as Chatham House appoints Tim Benton as Research Director for Energy, Environment and Resources By feedproxy.google.com Published On :: Thu, 30 May 2019 08:44:55 +0000 30 May 2019 Chatham House is pleased to announce that Professor Tim Benton has been appointed as research director of the Energy, Environment and Resources Department. BentonTim3.jpg He brings substantial expertise on food systems and environmental change to the role and will focus on establishing new initiatives at the intersection of research and policymaking.Tim was appointed as a distinguished visiting fellow of Chatham House in the Energy, Environment and Resources Department in 2016. He has since contributed to the institute in a number of ways, not least through leading the GCRF-AFRICAP project which aims to enhance policy making in Sub-Saharan Africa, through building climate-smart food systems.Tim’s research focuses on food security and building food systems that are resilient and sustainable, working within the broader areas of ecology, natural resources and climate change impacts. He has published over 150 academic papers, most tackling the core themes of agriculture’s environmental impact and more generally how systems respond to environmental change. He is a lead author of the upcoming Intergovernmental Panel on Climate Change (IPCC) special report on climate change and land. He is also coordinating lead author on international risks for the UK’s Climate Change Risk Assessment, which draws on his broader interests in sustainable finance, trade and energy. He has advised other governments as well as global companies on related issues.Tim joins Chatham House in his new capacity from the University of Leeds where he is dean of strategic research initiatives. Prior to this, from 2011 to 2016, Tim was the champion of the UK’s Global Food Security programme, a large multi-agency partnership of the UK’s public bodies involved in addressing challenges around food. He has also been research dean in the Faculty of Biological Sciences, and head of department, at Leeds.Dr Robin Niblett, director of Chatham House, said: 'Tim’s wealth of experience will be especially valuable as we build up our interdisciplinary Chatham House research theme of promoting sustainable growth. We look forward to welcoming Tim to his new role in early July.'Tim Benton said: 'I am honoured to be joining Chatham House as Research Director for Energy, Environment and Resources. Chatham House has a global reputation in these areas, on which we can build. Informed analysis, combined with effective action to transition towards sustainable economies, is needed now, more than ever.'About the Energy, Environment and Resources DepartmentThe Energy, Environment and Resources department at Chatham House seeks to advance the international debate on energy, environment and development policy and to influence and enable decision-makers – governments, NGOs and business – to take well-informed decisions that contribute to achieving sustainable development. Independent of any actor or ideology, we do this by carrying out innovative research on major policy challenges, bringing together diverse perspectives and constituencies and injecting new ideas into the international arena.Tim Benton takes over the role from Rob Bailey who has joined Marsh & McLennan Insights as Director, Climate Resilience. Full Article
as Chatham House appoints Rob Yates as the new head of the Centre on Global Health Security By feedproxy.google.com Published On :: Thu, 27 Jun 2019 09:35:01 +0000 27 June 2019 Chatham House is pleased to announce that Rob Yates has been appointed as head of the Centre on Global Health Security. Yates.jpg He brings decades of experience as a health economist working in international development and health and is an internationally recognized expert on universal health coverage (UHC) and progressive health financing, operating at the highest political levels.For the past five years, Rob has led the Centre’s work on Universal Health Coverage (UHC) as director of its UHC Policy Forum, which works on the political economy of UHC reform processes and advises political leaders and government ministries on how to plan, finance and implement national UHC reforms.He has also worked closely with The Elders on presenting policy options on universal health reforms to heads of state across the world. Before leading the UHC Policy Forum at Chatham House, Rob was a senior health economist at the World Health Organization from 2011 to 2014, after moving from the UK Department for International Development (DFID), where he was a senior health economist. Prior to that, Rob was the deputy head of the Integrated UN Office in the Democratic Republic of Congo. He also spent five years working for the government of Uganda as a senior health economist, on secondment from DFID during the early 2000s.'I am delighted to welcome Rob Yates as the head of the Centre on Global Health Security. He will bring a wealth of experience to the role at a time of risk but also great opportunity in the sector,' said Dr Robin Niblett, director of Chatham House. 'Rob will continue to work on his own area of expertise – universal health coverage – while ensuring the Centre continues to address other major global health challenges that manifest themselves as foreign policy and international affairs problems.'Rob replaces David Heymann, who retires from the role as the Centre marks its 10th anniversary but will remain involved in several of the Centre’s projects.'I would also like to pay tribute to David Heymann, who launched the Centre on Global Health Security in 2009 to examine key global health challenges in international affairs and world politics,' Niblett added. 'Without David the Centre would not have had the impact that it has and I am truly grateful for his hard work and achievements over the last 10 years.'Yates takes up his post this week.'I am honoured to become the new head of the Centre on Global Health Security and build on the successes delivered by David Heymann and the team over the last decade,' he said. 'My priority as the new head will be to ensure that our research and activities have a real impact in accelerating progress towards the Sustainable Development Goals by focusing on improving health security and health coverage in countries across the world. Engaging in issues related to the political economy of health and health care reforms will be critical in achieving this impact.' Full Article
as Transatlantic Cooperation to Prevent and Stop Mass Atrocities By feedproxy.google.com Published On :: Tue, 10 Feb 2015 16:15:01 +0000 Invitation Only Research Event 16 February 2015 - 1:00pm to 5:00pm Chatham House, London Meeting Summarypdf | 305.38 KB Event participants Ambassador Lee Feinstein, Founding Dean, School of Global & International Studies, Indiana UniversityXenia Wickett, Project Director, US; Dean, The Queen Elizabeth II Academy, Chatham HousePaul Arkwright, Director, Multilateral Policy, Foreign & Commonwealth OfficeDr Patricia Lewis, Research Director, International Security Programme, Chatham HouseJonathan Prentice, Director, London Office & Senior Adviser for European Advocacy, International Crisis GroupSir John Holmes, Director, The Ditchley Foundation The international community is in urgent need of successful, cooperative strategies for both preventing mass atrocities before they begin and stopping those in progress. As recent crises have highlighted, effective international cooperation to save lives and preserve peace and security remains largely aspirational. Participants will discuss current thinking on mass atrocity prevention and intervention, and identify how transatlantic cooperation in this space could be more effective.Attendance at this event is by invitation only. Department/project US and the Americas Programme Richard Gowing Programme Administrator +44 (0)20 7389 3270 Email Full Article
