary resistance of CLL to these drugs.




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Amylin/Calcitonin Receptor-Mediated Signaling in POMC Neurons Influences Energy Balance and Locomotor Activity in Chow-Fed Male Mice

Amylin, a pancreatic hormone and neuropeptide, acts principally in the hindbrain to decrease food intake and has been recently shown to act as a neurotrophic factor to control the development of AP->NTS and ARC->PVN axonal fiber outgrowth. Amylin is also able to activate ERK signaling specifically in POMC neurons independently of leptin. To investigate the physiological role of amylin signaling in POMC neurons, the core component of the amylin receptor, calcitonin receptor (CTR) was depleted from POMC neurons using an inducible mouse model. The loss of CTR in POMC neurons leads to increased body weight gain, increased adiposity, and glucose intolerance in male knockout mice, characterized by decreased energy expenditure (EE) and decreased expression of uncoupling protein 1 (UCP1) in brown adipose tissue (BAT). Furthermore, a decreased spontaneous locomotor activity and absent thermogenic reaction to the application of the amylin receptor agonist were observed in male and female mice. Together, these results show a significant physiological impact of amylin/calcitonin signaling in CTR-POMC neurons on energy metabolism and demonstrate the need for sex-specific approaches in obesity research and potentially treatment.




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Elevated First-Trimester Neutrophil Count Is Closely Associated with the Development of Maternal Gestational Diabetes Mellitus and Adverse Pregnancy Outcomes

Chronic low-grade inflammation plays a central role in the pathophysiology of gestational diabetes mellitus (GDM). In order to investigate the ability of different inflammatory blood cell parameters in predicting the development of GDM and pregnancy outcomes, 258 women with GDM and 1154 women without were included in this retrospective study. First-trimester neutrophil count outperformed white blood cell (WBC) count, and neutrophil-to-lymphocyte ratio (NLR) in the predictability for GDM. Subjects were grouped based on tertiles of neutrophil count during their first-trimester pregnancy. The results showed that as the neutrophil count increased, there was a step-wise increase in GDM incidence, as well as glucose and glycosylated hemoglobin (HbA1c) level, Homeostasis Model Assessment for Insulin Resistance (HOMA-IR), macrosomia incidence and newborn weight. Neutrophil count was positively associated with pre-pregnancy Body Mass Index (BMI), HOMA-IR and newborn weight. Additionally, neutrophil count was an independent risk factor for the development of GDM, regardless of the history of GDM. Spline regression showed that there was a significant linear association between GDM incidence and continuous neutrophil count when it exceeded 5.0 x 109/L. This work suggested that first-trimester neutrophil count is closely associated with the development of GDM and adverse pregnancy outcomes.




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Central {alpha}-Klotho Suppresses NPY/AgRP Neuron Activity and Regulates Metabolism in Mice

α-Klotho is a circulating factor with well-documented anti-aging properties; however, the central role of α-klotho in metabolism remains largely unexplored. The current study investigated the potential role of central α-klotho to modulate NPY/AgRP neurons, energy balance, and glucose homeostasis. Intracerebroventricular (ICV) administration of α-klotho suppressed food intake, improved glucose profiles, and reduced body weight in mouse models of Type I and II diabetes. Furthermore, central α-klotho inhibition via an anti-α-klotho antibody impaired glucose tolerance. Ex vivo patch clamp electrophysiology and immunohistochemical analysis revealed that α-klotho suppresses NPY/AgRP neuron activity, at least in part, by enhancing mIPSC’s. Experiments in hypothalamic GT1-7 cells observed α-klotho induces phosphorylation of AKTser473, ERKthr202/tyr204, and FOXO1ser256, as well as blunts AgRP gene transcription. Mechanistically, fibroblast growth factor 1 (FGFR1) inhibition abolished the downstream signaling of α-klotho, negated its ability to modulate NPY/AgRP neurons, and blunted its therapeutic effects. PI3 kinase inhibition also abolished α-klotho’s ability to suppress food intake and improve glucose clearance. These results indicate a prominent role of hypothalamic α-klotho/FGFR1/PI3K signaling in the modulation of NPY/AgRP neuron activity and maintenance of energy homeostasis, thus providing new insight into the pathophysiology of metabolic disease.




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Two- and three-color STORM analysis reveals higher-order assembly of leukotriene synthetic complexes on the nuclear envelope of murine neutrophils [Computational Biology]

Over the last several years it has become clear that higher order assemblies on membranes, exemplified by signalosomes, are a paradigm for the regulation of many membrane signaling processes. We have recently combined two-color direct stochastic optical reconstruction microscopy (dSTORM) with the (Clus-DoC) algorithm that combines cluster detection and colocalization analysis to observe the organization of 5-lipoxygenase (5-LO) and 5-lipoxygenase–activating protein (FLAP) into higher order assemblies on the nuclear envelope of mast cells; these assemblies were linked to leukotriene (LT) C4 production. In this study we investigated whether higher order assemblies of 5-LO and FLAP included cytosolic phospholipase A2 (cPLA2) and were linked to LTB4 production in murine neutrophils. Using two- and three-color dSTORM supported by fluorescence lifetime imaging microscopy we identified higher order assemblies containing 40 molecules (median) (IQR: 23, 87) of 5-LO, and 53 molecules (62, 156) of FLAP monomer. 98 (18, 154) molecules of cPLA2 were clustered with 5-LO, and 77 (33, 114) molecules of cPLA2 were associated with FLAP. These assemblies were tightly linked to LTB4 formation. The activation-dependent close associations of cPLA2, FLAP, and 5-LO in higher order assemblies on the nuclear envelope support a model in which arachidonic acid is generated by cPLA2 in apposition to FLAP, facilitating its transfer to 5-LO to initiate LT synthesis.




