art Mother Nature blankets parts of Muskoka with spring snowfall By barrie.ctvnews.ca Published On :: Fri, 8 May 2020 15:03:52 -0400 The calendar may say May, but that didn't stop Mother Nature from blasting some wintry weather in Muskoka on Friday. Full Article
art BREAKING: MI Lawmakers File Lawsuit Challenging Governor’s “Improper” and “Invalid” Emergency Orders: “We’ve attempted to partner with our governor, but she’s rejected” By 100percentfedup.com Published On :: Wed, 06 May 2020 20:54:20 +0000 The following article, BREAKING: MI Lawmakers File Lawsuit Challenging Governor’s “Improper” and “Invalid” Emergency Orders: “We’ve attempted to partner with our governor, but she’s rejected”, was first published on 100PercentFedUp.com. In addition to crushing Michigan's economy, the governor's reckless, one-size-fits-all executive orders are harming an untold number of Michigan citizens. Continue reading: BREAKING: MI Lawmakers File Lawsuit Challenging Governor’s “Improper” and “Invalid” Emergency Orders: “We’ve attempted to partner with our governor, but she’s rejected” ... Full Article Featured Politics
art Breaking: Justice Department Dropping Michael Flynn Criminal Case By 100percentfedup.com Published On :: Thu, 07 May 2020 18:47:49 +0000 The following article, Breaking: Justice Department Dropping Michael Flynn Criminal Case, was first published on 100PercentFedUp.com. Michael Flynn has finally been exonerated. The Associated Press is reporting exclusively that the Justice Department said it is dropping the criminal case against President Trump’s first national security adviser, Michael Flynn. In court documents being filed Thursday, the Justice Department said it is dropping the case “after a considered review of all the facts […] Continue reading: Breaking: Justice Department Dropping Michael Flynn Criminal Case ... Full Article Breaking Crime Featured Politics
art 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
art Brexit: What Now for UK Trade Policy? (Part 2) By feedproxy.google.com Published On :: Fri, 06 Sep 2019 13:45:01 +0000 Research Event 1 October 2019 - 12:30pm to 1:30pm Chatham House | 10 St James's Square | London | SW1Y 4LE Event participants Professor Jagjit S. Chadha, Director, NIESRDr Kamala Dawar, Senior Lecturer in Law, University of Sussex; Fellow, UKTPODr Michael Gasiorek, Senior Lecturer in Economics, University of Sussex; Director, Interanalysis; Fellow, UKTPOChair: Professor Jim Rollo, Deputy Director, UKTPO; Associate Fellow, Chatham House In the five months since the last extension of the Brexit deadline, the questions about the UK’s trading relationship with the EU remain as open as before, as do those about what sort of relationship it should seek with other partners.The world has not stood still, however, and so the UKTPO is convening another panel to consider constructive ways of moving forward. The panel will discuss potential trajectories for UK trade policy, followed by a question and answer session.The UK Trade Policy Observatory (UKTPO) is a partnership between Chatham House and the University of Sussex which provides independent expert comment on, and analysis of, trade policy proposals for the UK as well as training for British policymakers through tailored training packages. Department/project Global Economy and Finance Programme, UK Trade Policy Observatory Full Article
art 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
art Webinar: Can the Justice and Development Party Still Absorb Popular Anger in Morocco? By feedproxy.google.com Published On :: Tue, 31 Mar 2020 13:50:01 +0000 Webinar Research Event 8 April 2020 - 1:00pm to 2:00pm Event participants Mohammed Masbah, Director, Moroccan Institute for Policy Analysis; Associate Fellow, MENA Programme, Chatham HouseModerator: Lina Khatib, Director, MENA Programme, Chatham House Ever since independence, the Moroccan monarchy has used political parties to legitimize the country’s authoritarian political process and structure, and to absorb social and political anger. The palace puts successive governments and other elected institutions, such as local and regional councils, at the frontline of public blame, and replaces them once they fail this function.In a recent article, MENA Programme Associate Fellow, Mohammed Masbah, examines how the Moroccan monarchy has used this strategy with the ruling Justice and Development Party (PJD) so that the palace remains the centre of political power, while the PJD – and other political parties before it– takes responsibility for coping with the mounting socio-economic crisis.In this webinar, part of the Chatham House project on The Future of the State in the Middle East and North Africa, the article’s author will discuss the risks this approach presents for the long-term stability of Morocco and what reforms are needed to increase citizens’ dwindling confidence in the political process.You can express your interest in attending by following this link. You will receive a Zoom confirmation email should your registration be successful. Department/project Middle East and North Africa Programme, The Future of the State in the Middle East Full Article
art Moving Energy Initiative Starts Clean Energy Projects for Refugees By feedproxy.google.com Published On :: Mon, 26 Jun 2017 12:25:21 +0000 26 June 2017 The Moving Energy Initiative starts four new clean energy projects for refugees. Combo_large_LCP (2).jpg Refugees in Burkina Faso, Kenya and Jordan will benefit from greater access to affordable, clean energy for domestic use and to power ‘microbusinesses’, following a grant scheme from the Moving Energy Initiative which launches today.The Moving Energy Initiative is supporting projects ranging from a solar-powered ICT hub in Kenya’s Kakuma camp and vegetable growing zones watered by solar-powered pumps in Burkina Faso’s Goudoubo camp, to reliable energy generation for north Jordan’s Al Mafraq hospital where Syrian refuges and local residents access health care.Embed this image <img src="https://www.chathamhouse.org/sites/default/files/images/Combo_large_LCP.jpg" alt="" title="" />In total, four projects will be implemented over the next 12 months, with all involving training for refugees and local staff to use and maintain the clean energy technologies. They aim to deliver tangible reductions in CO2 emissions whilst increasing access to vital services, saving costs and providing livelihood opportunities for local communities and refugees. The projects are also expected to fuel entrepreneurship, opening up the potential for setting up businesses, small shops and restaurants which can expand beyond this initial grant. Project partners were chosen through an open and competitive process kicked off in February 2017 in Burkina Faso, Kenya and Jordan. Bidders were asked to demonstrate their ability to provide solutions that reduce fossil fuel consumption and increase access to energy in camps. The successful projects were chosen on the basis of the applicants’ ability to innovate in a humanitarian setting, as well as their track record and their approach to sustainability.Find out more about why these projects are needed and the impact they aim to have by watching the video: Check out the Moving Energy Initiative website for more information.Keep updated on the progress of these projects as they develop by following us on Twitter @CH_EERD. Related contentMoving Energy Initiative: Sustainable Energy for Refugees and Displaced PeopleThe Moving Energy Initiative Expert WorkshopToolkits for the Moving Energy Initiative Full Article