as Transatlantic Strategy Group on the Future of US Global Leadership: Transatlantic Security Policy Towards a Changing Middle East By feedproxy.google.com Published On :: Thu, 05 Mar 2015 11:45:02 +0000 Invitation Only Research Event 6 February 2015 - 8:45am to 4:30pm Residence of the British Ambassador to France, Paris Meeting Summarypdf | 95.65 KB With the Middle East in chaos and the future of many states increasingly uncertain, there is a large amount of attention as to how policy-makers in Europe and the US should respond. In particular, many in Europe are unsure of long-term US policy in light of competing American priorities, budgetary constraints and a public adverse to committing further resources abroad. In this context, it is important that European and American policy-makers understand each other’s positions.At this all-day event, a group of experts will discuss how US policy towards the Middle East is changing, what this means for Europe and, subsequently, how Europe should respond. Attendance at this event is by invitation only.The workshop is held as part of the Transatlantic Strategy Group on the Future of US Global Leadership run jointly with the German Marshall Fund of the United States. Over the course of a year, this group will discuss how US policy is changing on key issues and the implications for Europe. This project is supported by the Fritz Thyssen Foundation, with support for this event provided by the Delegation of Strategic Affairs of the French Ministry of Defence and the British Embassy in Paris. Event attributes External event Department/project US and the Americas Programme Full Article
as Transatlantic Rifts: Asia-Pacific Scenario Case Study By feedproxy.google.com Published On :: Wed, 03 Feb 2016 09:49:12 +0000 3 February 2016 Drawing on the findings of a recent workshop exploring a potential conflict between China and Japan over disputed islands, this paper suggests there are significant differences between how the United States and Europe prioritize their interests in the Asia-Pacific. 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 Dr Jacob Parakilas Former Deputy Head, US and the Americas Programme 2016-02-03-transatlantic-rift.jpg A Japanese activist on board a boat is silhouetted at sunrise as it approaches the Senkaku/Diaoyu Islands, 19 August 2012. Photo by Getty Images. SummaryChatham House brought together European, Asian and American policy-makers and experts over the course of a two-day scenario workshop in November 2015. The participants were asked to take part in a structured role-playing exercise imagining a potential near-future conflict between China and Japan over disputed islands.The findings of the workshop, and the actions of participants in the simulation, suggested significant differences between how the United States and Europe prioritize their interests in the Asia-Pacific. In particular, the perception was that the European Union and its member states consider challenges from their ‘near abroad’ as more tangible than those emanating from Asia, and that they focus on commercial opportunities in the region. In contrast, US foreign policy in the Asia-Pacific is seen as emphasizing strategic and geopolitical challenges.In terms of military capabilities, Europeans view themselves as having few assets to bring to bear in Asia. European, American and Asian observers are largely unaware of French and British military capabilities in or near the region.Beyond the military, Europe’s other tools of leverage – diplomatic, development, economic and other soft-power instruments – are also ignored. Europeans are often unaware of the activities of their own governments in the region. This is equally true in reverse – Japan’s engagement vis-à-vis European interests (such as with respect to Russia or Syria) is little recognized by Europeans.European nations prefer to engage unilaterally with Asia on trade and multilaterally, through the EU, on security and geopolitical issues. However, no ideal forum for multilateral coordination exists (given the fact that the EU is not a member of most Asian regional organizations).The US’s greater engagement in Asia reflects the fact that the US, unlike its European counterparts, is a Pacific nation. But it can also be explained by greater domestic public support for such engagement. This reflects the presence of significant numbers of US troops in Asia and the relatively high proportion of ethnic Asians in the US compared with the EU. Department/project US and the Americas Programme Full Article
as NATO Hopes to Assure Allies While Saving Refugees By feedproxy.google.com Published On :: Fri, 11 Mar 2016 10:05:37 +0000 11 March 2016 Dr Beyza Unal Senior Research Fellow, International Security Programme @beyzaunal Google Scholar NATO’s mission in the Aegean Sea seems aimed as much at deterring Russia as saving lives. It could lead to confrontation. 2016-03-11-BundesmarineB.jpg Early last month NATO launched a new maritime security mission, ostensibly to prevent people smuggling across the Aegean Sea. This mission, however, was not originally a reaction to the humanitarian catastrophe at sea. Instead, it was a response to growing Russian assertiveness.A maritime patrol unit was first discussed in the North Atlantic Council in December 2015, when the Alliance agreed to provide a ‘tailored package of assurances’ to Ankara in a period of heightened tensions after Turkey shot down a Russian jet. The package included measures such as early reconnaissance planes (AWACS), air policing, naval presence in the Eastern Mediterranean, provisions for Maritime Patrol Aircrafts (MPA) and Intelligence, Surveillance & Reconnaissance (ISR), and port visits. None of the discussion at the time linked it with protecting refugees. Now framing this decision in that light creates a new mission for NATO’s Maritime Command (MARCOM), a mission that it has never conducted before.Neither NATO’s founding documents or the most recent 2010 Strategic Concept provide for this type of mission, and NATO units are not trained to carry out an actual rescue mission. Protecting strategic assets and goods, such as oil tankers, escorting naval vessels providing food into conflict zones, deterring piracy and monitoring the Mediterranean for terrorist activity have been the main priorities for MARCOM in the post-Cold War period. These activities and maritime exercises were aimed at defence against non-state actors.The positioning of NATO’s maritime fleet in the Aegean Sea to save refugees, however, has the potential to be used as a deterrent against Russia’s Anti Access/Anti-Denial capacity in the eastern Mediterranean. Russia, meanwhile, has increased its naval presence at the Tartus naval base in Syria, which it has used to support its air campaigns in Syria. This level of reciprocated military build-up is hard to sustain in the long-run. NATO−Russia tensionsOver the past few years, Russia’s assertive policies – its multiple military operations, the continuing modernization of its army and ‘simulated attacks’ such as the one in 2013 that tested Sweden’s air defence response mechanisms − have increasingly worried the Alliance and its partners. Clashing