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A Divided Island: Sri Lanka's Constitutional Crisis




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Une Nouvelle Révolution? Macron and the Gilets Jaunes




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Is Technology Destroying Democracy?




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Screening Room: About a War




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Stacey Abrams: Democracy and the Politics of Identity




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The Militarization of the Black Sea After the Annexation of Crimea




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Screening Room: Inside Europe - We Quit




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What Brexit Satisfies the Democratic Will of the People?




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Undercurrents: Episode 30 - The Crisis in Kashmir, and How to Regulate Big Tech




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Are ‘Digital Parties’ the Future of Democracy in Europe?




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Screening Room: RBG




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Screening Room: Displaced




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A Gulf Divided: The Anatomy of a Crisis




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Direct Democracy: Participation Without Populism?




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Screening Room: Brexit - Behind Closed Doors




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Iran, Islam and Democracy: The Politics of Managing Change 20 Years On




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How Democratic Is the EU?




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Screening Room: For Sama




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Screening Room: Port of Destiny




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Undercurrents: Episode 44 - The Iran Crisis, and Politics in Iraq




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A Conversation With: Steven T Mnuchin, Secretary, US Treasury




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The State of Democracy in Turkey




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Chatham House Primer: Democratic Socialism




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Screening Room: Parts of a Circle - History of the Karabakh Conflict




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Undercurrents: Episode 50 - The Coronavirus Communications Crisis, and Justice in Myanmar




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Proteomic Analysis of Salmonella-modified Membranes Reveals Adaptations to Macrophage Hosts [Research]

Systemic infection and proliferation of intracellular pathogens require the biogenesis of a growth-stimulating compartment. The gastrointestinal pathogen Salmonella enterica commonly forms highly dynamic and extensive tubular membrane compartments built from Salmonella-modified membranes (SMMs) in diverse host cells. Although the general mechanism involved in the formation of replication-permissive compartments of S. enterica is well researched, much less is known regarding specific adaptations to different host cell types. Using an affinity-based proteome approach, we explored the composition of SMMs in murine macrophages. The systematic characterization provides a broader landscape of host players to the maturation of Salmonella-containing compartments and reveals core host elements targeted by Salmonella in macrophages as well as epithelial cells. However, we also identified subtle host specific adaptations. Some of these observations, such as the differential involvement of the COPII system, Rab GTPases 2A, 8B, 11 and ER transport proteins Sec61 and Sec22B may explain cell line-dependent variations in the pathophysiology of Salmonella infections. In summary, our system-wide approach demonstrates a hitherto underappreciated impact of the host cell type in the formation of intracellular compartments by Salmonella.




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Quantitative Profiling of the Human Substantia Nigra Proteome from Laser-capture Microdissected FFPE Tissue [Research]

Laser-capture microdissection (LCM) allows the visualization and isolation of morphologically distinct subpopulations of cells from heterogeneous tissue specimens. In combination with formalin-fixed and paraffin-embedded (FFPE) tissue it provides a powerful tool for retrospective and clinically relevant studies of tissue proteins in a healthy and diseased context. We first optimized the protocol for efficient LCM analysis of FFPE tissue specimens. The use of SDS containing extraction buffer in combination with the single-pot solid-phase-enhanced sample preparation (SP3) digest method gave the best results regarding protein yield and protein/peptide identifications. Microdissected FFPE human substantia nigra tissue samples (~3,000 cells) were then analyzed, using tandem mass tag (TMT) labeling and LC-MS/MS, resulting in the quantification of >5,600 protein groups. Nigral proteins were classified and analyzed by abundance, showing an enrichment of extracellular exosome and neuron-specific gene ontology (GO) terms among the higher abundance proteins. Comparison of microdissected samples with intact tissue sections, using a label-free shotgun approach, revealed an enrichment of neuronal cell type markers, such as tyrosine hydroxylase and alpha-synuclein, as well as proteins annotated with neuron-specific GO terms. Overall, this study provides a detailed protocol for laser-capture proteomics using FFPE tissue and demonstrates the efficiency of LCM analysis of distinct cell subpopulations for proteomic analysis using low sample amounts.




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Human Hepatocyte Nuclear Factor 4-{alpha} Encodes Isoforms with Distinct Transcriptional Functions [Research]

HNF4α is a nuclear receptor produced as 12 isoforms from two promoters by alternative splicing. To characterize the transcriptional capacities of all 12 HNF4α isoforms, stable lines expressing each isoform were generated. The entire transcriptome associated with each isoform was analyzed as well as their respective interacting proteome. Major differences were noted in the transcriptional function of these isoforms. The α1 and α2 isoforms were the strongest regulators of gene expression whereas the α3 isoform exhibited significantly reduced activity. The α4, α5, and α6 isoforms, which use an alternative first exon, were characterized for the first time, and showed a greatly reduced transcriptional potential with an inability to recognize the consensus response element of HNF4α. Several transcription factors and coregulators were identified as potential specific partners for certain HNF4α isoforms. An analysis integrating the vast amount of omics data enabled the identification of transcriptional regulatory mechanisms specific to certain HNF4α isoforms, hence demonstrating the importance of considering all isoforms given their seemingly diverse functions.




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The Secretome Profiling of a Pediatric Airway Epithelium Infected with hRSV Identified Aberrant Apical/Basolateral Trafficking and Novel Immune Modulating (CXCL6, CXCL16, CSF3) and Antiviral (CEACAM1) Proteins [Research]

The respiratory epithelium comprises polarized cells at the interface between the environment and airway tissues. Polarized apical and basolateral protein secretions are a feature of airway epithelium homeostasis. Human respiratory syncytial virus (hRSV) is a major human pathogen that primarily targets the respiratory epithelium. However, the consequences of hRSV infection on epithelium secretome polarity and content remain poorly understood. To investigate the hRSV-associated apical and basolateral secretomes, a proteomics approach was combined with an ex vivo pediatric human airway epithelial (HAE) model of hRSV infection (data are available via ProteomeXchange and can be accessed at https://www.ebi.ac.uk/pride/ with identifier PXD013661). Following infection, a skewing of apical/basolateral abundance ratios was identified for several individual proteins. Novel modulators of neutrophil and lymphocyte activation (CXCL6, CSF3, SECTM1 or CXCL16), and antiviral proteins (BST2 or CEACAM1) were detected in infected, but not in uninfected cultures. Importantly, CXCL6, CXCL16, CSF3 were also detected in nasopharyngeal aspirates (NPA) from hRSV-infected infants but not healthy controls. Furthermore, the antiviral activity of CEACAM1 against RSV was confirmed in vitro using BEAS-2B cells. hRSV infection disrupted the polarity of the pediatric respiratory epithelial secretome and was associated with immune modulating proteins (CXCL6, CXCL16, CSF3) never linked with this virus before. In addition, the antiviral activity of CEACAM1 against hRSV had also never been previously characterized. This study, therefore, provides novel insights into RSV pathogenesis and endogenous antiviral responses in pediatric airway epithelium.




