Richard Moeckel and Richard Montgomery
J. Amer. Math. Soc. 38 (), 225-241.
Abstract, references and article information

Alexander Kupers and Oscar Randal-Williams
J. Amer. Math. Soc. 38 (), 63-178.
Abstract, references and article information

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.

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.

Russia-China Defence and Security Relations

This project explores the military and security linkages between Russia and China.

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.

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.

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.

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.   

China’s high-stakes incursion in the heights of Bhutan The World Today mhiggins.drupal 28 September 2022

Why is Beijing establishing settlements over the Bhutanese border? To undermine India’s strategic security, say John Pollock and Damien Symon.

A confrontation is fomenting on the roof of the world in a country that rarely warrants international attention.

In the tiny Kingdom of Bhutan, China is building villages in isolated, mountainous regions, upping the pressure on the capital Thimphu to yield contested areas to Beijing. In doing so, China risks a collision with South Asia’s largest state and Bhutan’s principal security guarantor, India.

Sitting on top of fragile geopolitical fault lines in the Himalayas, China’s Central Military Commission has seemingly authorized a series of incursions into the Bhutanese regions of Doklam, Jakarlung, and Pasamlung. Beijing has also announced fresh claims in the east towards Sakteng. Taken together, these amount to 12 per cent of Bhutan’s total territory according to Nathan Ruser, an analyst at the Australian Strategic Policy Institute.

India is wary of Beijing’s increased assertiveness in the Himalayas following a large-scale incursion by the Chinese People’s Liberation Army (PLA) into Ladakh two years ago when dozens of Indian and Chinese soldiers were killed in a stand-off.

The appearance of Chinese roads, villages and a host of other infrastructure projects within largely uninhabited areas of Bhutan close to Tibet, have, for sections of India’s national security establishment, confirmed their worst fears – Beijing is altering the status quo across the Himalayas in a bid to undermine India’s strategic security through territorial alterations.

As a country of only 780,000 people, Bhutan is greatly influenced by New Delhi when it comes to its foreign affairs. In exchange, India guarantees the defence of the kingdom and trains the Royal Bhutanese Army. The appearance of Chinese villages on its territory risks Bhutan becoming a victim of the wider regional tensions.

The trauma of China-Bhutan border relations

Bhutan is no stranger to the territorial aspirations of its northern neighbour. Thousands of refugees fled into the country after China annexed Tibet, damaging longstanding cultural and religious links between the Tibetan and Bhutanese people – a trauma still being felt today.

Now, Beijing is laying claim to three areas within Bhutan, including Doklam in the west. This plateau is close to the Siliguri Corridor which connects to the ‘Seven Sister’ states in northeast India. Indeed, such is India’s concern over any Chinese presence near Doklam that in 2017 local Indian commanders sent troops into Bhutan to prevent PLA engineers building a road near the Doka La pass, resulting in a 72-day stand-off on Bhutanese soil between India and China, an experience Thimphu is unwilling to repeat.

Once again, China is looking to force the border issue unilaterally, altering the status quo and building villages and outposts on Bhutanese soil. On the available evidence, it has been doing so for at least three years.

The presence of Chinese villages in uninhabited areas of Bhutan serves a strategic purpose. They appear to be intended to pressure Bhutan into accepting an earlier version of a border deal that concedes Doklam to the Chinese.

Bhutan’s increasing concern is that China now views the Sino-Bhutanese border dispute as a way of unravelling India’s strategic position by stealth. Here we see a growing pattern of behaviour across the Himalayas. China is testing the boundaries in isolated and contested areas of India to attain local advantages that ensure New Delhi’s gaze remains fixed on the Himalayas.

The costly choice facing Bhutan

Bhutan for its part has very deliberately opted to remain silent, despite clear violations of its border deal with Beijing. Thimphu has made no public comment on any of the Chinese incursions.

