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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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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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Proximity Dependent Biotinylation: Key Enzymes and Adaptation to Proteomics Approaches [Reviews]

The study of protein subcellular distribution, their assembly into complexes and the set of proteins with which they interact with is essential to our understanding of fundamental biological processes. Complementary to traditional assays, proximity-dependent biotinylation (PDB) approaches coupled with mass spectrometry (such as BioID or APEX) have emerged as powerful techniques to study proximal protein interactions and the subcellular proteome in the context of living cells and organisms. Since their introduction in 2012, PDB approaches have been used in an increasing number of studies and the enzymes themselves have been subjected to intensive optimization. How these enzymes have been optimized and considerations for their use in proteomics experiments are important questions. Here, we review the structural diversity and mechanisms of the two main classes of PDB enzymes: the biotin protein ligases (BioID) and the peroxidases (APEX). We describe the engineering of these enzymes for PDB and review emerging applications, including the development of PDB for coincidence detection (split-PDB). Lastly, we briefly review enzyme selection and experimental design guidelines and reflect on the labeling chemistries and their implication for data interpretation.




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Structure-based discovery of a small-molecule inhibitor of methicillin-resistant Staphylococcus aureus virulence [Molecular Biophysics]

The rapid emergence and dissemination of methicillin-resistant Staphylococcus aureus (MRSA) strains poses a major threat to public health. MRSA possesses an arsenal of secreted host-damaging virulence factors that mediate pathogenicity and blunt immune defenses. Panton–Valentine leukocidin (PVL) and α-toxin are exotoxins that create lytic pores in the host cell membrane. They are recognized as being important for the development of invasive MRSA infections and are thus potential targets for antivirulence therapies. Here, we report the high-resolution X-ray crystal structures of both PVL and α-toxin in their soluble, monomeric, and oligomeric membrane-inserted pore states in complex with n-tetradecylphosphocholine (C14PC). The structures revealed two evolutionarily conserved phosphatidylcholine-binding mechanisms and their roles in modulating host cell attachment, oligomer assembly, and membrane perforation. Moreover, we demonstrate that the soluble C14PC compound protects primary human immune cells in vitro against cytolysis by PVL and α-toxin and hence may serve as the basis for the development of an antivirulence agent for managing MRSA infections.




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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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A neuroglobin-based high-affinity ligand trap reverses carbon monoxide-induced mitochondrial poisoning [Molecular Biophysics]

Carbon monoxide (CO) remains the most common cause of human poisoning. The consequences of CO poisoning include cardiac dysfunction, brain injury, and death. CO causes toxicity by binding to hemoglobin and by inhibiting mitochondrial cytochrome c oxidase (CcO), thereby decreasing oxygen delivery and inhibiting oxidative phosphorylation. We have recently developed a CO antidote based on human neuroglobin (Ngb-H64Q-CCC). This molecule enhances clearance of CO from red blood cells in vitro and in vivo. Herein, we tested whether Ngb-H64Q-CCC can also scavenge CO from CcO and attenuate CO-induced inhibition of mitochondrial respiration. Heart tissue from mice exposed to 3% CO exhibited a 42 ± 19% reduction in tissue respiration rate and a 33 ± 38% reduction in CcO activity compared with unexposed mice. Intravenous infusion of Ngb-H64Q-CCC restored respiration rates to that of control mice correlating with higher electron transport chain CcO activity in Ngb-H64Q-CCC–treated compared with PBS-treated, CO-poisoned mice. Further, using a Clark-type oxygen electrode, we measured isolated rat liver mitochondrial respiration in the presence and absence of saturating solutions of CO (160 μm) and nitric oxide (100 μm). Both CO and NO inhibited respiration, and treatment with Ngb-H64Q-CCC (100 and 50 μm, respectively) significantly reversed this inhibition. These results suggest that Ngb-H64Q-CCC mitigates CO toxicity by scavenging CO from carboxyhemoglobin, improving systemic oxygen delivery and reversing the inhibitory effects of CO on mitochondria. We conclude that Ngb-H64Q-CCC or other CO scavengers demonstrate potential as antidotes that reverse the clinical and molecular effects of CO poisoning.




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How Qatar’s Food System Has Adapted to the Blockade

14 November 2019

Laura Wellesley

Research Fellow, Energy, Environment and Resources Programme
Two-and-a-half years on from the imposition of a trade blockade against Qatar by the Arab Quartet, Qatar’s food system has undergone a remarkable transformation – but it is one that brings new risks to Qatar’s future food and resource security.

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Cows are are fed at a dairy factory at Baladna farm in al-Khor, Qatar. Photo: Karim Jaafar/AFP via Getty Images.

Earlier this month, Sheikh Tamim – the emir of Qatar – hailed the country’s success in overcoming the impacts of the embargo levied by the so-called Arab Quartet – Bahrain, Egypt, Saudi Arabia and the United Arab Emirates (UAE). Qatar will post a budget surplus for the first time in three years, and the country’s long-term plan for economic diversification has taken great strides, according to the emir. Key among the achievements cited was the advancement of Qatar’s domestic food industry.

When the blockade was introduced in June 2017, it threw the vulnerability of Qatar’s domestic food supply to outside interruption into sharp relief. Qatar is poorly suited to growing food. The desert country ranks as the most water-stressed in the world. As one of the hottest, most arid countries in the world, trade is critical to feeding the nation; over 90 per cent of its food supply is imported.

