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MANF Promotes Diabetic Corneal Epithelial Wound Healing and Nerve Regeneration by Attenuating Hyperglycemia-Induced Endoplasmic Reticulum Stress

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a neurotrophic factor widely expressed in mammalian tissues, and it exerts critical protective effects on neurons and other cell types in various disease models, such as those for diabetes. However, to date, the expression and roles of MANF in the cornea, with or without diabetic keratopathy (DK), remain unclear. Here, we demonstrate that MANF is abundantly expressed in normal corneal epithelial cells; however, MANF expression was significantly reduced in both unwounded and wounded corneal epithelium in streptozotocin-induced type 1 diabetic C57BL/6 mice. Recombinant human MANF significantly promoted normal and diabetic corneal epithelial wound healing and nerve regeneration. Furthermore, MANF inhibited hyperglycemia-induced endoplasmic reticulum (ER) stress and ER stress–mediated apoptosis. Attenuation of ER stress with 4-phenylbutyric acid (4-PBA) also ameliorated corneal epithelial closure and nerve regeneration. However, the beneficial effects of MANF and 4-PBA were abolished by an Akt inhibitor and Akt-specific small interfering RNA (siRNA). Finally, we reveal that the subconjunctival injection of MANF-specific siRNA prevents corneal epithelial wound healing and nerve regeneration. Our results provide important evidence that hyperglycemia-suppressed MANF expression may contribute to delayed corneal epithelial wound healing and impaired nerve regeneration by increasing ER stress, and MANF may be a useful therapeutic modality for treating DK.




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The cytochrome P450 enzyme CYP24A1 increases proliferation of mutant KRAS-dependent lung adenocarcinoma independent of its catalytic activity [Cell Biology]

We previously reported that overexpression of cytochrome P450 family 24 subfamily A member 1 (CYP24A1) increases lung cancer cell proliferation by activating RAS signaling and that CYP24A1 knockdown inhibits tumor growth. However, the mechanism of CYP24A1-mediated cancer cell proliferation remains unclear. Here, we conducted cell synchronization and biochemical experiments in lung adenocarcinoma cells, revealing a link between CYP24A1 and anaphase-promoting complex (APC), a key cell cycle regulator. We demonstrate that CYP24A1 expression is cell cycle–dependent; it was higher in the G2-M phase and diminished upon G1 entry. CYP24A1 has a functional destruction box (D-box) motif that allows binding with two APC adaptors, CDC20-homologue 1 (CDH1) and cell division cycle 20 (CDC20). Unlike other APC substrates, however, CYP24A1 acted as a pseudo-substrate, inhibiting CDH1 activity and promoting mitotic progression. Conversely, overexpression of a CYP24A1 D-box mutant compromised CDH1 binding, allowing CDH1 hyperactivation, thereby hastening degradation of its substrates cyclin B1 and CDC20, and accumulation of the CDC20 substrate p21, prolonging mitotic exit. These activities also occurred with a CYP24A1 isoform 2 lacking the catalytic cysteine (Cys-462), suggesting that CYP24A1's oncogenic potential is independent of its catalytic activity. CYP24A1 degradation reduced clonogenic survival of mutant KRAS-driven lung cancer cells, and calcitriol treatment increased CYP24A1 levels and tumor burden in Lsl-KRASG12D mice. These results disclose a catalytic activity-independent growth-promoting role of CYP24A1 in mutant KRAS-driven lung cancer. This suggests that CYP24A1 could be therapeutically targeted in lung cancers in which its expression is high.




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SUMOylation of the transcription factor ZFHX3 at Lys-2806 requires SAE1, UBC9, and PIAS2 and enhances its stability and function in cell proliferation [Protein Synthesis and Degradation]

SUMOylation is a posttranslational modification (PTM) at a lysine residue and is crucial for the proper functions of many proteins, particularly of transcription factors, in various biological processes. Zinc finger homeobox 3 (ZFHX3), also known as AT motif-binding factor 1 (ATBF1), is a large transcription factor that is active in multiple pathological processes, including atrial fibrillation and carcinogenesis, and in circadian regulation and development. We have previously demonstrated that ZFHX3 is SUMOylated at three or more lysine residues. Here, we investigated which enzymes regulate ZFHX3 SUMOylation and whether SUMOylation modulates ZFHX3 stability and function. We found that SUMO1, SUMO2, and SUMO3 each are conjugated to ZFHX3. Multiple lysine residues in ZFHX3 were SUMOylated, but Lys-2806 was the major SUMOylation site, and we also found that it is highly conserved among ZFHX3 orthologs from different animal species. Using molecular analyses, we identified the enzymes that mediate ZFHX3 SUMOylation; these included SUMO1-activating enzyme subunit 1 (SAE1), an E1-activating enzyme; SUMO-conjugating enzyme UBC9 (UBC9), an E2-conjugating enzyme; and protein inhibitor of activated STAT2 (PIAS2), an E3 ligase. Multiple analyses established that both SUMO-specific peptidase 1 (SENP1) and SENP2 deSUMOylate ZFHX3. SUMOylation at Lys-2806 enhanced ZFHX3 stability by interfering with its ubiquitination and proteasomal degradation. Functionally, Lys-2806 SUMOylation enabled ZFHX3-mediated cell proliferation and xenograft tumor growth of the MDA-MB-231 breast cancer cell line. These findings reveal the enzymes involved in, and the functional consequences of, ZFHX3 SUMOylation, insights that may help shed light on ZFHX3's roles in various cellular and pathophysiological processes.




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A flexible network of vimentin intermediate filaments promotes migration of amoeboid cancer cells through confined environments [Cell Biology]

Tumor cells can spread to distant sites through their ability to switch between mesenchymal and amoeboid (bleb-based) migration. Because of this difference, inhibitors of metastasis must account for each migration mode. However, the role of vimentin in amoeboid migration has not been determined. Because amoeboid leader bleb–based migration (LBBM) occurs in confined spaces and vimentin is known to strongly influence cell-mechanical properties, we hypothesized that a flexible vimentin network is required for fast amoeboid migration. To this end, here we determined the precise role of the vimentin intermediate filament system in regulating the migration of amoeboid human cancer cells. Vimentin is a classic marker of epithelial-to-mesenchymal transition and is therefore an ideal target for a metastasis inhibitor. Using a previously developed polydimethylsiloxane slab–based approach to confine cells, RNAi-based vimentin silencing, vimentin overexpression, pharmacological treatments, and measurements of cell stiffness, we found that RNAi-mediated depletion of vimentin increases LBBM by ∼50% compared with control cells and that vimentin overexpression and simvastatin-induced vimentin bundling inhibit fast amoeboid migration and proliferation. Importantly, these effects were independent of changes in actomyosin contractility. Our results indicate that a flexible vimentin intermediate filament network promotes LBBM of amoeboid cancer cells in confined environments and that vimentin bundling perturbs cell-mechanical properties and inhibits the invasive properties of cancer cells.