The choice now facing Bhutan is a costly one. To concede Doklam would devastate relations with India, its closest partner. But to ignore China’s ambitions would be to risk further violations of its sovereign territory.

Bhutan may yet agree in principle to a land swap but then delay its implementation in the hope China limits any further advances. Thus Bhutan, India and China stand at a crossroads, with an impending confrontation that has not yet arrived and one that through Thimphu’s delicate diplomacy, Bhutan hopes never does.

China’s incursions into Bhutan

1. Pangda

The most high-profile incursion is in the disputed areas in Doklam. Running adjacent to the previous Doka La stand-off site, a series of Chinese projects are visible, following the Amo Chu River that runs from the Chumbi Valley in Tibet into Bhutan.

The most well-known of these xiaokang – meaning peaceful and prosperous – border projects is Pangda, a village of 124 people that sits roughly two kilometres within Bhutan from the border. First spotted by open-source intelligence analysts in October-November 2020, Chinese state media says that 27 households were moved from the Shangdui village to Pangda in September of that year and that the village is located in Yadong County, Tibet. Pangda, however, lies on territory internationally recognized as belonging to Bhutan.

Since Pangda was first identified, two more villages and an additional excavation site have been noted through satellite photographs taken in March this year, steadily following the river further into Bhutanese territory. In recent reporting by journalist Vishnu Som, a connecting road is also visible that runs 9km into Bhutan.

Given the geopolitical sensitivities of the area vis-a-vis India, speculation points to Chinese attempts to increase pressure on the Jampheri ridge overlooking the 2017 stand-off site, which according to journalist Tenzing Lamsang, is currently occupied by a small Royal Bhutanese Army detachment. As ever in the Himalayas, small tactical alterations have strategic implications. Chinese control of the Jampheri ridge would command views towards Sikkim, increase the scope of China’s surveillance operations near the border and place India’s Eastern Theatre Command at a terrain disadvantage were it to intervene as it did at Doka La.

2. Dramana and Shakhatoe

Further north of Doklam, at Dramana and Shakhatoe, more villages have been identified, with recent photographs taken in November 2021 showing a collection of structures nestled between snow-capped mountains. Varying in size, the largest village identified by journalist Devjyot Ghoshal comprises more than 84 buildings with construction having been started in December 2020 and seemingly completed by December 2021.

Little is known about the nature of these villages or their occupants other than their size and location. However, the Chinese PLA has patrolled these areas aggressively, warning away Bhutanese herders and challenging counter patrols by the Royal Bhutanese Army.

A permanent PLA presence in the area would be a significant change to the status quo. Informed speculation suggests that these may house either civilian contractors brought in from Tibet to oversee construction projects in the area, Tibetan or Chinese citizens brought across the border, or they could even be barracks for the PLA to help facilitate increased patrols in these contested areas.

3. Menchuma Valley

Amid the sustained activity in the west of Bhutan, we are seeing similar levels of activity mirrored in the northern contested areas in Jakarlung, Pasumlung and the Menchuma Valley, a well-known entry point into Tibet for Bhutanese pilgrims.

In May 2021, a team of researchers led by Robert Barnett from the London School of Oriental and African Studies discovered three additional villages in these contested areas, alongside a series of infrastructure projects, sitting between 3km and 5km south of the Chinese border in Bhutan. Barnett identified what appears to be police and military posts near these villages, as well as a communications tower.

While the building efforts at Doklam are seen as having a geopolitical intent towards India, these villages and their locations are seemingly aimed to maximize China’s leverage over Bhutan. They are considered sacred in Tibetan Buddhist teachings as the birthplace of ancient Himalayan cultural heroes, with strong links to the Bhutanese royal family. Today they are the home to holy sites and temples, such as the Singye Dzong.

For China to intrude on this area, and in some cases even deny entry to parts of it, is suppression of Bhutanese history, culture and traditions. By design or by default, Beijing is managing Tibetan religion and culture beyond the borders of the Tibetan Administrative Region.