Most of Qatar’s cereal imports – including 80 per cent of its wheat supply – arrive by sea from exporters including India, Russia and Australia. Sitting on the eastern edge of the Persian Gulf, Qatar’s only maritime gateway to the world is the Strait of Hormuz. This narrow body of water can, as events this summer have shown, be disrupted by geopolitical events. But for 40 per cent of overall food imports, overland trade from Saudi Arabia was Qatar’s primary supply channel before June 2017 – particularly so for dairy products and fresh fruit and vegetables coming from the EU, Turkey and Jordan.

The abrupt closure of Saudi Arabia’s borders prompted significant private investment in Qatar’s own food industry; domestic production has reportedly increased four-fold since the blockade was introduced. Prior to the blockade, Qatar imported 85 per cent of its vegetables; it now hopes to produce 60 per cent within the next three years. Perhaps even more remarkably, the country is now self-sufficient in dairy, having previously relied on imports for 72 per cent of its supply.

This progress has come at a cost. Qatar’s booming domestic industry is highly resource-intensive. To fill the gap in the dairy sector, Baladna – the country’s principal dairy producer – imported around 18,000 Holstein dairy cows from the EU and US. The company is thriving; in June of this year, it made its first dairy exports.

But the desert is not a natural environment for these cows; they must be kept indoors, at temperatures around 15°C cooler than the outside air, and misted with water to prevent overheating. The cooling systems are a huge drain on local resources. Each dairy cow requires an average of 185 gallons of water a day, almost twice the volume used by the average Qatari household. The majority of this water comes from oil- or gas-powered desalination plants; the cooling systems themselves run on gas-fired electricity.

Qatar has traditionally invested in production overseas – particularly in Sudan and Tanzania – to secure its fodder supply, but the government has plans to become self-sufficient in fodder crops such as lucerne (alfalfa) and Rhodes grass. This will require irrigation on a vast scale. Qatar’s farmland is mostly located in the north of the country where it benefits from aquifers; fodder production already accounts for half of the groundwater extracted for use in agriculture.

Despite commitments made under the National Food Security Programme to improving the water efficiency of Qatar’s food production, the rate of draw-down of these aquifers exceeds their recharge rates. Overexploitation has resulted in saline intrusion, threatening their long-term viability. With 92 per cent of all extracted groundwater given to farmers free of charge, there is little incentive for economizing on its use.

Increasing production will also likely mean increasing fertilizer use; rates of fertilizer use in Qatar are among the highest in the world, second only to those in Singapore.

Both government and industry are taking small steps to ‘green’ the country’s food production. Certain local authorities plan to ban the use of groundwater for fodder production by 2025, requiring producers to use treated sewage water instead and reserving the use of groundwater for crop production.

A number of companies are also adopting so-called ‘circular’ practices to achieve more efficienct resource use; Agrico, a major vegetable producer, has expanded its organic hydroponics operations, a move the company reports has led to a 90 per cent reduction in water use. But, with a target to produce up to 50 per cent of Qatar’s fresh food supply domestically within just a few years, scattered examples of resource-saving strategies will not be enough to mitigate the rise in water demand.

As Qatar looks to continue growing its food industry in the wake of the blockade, it is from Saudi Arabia – ironic though it may be – that Qatar stands to learn important lessons.

Saudi Arabia’s scaling up of domestic wheat production – initially to achieve self-sufficiency and then to support a prosperous export industry – was ultimately a failed effort. The unsustainable extraction of groundwater – fuelled by generous subsidies for wheat producers and the nominal cost of diesel for pumping – brought the country’s water table to the brink of collapse, and the government was forced to make a dramatic U-turn, reducing then removing the subsidies and shrinking its wheat sector.

The UAE also provides an instructive example for how domestic food production may be supported – this time positive. This summer, the Department of Environment in Abu Dhabi announced its Recycled Water Policy, laying out a policy framework to promote and facilitate reused water across all major sectors, including agriculture.

Back in 2014, the Ministry of Climate Change and Environment set hydroponics as a key priority, launching a 100 million Emirati dirham fund to incentivize and support farmers establishing hydroponic farms. And the International Center for Biosaline Agriculture, based in Dubai and supported by the UAE government, undertakes pioneering research into sustainable food production in saline environments.

On the face of it, Qatar has indeed bounced back from the blockade. As and when cross-border trade is re-established with Saudi Arabia, Qatar will boast a more diverse – and more resilient – network of trade relationships than it did prior to June 2017.

In addition to investment in domestic food production, the blockade also provoked a rapid recalibration of Qatar’s trade relationships. Allies in the region – most notably Turkey and Iran – were quick to come to Qatar’s assistance, delivering fresh produce by air. Since then, Qatar has scaled up its trading relationship with both countries.

It has also leveraged its position as the world’s largest exporter of liquid natural gas to establish new maritime trade lines with major food exporters, including India. Should tensions spike again in the future, it will be in a stronger position to weather the storm.

But, in the absence of a commitment to support the widespread adoption of circular agricultural technologies and practices, Qatar’s commitment to increasing its self-sufficiency and expanding its domestic production could ultimately undermine its long-term food security.

Rising average temperatures and increasingly frequent extreme weather events – like the heatwave in 2010 when temperatures soared to over 50°C – will exacerbate already high resource stress in the country. Unsustainable exploitation of finite land, water and energy reserves will limit the country’s long-term capacity to produce food and weaken its ability to withstand future disruptions to regional and international supply channels.

As Qatar continues in its efforts to secure a reliable food supply, it would do well to heed the experience of its neighbours, be they friend or foe.