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

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




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Zinc promotes liquid-liquid phase separation of tau protein [Protein Structure and Folding]

Tau is a microtubule-associated protein that plays a major role in Alzheimer's disease (AD) and other tauopathies. Recent reports indicate that, in the presence of crowding agents, tau can undergo liquid–liquid phase separation (LLPS), forming highly dynamic liquid droplets. Here, using recombinantly expressed proteins, turbidimetry, fluorescence microscopy imaging, and fluorescence recovery after photobleaching (FRAP) assays, we show that the divalent transition metal zinc strongly promotes this process, shifting the equilibrium phase boundary to lower protein or crowding agent concentrations. We observed no tau LLPS-promoting effect for any other divalent transition metal ions tested, including Mn2+, Fe2+, Co2+, Ni2+, and Cu2+. We also demonstrate that multiple zinc-binding sites on tau are involved in the LLPS-promoting effect and provide insights into the mechanism of this process. Zinc concentration is highly elevated in AD brains, and this metal ion is believed to be an important player in the pathogenesis of this disease. Thus, the present findings bring a new dimension to understanding the relationship between zinc homeostasis and the pathogenic process in AD and related neurodegenerative disorders.




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Structural basis of substrate recognition and catalysis by fucosyltransferase 8 [Protein Structure and Folding]

Fucosylation of the innermost GlcNAc of N-glycans by fucosyltransferase 8 (FUT8) is an important step in the maturation of complex and hybrid N-glycans. This simple modification can dramatically affect the activities and half-lives of glycoproteins, effects that are relevant to understanding the invasiveness of some cancers, development of mAb therapeutics, and the etiology of a congenital glycosylation disorder. The acceptor substrate preferences of FUT8 are well-characterized and provide a framework for understanding N-glycan maturation in the Golgi; however, the structural basis of these substrate preferences and the mechanism through which catalysis is achieved remain unknown. Here we describe several structures of mouse and human FUT8 in the apo state and in complex with GDP, a mimic of the donor substrate, and with a glycopeptide acceptor substrate at 1.80–2.50 Å resolution. These structures provide insights into a unique conformational change associated with donor substrate binding, common strategies employed by fucosyltransferases to coordinate GDP, features that define acceptor substrate preferences, and a likely mechanism for enzyme catalysis. Together with molecular dynamics simulations, the structures also revealed how FUT8 dimerization plays an important role in defining the acceptor substrate-binding site. Collectively, this information significantly builds on our understanding of the core fucosylation process.




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Effect of a Sustained Reduction in Plasma Free Fatty Acid Concentration on Intramuscular Long-Chain Fatty Acyl-CoAs and Insulin Action in Type 2 Diabetic Patients

Mandeep Bajaj
Nov 1, 2005; 54:3148-3153
Metabolism




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Pancreas Pathology of Latent Autoimmune Diabetes in Adults (LADA) in Patients and in a LADA Rat Model Compared With Type 1 Diabetes

Anne Jörns
Apr 1, 2020; 69:624-633
Islet Studies




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Evidence Against an Important Role of Plasma Insulin and Glucagon Concentrations in the Increase in EGP Caused by SGLT2 Inhibitors

Mariam Alatrach
Apr 1, 2020; 69:681-688
Pathophysiology




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PPARA Polymorphism Influences the Cardiovascular Benefit of Fenofibrate in Type 2 Diabetes: Findings From ACCORD-Lipid

Mario Luca Morieri
Apr 1, 2020; 69:771-783
Genetics/Genomes/Proteomics/Metabolomics




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Vitamin D Receptor Overexpression in {beta}-Cells Ameliorates Diabetes in Mice

Meritxell Morró
May 1, 2020; 69:927-939
Islet Studies




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Effect of a High-Protein, Low-Carbohydrate Diet on Blood Glucose Control in People With Type 2 Diabetes

Mary C. Gannon
Sep 1, 2004; 53:2375-2382
Pathophysiology




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From the Triumvirate to the Ominous Octet: A New Paradigm for the Treatment of Type 2 Diabetes Mellitus

Ralph A. DeFronzo
Apr 1, 2009; 58:773-795
Banting Lecture




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Correction: Comparative structure-function analysis of bromodomain and extraterminal motif (BET) proteins in a gene-complementation system. [Additions and Corrections]

VOLUME 295 (2020) PAGES 1898–1914Yichen Zhong's name was misspelled. The correct spelling is shown above.




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Correction: Rational design, synthesis, and evaluation of uncharged, “smart” bis-oxime antidotes of organophosphate-inhibited human acetylcholinesterase. [Additions and Corrections]

VOLUME 295 (2020) PAGES 4079–4092There was an error in the abstract. “The pyridinium cation hampers uptake of OPs into the central nervous system (CNS)” should read as “The pyridinium cation hampers uptake into the central nervous system (CNS).”




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Bumgarner not a fan of the opener strategy

Madison Bumgarner has made it known he's not a fan of the "opener," a strategy of utilizing a pitcher -- usually a reliever -- to get the first few outs of a game before bringing in a pitcher who would usually start or pitch long relief.




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Widening the drug trial net has the potential to reduce respiratory failure




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Supervised physiotherapy for mild or moderate ankle sprain




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Don’t Overstretch on Regional Integration

12 June 2019

Hans Kundnani

Senior Research Fellow, Europe Programme
How the European Union took the idea of a ‘rules-based order’ too far – and how it can regain legitimacy.

Young woman at the March for Europe in May 2018

Young woman at the March for Europe in May 2018. Photo by Emanuele Cremaschi/Getty Images

The European Union is the ultimate ‘rules-based order’. Since the end of the Cold War, the world has become increasingly integrated, in a process that Dani Rodrik has called ‘hyper-globalization’ to distinguish this from the more moderate form of globalization that occurred during the Cold War period.

But Europe, which was already more integrated than the rest of the world, has gone even further in removing barriers to the internal movement of capital, goods and people. The consequence of this has been the need for a more developed system of rules to govern this deep integration.

For much of this period, many Europeans – and also many outside Europe who had a liberal view of international politics – believed that the EU was a kind of blueprint for global governance.

They believed that the rest of the world would simply catch up with the enlightened and apparently successful approach that Europeans had taken. In short, Europeans were showing the way forward for the world.

However, after a decade of crisis, it now seems as if Europe may have overreached. In particular with the creation of the single currency, European rules increasingly extended into areas of life in which member states had previously had relative autonomy.

Since the beginning of the euro crisis in 2010, there has been a backlash against EU rules, which has raised the difficult question of whether international rule-making can go too far.

What makes international rules problematic is that they depoliticize – that is, they take the policy areas they cover out of the realm of democratic contestation. This can be a good thing when applied to policy areas that we think should be non-negotiable, like human rights.

But since the 1980s, and especially since the end of the Cold War, international rules have increasingly applied to areas of policy that not only should be contested but that should be at the centre of contestation – in particular, economic policy areas that have distributional consequences (that is, they create winners and losers).

The EU’s rules constrain its member states even more than global rules – for example, those of the World Trade Organization (WTO) – or rules associated with other regional integration projects constrain nation states elsewhere in the world. In particular, the EU’s fiscal rules – created along with the euro – set strict limits on the ability of member states to run budget deficits and accumulate debt.

Since the beginning of the euro crisis, these fiscal rules have been further tightened, which in turn has magnified the political backlash against the EU system and fuelled tensions between member states.

In democratic nation states, rules are made through a process that gives them what is sometimes called ‘input legitimacy’. International rule-making, by contrast, is essentially the product of power relations between states and therefore lacks this specific kind of legitimacy.

Supporters of European integration as currently constituted – whom one might term ‘pro-Europeans’ – would argue that EU rules are more like domestic rules than international rules: after all, they are agreed through a process involving democratic institutions such as the European Parliament. But even within the EU, power matters – as notably illustrated by Germany’s prominent (and controversial) role in driving the development of fiscal rules since the beginning of the euro crisis.