interests over Syria’s future and Russia’s attacks against the Western-supported rebel groups have also served to increase tensions between NATO member states and Russia. Recent analysis logged 60 dangerous incidents in the Euro-Atlantic area between Russia and NATO counties in the period between March 2014 and March 2015. NATO’s preparedness has been severely tested by these incidents, and has led the alliance to strengthen its presence on Europe’s southern flank.Such increased tensions could create a situation whereby accidents and miscalculations lead to escalation. NATO forces and Russia are already engaged in further force posturing − the decision to accelerate Montenegro’s accession to NATO and the increased conduct of wartime exercises, such as NATO’s search for submarines in open waters (Dynamic Manta 2016), reconnaissance operations (Cold Operation 16) or Russia’s simulated exercises, for instance – which could undermine global stability. Three weeks after the Russian jet was shot down, a Russian patrol ship fired warning shots at a Turkish vessel to attract attention and avoid a collision. This event did not escalate but given the heightened tensions, similar events may spiral out of control. The tentative cease-fire in Syria is a confidence building measure that could normalize and rebuild relations. But further steps should be taken to establish political dialogue, open up the channels for potential meetings at the NATO−Russia Council, and increase transparency and risk mitigation in exercises and activities. The longer both sides wait, the more likely a confrontation will be.To comment on this article, please contact Chatham House Feedback Full Article
as One Year of Donald Trump: Assessing the Future of the Transatlantic Relationship By feedproxy.google.com Published On :: Mon, 11 Dec 2017 14:00:00 +0000 Members Event Webinar 18 January 2018 - 11:30am to 12:00pm Online Event participants Xenia Wickett, Head, US and the Americas Programme; Dean, The Queen Elizabeth II Academy for Leadership in International Affairs, Chatham House Events over the past 18 months, in particular with the UK’s decision to leave the European Union and the election of Donald Trump, have elevated concerns among many Europeans and Americans over the health of the transatlantic relationship. With the EU looking inward and President Trump’s rejection of a number of historically common US-European interests, such as NATO, the JCPOA on Iran, and the Paris Agreement, the continuation of close transatlantic collaboration is in question.Xenia Wickett will discuss the future of the transatlantic relationship. Is there a clear structural divergence between the US and the UK or is the partnership merely going through a temporary hiccup? She will explore the importance of recent events as well as structural, long-term factors that affect the US and Europe similarly. And what actions, if any, can be taken to mitigate differences and best manage the current situation of uncertainty?Please note, this event is online only. Members will be able to watch the webinar from a computer or other internet-ready device and do not need to come to Chatham House to attend. Full Article
as Making the Business Case for Nutrition Workshop By feedproxy.google.com Published On :: Thu, 05 Dec 2019 12:15:01 +0000 Invitation Only Research Event 28 January 2020 - 9:30am to 5:00pm Chatham House | 10 St James's Square | London | SW1Y 4LE A ground-breaking research project from Chatham House, supported by The Power of Nutrition, is exploring the business case for tackling undernutrition, micronutrient deficiencies and overnutrition. Companies across all sectors hold huge, transformative power to save countless lives and transform their own financial prospects. To act, they need more compelling evidence of the potential for targeted investments and strategies to promote better nutrition and create healthier, more productive workforces and consumers.At this workshop, Chatham House will engage business decision-makers in a scenario exercise that explores different nutrition futures and their commercial prospects in each before examining what different strategies business can pursue to maximize future profitability through investments in nutrition.Attendance at this event is by invitation only. Department/project Energy, Environment and Resources Programme Full Article
as South Africa Can Easily Afford National Health Insurance By feedproxy.google.com Published On :: Mon, 09 Dec 2019 06:07:40 +0000 9 December 2019 Robert Yates Director, Global Health Programme; Executive Director, Centre for Universal Health @yates_rob Countries with much lower per capita GDP have successfully implemented universal healthcare. 2019-12-06-NMCH.jpg Builders work on an outside yard at the Nelson Mandela Children's Hospital in Johannesburg in 2016. Photo: Getty Images. At the United Nations general assembly in September, all countries, including South Africa, reaffirmed their commitment to achieving universal health coverage by 2030. This is achieved when everybody accesses the health services they need without suffering financial hardship.As governments outlined their universal health coverage plans, it was noticeable that some had made much faster progress than others, with some middle-income countries outperforming wealthier nations. For example, whereas Thailand, Ecuador and Georgia (with national incomes similar to South Africa) are covering their entire populations, in the United States, 30 million people still lack health insurance and expensive health bills are the biggest cause of personal bankruptcy.The key factor in financing universal health coverage is, therefore, not so much the level of financing but rather how the health sector is financed. You cannot cover everyone through private financing (including insurance) because the poor will be left behind. Instead, the state must step in to force wealthy and healthy members of society to subsidise services for the sick and the poor.Switching to a predominantly publicly financed health system is, therefore, a prerequisite for achieving universal health coverage.The National Health Insurance (NHI) Bill, recently presented to parliament, is President Cyril Ramaphosa’s strategy to make this essential transition. In essence, it proposes creating a health-financing system in which people pay contributions (mostly through taxes) according to their ability to pay and then receive health services according to their health needs.Surprisingly, these reforms have been dubbed 'controversial' by some commentators in the South African media, even though this is the standard route to universal health coverage as exhibited by countries across Europe, Asia, Australasia, Canada and much of Latin America.In criticising the NHI other stakeholders (often with a vested interest in preserving the status quo) have said that the government’s universal health coverage strategy is unaffordable because it will require higher levels of public financing for health.Evidence from across the world shows that this is patently false. South Africa already spends more than 8% of its national income on its health sector, which is very high for its income level. Turkey, for example (a good health performer and slightly richer than South Africa), spends 4.3% of its GDP and Thailand (a global universal health coverage leader) spends only 3.7%. Thailand shows what can be accomplished, because it launched its celebrated universal health coverage reforms in 2002 when its GDP per capita was only $1 900 — less than