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Democratize Trade Policymaking to Better Protect Human Rights
12 June 2019
There is growing interest in the use of human rights impact assessment to screen proposed trade agreements for human rights risks, and to ensure appropriate risk mitigation steps are taken.2019-02-15-HumanRightsTradeAgreements-Smaller.jpg
Tea pickers walk at dawn through the tea plantations of Munnar, Kerala, on 7 May 2017. Copyright: Pardeep Singh Gill/Getty Images
With international trade discourse taking an increasingly transactional and sometimes belligerent tone, it would be easy to overlook the quiet revolution currently under way to bring new voices into trade policy development and monitoring. The traditional division of responsibilities between the executive and legislature – whereby treaties are negotiated and signed by the executive, and the legislature does what is necessary to implement them – may be undergoing some change.
Growing awareness of the implications of trade and investment treaties for many aspects of day-to-day life – food standards, employment opportunities, environmental quality, availability of medicines and data protection, just to name a few – is fuelling demands by people and businesses for more of a say in the way these rules are formulated and developed.
Various options for enhancing public and parliamentary scrutiny of trading proposals have recently been examined by two UK parliamentary select committees.[1] The reason for this interest is obviously Brexit, which has presented UK civil servants and parliamentarians with the unusual (some would say exciting) opportunity to design an approval and scrutiny process for trade agreements from scratch.
Doubtless, EU authorization, liaison and approval procedures (which include a scrutinizing role for the European Parliament) will be influential,[2] as will the European Commission’s experience with stakeholder engagement on trade issues.[3] The recommendations of both UK select committees to include human rights impact assessment processes as part of pre-negotiation preparations[4] echo calls from UN agencies and NGOs for more rigorous and timely analysis of the human rights risks that may be posed by new trading relationships.[5] Again, EU practice with what it terms ‘sustainability impact assessment’ of future trade agreements provides a potential model to draw from.[6]
However, process is no substitute for action. Human rights impact assessment is never an end in itself; rather, it is a means to a positive end, in this case a trade agreement which is aligned with the trading partners’ respective human rights obligations and aspirations. It bears remembering, though, that the idea of assessing trade proposals for future human rights risks is a relatively recent one. Do we have the tools and resources to make sure that this is a meaningful compliance and risk management exercise?
Thus far there is little evidence that human rights impact assessment and stakeholder engagement exercises are having any real impact on the content of trade agreements.[7] This is the case even in the EU, where practice in these areas is the most advanced and systematic.[8]
There are several possible reasons for this. First, the methodological challenges are enormous. Aside from the crystal-ball gazing needed to forecast the social, economic and environmental effects of a trade intervention well into the future, demonstrating causal links between a trade agreement and a predicted adverse impact is often highly problematic given the number of other economic and political factors that may be in play.[9]
Secondly, there are many challenges around the need to engage with affected people and listen to their views.[10] The sheer number of possible impacts of a trade agreement on different individuals and communities, as well as the range of rights potentially engaged, makes this a difficult (some would say impossible) task. Some prioritization is always necessary.
This makes for difficult decisions about who to engage with and how. Perceived bias or an apparent lack of even-handedness – favouring business compared to civil society, for instance – can sow mistrust about the true aims of such a process, undermining its future effectiveness as participants begin to question whether it is genuine or worthwhile.[11]
The challenges are even more acute where impact assessment practitioners are tasked with investigating potential human rights impacts in other countries. Even if it is possible to get past the inevitable political sensitivities,[12] the sort of in-depth consultations required will be beyond the budget and time constraints of most assignments.[13]
There are good reasons why trade policy should be subject to greater public and parliamentary scrutiny, and why there should be more opportunities for public participation in the formation of new trading regimes. By building more opportunities for stakeholder consultation at these stages, we can acquire perspectives on trade that are not available from other forms of assessment and analysis.
However, policymakers should be wary of overstating the benefits of existing procedural models. Human rights impact assessment processes are still struggling to provide compelling analyses of the relationships between trade agreements and the enjoyment of human rights, let alone a roadmap for policymakers and trade negotiators as to what should be done.[14]
And financial and practical barriers to participation in stakeholder engagement exercises mean that, at best, these will provide only a partial picture of stakeholder impacts and views.
Experiences with human rights impact assessment of trade agreements so far demonstrate the need for realism about two things: first, the extent to which one can sensibly anticipate and analyse human rights-related risks and opportunities in the preparation stages for a new trading agreement; and, second, the extent to which problems identified in this way can be headed off with the right form of words in the treaty itself.
Both recent UK select committee reports place considerable faith in the ability of pre-project transparency and scrutiny processes to flush out potential problems and prescribe solutions. Of course, there may be cases where frontloading the analysis in this way could be useful, for instance where the human rights implications are so clear that they can readily be addressed through upfront commitments by the parties concerned, whether by bespoke or standardized approaches.
More often, though, for a trade agreement running many years into the future, human rights impacts and implications will take time to emerge, suggesting the need for robust monitoring and mitigation frameworks designed with longevity in mind. Ideally, pre-signing approval and assessment processes would lay the groundwork for future action by both trading partners, either jointly or separately (though preferably both).
To this end, as well as developing ideas for more robust substantive provisions on human rights, policymakers should consider the institutional arrangements required – whether pursuant to the trade agreement or by complementary processes – to ensure that human rights-related risks identified during the planning stages are properly and proactively followed up, that emerging risks are tackled in a timely fashion, and that there are opportunities for meaningful stakeholder contributions to these processes.
What needs to happen
- Trade policymakers can use human rights impact assessment to screen proposed trade treaties for human rights-related risks and to identify possible ways of mitigating those risks, whether through the terms of the agreement itself, domestic law reform or flanking measures.
- Building more opportunities for stakeholder consultations can enable perspectives on trade to be highlighted that are not available from other forms of assessment.
- Assessment is complicated, however, by methodological challenges and the difficulties of forecasting a trade agreement’s future impacts. Policymakers need to be realistic about the risks that can be anticipated, and the extent to which many of those identified can be addressed upfront in trade agreements’ terms.
- These inherent limitations may be overcome to some extent by better ongoing monitoring. Future trade agreements should include more robust human rights risk monitoring and mitigation frameworks, designed with longevity in mind.
Notes
[1] UK Joint Committee on Human Rights (2019), ‘Human Rights Protections in International Agreements, Seventeenth Report of Session 2017–19’, HC 1833 HL paper 310, 12 March 2019, https://publications.parliament.uk/pa/jt201719/jtselect/jtrights/1833/1833.pdf; and House of Commons International Trade Committee (2018), ‘UK Trade Policy Transparency and Scrutiny, Sixth Report of Session 2017-2019’, HC 1043, 29 December 2018.
[2] European Parliament and Directorate General for External Policies (2019), Parliamentary scrutiny of trade policies across the western world, study paper, March 2019, http://www.europarl.europa.eu/RegData/etudes/STUD/2019/603477/EXPO_STU(2019)603477_EN.pdf.
[3] European Commission (2019), ‘Trade policy and you’, http://ec.europa.eu/trade/trade-policy-and-you/index_en.htm.
[4] See UK Joint Committee on Human Rights (2019), ‘Human Rights Protections in International Agreements’, para 12; and House of Commons International Trade Committee (2018), ‘UK Trade Policy Transparency and Scrutiny’, paras 124–34.
[5] OHCHR (2003), Report of the High Commissioner for Human Rights on Human Rights, Trade and Investment, 2 July 2003, E/CN.4/Sub.2/2003/9, Annex, at para 63; UN Economic and Social Council (2017), ‘General Comment No 24 (2017) of the Committee on Economic, Social and Cultural Rights on State obligations under the International Covenant on Economic, Social and Cultural Rights in the context of business activities’, UN Doc. E/C.12/GC/24, 10 August 2017, para 13; and UN General Assembly (2011), ‘Guiding principles on human rights impact assessment of trade and investment agreements’, Report of the Special Rapporteur on the Right to Food, Olivier De Schutter, UN Doc. A/HRC/19/59/Add.5, 19 December 2011.
[6] European Commission (2016), Handbook for Sustainability Impact Assessment (2nd ed.), Brussels: European Union, http://trade.ec.europa.eu/doclib/docs/2016/april/tradoc_154464.PDF.
[7] Zerk, J. (2019), Human Rights Impact Assessment of Trade Agreements, Chatham House Research Paper, London: Royal Institute of International Affairs, https://www.chathamhouse.org/publication/human-rights-impact-assessment-trade-agreements.
[8] Ibid., pp. 11–13. For a detailed explanation of the EU’s approach to human rights impact assessment, see European Commission (2016), Handbook for Sustainability Impact Assessment.
[9] Zerk (2019), Human Rights Impact Assessment of Trade Agreements, pp. 14–21.
[10] Ibid., pp. 21–22.
[11] Ergon Associates (2011), Trade and Labour: Making effective use of trade sustainability impact assessments and monitoring mechanisms, Final Report to DG Employment, Social Affairs and Inclusion European Commission, September 2011; and Gammage, C. (2010), ‘A Sustainability Impact Assessment of the Economic Partnership Agreements: Challenging the Participatory Process’, Law and Development Review, 3(1): pp. 107–34. For a civil society view, see Trade Justice Movement (undated), ‘Trade Justice Movement submission to the International Trade Committee inquiry into UK Trade Policy Transparency and Scrutiny’, https://www.tjm.org.uk/resources/briefings/tjm-submission-to-the-international-trade-committee-inquiry-into-uk-trade-policy-transparency-and-scrutiny, esp. paras 23–32.
[12] Zerk (2019), Human Rights Impact Assessment of Trade Agreements, pp. 20–21.
[13] Ibid., pp. 21–22.
[14] Ibid.
This essay was produced for the 2019 edition of Chatham House Expert Perspectives – our annual survey of risks and opportunities in global affairs – in which our researchers identify areas where the current sets of rules, institutions and mechanisms for peaceful international cooperation are falling short, and present ideas for reform and modernization.