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

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




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Certain ortho-hydroxylated brominated ethers are promiscuous kinase inhibitors that impair neuronal signaling and neurodevelopmental processes [Cell Biology]

The developing nervous system is remarkably sensitive to environmental signals, including disruptive toxins, such as polybrominated diphenyl ethers (PBDEs). PBDEs are an environmentally pervasive class of brominated flame retardants whose neurodevelopmental toxicity mechanisms remain largely unclear. Using dissociated cortical neurons from embryonic Rattus norvegicus, we found here that chronic exposure to 6-OH–BDE-47, one of the most prevalent hydroxylated PBDE metabolites, suppresses both spontaneous and evoked neuronal electrical activity. On the basis of our previous work on mitogen-activated protein kinase (MAPK)/extracellular signal-related kinase (ERK) (MEK) biology and our observation that 6-OH–BDE-47 is structurally similar to kinase inhibitors, we hypothesized that certain hydroxylated PBDEs mediate neurotoxicity, at least in part, by impairing the MEK–ERK axis of MAPK signal transduction. We tested this hypothesis on three experimental platforms: 1) in silico, where modeling ligand–protein docking suggested that 6-OH–BDE-47 is a promiscuous ATP-competitive kinase inhibitor; 2) in vitro in dissociated neurons, where 6-OH–BDE-47 and another specific hydroxylated BDE metabolite similarly impaired phosphorylation of MEK/ERK1/2 and activity-induced transcription of a neuronal immediate early gene; and 3) in vivo in Drosophila melanogaster, where developmental exposures to 6-OH–BDE-47 and a MAPK inhibitor resulted in offspring displaying similarly increased frequency of mushroom-body β–lobe midline crossing, a metric of axonal guidance. Taken together, our results support that certain ortho-hydroxylated PBDE metabolites are promiscuous kinase inhibitors and can cause disruptions of critical neurodevelopmental processes, including neuronal electrical activity, pre-synaptic functions, MEK–ERK signaling, and axonal guidance.




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A kinesin adapter directly mediates dendritic mRNA localization during neural development in mice [Neurobiology]

Motor protein-based active transport is essential for mRNA localization and local translation in animal cells, yet how mRNA granules interact with motor proteins remains poorly understood. Using an unbiased yeast two–hybrid screen for interactions between murine RNA-binding proteins (RBPs) and motor proteins, here we identified protein interaction with APP tail-1 (PAT1) as a potential direct adapter between zipcode-binding protein 1 (ZBP1, a β-actin RBP) and the kinesin-I motor complex. The amino acid sequence of mouse PAT1 is similar to that of the kinesin light chain (KLC), and we found that PAT1 binds to KLC directly. Studying PAT1 in mouse primary hippocampal neuronal cultures from both sexes and using structured illumination microscopic imaging of these neurons, we observed that brain-derived neurotrophic factor (BDNF) enhances co-localization of dendritic ZBP1 and PAT1 within granules that also contain kinesin-I. PAT1 is essential for BDNF-stimulated neuronal growth cone development and dendritic protrusion formation, and we noted that ZBP1 and PAT1 co-locate along with β-actin mRNA in actively transported granules in living neurons. Acute disruption of the PAT1–ZBP1 interaction in neurons with PAT1 siRNA or a dominant-negative ZBP1 construct diminished localization of β-actin mRNA but not of Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα) mRNA in dendrites. The aberrant β-actin mRNA localization resulted in abnormal dendritic protrusions and growth cone dynamics. These results suggest a critical role for PAT1 in BDNF-induced β-actin mRNA transport during postnatal development and reveal a new molecular mechanism for mRNA localization in vertebrates.