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’.

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.

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.

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.

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.

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.

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.

Review: The Cultural Revolution still haunts China The World Today mhiggins.drupal 30 January 2023

Tania Branigan’s searching ‘Red Memory’ reveals the costs to Chinese society of not addressing that upheaval’s lingering injustices, writes Nathan Law.

Red Memory: Living, Remembering and Forgetting China’s Cultural Revolution
Tania Branigan, Faber, £20

The Cultural Revolution, a decade-long socio-political upheaval initiated by Chairman Mao Zedong in 1966, caused as many as two million deaths and reshaped China. Under the influence of Mao’s personality cult, an entire nation was mobilized to purge the ‘reactionary elements’ in society and the Chinese Communist Party through public denunciation and demolition of traditional heritages.

Children turned on their parents; pupils murdered their teachers, and those who survived the summary public trials were often banished – as a young Xi Jinping himself was, living in a cave for seven years, after his father fell from favour.

Impossible moral choices

In her engaging and sensitive narrative account of the revolution’s upheaval and its consequences, Tania Branigan, the Guardian’s China correspondent between 2008 and 2015, speaks to some of those who survived those terrible years, considers their impossible moral choices and explores the far-reaching legacy of the revolution in present-day China.

Mao urged the party to cleanse itself of its ‘class enemies’: ‘capitalists’ such as landowners and shopkeepers, but also artists, farmers and university professors. Often their family members were tainted by association and persecuted. Branigan captures the awful sense of intimate betrayal and tragedy nowhere more than in the testimony of Zhang Hongbing, a lawyer turned zealous Red Guard.

Zhang denounced his mother, a hospital worker, as a ‘counter-revolutionary’ because her father owned land. She was eventually executed but not before her son struck her twice during her arrest to show his party loyalty. ‘What I did to my mother was worse even than to an animal,’ the remorseful Zhang tells Branigan.

Zhang points out that his actions were far from uncommon: ‘The whole country was doing it.’ This unreconciled sense of betrayal and fear still blights China: ‘Our society is ethically hollow. If we trace these problems to their roots, we are likely to find them in the Cultural Revolution,’ one survivor is quoted as writing.

Branigan encapsulates the difficulties around reconciliation and remembering in the story of Song Binbin. As a schoolgirl in 1966, she and two classmates were the first to pin up a poster attacking teachers for urging students to focus on their work instead of the revolution. Song’s classmates then beat the school vice principal Bian Zhongyun to death in the playground. The case was never properly investigated, and the death was dismissed as an accident.

The pain of remembering

In 2014, Song apologized publicly for the poster and expressed a sense of guilt for not intervening on Bian’s behalf. But Bian’s widower rejected the apology. Song did not speak to Branigan herself, instead allowing her friends to speak in her defence. ‘They had spoken of truth and reconciliation, but not once of justice. Every remark brought them towards closure, not accountability,’ Branigan writes.

The inability to come to terms with the past pervades the book, most of whose interviewees express feelings of resentment, fear and shame about the Cultural Revolution. I sensed the same emotions when, as a boy, I talked to a neighbour in Hong Kong who was then in his 70s. He escaped from China in the late 1960s due to political and economic strains. He simply nodded and fell silent when I asked him to elaborate.

As Branigan writes: ‘Most Cultural Revolution survivors had learnt to bend with the will of the time; not only to do as they were told but to imply that doing so was their own idea. It was better – safer – to stay silent or lie.’

This collective trauma is exacerbated by official unwillingness to address the past. The Cultural Revolution warrants no more than a few paragraphs in official textbooks with no mention of the suffering it unleashed. Documents of the period that might tarnish the CCP remain unavailable; any attempts to interrogate the Cultural Revolution are condemned as ‘historical nihilism’ by the party.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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?

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? 

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?

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.

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. 