In addition, because European integration is meant to be an irreversible process, it is extremely difficult to change or abolish rules that have already been agreed. To do so would be ‘disintegration’ in the sense that powers would be returned to member states.

For example, there are good economic and political arguments for abolishing the ‘debt brake’, based on a German model, that EU member states agreed to incorporate into their national constitutions as part of the Fiscal Compact in 2011. But anyone making those arguments is labelled as Eurosceptic or ‘anti-European’.

There is also insufficient differentiation between EU rules. Any decision taken at a European level – even those decisions, such as on the Fiscal Compact, that are outside the EU treaties – becomes part of the EU’s system of rules. To challenge such a decision is therefore to violate the rule of law and therefore the EU’s ‘values’.

As Dieter Grimm has shown, legislation that would normally have the status of secondary law in a nation state has constitutional status in EU law and is therefore ‘immunized against political correction’.[1]

Though European leaders still often speak of the EU as a model for the rest of the world, the reality is that it now illustrates what other regional integration projects should avoid as much as what they should emulate. Even before the euro crisis, few other regions were thinking of creating a common currency.

But they will now think even more carefully about how far to follow Europe down the route of economic integration it has taken – and in particular will be unlikely to introduce EU-style fiscal rules.

The difficult question is where exactly the limits of international rule-making should be set. The European experience in the past decade suggests that rules on economic policy are particularly problematic because of the distributional consequences they have.

But European integration focused on economic policy from its beginnings with the European Coal and Steel Community in the 1950s. Moreover, because globalization is to a large extent an economic phenomenon, economic policy is precisely where international rules are needed.

A good place to start in thinking about where to set the limits of international rule-making may be in terms of the objectives of rules. During the early phase of European integration and the more moderate phase of globalization in the 30 years after the end of the Second World War, integration strengthened nation states – indeed, Alan Milward argued that integration ‘rescued’ the nation state in Europe.[2]

But since the end of the Cold War, rules at both the global level and a European level have been driven by the maximization of economic efficiency. This has undermined the nation state. As Rodrik has argued, a reprioritization is now needed – rules should be made above all with their impact on democracy in mind.[3]

In order to regain legitimacy, Europe should apply this idea of democracy-enhancing rules to its own approach to integration. It should begin by differentiating more clearly between rules that are fundamental to the European project and those about which Europeans can – and should – disagree.

The consequence of thinking of rules above all in terms of legitimacy may be that in some policy areas, particularly those with distributive consequences, rules should be abolished and power returned to member states.

‘Pro-Europeans’ should be open to this kind of ‘disintegration’ as a way to help the EU regain legitimacy and thus be sustainable in the medium term. It is also only by successfully recalibrating the balance between rules and democracy that the EU will once again be seen as a model for regional integration projects in the rest of the world, and for global governance more generally.

What needs to happen

  • The EU offers a cautionary tale on the limits of regional integration, with its status as a model for international governance eroded by a decade of crisis.
  • In certain areas, notably fiscal policy, democratically contested decision-making has been subordinated to ‘depoliticized’ supranational rules. The crisis over the single currency exemplifies the tensions between autonomy and integration.
  • To restore its legitimacy, the EU needs to recalibrate the balance between rules and democracy. Policymakers should ensure that laws are made with their impact on democracy in mind.
  • Politicians and policymakers should differentiate more clearly between rules that are fundamental to the European project and those about which Europeans can – and should – disagree.
  • In some policy areas, this could include returning powers to member states. Though politically challenging, this will require ‘pro-Europeans’ to tolerate some ‘disintegration’ as the price of ensuring the future stability of the EU.

Notes

[1] Grimm, D. (2015), ‘The Democratic Costs of Constitutionalisation: The European Case’, European Law Journal, Volume 21, Issue 4, July 2015, https://onlinelibrary.wiley.com/doi/abs/10.1111/eulj.12139.

[2] Milward, A. (1999), The European Rescue of the Nation State, London: Routledge.

[3] Rodrik, D. (2006), ‘Put Globalization to Work for Democracies’, New York Times, 17 September 2006, https://www.nytimes.com/2016/09/18/opinion/sunday/put-globalization-to-work-for-democracies.html.

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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Taking Inspiration From Kofi Annan

31 May 2019

Robin Niblett

Director and Chief Executive, Chatham House
Robin Niblett reflects on the legacy of the former UN secretary-general and what current leaders can learn from his example.

2019-05-31-Annan.jpg

Kofi Annan in 2017. Photo: Getty Images.

On 3 and 4 June, Chatham House will host a major conference in partnership with the UN Association (UK), supported by the Bill and Melinda Gates and Open Society Foundations, to reflect on the lessons learned from the remarkable life of Kofi Annan, who served as UN secretary-general from 1997 to 2006 and passed away almost a year ago, on 18 August 2018.

The conference will fall on the same days as Donald Trump’s state visit to the United Kingdom, which, though unplanned, brings into stark relief the ways in which current changes in international relations are affecting Kofi Annan’s legacy of UN-led multilateralism that Ban Ki-moon and now Antonio Guterres have carried forward.

A vision of multilateral governance

Kofi Annan advocated a vision of multilateral governance anchored in shared responsibility for global challenges and in promoting the rights and dignity of the individual. He placed the importance of individual freedom and justice alongside the global challenges of poverty and health. The launch of the Millennium Development Goals (MDGs) and the UN Global Fund on HIV/Aids, which brought together both strands of his approach to global governance, stand among his landmark contributions to international affairs.

Kofi Annan’s time as secretary-general also saw him involved in managing numerous crises. The 2003 US-led military intervention in Iraq raised acute questions about the purpose and future of the UN Security Council. The aftermath of the conflict also exposed serious failings in the broader UN system under his leadership.

It was to his credit that he leveraged the investigation into the corruption surrounding the UN’s 1995–2003 ‘oil-for-food’ programme in order to introduce procedures for greater scrutiny over UN financial programmes and personnel appointments. In 2000, he set up and then took on board the criticisms of the Brahimi Report into the failed UN peacekeeping operations in Rwanda and Srebrenica during his tenure as undersecretary-general for peacekeeping.

Global governance on the defensive

One can look back at Kofi Annan’s term as UN secretary-general as a period when ideas for how to improve global governance were in the ascendant, despite the persistence of civil wars and interstate disputes. Today, the persistence of long-standing conflicts and growing competition between the world’s major powers appear to be overwhelming the global agenda, putting ideas for global governance on the defensive.

America’s purposeful disengagement from and disruption of the multilateral institutions that it helped establish during the 20th century is a major factor in this shift. The principal difference with the Cold War is that China’s rise might divide America from its allies rather than unite them. 

China has become embedded in the global economy that America championed, creating new webs of interdependence. On the other hand, China is promoting a system of domestic and international governance that gives primacy to the state over the rights of the individual. In recent years, China has not only supported the world’s most repressive regimes, like North Korea, Venezuela and Zimbabwe, but also corrupt and opaque practices in countries in southeast Asia and Africa. And it is offering new digital surveillance tools that leaders in these countries can use to suppress popular dissent.

Despite concerns over its direction, most states around the world continue to engage China, even US allies in Europe and Asia. America, however, has decided to challenge it. With the world’s two most powerful states in confrontation, and Russia happy to play a disruptive role in between, there is little scope for state-led multilateralism to regain its momentum.