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Subsidies and Sustainable Agriculture: Mapping the Policy Landscape

11 December 2019

Agricultural subsidies shape production and consumption patterns, with potentially significant effects on poverty, nutrition and other sustainability concerns. This paper maps the different types of support provided by governments to the agricultural sector, and highlights some of the complex political economy dynamics that underpin the relevant policies. 

Christophe Bellmann

Associate Fellow, Hoffmann Centre for Sustainable Resource Economy, Chatham House

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Aerial view of a wheat field on 24 May 2019 in Linyi, Shandong Province of China. Photo: Getty Images.

Summary

  • Agricultural subsidies, a mainstay of government policy, have a large part in shaping production and consumption patterns, with potentially significant effects as regards poverty, food security, nutrition, and other sustainability concerns such as climate change, land use practices and biodiversity.
  • There are multiple types of direct and indirect support provided by governments to various actors in the agricultural sector; and in terms of political economy, there are complex dynamics underpinning the policies that sustain these subsidies.
  • Overall, subsidies targeting producers have the most significant effect on production, and the greater trade-distorting effect. These subsidies promote domestic production and discourage imports, leading to overproduction that is largely disposed of on the international market, with the help of export subsidies. This can tend to intensify negative environmental agricultural practices, such as cultivating marginal land, unsustainable types of intensification, or incentivizing excessive pesticide and fertilizer use.
  • On the other hand, producer subsidies that are not tied to output of a specific commodity (i.e. delinked) have far fewer distorting impacts and could help to deliver sustainable outcomes. For example, this type of subsidies can require crop diversification or be linked to conservation of permanent grassland.
  • Subsidies that enable transfers to consumers, for example through food stamp programmes, also serve to delink production from consumption, can foster healthier diets, can play an important role in delivering food accessibility and security among low-income groups, and can represent one of the less trade-distorting subsidies.
  • If subsidies are to be reformed to help promote healthier diets and encourage more sustainable production, it is essential to understand not only the type and amount of support that key countries provide, but also the domestic dynamics that can shape such policies.
  • While price support, input subsidies or investment aids remain the central pillars of programmes in large developing countries such as Brazil, China or India, other economies – notably including the EU and Japan – focus on direct payments, support for general services and set-aside schemes, as well as significant border protection. The US, for its part, has tended to focus on subsidized insurance schemes and food programmes for poorer consumers.
  • If subsidies are to deliver policy objectives, their design and implementation should delink production from consumption. For example, consumer subsidies designed to deliver nutrition and food security, or payments for environmental services to enable more environmentally friendly production systems, could prove to be the most effective, least trade-distorting means of achieving more sustainable and equitable agricultural production.
  • The political economy of food means that the removal of subsidies is often highly sensitive, and tends to be met with significant resistance. However, reform that delinks support from production through a gradual transition process could ultimately prove successful in delivering effective subsidy schemes.
  • Effective subsidy schemes must by design be truly result- and performance-based, supported by robust and objective indicators. At the same time, engaging multiple actors along key commodity value chains – including leading importing and exporting countries, traders and transporters – could lead to the development of international, commodity-specific arrangements that are able to deliver effective nutrition and sustainability goals.




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Net Zero and Beyond: What Role for Bioenergy with Carbon Capture and Storage?

Invitation Only Research Event

23 January 2020 - 8:30am to 10:00am

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

Event participants

Richard King, Senior Research Fellow, Energy, Environment and Resources Department, Chatham House
Chair: Duncan Brack, Associate Fellow, Energy, Environment and Resources Department, Chatham House

In the context of the feasibility of reducing greenhouse gas emissions to net zero, policymakers are beginning to pay more attention to options for removing carbon dioxide from the atmosphere. A wide range of potential carbon dioxide removal (CDR) options are currently being discussed and modelled though the most prominent among them are bioenergy with carbon capture and storage (BECCS) and afforestation and reforestation.

There are many reasons to question the reliance on BECCS assumed in the models including the carbon balances achievable, its substantial needs for land, water and other inputs and technically and economically viable carbon capture and storage technologies.

This meeting will examine the potentials and challenges of BECCS in the context of other CDR and emissions abatement options. It will discuss the requisite policy and regulatory frameworks to minimize sustainability and socio-political risks of CDR approaches while also avoiding overshooting climate goals.

Attendance at this event is by invitation only.

Event attributes

Chatham House Rule

Chloé Prendleloup




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Net Zero and Beyond: What Role for Bioenergy with Carbon Capture and Storage?

29 January 2020

Policymakers are in danger of sleepwalking into ineffective carbon dioxide removal solutions in the quest to tackle climate change. This paper warns against overreliance on bioenergy with carbon capture and storage (BECCS). 

Duncan Brack

Associate Fellow, Energy, Environment and Resources Programme

Richard King

Senior Research Fellow, Energy, Environment and Resources Programme

Reaching Net Zero: Does BECCS Work?

Policymakers can be influenced by ineffective carbon dioxide removal solutions in the quest to tackle climate change. This animation explores the risks of using bioenergy with carbon capture and storage (BECCS).