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Decreased Immunoglobulin G Core Fucosylation, A Player in Antibody-dependent Cell-mediated Cytotoxicity, is Associated with Autoimmune Thyroid Diseases [Research]

Autoimmune thyroid diseases (AITD) are the most common group of autoimmune diseases, associated with lymphocyte infiltration and the production of thyroid autoantibodies, like thyroid peroxidase antibodies (TPOAb), in the thyroid gland. Immunoglobulins and cell-surface receptors are glycoproteins with distinctive glycosylation patterns that play a structural role in maintaining and modulating their functions. We investigated associations of total circulating IgG and peripheral blood mononuclear cells glycosylation with AITD and the influence of genetic background in a case-control study with several independent cohorts and over 3,000 individuals in total. The study revealed an inverse association of IgG core fucosylation with TPOAb and AITD, as well as decreased peripheral blood mononuclear cells antennary α1,2 fucosylation in AITD, but no shared genetic variance between AITD and glycosylation. These data suggest that the decreased level of IgG core fucosylation is a risk factor for AITD that promotes antibody-dependent cell-mediated cytotoxicity previously associated with TPOAb levels.




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Atomic force microscopy-based characterization of the interaction of PriA helicase with stalled DNA replication forks [DNA and Chromosomes]

In bacteria, the restart of stalled DNA replication forks requires the DNA helicase PriA. PriA can recognize and remodel abandoned DNA replication forks, unwind DNA in the 3'-to-5' direction, and facilitate the loading of the helicase DnaB onto the DNA to restart replication. Single-stranded DNA–binding protein (SSB) is typically present at the abandoned forks, but it is unclear how SSB and PriA interact, although it has been shown that the two proteins interact both physically and functionally. Here, we used atomic force microscopy to visualize the interaction of PriA with DNA substrates with or without SSB. These experiments were done in the absence of ATP to delineate the substrate recognition pattern of PriA before its ATP-catalyzed DNA-unwinding reaction. These analyses revealed that in the absence of SSB, PriA binds preferentially to a fork substrate with a gap in the leading strand. Such a preference has not been observed for 5'- and 3'-tailed duplexes, suggesting that it is the fork structure that plays an essential role in PriA's selection of DNA substrates. Furthermore, we found that in the absence of SSB, PriA binds exclusively to the fork regions of the DNA substrates. In contrast, fork-bound SSB loads PriA onto the duplex DNA arms of forks, suggesting a remodeling of PriA by SSB. We also demonstrate that the remodeling of PriA requires a functional C-terminal domain of SSB. In summary, our atomic force microscopy analyses reveal key details in the interactions between PriA and stalled DNA replication forks with or without SSB.




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Crystallographic and kinetic analyses of the FdsBG subcomplex of the cytosolic formate dehydrogenase FdsABG from Cupriavidus necator [Molecular Biophysics]

Formate oxidation to carbon dioxide is a key reaction in one-carbon compound metabolism, and its reverse reaction represents the first step in carbon assimilation in the acetogenic and methanogenic branches of many anaerobic organisms. The molybdenum-containing dehydrogenase FdsABG is a soluble NAD+-dependent formate dehydrogenase and a member of the NADH dehydrogenase superfamily. Here, we present the first structure of the FdsBG subcomplex of the cytosolic FdsABG formate dehydrogenase from the hydrogen-oxidizing bacterium Cupriavidus necator H16 both with and without bound NADH. The structures revealed that the two iron-sulfur clusters, Fe4S4 in FdsB and Fe2S2 in FdsG, are closer to the FMN than they are in other NADH dehydrogenases. Rapid kinetic studies and EPR measurements of rapid freeze-quenched samples of the NADH reduction of FdsBG identified a neutral flavin semiquinone, FMNH•, not previously observed to participate in NADH-mediated reduction of the FdsABG holoenzyme. We found that this semiquinone forms through the transfer of one electron from the fully reduced FMNH−, initially formed via NADH-mediated reduction, to the Fe2S2 cluster. This Fe2S2 cluster is not part of the on-path chain of iron-sulfur clusters connecting the FMN of FdsB with the active-site molybdenum center of FdsA. According to the NADH-bound structure, the nicotinamide ring stacks onto the re-face of the FMN. However, NADH binding significantly reduced the electron density for the isoalloxazine ring of FMN and induced a conformational change in residues of the FMN-binding pocket that display peptide-bond flipping upon NAD+ binding in proper NADH dehydrogenases.




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Quantification of the affinities of CRISPR-Cas9 nucleases for cognate protospacer adȷacent motif (PAM) sequences [Molecular Biophysics]

The CRISPR/Cas9 nucleases have been widely applied for genome editing in various organisms. Cas9 nucleases complexed with a guide RNA (Cas9–gRNA) find their targets by scanning and interrogating the genomic DNA for sequences complementary to the gRNA. Recognition of the DNA target sequence requires a short protospacer adjacent motif (PAM) located outside this sequence. Given that the efficiency of target location may depend on the strength of interactions that promote target recognition, here we sought to compare affinities of different Cas9 nucleases for their cognate PAM sequences. To this end, we measured affinities of Cas9 nucleases from Streptococcus pyogenes, Staphylococcus aureus, and Francisella novicida complexed with guide RNAs (gRNAs) (SpCas9–gRNA, SaCas9–gRNA, and FnCas9–gRNA, respectively) and of three engineered SpCas9–gRNA variants with altered PAM specificities for short, PAM-containing DNA probes. We used a “beacon” assay that measures the relative affinities of DNA probes by determining their ability to competitively affect the rate of Cas9–gRNA binding to fluorescently labeled target DNA derivatives called “Cas9 beacons.” We observed significant differences in the affinities for cognate PAM sequences among the studied Cas9 enzymes. The relative affinities of SpCas9–gRNA and its engineered variants for canonical and suboptimal PAMs correlated with previous findings on the efficiency of these PAM sequences in genome editing. These findings suggest that high affinity of a Cas9 nuclease for its cognate PAM promotes higher genome-editing efficiency.