This rise of a more competitive international system has had a negative effect on Kofi Annan’s legacy, eroding some of its highlights, such as expectations for Responsibility to Protect, and weakening multilateralism and respect for human rights in general.

The question for the future is whether Annan’s successors can build on the more radical, transformative aspects of his tenure and bypass this state-led confrontation. The shift from the MDGs to the Sustainable Development Goals (SDGs) could prove critical in this respect.

A more inclusive approach to complex problem-solving

In order to have a chance of achieving the SDGs, the world needs to deploy a more inclusive approach to complex problem-solving of the sort that Kofi Annan promoted with his Global Compact. Bringing the private sector and civil society proactively into multilateral responses offers the only prospect to end poverty and reduce inequality, build sustainable cities, and shift to responsible production and consumption, along with the other SDGs.

A more inclusive approach also means giving a greater sense of agency to individuals, who can now mobilize digitally and engage in responding to global challenges, such as creating more energy-efficient and climate-friendly lifestyles, with minimal government support. Annan was a pioneer of this more bottom-up approach to development and rights issues after leaving the UN, through his work on youth leadership against violent extremism and on transforming agriculture in Africa.

Thinking of systemic change as a more societal rather than government-led process demands leaders capable of mobilizing mass individual action towards public policy goals, as reflected, for example, in Secretary-General Guterres’ High Level Panel on Digital Cooperation.

The fact that Kofi Annan was dubbed by some ‘the secular pope’ points to people’s search for leadership towards shared global challenges that goes beyond what can be achieved by national action alone. If an important part of his legacy is the idea of more inclusive forms of global governance, then Kofi Annan has provided an essential starting point for the debates that will accompany the UN’s upcoming 75th anniversary.




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Democratize Trade Policymaking to Better Protect Human Rights

12 June 2019

Dr Jennifer Ann Zerk

Associate Fellow, International Law Programme
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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Sovereignty and Non-Intervention: The Application of International Law to State Cyberattacks

Research Event

4 December 2019 - 5:30pm to 7:00pm

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

Event participants

Douglas, Legal Director, GCHQ
Zhixiong Huang, Luojia Chair of International Law, Wuhan University
Nemanja Malisevic, Director of Digital Diplomacy, Microsoft
Harriet Moynihan, Associate Fellow, International Law Programme, Chatham House
Chair: Elizabeth Wilmshurst, Distinguished Fellow, International Law Programme, Chatham House

International law applies to cyber operations – but views differ on exactly how. Does state-sponsored interference in another state's affairs using cyber means – for example,  disinformation campaigns in elections, disabling government websites, or disrupting transport systems – breach international law? If so, on what basis and how are the principles of sovereignty and non-intervention relevant? States are increasingly attributing cyber operations to other states and engaging in the debate on how international law applies, including circumstances that would justify countermeasures.

As states meet to debate these issues at the UN, the panel will explore how international law regulates cyberoperations by states, consider the prospects of progress at the UN, and assess the value of other initiatives.

This event coincides with the launch of a Chatham House research paper which analyses how the principles of sovereignty and intervention apply in the context of cyberoperations, and considers a way forward for agreeing a common understanding of cyber norms.

This event will bring together a broad group of actors, including policymakers, the private sector, legal experts and civil society, and will be followed by a drinks reception.

 

Jacqueline Rowe

Programme Assistant, International Law Programme
020 7389 3287




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The Application of International Law to State Cyberattacks: Sovereignty and Non-Intervention

2 December 2019

Hostile cyber operations by one state against another state are increasingly common. This paper analyzes the application of the sovereignty and non-intervention principles in relation to states’ cyber operations in another state below the threshold of the use of force. 

Harriet Moynihan

Senior Research Fellow, International Law Programme

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A computer hacked by a virus known as Petya. The Petya ransomware cyberattack hit computers of Russian and Ukrainian companies on 27 June 2017. Photo: Getty Images.

Summary

  • The vast majority of state-to-state cyberattacks consist of persistent, low-level intrusions that take place below the threshold of use of force. International law, including the principle of non-intervention in another state’s internal affairs and the principle of sovereignty, applies to these cyber operations.
  • It is not clear whether any unauthorized cyber intrusion would violate the target state’s sovereignty, or whether there is a threshold in operation. While some would like to set limits by reference to effects of the cyber activity, at this time such limits are not reflected in customary international law. The assessment of whether sovereignty has been violated therefore has to be made on a case by case basis, if no other more specific rules of international law apply.
  • In due course, further state practice and opinio iuris may give rise to an emerging cyber-specific understanding of sovereignty, just as specific rules deriving from the sovereignty principle have crystallized in other areas of international law.
  • Before a principle of due diligence can be invoked in the cyber context, further work is needed by states to agree upon rules as to what might be expected of a state in this context.
  • The principle of non-intervention applies to a state’s cyber operations as it does to other state activities. It consists of coercive behaviour by one state that deprives the target state of its free will in relation to the exercise of its sovereign functions in order to compel an outcome in, or conduct with respect to, a matter reserved to the target state.
  • In practice, activities that contravene the non-intervention principle and activities that violates sovereignty will often overlap.
  • In order to reach agreement on how international law applies to states’ cyber operations below the level of use of force, states should put their views on record, where possible giving examples of when they consider that an obligation may be breached, as states such as the UK, Australia, France and the Netherlands have done.
  • Further discussion between states should focus on how the rules apply to practical examples of state-sponsored cyber operations. There is likely to be more commonality about specific applications of the law than there is about abstract principles.
  • The prospects of a general treaty in this area are still far off. In due course, there may be benefit in considering limited rules, for example on due diligence and a prohibition on attacking critical infrastructure, before tackling broad principles.




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US–China Strategic Competition: The Quest for Global Technological Leadership

7 November 2019

The current dispute between the US and China goes far beyond trade tariffs and tit-for-tat reprisals: the underlying driver is a race for global technological supremacy. This paper examines the risks of greater strategic competition as well as potential solutions for mitigating the impacts of the US–China economic confrontation.

Marianne Schneider-Petsinger

Senior Research Fellow, US and the Americas Programme

Dr Jue Wang

Associate Fellow, Asia-Pacific Programme (based in Holland)

Dr Yu Jie

Senior Research Fellow on China, Asia-Pacific Programme

James Crabtree

Associate Fellow, Asia-Pacific Programme

Video: Marianne Schneider-Petsinger and Dr Yu Jie discuss key themes from the research paper

Summary

  • The underlying driver of the ongoing US–China trade war is a race for global technological dominance. President Trump has raised a number of issues regarding trade with China – including the US’s trade deficit with China and the naming of China as a currency manipulator. But at the heart of the ongoing tariff escalation are China’s policies and practices regarding forced technology transfer, intellectual property theft and non-market distortions.
  • As China’s international influence has expanded it has always been unlikely that Beijing would continue to accept existing global standards and institutions established and widely practised by developed countries based on ‘the Washington Consensus’.
  • China’s desire to be an alternative champion of technology standard-setting remains unfulfilled. Its ample innovation talent is a solid foundation in its quest for global technology supremacy but tightening controls over personal freedoms could undermine it and deter potential global partners.
  • It is unclear if Chinese government interventions will achieve the technological self-sufficiency Beijing has long desired. China’s approach to macroeconomic management diverges significantly from that of the US and other real market economies, particularly in its policy towards nurturing innovation.
  • Chinese actors are engaged in the globalization of technological innovation through exports and imports of high-tech goods and services; cross-border investments in technology companies and research and development (R&D) activities; cross-border R&D collaboration; and international techno-scientific research collaboration.
  • While the Chinese state pushes domestic companies and research institutes to engage in the globalization of technological innovation, its interventions in the high-tech sector have caused uneasiness in the West.
  • The current US response to its competition with China for technological supremacy, which leans towards decoupling, is unlikely to prove successful. The US has better chances of success if it focuses on America’s own competitiveness, works on common approaches to technology policy with like-minded partners around the globe and strengthens the international trading system.
  • A technically sound screening mechanism of foreign investment can prevent normal cross-border collaboration in technological innovation from being misused by geopolitical rival superpowers.