Summary

  • Current climate efforts are not progressing quickly enough to prevent the world from overshooting the global emissions targets set in the Paris Agreement; accordingly, attention is turning increasingly to options for removing carbon dioxide from the atmosphere – ‘carbon dioxide removal’ (CDR).
  •  Alongside afforestation and reforestation, the main option under discussion is bioenergy with carbon capture and storage (BECCS): processes through which the carbon emissions from burning biomass for energy are captured before release into the atmosphere and stored in underground reservoirs.
  • This pre-eminent status is not, however, based on a comprehensive analysis of the feasibility and impacts of BECCS. In reality, BECCS has many drawbacks.
  • Models generally assume that biomass for energy is inherently carbon-neutral (and thus that BECCS, by capturing and storing the emissions from combustion, is carbon-negative), but in reality this is not a valid assumption.
  • On top of this, the deployment of BECCS at the scales assumed in most models would consume land on a scale comparable to half that currently taken up by global cropland, entailing massive land-use change, potentially endangering food security and biodiversity. There is also significant doubt about the likely energy output of BECCS solutions.
  • BECCS may still have some role to play in strategies for CDR, depending mainly on the feedstock used; but it should be evaluated on the same basis as other CDR options, such as nature-based solutions or direct air carbon capture and storage (DACCS). Analysis should take full account of carbon balances over time, the requirements of each CDR option in terms of demand for land, water and other inputs, and the consequences of that demand.
  • There is an urgent need for policymakers to engage with these debates. The danger at the moment is that policymakers are ‘sleepwalking towards BECCS’ simply because most models incorporate it – or, almost as bad, it may be that they are simply ignoring the need for any meaningful action on CDR as a whole.




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Global aid and faith actors: the case for an actor-orientated approach to the ‘turn to religion’

4 March 2020 , Volume 96, Number 2

Emma Tomalin

In this article, drawing on the work of the development sociologist Norman Long, I make the case for an actor-oriented approach to understanding the ‘turn to religion’ by global aid actors over the past couple of decades. I ask, is the ‘turn to religion’ evidence of the emergence of post-secular partnerships or are faith actors being instrumentalized to serve neo-liberal development goals? I argue that neither option captures the whole story and advocate that the study of religion and development needs to move beyond a binary between the ‘turn to religion’ as either evidence of post-secular partnerships or of the ‘instrumentalization’ of religion by the secular global aid business, and instead to think about how faith actors themselves encounter and shape development discourses and frameworks, translate them into relevant formats and strategically employ them. Alongside the adoption of an actor-orientated approach, I build on the work of Lewis and Mosse, Olivier de Sardan and Bierschenk to view international faith-based organizations (IFBOs) as development brokers and translators. This approach allows me to articulate the distinctive role that many members of IFBOs report they play as intermediaries who shift register between the secular development language and the faith-inspired language of their local faith partners. I take the engagement of faith actors with the new Sustainable Development Goals framework as a case-study to explore this.




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Mapping the field of religious environmental politics

4 March 2020 , Volume 96, Number 2

Jeremy Kidwell

Until fairly recently, consideration of religion has been marginal or even non-existent in the scholarly discourse about environmental politics. Renewed attention to the intersection of these fields has been encouraged by a recent widening in discussions of ‘environmental values’ to include the role of religious institutions and personal belief in forming spiritual environmental values and renewed attention to the place of ethics and religious institutions in global environmental politics. Following a range of historic declarations by religious leaders, the recent encyclical by Pope Francis signalled a new level of integration between Catholic concerns for social and environmental justice. Yet, much of the continued engagement by large environmental NGOs and governments has continued to ignore the complex interrelation of local, intermediate and transnational religious political ecology. In this article, which is based on data gathered during five years of fieldwork, primarily with British Christian REMOs (religious environmental movement organizations), I probe the complexities of political engagement with religious environmentalism which arise from the many different organizational iterations these groups may take. On the basis of such investigation I suggest that effective high-level engagement with REMO groups will be greatly enhanced by a nuanced understanding of the many different shapes that these groups can take, the various scales at which these groups organize, and the unique inflection that political action and group identity can take in a religious context.




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Closing the Global Access Gap in Palliative Care and Pain Relief: A Top Priority in Achieving Universal Health Coverage

Invitation Only Research Event

17 July 2019 - 12:30pm to 5:00pm

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

Event participants

Dr Tedros Adhanom Ghebreyesus, Director-General, World Health Organization 

The Lancet Commission on Palliative Care and Pain Relief estimated that in 2015, 61 million people experienced serious health-related suffering (SHS) that could have been ameliorated by palliative care. A large proportion of this burden – more than 80 per cent – fell on low- and middle-income countries (LMICs) despite an essential package of palliative care and pain relief services being cost-effective and affordable. As the director general of the World Health Organization (WHO) argues, there cannot be UHC without palliative care and thus, closing this coverage gap should be a top priority for the global UHC movement.

The Centre on Global Health Security at Chatham House, building on the momentum of the Lancet Commission, is hosting a roundtable focused on the global unmet need for palliative care and effective pain relief. The primary purpose of this roundtable is to convene leading experts, palliative care service users and advocates with key figures from the UHC movement and global health to highlight the importance of prioritizing this vital part of the continuum of care in UHC reform processes. The roundtable will serve as a scholarly discourse in translating the recommendations of the Lancet Commission into concrete actions, focusing on the political and economic dimensions.

Alexandra Squires McCarthy

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




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Strengthening National Accountability and Preparedness for Global Health Security (SNAP-GHS)

The project aims to identify the enablers and barriers to enhance data use by National Public Health Institutes (NPHIs), producing outputs that will facilitate strengthening of the role of NPHIs in monitoring potential public health threats, and in shaping and informing domestic policies on health security and preparedness.

Global health security is underpinned by the actions taken at a national level to ensure capacities exist to sufficiently prepare for and respond to acute threats and crises. In many contexts, National Public Health Institutes (NPHIs) were first established because of, and in response to, specific public health challenges typically related to infectious diseases.