a third of South Africa’s today.In fact, Thailand’s prime minister famously ignored advice from the World Bank that it could not afford publicly financed, universal health coverage in the aftermath of the Asian financial crisis when it extended universal, tax-financed healthcare to the entire population. When these reforms proved a great success, a subsequent president of the World Bank, Dr Jim Kim, congratulated the Thai government for ignoring its previous advice.Similarly the United Kingdom, Japan and Norway all launched successful universal health coverage reforms at times of great economic difficulty at the end of World War II. These should be salutary lessons for those saying that South Africa can’t afford the NHI. If anything, because universal health reforms generate economic growth (with returns 10 times the public investment), now is exactly the time to launch the NHI.So there is enough overall funding in the South African health sector to take a giant step towards universal health coverage. The problem is that the current system is grossly inefficient and inequitable because more than half of these funds are spent through private insurance schemes that cover only 16% of the population — and often don’t cover even this population effectively.Were the bulk of these resources to be channelled through an efficient public financing system, evidence from around the world shows that the health sector would achieve better health outcomes, at lower cost. Health and income inequalities would fall, too.It’s true that in the long term, the government will have to increase public financing through reducing unfair subsidies to private health insurance and increasing taxes. But what the defenders of the current system don’t acknowledge is that, at the same time, private voluntary financing will fall, rapidly. Most families will no longer feel the need to purchase expensive private insurance when they benefit from the public system. It’s this fact that is generating so much opposition to the NHI from the private insurance lobby.This is the situation with the National Health Service in the UK and health systems across Europe, where only a small minority choose to purchase additional private insurance. Among major economies, only the United States continues to exhibit high levels of private, voluntary financing.As a consequence, it now spends an eye-watering 18% of its GDP on health and has some of the worst health indicators in the Organisation for Economic Co-operation and Development, including rising levels of maternal mortality. If South Africa doesn’t socialise health financing this is where its health system will end up — a long way from universal health coverage.What countries celebrating their universal health coverage successes at the UN have shown is that it is cheaper to publicly finance health than leave it to the free market. This is because governments are more efficient and fairer purchasers of health services than individuals and employers. As Dr Gro Harlem Brundtland, the former director general of the World Health Organization, said in New York: 'If there is one lesson the world has learnt, it is that you can only reach UHC [universal health coverage] through public financing.'This is a step South Africa must take — it can’t afford not to.This article was originally published by the Mail & Guardian. Full Article
as Coronavirus: Why The EU Needs to Unleash The ECB By feedproxy.google.com Published On :: Wed, 18 Mar 2020 13:00:36 +0000 18 March 2020 Pepijn Bergsen Research Fellow, Europe Programme @pbergsen LinkedIn COVID-19 presents the eurozone with an unprecedented economic challenge. So far, the response has been necessary, but not enough. 2020-03-18.jpg EU President of Council Charles Michel chairs the coronavirus meeting with the leaders of EU member countries via teleconference on March 17, 2020. Photo by EU Council / Pool/Anadolu Agency via Getty Images. The measures taken to limit the spread of the coronavirus - in particular social distancing - come with significant economic costs, as the drop both in demand for goods and services and in supply due to workers being at home sick will create a short-term economic shock not seen in modern times.Sectors that are usually less affected by regular economic swings such as transport and tourism are being confronted with an almost total collapse in demand. In the airline sector, companies are warning they might only be able to hold out for a few months more.Building on the calls to provide income support to all citizens and shore up businesses, European leaders should now be giving explicit permission to the European Central Bank (ECB) to provide whatever financial support is needed.Although political leaders have responded to the economic threat, the measures announced across the continent have mainly been to support businesses. The crisis is broader and deeper than the current response.Support for weaker governmentsThe ECB already reacted to COVID-19 by announcing measures to support the banking system, which is important to guarantee the continuity of the European financial system and to ensure financially weaker European governments do not have to confront a failing banking system as well.Although government-subsidised reduced working hours and sick pay are a solution for many businesses and workers, crucially they are not for those working on temporary contracts or the self-employed. They need direct income support.This might come down to instituting something that looks like a universal basic income (UBI), and ensuring money keeps flowing through the economy as much as possible to help avoid a cascade of defaults and significant long-term damage.But while this is likely to be the most effective remedy to limit the medium-term impact on the economy, it is particularly costly. Just as an indication, total compensation of employees was on average around €470bn per month in the eurozone last year.Attempting to target payments using existing welfare payment channels would reduce costs, but is difficult to implement and runs the risk of many households and businesses in need missing out.The increase in spending and lost revenue associated with these support measures dwarf the fiscal response to the 2008-09 financial crisis. The eurozone economy could contract by close to 10% this year and budget deficits are likely be in double digits throughout the bloc.The European Commission has already stated member states are free to spend whatever is necessary to combat the crisis, which is not surprising given the Stability and Growth Pact - which includes the fiscal rules - allows for such eventualities.Several eurozone countries do probably have the fiscal space to deal with this. Countries such as Germany and the Netherlands have run several years of balanced budgets recently and significantly decreased their debt levels. For countries such as Italy, and even France, it is a different story and the combination of much higher spending and a collapse in tax revenue is more likely to lead to questions in the market over the sustainability of their debt levels. In order to avoid this, the Covid-19 response must be financed collectively.The Eurogroup could decide to use the European Stability Mechanism (ESM) to provide states with the funds, while suitably ditching the political conditionality that came with previous bailout. But the ESM currently has €410bn in remaining lending capacity, which is unlikely to be enough and difficult to rapidly increase.So this leaves the ECB to pick up the tab of national