at Investigation: Waste of the Day – Florida Hospitals Spent $566 Million Caring for Illegal Immigrants By deneenborelli.com Published On :: Tue, 01 Oct 2024 20:25:26 +0000 Investigation by Jeremy Portnoy originally published by RealClearInvestigations and RealClearWire Topline: Florida hospitals spent $566 million providing care for illegal immigrants in the last six months of 2023, according to a recent report from the state’s Agency for Healthcare Administration. Key facts: Gov. Ron DeSantis passed a law in May 2023 instructing all hospitals that … Full Article Commentaries Government Policies News
at Investigation: Waste of the Day – New Yorkers Spend $25 Million on Ex-Governor’s Legal Troubles By deneenborelli.com Published On :: Tue, 08 Oct 2024 17:53:10 +0000 Investigation by Jeremy Portnoy originally published by RealClearInvestigations and RealClearWire Topline: The State of New York has spent $25.4 million to defend former Gov. Andrew Cuomo from sexual harassment lawsuits and criminal investigations over the last three years, The New York Times reported this month. Key facts: More than half of the money was spent … Full Article Commentaries News
at Investigation: Waste of the Day – Walz Campaign Donors Received $15 Billion in State Business By deneenborelli.com Published On :: Tue, 08 Oct 2024 18:13:14 +0000 Investigation by Jeremy Portnoy originally published by RealClearInvestigations and RealClearWire Topline: Minnesota Gov. Tim Walz accepted $890,000 in campaign donations from employees – including C-suite executives – of 434 state vendors between 2019 and 2022, a new report from OpenTheBooks found. Those same companies collected nearly $15 billion in payments from the state between 2019 … Full Article Commentaries News
at The singularity probability of a random symmetric matrix is exponentially small By www.ams.org Published On :: Wed, 16 Oct 2024 14:24 EDT Marcelo Campos, Matthew Jenssen, Marcus Michelen and Julian Sahasrabudhe J. Amer. Math. Soc. 38 (), 179-224. Abstract, references and article information Full Article
at A novel method produces native light-harvesting complex II aggregates from the photosynthetic membrane revealing their role in nonphotochemical quenching [Bioenergetics] By www.jbc.org Published On :: 2020-12-18T00:06:18-08:00 Nonphotochemical quenching (NPQ) is a mechanism of regulating light harvesting that protects the photosynthetic apparatus from photodamage by dissipating excess absorbed excitation energy as heat. In higher plants, the major light-harvesting antenna complex (LHCII) of photosystem (PS) II is directly involved in NPQ. The aggregation of LHCII is proposed to be involved in quenching. However, the lack of success in isolating native LHCII aggregates has limited the direct interrogation of this process. The isolation of LHCII in its native state from thylakoid membranes has been problematic because of the use of detergent, which tends to dissociate loosely bound proteins, and the abundance of pigment–protein complexes (e.g. PSI and PSII) embedded in the photosynthetic membrane, which hinders the preparation of aggregated LHCII. Here, we used a novel purification method employing detergent and amphipols to entrap LHCII in its natural states. To enrich the photosynthetic membrane with the major LHCII, we used Arabidopsis thaliana plants lacking the PSII minor antenna complexes (NoM), treated with lincomycin to inhibit the synthesis of PSI and PSII core proteins. Using sucrose density gradients, we succeeded in isolating the trimeric and aggregated forms of LHCII antenna. Violaxanthin- and zeaxanthin-enriched complexes were investigated in dark-adapted, NPQ, and dark recovery states. Zeaxanthin-enriched antenna complexes showed the greatest amount of aggregated LHCII. Notably, the amount of aggregated LHCII decreased upon relaxation of NPQ. Employing this novel preparative method, we obtained a direct evidence for the role of in vivo LHCII aggregation in NPQ. Full Article
at Russia–China defence and security relations: Insights from the expert community By www.chathamhouse.org Published On :: Wed, 31 Aug 2022 13:22:13 +0000 Russia–China defence and security relations: Insights from the expert community 13 September 2022 — 3:00PM TO 4:00PM Anonymous (not verified) 31 August 2022 Online Experts share insights on Russia–China military, defence, and security relations. In the defence and security realms, Russia–China relations resemble more pragmatic cooperation based on shared, calculated interests than an alliance. This event presents and discusses key findings from a recent expert survey conducted by Chatham House with the aim to gather insights on Russia–China military, defence, and security relations. Survey responses helped identify areas of bilateral cooperation but also crucial friction points and obstacles that prevent the relationship from developing further, as well as policy pathways for the West. Full Article
at Russia-China Defence and Security Relations By www.chathamhouse.org Published On :: Mon, 05 Sep 2022 11:16:50 +0000 Russia-China Defence and Security Relations This project explores the military and security linkages between Russia and China. jon.wallace 5 September 2022 The project seeks to provide a nuanced understanding of Russia-China relations in the defence and security realms. It also seeks to understand Russian political and security perceptions regarding Chinese inroads into what Russia considers its ‘near abroad’, as well as other sources of irritation and tension in the bilateral relationship. It offers recommendations to guide NATO policy responses. Full Article
at A guide to the Chinese Communist Party's National Congress By www.chathamhouse.org Published On :: Wed, 21 Sep 2022 13:08:23 +0000 A guide to the Chinese Communist Party's National Congress The World Today rescobales.drupal 21 September 2022 In the first of a three-part series examining the global importance of the CCP’s 20th National Congress, Yu Jie explains how it makes its big decisions. Why does the CCP National Congress matter? The world’s most populous country and its smallest state have little in common with one exception: how they select their leader. Like the Vatican, the Chinese Communist Party (CCP) shrouds its leadership selection process in secrecy. Every five years, a week-long conclave – the Party Congress – is held and at its end a new cohort of leaders is presented that will steer the world’s second largest economy for the next five years. October’s Congress will reveal the depth and breadth of Xi Jinping’s power The congress is the most important date in China’s political calendar. It not only selects China’s leadership team but acts as a signpost indicating the direction the country will be heading in the near future, with implications for decades to come. It also reveals the breadth and depth of power held by Xi Jinping, the party’s general-secretary. The 20th CCP National Congress, opening on October 16 and expected to last a week, is taking place during unsettling times. While Xi Jinping is expected to embark on his third term as general-secretary of the party after the removal of a two-term limit in February 2018, it is hardly a crowning glory. Xi’s China is battling an economic maelstrom at home while juggling fraught foreign relations abroad. What does the National Congress do? Quite simply, the CCP National Congress is the gathering that defines China’s political leadership and sets the tone for its relationship with the rest of the world. It serves to fulfil three primary functions: First, it sets the party’s principal agenda across all policy sectors, from macroeconomics to the price of food. During the week, it draws up a consensus-based evaluation of the party’s work over the past five years, which includes a detailed examination of the party’s current situation. Second, it introduces any revisions to the party constitution deemed necessary, for instance on changes to the criteria for leadership recruitment or amendments to the party’s ‘guiding ideology’. Third, it selects the leadership team that will steer China for the next five years, a function that attracts the most international attention but is not the sole purpose of the congress. How is the party leadership team chosen? The congress comprises 2,300 delegates representing all levels of the party hierarchy across 34 provinces and regions – from the governors of towns and cities, to Olympic champions, astronauts, and even the odd stand-up comedian to mark the ‘inclusiveness’ of the party. The votes that decide the next cohort of party leaders come from three committees only: the Central Commission for Discipline Inspection, with 205 members and 171 alternate members (alternate members are simply substitutes to replace a member if they die, retire or are dismissed); the Central Committee, with 204 members; and the Politburo, with 25 members, only one of whom is a woman. Unlike multiparty elections in liberal democracies, neither the full 25 members of the Politburo nor the seven members of its Standing Committee are nominated by or directly voted for by constituents. A procedure known as ‘democratic recommendation’ is essentially a straw poll that includes all congress participants. They are then given a ballot listing the names of around 200 Politburo candidates in stroke order – the Chinese equivalent to alphabetical order. This short-listing process is completed in the run-up to the congress. Some pundits asserted that this process was put on hold after 2017, yet this has not been formally confirmed within the party constitution. A few senior delegates may express their preferences to their colleagues anonymously during this process. All the shortlisted candidates must meet the criteria for Politburo membership, which means serving at either a ministerial rank or above or in the People’s Liberation Army at military region level or above and being younger than 62. Based on the result of this straw poll, and more importantly on the preferences of current Politburo members, the incumbent Politburo and its Standing Committee will approve the nominees, conclude the Seventh Plenum of the 19th Party Congress and call for the 20th Congress. The delegates at the Party Congress then ceremonially cast their votes for the Politburo at the Party Congress although the result is pre-agreed, a procedure somewhat similar to the US Electoral College. What are the rules for choosing Politburo members? The Politburo Standing Committee (PSC) consists of between five and nine members, with seven selected at the 19th Congress. It is the supreme decision-making body of the Communist Party as well as the People’s Republic of China. If the 20th Congress follows convention, there are three de-facto rules to be followed: First, Politburo and Standing Committee members must retire at 68. This age limit is known as ‘Eight down, Seven up’. Second, new appointments to the PSC are drawn exclusively from regular Politburo members. The only exceptions to this rule have been Xi Jinping and Li Keqiang, who were appointed at the 17th Party Congress in 2007. Standing Committee members must retire at 68, but it is highly unlikely that 69-year-old Xi Jinping will stand down This exception follows the third convention, under which PSC appointees are among the youngest senior party leaders eligible. Potentially three vacancies could arise in 2022, as Xi himself is 69 but it is highly unlikely that he would step down. That would be a radical departure from past precedents. The extent to which past procedure is applied could act as a signal as to whether Xi Jinping is consolidating his power, while the size of the standing committee will be scrutinized to assess how much power Xi wields. If the procedure for leadership appointments at the 20th Congress deviates from these conventions, it could indicate two things. First, the CCP faces a new set of challenges and requires the introduction of new rules to shape the top leadership. Or, second, Xi has gained substantial personal power that allows him to bypass the collective leadership system endorsed by Deng Xiaoping and choose appointees to suit his own taste. There has thus far been little evidence from the official media to reflect on any changes. Changes in party institutional constraints, however, raise the danger of undermining governance at home and China’s relations abroad. Read the two further articles in this series: the second discusses the key domestic policy themes that Xi Jinping is expected to outline at this year’s congress; the third analyses the foreign policy issues likely to be discussed at the congress. Full Article
at Book preview: Guide to Chinese Climate Policy 2022 By www.chathamhouse.org Published On :: Wed, 28 Sep 2022 15:52:14 +0000 Book preview: Guide to Chinese Climate Policy 2022 20 October 2022 — 10:00AM TO 11:15AM Anonymous (not verified) 28 September 2022 Chatham House and Online Join authors David Sandalow and Michal Meidan to discuss their upcoming book. China is the world’s largest emitter of greenhouse gases and a key player in tackling the global climate crisis. Its stated climate policies, namely its high-level targets to peak emissions by 2030 and to achieve carbon neutrality by 2060, are significant. But while national-level ministries, local governments and businesses are setting climate roadmaps, implementation is challenging at times. In the current context of the global energy market and geopolitical turmoil, China’s need to maintain energy security can seem at odds with its climate pledges. The authors will present the book, which examines Chinese emissions, the impacts of climate change in China, as well as China’s domestic and international climate change policies and the main implementation challenges these policies face. Full Article