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The Morass of Central American Migration: Dynamics, Dilemmas and Policy Alternatives

Invitation Only Research Event

22 November 2019 - 8:15am to 9:30am

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

Event participants

Anita Isaacs, Professor of Political Science, Haverford College; Co-Director, Migration Encounters Project
Juan Ricardo Ortega, Principal Advisor for Central America, Inter-American Development Bank
Chair: Amy Pope, Associate Fellow, Chatham House; US Deputy Homeland Security Adviser for the Obama Administration (2015-17)

2019 has seen a record number of people migrating from Central America’s Northern Triangle – an area that covers El Salvador, Guatemala and Honduras. Estimates from June 2019 have placed the number of migrants at nearly double of what they were in 2018 with the increase in numbers stemming from a lack of economic opportunity combined with a rise in crime and insecurity in the region. The impacts of migration can already be felt within the affected states as the exodus has played a significant role in weakening labour markets and contributing to a ‘brain drain’ in the region. It has also played an increasingly active role in the upcoming US presidential election with some calling for more security on the border to curb immigration while others argue that a more effective strategy is needed to address the sources of migration. 

What are the core causes of Central American migration and how have the US, Central American and now also Mexican governments facilitated and deterred migration from the region? Can institutions be strengthened to alleviate the causes of migration? And what possible policy alternatives and solutions are there that could alleviate the pressures individuals and communities feel to migrate?   

Anita Isaacs, professor of Political Science at Haverford College and co-director of the Migration Encounters Project, and Juan Ricard Ortega, principal advisor for Central America at the Inter-American Development Bank, will join us for a discussion on the core drivers of migration within and across Central America.

Attendance at this event is by invitation only. 

Event attributes

Chatham House Rule

Department/project

US and Americas Programme




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US 2020: America’s National Security Strategy and Middle East Policy

Invitation Only Research Event

10 February 2020 - 10:30am to 11:30am

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

Event participants

Dr Kori Schake, Resident Scholar and Director of Foreign and Defense Policy Studies, American Enterprise Institute 
Chair: Dr Leslie Vinjamuri, Director, US and Americas Programme

In the run-up to the 2016 US presidential election, then-candidate Donald Trump made a series of campaign promises concerning US foreign policy towards the Middle East. Since assuming office, President Trump has withdrawn the US from the Joint Comprehensive Plan of Action, withdrawn troops from Syria, relocated the US embassy in Israel to Jerusalem and orchestrated the strike against ISIS leader Abu Bakr al-Baghdadi.

Against a backdrop of Trump's inclination towards withdrawing from the region, countries across the Middle East are being rocked by protests, Turkey’s purchase of Russia’s S-400 missile has threatened to undermine cohesion within NATO and the much hoped for ceasefire in Libya between UN-backed government leader, Fayez al-Sarraj, and opposition leader, Khalifa Haftar, failed to materialize.

In light of the upcoming US elections in November 2020, the future of US national security policy promises to be a prominent issue for the next administration. In this vein, the US and Americas Programme at Chatham House plans a yearlong focus on the pivotal US 2020 elections.

At this event, Dr Kori Schake, director of foreign and defense policy studies at the American Enterprise Institute will discuss the future of US foreign policy towards the Middle East. How have domestic and party politics in the US – and the unfolding presidential campaign – shaped recent policy decisions by the Trump administration? Should we expect policy objectives in the Middle East to remain consistent or shift under a second Trump term? And what direction could US foreign policy towards the region take under a Democratic administration?

Attendance at this event is by invitation only. 

Event attributes

Chatham House Rule

Department/project

US and Americas Programme




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Democrats Have Set Themselves Up to Fail in November's Election

21 February 2020

Dr Lindsay Newman

Senior Research Fellow, US and the Americas Programme
Debates and caucuses are proving that the party took the wrong lesson from the midterms. They're now applying that lesson to 2020 with potentially disastrous results.

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2020 Democratic presidential candidates at the debate in Las Vegas on 19 February. Photo: Getty Images.

The Democratic Party’s struggle for its future policy direction is evident this election season. The primary results in Iowa and New Hampshire, narrow first- and second-place finishes for Senator Bernie Sanders (a progressive) and former South Bend mayor Pete Buttigieg (a moderate), were just two indicators. During Wednesday night’s debate in Las Vegas, the split became even more obvious.

The six candidates onstage clashed on ideology (socialism and capitalism, progressivism and centrism) as well as policy (healthcare, climate change, fossil fuels, criminal justice, China). Buttigieg made plain the stakes for Democrats, saying, 'We’ve got to wake up as a party.'

If a Democratic candidate is elected to be the United States’ 46th president on 3 November, it will be despite this unresolved intra-party struggle.

One lesson the Democratic Party has taken from the 2018 midterm elections is that running candidates across the ideological spectrum is a winning formula.

It is easy to see how they came to this conclusion following the 2016 presidential and 2018 Congressional election experiences. In 2016, the favoured candidate status of former secretary of state Hillary Clinton deterred other aspirants from entering the Democratic primary ahead of a general election she went on to lose to Republican Donald Trump. In 2018, progressive and moderate centrist candidates, both first-timers and incumbents, ran and Democrats retook leadership in the House of Representatives with a 235-seat majority.

But what if this conclusion was noise and not the signal?

The Democratic National Committee (DNC) set the rules for the 2020 election based on the theory that by allowing an inclusive field (more than two dozen candidates entered the presidential race) the campaign processes, including debates, caucuses and primaries, would ultimately identify the most robust, representative candidate to go up against Donald Trump. Perhaps, and somewhat ironically, the 2016 Republican primary process, which involved a wide field culled by Trump’s unexpected success, informed the DNC’s reforms. And while very nice as a hypothesis of Bayesian updating, what has unfolded instead is a scattershot four-way — at times even five-way — race.

In the midst of this party divide, whoever ends up being the Democratic nominee will likely not represent the views of some meaningful proportion of the Democratic base. While healthcare remains the top issue across the Democratic electorate, there are those (candidates and voters) who want a single-payer option for all without a private insurance option and those who want to expand healthcare access while maintaining private insurers. Likewise, on foreign policy, there are those who link US trade policy with protecting American workers and who would therefore continue to use tariffs as a key trade policy, as well as those critical of Trump’s reliance on tariffs.

Compare that with the current state of the Republican Party. Trump’s approval with Republicans is in the high 80s, sometimes even low 90s, and after all but one Republican senator voted to acquit him in the Senate impeachment trial, the party is undeniably Trump’s. A sure sign is the historic turnout for Trump in his essentially uncontested Iowa and New Hampshire primaries.

