Marcelo Campos, Matthew Jenssen, Marcus Michelen and Julian Sahasrabudhe
J. Amer. Math. Soc. 38 (), 179-224.
Abstract, references and article information

Junyi Xie
J. Amer. Math. Soc. 38 (), 1-62.
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.

China Party Congress: Xi’s political blueprint The World Today rescobales.drupal 28 September 2022

In the second of her three-part series on the 20th National Congress of the Chinese Communist Party, Yu Jie outlines two key policy themes we can expect Xi to define: ‘common prosperity’ and ‘self-reliance’.

What can we expect from the Party Congress?

In mid-October five years ago, the 19th Party Congress opened with Xi Jinping delivering a political report lasting three-and-a-half hours. He will repeat the performance on October 16, the opening day of this year’s 20th Party congress.

Bland as its name may be, this political report is one of the Party Congress’s core items of business. It remains the most authoritative public account of the Chinese Communist Party’s path on all major policy fronts, containing a laundry list of policies undertaken by the outgoing Central Committee in the past five years, while putting forward guidance for future policy.

It represents the view of the current Politburo Standing Committee and that of the CCP. The 20th Congress report is a collegial effort and should not be considered Xi’s personal manifesto, nor should it be counted as another of his speeches to his comrades.

However, as general-secretary of the party for the past decade, it will most probably reflect many of the elements that Xi has influenced.

What are China’s political priorities?

No matter how complicated the geopolitics of the world becomes, Xi sticks to the conservative approach that has served his country well for past centuries: that China prioritizes the management of its own affairs.

Since the Cold War ended, two recurring themes have dominated the political report: the economy and security. For the 20th session, Xi will use the phrases ‘common prosperity’ as shorthand for the economy and ‘self-reliance’ for security.

Xi introduced the slogan ‘common prosperity’ at the start of his third term in August 2021. His aim was to close the income gap, address regional economic inequality and improve social welfare provision. Rebalancing social inequality was seen as essential to avoid the social disruption witnessed in other parts of the world.

Xi’s concept of ‘common prosperity’ was influenced by his childhood experiences living in exile in a remote village in Shanxi Province, in northwest China, during the Cultural Revolution. The ensuing upheaval was to prove a tragedy for his family and a disaster for the country.

His ambition is to define progress not in terms of producing double-digit growth but in dealing with the long-standing challenge of scarcities across different sections of society to meet ‘people’s ever-growing needs for a better life’. This direction was indicated at the 19th Party Congress by the term ‘shifting the principal contradiction’.

What state is the Chinese economy in?

Xi may have arrived at the right diagnosis but he has so far failed to find a cure that invokes ‘common prosperity’. After sweeping regulatory measures, the CCP has clamped down on its most successful private companies and spooked investors. While providing 80 per cent of China’s jobs, private enterprises are worried that the ‘common prosperity’ initiative may jeopardize their business.

Equally, Beijing’s zero-Covid policy has discouraged much-needed investment and failed to win the hearts and minds of Chinese youth, who have suffered most, both economically and socially.

The challenge facing Xi over the next five years will be to manage the financial risks in downsizing China’s property sector while coming out of a rigidly imposed Covid lockdown without reducing economic growth to such an extent that it damages the personal wealth of millions of people.

One hopes that Xi’s policies in future will be based on an innovative reading of the first-century phrase ‘seeking truth from facts’ adopted by Mao Zedong and last promoted as the political philosophy of Deng Xiaoping in the Seventies. A healthy market economy is not only essential for China’s development but as the only means of maintaining the party’s legitimacy, something vital for Xi.

Does China need more security?

China’s weakened export markets and less-friendly relations with the United States have encouraged it to become more self-reliant. Expect an emphasis on greater self-sufficiency in sectors of strategic importance to form a substantial part of this year’s political report.

In view of increased international hostility, Xi and his lieutenants have publicly recognized the need to take control of production and supply chains. These supply chains need to become ‘self-determined, self-controlled’ they have said, voicing frustration that the highest value-added elements of the Chinese tech sector remain reliant on overseas suppliers and vulnerable to geopolitical tensions.

Equally, on food and energy security, Russia’s invasion in Ukraine has exacerbated China’s already fragile food supplies as both countries are vital sources of food imports. Xi has already called for a ‘comprehensive thrift strategy’ to manage China’s food and energy needs.

