on Video: Salon Owner Shelley Luther Released from Jail After Obama-Loyalist Judge Sentenced Her to 7 Days By 100percentfedup.com Published On :: Thu, 07 May 2020 19:37:43 +0000 The following article, Video: Salon Owner Shelley Luther Released from Jail After Obama-Loyalist Judge Sentenced Her to 7 Days, was first published on 100PercentFedUp.com. Salon A La Mode owner Shelley Luther was just released from jail today. The Texas Supreme Court and Texas Governor Greg Abbott both called for her release today (see below). When Luther left jail she was greeted by supporters who yelled “Shelley’s Free!” She thanked all of the new friends she’s made during this difficult […] Continue reading: Video: Salon Owner Shelley Luther Released from Jail After Obama-Loyalist Judge Sentenced Her to 7 Days ... Full Article Breaking Crime Featured Government Uncategorized
on BREAKING: Michigan’s Radical Governor Extends Lockdown AGAIN…Only One Day After Church Leaders and MI Lawmakers File Suit Against Her By 100percentfedup.com Published On :: Thu, 07 May 2020 22:53:35 +0000 The following article, BREAKING: Michigan’s Radical Governor Extends Lockdown AGAIN…Only One Day After Church Leaders and MI Lawmakers File Suit Against Her, was first published on 100PercentFedUp.com. Michigan was the first state to see protests against draconian lockdown measures by an overreaching governor. On April 15, the Michigan Conservative Coalition organized an in-vehicle protest in Lansing, MI that drew an estimated 15,000 vehicles. Since that time, several protests by Michigan workers who are being devastated by the one-size-fits-all shut down of the […] Continue reading: BREAKING: Michigan’s Radical Governor Extends Lockdown AGAIN…Only One Day After Church Leaders and MI Lawmakers File Suit Against Her ... Full Article Featured Politics
on Mother of the Year, Michelle Obama Explains How Having Kids Was A “Concession”… Had To Give Up Her “Aspirations and Dreams” [VIDEO] By 100percentfedup.com Published On :: Fri, 08 May 2020 00:05:56 +0000 The following article, Mother of the Year, Michelle Obama Explains How Having Kids Was A “Concession”… Had To Give Up Her “Aspirations and Dreams” [VIDEO], was first published on 100PercentFedUp.com. While campaigning for her community organizer turned presidential candidate husband, Barack, Michelle Obama told a crowd of his supporters in Milwaukee, Wisconsin that for the first time in her life, she was proud to be an American. Four years later, Michelle Obama was a keynote speaker at the DNC convention, where she told Democrats how […] Continue reading: Mother of the Year, Michelle Obama Explains How Having Kids Was A “Concession”… Had To Give Up Her “Aspirations and Dreams” [VIDEO] ... Full Article Featured Left News Politics
on Woman Shoots Three Teenage McDonald’s Workers For Telling Her She Couldn’t Eat In Dining Room Over COVID19 Restrictions By 100percentfedup.com Published On :: Fri, 08 May 2020 02:10:36 +0000 The following article, Woman Shoots Three Teenage McDonald’s Workers For Telling Her She Couldn’t Eat In Dining Room Over COVID19 Restrictions, was first published on 100PercentFedUp.com. An angry Oklahoma woman shot at a group of teenagers working at a local McDonald’s after they explained to her that the dining room was closed due to coronavirus restrictions. 32-year-old Gloricia Woody was arrested by the Oklahoma City Police and charged with the shooting. From the Oklahoma City Police -Last night, officers were called […] Continue reading: Woman Shoots Three Teenage McDonald’s Workers For Telling Her She Couldn’t Eat In Dining Room Over COVID19 Restrictions ... Full Article Featured Politics
on BREAKING: Ex-Cop Father and Son Arrested and Charged With Murder of Black Man Jogging In Neighborhood…President Trump Responds [VIDEO] By 100percentfedup.com Published On :: Fri, 08 May 2020 02:55:40 +0000 The following article, BREAKING: Ex-Cop Father and Son Arrested and Charged With Murder of Black Man Jogging In Neighborhood…President Trump Responds [VIDEO], was first published on 100PercentFedUp.com. The Georgia Bureau of Investigations has arrested a father and son duo, 64-year-old ex-cop, Gregory McMichael, and his son, 34-year-old Travis McMichael for the February murder of 24-year-old Ahmaud Arbery, a black man who was jogging through their neighborhood when they jumped in their truck and pursued him. Yashar Ali shared the news of the […] Continue reading: BREAKING: Ex-Cop Father and Son Arrested and Charged With Murder of Black Man Jogging In Neighborhood…President Trump Responds [VIDEO] ... Full Article Featured
on BREAKING: New Docs Prove Obama Knew Details Of Flynn Wiretapping…Newly Surfaced Video Shows Obama Explaining How He Stays Out Of FBI Investigations By 100percentfedup.com Published On :: Fri, 08 May 2020 16:25:07 +0000 The following article, BREAKING: New Docs Prove Obama Knew Details Of Flynn Wiretapping…Newly Surfaced Video Shows Obama Explaining How He Stays Out Of FBI Investigations, was first published on 100PercentFedUp.com. Barack Obama knew. Documents released yesterday that were used to exonerate President Trump’s new NSA General Flynn, prove that President Barack Obama was aware of the details of Michael Flynn’s intercepted phone calls on December 16 with then-Russian Ambassador Sergey Kislyak. On January 5, 2017, then-Deputy Attorney General, Sally Yates attended an Oval Office meeting […] Continue reading: BREAKING: New Docs Prove Obama Knew Details Of Flynn Wiretapping…Newly Surfaced Video Shows Obama Explaining How He Stays Out Of FBI Investigations ... Full Article Featured Left News Political Correctness
on BREAKING: President Trump’s Fiery Interview On Fox & Friends…”These are dirty politicians and dirty cops…They put our nation in danger with other nations, including Russia” [VIDEO] By 100percentfedup.com Published On :: Fri, 08 May 2020 17:34:35 +0000 The following article, BREAKING: President Trump’s Fiery Interview On Fox & Friends…”These are dirty politicians and dirty cops…They put our nation in danger with other nations, including Russia” [VIDEO], was first published on 100PercentFedUp.com. This morning during a nearly one hour interview with Fox & Friends, President Trump addressed the decision by the DOJ to drop the case against the innocent General Michael Flynn. Trump ripped into the “dirty politicians and dirty cops” who went after General Michael Flynn. President Trump called the players involved in the horrible plot […] Continue reading: BREAKING: President Trump’s Fiery Interview On Fox & Friends…”These are dirty politicians and dirty cops…They put our nation in danger with other nations, including Russia” [VIDEO] ... Full Article Featured Politics
on Fed Judge Releases 21-Yr-Old Man To “Clean and Sober House” After Appearing In Court For Sexually Assaulting 12-Yr-Old Girl For One Month While Hiding In Her Bedroom By 100percentfedup.com Published On :: Fri, 08 May 2020 18:49:10 +0000 The following article, Fed Judge Releases 21-Yr-Old Man To “Clean and Sober House” After Appearing In Court For Sexually Assaulting 12-Yr-Old Girl For One Month While Hiding In Her Bedroom, was first published on 100PercentFedUp.com. The normalizing of pedophilia is not a far-right conspiracy theory... Continue reading: Fed Judge Releases 21-Yr-Old Man To “Clean and Sober House” After Appearing In Court For Sexually Assaulting 12-Yr-Old Girl For One Month While Hiding In Her Bedroom ... Full Article Featured Left News
on Greg Gutfeld Levels Ilhan Omar With Epic Response To Her Claim That “White Privilege” Is Reason Charges Were Dropped Against General Flynn By 100percentfedup.com Published On :: Fri, 08 May 2020 19:54:46 +0000 The following article, Greg Gutfeld Levels Ilhan Omar With Epic Response To Her Claim That “White Privilege” Is Reason Charges Were Dropped Against General Flynn, was first published on 100PercentFedUp.com. Yesterday, after 3 1/2 years of having his character and integrity called into question, President Trump's first NSA, General Michael Flynn was finally... Continue reading: Greg Gutfeld Levels Ilhan Omar With Epic Response To Her Claim That “White Privilege” Is Reason Charges Were Dropped Against General Flynn ... Full Article Featured Politics
on Rush Limbaugh Predicts Joe Biden Won’t Be The Dem Nominee: “Something’s Gonna Happen” By 100percentfedup.com Published On :: Sat, 09 May 2020 02:15:43 +0000 The following article, Rush Limbaugh Predicts Joe Biden Won’t Be The Dem Nominee: “Something’s Gonna Happen”, was first published on 100PercentFedUp.com. Is Joe Biden going to become the Democrat nominee and run against Trump in the fall? Continue reading: Rush Limbaugh Predicts Joe Biden Won’t Be The Dem Nominee: “Something’s Gonna Happen” ... Full Article Featured Left News Politics
on Video: Dallas Salon Owner Shelley Luther Gets Surprise Visit from Sen Ted Cruz for a Celebratory Haircut By 100percentfedup.com Published On :: Sat, 09 May 2020 13:19:16 +0000 The following article, Video: Dallas Salon Owner Shelley Luther Gets Surprise Visit from Sen Ted Cruz for a Celebratory Haircut, was first published on 100PercentFedUp.com. When Dallas, Texas salon owner Shelley Luther opened her salon in defiance of the lockdown order in Texas, she was visited numerous times by the local police and then sentenced to 7 days in jail with a fine of $7,000. After public outrage at her punishment, the Texas Supreme Court stepped in to demand her […] Continue reading: Video: Dallas Salon Owner Shelley Luther Gets Surprise Visit from Sen Ted Cruz for a Celebratory Haircut ... Full Article Breaking Featured Government News Politics
on Council votes against proposed cannabis store location in Lakeshore By windsor.ctvnews.ca Published On :: Fri, 8 May 2020 16:54:00 -0400 In Lakeshore, it may be a little while longer before a retail cannabis store opens. Full Article
on Windsor Assembly Plant on track for May 19 restart By windsor.ctvnews.ca Published On :: Fri, 8 May 2020 16:21:00 -0400 The Fiat-Chrysler Windsor Assembly Plant looks to be on track for a May 19 reopening according to union leadership. Full Article
on Traffic stop in Windsor leads to multiple charges and discovery of homemade conducted energy weapon By windsor.ctvnews.ca Published On :: Fri, 8 May 2020 15:00:00 -0400 After being pulled over for what started as a traffic violation, two Windsor men were arrested and face multiple drug, property, and weapon related charges. Full Article
on Owners of new retail cannabis store hoping to open soon in Pillette Village By windsor.ctvnews.ca Published On :: Fri, 8 May 2020 16:51:00 -0400 At a time when store front vacancies are growing thanks to COVID-19, a new retail cannabis store in Pillette Village is hoping to open soon. Full Article
on OPP release composite drawing of man who allegedly impersonated an officer By windsor.ctvnews.ca Published On :: Fri, 8 May 2020 12:53:00 -0400 Essex County OPP have released a composite drawing of a suspect reported to be impersonating a police officer in Lakeshore. Full Article
on Ontario government to prop-up child-care providers with financial supports By toronto.ctvnews.ca Published On :: Sat, 9 May 2020 10:39:00 -0400 The provincial government has announced it will support child care centres that have been closed since March with their fixed operating costs as the fight against COVID-19 continues. Full Article
on Provincial parks will reopen but for day-use only By toronto.ctvnews.ca Published On :: Sat, 9 May 2020 07:43:00 -0400 Ontario’s provincial parks and conservation areas will reopen this week but campgrounds and beaches will continue to be off-limits for now. Full Article
on One new death and nine new COVID-19 cases in Windsor-Essex By windsor.ctvnews.ca Published On :: Sat, 9 May 2020 13:18:00 -0400 One more person has died from the coronavirus in the Windsor-Essex region on Saturday and nine new cases have been reported by the health unit. Full Article