A world in transition and the future of the global workforce 15 October 2024 — 9:00AM TO 10:00AM Anonymous (not verified) 22 August 2024 Chatham House and Online

How are migration and global megatrends shaping international labour?

As the fallout of 2024’s ‘Election Super-Year’ becomes clearer, international policymakers and business leaders must now equip themselves to face the challenges and opportunities of the three key transitions that will dominate the next few decades: the journey toward a greener and healthier world; the transition to a more technologically adept society; and the development of a secure and productive economy for all.

The adaption and evolution of the global workforce is an essential component of all three of these transitions and therefore a prescient analysis of how migration, workforce policies and modern technology trends will impact this ecosystem is essential.

Upskilling the workforce will no doubt remain a key focus for stakeholders. But the question remains, how do these plans move beyond the ‘ideas-phase’ and become policies that will keep pace in the fast-paced, modern and digital workplace?

It may prove harder than ever for these ideas to come to fruition, with the rise of populist and nationalist political thinking fragmenting the balance between local and international labour. Indeed, this often leads to reduced attractiveness of skilled foreign labour in domestic markets.

This puts global business in a very powerful position though, as companies can play an important role in readdressing these narratives, shaping the future of workforce policies and using examples of best practice to improve access, mobility and ultimately economic productivity, for the benefit of all.

Through this event, in partnership with EY, the panel analyses how migration, skills development agendas and global megatrends, such as technology, sustainability and the global economy, will shape developments in the years to come.

A networking breakfast precedes this event, served between 0800 and 0900 BST.

Member’s question time: Is Russia losing the South Caucasus? 22 October 2024 — 1:00PM TO 1:30PM Anonymous (not verified) 2 September 2024 Online

Join us and ask Chatham House Senior Research Fellow, Natalie Sabanadze anything about the situation in the Caucasus. Submit your questions in advance.

Whilst Russia focuses on its illegal invasion of Ukraine, the situation at its southern border is evolving. Relations between the three states in the South Caucasus and Moscow have never been easy as Russia tried to maintain its dominance by leveraging vulnerabilities, playing one side against another to keep conflicts simmering and even engaging in open military aggression.  Although the violence seen in the 1990s and early 2000s has abated, the war in Ukraine has had an indirect impact on the region, bringing a change to the status quo.

Russia abandoned its long-standing support for Armenia, allowing for the collapse of Nagorny-Karabakh and the restoration of the territorial integrity of Azerbaijan with the backing of Turkey. As a result, Azerbaijan has emerged as a dominant regional player with Baku recently declaring its interest to join BRICS.  Turkey’s influence has grown, while Armenia frustrated by Russia’s change of heart has been turning cautiously towards the EU and the US.

In Georgia, meanwhile, the ruling party has been consolidating its grasp on power, rolling back democratic reforms and pivoting away from the West. Georgia’s long-awaited European integration process has been suspended, following the adoption of the Russian-style foreign agents legislation.

Join us as our Senior Research Fellow in the Russia and Eurasia Programme answers your questions in this quick-fire session assessing the extent to which the Russian influence has changed since the start of the invasion of Ukraine and who is there to fill the vacuum; how geopolitical contestation in the region is going to impact aspirations of Armenia, Azerbaijan and Georgia; and much more.

Submit your questions to Natalie Sabanadze in advance of the event. Your questions will drive the conversation.

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.

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.

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 2024 US Election: Global Consequences 26 September 2024 — 5:30PM TO 6:45PM Anonymous (not verified) 17 September 2024 Online

This webinar explores what is at stake for US policy in key regions around the globe.

In the lead up to the 2024 US presidential election, Chatham House experts discuss:

• What is at stake for US policy towards China, Europe, and Latin America and what challenges will confront the next US president?

• Can the US lead when its partners and allies are continually dissatisfied by the new turn in its trade and economic policy?

• What are the core humanitarian challenges and how can they be addressed?

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?

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.