Beijing is equally worried about the increase in oil and commodity prices which is driving up the cost of living. This may push parts of Chinese society out of ‘common prosperity’ and into ‘common poverty’, as it threatens to in some parts of Europe.

For the next five years, Xi needs to strike a balance between ‘common prosperity’ and ‘self-reliance’ to mitigate the storms ahead. He cannot afford to lockdown the world’s second largest economy indefinitely.

The hope is that the 20th Party congress will bring much-needed course corrections.

Read the two further articles in this series: the first provides a guide to why the Chinese Communist Party Congress matters; the third analyses the foreign policy issues likely to be discussed at the congress.  

Xi Jinping shows the world he is taking a tougher line Expert comment NCapeling 16 October 2022

Xi opens the 20th National Congress of the Chinese Communist Party with a political report which demonstrates both change and continuity in the approach of his leadership.

The 20th Party Congress report is significantly shorter than the 19th, which is a clear indication of Xi’s success in centralizing power. The report acts as a summary of the party’s achievements and its plans – expressed as the lowest common denominator of consensus between competing factions. A shorter political report would seem to represent fewer factions now seeking consensus.

In the 20th Party Congress report, the language on Taiwan has been revised, reflecting the changes in tone and the policies of the CCP senior leadership. In addition to the conventional ‘peaceful reunification’ term, there is also an addition of more hawkish language on Taiwan to ‘not exclude the use of force as a last resort’.

Xi also suggested that ‘resolving Taiwan Question should be in hands of the Chinese’, sending a further warning to the US and other Western allies which are perceived as interfering in Taiwan affairs.

In his remarks, Xi suggested the ‘zero-COVID’ strategy has worked for China although he gave no clear timeline on when the policy will end. He also proposed building a healthcare system able to cope with future pandemics. This implies that China is still in short supply of sufficient healthcare resources to cope with a disease like COVID.

Economic policy reveals anxiety

On economic policy, much of the emphasis is given to the extent to which security and economic growth should go hand in hand, which illustrates Beijing’s deep anxieties on supply chains and the high-tech sector. These supply chains need to become more ‘self-determined, self-controlled’, voicing frustration that the highest value-added elements of the Chinese tech sector remain reliant on overseas suppliers and vulnerable to geopolitical tensions.

Also, he expected the Common Prosperity Initiative will further adjust uneven income distribution to increase the amount of middle-income population. He gave little favours for financial services and fin-tech companies but insisted that China should remain as a manufacturing-led economy with qualitative growth. That implies Beijing will tolerate much slower growth so long as the income gap between the rich and poor is closing.

On foreign affairs, Xi has completely abandoned the ‘new types of great power relations’ – instead he has stressed that China should further develop its ties with the Global South through the Global Development Initiative and the Global Security Initiative.

Xi Jinping prepares the Communist party for new reality Expert comment NCapeling 20 October 2022

Political report reflects a worsened economic and diplomatic position as Xi knows his unprecedented third term as leader will be judged on results.

In stark contrast to the aura of triumphant glory that greeted Xi Jinping at the last National Congress of the Chinese Communist Party in 2017, this week’s convocation opened with an air of sobriety.

Amid a domestic economic downturn and a return to enmity with Western liberal democracies, Xi offered his own recipe for party legitimacy and the country’s economic survival in the lengthy executive summary of his political report to the CCP congress. The prime keyword was security, with some 73 mentions, underscored with a message of self-reliance.

The periodic report acts as a summary of the party’s achievements and of its future plans, with both expressed as the lowest common denominator of consensus between competing voices in the CCP. It thus typically sheds some light on relationships among senior party members and insights into the political fortunes of important intraparty groups.

Most portions of the new report combined Xi’s personal preferences with concessions to the reality of what is necessary for China’s economic survival. Both ends point to an urgent prioritization of economic and political self-reliance for Xi’s third term as party general secretary.

Holistic concept of security

On the domestic front, much emphasis was given to enhancing national security and promoting equitable growth.