on Little Richard, flamboyant rock 'n' roll pioneer, dead at 87 By www.ctvnews.ca Published On :: Sat, 9 May 2020 08:55:00 -0600 Little Richard, the self-proclaimed "architect of rock 'n' roll" whose piercing wail, pounding piano and towering pompadour irrevocably altered popular music while introducing black R&B to white America, has died Saturday. He was 87. Full Article
on The New Macroeconomics of Populism By feedproxy.google.com Published On :: Mon, 17 Jun 2019 07:23:37 +0000 17 June 2019 David Lubin Associate Fellow, Global Economy and Finance Programme @davidlubin The nationalist urge to keep the world off your back extends to foreign finance. 2019-06-17-AMLO.jpg Mexican president Andrés Manuel López Obrador throws out the first pitch at a baseball game in March. Photo: Getty Images. It is nearly 30 years since Rudiger Dornbusch and Sebastian Edwards published a seminal book, The Macroeconomics of Populism. Their conclusion back then was that the economic policies of populist leaders were quintessentially irresponsible. These governments, blinded by an aim to address perceived social injustices, specialised in profligacy, unbothered by budget constraints or whether they might run out of foreign exchange.Because of this disregard for basic economic logic, their policy experiments inevitably ended badly, with some combination of inflation, capital flight, recession and default. Salvador Allende’s Chile in the 1970s, or Alan García’s Peru in the 1980s, capture this story perfectly.These days, the macroeconomics of populism looks different. Of course there are populist leaders out there whose policies follow, more or less, the playbook of the 1970s and 1980s. Donald Trump may prove to be one of those, with a late-cycle fiscal expansion that seemed to have no basis in economic reasoning; Recep Tayyip Erdogan, by some accounts, may be another.But a much more interesting phenomenon is the apparent surge in populist leaders whose economic policies are remarkably disciplined.Take Mexico’s president, Andrés Manuel López Obrador. When it comes to fiscal policy, it is odd indeed that this fiery critic of neoliberalism seems fully committed to austerity. His budget for 2019 targets a surplus before interest payments of 1 per cent of GDP, and on current plans he intends to increase that surplus next year to 1.3 per cent of GDP. He has upheld the autonomy of the central bank and, so far at least, his overall macroeconomic framework is anything but revolutionary.Hungary’s prime minister Viktor Orban offers another example of conservative populism. Under his watch, budget deficits have been considerably lower than they had been previously, helping to push the stock of public debt down from 74 per cent of GDP in 2010, the year Orban took over, to 68 per cent last year.This emphasis on the virtues of fiscal prudence is also visible in Poland, where Jaroslaw Kaczynski’s PiS has managed public finances with sufficient discipline in the past few years to push the debt/GDP ratio below 50 per cent last year, the first time this has happened since 2009.The obvious question is: what has changed in the decades since Dornbusch and Edwards went into print?One answer is that today’s populists tend to strive for national self-reliance, which encourages them to avoid building up any dependence on foreign capital. And since that goal is achieved by keeping a tight rein on macro policy, fiscal indiscipline is avoided in order to limit vulnerability to foreign influences.Perhaps this is because the 'them', or the perceived enemy, for many of today’s populists tends to be outside the country rather than inside. Broadly speaking, it is the forces of globalisation — and global capital in particular — that are the problem for these leaders, and self-reliance is the only way to keep those forces at arm’s length. This helps to explain why, for example, Orban has been so keen to repay debt to Hungary’s external creditors. He has relied instead on selling bonds to Hungarian households to finance his deficits, even though the interest rates on those bonds are much higher than he would pay to foreign creditors. It also helps explain why the PiS in Poland has presided over a decline in foreign holdings of its domestic bonds. Foreign investors owned 40 per cent of Poland’s domestic government debt back in 2015, but only 26 per cent now.In other words, among many of today’s populists there is a blurring of the distinction between populism and nationalism. And the nationalistic urge to keep the rest of the world off your back seems to dominate the populist urge to spend money. The perfect example of that instinct is Vladimir Putin: not necessarily a populist, but his administration has been emphatic about the need to keep public spending low and to build solid financial buffers. National self-reliance is an economic obsession for the Russian government, and provides a model for other countries who wish to insulate themselves from international finance.One of the reasons why the macroeconomics of populism have changed in this way is the historical legacy of economic disaster. If you are a populist leader in a country where financial crisis is part of living memory — as it is in Mexico, Hungary and Russia, say — you might do well to err on the side of conservatism for fear of repeating the mistakes of your predecessors.But another reason why populism looks different for countries like Poland, Hungary, Mexico and Russia has to do with mere luck. Hungary and Poland, in particular, enjoy the luck of geography: having been absorbed into the EU, they have received financial transfers from Brussels averaging some 3-4 per cent of GDP in the past few years, so that populism in these countries has been solidly underpinned by the terms of their EU membership. López Obrador is enjoying the inheritance of his predecessor’s sound macro policy, together with a buoyant US economy and low US interest rates. Russia has had the good fortune of oil exports to rely on.The thing about luck is that it can run out. So maybe it’s not quite time yet to bury the old macroeconomics of populism. But for the time being, it seems true to say that many of today’s populists have an unexpectedly robust sense of economic discipline.This article was originally published in the Financial Times. Full Article
on Dorothy Gordon By feedproxy.google.com Published On :: Thu, 01 Aug 2019 15:21:32 +0000 Associate Fellow, International Security Programme and Global Economy and Finance Programme Biography Dorothy was the founding director general of the Ghana-India Kofi Annan Centre of Excellence in ICT, a position which she held for over a decade.She works globally as a policy adviser, evaluator, project manager and organizational management consultant.Over the course of her 30-year career in international development and technology she has held management positions with the UN and global management consulting firms on four continents.As a strong advocate of the importance of building robust local innovation ecosystems based on open source technologies, she serves on the board and as a mentor to a number of start-ups and NGOs focused on women in tech. Full Article
on New Dimensions in Trade Law By feedproxy.google.com Published On :: Tue, 01 Oct 2019 10:25:01 +0000 Research Event 6 November 2019 - 9:15am to 4:15pm Chatham House | 10 St James's Square | London | SW1Y 4LE Event participants Speakers include:Dr Lorand Bartels, Reader in International Law; Fellow, Trinity House, University of CambridgeLaura Bannister, Senior Adviser on EU-UK Trade, Trade Justice MovementPeter Holmes, Fellow, UKTPO; Reader in Economics, University of SussexAndrew Hood, Partner, Regulatory & Trade, FieldFisher LLP At this event, which forms the second annual UK Trade Policy Observatory conference, there will be six presentations over the course of the day before concluding with a panel discussion and Q&A. This year’s conference will focus on the following legal areas of trade policy:Blockchain: Creating and Eliminating Trade in ServicesChina's Role in the International Trading SystemOfficial Export Support: Compliance and Competition ConcernsStrategic Litigation and Health Regulation: Implications for International Economic LawDevelopment, Labour Standards and Sustainability in Trade AgreementsRetaining Versus Reforming EU Food Safety Legislation: Selected Issues for a US-UK Trade NegotiationTo register for this event, please click here. Department/project Global Economy and Finance Programme, UK Trade Policy Observatory Full Article
on Can the World Economy Find a New Leader? By feedproxy.google.com Published On :: Mon, 07 Oct 2019 11:54:39 +0000 10 October 2019 This paper examines the governance problems in the monetary system and global trade and regulation. It then explores whether issues have arisen because the US has given up its dominant role, and if so how these might be rectified. Read online Download PDF Alan Beattie Associate Fellow, Global Economy and Finance Programme and Europe Programme @alanbeattie LinkedIn 2019-10-07-RMB.jpg An employee counts money at a branch of the Industrial and Commercial Bank of China, Anhui Province, on 26 July 2011. Photo: Getty Images. SummaryMultilateralism may, in theory, put countries on an equal economic footing. But in practice the concept has often relied on an anchor government to create and preserve global norms. Under the presidency of Donald Trump, the US has accelerated its move away from leadership in global economic governance. This shift threatens the monetary and trading systems that have long underpinned globalization. Does the global economy need – and can it find – another leader to take America’s place?In the monetary sphere, the US role in providing an internationalized currency has endured relatively well, even though the US’s formal anchoring of the global exchange rate system collapsed nearly half a century ago. Governance of the US dollar and of the dollar-based financial system has largely been left to competent technocrats.Recent US political uncertainty has encouraged other governments, particularly in the eurozone and China, in their long-standing quest to supplant the dollar. But these economies’ internal weaknesses have prevented their respective currencies from playing a wider role. Arguments for a multipolar system exist, yet network effects plus the dollar’s superior institutions mean it has retained its dominance.In trade, the US role as anchor of the global legal order was already looking unreliable before Trump’s election. Washington has faced growing resistance at home to its global responsibilities. This, together with the idiosyncratic rise of countries such as China, has made the US an increasingly unreliable and narrowly transactional leader.More recently, hard-to-regulate issues such as foreign direct investment, technology transfer and data flows, often with national security implications, are increasingly undermining the ideal of multilateral global governance. Institutions such as the World Trade Organization, focused on cross-border trade in goods and services, are becoming less relevant.Recent US actions against the Chinese technology firm Huawei show the Trump administration’s willingness to decouple the US market from China and try to drag other economies with it. As far as possible, other governments should resist taking sides. A complete separation of the global economy into rival spheres is probably unfeasible, and certainly highly undesirable.Although future US administrations may be less wantonly destructive, it is not realistic to expect them to resume America’s former role. Nor can the US simply be replaced with another power. Instead, coalitions of governments with interests in international rules-based orders will need to form. These coalitions will need to show due deference to issues like investment and national security, especially where attempts to bind governments by multilateral rules are likely to provoke a severe backlash from domestic constituencies. Department/project Global Economy and Finance Programme Full Article