at 20th CCP National Congress: Five issues to watch By www.chathamhouse.org Published On :: Thu, 13 Oct 2022 10:01:35 +0000 20th CCP National Congress: Five issues to watch Expert comment LJefferson 13 October 2022 Interpreters of the Chinese Communist Party’s tea leaves will be paying close attention to the issues that will shape China’s trajectory for the next five years. Xi Jinping’s expected anointment for an unprecedented third term as general secretary of the Chinese Communist Party (CCP) is likely to generate global headlines when the party’s five-yearly National Congress begins on 16 October. But with that outcome so widely forecast, interpreters of the CCP’s tea leaves will be paying closer attention to a range of more contested – and sometimes byzantine – issues that will shape China’s trajectory for the next five years, and reverberate around the world. These are five key issues to watch out for during Xi’s political report, a dry but authoritative account of the CCP’s policy priorities for the next five years, and the subsequent deliberations over personnel appointments. 1. From market economy to ‘common prosperity’ As the world grapples with the economic impact of Russia’s invasion of Ukraine, the Chinese economy is entering particularly choppy waters. China is forecast to grow at a slower rate than the rest of Asia for the first time in more than 30 years, according to the World Bank, as the impact of Xi’s COVID zero policies compounds a growing list of structural and cyclical challenges. Xi is under pressure to offer some new prescriptions for the world’s second biggest economy, and he is likely to signal further shifts away from the market economics that propelled Chinese growth for decades toward his vision of ‘common prosperity’. China is forecast to grow at a slower rate than the rest of Asia for the first time in more than 30 years. His ambition is to redefine progress, not in terms of producing double-digit growth, but in tackling long-standing challenges such as demographic decline, social inequality and high property prices – thereby meeting ‘people’s ever-growing needs for a better life’. China’s leader may have arrived at the right diagnosis, but he has so far failed to find measures that deliver common prosperity. He will use the Party Congress to redesign some policy measures, likely putting a stronger focus on the development of rural areas to promote economic dynamism and generate employment opportunities. 2. COVID zero to endure? While most of the world has opened up and learned to live with COVID-19, China is still pursuing a COVID zero policy that requires frequent lockdowns, stringent movement controls and closed borders. This approach has intensified economic pressures, exacerbated high youth unemployment, and is testing the patience of China’s upwardly mobile middle classes. Those not employed by the state have been particularly hard hit and it is difficult to see how China’s economy can start to crank up again until Beijing reduces internal restrictions and reconnects with the world. COVID zero has intensified economic pressures, exacerbated high youth unemployment, and is testing the patience of China’s upwardly mobile middle classes. Xi has championed the COVID zero policy, which Beijing continues to insist is vital to protect vulnerable people and support economic and social stability. So, observers will be playing close attention to his political report for any signs of a possible softening or indications of alternative future pathways for managing the pandemic. But a wholesale shift does not appear to be on the cards. 3. Xi Jinping’s team Sinologists’ enthusiasm for predicting leadership changes in the CCP is not matched by their ability to do so. The party’s roots as a secret organization ensure that it keeps a tight lid on information about top leaders. Observers will be closely following appointments to the seven-member Politburo Standing Committee, the apex of power for the CCP and China’s supreme decision-making body. These choices will shape China’s future policy trajectory and give some signals about the extent of Xi’s concentration of power and his future plans. The party’s roots as a secret organization ensure that it keeps a tight lid on information about top leaders. Names to watch for possible promotion include Xi allies such as He Lifeng, currently head of the National Development Reform Commission, a key economic planning entity, and Zhang Qingwei, currently the party secretary of Hunan, an important and populous province. As Vice Premier Sun Chunlan, the only woman on the Politburo, reaches the retirement age, there is also likely to be a slot open for her replacement, with Shan Yiqin, the party secretary of Guizhou, one potential option. Tracking the fate of key Xi allies will also indicate how far he has managed to overturn the collective leadership system he inherited in 2012 and how comprehensively the CCP endorses this more centralized approach to governing China. 4. Taiwan After the escalating tensions of the last few months, analysts will be looking for any possible change in tone when Xi speaks about Taiwan, a self-governing island that China claims as a renegade province. During the past five years, Xi has approached the outside world with a mix of high-octane rhetoric with pragmatism and patience. Full Article
at Climate justice with Chinese characteristics? By www.chathamhouse.org Published On :: Mon, 07 Nov 2022 11:36:21 +0000 Climate justice with Chinese characteristics? Expert comment NCapeling 7 November 2022 China’s latest grand concept, the Global Development Initiative (GDI), claims to be making sustainability a key feature of the programme. Since joining the World Trade Organization (WTO) in 2001, China has regularly unveiled a grand new strategic concept every four years or so. Each has been deeply rooted in the Chinese political system and communicated via ambitious slogans, such as A Harmonious World, or New Types of Great Power Relations. And all have reliably generated both excitement and confusion abroad and within China. China’s latest grand concept, the Global Development Initiative (GDI), is no exception. When Chinese president Xi Jinping introduced it at the United Nations General Assembly (UNGA) in September 2021, it made hardly any splash in the West, perhaps because China has already signalled its determination to shape international development in the post-COVID era. But the GDI is more than just a new label for an ongoing project. One of its core political functions is to deflect some of the fierce criticism directed at its older sibling, the gigantic Belt and Road Initiative (BRI), which has a tarnished reputation for being neither transparent nor sufficiently ‘green’. Focus on grants and capacity-building According to the Chinese government’s initial description of the GDI, sustainability is a key feature of the programme. Unlike the BRI, the GDI will focus less on physical infrastructure projects – such as roads, bridges, digital networks, and coal-fired power plants – and more on sustainable-development grants and capacity-building. China may be ruled by one party, but that doesn’t mean its central administration system can always speak with one voice in supporting sustainable development abroad In his remarks about GDI in 2021, Xi placed special emphasis on advancing the UN Sustainable Development Goals (SDGs) and helping developing countries manage the transition to a low-carbon economy. On paper, then, the GDI appears a laudable initiative. While ongoing geopolitical tensions have deepened divisions between China and the US, derailing collaboration on combatting climate change, China at least is adjusting its diplomacy and aid programmes to position itself as a more attractive partner for those seeking climate security. Since launching the GDI, it has already created the China-Pacific Island Countries Climate Action Cooperation Centre to help some of the world’s most vulnerable countries mitigate the damage from climate change. But the GDI is still very much in line with China’s past grand initiatives. Its implementation is opaque and there is considerable flexibility in how it will deliver projects and offer grants. This approach is well understood and frequently practiced by Chinese political elites, following Deng Xiaoping’s famous reform ethos of ‘crossing the river by feeling the stones’. Xi has clearly adopted this approach in introducing the GDI. But whereas Deng was steering China’s domestic economy during a period of isolation after the Cultural Revolution, Xi needs to involve many other countries in his vision. That will not be easy now that Russia’s war in Ukraine and other recent developments have complicated many of China’s international relationships. China’s leaders recognize the BRI was not warmly received in global development circles, owing partly to its role in increasing both climate and financial risks. In implementing the GDI, they need to rethink some basic assumptions. Although gigantic infrastructure investments drove China’s own economic miracle, the same approach is not necessarily applicable everywhere. Nor should China’s development aid be relentlessly used to seek diplomatic endorsement from other countries. Instead, producing a clear, concrete action plan with specific regional and thematic points of focus would enhance the GDI’s clarity and credibility. Consider Xi’s recent pledge to add $1 billion to the $3.1 billion South-South Cooperation Assistance Fund, which will be renamed the Global Development and South-South Cooperation Fund. If China is serious about the GDI’s green credentials, this money should go towards supporting the clean-energy transition in response to the current oil and gas price crunch. But the GDI’s success ultimately depends on how China deploys not just financial but political capital. It needs to show it can cooperate constructively with countries in the ‘GDI Friends Group’ launched at the UN in January 2022. Producing a clear, concrete action plan with specific regional and thematic points of focus would enhance the GDI’s clarity and credibility For many group members, the pandemic showed that existing development assistance programs urgently need to be updated to account for their recipients’ specific interests and priorities. After years of hollow diplomatic rhetoric, there is a craving for more meaningful assistance to help countries build resilience against climate-driven natural disasters and other growing threats. China could help meet this demand, but it also will need to manage expectations. Many in the Global South assume a grand-concept policy such as the GDI will be meticulously planned from within Xi’s cabinet and thus executed to deliver large-scale, rapid results. But the GDI will require broad coordination across a wide range of ministries, agencies, and state-owned banks. One party but not one voice China may be ruled by one party, but that doesn’t mean its central administration system can always speak with one voice in supporting sustainable development abroad. Since launching the BRI in 2013, China has showered the Global South with hundreds of billions of dollars in physical infrastructure investment. With the global climate debate increasingly focusing on the need to mobilize international financing for climate mitigation and adaptation in low and middle-income countries, many will be looking to both China and the advanced economies to provide the necessary support. Full Article
at Russia and China in Antarctica: Implications for the Five Eyes By www.chathamhouse.org Published On :: Fri, 02 Dec 2022 14:17:13 +0000 Russia and China in Antarctica: Implications for the Five Eyes 15 December 2022 — 11:00AM TO 12:00PM Anonymous (not verified) 2 December 2022 Online This event explores Russia’s and China’s postions on the Antarctic and offers a critical assessment of their actions in the region. Ever since the 1959 Antarctic Treaty System (ATS), signed at the height of Cold War, Antarctica has remained a demilitarized continent. Today, even though the ATS is not in immediate danger of collapse, Antarctica and the Southern Ocean are no longer insulated from wider geopolitical tension, with China and Russia posing challenges to regional governance. This event also discusses key recommendations for the Five Eyes regarding Russian and Chinese current and future efforts at undermining the ATS and Antarctic governance. The discussion is informed by Mathieu Boulègue’s paper ‘Russia and China in Antarctica and the Southern Ocean: Implications for the Five Eyes’ published by the Sea Power Centre of the Royal Australian Navy. Full Article