art NATO: Charting the Way Forward By feedproxy.google.com Published On :: Tue, 24 Jun 2014 09:00:01 +0000 Research Event 25 July 2014 - 5:00pm to 6:00pm Chatham House, London Event participants Xenia Wickett, Project Director, US; Acting Dean, Academy for Leadership in International Affairs, Chatham HousePeter Jones, Director for Defence and International Security, Foreign & Commonwealth OfficeDr Jamie Shea, Deputy Assistant Secretary General for Emerging Security Challenges, NATOChair: Steven Erlanger, London Bureau Chief, New York Times This event will launch the US Project’s latest research paper on the way ahead for NATO and, in particular, examine what can be achieved at the NATO summit in September. The paper crystallizes the principal findings of a series of workshops and makes recommendations on the next steps for NATO. This event will bring together senior representatives from NATO and the Foreign & Commonwealth Office to discuss the paper, respond to its key conclusions, and share their own thoughts on the future of NATO.This event will be followed by a drinks reception until 19:00.About the project2014 is a pivotal year for NATO. Prompted by defence austerity, Russian activities in Ukraine, and the conclusion of NATO’s major operations in Afghanistan, allies are raising important questions about NATO’s future in the run-up to the summit in September. As part of the project, NATO: Charting the Way Forward, Chatham House has held a series of expert roundtables to discuss these challenges and NATO’s role for the coming decades. Bringing together senior officials from both the public and private sectors, as well as from the academic and think-tank communities, these workshops have explored different aspects of NATO’s purpose, priorities and capabilities. This project is supported by the Foreign & Commonwealth Office, the NATO Public Diplomacy Division, and the Canadian Department of National Defence. Department/project US and the Americas Programme, NATO: Charting the Way Forward Richard Gowing Programme Administrator +44 (0)20 7389 3270 Email Full Article
art NATO: Charting the Way Forward By feedproxy.google.com Published On :: Fri, 18 Jul 2014 10:38:44 +0000 21 July 2014 For more than 60 years the North Atlantic Treaty Organization (NATO) has played a critical role in enabling transatlantic security and leading crisis management operations. However, given the current climate of austerity, the imminent end of the Afghanistan operation and recent events in Ukraine, crucial questions are being raised regarding the Alliance’s future priorities. Summary Download PDF Xenia Wickett Former Head, US and the Americas Programme; Former Dean, The Queen Elizabeth II Academy for Leadership in International Affairs @xeniawickett LinkedIn Kathleen McInnis Former Chatham House Expert 20140718NATOW.jpg DOD photo by US Air Force Master Sgt Jerry Morrison / Wikimedia Commons / Public Domain. Over the course of this year, Chatham House convened a series of expert roundtables to answer some of these questions. This report draws on the findings of those meetings and makes recommendations for NATO’s next steps in the lead-up to its 2014 Summit in Wales.The paper suggests six principal actions for NATO:Find ways to caucus smaller groups within NATO rather than requiring all 28 members to make all decisions. NATO’s 28 member states all have their own interests and appetites for risk and bring diverse capabilities to the table. Yet rather than being a source of weakness, these differences of opinion can become a strength if properly managed. Enhance interoperability. With operations in Afghanistan winding down, and in light of declining defence spending, NATO militaries must find new ways to improve their ability to work with one another on the ground, at sea and in the air. Improve planning and positioning of forces together. For meaningful joint defence planning, and to share the burden of resources and responsibilities, NATO needs to facilitate collaborative discussions on challenges and capabilities. Develop better acquisition systems. In the context of declining defence spending, bridging the gap between strategy and resources will require NATO members to streamline acquisition systems, make tough choices about national defence industries, and become more collaborative on procurement. Rebuild public understanding and support for NATO. Public support is vital if member-state politicians are to make hard internal decisions on resources and to demonstrate the will and resilience required for effective deterrence and reassurance. Build on NATO’s partnerships and differentiate them better. With defence budgets tightening, NATO needs to recognize and take advantage of the fact that many non-NATO states and other institutions have similar interests to those of members. Department/project US and the Americas Programme, NATO: Charting the Way Forward Full Article
art Close but Distracted: The Future of the UK-US Partnership By feedproxy.google.com Published On :: Thu, 16 Oct 2014 14:00:01 +0000 Invitation Only Research Event 16 October 2014 - 9:00am to 10:30am Chatham House, London Meeting Summarypdf | 145.17 KB Transcriptpdf | 45.62 KB In an open podcast recorded following the event, Robin Niblett discussed the state of the transatlantic relationship with International New York Times London Bureau Chief Steven Erlanger, former UK defence secretary Liam Fox and former Foreign Affairs Committee chair Mike Gapes.The roundtable was held under the Chatham House Rule. While revelations about the activities of the NSA and GCHQ confirmed the depth of cooperation between the US and the UK over intelligence, the debate over the UK’s membership of the EU and difficulties in coordinating a response to the Syria crisis have raised tensions between policy-makers in Washington and London. With the two countries now facing an array of shared international challenges – not least in Ukraine, Afghanistan and Iraq – this roundtable will examine the current state of the transatlantic relationship. Event attributes Chatham House Rule Full Article
art Building Global Partnerships for Stronger Local Economies By feedproxy.google.com Published On :: Tue, 03 Feb 2015 14:45:01 +0000 Members Event 11 February 2015 - 6:00pm to 7:00pm Chatham House, London Transcriptpdf | 110.44 KB Transcript Q&Apdf | 173.45 KB Event participants Scott Walker, Governor, Wisconsin, United StatesChair: Justin Webb, Presenter, Today Programme, BBC Radio 4 Drawing on his experience as governor of Wisconsin, Scott Walker will outline the importance of forging strong global partnerships to fuel business growth and build prosperous local economies. Governor Walker will consider how mutually beneficial partnerships can be developed within the global community and the impact of these on local communities.LIVE STREAM: This event will be live streamed. The live stream will be made available at 18:00 GMT on Wednesday 11 February.ASK A QUESTION: Send questions for the speaker by email to questions@chathamhouse.org or using #CHEvents on Twitter. A selection will be put to him during the event. Event attributes Livestream Members Events Team Email Full Article
art Review article: The 100 billion dollar brain: central intelligence machinery in the UK and the US By feedproxy.google.com Published On :: Thu, 12 Mar 2015 13:54:57 +0000 12 March 2015 , Volume 91, Number 2 Richard J. Aldrich Full Article
art Why We Need a Transatlantic Charter for Data Security and Mobility By feedproxy.google.com Published On :: Tue, 27 Jun 2017 09:59:17 +0000 28 June 2017 Dr Christopher Smart @csmart Former Associate Fellow, US and the Americas Programme Setting common guidelines for data flows is crucial both to protect the goods and services that already depend on big data and to support the next generation of productivity gains and business opportunities. 2017-06-23-TsystemsData.jpg Data centre for T-Systems, a subsidiary of Deutsche Telekom. Photo by: Thomas Trutschel/Photothek/Getty Images While trade and tax remain at the heart of the difficult economic conversations between Europe and the US, a new issue has emerged as a potential source of even greater friction: data.Growth in the traditional global trade in goods and services has levelled off, but cross-border data flows continue to expand rapidly and the challenges of developing policies that protect privacy, security and innovation are already tremendous. For example, data analytics are driving dramatic productivity gains in industry, particularly for large and complex installations whose safety and efficiency will increasingly depend on flows of those data across jurisdictions. Meanwhile, ‘fintech’ (financial technology) start-ups and large banks alike are testing new modes of accumulating, analysing and deploying customer data to provide less expensive services and manage the risk profile of their businesses.The rules that govern the collection, transmission and storage of data are perhaps one of the more surprising controversies in the transatlantic relationship. Similar liberal democracies with similar geostrategic interests might be expected to approach the handling of personal, corporate and government data in more or less the same way. And yet the US and its key European partners have struck different balances in the trade-offs between national security