governments’ increase in spending, as the only institution with effectively unlimited monetary firepower. But a collective EU response is complicated by the common currency, and particularly by the role of the ECB.The ECB can’t just do whatever it likes and is limited more than other major central banks in its room for manoeuvre. It does have a programme to buy government bonds but this relies on countries agreeing to a rescue programme within the context of the ESM, with all the resulting political difficulties.There are two main ways that the ECB could finance the response to the crisis. First, it could buy up more or all bonds issued by the member states. A first step in this direction would be to scrap the limits on the bonds it can buy. Through self-imposed rules, the ECB can only buy up to a third of every country’s outstanding public debt. There are good reasons for this in normal times, but these are not normal times. With the political blessing of the European Council, the Eurosystem of central banks could then start buying bonds issued by governments to finance whatever expenditure they deem necessary to combat the crisis.Secondly, essentially give governments an overdraft with the ECB or the national central banks. Although a central bank lending directly to governments is outlawed by the European treaties, the COVID-19 crisis means these rules should be temporarily suspended by the European Council.Back in 2012, the then president of the ECB, Mario Draghi, proclaimed the ECB would do whatever it takes, within its mandate, to save the euro, which was widely seen as a crucial step towards solving the eurozone crisis. The time is now right for eurozone political leaders to explicitly tell the ECB that together they can do whatever it takes to save the eurozone economy through direct support for businesses and households. Full Article
as The histone H4 basic patch regulates SAGA-mediated H2B deubiquitination and histone acetylation [DNA and Chromosomes] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Histone H2B monoubiquitylation (H2Bub1) has central functions in multiple DNA-templated processes, including gene transcription, DNA repair, and replication. H2Bub1 also is required for the trans-histone regulation of H3K4 and H3K79 methylation. Although previous studies have elucidated the basic mechanisms that establish and remove H2Bub1, we have only an incomplete understanding of how H2Bub1 is regulated. We report here that the histone H4 basic patch regulates H2Bub1. Yeast cells with arginine-to-alanine mutations in the H4 basic patch (H42RA) exhibited a significant loss of global H2Bub1. H42RA mutant yeast strains also displayed chemotoxin sensitivities similar to, but less severe than, strains containing a complete loss of H2Bub1. We found that the H4 basic patch regulates H2Bub1 levels independently of interactions with chromatin remodelers and separately from its regulation of H3K79 methylation. To measure H2B ubiquitylation and deubiquitination kinetics in vivo, we used a rapid and reversible optogenetic tool, the light-inducible nuclear exporter, to control the subcellular location of the H2Bub1 E3 ligase, Bre1. The ability of Bre1 to ubiquitylate H2B was unaffected in the H42RA mutant. In contrast, H2Bub1 deubiquitination by SAGA-associated Ubp8, but not by Ubp10, increased in the H42RA mutant. Consistent with a function for the H4 basic patch in regulating SAGA deubiquitinase activity, we also detected increased SAGA-mediated histone acetylation in H4 basic patch mutants. Our findings uncover that the H4 basic patch has a regulatory function in SAGA-mediated histone modifications. Full Article
as RNA helicase-regulated processing of the Synechocystis rimO-crhR operon results in differential cistron expression and accumulation of two sRNAs [Gene Regulation] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 The arrangement of functionally-related genes in operons is a fundamental element of how genetic information is organized in prokaryotes. This organization ensures coordinated gene expression by co-transcription. Often, however, alternative genetic responses to specific stress conditions demand the discoordination of operon expression. During cold temperature stress, accumulation of the gene encoding the sole Asp–Glu–Ala–Asp (DEAD)-box RNA helicase in Synechocystis sp. PCC 6803, crhR (slr0083), increases 15-fold. Here, we show that crhR is expressed from a dicistronic operon with the methylthiotransferase rimO/miaB (slr0082) gene, followed by rapid processing of the operon transcript into two monocistronic mRNAs. This cleavage event is required for and results in destabilization of the rimO transcript. Results from secondary structure modeling and analysis of RNase E cleavage of the rimO–crhR transcript in vitro suggested that CrhR plays a role in enhancing the rate of the processing in an auto-regulatory manner. Moreover, two putative small RNAs are generated from additional processing, degradation, or both of the rimO transcript. These results suggest a role for the bacterial RNA helicase CrhR in RNase E-dependent mRNA processing in Synechocystis and expand the known range of organisms possessing small RNAs derived from processing of mRNA transcripts. Full Article
as Rigid continuation paths I. Quasilinear average complexity for solving polynomial systems By www.ams.org Published On :: Tue, 10 Mar 2020 10:59 EDT Pierre Lairez J. Amer. Math. Soc. 33 (2019), 487-526. Abstract, references and article information Full Article
as On the measure of maximal entropy for finite horizon Sinai Billiard maps By www.ams.org Published On :: Tue, 10 Mar 2020 10:59 EDT Viviane Baladi and Mark F. Demers J. Amer. Math. Soc. 33 (2020), 381-449. Abstract, references and article information Full Article
as Weak functoriality of Cohen-Macaulay algebras By www.ams.org Published On :: Tue, 10 Mar 2020 10:59 EDT Yves André J. Amer. Math. Soc. 33 (2020), 363-380. Abstract, references and article information Full Article
as Cohomologie ????-adique de la tour de Drinfeld: le cas de la dimension 1 By www.ams.org Published On :: Tue, 10 Mar 2020 10:59 EDT Pierre Colmez, Gabriel Dospinescu and Wiesława Nizioł J. Amer. Math. Soc. 33 (2019), 311-362. Abstract, references and article information Full Article
as The Human Plasma Proteome: A Nonredundant List Developed by Combination of Four Separate Sources By feedproxy.google.com Published On :: 2004-04-01 N. Leigh AndersonApr 1, 2004; 3:311-326Research Full Article
as Proteomics of the Chloroplast Envelope Membranes from Arabidopsis thaliana By feedproxy.google.com Published On :: 2003-05-01 Myriam FerroMay 1, 2003; 2:325-345Research Full Article
as Mass Spectrometry of Human Leukocyte Antigen Class I Peptidomes Reveals Strong Effects of Protein Abundance and Turnover on Antigen Presentation By feedproxy.google.com Published On :: 2015-03-01 Michal Bassani-SternbergMar 1, 2015; 14:658-673Research Full Article
as A PP2A Phosphatase High Density Interaction Network Identifies a Novel Striatin-interacting Phosphatase and Kinase Complex Linked to the Cerebral Cavernous Malformation 3 (CCM3) Protein By feedproxy.google.com Published On :: 2009-01-01 Marilyn GoudreaultJan 1, 2009; 8:157-171Research Full Article
as Parallel Reaction Monitoring for High Resolution and High Mass Accuracy Quantitative, Targeted Proteomics By feedproxy.google.com Published On :: 2012-11-01 Amelia C. PetersonNov 1, 2012; 11:1475-1488Technological Innovation and Resources Full Article