Their own divisions pose a number of risks, then, for Democrats heading into November’s general election. The first one relates to vulnerabilities arising out of the primary process itself. If the fractures emerging from Iowa and New Hampshire persist, the likelihood of a quick wrap-up of the Democratic primary by April reduces, and the possibility of a contested Democratic convention in July increases (even if from a low base). While exciting television and Twitter fodder, a lengthy primary positions Democrats to go into the fall facing questions of party disunity behind the eventual nominee.

Although complicated to demonstrate empirically, some work has been done to understand whether the protracted 2016 Democratic primary and Sanders’ slow support for Democratic nominee Clinton in 2016 played a part in her defeat and Trump’s electoral success. A delayed general election campaign for the eventual Democratic nominee in 2020 almost certainly advantages President Trump’s money machine, which reportedly has more than twice as much on hand as then-president Barack Obama had going into his 2012 re-election. Further, unlike 2016, which was an open-seat election for the presidency, in 2020 Trump will have a demonstrated incumbent advantage.

The Democratic Party’s succession battle also raises risks around general election turnout. If Sanders is the party’s nominee, Biden or Buttigieg’s constituency may not come out to vote for him. More worrisome for Democrats, if Sanders is the party’s nominee then centrist voters, including those representing the finance industry, may peel off and vote for Trump, who has overseen economic expansion and record unemployment rates following the 2017 tax overhaul and various deregulations.

Alternatively, if Biden, Buttigieg or former mayor Michael Bloomberg become the nominee, Sanders’ many loyal supporters are likely to feel their policy priorities are not represented. And if those voters stay home because the Democratic nominee is not promising a political revolution, evidence suggests that depressed turnout levels may favour Republicans.

A third political peril relates to the business of legislating after the election. If despite the potential pitfalls a Democratic candidate manoeuvres and manages to build a winning coalition on 3 November, they will face the reality of legislative politics, which over the last 10 years have been defined by policy gridlock. Obama managed to get Obamacare through both Democratic-majority congressional chambers, but presided over divided chambers for the remainder of his term. Similarly, Trump’s major legislative accomplishment — the 2017 tax overhaul — was a result of Republican control in both the House of Representatives and the Senate.

A Democratic president will have to make progress on his or her agenda given not only the typical Republican-Democrat divide in Congress, but also facing potential raw divisions within the Democratic Party itself. In such a scenario, a Democratic administration may be tempted to take an expansive view of the president’s authority as we have seen under Trump, including relying on executive actions (tariffs and sanctions) on foreign policy.

The Democratic National Convention in Milwaukee, Wisconsin, beginning 13 July, and the party platform crafted over those four days present an essential opportunity to resolve the party’s divisions before November. If left unchecked, the party might find that its ex ante strategy for the 2020 Democratic primary ends in Trump’s re-election.

This article was originally published in the Independent.




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Coronavirus in Latin America and Mexico: Infection Rates, Immigration and Policy Responses

Invitation Only Research Event

25 March 2020 - 4:00pm to 5:00pm

Event participants

Jude Webber, Mexico and Central America Correspondent, Financial Times
Michael Stott, Latin America Editor, Financial Times
Chair: Dr Christopher Sabatini, Senior Research Fellow for Latin America, US and the Americas Programme, Chatham House

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

US and Americas Programme




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Webinar: COVID-19 and the Impact on Latin American Migration

Research Event

14 May 2020 - 3:00pm to 4:00pm
Add to Calendar

Ambassador Arturo Sarukhan, Associate Fellow, US and the Americas Programme, Chatham House; Mexican Ambassador to the US, 2007 - 13
Professor Anita Isaacs, Benjamin R. Collins Professor of Social Sciences, Haverford College
Chair: Dr Christopher Sabatini, Senior Research Fellow for Latin America, US and the Americas Programme, Chatham House

The US government recently announced restrictions on immigration, stating the new measures were necessary due to COVID-19 and the effect the pandemic has had on the US economy. But what is the role of immigrants in the essential official and unofficial services in the COVID-19 stay-at-home era? How is COVID-19 affecting immigration from Central America and Mexico? 

Separately, there have also been instances of outbreaks among detainees in US Immigration and Customs Enforcement centers and claims that immigrants who are returning to Guatemala are spreading the virus. How have US immigration policies affected infection rates in Central America and Mexico and among its citizens?

Arturo Sarukhan, Mexican Ambassador to the US from 2007 - 13, and Anita Isaacs, Benjamin R. Collins Professor of Social Sciences, Haverford College, will join us to discuss the impact COVID-19 is having on migrants.

Chatham House would like to thank BTG Pactual, Cairn Energy plc, Diageo plc, Equinor, Fresnillo Management Services, HSBC Holdings plc and Wintershall Dea for their generous support of the Latin America Initiative.

This event is scheduled to take place from 15:00 – 16:00 BST.

US and Americas Programme




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Diabetes Core Update: Covid-19 and Diabetes – Considerations for Health Care Professionals - April 2019

Diabetes Core Update: Covid-19 and Diabetes – Considerations for Health Care Professionals - April 2019

This special issue is an audio version of the American Diabetes Associations Covid-19 leadership team discussing a range of issues on Covid-19 and Diabetes.

Recorded March 31, 2020.

Topics include:

  1. Access to medications
  2. Effect on Diabetes Self-management
  3. Can Patients take their own Supplies if they are an inpatient in the hospital – particularly insulin pumps and CGM
  4. Considerations for Specific Hypoglycemic Medications during Inpatient Hospitalization
  5. Differences in Management for Persons with Type 1 and Type 2 Diabetes
  6. SGLT-2 inhibitors and GLP-1 Receptor Agonists use During Covid-19 Infection
  7. Diabetes and Cardiovascular Disease during Covid-19
  8. ACEs and ARBs
  9. Stress among Healthcare Professionals

Intended for practicing physicians and health care professionals, Diabetes Core Update discusses how the latest research and information published in journals of the American Diabetes Association are relevant to clinical practice and can be applied in a treatment setting.

Presented by:

Robert Eckel, MD
ADA President, Medicine & Science
University of Colorado

Mary de Groot, PhD
ADA President, Health Care & Education
Indiana University

Irl Hirsch, MD
University of Washington

Anne Peters, MD
University of Southern California    

Louis Philipson, MD, PhD
ADA Past President, Medicine & Science
University of Chicago

Neil Skolnik, MD
Abington Jefferson Health




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More changes announced to court operations

Additional changes have been made to the operations of the island's courts in light of COVID-19. Changes below: Criminal Cases All hearings in the Home Circuit Court Division of the Gun Court, the High Court Division of the Gun Court, the...




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The Changing Nature of Russia’s Military Strategy and Its Tactical Application

Invitation Only Research Event

12 November 2019 - 4:00pm to 5:30pm

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

Event participants

Oscar Jonsson, Director, Stockholm Free World Forum (Frivärld)
Mathieu Boulègue, Research Fellow, Russia and Eurasia Programme, Chatham House
Chair: ​Alice Billon-Galland, Research Associate, Europe Programme, Chatham House

Russia’s military strategy is increasingly blurring the boundaries between war and peace. As the nature of warfare changes, the Kremlin is adapting its strategies to pursue conflict, especially through non-military means - below the threshold of armed violence. 

Russian military tactics are often mistaken for strategy in the West. Oscar Jonson, author of The Russian Understanding of War, will talk through this debate and explore how the Russian leadership now understands military strategy in the context of modern warfare. Mathieu Boulègue will address the more operational aspects of contemporary warfare for Russia, notably grey zone operations. 