and citizens’ rights, between freedom of expression and personal privacy, and between free enterprise and market regulation.While the US debate on the use of data has often been framed around the trade-off between national security and personal privacy, Europeans often face an even more complex set of concerns that include worries that their digital and technology firms lag behind dominant US competitors. The political and regulatory uncertainty helps neither side, and leaves transatlantic companies struggling to comply with uncertain and conflicting rules in different jurisdictions.This makes more determined efforts by US and European policymakers to agree basic principles that will guide the usage and protection of personal and commercial data all the more important. While common regulations or even greater alignment among regulators seem out of reach, a ‘Transatlantic Charter for Data Security and Mobility’ would provide a set of principles for more specific rules amid political landscapes and technological developments that are evolving rapidly. It could also provide the basis for firms, whether in manufacturing or financial services or health care, to draft their own voluntary standards on how they protect data even as they develop new algorithms that improve productivity, safety and customer satisfaction.Embarrassing leaks, careful denials and endless lawsuits will continue to shape the awkward efforts of policymakers to find common ground around issues like cyberespionage, defence of common networks and the sharing of personal data with law enforcement. Cyberattacks with the aim of disrupting government operations or influencing election campaigns will add still further pressures. These will all serve as a noisy backdrop to a related but separate debate over how commercial firms should exploit the opportunities of global networks and ‘big data’ analytics while protecting national interests and privacy.Yet, setting common guidelines for commercial data transmission and storage remains crucial both to protect the goods and services that already depend on sophisticated data-gathering and analysis, and to support the next generation of productivity gains and business opportunities.Global firms yearn for clarity and predictability as they organize themselves to make the most of the data revolution. Neither is likely to become a reality soon. The EU’s new General Data Protection Regulation will take effect in 2018, but its implementation will inevitably be coloured by the fact that American firms currently dominate the information technology business. Last year’s ‘Privacy Shield’ agreement between the US and the EU renews the permission for firms with transatlantic business interests to transfer data, subject to compliance with basic standards of protection, but the agreement remains vulnerable to European court challenges. Britain’s decision to leave the EU adds a further complication, as it establishes its own set of data protection rules that may not easily align with either European or US requirements. Meanwhile, the World Trade Organization continues to debate new rules for digital trade, even as markets like China, Russia and Brazil make up their own.If this ‘Transatlantic Charter for Data Security and Mobility’ were adopted bilaterally, say as part of the annual reviews of the US–EU Privacy Shield agreement, it could form the basis for broader cooperation on these issues, helping to drive progress in the G7 and G20 and ultimately perhaps in trade agreements under the WTO. It would hardly secure complete alignment on these questions, but it could help establish the framework for a debate that all too often lurches to extremes and risks damaging a fundamental alliance for global stability – along with a fundamental driver of 21st-century economic progress.To comment on this article, please contact Chatham House Feedback Full Article
art Analysis of the Subunit Composition of Complex I from Bovine Heart Mitochondria By feedproxy.google.com Published On :: 2003-02-01 Joe CarrollFeb 1, 2003; 2:117-126Research Full Article
art Parts per Million Mass Accuracy on an Orbitrap Mass Spectrometer via Lock Mass Injection into a C-trap By feedproxy.google.com Published On :: 2005-12-01 Jesper V. OlsenDec 1, 2005; 4:2010-2021Technology Full Article
art DHHC7-mediated palmitoylation of the accessory protein barttin critically regulates the functions of ClC-K chloride channels [Cell Biology] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 Barttin is the accessory subunit of the human ClC-K chloride channels, which are expressed in both the kidney and inner ear. Barttin promotes trafficking of the complex it forms with ClC-K to the plasma membrane and is involved in activating this channel. Barttin undergoes post-translational palmitoylation that is essential for its functions, but the enzyme(s) catalyzing this post-translational modification is unknown. Here, we identified zinc finger DHHC-type containing 7 (DHHC7) protein as an important barttin palmitoyl acyltransferase, whose depletion affected barttin palmitoylation and ClC-K-barttin channel activation. We investigated the functional role of barttin palmitoylation in vivo in Zdhhc7−/− mice. Although palmitoylation of barttin in kidneys of Zdhhc7−/− animals was significantly decreased, it did not pathologically alter kidney structure and functions under physiological conditions. However, when Zdhhc7−/− mice were fed a low-salt diet, they developed hyponatremia and mild metabolic alkalosis, symptoms characteristic of human Bartter syndrome (BS) type IV. Of note, we also observed decreased palmitoylation of the disease-causing R8L barttin variant associated with human BS type IV. Our results indicate that dysregulated DHHC7-mediated barttin palmitoylation appears to play an important role in chloride channel dysfunction in certain BS variants, suggesting that targeting DHHC7 activity may offer a potential therapeutic strategy for reducing hypertension. Full Article
art Brexit, Party Politics and the Next Prime Minister By feedproxy.google.com Published On :: Fri, 28 Jun 2019 13:45:01 +0000 Invitation Only Research Event 15 July 2019 - 8:30am to 9:30am Chatham House | 10 St James's Square | London | SW1Y 4LE Event participants Daniel Finkelstein OBE, Associate Editor, The Times; Conservative Member of the House of Lords; Chairman, Onward Chair: Thomas Raines, Head, Europe Programme, Chatham House With the new leader of the Conservative party due to be announced on 23 July, what are the prospects for the party and the country?On Brexit, the new prime minister faces most of the same challenges and constraints as Theresa May. The leadership contenders have outlined their ambitions for a revised deal, but with the EU insisting negotiations are over, their room for manoeuvre appears to be limited. Furthermore, even with a new leader at the helm, important divisions remain among voters about what shape Brexit and the future UK-EU relationship should take. If the EU won’t change the deal, and parliament won’t accept it, how can the deadlock be broken? Is a 'No Deal' Brexit politically deliverable? Or could there be a general election later in 2019? Can the Conservative party survive a pre-Brexit election intact?Beyond Brexit, what are the other choices, in both domestic and foreign policy, facing the next prime minister? How might the decisions he makes affect the future of the party and British politics more broadly?In this session, the speaker will share his reflections on the likely result of the leadership election, and what lies beyond it.Attendance at this event is by invitation only. Event attributes Chatham House Rule Department/project Europe Programme, Britain and Europe: The Post-Referendum Agenda Alina Lyadova Europe Programme Coordinator Email Full Article