at Beijing briefing: China bets on warmer EU relations By www.chathamhouse.org Published On :: Mon, 30 Jan 2023 11:13:40 +0000 Beijing briefing: China bets on warmer EU relations The World Today mhiggins.drupal 30 January 2023 With the Sino-US Xi relationship cooling, Xi Jinping is sending a new diplomatic team to Europe – but his ties to Putin may mean slow progress, writes Yu Jie. It has been a momentous year for Beijing. Twelve months after Russia’s invasion of Ukraine, its relations with the West have become more strained than ever. And after President Xi Jinping secured an unprecedented third term in office at the 20th Party Congress, the country has embarked on a chaotic exit from the Covid lockdown amid hopes the economy will rebound quickly. Some are already asking if Beijing will set a course correction in its diplomatic priorities to spare itself some of the setbacks it incurred in 2022. But when it comes to foreign affairs, China’s priorities rarely change. The Chinese leadership seeks to create a stable external environment to allow its domestic economic development. This conservative maxim was adopted in the 1980s by Deng Xiaoping, and President Xi is likely to follow it as a time-honoured recipe for diplomatic reconciliation. China’s awkward position Beijing’s close relationship with Moscow and its failure to oppose Russia’s invasion of Ukraine have put China in an awkward position. Xi and his colleagues have begun to realize that cooperation with Russia comes with substantial limits to avoid undermining China’s own political priorities and longer-term economic interests. Interestingly, pundits interpreted the omission of ‘pursuing new types of great power relations’ in the 20th Party Congress report as an acceptance by the party leadership that its fraught relationship with advanced developed nations is likely to remain, with little prospect of improvement in the short term. Chinese diplomatic literature has always presented Russia as a great power, but the abandonment of such terms signals that Beijing is keen to put clear daylight between itself and Vladimir Putin, although international commentators may argue this is not enough and nothing has changed. There has been little sign of China using its influence to help resolve the Ukraine conflict. Facing, as it feels it now does, a ‘collective West’ and not the Americans alone, Beijing has concluded there are few reasons not to move closer to Russia. China’s neutrality towards Russia makes warmer relations with the EU difficult But a reset would appear necessary if China is to tackle its domestic economic woes. So far, Beijing’s main political tactic has been to reassure European countries that it is willing to use its ties with Russia to restrain Putin from entertaining the deployment of nuclear weapons. That was the message conveyed during the visit of Olaf Scholz, the German Chancellor, and it will be said again when both President Emmanuel Macron of France and Giorgia Meloni, Italy’s prime minister, each visit later this year. Economically, China has traditionally relied on its relationships with the European Union and the United States to support innovation and growth. So, a perceived isolation from ‘a collective West’ is not an attractive option given Xi’s hopes of achieving a robust economic rebound after dropping the country’s ‘zero-covid’ policy. A precarious bilateral tie with the US has already reduced Beijing’s choice of partners and consumers. Worsening Sino-US relations and a tightening of access to overseas markets for Chinese companies have prompted Beijing not only to reconsider the country’s sources of economic growth but to reconfigure its approach to foreign affairs. China is making a renewed push to strengthen ties with the Global South, which does not see the war in Ukraine as black and white as the West does. Such a move is only possible because five decades of engagement with the ‘collective West’ has allowed China to emerge from poverty and become a global economic powerhouse. A new diplomatic team In an attempt to reset the tone of China’s relations with the EU, its largest trading partner, Xi has formed a new diplomatic team headed by Qin Gang, as Minister of Foreign Affairs, who is returning from his post in Washington as ambassador to the US and who has a background in European affairs. Achieving warmer relations will be easier said than done, however, as China has maintained its ‘neutrality’ at Russia’s aggression since February 2022. Full Article
at China is attempting a precarious balancing act By www.chathamhouse.org Published On :: Thu, 09 Mar 2023 15:43:31 +0000 China is attempting a precarious balancing act Expert comment NCapeling 9 March 2023 In its efforts to maintain ties with both Russia and Europe, China is having to wade through conflicting interests and rapidly changing sentiments. Precisely how far China will go in supporting Russia has been one of the most important questions of the war in Ukraine. On 20 February, US secretary of state Antony Blinken warned China may soon provide arms (‘lethal support’) to Moscow. But then, on 24 February – the anniversary of Russia’s invasion – China released a position paper calling for a political settlement to end the conflict, tellingly omitting any mention of its ‘no-limits partnership’ with Russia. China’s goal was to present itself as a neutral mediator. In fact, Beijing’s ties with Russia remain unchanged, even if this relationship has grown more exasperating for Chinese diplomats over the past year. Their job is to continue striking a delicate balance, a task that is becoming increasingly difficult as Russian president Vladimir Putin doubles down on nuclear brinkmanship and reckless rhetoric. Staying out of the Ukraine war With Putin extolling the law of the jungle in its most brutal form, China must be careful not to involve itself too much in the conflict. After all, Russia is clearly losing, and China has high hopes of repairing ties with major European economies. With China focused on moves by the US and its allies in East Asia and the Indo-Pacific, it simply cannot afford sabre-rattling or unrest on its other borders But Putin is of course keen to signal that China has his back. That is why he recently rolled out the red carpet for China’s top diplomat Wang Yi and then alluded to an (unconfirmed) upcoming visit by Chinese president Xi Jinping. Such diplomatic developments allow him to present China’s ambivalent position as, in fact, an endorsement of the invasion. While the costs of aligning with Russia could easily outweigh the benefits for China, one must remember that China’s reasons for maintaining good relations with the Kremlin go beyond the war in Ukraine. For starters, the two countries share a 2,672-mile (4,300-kilometer) border – roughly equivalent to the width of Europe – and the frontier’s exact location was not even finally settled until the beginning of this century, after generations of negotiations that included some 2,000 meetings. Yet to this day, the spectre of the Sino-Soviet split in the 1950s and 1960s looms large on both sides and it is not likely to be exorcised anytime soon. With China focused on moves by the US and its allies in East Asia and the Indo-Pacific, it simply cannot afford sabre-rattling or unrest on its other borders. Moreover, unlike the collective West, China’s foreign policy has always been shaped by interests rather than by values. Even with respect to Russia, the two countries’ bond is based mainly on shared resentment of US hegemony. By deepening their bilateral cooperation in recent years, they have been able to achieve a level of great-power status with which to counterbalance America. Being isolated from the ‘collective West’ is not an attractive option for China, given its hopes of achieving a robust economic rebound after years of the zero-COVID policy But Putin’s misadventure in Ukraine has forced Xi and China’s newly minted Politburo to manage a new set of economic, financial, and political risks. Russia’s war has left the West more firmly united than it has been in years. As China’s relations with the US have reached new lows, Chinese leaders want to avoid also alienating the European Union (EU), which is one of the country’s biggest trading partners. This is why Xi and Chinese diplomats have been so careful not to accept the Kremlin’s talking points in full. Being isolated from the ‘collective West’ is not an attractive option for China, given its hopes of achieving a robust economic rebound after years of the zero-COVID policy. Balancing Europe with the Global South In seeking to keep diplomatic and trade channels open, China’s main tactic has been to reassure European countries that it will use its own ties with Russia to restrain Putin from deploying nuclear weapons. At the same time, China is making a renewed push to strengthen its ties with the Global South where many countries do not see the war in Ukraine in the same stark moral terms as the West does. The emphasis on energy and food security in China’s recent position paper may have struck a chord with developing countries that have been reeling from the war’s negative knock-on effects on their economies. Full Article
at India-China relations: Is the Quad the answer? By www.chathamhouse.org Published On :: Tue, 28 Mar 2023 15:16:51 +0000 India-China relations: Is the Quad the answer? Interview NCapeling 28 March 2023 The threat of China’s military aggression is being felt across the world, but this is a phenomenon India has been contending with for decades. India’s border with China became the site of tense conflict in 2020, which led to India reinvesting in the Quad. Arzan Tarapore discusses key issues from his International Affairs article, such as how India is responding to increased aggression at the border and how a reinvigorated Quad may hold answers to balancing China in the Indo-Pacific. What have India-China relations been like in the past? Relations between India and China have varied over the decades. In the years following World War Two there was some hope they would find common cause in their international outlooks but that was quite quickly extinguished with their border war of 1962. Since then, the two countries have oscillated between detente and tension. It took decades for them to normalize their relations and slowly build trust through several confidence-building agreements. This was a dynamic, iterative process, with incursions prompting India to accelerate its infrastructure development, which in turn probably prompted more incursions by China More recently it seemed the two countries were both willing to set aside their border dispute in order to profit from their burgeoning economic relationship – as, for both, there is no question development and economic growth is the primary national objective. The question has been the extent to which their unresolved sovereignty and security issues undermine those goals as, at the same time, they both began paying more attention to the security of their territorial claims. China in particular matched its explosive economic growth with startling military modernization and assertiveness. Its long-standing military doctrine and terrain advantages means it relies heavily on quality military infrastructure on the Tibetan plateau and it has accelerated the pace of those infrastructure upgrades and expansion. In the 2010s, India belatedly began to improve its own transport infrastructure near the border, which threatened to reduce China’s military advantages. The earlier quiet on the border began to crack and China began launching border incursions with increasing frequency and scale. This was a dynamic, iterative process, with incursions prompting India to accelerate its infrastructure development, which in turn probably prompted more incursions by China. What happened around 2020 to change their relationship? The cycle of competitive security policies on the border reached a tipping point in 2020 with Chinese incursions at multiple points simultaneously in Ladakh, apparently designed to establish a new status quo on the Line of Actual Control (LAC) separating Indian and Chinese-controlled territory. The Indian political leadership played down the incursions but both Indian and Chinese militaries rushed to reinforce their positions near the border. They held multiple rounds of military talks which made halting progress. On 15 June 2020, a skirmish resulted in the loss of 20 Indian troops, and an unknown number of Chinese troops. In the weeks that followed, both sides further reinforced their positions in a scramble to gain positional advantage. How has India responded to China’s increasing military might? The Indian government’s response to the Chinese landgrab was to threaten the entire bilateral relationship. In a reversal of decades of policy, it argued China had demolished the painstakingly constructed confidence-building measures on the border, and so the relationship could not continue as normal until the border crisis was resolved. It imposed new restrictions on Chinese investment in India – even as overall trade continued to increase – and adopted a more assertive diplomatic posture. Strategically, the 2020 border crisis had two major effects. First, it reinforced the Indian proclivity to see its northern borders as the primary threat to Indian national security. India has heavily reinforced the border, reassigning some major formations and making numerous new investments in military capability to manage the threat. The significance of this however is that, in the context of budget scarcity, these military improvements come at the cost of potential increases in India’s capability in the Indian Ocean region – ultimately a more consequential zone of competition in the Indo-Pacific. The Indian government may yet change course and reallocate resources for power projection but, at this stage, I see no evidence of that. The second major strategic effect of the crisis was to unleash Indian cooperation with its partners, especially the US and the reinvigorated Quad grouping of Australia, India, Japan and the US. India has generally avoided formal international alliances, and the Quad was in hiatus for years – why has India invested in it now? India had always been mindful not to embrace external partners too closely so as to maintain its freedom of action and to not provoke a Chinese reaction. But since the Ladakh crisis, New Delhi has a newfound willingness to work more closely with the US, Japan, and Australia – because it calculates correctly that these partnerships enhance its freedom to act, and that China has already adopted the aggressive posture India feared. It is important to note however that the border crisis was not the only driver of India’s strategic adjustment. The crisis coincided with the COVID-19 pandemic which highlighted to India the ineffectiveness of existing international institutional arrangements. For New Delhi, then, the twin crises of Ladakh and the pandemic stressed the need for new international arrangements, and the Quad offered the best combination of agility and capability to meet the most pressing challenges of the Indo-Pacific region. What do the Quad partners hope to achieve in their renewed partnership? Beginning in 2021, the Quad assumed far greater significance. The first national leader summits happened – which have