The Strengthening National Accountability and Preparedness for Global Health Security (SNAP-GHS) project evolved from a series of roundtables and discussions hosted by the Centre on Global Health Security at Chatham House, in collaboration with the Graduate Institute of Geneva.

The outcome of the project is a SNAP-GHS Toolkit to support NPHIs in better diagnosing and understanding the challenges to data use within their own institutes, as well as in relation to external stakeholders and agencies. The toolkit is intended to be used for further circulation and dissemination by the International Association of National Public Health Institutes (IANPHI).

The project is led by the Centre on Global Health Security at Chatham House in collaboration with the Ethiopian Public Health Institute, the Nigeria Centre for Disease Control, and the National Institute for Health in Pakistan.




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The grease trap: uncovering the mechanism of the hydrophobic lid in Cutibacterium acnes lipase [Research Articles]

Acne is one of the most common dermatological conditions, but the details of its pathology are unclear, and current management regimens often have adverse effects. Cutibacterium acnes is known as a major acne-associated bacterium that derives energy from lipase-mediated sebum lipid degradation. C. acnes is commensal, but lipase activity has been observed to differ among C. acnes types. For example, higher populations of the type IA strains are present in acne lesions with higher lipase activity. In the present study, we examined a conserved lipase in types IB and II that was truncated in type IA C. acnes strains. Closed, blocked, and open structures of C. acnes ATCC11828 lipases were elucidated by X-ray crystallography at 1.6–2.4 Å. The closed crystal structure, which is the most common form in aqueous solution, revealed that a hydrophobic lid domain shields the active site. By comparing closed, blocked, and open structures, we found that the lid domain-opening mechanisms of C. acnes lipases (CAlipases) involve the lid-opening residues, Phe-179 and Phe-211. To the best of our knowledge, this is the first structure-function study of CAlipases, which may help to shed light on the mechanisms involved in acne development and may aid in future drug design.




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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 as signaling hubs in cancer cell survival/death and invasion: implications in tumor progression and therapy [Thematic Reviews]

Cholesterol/sphingolipid-rich membrane domains, known as lipid rafts or membrane rafts, play a critical role in the compartmentalization of signaling pathways. Physical segregation of proteins in lipid rafts may modulate the accessibility of proteins to regulatory or effector molecules. Thus, lipid rafts serve as sorting platforms and hubs for signal transduction proteins. Cancer cells contain higher levels of intracellular cholesterol and lipid rafts than their normal non-tumorigenic counterparts. Many signal transduction processes involved in cancer development (insulin-like growth factor system and phosphatidylinositol 3-kinase-AKT) and metastasis [cluster of differentiation (CD)44] are dependent on or modulated by lipid rafts. Additional proteins playing an important role in several malignant cancers (e.g., transmembrane glycoprotein mucin 1) are also being detected in association with lipid rafts, suggesting a major role of lipid rafts in tumor progression. Conversely, lipid rafts also serve as scaffolds for the recruitment and clustering of Fas/CD95 death receptors and downstream signaling molecules leading to cell death-promoting raft platforms. The partition of death receptors and downstream signaling molecules in aggregated lipid rafts has led to the formation of the so-called cluster of apoptotic signaling molecule-enriched rafts, or CASMER, which leads to apoptosis amplification and can be pharmacologically modulated. These death-promoting rafts can be viewed as a linchpin from which apoptotic signals are launched. In this review, we discuss the involvement of lipid rafts in major signaling processes in cancer cells, including cell survival, cell death, and metastasis, and we consider the potential of lipid raft modulation as a promising target in cancer therapy.




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GPIHBP1, a partner protein for lipoprotein lipase, is expressed only in capillary endothelial cells [Images In Lipid Research]






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A kainate receptor-selective RNA aptamer [Neurobiology]

Kainate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are two major, closely related receptor subtypes in the glutamate ion channel family. Excessive activities of these receptors have been implicated in a number of central nervous system diseases. Designing potent and selective antagonists of these receptors, especially of kainate receptors, is useful for developing potential treatment strategies for these neurological diseases. Here, we report on two RNA aptamers designed to individually inhibit kainate and AMPA receptors. To improve the biostability of these aptamers, we also chemically modified these aptamers by substituting their 2'-OH group with 2'-fluorine. These 2'-fluoro aptamers, FB9s-b and FB9s-r, were markedly resistant to RNase-catalyzed degradation, with a half-life of ∼5 days in rat cerebrospinal fluid or serum-containing medium. Furthermore, FB9s-r blocked AMPA receptor activity. Aptamer FB9s-b selectively inhibited GluK1 and GluK2 kainate receptor subunits, and also GluK1/GluK5 and GluK2/GluK5 heteromeric kainate receptors with equal potency. This inhibitory profile makes FB9s-b a powerful template for developing tool molecules and drug candidates for treatment of neurological diseases involving excessive activities of the GluK1 and GluK2 subunits.




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Unified approach to critical-contrast homogenisation with explicit links to time-dispersive media

K. D. Cherednichenko, Yu. Yu. Ershova, A. V. Kiselev and S. N. Naboko
Trans. Moscow Math. Soc. 80 (2020), 251-294.
Abstract, references and article information




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The finiteness of the spectrum of boundary value problems defined on a geometric graph

V. A. Sadovnichii, Ya. T. Sultanaev and A. M. Akhtyamov
Trans. Moscow Math. Soc. 80 (2020), 123-131.
Abstract, references and article information




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Finite-dimensional approximations to the Poincaré–Steklov operator for general elliptic boundary value problems in domains with cylindrical and periodic exits to infinity

S. A. Nazarov
Trans. Moscow Math. Soc. 80 (2020), 1-51.
Abstract, references and article information





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Terapia inédita reverte leucemia incurável em bebê de 1 ano

Tratamento genético foi testado em Layla Richards que estava desenganada pelos médicos. Especialistas ressaltam que os resultados são iniciais e podem não ocorrer em outros pacientes.