as High Resolution Clear Native Electrophoresis for In-gel Functional Assays and Fluorescence Studies of Membrane Protein Complexes By feedproxy.google.com Published On :: 2007-07-01 Ilka WittigJul 1, 2007; 6:1215-1225Research Full Article
as In Vivo Identification of Human Small Ubiquitin-like Modifier Polymerization Sites by High Accuracy Mass Spectrometry and an in Vitro to in Vivo Strategy By feedproxy.google.com Published On :: 2008-01-01 Ivan MaticJan 1, 2008; 7:132-144Research Full Article
as Fluorescent Proteins as Proteomic Probes By feedproxy.google.com Published On :: 2005-12-01 Ileana M. CristeaDec 1, 2005; 4:1933-1941Research Full Article
as PaxDb, a Database of Protein Abundance Averages Across All Three Domains of Life By feedproxy.google.com Published On :: 2012-08-01 M. WangAug 1, 2012; 11:492-500Technological Innovation and Resources Full Article
as Quantitative, Multiplexed Assays for Low Abundance Proteins in Plasma by Targeted Mass Spectrometry and Stable Isotope Dilution By feedproxy.google.com Published On :: 2007-12-01 Hasmik KeshishianDec 1, 2007; 6:2212-2229Research Full Article
as Time-resolved Mass Spectrometry of Tyrosine Phosphorylation Sites in the Epidermal Growth Factor Receptor Signaling Network Reveals Dynamic Modules By feedproxy.google.com Published On :: 2005-09-01 Yi ZhangSep 1, 2005; 4:1240-1250Research Full Article
as Toward a Comprehensive Atlas of the Physical Interactome of Saccharomyces cerevisiae By feedproxy.google.com Published On :: 2007-03-01 Sean R. CollinsMar 1, 2007; 6:439-450Research Full Article
as Discordant Protein and mRNA Expression in Lung Adenocarcinomas By feedproxy.google.com Published On :: 2002-04-01 Guoan ChenApr 1, 2002; 1:304-313Research Full Article
as GPS 2.0, a Tool to Predict Kinase-specific Phosphorylation Sites in Hierarchy By feedproxy.google.com Published On :: 2008-09-01 Yu XueSep 1, 2008; 7:1598-1608Research Full Article
as A Human Protein Atlas for Normal and Cancer Tissues Based on Antibody Proteomics By feedproxy.google.com Published On :: 2005-12-01 Mathias UhlénDec 1, 2005; 4:1920-1932Research Full Article
as Quantitative Mass Spectrometric Multiple Reaction Monitoring Assays for Major Plasma Proteins By feedproxy.google.com Published On :: 2006-04-01 Leigh AndersonApr 1, 2006; 5:573-588Research Full Article
as The Paragon Algorithm, a Next Generation Search Engine That Uses Sequence Temperature Values and Feature Probabilities to Identify Peptides from Tandem Mass Spectra By feedproxy.google.com Published On :: 2007-09-01 Ignat V. ShilovSep 1, 2007; 6:1638-1655Technology Full Article
as Quantitative Phosphoproteomics Applied to the Yeast Pheromone Signaling Pathway By feedproxy.google.com Published On :: 2005-03-01 Albrecht GruhlerMar 1, 2005; 4:310-327Research Full Article
as The Human Plasma Proteome: History, Character, and Diagnostic Prospects By feedproxy.google.com Published On :: 2002-11-01 N. Leigh AndersonNov 1, 2002; 1:845-867Reviews/Perspectives Full Article
as Analysis of the Human Tissue-specific Expression by Genome-wide Integration of Transcriptomics and Antibody-based Proteomics By feedproxy.google.com Published On :: 2014-02-01 Linn FagerbergFeb 1, 2014; 13:397-406Research Full Article
as 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
as Stable Isotope Labeling by Amino Acids in Cell Culture, SILAC, as a Simple and Accurate Approach to Expression Proteomics By feedproxy.google.com Published On :: 2002-05-01 Shao-En OngMay 1, 2002; 1:376-386Research Full Article
as The cytochrome P450 enzyme CYP24A1 increases proliferation of mutant KRAS-dependent lung adenocarcinoma independent of its catalytic activity [Cell Biology] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 We previously reported that overexpression of cytochrome P450 family 24 subfamily A member 1 (CYP24A1) increases lung cancer cell proliferation by activating RAS signaling and that CYP24A1 knockdown inhibits tumor growth. However, the mechanism of CYP24A1-mediated cancer cell proliferation remains unclear. Here, we conducted cell synchronization and biochemical experiments in lung adenocarcinoma cells, revealing a link between CYP24A1 and anaphase-promoting complex (APC), a key cell cycle regulator. We demonstrate that CYP24A1 expression is cell cycle–dependent; it was higher in the G2-M phase and diminished upon G1 entry. CYP24A1 has a functional destruction box (D-box) motif that allows binding with two APC adaptors, CDC20-homologue 1 (CDH1) and cell division cycle 20 (CDC20). Unlike other APC substrates, however, CYP24A1 acted as a pseudo-substrate, inhibiting CDH1 activity and promoting mitotic progression. Conversely, overexpression of a CYP24A1 D-box mutant compromised CDH1 binding, allowing CDH1 hyperactivation, thereby hastening degradation of its substrates cyclin B1 and CDC20, and accumulation of the CDC20 substrate p21, prolonging mitotic exit. These activities also occurred with a CYP24A1 isoform 2 lacking the catalytic cysteine (Cys-462), suggesting that CYP24A1's oncogenic potential is independent of its catalytic activity. CYP24A1 degradation reduced clonogenic survival of mutant KRAS-driven lung cancer cells, and calcitriol treatment increased CYP24A1 levels and tumor burden in Lsl-KRASG12D mice. These results disclose a catalytic activity-independent growth-promoting role of CYP24A1 in mutant KRAS-driven lung cancer. This suggests that CYP24A1 could be therapeutically targeted in lung cancers in which its expression is high. Full Article
as SUMOylation of the transcription factor ZFHX3 at Lys-2806 requires SAE1, UBC9, and PIAS2 and enhances its stability and function in cell proliferation [Protein Synthesis and Degradation] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 SUMOylation is a posttranslational modification (PTM) at a lysine residue and is crucial for the proper functions of many proteins, particularly of transcription factors, in various biological processes. Zinc finger homeobox 3 (ZFHX3), also known as AT motif-binding factor 1 (ATBF1), is a large transcription factor that is active in multiple pathological processes, including atrial fibrillation and carcinogenesis, and in circadian regulation and development. We have previously demonstrated that ZFHX3 is SUMOylated at three or more lysine residues. Here, we investigated which enzymes regulate ZFHX3 SUMOylation and whether SUMOylation modulates ZFHX3 stability and function. We found that SUMO1, SUMO2, and SUMO3 each are conjugated to ZFHX3. Multiple lysine residues in ZFHX3 were SUMOylated, but Lys-2806 was the major SUMOylation site, and we also found that it is highly conserved among ZFHX3 orthologs from different animal species. Using molecular analyses, we identified the enzymes that mediate ZFHX3 SUMOylation; these included SUMO1-activating enzyme subunit 1 (SAE1), an E1-activating enzyme; SUMO-conjugating enzyme UBC9 (UBC9), an E2-conjugating enzyme; and protein inhibitor of activated STAT2 (PIAS2), an E3 ligase. Multiple analyses established that both SUMO-specific peptidase 1 (SENP1) and SENP2 deSUMOylate ZFHX3. SUMOylation at Lys-2806 enhanced ZFHX3 stability by interfering with its ubiquitination and proteasomal degradation. Functionally, Lys-2806 SUMOylation enabled ZFHX3-mediated cell proliferation and xenograft tumor growth of the MDA-MB-231 breast cancer cell line. These findings reveal the enzymes involved in, and the functional consequences of, ZFHX3 SUMOylation, insights that may help shed light on ZFHX3's roles in various cellular and pathophysiological processes. Full Article