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Inhibition of glycosphingolipid biosynthesis reverts multidrug resistance by differentially modulating ABC transporters in chronic myeloid leukemias [Cell Biology]

Multidrug resistance (MDR) in cancer arises from cross-resistance to structurally- and functionally-divergent chemotherapeutic drugs. In particular, MDR is characterized by increased expression and activity of ATP-binding cassette (ABC) superfamily transporters. Sphingolipids are substrates of ABC proteins in cell signaling, membrane biosynthesis, and inflammation, for example, and their products can favor cancer progression. Glucosylceramide (GlcCer) is a ubiquitous glycosphingolipid (GSL) generated by glucosylceramide synthase, a key regulatory enzyme encoded by the UDP-glucose ceramide glucosyltransferase (UGCG) gene. Stressed cells increase de novo biosynthesis of ceramides, which return to sub-toxic levels after UGCG mediates incorporation into GlcCer. Given that cancer cells seem to mobilize UGCG and have increased GSL content for ceramide clearance, which ultimately contributes to chemotherapy failure, here we investigated how inhibition of GSL biosynthesis affects the MDR phenotype of chronic myeloid leukemias. We found that MDR is associated with higher UGCG expression and with a complex GSL profile. UGCG inhibition with the ceramide analog d-threo-1-(3,4,-ethylenedioxy)phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol (EtDO-P4) greatly reduced GSL and monosialotetrahexosylganglioside levels, and co-treatment with standard chemotherapeutics sensitized cells to mitochondrial membrane potential loss and apoptosis. ABC subfamily B member 1 (ABCB1) expression was reduced, and ABCC-mediated efflux activity was modulated by competition with nonglycosylated ceramides. Consistently, inhibition of ABCC-mediated transport reduced the efflux of exogenous C6-ceramide. Overall, UGCG inhibition impaired the malignant glycophenotype of MDR leukemias, which typically overcomes drug resistance through distinct mechanisms. This work sheds light on the involvement of GSL in chemotherapy failure, and its findings suggest that targeted GSL modulation could help manage MDR leukemias.




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Affinity maturation, humanization, and co-crystallization of a rabbit anti-human ROR2 monoclonal antibody for therapeutic applications [Immunology]

Antibodies are widely used as cancer therapeutics, but their current use is limited by the low number of antigens restricted to cancer cells. A receptor tyrosine kinase, receptor tyrosine kinase-like orphan receptor 2 (ROR2), is normally expressed only during embryogenesis and is tightly down-regulated in postnatal healthy tissues. However, it is up-regulated in a diverse set of hematologic and solid malignancies, thus ROR2 represents a candidate antigen for antibody-based cancer therapy. Here we describe the affinity maturation and humanization of a rabbit mAb that binds human and mouse ROR2 but not human ROR1 or other human cell-surface antigens. Co-crystallization of the parental rabbit mAb in complex with the human ROR2 kringle domain (hROR2-Kr) guided affinity maturation by heavy-chain complementarity-determining region 3 (HCDR3)-focused mutagenesis and selection. The affinity-matured rabbit mAb was then humanized by complementarity-determining region (CDR) grafting and framework fine tuning and again co-crystallized with hROR2-Kr. We show that the affinity-matured and humanized mAb retains strong affinity and specificity to ROR2 and, following conversion to a T cell–engaging bispecific antibody, has potent cytotoxicity toward ROR2-expressing cells. We anticipate that this humanized affinity-matured mAb will find application for antibody-based cancer therapy of ROR2-expressing neoplasms.




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Risk Factors for Diabetic Peripheral Neuropathy and Cardiovascular Autonomic Neuropathy in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study

Barbara H. Braffett
May 1, 2020; 69:1000-1010
Complications




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Muscle Weakness: A Progressive Late Complication in Diabetic Distal Symmetric Polyneuropathy

Christer S. Andreassen
Mar 1, 2006; 55:806-812
Complications




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Correction: Metabolic fingerprinting for diagnosis of fibromyalgia and other rheumatologic disorders. [Additions and Corrections]

VOLUME 294 (2019) PAGES 2555–2568Due to publisher error, “150 l/mm” was changed to “150 liters/mm” in the second paragraph of the “Vibrational spectroscopy of samples” section under “Experimental Procedures.” The correct phrase should be “150 l/mm.”




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Trial of novel leukaemia drug is stopped for second time after two more deaths




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Trade, Technology and National Security: Will Europe Be Trapped Between the US and China?

Invitation Only Research Event

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

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

Event participants

Sir Simon Fraser, Managing Partner of Flint Global; Deputy Chairman, Chatham House
Chair: Marianne Schneider-Petsinger, Senior Research Fellow, US and the Americas Programme, Chatham House

The US and China have entered into an increasingly confrontational relationship over trade and technology. This may force Europe to make difficult choices between the two economic superpowers – or perform a balancing act. Although the recent US-China phase-1 trade deal has eased the relationship for now, the trade and technology tensions are a structural issue and are likely to persist.

The debate over Huawei’s participation in 5G networks is an example of how the UK and other countries may face competing priorities in economic, security and foreign policy. Can Europe avoid a binary choice between the US and China? Is it possible for the EU to position itself as a third global power in trade, technology and standard-setting? What strategies should Europeans adopt to keep the US and China engaged in the rules-based international order and what does the future hold for trade multilateralism?

Sir Simon Fraser will join us for a discussion on Europe’s future role between the US and China. Sir Simon is Managing Partner of Flint Global and Deputy Chairman of Chatham House. He previously served as Permanent Secretary at the Foreign and Commonwealth Office (FCO) and Head of the UK Diplomatic Service from 2010 to 2015. Prior to that he was Permanent Secretary at the UK Department for Business, Innovation and Skills. He has also served as Director General for Europe in the FCO and Chief of Staff to European Trade Commissioner Peter Mandelson.

