to Ligand bias in receptor tyrosine kinase signaling [Signal Transduction] By www.jbc.org Published On :: 2020-12-25T00:06:31-08:00 Ligand bias is the ability of ligands to differentially activate certain receptor signaling responses compared with others. It reflects differences in the responses of a receptor to specific ligands and has implications for the development of highly specific therapeutics. Whereas ligand bias has been studied primarily for G protein–coupled receptors (GPCRs), there are also reports of ligand bias for receptor tyrosine kinases (RTKs). However, the understanding of RTK ligand bias is lagging behind the knowledge of GPCR ligand bias. In this review, we highlight how protocols that were developed to study GPCR signaling can be used to identify and quantify RTK ligand bias. We also introduce an operational model that can provide insights into the biophysical basis of RTK activation and ligand bias. Finally, we discuss possible mechanisms underpinning RTK ligand bias. Thus, this review serves as a primer for researchers interested in investigating ligand bias in RTK signaling. Full Article
to FUS contributes to mTOR-dependent inhibition of translation [Signal Transduction] By www.jbc.org Published On :: 2020-12-25T00:06:31-08:00 The amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)–linked RNA-binding protein called FUS (fused in sarcoma) has been implicated in several aspects of RNA regulation, including mRNA translation. The mechanism by which FUS affects the translation of polyribosomes has not been established. Here we show that FUS can associate with stalled polyribosomes and that this association is sensitive to mTOR (mammalian target of rapamycin) kinase activity. Specifically, we show that FUS association with polyribosomes is increased by Torin1 treatment or when cells are cultured in nutrient-deficient media, but not when cells are treated with rapamycin, the allosteric inhibitor of mTORC1. Moreover, we report that FUS is necessary for efficient stalling of translation because deficient cells are refractory to the inhibition of mTOR-dependent signaling by Torin1. We also show that ALS-linked FUS mutants R521G and P525L associate abundantly with polyribosomes and decrease global protein synthesis. Importantly, the inhibitory effect on translation by FUS is impaired by mutations that reduce its RNA-binding affinity. These findings demonstrate that FUS is an important RNA-binding protein that mediates translational repression through mTOR-dependent signaling and that ALS-linked FUS mutants can cause a toxic gain of function in the cytoplasm by repressing the translation of mRNA at polyribosomes. Full Article
to Disease-associated mutations in inositol 1,4,5-trisphosphate receptor subunits impair channel function [Molecular Bases of Disease] By www.jbc.org Published On :: 2020-12-25T00:06:30-08:00 The inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs), which form tetrameric channels, play pivotal roles in regulating the spatiotemporal patterns of intracellular calcium signals. Mutations in IP3Rs have been increasingly associated with many debilitating human diseases such as ataxia, Gillespie syndrome, and generalized anhidrosis. However, how these mutations affect IP3R function, and how the perturbation of as-sociated calcium signals contribute to the pathogenesis and severity of these diseases remains largely uncharacterized. Moreover, many of these diseases occur as the result of autosomal dominant inheritance, suggesting that WT and mutant subunits associate in heterotetrameric channels. How the in-corporation of different numbers of mutant subunits within the tetrameric channels affects its activities and results in different disease phenotypes is also unclear. In this report, we investigated representative disease-associated missense mutations to determine their effects on IP3R channel activity. Additionally, we designed concatenated IP3R constructs to create tetrameric channels with a predefined subunit composition to explore the functionality of heteromeric channels. Using calcium imaging techniques to assess IP3R channel function, we observed that all the mutations studied resulted in severely attenuated Ca2+ release when expressed as homotetramers. However, some heterotetramers retained varied degrees of function dependent on the composition of the tetramer. Our findings suggest that the effect of mutations depends on the location of the mutation in the IP3R structure, as well as on the stoichiometry of mutant subunits assembled within the tetrameric channel. These studies provide insight into the pathogenesis and penetrance of these devastating human diseases. Full Article
to Managing Risk to Build a Better Belt and Road By www.chathamhouse.org Published On :: Wed, 04 Jul 2018 13:56:52 +0000 Managing Risk to Build a Better Belt and Road Expert comment sysadmin 4 July 2018 Risk management is a key part of economic development. China could use some simple principles for managing risk to improve the prospects of its flagship infrastructure initiative. — China hosts the Belt and Road Forum in 2017. Photo: Getty Images. One of the original motivating forces for China’s Belt and Road Initiative is risk management: the aim being to use infrastructure to drive economic development, so improving political stability and creating a favorable impression of China in countries bordering China and beyond.Yet these investments themselves are inherently risky: large-scale, debt-financed, long-term infrastructure projects in countries that often have weak governance, undefined or poorly-executed rule of law and corruption. China has experience managing infrastructure risks within its borders in its own ways, but it has much less experience overseas. And, while well-executed investments can enhance stability, the same investments, executed poorly, can create their own backlash in countries that see costs exceed benefits. This increases rather than reduces risks – not just the risks of defaulting on loans, but also the risk of damage to physical assets, loss of life and deteriorating relations with China.Moreover, China states its desire for greater private sector and non-Chinese involvement in Belt and Road. This will be needed if China is to realize some of its larger ambitions for the initiative. But companies seek attractive returns – adjusted for risk. It is the perceived and actual riskiness of projects that makes commercial involvement a challenge. Focusing on the risk rather than return may be the better place to start to attract partners alongside Chinese institutions.The risks on the Belt and RoadOverall, these risks fall into four categories.The first and most critical issues are when projects cannot even get initial funding. Concerns about compliance, corruption and project governance combined with high costs and low revenues mean that the numbers simply do not add up. Working on any of these dimensions to improve them means more projects will get off the ground.Secondly, there are the familiar risks during construction – budget overruns, unforeseen design issues and work delays, all commonplace in such challenging operating environments. Alongside these are risks to personnel caused by internal tensions and security challenges.Thirdly, once completed, financial and non-financial risks remain. At its simplest, revenues may fall short and the project debt cannot be repaid. A series of other factors may reduce willingness to pay: difficulties in enforcing penalties against non-repayment; fiscal pressures elsewhere in the budget; popular resistance to sending money to overseas financiers. And the completed projects and individuals operating them often remain at risk to local political tensions and security challenges. Finally, throughout the whole process, projects risk stirring up resentment and hostility rather building stability through economic growth. Incumbent governments may make project commitments that fit their own interests rather than those of the country – or at least are perceived to do so. Sri Lanka and Malaysia offer current examples. The way in which projects are implemented can compound the problem – for example, if promised job creation among local contractors does not happen or local ethnic rivalries are not taken into account.Approaches to riskHow then to address these risks? Some simple principles about risk management highlight avenues to explore and institutions to get involved. First, what can actions be taken to mitigate or reduce the risks and who is best-placed to do this? Secondly, who is best-placed to bear and accept risks that cannot be reduced at an economical cost? Should the risk be diversified across many different parties so that each bears only a portion of the risk or rather concentrated and held by those who are knowledgeable on the specifics of the risk? Thirdly, for those who end up bearing the remaining risk, how large is it and what actions are needed now to protect against future loss? The myriad of risks along the Belt and Road suggests a myriad of risk solutions and participants. Putting that all together is in itself a skill and will not happen of its own accord. It requires active planning and structuring of which partners to involve where in a way that makes sense for all involved. Three areas stand out.Successful construction is more than an engineering exercise. It requires positive engagement with local communities; credible, active communication of the benefits that the project brings; and protection of the people and equipment involved in the work. Doing this well means understanding the specific situation on the ground in often remote regions and acting accordingly. Donor agencies, NGOs, other multinationals and provincial and national governments all have experience to bring to the table. Chinese contractors have demonstrated success in rapid, low-cost implementation and are learning about how to work in a wide range of countries. This is, though, an opportunity to draw on the experience of contractors from other countries, local subcontractors and the experience of multilateral organizations. Financing is at core about the risk/return-based allocation of capital. The raison d’etre of the insurance sector is risk management. Multilateral institutions have a complementary role to play alongside private sector financial institutions. Drawing on this experience