The post Terapia inédita reverte leucemia incurável em bebê de 1 ano appeared first on Saúde Próspera.



  • Dicas de Saúde


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What happens to a fund that is listed pursuant to a product specific rule filing once the fund is eligible to operate under Rule 6c-11 and elects to list on Nasdaq under Rule 5704?

Publication Date: Apr 10 2020 The SEC will withdraw the existing approval order and the fund will become subject to the requirements of Rule 6c-11 and Nasdaq Rule 5704....




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What happens if an ETF is no longer compliant with Rule 6c-11?

Publication Date: Apr 10 2020 On or before December 22, 2020, all ETFs that meet the definition of "Exchange Traded Fund" in Nasdaq Rule 5704(a)(1)(A) will need to be compliant with Rule 6c-11. If it is determined that an ETF no longer complies with Rule 6c-11 and therefore no longer complies Nasdaq Rule 5704, Nasdaq will generally issue a letter of deficiency. The ETF will generally be given 45 days to submit a plan to regain compliance. If the plan is accepted, Nasdaq Staff can grant an...




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How can a company rely on the COVID-19 exception to shareholder approval requirements?

Publication Date: May 4 2020 On May 1, 2020, Nasdaq adopted Rule 5636T, operative through, and including, June 30, 2020, to provide listed companies with a temporary exception from certain shareholder approval requirements. A Company must submit an application to Nasdaq’s Listing Qualifications Department demonstrating that the transaction satisfies the requirements in Rule 5636T and must provide the Notification Form: Listing of Additional Shares (“LAS Form”) required by...




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Air gap security beaten by turning PC capacitors into speakers

Researchers have poked another small hole in air gapped security by showing how the electronics inside computer power supply units (PSUs) can be turned into covert data transmission devices.




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Japan's ‘Indo-Pacific’ question: countering China or shaping a new regional order?

8 January 2020 , Volume 96, Number 1

Kei Koga

Japan's primary objective of the ‘free and open Indo-Pacific’ (FOIP) strategy is to shape and consolidate regional order in the Indo-Pacific region based on the existing rules-based international order. The concept initially aimed to achieve two different objectives—shaping a regional order in the Indo-Pacific and ensuring the defence of Japan; however, Japan has gradually shifted its strategic focus onto the former, separating national defence from the FOIP concept, which reflects a change in the degree of its commitment to the two objectives. On the one hand, as its overall security strategy, Japan has determined to steadily enhance its national defence by increasing its own defence capabilities and strengthening the US–Japan alliance, while transforming its partnerships with like-minded states, such as Australia and India, into a diplomatic, and potentially military, alignment. This has been brought about by shifts in the regional balance of power, particularly the rise of China and the relative decline of the United States. On the other hand, as part of its FOIP strategy, Japan's attempts to build a new regional order in the Indo-Pacific region aim to defend the existing rules-based order established by the United States from challengers, particularly China. Yet, given the strategic uncertainty over Japan's international coalition-building efforts to create a new regional order, Japan has made its approach flexible; Tokyo is using its ambiguous FOIP concept to gauge other states' responses, understand their perspectives, and change its strategic emphases accordingly—so-called ‘tactical hedging’. Japan has pursued similar means to achieve the two key objectives. Nevertheless, the country's core interest, the defence of Japan, is more imperative than building a regional order in the Indo-Pacific region, and Japan faces different types of challenges in the future.




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Bridging an Impossible Gap? Japan-South Korea Cooperation in a Changing Asia

Research Event

10 February 2020 - 12:00pm to 1:00pm

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

Event participants

Jennifer Lind, Associate Fellow, US and the Americas Programme and Asia-Pacific Programme, Chatham House
Chair: Tania Branigan, Leader Writer, The Guardian  

China’s growing power and assertiveness in Asia has led the United States and other liberal partners to move toward an Indo-Pacific strategy. While Japan embraces this, South Korea remains noticeably reticent. Moreover, tensions between the two countries have escalated into crisis with the reinvigoration of historical disputes. This roundtable will explore the root causes of current animosity between Seoul and Tokyo, and the potential ways it can be overcome.

This event is co-hosted with Dartmouth College. 

THIS EVENT IS NOW FULL AND REGISTRATION HAS CLOSED.

Lucy Ridout

Programme Administrator, Asia-Pacific Programme
+44 (0) 207 314 2761




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Asian States Must Rethink Their Approach to Digital Governance

17 January 2020

Vasuki Shastry

Associate Fellow, Asia-Pacific Programme
Too many governments in the region are focusing on control and surveillance instead of citizens’ rights.

2020-01-17-KashInt.jpg

Kashmiri students use the internet at a tourist reception centre in Srinagar, after internet facilities were suspended across the region in December 2019. Photo: Getty Images.

Asia’s political class learnt many lessons on digital governance in 2019, not all of them positive.

The prolonged protests in Hong Kong and India, led by disaffected young citizenry and enabled by social media tools, powerfully demonstrated how things could spiral out of control when the virtual and the real streets come together.