on UK General Election 2019: What the Political Party Manifestos Imply for Future UK Trade By feedproxy.google.com Published On :: Mon, 25 Nov 2019 15:50:01 +0000 Research Event 4 December 2019 - 12:30pm to 1:30pm Chatham House | 10 St James's Square | London | SW1Y 4LE Event participants Michael Gasiorek, Professor of Economics, University of Sussex; Director, Interanalysis; Fellow, UK Trade Policy Observatory, University of SussexJulia Magntorn Garrett, Research Officer, UK Trade Policy Observatory, University of SussexProf Jim Rollo, Deputy Director, UK Trade Policy Observatory, University of Sussex; Associate Fellow, Global Economy and Finance Department, Chatham HouseNicolo Tamberi, Research Officer in the Economics of Brexit, University of SussexL. Alan Winters, Professor of Economics, Director, UK Trade Policy Observatory, University of Sussex The upcoming UK general election is arguably a 'Brexit election', and as such, whoever wins the election will have little time to get their strategy for Brexit up and running to meet the new Brexit deadline of 31 January 2020. But what are the political parties’ policies for the UK's future trade? This event will present and discuss what the five main parties’ manifestos imply for future UK trade. Each manifesto will be presented and analysed by a fellow of the UK Trade Policy Observatory (UKTPO) and will be followed by a Q&A session. Department/project Global Economy and Finance Programme, UK Trade Policy Observatory Michela Gariboldi Research Assistant, Global Economy and Finance Programme 02073143692 Email Full Article
on Creon Butler By feedproxy.google.com Published On :: Mon, 06 Jan 2020 16:05:39 +0000 Research Director, Trade, Investment & New Governance Models: Director, Global Economy and Finance Programme Biography Creon Butler joined Chatham House from the Cabinet Office where he served as director for international economic affairs in the National Security Secretariat and G7/G20 ‘sous sherpa’, advising on global policy issues such as climate change, natural resource security, global health threats and the future of the international economic architecture.Creon first joined the Cabinet Office in 2013 as director in the European and Global Issues Secretariat, advising prime minister David Cameron on international economic and financial issues, ranging from country-specific developments in China and Germany to global challenges such as antimicrobial resistance and anticorruption.He designed and organized the UK’s global Anti-Corruption Summit in May 2016.Earlier in his career, he served in the Bank of England, HM Treasury and in the Foreign and Commonwealth Office, where he was director for economic policy and chief economic adviser. He was also deputy high commissioner in New Delhi from 2006 to 2009. Areas of expertise International financial marketsInternational macroeconomicsInternational trade and investmentGlobal economic architectureGood governance and anti-corruption policiesIndia and China economic developments Past experience 2016-19Director, National Security Secretariat Cabinet Office2013-16Director, European and Global Issues Secretariat, Cabinet Office2009-12Senior Adviser, International and EU, HM Treasury2006-09Minister and Deputy High Commissioner, British High Commission, New Delhi2004-06Director, Economic Policy, Foreign and Commonwealth Office1999-04Chief Economic Adviser, Foreign and Commonwealth Office1994-99Head, Monetary Instruments and Markets Division, Bank of England1993-94Adviser, Monetary and Exchange Rate Policy, Bank of England1991-93Principle Private Secretary to the Deputy Governor (Eddie George), Bank of England1984-91Economist, various departments, Bank of England1982-84Researcher, London School of Economics1981-82MSc (Econometrics and Mathematical Economics), London School of Economics1978-81BSc (Economics), London School of Economics Email LinkedIn Full Article
on The EU Cannot Build a Foreign Policy on Regulatory Power Alone By feedproxy.google.com Published On :: Tue, 11 Feb 2020 16:33:26 +0000 11 February 2020 Alan Beattie Associate Fellow, Global Economy and Finance Programme and Europe Programme @alanbeattie LinkedIn Brussels will find its much-vaunted heft in setting standards cannot help it advance its geopolitical interests. 2020-02-11-Leyen.jpg EU Commission President Ursula von der Leyen speaks at the European Parliament in Strasbourg in February. Photo: Getty Images. There are two well-established ideas in trade. Individually, they are correct. Combined, they can lead to a conclusion that is unfortunately wrong.The first idea is that, across a range of economic sectors, the EU and the US have been engaged in a battle to have their model of regulation accepted as the global one, and that the EU is generally winning.The second is that governments can use their regulatory power to extend strategic and foreign policy influence.The conclusion would seem to be that the EU, which has for decades tried to develop a foreign policy, should be able to use its superpower status in regulation and trade to project its interests and its values abroad.That’s the theory. It’s a proposition much welcomed by EU policymakers, who know they are highly unlikely any time soon to acquire any of the tools usually required to run an effective foreign policy.The EU doesn’t have an army it can send into a shooting war, enough military or political aid to prop up or dispense of governments abroad, or a centralized intelligence service. Commission President Ursula von der Leyen has declared her outfit to be a ‘geopolitical commission’, and is casting about for any means of making that real.Through the ‘Brussels effect’ whereby European rules and standards are exported via both companies and governments, the EU has indeed won many regulatory battles with the US.Its cars, chemicals and product safety regulations are more widely adopted round the world than their American counterparts. In the absence of any coherent US offering, bar some varied state-level systems, the General Data Protection Regulation (GDPR) is the closest thing the world has to a single model for data privacy, and variants of it are being adopted by dozens of countries.The problem is this. Those parts of global economic governance where the US is dominant – particularly the dollar payments system – are highly conducive to projecting US power abroad. The extraterritorial reach of secondary sanctions, plus the widespread reliance of banks and companies worldwide on dollar funding – and hence the American financial system – means that the US can precisely target its influence.The EU can enforce trade sanctions, but not in such a powerful and discriminatory way, and it will always be outgunned by the US. Donald Trump could in effect force European companies to join in his sanctions on Iran when he pulled out of the nuclear deal, despite EU legislation designed to prevent their businesses being bullied. He can go after the chief financial officer of Huawei for allegedly breaching those sanctions.By contrast, the widespread adoption of GDPR or data protection regimes inspired by it may give the EU a warm glow of satisfaction, but it cannot be turned into a geopolitical tool in the same way.Nor, necessarily, does it particularly benefit the EU economy. Europe’s undersized tech sector seems unlikely to unduly benefit from the fact that data protection rules were written in the EU. Indeed, one common criticism of the regulations is that they entrench the power of incumbent tech giants like Google.There is a similar pattern at work in the adoption of new technologies such as artificial intelligence and the Internet of Things. In that field, the EU and its member states are also facing determined competition from China, which has been pushing its technologies and standards through forums such as the International Telecommunication Union.The EU has been attempting to write international rules for the use of AI which it hopes to be widely adopted. But again, these are a constraint on the use of new technologies largely developed by others, not the control of innovation.By contrast, China has created a vast domestic market in technologies like facial recognition and unleashed its own companies on it. The resulting surveillance kit can then be marketed to emerging market governments as part of China’s enduring foreign policy campaign to build up supporters in the developing world.If it genuinely wants to turn its economic power into geopolitical influence – and it’s not entirely clear what it would do with it if it did – the EU needs to recognize that not all forms of regulatory and trading dominance are the same.Providing public goods to the world economy is all very well. But unless they are so particular in nature that they project uniquely European values and interests, that makes the EU a supplier of useful plumbing but not a global architect of power.On the other hand, it could content itself with its position for the moment. It could recognize that not until enough hard power – guns, intelligence, money – is transferred from the member states to the centre, or until the member states start acting collectively, will the EU genuinely become a geopolitical force. Speaking loudly and carrying a stick of foam rubber is rarely a way to gain credibility in international relations.This article is part of a series of publications and roundtable discussions in the Chatham House Global Trade Policy Forum. Full Article
on How to Fight the Economic Fallout From the Coronavirus By feedproxy.google.com Published On :: Wed, 04 Mar 2020 03:56:03 +0000 4 March 2020 Creon Butler Research Director, Trade, Investment & New Governance Models: Director, Global Economy and Finance Programme LinkedIn Finance ministries and central banks have a critical role to play to mitigate the threat Covid-19 poses to the global economy. 2020-03-03-TokyoCV.jpg A pedestrian wearing a face mask walks past stock prices in Tokyo on 25 February. Photo: Getty Images. Epidemics, of the size of Covid-19, have huge economic impacts – not just from the costs of managing the health of people, but stopping them, and keeping the economy working. The 10% fall in global stock markets since it became clear that Covid-19 would not be limited to China has boldly highlighted this.Suppressing the epidemic, but allowing the economy to still function, requires key decisions, in which central banks and finance ministries play a part.The role of fiscal and monetary authorities in managing an epidemic economyThe scope to use monetary policy to manage the economic impact of Covid-19 is limited. The fact that the underlying cause of the shock is an infectious disease outbreak (rather than a banking crisis, as in 2008-09) and nominal interest rates are currently close to zero in most major advanced economies reduces the effectiveness of monetary policy.Since 2010, reductions in fiscal deficits mean there is more scope for supportive fiscal action. But even here, high public debt levels and the desire not to underwrite ‘zombie’ companies that may have been sustained by a decade of ultra-low interest rates remain constraints. However, outside broad based fiscal and monetary policies there are six ways in which finance ministries and central banks will play a critical role in responding to the crisis.A first crucial role for finance ministries and central banks is in helping provide the best possible economic evaluation of strict containment measures (trying to isolate each potential case) versus managing the epidemic (delaying the spread of the virus, protecting the most vulnerable and treating the sick, while enabling the majority of people to get on with daily life). Given the economic consequences, they must play a full part, alongside health experts, in advising political leaders on this key decision.Second, if large numbers of staff are required to work from home to manage the epidemic, they have the lead role in doing whatever is necessary to ensure that financial markets – and thus the wider economy – will continue to function smoothly.Third, they need to ensure adequate funding for the public health response. Steps that can make an enormous difference to the success of containment strategies, such as