art What Europe Can Learn From the Law and Justice Party’s Victory in Poland By feedproxy.google.com Published On :: Tue, 15 Oct 2019 14:39:52 +0000 15 October 2019 Dr Angelos Chryssogelos Associate Fellow, Europe Programme @AChryssogelos Google Scholar The EU must remain vigilant about threats to liberal democracy in Poland, but European leaders must also accept that PiS’s electoral success is reflective of its ability to deliver on things that other political parties in Europe have long neglected. 2019-10-15-PiS.jpg The button of a PiS supporter on election day. Photo: Getty Images. The Polish election on 13 October resulted, as expected, in a victory for of the ruling Law and Justice party (PiS).But despite again securing a slim majority in parliament, it has not been wholly a triumph for PiS. And though there continue to be concerns about the party’s authoritarian tendencies, the election has illuminated some important nuances to its support and appeal, which hold lessons for politics across Europe.Even though some opinion polls had suggested PiS were close to winning a supermajority in parliament that would have allowed it to pursue constitutional changes, the party fell short of that target, while it lost its majority in the Senate. Thus, while PiS may well renew its efforts to consolidate its control over the state apparatus and the media or meddle with the justice system, it becomes much more difficult with the opposition controlling the Senate and being able to scrutinize laws or have a say in the appointment of public officials.Most importantly, the election result has shown that while Polish citizens were willing to reward a party that delivered on promises of economic growth and redistribution, they were not ready to hand a blank cheque for full-blown institutional realignment to PiS. Tellingly, many moderate candidates in PiS lists performed quite well among the party’s voters. Even though they rewarded a party that at times employed harsh rhetoric against Brussels, Polish voters have long expressed some of the strongest rates of support for EU membership, according to Eurobarometer surveys. The government has also faced massive protests against its most radical initiatives, such as reform of the judicial system and a law to almost completely ban abortion that was ultimately scrapped. It is therefore more likely that the party’s radicalism kept it from increasing its share, rather than helping it to secure victory.This is not to say that the threat of illiberalism does not remain alive in Poland. But it shows that the degree of PiS dominance in Poland has never been comparable to that of Fidesz in Hungary, with which it is often compared.This was reflected in the party’s own rhetoric. In the election campaign the government mostly focused on its economic record, recognizing that much of its support is conditional on conventional measures of political success like voter welfare. PiS may not give up on its ambition to establish a ‘new Polish republic’, but the elections have made it clear that economic stability rather than political radicalism will ensure its longevity in power – with the latter perhaps even being a liability as the party experiences fatigue in office.Similarly, despite the government’s antagonistic stance towards the EU on various issues, PiS never entertained ideas of withdrawing from the EU, as some of its critics feared earlier in its term. With the Polish economy deeply entwined with the European market and Poland expecting – probably for the last time – to receive substantial subsidies from the next EU budget, EU membership is a necessary precondition for the economic success for which PiS is claiming credit.With the pro-European left returning to parliament but also an extreme party of the right winning representation, the next government will have a difficult balancing act as it tries to draw on the benefits of EU membership while maintaining its defiant image towards Brussels.Ultimately, beneath the rhetoric and the posturing, PiS is a party that has shrewdly combined popular policies from the left and right, fulfilling promises of both cultural sovereignty and economic redistribution. Its reelection should not come as a surprise given that it fulfilled its electoral pledges by delivering some of the things that many voters in western Europe also crave but that mainstream parties there have largely failed to provide. Full Article
art The Smart Peace Initiative: An Integrated and Adaptive Approach to Building Peace By feedproxy.google.com Published On :: Tue, 11 Feb 2020 10:55:01 +0000 Invitation Only Research Event 12 May 2020 - 10:00am to 11:30amAdd to CalendariCalendar Outlook Google Yahoo Smart Peace brings together global expertise in conflict analysis and research, peacebuilding and mediation programming, and behavioural science and evaluation. Together, Smart Peace partners are developing integrated and adaptive peace initiatives, working with local partners to prevent and resolve complex and intractable conflicts in Central African Republic, Myanmar and northern Nigeria. This roundtable is an opportunity for Smart Peace partners to share the Smart Peace concept, approach and objectives, and experiences of the first phases of programme implementation. Roundtable discussions among participants from policy, practice and research communities will inform future priorities and planning for Smart Peace learning, advocacy and communication. Smart Peace partners include Conciliation Resources, Behavioural Insights Team, The Centre for Humanitarian Dialogue, Chatham House, ETH Zurich, International Crisis Group and The Asia Foundation. Nilza Amaral Project Manager, International Security Programme Email Department/project International Security Programme, Smart Peace Full Article
art Wartime paradigms and the future of western military power By feedproxy.google.com Published On :: Wed, 04 Mar 2020 13:23:13 +0000 4 March 2020 , Volume 96, Number 2 Olivier Schmitt Read Online From the perception of the imminence of threats at the political level to the seizing of initiative through proper timing at the tactical level, temporality is directly related to war and warfare. Yet, despite some analyses of the importance of time at the political/grand strategic level (usually by scholars) and at the tactical level (usually by military professionals) there is surprisingly little discussion of the impact of time on the preparation and the conduct of warfare. This article introduces the concept of ‘wartime paradigm’ as a heuristic device to understand the relationship between the perception of time and the conduct of warfare, and argues that after the Cold War, a specific ‘wartime paradigm’ combining an optimization for speed and an understanding of war as risk management has guided western warfare, from force structure to the conduct of actual operations. It shows how the changing character of warfare directly challenges this wartime paradigm and why, if western forces want to prevail in future conflicts, the establishment of a new wartime paradigm guiding technological improvements and operational concepts is critical. Full Article
art A Transatlantic Partnership for WTO Reform in the Age of Coronavirus By feedproxy.google.com Published On :: Thu, 23 Apr 2020 13:45:01 +0000 Webinar Research Event 28 April 2020 - 2:00pm to 3:00pm Event participants Ignacio Garcia Bercero, Director, Directorate General for Trade of the European Commission; European Union Visiting Fellow, Oxford UniversityJennifer Hillman, Senior Fellow for Trade and International Political Economy, Council on Foreign Relations; Member, WTO Appellate Body, 2007 - 11Chair: Marianne Schneider-Petsinger, Senior Research Fellow, US and Americas Programme, Chatham House Global trade and the WTO – which has been at the heart of the rules-based international trade system since its creation in 1995 – faced a critical moment even before COVID-19. The Appellate Body’s demise in December 2019 led to a renewed focus on the future of the WTO. But the challenges facing the WTO run deeper than that – the organization has lost relevance as a negotiation forum, resulting in the global trade rules not having kept pace with changes in technology and the rise of China. While the WTO provides a forum for international cooperation to address the trade fallout from COVID-19, what implications will the pandemic have for the long-term reform of the global trade system?Both the US and EU have proposed various WTO reform strategies and taken steps towards collaboration, but is a transatlantic partnership for WTO reform feasible? Do the US and EU believe that a rules-based international trade system is in their interest – especially in light of COVID-19? What are the biggest issues dividing the US and EU on reforming the WTO, and is there a common assessment of the key problems? What steps can the US and EU take to address the dispute settlement function of the WTO and to modernize the trade rules? Are there broader issues, such as environmental and social sustainability, that should be included in a transatlantic agenda for WTO reform?This event is part of the Chatham House Global Trade Policy Forum and will take place virtually only.We would like to take this opportunity to thank founding partner AIG and supporting partners Clifford Chance LLP, Diageo plc, and EY for their generous support of the Chatham House Global Trade Policy Forum. Department/project US and the Americas Programme, Global Trade Policy Forum Full Article
