es Thematic review series: Brain Lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal By feedproxy.google.com Published On :: 2004-08-01 John M. DietschyAug 1, 2004; 45:1375-1397Thematic Reviews Full Article
es Perilipin is located on the surface layer of intracellular lipid droplets in adipocytes By feedproxy.google.com Published On :: 1995-06-01 EJ Blanchette-MackieJun 1, 1995; 36:1211-1226Articles Full Article
es Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans By feedproxy.google.com Published On :: 1993-10-01 JM DietschyOct 1, 1993; 34:1637-1659Reviews Full Article
es Apolipoprotein-mediated removal of cellular cholesterol and phospholipids By feedproxy.google.com Published On :: 1996-12-01 JF OramDec 1, 1996; 37:2473-2491Reviews Full Article
es Thematic review series: The Pathogenesis of Atherosclerosis. Effects of infection and inflammation on lipid and lipoprotein metabolism mechanisms and consequences to the host By feedproxy.google.com Published On :: 2004-07-01 Weerapan KhovidhunkitJul 1, 2004; 45:1169-1196Thematic Reviews Full Article
es Identification of multiple subclasses of plasma low density lipoproteins in normal humans By feedproxy.google.com Published On :: 1982-01-01 Ronald M. KraussJan 1, 1982; 23:97-104Articles Full Article
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es Thematic review series: Adipocyte Biology. The perilipin family of structural lipid droplet proteins: stabilization of lipid droplets and control of lipolysis By feedproxy.google.com Published On :: 2007-12-01 Dawn L. BrasaemleDec 1, 2007; 48:2547-2559Thematic Reviews Full Article
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es Quantitation of atherosclerosis in murine models: correlation between lesions in the aortic origin and in the entire aorta, and differences in the extent of lesions between sexes in LDL receptor-deficient and apolipoprotein E-deficient mice By feedproxy.google.com Published On :: 1995-11-01 RK TangiralaNov 1, 1995; 36:2320-2328Articles Full Article
es Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression By feedproxy.google.com Published On :: 1996-05-01 K SchoonjansMay 1, 1996; 37:907-925Reviews Full Article
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es Direct transesterification of all classes of lipids in a one-step reaction By feedproxy.google.com Published On :: 1986-01-01 G LepageJan 1, 1986; 27:114-120Articles Full Article
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es Lipoprotein lipase and lipolysis: central roles in lipoprotein metabolism and atherogenesis By feedproxy.google.com Published On :: 1996-04-01 IJ GoldbergApr 1, 1996; 37:693-707Reviews Full Article
es Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans By feedproxy.google.com Published On :: 2005-11-01 Saverio CintiNov 1, 2005; 46:2347-2355Research Articles Full Article
es The plasma lecithin:cholesterol acyltransferase reaction By feedproxy.google.com Published On :: 1968-03-01 John A. GlomsetMar 1, 1968; 9:155-167Reviews Full Article
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es Cuba's New Policy Framework: Opportunities for Growth and Investment By feedproxy.google.com Published On :: Fri, 01 Nov 2019 09:45:02 +0000 Invitation Only Research Event 15 November 2019 - 8:15am to 9:30am Chatham House | 10 St James's Square | London | SW1Y 4LE Event participants Rodrigo Malmierca, Minister for Foreign Trade and Investment, CubaChair: Dr Christopher Sabatini, Senior Research Fellow for Latin America, Chatham House; Lecturer, Columbia University, School of International and Public Affairs Since 2010-11, Cuba has engaged in legal and constitutional reform intended to provide a greater role for private enterprise and foreign investment in the country's state-run economy. New rules have been introduced to provide greater scope and guarantees for foreign investment and adjustments have been made to allow private ownership of land – and in a handful of cases 100 per cent share in ownership of investments.At the same time, Cuba remains subject to US sanctions and an embargo regime that has left foreign investors weary when deciding whether or not to invest in the country. To what extent have these changes provided the security and confidence for foreign investors to seize on Cuba’s efforts to engage internationally around a range of industries including infrastructure, hospitality, hydrocarbons and small and medium enterprise.Rodrigo Malmierca, Cuba's minister for trade and investment since 2009, will discuss the most recent changes in Cuba, their implications for development and investors and the viability of the official Economic Development Zone situated at Mariel.The US and Americas Programme would like to thank BTG Pactual, Cairn Energy plc, Diageo, Fresnillo Management Services, HSBC Holdings plc and Wintershall Dea for their generous support of the Latin America Initiative.Attendance at this event is by invitation only. Event attributes Chatham House Rule Department/project US and the Americas Programme, Latin America Initiative US and Americas Programme Email Full Article
es US–China Strategic Competition: The Quest for Global Technological Leadership By feedproxy.google.com Published On :: Wed, 06 Nov 2019 18:26:46 +0000 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. Read online Download PDF Marianne Schneider-Petsinger Senior Research Fellow, US and the Americas Programme @mpetsinger Dr Jue Wang Associate Fellow, Asia-Pacific Programme (based in Holland) LinkedIn Dr Yu Jie Senior Research Fellow on China, Asia-Pacific Programme @yu_jiec LinkedIn James Crabtree Associate Fellow, Asia-Pacific Programme @jamescrabtree LinkedIn Examining the US-China Trade Competition Video: Marianne Schneider-Petsinger and Dr Yu Jie discuss key themes from the research paperSummaryThe 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. Department/project Asia-Pacific Programme, Trade, Investment and Economics, US and the Americas Programme, US Geoeconomic Trends and Challenges Full Article
es The Morass of Central American Migration: Dynamics, Dilemmas and Policy Alternatives By feedproxy.google.com Published On :: Mon, 11 Nov 2019 16:10:01 +0000 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 ProjectJuan Ricardo Ortega, Principal Advisor for Central America, Inter-American Development BankChair: 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 the Americas Programme US and Americas Programme Email Full Article
es Harnessing the Potential of Cities By feedproxy.google.com Published On :: Fri, 22 Nov 2019 11:55:02 +0000 Corporate Members Event 13 December 2019 - 12:30pm to 2:00pm Chatham House | 10 St James's Square | London | SW1Y 4LE Event participants Penny Abeywardena, Commissioner for International Affairs, New York CityChair: Dr Beyza Unal, Senior Research Fellow, International Security Department, Chatham House Cities are strong engines of growth and job creation accounting for some 85 per cent of global GDP. By 2030, more than 60 per cent of people worldwide will live in cities and they will be on the front lines of managing issues transcending borders such as climate, migration and sustainability. International organizations like the United Nations are striving to meet these challenges but relying on traditional multilateral agreements is growing ever more unpredictable. If cities and local governments are key to global prosperity, how can their power and influence be harnessed to accelerate impact for their citizens?Drawing on the pioneering work of New York City in the area of foreign policy leadership at a municipal level, Penny Abeywardena will discuss how the influence of subnational leadership and diplomacy is more important than ever as national governments are abdicating their responsibility at the multilateral level. How can the Sustainable Development Goals be localized among cities on policy issues that impact communities? And what can large cities, beyond the capital, do to remain influential and harness job growth? This event will be preceded by an informal sandwich reception from 12.30pm-1pm. The roundtable discussion to follow will take place from 1pm-2pm.This event is corporate members only. If you'd like to attend, please RSVP to Linda Bedford.To enable as open a debate as possible, this event will be held under the Chatham House Rule. Members Events Team Email Full Article