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

Event attributes

Chatham House Rule

US and Americas Programme




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The EU Cannot Build a Foreign Policy on Regulatory Power Alone

11 February 2020

Alan Beattie

Associate Fellow, Global Economy and Finance Programme and Europe Programme
Brussels will find its much-vaunted heft in setting standards cannot help it advance its geopolitical interests.

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EU Commission President Ursula von der Leyen speaks at the European Parliament in Strasbourg in February. Photo: Getty Images.

There are two well-established ideas in trade. Individually, they are correct. Combined, they can lead to a conclusion that is unfortunately wrong.

The first idea is that, across a range of economic sectors, the EU and the US have been engaged in a battle to have their model of regulation accepted as the global one, and that the EU is generally winning.

The second is that governments can use their regulatory power to extend strategic and foreign policy influence.

The conclusion would seem to be that the EU, which has for decades tried to develop a foreign policy, should be able to use its superpower status in regulation and trade to project its interests and its values abroad.

That’s the theory. It’s a proposition much welcomed by EU policymakers, who know they are highly unlikely any time soon to acquire any of the tools usually required to run an effective foreign policy.

The EU doesn’t have an army it can send into a shooting war, enough military or political aid to prop up or dispense of governments abroad, or a centralized intelligence service. Commission President Ursula von der Leyen has declared her outfit to be a ‘geopolitical commission’, and is casting about for any means of making that real.

Through the ‘Brussels effect’ whereby European rules and standards are exported via both companies and governments, the EU has indeed won many regulatory battles with the US.

Its cars, chemicals and product safety regulations are more widely adopted round the world than their American counterparts. In the absence of any coherent US offering, bar some varied state-level systems, the General Data Protection Regulation (GDPR) is the closest thing the world has to a single model for data privacy, and variants of it are being adopted by dozens of countries.

The problem is this. Those parts of global economic governance where the US is dominant – particularly the dollar payments system – are highly conducive to projecting US power abroad. The extraterritorial reach of secondary sanctions, plus the widespread reliance of banks and companies worldwide on dollar funding – and hence the American financial system – means that the US can precisely target its influence.

The EU can enforce trade sanctions, but not in such a powerful and discriminatory way, and it will always be outgunned by the US. Donald Trump could in effect force European companies to join in his sanctions on Iran when he pulled out of the nuclear deal, despite EU legislation designed to prevent their businesses being bullied. He can go after the chief financial officer of Huawei for allegedly breaching those sanctions.

By contrast, the widespread adoption of GDPR or data protection regimes inspired by it may give the EU a warm glow of satisfaction, but it cannot be turned into a geopolitical tool in the same way.

Nor, necessarily, does it particularly benefit the EU economy. Europe’s undersized tech sector seems unlikely to unduly benefit from the fact that data protection rules were written in the EU. Indeed, one common criticism of the regulations is that they entrench the power of incumbent tech giants like Google.

There is a similar pattern at work in the adoption of new technologies such as artificial intelligence and the Internet of Things. In that field, the EU and its member states are also facing determined competition from China, which has been pushing its technologies and standards through forums such as the International Telecommunication Union.

The EU has been attempting to write international rules for the use of AI which it hopes to be widely adopted. But again, these are a constraint on the use of new technologies largely developed by others, not the control of innovation.

By contrast, China has created a vast domestic market in technologies like facial recognition and unleashed its own companies on it. The resulting surveillance kit can then be marketed to emerging market governments as part of China’s enduring foreign policy campaign to build up supporters in the developing world.

If it genuinely wants to turn its economic power into geopolitical influence – and it’s not entirely clear what it would do with it if it did – the EU needs to recognize that not all forms of regulatory and trading dominance are the same.

Providing public goods to the world economy is all very well. But unless they are so particular in nature that they project uniquely European values and interests, that makes the EU a supplier of useful plumbing but not a global architect of power.

On the other hand, it could content itself with its position for the moment. It could recognize that not until enough hard power – guns, intelligence, money – is transferred from the member states to the centre, or until the member states start acting collectively, will the EU genuinely become a geopolitical force. Speaking loudly and carrying a stick of foam rubber is rarely a way to gain credibility in international relations.

This article is part of a series of publications and roundtable discussions in the Chatham House Global Trade Policy Forum.




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Virtual Roundtable: US and European Responses to Coronavirus

Invitation Only Research Event

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

Event participants

Anne Applebaum, Staff Writer, The Atlantic; Pulitzer-Prize Winning Historian
Amy Pope, Partner, Schillings; Deputy Homeland Security Advisor, US National Security Council, 2015 - 17
Chair: Dr Leslie Vinjamuri, Director, US and the Americas Programme, Chatham House

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

Department/project

US and Americas Programme




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Diabetes Core Update: Therapeutic Inertia – April 2020

In this first episode of a three-part series on “Disrupting Therapeutic Inertia in Diabetes Management,” Drs. John Russell and Neil Skolnik examine a case study of a 55-year-old man with type 2 diabetes (3 years duration, A1C 8.2%). In so doing, they review six articles that define achievement gaps in reaching A1C goals and the reasons for why those gaps exist. In episodes 2 and 3 of this series, Drs. Russell and Skolnik we will look at additional causes of therapeutic inertia and solutions for overcoming it. This special three-part series on therapeutic inertia is supported by independent educational grant from Sanofi (https://www.sanofi.com).