Since even before COVID-19, Xi has advocated a holistic conceptualization of security that includes food, the internet, energy and manpower. Reflecting Beijing’s deep anxieties about high-tech development and its frustrations with dependence on overseas suppliers vulnerable to the vagaries of geopolitical tensions, the political report noted the need for China’s supply chains to become more “self-determined and self-controlled.”

Xi, though, went further to stress the importance of improving scientific education and grooming and attracting the necessary talent to accelerate China’s quest to achieve breakthroughs in semiconductor production and overcome development choke points created by Western technological monopolies.

As China has traditionally relied on connectivity with the rest of the world to support innovation and attract talent, a turn toward autarky is not a viable option, given Xi’s technological priorities. Yet the renewed mention of his ‘dual circulation’ strategy in the report signals that Beijing is indeed turning to domestic consumption and homegrown technological prowess as the means to provide the rising wealth that the Chinese people have come to expect from the Communist Party.

Worsening Sino-US relations and tightening access to overseas markets for Chinese companies have prompted party leaders not only to reconsider the country’s sources of economic growth but have also forced them to reconfigure their approach to foreign affairs.

Judging by his report summary, Xi has completely abandoned the ‘new type of great power relations’ concept used repeatedly in the last two editions of his congressional update to refer to his preferred approach to relations with the US-led West.

The omission shows that Beijing has concluded that its fraught relationship with advanced developed nations is here to stay, with little prospect of improvement soon. To this end, China needs to prepare for the worst of decoupling and become more self-reliant in terms of markets and technologies.

In place of the discarded concept, Xi stressed that China should further develop its ties with the global South through the Global Development Initiative and the Global Security Initiative he announced earlier this year. These efforts aim to reshape the global governance agenda in multilateral forums and to project Beijing’s influence on the developing world.

Meanwhile, the party’s latest official rhetoric about the Belt and Road Initiative shows it is no longer a one-size-fits-all slogan but on its way to becoming a genuine tool of trade and investment promotion with China’s near neighbors but with provincial governments taking the lead rather than Beijing.

With the central government grappling with the country’s domestic economic woes, its spending spree on development assistance has had to come to an end. The new political report clearly signals this change.

A modern socialist society is still the aim

The current economic downturn and dangerous geopolitical tensions have not dented the CCP’s ambitions to build a modern socialist society by 2035 and thus join the world’s club of upper middle-income countries, but this is easier said than done.

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.

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?

Director’s Briefing: Assessing foreign policy challenges for the next US president 5 September 2024 — 2:00PM TO 3:00PM Anonymous (not verified) 27 August 2024 Chatham House and Online

This briefing will explore what challenges might await the winner of 2024 US presidential election.

As the 2024 US Presidential election draws closer, the future direction of American foreign policy seems ever more uncertain. Kamala Harris, the Democratic presidential candidate, appears to be embracing many of Biden’s policies, but she brings a different background, and most likely a different team, so change is likely.  Donald Trump has more well-known views on foreign policy, but the context for a second Trump administration would be very different than the first.

The next U.S. President will be confronted a world in need of leadership with two major wars, a more assertive and capable China, a climate crisis, ungoverned technological change, emerging powers that demand a seat at the table, and debt distress across much of the developing world.

Please join us for this critical conversation covering:

• How will US-China strategic competition and the threat of conflict over Taiwan challenge US policy makers?
• What are the risks and challenges posed by Russia’s illegal full-scale invasion of Ukraine?
• How does war in the Middle East and the threat of regional escalation shape US foreign policy?

Is the world ready for the next pandemic? 29 October 2024 — 6:00PM TO 7:00PM Anonymous (not verified) 9 October 2024 Chatham House and Online

In a joint event with The Elders, Helen Clark, Ban Ki-moon and other experts discuss the policies needed to prevent the next health catastrophe. A drinks reception will follow this event.

The world faces multiple interlinked existential threats such as pandemics and the climate crisis, exacerbated by conflict and extreme poverty. However, the multilateral system is failing to respond with sufficient urgency or impact. As the fifth anniversary of the COVID-19 pandemic approaches, Chatham House and The Elders will discuss the risk of a general slide into complacency. 

Amid the expanding outbreak of mpox in Africa, rich countries continue to withhold stockpiled mpox vaccines. The failure to release the required amount is contributing to the diseases spread across the continent. 