art Writing Groups Part 2 By mythicscribes.com Published On :: Sun, 19 Jan 2020 22:31:53 +0000 In my previous article on writing groups (which you can read here), I talked about some popular ways writers connect. From online forums like the Mythic Scribes writing forums to community workshops, there’s no shortage of ways writers find each other, and just as many reasons they’re out there searching in the first place. In this follow-up article I’d like to explore some ways to start a writing group, and to keep a good group running by avoiding common pitfalls that lead to trouble. What’s the Point? Whether you’ve been searching for an established group and have had zero luck finding the right one, or you’re trying to start a specific group to fill a niche, the first thing to consider when starting a group is the scope—what you’re hoping to get from it. Writing solo can work for years, until one day…it just doesn’t, and it helps to know what you’re looking for in a writers’ group. Motivation, accountability, advice, feedback, critique, support—you name it, there’s a group for it, or at least other folks looking for the same thing. Are you searching for a relaxed place for people to share their journey as writers? Continue reading Writing Groups Part 2 at Mythic Scribes. Full Article Miscellaneous Writing Life writing groups
art Fantasy Fortifications — Part 3: Design By mythicscribes.com Published On :: Mon, 27 Jan 2020 03:06:24 +0000 This article is part 3 of a series on Fantasy Fortifications by Toni Šušnjar. The design of a fortification depends on its purpose and on the threats it is expected to face. A fortification facing only infantry-held weapons, one facing mechanical artillery, and one facing gunpowder artillery will all significantly differ in design characteristics. Some characteristics however will be the same – geography will always provide advantage (or disadvantage) in defending a fort or a city, and thus location has to be carefully chosen. In some cases, location may be good enough to allow the defender to skimp on certain design features – as seen with e.g. Klis fortress, where northern wall is waist-tall at best, thanks to its position on an inaccessible cliff (clissa). In other cases, disadvantageous terrain may have to be compensated with by massive man-made features. General Design In order to cope with development of artillery, design of fortifications changed with time. First fortifications, which only had to deal with handheld weapons, were simple wooden palisades. These were later supplemented with earthen ramparts As siege weapons developed, fortifications grew both in height and thickness. Continue reading Fantasy Fortifications — Part 3: Design at Mythic Scribes. Full Article History Fantasy Fortifications
art Fantasy Fortifications — Part 4: Types of Castles By mythicscribes.com Published On :: Fri, 28 Feb 2020 23:01:05 +0000 This article is part 4 of a series on Fantasy Fortifications by Toni Šušnjar. Building a Fort Build time of a castle, depending on design and available funds, may last from half a year to half a century. It also depends on the situation before the building: a ruined castle is a half-built castle after all, and rennovating (and/or updating) walls is much cheaper than building new ones. This can be seen with city of Dubrovnik, where (massive) medieval fortifications were, after the fall of Constantinople in 1453., reinforced with outer line of walls to reinforce them against cannon fire. Both build time and extent of fortifications depend on material (financial, logistical, humane) capacities of the builder, as well as the perceived need. Many castles were never finished for lack of resources. Builders are professionals; peasants, soldiers and other amateurs were used for muscle work only. This means that they have to be paid, and many in fact travel from a building place to a building place. Beaumaris Castle in England required 400 masons and 1,000 assistants to be built in a nearly record time (from 1278 to 1280). Types of Castles Motte and bailey castle Motte and bailey castle is the earliest and simplest type of a castle. Continue reading Fantasy Fortifications — Part 4: Types of Castles at Mythic Scribes. Full Article History Fantasy Fortifications
art Partisanship Meets Trump’s Impeachment By feedproxy.google.com Published On :: Thu, 19 Dec 2019 20:38:54 +0000 19 December 2019 Dr Lindsay Newman Senior Research Fellow, US and the Americas Programme @lindsayrsnewman LinkedIn History shows that if those pushing for impeachment and removal want to succeed, they need to drive up popular support for a senate conviction. GettyImages-1189454843.jpg Opposing protests during the House of Representatives debate on whether to charge President Donald Trump with two articles of impeachment. Photo by Sarah Silbiger/Getty Images. The vote to impeach Donald Trump holds almost no surprises - on both the abuse of power and obstruction of congress articles, the votes were split entirely on party lines with nearly all the majority-led House Democrats but not a single Republican voting to impeach Trump.However, this ‘pre-ordained’ outcome of the House impeachment inquiry does serve to highlight that the US is in the midst of a hyper-partisan political moment. Policy gridlock has led to two government shutdowns during Donald Trump’s presidency, with one further budgetary fight narrowly avoided.With a few notable exceptions (such as USMCA), policy areas that lend themselves to bipartisanship - including infrastructure and drug pricing - have seen very little progress under divided congressional chambers. Party identification can now be overlaid with the cable news channel one watches or the newspaper one reads.Impeachment now moves to the Senate for a trial, requiring a two-thirds majority of the Republican-led senate (or 67 senators) for a conviction. Given the congressional partisanship we are seeing, the baseline scenario continues to be that the senate will not vote to convict Trump and remove him from office - despite much being made of how many senators are likely to vote for a Senate conviction.Why public opinion could be crucialThere is another story to keep a close eye on. The number to track is 47.2 – the current polling average of public support for Trump’s impeachment. Polling averages from the end of September 2019 (before the hearings began, but after House Speaker Nancy Pelosi announced a formal inquiry) had 49.4% supporting impeachment versus 47.2% this week.Here’s why this number matters. If those pushing for impeachment and removal are unable to drive popular support across a critical threshold level, then those against impeachment and removal are not going to abandon the president and vote for a senate conviction. With Trump consistently polling in the low 40s on job approval, but in the high 80s/low 90s within the Republican party, this means Republican congress members concerned about re-election are extremely hesitant to distance themselves from him without a clear mandate from the domestic public. A tale of the two most recent presidents to face impeachment underscores this point. Gallup polling claimed 58% of adults supported impeaching and removing President Richard Nixon from office in August 1974, whereas only 35% of the public supported impeaching President Bill Clinton in December 1998, the month he was impeached.Given the respective outcomes of those two impeachments, it suggests public support for impeachment and removal needs to increase well beyond the current 47.2%, to avoid the foregone conclusion of acquittal in the Senate (even if there are signs of the tide moving in the opposite direction with those against impeachment overtaking support for the first time in December). What does this mean for Democrats?In the short term, if the Democrats want to make inroads into the hearts and minds of those across the partisan gulf, it will be critical to secure senate testimony from those in Trump’s inner circle at the time of the Ukrainian affair.After Trump ordered individuals with first-hand knowledge of the administration’s efforts vis-à-vis Ukraine not to testify, House investigators were unable to call many witnesses with direct evidence (which in fact left the House testimony exposed to Republican claims of hearsay). With Trump impeached, more of the public is likely to tune in to the senate proceedings, and direct evidence by inner circle administration officials required to testify presents an opportunity to move public opinion.House speaker Nancy Pelosi recognizes how crucial the procedures and participants for the senate trial will be, and has said she could delay sending the articles of impeachment to the senate as leverage for a 'fair trial'.Democrats also have to consider how an impeachment inquiry that - at least from this vantage point - does not end in a conviction of the president plays out for the 2020 election campaign, especially if this also likely means that public opinion - and certainly Republican-party views - of Trump have not shifted. Full Article