Department/project

Anna Morgan

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




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Corporate Raiding in Russia, Ukraine and Kazakhstan

Invitation Only Research Event

5 November 2019 - 9:00am to 1:00pm

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

Event participants

John Patton, Argentem Creek
Rachel Cook, Peters & Peters
Tom Mayne, University of Exeter
Olga Bischof, Brown Rudnick LLP
Isobel Koshiw, Global Witness
Anton Moiseienko, RUSI

The widespread practice of illicit acquisition of a business or part of a business in the former Soviet states, known as ‘reiderstvo’ or asset-grabbing, is a major risk that disincentivises investment in the region.

It is distinct from the way corporate raiding occurs in the West and enabled by factors such as corruption and weak protection of property rights.

This roundtable will assess the practice of corporate raiding in Russia, Ukraine and Kazakhstan: its evolution over time, knock-on effects and potential solutions. The speakers will also address the implications for the UK legal system and possible policy responses.

Event attributes

Chatham House Rule

Department/project

Anna Morgan

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




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Integration on Hold for Russia and Belarus

14 January 2020

John Lough

Associate Fellow, Russia and Eurasia Programme

Katia Glod

Academy Robert Bosch Fellow (2012)
Despite intense efforts by the two governments to finalize plans for deeper integration between the countries, agreement remains elusive.

2020-01-14-BelRus.jpg

Vladimir Putin and Alexander Lukashenka at a Collective Security Treaty Organization meeting in Kyrgyzstan in November 2019. Photo: Getty Images.

Two December meetings between Presidents Vladimir Putin and Alexander Lukashenka failed to deliver Moscow’s hopes of securing Minsk’s acceptance of closer alignment between Russia and Belarus.

Over the past year, relations between Belarus and Russia have been under unprecedented strain as Moscow has tried to encourage Minsk to sign up to a different format of relations designed to keep Belarus firmly in a Russian orbit. Details of the negotiations have remained secret, yet issues on the table appear to include unification of tax and customs systems, a common energy regulator and joint governing bodies.

The Kremlin believes that Belarus needs to deliver more in return for Russia’s continued economic support, worth around $10 billion per year. In December 2018, it issued an ultimatum: Belarus would only continue to receive a discounted price for oil and gas and enjoy preferential access to the Russian market if it agreed to reanimate the largely dormant 1999 Union Treaty that called for the unification of Belarus with Russia.

During 2019, frantic work took place on both sides to prepare a detailed framework for achieving deeper integration between the two countries. This did not succeed in overcoming a set of long-standing issues related to economic relations.

To step up pressure, the Russian prime minister, Dmitri Medvedev, signalled in early December that Russia would withhold economic privileges for Belarus pending full implementation of 30 integration road maps that he claimed had already been agreed. To the alarm of Minsk, he also suggested that discussion of a 31st roadmap would follow to include the creation of a single currency and supranational institutions. The Belarusian authorities view this level of integration as a threat to national sovereignty.

On the surface, Belarus’ negotiating position is weak. By resisting market reforms that could have diversified imports and exports, Lukashenka has instead kept the economy tied to Russia; 40% of Belarusian exports go to Russia. In addition, Russia has decreased its reliance on imports from Belarus as part of a broad policy of import substitution.

Raising the gas price will deprive Belarusian companies of their comparative advantage.  Approximately 90% of Belarus’s electricity and heat is generated by natural gas imported from Russia at below market prices. Petroleum products refined from Russian crude oil that is supplied duty-free to Belarus account for the largest source of the country’s export earnings.

Minsk fears that the current oil taxation reform in Russia could cause Belarus losses of up to $9 billion by 2024 as a result of higher prices for Russian oil and the loss of export duties. Economic growth slowed from 3% in 2018 to just over 1% in 2019 and could fall further if Russia does not grant concessions on the oil price.

The country’s high level of public debt denominated in foreign currency makes the need to find cash more urgent and exacerbates the Russian pressure. Russia is Belarus’ biggest creditor, accounting for 38% of state debt.

However, Lukashenka is a master of negotiation with the Kremlin, with a talent for turning weakness into strength.

First, by eliminating political competition in Belarus, he has given Putin no option but to deal with him personally. Second, he understands that Moscow needs to present integration between the two countries as voluntary and does not want to use economic sanctions or other tools of persuasion that could destabilize Belarus. Third, he knows that there is no consensus in Moscow on creating a single currency. Unification of the tax systems would also be problematic because of their different structures. If these measures were implemented, Moscow could end up paying much larger subsidies to keep Belarus stable.

Minsk is therefore likely to pursue three options: dragging out the negotiations with Moscow, while continuing to declare its commitment to closer union with Russia; seeking alternative sources of energy and credits; and reforming the economy to lower its dependency on Russia.

Although Lukashenka is mindful of potential risks and threats to his power from economic liberalization, he is open to changes in some areas, such as further developing the successful IT sector, privatising non-strategic state-owned enterprises and increasing trade with EU countries.

These reforms will most likely continue, although this year’s presidential election may distract attention, as Lukashenka seeks a sixth term in the knowledge that his popularity is falling. He may also need to divert some economic resources to maintain the support of his core electorate.

For the moment, Moscow does not appear to be in a hurry, believing that Lukashenka and Belarus are going nowhere and that concessions by Minsk are only a matter of time.




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Virtual Roundtable: Re-integration or Dis-integration: What Does the Future Hold for Occupied Donbas?

Invitation Only Research Event

28 April 2020 - 4:00pm to 5:30pm

Event participants

Paul D’anieri, Professor of Public Policy and Political Science, University of California, Riverside
Vlad Mykhnenko, Associate Professor of Sustainable Urban Development, St Peter’s College, University of Oxford
Chair: Orysia Lutsevych, Research Fellow and Manager, Ukraine Forum, Chatham House

The armed conflict in Donbas has now entered its seventh year. President Zelenskyy, who came to power in May 2019, promised to end the war with Russia and bring peace to Ukraine.

Since assuming office, Zelenskyy has managed to revive the Normandy Format talks, complete military disengagement at three points along the line of contact and negotiate the release of over a hundred Ukrainians held as prisoners of war in Russia. However, ceasefire violations continue to occur frequently.

Looking at the origins of the armed conflict in Donbas and the region’s economic role in Ukraine’s economy, this event discusses the prospects for conflict resolution. Do the recent events signify an opportunity for peace? Does Zelenskyy have a viable plan for re-integrating Donbas or will the region be cut off from mainland Ukraine for the foreseeable future?

The speakers assess the strategy and track record of the Ukrainian government and its Western allies in bringing parts of the occupied Donbas under Kyiv’s control. They also review possible policy implications of the COVID-19 pandemic for the conflict.

Anna Morgan

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




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

Invitation Only Research Event

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

Anna Morgan

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

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Tonga Energy Road Map: Energy Security, the Aid Paradigm, and Pacific Geostrategy

Research Event

3 June 2013 - 2:00pm to 4:00pm

Chatham House, London

Event participants

Lord Tu'ivakano, Prime Minister of the Kingdom of Tonga

Lord Tu'ivakano, will deliver a keynote address on the development of the Tonga Energy Road Map (TERM), which plans for 50% of the country's energy to come from renewable energy sources by 2020. 