Meanwhile, the Pandemic Accord negotiations are in overtime, with nations unable to reach agreement over concerns around sovereignty and resource distribution in any future pandemic. Similarly, a proposal to include a UN Emergency Platform in the recent Summit of the Future to strengthen the multilateral response to complex global shocks was shelved due to political deadlock.

Can the world learn from past mistakes and break the cycle of panic and neglect? In today’s fractious and polarized geopolitical context, what would it take for leaders to do what’s necessary? And why is it so critical to have equity at the heart of any sustainable global response?

Join Chatham House for this event in which the panel discuss key questions including:

• Five years on from COVID-19, who is showing global leadership today in preparing for future pandemics?
• Are international organizations and institutions fit for purpose to respond to pandemics in a multipolar geopolitical environment? How can they best adapt?
• What can be done to clarify and detoxify current debates around sovereignty to improve global pandemic prevention, preparedness and response?

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 novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) has emerged to a pandemic and caused global public health crisis. Human angiotensin-converting enzyme 2(ACE2) was identified as the entry receptor for SARS-CoV-2. As a carboxypeptidase, ACE2 cleaves many biological substrates besides angiotensin II to control vasodilatation and vascular permeability. Given the nanomolar high affinity between ACE2 and SARS-CoV-2 spike protein, we investigated how this interaction would affect the enzymatic activity of ACE2. Surprisingly, SARS-CoV-2 trimeric spike protein increased ACE2 proteolytic activity ∼3-10 fold against model peptide substrates, such as caspase-1 substrate and Bradykinin-analog. The enhancement in ACE2 enzymatic function was mediated by the binding of SARS-CoV-2 spike RBD domain. These results highlighted the potential for SARS-CoV-2 infection to enhance ACE2 activity, which may be relevant to the cardiovascular symptoms associated with COVID-19.

In their comment (1) on our publication (2), the authors make two points: (i) they raise concerns about the possible effect of residual NONOate in our study, and (ii) they promote nitrosylcobalamin (NOCbl) supplied by their own company. Both points lack merit for the following reasons. The authors make the astonishing claim that the spectra of nitric oxide (NO•) and cobalamins overlap. Unlike NO•, cobalamin absorbs in the visible region, permitting unequivocal spectral assignment of NOCbl as reported (3). We demonstrated that whereas NOCbl is highly unstable in solution, it is stabilized by the B12 trafficking protein CblC. So even if present, residual NONOate (which is unstable at neutral pH and is removed during the work-up (3)) could not account for the observed difference.The authors then misrepresent our synthetic method, claiming that anaerobic conditions were used to generate nitrocobalamin (NO2Cbl), which results in the transient formation of NOCbl. We synthesized NO2Cbl aerobically using nitrite as described (4); NOCbl is not an intermediate in this ligand exchange reaction. The aerobic instability of NOCbl has been rigorously described by inorganic chemists (3, 5) and raises obvious questions about its purported biological effects as exemplified by the authors' own 2003 JBC publication, which was later withdrawn.As to promoting NOCbl from their company, the authors refer to a synthetic route from a mixture of NO• gas and aquocobalamin. The authors' method (6) has been described as “dubious” by chemists (5). Whereas DEAE NONOate used in our method is widely known as an NO• donor,...

After a thorough read of this paper (1), we wish to clarify that the authors' anaerobic method of synthesis for the production of nitrocobalamin results in the transient formation of nitrosylcobalamin, an unstable intermediate upon exposure to air. We concur that the authors' method results in the production of nitrocobalamin based on the UV-visible data as shown. The authors' adapted anaerobic method consists of mixing hydroxocobalamin hydrochloride with diethylamine NONOate diethylammonium salt in aqueous solution. Of concern, the UV spectrum of nitric oxide overlaps that of all cobalamin species under anaerobic conditions, making any assignments of the binding of nitric oxide to hydroxocobalamin suspect (2). Additionally, the use of acetone to precipitate the authors' product causes precipitation of diethylamine NONOate, resulting in an impure product. As a result, its utility for drawing experimental conclusions is faulty.The product from the authors' anaerobic synthetic method has not been assessed for purity, and the synthetic method itself has not been validated using a stability-indicating method as required by the International Conference on Harmonization (ICH) (ICH Q2B, Validation of Analytical Procedures) methodology, which is a hallmark for analytical characterization. Our nitrosylcobalamin synthesis involves reacting nitric oxide gas with hydroxocobalamin acetate as a heterogeneous mixture in a non-electron-donating solvent followed by rotary evaporation. Our nitrosylcobalamin product is stable in air, releases nitric oxide gas in situ (3), and meets ICH stability guidelines (4). Additionally, our nitrosylcobalamin product demonstrates biological activity, which has not been observed for nitrocobalamin (3, 5).