can play an important role in making investment projects economically attractive and bankable. The opportunity to match the investment portfolios of long-term institutional investors with the long-term financing needs of infrastructure has long been a topic of discussion: the Belt and Road provides a new menu of projects. These approaches all thrive on verifiable data, standardization and transparency clarity and standardization. Not all projects will fit these requirements, but some will. And in all cases, drawing on sector- and country-specific risk management experience from banks and insurers can reduce risks. Government can be thought of as the ultimate back-stop, a risk manager for its people across the entire risk spectrum. Actions that strengthen the capacity of all governments involved to assess and address risk mean more effective risk management, greater success and the avoidance of ‘debt traps’. Examples include sharing experience between countries; multilateral or bilateral support with the assessment of financial burden and debt terms; support to strengthen governance and oversight of project implementation; and approaches that ensure the involvement of affected local populations. Making use of dispute resolution procedures that are accepted by the key participants reduces risk all round.Countries, businesses and individuals grow through the judicious taking of risks. But unnecessary risk-taking is wasted effort. Belt and Road projects will be most effective when those best-placed to tackle risks and opportunities are encouraged to do so. Full Article
to China Needs to Make the Belt and Road Initiative More Transparent and Predictable By www.chathamhouse.org Published On :: Mon, 29 Apr 2019 09:49:04 +0000 China Needs to Make the Belt and Road Initiative More Transparent and Predictable Expert comment sysadmin 29 April 2019 The global infrastructure project must move beyond mish-mash of opaque bilateral deals — Beijing hosts the Second Belt and Road Forum for International Cooperation. Photo: Getty Images. As China welcomes dozens of world leaders to Beijing for its second Belt and Road forum, it has one simple aim: relaunching President Xi Jinping’s controversial global infrastructure drive. Since it began five years ago, the Belt and Road Initiative (BRI) has sunk hundreds of billions into port, railway and power projects stretching from south-east Asia to central Europe. But its path has been bumpy, drawing sharp criticism over the ruinous debts that some countries have racked up amid Chinese largesse. Xi will stress sustainable financing and transparency this week, amid the usual talk of ‘win win’ cooperation. Yet BRI’s problems are structural, not presentational. For any pledges to be meaningful, China must move beyond its present mish-mash of opaque, bilateral deals. After bad headlines last year, BRI has in fact enjoyed a good run in recent weeks. Malaysia announced it would resume a previously cancelled high-speed rail project, while Italy’s decision to join up last month marked a further European incursion. Indeed, if attendance is any guide to success, BRI looks in fine fettle. The first forum in 2017 attracted 29 world leaders. China says 37 will turn up this week. Phillip Hammond, UK chancellor, arrives hunting deals too, just a day after news that Chinese technology group Huawei will be allowed to help build 5G networks in Britain. Even so, three interlinked problems remain at the heart of President Xi’s pet project, all of which must be addressed if BRI is to move beyond the pitfalls that have damaged its reputation. The first and most obvious is debt. Critics allege that China ‘traps’ its BRI partners financially, often pointing to a debt-for-equity deal that handed China control of a port in Sri Lanka. These claims are exaggerated — few other projects have ended up this way. Yet poorer nations from Laos to Tajikistan are still signing up to vastly expensive Chinese schemes that offer poor value for money while straining their public finances. The second problem is transparency. Despite its grand scale there is still no reliable list of BRI projects, no disclosure of the lending standards China follows, nor even the amount China has invested. Beijing claims more than $1 trillion; independent estimates suggest perhaps a few hundred billion. Either way, it will be hard for China to convince doubters on debts until it is open about the criteria it uses in deciding who to lend to and why. BRI’s third and most important challenge is its muddled organization. Despite BRI’s image as a centrally run mega-project, China has allowed many deals to be struck locally, via a mix of state-backed companies, public sector banks and freewheeling regional governments. And it is here that the problems began. Infrastructure deals are notoriously complex, especially for transnational projects like high-speed rail. Renegotiations are common, even for experienced bodies like the World Bank. Yet BRI has repeatedly seen terms negotiated behind closed doors, in countries such as Malaysia and Pakistan, come unstuck in the face of public outcry. Rather than seeking to trap others with debt, China’s central government more often has to step in to fix dubious projects agreed by underlings lower down the chain. These negotiations go one of two ways. Either China’s partners complain and win terms, as was true in Malaysia and in Myanmar over a multibillion-dollar deep-sea port. Or, as in the case of Sri Lanka, the renegotiations go in China’s favour, but at the cost of accusations of debt trickery. In both cases China looks bad. Speaking last year, Xi responded to criticism of BRI by describing it as ‘an open platform for cooperation’. Yet, so far, he has proved resistant to the step that would deliver on that vision — namely turning BRI into an institution with open standards and international partners. The reasons for his reluctance are obvious. Ending BRI’s reliance on loose bilateral deals would limit Beijing’s room for geopolitical manoeuvre. Yet what might be lost in political flexibility could easily be gained in economic credibility, while avoiding some of the painful renegotiations that have dogged many BRI projects. At a time when China’s economy is slowing and its current account surplus is shrinking, formalising and institutionalising, BRI could also help avoid wasting scarce public resources on white elephant projects. China even has an easy template in the form of the Asian Infrastructure Investment Bank, the Beijing-based institution that has won plaudits for its project quality and openness since it started in 2016. Whichever model is chosen, a dose of Chinese-style central planning is called for, along with more openness. Without it, the oddly chaotic and decentralised model pioneered in BRI’s first five years is unlikely to help the project thrive over the next five. This article was originally published in the Financial Times. Full Article
to The Indo-Pacific: Geostrategic Perspectives to 2024 - Workshop 3 By www.chathamhouse.org Published On :: Mon, 14 Oct 2019 09:10:01 +0000 The Indo-Pacific: Geostrategic Perspectives to 2024 - Workshop 3 17 October 2019 — 9:30AM TO 2:00PM Anonymous (not verified) 14 October 2019 Institut Francais des Relations Internationales, 27 rue de la Procession, 75740 Paris Cedex 15, France The roundtable brought together stakeholders within the French strategic and policymaking community to explore French perceptions of evolving strategic shifts in the Indo-Pacific until 2024. The roundtable was organized in cooperation with, and was held at, the Institut français des relations internationals in Paris. The report below contains a summary of the discussions and an essay by Céline Pajon, Research Fellow, Center for Asian Studies, Institut français des relations internationals. Read a summary and essay Full Article
to The Indo-Pacific: Geostrategic Outlook to 2024 - Workshop 4 By www.chathamhouse.org Published On :: Thu, 09 Jan 2020 11:15:01 +0000 The Indo-Pacific: Geostrategic Outlook to 2024 - Workshop 4 26 November 2019 — 9:30AM TO 12:00PM Anonymous (not verified) 9 January 2020 Gateway House, Stevens Street, Colaba The roundtable brought together stakeholders within India’s strategic and policymaking communities to explore Indian perceptions of evolving strategic shifts in the Indo-Pacific until 2024. The roundtable was organized in cooperation with, and was held at, Gateway House in Mumbai. The report below contains a summary of the discussions and an essay by the International Security Studies Programme at Gateway House. Read a summary and essay Full Article
to The Indo-Pacific: Geostrategic Outlook From Now to 2024 - Workshop 5 By www.chathamhouse.org Published On :: Mon, 17 Feb 2020 14:25:01 +0000 The Indo-Pacific: Geostrategic Outlook From Now to 2024 - Workshop 5 18 February 2020 — 12:00PM TO 4:30PM Anonymous (not verified) 17 February 2020 Langafonua Centre The roundtable brought together stakeholders within Tonga’s strategic and policymaking communities to explore Tongan perceptions of evolving strategic shifts in the Indo-Pacific until 2024. The roundtable took place in Nuku’alofa and was co-hosted by the Royal Oceania Institute in Tonga. The report below contains a summary of the discussions and an essay by Lady Fane Fakafanua, Director of Operations at the Royal Oceania Institute. Read a summary and essay Full Article