since continued at regular intervals – and its members have all agreed to a continually expanding agenda of work. It seeks to provide international public goods, and everything from climate action to telecommunications regulations. Critically, it has limited its security role to some niche and relatively unprovocative areas, such as humanitarian assistance and maritime domain awareness – issues which benefit the Indo-Pacific as a whole and do not intensify security competition. It has certainly eschewed military cooperation. Interestingly, the four Quad countries have also separately accelerated their military cooperation, bilaterally, trilaterally, and even quadrilaterally. But that cooperation lies outside the formal mechanisms of the Quad. What impact will these Quad actions have on Chinese aggression and the Indo-Pacific region? This Quad approach, which I call ‘zone balancing’ in my article, is specifically designed to build the capacity and resilience of regional states, and to not inflame dyadic security competition. The relatively uncompetitive character of these activities helps to deflate Chinese claims that the Quad is an antagonistic new bloc, and to ameliorate southeast Asian states’ concerns over the potential intensification of strategic competition. New Delhi has a newfound willingness to work more closely with the US, Japan, and Australia – because it calculates correctly that these partnerships enhance its freedom to act But the Quad’s agenda is not fixed and not bounded. It has expanded year on year and may continue to extend into new areas. This gives it a degree of flexibility and coercive leverage as Beijing cannot be confident about the Quad’s future direction. This slate of activities has a lot of utility in building the Quad’s regional legitimacy and habits of cooperation among its members. But it conspicuously does not address the region’s most pressing security challenges. It is not, in its current form, equipped to manage the challenge of territorial disputes or aggression. So the Quad will not address India’s unresolved border dispute with China, potential crises over Taiwan, or the South China Sea. I would argue, however, that the four members of the Quad have unparalleled advantages of capacity and geography. With further military cooperation, even outside the formal structures of the Quad, they have the potential to deter Chinese aggression, but that remains subject to their political preferences. Will other countries in different parts of the world adopt similar balancing strategies? Zone balancing could be an attractive strategy for other countries which want to either avoid the costs of hard military balancing, or to not provoke their rivals. It has been used in the past – such as the Marshall Plan during the early Cold War – and I would not be surprised if other countries competing with China, or even China itself, use it. Full Article
at Analysis of {beta}-lactone formation by clinically observed carbapenemases informs on a novel antibiotic resistance mechanism [Enzymology] By www.jbc.org Published On :: 2020-12-04T00:06:05-08:00 An important mechanism of resistance to β-lactam antibiotics is via their β-lactamase–catalyzed hydrolysis. Recent work has shown that, in addition to the established hydrolysis products, the reaction of the class D nucleophilic serine β-lactamases (SBLs) with carbapenems also produces β-lactones. We report studies on the factors determining β-lactone formation by class D SBLs. We show that variations in hydrophobic residues at the active site of class D SBLs (i.e. Trp105, Val120, and Leu158, using OXA-48 numbering) impact on the relative levels of β-lactones and hydrolysis products formed. Some variants, i.e. the OXA-48 V120L and OXA-23 V128L variants, catalyze increased β-lactone formation compared with the WT enzymes. The results of kinetic and product studies reveal that variations of residues other than those directly involved in catalysis, including those arising from clinically observed mutations, can alter the reaction outcome of class D SBL catalysis. NMR studies show that some class D SBL variants catalyze formation of β-lactones from all clinically relevant carbapenems regardless of the presence or absence of a 1β-methyl substituent. Analysis of reported crystal structures for carbapenem-derived acyl-enzyme complexes reveals preferred conformations for hydrolysis and β-lactone formation. The observation of increased β-lactone formation by class D SBL variants, including the clinically observed carbapenemase OXA-48 V120L, supports the proposal that class D SBL-catalyzed rearrangement of β-lactams to β-lactones is important as a resistance mechanism. Full Article
at Mutation of an atypical oxirane oxyanion hole improves regioselectivity of the {alpha}/{beta}-fold epoxide hydrolase Alp1U [Enzymology] By www.jbc.org Published On :: 2020-12-11T00:06:20-08:00 Epoxide hydrolases (EHs) have been characterized and engineered as biocatalysts that convert epoxides to valuable chiral vicinal diol precursors of drugs and bioactive compounds. Nonetheless, the regioselectivity control of the epoxide ring opening by EHs remains challenging. Alp1U is an α/β-fold EH that exhibits poor regioselectivity in the epoxide hydrolysis of fluostatin C (compound 1) and produces a pair of stereoisomers. Herein, we established the absolute configuration of the two stereoisomeric products and determined the crystal structure of Alp1U. A Trp-186/Trp-187/Tyr-247 oxirane oxygen hole was identified in Alp1U that replaced the canonical Tyr/Tyr pair in α/β-EHs. Mutation of residues in the atypical oxirane oxygen hole of Alp1U improved the regioselectivity for epoxide hydrolysis on 1. The single site Y247F mutation led to highly regioselective (98%) attack at C-3 of 1, whereas the double mutation W187F/Y247F resulted in regioselective (94%) nucleophilic attack at C-2. Furthermore, single-crystal X-ray structures of the two regioselective Alp1U variants in complex with 1 were determined. These findings allowed insights into the reaction details of Alp1U and provided a new approach for engineering regioselective epoxide hydrolases. Full Article
at Structure, mechanism, and regulation of mitochondrial DNA transcription initiation [Enzymology] By www.jbc.org Published On :: 2020-12-25T00:06:31-08:00 Mitochondria are specialized compartments that produce requisite ATP to fuel cellular functions and serve as centers of metabolite processing, cellular signaling, and apoptosis. To accomplish these roles, mitochondria rely on the genetic information in their small genome (mitochondrial DNA) and the nucleus. A growing appreciation for mitochondria's role in a myriad of human diseases, including inherited genetic disorders, degenerative diseases, inflammation, and cancer, has fueled the study of biochemical mechanisms that control mitochondrial function. The mitochondrial transcriptional machinery is different from nuclear machinery. The in vitro re-constituted transcriptional complexes of Saccharomyces cerevisiae (yeast) and humans, aided with high-resolution structures and biochemical characterizations, have provided a deeper understanding of the mechanism and regulation of mitochondrial DNA transcription. In this review, we will discuss recent advances in the structure and mechanism of mitochondrial transcription initiation. We will follow up with recent discoveries and formative findings regarding the regulatory events that control mitochondrial DNA transcription, focusing on those involved in cross-talk between the mitochondria and nucleus. Full Article
at The endosomal trafficking regulator LITAF controls the cardiac Nav1.5 channel via the ubiquitin ligase NEDD4-2 [Computational Biology] By www.jbc.org Published On :: 2020-12-25T00:06:30-08:00 The QT interval is a recording of cardiac electrical activity. Previous genome-wide association studies identified genetic variants that modify the QT interval upstream of LITAF (lipopolysaccharide-induced tumor necrosis factor-α factor), a protein encoding a regulator of endosomal trafficking. However, it was not clear how LITAF might impact cardiac excitation. We investigated the effect of LITAF on the voltage-gated sodium channel Nav1.5, which is critical for cardiac depolarization. We show that overexpressed LITAF resulted in a significant increase in the density of Nav1.5-generated voltage-gated sodium current INa and Nav1.5 surface protein levels in rabbit cardiomyocytes and in HEK cells stably expressing Nav1.5. Proximity ligation assays showed co-localization of endogenous LITAF and Nav1.5 in cardiomyocytes, whereas co-immunoprecipitations confirmed they are in the same complex when overexpressed in HEK cells. In vitro data suggest that LITAF interacts with the ubiquitin ligase NEDD4-2, a regulator of Nav1.5. LITAF overexpression down-regulated NEDD4-2 in cardiomyocytes and HEK cells. In HEK cells, LITAF increased ubiquitination and proteasomal degradation of co-expressed NEDD4-2 and significantly blunted the negative effect of NEDD4-2 on INa. We conclude that LITAF controls cardiac excitability by promoting degradation of NEDD4-2, which is essential for removal of surface Nav1.5. LITAF-knockout zebrafish showed increased variation in and a nonsignificant 15% prolongation of action potential duration. Computer simulations using a rabbit-cardiomyocyte model demonstrated that changes in Ca2+ and Na+ homeostasis are responsible for the surprisingly modest action potential duration shortening. These computational data thus corroborate findings from several genome-wide association studies that associated LITAF with QT interval variation. Full Article
at Business Briefing: Assessing the geopolitical implications of EU AI regulation By www.chathamhouse.org Published On :: Thu, 08 Aug 2024 14:42:14 +0000 Business Briefing: Assessing the geopolitical implications of EU AI regulation 17 September 2024 — 4:00PM TO 5:00PM Anonymous (not verified) 8 August 2024 Chatham House Join us for this critical discussion of how the EU AI Act will shape the world’s approach to the technology. Join us for this critical discussion of how the EU AI Act will shape the world’s approach to the technology Governments, technology companies and civil society groups across the world are now advocating firmer AI regulation. Machine learning algorithms have changed the way we interact with technology and powered much of our online lives for decades: why has this pendulum swung back so far toward greater control, and why now?In 2023 the UK government seized the initiative with its Bletchley AI Safety Summit. The event attempted to address the so called ‘frontier risks’ associated with AI development. Global competition on AI is reflected in AI governance efforts in China, US, the Gulf and beyond. But to date, it is the EU that has led the West in passing AI legislation. The EU AI Act, has separated AI systems into graded risk categories carrying different regulatory requirements, and it remains to be seen whether global AI will feel the Brussels effect.This conversation will cover the following questions:Critics have painted regulation including the AI Act as anti-innovation. Is this a fair assessment?What lessons can we learn from the successes and shortcomings of GDPR?How do we tackle the challenge of low public trust in AI and low public trust in government technology projects, particularly in Western democracies?Does the proliferation of safety institutes, and the AI office, point to the emergence of a new type of technical governance institution? What is its future? Full Article
at 30 Years of Non-Maghreb: What next for Algeria-Morocco relations? By www.chathamhouse.org Published On :: Tue, 13 Aug 2024 16:27:13 +0000 30 Years of Non-Maghreb: What next for Algeria-Morocco relations? 10 September 2024 — 2:00PM TO 3:15PM Anonymous (not verified) 13 August 2024 Online Experts discuss Algeria-Morocco relations and implications for regional actors. In 1989, the establishment of the Arab Maghreb Union (UMA) brought a promise of economic integration and strengthening of ties between Algeria, Libya, Mauritania, Morocco and Tunisia for the benefit and prosperity of their societies.Decades on, very little has been accomplished in developing the Maghreb project, and the region remains one of the least integrated in the world, despite significant social and cultural similarities between member countries. The last time the full UMA leadership met was back in 1994, with August 2024 marking 30 years of closed borders between Algeria and Morocco.Relations between the two largest Maghreb countries have deteriorated further since 2020 due to disagreements over issues of Western Sahara, and, most recently, the Abraham Accords, with Algeria cutting diplomatic ties with Morocco in 2021.In this webinar, experts will discuss:Which primary obstacles are hindering Maghreb integration and Algeria-Morocco relations?What are the costs and implications for regional countries?What are the positions of Libya, Tunisia, and Mauritania?What is required for a rapprochement and how can external partners support this? Full Article