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.

Brexit: Implications for EU–China Relations Research paper sysadmin 10 May 2017

For Beijing, the EU–China relationship will take priority over UK–China ties – with China’s relative focus on Germany becoming even more significant.

Summary

• The extent of current UK relations with China means that Brexit will notably reduce the scale and diversity of overall EU–China economic and commercial interactions. But the impact will vary across different areas.
• In policy terms, liberal voices on economic policy towards China will be somewhat weaker among the post-Brexit EU27. Brexit will not be the most important factor determining the future level of strategic coherence in EU policy towards China.
• The impact on post-Brexit EU27 trade with China will be felt both in the volume of trade and its composition. Following Brexit the EU will no longer be China’s largest trading partner.
• There will be some relative shift in Chinese investment in Europe away from the UK, though over time the impact of Europe-wide policy approaches to Chinese investment will have more impact than Brexit per se.
• EU–China educational exchanges will be weakened after Brexit, but inbound Chinese tourism will be less affected by Brexit.
• By 2025, the EU will have compensated for Brexit’s impact in some areas, but much depends on the EU’s own trajectory over the next decade.
• For Beijing, the EU–China relationship will take priority over UK–China ties. Within the EU, China’s relative focus on Germany will be even more significant.

International Arbitration: Exploring India’s Potential 15 November 2019 — 9:30AM TO 5:30PM Anonymous (not verified) 17 October 2019 Chatham House | 10 St James's Square | London | SW1Y 4LE

As India’s economic clout grows, so does its aspiration to become a favoured arbitration destination in a globalized world dominated by foreign investments flows and cross border transactions. India’s bid to enhance its status as an arbitration destination depends largely on the suitability of its legal environment in meeting the demands of an increasingly sophisticated approach to disputed resolution. This conference will assess these, and other related, issues.

To register your interest in attending this event, please contact Nisha Ramdas by phone +91 9650977833 or by e-mail nisha@globaldialoguereview.com.

US midterms: What to expect? Expert comment LJefferson 4 November 2022

The 2022 midterms have a heightened importance with long-term implications for the future of American democracy.

US voters will head to the polls on 8 November 2022 to cast their ballots for the midterm elections, which will see 35 of 100 Senate seats and all 435 seats in the House of Representatives up for re-election.

Midterm elections serve as a benchmark on voter’s approval of the sitting president’s party, but following a turbulent 2020 presidential election, with claims of a stolen election and voter fraud, the midterms have taken on a heightened importance with the processes and results having long-term implications for the future of democracy in the US.

When will we see results?

While many US voters expect to see results the night of an election, the complex voting process in the US often makes it difficult to ascertain the success of candidates in certain states after the polls close.

In Arizona, state laws allow 20 days for election officials to certify results while Nevada allows for additional time to count mail-in ballots following election day. Pennsylvania state laws prevent mail-in ballots from being counted before 7am on election day and the combined effect of counting in-person and mail-in ballots simultaneously, as well as the need to present votes to a state canvassing board could delay official results for weeks, and votes will not be officially certified by the state until 28 November.

In Georgia, the presence of a third-party candidate may lead to a run-off election if neither the Democrat or Republican contender receives over 50 per cent of the vote, which would take place on 6 December with results expected soon after.

Delays in determining election results may bolster claims made by Republican candidates that election results were fraudulent, especially if races are tight, as delays  counting mail-in ballots might cause results to differ over time. Early results favouring Republican candidates may also differ from the final tally as more mail-in ballots get counted, creating a ‘red mirage’, as the majority of Republican voters are expected to vote in-person, as seen in 2020.