es 'The Truth is, Chile is Unequal': What's Behind Chile's Protests By feedproxy.google.com Published On :: Tue, 17 Dec 2019 19:33:39 +0000 18 December 2019 Dr Christopher Sabatini Senior Research Fellow for Latin America, US and the Americas Programme @ChrisSabatini LinkedIn Lyndsey Jefferson Digital Editor, Communications and Publishing Department @LyndseyLdn As part of a series on global protests, Dr Christopher Sabatini tells Lyndsey Jefferson why Chileans are taking to the streets. GettyImages-1177498531.jpg A demonstrator waves a Chilean flag during a protest in Santiago on 21 October 2019. Photo: Getty Images. Why are these protests happening now?The truth is, Chile is unequal, even though it actually reduced poverty from 1989, the time of the democratic transition, until today, from 40% to 16%.There are a number of reasons for the protests. One is the most proximate cause, which is the increase in the subway fares, but that really doesn’t explain the underlying tensions.One of those tensions is despite reductions in poverty, social mobility remains a large problem in Chile. It remains a very elitist country with limited social mobility. So, poverty may be reduced, but the likelihood that someone in the working middle class would reach the upper middle class has always been a stretch.The second issue is a lack of political change. The last four presidents were the same two people.Chile’s been governed, with the exception of Piñera, basically by the same political coalition, La Concertación, which is a combination of the Christian Democratic and Socialist parties. Piñera came from the right, an outside party, but even he has remained. There has been no renewal of the political leadership which again reinforces that lack of social mobility. Do the protesters have any other demands or grievances? The demands are amorphous and that’s part of the issue – they’re going to be difficult to meet. People are expressing a genuine desire for change but what would that change mean?Chileans don’t necessarily want to change the economic model; they simply want more mobility. That’s difficult to do and these are untested demands. Chileans also want political reform. What Piñera offered is to rewrite the constitution, which was created under military government in 1980. Other than some changes here and there in terms of the electoral system and reduction of military power, it has pretty much remained intact.Will constitutional change really address these demands? It’s simply a document that may create the rules for how power is allocated and conducted, but it’s not going to dramatically remake Chilean society.You mentioned inequality as a key driver of the protests. Can you expand a bit more on the current economic situation of ordinary Chileans?Chile is going to grow at only around 2-3%, but it was growing at around 4-5% earlier. A lot of those funds were ploughed into social programmes that have since been reduced. Chile’s economy really boomed in the early 2000s because of Chinese demands of Chilean imports. But as with any sort of commodities-based economy, the jobs it provides tend to be lower wage.As a result, despite the fact that Chile tried to diversify its economy by investing in entrepreneurship and innovation, it hasn’t grown in a way that provides jobs that many associate with upward mobility. As Chile's economy cooled, its ability to lift people out of poverty lagged as well. Demonstrators hold placards depicting eyes – in reference to police pellets hitting demonstrators' eyes – during a protest in Santiago on 10 December 2019. Photo: Getty Images. Two major issues for the protesters are education and pensions – can you explain why this is?These are two issues of the economic and social model that was held up at one time as being a model for the region, the neoliberal models that are really coming under question and are in some ways at the heart of this.One is the privatized pension system which is failing to produce the returns that retirees need to survive. The second is the education system. Chile created a voucher system where parents can shop around and send their kids to the best schools. The idea was to create competition among schools to improve.The problem was like any market, it created a certain amount of inequality among schools. There was a problem of some schools underperforming and being relegated poorer performing students, or students being forced to go to those schools because the more successful schools were already spoken for. At the end of October, the government announced a series of social reforms. Will this be enough to satisfy the protesters’ demands?Social reforms may address some of the issues of insufficient pensions or lack of quality education, but it will take a while for them to have an effect.The second thing is, social reforms don’t address the issues of power. At the heart of this is this idea of closed economic, political and social power. That comes about through economic growth and how you break up concentrations of wealth. Social reforms aren’t going to do that, although they’ll help on the margins. We’re seeing horrific scenes of police violence against protesters and dozens of people have died. Has this deterred the protesters in any way? No, in many ways it has sort of inspired them. It has, I think, sustained the protests.We’re not talking massive repression and tanks rolling in like Tiananmen Square. We’re talking about tear gas, rubber bullets, some injuries and deaths, and even credible reports of torture.It’s funny you should mention this – a class I’m teaching today is about social media and protests. One of the central arguments is that successful social protests need a martyr; they need a rallying cry.The deaths and the repression sort of help sustain that, but moreover, social media helps communicate what’s happening through videos and pictures. It really helps maintain this sense of righteousness, disdain for the government, and this idea of the need to demand change.Where do you see this going next?I don’t think we know. In the 60s and 70s, the political scientist Samuel Huntington argued in Political Order in Changing Societies that as economies grow, political institutions often strain to contain and channel demands. I think we’re seeing this now.This social ferment over political, economic and social demands is uncharted water. I don’t know where this will go, but I think we’ll see a change in the constitution. We’ve already seen a fragmenting of the party system, which I think will continue. Hopefully, that will lead to new leadership that can help reflect a change in Chile itself. Full Article