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Exploring the Looming Water Crisis

28 November 2019

Gitika Bhardwaj

Editor, Communications & Publishing, Chatham House

Loïc Fauchon

President, World Water Council
Loïc Fauchon, president of the World Water Council, speaks to Gitika Bhardwaj about the causes of water scarcity around the world and how best to implement sustainable solutions.

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Dry sand and a narrow body of water near the Theewaterskloof Dam in South Africa which has had less than 20 per cent of its normal water capacity during recent water shortages. This dam, about 108km from Cape Town, is the main water source for residents of the city. Photo: Getty Images.

One-quarter of humanity faces a looming water crisis, including the prospect of running out of water, which may seem inconceivable when 70 per cent of the Earth’s surface is water. Nevertheless up to 80 per cent of available surface and groundwater is being used every year and water demand globally is projected to increase by 55 per cent by 2050. Why is the world facing a crisis of water scarcity and what is driving the increasing demand for water?

The first reason that is causing water stress around the world is the growing human population at the same time as the water supply has remained the same. Given that there are almost one billion more inhabitants on Earth every 15-20 years, this has led to a progressive deficit in the global water supply. 

The second reason is due to the uneven concentration of the global population. There is not a clear link between the presence of the population in some regions and the presence of water, in other words, water is not where we want it to be every time.

For example, there is, what we call, a ‘triangle of thirst’ from southern Spain, to Pakistan, to the Horn of Africa and back again. In this triangle, you have around two billion people in a very water-scarce region.

Comparatively, if you go to Russia or Canada, they have more water than they need in terms of the size of their population. So this is another crucial reason we are facing a crisis of water scarcity in some regions of the world – but not everywhere. 

Climate [change] will be the fruit on the cake. Currently we have global population growth and then later we will have climate change affecting water availability. But at this very moment, however, the problem for water suppliers and for political leaders is the demographic crisis we are facing – not the climate.

Water use has grown at more than twice the rate of the human population over the last century in part due to industries, such as agriculture, which account for 70 per cent of global freshwater use.

Given that food production will need to grow by up to 70 per cent by 2035 to feed the growing human population, how do we balance the use of water with the need to provide food?

There are some solutions. The first is that we need to improve water efficiency in the agricultural sector. We need to have all around the world, but mostly in developing countries, a better capacity to increase the water efficiency of agriculture without increasing the use of industrial chemical products and to move, step-by-step, to an economical system of organic farming. It will take time – it will not be done in one or even five years but more likely over a generation – but it is the best way.   

Secondly, which could be a faster solution, is that we have to reduce all kind of food waste which represents around 30-40 per cent of all agricultural production. Agriculture is a large sector involving the growing of crops but also livestock. There’s not only waste in terms of consumption but also during the production line, for example, during the transportation of food products. So there is this, sort of, waste cycle which is very important to consider. If you are able to reduce the water waste during the production line by 30-40 per cent, then you use less water, obviously.

The third solution is to be able to, step-by-step, change our consumption patterns. Use less meat, all kinds of agricultural products which need a lot of water etc. I think we will be obliged to do this over the next couple of decades, and we will probably have low animal protein diets in the future, which will mean we have to think of different ways to be able to provide food to the increasing global population.

There are other industries that are water-intensive that also need to be looked at in terms of their water waste such as the clothing and automobile industries. One piece of paper, for example, takes about 100 litres of water to produce while one litre of milk takes about 1,000 litres of water. Another example is that one cup of coffee takes 150 litres of water – just one cup of coffee – that’s because there is not only the water you are drinking but the water needed to prepare the coffee beans and the water used in the materials that make the coffee cup and so on.

So everything consumes water and that’s why humans will be obliged to consume less water over the coming years. 

More than one in three people globally do not have access to safe drinking water and more than 4 billion people lack adequate sanitation. How can waste water be more efficiently used and do you think global goals to provide everyone with safe and clean drinking water are still realistic?

In French, we use a phrase, parent pauvre, which means poor relative. Most of the decisions concerning access to water are not acceptable in the long term. That’s why we at the World Water Council are pushing for the financing of water and sanitation goals [concurrently].

For example, if you have a programme for a city to increase access to water for its citizens, they also need a sanitation programme. If we don’t do that, the mismatch that currently exists between water and sanitation will remain. 

There’s also another important solution which political leaders will be obliged to invest more in which is having more water coming from water reuse. If you produce water from water reuse processes then it means that it will likely have undergone sanitation treatment already which is a win-win solution [for providing safe and clean drinking water].

It’s all moving slowly but I’m optimistic concerning the increasing consciousness of people regarding water pollution – for example the pollution of our rivers, seas and oceans – and I think we will move faster in the sanitation area than in the water access area over the next decade.

Personally, I do not think that global goals to provide everyone with safe and clean drinking water [are the best solution]. I am more in favour of national and local commitments rather than global commitments. National and local efforts are stronger then [the rhetoric] around global goals where there is no authority to oversee the progress they are making. Only the population of a country or of a city can see if their leaders have done their job regarding providing access to safe and clean water.

People queue up to collect water from taps fed by a spring in Newlands in 15 May 2017 in Cape Town, South Africa. South Africa's Western Cape region declared a drought disaster on 22 May 2017 as the province battled its worst water shortages for more than 112 years. Photo: Getty Images.

With the depletion of global water supplies, how can governments avoid the politicization of water, as seen in cases such as the Nile River Basin and across the Middle East, to avoid conflicts over water?

This is a complicated issue because politicians will always do politics so it will always be difficult to avoid attempts to politicize situations. But the key is dialogue, dialogue and dialogue. That is the only way to solve water conflicts as well as better management of water because, in some regions, some of these conflicts are arising from the mismanagement of water supplies – not because of water scarcity. 

If you look at Egypt and the US, people are consuming around 800 litres [of water] per day whereas in Europe people are consuming around 200 litres per day. But why is [water consumption] in Egypt, rather than Europe, the same as in the US? Because they have considerable water losses in industries such as agriculture.

In addition, in the main cities like Cairo, there is not an adequate range of water networks, so, if in the future those living in Cairo are able to consume less water, they will need less water coming from the Nile River which will make politicization of water by politicians less likely. 

In the future, social unrest from water shortages is likely, however, I do not think it will ever lead to wars. 

Countries across the Middle East have invested in modern techniques, such as desalination plants, as an answer to water scarcity, but this can have a negative impact, notably on marine life. In contrast, some of the more ancient techniques, like rainwater harvesting, are being repurposed in cities around the world today. What is your view on these practices and what other solutions are available?