to International relations: The ‘how not to’ guide By www.chathamhouse.org Published On :: Tue, 11 Oct 2022 14:48:57 +0000 International relations: The ‘how not to’ guide Expert comment NCapeling 11 October 2022 A centenary special issue of International Affairs explores past foreign policy failures to help policymakers avoid future catastrophes. Policy decisions in international relations frequently have a long-lasting effect on the world order, shaping the lives of millions. Often acting under pressure and severe time constraints, decision-makers must rely on their own experience and the best expertise available. And so, despite many striving for a more peaceful and prosperous world, policy failures are all too common. The second of International Affairs’ centenary special issues – devised and guest-edited by Amrita Narlikar and Daniel W. Drezner – is a ‘how not to guide’ for international relations. Focusing on historic failures, 14 experts examine what went wrong, and how policy practitioners and researchers can get it right together. Between theory and outcome fall two ‘shadows’: one of decision-makers not taking advantage of sound academic policy advice – in some cases ignoring it because they think they already know best – and a second of bias in academic analyses and researchers simply erring, or erring on the side of their own self-importance. Between these two, there lies a joint path toward better policies. The special issue provides policymakers with cautionary lessons, transforming well-known cases into a guide of what not to do in international politics. Building on that, the collection also suggests ways forward, including borrowing the medical Hippocratic Oath of ‘do no harm’, which in international relations serves as a cautionary warning against action merely for action’s sake, and then going decidedly beyond this minimum requirement. A series of comics also accompanies the articles, produced in collaboration with Sequential Potential comics. In their introduction, Drezner and Narlikar draw out four overarching factors which increase the likelihood of foreign policy failure – these are a focus on short-term successes, underestimating the power of narratives, hubris, and technocratic bubbles. If academics and policymakers can work together with these careful considerations, perhaps mistakes can avoid being repeated. Richard Toye examines three pivotal moments in the UK’s history – the Munich crisis of 1938, the Suez crisis and war of 1956, and the Iraq war of 2003. He finds that in these cases the failures were over-determined, a consequence of Britain’s relative decline rather than its cause. Daniel W. Drezner reviews two high profile failures of sanction use – United Nations (UN) sanctions on Iraq during the two Gulf wars, and the US re-imposition of sanctions on Iran in 2018. In both cases the main goals were not achieved and the costs were great. Drezner highlights ten ‘do’s and don’ts’ for sanctions as a result. Amrita Narlikar shows how the World Trade Organization (WTO) has become an almost perfect example of how not to negotiate, even when taking into account recent limited successes. She identifies three broad categories of bargaining failures and explores the impact of narratives on the course of events, giving a clear list of do’s and don’ts for international negotiation. Harold James also looks at three historic moments, the financial crises in 1931, 1997, and 2008. While responses to the crises initially looked successful, ironically in each case the drive to avoid past mistakes opened the door for the next crisis. Cecilia Emma Sottilotta considers recent disasters in the European Union (EU) – the eurozone crisis and COVID-19 pandemic – and recommends for policymakers to find a middle ground between supranationalism and intergovernmentalism in crisis situations. The growth of Chinese influence is a key issue in international relations today. Various articles in the special issue explain how not to deal with a rising China, coming from different angles. Exploring the US-China relationship, Janice Gross Stein is critical of the narrative around US decline and Chinese growth. The world should look beyond GDP as an indicator of a country’s growth and pay attention to strategic choices made by leaders in both states. Joseph S. Nye Jr also provides a US perspective, arguing that while some historic analogies are misleading, the US should contemplate the cautionary narrative of sleepwalking into World War One when thinking about its relationship with China. Amitabh Mattoo gives a south Asian view, asserting there is a need to understand Chinese policies in the region. Through examining China’s relations with India, Pakistan, and Sri Lanka he concludes that because China is adopting aggressive policies in the region, states must start cooperating with like-minded allies. Yuen Foong Khong answers two questions in his paper tackling which ‘how not to’s’ are relevant when learning from history, and whether policymakers are aware of them. His research points to four things to avoid, which he then applies to how the Cold War analogy is used to understand contemporary US-China relations. On the theme of foreign interference, Igor Istomin looks at the Soviet support for Mao Zedong’s Communist Party in the 1920s to 1940s. He argues strongly against interfering with major powers, as short-term gains cannot last. From Iraq and Afghanistan to Somalia and the Balkans, there have been many failed interventions by the West since the end of the Cold War. Stephanie Carvin asserts the overreliance on automated weaponry has allowed supposedly ‘easy wars’ to turn into ‘forever wars’ – and this is not likely to stop. Full Article
to US midterms: What to expect? By www.chathamhouse.org Published On :: Fri, 04 Nov 2022 10:51:39 +0000 US midterms: What to expect? Expert comment LJefferson 4 November 2022 The 2022 midterms have a heightened importance with long-term implications for the future of American democracy. US voters will head to the polls on 8 November 2022 to cast their ballots for the midterm elections, which will see 35 of 100 Senate seats and all 435 seats in the House of Representatives up for re-election. Midterm elections serve as a benchmark on voter’s approval of the sitting president’s party, but following a turbulent 2020 presidential election, with claims of a stolen election and voter fraud, the midterms have taken on a heightened importance with the processes and results having long-term implications for the future of democracy in the US. When will we see results? While many US voters expect to see results the night of an election, the complex voting process in the US often makes it difficult to ascertain the success of candidates in certain states after the polls close. In Arizona, state laws allow 20 days for election officials to certify results while Nevada allows for additional time to count mail-in ballots following election day. Pennsylvania state laws prevent mail-in ballots from being counted before 7am on election day and the combined effect of counting in-person and mail-in ballots simultaneously, as well as the need to present votes to a state canvassing board could delay official results for weeks, and votes will not be officially certified by the state until 28 November. In Georgia, the presence of a third-party candidate may lead to a run-off election if neither the Democrat or Republican contender receives over 50 per cent of the vote, which would take place on 6 December with results expected soon after. Early results favouring Republican candidates may also differ from the final tally as more mail-in ballots get counted, creating a ‘red mirage’, as the majority of Republican voters are expected to vote in-person. Delays in determining election results may bolster claims made by Republican candidates that election results were fraudulent, especially if races are tight, as delays counting mail-in ballots might cause results to differ over time. Early results favouring Republican candidates may also differ from the final tally as more mail-in ballots get counted, creating a ‘red mirage’, as the majority of Republican voters are expected to vote in-person, as seen in 2020. In the vast majority of elections since World War II, the president’s party has often lost seats in the first midterm elections after taking office. While there have been exceptions and instances of the sitting party avoiding major losses during wartime, such as after the Gulf War and the 9/11 attacks, it’s unlikely Russia’s war in Ukraine will create the same rally around the flag effect. Issues influencing voters There are signs that US support for Ukraine on both sides of the aisle is starting to waver, as evidenced by the now recalled letter by the House Democratic Progressive Caucus pushing for a ceasefire and Republican House Leader, Kevin McCarthy’s recent comments about limiting US financial support for Ukraine. US voters in general are more concerned with domestic issues rather than foreign policy, and both Democrats and Republicans have shaped their messaging around issues that will resonate with voters in key battleground states, with Democrats focusing heavily on abortion and reproductive rights and Republicans pushing the issues of crime and safety. US voters in general are more concerned with domestic issues rather than foreign policy, and both Democrats and Republicans have shaped their messaging around issues that will resonate with voters in key battleground states. Democrats are hoping their focus on reproductive rights will motivate a higher turnout at the polls and have likely been encouraged by a recent referendum in Kansas where voters chose to protect abortion rights in the traditionally conservative state. In 2020, 52 per cent of the electorate in the swing state of Pennsylvania were female, and while not a huge majority, the difference could be enough to push the Democrats ahead. Though the issue of abortion has gained more focus among Democratic voters, with 75 per cent of registered Democrats saying the issue was very important, 92 per cent of Republican voters rank the economy as their top issue. A potential victory by Johnson in Michigan, who has accused Barnes of being soft on crime and has shaped his messaging around growing the economy, may indicate whether Democrats need to reshape their messaging ahead of the 2024 presidential election. The Senate race in Wisconsin, for example, was initially considered one of the Democrat’s most likely prospects for unseating an incumbent Republican senator, following US President Joe Biden’s win in the state in 2020. Despite heavy fundraising from the Democratic party and a campaign visit by former US president Barack Obama, incumbent Senator Ron Johnson is now four points ahead of Democrat contender, Lieutenant Governor Mandela Barnes. A potential victory by Johnson, who has accused Barnes of being soft on crime and has shaped his messaging around growing the economy, may indicate whether Democrats need to reshape their messaging ahead of the 2024 presidential election. Threats of political violence The risk of political violence in the US has increased in recent years, with many key officials under threat, as evidenced by the recent attack on US Speaker of the House, Nancy Pelosi’s, husband. A bulletin sent out by US agencies, including the Department of Homeland Security