as Cross-regulation between LUBAC and caspase-1 modulates cell death and inflammation [Signal Transduction] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 The linear ubiquitin assembly complex (LUBAC) is an essential component of the innate and adaptive immune system. Modification of cellular substrates with linear polyubiquitin chains is a key regulatory step in signal transduction that impacts cell death and inflammatory signaling downstream of various innate immunity receptors. Loss-of-function mutations in the LUBAC components HOIP and HOIL-1 yield a systemic autoinflammatory disease in humans, whereas their genetic ablation is embryonically lethal in mice. Deficiency of the LUBAC adaptor protein Sharpin results in a multi-organ inflammatory disease in mice characterized by chronic proliferative dermatitis (cpdm), which is propagated by TNFR1-induced and RIPK1-mediated keratinocyte cell death. We have previously shown that caspase-1 and -11 promoted the dermatitis pathology of cpdm mice and mediated cell death in the skin. Here, we describe a reciprocal regulation of caspase-1 and LUBAC activities in keratinocytes. We show that LUBAC interacted with caspase-1 via HOIP and modified its CARD domain with linear polyubiquitin and that depletion of HOIP or Sharpin resulted in heightened caspase-1 activation and cell death in response to inflammasome activation, unlike what is observed in macrophages. Reciprocally, caspase-1, as well as caspase-8, regulated LUBAC activity by proteolytically processing HOIP at Asp-348 and Asp-387 during the execution of cell death. HOIP processing impeded substrate ubiquitination in the NF-κB pathway and resulted in enhanced apoptosis. These results highlight a regulatory mechanism underlying efficient apoptosis in keratinocytes and provide further evidence of a cross-talk between inflammatory and cell death pathways. Full Article
as Heterotrimeric Gq proteins as therapeutic targets? [Molecular Bases of Disease] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 Heterotrimeric G proteins are the core upstream elements that transduce and amplify the cellular signals from G protein–coupled receptors (GPCRs) to intracellular effectors. GPCRs are the largest family of membrane proteins encoded in the human genome and are the targets of about one-third of prescription medicines. However, to date, no single therapeutic agent exerts its effects via perturbing heterotrimeric G protein function, despite a plethora of evidence linking G protein malfunction to human disease. Several recent studies have brought to light that the Gq family–specific inhibitor FR900359 (FR) is unexpectedly efficacious in silencing the signaling of Gq oncoproteins, mutant Gq variants that mostly exist in the active state. These data not only raise the hope that researchers working in drug discovery may be able to potentially strike Gq oncoproteins from the list of undruggable targets, but also raise questions as to how FR achieves its therapeutic effect. Here, we place emphasis on these recent studies and explain why they expand our pharmacological armamentarium for targeting Gq protein oncogenes as well as broaden our mechanistic understanding of Gq protein oncogene function. We also highlight how this novel insight impacts the significance and utility of using G(q) proteins as targets in drug discovery efforts. Full Article
as Learning the ABCs of ATP release [Signal Transduction] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 ATP plays important roles outside the cell, but the mechanism by which it is arrives in the extracellular environment is not clear. Dunn et al. now show that decreases in cellular cholesterol levels mediated by the ABCG1 transporter increase ATP release by volume-regulated anion channels under hypotonic conditions. Importantly, these results may imply that cells that handle cholesterol differently might experience differential extracellular ATP release during hypotonicity. Full Article
as ABC transporters control ATP release through cholesterol-dependent volume-regulated anion channel activity [Signal Transduction] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 Purinergic signaling by extracellular ATP regulates a variety of cellular events and is implicated in both normal physiology and pathophysiology. Several molecules have been associated with the release of ATP and other small molecules, but their precise contributions have been difficult to assess because of their complexity and heterogeneity. Here, we report on the results of a gain-of-function screen for modulators of hypotonicity-induced ATP release using HEK-293 cells and murine cerebellar granule neurons, along with bioluminescence, calcium FLIPR, and short hairpin RNA–based gene-silencing assays. This screen utilized the most extensive genome-wide ORF collection to date, covering 90% of human, nonredundant, protein-encoding genes. We identified two ABCG1 (ABC subfamily G member 1) variants, which regulate cellular cholesterol, as modulators of hypotonicity-induced ATP release. We found that cholesterol levels control volume-regulated anion channel–dependent ATP release. These findings reveal novel mechanisms for the regulation of ATP release and volume-regulated anion channel activity and provide critical links among cellular status, cholesterol, and purinergic signaling. Full Article
as Noncatalytic Bruton's tyrosine kinase activates PLC{gamma}2 variants mediating ibrutinib resistance in human chronic lymphocytic leukemia cells [Membrane Biology] By feedproxy.google.com Published On :: 2020-04-24T06:08:45-07:00 Treatment of patients with chronic lymphocytic leukemia (CLL) with inhibitors of Bruton's tyrosine kinase (BTK), such as ibrutinib, is limited by primary or secondary resistance to this drug. Examinations of CLL patients with late relapses while on ibrutinib, which inhibits BTK's catalytic activity, revealed several mutations in BTK, most frequently resulting in the C481S substitution, and disclosed many mutations in PLCG2, encoding phospholipase C-γ2 (PLCγ2). The PLCγ2 variants typically do not exhibit constitutive activity in cell-free systems, leading to the suggestion that in intact cells they are hypersensitive to Rac family small GTPases or to the upstream kinases spleen-associated tyrosine kinase (SYK) and Lck/Yes-related novel tyrosine kinase (LYN). The sensitivity of the PLCγ2 variants to BTK itself has remained unknown. Here, using genetically-modified DT40 B lymphocytes, along with various biochemical assays, including analysis of PLCγ2-mediated inositol phosphate formation, inositol phospholipid assessments, fluorescence recovery after photobleaching (FRAP) static laser microscopy, and determination of intracellular calcium ([Ca2+]i), we show that various CLL-specific PLCγ2 variants such as PLCγ2S707Y are hyper-responsive to activated BTK, even in the absence of BTK's catalytic activity and independently of enhanced PLCγ2 phospholipid substrate supply. At high levels of B-cell receptor (BCR) activation, which may occur in individual CLL patients, catalytically-inactive BTK restored the ability of the BCR to mediate increases in [Ca2+]i. Because catalytically-inactive BTK is insensitive to active-site BTK inhibitors, the mechanism involving the noncatalytic BTK uncovered here may contribute to preexisting reduced sensitivity or even primary resistance of CLL to these drugs. Full Article