This issue will review:

  1. Achievement of target therapeutic goals in persons with T2DM
  2. Achievement of therapeutic goals from 2005 – 2015
  3. Clinical Inertia in Newly Diagnosed Type 2 DM
  4. Clinical Inertia over Time in Type 2 DM
  5. Gap Between Efficacy in Randomized Controlled Trials and Effectiveness in Real-World Use
  6. Difference between Clinical Trial and Real-World Studies Achievement of Target A1C <7.0% in Patients Treated with Basal Insulin in RCTs and Clinical Practice

For more information about each of ADA’s science and medical journals, please visit www.diabetesjournals.org.

Presented by:

Neil Skolnik, M.D., Professor of Family and Community Medicine, Sidney Kimmel Medical College, Thomas Jefferson University; Associate Director, Family Medicine Residency Program, Abington Jefferson Health

John J. Russell, M.D., Professor of Family and Community Medicine, Sidney Kimmel Medical College, Thomas Jefferson University; Director, Family Medicine Residency Program, Chair-Department of Family Medicine, Abington Jefferson Health




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Covid-19: Doctors face shortages of vital drugs, gases, and therapeutics, survey finds




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Covid-19: UK death toll overtakes Italy’s to become worst in Europe




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The soaring joy of a family reunion




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EU makes second donation of medical supplies to Jamaica

(CMC): The European Union (EU) will be making a second donation of medical supplies and equipment to Jamaica in support of the country’s efforts to tackle COVID-19, the Head of the EU Delegation to Jamaica, Ambassador Malgorzata Wasilewska,...




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Is Europe Ready for Another Ash Shock?

24 May 2011

Bernice Lee OBE

Research Director; Executive Director, Hoffmann Centre for Sustainable Resource Economy


The eruption of another Icelandic volcano this week, ejecting ash plume into the atmosphere, reminds us afresh of Europe's vulnerability to 'low probability, high impact' events. Will Europe respond better this time? A forthcoming Chatham House Report shows that in such crises our governments and global businesses are in a better place to cope for a week - but no longer. This is because the full consequences of worst case scenarios are rarely factored in.

The ash cloud in 2010 is estimated to have cost the EU around $ 5-10 billion - the airlines bore about $ 1.7 billion in lost revenues and the tourism industry was hit hard. The greatest impact felt by many organisations was in human resources - the absence of stranded employees and dislocated management structures - but some companies fared better than others having learnt lessons from 9/11, SARS and other shocks to aviation. Businesses responding to a Chatham House survey on the impact of the ash cloud said that if the ash event last year had persisted just a few more days there would have been far more serious consequences.

This is not surprising given our dependence on long supply chains and the just-in-time business model. Since the earthquake and tsunami in March, for example, Japanese national infrastructure has been struggling to cope with fraying supply-chains and significantly slowed production. Carmakers and mobile phone manufacturers across the world were forced to halt or slow production as inventories of essential products - electronic components, car parts and fine chemicals - were quickly run down. Major cities for production, trade and travel are often badly affected by any international shocks, irrespective of the source, rendering the apparent resilience of having multiple suppliers meaningless.

A major scenario planning exercise conducted by Eurocontrol, five weeks ago suggests that the EU might be better prepared for an ash cloud disruption than a year ago. A key test for Europe now lies in whether member states will succeed in working together better in coordinating responses to ash threat and building public confidence in science-based risk management and planning.

Policy-makers face again the challenge of communicating a complex problem to a frustrated public. The ash cloud last year demonstrated the complication of crisis management in the media-saturated world, where opinion can be swayed by the most audible, the most active or the most politically powerful voices rather than the best informed or the most legitimate. There are important lessons here on the advantages and potential pitfalls of engaging stakeholders and the public via social and online media.

Our forthcoming report also shows a bias in the traditional media towards industry voices rather than those of the scientific community and policy-makers. During the crisis last year, there was scant public defence of the precautionary principles or safety, merely airlines duelling through the airwaves to step up pressure to remove the flight ban. First off the gate, Ryanair had already started its public relations battle last night. This time around, let's hope that traditional media will give greater airplay to voices beyond industry commentators, including scientists and experts. In-depth explanations of the science and technology involved in an event can help people assess the levels of uncertainty and risk involved in a situation, and what it means for them.




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EU Lays Down Marker for Global Climate Action

24 October 2014

Antony Froggatt

Senior Research Fellow, Energy, Environment and Resources Programme

Shane Tomlinson

Former Senior Research Fellow, Energy, Environment and Resources
The EU’s climate and energy package represents an important step ahead of a potential global deal next year in Paris. But a disappointing approach to energy efficiency and uncertainty over governance threatens to undermine delivery.