es US 2020: Super Tuesday and Implications for the General Election By feedproxy.google.com Published On :: Mon, 17 Feb 2020 10:10:01 +0000 Invitation Only Research Event 5 March 2020 - 12:00pm to 1:30pm Chatham House | 10 St James's Square | London | SW1Y 4LE Event participants Dr Lindsay Newman, Senior Research Fellow, US and the Americas Programme, Chatham HouseProfessor Peter Trubowitz, Professor of International Relations, London School of Economics and Political Science; Associate Fellow, US and the Americas Programme, Chatham HouseAmy Pope, Associate Fellow, US and the Americas Programme, Chatham House; Deputy Homeland Security Advisor, US National Security Council, 2015-17Chair: Dr Leslie Vinjamuri, Director, US and the Americas Programme, Chatham House The US 2020 election season enters a potentially decisive next phase with the Super Tuesday primaries on 3 March. With these fifteen, simultaneously-held state elections, the Democrats hope to have greater clarity about their party’s likely nominee for the general race against President Donald Trump in November. Concerns around intraparty divisions in the Democratic party between progressives (represented by Senators Elizabeth Warren and Bernie Sanders) and moderates (represented by former Vice President Joe Biden and former mayor Pete Buttigieg) have surrounded the primary races so far, and are unlikely to dissipate even if one candidate emerges from the field on 3 March.Against this backdrop, Chatham House brings together a panel of experts to discuss the state of the Democratic primary race, implications for the general election, and the Trump campaign’s priorities ahead of its re-election bid. Will the Democratic party resolve its divisions and unite behind a progressive or moderate in light of the Super Tuesday election results? How is Trump positioned to fair against the Democratic candidates left in the race? Did Former Mayor of New York Michael Bloomberg’s primary gamble to focus on Super Tuesday pay off? And what policy priorities are likely to be pursued under either a Trump 2.0 or a Democratic administration? Event attributes Chatham House Rule Department/project US and the Americas Programme, Chatham House US 2020 Election Series US and Americas Programme Email Full Article
es Exploring the Obstacles and Opportunities for Expanded UK-Latin American Trade and Investment By feedproxy.google.com Published On :: Thu, 27 Feb 2020 12:40:01 +0000 Invitation Only Research Event 14 January 2020 - 8:30am to 11:00am Chatham House | 10 St James's Square | London | SW1Y 4LE Trade and investment between the UK and Latin America is woefully underdeveloped. Latin America’s agricultural powerhouses Brazil and Argentina only accounted for a total of 1.6% of the UK’s agricultural market across eight sectors in 2018, all of those areas in which Argentina and Brazil have substantial comparative advantages. Conversely, UK exports to the large Latin American economies remain far below their potential. To cite a few examples, in 2018 in the electrical equipment sector, the UK only exported $95.7 million of those products to Brazil, making the ninth largest economy in the world only the 42nd export market for those goods from the UK; Mexico only imported $91.4 million of UK-made electrical goods, placing it directly behind Brazil as UK’s market for those goods.As we look to the future, any improvement to the relationship will depend on two factors: 1) how the UK leaves the EU and 2) whether Latin American agricultural producers can improve their environmental practices and can meet the production standards established by the EU and likely maintained by a potential post-Brexit Britain.In the first meeting of the working group, Chatham House convened a range of policymakers, practitioners and academics to explore this topic in depth, identify the key issues driving this trend, and begin to consider how improvements might best be made. Subsequent meetings will focus on specific sectors in commerce and investment.We would like to thank BTG Pactual, Cairn Energy plc, Diageo, Equinor, Fresnillo Management Services, HSBC Holdings plc and Wintershall Dea for their generous support of the Latin America Initiative. Event attributes Chatham House Rule Department/project US and the Americas Programme, Latin America Initiative US and Americas Programme Email Full Article
es Immature leadership: Donald Trump and the American presidency By feedproxy.google.com Published On :: Wed, 04 Mar 2020 13:20:12 +0000 4 March 2020 , Volume 96, Number 2 Read online Daniel W. Drezner There has been a renaissance in the study of how the backgrounds of individual leaders affect foreign policy outcomes. Donald Trump's presidency highlights the limits of this approach. Trump's psychology is so unique, and so akin to that of a small child, that studying his background alone is insufficient to explain his decision-making. The evidence for this characterization of Trump's leadership comes not from his political opponents, but his allies, staffers and subordinates. Trump's lack of impulse control, short attention span and frequent temper tantrums have all undercut his effectiveness as president as compared to his predecessors. Nonetheless, the 45th president helps to clarify ongoing debates in American politics about the relative strength of the presidency as an institution. In particular, the powers of the presidency have become so enhanced that even comparatively weak and inexperienced leaders can execute dramatic policy shifts. The formal checks on presidential power, from the legislative, judicial and executive branches have all eroded. Similarly, the informal checks on the presidency had also degraded before Trump's inauguration. This article uses Trump's presidency—and his severe limitations as a decision-maker—to highlight the ways in which even a weak leader can affect change by holding a powerful office. Full Article
es Civil society perspectives on sexual violence in conflict: patriarchy and war strategy in Colombia By feedproxy.google.com Published On :: Wed, 04 Mar 2020 13:31:21 +0000 4 March 2020 , Volume 96, Number 2 Anne-Kathrin Kreft Read Online In international policy circles, conflict-related sexual violence (CRSV) is commonly viewed as a weapon of war, a framing that researchers have criticized as overly simplistic. Feminist scholars in particular caution that the ‘weapon of war’ framing decontextualizes sexual violence in conflict from the structural factors of gender inequality that underpin its perpetration. In light of these tensions, how do politically relevant local actors perceive the nature and the origins of conflict-related sexual violence? Civil society organizations often actively confront conflict-related sexual violence on the ground. A better understanding of how their perceptions of this violence align or clash with the globally dominant ‘weapon of war’ narratives therefore has important policy implications. Interviews with representatives of Colombian women's organizations and victims' associations reveal that these civil society activists predominantly view conflict-related sexual violence as the result of patriarchal structures. The mobilized women perceive sexual violence as a very gendered violence that exists on a continuum extending through peace, the everyday and war, and which the presence of arms exacerbates. Strategic sexual violence, too, is understood to ultimately have its basis in patriarchal structures. The findings expose a disconnect between the globally dominant ‘weapon of war’ understanding that is decontextualized from structural factors and a local approach to CRSV that establishes clear linkages to societal gender inequality. Full Article