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12-LOX catalyzes the oxidation of 2-arachidonoyl-lysolipids in platelets generating eicosanoid-lysolipids that are attenuated by iPLA2{gamma} knockout [Signal Transduction]
The canonical pathway of eicosanoid production in most mammalian cells is initiated by phospholipase A2-mediated release of arachidonic acid, followed by its enzymatic oxidation resulting in a vast array of eicosanoid products. However, recent work has demonstrated that the major phospholipase in mitochondria, iPLA2γ (patatin-like phospholipase domain containing 8 (PNPLA8)), possesses sn-1 specificity, with polyunsaturated fatty acids at the sn-2 position generating polyunsaturated sn-2-acyl lysophospholipids. Through strategic chemical derivatization, chiral chromatographic separation, and multistage tandem MS, here we first demonstrate that human platelet-type 12-lipoxygenase (12-LOX) can directly catalyze the regioselective and stereospecific oxidation of 2-arachidonoyl-lysophosphatidylcholine (2-AA-LPC) and 2-arachidonoyl-lysophosphatidylethanolamine (2-AA-LPE). Next, we identified these two eicosanoid-lysophospholipids in murine myocardium and in isolated platelets. Moreover, we observed robust increases in 2-AA-LPC, 2-AA-LPE, and their downstream 12-LOX oxidation products, 12(S)-HETE-LPC and 12(S)-HETE-LPE, in calcium ionophore (A23187)-stimulated murine platelets. Mechanistically, genetic ablation of iPLA2γ markedly decreased the calcium-stimulated production of 2-AA-LPC, 2-AA-LPE, and 12-HETE-lysophospholipids in mouse platelets. Importantly, a potent and selective 12-LOX inhibitor, ML355, significantly inhibited the production of 12-HETE-LPC and 12-HETE-LPE in activated platelets. Furthermore, we found that aging is accompanied by significant changes in 12-HETE-LPC in murine serum that were also markedly attenuated by iPLA2γ genetic ablation. Collectively, these results identify previously unknown iPLA2γ-initiated signaling pathways mediated by direct 12-LOX oxidation of 2-AA-LPC and 2-AA-LPE. This oxidation generates previously unrecognized eicosanoid-lysophospholipids that may serve as biomarkers for age-related diseases and could potentially be used as targets in therapeutic interventions.
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Glucocerebrosidases catalyze a transgalactosylation reaction that yields a newly-identified brain sterol metabolite, galactosylated cholesterol [Glycobiology and Extracellular Matrices]
β-Glucocerebrosidase (GBA) hydrolyzes glucosylceramide (GlcCer) to generate ceramide. Previously, we demonstrated that lysosomal GBA1 and nonlysosomal GBA2 possess not only GlcCer hydrolase activity, but also transglucosylation activity to transfer the glucose residue from GlcCer to cholesterol to form β-cholesterylglucoside (β-GlcChol) in vitro. β-GlcChol is a member of sterylglycosides present in diverse species. How GBA1 and GBA2 mediate β-GlcChol metabolism in the brain is unknown. Here, we purified and characterized sterylglycosides from rodent and fish brains. Although glucose is thought to be the sole carbohydrate component of sterylglycosides in vertebrates, structural analysis of rat brain sterylglycosides revealed the presence of galactosylated cholesterol (β-GalChol), in addition to β-GlcChol. Analyses of brain tissues from GBA2-deficient mice and GBA1- and/or GBA2-deficient Japanese rice fish (Oryzias latipes) revealed that GBA1 and GBA2 are responsible for β-GlcChol degradation and formation, respectively, and that both GBA1 and GBA2 are responsible for β-GalChol formation. Liquid chromatography–tandem MS revealed that β-GlcChol and β-GalChol are present throughout development from embryo to adult in the mouse brain. We found that β-GalChol expression depends on galactosylceramide (GalCer), and developmental onset of β-GalChol biosynthesis appeared to be during myelination. We also found that β-GlcChol and β-GalChol are secreted from neurons and glial cells in association with exosomes. In vitro enzyme assays confirmed that GBA1 and GBA2 have transgalactosylation activity to transfer the galactose residue from GalCer to cholesterol to form β-GalChol. This is the first report of the existence of β-GalChol in vertebrates and how β-GlcChol and β-GalChol are formed in the brain.
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COQ11 deletion mitigates respiratory deficiency caused by mutations in the gene encoding the coenzyme Q chaperone protein Coq10 [Lipids]
Coenzyme Q (Qn) is a vital lipid component of the electron transport chain that functions in cellular energy metabolism and as a membrane antioxidant. In the yeast Saccharomyces cerevisiae, coq1–coq9 deletion mutants are respiratory-incompetent, sensitive to lipid peroxidation stress, and unable to synthesize Q6. The yeast coq10 deletion mutant is also respiratory-deficient and sensitive to lipid peroxidation, yet it continues to produce Q6 at an impaired rate. Thus, Coq10 is required for the function of Q6 in respiration and as an antioxidant and is believed to chaperone Q6 from its site of synthesis to the respiratory complexes. In several fungi, Coq10 is encoded as a fusion polypeptide with Coq11, a recently identified protein of unknown function required for efficient Q6 biosynthesis. Because “fused” proteins are often involved in similar biochemical pathways, here we examined the putative functional relationship between Coq10 and Coq11 in yeast. We used plate growth and Seahorse assays and LC-MS/MS analysis to show that COQ11 deletion rescues respiratory deficiency, sensitivity to lipid peroxidation, and decreased Q6 biosynthesis of the coq10Δ mutant. Additionally, immunoblotting indicated that yeast coq11Δ mutants accumulate increased amounts of certain Coq polypeptides and display a stabilized CoQ synthome. These effects suggest that Coq11 modulates Q6 biosynthesis and that its absence increases mitochondrial Q6 content in the coq10Δcoq11Δ double mutant. This augmented mitochondrial Q6 content counteracts the respiratory deficiency and lipid peroxidation sensitivity phenotypes of the coq10Δ mutant. This study further clarifies the intricate connection between Q6 biosynthesis, trafficking, and function in mitochondrial metabolism.
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Tandem Mass Tag Approach Utilizing Pervanadate BOOST Channels Delivers Deeper Quantitative Characterization of the Tyrosine Phosphoproteome
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Characterization of Prenylated C-terminal Peptides Using a Thiopropyl-based Capture Technique and LC-MS/MS
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Flow-induced reorganization of laminin-integrin networks within the endothelial basement membrane uncovered by proteomics
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Cell Cycle Profiling Reveals Protein Oscillation, Phosphorylation, and Localization Dynamics
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Robust summarization and inference in proteome-wide label-free quantification
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Characterization of signaling pathways associated with pancreatic {beta}-cell adaptive flexibility in compensation of obesity-linked diabetes in db/db mice
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Acquiring and Analyzing Data Independent Acquisition Proteomics Experiments without Spectrum Libraries
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Proximity Dependent Biotinylation: Key Enzymes and Adaptation to Proteomics Approaches
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LockBit ransomware borrows tricks to keep up with REvil and Maze
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The Destabilizing Danger of Cyberattacks on Missile Systems
2 July 2019
‘Left-of-launch’ attacks that aim to disable enemy missile systems may increase the chance of them being used, not least because the systems are so vulnerable.2019-07-02-NKMissile.jpg
This undated photo released by North Korea's news agency in March 2017 shows the launch of four ballistic missiles during a military drill at an undisclosed location in North Korea. Photo: STR/AFP/Getty Images.
After President Trump decided to halt a missile attack on Iran in response to the downing of a US drone, it was revealed that the US had conducted cyberattacks on Iranian weapons systems to prevent Iran launching missiles against US assets in the region.
This ‘left-of-launch’ strategy – the pre-emptive action to prevent an adversary launch missiles – has been part of the US missile defence strategy for some time now. President George W Bush asked the US military and intelligence community to infiltrate the supply chain of North Korean missiles. It was claimed that the US hacked the North Korean ballistic missile programme, causing a failed ballistic missile test, in 2012.
It was not clear then – or now – whether these ‘left-of-launch’ cyberattacks aimed at North Korea were successful as described or whether they were primarily a bluff. But that is somewhat irrelevant; the belief in the possibility and the understanding of the potential impact of such cyber capabilities undermines North Korean or Iranian confidence in their abilities to launch their missiles. In times of conflict, loss of confidence in weapons systems may lead to escalation.
In other words, the adversary may be left with no option but to take the chance to use these missiles or to lose them in a conflict setting. ‘Left of launch’ is a dangerous game. If it is based on a bluff, it could be called upon and lead to deterrence failure. If it is based on real action, then it could create an asymmetrical power struggle. If the attacker establishes false confidence in the power of a cyber weapon, then it might lead to false signalling and messaging.
This is the new normal. The cat-and-mouse game has to be taken seriously, not least because missile systems are so vulnerable.
There are several ways an offensive cyber operation against missile systems might work. These include exploiting missile designs, altering software or hardware, or creating clandestine pathways to the missile command and control systems.
They can also be attacked in space, targeting space assets and their link to strategic systems.
Most missile systems rely, at least in part, on digital information that comes from or via space-based or space-dependent assets such as: communication satellites; satellites that provide position, navigation and timing (PNT) information (for example GPS or Galileo); weather satellites to help predict flight paths, accurate targeting and launch conditions; and remote imagery satellites to assist with information and intelligence for the planning and targeting.
Missile launches themselves depend on 1) the command and control systems of the missiles, 2) the way in which information is transmitted to the missile launch facilities and 3) the way in which information is transmitted to the missiles themselves in flight. All these aspects rely on space technology.
In addition, the ground stations that transmit and receive data to and from satellites are also vulnerable to cyberattack – either through their known and unknown internet connectivity or through malicious use of flash drives that contain a deliberate cyber infection.
Non-space-based communications systems that use cable and ground-to-air-to-ground masts are likewise under threat from cyberattacks that find their way in via internet connectivity, proximity interference or memory sticks. Human error in introducing connectivity via phones, laptops and external drives, and in clicking on malicious links in sophisticated phishing lures, is common in facilitating inadvertent connectivity and malware infection.