art Arturo Sarukhan By feedproxy.google.com Published On :: Wed, 12 Feb 2020 11:57:22 +0000 Associate Fellow, US and the Americas Programme (based in the US) Biography Ambassador Arturo Sarukhan is the founder and president of Sarukhan + Associates. Now a consultant and public speaker, he was a career diplomat in the Mexican foreign service for 22 years, receiving the rank of career ambassador in 2006.From 2007 to 2013, he served as Mexico's ambassador to the US. Previously, he served, among other positions, as consul general in New York, chief of policy planning and deputy director general for inter-American affairs.In 2006 he requested a leave of absence from the foreign service to become foreign policy advisor and international spokesperson for the Calderon presidential campaign. He subsequently led the foreign policy transition team.A digital diplomacy pioneer, he became the first ambassador accredited in Washington to use Twitter as a public diplomacy tool. He publishes regularly and appears frequently on US and international media.He sits on several non-profit and corporate boards, and has several academic and think-tank affiliations in the US.He holds a BA in international relations from El Colegio de Mexico and an MA in American Foreign Policy from SAIS-Johns Hopkins. Areas of expertise US foreign and domestic policyMexican foreign and domestic policy; US-Mexico and North American relationsDigital Diplomacy/Public DiplomacyInter-American affairsNew global challenges: migration; transnational organized crime; disinformation and weaponization of social media Past experience 2014 - presentPresident and founder, Sarukhan + Associates, LLC 2007-13Mexican Ambassador to the US 2006Coordinator, Presidential Foreign Policy Transition Team2006Foreign Policy Advisor and international spokesperson, Calderon presidential campaign2003-06Consul General, New York City2000-03Chief for Policy Planning, Mexican Foreign Ministry1989-2000Senior Advisor to the Foreign Minister1995-98Head of the Counternarcotics section, Mexican Embassy USA1993-95Chief of Staff to the Ambassador, Mexican Embassy USA1992-93Deputy Director General for Inter-American Affairs1992Admission to the Foreign Service, Instituto Matias Romero1989-91MA, School of Advanced International Studies, Johns Hopkins University1987-89Executive Assistant, Ford Foundation Bilateral Commission on the Future of US-Mexico Relations1984-88BA, International Relations, El Colegio de México1982-84BA studies, History, Universidad Nacional Autónoma de México +(202) 4132005 Email @Arturo_Sarukhan LinkedIn Full Article
art A Transatlantic Partnership for WTO Reform in the Age of Coronavirus By feedproxy.google.com Published On :: Thu, 23 Apr 2020 13:45:01 +0000 Webinar Research Event 28 April 2020 - 2:00pm to 3:00pm Event participants Ignacio Garcia Bercero, Director, Directorate General for Trade of the European Commission; European Union Visiting Fellow, Oxford UniversityJennifer Hillman, Senior Fellow for Trade and International Political Economy, Council on Foreign Relations; Member, WTO Appellate Body, 2007 - 11Chair: Marianne Schneider-Petsinger, Senior Research Fellow, US and Americas Programme, Chatham House Global trade and the WTO – which has been at the heart of the rules-based international trade system since its creation in 1995 – faced a critical moment even before COVID-19. The Appellate Body’s demise in December 2019 led to a renewed focus on the future of the WTO. But the challenges facing the WTO run deeper than that – the organization has lost relevance as a negotiation forum, resulting in the global trade rules not having kept pace with changes in technology and the rise of China. While the WTO provides a forum for international cooperation to address the trade fallout from COVID-19, what implications will the pandemic have for the long-term reform of the global trade system?Both the US and EU have proposed various WTO reform strategies and taken steps towards collaboration, but is a transatlantic partnership for WTO reform feasible? Do the US and EU believe that a rules-based international trade system is in their interest – especially in light of COVID-19? What are the biggest issues dividing the US and EU on reforming the WTO, and is there a common assessment of the key problems? What steps can the US and EU take to address the dispute settlement function of the WTO and to modernize the trade rules? Are there broader issues, such as environmental and social sustainability, that should be included in a transatlantic agenda for WTO reform?This event is part of the Chatham House Global Trade Policy Forum and will take place virtually only.We would like to take this opportunity to thank founding partner AIG and supporting partners Clifford Chance LLP, Diageo plc, and EY for their generous support of the Chatham House Global Trade Policy Forum. Department/project US and the Americas Programme, Global Trade Policy Forum Full Article
art Somaliland's Regional Priorities and Strategic Partnerships By feedproxy.google.com Published On :: Thu, 19 Apr 2018 00:00:00 +0100 Full Article
art Undercurrents: Episode 10 - Artificial Intelligence in International Affairs, and Women Drivers in Saudi Arabia By feedproxy.google.com Published On :: Fri, 15 Jun 2018 00:00:00 +0100 Full Article
art The Kremlin Letters: Wartime Exchanges of the Big Three By feedproxy.google.com Published On :: Wed, 07 Nov 2018 00:00:00 +0000 Full Article
art Martin Wight Memorial Lecture: The Future of Think-Tanks By feedproxy.google.com Published On :: Wed, 21 Nov 2018 00:00:00 +0000 Full Article
art China’s Dream: The Chinese Communist Party’s Culture, Resilience and Power By feedproxy.google.com Published On :: Thu, 31 Jan 2019 00:00:00 +0000 Full Article
art Podcast: Examining The Post-Brexit Japan-UK Partnership By feedproxy.google.com Published On :: Wed, 13 Feb 2019 00:00:00 +0000 Full Article
art Are ‘Digital Parties’ the Future of Democracy in Europe? By feedproxy.google.com Published On :: Tue, 07 May 2019 00:00:00 +0100 Full Article
art Direct Democracy: Participation Without Populism? By feedproxy.google.com Published On :: Mon, 24 Jun 2019 00:00:00 +0100 Full Article
art Artificial Intelligence and the Public: Prospects, Perceptions and Implications By feedproxy.google.com Published On :: Fri, 28 Jun 2019 00:00:00 +0100 Full Article
art Undercurrents: Summer Special - Allison Gardner on Artificial Intelligence By feedproxy.google.com Published On :: Thu, 08 Aug 2019 00:00:00 +0100 Full Article
art Screening Room: Parts of a Circle - History of the Karabakh Conflict By feedproxy.google.com Published On :: Tue, 18 Feb 2020 00:00:00 +0000 Full Article
art France, the UK and Europe: New Partnerships and Common Challenges By feedproxy.google.com Published On :: Fri, 28 Feb 2020 00:00:00 +0000 Full Article