es America's Coronavirus Response Is Shaped By Its Federal Structure By feedproxy.google.com Published On :: Mon, 16 Mar 2020 09:00:36 +0000 16 March 2020 Dr Leslie Vinjamuri Dean, Queen Elizabeth II Academy for Leadership in International Affairs; Director, US and the Americas Programme @londonvinjamuri Google Scholar The apparent capacity of centralized state authority to respond effectively and rapidly is making headlines. In the United States, the opposite has been true. 2020-03-16-Coronavirus-America.jpg Harvard asked its students to move out of their dorms due to the coronavirus risk, with all classes moving online. Photo by Maddie Meyer/Getty Images. As coronavirus spreads across the globe, states grapple to find the ideal strategy for coping with the global pandemic. And, in China, Singapore, South Korea, the US, the UK, and Europe, divergent policies are a product of state capacity and legal authority, but they also reveal competing views about the optimal role of centralized state authority, federalism, and the private sector.Although it is too soon to know the longer-term effects, the apparent capacity of centralized state authority in China, South Korea and Singapore to respond effectively and rapidly is making headlines. In the United States, the opposite has been true. America’s response is being shaped by its federal structure, a dynamic private sector, and a culture of civic engagement. In the three weeks since the first US case of coronavirus was confirmed, state leaders, public health institutions, corporations, universities and churches have been at the vanguard of the nation’s effort to mitigate its spread.Images of safety workers in hazmat suits disinfecting offices of multinational corporations and university campuses populate American Facebook pages. The contrast to the White House effort to manage the message, downplay, then rapidly escalate its estimation of the crisis is stark.Bewildering responseFor European onlookers, the absence of a clear and focused response from the White House is bewildering. By the time President Donald Trump declared a national emergency, several state emergencies had already been called, universities had shifted to online learning, and churches had begun to close.By contrast, in Italy, France, Spain and Germany, the state has led national efforts to shutter borders and schools. In the UK, schools are largely remaining open as Prime Minister Boris Johnson has declared a strategy defined by herd immunity, which hinges on exposing resilient populations to the virus.But America has never shared Europe’s conviction that the state must lead. The Center for Disease Control and Prevention, the leading national public health institute and a US federal agency, has attempted to set a benchmark for assessing the crisis and advising the nation. But in this instance, its response has been slowed due to faults in the initial tests it attempted to rollout. The Federal Reserve has moved early to cut interest rates and cut them again even further this week.But states were the real first movers in America’s response and have been using their authority to declare a state of emergency independent of the declaration of a national emergency. This has allowed states to mobilize critical resources, and to pressure cities into action. After several days delay and intense public pressure, New York Governor Andrew Cuomo forced New York City Mayor Bill de Blasio to close the city’s schools.Declarations of state emergencies by individual states have given corporations, universities and churches the freedom and legitimacy to move rapidly, and ahead of the federal government, to halt the spread in their communities.Washington state was the first to declare a state of emergency. Amazon, one of the state’s leading employers, quickly announced a halt to all international travel and, alongside Microsoft, donated $1million to a rapid-response Seattle-based emergency funds. States have nudged their corporations to be first movers in the sector’s coronavirus response. But corporations have willingly taken up the challenge, often getting ahead of state as well as federal action.Google moved rapidly to announce a move allowing employees to work from home after California declared a state of emergency. Facebook soon followed with an even more stringent policy, insisting employees work from home. Both companies have also met with World Health Organization (WHO) officials to talk about responses, and provided early funding for WHO’s Solidarity Response Fund set up in partnership with the UN Foundation and the Swiss Philanthropy Foundation.America’s leading research universities, uniquely positioned with in-house public health and legal expertise, have also been driving preventive efforts. Just days after Washington declared a state of emergency, the University of Washington became the first to announce an end to classroom teaching and move courses online. A similar pattern followed at Stanford, Harvard, Princeton and Columbia - each also following the declaration of a state of emergency.In addition, the decision by the Church of the Latter Day Saints to cancel its services worldwide followed Utah’s declaration of a state of emergency.The gaping hole in the US response has been the national government. President Trump’s declaration of a national emergency came late, and his decision to ban travel from Europe but - at least initially - exclude the UK, created uncertainty and concern that the White House response is as much driven by politics as evidence.This may soon change, as the House of Representatives has passed a COVID-19 response bill that the Senate will consider. These moves are vital to supporting state and private efforts to mobilize an effective response to a national and global crisis.Need for public oversightIn the absence of greater coordination and leadership from the centre, the US response will pale in comparison to China’s dramatic moves to halt the spread. The chaos across America’s airports shows the need for public oversight. As New York State Governor Cuomo pleaded for federal government support to build new hospitals, he said: ‘I can’t do it. You can’t leave it to the states.'When it comes to global pandemics, we may be discovering that authoritarian states can have a short-term advantage, but already Iran’s response demonstrates that this is not universally the case. Over time, the record across authoritarian states as they tackle the coronavirus will become more apparent, and it is likely to be mixed.Open societies remain essential. Prevention requires innovation, creativity, open sharing of information, and the ability to inspire and mobilize international cooperation. The state is certainly necessary, but it is not sufficient alone. Full Article
es Virtual Roundtable: Tectonic Plates of 2020 – Developments in the US Presidential Race By feedproxy.google.com Published On :: Mon, 16 Mar 2020 12:00:01 +0000 Invitation Only Research Event 18 March 2020 - 1:00pm to 1:45pm Event participants John Zogby, Founder and Senior Partner, John Zogby StrategiesChair: Dr Lindsay Newman, Senior Research Fellow, US and Americas Programme, Chatham House This event is part of the Inaugural Virtual Roundtable Series on the US, Americas and the State of the World and will take place virtually only. Participants should not come to Chatham House for these events. Department/project US and the Americas Programme, Chatham House US 2020 Election Series US and Americas Programme Email Full Article
es Virtual Roundtable: US and European Responses to Coronavirus By feedproxy.google.com Published On :: Mon, 16 Mar 2020 12:00:01 +0000 Invitation Only Research Event 20 March 2020 - 1:00pm to 1:45pm Event participants Anne Applebaum, Staff Writer, The Atlantic; Pulitzer-Prize Winning HistorianAmy Pope, Partner, Schillings; Deputy Homeland Security Advisor, US National Security Council, 2015 - 17Chair: Dr Leslie Vinjamuri, Director, US and the Americas Programme, Chatham House This event is part of the Inaugural Virtual Roundtable Series on the US, Americas and the State of the World and will take place virtually only. Participants should not come to Chatham House for these events. Department/project US and the Americas Programme US and Americas Programme Email Full Article
es Coronavirus in Latin America and Mexico: Infection Rates, Immigration and Policy Responses By feedproxy.google.com Published On :: Mon, 23 Mar 2020 17:20:01 +0000 Invitation Only Research Event 25 March 2020 - 4:00pm to 5:00pm Event participants Jude Webber, Mexico and Central America Correspondent, Financial TimesMichael Stott, Latin America Editor, Financial TimesChair: 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 Department/project US and the Americas Programme, Latin America Initiative US and Americas Programme Email Full Article