There are a lot of solutions and desalination is among them. Currently probably 100 countries in the world are using, or preparing to use, desalination as a solution so it surely is an important solution. But at the same time, reused water is developing fast and is a much cheaper option than desalination. 

Nevertheless, the price of desalination has been decreasing over the past 20 years and is now less than $1 a cubic metre, whereas 15 years ago, it was $10 a cubic metre.

Some of the negative impacts of desalination exist when you are separating the water from the salt, which can lead to disasters, for example, what has happened in the Persian Gulf. When Kuwait, Saudi Arabia, Bahrain and Qatar first used desalination treatments, the temperature of the sea was around 30°C, whereas today, it can be up to 40°C. This increasing sea temperature as a result of the desalination plants has contributed to changes in biodiversity. For example, we are seeing fish disappearing and even the growing population of giant jellyfish – which some desalination plants in Saudi Arabia are dealing with by using shredders which is another type of disaster.

Furthermore, in some regions, we need to keep in mind that desalination is not only along the coast but it’s also in the middle of the land too. For example, in the Sahara region, like in Algeria or Morocco, the water coming from the ground is salted so you need to have desalination plants inland and not on the coast. But where they keep the salt inland, that salt mixes with the rain and enters the ground, thereby destroying some of the biodiversity there too. So it must be used prudently. 

Rainwater harvesting is a technique from centuries ago and I am a great supporter of it as a solution to water scarcity in India, particularly in Rajasthan, and I think it could also be part of the solutions in some places across Africa.

That’s why I believe there needs to be an exchange of solutions because something which is successful here could be successful somewhere else. In this way, we need to be able to show a Senegalese farmer a solution which has been implemented elsewhere, such as in India, and show him this can work for you too – it’s sort of like when the Japanese built the Toyota by looking at the British Land Rover.

With billions of people threatened by the global water crisis, increased water stress could lead to more ‘Day Zeroes’, a term used in 2018 as Cape Town in South Africa came dangerously close to running out of water. In your view, what will happen if the world doesn’t adequately address the global crisis of water scarcity?

The increasing absence of water would mean not only the migration of humans to more water-abundant regions but also the absence of socioeconomic growth of any kind in some places because water scarcity will pose a risk to businesses who will be forced to move to new areas – from small businesses like a hairdresser to factories that are unable to produce any goods or provide any services. So not tackling the water crisis means not being able to tackle our own capacity to prosper by not protecting the environment we depend on.

In Cape Town, there was a lack of rain in the city which contributed to the water crisis there but there was also a lack of water management. They knew they could have a lack of rain, and when you have a lack of rain, you have the obligation to prepare a reservoir of water for the year to the next year and so on but that did not happen.

There is a French poem from Jean de La Fontaine about a grasshopper and an ant. The grasshopper just spends his time in the summer enjoying life but the ant keeps working hard throughout the summer to save all of his supplies for the winter. In this way, we need to be like the ant, preparing water supplies for today and for tomorrow.

In the case of Cape Town, there was also another element, which was that the water supplies were being used by the central government as a tool to isolate the regional governor there who was part of the opposition. So the lack of water management was almost used as a political tool as we discussed earlier.

Some say that the water scarcity we are seeing is because of climate change. Yes it is but there is also a lack of water management by humans. If you look at the people living throughout the centuries all the way to antiquity, you see that people around the world prepared reservoirs of water to keep water from the winter to the summer, from the one year to the next, whereas today, we are seeing bad water management. So, in this way, I believe climate change should not be the scapegoat of human error.




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Iran Crisis: The Impact on Oil Markets

14 January 2020

Professor Paul Stevens

Distinguished Fellow, Energy, Environment and Resources Programme
The assassination of Qassem Soleimani has exacerbated the sensitivity of oil markets to political events and brought geopolitics back into global oil prices.

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Satellite image of the Strait of Hormuz. Photo: Getty Images.

The assassination of General Qassem Soleimani has created much speculation about the possible impact on oil markets and – although any impact will very much depend upon what happens next in terms of political and military responses – theoretically the potential exists for Iran to seriously destabilize oil markets, raising oil prices.

Arguably, it would be in Iran’s interest to do so. It would certainly hurt Trump’s possibility of a second term if higher prices were to last for some time as the 2020 presidential election gets underway. And it would also help shore up Iran’s failing economy. 

The assassination did initially cause oil prices to rise by a few dollars before quickly falling back, and the missile attacks by Iran produced a similar response. However, direct action by Iran to raise prices – for example by trying to close the Strait of Hormuz – is unlikely.

Around one-fifth of the world's oil supplies passes through the Strait of Hormuz, a narrow choke point between Iran and the Arabian Peninsula. Closing it would invite serious military action by the Americans and many of its allies who, so far, have been rather lukewarm over Trump’s actions. It would also possibly limit Iran’s own oil exports.

Similarly, overt attacks on American allies in the region such as Saudi Arabia and the UAE would probably invite too heavy a reaction, although this is uncertain given the lack of response after the alleged Iranian attacks on Abqaiq and Khurais in mid-September.

Indirect action by Iran to affect oil supplies is much more likely as they have many options by using their proxies to affect others’ oil production. This is especially true for Iraq, which is now an important source of global oil supply as Iraqi exports in 2019 averaged 3.53 million barrels per day (Mb/d), a significant amount.

Iraq’s future production has already been damaged as international oil companies are withdrawing staff for safety reasons, anticipating potential attacks by both Iraqi and Iranian sources. It is now very unlikely that the crucial ‘common seawater supply project’ being run by Exxon – essential for expanding production capacity – will go ahead in the near future.

However, one important consequence of the assassination that has attracted little attention is that it has almost fully restored the role of geopolitics into the determination of oil prices. Up to 2014, geopolitics played a key role in determining oil prices in the paper markets where perceptions and expectations ruled.

Prices determined in these markets – NYMEX in New York, ICE in London and other lesser futures markets throughout the world – then influence wet barrel markets where real barrels of oil are traded. 

In 2014, the world was so oversupplied with real oil barrels that the oil price collapsed – the price of Brent crude fell from $110.72 on 23 May to $46.44 eight months later. Thereafter, little if any attention was given to geopolitical events, and geopolitics became marginalized in the determination of crude oil prices.

This began to change in 2019. The market remained physically over-supplied but events in the Gulf began to attract attention. In June, there were a series of attacks on oil tankers close to the Gulf, followed by attacks on Saudi Arabia’s Abqaiq processing facility and the Khurais oil field in September.