All of these can create a military capacity able to interfere with missile launches. Malware might have been sitting on the missile command and control system for months or even years, remaining inactivated until a chosen time or by a trigger that sets in motion a disruption either to the launch or to the flight path of the missile. The country that launches the missile that either fails to launch or fails to reach the target may never know if this was the result of a design flaw, a common malfunction or a deliberate cyberattack.
States with these capabilities must exercise caution: cyber offence manoeuvres may prevent the launch of missile attacks against US assets in the Middle East or in the Pacific regions, but they may also interfere with US missile launches in the future. Even, as has recently been revealed, US cyber weapons targeting an adversary may blow back and inadvertently infect US systems. Nobody is invulnerable.
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AI-driven Personalization in Digital Media: Political and Societal Implications
2 December 2019
The fallout from disinformation and online manipulation strategies have alerted Western democracies to the novel, nuanced vulnerabilities of our information society. This paper outlines the implications of the adoption of AI by the the legacy media, as well as by the new media, focusing on personalization.
2019-12-02-AI-Driven-Personalization-small.jpg
The Reuters and other news apps seen on an iPhone, 29 January 2019. Photo: Getty Images.
Summary
- Machine learning (ML)-driven personalization is fast expanding from social media to the wider information space, encompassing legacy media, multinational conglomerates and digital-native publishers: however, this is happening within a regulatory and oversight vacuum that needs to be addressed as a matter of urgency.
- Mass-scale adoption of personalization in communication has serious implications for human rights, societal resilience and political security. Data protection, privacy and wrongful discrimination, as well as freedom of opinion and of expression, are some of the areas impacted by this technological transformation.
- Artificial intelligence (AI) and its ML subset are novel technologies that demand novel ways of approaching oversight, monitoring and analysis. Policymakers, regulators, media professionals and engineers need to be able to conceptualize issues in an interdisciplinary way that is appropriate for sociotechnical systems.
- Funding needs to be allocated to research into human–computer interaction in information environments, data infrastructure, technology market trends, and the broader impact of ML systems within the communication sector.
- Although global, high-level ethical frameworks for AI are welcome, they are no substitute for domain- and context-specific codes of ethics. Legacy media and digital-native publishers need to overhaul their editorial codes to make them fit for purpose in a digital ecosystem transformed by ML. Journalistic principles need to be reformulated and refined in the current informational context in order to efficiently inform the ML models built for personalized communication.
- Codes of ethics will not by themselves be enough, so current regulatory and legislative frameworks as they relate to media need to be reassessed. Media regulators need to develop their in-house capacity for thorough research and monitoring into ML systems, and – when appropriate –proportionate sanctions for actors found to be employing such systems towards malign ends. Collaboration with data protection authorities, competition authorities and national electoral commissions is paramount for preserving the integrity of elections and of a political discourse grounded on democratic principles.
- Upskilling senior managers and editorial teams is fundamental if media professionals are to be able to engage meaningfully and effectively with data scientists and AI engineers.
Department/project
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Webinar: Federalism in a Fragmented State: Rethinking Decentralization in Yemen
Research Event
15 April 2020 - 1:00pm to 2:00pm
Event participants
Osamah Al Rawhani, Deputy Director, Sana’a Center for Strategic Studies
Moderator: Nadim Houry, Executive Director, Arab Reform Initiative
Yemen suffered from the excessive control of the central government prior to the current conflict. Federalism has been put forward by many Yemeni political parties since the National Dialogue Conference (NDC) as the supposed magic cure for this significant problem. Today, Yemen is more fragmented than ever, its state central institutions have been scattered and lack leadership and the state has lost most of its sovereignty. The prevailing narrative that decentralization through federalism is Yemen’s inevitable path post-conflict often fails to acknowledge that there are prerequisites for effective local governance, beyond political will.
In a recent article, Osamah Al Rawhani addressed how the weakness of central state institutions is the key challenge to proceeding with federalism in Yemen and highlighted prerequisites and contextual factors that need to be addressed before reforming the structure of the state. He argued that the viability of decentralization relies on the presence of a functioning, representative central government that is capable of devolving power but also able to keep the state from further fragmentation.
In this webinar, part of the Chatham House project on The Future of the State in the Middle East and North Africa, the article’s author will discuss recent developments in Yemen, where shifting frontlines and regional divisions are fragmenting the country in new ways. The speaker will explore alternative approaches to pursue the path of federalism that recognize the current realities and the critical need for strong central institutions. He will also survey the internal and external factors that must be considered to rebuild a stable state in Yemen.
You can express your interest in attending by following this link. You will receive a Zoom confirmation email should your registration be successful. Alternatively, you can watch the event live on the MENA Programme Facebook page.
Department/project
Reni Zhelyazkova
Programme Coordinator, Middle East and North Africa Programme
+44 (0)20 7314 3624
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COVID-19 Crisis – Business as Usual for Gaza?
6 May 2020
The COVID-19 pandemic has brought unprecedented challenges, economic collapse and strict lockdowns in many parts of the world. For the people of Gaza, this reality is nothing new.2020-05-06-covid-19-gaza.jpg
Palestinians light fireworks above the rubble during the Muslim holy month of Ramadan amid concerns about the spread of the coronavirus disease (COVID-19), in Gaza City , 30 April 2020. Photo by Majdi Fathi/NurPhoto via Getty Images.
In August 2012, when the UN released its report Gaza in 2020: A liveable place?, they could not have imagined what the world would look like in 2020: cities under lockdown, restrictions on movement, border closures, widespread unemployment, economic collapse, fear and anxiety and, above all, uncertainty about what the future holds.
For Gaza’s population of 2 million people this reality is nothing new. The conditions that the rest of the world are currently experiencing as a result of the COVID-19 pandemic is similar to the tight blockade Gaza has been living under ever since Hamas took over in 2007. Israel has imposed severe restrictions on the movement of people and goods, youth unemployment has reached 60 per cent, and over 80 per cent of Gaza’s population are now dependent on international aid.
The people of Gaza are having to face the COVID-19 crisis already at a disadvantage, with poor infrastructure, limited resources and a shortage of the most basic services, such as water and power supply. It also has a fragile health system, with hospitals lacking essential medical supplies and equipment, as well as the capacity to deal with the outbreak as there are only 84 ICU beds and ventilators available.
Meanwhile, intra-Palestinian divisions have persisted and were evident in the initial reaction to the pandemic. When President Mahmoud Abbas announced a state of emergency, it took two days for the Hamas-led government in Gaza to follow suit and shut down schools and universities. They later made a separate emergency appeal to address the crisis and prepare for a COVID-19 response in Gaza. This lack of coordination is typical of the way the Palestinian Authority and Hamas approach crisis situations.
After the initial uncoordinated response, Hamas, as the de-facto ruler of Gaza, has asserted its ability to control Gaza’s borders by putting in place quarantine measures for everyone who enters the strip, whether through the Erez checkpoint with Israel or the Rafah border with Egypt. They have also assigned 21 hospitals, hotels, and schools as compulsory quarantine centres for all arrivals from abroad, who have to stay in quarantine for 21 days. In comparison, there are 20 quarantine centres in the West Bank. These strict measures have prevented the spread of the virus in the community and confined it to the quarantine centres, with only 20 confirmed cases of COVID-19 as of 6 May. Gaza’s de-facto authorities have also been able to monitor markets and prices to ensure the availability of essential goods.
Faced with a major crisis, Al-Qassam Brigades – the armed wing of Hamas – have tried to play the role of a national army by participating in efforts to fight the pandemic. They have relatively good logistical capacity and have contributed to the construction of two quarantine facilities with a total capacity of 1,000 units to prepare for more arrivals into Gaza. At the local level, municipalities have been disinfecting public spaces and facilities in addition to disseminating information about the virus and related preventative and protective measures. Other precautionary measures put in place include closing the weekly open markets, and restricting social gatherings like weddings and funerals.
Despite COVID-19, it’s business as usual when it comes to international dealings with Gaza. The key parties in the conflict – Israel, Hamas and the Palestinian Authority – along with the main external actors – Egypt, the United Nations and Qatar – have continued to stick to their policies aimed at keeping the security situation under control and preventing further escalation. Although Israel has allowed entry of pharmaceutical supplies and medical equipment into Gaza during the pandemic, it has kept its restrictions on the movement of goods and people in place, while keeping a close eye on the development of the COVID-19 outbreak in Gaza – a major outbreak here would be a nightmare scenario for Israel.
Meanwhile, Qatar has continued to address the humanitarian and economic needs of Gaza in an attempt to ease the pressure and prevent further escalation. It has pledged $150 million over the next six months to help families in Gaza from poorer backgrounds. Gaza has also been discussed by the Middle East Quartet, as Nickolay Mladenov, the UN special coordinator for the Middle East Peace Process, expressed his concern about the risk of a disease outbreak in Gaza during a call with the members of the Quartet.
Amid the pandemic, threats are still being exchanged between Israel and Hamas. The Israeli defence minister, Naftali Bennett, requested that in return for providing humanitarian aid to Gaza, Hamas agrees to return the remains of two Israeli soldiers killed in the 2014 war. While openly rejecting Bennett's statement, the leader of Hamas in Gaza, Yahya Sinwar, has offered to move forward with a prisoner swap deal if Israel agrees to release elderly prisoners and detainees in addition to detained women and children. Though dealing with its own COVID-19 outbreak, Egypt has started to mediate between the two parties in an attempt to stabilize the situation and reach a prisoner swap deal.
In the wake of this pandemic, lessons should be learned and policies should be examined, by all parties. Firstly, Israel should re-evaluate its security measures towards Gaza by easing restrictions on movement and trade which would have a positive impact on living conditions for Gaza’s population. The current measures have proven to be unsustainable and have contributed to the endless cycle of violence. Secondly, the intra-Palestinian division should end, to save Palestinians from contradictory policies and insufficient capacity on both sides. In fact, all previous attempts have failed to end this self-destructive division and this is due to the absence of political will on both sides. Elections seem to be the only viable path towards unity. Finally, efforts by the international community should go beyond stabilizing the security situation and ongoing crisis inside Gaza, where disruption of normal life is the norm.