es Virtual Roundtable: The End of Globalism? Remaining Interconnected While Under Increased Pressure to Isolate By feedproxy.google.com Published On :: Wed, 25 Mar 2020 14:30:01 +0000 Invitation Only Research Event 30 March 2020 - 1:00pm to 2:00pm Zoom Audio Call Event participants Fred Hochberg, Chairman and President, Export-Import Bank of the United States, 2009 -17Chair: Dr Leslie Vinjamuri, Director, US and the Americas Programme, Chatham House This event is part of the Chatham House Global Trade Policy Forum. We would like to take this opportunity to to thank founding partner AIG and supporting partners Clifford Chance LLP, Diageo plc and EY for their generous support of the forum. Department/project US and the Americas Programme, Global Trade Policy Forum US and Americas Programme Email Full Article
es Virtual Roundtable: Global Cities and the Response to Coronavirus By feedproxy.google.com Published On :: Mon, 30 Mar 2020 15:55:01 +0000 Research Event 8 April 2020 - 4:00pm to 5:00pm Chatham House | 10 St James's Square | London | SW1Y 4LE Event participants Penny Abeywardena, Commissioner, International Affairs, City of New YorkAmbassador Nina Hachigian, Deputy Mayor for International Affairs, City of Los Angeles; US Ambassador to the Association of Southeast Asian Nations (2014-17)Steven Erlanger, Chief Diplomatic Correspondent, Europe, The New York Times Chair: Dr Leslie Vinjamuri, Director, US and the Americas Programme, Chatham House This event is part of the Inaugural Virtual Roundtable Series on the US, Americas and the State of the World and will take place virtually only. Participants should not come to Chatham House for these events. Department/project US and the Americas Programme US and Americas Programme Email Full Article
es Webinar: Does COVID-19 Spell the End of America's Interest in Globalization? By feedproxy.google.com Published On :: Mon, 20 Apr 2020 09:40:01 +0000 Research Event 19 May 2020 - 2:00pm to 3:00pmAdd to CalendariCalendar Outlook Google Yahoo Dr Anne-Marie Slaughter, CEO, New AmericaProfessor Stephen Walt, Robert and Renee Belfer Professor of International Affairs, Harvard Kennedy SchoolChair: Dr Leslie Vinjamuri, Director, US and Americas Programme, Chatham House This event is part of the US and Americas Programme Inaugural Virtual Roundtable Series on the US and the State of the World and will take place virtually only. Please note this event is taking place between 2pm to 3pm BST. US and Americas Programme Email Department/project US and the Americas Programme Full Article
es Webinar: Homeland Security and the Emergency Response to Coronavirus in the US By feedproxy.google.com Published On :: Mon, 20 Apr 2020 09:40:01 +0000 Research Event 26 May 2020 - 2:00pm to 3:00pmAdd to CalendariCalendar Outlook Google Yahoo Secretary Jeh Johnson, Partner, Paul, Weiss; US Secretary of Homeland Security, 2013 - 17Chair: Amy Pope, Partner, Schillings; Associate Fellow, US and Americas Programme, Chatham House This event is part of the US and Americas Programme Inaugural Virtual Roundtable Series on the US and the State of the World and will take place virtually only.Please note this event is taking place between 2pm to 3pm BST. US and Americas Programme Email Department/project US and the Americas Programme Full Article
es Reimagining Trade Rules to Address Climate Change in a Post-Pandemic World By feedproxy.google.com Published On :: Fri, 24 Apr 2020 10:25:01 +0000 Webinar Research Event 5 May 2020 - 2:00pm to 3:00pm Event participants James Bacchus, Distinguished University Professor of Global Affairs and Director of the Center for Global Economic and Environmental Opportunity at the University of Central Florida; Member and Chair, WTO Appellate Body, 1995 - 2003Chair: Creon Butler, Director, Global Economy and Finance Programme, Chatham House This event is part of the Chatham House Global Trade Policy Forum and will take place virtually only.International trade has a crucial role to play in tackling climate change. The production and transport of goods is a major contributor to green-house gas emissions, as is the delivery of certain cross-border services. At the same time, it looks inevitable that the COVID-19 pandemic will lead to a radical re-think of global supply chains as companies and governments seek to build in greater resilience while at the same time preserving as far as possible the efficiency gains and lower costs that global supply chains generate when operating normally.Future international trade rules will have a crucial role to play in addressing both challenges; they represent both an opportunity and a risk. If designed well, they could play a very important role in re-enforcing moves towards a more sustainable use of resources, greater overall alignment of economies with the Paris Agreement, and greater economic resilience. But they could also, if poorly designed and implemented, or overly influenced by strategic political considerations, have significant unintended and negative implications. These include: reduced economic efficiency, increased poverty, unnecessary economic decoupling and reduced consensus on the broader mitigation and adaptation measures required to meet the challenge of climate change.Against this background, a number of key questions arise: In what areas, if any, do we need to modify or adapt key principles underlying the system of global trade rules in order to respond to the twin challenges of responding to climate change and building greater economic resilience? Which are the most promising/practical areas on which trade policy experts should focus now to re-launch/re-energize discussions on WTO reform, including, for example, dispute settlement? What national economic policies will be needed to complement the development of new/reformed trade disciplines in these areas? How might future political changes, such as a change in the US administration, affect the prospects for and political momentum behind such deliberations? What in any eventuality is the best way to build the required political momentum? This roundtable is convened by the Global Economy and Finance Programme and the US and the Americas Programme and it is part of the Chatham House Global Trade Policy Forum. The event will take place virtually only.We would like to take this opportunity to thank founding partner AIG and supporting partners Clifford Chance LLP, Diageo plc, and EY for their generous support of the Chatham House Global Trade Policy Forum.Please note this event is taking place between 2pm to 3pm BST. Department/project US and the Americas Programme, Global Trade Policy Forum Full Article