strengthening surveillance, and guaranteeing the availability of testing kits and protective equipment for front line health workers, must not fail because of a lack of funding. Fourth, they have a lead role in designing targeted economic interventions for the wider economy. Some of these are needed immediately to re-enforce and incentivize strict containment strategies, such as ensuring that employees without full or adequate sick leave cover have the financial support to enable them to report and self-isolate when they get sick. Other interventions may help improve the resilience of the economy in accommodating moderate ‘social distancing’ measures; for example, by providing assistance to small firms to help them gear up for home working.Yet others are needed, as a contingency, to safeguard the most vulnerable sectors (such as tourism, retail and transport) in circumstances where there is a prolonged downturn. The latter may include schemes to allow deferral of tax payments by SMEs, or steps to encourage loan extensions and other forms of liquidity support from the banking system, or by moves to underwrite continued provision of business insurance.Fifth, national economic authorities will need to play their part in combatting ‘fake news’ through providing transparent and high-quality analysis. This includes providing forecasts on the likely economic impact of the virus under different scenarios, but also detailed information on the support and contingency measures they are considering, so they can be improved and refined through feedback. Sixth, they will need to ensure that there is generous international support for poor countries, by ensuring the available multilateral support facilities from the international financial institutions and multilateral development banks are adequately funded and fit for purpose. The World Bank has already announced an initial $12 billion financing package, but much more is likely to be needed.They also need to support coordinated bilateral aid where this is more effective, as well as special measures to support particularly vulnerable groups, for example, in refugee camps and prisons. Given the importance of distributing sophisticated medical equipment and expertise quickly, it is also important that every effort is made to avoid delays due to customs and migration checks.Managing the futureThe response to the immediate crisis will rightly take priority now, but economic authorities must also play their part in ensuring the world finally takes decisive steps to prevent a repeat of Covid-19 in future.The experience with SARS, H1N1 and Ebola shows that, while some progress is made after each outbreak, this is often not sustained. This epidemic shows that managing diseases is absolutely critical to the long-term health of global economy, and doubly so in circumstances where traditional central bank and finance ministry tools for dealing with major global economic shocks are limited.Finance ministries and central banks therefore need to push hard within government to ensure sustained long-term funding of research on prevention and strengthening of public health systems. They also need to ensure that the right lessons are drawn by the private sector on making international supply chains more robust.Critical to the overall success of the economic effort will be effective international coordination. The G20 was established as the premier economic forum for international economic cooperation in 2010, and global health issues have been a substantive part of the G20 agenda since the 2017 Hamburg Summit. At the same time, G7 finance ministers and deputies remain one of the most effective bodies for managing economic crises on a day-to-day basis and should continue this within the framework provided by the G20.However, to be effective, the US, as current president of the G7, will need to put aside its reservations on multilateral economic cooperation and working with China to provide strong leadership. Full Article
on Coronavirus: Global Response Urgently Needed By feedproxy.google.com Published On :: Sun, 15 Mar 2020 14:33:11 +0000 15 March 2020 Jim O'Neill Chair, Chatham House Robin Niblett Director and Chief Executive, Chatham House @RobinNiblett Creon Butler Research Director, Trade, Investment & New Governance Models: Director, Global Economy and Finance Programme LinkedIn There have been warnings for several years that world leaders would find it hard to manage a new global crisis in today’s more confrontational, protectionist and nativist political environment. 2020-03-15-Korea-Stock-Exchange.jpg A currency dealer wearing a face mask monitors exchange rates in front of a screen showing South Korea's benchmark stock index in Seoul on March 13, 2020. Photo by JUNG YEON-JE/AFP via Getty Images. An infectious disease outbreak has long been a top national security risk in several countries, but the speed and extent of COVID-19’s spread and the scale of its social and economic impact has come as an enormous and deeply worrying shock.This pandemic is not just a global medical and economic emergency. It could also prove a decisive make-or-break point for today’s system of global political and economic cooperation.This system was built up painstakingly after 1945 as a response to the beggar-thy-neighbour economic policies of the 1930s which led to the Second World War. But it has been seriously weakened recently as the US and China have entered a more overt phase of strategic competition, and as they and a number of the other most important global and regional players have pursued their narrowly defined self-interest.Now, the disjointed global economic response to COVID-19, with its enormous ramifications for global prosperity and economic stability, has blown into the open the urgent need for an immediate reaffirmation of international political and economic cooperation.What is needed is a clear, coordinated and public statement from the leaders of the world’s major countries affirming the many things on which they do already agree, and some on which they should be able to agree.In particular that:they will give the strongest possible support for the WHO in leading the medical response internationally;they will be transparent and tell the truth to their peoples about the progress of the disease and the threat that it represents;they will work together and with the international financial institutions to provide businesses, particularly SMEs, and individuals whatever support they need to get through the immediate crisis and avoid long-term damage to the global economy; they will ensure the financial facilities for crisis support to countries - whether at global or regional level - have whatever resources they need to support countries in difficulty;they will avoid new protectionist policies - whether in trade or finance;they commit not to forget the poor and vulnerable in society and those least able to look after themselves.Such a statement could be made by G20 leaders, reflecting the group’s role since 2010 as the premier forum for international economic cooperation.But it could be even more appropriate coming from the UN Security Council, recognising that COVID-19 is much more than an economic challenge; and also reflecting the practical fact, in a time when international travel is restricted, the UNSC has an existing mechanism in New York to negotiate and quickly agree such a statement.A public statement by leading countries could do a great deal to help arrest a growing sense of powerlessness among citizens and loss of confidence among businesses worldwide as the virus spreads.It could also set a new course for international political and economic cooperation, not just in relation to the virus, but also other global threats with potentially devastating consequences for economic growth and political stability in the coming years. Full Article
on COVID-19: How Do We Re-open the Economy? By feedproxy.google.com Published On :: Tue, 21 Apr 2020 14:41:47 +0000 21 April 2020 Creon Butler Research Director, Trade, Investment & New Governance Models: Director, Global Economy and Finance Programme LinkedIn Following five clear steps will create the confidence needed for both the consumer and business decision-making which is crucial to a strong recovery. 2020-04-21-Shop-Retail-Closed Chain wrapped around the door of a Saks Fifth Avenue Inc. store in San Francisco, California, during the COVID-19 crisis. Photo by David Paul Morris/Bloomberg via Getty Images With the IMF forecasting a 6.1% fall in advanced economy GDP in 2020 and world trade expected to contract by 11%, there is intense focus on the question of how and when to re-open economies currently in lockdown.But no ‘opening up’ plan has a chance of succeeding unless it commands the confidence of all the main actors in the economy – employees, consumers, firms, investors and local authorities.Without public confidence, these groups may follow official guidance only sporadically; consumers will preserve cash rather than spend it on goods and services; employees will delay returning to work wherever possible; businesses will face worsening bottlenecks as some parts of the economy open up while key suppliers remain closed; and firms will continue to delay many discretionary investment and hiring decisions.Achieving public confidenceTaken together, these behaviours would substantially reduce the chances of a strong economic bounce-back even in the absence of a widespread second wave of infections. Five key steps are needed to achieve a high degree of public confidence in any reopening plan.First, enough progress must be made in suppressing the virus and in building public health capacity so the public can be confident any new outbreak will be contained without reverting to another full-scale lockdown. Moreover, the general public needs to feel that the treatment capacity of the health system is at a level where the risk to life if someone does fall ill with the virus is at an acceptably low level.Achieving this requires the government to demonstrate the necessary capabilities - testing, contact tracing, quarantine facilities, supplies of face masks and other forms of PPE (personal protective equipment) - are actually in place and can be sustained, rather than relying on future commitments. It also needs to be clear on the role to be played going forward by handwashing and other personal hygiene measures.Second, the authorities need to set out clear priorities on which parts of the economy are to open first and why. This needs to take account of both supply side and demand side factors, such as the importance of a particular sector to delivering essential supplies, a sector’s ability to put in place effective protocols to protect its employees and customers, and its importance to the functioning of other parts of the economy. There is little point in opening a car assembly plant unless its SME suppliers are able to deliver the required parts.Detailed planning of the phasing of specific relaxation measures is essential, as is close cooperation between business and the authorities. The government also needs to establish a centralised coordination function capable of dealing quickly with any unexpected supply chain glitches. And it must pay close attention to feedback from health experts on how the process of re-opening the economy sector-by-sector is affecting the rate of infection. Third, the government needs to state how the current financial and economic support measures for the economy will evolve as the re-opening process continues. It is critical to avoid removing support measures too soon, and some key measures may have to continue to operate even as firms restart their operations. It is important to show how - over time - the measures will evolve from a ‘life support’ system for businesses and individuals into a more conventional economic stimulus.This transition strategy could initially be signalled through broad principles, but the government needs to follow through quickly by detailing specific measures. The transition strategy must target