In the vast majority of elections since World War II, the president’s party has often lost seats in the first midterm elections after taking office. While there have been exceptions and instances of the sitting party avoiding major losses during wartime, such as after the Gulf War and the 9/11 attacks, it’s unlikely Russia’s war in Ukraine will create the same rally around the flag effect.

Issues influencing voters

There are signs that US support for Ukraine on both sides of the aisle is starting to waver, as evidenced by the now recalled letter by the House Democratic Progressive Caucus pushing for a ceasefire and Republican House Leader, Kevin McCarthy’s recent comments about limiting US financial support for Ukraine.

US voters in general are more concerned with domestic issues rather than foreign policy, and both Democrats and Republicans have shaped their messaging around issues that will resonate with voters in key battleground states, with Democrats focusing heavily on abortion and reproductive rights and Republicans pushing the issues of crime and safety.

Democrats are hoping their focus on reproductive rights will motivate a higher turnout at the polls and have likely been encouraged by a recent referendum in Kansas where voters chose to protect abortion rights in the traditionally conservative state. In 2020, 52 per cent of the electorate in the swing state of Pennsylvania were female, and while not a huge majority, the difference could be enough to push the Democrats ahead.

Though the issue of abortion has gained more focus among Democratic voters, with 75 per cent of registered Democrats saying the issue was very important, 92 per cent of Republican voters rank the economy as their top issue.

The Senate race in Wisconsin, for example, was initially considered one of the Democrat’s most likely prospects for unseating an incumbent Republican senator, following US President Joe Biden’s win in the state in 2020.

Despite heavy fundraising from the Democratic party and a campaign visit by former US president Barack Obama, incumbent Senator Ron Johnson is now four points ahead of Democrat contender, Lieutenant Governor Mandela Barnes. A potential victory by Johnson, who has accused Barnes of being soft on crime and has shaped his messaging around growing the economy, may indicate whether  Democrats need to reshape their messaging ahead of the 2024 presidential election.

Threats of political violence

The risk of political violence in the US has increased in recent years, with many key officials under threat, as evidenced by the recent attack on US Speaker of the House, Nancy Pelosi’s, husband. A bulletin sent out by US agencies, including the Department of Homeland Security and the FBI, warned of attacks against not only political figures in the US, but also of attacks at locations like polling places, ballot box locations and voter registration sites.

The myth of a stolen election

Electoral integrity in 2022 has become especially significant, with over 300 candidates who believe the 2020 election was stolen up for election in various races across the United States.

The role of governors, secretaries of states and attorneys general (state officials charged with approving election results) has become a key issue in 2022. Proposals to give state legislatures the ability to certify election results, a role typically occupied by state officials, have already been made in Wisconsin, Pennsylvania and Arizona, all of which have Republican legislature majorities.

While these measures have not been successful thus far, a number of election deniers who would have the ability to influence how election results are certified are on the ballot for 2022. In Arizona, for example, Republican candidate for governor, Kari Lakes, and for attorney general, Abe Hamadeh have both been endorsed by Trump and have also supported his claims that the 2020 elections were fraudulent.

The Republican candidate for Arizona secretary of state, Mark Finchem publicly made calls to decertify Arizona’s electors, and was placed at receiving 49 per cent of votes in a poll conducted by CNN in early October. If Republicans are successful in both the state governor and secretary of state races, the role of the attorney general in certifying the election results in a state Biden closely won in 2020 becomes ever more crucial given their ability to govern how elections are run in the state, as well as their ability to challenge certification in court.

Director's briefing: What next for America? 17 November 2022 — 8:00AM TO 9:15AM Anonymous (not verified) 7 November 2022 Chatham House

Chatham House’s Director of the US and America’s Programme discusses what is next for America following one of the most contentious midterms races to date.

Hosted by Bronwen Maddox, Director, Chatham House, this Director’s Briefing is an opportunity to digest the outcomes of the US Midterm elections with Chatham House’s Director of the US and Americas Programme, Dr Leslie Vinjamuri. 

Arguably one of the most contentious midterm races to date, this election has key implications for the rest of the world also. At this event, Dr Leslie Vinjamuri and Bronwen Maddox will discuss the crucial themes coming out of the election and the key issues on voters’ minds. What impact will the results have on US foreign policy more broadly? What might the outcome of the election signal about Trumpism? And how confident can we be about the strength of US democracy?