es Latin America’s COVID-19 Moment: Differences and Solidarity By feedproxy.google.com Published On :: Thu, 30 Apr 2020 11:37:25 +0000 30 April 2020 Dr Christopher Sabatini Senior Research Fellow for Latin America, US and the Americas Programme @ChrisSabatini LinkedIn There has been no better example of the political diversity in Latin America than the varying responses of governments to the coronavirus crisis. 2020-04-30-Chile-Covid.jpg A municipal cleaning worker disinfects the central market in Santiago, Chile on 7 April 2020 amid the coronavirus pandemic. Photo: Getty Images. Differing approaches across the hemisphere have had different impacts on presidential popularity and, at least in one case, on democratic institutions and human rights. Yet, even within that diversity, South America’s Southern Cone countries (Argentina, Chile, Paraguay and Uruguay) have shown a sign of solidarity: protecting and facilitating trade flows, sponsoring cross-border research and ensuring citizens’ return to their home countries. The response from populist leadersOn the extreme have been the responses of presidents of Brazil, Nicaragua and Mexico, all of whom have ignored the science of the virus and of experts and refused to implement isolation policies. President Jair Bolsonaro of Brazil fired his health minister, Luis Henrique Mandetta on 16 April for contradicting him and earlier had claimed that the pandemic was a hoax or little more than a ‘measly cold.' Meanwhile, Nicaraguan president Daniel Ortega has resisted closing businesses and schools. After a mysterious 34-day absence, Ortega appeared on television on 15 April reinforcing his refusal to close businesses saying that Nicaraguans must work or they will die and claiming that the virus was ‘imported.’ Mexico’s Andres Manuel Lopez Obrador (AMLO) has also resisted the call for strict stay-at-home policies, though with his Deputy Health Minister, Hugo López-Gatell, has closed schools – recently extending the closure to the 1st of June and urging non-essential businesses to close – but focusing primarily on social distancing. In contrast to his deputy health minister and Foreign Minister Marcelo Ebrard – who had declared the situation a health emergency on 30th March, later than many neighbouring countries – AMLO has largely attempted to avoid discussion of the pandemic, claiming that in his case he has lucky charms that prevent him from contracting the virus. And both Bolsonaro and AMLO have participated in large public rallies, doing all the things that politicians love, shaking hands and hugging babies, and in the case of the former even wiping his nose before embracing an elderly woman.The Nicaraguan, Brazilian and Mexican presidents make an odd grouping since one (Bosonaro) is considered of the extreme populist right and the others (Ortega and AMLO) of the populist left. What unites them is good old-fashioned populism, a belief in a leader who represents the amorphous popular will and should be unfettered by checks and balances on his power, including something like… science. An eclectic groupAt the other extreme have been the quick responses by governments in Peru, Argentina, Chile, El Salvador and Colombia which put quarantine measures in place in mid-March. In these cases, governments have even banned outdoor activities and in the case of Peru and Colombia (in the large cities) have imposed alternating days for when women and men can leave the house so as to better control outside movement. This too, though, is an eclectic group. It includes a Peronist president Alberto Fernández in Argentina, conservative presidents Sebastian Piñera in Chile and Ivan Duque in Colombia, interim president and relative political neophyte Martin Vizcarra in Peru and outsider president Nayib Bukele in El Salvador. El Salvador’s strict quarantine measures have led to rising concerns that Bukele is using the crisis to consolidate personal power, using the national police and the armed forces to enforce the quarantine and ignoring three rulings by the Supreme Court urging the president to end the abuses. In Argentina, Peronist Fernández has shown a surprising commitment to containment even as it hurts his party’s working-class base, not something typically expected of the populist Peronist Party. In all of these cases, the quick, strong responses by the presidents shored up their popularity. Peru’s Vizcarra saw his popularity shoot up 35 points in a week to 82 per cent according to surveys taken in March. In late March 2020, Fernández in Argentina saw his approval ratings swell to 79.2 per cent with 94.7 percent of citizens approving of the government’s strict shelter-at-home policies. Even presidents Piñera and Duque who had struggled with low approval ratings throughout 2019 and saw those numbers sink even lower after the social protests that ended the year have seen their numbers rise. According to an 20th April poll, Piñera’s popular approval rating swelled from 13 percent in March 18th at the start of the crisis to 25 per cent by 20th April; while hardly a sweeping popular mandate, even that level was unthinkable only a few months ago when administration was battered by social protests. In Colombia, after a series of political missteps and the popular protests, Duque’s popular approval rating had slumped to 26 per cent; by April 2nd, 62 percent of Colombians supported the once-beleaguered president. (No recent surveys were available for Bukele in El Salvador.)In contrast, Bolsonaro’s in Brazil has only nudged up. Before the crisis hit, the president’s popularity had been in steady decline from a high of 49 per cent in January 2019 to 30 per cent by early December 2019. But by the first week in April, in the midst of a crisis in which other presidents saw their approval ratings increase by double digits, after his public disagreements with the health minister, Bolsonaro’s had sunk to 33 per cent while the soon-to-be-fired Mandetta’s stood at 76 per cent. AMLO in Mexico has fared no better. The populist leftist scored a high 86 per cent approval rating in February 1, 2019. By March 28, 2020 with concerns over his weak and flippant COVID-19 response and a severe contraction in economic growth, AMLO’s approval rating had sunk 26 points to 60 per cent and his disapproval stood at 37 per cent. In the midst of disharmony, coordinationDespite these differences, many countries in the region have shown the solidarity they often speak of but rarely follow in policy or practice. Peru, Chile and other countries have collaborated in repatriating citizens back to their home countries in the midst of the crisis. Even the countries of the Southern Cone common market, MERCOSUR, have pulled together on a number of fronts. The trade bloc had effectively been ruled a dead-man-walking after its failed efforts to integrate Venezuela into the bloc, lowering its standards to let in the petroleum dependent semi-authoritarian government of then President Hugo Chávez. Even on the basics of internal cooperation, the block was struggling, unable to coordinate monetary policies and non-tariff trade barriers between the original founding member states, Argentina, Brazil, Paraguay and Uruguay.The 35-year-old customs union seemed to get a breath a new life with the announcement that it had concluded 20-year-long negotiations with the EU for a free trade deal. Ratification of that deal, however, ran aground on the political differences between the recently elected governments of Bolsonaro in Brazil and the Peronist Fernández in Argentina. Bolsonaro refused to attend the Fernández December 2019 inauguration, in protest of the newly elected president’s leftist leanings. And this was well before their sharply divergent reactions to the COVID-19 virus. How surprising then that Mercosur has served as an effective coordination mechanism for these different and once opposed governments. The trade body is collaborating among member states to ensure the repatriation of citizens and has agreed to coordinate to ensure that trade flows, especially of medical supplies, are not interrupted by shutdown measures. Mercosur has even gone one step further than several other bodies have failed to take. In early April the bloc’s governing body, based in Montevideo, Uruguay created a $16 million (12 million pound) fund to augment country research and assist in the purchase of supplies needed to combat the virus. Now if Brazil, Argentina and the others could only coordinate their domestic coronavirus responses and economic policy. In late March Fernández announced he was pulling Argentina out of a possible Mercosur-EU trade deal. Full Article