sectors where most damage has been done, including the SME sector in general and specific areas such as transport, leisure and retail. It needs to factor in the hard truth that some businesses will be no longer be viable after the crisis and set out how the government is going to support employees and entrepreneurs who suffer as a result.The government must also explain how it intends to learn the lessons and capture the upsides from the crisis by building a more resilient economy over the longer term. Most importantly, it has to demonstrate continued commitment to tackling climate change – which is at least as big a threat to mankind’s future as pandemics.Fourth, the authorities should explain how they plan to manage controls on movement of people across borders to minimise the risk of new infection outbreaks, but also to help sustain the opening-up measures. This needs to take account of the fact that different countries are at different stages in the progress of the pandemic and may have different strategies and trade-offs on the risks they are willing to take as they open up.As a minimum, an effective border plan requires close cooperation with near neighbours as these are likely to be the most important economic counterparts for many countries. But ideally each country’s plan should be part of a wider global opening-up strategy coordinated by the G20. In the absence of a reliable antibody test, border control measures will have to rely on a combination of imperfect testing, quarantine, and new, shared data requirements for incoming and departing passengers. Fifth, the authorities must communicate the steps effectively to the public, in a manner that shows not only that this is a well thought-through plan, but also does not hide the extent of the uncertainties, or the likelihood that rapid modifications may be needed as the plan is implemented. In designing the communications, the authorities should develop specific measures to enable the public to track progress.Such measures are vital to sustaining business, consumer and employee confidence. While some smaller advanced economies appear close to completing these steps, for many others there is still a long way to go. Waiting until they are achieved means higher economic costs in the short-term. But, in the long-term, they will deliver real net benefits.Authorities are more likely to sustain these measures because key economic actors will actually follow the guidance given. Also, by instilling confidence, the plan will bring forward the consumer and business decision-making crucial to a strong recovery. In contrast, moving ahead without proper preparation risks turning an already severe economic recession into something much worse. Full Article
on IMF Needs New Thinking to Deal with Coronavirus By feedproxy.google.com Published On :: Mon, 27 Apr 2020 08:59:48 +0000 27 April 2020 David Lubin Associate Fellow, Global Economy and Finance Programme @davidlubin The IMF faces a big dilemma in its efforts to support the global economy at its time of desperate need. Simply put, the Fund’s problem is that most of the $1tn that it says it can lend is effectively unusable. 2020-04-27-IMF-Virtual-News Kristalina Georgieva, managing director of the International Monetary Fund (IMF), speaks during a virtual news conference on April 15, 2020. Photo by Andrew Harrer/Bloomberg via Getty Images There were several notable achievements during last week’s Spring meetings. The Fund’s frank set of forecasts for world GDP growth are a grim but valuable reminder of the scale of the crisis we are facing, and the Fund’s richer members will finance a temporary suspension on payments to the IMF for 29 very poor countries.Most importantly, a boost to the Fund’s main emergency facilities - the Rapid Credit Facility and the Rapid Financing Instrument - now makes $100bn of proper relief available to a wide range of countries. But the core problem is that the vast bulk of the Fund’s firepower is effectively inert.This is because of the idea of 'conditionality', which underpins almost all of the IMF’s lending relationships with member states. Under normal circumstances, when the IMF is the last-resort lender to a country, it insists that the borrowing government tighten its belt and exercise restraint in public spending.This helps to achieve three objectives. One is to stabilise the public debt burden, to ensure that the resources made available are not wasted. The second is to limit the whole economy’s need for foreign exchange, a shortage of which had prompted a country to seek IMF help in the first place. And the third is to ensure that the IMF can get repaid.Role within the international monetary systemSince the IMF does not take any physical collateral from countries to whom it is lending, the belt-tightening helps to act as a kind of collateral for the IMF. It helps to maximise the probability that the IMF does not suffer losses on its own loan portfolio — losses that would have bad consequences for the Fund’s role within the international monetary system.This is a perfectly respectable goal. Walter Bagehot, the legendary editor of The Economist, established modern conventional wisdom about managing panics. Relying on a medical metaphor that feels oddly relevant today, he said that a panic 'is a species of neuralgia, and according to the rules of science you must not starve it.' Managing a panic, therefore, requires lending to stricken borrowers 'whenever the security is good', as Bagehot put it. The IMF has had to invent its own form of collateral, and conditionality is the result. The problem, though, is that belt-tightening is a completely inappropriate approach to managing the current crisis.Countries are stricken not because they have indulged in any irresponsible spending sprees that led to a shortage of foreign exchange, but because of a virus beyond their control. Indeed, it would seem almost grotesque for the Fund to ask countries to cut spending at a time when, if anything, more spending is needed to stop people dying or from falling into a permanent trap of unemployment.The obvious solution to this problem would be to increase the amount of money that any country can access from the Fund’s emergency facilities well beyond the $100bn now available. But that kind of solution would quickly run up against the IMF’s collateral problem.The more the IMF makes available as 'true' emergency financing with few or no strings attached, the more it begins to undermine the quality of its loan portfolio. And if the IMF’s senior creditor status is undermined, then an important building block of the international monetary system would be at risk.One way out of this might have been an emergency allocation of Special Drawing Rights, a tool last used in 2009. This would credit member countries’ accounts with new, unconditional liquidity that could be exchanged for the five currencies that underpin the SDR: the dollar, the yen, the euro, sterling and the renminbi. That will not be happening, though, since the US is firmly opposed, for reasons bad and good.So in the end the IMF and its shareholders face a huge problem. It either lends more money on easy terms without the 'collateral' of conditionality, at the expense of undermining its own balance sheet - or it remains, in systemic terms, on the sidelines of this crisis.And since the legacy of this crisis will be some eye-watering increases in the public debt burdens of many emerging economies, the IMF’s struggle to find a way to administer its medicine will certainly outlive this round of the coronavirus outbreak.This article is a version of a piece which was originally published in the Financial Times Full Article
on Coronavirus: Could a People’s Bailout Help? By feedproxy.google.com Published On :: Wed, 06 May 2020 12:42:49 +0000 7 May 2020 Jim O'Neill Chair, Chatham House Lyndsey Jefferson Digital Editor, Communications and Publishing Department @LyndseyLdn The coronavirus crisis has resulted in an unprecedented economic downturn. Conventional quantitative easing measures used after the 2008 financial crisis will not be enough this time. 2020-05-06-Coronavirus-Food-Bank-NYC.jpg Local residents line up outside a food pantry during the COVID-19 pandemic on 23 April 2020 in Brooklyn, New York. Due to increased levels of unemployment, the lines at the daily food pantry have been getting longer. Photo: Getty Images. What is quantitative easing? How was it used after the 2008 financial crisis?Quantitative easing (QE) has been in existence since the Japanese central bank introduced it at the turn of the millennium. The simplest way to think about it is this: when interest rates can't go down anymore and play their normal role of stimulating growth, central banks try to expand the money supply. So, they're expanding the quantitative amount of money they put into the system. Of course, after 2008 because of the scale of the financial and economic collapse, many Western countries resorted to QE. Some have never gotten rid of it. Others have started to, but as a result of this crisis, have gone straight back to that playbook.33 million Americans have now filed for unemployment and one in five American workers have lost their jobs due to COVID-19. These are levels not seen since the Great Depression. You recently called for G20 countries to provide income support for all citizens. Why is this so urgent to implement now?It is incredible to reflect back on the short time since I published that piece. I entitled it the need for a so-called people's QE, and in some ways a number of European countries, including the UK, have executed some aspects of what I was suggesting. The United States has not, even though the absolute amounts of money the US authorities have put through their fiscal system to try and support the economy is actually bigger as a percentage of GDP than many in Europe. What they haven't done is support ongoing employment through various schemes that many European countries have done, of which the UK has, to some degree, been one of the most ambitious.That’s partly why you see such enormous filing for unemployment claims in the US. There’s no direct support to encourage employers to keep their employees on, in complete contrast to what you see in many Scandinavian countries who were the first to do it in Europe, and something the UK has since done. On a practical level, what might a smart people’s QE look like? We are living in an extraordinary time. Like many others in my generation, it’s nothing that any of us have gone through. Perhaps economically, the only parallel one can find is from the 1920s and 1930s.It became obvious to me in early March that governments are going to have to essentially force as many of us as possible, if we weren't doing absolutely crucial necessities, to stop working or to work from home. It was pretty obvious that the consequences could be horrific. So, the idea of a people's QE that I suggested then, some would have regarded as quite audacious. The most dramatic thing that could be done was, to put it simply, governments effectively pay for every business and every employee to have a two month paid holiday. Obviously, this would cost a very large amount of money for governments, but it would be the least disruptive way of getting us all to stay home.And when the time is right to start letting us get back to anything vaguely like normality, there wouldn't be as much permanent disruption. I think about six weeks have passed since I wrote that piece. Actually, given the policies many governments have announced, I'm not sure undertaking the audacity in generosity of what I suggested would have cost any more. Over the long term, it might have actually turned out to be less. Of course, there are ethics issues around whether the system could be gamed or not, amongst other issues. But six weeks later, I still believe that would have been the smartest thing to do. It certainly would have been much better than trying to encourage many businesses, particularly smaller ones, to take out loans.A couple of countries got close to