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German Chancellor Angela Merkel talks with European parliament president Martin Schulz during an EU climate summit on 23 October 2014. Photo by Getty Images.

The European Union has reached agreement on its 2030 climate and energy package in preparation for the next major international climate summit in Paris in December 2015. In the agreement member states have signed up to reducing greenhouse gas (GHG) emissions by at least 40% by 2030 – compared to 1990 levels. Currently emissions are approximately 20% below 1990 levels and so the 2030 target represents a continuation of current decarbonization trends, but it is below the rate of reductions required to meet the longer term objective of cutting emission by 80-95% by 2050.

However, the overall 40% reduction will still drive structural changes in Europe’s economy and the energy sector. This could and should be seen as an opportunity for the EU to become a world leader in the innovation of both the new technologies and systems, such as electricity storage, dynamic demand responses and the deployment of electric vehicles, all of which are experiencing a rapid increase in the size of their global markets.

But there are some concerns. The climate and energy package has put forward a collective target to double the current level of renewables so that it will provide at least 27% of energy by 2030. However, the target is binding on the EU as a whole but not on individual member states, which creates uncertainty and is further complicated by a lack of clarity on the enforcement mechanism, which remains vague. To avoid loss of investor and industrial confidence a transparent process needs to be rapidly developed that ensures compliance. 

The EU has also failed to give energy efficiency the priority it deserves, downgrading it to an indicative target (i.e. one that is aspirational only) of a 27% reduction in energy use from business as usual. However, this is equivalent to, at most, a 19% reduction from Europe's pre-recession trajectory. The weaker energy efficiency and renewable energy elements of the package reflects the resistance of a relatively small number of countries to further EU-wide legal commitments, either because they prefer market inducement or due to their reluctance to reform their energy sectors. The package also makes clear that the a reformed Emissions Trading Scheme will be the main instrument to achieve the GHG reduction target and proposes to accelerate the reduction of the cap on maximum permitted emissions. However, this would only kick in after 2021, meaning the scheme will remain relatively ineffective for at least another five years. 

The crisis in Ukraine and the potential implications for security of supply once again highlights the importance of both domestic energy production and common European approaches to energy suppliers. Every 1% of energy saved across the EU reduces gas imports by 2.6%, and a stronger target would do more to reduce dependence on Russian gas imports. The EU’s failure to adopt a more far reaching and binding target on energy efficiency is a missed opportunity given that it is one  of the only approaches that delivers on the three pillars on energy policy, namely environmental protection, competitiveness and security of supply, simultaneously.

It is important to note the progress that the EU has made in both meeting its climate targets over the last decade and the impact that this has had on its other energy policy objectives. Currently, the EU’s 2020 target for reducing GHG emissions by 20% has or is very close to being met, in part due to the economic downturn, but also due to efficiency, renewable energy and changing industrial patterns and technologies. Furthermore, the use of renewable energy is now estimated to save around €30 billion per year in imported energy, improving balance of payments and improving security of supply. Likewise improvements in energy efficiency have been shown since the turn of the century to have contributed to a 1% annual reduction in energy consumption in the EU.

But the EU is not alone in preparing national carbon reduction targets for the UNFCCC conference in Paris 2015. Both China and the US, the world’s first and second largest emitters, are preparing their own emission reduction plans. China announced in September that it would put forward a new target for the peaking of its carbon dioxide emissions as early as possible. It is suggested that this might be as early as in 2025, with the potential for peak coal use coming even earlier in 2020. The US has proposed to set limits on the emissions from new coal-fired power stations and a 30% reduction in US power sector emissions by 2030 (relative to their 2005 baseline), and President Obama is expected to go further with new climate measures next year.

In the year ahead all countries that are party to the UNFCCC are expected to put on the table their national carbon abatement plans for 2030.  Some will be conditional upon further international assistance and commitments. The package agreed by Europe has scope to respond to increased efforts by other countries. This could include increasing the EU’s own domestic target (currently framed as ‘at least 40%’) or through international offsets and climate finance. How the EU responds to other countries efforts will be a test of its global leadership on climate issues.

To comment on this article, please contact Chatham House Feedback 




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Europe’s Energy Union: Foreign Policy Implications for Energy Security, Climate and Competitiveness

31 March 2016

By addressing structural divisions between member states, the Energy Union could have a beneficial effect on the EU’s capacity to conduct a unified and effective foreign policy, write Thomas Raines and Shane Tomlinson.

Thomas Raines

Director, Europe Programme

Shane Tomlinson

Former Senior Research Fellow, Energy, Environment and Resources, Chatham House

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True colour satellite image of Europe at night. Photo via Getty Images.