at In conversation with David Miliband: Finding a new approach to tackle conflict, climate and extreme poverty By www.chathamhouse.org Published On :: Thu, 15 Aug 2024 09:57:13 +0000 In conversation with David Miliband: Finding a new approach to tackle conflict, climate and extreme poverty 11 September 2024 — 5:00PM TO 5:45PM Anonymous (not verified) 15 August 2024 Chatham House and Online David Miliband discusses how the climate crisis, extreme poverty and conflict are becoming inextricably linked and how the global community must respond. Combatting the climate crisis, ending protracted conflicts, and alleviating poverty are three of the greatest priorities for international action. However, these three challenges become increasingly concentrated in a handful of countries. The subsequent feedback loop makes addressing these challenges even more complex.The International Rescue Committee’s (IRC’s) work in crisis-affected communities highlights this new geography of crisis. Just 16 countries, which are both climate-vulnerable and conflict-affected. This represents 43% of all people living in extreme poverty, 44% of all people affected by natural disasters and 79% of all people in humanitarian need. This trend towards the concentration of crisis is only deepening. In three decades, the number of conflict-affected, climate-vulnerable states has increased from 44% to more than two-thirds.Affected countries - like Sudan, Myanmar, and Syria - are also among the least supported financially. Debt burdens are siphoning away critical resources needed for adaptation and resilience. Humanitarian aid budgets are being slashed by donor governments. The private sector refuses to invest in these communities they view as too risky. And the international financial institutions meant to alleviate poverty and spur climate action are not well-designed to work with crisis-affected states or local communities. With the upcoming COP29 Summit in Azerbaijan focused on the New Collective Quantified Goal for climate finance, vulnerable communities will be watching closely whether they will get support in their fight against the worst impacts of the climate crisis.Conflict, the climate crisis, and extreme poverty are taking their toll. But how can the world best respond?Key questions to be discussed during the session include:At a time of political disruption, how does the West engage with vulnerable countries? What actions should be prioritised in providing support to such countries?Can global institutions evolve to better protect vulnerable and displaced people from conflict and climate-risk, particularly as geopolitical rivalries reduce space for cooperation?What is the UK’s role in supporting climate action in fragile states and how does this align with its agenda on the Sustainable Development Goals and extreme poverty? Full Article
at What is the future of cross-border data flows? By www.chathamhouse.org Published On :: Thu, 15 Aug 2024 17:27:13 +0000 What is the future of cross-border data flows? 16 September 2024 — 6:00PM TO 7:00PM Anonymous (not verified) 15 August 2024 Chatham House and Online Navigating long-standing tensions and newfound difficulties for unlocking shared prosperity among modern, digital economies. Cross-border data flows can unlock shared prosperity among digital economies, advance international security, and address cybercrime and global crises. But ensuring the free flow of data across borders involves navigating complex regulatory, security, trust, political, and technical challenges. Developing effective frameworks and agreements to support data flows is a significant undertaking.Recent bilateral and multilateral agreements and initiatives have advanced data-sharing, respecting the right to privacy and upholding notions of sovereignty. This has contributed to clearer rules and (potentially) better solutions such as the OECD declaration on government access to data held by companies. Further progress, supportive of public safety and national security, is on the horizon, like G7 support for data free flow with trust and industry-led, trusted cloud principles on protecting human rights and competitiveness.More work is needed to operationalize commitments and advance ongoing negotiations, like US–EU negotiations on e-evidence in criminal proceedings. This is key for ensuring ‘hard’ legal and regulatory mechanisms complement OECD principles. Stakeholders from law enforcement, national security, data protection and industry must confront tensions between sovereign prerogatives and cooperation. They must also overcome traditional silos between law enforcement and national security work. On the horizon are newfound challenges (for example, in harmonizing legal frameworks and responding to advances in technology). All the while, stakeholders must work together to promote economic interests, data protection, privacy and cybersecurity.This expert panel discusses the future of cross-border data-sharing, raising questions including:What value does cross-border data-sharing bring and where are its current ‘pain points’?To enable data free flows, how should principles complement ‘hard’ legal and regulatory mechanisms?Beyond states, law enforcement, major industry players and international organizations, what roles should SMEs, the technical community and civil society stakeholders play in shaping and operationalizing principles?Looking ahead, where is progress in data-sharing principles and arrangements expected or possible?A drinks reception follows the event.This event is supported by Microsoft as part of a project on data sharing. The project has benefited greatly from the insights of a multi-stakeholder taskforce and concludes with an open-access special issue of the Journal of Cyber Policy. Full Article
at In conversation with HRH Prince Turki AlFaisal By www.chathamhouse.org Published On :: Fri, 16 Aug 2024 09:27:14 +0000 In conversation with HRH Prince Turki AlFaisal 13 September 2024 — 11:00AM TO 12:00PM Anonymous (not verified) 16 August 2024 Chatham House and Online This event will discuss how the ongoing Gaza war is impacting the region and the role external actors can play to support de-escalation. The Gaza war, now in its tenth month, continues with ever-worsening consequences for Palestinians and no end in sight. The Israeli-Palestinian conflict has also heightened tensions across the Middle East with fears of a broader regional war that would include Iran and aligned groups from the ‘axis of resistance’.Against this backdrop, ceasefire negotiations supported by regional and international mediators, have not amounted to an agreement nor have there been any concrete proposals for a way forward out of the crisis by key actors such as the United States, Gulf countries or other key stakeholders.In this event, His Royal Highness Prince Turki AlFaisal will discuss how the Gaza war and related developments are impacting the Middle East, and will share his views on the role of regional and external actors in supporting de-escalation efforts.The addresses:How are Middle Eastern countries managing regional security and heightened tensions with Iran and aligned groups in Iraq, Lebanon and Yemen?What role are Gulf countries playing in efforts to de-escalate tensions?How can they support short- and long-term planning for a way forward in the Israeli-Palestinian conflict?How are relationships between Middle East countries and external powers such as the United States changing as a result of the Gaza war?In person places for this event are balloted. Confirmations will be sent by email on Monday 9 September at 3pm or a placed on the waiting list. Virtual registrations are confirmed immediately.Individual membership provides you with the complete Chatham House experience, connecting you with a unique global policy community. Find out more about membership. Full Article
at Sustainability Accelerator Summer Drinks 2024 By www.chathamhouse.org Published On :: Mon, 19 Aug 2024 09:17:13 +0000 Sustainability Accelerator Summer Drinks 2024 6 September 2024 — 5:30PM TO 7:30PM Anonymous (not verified) 19 August 2024 Chatham House Join us for the Sustainability Accelerator’s annual summer drinks reception. This event brings together a diverse group of thinkers and changemakers from our network, as well as our collaboration partners, to reflect on our successes over the past year and give an opportunity to meet new people.The reception will follow the Sustainability Accelerator’s annual UnConference, but is a separate event. Unless you have received confirmation of your place at UnConference, you must register for the summer drinks reception via this webpage to secure your place. Full Article
at Islamic radicalisation in Central Asia By www.chathamhouse.org Published On :: Tue, 20 Aug 2024 15:47:13 +0000 Islamic radicalisation in Central Asia 18 September 2024 — 10:00AM TO 11:30AM Anonymous (not verified) 20 August 2024 Chatham House and Online Experts analyse rising foreign recruitment, current counter-radicalisation efforts and challenge past Chatham House predictions made of the Central Asia region. In 2014, Chatham House released a report titled The Myth of Post-Soviet Muslim Radicalisation in the Central Asian Republics. At that time, a significant, Western-funded counter-radicalisation industry was addressing what was believed to be a major issue of Islamic violent extremism in the region.Over the past decade, two key developments have occurred. First, Western interest in the region has declined in favour of traditional geopolitical concerns. Second, while violent extremism incidents within Central Asia remain rare, there has been a notable recruitment of Central Asians by foreign groups, with several attacks carried out by Central Asians overseas.In this event, the original report’s authors, John Heathershaw and David Montgomery, will discuss whether the report’s arguments are still valid and how we might answer these questions today.This raises several questions:What did the report accurately predict, and where did it fall short?How can we explain the lack of violent extremist organisations (VEOs) within Central Asia but the presence of Central Asians in VEOs abroad?Could repression by Central Asian states both domestically and transnationally have contributed to this issue?What, if anything, can the counter-radicalisation industry do today to address this problem more effectively?Please note that in-person places are limited. Please wait for confirmation before participating. Full Article
at Labour Party Conference – International affairs networking brunch By www.chathamhouse.org Published On :: Mon, 16 Sep 2024 10:32:13 +0000 Labour Party Conference – International affairs networking brunch 24 September 2024 — 11:00AM TO 12:00PM Anonymous (not verified) 16 September 2024 Labour – Grace 1 Suite, Hilton Hotel, Liverpool Hosted by Sir Simon Fraser, Chairman of Chatham House. This event is taking place at the Hilton Hotel, Grace 1 Suite, Liverpool. You are warmly invited to join us for an exclusive networking brunch at the 2024 Labour Party Conference.Sir Simon Fraser, Chairman of Chatham House, and Olivia O’Sullivan, Director of Chatham House’s UK in the World Programme, will deliver opening remarks, followed by an interactive networking session where you will have the chance to engage with a wide range of stakeholders. Join us to connect with key senior parliamentary, corporate and media attendees at the Labour Party Conference.This event will be taking place outside of the secure zone. Full Article
at In conversation with Valerii Zaluzhnyi, Ukrainian Ambassador to the UK By www.chathamhouse.org Published On :: Mon, 16 Sep 2024 19:47:13 +0000 In conversation with Valerii Zaluzhnyi, Ukrainian Ambassador to the UK 17 October 2024 — 10:00AM TO 11:00AM Anonymous (not verified) 16 September 2024 Chatham House and Online The former Commander-in-Chief of the Armed Forces of Ukraine offers insight into the evolution of Russia’s war against his country, and what to expect next. More than two and a half years since Russia launched its full-scale invasion, Ukraine has consistently adapted to Moscow’s advances by implementing new strategies.Ukraine’s recent incursion into Russia’s Kursk region demonstrated operational tactical ingenuity, surprising both Russia and Ukraine’s Western supporters. Success against the Russian Black Sea Fleet has already showcased how Ukraine can skilfully beat back Russian aggression. And increasing numbers of targeted strikes on Russian supply depots and airfields are disrupting Russian operations behind the front lines.Critical Western supplies continue to resource Ukraine’s military. But questions linger over the quantity and sustainability of these supplies. Kyiv will be watching the US presidential election in November as its biggest backer goes to the polls with the possibility of an outcome that could seriously affect the war. Meanwhile, Russian forces continue to edge forward in Donbas, despite heavy casualties, and strike at Ukrainian towns and cities from the air, demonstrating that President Putin has no intention of relinquishing the fight.Amid these complexities, Ambassador Zaluzhnyi will discuss how the war is changing both sides, advances on the battlefield, and what dangers lie ahead for Ukraine in the coming months. Other key questions include:What kind of enemy is Russia today and how to secure its strategic defeat in Ukraine;How have new strategies, such as the recent incursion into the Kursk region, affected the state of play on the battlefield?What technologies and armaments does Ukraine need from its Western allies in both the short and long term?Individual membership provides you with the complete Chatham House experience, connecting you with a unique global policy community. Find out more about membership. Full Article