and the FBI, warned of attacks against not only political figures in the US, but also of attacks at locations like polling places, ballot box locations and voter registration sites. The myth of a stolen election Electoral integrity in 2022 has become especially significant, with over 300 candidates who believe the 2020 election was stolen up for election in various races across the United States. The role of governors, secretaries of states and attorneys general (state officials charged with approving election results) has become a key issue in 2022. Proposals to give state legislatures the ability to certify election results, a role typically occupied by state officials, have already been made in Wisconsin, Pennsylvania and Arizona, all of which have Republican legislature majorities. Electoral integrity in 2022 has become especially significant, with over 300 candidates who believe the 2020 election was stolen up for election in various races across the United States. While these measures have not been successful thus far, a number of election deniers who would have the ability to influence how election results are certified are on the ballot for 2022. In Arizona, for example, Republican candidate for governor, Kari Lakes, and for attorney general, Abe Hamadeh have both been endorsed by Trump and have also supported his claims that the 2020 elections were fraudulent. The Republican candidate for Arizona secretary of state, Mark Finchem publicly made calls to decertify Arizona’s electors, and was placed at receiving 49 per cent of votes in a poll conducted by CNN in early October. If Republicans are successful in both the state governor and secretary of state races, the role of the attorney general in certifying the election results in a state Biden closely won in 2020 becomes ever more crucial given their ability to govern how elections are run in the state, as well as their ability to challenge certification in court. Full Article
to Director's briefing: What next for America? By www.chathamhouse.org Published On :: Mon, 07 Nov 2022 13:27:14 +0000 Director's briefing: What next for America? 17 November 2022 — 8:00AM TO 9:15AM Anonymous (not verified) 7 November 2022 Chatham House Chatham House’s Director of the US and America’s Programme discusses what is next for America following one of the most contentious midterms races to date. Hosted by Bronwen Maddox, Director, Chatham House, this Director’s Briefing is an opportunity to digest the outcomes of the US Midterm elections with Chatham House’s Director of the US and Americas Programme, Dr Leslie Vinjamuri. Arguably one of the most contentious midterm races to date, this election has key implications for the rest of the world also. At this event, Dr Leslie Vinjamuri and Bronwen Maddox will discuss the crucial themes coming out of the election and the key issues on voters’ minds. What impact will the results have on US foreign policy more broadly? What might the outcome of the election signal about Trumpism? And how confident can we be about the strength of US democracy? This event is only open to Chatham House Partners and Major Corporate Members as well as selected giving circles of Chatham House. If you would like to attend, please RSVP to Linda Bedford at RSVP@chathamhouse.org. Full Article
to World in brief: Biden seeks to win over African leaders By www.chathamhouse.org Published On :: Tue, 29 Nov 2022 14:49:31 +0000 World in brief: Biden seeks to win over African leaders The World Today mhiggins.drupal 29 November 2022 At the US-Africa Leaders Summit, Washington will need to go beyond strategic geopolitical interest to compete with China’s offer, says James Orr. African heads of state will join President Joe Biden in Washington in mid-December to take part in the second United States-Africa Leaders Summit. Some 50 African leaders will travel to the US capital for the two-day conference, which starts on December 13. Senior policymakers say talks will focus on economic engagement, human rights, food security and climate, with an emphasis on partnerships that demonstrate an intention to go beyond strategic geo-political interest. President Biden has said he hopes to ‘reinforce the US-Africa commitment to democracy; mitigate the impact of Covid, respond to the climate crisis and amplify diaspora ties’. The White House will seek to offer reassurance to African governments concerned by a perceived cooling in relations with the US. Africa’s cooling relations with the US ‘As trite as it might sound, the key objective of this conference should really be to enhance trust between African leaders and the United States,’ said Gilbert Kaplan, a former under-secretary at the US Department of Commerce. ‘I was in Africa in 2018 leading the President’s Advisory Council on Doing Business in Africa and the foreign minister of Ethiopia said to me: “Well you’re here but are you really here?” What he meant was: is the United States really committed to a long-term, strong relationship with the African continent or is it just a drive-through and a hello without making major commitments?’ The first summit was held by President Barack Obama in 2014. Addressing the inaugural conference, he spoke of the ‘blood of Africa’ that ran through his veins and how ‘the bonds between our countries are deeply personal’. Today, however, a succession of abstentions or no votes from African states over United Nations resolutions on Russia’s invasion of Ukraine points to a growing misalignment in the relationship. This is indicative of expanding Chinese and Russian influence on the continent, say analysts. The US and an international system supports autocratic and dysfunctional governments – we can’t continue this way Kah Walla, president of the Cameroon People’s Party ‘Africa is faced with some of the biggest governance challenges on the globe,’ said Kah Walla, president of the Cameroon People’s Party and the first woman in the nation’s history to run as a presidential candidate in 2011. ‘We need government that is functional, competent and innovative, and what we are getting instead is the US and a global international system that is supporting [via financial aid] autocratic and dysfunctional governments. We can’t continue in this way.’ Africa’s 54 nation states span six time zones and the continent’s population of 1.4 billion is on course to make up a quarter of the global population by 2050. It boasts the youngest demographic in the world, a potentially huge labour resource for private sector investors seeking to expand in manufacturing and processing, for example. The current median age in Africa is 18.8 years, compared with a global median age of 30. In July this year, the US provided nearly $1.3 billion in humanitarian assistance to help stave off hunger due to drought in the Horn of Africa. Since June 2019, the US, under its Prosper Africa programme, has also helped close some 800 export and investment deals across 45 African nations with an estimated value of $50 billion. The US is losing out to China in Africa Meanwhile, China surpassed the US as Africa’s largest trade partner in 2009, with total bilateral trade reaching more than $254 billion in 2021, a 35 per cent rise on 2020. ‘Despite Africa’s tremendous economic potential, the US has lost substantial ground to traditional and emerging partners, especially China,’ Landry Signé, a member of the World Economic Forum’s Regional Action Group for Africa, told a Senate subcommittee on Africa last year. ‘While recent trends indicate that the US engagement with the region has fallen, it has not and should not cede its relationship with the region to other powers.’ Full Article
to National security and transatlantic unity top Biden’s agenda By www.chathamhouse.org Published On :: Wed, 01 Feb 2023 14:11:35 +0000 National security and transatlantic unity top Biden’s agenda Expert comment NCapeling 1 February 2023 The timing of the State of the Union address is significant as Joe Biden tries to maintain focus on Ukraine and China while navigating partisanship at home. Although primarily a domestic affair, the president’s remarks in the annual State of the Union (SOTU) telegraph the US’s foreign policy priorities to the rest of the world. They reveal the prism through which the US understands its national security and its role in the world. The 2023 address comes as the first anniversary of the Ukraine invasion rapidly approaches, and the US is also trying to build international support for tough economic measures towards China. Domestically, Republican control of the House of Representatives will exert new pressure on US foreign policy choices. Electoral pressures are also around the corner and Joe Biden should announce soon whether he plans to run for president in 2024. Alliances and partnerships are a driving force for Biden. As pressure to end the war in Ukraine intensifies, maintaining transatlantic unity on Ukraine will be a key priority for the president. And as US electoral politics rise to the fore, ensuring the visibility of Europe’s role as a security provider in its own backyard will be essential. For a US president who sees China and the Indo-Pacific as America’s most significant long-term geopolitical challenge – and the only peer competitor to the US – transatlantic unity on China will also come under pressure. Ukraine, China, and controlling domestic division Republican leaders who now chair key committees in the House of Representatives continue to signal support for Ukraine, and polling shows a majority of US public opinion (54 per cent) favours sending either weapons or air defence systems. But recent polls also reveal a growing gap between Democrat and Republican supporters with a slight majority of Republicans (52 per cent) now opposing further support for Ukraine. Biden’s ability to demonstrate that America and its European partners remain unified in their policy towards Ukraine and Russia will help him ward off partisanship at home. Congressional approval of $45 billion for Ukraine in its end of year spending budget will help the president remain above the fray of partisan politics for now. But if there is an absence of clear signs Ukraine is succeeding in its war aims, the challenge of maintaining domestic support could become more difficult. Bipartisanship is strong on China, Republicans are more singular and hawkish in their approach to China than the US