While the world has reacted to this pandemic with a whole host of new policies and emergency measures, it has remained business as usual when dealing with Gaza. Should COVID-19 spread in Gaza, its people – who have already paid the price of a continuous blockade and intra-Palestinian division for 13 years – will pay a heavy price yet again. However, this time it is not a crisis that they alone will have to face.
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Tau PET imaging with 18F-PI-2620 in patients with Alzheimer's disease and healthy controls: a first-in-human study
18F-PI-2620 is a positron emission tomography (PET) tracer with high binding affinity for aggregated tau, a key pathologic feature of Alzheimer’s disease (AD) and other neurodegenerative disorders. Preclinically, 18F-PI-2620 binds to both, 3R and 4R tau isoforms. The purpose of this first-in-human study was to evaluate the ability of 18F-PI-2620 to detect tau pathology in AD patients using PET imaging, as well as to assess its safety and tolerability of this new tau PET tracer. Methods: Participants with clinical diagnosis of probable AD and healthy controls (HC) underwent dynamic 18F-PI-2620 PET imaging for 180 min. 18F-PI-2620 binding was assessed visually and quantitatively using Distribution Volume Ratios (DVR) estimated from non-invasive tracer kinetics and standardized uptake value ratios (SUVR) measured at different time points post-injection (p.i.) with the cerebellar cortex as the reference region. Time-activity curves and SUVR were assessed in AD and HC, as well as DVR and SUVR correlations and effect size (Cohen’s d) over time. Results: 18F-PI-2620 showed peak brain uptake around 5 min p.i. and fast wash-out in non-target regions. In AD subjects, focal asymmetric uptake was evident in temporal and parietal lobes, precuneus, and posterior cingulate cortex. DVR and SUVR in these regions were significantly higher in AD compared to HC. Very low background signal was observed in HC. 18F-PI-2620 administration was safe and well tolerated. SUVR time activity curves in most regions and subjects achieved a secular equilibrium after 40 min p.i.. A strong correlation (R2 > 0.93) was found between non-invasive DVR and SUVR for all imaging windows starting >30 min p.i.. Similar effect sizes between AD and HC groups were obtained across the different imaging windows. 18F-PI-2620 uptake in neocortical regions was significantly correlated with the degree of cognitive impairment. Conclusion: Initial clinical data obtained in AD and HC demonstrate the high image quality with excellent signal-to-noise of 18F-PI-2620 PET for imaging tau deposition in AD subjects. Non-invasive quantification using DVR and SUVR for 30 min imaging windows between 30-90 min p.i., e.g. 45-75 min, provides robust and significant discrimination between AD and HC subjects. 18F-PI-2620 uptake in expected regions is highly correlated to neurocognitive performance.
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Initial studies with [11C]vorozole positron emission tomography detect over-expression of intra-tumoral aromatase in breast cancer
Introduction: Aromatase inhibitors are the mainstay of hormonal therapy in estrogen receptor positive, postmenopausal breast cancer, although response rate is just over 50%. The goal of the present study was to validate and optimize positron emission tomography (PET) with 11C-vorozole for measuring aromatase expression in postmenopausal breast cancer. Methods: Ten newly diagnosed, postmenopausal women with biopsy confirmed breast cancer were administered 11C-vorozole intravenously and PET emission data collected between 40 – 90 minutes post-injection. Tracer injection and scanning were repeated 2 hours after ingestion of 2.5mg letrozole p.o. Mean and maximal standard uptake values and ratios to non-tumor tissue (SUVs, SUVRs) were calculated for tumor and non-tumor regions at baseline and after letrozole. Biopsy specimens from the same tumors were stained for aromatase using immunohistochemistry and evaluated for stain intensity and the percentage of immune-positive cells. Results: Seven of the 10 women (70%) demonstrated increased focal uptake of tracer (SUVR>1.1) coinciding with the mammographic location of the lesion. The other 3 women (30%) did not show increased uptake in the tumor (SUVR <1.0). All of the cases with SUVR above 1.1 had SUVs above 2.4 and there was no overlap in SUV between the two groups, with mean SUV in tumors overexpressing aromatase (SUVR>1.1) ranging from 2.47 to 13.6, while tumors not overexpressing aromatase (SUVR<1) ranged from 0.8 to 1.8. Pretreatment with letrozole reduced tracer uptake in the majority of subjects; although the %blocking varied across and within tumors. Tumors with high SUV in vivo also showed high staining intensity on IHC. Conclusion: PET with 11C-vorozole is a useful technique for measuring aromatase expression in individual breast lesions, enabling a non-invasive quantitative measurement of baseline and post-treatment aromatase availability in primary tumors and metastatic lesions.
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Label-free Visualization of Early Cancer Hepatic Micrometastasis and Intraoperative Image-guided Surgery by Photoacoustic Imaging
Objectives: The detection of cancer micrometastasis for early diagnosis and treatment poses a great challenge for conventional imaging techniques. The aim of study is to evaluate the performance of photoacoustic imaging (PAI) in detecting hepatic micrometastases from melanoma in a very early stage and perform tumor resection by intraoperative photoacoustic image-guidance. Methods: In vivo studies were performed by following protocols approved by the Ethical Committee for Animal Research at Xiamen University. First, a B16 melanoma hepatic metastasis mouse model (n = 10) was established to study the development of micrometastases in vivo. Next, the hepatic metastasis mice models were imaged by scalable PAI instrument, ultrasound, 9.4 T high-resolution magnetic resonance imaging (MRI), positron emission tomography/computed tomography (PET/CT), and bioluminescence imaging. Photoacoustic images acquired with optical wavelengths spanning from 680 to 850 nm were spectrally unmixed by using a linear least-squares method to differentiate various components. Differences in the signal-to-background ratios among different modalities were determined with the two-tailed paired t test. The diagnosis results were assessed with histologic examinations. Excised liver samples from patients diagnosed with hepatic cancer were also examined to identify tumor boundary. In vivo metastatic melanoma removal in surgery was precisely guided by the portable PAI system. Results: PAI achieved as small as ~400 µm hepatic melanoma detection at a depth up to 7 mm in vivo, which could early detect small melanoma compared with ultrasound and MRI in mouse models. The signal ratio of tumor-to-liver acquired with PAI in micrometastases at 8 days (4.2 ± 0.2, n = 6) and 14 days (9.2 ± 0.4, n = 5) were significantly higher than those obtained with PET/CT (1.8 ± 0.1, n = 5 and 4.5 ± 0.2, n = 5, P <0.001 for both). Functional PAI provided dynamic oxygen saturation changes during tumor growth. The limit of detection was measured to be approximately 219 cells per microliter in vitro. We successfully performed intraoperative photoacoustic image-guided surgery in vivo using the rapid portable PAI system. Conclusion: Our findings offer a rapid and effective tool to noninvasively detect micrometastases and guide intraoperative resection as a complementary clinical imaging application.
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Does 2-FDG-PET Accurately Reflect Quantitative In vivo Glucose Utilization?
2-Deoxy-2-[18F]fluoro-D-glucose (2-FDG) with positron emission tomography (2-FDG-PET) is undeniably useful in the clinic, among other uses, to monitor change over time using the 2-FDG standardized uptake values (SUV) metric. This report suggests some potentially serious caveats for this and related roles for 2-FDG PET. Most critical is the assumption that there is an exact proportionality between glucose metabolism and 2-FDG metabolism, called the lumped constant, LC. This report describes that LC is not constant for a specific tissue and may be variable before and after disease treatment. The purpose of this work is not to deny the clinical value of 2-FDG PET; it is a reminder that when one extends the use of an appropriately qualified imaging method, new observations may arise and further validation would be necessary. Current understanding of glucose-based energetics in vivo is based on the quantification of glucose metabolic rates with 2-FDG PET, a method that permits the non-invasive assessment in various human disorders. However, 2-FDG is only a good substrate for facilitated-glucose transporters (GLUTs) but not for sodium-dependent glucose co-transporters (SGLTs), which have recently been shown to be distributed in multiple human tissues. Thus, the GLUT-mediated in vivo glucose utilization measured by 2-FDG PET would be blinded to the potentially substantial role of functional SGLTs in glucose transport and utilization. Therefore, in these circumstances the 2-FDG LC used to quantify in vivo glucose utilization should not be expected to remain constant. 2-FDG LC variations have been especially significant in tumors, particularly at different stages of cancer development, affecting the accuracy of quantitative glucose measures and potentially limiting the prognostic value of 2-FDG, as well as its accuracy in monitoring treatments. SGLT-mediated glucose transport can be estimated using α-methyl-4-deoxy-4-[18F]fluoro-D-glucopyranoside (Me-4FDG). Utilizing both 2-FDG and Me-4FDG should provide a more complete picture of glucose utilization via both GLUT and SGLT transporters in health and disease stages. Given the widespread use of 2-FDG PET to infer glucose metabolism, appreciating the potential limitations of 2-FDG as a surrogate for glucose metabolic rate and the potential reasons for variability in LC is relevant. Even when the readout for the 2-FDG PET study is only an SUV parameter, variability in LC is important, particularly if it changes over the course of disease progression (e.g., an evolving tumor).