at In conversation with Martin Griffiths: How can a divided world address conflict? By www.chathamhouse.org Published On :: Mon, 16 Sep 2024 19:52:13 +0000 In conversation with Martin Griffiths: How can a divided world address conflict? 1 October 2024 — 10:00AM TO 11:00AM Anonymous (not verified) 16 September 2024 Chatham House and Online The former United Nations Under-Secretary-General describes how a weakening multilateralism system and dysfunctional political diplomacy can be revitalized by a humanitarian approach. The international community is failing to stop conflict. Despite efforts by international organisations and state actors to resolve or prevent it from breaking out, wars around the world have left millions of people suffering. Unstable governments and global insecurity are contributing to an age of poly-crisis, compounded by growing inequity and impunity.How can a divided world work better to prevent and resolve conflict and reduce the suffering of the civilians affected?Martin Griffiths has spent decades working within the United Nations system and other institutions on conflict resolution and humanitarian action, most recently as Under-Secretary General for Humanitarian Affairs and the Emergency Relief Coordinator. He worked on peace deals in Indonesia, Spain, Thailand, Myanmar, Darfur, Syria and Yemen and responded to emergencies in Ethiopia, Haiti, Afghanistan, Syria, Ukraine, Sudan, Turkiye and Gaza and elsewhere. In this discussion, he casts his expertise over the biggest challenges in the world today and assess the prospects for international cooperation on conflict resolution in the future.Key questions to be discussed include:How can a lasting peace be secured in the conflict between Israel and Palestine ?Is the world too fragmented to prevent or resolve conflicts around the world?What role can the United Nations play in today’s geopolitical environment?How can the West and Global South better engage to limit conflict ?Individual membership provides you with the complete Chatham House experience, connecting you with a unique global policy community. Find out more about membership. Full Article
at US domestic polarization and implications for the presidential election By www.chathamhouse.org Published On :: Thu, 19 Sep 2024 09:07:13 +0000 US domestic polarization and implications for the presidential election 30 September 2024 — 5:00PM TO 6:00PM Anonymous (not verified) 19 September 2024 Online This webinar explores the rise of polarization amongst the US public and implications for the upcoming election. Domestic polarization has been on the rise in the US in recent years, with Democrats and Republicans moving further away from the centre on key policy issues. As polarization increases, so too do concerns about the state of US democracy and prospects of political violence surrounding the upcoming presidential election. This expert panel discusses key questions including:What are the driving forces of the growing political divide in the US?How far apart are voters on key election issues, from healthcare to immigration to national security?How is partisan polarisation altering the effectiveness of US foreign policy and influencing America’s role in the world? Full Article
at In conversation with Speaker Emerita Nancy Pelosi By www.chathamhouse.org Published On :: Thu, 19 Sep 2024 10:52:13 +0000 In conversation with Speaker Emerita Nancy Pelosi 14 October 2024 — 12:00PM TO 1:00PM Anonymous (not verified) 19 September 2024 Chatham House and Online The former Speaker of the House of Representatives discusses challenges to American democracy and the importance of leadership in an election year. As the US gears up for the 2024 Presidential election, the importance of leadership in politics has come to the fore. As the Harris and Trump campaigns move towards election day, the heightened sense of strong leadership is central to the position of both candidates.Following her first election to the House in 1987, Speaker Emerita Nancy Pelosi has been central to American political leadership for over two decades. Serving as the 52nd Speaker of the House of Representative, Speaker Pelosi rose to become one of the most powerful and consequential Speakers in American political history.Following the release of her recent book The Art of Power, Speaker Pelosi will discuss how she became a master legislator, working with numerous presidents, her political legacy in the house and her leadership during a contentious time in US politics. Full Article
at What are MENA countries’ priorities for climate action and COP? By www.chathamhouse.org Published On :: Wed, 02 Oct 2024 08:47:13 +0000 What are MENA countries’ priorities for climate action and COP? 24 October 2024 — 1:00PM TO 2:00PM Anonymous (not verified) 2 October 2024 Online Experts discuss the impacts of COP27 and 28 on the region and priorities for COP29. In November this year, all eyes will be on Azerbaijan as Baku hosts the 29th UN Climate Conference (COP). Hosting COP offers an opportunity to push for climate action that reflects the host country’s unique circumstances, as well as regional interests. COP28 in the United Arab Emirates and COP27 in Egypt highlighted the climate priorities for the Middle East and North Africa (MENA), one of the world’s most vulnerable regions to the impacts of climate change.From rising temperatures and deadly heatwaves, to extreme weather events such as heavy rainstorms, sandstorms, and cyclones, climate change exacerbates existing vulnerabilities. These vulnerabilities include water scarcity, food security, and the preservation of livelihoods increasingly threatening the region’s social and economic stability.While there has been some progress in advancing formal negotiations on key issues, the gap between COP agreements and tangible actions to address the increasingly severe effects of climate change in the MENA region remains vast. This webinar aims to assess:What are the key tangible impacts of COP27 and COP28 in Egypt and the UAE respectively on driving climate action in the region?How do MENA countries balance COP28’s landmark agreement to transition away from fossil fuels with their unique national circumstances?How will the region benefit from COP28 breakthrough in integrating the issues of climate, peace and security in climate action through the ‘Declaration of Climate, Relief, Recovery and Peace’?What are the priorities for COP29 and how do they align with the climate agenda in the MENA region? Full Article
at Celebrating Black History Month at Chatham House By www.chathamhouse.org Published On :: Wed, 02 Oct 2024 15:12:13 +0000 Celebrating Black History Month at Chatham House 24 October 2024 — 6:00PM TO 8:00PM Anonymous (not verified) 2 October 2024 Chatham House Join us for the ‘Beyond expectations: The impact and legacy of migration exhibition 2024’ exhibition and drinks reception. About the Photographer Neil Kenlock, a photographer and media professional, has lived in London since arriving from Jamaica in 1963 to join his parents. He spent the early years of his career as a professional photographer, specialising in fashion, beauty, celebrities, and the cultural lifestyles of Black people in the UK. In the late 1960s and 1970s, he captured images of the UK Black Panther movement and documented demonstrations and anti-racism protests across the country.“Neil Kenlock helps us to better understand the story of London’s Black communities and to appreciate the huge artistic and cultural impact they have had on all our lives. He is a significant photographer whose work documents a key chapter in London’s post-war history.” — Mike Seaborne, former curator of photographs at the Museum of London.About the exhibitionThis exhibition unveils a collection of photographs by Neil Kenlock, capturing Black British individuals who migrated from their homelands and settled in the UK. Curated by his daughter Emelia Kenlock, the series explores the theme of ‘expectations’ and its enduring legacy, featuring African and Caribbean subjects who brought their skills, passions, and dreams—contributions that have profoundly shaped British culture today.Reflecting on the work, Kenlock stated: “Over 50 years since the concept of ‘black excellence’ first manifested, and more than 70 years since the Windrush, I truly hope this exhibition will add to the national cultural narrative and resonate with new audiences.” Full Article
at Iraq Initiative Conference 2024 By www.chathamhouse.org Published On :: Fri, 04 Oct 2024 10:12:13 +0000 Iraq Initiative Conference 2024 20 November 2024 — 9:30AM TO 5:00PM Anonymous (not verified) 4 October 2024 Chatham House and Online Our sixth annual Iraq Initiative conference will convene Iraqi and international policymakers, experts and civil society in London to discuss the critical questions for Iraq’s future, and the country’s trajectory in the year ahead. Over two decades following regime change, Iraq appears to be on a path to recovery and growth. With the support of high oil prices, Prime Minister Mohammed Shia’ al-Sudani’s government is implementing an ambitious plan to develop critical infrastructure, enhance ties with neighbouring countries, and renegotiate relationships with international partners like the US and UN. The political system has rebounded from a series of shocks and is in the process of consolidating and centralising power in Baghdad under the governing Shia Coordination Framework.However, underlying political, economic, security, and regional challenges, if not addressed, threaten this apparent stability and frustrate longer-term hope for a better future. Despite the country’s wealth, many young Iraqis struggle to find jobs while the space for civic activism shrinks. Meanwhile, the escalation of violence across the region threatens to engulf Iraq in further conflict. With the 2025 parliamentary election approaching, infighting within the governing coalition also suggests political turmoil in the year ahead.The key questions explored through each session include:How can the Sudani government tackle the roots of these obstacles to ensure that development can be sustained over time?What are the key steps to coherent and effective state-building?And how can regional and international actors support this process?This conference is part of Chatham House’s Iraq Initiative.This year’s conference features RE-PLAY – a video art exhibition curated by Dr Tamara Chalabi of the Ruya Foundation. The artists featured in this exhibition, spanning multiple generations both within Iraq and in the Iraqi diaspora, use their work to grapple with complex notions of Iraqi identity through the thematic issues of heritage, exile, disconnection, freedom of expression, and other persistent issues explored in this show.Simultaneous English-Arabic interpretation will be available for all conference sessions. This event is part of Chatham House’s Iraq Initiative. Iraq Initiative conference 2024 agenda [English] (PDF, 2.97MB) Iraq Initiative conference 2024 agenda [Arabic] (PDF, 2.29MB) RE-PLAY Video Art Exhibition [English] (PDF, 0.23MB) RE-PLAY Video Art Exhibition [Arabic] (PDF, 0.22MB) The institute occupies a position of respect and trust, and is committed to fostering inclusive dialogue at all events. Event attendees are expected to uphold this by adhering to our code of conduct. Full Article
at [4Fe-4S] cluster trafficking mediated by Arabidopsis mitochondrial ISCA and NFU proteins [Enzymology] By www.jbc.org Published On :: 2020-12-25T00:06:31-08:00 Numerous iron-sulfur (Fe-S) proteins with diverse functions are present in the matrix and respiratory chain complexes of mitochondria. Although [4Fe-4S] clusters are the most common type of Fe-S cluster in mitochondria, the molecular mechanism of [4Fe-4S] cluster assembly and insertion into target proteins by the mitochondrial iron-sulfur cluster (ISC) maturation system is not well-understood. Here we report a detailed characterization of two late-acting Fe-S cluster-carrier proteins from Arabidopsis thaliana, NFU4 and NFU5. Yeast two-hybrid and bimolecular fluorescence complementation studies demonstrated interaction of both the NFU4 and NFU5 proteins with the ISCA class of Fe-S carrier proteins. Recombinant NFU4 and NFU5 were purified as apo-proteins after expression in Escherichia coli. In vitro Fe-S cluster reconstitution led to the insertion of one [4Fe-4S]2+ cluster per homodimer as determined by UV-visible absorption/CD, resonance Raman and EPR spectroscopy, and analytical studies. Cluster transfer reactions, monitored by UV-visible absorption and CD spectroscopy, showed that a [4Fe-4S]2+ cluster-bound ISCA1a/2 heterodimer is effective in transferring [4Fe-4S]2+ clusters to both NFU4 and NFU5 with negligible back reaction. In addition, [4Fe-4S]2+ cluster-bound ISCA1a/2, NFU4, and NFU5 were all found to be effective [4Fe-4S]2+ cluster donors for maturation of the mitochondrial apo-aconitase 2 as assessed by enzyme activity measurements. The results demonstrate rapid, unidirectional, and quantitative [4Fe-4S]2+ cluster transfer from ISCA1a/2 to NFU4 or NFU5 that further delineates their respective positions in the plant ISC machinery and their contributions to the maturation of client [4Fe-4S] cluster-containing proteins. Full Article
at Calpain activation mediates microgravity-induced myocardial abnormalities in mice via p38 and ERK1/2 MAPK pathways [Molecular Bases of Disease] By www.jbc.org Published On :: 2020-12-04T00:06:06-08:00 The human cardiovascular system has adapted to function optimally in Earth's 1G gravity, and microgravity conditions cause myocardial abnormalities, including atrophy and dysfunction. However, the underlying mechanisms linking microgravity and cardiac anomalies are incompletely understood. In this study, we investigated whether and how calpain activation promotes myocardial abnormalities under simulated microgravity conditions. Simulated microgravity was induced by tail suspension in mice with cardiomyocyte-specific deletion of Capns1, which disrupts activity and stability of calpain-1 and calpain-2, and their WT littermates. Tail suspension time-dependently reduced cardiomyocyte size, heart weight, and myocardial function in WT mice, and these changes were accompanied by calpain activation, NADPH oxidase activation, and oxidative stress in heart tissues. The effects of tail suspension were attenuated by deletion of Capns1. Notably, the protective effects of Capns1 deletion were associated with the prevention of phosphorylation of Ser-345 on p47phox and attenuation of ERK1/2 and p38 activation in hearts of tail-suspended mice. Using a rotary cell culture system, we simulated microgravity in cultured neonatal mouse cardiomyocytes and observed decreased total protein/DNA ratio and induced calpain activation, phosphorylation of Ser-345 on p47phox, and activation of ERK1/2 and p38, all of which were prevented by calpain inhibitor-III. Furthermore, inhibition of ERK1/2 or p38 attenuated phosphorylation of Ser-345 on p47phox in cardiomyocytes under simulated microgravity. This study demonstrates for the first time that calpain promotes NADPH oxidase activation and myocardial abnormalities under microgravity by facilitating p47phox phosphorylation via ERK1/2 and p38 pathways. Thus, calpain inhibition may be an effective therapeutic approach to reduce microgravity-induced myocardial abnormalities. Full Article