The Americans claimed these attacks were launched by Iran, but no convincing evidence for the claim was provided. Both attacks produced an initial price response but it was surprisingly limited and short-lived. However, it did suggest that geopolitics might be creeping back into influencing oil prices.

This became ever more noticeable in the third and fourth quarters as rumours regarding the trade talks between China and US clearly began to affect price – talks going well meant higher oil demand, and prices rose; talks going badly meant lower oil demand, and prices fell.

Meanwhile, the oil market showed signs of tightening towards the end of 2019. Although there was much cheating on the OPEC+ agreement that was trying to restrain production and protect prices, the OPEC meeting last December saw both Iraq and Nigeria agreeing to restrain production. 

US stock levels also began to fall in December and the futures markets began to price in a tightening market towards the end of 2020. Significantly, the tighter the market appears, the greater attention is paid to the level of spare producing capacity.

Just before the attack on Abqaiq, the International Energy Agency (IEA) estimated there was 3.5 Mb/d spare capacity in OPEC which, historically, is quite comfortable. However, 2.5 of this was estimated to be in Saudi Arabia, so how much of this spare capacity still existed after the Abqaiq attack?

The Saudis claimed the Abqaiq capacity was quickly restored but technical experts greeted this with considerable skepticism, not least because the Abqaiq equipment was highly specialized. If spare capacity is tight, this makes the oil price vulnerable to geopolitical scares and rumours, real or imagined. 

Although the assassination of General Soleimani has exacerbated the sensitivity of oil markets to geopolitical events, this becomes irrelevant if a serious shooting war starts in the region. Saudi Arabia, the UAE and Iraq’s oil infrastructure remains highly vulnerable to attack either directly by Iran or one of its many proxies, suggesting oil prices will become increasingly volatile but, at the same time, benefit from a rising geopolitical premium.




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Why an Inclusive Circular Economy is Needed to Prepare for Future Global Crises

15 April 2020

Patrick Schröder

Senior Research Fellow, Energy, Environment and Resources Programme
The risks associated with existing production and consumption systems have been harshly exposed amid the current global health crisis but an inclusive circular economy could ensure both short-term and long-term resilience for future challenges.

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Lima city employees picking up garbage during lockdown measures in Peru amid the COVID-19 crisis. Photo: Getty Images.

The world is currently witnessing how vulnerable existing production and consumption systems are, with the current global health crisis harshly exposing the magnitude of the risks associated with the global economy in its current form, grounded, as it is, in a linear system that uses a ‘take–make–throw away’ approach.

These ‘linear risks’ associated with the existing global supply chain system are extremely high for national economies overly dependent on natural resource extraction and exports of commodities like minerals and metals. Equally vulnerable are countries with large manufacturing sectors of ready-made garments and non-repairable consumer goods for western markets. Furthermore, workers and communities working in these sectors are vulnerable to these changes as a result of disruptive technologies and reduced demand.

In a recently published Chatham House research paper, ‘Promoting a Just Transition to an Inclusive Circular Economy’, we highlight why a circular economy approach presents the world with a solution to old and new global risks – from marine plastic pollution to climate change and resource scarcity.

Taking the long view

So far, action to transition to a circular economy has been slow compared to the current crisis which has mobilized rapid global action. For proponents of transitioning to a circular economy, this requires taking the long view. The pandemic has shown us that global emergencies can fast-forward processes that otherwise might take years, even decades, to play out or reverse achievements which have taken years to accomplish.

In this vein, there are three striking points of convergence between the COVID-19 pandemic and the need to transition to an inclusive circular economy.

Firstly, the current crisis is a stark reminder that the circular economy is not only necessary to ensure long-term resource security but also short-term supplies of important materials. In many cities across the US, the UK and Europe, councils have suspended recycling to focus on essential waste collection services. The UK Recycling Association, for example, has warned about carboard shortages due to disrupted recycling operations with possible shortages for food and medicine packaging on the horizon.

Similarly, in China, most recycling sites were shut during the country’s lockdown presenting implications for global recycling markets with additional concerns that there will be a fibre shortage across Europe and possibly around the world.

Furthermore, worldwide COVID-19 lockdowns are resulting in a resurgence in the use of single-use packaging creating a new wave of plastic waste especially from food deliveries – already seen in China – with illegal waste fly-tipping dramatically increasing in the UK since the lockdown.

In this vein, concerns over the current global health crisis is reversing previous positive trends where many cities had established recycling schemes and companies and consumers had switched to reusable alternatives.

Secondly, the need to improve the working conditions of the people working in the informal circular economy, such as waste pickers and recyclers, is imperative. Many waste materials and recyclables that are being handled and collected may be contaminated as a result of being mixed with medical waste.

Now, more than ever, key workers in waste management, collection and recycling require personal protective equipment and social protection to ensure their safety as well as the continuation of essential waste collection so as not to increase the potential for new risks associated with additional infectious diseases.

In India, almost 450 million workers including construction workers, street vendors and landless agricultural labourers, work in the informal sector. In the current climate, the poorest who are unable to work pose a great risk to the Indian economy which could find itself having to shut down.

Moreover, many informal workers live in make-shift settlements areas such as Asia’s largest slum, Dharavi in Mumbai, where health authorities are now facing serious challenges to contain the spread of the disease. Lack of access to handwashing and sanitation facilities, however, further increase these risks but circular, decentralized solutions could make important contributions to sustainable sanitation, health and improved community resilience.

Thirdly, it is anticipated that in the long term several global supply chains will be radically changed as a result of transformed demand patterns and the increase in circular practices such as urban mining for the recovery and recycling of metals or the reuse and recycling of textile fibres and localized additive manufacturing (e.g. 3D printing).

Many of these supply chains and trade flows have now been already severely disrupted due to the COVID-19 pandemic. For example, the global garment industry has been particularly hard-hit due to the closure of outlets amid falling demand for apparel.

It is important to note, workers at the bottom of these garment supply chains are among the most vulnerable and most affected by the crisis as global fashion brands, for example, have been cancelling orders – in the order of $6 billion in the case of Bangladesh alone. Only after intense negotiations are some brands assuming financial responsibility in the form of compensation wage funds to help suppliers in Myanmar, Cambodia and Bangladesh to pay workers during the ongoing crisis.