The Kingdom of Tonga is highly susceptible to both climate change as well as changes in global energy prices due to its high dependency on imported oil. The TERM has required both ground-breaking whole-of-sector institutional changes in Tonga as well as innovative coordination across a range of development partners, including the World Bank, ADB and the UN. Key players in the international community have closely watched the development and implementation of the TERM as it presents a complete change in the aid paradigm that is not just specific to Tonga, or the energy sector. 

Registration for this event has now closed.




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Accelerating Innovation for a Circular Economy

Invitation Only Research Event

12 July 2016 - 9:30am to 5:30pm

Chatham House, London

Over the next two decades, a combination of ‘circular economy’ approaches and distributed manufacturing methods such as 3D printing raise the prospect of fundamental changes to the nature of production, the reconfiguration of supply chains and changes to patterns of resource consumption – with profound implications for sustainability. This roundtable will bring together expert participants from companies, government, civil society and academia to discuss the state of innovation in the ‘circular economy,’ with a particular focus on the approaches and activities of entrepreneurs and investors, what is needed to scale up and accelerate innovation, how to track and measure progress, and how to ensure that innovation in the ‘circular economy’ makes a significant contribution to the meeting of short and medium term climate and sustainability goals.

Attendance at this event is by invitation only. 

Johanna Lehne

Research Associate, Energy, Environment and Resources
+44 (0)20 7314 3629




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#WeAreInThisTogether against COVID-19 - Bay-C, ListenMiNews, Red Cross collaborate on anti-stigma music video

IN AN effort to alleviate misconceptions and misinterpretations of our current COVID-19 reality, and to create the idea that human beings deserve respect, especially when they are ill, ListenMi News has collaborated with the International...




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Colin Steer | Cooperation, creativity and challenges in education amid COVID-19

Public reaction to the initial threat of the coronavirus (COVID-19) was predictably mixed. While international news of the contagion across continents helped people to appreciate that this was not restricted to a particular region, not many people...




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Serotonin Regulates Adult {beta}-Cell Mass by Stimulating Perinatal {beta}-Cell Proliferation

A sufficient β-cell mass is crucial for preventing diabetes, and perinatal β-cell proliferation is important in determining the adult β-cell mass. However, it is not yet known how perinatal β-cell proliferation is regulated. Here, we report that serotonin regulates β-cell proliferation through serotonin receptor 2B (HTR2B) in an autocrine/paracrine manner during the perinatal period. In β-cell–specific Tph1 knockout (Tph1 βKO) mice, perinatal β-cell proliferation was reduced along with the loss of serotonin production in β-cells. Adult Tph1 βKO mice exhibited glucose intolerance with decreased β-cell mass. Disruption of Htr2b in β-cells also resulted in decreased perinatal β-cell proliferation and glucose intolerance in adulthood. Growth hormone (GH) was found to induce serotonin production in β-cells through activation of STAT5 during the perinatal period. Thus, our results indicate that GH-GH receptor-STAT5-serotonin-HTR2B signaling plays a critical role in determining the β-cell mass by regulating perinatal β-cell proliferation, and defects in this pathway affect metabolic phenotypes in adults.




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HB-EGF Signaling Is Required for Glucose-Induced Pancreatic {beta}-Cell Proliferation in Rats

The molecular mechanisms of β-cell compensation to metabolic stress are poorly understood. We previously observed that nutrient-induced β-cell proliferation in rats is dependent on epidermal growth factor receptor (EGFR) signaling. The aim of this study was to determine the role of the EGFR ligand heparin-binding EGF-like growth factor (HB-EGF) in the β-cell proliferative response to glucose, a β-cell mitogen and key regulator of β-cell mass in response to increased insulin demand. We show that exposure of isolated rat and human islets to HB-EGF stimulates β-cell proliferation. In rat islets, inhibition of EGFR or HB-EGF blocks the proliferative response not only to HB-EGF but also to glucose. Furthermore, knockdown of HB-EGF in rat islets blocks β-cell proliferation in response to glucose ex vivo and in vivo in transplanted glucose-infused rats. Mechanistically, we demonstrate that HB-EGF mRNA levels are increased in β-cells in response to glucose in a carbohydrate-response element–binding protein (ChREBP)–dependent manner. In addition, chromatin immunoprecipitation studies identified ChREBP binding sites in proximity to the HB-EGF gene. Finally, inhibition of Src family kinases, known to be involved in HB-EGF processing, abrogated glucose-induced β-cell proliferation. Our findings identify a novel glucose/HB-EGF/EGFR axis implicated in β-cell compensation to increased metabolic demand.




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Pancreas Pathology of Latent Autoimmune Diabetes in Adults (LADA) in Patients and in a LADA Rat Model Compared With Type 1 Diabetes

Approximately 10% of patients with type 2 diabetes suffer from latent autoimmune diabetes in adults (LADA). This study provides a systematic assessment of the pathology of the endocrine pancreas of patients with LADA and for comparison in a first rat model mimicking the characteristics of patients with LADA. Islets in human and rat pancreases were analyzed by immunohistochemistry for immune cell infiltrate composition, by in situ RT-PCR and quantitative real-time PCR of laser microdissected islets for gene expression of proinflammatory cytokines, the proliferation marker proliferating cell nuclear antigen (PCNA), the anti-inflammatory cytokine interleukin (IL) 10, and the apoptosis markers caspase 3 and TUNEL as well as insulin. Human and rat LADA pancreases showed differences in areas of the pancreas with respect to immune cell infiltration and a changed ratio between the number of macrophages and CD8 T cells toward macrophages in the islet infiltrate. Gene expression analyses revealed a changed ratio due to an increase of IL-1β and a decrease of tumor necrosis factor-α. IL-10, PCNA, and insulin expression were increased in the LADA situation, whereas caspase 3 gene expression was reduced. The analyses into the underlying pathology in human as well as rat LADA pancreases provided identical results, allowing the conclusion that LADA is a milder form of autoimmune diabetes in patients of an advanced age.




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Aaron's 85th birthday a celebration of a great life

Henry "Hank" Aaron was born in Alabama three years after Willie Mays, 85 years ago Tuesday. Now, all this time later, Aaron is as much the conscience and the soul of baseball as any man alive. But we don't just celebrate a great baseball life today. We celebrate a great American life.




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Orioles considering using 'opener' strategy

Since the Rays debuted "the opener" last May, no fewer than eight teams have helped transform the concept from a fad into a mini-movement. Consider the Orioles a candidate to dive in next.




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Cole wins arbitration case vs. Astros

All-Star right-hander Gerrit Cole won his arbitration case against the Astros on Wednesday, meaning he will make $13.5 million this season. The team offerred $11.425 million, a difference of $2,075,000.




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Brathwaite for Tallawahs

The Jamaica Tallawahs have wasted little time in finding a replacement for the ‘Universe Boss’ Chris Gayle, as they have snapped up the captain of the St Kitts and Nevis Patriots, Carlos Brathwaite. The Gleaner has been reliably informed that...




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Caymanas Track operations resume tomorrow

Supreme Ventures Racing and Entertainment Limited, operators of Caymanas Track, has announced the re-opening of the main track, effective tomorrow. The company said in a press release on Thursday evening that the track will be opened for two days...




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Musical (operating) theatre

One hundred years ago, Pennsylvanian surgeon Evan Kane penned a brief letter to JAMA in which he declared himself a rigorous proponent of the “benefic [sic] effects of the phonograph within the operating room.” Now David Bosenquet, a surgeon from University Hospital of Wales in Cardiff has written a Christmas editorial about the evidence for the...