This event is only open to Chatham House Partners and Major Corporate Members as well as selected giving circles of Chatham House. If you would like to attend, please RSVP to Linda Bedford at RSVP@chathamhouse.org.

Next steps for EU-US cooperation on trade and technology 8 December 2022 — 3:00PM TO 4:00PM Anonymous (not verified) 21 November 2022 Online

How can the EU and US increase cooperation on AI, semi-conductors and funding information communication technology services?

On trade and technology policy, the EU and the US are making meaningful progress towards cooperation while at the same time navigating tensions. As senior officials meet on 5 December for the third meeting of the Trade and Technology Council (TTC), both sides have vowed to move towards concrete results. But can the US and EU increase cooperation on artificial intelligence, semiconductors, and funding information communication technology services? 

This event draws on insights from a forthcoming Briefing Paper by Marianne Schneider-Petsinger that explores next steps for US-EU cooperation on trade and technology, which is part of a project supported by the Hanns Seidel Foundation. 

Ilka Wittig
Jul 1, 2007; 6:1215-1225
Research

Hasmik Keshishian
Dec 1, 2007; 6:2212-2229
Research

M. Wang
Aug 1, 2012; 11:492-500
Technological Innovation and Resources

Qin Liu
Aug 1, 2007; 6:1299-1317
Research

Mitsunori Fukuda
Jun 1, 2008; 7:1031-1042
Research

Tamar Geiger
Mar 1, 2012; 11:M111.014050-M111.014050
Special Issue: Prospects in Space and Time

Timothy J. Griffin
Apr 1, 2002; 1:323-333
Research

Roland Bruderer
May 1, 2015; 14:1400-1410
Research

Christian Tagwerker
Apr 1, 2006; 5:737-748
Research

Guoan Chen
Apr 1, 2002; 1:304-313
Research

Qiang Tian
Oct 1, 2004; 3:960-969
Research

Jesper V. Olsen
Jun 1, 2004; 3:608-614
Technology

Ludovic C. Gillet
Jun 1, 2012; 11:O111.016717-O111.016717
Research

Ignat V. Shilov
Sep 1, 2007; 6:1638-1655
Technology

Martin R. Larsen
Jul 1, 2005; 4:873-886
Technology

Yasushi Ishihama
Sep 1, 2005; 4:1265-1272
Research

Linn Fagerberg
Feb 1, 2014; 13:397-406
Research

Philip L. Ross
Dec 1, 2004; 3:1154-1169
Research

Jürgen Cox
Sep 1, 2014; 13:2513-2526
Technological Innovation and Resources

Shao-En Ong
May 1, 2002; 1:376-386
Research

HIV Type 1 (HIV-1) and simian immunodeficiency virus (SIV) display differential replication kinetics in macrophages. This is because high expression levels of the active host deoxynucleotide triphosphohydrolase sterile α motif domain and histidine-aspartate domain–containing protein 1 (SAMHD1) deplete intracellular dNTPs, which restrict HIV-1 reverse transcription, and result in a restrictive infection in this myeloid cell type. Some SIVs overcome SAMHD1 restriction using viral protein X (Vpx), a viral accessory protein that induces proteasomal degradation of SAMHD1, increasing cellular dNTP concentrations and enabling efficient proviral DNA synthesis. We previously reported that SAMHD1-noncounteracting lentiviruses may have evolved to harbor RT proteins that efficiently polymerize DNA, even at low dNTP concentrations, to circumvent SAMHD1 restriction. Here we investigated whether RTs from SIVmac239 virus lacking a Vpx protein evolve during in vivo infection to more efficiently synthesize DNA at the low dNTP concentrations found in macrophages. Sequence analysis of RTs cloned from Vpx (+) and Vpx (−) SIVmac239–infected animals revealed that Vpx (−) RTs contained more extensive mutations than Vpx (+) RTs. Although the amino acid substitutions were dispersed indiscriminately across the protein, steady-state and pre-steady-state analysis demonstrated that selected SIVmac239 Vpx (−) RTs are characterized by higher catalytic efficiency and incorporation efficiency values than RTs cloned from SIVmac239 Vpx (+) infections. Overall, this study supports the possibility that the loss of Vpx may generate in vivo SIVmac239 RT variants that can counteract the limited availability of dNTP substrate in macrophages.