at Fluorescence assay for simultaneous quantification of CFTR ion-channel function and plasma membrane proximity [Methods and Resources] By www.jbc.org Published On :: 2020-12-04T00:06:05-08:00 The cystic fibrosis transmembrane conductance regulator (CFTR) is a plasma membrane anion channel that plays a key role in controlling transepithelial fluid movement. Excessive activation results in intestinal fluid loss during secretory diarrheas, whereas CFTR mutations underlie cystic fibrosis (CF). Anion permeability depends both on how well CFTR channels work (permeation/gating) and on how many are present at the membrane. Recently, treatments with two drug classes targeting CFTR—one boosting ion-channel function (potentiators) and the other increasing plasma membrane density (correctors)—have provided significant health benefits to CF patients. Here, we present an image-based fluorescence assay that can rapidly and simultaneously estimate both CFTR ion-channel function and the protein's proximity to the membrane. We monitor F508del-CFTR, the most common CF-causing variant, and confirm rescue by low temperature, CFTR-targeting drugs and second-site revertant mutation R1070W. In addition, we characterize a panel of 62 CF-causing mutations. Our measurements correlate well with published data (electrophysiology and biochemistry), further confirming validity of the assay. Finally, we profile effects of acute treatment with approved potentiator drug VX-770 on the rare-mutation panel. Mapping the potentiation profile on CFTR structures raises mechanistic hypotheses on drug action, suggesting that VX-770 might allow an open-channel conformation with an alternative arrangement of domain interfaces. The assay is a valuable tool for investigation of CFTR molecular mechanisms, allowing accurate inferences on gating/permeation. In addition, by providing a two-dimensional characterization of the CFTR protein, it could better inform development of single-drug and precision therapies addressing the root cause of CF disease. Full Article
at Unusual zwitterionic catalytic site of SARS-CoV-2 main protease revealed by neutron crystallography [Enzymology] By www.jbc.org Published On :: 2020-12-11T00:06:21-08:00 The main protease (3CL Mpro) from SARS–CoV-2, the etiological agent of COVID-19, is an essential enzyme for viral replication. 3CL Mpro possesses an unusual catalytic dyad composed of Cys145 and His41 residues. A critical question in the field has been what the protonation states of the ionizable residues in the substrate-binding active-site cavity are; resolving this point would help understand the catalytic details of the enzyme and inform rational drug development against this pernicious virus. Here, we present the room-temperature neutron structure of 3CL Mpro, which allowed direct determination of hydrogen atom positions and, hence, protonation states in the protease. We observe that the catalytic site natively adopts a zwitterionic reactive form in which Cys145 is in the negatively charged thiolate state and His41 is doubly protonated and positively charged, instead of the neutral unreactive state usually envisaged. The neutron structure also identified the protonation states, and thus electrical charges, of all other amino acid residues and revealed intricate hydrogen-bonding networks in the active-site cavity and at the dimer interface. The fine atomic details present in this structure were made possible by the unique scattering properties of the neutron, which is an ideal probe for locating hydrogen positions and experimentally determining protonation states at near-physiological temperature. Our observations provide critical information for structure-assisted and computational drug design, allowing precise tailoring of inhibitors to the enzyme's electrostatic environment. Full Article
at M8R tropomyosin mutation disrupts actin binding and filament regulation: The beginning affects the middle and end [Molecular Bases of Disease] By www.jbc.org Published On :: 2020-12-11T00:06:20-08:00 Dilated cardiomyopathy (DCM) is associated with mutations in cardiomyocyte sarcomeric proteins, including α-tropomyosin. In conjunction with troponin, tropomyosin shifts to regulate actomyosin interactions. Tropomyosin molecules overlap via tropomyosin–tropomyosin head-to-tail associations, forming a continuous strand along the thin filament. These associations are critical for propagation of tropomyosin's reconfiguration along the thin filament and key for the cooperative switching between heart muscle contraction and relaxation. Here, we tested perturbations in tropomyosin structure, biochemistry, and function caused by the DCM-linked mutation, M8R, which is located at the overlap junction. Localized and nonlocalized structural effects of the mutation were found in tropomyosin that ultimately perturb its thin filament regulatory function. Comparison of mutant and WT α-tropomyosin was carried out using in vitro motility assays, CD, actin co-sedimentation, and molecular dynamics simulations. Regulated thin filament velocity measurements showed that the presence of M8R tropomyosin decreased calcium sensitivity and thin filament cooperativity. The co-sedimentation of actin and tropomyosin showed weakening of actin-mutant tropomyosin binding. The binding of troponin T's N terminus to the actin-mutant tropomyosin complex was also weakened. CD and molecular dynamics indicate that the M8R mutation disrupts the four-helix bundle at the head-to-tail junction, leading to weaker tropomyosin–tropomyosin binding and weaker tropomyosin–actin binding. Molecular dynamics revealed that altered end-to-end bond formation has effects extending toward the central region of the tropomyosin molecule, which alter the azimuthal position of tropomyosin, likely disrupting the mutant thin filament response to calcium. These results demonstrate that mutation-induced alterations in tropomyosin–thin filament interactions underlie the altered regulatory phenotype and ultimately the pathogenesis of DCM. Full Article
at Reply to Sysel et al.: Comment on the importance of using nitric oxide gas in the synthesis of nitrosylcobalamin and ICH-validated methods to assess purity and stability [Letters to the Editor] By www.jbc.org Published On :: 2020-10-23T00:06:00-07:00 In their comment (1) on our publication (2), the authors make two points: (i) they raise concerns about the possible effect of residual NONOate in our study, and (ii) they promote nitrosylcobalamin (NOCbl) supplied by their own company. Both points lack merit for the following reasons. The authors make the astonishing claim that the spectra of nitric oxide (NO•) and cobalamins overlap. Unlike NO•, cobalamin absorbs in the visible region, permitting unequivocal spectral assignment of NOCbl as reported (3). We demonstrated that whereas NOCbl is highly unstable in solution, it is stabilized by the B12 trafficking protein CblC. So even if present, residual NONOate (which is unstable at neutral pH and is removed during the work-up (3)) could not account for the observed difference.The authors then misrepresent our synthetic method, claiming that anaerobic conditions were used to generate nitrocobalamin (NO2Cbl), which results in the transient formation of NOCbl. We synthesized NO2Cbl aerobically using nitrite as described (4); NOCbl is not an intermediate in this ligand exchange reaction. The aerobic instability of NOCbl has been rigorously described by inorganic chemists (3, 5) and raises obvious questions about its purported biological effects as exemplified by the authors' own 2003 JBC publication, which was later withdrawn.As to promoting NOCbl from their company, the authors refer to a synthetic route from a mixture of NO• gas and aquocobalamin. The authors' method (6) has been described as “dubious” by chemists (5). Whereas DEAE NONOate used in our method is widely known as an NO• donor,... Full Article
at Comment on the importance of using nitric oxide gas in the synthesis of nitrosylcobalamin and ICH-validated methods to assess purity and stability [Letters to the Editor] By www.jbc.org Published On :: 2020-10-23T00:06:00-07:00 After a thorough read of this paper (1), we wish to clarify that the authors' anaerobic method of synthesis for the production of nitrocobalamin results in the transient formation of nitrosylcobalamin, an unstable intermediate upon exposure to air. We concur that the authors' method results in the production of nitrocobalamin based on the UV-visible data as shown. The authors' adapted anaerobic method consists of mixing hydroxocobalamin hydrochloride with diethylamine NONOate diethylammonium salt in aqueous solution. Of concern, the UV spectrum of nitric oxide overlaps that of all cobalamin species under anaerobic conditions, making any assignments of the binding of nitric oxide to hydroxocobalamin suspect (2). Additionally, the use of acetone to precipitate the authors' product causes precipitation of diethylamine NONOate, resulting in an impure product. As a result, its utility for drawing experimental conclusions is faulty.The product from the authors' anaerobic synthetic method has not been assessed for purity, and the synthetic method itself has not been validated using a stability-indicating method as required by the International Conference on Harmonization (ICH) (ICH Q2B, Validation of Analytical Procedures) methodology, which is a hallmark for analytical characterization. Our nitrosylcobalamin synthesis involves reacting nitric oxide gas with hydroxocobalamin acetate as a heterogeneous mixture in a non-electron-donating solvent followed by rotary evaporation. Our nitrosylcobalamin product is stable in air, releases nitric oxide gas in situ (3), and meets ICH stability guidelines (4). Additionally, our nitrosylcobalamin product demonstrates biological activity, which has not been observed for nitrocobalamin (3, 5). Full Article
at Naturally occurring hotspot cancer mutations in G{alpha}13 promote oncogenic signaling [Molecular Bases of Disease] By www.jbc.org Published On :: 2020-12-04T00:06:06-08:00 Heterotrimeric G-proteins are signaling switches broadly divided into four families based on the sequence and functional similarity of their Gα subunits: Gs, Gi/o, Gq/11, and G12/13. Artificial mutations that activate Gα subunits of each of these families have long been known to induce oncogenic transformation in experimental systems. With the advent of next-generation sequencing, activating hotspot mutations in Gs, Gi/o, or Gq/11 proteins have also been identified in patient tumor samples. In contrast, patient tumor-associated G12/13 mutations characterized to date lead to inactivation rather than activation. By using bioinformatic pathway analysis and signaling assays, here we identified cancer-associated hotspot mutations in Arg-200 of Gα13 (encoded by GNA13) as potent activators of oncogenic signaling. First, we found that components of a G12/13-dependent signaling cascade that culminates in activation of the Hippo pathway effectors YAP and TAZ is frequently altered in bladder cancer. Up-regulation of this signaling cascade correlates with increased YAP/TAZ activation transcriptional signatures in this cancer type. Among the G12/13 pathway alterations were mutations in Arg-200 of Gα13, which we validated to promote YAP/TAZ-dependent (TEAD) and MRTF-A/B-dependent (SRE.L) transcriptional activity. We further showed that this mechanism relies on the same RhoGEF-RhoGTPase cascade components that are up-regulated in bladder cancers. Moreover, Gα13 Arg-200 mutants induced oncogenic transformation in vitro as determined by focus formation assays. In summary, our findings on Gα13 mutants establish that naturally occurring hotspot mutations in Gα subunits of any of the four families of heterotrimeric G-proteins are putative cancer drivers. Full Article
at Allosteric activation of proto-oncogene kinase Src by GPCR-beta-arrestin complexes [Enzymology] By www.jbc.org Published On :: 2020-12-04T00:06:06-08:00 G protein–coupled receptors (GPCRs) initiate signaling cascades via G-proteins and beta-arrestins (βarr). βarr-dependent actions begin with recruitment of βarr to the phosphorylated receptor tail and are followed by engagement with the receptor core. βarrs are known to act as adaptor proteins binding receptors and various effectors, but it is unclear whether in addition to the scaffolding role βarrs can allosterically activate their downstream targets. Here we demonstrate the direct allosteric activation of proto-oncogene kinase Src by GPCR–βarr complexes in vitro and establish the conformational basis of the activation. Whereas free βarr1 had no effect on Src activity, βarr1 in complex with M2 muscarinic or β2-adrenergic receptors reconstituted in lipid nanodiscs activate Src by reducing the lag phase in Src autophosphorylation. Interestingly, receptor–βarr1 complexes formed with a βarr1 mutant, in which the finger-loop, required to interact with the receptor core, has been deleted, fully retain the ability to activate Src. Similarly, βarr1 in complex with only a phosphorylated C-terminal tail of the vasopressin 2 receptor activates Src as efficiently as GPCR–βarr complexes. In contrast, βarr1 and chimeric M2 receptor with nonphosphorylated C-terminal tail failed to activate Src. Taken together, these data demonstrate that the phosphorylated GPCR tail interaction with βarr1 is necessary and sufficient to empower it to allosterically activate Src. Our findings may have implications for understanding more broadly the mechanisms of allosteric activation of downstream targets by βarrs. Full Article