In addition, the current pandemic is damaging demand for raw materials thereby affecting mining countries. Demand for Africa’s commodities in China, for example, has declined significantly, with the impact on African economies expected to be serious, with 15 per cent of the world’s copper and 20 per cent of the world’s zinc mines currently going offline

A further threat is expected to come from falling commodity prices as a result of the curtailment of manufacturing activity in China particularly for crude oil, copper, iron ore and other industrial commodities which, in these cases, will have direct impacts on the Australian and Canadian mining sectors.

This is all being compounded by an associated decline in consumer demand worldwide. For example, many South African mining companies – leading producers of metals and minerals – have started closing their mining operations following the government’s announcement of a lockdown in order to prevent the transmission of the virus among miners who often work in confined spaces and in close proximity with one another. As workers are laid off due to COVID-19, there are indications that the mining industry will see fast-tracking towards automated mining operations

All of these linear risks that have been exposed through the COVID-19 pandemic reinforce the need for a just transition to a circular economy. But while the reduction in the consumption of resources is necessary to achieve sustainability, the social impacts on low- and middle- income countries and their workers requires international support mechanisms.

In addition, the current situation also highlights the need to find a new approach to globalized retail chains and a balance between local and global trade based on international cooperation across global value chains rather than implementation of trade protectionist measures.

In this vein, all of the recovery plans from the global COVID-19 pandemic need to be aligned with the principles of an inclusive circular economy in order to ensure both short-term and long-term resilience and preparedness for future challenges and disruptions.  




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Same Old Politics Will Not Solve Iraq Water Crisis

15 April 2020

Georgia Cooke

Project Manager, Middle East and North Africa Programme

Dr Renad Mansour

Senior Research Fellow, Middle East and North Africa Programme; Project Director, Iraq Initiative

Glada Lahn

Senior Research Fellow, Energy, Environment and Resources Programme
Addressing Iraq’s water crisis should be a priority for any incoming prime minister as it is damaging the country’s attempts to rebuild. But successive governments have allowed the problem to fester.

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Punting in the marshes south of the Iraqi city of Ammarah. Photo by Ghaith Abdul-Ahad/Getty Images.

Historically, Iraq lay claim to one of the most abundant water supplies in the Middle East. But the flow of the Tigris and Euphrates rivers has reduced by up to 40% since the 1970s, due in part to the actions of neighbouring countries, in particular Turkey, upstream.

Rising temperatures and reduced rainfall due to climate change are also negatively impacting Iraq’s water reserves. Evaporation from dams and reservoirs is estimated to lose the country up to 8 billion cubic metres of water every year.

A threat to peace and stability

Shortages have dried up previously fertile land, increasing poverty in agricultural areas. Shortages have also served to fuel conflict: communities faced with successive droughts and government inertia proved to be easy targets for ISIS recruiters, who lured farmers into joining them by offering money and food to feed their families. Economic hardship for those whose livelihoods relied upon river water has also driven rural to urban migration, putting significant strain on already over-populated towns and cities, exacerbating housing, job and electricity shortages, and widening the gap between haves and have-nots.

But scarcity isn’t the most crucial element of Iraq’s water crisis – contamination is. Decades of local government mismanagement, corrupt practices and a lack of regulation of dumping (it is estimated up to 70% of Iraq’s industrial waste is dumped directly into water) has left approximately three in every five citizens without a reliable source of potable water.

In 2018, 118,000 residents of Basra province were hospitalised with symptoms brought on by drinking contaminated water, which not only put a spotlight on the inadequacies of a crumbling healthcare system but sparked mass protests and a subsequent violent crackdown.

The water crisis is also undermining the stability of the country’s federal governance model, by occasionally sparking disputes between Baghdad and the Kurdistan Regional Government, as well as between governorates in the south.

The crisis is both a symptom and a cause of poor governance. Iraq is stuck in a cycle whereby government inaction causes shortages and contamination, which result in economic losses, reduced food supply, increased prices and widespread poor health. This in turn leads to increasing levels of poverty, higher demand on services and civil unrest, increasing the pressure on a weak, dysfunctional system of government.

What can be done?

The first priority should be modernising existing water-management infrastructure - a relic of a time when the problem was an excess rather than a shortage of water (the last time Iraq’s flood defences were required was 1968). Bureaucratic hurdles, widespread corruption and an endless cycle of other crises taking precedent prevent good initiatives from being implemented or scaled up.

Diversifying energy sources to improve provision is crucial. Baghdad has a sewage treatment plant that originally ran on its own electricity source, but this capacity was destroyed in 1991 and was never replaced. The city continues to suffer from dangerous levels of water pollution because the electricity supply from the grid is insufficient to power the plant. Solar energy has great potential in sun-drenched Iraq to bridge the gaping hole in energy provision, but successive governments have chosen to focus on fossil fuels rather than promoting investment to grow the renewables sector.

Heightened tension with upstream Turkey could turn water into another cause of regional conflict. But, if approached differently, collaboration between Iraq and its neighbour could foster regional harmony.

Turkey’s elevated geography and cooler climate mean its water reserves suffer 75% less evaporation than Iraq’s. Given that Turkey’s top energy priority is the diversification of its supply of imported hydrocarbons, a win-win deal could see Turkey exchange access to its water-management infrastructure for delivery of reduced cost energy supplies from Iraq.

German-French cooperation on coal and steel in the 1950s and the evolution of economic integration that followed might provide a model for how bilateral cooperation over one issue could result in cooperation with other regional players (in this case Iran and Syria) on a range of other issues. This kind of model would need to consider the future of energy, whereby oil and gas would be replaced by solar-power exports.

These solutions have been open to policymakers for years and yet they have taken little tangible action. While there are leaders and bureaucrats with the will to act, effective action is invariably blocked by a complex and opaque political system replete with vested interests in maintaining power and wealth via a weak state and limited services from central government.

Breaking the cycle

To break this cycle, Iraq needs a group of professional and able actors outside of government to work with willing elements of the state bureaucracy as a taskforce to pressure for action and accountability. Publishing the recommendations from a hitherto withheld report produced in the aftermath of Basra’s 2018 heath crisis would be a great start.

In time, this taskforce could champion the prioritisation of water on the national agenda, the implementation of infrastructure upgrades, and hold more productive conversations with neighbour states.

With such a high degree of state fragmentation and dysfunction in Iraq, looking to the central government to provide leadership will not yield results. Engagement with a coalition of non-state actors can begin to address the water crisis and also open a dialogue around new models of governance for other critical issues. This might even be a starting point for rewriting the tattered social contract in Iraq.

This piece is based on insights and discussion at a roundtable event, Conflict and the Water Crisis in Iraq, held at Chatham House on March 9 as part of the Iraq Initiative.