president, and the public support tough measures A greater US focus on China, India, and on the Indo-Pacific in 2023 is also likely. Bipartisanship is strong on China, Republicans are more singular and hawkish in their approach to China than the US president, and the public support tough measures. At a time of war in Europe, the president will place great emphasis on the need to maintain transatlantic unity and to work with a broader coalition of partners in the Indo-Pacific. The groundwork for focus on China has already been laid. Throughout 2022, the Biden administration worked steadily, but quietly, to set out its China policy. Just before Russia’s invasion of Ukraine in February 2022, the US released its new US-Indo Pacific Strategy stressing regional partnerships – especially the Quad and ASEAN – and it’s determination to shape essential norms for the region. It stated boldly – albeit in a document which was largely unnoticed – that the objective is not to change China but to ‘shape the strategic environment in which it operates’, a policy which signifies a clear departure from the more ideological approach pursued by the US during Donald Trump’s final year in office. And in May, the US announced its economic strategy for the region, the Indo-Pacific Economic Framework. Now the terrain for competition with China and alignment with US partners and allies is heavily focused on technology and the daylight between national security and economic strategy in US China policy is rapidly disappearing. Biden’s policy focus of ‘invest (at home), align (with allies and partners), and compete (with China)’ has overshadowed earlier talk of cooperation between the US and China. Those listening carefully to the State of the Union and who have followed US policy will also note the unchallenged hegemony of neoliberalism is rapidly vanishing But as China opens its doors and Europe looks to bolster its economies, the US will have to work far harder to maintain transatlantic unity. Japan and the Netherlands embracing the US adoption of export controls on semiconductor chips is a positive sign, but the US’s economic strategy towards China may present harder choices to come for Europe. If China leans into its diplomacy, the pressure on transatlantic unity will also grow. The new US Congress will only sharpen the president’s tough stance on China. Some Republican leaders still deny climate change and have demonstrated little interest in cooperating with China on debt relief for developing countries. The prospects for addressing critical global challenges appear dim without China’s collaboration, and the UK and Europe should work with the US president and Congress to correct this. President Biden has clearly recognized that diplomacy will be critical in the months ahead. At a time of growing tensions, the potential for misperceptions or misunderstandings to create conflict will also increase, and so a US – and also European – commitment to broadening and deepening diplomacy with China is urgent but it also needs to be patient and sustained. A new American industrial policy? Those listening carefully to the State of the Union and who have followed US policy will also note the unchallenged hegemony of neoliberalism is rapidly vanishing. The American state appeared to be disturbingly absent in the early months of the US pandemic response – but now it is back and, in a surprising turn of events, is being cast as a solution not a problem. Full Article
to Directors Briefing: Constraints on US foreign policy By www.chathamhouse.org Published On :: Wed, 08 Feb 2023 10:07:13 +0000 Directors Briefing: Constraints on US foreign policy 20 February 2023 — 8:00AM TO 9:15AM Anonymous (not verified) 8 February 2023 Chatham House In conversation with Dr Richard Haass. The US is facing external threats from foreign actors including Russia, China and North Korea. Alongside geopolitical challenges, the US is also experiencing threats from within. Though the US has a long history of enshrining civic rights and democratic freedoms, the institutions of democracy are being weakened through polarization and disinformation. To combat this challenge, the idea of citizenship must be revised and expanded to allow for a functioning, and even a flourishing, democracy. What are the implications of a weakening democracy at home for US foreign policy? How can civic rights in the US be reimagined to reduce divisions within America and protect the future of democracy? Full Article
to US and Europe Strategic Security Cooperation: The View from Washington By www.chathamhouse.org Published On :: Thu, 09 Mar 2023 11:17:13 +0000 US and Europe Strategic Security Cooperation: The View from Washington 27 March 2023 — 9:00AM TO 10:00AM Anonymous (not verified) 9 March 2023 Chatham House As the US prepares to enter the next presidential election cycle, can the transatlantic alliance stay the course, especially against a deepening Russia-China partnership? Thank you for your interest in joining our event. Please plan to arrive at Chatham House from 08:45 GMT as the event will begin promptly at 09:00. The Biden administration’s response to Russia’s war in Ukraine and the rise of a globally assertive China, as articulated in the 2022 US national strategy, is to ‘constrain Russia and out-compete China’. It needs Europe as a partner and ally for both – yet Europe is also an object and a battleground in this era of strategic competition. As the US prepares to enter the next presidential election cycle, can the transatlantic alliance stay the course, especially against a deepening Russia-China partnership? Can Europeans, in particular, move from deepening dependency to greater agency and self-reliance? What is the role for Germany – and for the UK? Full Article
to Europe's response to the US Inflation Reduction Act By www.chathamhouse.org Published On :: Thu, 09 Mar 2023 14:12:13 +0000 Europe's response to the US Inflation Reduction Act 27 March 2023 — 2:00PM TO 3:15PM Anonymous (not verified) 9 March 2023 Chatham House and Online This event explores the implications of the US Inflation Reduction Act, how Europe can respond and what options the UK has. While the US Inflation Reduction Act (IRA) has led to an outcry in the EU, member states have different concerns and preferences for how to respond. The European Commission’s proposed ‘Green Deal Industrial Plan’ includes the relaxation of state aid rules to drive funding. But will this lead to a ‘subsidies race’ between the US and EU and is a ‘green trade war’ brewing? The UK’s response to the IRA has been much more muted than the EU’s. But caught between US subsidies and EU subsidies, can the UK compete and create an independent response to the IRA? And what steps can be taken to facilitate global cooperation and to make trade work for the green transition? Dr Martin Porter, Executive Chair at the Cambridge Institute for Sustainability Leadership, will kick off the discussion with short remarks followed by an interactive discussion among all participants This discussion is part of the Chatham House Global Trade Policy Forum. We would like to take this opportunity to thank our founding partner and supporting partners for their generous support of the forum. Full Article
to World in brief: Ukraine and nuclear proliferation to dominate G7 By www.chathamhouse.org Published On :: Tue, 28 Mar 2023 09:29:37 +0000 World in brief: Ukraine and nuclear proliferation to dominate G7 The World Today mhiggins.drupal 28 March 2023 Following Russia’s ongoing intimidation, Japan will use its presidency of the G7 – and its history – to prioritize the dangers of nuclear threats, writes James Orr. Two issues are expected to dominate the agenda as Japan hosts the G7 summit in Hiroshima from May 19-21. Central to talks will be the conflict in Ukraine, with member states eager to highlight a message of unity and resolve in the face of Russia’s continuing aggression. Fumio Kishida, Japan’s prime minister, made an unannounced visit to Kyiv on March 21, meeting the Ukrainian president Volodymyr Zelenskyy. This coincided with a visit to Moscow by China’s leader Xi Jinping, who described Russian president Vladimir Putin as a friend and partner. ‘Absolutely unacceptable’ Hosting the G7 summit in Hiroshima is significant, too, with Kishida expected to emphasize the ‘absolutely unacceptable’ threat of nuclear proliferation. Ongoing tensions between China and Taiwan, together with recent North Korean ballistic missile tests, have heightened fears of a breakdown in security in the region. A North Korean ballistic missile recently went into the sea near the Japanese island of Hokkaido Meanwhile, President Vladimir Putin’s menacing references to the use of nuclear weapons in Ukraine has raised the prospect of a potentially devastating conflict with NATO. ‘Kishida’s principal goal for the presidency of the G7 is to try to draw the world away from the path of destruction that is another nuclear conflict,’ said Duncan Bartlett, a research associate at SOAS, the School of Oriental and African Studies, in London. ‘Early last year, Putin warned of terrible consequences if NATO and the West interfered in the Ukraine conflict, and that was widely seen as being a nuclear threat. North Korea is also pursuing its nuclear weapons programme, and in February an intercontinental ballistic missile went into the sea just near the northern Japanese island of Hokkaido,’ said Bartlett. After Russia invaded Ukraine in February 2022, Kishida has taken a firm position on Putin, in line with his G7 peers. President Zelenskyy has addressed the Japanese parliament via video link and Dmytro Kuleba, Ukraine’s minister of foreign affairs, was invited by his Japanese counterpart to a G7 meeting held during the Munich Security Conference earlier this year. Kishida committed $600 million in financial support to Ukraine and his government may well announce the provision of further non-lethal assistance to Zelenskyy at the summit. The country’s constitution effectively outlaws the export of deadly weapons to foreign forces. On his visit to Kyiv, Kishida promised a further $30 million to Ukraine. We are witnessing a shift in the identity and purpose of the G7 Tristen Naylor, University of Cambridge ‘Kishida has revised key defence documents and is pursuing a radical and controversial expansion of Japan’s defence budget and capabilities,’ said Hugo Dobson, Professor of Japan’s International Relations at the University of Sheffield. ‘He and his G7 partners have signed historic defence agreements, pledged to strengthen ties or declared the inseparability of their security in light of actual conflict in Ukraine and potential conflict in East Asia. Kishida has linked the two by emphasizing that Ukraine today may be East Asia tomorrow,’ said Dobson. Aside from security matters, Kishida will at the summit address issues on clean energy, climate change, global health and boosting multilateral cooperation to drive post-pandemic economic recovery. Invitation to Nagasaki He is understood to have invited President Joe Biden to visit Nagasaki, where the second of America’s two atomic bombs is estimated to have killed 60,000 people in August 1945. No sitting US president has ever visited the city, and Kishida, who grew up in Hiroshima, may see the visit as an opportunity to boost his flagging domestic approval ratings. It may also serve as a timely reminder to Russia and others that the G7 opposes any future nuclear weapon use. Full Article