Summary

  • Plans for an EU-wide Energy Union are taking shape, following the European Commission’s adoption in February 2015 of a ‘Framework Strategy for a Resilient Energy Union with a Forward-Looking Climate Change Policy’. The strategy underlines the EU’s ambition to attain ‘secure, sustainable, competitive, affordable energy for every European’.
  • The initiative seeks to transform energy markets and energy/climate policy across the EU. Its goals include cross-border coordination and integration in energy security, supply, market operations, regulation, energy efficiency, low-carbon development, and research and innovation.
  • There is an important foreign policy aspect to the Energy Union, given the imperative of managing security and supply risks in Europe’s neighbourhood and further afield. By addressing structural divisions between member states, the Energy Union could have a marked beneficial effect on the EU’s capacity to conduct a unified and effective foreign policy.
  • Development of the Energy Union presents abundant challenges, however. Policy and legislative changes will need to be coordinated across 28 countries. Variations in EU member states’ attitudes to security and energy policy may lead to differences in, or clashes between, priorities. The wider context is also complicated. Interrelated challenges rooted in broader policy issues include the partial transition to low-carbon energy, and concerns over competitiveness relative to other major economies.
  • The current EU approach to energy security and infrastructure focuses on natural gas. This ‘gas first’ approach risks crowding out other responses to the energy security challenge. It could result in the creation of ‘stranded assets’, if the future gas demand on which investments are predicated does not match projections. A narrow focus on new gas infrastructure could also impede development of other dimensions of the Energy Union.
  • The markets for coal, oil, gas and renewables are changing significantly. The shale oil and gas ‘revolution’ in the United States has altered the economics of hydrocarbon fuels, and the plunge in oil prices since mid-2014 is causing energy businesses in the EU to reassess investment plans.
  • The EU is rapidly expanding the use of renewable energy. Dramatically falling prices for renewables will challenge traditional energy utility business models. How the Energy Union enables market access for new business models will be key to determining future energy trajectories.




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The UK's Decision to Leave the EU: What Next for UK Energy and Climate?

Invitation Only Research Event

12 July 2016 - 3:00pm to 6:30pm

Chatham House, London

In May 2016, Chatham House published a research paper that assessed the options for the UK’s climate and energy policy in the event of a British vote to leave the EU. It determined that:

  • The UK’s energy market is deeply integrated with that of its European neighbours and that it would be neither possible nor desirable to ‘unplug’ the UK from Europe’s energy networks. A degree of continued adherence to EU market regulations, energy efficiency standards of appliances, environmental and governance rules would be inevitable. 
  • The EU’s collective negotiation on international climate issues has given the UK greater political weight than any member state has alone.
  • The EU’s coordinated approach in engaging with major fossil fuel producers such as Russia and countries in the Middle East has helped support price stability and security of supply, including through infrastructure investment to make existing pipeline systems more efficient and improve storage and capacity.   

In light of the decision to leave, Chatham House is hosting a roundtable to reassess the options for a future UK-EU energy and climate change partnership. The meeting will bring together those experienced on UK and EU policy in both climate change and energy and explore the short and medium-term climate and energy policy considerations. 

Attendance at this event is by invitation only.

Owen Grafham

Manager, Energy, Environment and Resources Programme
+44 (0)20 7957 5708




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Wood Is Not a Carbon-Neutral Energy Source

1 March 2017

Duncan Brack

Associate Fellow, Energy, Environment and Resources Programme
Treating it as such – and supporting it with subsidies, as the UK and many other EU member states do – is a flawed path to climate action.

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Fuel composed of wood chips to be used for the UEM (Usine d’Electricité de Metz) biomass plant in Metz, eastern France. Photo: Getty Images.

Chatham House’s recent paper, Woody Biomass for Power and Heat: Impacts on the Global Climate, highlights how the use of wood for electricity generation and heat in modern (non-traditional) technologies has grown rapidly in recent years, and has the potential to continue to do so. EU member states’ national targets for renewable energy generation agreed in 2009 have helped ensure that the EU is now the world’s largest producer and consumer of wood for energy. And although other member states use wood more extensively for heat, the UK is the EU’s largest user for electricity generation, mostly sourced from the US and Canada.

Wood for energy often has a positive image: a natural product of growing forests. The biomass energy industry, which has grown rapidly on the back of government subsidies, likes to contrast it with dirty coal or oil. They point to the government’s sustainability criteria, which notionally guarantee a reduction of at least 60 per cent in greenhouse gas emissions compared to the fossil fuels the biomass replaces.

The problem with this happy picture, however, is that in fact biomass, when burnt, emits more carbon per unit of energy than most fossil fuels. The exact amount varies with the type of biomass and the type and age of the power plant, but figures from the Drax power station, Europe’s largest consumer of wood pellets, show that in 2013 it emitted about 13 per cent more carbon dioxide per unit of energy generated from biomass than from coal.

How is this consistent with meeting the government’s requirement for a 60 per cent reduction in emissions? Only by completely ignoring the carbon emitted when the wood is burnt; the sustainability criteria measure only supply-chain emissions from harvesting, processing and transporting the wood. (Direct land-use change – for example, clearance of the forest for agriculture or urban development – also falls outside the criteria, but biomass for energy generally originates from existing forests.)

This treatment of combustion emissions as zero – and thus, the awarding to wood the same kind of financial and regulatory support as other renewables such as solar PV and wind – is justified on the basis that the carbon contained in woody biomass is part of the natural forest cycle. The carbon released during combustion was absorbed by forest growth in the past and will be reabsorbed by forest growth in the future; in contrast, fossil fuels originate outside this cycle and their combustion adds carbon to the atmosphere.