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Webinar: The Opportunity of Crisis? Transitioning to a Sustainable Global Economy

Corporate Members Event Webinar

22 April 2020 - 1:00pm to 1:45pm

Event participants

Professor Tim Benton, Research Director, Emerging Risks and Director, Energy, Environment and Resources Programme, Chatham House

Creon Butler, Research Director, Trade, Investment & New Governance Models; Director, Global Economy and Finance Programme, Chatham House

Elsa Palanza, Managing Director, Global Head of Sustainability and ESG, Barclays

Chair: Laura Wellesley, Research Fellow, Energy, Environment and Resources Programme, Chatham House

With the Asian Development Bank estimating that the COVID-19 outbreak’s global cost could reach $4.1 trillion and the OECD warning that the shock caused by the pandemic is already greater than the financial crisis of 2007, the global economic impact of the health emergency is not only vast but also unpredictable. The disruption to a number of industries and sectors including, but not limited to, the airline and energy industries, could result in long-term damage to global trade flows, supply and demand. But does the pandemic also present an opportunity to build sustainable economies that can cope with such threats?

This panel will explore the ways in which the coronavirus outbreak has highlighted vulnerabilities in global systems and what this might mean for a transition towards a sustainable economy. How do we explain the failure of businesses and governments to prepare for systemic shocks and the lack of resilience in global structures and models? How should governments prepare to reshape policy, business practices and societal behaviour to better tackle climate change while addressing the current emergency? And might the emergency offer opportunities to kick start a sustainable path towards a greener future?

This event is part of a fortnightly series of 'Business in Focus' webinars reflecting on the impact of COVID-19 on areas of particular professional interest for our corporate members and giving circles.

Not a corporate member? Find out more.




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Reviewing Antimicrobial Resistance: Where Are We Now and What Needs to Be Done?

Research Event

8 October 2019 - 10:30am to 12:00pm

RSA House, 8 John Adam Street, London, WC2N 6EZ

Event participants

Tim Jinks, Head of Drug-Resistant Infections Programme, Wellcome
Jim O’Neill, Chair, Review on Antimicrobial Resistance; Chair, Chatham House
Haileyesus Getahun, Director of Global Coordination and Partnership on Antimicrobial Resistance, World Health Organization 
Juan Lubroth, Chief Veterinary Officer, Food and Agriculture Organization (Videolink)
Jyoti Joshi, Head, South Asia, Center for Disease Dynamics, Economics & Policy
Estelle Mbadiwe, Coordinator-Nigeria, Global Antibiotic Resistance Partnership
Charles Clift, Senior Consulting Fellow, Chatham House; Report Author

The Review on Antimicrobial Resistance, chaired by Jim O’Neill, was commissioned by former UK prime minister, David Cameron, in July 2014. Supported by the UK government and the Wellcome Trust, the final report of the review was published in May 2016 and has had a global impact in terms of motivating political leaders and decision-makers to take more seriously the threat posed by antimicrobial resistance.

Yet there is now a perception that the political momentum to address the issue is waning and needs to be reinvigorated.

In a further report produced by Chatham House, the progress of the recommendations of the review is assessed and the key ways to move forward are identified.

Panellists at this event, where highlights of the report are presented, provide their assessment of the progress so far and discuss priorities for future action.

The report was funded by Wellcome.

Alexandra Squires McCarthy

Programme Coordinator, Global Health Programme
+44 (0)207 314 2789




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Review of Progress on Antimicrobial Resistance

8 October 2019

A startling lack of progress on critical recommendations to tackle antimicrobial resistance is highlighted in this new global progress report, as well as opportunities for further action and key obstacles that need to be overcome.

Use the Download button to choose either the Research Paper, or the Background and Analysis Paper.

Dr Charles Clift

Senior Consulting Fellow, Global Health Programme

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A PhD student at Melbourne’s Doherty Institute inspects the superbug Staphylcocus epidermidis on an agar plate on 4 September 2018. Photo: Getty Images.
  • The 2016 Review on Antimicrobial Resistance has had a global impact: as an advocacy tool, in raising the profile of antimicrobial resistance (AMR) on the international agenda, and in helping to stimulate a number of new initiatives, in particular relating to the funding of early-stage research.
  • However, there has been very little progress on the review’s central and most expensive recommendations for transforming research and development incentives for antibiotics, vaccines and diagnostics.
  • There have been significant advances in reducing antibiotic use in agriculture, particularly in high-income countries, but there is a long way to go in low- and middle-income countries (LMICs).
  • There has been greater investment in awareness raising but questions remain about its impact and effectiveness in changing behaviour.
  • Proposals to restrict over-the-counter sales of antibiotics, as recommended by the Review, have foundered in the face of poor living conditions and access to healthcare in LMICs.
  • A major reason for the use of antibiotics in LMICs is the prevalence of unhygienic conditions in the community and in healthcare facilities, which contribute to infection and limit the impact of messages about awareness and infection prevention and control.
  • Providing quality healthcare to all and moving towards universal health coverage in LMICs will be crucial in addressing the problems of both adequate access to antibiotics and in restricting over-the-counter sales.
  • A greater emphasis on investments in water, sanitation and housing will be central to reducing reliance on antibiotics in LMICs in the longer term. This agenda should inform the operations of governments and funding agencies such as the International Monetary Fund (IMF) and the World Bank.
  • Investments have been made in improving surveillance of antibiotic use and resistance, particularly for humans, but more effort is required to create surveillance systems that provide data sufficiently accurate to influence policy and action. This applies also to antibiotics and resistant genes circulating in the environment.
  • The emerging innovations in the global governance of AMR need to lead to action rather than more words.




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Biosecurity: Preparing for the Aftermath of Global Health Crises

9 January 2020

Professor David R Harper CBE

Senior Consulting Fellow, Global Health Programme

Benjamin Wakefield

Research Associate, Global Health Programme
The Ebola outbreak in the Democratic Republic of the Congo is a reminder that the security of samples taken during global health emergencies is a vital part of safeguarding biosecurity.

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A nurse prepares a vaccine against Ebola in Goma in August 2019. Photo: Getty Images.

The world’s second-largest Ebola outbreak is ongoing in the Democratic Republic of the Congo (DRC) and experts from around the world have been parachuted in to support the country’s operation to stamp out the outbreak. The signs are encouraging, but we need to remain cautious.

In such emergencies, little thought is usually given to what happens to the body-fluid samples taken during the course of the outbreak after the crisis is over. What gets left behind has considerable implications for global biosecurity.