to Lysine Propionylation and Butyrylation Are Novel Post-translational Modifications in Histones By www.mcponline.org Published On :: 2007-05-01 Yue ChenMay 1, 2007; 6:812-819Research Full Article
to 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 www.mcponline.org Published On :: 2008-01-01 Ivan MaticJan 1, 2008; 7:132-144Research Full Article
to Quantitative, Multiplexed Assays for Low Abundance Proteins in Plasma by Targeted Mass Spectrometry and Stable Isotope Dilution By www.mcponline.org Published On :: 2007-12-01 Hasmik KeshishianDec 1, 2007; 6:2212-2229Research Full Article
to The Proteome of the Mouse Photoreceptor Sensory Cilium Complex By www.mcponline.org Published On :: 2007-08-01 Qin LiuAug 1, 2007; 6:1299-1317Research Full Article
to Large Scale Screening for Novel Rab Effectors Reveals Unexpected Broad Rab Binding Specificity By www.mcponline.org Published On :: 2008-06-01 Mitsunori FukudaJun 1, 2008; 7:1031-1042Research Full Article
to Comparative Proteomic Analysis of Eleven Common Cell Lines Reveals Ubiquitous but Varying Expression of Most Proteins By www.mcponline.org Published On :: 2012-03-01 Tamar GeigerMar 1, 2012; 11:M111.014050-M111.014050Special Issue: Prospects in Space and Time Full Article
to Time-resolved Mass Spectrometry of Tyrosine Phosphorylation Sites in the Epidermal Growth Factor Receptor Signaling Network Reveals Dynamic Modules By www.mcponline.org Published On :: 2005-09-01 Yi ZhangSep 1, 2005; 4:1240-1250Research Full Article
to Complementary Profiling of Gene Expression at the Transcriptome and Proteome Levels in Saccharomyces cerevisiae By www.mcponline.org Published On :: 2002-04-01 Timothy J. GriffinApr 1, 2002; 1:323-333Research Full Article
to Parallel Reaction Monitoring for High Resolution and High Mass Accuracy Quantitative, Targeted Proteomics By www.mcponline.org Published On :: 2012-11-01 Amelia C. PetersonNov 1, 2012; 11:1475-1488Technological Innovation and Resources Full Article
to Toward a Comprehensive Atlas of the Physical Interactome of Saccharomyces cerevisiae By www.mcponline.org Published On :: 2007-03-01 Sean R. CollinsMar 1, 2007; 6:439-450Research Full Article
to Extending the Limits of Quantitative Proteome Profiling with Data-Independent Acquisition and Application to Acetaminophen-Treated Three-Dimensional Liver Microtissues By www.mcponline.org Published On :: 2015-05-01 Roland BrudererMay 1, 2015; 14:1400-1410Research Full Article
to A Proteome-wide, Quantitative Survey of In Vivo Ubiquitylation Sites Reveals Widespread Regulatory Roles By www.mcponline.org Published On :: 2011-10-01 Sebastian A. WagnerOct 1, 2011; 10:M111.013284-M111.013284Research Full Article
to Quantitative Phosphoproteomics of Early Elicitor Signaling in Arabidopsis By www.mcponline.org Published On :: 2007-07-01 Joris J. BenschopJul 1, 2007; 6:1198-1214Research Full Article
to Trypsin Cleaves Exclusively C-terminal to Arginine and Lysine Residues By www.mcponline.org Published On :: 2004-06-01 Jesper V. OlsenJun 1, 2004; 3:608-614Technology Full Article
to GPS 2.0, a Tool to Predict Kinase-specific Phosphorylation Sites in Hierarchy By www.mcponline.org Published On :: 2008-09-01 Yu XueSep 1, 2008; 7:1598-1608Research Full Article
to Quantitative Mass Spectrometric Multiple Reaction Monitoring Assays for Major Plasma Proteins By www.mcponline.org Published On :: 2006-04-01 Leigh AndersonApr 1, 2006; 5:573-588Research Full Article
to A Multidimensional Chromatography Technology for In-depth Phosphoproteome Analysis By www.mcponline.org Published On :: 2008-07-01 Claudio P. AlbuquerqueJul 1, 2008; 7:1389-1396Research Full Article
to The Paragon Algorithm, a Next Generation Search Engine That Uses Sequence Temperature Values and Feature Probabilities to Identify Peptides from Tandem Mass Spectra By www.mcponline.org Published On :: 2007-09-01 Ignat V. ShilovSep 1, 2007; 6:1638-1655Technology Full Article
to Quantitative Phosphoproteomics Applied to the Yeast Pheromone Signaling Pathway By www.mcponline.org Published On :: 2005-03-01 Albrecht GruhlerMar 1, 2005; 4:310-327Research Full Article
to The Human Plasma Proteome: History, Character, and Diagnostic Prospects By www.mcponline.org Published On :: 2002-11-01 N. Leigh AndersonNov 1, 2002; 1:845-867Reviews/Perspectives Full Article
to Analysis of the Human Tissue-specific Expression by Genome-wide Integration of Transcriptomics and Antibody-based Proteomics By www.mcponline.org Published On :: 2014-02-01 Linn FagerbergFeb 1, 2014; 13:397-406Research Full Article
to Parts per Million Mass Accuracy on an Orbitrap Mass Spectrometer via Lock Mass Injection into a C-trap By www.mcponline.org Published On :: 2005-12-01 Jesper V. OlsenDec 1, 2005; 4:2010-2021Technology Full Article
to Phosphate-binding Tag, a New Tool to Visualize Phosphorylated Proteins By www.mcponline.org Published On :: 2006-04-01 Eiji KinoshitaApr 1, 2006; 5:749-757Technology Full Article
to Stable Isotope Labeling by Amino Acids in Cell Culture, SILAC, as a Simple and Accurate Approach to Expression Proteomics By www.mcponline.org Published On :: 2002-05-01 Shao-En OngMay 1, 2002; 1:376-386Research Full Article
to Development and validation of a high-throughput whole cell assay to investigate Staphylococcus aureus adhesion to host ligands [Microbiology] By www.jbc.org Published On :: 2020-12-04T00:06:05-08:00 Staphylococcus aureus adhesion to the host's skin and mucosae enables asymptomatic colonization and the establishment of infection. This process is facilitated by cell wall-anchored adhesins that bind to host ligands. Therapeutics targeting this process could provide significant clinical benefits; however, the development of anti-adhesives requires an in-depth knowledge of adhesion-associated factors and an assay amenable to high-throughput applications. Here, we describe the development of a sensitive and robust whole cell assay to enable the large-scale profiling of S. aureus adhesion to host ligands. To validate the assay, and to gain insight into cellular factors contributing to adhesion, we profiled a sequence-defined S. aureus transposon mutant library, identifying mutants with attenuated adhesion to human-derived fibronectin, keratin, and fibrinogen. Our screening approach was validated by the identification of known adhesion-related proteins, such as the housekeeping sortase responsible for covalently linking adhesins to the cell wall. In addition, we also identified genetic loci that could represent undescribed anti-adhesive targets. To compare and contrast the genetic requirements of adhesion to each host ligand, we generated a S. aureus Genetic Adhesion Network, which identified a core gene set involved in adhesion to all three host ligands, and unique genetic signatures. In summary, this assay will enable high-throughput chemical screens to identify anti-adhesives and our findings provide insight into the target space of such an approach. Full Article
to Biosynthesis of the sactipeptide Ruminococcin C by the human microbiome: Mechanistic insights into thioether bond formation by radical SAM enzymes [Microbiology] By www.jbc.org Published On :: 2020-12-04T00:06:05-08:00 Despite its major importance in human health, the metabolic potential of the human gut microbiota is still poorly understood. We have recently shown that biosynthesis of Ruminococcin C (RumC), a novel ribosomally synthesized and posttranslationally modified peptide (RiPP) produced by the commensal bacterium Ruminococcus gnavus, requires two radical SAM enzymes (RumMC1 and RumMC2) catalyzing the formation of four Cα-thioether bridges. These bridges, which are essential for RumC's antibiotic properties against human pathogens such as Clostridium perfringens, define two hairpin domains giving this sactipeptide (sulfur-to-α-carbon thioether–containing peptide) an unusual architecture among natural products. We report here the biochemical and spectroscopic characterizations of RumMC2. EPR spectroscopy and mutagenesis data support that RumMC2 is a member of the large family of SPASM domain radical SAM enzymes characterized by the presence of three [4Fe-4S] clusters. We also demonstrate that this enzyme initiates its reaction by Cα H-atom abstraction and is able to catalyze the formation of nonnatural thioether bonds in engineered peptide substrates. Unexpectedly, our data support the formation of a ketoimine rather than an α,β-dehydro-amino acid intermediate during Cα-thioether bridge LC–MS/MS fragmentation. Finally, we explored the roles of the leader peptide and of the RiPP precursor peptide recognition element, present in myriad RiPP-modifying enzymes. Collectively, our data support a more complex role for the peptide recognition element and the core peptide for the installation of posttranslational modifications in RiPPs than previously anticipated and suggest a possible reaction intermediate for thioether bond formation. Full Article