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Light-induced radiosynthesis of 89ZrDFO-azepin-onartuzumab for imaging the hepatocyte growth factor receptor
Methods that provide rapid access to radiolabeled antibodies are vital in the development of diagnostic and radiotherapeutic agents for positron emission tomography (PET) or radioimmunotherapy. The human hepatocyte growth factor receptor (c-MET) signaling pathway is dysregulated in a number of malignancies including gastric cancer, and is an important biomarker in drug discovery. Here, we used a photoradiochemical approach to produce 89Zr-radiolabeled onartuzumab (a monovalent, anti-human c-MET antibody), starting directly from the fully formulated drug (MetMAb). Methods: Simultaneous 89Zr-radiolabeling and protein conjugation was performed in one-pot reactions containing 89Zr-oxalate, the photoactive chelate DFO-aryl azide (DFO-ArN3) and MetMAb to give 89ZrDFO-azepin-onartuzumab. As a control, 89ZrDFO-Bn-NCS-onartuzumab was prepared via a conventional two-step process using pre-purified onartuzumab and DFO-Bn-NCS. Radiotracers were purified by using size-exclusion methods and evaluated by radiochromatography. Radiochemical stability was studied in human serum and immunoreactivity was determined by cellular binding assays using MKN-45 gastric carcinoma cells. PET imaging at multiple time points (0–72 h) was performed in female athymic nude mice bearing subcutaneous MKN-45 xenografts. Biodistribution experiments were performed after the final image. Tumor specificity of 89ZrDFO-azepin-onartuzumab was assessed by competitive inhibition (blocking) studies. Results: Initial photoradiosynthesis experiments produced 89ZrDFO-azepin-onartuzumab in <15 min. with an isolated decay-corrected radiochemical yield (RCY) of 24.8%, a radiochemical purity (RCP) ~90% and a molar activity (Am) of ~1.5 MBq nmol-1. Reaction optimization improved the radiochemical conversion (RCC) of 89ZrDFO-azepin-onartuzumab to 56.9±4.1% (n = 3), with isolated RCYs of 41.2±10.6% (n = 3), and RCPs >90%. Conventional methods produced 89ZrDFO-Bn-NCS-onartuzumab with isolated RCY >97%, RCP >97% and Am ~14.0 MBq nmol-1. Both radiotracers were immunoreactive and stable in human serum. PET imaging and biodistribution studies showed high tumor uptake for both radiotracers. By 72 h, tumor and liver uptake reached 15.37±5.21 %ID g-1, 6.56±4.03 %ID g-1, respectively for 89ZrDFO-azepin-onartuzumab (n = 4), and 21.38±11.57 %ID g-1 and 18.84±6.03 %ID g-1 for 89ZrDFO-Bn-NCS-onartuzumab (n = 4). Blocking experiments gave a statistically significant reduction in tumor uptake (6.34±0.47 %ID g-1) of 89ZrDFO-azepin-onartuzumab (n = 4). Conclusion: Experiments demonstrate that photoradiosynthesis is a viable alternative approach for producing 89Zr-radiolabeled antibodies direct in protein formulation buffer which reduces protein aggregation and liver uptake.
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Immune checkpoint imaging in oncology - a game changer towards personalized immunotherapy?
Immune checkpoint blockade represents a promising approach in oncology, showing anti-tumor activities in various cancers. However, although being generally far more well-tolerated than classical cytotoxic chemotherapy, this treatment, too, may be accompanied by considerable side effects and not all patients benefit equally. Therefore, careful patient selection and monitoring of the treatment response is mandatory. At present, checkpoint-specific molecular imaging is increasingly investigated as a tool for patient selection and response evaluation. Here, an overview of the current developments in immune checkpoint imaging is provided.
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18F-DCFPyL PET/CT in Patients with Subclinical Recurrence of Prostate Cancer: Effect of Lesion Size, Smooth Filter and Partial Volume Correction on Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) criteria
Purpose: To determine the effect of smooth filter and partial volume correction (PVC) method on measured prostate-specific membrane antigen (PSMA) activity in small metastatic lesions and to determine the impact of these changes on the molecular imaging (mi) PSMA scoring. Materials & Methods: Men with biochemical recurrence of prostate cancer with negative CT and bone scintigraphy were referred for 18F-DCFPyL PET/CT. Examinations were performed on one of 2 PET/CT scanners (GE Discovery 610 or Siemens mCT40). All suspected tumor sites were manually contoured on co-registered CT and PET images, and each was assigned a miPSMA score as per the PROMISE criteria. The PVC factors were calculated for every lesion using the anatomical CT and then applied to the unsmoothed PET images. The miPSMA scores, with and without the corrections, were compared, and a simplified "rule of thumb" (RoT) correction factor (CF) was derived for lesions at various sizes (<4mm, 4-7mm, 7-9mm, 9-12mm). This was then applied to the original dataset and miPSMA scores obtained using the RoT CF were compared to those found using the actual corrections. Results: There were 75 men (median age, 69 years; median serum PSA of 3.69 ug/L) with 232 metastatic nodes < 12 mm in diameter (mean lesion volume of 313.5 ± 309.6 mm3). Mean SUVmax before and after correction was 11.0 ± 9.3 and 28.5 ± 22.8, respectively (p<0.00001). The mean CF for lesions <4mm (n = 22), 4-7mm (n = 140), 7-9mm (n = 50), 9-12 mm (n = 20) was 4 (range: 2.5-6.4), 2.8 (range: 1.6-4.9), 2.3 (range: 1.6-3.3) and 1.8 (range 1.4-2.4), respectively. Overall miPSMA scores were concordant between the corrected dataset and RoT in 205/232 lesions (88.4%). Conclusion: There is a significant effect of smooth filter and partial volume correction on measured PSMA activity in small nodal metastases, impacting the miPSMA score.
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Yttrium-90 Radioembolization: Telemedicine during COVID-19 outbreak, opportunity for prime time.
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Reshaping the amyloid buildup curve in Alzheimer's disease? - Partial volume effect correction of longitudinal amyloid PET data
It was hypothesized that the brain β-amyloid buildup curve plateaus at an early symptomatic Alzheimer's disease (AD) stage. Atrophy-related partial volume effects (PVEs) degrade signal in hot-spot imaging techniques, such as amyloid positron emission tomography (PET). This longitudinal analysis of amyloid-sensitive PET data investigated the shape of the β-amyloid curve in AD applying PVE correction (PVEC). We analyzed baseline and 2-year follow-up data of 216 symptomatic individuals on the AD continuum (positive amyloid status) enrolled in Alzheimer's Disease Neuroimaging Initiative (17 AD dementia, 199 mild cognitive impairment), including 18F-florbetapir PET, magnetic resonance imaging and mini mental state examination (MMSE) scores. For PVEC, the modified Müller-Gärtner method was performed. Compared to non-PVE-corrected data, PVE-corrected data yielded significantly higher regional and composite standardized uptake value ratio (SUVR) changes over time (P=0.0002 for composite SUVRs). Longitudinal SUVR changes in relation to MMSE decreases showed a significantly higher slope of the regression line in the PVE-corrected as compared to the non-PVE-corrected PET data (F=7.1, P=0.008). These PVEC results indicate that the β-amyloid buildup curve does not plateau at an early symptomatic disease stage. A further evaluation of the impact of PVEC on the in-vivo characterization of time-dependent AD pathology, including the reliable assessment and comparison of other amyloid tracers, is warranted.
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The effects of monosodium glutamate on PSMA radiotracer uptake in men with recurrent prostate cancer: a prospective, randomized, double-blind, placebo-controlled intra-individual imaging study.
The prostate-specific membrane antigen (PSMA) is an excellent target for theranostic applications in prostate cancer (PCa). However, PSMA-targeted radioligand therapy can cause undesirable effects due to high accumulation of PSMA radiotracers in salivary glands and kidneys. This study assessed orally administered monosodium glutamate (MSG) as a potential means of reducing kidney and salivary gland radiation exposure using a PSMA targeting radiotracer. Methods: This prospective, double-blind, placebo-controlled study enrolled 10 biochemically recurrent PCa patients. Each subject served as his own control. [18F]DCFPyl PET/CT imaging sessions were performed 3 – 7 days apart, following oral administration of either 12.7 g of MSG or placebo. Data from the two sets of images were analyzed by placing regions of interest on lacrimal, parotid and submandibular glands, left ventricle, liver, spleen, kidneys, bowel, urinary bladder, gluteus muscle and malignant lesions. The results from MSG and placebo scans were compared by paired analysis of the ROI data. Results: A total of 142 pathological lesions along with normal tissues were analyzed. As hypothesized a priori, there was a significant decrease in maximal standardized uptake values corrected for lean body mass (SULmax) on images obtained following MSG administration in the parotids (24 ± 14%, P = 0.001), submandibular glands (35 ± 11%, P<0.001) and kidneys (23 ± 26%, P = 0.014). Significant decreases were also observed in lacrimal glands (49 ± 13%, P<0.001), liver (15 ± 6%, P<0.001), spleen (28 ± 13%, P = 0.001) and bowel (44 ± 13%, P<0.001). Mildly lower blood pool SULmean was observed after MSG administration (decrease of 11 ± 13%, P = 0.021). However, significantly lower radiotracer uptake in terms of SULmean, SULpeak, and SULmax was observed in malignant lesions on scans performed after MSG administration compared to the placebo studies (SULmax median decrease 33%, range -1 to 75%, P<0.001). No significant adverse events occurred and vital signs were stable following placebo or MSG administration. Conclusion: Orally administered MSG significantly decreased salivary gland, kidney and other normal organ PSMA radiotracer uptake in human subjects, using [18F]DCFPyL as an exemplar. However, MSG caused a corresponding reduction in tumor uptake, which may limit the benefits of this approach for diagnostic and therapeutic applications.
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Sudan Stakeholder Dialogues: Options for Economic Stabilization, Recovery and Inclusive Growth
3 October 2019
The Chatham House Africa Programme designed the Sudan Stakeholder Dialogues series to help identify the factors that have led to the current economic crisis, the immediate steps that need to be taken to avert collapse and stabilize the economy, and the longer-term structural reforms required to set Sudan on the path to recovery. The project is funded by Humanity United.
2019-10-03-Sudan.jpg
An employee removes bread from the oven at a bakery in the Sudanese capital, Khartoum, on 24 May 2019. Photo: Getty Images.
Three private roundtable meetings were convened in the first quarter of 2019, with the aim of generating informed and constructive new thinking on policy options and reforms that could help Sudan build a more economically prosperous, stable and inclusive nation. The roundtables were held under the Chatham House Rule.
The project sought to offer a neutral space for discussion to policymakers and influencers from a broad range of backgrounds: Sudanese government officials, opposition figures, economists, experts on Sudan’s political economy and governance, civil society figures, representatives of international financial institutions, and other international policymakers.
This paper draws together the key themes and findings from each of the three roundtables, ranging from broad structural economic issues to sector-specific priority interventions. It presents options and recommendations for Sudanese leaders, including the transitional government, in support of building a more economically prosperous, peaceful and inclusive nation.