at Hdac3 regulates bone modeling by suppressing osteoclast responsiveness to RANKL [Signal Transduction] By www.jbc.org Published On :: 2020-12-18T00:06:18-08:00 Hdac3 is a lysine deacetylase that removes acetyl groups from histones and additional proteins. Although Hdac3 functions within mesenchymal lineage skeletal cells are defined, little is known about Hdac3 activities in bone-resorbing osteoclasts. In this study we conditionally deleted Hdac3 within Ctsk-expressing cells and examined the effects on bone modeling and osteoclast differentiation in mice. Hdac3 deficiency reduced femur and tibia periosteal circumference and increased cortical periosteal osteoclast number. Trabecular bone was likewise reduced and was accompanied by increased osteoclast number per trabecular bone surface. We previously showed that Hdac3 deacetylates the p65 subunit of the NF-κB transcriptional complex to decrease DNA-binding and transcriptional activity. Hdac3-deficient osteoclasts demonstrate increased K310 NF-κB acetylation and NF-κB transcriptional activity. Hdac3-deficient osteoclast lineage cells were hyper-responsive to RANKL and showed elevated ex vivo osteoclast number and size and enhanced bone resorption in pit formation assays. Osteoclast-directed Hdac3 deficiency decreased cortical and trabecular bone mass parameters, suggesting that Hdac3 regulates coupling of bone resorption and bone formation. We surveyed a panel of osteoclast-derived coupling factors and found that Hdac3 suppression diminished sphingosine-1-phosphate production. Osteoclast-derived sphingosine-1-phosphate acts in paracrine to promote bone mineralization. Mineralization of WT bone marrow stromal cells cultured with conditioned medium from Hdac3-deficient osteoclasts was markedly reduced. Expression of alkaline phosphatase, type 1a1 collagen, and osteocalcin was also suppressed, but no change in Runx2 expression was observed. Our results demonstrate that Hdac3 controls bone modeling by suppressing osteoclast lineage cell responsiveness to RANKL and coupling to bone formation. Full Article
at 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
at 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
at Tyrosine phosphorylation of the scaffold protein IQGAP1 in the MET pathway alters function [Signal Transduction] By www.jbc.org Published On :: 2020-12-25T00:06:30-08:00 IQGAP1 is a key scaffold protein that regulates numerous cellular processes and signaling pathways. Analogous to many other cellular proteins, IQGAP1 undergoes post-translational modifications, including phosphorylation. Nevertheless, very little is known about the specific sites of phosphorylation or the effects on IQGAP1 function. Here, using several approaches, including MS, site-directed mutagenesis, siRNA-mediated gene silencing, and chemical inhibitors, we identified the specific tyrosine residues that are phosphorylated on IQGAP1 and evaluated the effect on function. Tyr-172, Tyr-654, Tyr-855, and Tyr-1510 were phosphorylated on IQGAP1 when phosphotyrosine phosphatase activity was inhibited in cells. IQGAP1 was phosphorylated exclusively on Tyr-1510 under conditions with enhanced MET or c-Src signaling, including in human lung cancer cell lines. This phosphorylation was significantly reduced by chemical inhibitors of MET or c-Src or by siRNA-mediated knockdown of MET. To investigate the biological sequelae of phosphorylation, we generated a nonphosphorylatable IQGAP1 construct by replacing Tyr-1510 with alanine. The ability of hepatocyte growth factor, the ligand for MET, to promote AKT activation and cell migration was significantly greater when IQGAP1-null cells were reconstituted with IQGAP1 Y1510A than when cells were reconstituted with WT IQGAP1. Collectively, our data suggest that phosphorylation of Tyr-1510 of IQGAP1 alters cell function. Because increased MET signaling is implicated in the development and progression of several types of carcinoma, IQGAP1 may be a potential therapeutic target in selected malignancies. Full Article
at Water, Ecosystems and Energy in South Asia: Making Cross-Border Collaboration Work By www.chathamhouse.org Published On :: Wed, 29 Jun 2016 13:19:15 +0000 Water, Ecosystems and Energy in South Asia: Making Cross-Border Collaboration Work Research paper sysadmin 29 June 2016 A new paper sets out the factors that have made previous cross-border projects in South Asia successful, arguing that cooperation around water is feasible despite the region’s political differences and economic assymetries. — Indian people walk in the Ganga riverbed in Allahabad on 1 September 2015. Photo: Getty images. The countries of South Asia share some of the world’s major river basins – the Ganga (or Ganges), the Brahmaputra and the Indus. These rivers and their tributaries flow through seven countries, support more than 1 billion people, irrigate millions of hectares of land and are of cultural importance to many of those who rely on them. River management presents common challenges across the region. These include physical factors such as droughts, flooding, cyclones and climate change, as well political and institutional factors impeding the development of solutions and policies to improve resource management and reduce vulnerability. Water is increasingly seen as a source of competition, with population growth, industrialization and urbanization exacerbating the pressures on supply. Although South Asian examples of regional cooperation in general are limited, there is a clear positive trend. In areas such as disaster response and cross-border power trading, regional and bilateral engagement is beginning to take place. Multilateral official arrangements exist for trade and other economic issues, but there is none on water or ecosystems. However, as the benefits from cooperation become proven, its desirability is likely to gradually enter mainstream policy thinking on water issues. This research paper sets out the factors that have enabled cooperation, and the processes adopted, in previous successful cross-border projects. It focuses on four categories of cooperation: development of early-warning systems for natural disasters, in particular floods; protection of cross-border ecosystems; sharing of learning, through the showcasing of innovative approaches in one country that can be adopted by others; and power trading, in particular the development of hydropower in Bhutan and its export to India. The paper argues that cooperation around water in South Asia is feasible despite political differences and economic asymmetries. Different forms of collective action, and common understanding of both the threats and the shared benefits from cooperation, are required to foster more partnerships within the river basin states. 2016-06-30-water-south-asia-price-mittra (PDF) Full Article
at Brexit: Implications for EU–China Relations By www.chathamhouse.org Published On :: Wed, 10 May 2017 09:30:14 +0000 Brexit: Implications for EU–China Relations Research paper sysadmin 10 May 2017 For Beijing, the EU–China relationship will take priority over UK–China ties – with China’s relative focus on Germany becoming even more significant. — Containers are loaded onto a freight train at a depot in Corringham, east of London, en route to Yiwu, China, on 10 April 2017. Photo: Getty Images. Summary The extent of current UK relations with China means that Brexit will notably reduce the scale and diversity of overall EU–China economic and commercial interactions. But the impact will vary across different areas. In policy terms, liberal voices on economic policy towards China will be somewhat weaker among the post-Brexit EU27. Brexit will not be the most important factor determining the future level of strategic coherence in EU policy towards China. The impact on post-Brexit EU27 trade with China will be felt both in the volume of trade and its composition. Following Brexit the EU will no longer be China’s largest trading partner. There will be some relative shift in Chinese investment in Europe away from the UK, though over time the impact of Europe-wide policy approaches to Chinese investment will have more impact than Brexit per se. EU–China educational exchanges will be weakened after Brexit, but inbound Chinese tourism will be less affected by Brexit. By 2025, the EU will have compensated for Brexit’s impact in some areas, but much depends on the EU’s own trajectory over the next decade. For Beijing, the EU–China relationship will take priority over UK–China ties. Within the EU, China’s relative focus on Germany will be even more significant. 2017-05-11-brexit-eu-china-summers-final (PDF) Full Article
at Arguments Over Innovation Capacity Miss How Much the US and China Are Intertwined By www.chathamhouse.org Published On :: Wed, 30 May 2018 11:28:56 +0000 Arguments Over Innovation Capacity Miss How Much the US and China Are Intertwined Expert comment sysadmin 30 May 2018 Most discussions of current US–China trade tensions fundamentally misrepresent the globalized nature of innovation. — The C919 aircraft, China’s first modern passenger jet, is a flagship project of President Xi Jinping’s ambition to build the country’s domestic manufacturing capabilities. Photo: Getty Images. Among the many issues at play in the ongoing economic and trade tensions between the US and China are questions of technological capability and innovation.Two of the main complaints in the US Section 301 report were that American companies have been forced to transfer technology to China and been the subject of cyber espionage. The presentation of the issues in this report has been disputed, but behind it lies concern in the US that Chinese innovative and technological capability is catching up with that in the US, thanks partly to the support of state policies set out in the Made in China 2025 initiative.One important feature of the package of measures announced by the US last month is that it was designed to contain China’s technological development as much as to reduce the trade deficit, even though the latter has been the focus of President Donald Trump’s rhetoric.(Some have cast doubt on this picture of Chinese innovation, suggesting that China is more of a ‘fat tech dragon’ whose massive inputs into research and development do not translate into real innovative capacity.)The problem with the debate comparing Chinese and American technological capability is that it misunderstands or misrepresents the globalized nature of innovation in today’s world.Contrary to the economic nationalist rhetoric emanating mainly from Washington, and to a lesser extent from Beijing, the US and China are not two separate economies competing for economic hegemony. As part of the globalization of manufacturing and production over the last 40 years and the more recent globalization of consumption, the shape and structure of innovation has also changed.As we argue in a new paper, the key to understanding this is to think of innovation as being carried out through global or transnational networks linking economic actors, not within separated economies. What the recent phase of globalization has demonstrated is that innovation is achieved most effectively and efficiently when those engaged in innovation are connected not just within national borders but across them.China has become integrated into these global innovation networks in ways which reflect its relative strengths and weaknesses in research and development. China’s extensive manufacturing ecosystem has enabled its companies to perform well in production-related and efficiency-driven innovation. Moreover the rapid growth in its large and dynamic consumer market provides fertile ground for consumer-related innovation by Chinese and foreign-invested enterprises alike. The rapidly increasing talent pool in China also provides additional human capital for innovation and technology.Apart from the increased emphasis by Chinese enterprises on innovation, multinationals have also been stepping up their research and development (R&D) efforts in China. These now consitute a significant part of China’s R&D landscape, and are an increasingly important part of the global innovation by multinationals.Things are of course changing. China’s overall innovation capacity is improving, and there are concerns in both in the US and Europe that Chinese policy is moving backwards towards the promotion of ‘indigenous innovation’ – or self-reliant innovation – and away from openness. In other words, we may be seeing a more ‘techno-nationalist’ China as well as a protectionist US.China has also been criticized for inadequate protection of intellectual property rights, though the establishment of special courts for such disputes marks a commitment to improve – and the rights of Chinese companies increasingly need protection too.As the benefits of globalization increasingly come under question, and with some degree of nationalist political pressure in both the West and China, it is not going to be possible – or politically desirable – to do away with national borders when it comes to innovation. But at the same time, the extent to which businesses and consumers have globalized means that fully ‘indigenous’ innovation is not possible, even if it were politically desirable.EU-China innovation relations, as well as those between Washington and Beijing, therefore need careful management. But both Americans and Europeans should have more confidence in their innovation capability, given the relative strengths and weaknesses of Chinese innovation.Americans and Europeans should acknowledge and promote the opportunities that come from globally networked innovation processes. Taking advantage of the comparative advantage of all the players in these networks means working with China as an innovation partner. Full Article