to Identification of a domain critical for Staphylococcus aureus LukED receptor targeting and lysis of erythrocytes [Molecular Bases of Disease] By www.jbc.org Published On :: 2020-12-11T00:06:21-08:00 Leukocidin ED (LukED) is a pore-forming toxin produced by Staphylococcus aureus, which lyses host cells and promotes virulence of the bacteria. LukED enables S. aureus to acquire iron by lysing erythrocytes, which depends on targeting the host receptor Duffy antigen receptor for chemokines (DARC). The toxin also targets DARC on the endothelium, contributing to the lethality observed during bloodstream infection in mice. LukED is comprised of two monomers: LukE and LukD. LukE binds to DARC and facilitates hemolysis, but the closely related Panton–Valentine leukocidin S (LukS-PV) does not bind to DARC and is not hemolytic. The interaction of LukE with DARC and the role this plays in hemolysis are incompletely characterized. To determine the domain(s) of LukE that are critical for DARC binding, we studied the hemolytic function of LukE–LukS-PV chimeras, in which areas of sequence divergence (divergence regions, or DRs) were swapped between the toxins. We found that two regions of LukE's rim domain contribute to hemolysis, namely residues 57–75 (DR1) and residues 182–196 (DR4). Interestingly, LukE DR1 is sufficient to render LukS-PV capable of DARC binding and hemolysis. Further, LukE, by binding DARC through DR1, promotes the recruitment of LukD to erythrocytes, likely by facilitating LukED oligomer formation. Finally, we show that LukE targets murine Darc through DR1 in vivo to cause host lethality. These findings expand our biochemical understanding of the LukE–DARC interaction and the role that this toxin-receptor pair plays in S. aureus pathophysiology. Full Article
to ZBP1 promotes fungi-induced inflammasome activation and pyroptosis, apoptosis, and necroptosis (PANoptosis) [Microbiology] By www.jbc.org Published On :: 2020-12-25T00:06:31-08:00 Candida albicans and Aspergillus fumigatus are dangerous fungal pathogens with high morbidity and mortality, particularly in immunocompromised patients. Innate immune-mediated programmed cell death (pyroptosis, apoptosis, necroptosis) is an integral part of host defense against pathogens. Inflammasomes, which are canonically formed upstream of pyroptosis, have been characterized as key mediators of fungal sensing and drivers of proinflammatory responses. However, the specific cell death pathways and key upstream sensors activated in the context of Candida and Aspergillus infections are unknown. Here, we report that C. albicans and A. fumigatus infection induced inflammatory programmed cell death in the form of pyroptosis, apoptosis, and necroptosis (PANoptosis). Further, we identified the innate immune sensor Z-DNA binding protein 1 (ZBP1) as the apical sensor of fungal infection responsible for activating the inflammasome/pyroptosis, apoptosis, and necroptosis. The Zα2 domain of ZBP1 was required to promote this inflammasome activation and PANoptosis. Overall, our results demonstrate that C. albicans and A. fumigatus induce PANoptosis and that ZBP1 plays a vital role in inflammasome activation and PANoptosis in response to fungal pathogens. Full Article
to A drug-resistant {beta}-lactamase variant changes the conformation of its active-site proton shuttle to alter substrate specificity and inhibitor potency [Microbiology] By www.jbc.org Published On :: 2020-12-25T00:06:31-08:00 Lys234 is one of the residues present in class A β-lactamases that is under selective pressure due to antibiotic use. Located adjacent to proton shuttle residue Ser130, it is suggested to play a role in proton transfer during catalysis of the antibiotics. The mechanism underpinning how substitutions in this position modulate inhibitor efficiency and substrate specificity leading to drug resistance is unclear. The K234R substitution identified in several inhibitor-resistant β-lactamase variants is associated with decreased potency of the inhibitor clavulanic acid, which is used in combination with amoxicillin to overcome β-lactamase–mediated antibiotic resistance. Here we show that for CTX-M-14 β-lactamase, whereas Lys234 is required for hydrolysis of cephalosporins such as cefotaxime, either lysine or arginine is sufficient for hydrolysis of ampicillin. Further, by determining the acylation and deacylation rates for cefotaxime hydrolysis, we show that both rates are fast, and neither is rate-limiting. The K234R substitution causes a 1500-fold decrease in the cefotaxime acylation rate but a 5-fold increase in kcat for ampicillin, suggesting that the K234R enzyme is a good penicillinase but a poor cephalosporinase due to slow acylation. Structural results suggest that the slow acylation by the K234R enzyme is due to a conformational change in Ser130, and this change also leads to decreased inhibition potency of clavulanic acid. Because other inhibitor resistance mutations also act through changes at Ser130 and such changes drastically reduce cephalosporin but not penicillin hydrolysis, we suggest that clavulanic acid paired with an oxyimino-cephalosporin rather than penicillin would impede the evolution of resistance. Full Article
to Lessons from the UFC: How to Keep Blood-Sports Interesting By mythicscribes.com Published On :: Tue, 30 Nov 2021 21:34:14 +0000 It sounds like an oxymoron: “How to keep blood-sports interesting?” You’ve got blood and you’ve got sports, the term does its own advertising! And yet, fighting promotions rise and fall, where Pride and Strikeforce once reigned, now stand One and Bellator, but one promotion stands above all its competitors. The world of MMA knows one promotion which has clawed its way to the international top and established itself as the gold standard upon whose hallowed surface skulls are crushed and blood is poured. I’m talking about none other than the UFC. Having established itself over the years as a beacon of both quality matches and consistent drama, the UFC attracts the lion’s share of international talent in the MMA world, and with it the eyes and ears of MMA fans everywhere. Having well and truly stroked the ego of the promotion, you might be wondering what on earth any of this has to do with writing or fantasy? Well, does your world happen to feature prizefighting, ritual combat, or the eternally popular fantasy fixture called the gladiatorial arena? If so, there are a lot of writing and worldbuilding lessons you can learn from observing the biggest promotion in the biggest modern blood-sport of the world. Continue reading Lessons from the UFC: How to Keep Blood-Sports Interesting at Mythic Scribes. Full Article World Building Writing Craft & Technique
to Time to accelerate the sustainability pivot By www.chathamhouse.org Published On :: Wed, 26 May 2021 18:14:17 +0000 Time to accelerate the sustainability pivot Expert comment NCapeling 26 May 2021 Higher stakes make it more important than ever to safeguard the integrity of sustainability commitments, and ensure high quality in delivery and implementation. Regular headlines reaffirm the rise of sustainability on the global stage. Political momentum behind climate action has not been derailed by COVID-19, sustainability is increasingly central to national political debates, and what once might have been confined to scientific pursuits and UN conferences has now percolated through to international financial affairs and the wider political summits. Much is made of the scale of the challenge, from climate change, water stresses, and biodiversity loss to the looming spectre of environment-induced societal breakdown triggering unprecedented civilizational challenges on the back of decades of systemic neglect over the true cost of social and environmental imbalances and unencumbered consumption. Getting up to scale is an ongoing and daunting challenge not least because exponential growth has brought growing pains But the good news is that talk of sustainability solutions is picking up pace and growing in its reach into the mainstream. The Wall Street Journal recently charted the shift of sustainable finance from being a niche interest of socially conscious investors into a sustainable ‘gold rush’, further bolstering its financial credentials with trillions of dollars designated for the global energy transition. Assets in investment funds with links to the environment came to almost $2 trillion globally in the first quarter of 2021, more than tripling in just three years, and investors are putting some $3 billion a day into these funds while bonds and loans worth $5 billion looking to bankroll green initiatives are issued every day. Climate ambitions and power diplomacy Should the number of zeros fail to persuade, other signs of a sustainability pivot abound. Climate ambition was the driving force in major power diplomacy as France, Germany, China, and the US jostled for leadership positions in a high octane theatre of ‘climate one upmanship’ in the run-up to the Climate Summit hosted by US president Joe Biden. The G7 has agreed to stop international financing of coal projects, and an International Energy Agency report says delivering net zero emissions by 2050 means no new coal, oil, or gas development from now on. The move from ‘what’ to ‘how’ points to a clear demand for new, innovative collaborative efforts to help mitigate myriad political economy challenges associated with the upcoming great transition Governments are sending unmistakable policy signals which are redrawing multiple frontiers of the real economy, such as the banning of single use plastic in multiple jurisdictions from Europe, China, and more than 30 African states as well as New York and California. The sale of internal combustion engine vehicles is also set to end by 2035 or sooner in the EU, the UK, and California, and China is expected to follow suit with similar plans. France has proposed a ban on domestic flights when there are less carbon intensive alternatives on the ground. But these signals did not spring out of a political vacuum. A global climate poll conducted by the United Nations (UN) in 50 countries showed two-thirds of the 1.2 million people polled thought there is a global climate emergency, and most indicated their support for stronger climate action even in countries with strong fossil energy interest. Real economy responses to noticeable changes in risk calculus and political appetite will likely underpin further rapid shifts in market sentiment as investors begin to fully factor in the scale of the challenge and escalate their interrogation of company-level climate action plans. Rapid pace of change still needed But despite this ever-clearer direction of travel and growing availability of new technology and policy options, the need for speed remains. The rationale for moving fast in the next decade and a half to avoid the clear and present threats of environmental and breakdown is increasingly clear. Getting up to scale is an ongoing and daunting challenge not least because exponential growth has brought growing pains. The recent spat over the definition and the usefulness of net zero targets for corporations and investors as seen in the shareholder votes over the climate plans put forward by Shell and other companies are all testimony to the challenge of mainstreaming. Subscribe to our weekly newsletterOur flagship newsletter provides a weekly round-up of content, plus receive the latest on events and how to connect with the institute. Enter email address Subscribe While some have characterized these debates as political infighting, the reality is higher stakes simply mean it is more important than ever to safeguard the integrity of sustainability commitments as well as the quality of their delivery and implementation. The move from ‘what’ to ‘how’ points to a clear demand for new, innovative collaborative efforts to help mitigate myriad political economy challenges associated with the upcoming great transition and ensure this sustainability pivot will deliver the promised outcomes. Launching the Chatham House Sustainability Accelerator in support of these once-in-a-generation efforts is a proud moment for the institute, and a clear sign that this pivot to sustainability is here to stay. Full Article