what I was suggesting – Germany and Switzerland were very quick to give 100% government guarantees to business, as well as generous wage support systems. But a number of other countries haven't, like the US, even though they wrote a $1200 check for each citizen. Should a people’s QE involve the purchase and write off of consumer debt and student debt by a central bank? I think these things might have to be considered. I remember being on a conference call to Chatham House members where we discussed what would be the likely economic consequences and what policymakers should do. One person on the call was talking about quite conventional forms of policy just through various forms of standard QE. During the Q&A, someone asked whether we thought the US Federal Reserve might end up buying equities. And I said, well, why not? Eventually, it might come to that. Actually, before that discussion was over, the Fed coincidentally announced they were going to buy high-yield corporate bonds, or very risky company debt. This is something that would have been unheard of even by the playbook of 2008. So, I don't think ideas like a kind of provision to help student debtors is entirely crazy. These are things that our policymakers are going to have to think about as we go forward in the challenging and unpredictable days and weeks ahead. Poorer countries like El Salvador have gone as far as cancelling rent and major utility bills for its citizens. Do you think countries like the US and UK have gone far enough to help people during the crisis?Going one step further than a people’s QE and postponing major payments is a pretty interesting concept. I think in reality, it would be very disruptive to the medium to long-term mechanism of our societies. It could be very, very complicated. But, of course, some parts of the G20 nations, including the UK, have moved significantly in these areas as it relates to rent payments or mortgage payments. There have been significant mortgage holidays being introduced for many sectors of our community. I think the British government has been quite thoughtful about it without doing the whole hog of potentially getting rid of our transaction system for two months or beyond.You know, this may well be something that has to be considered if, God forbid, there is a second peak of the virus. If countries come out of a lockdown and all that results in is a dramatic rise in infections and then death again, we're going to end up right back where we are. Policymakers may have to implement more generous versions of what we've done already, despite what the long term debt consequences could be.The Coronavirus Aid, Relief, and Economic Security (CARES) Act in the US has been criticized as a corporate bailout while offering little to the American people. It was recently reported that hedge fund managers are applying for bailouts as ‘small businesses.’ Do you think more oversight is needed in how the stimulus funds are allocated? The speed at which many countries have responded and introduced policies means that there's going to be some gaping holes which allow people to unfairly benefit from the system. And if indeed, that were to be the case, I cannot see why a hedge fund should benefit from government generosity.A true hedge fund is supposed to be a form of investment manager that thrives in times of great volatility, and knows how to better navigate such financial markets than more conventional funds. So this shouldn’t be an environment where hedge funds seek the same kind of help as small businesses. That is certainly something the government should be very careful about.Some economists argue that central banks are not independent as they finance fiscal spending through purchase of government bonds. Do the strong measures taken by central banks in response to the crisis undermine the argument for central bank independence? In my view, an effective central bank has to do whatever is necessary, including doing very unconventional things, when the society in which that central bank operates needs it. Most of the time, central banks are pretty boring places, but they really become crucial organizations when we go through times like the 1920s, 1930s, 2008, and of course, this current crisis. If they want to maintain their legitimacy, whatever the true parliamentary or congressional legal standing is, they have to do things quickly and as we've seen in this case, differently than the convention in order to do what our societies need. Somebody was asking me just last week whether the Fed buying high grade debt was legal or not. I think that’s a pretty irrelevant conversation because if it’s not legal now, it will be made legal tomorrow. So, I think central banks have to keep their legitimacy and they have to do what is necessary when the time requires it. In that sense, I think most central banks have handled this crisis so far pretty well. Full Article
on A comprehensive evaluation of a typical plant telomeric G-quadruplex (G4) DNA reveals the dynamics of G4 formation, rearrangement, and unfolding [Plant Biology] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 Telomeres are specific nucleoprotein structures that are located at the ends of linear eukaryotic chromosomes and play crucial roles in genomic stability. Telomere DNA consists of simple repeats of a short G-rich sequence: TTAGGG in mammals and TTTAGGG in most plants. In recent years, the mammalian telomeric G-rich repeats have been shown to form G-quadruplex (G4) structures, which are crucial for modulating telomere functions. Surprisingly, even though plant telomeres are essential for plant growth, development, and environmental adaptions, only few reports exist on plant telomeric G4 DNA (pTG4). Here, using bulk and single-molecule assays, including CD spectroscopy, and single-molecule FRET approaches, we comprehensively characterized the structure and dynamics of a typical plant telomeric sequence, d[GGG(TTTAGGG)3]. We found that this sequence can fold into mixed G4s in potassium, including parallel and antiparallel structures. We also directly detected intermediate dynamic transitions, including G-hairpin, parallel G-triplex, and antiparallel G-triplex structures. Moreover, we observed that pTG4 is unfolded by the AtRecQ2 helicase but not by AtRecQ3. The results of our work shed light on our understanding about the existence, topological structures, stability, intermediates, unwinding, and functions of pTG4. Full Article
on Repression of sphingosine kinase (SK)-interacting protein (SKIP) in acute myeloid leukemia diminishes SK activity and its re-expression restores SK function [Molecular Bases of Disease] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 Previous studies have shown that sphingosine kinase interacting protein (SKIP) inhibits sphingosine kinase (SK) function in fibroblasts. SK phosphorylates sphingosine producing the potent signaling molecule sphingosine-1-phosphate (S1P). SKIP gene (SPHKAP) expression is silenced by hypermethylation of its promoter in acute myeloid leukemia (AML). However, why SKIP activity is silenced in primary AML cells is unclear. Here, we investigated the consequences of SKIP down-regulation in AML primary cells and the effects of SKIP re-expression in leukemic cell lines. Using targeted ultra-HPLC-tandem MS (UPLC-MS/MS), we measured sphingolipids (including S1P and ceramides) in AML and control cells. Primary AML cells had significantly lower SK activity and intracellular S1P concentrations than control cells, and SKIP-transfected leukemia cell lines exhibited increased SK activity. These findings show that SKIP re-expression enhances SK activity in leukemia cells. Furthermore, other bioactive sphingolipids such as ceramide were also down-regulated in primary AML cells. Of note, SKIP re-expression in leukemia cells increased ceramide levels 2-fold, inactivated the key signaling protein extracellular signal-regulated kinase, and increased apoptosis following serum deprivation or chemotherapy. These results indicate that SKIP down-regulation in AML reduces SK activity and ceramide levels, an effect that ultimately inhibits apoptosis in leukemia cells. The findings of our study contrast with previous results indicating that SKIP inhibits SK function in fibroblasts and therefore challenge the notion that SKIP always inhibits SK activity. Full Article
on The FKH domain in FOXP3 mRNA frequently contains mutations in hepatocellular carcinoma that influence the subcellular localization and functions of FOXP3 [Molecular Bases of Disease] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 The transcription factor forkhead box P3 (FOXP3) is a biomarker for regulatory T cells and can also be expressed in cancer cells, but its function in cancer appears to be divergent. The role of hepatocyte-expressed FOXP3 in hepatocellular carcinoma (HCC) is unknown. Here, we collected tumor samples and clinical information from 115 HCC patients and used five human cancer cell lines. We examined FOXP3 mRNA sequences for mutations, used a luciferase assay to assess promoter activities of FOXP3's target genes, and employed mouse tumor models to confirm in vitro results. We detected mutations in the FKH domain of FOXP3 mRNAs in 33% of the HCC tumor tissues, but in none of the adjacent nontumor tissues. None of the mutations occurred at high frequency, indicating that they occurred randomly. Notably, the mutations were not detected in the corresponding regions of FOXP3 genomic DNA, and many of them resulted in amino acid substitutions in the FKH region, altering FOXP3's subcellular localization. FOXP3 delocalization from the nucleus to the cytoplasm caused loss of transcriptional regulation of its target genes, inactivated its tumor-inhibitory capability, and changed cellular responses to histone deacetylase (HDAC) inhibitors. More complex FKH mutations appeared to be associated with worse prognosis in HCC patients. We conclude that mutations in the FKH domain of FOXP3 mRNA frequently occur in HCC and that these mutations are caused by errors in transcription and are not derived from genomic DNA mutations. Our results suggest that transcriptional mutagenesis of FOXP3 plays a role in HCC. Full Article
on Inhibition of the erythropoietin-producing receptor EPHB4 antagonizes androgen receptor overexpression and reduces enzalutamide resistance [Molecular Bases of Disease] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 Prostate cancer (PCa) cells heavily rely on an active androgen receptor (AR) pathway for their survival. Enzalutamide (MDV3100) is a second-generation antiandrogenic drug that was approved by the Food and Drug Administration in 2012 to treat patients with castration-resistant prostate cancer (CRPC). However, emergence of resistance against this drug is inevitable, and it has been a major challenge to develop interventions that help manage enzalutamide-resistant CRPC. Erythropoietin-producing human hepatocellular (Eph) receptors are targeted by ephrin protein ligands and have a broad range of functions. Increasing evidence indicates that this signaling pathway plays an important role in tumorigenesis. Overexpression of EPH receptor B4 (EPHB4) has been observed in multiple types of cancer, being closely associated with proliferation, invasion, and metastasis of tumors. Here, using RNA-Seq analyses of clinical and preclinical samples, along with several biochemical and molecular methods, we report that enzalutamide-resistant PCa requires an active EPHB4 pathway that supports drug resistance of this tumor type. Using a small kinase inhibitor and RNAi-based gene silencing to disrupt EPHB4 activity, we found that these disruptions re-sensitize enzalutamide-resistant PCa to the drug both in vitro and in vivo. Mechanistically, we found that EPHB4 stimulates the AR by inducing proto-oncogene c-Myc (c-Myc) expression. Taken together, these results provide critical insight into the mechanism of enzalutamide resistance in PCa, potentially offering a therapeutic avenue for enhancing the efficacy of enzalutamide to better manage this common malignancy. Full Article