art SSO and other putative inhibitors of FA transport across membranes by CD36 disrupt intracellular metabolism, but do not affect FA translocation [Research Articles] By feedproxy.google.com Published On :: 2020-05-01T00:05:28-07:00 Membrane-bound proteins have been proposed to mediate the transport of long-chain FA (LCFA) transport through the plasma membrane (PM). These proposals are based largely on reports that PM transport of LCFAs can be blocked by a number of enzymes and purported inhibitors of LCFA transport. Here, using the ratiometric pH indicator (2',7'-bis-(2-carboxyethyl)-5-(and-6-)-carboxyfluorescein and acrylodated intestinal FA-binding protein-based dual fluorescence assays, we investigated the effects of nine inhibitors of the putative FA transporter protein CD36 on the binding and transmembrane movement of LCFAs. We particularly focused on sulfosuccinimidyl oleate (SSO), reported to be a competitive inhibitor of CD36-mediated LCFA transport. Using these assays in adipocytes and inhibitor-treated protein-free lipid vesicles, we demonstrate that rapid LCFA transport across model and biological membranes remains unchanged in the presence of these purported inhibitors. We have previously shown in live cells that CD36 does not accelerate the transport of unesterified LCFAs across the PM. Our present experiments indicated disruption of LCFA metabolism inside the cell within minutes upon treatment with many of the "inhibitors" previously assumed to inhibit LCFA transport across the PM. Furthermore, using confocal microscopy and a specific anti-SSO antibody, we found that numerous intracellular and PM-bound proteins are SSO-modified in addition to CD36. Our results support the hypothesis that LCFAs diffuse rapidly across biological membranes and do not require an active protein transporter for their transmembrane movement. Full Article
art Hepatic monoamine oxidase B is involved in endogenous geranylgeranoic acid synthesis in mammalian liver cells [Research Articles] By feedproxy.google.com Published On :: 2020-05-01T00:05:28-07:00 Geranylgeranoic acid (GGA) originally was identified in some animals and has been developed as an agent for preventing second primary hepatoma. We previously have also identified GGA as an acyclic diterpenoid in some medicinal herbs. Recently, we reported that in human hepatoma-derived HuH-7 cells, GGA is metabolically labeled from 13C-mevalonate. Several cell-free experiments have demonstrated that GGA is synthesized through geranylgeranial by oxygen-dependent oxidation of geranylgeraniol (GGOH), but the exact biochemical events giving rise to GGA in hepatoma cells remain unclear. Monoamine oxidase B (MOAB) has been suggested to be involved in GGOH oxidation. Here, using two human hepatoma cell lines, we investigated whether MAOB contributes to GGA biosynthesis. Using either HuH-7 cell lysates or recombinant human MAOB, we found that: 1) the MAO inhibitor tranylcypromine dose-dependently downregulates endogenous GGA levels in HuH-7 cells; and 2) siRNA-mediated MAOB silencing reduces intracellular GGA levels in HuH-7 and Hep3B cells. Unexpectedly, however, CRISPR/Cas9-generated MAOB-KO human hepatoma Hep3B cells had GGA levels similar to those in MAOB-WT cells. A sensitivity of GGA levels to siRNA-mediated MAOB downregulation was recovered when the MAOB-KO cells were transfected with a MAOB-expression plasmid, suggesting that MAOB is the enzyme primarily responsible for GGOH oxidation and that some other latent metabolic pathways may maintain endogenous GGA levels in the MAOB-KO hepatoma cells. Along with the previous findings, these results provide critical insights into the biological roles of human MAOB and provide evidence that hepatic MAOB is involved in endogenous GGA biosynthesis via GGOH oxidation. Full Article
art A novel GPER antagonist protects against the formation of estrogen-induced cholesterol gallstones in female mice [Research Articles] By feedproxy.google.com Published On :: 2020-05-01T00:05:27-07:00 Many clinical studies and epidemiological investigations have clearly demonstrated that women are twice as likely to develop cholesterol gallstones as men, and oral contraceptives and other estrogen therapies dramatically increase that risk. Further, animal studies have revealed that estrogen promotes cholesterol gallstone formation through the estrogen receptor (ER) α, but not ERβ, pathway. More importantly, some genetic and pathophysiological studies have found that G protein-coupled estrogen receptor (GPER) 1 is a new gallstone gene, Lith18, on chromosome 5 in mice and produces additional lithogenic actions, working independently of ERα, to markedly increase cholelithogenesis in female mice. Based on computational modeling of GPER, a novel series of GPER-selective antagonists were designed, synthesized, and subsequently assessed for their therapeutic effects via calcium mobilization, cAMP, and ERα and ERβ fluorescence polarization binding assays. From this series of compounds, one new compound, 2-cyclohexyl-4-isopropyl-N-(4-methoxybenzyl)aniline (CIMBA), exhibits superior antagonism and selectivity exclusively for GPER. Furthermore, CIMBA reduces the formation of 17β-estradiol-induced gallstones in a dose-dependent manner in ovariectomized mice fed a lithogenic diet for 8 weeks. At 32 μg/day/kg CIMBA, no gallstones are found, even in ovariectomized ERα (–/–) mice treated with 6 μg/day 17β-estradiol and fed the lithogenic diet for 8 weeks. In conclusion, CIMBA treatment protects against the formation of estrogen-induced cholesterol gallstones by inhibiting the GPER signaling pathway in female mice. CIMBA may thus be a new agent for effectively treating cholesterol gallstone disease in women. Full Article
art Nanodomains can persist at physiologic temperature in plasma membrane vesicles and be modulated by altering cell lipids [Research Articles] By feedproxy.google.com Published On :: 2020-05-01T00:05:27-07:00 The formation and properties of liquid-ordered (Lo) lipid domains (rafts) in the plasma membrane are still poorly understood. This limits our ability to manipulate ordered lipid domain-dependent biological functions. Giant plasma membrane vesicles (GPMVs) undergo large-scale phase separations into coexisting Lo and liquid-disordered lipid domains. However, large-scale phase separation in GPMVs detected by light microscopy is observed only at low temperatures. Comparing Förster resonance energy transfer-detected versus light microscopy-detected domain formation, we found that nanodomains, domains of nanometer size, persist at temperatures up to 20°C higher than large-scale phases, up to physiologic temperature. The persistence of nanodomains at higher temperatures is consistent with previously reported theoretical calculations. To investigate the sensitivity of nanodomains to lipid composition, GPMVs were prepared from mammalian cells in which sterol, phospholipid, or sphingolipid composition in the plasma membrane outer leaflet had been altered by cyclodextrin-catalyzed lipid exchange. Lipid substitutions that stabilize or destabilize ordered domain formation in artificial lipid vesicles had a similar effect on the thermal stability of nanodomains and large-scale phase separation in GPMVs, with nanodomains persisting at higher temperatures than large-scale phases for a wide range of lipid compositions. This indicates that it is likely that plasma membrane nanodomains can form under physiologic conditions more readily than large-scale phase separation. We also conclude that membrane lipid substitutions carried out in intact cells are able to modulate the propensity of plasma membranes to form ordered domains. This implies lipid substitutions can be used to alter biological processes dependent upon ordered domains. Full Article
art Schnyder corneal dystrophy-associated UBIAD1 is defective in MK-4 synthesis and resists autophagy-mediated degradation [Research Articles] By feedproxy.google.com Published On :: 2020-05-01T00:05:27-07:00 The autosomal dominant disorder Schnyder corneal dystrophy (SCD) is caused by mutations in UbiA prenyltransferase domain-containing protein-1 (UBIAD1), which uses geranylgeranyl pyrophosphate (GGpp) to synthesize the vitamin K2 subtype menaquinone-4 (MK-4). SCD is characterized by opacification of the cornea, owing to aberrant build-up of cholesterol in the tissue. We previously discovered that sterols stimulate association of UBIAD1 with ER-localized HMG-CoA reductase, which catalyzes a rate-limiting step in the synthesis of cholesterol and nonsterol isoprenoids, including GGpp. Binding to UBIAD1 inhibits sterol-accelerated ER-associated degradation (ERAD) of reductase and permits continued synthesis of GGpp in cholesterol-replete cells. GGpp disrupts UBIAD1-reductase binding and thereby allows for maximal ERAD of reductase as well as ER-to-Golgi translocation of UBIAD1. SCD-associated UBIAD1 is refractory to GGpp-mediated dissociation from reductase and remains sequestered in the ER to inhibit ERAD. Here, we report development of a biochemical assay for UBIAD1-mediated synthesis of MK-4 in isolated membranes and intact cells. Using this assay, we compared enzymatic activity of WT UBIAD1 with that of SCD-associated variants. Our studies revealed that SCD-associated UBIAD1 exhibited reduced MK-4 synthetic activity, which may result from its reduced affinity for GGpp. Sequestration in the ER protects SCD-associated UBIAD1 from autophagy and allows intracellular accumulation of the mutant protein, which amplifies the inhibitory effect on reductase ERAD. These findings have important implications not only for the understanding of SCD etiology but also for the efficacy of cholesterol-lowering statin therapy, which becomes limited, in part, because of UBIAD1-mediated inhibition of reductase ERAD. Full Article