Not surprisingly, governments across the region are taking a step back. Instead of placing the citizen at the heart of digital public policy – with privacy, trust, security and inclusion as drivers of digital governance – Asian governments are focusing instead on surveillance and command and control, which contradicts the spirit of a decentralized Internet and undermines citizen’s rights.

Asia’s digital governance is fragmenting from the global norm and morphing into two platforms with remarkably similar characteristics.

One is a China-driven model aptly called the Great Firewall where surveillance of citizens is an explicit objective and any external material deemed to be subversive is kept out. A complementary model has also emerged more recently, which can best be described as China-light, which seeks to emulate the control aspects of the Great Firewall.

There are of course overlaps between emulators of the China model (this list includes Vietnam, Myanmar, Cambodia and Laos) and those pursuing China-light (Singapore, India, Indonesia, Bangladesh, Sri Lanka, the Philippines, Thailand and Malaysia). A common thread running through these two approaches, which differ only in intensity and scope, is the belief that the state is best positioned to police social media and protect the rights of citizens.

This was not how it was supposed to be. A decade ago, Asian political leaders spoke about the virtues of an open internet. Such talk has faded, and a narrowing of Asia’s digital space is taking place against a backdrop of an intensifying trade war between America and China, where regional supply chains run the risk of a decoupling into distinct Sino and American spheres, upending Asia’s durable economic model of the past few decades.

Digital fragmentation in the world’s fastest growing region, with five G20 members, will complicate efforts to build global governance and standards.

Asia’s digital landscape

Asian governments, including democratic ones, have developed an unhealthy obsession with what their citizens are up to on a daily basis. Their solution is round-the-clock monitoring in cities and towns, powered by new surveillance technologies.

Name tagging and facial recognition to track movement of citizens has become pervasive across the region, with China emerging as the preferred source of technology, knowledge, and techniques. While India’s Supreme Court has ruled that privacy is a fundamental right, translating this into concrete citizen’s protections will be difficult with the Modi government eager to emulate China’s approach.

Asian governments are also following China in requiring that their citizen’s data be housed within national borders and are rebelling against the established practice of data offshoring.

In the post-Snowden era and amidst increasing cyber risks, there are rational national security reasons for why governments may want to ring-fence customer data within national boundaries. However, Asian governments are paying little or no attention to how companies are using customer data within national boundaries, with widespread abuses going unchecked.

Global standards are still evolving and there is a strong case here for a uniform regional approach, perhaps via ASEAN or APEC, on standards governing customer privacy, payments, data collection and handling. Big tech companies and platforms operate across much of Asia and a regional approach will curb their current instinct of conducting regulatory arbitrage.

There is a genuine problem in Asia, as elsewhere in the world, with the proliferation of fake news and extremism. But instead of addressing the source of this problem, governments are clamping down by generously expanding the definition of fake news (Singapore) or by shutting down the internet altogether (India, Sri Lanka, and China being serial offenders).

As disseminators of news of all stripes, including the fake variant, the big tech firms have a primary responsibility in policing their platforms. However, the regulatory capacity of many Asian governments to monitor this is weak and in crisis situations, governments prefer to shut the pipes altogether.

Digitalization of course is not all about surveillance and holds the promise of driving inclusion. There is considerable hype within Asia on the promise of fintech as an enabler of this inclusion.

Hong Kong and Singapore are licensing new digital banks, India’s UPI (unified payments interface) is reducing friction in domestic payments and China’s BAT companies (Baidu, Alibaba, Tencent) are disrupting traditional commerce and payments, and seeking to expand in the region.

However, there is an elite focus in many of these initiatives, with the target market being the region’s rising middle class rather than those at the bottom of the income ladder. Making fintech work for all will require micro-initiatives with the support of NGOs, local governments and small enterprises, with the objective of digitalizing microfinance.

Here developing Asia will again benefit from learning from each other and in building regional approaches. India’s Aadhar for example, with appropriate security safeguards, is a model for Asia in terms of building digital identity.

Given differing regional and national objectives, it is difficult to imagine a global accord for digital governance any time soon. However, by signing on to the Regional Comprehensive Economic Partnership (RCEP) and the Comprehensive and Progressive Agreement for Transpacific Partnership (CPTPP, the successor to the TPP), Asia has consistently demonstrated its leadership in trade and regional governance.

This is why the region needs to come together to ensure that the promise and potential of digitalization flows evenly and equitably to the region, with the region’s 3.8 billion citizens at the heart, rather than at the margins of sensible public policy.




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Global Governance: Tackling Economic Nationalism – Japan-UK Partnership Perspectives

Invitation Only Research Event

20 February 2020 - 4:30pm to 21 February 2020 - 4:45pm

Tokyo, Japan

Event participants

Dr Robin Niblett CMG, Director, Chatham House  
Toshiro Mutoh, Honorary Chairman, Daiwa Institute of Research; CEO, Tokyo Organising Committee of the Olympic and Paralympic Game
José Manuel Barroso, Senior Adviser, Chatham House; President of the European Commission (2004-14); Prime Minister of Portugal (2002-04)
Akihiko Tanaka, President, National Graduate Institute for Policy Studies

This conference will be the fifth in an annual conference series exploring global geopolitical and geoeconomic trends and their respective influences on Japan and the UK.

This conference will be held in partnership with the Daiwa Institute of Research.

Attendance at this event is by invitation only. 