es Virtual Roundtable: As COVID-19 Hits the Developing World, Where is the American-led Global Response? By feedproxy.google.com Published On :: Wed, 06 May 2020 11:05:01 +0000 Research Event 9 June 2020 - 2:00pm to 3:00pmAdd to CalendariCalendar Outlook Google Yahoo Lord Mark Malloch-Brown, Chairman, SGO; Former Deputy Secretary-General and Chief of Staff, United NationsDr Elizabeth Cousens, President and CEO, United Nations FoundationAmbassador Nicholas Burns, Roy and Barbara Goodman Family Professor of the Practice of Diplomacy and International Relations at the Harvard Kennedy School; US Under Secretary of State for Political Affairs, 2005 – 2008Chair: Dr Leslie Vinjamuri, Director, US and the Americas Programme, Chatham House This event is part of the US and Americas Programme Inaugural Virtual Roundtable Series on the US and the State of the World and will take place virtually only.This event will take place from 14:00 – 15:00 BST. US and Americas Programme Email Department/project US and the Americas Programme Full Article
es ABC transporters control ATP release through cholesterol-dependent volume-regulated anion channel activity [Signal Transduction] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 Purinergic signaling by extracellular ATP regulates a variety of cellular events and is implicated in both normal physiology and pathophysiology. Several molecules have been associated with the release of ATP and other small molecules, but their precise contributions have been difficult to assess because of their complexity and heterogeneity. Here, we report on the results of a gain-of-function screen for modulators of hypotonicity-induced ATP release using HEK-293 cells and murine cerebellar granule neurons, along with bioluminescence, calcium FLIPR, and short hairpin RNA–based gene-silencing assays. This screen utilized the most extensive genome-wide ORF collection to date, covering 90% of human, nonredundant, protein-encoding genes. We identified two ABCG1 (ABC subfamily G member 1) variants, which regulate cellular cholesterol, as modulators of hypotonicity-induced ATP release. We found that cholesterol levels control volume-regulated anion channel–dependent ATP release. These findings reveal novel mechanisms for the regulation of ATP release and volume-regulated anion channel activity and provide critical links among cellular status, cholesterol, and purinergic signaling. Full Article
es G{alpha}q splice variants mediate phototransduction, rhodopsin synthesis, and retinal integrity in Drosophila [Signal Transduction] By feedproxy.google.com Published On :: 2020-04-24T06:08:45-07:00 Heterotrimeric G proteins mediate a variety of signaling processes by coupling G protein–coupled receptors to intracellular effector molecules. In Drosophila, the Gαq gene encodes several Gαq splice variants, with the Gαq1 isoform protein playing a major role in fly phototransduction. However, Gαq1 null mutant flies still exhibit a residual light response, indicating that other Gαq splice variants or additional Gq α subunits are involved in phototransduction. Here, we isolated a mutant fly with no detectable light responses, decreased rhodopsin (Rh) levels, and rapid retinal degeneration. Using electrophysiological and genetic studies, biochemical assays, immunoblotting, real-time RT-PCR, and EM analysis, we found that mutations in the Gαq gene disrupt light responses and demonstrate that the Gαq3 isoform protein is responsible for the residual light response in Gαq1 null mutants. Moreover, we report that Gαq3 mediates rhodopsin synthesis. Depletion of all Gαq splice variants led to rapid light-dependent retinal degeneration, due to the formation stable Rh1-arrestin 2 (Arr2) complexes. Our findings clarify essential roles of several different Gαq splice variants in phototransduction and retinal integrity in Drosophila and reveal that Gαq3 functions in rhodopsin synthesis. Full Article
es S-Palmitoylation of the sodium channel Nav1.6 regulates its activity and neuronal excitability [Cell Biology] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 S-Palmitoylation is a reversible post-translational lipid modification that dynamically regulates protein functions. Voltage-gated sodium channels are subjected to S-palmitoylation and exhibit altered functions in different S-palmitoylation states. Our aim was to investigate whether and how S-palmitoylation regulates Nav1.6 channel function and to identify S-palmitoylation sites that can potentially be pharmacologically targeted. Acyl-biotin exchange assay showed that Nav1.6 is modified by S-palmitoylation in the mouse brain and in a Nav1.6 stable HEK 293 cell line. Using whole-cell voltage clamp, we discovered that enhancing S-palmitoylation with palmitic acid increases Nav1.6 current, whereas blocking S-palmitoylation with 2-bromopalmitate reduces Nav1.6 current and shifts the steady-state inactivation in the hyperpolarizing direction. Three S-palmitoylation sites (Cys1169, Cys1170, and Cys1978) were identified. These sites differentially modulate distinct Nav1.6 properties. Interestingly, Cys1978 is exclusive to Nav1.6 among all Nav isoforms and is evolutionally conserved in Nav1.6 among most species. Cys1978 S-palmitoylation regulates current amplitude uniquely in Nav1.6. Furthermore, we showed that eliminating S-palmitoylation at specific sites alters Nav1.6-mediated excitability in dorsal root ganglion neurons. Therefore, our study reveals S-palmitoylation as a potential isoform-specific mechanism to modulate Nav activity and neuronal excitability in physiological and diseased conditions. Full Article
es Roles of the DOCK-D family proteins in a mouse model of neuroinflammation [Neurobiology] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 The DOCK-D (dedicator of cytokinesis D) family proteins are atypical guanine nucleotide exchange factors that regulate Rho GTPase activity. The family consists of Zizimin1 (DOCK9), Zizimin2 (DOCK11), and Zizimin3 (DOCK10). Functions of the DOCK-D family proteins are presently not well-explored, and the role of the DOCK-D family in neuroinflammation is unknown. In this study, we generated three mouse lines in which DOCK9 (DOCK9−/−), DOCK10 (DOCK10−/−), or DOCK11 (DOCK11−/−) had been deleted and examined the phenotypic effects of these gene deletions in MOG35–55 peptide-induced experimental autoimmune encephalomyelitis, an animal model of the neuroinflammatory disorder multiple sclerosis. We found that all the gene knockout lines were healthy and viable. The only phenotype observed under normal conditions was a slightly smaller proportion of B cells in splenocytes in DOCK10−/− mice than in the other mouse lines. We also found that the migration ability of macrophages is impaired in DOCK10−/− and DOCK11−/− mice and that the severity of experimental autoimmune encephalomyelitis was ameliorated only in DOCK10−/− mice. No apparent phenotype was observed for DOCK9−/− mice. Further investigations indicated that lipopolysaccharide stimulation up-regulates DOCK10 expression in microglia and that microglial migration is decreased in DOCK10−/− mice. Up-regulation of C–C motif chemokine ligand 2 (CCL2) expression induced by activation of Toll-like receptor 4 or 9 signaling was reduced in DOCK10−/− astrocytes compared with WT astrocytes. Taken together, our findings suggest that DOCK10 plays a role in innate immunity and neuroinflammation and might represent a potential therapeutic target for managing multiple sclerosis. Full Article