Having unsecured samples poses the obvious risk of accidental exposures to people who might come into contact with them, but what of the risk of malicious use? Bioterrorists would have ready access to materials that have the characteristics essential to their purpose: the potential to cause disease that is transmissible from person to person, the capacity to result in high fatality rates and, importantly, the ability to cause panic and social disruption at the very mention of them.

Comparisons can be drawn with the significant international impact of the anthrax attacks in the US in 2001. Not only was there a direct effect in the US with five deaths and a further 17 people infected, but there was a paralysis of public health systems in other countries involved in the testing of countless samples from the so-called ‘white-powder incidents’ that followed.

Many laboratory tests were done purely on a precautionary basis to eliminate any possibility of a risk, no matter how remote. However, the UK was also hit when a hoaxer sent envelopes of white powder labelled as anthrax to 15 MPs.

The threat of the pathogen alone resulted in widespread fear, the deployment of officers trained in response to chemical, biological, radiological and nuclear incidents and the evacuation of a hospital emergency department.

We learned from the 2014–16 West Africa Ebola outbreaks that during the emergency, the future biosecurity implications of the many thousands of samples taken from people were given very little consideration. It is impossible to be sure where they all are and whether they have been secured.

It is widely recognized that the systems needed at the time for tracking and monitoring resources, including those necessary for samples, were weak or absent, and this has to be addressed urgently along with other capacity-building initiatives.

In Sierra Leone, for example, the remaining biosecurity risk is only being addressed after the fact. To help achieve this, the government of Canada is in the process of providing a secure biobank in the Sierra Leonean capital of Freetown. The aim is to provide the proper means of storage for these hazardous samples and to allow them to remain in-country, with Sierra Leonean ownership.

However, it is already more three years since the emergency was declared over by the then director-general of the World Health Organization (WHO), Margaret Chan, and the biobank and its associated laboratory are yet to be fully operational.

There are many understandable reasons for this delay, including the critical issue of how best to ensure the sustainability of any new facility. But what is clear is that these solutions take time to implement and must be planned for in advance.

The difficulties of responding to an outbreak in a conflict zone have been well documented, and the frequent violence in DRC has undoubtedly caused delays in controlling the outbreak. According to figures from WHO, during 2019 approximately 390 attacks on health facilities in DRC killed 11 and injured 83 healthcare workers and patients.

Not only does the conflict inhibit the response, but it could also increase the risk posed by unsecured samples. There are two main potential concerns.

First is the risk of accidental release during an attack on a health facility, under which circumstances sample containers may be compromised or destroyed. Second is that the samples may be stolen for malicious use or to sell them to a third-party for malicious use. It is very important in all outbreaks to ensure the necessary measures are in place to secure samples; in conflict-affected areas, this is particularly challenging.

The sooner the samples in the DRC are secured, the sooner this risk to global biosecurity is reduced. And preparations for the next emergency must be made without further delay.

The following steps need to be taken:

  • Affected countries must ‘own’ the problem, with clear national government commitment to take the required actions.
  • Funding partners must coordinate their actions and work closely with the countries to find the best solutions.
  • If samples are to be kept in-country, secure biobanks must be established to contain them.
  • Sustainable infrastructure must be built for samples to be kept secure into the future.
  • An international agreement should be reached on the best approach to take to prepare for the aftermath of global health emergencies.




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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.




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Vitamin E does not prevent Western diet-induced NASH progression and increases metabolic flux dysregulation in mice [Research Articles]

Fatty liver involves ectopic lipid accumulation and dysregulated hepatic oxidative metabolism, which can progress to a state of elevated inflammation and fibrosis referred to as nonalcoholic steatohepatitis (NASH). The factors that control progression from simple steatosis to NASH are not fully known. Here, we tested the hypothesis that dietary vitamin E (VitE) supplementation would prevent NASH progression and associated metabolic alterations induced by a Western diet (WD). Hyperphagic melanocortin-4 receptor-deficient (MC4R–/–) mice were fed chow, chow+VitE, WD, or WD+VitE starting at 8 or 20 weeks of age. All groups exhibited extensive hepatic steatosis by the end of the study (28 weeks of age). WD feeding exacerbated liver disease severity without inducing proportional changes in liver triglycerides. Eight weeks of WD accelerated liver pyruvate cycling, and 20 weeks of WD extensively upregulated liver glucose and oxidative metabolism assessed by 2H/13C flux analysis. VitE supplementation failed to reduce the histological features of NASH. Rather, WD+VitE increased the abundance and saturation of liver ceramides and accelerated metabolic flux dysregulation compared with 8 weeks of WD alone. In summary, VitE did not limit NASH pathogenesis in genetically obese mice, but instead increased some indicators of metabolic dysfunction.




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Myeloid-specific deficiency of pregnane X receptor decreases atherosclerosis in LDL receptor-deficient mice [Research Articles]

The pregnane X receptor (PXR) is a nuclear receptor that can be activated by numerous drugs and xenobiotic chemicals. PXR thereby functions as a xenobiotic sensor to coordinately regulate host responses to xenobiotics by transcriptionally regulating many genes involved in xenobiotic metabolism. We have previously reported that PXR has pro-atherogenic effects in animal models, but how PXR contributes to atherosclerosis development in different tissues or cell types remains elusive. In this study, we generated an LDL receptor-deficient mouse model with myeloid-specific PXR deficiency (PXRMyeLDLR–/–) to elucidate the role of macrophage PXR signaling in atherogenesis. The myeloid PXR deficiency did not affect metabolic phenotypes and plasma lipid profiles, but PXRMyeLDLR–/– mice had significantly decreased atherosclerosis at both aortic root and brachiocephalic arteries compared with control littermates. Interestingly, the PXR deletion did not affect macrophage adhesion and migration properties, but reduced lipid accumulation and foam cell formation in the macrophages. PXR deficiency also led to decreased expression of the scavenger receptor CD36 and impaired lipid uptake in macrophages of the PXRMyeLDLR–/– mice. Further, RNA-Seq analysis indicated that treatment with a prototypical PXR ligand affects the expression of many atherosclerosis-related genes in macrophages in vitro. These findings reveal a pivotal role of myeloid PXR signaling in atherosclerosis development and suggest that PXR may be a potential therapeutic target in atherosclerosis management.




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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.




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Commentary on SSO and other putative inhibitors of FA transport across membranes by CD36 disrupt intracellular metabolism, but do not affect fatty acid translocation [Commentaries]




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Membrane domains beyond the reach of microscopy [Commentaries]