Lucy Ridout

Programme Administrator, Asia-Pacific Programme
+44 (0) 207 314 2761




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Japan-Russia Relations in the Abe-Putin Era

Research Event

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

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

Event participants

Alexander Bukh, Senior Lecturer, International Relations, Victoria University, Wellington, New Zealand; Author of These Islands Are Ours: The Social Construction of Territorial Disputes in Northeast Asia (Stanford University Press 2020)
Chair: Mathieu Boulègue, Research Fellow, Russia and Eurasia Programme

Japan and Russia are often referred to as 'distant neighbours'. 

In the early days of Prime Minister Shinzo Abe's second term in 2012, Japan sought to open a new era of bilateral relations with Russia. However, recent negotiations on the Kuril Islands/Northern Territories territorial dispute have stalled. Despite Abe’s extensive efforts to resolve the dispute, no concrete agreement has been reached so far. 

The speaker will provide an overview of the current state of Japan-Russia relations, including the prospect of resolving the territorial dispute during Prime Minister Abe's remaining days in office.

 

Lucy Ridout

Programme Administrator, Asia-Pacific Programme
+44 (0) 207 314 2761




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Virtual Roundtable: Evaluating Outcomes in Fragile Contexts: Adapting Research Methods in the Time of COVID-19

Invitation Only Research Event

5 May 2020 - 12:00pm to 1:00pm

Event participants

Rebecca Wolfe, Lecturer, Harris School for Public Policy and Associate, Pearson Institute for the Study and Resolution of Global Conflicts, University of Chicago
Tom Gillhespy, Principal Consultant, Itad
Shodmon Hojibekov, Chief Executive Officer, Aga Khan Agency for Habitat (Afghanistan)
Chair: Champa Patel, Director, Asia-Pacific Programme, Chatham House

This virtual roundtable has been co-convened by Chatham House and the Aga Khan Foundation.  

While conducting research in fragile and conflict-affected contexts has always presented challenges, the outbreak of COVID-19 creates additional challenges including travel restrictions, ethical challenges, and disruptions to usual modes of working. This virtual roundtable will explore how organizations can adapt their research and monitoring and evaluation models in response to the coronavirus pandemic. This event aims to discuss the research methods being used to mitigate the impact of the COVID-19 crisis; the important role of technology; and ways to engage policy and decision-makers during this time.

 

Event attributes

Chatham House Rule

Lucy Ridout

Programme Administrator, Asia-Pacific Programme
+44 (0) 207 314 2761




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Putting Music on the Map

Mathematics and music have long been closely associated. Now a recent mathematical breakthrough uses topology (a generalization of geometry) to represent musical chords as points in a space called an orbifold, which twists and folds back on itself much like a Mobius strip does. This representation makes sense musically in that sounds that are far apart in one sense yet similar in another, such as two notes that are an octave apart, are identified in the space.This latest insight provides a way to analyze any type of music. In the case of Western music, pleasing chords lie near the center of the orbifolds and pleasing melodies are paths that link nearby chords. Yet despite the new connection between music and coordinate geometry, music is still more than a connect-the-dots exercise, just as mathematics is more than addition and multiplication. For More Information: The Geometry of Musical Chords, Dmitri Tymoczko, Science, July 7, 2006.




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euromicron AG successfully completes 2019 capital increase

euromicron AG, a medium-sized technology group and expert on the digital networking of business and production processes, has now fully placed the capital increase it resolved on July 10, 2019.




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euromicron AG: New appointments to and expansion of the Executive Board of euromicron AG

The Supervisory Board of euromicron AG (WKN A1K030) announced a new appointment and expansion of the Executive Board of euromicron AG today, thus initiating a first step for a new phase in the realignment of the Group. Effective January 1, 2020, Dr. Michael Hofer will be appointed Chief Financial Officer (CFO) and Dr. Andreas Schmid Chief Operations Officer (COO) on the Executive Board of euromicron AG.




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Barnes saw it coming... but coach 'disappointed' he was cut ahead of Gold Cup

GIVEN the financial position of the Jamaica Football Federation (JFF), John Barnes had resigned




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L.A. County's biodiversity is on the map, thanks to UCLA researchers

Located in a global hotspot for biodiversity, Los Angeles County is home to more than 4,000 distinct species of plants and animals, including 52 endangered species - more than any county outside of Hawaii. And with 1 million animal and plant species facing extinction due to human activity, according to the United Nations, efforts to better understand the factors that shape biodiversity in Los Angeles could help shape global conservation efforts.




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Using Digital Technology to Narrow the Opportunity Gap

Digital technology was not invented to tackle inequality, and there is even a risk that it could widen existing economic and social disparities. But, as the case of China illustrates, new platforms also offer many possible ways to narrow the opportunity gap.




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Web development ,Web Design & Graphic Design services - 16% Discount May 2020




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New Publication: Rules, Procedures and Mechanisms Applicable to Processes under the Cartagena Protocol on Biosafety.

New Publication: Rules, Procedures and Mechanisms Applicable to Processes under the Cartagena Protocol on Biosafety.




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Biosafety Protocol News Vol. 3 Issue 5 - Experiences and Lessons Learned in Capacity-Building




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Launch of the Website of the Online Survey on the Application of and Experience in the Use of Socio-Economic Considerations in Decision-Making on Living Modified Organisms




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Report of the Fifth Coordination Meeting for Governments and Organizations Implementing or Funding Biosafety Capacity-building Activities.




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Notification: Fifth Meeting of the Conference of the Parties serving as the meeting of the Parties to the Cartagena Protocol on Biosafety (COP MOP/5), 11 - 15 October 2010, Nagoya, Japan.




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Report of the sixth meeting of the Liaison Group on Capacity-Building for Biosafety.