es {alpha}-Synuclein filaments from transgenic mouse and human synucleinopathy-containing brains are maȷor seed-competent species [Molecular Bases of Disease] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Assembled α-synuclein in nerve cells and glial cells is the defining pathological feature of neurodegenerative diseases called synucleinopathies. Seeds of α-synuclein can induce the assembly of monomeric protein. Here, we used sucrose gradient centrifugation and transiently transfected HEK 293T cells to identify the species of α-synuclein from the brains of homozygous, symptomatic mice transgenic for human mutant A53T α-synuclein (line M83) that seed aggregation. The most potent fractions contained Sarkosyl-insoluble assemblies enriched in filaments. We also analyzed six cases of idiopathic Parkinson's disease (PD), one case of familial PD, and six cases of multiple system atrophy (MSA) for their ability to induce α-synuclein aggregation. The MSA samples were more potent than those of idiopathic PD in seeding aggregation. We found that following sucrose gradient centrifugation, the most seed-competent fractions from PD and MSA brains are those that contain Sarkosyl-insoluble α-synuclein. The fractions differed between PD and MSA, consistent with the presence of distinct conformers of assembled α-synuclein in these different samples. We conclude that α-synuclein filaments are the main driving force for amplification and propagation of pathology in synucleinopathies. Full Article
es A kinesin adapter directly mediates dendritic mRNA localization during neural development in mice [Neurobiology] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Motor protein-based active transport is essential for mRNA localization and local translation in animal cells, yet how mRNA granules interact with motor proteins remains poorly understood. Using an unbiased yeast two–hybrid screen for interactions between murine RNA-binding proteins (RBPs) and motor proteins, here we identified protein interaction with APP tail-1 (PAT1) as a potential direct adapter between zipcode-binding protein 1 (ZBP1, a β-actin RBP) and the kinesin-I motor complex. The amino acid sequence of mouse PAT1 is similar to that of the kinesin light chain (KLC), and we found that PAT1 binds to KLC directly. Studying PAT1 in mouse primary hippocampal neuronal cultures from both sexes and using structured illumination microscopic imaging of these neurons, we observed that brain-derived neurotrophic factor (BDNF) enhances co-localization of dendritic ZBP1 and PAT1 within granules that also contain kinesin-I. PAT1 is essential for BDNF-stimulated neuronal growth cone development and dendritic protrusion formation, and we noted that ZBP1 and PAT1 co-locate along with β-actin mRNA in actively transported granules in living neurons. Acute disruption of the PAT1–ZBP1 interaction in neurons with PAT1 siRNA or a dominant-negative ZBP1 construct diminished localization of β-actin mRNA but not of Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα) mRNA in dendrites. The aberrant β-actin mRNA localization resulted in abnormal dendritic protrusions and growth cone dynamics. These results suggest a critical role for PAT1 in BDNF-induced β-actin mRNA transport during postnatal development and reveal a new molecular mechanism for mRNA localization in vertebrates. Full Article
es Small-molecule agonists of the RET receptor tyrosine kinase activate biased trophic signals that are influenced by the presence of GFRa1 co-receptors [Neurobiology] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Glial cell line–derived neurotrophic factor (GDNF) is a growth factor that regulates the health and function of neurons and other cells. GDNF binds to GDNF family receptor α1 (GFRa1), and the resulting complex activates the RET receptor tyrosine kinase and subsequent downstream signals. This feature restricts GDNF activity to systems in which GFRa1 and RET are both present, a scenario that may constrain GDNF breadth of action. Furthermore, this co-dependence precludes the use of GDNF as a tool to study a putative functional cross-talk between GFRa1 and RET. Here, using biochemical techniques, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, and immunohistochemistry in murine cells, tissues, or retinal organotypic cultures, we report that a naphthoquinone/quinolinedione family of small molecules (Q compounds) acts as RET agonists. We found that, like GDNF, signaling through the parental compound Q121 is GFRa1-dependent. Structural modifications of Q121 generated analogs that activated RET irrespective of GFRa1 expression. We used these analogs to examine RET–GFRa1 interactions and show that GFRa1 can influence RET-mediated signaling and enhance or diminish AKT Ser/Thr kinase or extracellular signal-regulated kinase signaling in a biased manner. In a genetic mutant model of retinitis pigmentosa, a lead compound, Q525, afforded sustained RET activation and prevented photoreceptor neuron loss in the retina. This work uncovers key components of the dynamic relationships between RET and its GFRa co-receptor and provides RET agonist scaffolds for drug development. Full Article
es Reactive dicarbonyl compounds cause Calcitonin Gene-Related Peptide release and synergize with inflammatory conditions in mouse skin and peritoneum [Molecular Bases of Disease] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 The plasmas of diabetic or uremic patients and of those receiving peritoneal dialysis treatment have increased levels of the glucose-derived dicarbonyl metabolites like methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG). The elevated dicarbonyl levels can contribute to the development of painful neuropathies. Here, we used stimulated immunoreactive Calcitonin Gene–Related Peptide (iCGRP) release as a measure of nociceptor activation, and we found that each dicarbonyl metabolite induces a concentration-, TRPA1-, and Ca2+-dependent iCGRP release. MGO, GO, and 3-DG were about equally potent in the millimolar range. We hypothesized that another dicarbonyl, 3,4-dideoxyglucosone-3-ene (3,4-DGE), which is present in peritoneal dialysis (PD) solutions after heat sterilization, activates nociceptors. We also showed that at body temperatures 3,4-DGE is formed from 3-DG and that concentrations of 3,4-DGE in the micromolar range effectively induced iCGRP release from isolated murine skin. In a novel preparation of the isolated parietal peritoneum PD fluid or 3,4-DGE alone, at concentrations found in PD solutions, stimulated iCGRP release. We also tested whether inflammatory tissue conditions synergize with dicarbonyls to induce iCGRP release from isolated skin. Application of MGO together with bradykinin or prostaglandin E2 resulted in an overadditive effect on iCGRP release, whereas MGO applied at a pH of 5.2 resulted in reduced release, probably due to an MGO-mediated inhibition of transient receptor potential (TRP) V1 receptors. These results indicate that several reactive dicarbonyls activate nociceptors and potentiate inflammatory mediators. Our findings underline the roles of dicarbonyls and TRPA1 receptors in causing pain during diabetes or renal disease. Full Article
es Brain manganese and the balance between essential roles and neurotoxicity [Molecular Bases of Disease] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Manganese (Mn) is an essential micronutrient required for the normal development of many organs, including the brain. Although its roles as a cofactor in several enzymes and in maintaining optimal physiology are well-known, the overall biological functions of Mn are rather poorly understood. Alterations in body Mn status are associated with altered neuronal physiology and cognition in humans, and either overexposure or (more rarely) insufficiency can cause neurological dysfunction. The resultant balancing act can be viewed as a hormetic U-shaped relationship for biological Mn status and optimal brain health, with changes in the brain leading to physiological effects throughout the body and vice versa. This review discusses Mn homeostasis, biomarkers, molecular mechanisms of cellular transport, and neuropathological changes associated with disruptions of Mn homeostasis, especially in its excess, and identifies gaps in our understanding of the molecular and biochemical mechanisms underlying Mn homeostasis and neurotoxicity. Full Article