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Forging Inclusive Economic Growth in Zimbabwe: Insights from the Zimbabwe Futures 2030 Roundtable Series
10 October 2019
This briefing note is the result of a collaborative research process with the Zimbabwean private sector, government representatives, industry organizations and experts, drawing on best practice and senior-level insights to identify policy options for long-term economic revival and expansion in Zimbabwe, and pathways for inclusive development.
Central to the research process was the Zimbabwe Futures 2030 roundtable series, complemented by additional interviews and research. Participants at the three roundtables, held in Harare and Bulawayo in the first half of 2019, discussed the necessary policies and business strategies to enable and support the effective implementation of the Mnangagwa administration’s Transitional Stabilisation Programme, Vision 2030, and other longer-term national development plans.
This process was conducted by the Chatham House Africa Programme, the Zimbabwe Business Club and the Konrad-Adenauer-Stiftung (KAS); and in partnership with the Confederation of Zimbabwe Industries for a roundtable in Bulawayo. The project was supported by KAS and the Dulverton Trust.
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Mobilizing Multinational Military Operations in Africa: Quick Fixes or Sustainable Solutions?
Research Event
25 October 2019 - 9:30am to 11:15am
Chatham House | 10 St James's Square | London | SW1Y 4LE
Event participants
Professor Tony Chafer, University of Portsmouth
Professor Gordon Cumming, Cardiff University
Dr Roel van der Velde, Cardiff University
Ahmed Soliman, Research Fellow, Horn of Africa, Chatham House
Dr Elisa Lopez Lucia, Université Libre de Bruxelles; University of Portsmouth
Chair: Janet Adama Mohammed, West Africa Programme Director, Conciliation Resources
Peacekeeping missions which have sought to address evolving forms of conflict and instability on the African continent – led by the United Nations, African Union and European Union – have frequently been overstretched.
Across regions including the Sahel, the Horn and West Africa, the issues of violent extremism and criminality – often set against a backdrop of collapsing or severely weakened central states – have led to the mobilisation of a diverse set of new collective responses.
These include notable African-led efforts such as AMISOM in Somalia or more recently the G5 Sahel, where France have played a pivotal role in initiating new and more ad hoc approaches to coalition-building.
As existing multinational missions in Africa continue to evolve on the ground and while new collective opportunities increasingly present themselves, it is critical for policymakers to understand how far such efforts reflect meaningful long-term solutions to the challenges of conflict and insecurity.
At this roundtable event, participants will reflect on how such missions become mobilised and legitimised, the extent to which they can be defined as ‘new’, and whether they represent a truly sustainable means to tackle the issue of conflict in Africa.
This roundtable is held in partnership with Cardiff University and the University of Portsmouth and is supported by the Leverhulme Trust.
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The Relevance of Intergovernmental Organizations to African States: The International Organization of La Francophonie
Research Event
6 November 2019 - 10:00am to 11:15am
Chatham House | 10 St James's Square | London | SW1Y 4LE
Event participants
Louise Mushikiwabo, Secretary General, Organisation Internationale de la Francophonie (OIF)
Chair: Bob Dewar CMG, Associate Fellow, Africa Programme, Chatham House
African states are well represented in intergovernmental organizations linked by official language and colonial history such as the Organisation Internationale de la Francophonie (OIF), the Comunidade dos Países de Língua Portuguesa (CPLP) and the Commonwealth. These organizations aim to provide support in addressing matters of mutual interest – in addition to responding to significant policy challenges such as improving sustainable growth prospects and opportunities to young populations – and citizens are increasingly vocal on key issues such as democracy, human rights and the rule of law. This event series examines the importance of these intergovernmental organizations in working with their members to responsibly and sustainably respond to policy challenges in Africa.
At this event, Louise Mushikiwabo, secretary general of the Organisation Internationale de la Francophonie (OIF), will discuss the organisation’s relevance to African states and the future of the organization on the continent.
THIS EVENT IS NOW FULL AND REGISTRATION HAS NOW CLOSED.
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Angola's Business Promise: Evaluating the Progress of Privatization and Other Economic Reforms
Research Event
21 January 2020 - 2:30pm to 3:30pm
Chatham House | 10 St James's Square | London | SW1Y 4LE
Event participants
Hon. Manuel José Nunes Júnior, Minister of State for Economic Coordination, Republic of Angola
Chair: Dr Alex Vines OBE, Managing Director, Ethics, Risk & Resilience; Director, Africa Programme, Chatham House
Minister Nunes Júnior will discuss the progress of the Angolan government’s economic stabilization plans and business reform agenda including the privatization of some state-owned enterprises. These reforms could expand Angola’s exports beyond oil and stimulate new industries and more inclusive economic growth.
THIS EVENT IS NOW FULL AND REGISTRATION HAS CLOSED.
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The UK, US and Mauritius: Decolonization, Security, Chagos and the ICJ
Invitation Only Research Event
30 January 2020 - 8:15am to 9:15am
Chatham House | 10 St James's Square | London | SW1Y 4LE
Event participants
Professor Philippe Sands QC, Professor of Law, UCL
Richard Burt, Managing Partner, McLarty Associates
Chair: Dr Leslie Vinjamuri, Director, US and Americas Programme; Dean, Queen Elizabeth II Academy, Chatham House
The Chagos archipelago in the Indian Ocean has garnered media attention recently after the UK failed to abide by a UN deadline to return the islands to Mauritius. The US has landed in the middle of the dispute as a 1965 agreement with the UK has allowed the US to establish a military base on one of the islands, Diego Garcia, which has since become instrumental in US missions in the Asia-Pacific and the Middle East.
In February 2019, an Advisory Opinion of the International Court of Justice (ICJ) found that the Chagos archipelago was unlawfully dismembered from Mauritius, in violation of the right to self-determination and that the United Kingdom is under an obligation to end its administration of the Chagos archipelago ‘as rapidly as possible’. The UN General Assembly subsequently voted overwhelmingly in favour of the UK leaving the islands by the end of November 2019 and the right of the former residents who were removed by the UK to return. The UK does not accept the ICJ and UN rulings and argues that the islands are needed to protect Britain from security threats while Mauritius has made clear the base can remain.
Professor Philippe Sands QC, professor of law at University College London and lead counsel for Mauritius on the ICJ case on Legal Consequences of the Separation of the Chagos archipelago from Mauritius in 1965, will be joining Ambassador Richard Burt, US chief negotiator in the Strategic Arms Reduction Talks with the former Soviet Union for a discussion on the fate of the archipelago including the future of the military base and the right of return of former residents.
Attendance at this event is by invitation only.
Event attributes
Chatham House RuleDepartment/project
US and Americas Programme
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Decentralization and Cross-border Integration in the Horn of Africa
Research Event
4 February 2020 - 5:00pm to 6:15pm
Chatham House | 10 St James's Square | London | SW1Y 4LE
Event participants
Mohamed Guleid, Chief Executive Officer, Frontier Counties Development Council
Nuradin Dirie, Chair, Puntland Presidential Advisory Council
Aden Abdi, Horn of Africa Programme Director, Conciliation Resources
Chair: Dr Zahbia Yousuf, Senior Research Advisor, Saferworld
The interdependence of communities across the Horn of Africa results from social, familial, linguistic and cultural ties that cross territorial borders. Such linkages are reinforced by established patterns of movement and trade, often leading to stronger political and social connections between communities on either side of borders, than with their respective national capitals. States in the region are increasingly being challenged by demands for decentralization and more effective local governance. Improved understanding of the complexity of sub-national and cross-border political and economic contexts will be required to meet these demands and support enhanced governance so that challenges such as marginalization, intercommunal conflict and more equitable sharing of resources can be effectively addressed.
At this event, speakers will examine some of the key subnational and cross-border relations in the Horn of Africa. They will also discuss initiatives and stakeholders needed to support common solutions to building peace, furthering development and bolstering inclusive growth and integration.
THIS EVENT IS NOW FULL AND REGISTRATION HAS CLOSED.
Department/project
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Realizing South Sudan's Peace Deal
Invitation Only Research Event
24 February 2020 - 5:00pm to 6:15pm
Chatham House | 10 St James's Square | London | SW1Y 4LE
Event participants
Miklos Gosztonyi, Conflict Analyst, South Sudan, Norwegian Refugee Council
Matthew F. Pritchard, Research and Policy Specialist, McGill University
Joshua Craze, Writer and Researcher
Teohna Williams, CEO, Business Plan for Peace
South Sudan’s new power sharing government must be formed by 22 February 2020, as specified in the Revitalized Agreement on the Resolution of the Conflict in the Republic of South Sudan (R-ARCSS). There have been two extensions to this process already, reflecting the continued distrust among leaders and the complexity of the conflict.
The lack of progress in several contentious areas has delayed the formation of the Revitalized Transitional Government of National Unity (R-TGoNU) for nine months, but the recent decision taken by President Salva Kiir Mayardit to re-establish 10 states has been welcomed by opposition groups, regional mediators and international partners.
It is seen as the breakthrough needed for an agreement to be reached, despite some outstanding concerns. Further meaningful compromises and difficult decisions will be needed to implement a lasting peace agreement.
At this event, a panel of speakers will examine the status of the peace deal following the February deadline and the steps needed to progress the key issues underlying implementation.
Event attributes
Chatham House RuleDepartment/project
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Why The Insurgency in Northern Mozambique Has Got Worse
1 April 2020
Two attacks on towns in northern Mozambique by suspected jihadists point to a rapidly deteriorating security crisis.2020-04-01-Mozambique
Macomia, Cabo Delgado, Northern Mozambique. Photo by EMIDIO JOSINE/AFP via Getty Images.
On March 23 to 24, the centre of Mocimboa da Praia in Cabo Delgado province was occupied by up to 40 “jihadists”, who targeted government facilities, including a barracks, and brandished banners of affiliation to the so-called Islamic State.
On March 25, suspected jihadists raided the town of Quissanga and destroyed the district police headquarters. They too carried an Islamic State flag. Twenty to 30 members of Mozambique’s security forces were killed in both attacks.