on N{alpha}-Acetylation of the virulence factor EsxA is required for mycobacterial cytosolic translocation and virulence [Molecular Bases of Disease] By feedproxy.google.com Published On :: 2020-04-24T06:08:45-07:00 The Mycobacterium tuberculosis virulence factor EsxA and its chaperone EsxB are secreted as a heterodimer (EsxA:B) and are crucial for mycobacterial escape from phagosomes and cytosolic translocation. Current findings support the idea that for EsxA to interact with host membranes, EsxA must dissociate from EsxB at low pH. However, the molecular mechanism by which the EsxA:B heterodimer separates is not clear. In the present study, using liposome-leakage and cytotoxicity assays, LC-MS/MS–based proteomics, and CCF-4 FRET analysis, we obtained evidence that the Nα-acetylation of the Thr-2 residue on EsxA, a post-translational modification that is present in mycobacteria but absent in Escherichia coli, is required for the EsxA:B separation. Substitutions at Thr-2 that precluded Nα-acetylation inhibited the heterodimer separation and hence prevented EsxA from interacting with the host membrane, resulting in attenuated mycobacterial cytosolic translocation and virulence. Molecular dynamics simulations revealed that at low pH, the Nα-acetylated Thr-2 makes direct and frequent “bind-and-release” contacts with EsxB, which generates a force that pulls EsxB away from EsxA. In summary, our findings provide evidence that the Nα-acetylation at Thr-2 of EsxA facilitates dissociation of the EsxA:B heterodimer required for EsxA membrane permeabilization and mycobacterial cytosolic translocation and virulence. Full Article
on ER stress increases store-operated Ca2+ entry (SOCE) and augments basal insulin secretion in pancreatic beta cells [Molecular Bases of Disease] By feedproxy.google.com Published On :: 2020-04-24T06:08:45-07:00 Type 2 diabetes mellitus (T2DM) is characterized by impaired glucose-stimulated insulin secretion and increased peripheral insulin resistance. Unremitting endoplasmic reticulum (ER) stress can lead to beta-cell apoptosis and has been linked to type 2 diabetes. Although many studies have attempted to link ER stress and T2DM, the specific effects of ER stress on beta-cell function remain incompletely understood. To determine the interrelationship between ER stress and beta-cell function, here we treated insulin-secreting INS-1(832/13) cells or isolated mouse islets with the ER stress–inducer tunicamycin (TM). TM induced ER stress as expected, as evidenced by activation of the unfolded protein response. Beta cells treated with TM also exhibited concomitant alterations in their electrical activity and cytosolic free Ca2+ oscillations. As ER stress is known to reduce ER Ca2+ levels, we tested the hypothesis that the observed increase in Ca2+ oscillations occurred because of reduced ER Ca2+ levels and, in turn, increased store-operated Ca2+ entry. TM-induced cytosolic Ca2+ and membrane electrical oscillations were acutely inhibited by YM58483, which blocks store-operated Ca2+ channels. Significantly, TM-treated cells secreted increased insulin under conditions normally associated with only minimal release, e.g. 5 mm glucose, and YM58483 blocked this secretion. Taken together, these results support a critical role for ER Ca2+ depletion–activated Ca2+ current in mediating Ca2+-induced insulin secretion in response to ER stress. Full Article
on Mechanistic insights explain the transforming potential of the T507K substitution in the protein-tyrosine phosphatase SHP2 [Signal Transduction] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 The protein-tyrosine phosphatase SHP2 is an allosteric enzyme critical for cellular events downstream of growth factor receptors. Mutations in the SHP2 gene have been linked to many different types of human diseases, including developmental disorders, leukemia, and solid tumors. Unlike most SHP2-activating mutations, the T507K substitution in SHP2 is unique in that it exhibits oncogenic Ras-like transforming activity. However, the biochemical basis of how the SHP2/T507K variant elicits transformation remains unclear. By combining kinetic and biophysical methods, X-ray crystallography, and molecular modeling, as well as using cell biology approaches, here we uncovered that the T507K substitution alters both SHP2 substrate specificity and its allosteric regulatory mechanism. We found that although SHP2/T507K exists in the closed, autoinhibited conformation similar to the WT enzyme, the interactions between its N-SH2 and protein-tyrosine phosphatase domains are weakened such that SHP2/T507K possesses a higher affinity for the scaffolding protein Grb2-associated binding protein 1 (Gab1). We also discovered that the T507K substitution alters the structure of the SHP2 active site, resulting in a change in SHP2 substrate preference for Sprouty1, a known negative regulator of Ras signaling and a potential tumor suppressor. Our results suggest that SHP2/T507K's shift in substrate specificity coupled with its preferential association of SHP2/T507K with Gab1 enable the mutant SHP2 to more efficiently dephosphorylate Sprouty1 at pTyr-53. This dephosphorylation hyperactivates Ras signaling, which is likely responsible for SHP2/T507K's Ras-like transforming activity. Full Article
on Prominins control ciliary length throughout the animal kingdom: New lessons from human prominin-1 and zebrafish prominin-3 [Cell Biology] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 Prominins (proms) are transmembrane glycoproteins conserved throughout the animal kingdom. They are associated with plasma membrane protrusions, such as primary cilia, as well as extracellular vesicles derived thereof. Primary cilia host numerous signaling pathways affected in diseases known as ciliopathies. Human PROM1 (CD133) is detected in both somatic and cancer stem cells and is also expressed in terminally differentiated epithelial and photoreceptor cells. Genetic mutations in the PROM1 gene result in retinal degeneration by impairing the proper formation of the outer segment of photoreceptors, a modified cilium. Here, we investigated the impact of proms on two distinct examples of ciliogenesis. First, we demonstrate that the overexpression of a dominant-negative mutant variant of human PROM1 (i.e. mutation Y819F/Y828F) significantly decreases ciliary length in Madin–Darby canine kidney cells. These results contrast strongly to the previously observed enhancing effect of WT PROM1 on ciliary length. Mechanistically, the mutation impeded the interaction of PROM1 with ADP-ribosylation factor–like protein 13B, a key regulator of ciliary length. Second, we observed that in vivo knockdown of prom3 in zebrafish alters the number and length of monocilia in the Kupffer's vesicle, resulting in molecular and anatomical defects in the left-right asymmetry. These distinct loss-of-function approaches in two biological systems reveal that prom proteins are critical for the integrity and function of cilia. Our data provide new insights into ciliogenesis and might be of particular interest for investigations of the etiologies of ciliopathies. Full Article
on Modification of a PE/PPE substrate pair reroutes an Esx substrate pair from the mycobacterial ESX-1 type VII secretion system to the ESX-5 system [Molecular Bases of Disease] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 Bacterial type VII secretion systems secrete a wide range of extracellular proteins that play important roles in bacterial viability and in interactions of pathogenic mycobacteria with their hosts. Mycobacterial type VII secretion systems consist of five subtypes, ESX-1–5, and have four substrate classes, namely, Esx, PE, PPE, and Esp proteins. At least some of these substrates are secreted as heterodimers. Each ESX system mediates the secretion of a specific set of Esx, PE, and PPE proteins, raising the question of how these substrates are recognized in a system-specific fashion. For the PE/PPE heterodimers, it has been shown that they interact with their cognate EspG chaperone and that this chaperone determines the designated secretion pathway. However, both structural and pulldown analyses have suggested that EspG cannot interact with the Esx proteins. Therefore, the determining factor for system specificity of the Esx proteins remains unknown. Here, we investigated the secretion specificity of the ESX-1 substrate pair EsxB_1/EsxA_1 in Mycobacterium marinum. Although this substrate pair was hardly secreted when homologously expressed, it was secreted when co-expressed together with the PE35/PPE68_1 pair, indicating that this pair could stimulate secretion of the EsxB_1/EsxA_1 pair. Surprisingly, co-expression of EsxB_1/EsxA_1 with a modified PE35/PPE68_1 version that carried the EspG5 chaperone-binding domain, previously shown to redirect this substrate pair to the ESX-5 system, also resulted in redirection and co-secretion of the Esx pair via ESX-5. Our results suggest a secretion model in which PE35/PPE68_1 determines the system-specific secretion of EsxB_1/EsxA_1. Full Article
on Zinc promotes liquid-liquid phase separation of tau protein [Protein Structure and Folding] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 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. Full Article
on Effects of deficiency in the RLBP1-encoded visual cycle protein CRALBP on visual dysfunction in humans and mice [Cell Biology] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Mutations in retinaldehyde-binding protein 1 (RLBP1), encoding the visual cycle protein cellular retinaldehyde-binding protein (CRALBP), cause an autosomal recessive form of retinal degeneration. By binding to 11-cis-retinoid, CRALBP augments the isomerase activity of retinoid isomerohydrolase RPE65 (RPE65) and facilitates 11-cis-retinol oxidation to 11-cis-retinal. CRALBP also maintains the 11-cis configuration and protects against unwanted retinaldehyde activity. Studying a sibling pair that is compound heterozygous for mutations in RLBP1/CRALBP, here we expand the phenotype of affected individuals, elucidate a previously unreported phenotype in RLBP1/CRALBP carriers, and demonstrate consistencies between the affected individuals and Rlbp1/Cralbp−/− mice. In the RLBP1/CRALBP-affected individuals, nonrecordable rod-specific electroretinogram traces were recovered after prolonged dark adaptation. In ultrawide-field fundus images, we observed radially arranged puncta typical of RLBP1/CRALBP-associated disease. Spectral domain-optical coherence tomography (SD-OCT) revealed hyperreflective aberrations within photoreceptor-associated bands. In short-wavelength fundus autofluorescence (SW-AF) images, speckled hyperautofluorescence and mottling indicated macular involvement. In both the affected individuals and their asymptomatic carrier parents, reduced SW-AF intensities, measured as quantitative fundus autofluorescence (qAF), indicated chronic impairment in 11-cis-retinal availability and provided information on mutation severity. Hypertransmission of the SD-OCT signal into the choroid together with decreased near-infrared autofluorescence (NIR-AF) provided evidence for retinal pigment epithelial cell (RPE) involvement. In Rlbp1/Cralbp−/− mice, reduced 11-cis-retinal levels, qAF and NIR-AF intensities, and photoreceptor loss were consistent with the clinical presentation of the affected siblings. These findings indicate that RLBP1 mutations are associated with progressive disease involving RPE atrophy and photoreceptor cell degeneration. In asymptomatic carriers, qAF disclosed previously undetected visual cycle deficiency. Full Article
on {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