to G20 must live up to its crisis-solving legacy By www.chathamhouse.org Published On :: Fri, 29 Oct 2021 08:24:10 +0000 G20 must live up to its crisis-solving legacy Expert comment NCapeling 29 October 2021 The relevance of G20 is in question amid waning internal cohesion, but emerging economies could inject the group with inclusive ideas and greater legitimacy. ‘If we didn’t have it, we would have to invent it’ might well be the catchphrase for the Group of 20 (G20) as the international community rethinks global institutional architecture in the face of shifting power dynamics and geopolitical strife. To be fair, the same is often said of other venerable institutions such as the World Trade Organization (WTO), or even the United Nations (UN), often as a line of defence when questions are raised over their relevance or effectiveness. According to former Goldman Sachs Asset Management chairman and UK treasury minister Jim O’Neill, size also matters because the G20 is both too big and too small to be on the ball consistently. While he might be right, numbers alone suggest the G20 should be the room where it happens when it comes to fixing global challenges such as post-pandemic economic recovery, tackling climate change, or getting the world vaccines. Of all the international groupings, it boasts the most diverse and compelling mix of nations. It has 80 per cent of global income, three-quarters of global exports, 60 per cent of the global population and 80 per cent of global emissions. Coming of age The G20 was a forum of central bankers and finance ministers created when the 1997 Asian financial crisis laid bare the insufficiency of the G7. It came of age in 2008 when elevated to a leaders’ level summit two months after the Lehman Brothers collapse that precipitated the global financial crisis. The seeming parallel to 2008 this year, as the world faces the common threat of the COVID-19 pandemic amid a series of extreme weather and supply crunches, explains why expectations are running high for Rome Perhaps distance did make the heart grow fonder, or at least hindsight rosier. While the G20’s response to the 2008 global financial meltdown is often lauded as an exemplary economic crisis response, the reality is less straightforward. Barely two days after solemn promises were made in the 2008 communique, Russia broke rank and raised tariffs on imported cars. India followed by applying import duties on several iron and steel products. Even though the 2008 summit did not immediately result in a coordinated fiscal boost, the common threat of a global financial meltdown helped conjure a display of global unity and rally much-needed market confidence. It also resulted in a set of practical action plans unheard of to that point and specific tasks for several international organisations as a follow-up to summitry. The seeming parallel to 2008 this year, as the world faces the common threat of the COVID-19 pandemic amid a series of extreme weather and supply crunches, explains why expectations are running high for Rome and for G20 president Mario Draghi, the Italian prime minister. There is pressure to solve myriad global challenges, whether scaling climate action before the UN climate change conference in Glasgow or delivering vaccines and debt relief for developing countries, to name a few. Effective crisis response is how the G20 has cut its teeth, and the world is handling several emergencies right now. Draghi himself was chair of the Financial Stability Forum back in 2008. Inflated expectations also abound because the Rome gathering is a G20 summit without the long shadow of Jamal Khashoggi’s death over the Saudi G20 presidency. It also lacks former US president Donald Trump, who tried his best to put many international organisations and the spirit of global cooperation in deep freeze since 2016. If defrosting multilateralism was also a shared goal, in addition to economic recovery, general rustiness in the business of international cooperation – an understandable hangover from the Trump years – has also gummed up the works. Hence, the G20 will have to do much in the coming days to prove that, unlike the G7 in 2008, it has yet to outlive its usefulness, even when some have decried it as being missing in action over the COVID-19 crisis. Amid rising US-China tensions and at a critical juncture for the global economy, countries are wondering if the G20 will survive such a tense geopolitical atmosphere and whether the agenda will be overloaded with challenging foreign policy issues such as the plight of Afghanistan. Customary language aside, the G20’s problem-solving reputation can be oversold. Not surprisingly, it has worked best when members already agree on the next steps. Looking to the future, more hostile power plays are likely to further weaken the cohesiveness and effectiveness of institutions such as the G20. Looking to the future, more hostile power plays are likely to further weaken the cohesiveness and effectiveness of institutions such as the G20 Reviewing its track record would also suggest the institution’s prowess in crisis response tends to wane with the distance from the realm of monetary policy coordination. Not all areas of macroeconomics are created equal, in part because of the professional camaraderie and insularity of the central banking technocracy. As was evident even in 2008, the G20 was less effective where there were more actors and domestic political dynamics at play, such as in the arena of trade. The recent deal struck on corporate tax is an encouraging but notable exception. Gap between words and deeds As The Economist said in 2011: ‘the G20 … is a big improvement over the G7 because it takes emerging economies seriously. But do the emerging economies themselves take the G20 seriously?’ Any scorecards would point to severe gaps between words and deeds, most notably but not limited to the emerging economy members. If the G20 was born out of the need to increase the number of seats at the table, the next three years – with the G20 helmed by Indonesia in 2022 followed by India then Brazil – might prove to be the coming-out party for emerging economies. Full Article
to Saturday Club introduces young people to international affairs By www.chathamhouse.org Published On :: Thu, 24 Feb 2022 17:15:53 +0000 Saturday Club introduces young people to international affairs News release jon.wallace 24 February 2022 Clubs will help 13-16 year-olds learn more about the forces that are shaping the world and discover how young people can influence the future. National Saturday Club and Chatham House are delighted to announce the launch of the Society&Change Saturday Club. This new programme creates opportunities for UK 13–16-year-olds to develop a global mindset and build awareness of trends that will shape the world in the coming decades. Three pilot Society&Change Clubs will be hosted by the University of Sussex, Manchester Metropolitan University, and the University of Huddersfield. Chatham House will provide speakers and generate ideas for the clubs. National Saturday Club gives 13–16-year-olds across the country the opportunity to study subjects they love at their local university, college or cultural institution, for free. Society&Change Club members will be introduced to a wide range of careers including policy making and diplomacy, advocacy, media and journalism, international trade and business, and the international development and humanitarian sector. Weekly classes will be led by led by professional tutors from the host institutions. Club members will also take part in masterclasses with industry professionals, as well as an end of year summer show and graduation ceremonies. Lucy Kennedy, Chief Executive of the Saturday Club Trust said: ‘We are delighted to be partnering with Chatham House to launch the Society&Change Saturday Club, the sixth subject within the National Saturday Club programme. Over the past 12 years, working nationally with 13–16-year-olds, we have seen that young people are eager to share their hopes and ideas for the future and address the issues the world faces. ‘We hope this new Saturday Club will empower them to shape their own futures and will bring the urgent voice of young people to international debate.’ Rose Abdollahzadeh, Managing Director for Research Partnerships at Chatham House said: ‘We are really excited about the potential for this partnership to encourage young people across the UK to explore their role in the world. The National Saturday Club network will also give Chatham House opportunities to harness the energy, ideas and passion of young people towards positive change. ‘By introducing Club members to contemporary debates on global issues and a range of professions in foreign policy and international relations, our hope is that some Club members will choose to follow a career path into this sector.’ Learn more about the Society&Change Saturday Club. Full Article