Mocimboa da Praia is just south of the Afungi Peninsula, the location of gas projects worth $60- billion. Mocimboa was briefly occupied in late 2017, during attacks claimed by a group known as Ahlu Sunnah Wa-Jama (or al-Sunnah) that marked the start of a brutal low-intensity conflict, with widespread human rights abuses and attacks on civilians.
Up to 1,000 people have now been killed and 100,000 displaced. More recently, The Islamic State Central Africa Province (Iscap), affiliated with the Islamic State group, has claimed responsibility for the attacks. Video and photos of these most recent events, along with the testimony of frightened residents and overstretched government officials, suggest a shift of strategy by the insurgents.
There seems to have been an effort to avoid harming civilians, to win hearts and minds by redistributing stolen food, medicine and fuel to “loyal” residents, and to direct attacks on the state and its symbols, such as police stations and military barracks. It is difficult from a distance to assess if there was any genuine pleasure over these attacks among local people; while residents in both towns that did not flee seemed to welcome the attackers, this may well have been out of fear that the government is currently unable to guarantee their security.
These attacks also indicate that the jihadist-linked insurgents are growing in confidence. They are confronting government security forces with little appetite for fighting. The Mozambican government has been expecting setbacks like those of Mocimboa and Quissanga — its forces are demoralised and many commanders exhausted or corrupted by an emerging war economy. Jihadists are also taking tactical advantage before a reformed and more effective government counterinsurgency effort is introduced in response.
President Filipe Nyusi, inaugurated in January for his second term, has made this crisis his prime focus and has become the de-facto minister of defence.
Military reform and the role of private military companies
But there is no quick fix. Most importantly, the Mozambican military and security forces need to be restructured. They were unable to win the Mozambican civil war (1977-1992), even with international support, and have not improved in capacity or conduct since. They now face a complex, multilayered and asymmetrical conflict, mostly drawing upon local and regional grievances and networks but increasingly also attracting some limited encouragement and advice from further afield.
Nyusi will need to build-up trusted relationships in the military in the way he has successfully done with parts of the intelligence community. The Mozambican government has already reached out to international expertise — though not necessarily the right kind. The founder of the Blackwater private military company, Erik Prince, supplied two helicopters and support crew for the Mozambican military in mid-2019, before being replaced by some 170 Russian privateers linked to the Wagner Group.
The Wagner contingent arrived in September 2019 at Nacala airport with trucks, drones and a Mi-17 helicopter gunship, then deployed into the combat zone of northern Cabo Delgado. Setbacks, including at least two dead Russians, forced a tactical fallback to Nacala, though a new effort is reported to have been underway since late February 2020.
The Mozambican government is also considering a number of proposals from other private military companies. Maputo needs to consider these carefully; Israeli or Gulf State involvement in any form might exasperate rather than alleviate this crisis.
The Tanzanian connection
But market-led security and military providers will not end this insurgency. Nor will the engagement of states such as the United States, France, the United Kingdom or Angola, all of which have made their own offers of support. What would significantly make a difference is much closer to home: serious Tanzanian engagement.
This insurgency is concentrated in districts bordering Tanzania and there is clear-cut intelligence of connections into Tanzania and beyond. Swahili is also a lingua franca for the jihadists, connecting them up the East African coast, and into eastern Congo and elsewhere.
It is puzzling, given the deep shared history between Tanzania and Mozambique, that the bilateral relationship is as patchy as it is today: during the liberation struggle (1965-1974) against the Portuguese, Mozambique’s ruling party Frelimo maintained rear bases in Tanzania, and Nyusi was educated there.
Conspiracy theories circulate that Tanzania has encouraged the Cabo Delgado insurgency to weaken its neighbour, or at least displace radicalised individuals from Tanzanian soil into Mozambique.
President John Magafuli of Tanzania did not attend the January inauguration of Nyusi. It has become urgent that Magafuli (who is also the current chair of the regional body, the Southern African Development Community) and Nyusi meet face-to-face to map out improved intelligence sharing and a joint strategy to respond to an emerging regional threat.
Southern Africa is locking down because of Covid-19, which will distract the government’s ability to focus fully on this crisis and create a perfect moment for the infant insurgency in Cabo Delgado to grow. More military setbacks should be expected in coming months.
But the Mozambican government can still contain and prevail if it seriously reforms its military, builds strong alliances with its regional neighbours (especially Tanzania), chooses its private security contractors and international partnerships wisely, and backs military efforts with better intelligence and developmental interventions that offer alternative pathways to potential recruits.
But despite Maputo’s hope that significant progress will be made over the coming year, and the setting up of a presidential task force to evaluate progress and intelligence, it is likely that Mozambique and its partners will need to prepare themselves for a drawn-out struggle.
This article originally appeared in the Mail & Guardian
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Phosphoproteomic characterization of the signaling network resulting from activation of the chemokine receptor CCR2 [Genomics and Proteomics]
Leukocyte recruitment is a universal feature of tissue inflammation and regulated by the interactions of chemokines with their G protein–coupled receptors. Activation of CC chemokine receptor 2 (CCR2) by its cognate chemokine ligands, including CC chemokine ligand 2 (CCL2), plays a central role in recruitment of monocytes in several inflammatory diseases. In this study, we used phosphoproteomics to conduct an unbiased characterization of the signaling network resulting from CCL2 activation of CCR2. Using data-independent acquisition MS analysis, we quantified both the proteome and phosphoproteome in FlpIn-HEK293T cells stably expressing CCR2 at six time points after activation with CCL2. Differential expression analysis identified 699 significantly regulated phosphorylation sites on 441 proteins. As expected, many of these proteins are known to participate in canonical signal transduction pathways and in the regulation of actin cytoskeleton dynamics, including numerous guanine nucleotide exchange factors and GTPase-activating proteins. Moreover, we identified regulated phosphorylation sites in numerous proteins that function in the nucleus, including several constituents of the nuclear pore complex. The results of this study provide an unprecedented level of detail of CCR2 signaling and identify potential targets for regulation of CCR2 function.
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Multi-omic Characterization of the Mode of Action of a Potent New Antimalarial Compound, JPC-3210, Against Plasmodium falciparum [Research]
The increasing incidence of antimalarial drug resistance to the first-line artemisinin combination therapies underpins an urgent need for new antimalarial drugs, ideally with a novel mode of action. The recently developed 2-aminomethylphenol, JPC-3210, (MMV 892646) is an erythrocytic schizonticide with potent in vitro antimalarial activity against multidrug-resistant Plasmodium falciparum lines, low cytotoxicity, potent in vivo efficacy against murine malaria, and favorable preclinical pharmacokinetics including a lengthy plasma elimination half-life. To investigate the impact of JPC-3210 on biochemical pathways within P. falciparum-infected red blood cells, we have applied a "multi-omics" workflow based on high resolution orbitrap mass spectrometry combined with biochemical approaches. Metabolomics, peptidomics and hemoglobin fractionation analyses revealed a perturbation in hemoglobin metabolism following JPC-3210 exposure. The metabolomics data demonstrated a specific depletion of short hemoglobin-derived peptides, peptidomics analysis revealed a depletion of longer hemoglobin-derived peptides, and the hemoglobin fractionation assay demonstrated decreases in hemoglobin, heme and hemozoin levels. To further elucidate the mechanism responsible for inhibition of hemoglobin metabolism, we used in vitro β-hematin polymerization assays and showed JPC-3210 to be an intermediate inhibitor of β-hematin polymerization, about 10-fold less potent then the quinoline antimalarials, such as chloroquine and mefloquine. Further, quantitative proteomics analysis showed that JPC-3210 treatment results in a distinct proteomic signature compared with other known antimalarials. While JPC-3210 clustered closely with mefloquine in the metabolomics and proteomics analyses, a key differentiating signature for JPC-3210 was the significant enrichment of parasite proteins involved in regulation of translation. These studies revealed that the mode of action for JPC-3210 involves inhibition of the hemoglobin digestion pathway and elevation of regulators of protein translation. Importantly, JPC-3210 demonstrated rapid parasite killing kinetics compared with other quinolones, suggesting that JPC-3210 warrants further investigation as a potentially long acting partner drug for malaria treatment.
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Deep Characterization of the Human Antibody Response to Natural Infection Using Longitudinal Immune Repertoire Sequencing [Research]
Human antibody response studies are largely restricted to periods of high immune activity (e.g. vaccination). To comprehensively understand the healthy B cell immune repertoire and how this changes over time and through natural infection, we conducted immune repertoire RNA sequencing on flow cytometry-sorted B cell subsets to profile a single individual's antibodies over 11 months through two periods of natural viral infection. We found that 1) a baseline of healthy variable (V) gene usage in antibodies exists and is stable over time, but antibodies in memory cells consistently have a different usage profile relative to earlier B cell stages; 2) a single complementarity-determining region 3 (CDR3) is potentially generated from more than one VJ gene combination; and 3) IgG and IgA antibody transcripts are found at low levels in early human B cell development, suggesting that class switching may occur earlier than previously realized. These findings provide insight into immune repertoire stability, response to natural infections, and human B cell development.
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Characterizing Patients with Recurrent Urinary Tract Infections in Vesicoureteral Reflux: A Pilot Study of the Urinary Proteome [Research]
Recurrent urinary tract infections (UTIs) pose a significant burden on the health care system. Underlying mechanisms predisposing children to UTIs and associated changes in the urinary proteome are not well understood. We aimed to investigate the urinary proteome of a subset of children who have vesicoureteral reflux (VUR) and recurrent UTIs because of their risk of developing infection-related renal damage. Improving diagnostic modalities to identify UTI risk factors would significantly alter the clinical management of children with VUR. We profiled the urinary proteomes of 22 VUR patients with low grade VUR (1–3 out of 5), a history of recurrent UTIs, and renal scarring, comparing them to those obtained from 22 age-matched controls. Urinary proteins were analyzed by mass spectrometry followed by protein quantitation based on spectral counting. Of the 2,551 proteins identified across both cohorts, 964 were robustly quantified, as defined by meeting criteria with spectral count (SC) ≥2 in at least 7 patients in either VUR or control cohort. Eighty proteins had differential expression between the two cohorts, with 44 proteins significantly up-regulated and 36 downregulated (q <0.075, FC ≥1.2). Urinary proteins involved in inflammation, acute phase response (APR), modulation of extracellular matrix (ECM), and carbohydrate metabolism were altered among the study cohort.