on Non-photopic and photopic visual cycles differentially regulate immediate, early, and late phases of cone photoreceptor-mediated vision [Molecular Bases of Disease] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Cone photoreceptors in the retina enable vision over a wide range of light intensities. However, the processes enabling cone vision in bright light (i.e. photopic vision) are not adequately understood. Chromophore regeneration of cone photopigments may require the retinal pigment epithelium (RPE) and/or retinal Müller glia. In the RPE, isomerization of all-trans-retinyl esters to 11-cis-retinol is mediated by the retinoid isomerohydrolase Rpe65. A putative alternative retinoid isomerase, dihydroceramide desaturase-1 (DES1), is expressed in RPE and Müller cells. The retinol-isomerase activities of Rpe65 and Des1 are inhibited by emixustat and fenretinide, respectively. Here, we tested the effects of these visual cycle inhibitors on immediate, early, and late phases of cone photopic vision. In zebrafish larvae raised under cyclic light conditions, fenretinide impaired late cone photopic vision, while the emixustat-treated zebrafish unexpectedly had normal vision. In contrast, emixustat-treated larvae raised under extensive dark-adaptation displayed significantly attenuated immediate photopic vision concomitant with significantly reduced 11-cis-retinaldehyde (11cRAL). Following 30 min of light, early photopic vision was recovered, despite 11cRAL levels remaining significantly reduced. Defects in immediate cone photopic vision were rescued in emixustat- or fenretinide-treated larvae following exogenous 9-cis-retinaldehyde supplementation. Genetic knockout of Des1 (degs1) or retinaldehyde-binding protein 1b (rlbp1b) did not eliminate photopic vision in zebrafish. Our findings define molecular and temporal requirements of the nonphotopic or photopic visual cycles for mediating vision in bright light. Full Article
on Pro-515 of the dynamin-like GTPase MxB contributes to HIV-1 inhibition by regulating MxB oligomerization and binding to HIV-1 capsid [Microbiology] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Interferon-regulated myxovirus resistance protein B (MxB) is an interferon-induced GTPase belonging to the dynamin superfamily. It inhibits infection with a wide range of different viruses, including HIV-1, by impairing viral DNA entry into the nucleus. Unlike the related antiviral GTPase MxA, MxB possesses an N-terminal region that contains a nuclear localization signal and is crucial for inhibiting HIV-1. Because MxB previously has been shown to reside in both the nuclear envelope and the cytoplasm, here we used bioinformatics and biochemical approaches to identify a nuclear export signal (NES) responsible for MxB's cytoplasmic location. Using the online computational tool LocNES (Locating Nuclear Export Signals or NESs), we identified five putative NES candidates in MxB and investigated whether their deletion caused nuclear localization of MxB. Our results revealed that none of the five deletion variants relocates to the nucleus, suggesting that these five predicted NES sequences do not confer NES activity. Interestingly, deletion of one sequence, encompassing amino acids 505–527, abrogated the anti-HIV-1 activity of MxB. Further mutation experiments disclosed that amino acids 515–519, and Pro-515 in particular, regulate MxB oligomerization and its binding to HIV-1 capsid, thereby playing an important role in MxB-mediated restriction of HIV-1 infection. In summary, our results indicate that none of the five predicted NES sequences in MxB appears to be required for its nuclear export. Our findings also reveal several residues in MxB, including Pro-515, critical for its oligomerization and anti-HIV-1 function. Full Article
on A neuroglobin-based high-affinity ligand trap reverses carbon monoxide-induced mitochondrial poisoning [Molecular Biophysics] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Carbon monoxide (CO) remains the most common cause of human poisoning. The consequences of CO poisoning include cardiac dysfunction, brain injury, and death. CO causes toxicity by binding to hemoglobin and by inhibiting mitochondrial cytochrome c oxidase (CcO), thereby decreasing oxygen delivery and inhibiting oxidative phosphorylation. We have recently developed a CO antidote based on human neuroglobin (Ngb-H64Q-CCC). This molecule enhances clearance of CO from red blood cells in vitro and in vivo. Herein, we tested whether Ngb-H64Q-CCC can also scavenge CO from CcO and attenuate CO-induced inhibition of mitochondrial respiration. Heart tissue from mice exposed to 3% CO exhibited a 42 ± 19% reduction in tissue respiration rate and a 33 ± 38% reduction in CcO activity compared with unexposed mice. Intravenous infusion of Ngb-H64Q-CCC restored respiration rates to that of control mice correlating with higher electron transport chain CcO activity in Ngb-H64Q-CCC–treated compared with PBS-treated, CO-poisoned mice. Further, using a Clark-type oxygen electrode, we measured isolated rat liver mitochondrial respiration in the presence and absence of saturating solutions of CO (160 μm) and nitric oxide (100 μm). Both CO and NO inhibited respiration, and treatment with Ngb-H64Q-CCC (100 and 50 μm, respectively) significantly reversed this inhibition. These results suggest that Ngb-H64Q-CCC mitigates CO toxicity by scavenging CO from carboxyhemoglobin, improving systemic oxygen delivery and reversing the inhibitory effects of CO on mitochondria. We conclude that Ngb-H64Q-CCC or other CO scavengers demonstrate potential as antidotes that reverse the clinical and molecular effects of CO poisoning. Full Article
on 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
on Inhibition of the polyamine synthesis enzyme ornithine decarboxylase sensitizes triple-negative breast cancer cells to cytotoxic chemotherapy [Molecular Bases of Disease] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Treatment of patients with triple-negative breast cancer (TNBC) is limited by a lack of effective molecular therapies targeting this disease. Recent studies have identified metabolic alterations in cancer cells that can be targeted to improve responses to standard-of-care chemotherapy regimens. Using MDA-MB-468 and SUM-159PT TNBC cells, along with LC-MS/MS and HPLC metabolomics profiling, we found here that exposure of TNBC cells to the cytotoxic chemotherapy drugs cisplatin and doxorubicin alter arginine and polyamine metabolites. This alteration was because of a reduction in the levels and activity of a rate-limiting polyamine biosynthetic enzyme, ornithine decarboxylase (ODC). Using gene silencing and inhibitor treatments, we determined that the reduction in ODC was mediated by its negative regulator antizyme, targeting ODC to the proteasome for degradation. Treatment with the ODC inhibitor difluoromethylornithine (DFMO) sensitized TNBC cells to chemotherapy, but this was not observed in receptor-positive breast cancer cells. Moreover, TNBC cell lines had greater sensitivity to single-agent DFMO, and ODC levels were elevated in TNBC patient samples. The alterations in polyamine metabolism in response to chemotherapy, as well as DFMO-induced preferential sensitization of TNBC cells to chemotherapy, reported here suggest that ODC may be a targetable metabolic vulnerability in TNBC. Full Article
on Five Lessons From the New Arab Uprisings By feedproxy.google.com Published On :: Tue, 12 Nov 2019 09:11:56 +0000 12 November 2019 Dr Georges Fahmi Associate Fellow, Middle East and North Africa Programme @GeorgesFahmi Georges Fahmi examines how protesters across the region have adapted their tactics after the experiences of the Arab Spring. 2019-11-12-Lebanon.jpg The second wave of Arab uprisings that started in Sudan in December last year and extended to Algeria, Lebanon and Iraq this year have built on past experiences of political transitions during the Arab Spring, both its mistakes and achievements. Protesters from this new wave have already learned five lessons from previous transitions.The first lesson is that toppling the head of a regime does not mean that the political regime has fallen. In Tahrir Square on 11 February 2011, Egyptian protesters celebrated the decision of Hosni Mubarak to step down and left the square, thinking his resignation was enough to allow a democratic transition to take place. In contrast, in Sudan and Algeria, protesters continued to demonstrate after the resignation of Abdelaziz Bouteflika and the military-led ousting of Omar al-Bashir.Protesters understood the lesson that the regime is found not only in the head of the state, but rather in the rules that govern the political sphere. By extension, political change requires changing the rules, not just the names of those in charge of implementing them.The second lesson is that resorting to violence is the fastest way to end any hope for democratic change. Protesters who decided to take up arms offered their regimes the chance to reframe the political uprisings as civil war, as was the case in Syria. Even when armed groups manage to bring down the regime, their presence endangers the transitional phase afterwards, as is the case in Libya.Although protesters in Sudan and Iraq have been faced with government violence and repression, they have insisted on their non-violent approach. In Sudan, the protesters responded to the massacre outside of the General Command of the Armed Forces on 3 June by organizing a mass demonstration on 30 June, which put pressure on the military to resume talks with the revolutionary forces. The third lesson is that once the old regime has fallen, the transition period must be a collective decision-making process in which the opposition has, at least, veto power. The example of Tunisia after 2011 is a case in point. The Higher Authority for Realization of the Goals of the Revolution, Political Reform and Democratic Transition, which formulated the planned course of the transition, included representatives from across the political spectrum and civil society.Although the military forces in Algeria and Sudan will not cease to play a political role any time soon, this does not have to mean exerting complete control over the transitional period. Sudan could offer a positive example in this regard, if it succeeds in implementing a power-sharing deal according to which a joint civilian-military sovereign council will govern Sudan during the transitional period.The fourth lesson is that political transitions should achieve agreement on the rules of the game before proceeding to elections. In Egypt after 2011, rushed elections served to divide the political opposition and dramatically increase polarization in society. In this second wave, protesters have perceived elections as a trap which enable old regimes to reproduce themselves with new names.In both Algeria and Sudan, protesters have resisted attempts by the military to hold elections as soon as possible. In Sudan, the agreement between the revolutionary forces and the military council postponed the elections until after the end of a three-year transitional period of technocratic rule. In Algeria, protesters are taking to the streets every Friday to demonstrate against the authorities’ decision to hold presidential elections in December.The fifth and final lesson is that the call for change in the region goes beyond electoral democracy and extends to deep socioeconomic reforms. Iraq and Lebanon show this clearly: relatively free and fair elections have already been held but have served only to reinforce corrupt sectarian regimes.According to the fifth wave of the Arab Barometer, the economic situation and corruption are perceived as the main challenge for Algerians (62.2%), Sudanese (67.8%), Lebanese (57.9%), and Iraqis (50.2%), while democracy is perceived as the main challenge for only 2.3%, 3.9%, 5% and 1.4% respectively. The experience of the Arab Spring has shown people that democratic measures are only a means to an end.Unlike in 2011, when the Arab Spring revolts enjoyed broad international support, this second wave is taking place in a hostile environment, with stronger Russian and Iranian presences in the region and an indifferent international climate. But where protesters have the advantage is in experience, and across the region they are clearly adapting their tactics to lessons learned from the early part of the decade. Full Article