as Reduction of protein phosphatase 2A (PP2A) complexity reveals cellular functions and dephosphorylation motifs of the PP2A/B'{delta} holoenzyme [Enzymology] By feedproxy.google.com Published On :: 2020-04-24T06:08:45-07:00 Protein phosphatase 2A (PP2A) is a large enzyme family responsible for most cellular Ser/Thr dephosphorylation events. PP2A substrate specificity, localization, and regulation by second messengers rely on more than a dozen regulatory subunits (including B/R2, B'/R5, and B″/R3), which form the PP2A heterotrimeric holoenzyme by associating with a dimer comprising scaffolding (A) and catalytic (C) subunits. Because of partial redundancy and high endogenous expression of PP2A holoenzymes, traditional approaches of overexpressing, knocking down, or knocking out PP2A regulatory subunits have yielded only limited insights into their biological roles and substrates. To this end, here we sought to reduce the complexity of cellular PP2A holoenzymes. We used tetracycline-inducible expression of pairs of scaffolding and regulatory subunits with complementary charge-reversal substitutions in their interaction interfaces. For each of the three regulatory subunit families, we engineered A/B charge–swap variants that could bind to one another, but not to endogenous A and B subunits. Because endogenous Aα was targeted by a co-induced shRNA, endogenous B subunits were rapidly degraded, resulting in expression of predominantly a single PP2A heterotrimer composed of the A/B charge–swap pair and the endogenous catalytic subunit. Using B'δ/PPP2R5D, we show that PP2A complexity reduction, but not PP2A overexpression, reveals a role of this holoenzyme in suppression of extracellular signal–regulated kinase signaling and protein kinase A substrate dephosphorylation. When combined with global phosphoproteomics, the PP2A/B'δ reduction approach identified consensus dephosphorylation motifs in its substrates and suggested that residues surrounding the phosphorylation site play roles in PP2A substrate specificity. Full Article
as 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
as The focal adhesion protein kindlin-2 controls mitotic spindle assembly by inhibiting histone deacetylase 6 and maintaining {alpha}-tubulin acetylation [Signal Transduction] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 Kindlins are focal adhesion proteins that regulate integrin activation and outside-in signaling. The kindlin family consists of three members, kindlin-1, -2, and -3. Kindlin-2 is widely expressed in multiple cell types, except those from the hematopoietic lineage. A previous study has reported that the Drosophila Fit1 protein (an ortholog of kindlin-2) prevents abnormal spindle assembly; however, the mechanism remains unknown. Here, we show that kindlin-2 maintains spindle integrity in mitotic human cells. The human neuroblastoma SH-SY5Y cell line expresses only kindlin-2, and we found that when SH-SY5Y cells are depleted of kindlin-2, they exhibit pronounced spindle abnormalities and delayed mitosis. Of note, acetylation of α-tubulin, which maintains microtubule flexibility and stability, was diminished in the kindlin-2–depleted cells. Mechanistically, we found that kindlin-2 maintains α-tubulin acetylation by inhibiting the microtubule-associated deacetylase histone deacetylase 6 (HDAC6) via a signaling pathway involving AKT Ser/Thr kinase (AKT)/glycogen synthase kinase 3β (GSK3β) or paxillin. We also provide evidence that prolonged hypoxia down-regulates kindlin-2 expression, leading to spindle abnormalities not only in the SH-SY5Y cell line, but also cell lines derived from colon and breast tissues. The findings of our study highlight that kindlin-2 regulates mitotic spindle assembly and that this process is perturbed in cancer cells in a hypoxic environment. Full Article
as Polarization of protease-activated receptor 2 (PAR-2) signaling is altered during airway epithelial remodeling and deciliation [Immunology] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Protease-activated receptor 2 (PAR-2) is activated by secreted proteases from immune cells or fungi. PAR-2 is normally expressed basolaterally in differentiated nasal ciliated cells. We hypothesized that epithelial remodeling during diseases characterized by cilial loss and squamous metaplasia may alter PAR-2 polarization. Here, using a fluorescent arrestin assay, we confirmed that the common fungal airway pathogen Aspergillus fumigatus activates heterologously-expressed PAR-2. Endogenous PAR-2 activation in submerged airway RPMI 2650 or NCI–H520 squamous cells increased intracellular calcium levels and granulocyte macrophage–colony-stimulating factor, tumor necrosis factor α, and interleukin (IL)-6 secretion. RPMI 2650 cells cultured at an air–liquid interface (ALI) responded to apically or basolaterally applied PAR-2 agonists. However, well-differentiated primary nasal epithelial ALIs responded only to basolateral PAR-2 stimulation, indicated by calcium elevation, increased cilia beat frequency, and increased fluid and cytokine secretion. We exposed primary cells to disease-related modifiers that alter epithelial morphology, including IL-13, cigarette smoke condensate, and retinoic acid deficiency, at concentrations and times that altered epithelial morphology without causing breakdown of the epithelial barrier to model early disease states. These altered primary cultures responded to both apical and basolateral PAR-2 stimulation. Imaging nasal polyps and control middle turbinate explants, we found that nasal polyps, but not turbinates, exhibit apical calcium responses to PAR-2 stimulation. However, isolated ciliated cells from both polyps and turbinates maintained basolateral PAR-2 polarization, suggesting that the calcium responses originated from nonciliated cells. Altered PAR-2 polarization in disease-remodeled epithelia may enhance apical responses and increase sensitivity to inhaled proteases. Full Article
as Small-molecule agonists of the RET receptor tyrosine kinase activate biased trophic signals that are influenced by the presence of GFRa1 co-receptors [Neurobiology] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Glial cell line–derived neurotrophic factor (GDNF) is a growth factor that regulates the health and function of neurons and other cells. GDNF binds to GDNF family receptor α1 (GFRa1), and the resulting complex activates the RET receptor tyrosine kinase and subsequent downstream signals. This feature restricts GDNF activity to systems in which GFRa1 and RET are both present, a scenario that may constrain GDNF breadth of action. Furthermore, this co-dependence precludes the use of GDNF as a tool to study a putative functional cross-talk between GFRa1 and RET. Here, using biochemical techniques, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, and immunohistochemistry in murine cells, tissues, or retinal organotypic cultures, we report that a naphthoquinone/quinolinedione family of small molecules (Q compounds) acts as RET agonists. We found that, like GDNF, signaling through the parental compound Q121 is GFRa1-dependent. Structural modifications of Q121 generated analogs that activated RET irrespective of GFRa1 expression. We used these analogs to examine RET–GFRa1 interactions and show that GFRa1 can influence RET-mediated signaling and enhance or diminish AKT Ser/Thr kinase or extracellular signal-regulated kinase signaling in a biased manner. In a genetic mutant model of retinitis pigmentosa, a lead compound, Q525, afforded sustained RET activation and prevented photoreceptor neuron loss in the retina. This work uncovers key components of the dynamic relationships between RET and its GFRa co-receptor and provides RET agonist scaffolds for drug development. Full Article