Business Briefing: US election geopolitical and economic risk scenarios 10 October 2024 — 11:45AM TO 1:00PM Anonymous (not verified) 23 September 2024 Chatham House

Please join us for this critical discussion of the US Election related global business risks.

The outcome of the US presidential election will have significant, intersecting implications for global as well as American business. At stake will be the degree of continuity and stability on both the domestic and international fronts, with a Harris presidency pursuing policies building broadly on the Biden Administration and a second Trump Administration departing sharply from them—with both shaped and limited by control of Congress.

An already volatile geopolitical environment and global economy may become even more unpredictable in the face of potential American political instability and uncertain leadership in the international community.

Please join us for this critical session to discuss:

• How might trade policy differ between a Harris and Trump presidency? Will national security pressures, especially over China, lead to greater policy commonalities than expected?

• What might differing approaches to decarbonization and the energy transition mean for the future of policy toward EVs, critical mineral supply chains, and ‘green’ industrial subsidy?

• How might each Administration approach fiscal policy? Will either push for a tightening to the current loose policy—and what may be implications for US debt and the dollar?

• What economic effects can we expect in the case of a disputed election result or non-peaceful transfer of power—and will Corporate America be compelled to make public statements?

Looking ahead to the 2024 US Presidential Election 2 October 2024 — 6:00PM TO 7:00PM Anonymous (not verified) 23 September 2024 Chatham House and Online

This panel explores the state of the US presidential election following the vice presidential debate.

With only weeks to go, this panel looks at the state of the 2024 US presidential election.

Harris and Trump are campaigning to drive up voter enthusiasm and bring undecided voters to their side.

What are the key issues shaping voter’s preferences and how may this impact voter turnout? What can we expect in the weeks ahead?

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?

Civilian priorities for ending the war in Sudan 31 October 2024 — 12:30PM TO 1:30PM Anonymous (not verified) 8 October 2024 Chatham House and Online

Dr Abdalla Hamdok, former prime minister of Sudan and chairperson of the Coordination of Civil Democratic Forces (Tagadum), will discuss the prospects for conflict resolution in Sudan.

The intensification of fighting across Sudan demonstrates that both warring parties and their allies are continuing to pursue an outright military victory in the war, with little regard for the human cost. Diplomatic efforts, including the US-led Geneva talks in August, have produced little progress towards a ceasefire.  Meanwhile, the conflict has resulted in widespread devastation, mass displacement, and an escalating hunger crisis.

Civilian perspectives on ending the war, their vital efforts in providing lifesaving humanitarian assistance, and the aspiration of many Sudanese for a more inclusive and democratic Sudan, have been sidelined by the interests and actions of the belligerent parties.

At this event, Dr Abdalla Hamdok will discuss options for reaching a ceasefire and seeking a peaceful political resolution to the conflict. He will also address the urgent need for an international response to what has become the world’s largest humanitarian crisis.

Please note that in-person attendance for this event will be balloted. Guests looking to join in-person must ‘register interest’ in joining. Full confirmations to successful applicants will be sent on Monday 28 October at 15:00.

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.

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.

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.

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.

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.

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.

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.

Ligand bias is the ability of ligands to differentially activate certain receptor signaling responses compared with others. It reflects differences in the responses of a receptor to specific ligands and has implications for the development of highly specific therapeutics. Whereas ligand bias has been studied primarily for G protein–coupled receptors (GPCRs), there are also reports of ligand bias for receptor tyrosine kinases (RTKs). However, the understanding of RTK ligand bias is lagging behind the knowledge of GPCR ligand bias. In this review, we highlight how protocols that were developed to study GPCR signaling can be used to identify and quantify RTK ligand bias. We also introduce an operational model that can provide insights into the biophysical basis of RTK activation and ligand bias. Finally, we discuss possible mechanisms underpinning RTK ligand bias. Thus, this review serves as a primer for researchers interested in investigating ligand bias in RTK signaling.

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.

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.

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.

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.

• 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.