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Tandem Mass Tag Approach Utilizing Pervanadate BOOST Channels Delivers Deeper Quantitative Characterization of the Tyrosine Phosphoproteome [Technological Innovation and Resources]
Dynamic tyrosine phosphorylation is fundamental to a myriad of cellular processes. However, the inherently low abundance of tyrosine phosphorylation in the proteome and the inefficient enrichment of phosphotyrosine(pTyr)-containing peptides has led to poor pTyr peptide identification and quantitation, critically hindering researchers' ability to elucidate signaling pathways regulated by tyrosine phosphorylation in systems where cellular material is limited. The most popular approaches to wide-scale characterization of the tyrosine phosphoproteome use pTyr enrichment with pan-specific, anti-pTyr antibodies from a large amount of starting material. Methods that decrease the amount of starting material and increase the characterization depth of the tyrosine phosphoproteome while maintaining quantitative accuracy and precision would enable the discovery of tyrosine phosphorylation networks in rarer cell populations. To achieve these goals, the BOOST (
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Cell Cycle Profiling Reveals Protein Oscillation, Phosphorylation, and Localization Dynamics [Research]
The cell cycle is a highly conserved process involving the coordinated separation of a single cell into two daughter cells. To relate transcriptional regulation across the cell cycle with oscillatory changes in protein abundance and activity, we carried out a proteome- and phospho-proteome-wide mass spectrometry profiling. We compared protein dynamics with gene transcription, revealing many transcriptionally regulated G2 mRNAs that only produce a protein shift after mitosis. Integration of CRISPR/Cas9 survivability studies further highlighted proteins essential for cell viability. Analyzing the dynamics of phosphorylation events and protein solubility dynamics over the cell cycle, we characterize predicted phospho-peptide motif distributions and predict cell cycle-dependent translocating proteins, as exemplified by the S-adenosylmethionine synthase MAT2A. Our study implicates this enzyme in translocating to the nucleus after the G1/S-checkpoint, which enables epigenetic histone methylation maintenance during DNA replication. Taken together, this data set provides a unique integrated resource with novel insights on cell cycle dynamics.
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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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Biosynthesis of depsipeptides with a 3-hydroxybenzoate moiety and selective anticancer activities involves a chorismatase [Metabolism]
Neoantimycins are anticancer compounds of 15-membered ring antimycin-type depsipeptides. They are biosynthesized by a hybrid multimodular protein complex of nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS), typically from the starting precursor 3-formamidosalicylate. Examining fermentation extracts of Streptomyces conglobatus, here we discovered four new neoantimycin analogs, unantimycins B–E, in which 3-formamidosalicylates are replaced by an unusual 3-hydroxybenzoate (3-HBA) moiety. Unantimycins B–E exhibited levels of anticancer activities similar to those of the chemotherapeutic drug cisplatin in human lung cancer, colorectal cancer, and melanoma cells. Notably, they mostly displayed no significant toxicity toward noncancerous cells, unlike the serious toxicities generally reported for antimycin-type natural products. Using site-directed mutagenesis and heterologous expression, we found that unantimycin productions are correlated with the activity of a chorismatase homolog, the nat-hyg5 gene, from a type I PKS gene cluster. Biochemical analysis confirmed that the catalytic activity of Nat-hyg5 generates 3-HBA from chorismate. Finally, we achieved selective production of unantimycins B and C by engineering a chassis host. On the basis of these findings, we propose that unantimycin biosynthesis is directed by the neoantimycin-producing NRPS–PKS complex and initiated with the starter unit of 3-HBA. The elucidation of the biosynthetic unantimycin pathway reported here paves the way to improve the yield of these compounds for evaluation in oncotherapeutic applications.
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COQ11 deletion mitigates respiratory deficiency caused by mutations in the gene encoding the coenzyme Q chaperone protein Coq10 [Lipids]
Coenzyme Q (Qn) is a vital lipid component of the electron transport chain that functions in cellular energy metabolism and as a membrane antioxidant. In the yeast Saccharomyces cerevisiae, coq1–coq9 deletion mutants are respiratory-incompetent, sensitive to lipid peroxidation stress, and unable to synthesize Q6. The yeast coq10 deletion mutant is also respiratory-deficient and sensitive to lipid peroxidation, yet it continues to produce Q6 at an impaired rate. Thus, Coq10 is required for the function of Q6 in respiration and as an antioxidant and is believed to chaperone Q6 from its site of synthesis to the respiratory complexes. In several fungi, Coq10 is encoded as a fusion polypeptide with Coq11, a recently identified protein of unknown function required for efficient Q6 biosynthesis. Because “fused” proteins are often involved in similar biochemical pathways, here we examined the putative functional relationship between Coq10 and Coq11 in yeast. We used plate growth and Seahorse assays and LC-MS/MS analysis to show that COQ11 deletion rescues respiratory deficiency, sensitivity to lipid peroxidation, and decreased Q6 biosynthesis of the coq10Δ mutant. Additionally, immunoblotting indicated that yeast coq11Δ mutants accumulate increased amounts of certain Coq polypeptides and display a stabilized CoQ synthome. These effects suggest that Coq11 modulates Q6 biosynthesis and that its absence increases mitochondrial Q6 content in the coq10Δcoq11Δ double mutant. This augmented mitochondrial Q6 content counteracts the respiratory deficiency and lipid peroxidation sensitivity phenotypes of the coq10Δ mutant. This study further clarifies the intricate connection between Q6 biosynthesis, trafficking, and function in mitochondrial metabolism.
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Glucose availability but not changes in pancreatic hormones sensitizes hepatic AMPK activity during nutritional transition in rodents [Metabolism]
The cellular energy sensor AMP-activated protein kinase (AMPK) is a metabolic regulator that mediates adaptation to nutritional variations to maintain a proper energy balance in cells. We show here that suckling-weaning and fasting-refeeding transitions in rodents are associated with changes in AMPK activation and the cellular energy state in the liver. These nutritional transitions were characterized by a metabolic switch from lipid to glucose utilization, orchestrated by modifications in glucose levels and the glucagon/insulin ratio in the bloodstream. We therefore investigated the respective roles of glucose and pancreatic hormones on AMPK activation in mouse primary hepatocytes. We found that glucose starvation transiently activates AMPK, whereas changes in glucagon and insulin levels had no impact on AMPK. Challenge of hepatocytes with metformin-induced metabolic stress strengthened both AMPK activation and cellular energy depletion under limited-glucose conditions, whereas neither glucagon nor insulin altered AMPK activation. Although both insulin and glucagon induced AMPKα phosphorylation at its Ser485/491 residue, they did not affect its activity. Finally, the decrease in cellular ATP levels in response to an energy stress was additionally exacerbated under fasting conditions and by AMPK deficiency in hepatocytes, revealing metabolic inflexibility and emphasizing the importance of AMPK for maintaining hepatic energy charge. Our results suggest that nutritional changes (i.e. glucose availability), rather than the related hormonal changes (i.e. the glucagon/insulin ratio), sensitize AMPK activation to the energetic stress induced by the dietary transition during fasting. This effect is critical for preserving the cellular energy state in the liver.
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Inhibition of the polyamine synthesis enzyme ornithine decarboxylase sensitizes triple-negative breast cancer cells to cytotoxic chemotherapy [Molecular Bases of Disease]
Treatment of patients with triple-negative breast cancer (TNBC) is limited by a lack of effective molecular therapies targeting this disease. Recent studies have identified metabolic alterations in cancer cells that can be targeted to improve responses to standard-of-care chemotherapy regimens. Using MDA-MB-468 and SUM-159PT TNBC cells, along with LC-MS/MS and HPLC metabolomics profiling, we found here that exposure of TNBC cells to the cytotoxic chemotherapy drugs cisplatin and doxorubicin alter arginine and polyamine metabolites. This alteration was because of a reduction in the levels and activity of a rate-limiting polyamine biosynthetic enzyme, ornithine decarboxylase (ODC). Using gene silencing and inhibitor treatments, we determined that the reduction in ODC was mediated by its negative regulator antizyme, targeting ODC to the proteasome for degradation. Treatment with the ODC inhibitor difluoromethylornithine (DFMO) sensitized TNBC cells to chemotherapy, but this was not observed in receptor-positive breast cancer cells. Moreover, TNBC cell lines had greater sensitivity to single-agent DFMO, and ODC levels were elevated in TNBC patient samples. The alterations in polyamine metabolism in response to chemotherapy, as well as DFMO-induced preferential sensitization of TNBC cells to chemotherapy, reported here suggest that ODC may be a targetable metabolic vulnerability in TNBC.
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Petro-RMB? The oil trade and the internationalization of the renminbi
4 September 2019 , Volume 95, Number 5
In this article, we examine China's promotion of the renminbi (RMB) in international oil trade and explore its implications for the international currency system in the short and the long term. The article traces the rise of the RMB in international oil trade in recent years and provides an analysis of its impact on the internationalization of the Chinese currency. We argue that despite the increasing use of the yuan in oil trade in recent years, in the short term it is highly unlikely that a petro-RMB system will emerge to rival the petrodollar system. Unlike the petrodollar, which combines the qualities of a master currency, a top currency and a negotiated currency, China lacks the economic leadership and the political and geopolitical leverages to make the RMB a major petrocurrency. Although the emergence of the RMB-denominated Shanghai oil futures is an important development, the absence of highly developed financial markets and a strong legal system in China hinders its potential. In the long run, the RMB may take on a more prominent role in the international oil trade as China's weight as an oil importer rises. More importantly, the overuse of financial sanctions by the US government has begun to undermine the role of the dollar within and beyond the oil trade. In addition, the rise of alternative energy sources will diminish the centrality of oil in the world economy, thus reducing the significance of petrocurrencies—whether the dollar or the RMB—in shaping the international currency system.