art Slc43a3 is a regulator of free fatty acid flux [Research Articles] By feedproxy.google.com Published On :: 2020-05-01T00:05:27-07:00 Adipocytes take up long chain FAs through diffusion and protein-mediated transport, whereas FA efflux is considered to occur by diffusion. To identify potential membrane proteins that are involved in regulating FA flux in adipocytes, the expression levels of 55 membrane transporters without known function were screened in subcutaneous adipose samples from obese patients before and after bariatric surgery using branched DNA methodology. Among the 33 solute carrier (SLC) transporter family members screened, the expression of 14 members showed significant changes before and after bariatric surgery. One of them, Slc43a3, increased about 2.5-fold after bariatric surgery. Further investigation demonstrated that Slc43a3 is highly expressed in murine adipose tissue and induced during adipocyte differentiation in primary preadipocytes and in OP9 cells. Knockdown of Slc43a3 with siRNA in differentiated OP9 adipocytes reduced both basal and forskolin-stimulated FA efflux, while also increasing FA uptake and lipid droplet accumulation. In contrast, overexpression of Slc43a3 decreased FA uptake in differentiated OP9 cells and resulted in decreased lipid droplet accumulation. Therefore, Slc43a3 seems to regulate FA flux in adipocytes, functioning as a positive regulator of FA efflux and as a negative regulator of FA uptake. Full Article
art The grease trap: uncovering the mechanism of the hydrophobic lid in Cutibacterium acnes lipase [Research Articles] By feedproxy.google.com Published On :: 2020-05-01T00:05:27-07:00 Acne is one of the most common dermatological conditions, but the details of its pathology are unclear, and current management regimens often have adverse effects. Cutibacterium acnes is known as a major acne-associated bacterium that derives energy from lipase-mediated sebum lipid degradation. C. acnes is commensal, but lipase activity has been observed to differ among C. acnes types. For example, higher populations of the type IA strains are present in acne lesions with higher lipase activity. In the present study, we examined a conserved lipase in types IB and II that was truncated in type IA C. acnes strains. Closed, blocked, and open structures of C. acnes ATCC11828 lipases were elucidated by X-ray crystallography at 1.6–2.4 Å. The closed crystal structure, which is the most common form in aqueous solution, revealed that a hydrophobic lid domain shields the active site. By comparing closed, blocked, and open structures, we found that the lid domain-opening mechanisms of C. acnes lipases (CAlipases) involve the lid-opening residues, Phe-179 and Phe-211. To the best of our knowledge, this is the first structure-function study of CAlipases, which may help to shed light on the mechanisms involved in acne development and may aid in future drug design. Full Article
art Vitamin E does not prevent Western diet-induced NASH progression and increases metabolic flux dysregulation in mice [Research Articles] By feedproxy.google.com Published On :: 2020-05-01T00:05:27-07:00 Fatty liver involves ectopic lipid accumulation and dysregulated hepatic oxidative metabolism, which can progress to a state of elevated inflammation and fibrosis referred to as nonalcoholic steatohepatitis (NASH). The factors that control progression from simple steatosis to NASH are not fully known. Here, we tested the hypothesis that dietary vitamin E (VitE) supplementation would prevent NASH progression and associated metabolic alterations induced by a Western diet (WD). Hyperphagic melanocortin-4 receptor-deficient (MC4R–/–) mice were fed chow, chow+VitE, WD, or WD+VitE starting at 8 or 20 weeks of age. All groups exhibited extensive hepatic steatosis by the end of the study (28 weeks of age). WD feeding exacerbated liver disease severity without inducing proportional changes in liver triglycerides. Eight weeks of WD accelerated liver pyruvate cycling, and 20 weeks of WD extensively upregulated liver glucose and oxidative metabolism assessed by 2H/13C flux analysis. VitE supplementation failed to reduce the histological features of NASH. Rather, WD+VitE increased the abundance and saturation of liver ceramides and accelerated metabolic flux dysregulation compared with 8 weeks of WD alone. In summary, VitE did not limit NASH pathogenesis in genetically obese mice, but instead increased some indicators of metabolic dysfunction. Full Article
art Myeloid-specific deficiency of pregnane X receptor decreases atherosclerosis in LDL receptor-deficient mice [Research Articles] By feedproxy.google.com Published On :: 2020-05-01T00:05:27-07:00 The pregnane X receptor (PXR) is a nuclear receptor that can be activated by numerous drugs and xenobiotic chemicals. PXR thereby functions as a xenobiotic sensor to coordinately regulate host responses to xenobiotics by transcriptionally regulating many genes involved in xenobiotic metabolism. We have previously reported that PXR has pro-atherogenic effects in animal models, but how PXR contributes to atherosclerosis development in different tissues or cell types remains elusive. In this study, we generated an LDL receptor-deficient mouse model with myeloid-specific PXR deficiency (PXRMyeLDLR–/–) to elucidate the role of macrophage PXR signaling in atherogenesis. The myeloid PXR deficiency did not affect metabolic phenotypes and plasma lipid profiles, but PXRMyeLDLR–/– mice had significantly decreased atherosclerosis at both aortic root and brachiocephalic arteries compared with control littermates. Interestingly, the PXR deletion did not affect macrophage adhesion and migration properties, but reduced lipid accumulation and foam cell formation in the macrophages. PXR deficiency also led to decreased expression of the scavenger receptor CD36 and impaired lipid uptake in macrophages of the PXRMyeLDLR–/– mice. Further, RNA-Seq analysis indicated that treatment with a prototypical PXR ligand affects the expression of many atherosclerosis-related genes in macrophages in vitro. These findings reveal a pivotal role of myeloid PXR signaling in atherosclerosis development and suggest that PXR may be a potential therapeutic target in atherosclerosis management. Full Article
art The ins and outs of lipid rafts: functions in intracellular cholesterol homeostasis, microparticles, and cell membranes [Thematic Reviews] By feedproxy.google.com Published On :: 2020-05-01T00:05:27-07:00 Cellular membranes are not homogenous mixtures of proteins; rather, they are segregated into microdomains on the basis of preferential association between specific lipids and proteins. These microdomains, called lipid rafts, are well known for their role in receptor signaling on the plasma membrane (PM) and are essential to such cellular functions as signal transduction and spatial organization of the PM. A number of disease states, including atherosclerosis and other cardiovascular disorders, may be caused by dysfunctional maintenance of lipid rafts. Lipid rafts do not occur only in the PM but also have been found in intracellular membranes and extracellular vesicles (EVs). Here, we focus on discussing newly discovered functions of lipid rafts and microdomains in intracellular membranes, including lipid and protein trafficking from the ER, Golgi bodies, and endosomes to the PM, and we examine lipid raft involvement in the production and composition of EVs. Because lipid rafts are small and transient, visualization remains challenging. Future work with advanced techniques will continue to expand our knowledge about the roles of lipid rafts in cellular functioning. Full Article