But this argument rests on a basic fallacy. Carbon is carbon, wherever it comes from, and if you burn wood for energy, you increase carbon dioxide concentrations in the atmosphere (by more than if you had used fossil fuels), and thereby contribute to climate change. The fact that the carbon emitted was absorbed by growing trees in the past is simply irrelevant. After all, when it’s harvested you don’t have to burn it; you could use it for construction or furniture or window frames or a host of other uses, fixing the carbon in wood products rather than emitting it to the atmosphere.

Climate impacts

It is true that continued forest growth will absorb carbon in the future, but the process is a long one, taking decades or even centuries if whole trees are harvested and burnt. Replacing large mature trees, with plentiful leaf cover absorbing large volumes of carbon dioxide, with small young ones mean that the rate of carbon uptake will be far lower for years. On top of that, the impact of harvesting itself releases soil carbon into the atmosphere, further accelerating climate change.

The impact on the climate of using sawmill or forest residues for energy rather than whole trees is undoubtedly lower, since these tend to be wastes from other industries which harvest trees for their own purposes, and do not imply any additional harvesting. Sawmill wastes which, if left to themselves, would rot and release their stored carbon into the atmosphere in a matter of months or years, are in many ways the ideal feedstock; it makes sense to use them for energy rather than leave them to decay. However, mill residues are already intensively used and there seems little room for expansion; a survey in the US in 2011 found that over 99 per cent of mill residues were already used, mainly for energy and wood products such as particleboard.

Forest residues are the parts of harvested trees that are left in the forest after log products have been removed, including stumps, tops and small branches, and pieces too short or defective to be used; these can amount to as much as 40–60 per cent of the total tree volume. Their impact on the climate if used for energy varies significantly. While the smallest pieces tend to rot and release their stored carbon into the atmosphere quite quickly, if left in the forest, they are generally not suitable for use for energy, as they contain too much dirt and ash to be burnt cleanly. Larger pieces are more suitable but take much longer to decay; burning them for energy instead of leaving them in the forest thereby increases carbon concentrations in the atmosphere for years or decades. And on top of that, a portion of the carbon and other substances contained in the residues is transferred to the soil as they decay; their removal from the forest for energy may reduce both soil carbon and the levels of the nutrients trees need to grow, again with negative impacts on the climate.

The biomass industry generally likes to claim that it uses mainly mill and forest residues, though on closer inspection the categories they report often contain whole trees, perhaps classified as ‘unmerchantable’ or similar. (This is not helped by the fact the categories used by Ofgem, for example, to whom UK biomass users have to report, are confusing and potentially overlapping.) Several independent studies, however, have concluded that the use of mill and forest residues is in reality substantially lower; pellet plants in the US – the UK’s main source of supply – in fact source about 75 per cent whole trees.

Setting aside these arguments about feedstock, however, can it be safely assumed that future forest growth allows us to treat biomass as carbon-neutral? If the trees would have grown anyway, even in the absence of the biomass energy industry, it cannot be assumed that their future absorption of carbon cancels out the carbon emitted when wood is burnt. If the rate of carbon absorption in forests remains the same whether or not some of the harvested wood is burnt, then clearly, the best outcome for the climate in the short and probably medium term is not to burn it, but to use it for wood products or leave it to decay slowly in the forest. This is not an academic argument: the current global rate of emissions of greenhouse gases is incompatible with the aims of the Paris Agreement and may risk triggering irreversible tipping points in the Earth’s climate system. We need to reduce carbon emissions now, not in several decades’ or centuries’ time.

The biomass industry likes to point to the expansion of US forests in recent decades to show that forests overall have been absorbing more carbon even while increasing volumes are burnt for energy – sometimes implying that this forest growth has been encouraged by the demand for energy. But in fact US forest expansion started in the 1950s, decades before European subsidies stimulated the expansion of the modern biomass industry. And there is little evidence of recent overall forest growth in the US southeast, the location of almost all the pellet plants supplying European demand. In any case, the point is not whether US (or European) forests are expanding, but whether they would have grown at a different rate if part of their wood had not been burnt for energy. If they would have grown at the same rate, or faster, in the absence of biomass energy use then it cannot be assumed that using wood for biomass is good for forests, or the climate.

Redirecting public money

There is no question that renewable energy policy and forest policy both have a critical role to play in the mitigation of climate change. But governments have limited resources to deploy in their support, which is why the Chatham House paper questions whether it is really a good use of public money to subsidise activities which release stored forest carbon into the atmosphere, thereby increasing carbon emissions and accelerating climate change.

I argue instead that support should be limited to those feedstocks which genuinely reduce carbon emissions over the short term – i.e. mill residues and post-consumer wood waste. This would not only have a positive direct impact on the climate but would also release more resources for genuine zero-carbon technologies, such as solar, wind or tidal – and perhaps also for programmes encouraging afforestation and the more extensive use of wood in buildings and products. Use it, don’t burn it.

To comment on this article, please contact Chatham House Feedback




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