New essay anthology examines the future of the international order News release jon.wallace 7 May 2021

Featuring a new essay by Robin Niblett, Chief Executive of Chatham House, and Leslie Vinjamuri, Director of the US and Americas programme.

“Anchoring the World”, a new anthology, features an important new essay by Robin Niblett, Chief Executive of Chatham House, and Leslie Vinjamuri, Director of the US and Americas programme. The essay, “The Liberal Order Begins At Home”, argues powerfully for the revival of a liberal international order.

The essay collection has been produced by the Lloyd George Study Group on World Order, and celebrates the centennial years of Chatham House, Georgetown University’s School of Foreign Service, and the Council on Foreign Relations.

Robin Niblett said:

“In this excellent collection, some authors argue that the United Nations should continue to anchor the international system, while others argue for the creation of a new Concert of Powers.

“Our essay argues that it is both necessary and possible to revive the idea of a liberal international order: necessary (and urgent) because of heightened global competition with China, and possible only if western democracies repair their deep social and economic problems at home.

“We hope this volume carries forward the fortitude and creative spirit that the School of Foreign Service, Chatham House, and the Council on Foreign Relations have brought to the study and practice of international affairs over the past century.”

The Lloyd George Study Group and book were made possible by the generosity of the family of Robert Lloyd George, the great-grandson of British Prime Minister, David Lloyd George.

Anchoring the World is published by Foreign Affairs magazine.

Cross-border conflict, evidence, policy and trends (XCEPT)

This five-year policy-focused research programme seeks to respond to the challenges of long-term cross-border conflicts by exploring the drivers behind them.

Protracted conflicts in the Middle East and North Africa, Horn of Africa and parts of Asia, although usually arising from intra-state disputes, rarely remain contained within national borders. Their effects reverberate outward and external actors are drawn in.

The longer these wars last, the more difficult they are to resolve as the interests of international actors collide and the web of economic and political interactions which sustain violence and connect conflict across borders expand and deepen.

The Cross-border conflict, evidence, policy and trends (XCEPT) research programme brings together world-leading experts to examine conflict-affected borderlands, how conflicts connect across borders, and the drivers of violent and peaceful behaviour.

Chatham House provides research leadership to the programme, as part of the wider consortium, and our research explores:

• the intersection of conflict supply chains which sustain and embed violence
• coping supply chains for survival-based economic activity which occurs in the context of violence

Three geographic case studies will be supported by cross-cutting workstreams on gender and social inclusion, livelihoods, and border security. Each will produce analysis and recommendations to inform international policy responses to conflict across borders.

These case studies will focus on:

• armed actors and financial flows through Iraq and the Levant
• human smuggling across Libya, East and West Africa
• gold mining and weapons flows across Sudanese borderlands

The consortium is made up of a range of other organizations, including the Asia Foundation, the Malcolm H. Kerr Carnegie Middle East Center, the Rift Valley Institute, Chemonics UK and King’s College London.

XCEPT is funded by UK Aid from the UK government.

AUKUS reveals much about the new global strategic context Expert comment NCapeling 17 September 2021

The new AUKUS partnership as well as the furore in Paris surrounding its announcement says a lot about the new geopolitical landscape.

The growing diplomatic drama surrounding the announcement of the new Australia-UK-US (AUKUS) risks concealing rather than highlighting what the deal reveals about profound changes in the global strategic context. Several elements stand out.

First, Australia’s decision to break off the $66 billion contract it signed with France in 2016 to purchase a new fleet of diesel electric submarines underscores the heightened level of concern in Canberra about China’s growing naval capabilities.

Despite all the industrial, legal, and diplomatic disruption, the Australian government has decided only the stealthy nuclear-powered submarines developed by Britain with US support can provide the genuine naval capability it needs long-term.

Next, in helping Australia resolve this conundrum, the British government has revealed the versatility of its new foreign policy. Part of the reason UK prime minister Boris Johnson eschewed the concept of a formal foreign policy and security treaty in the post-Brexit deal with the European Union (EU) was to pursue freely new ventures such as the recent ‘G7-plus’ summit in Cornwall, and enhanced cooperation among the Five Eyes allies. AUKUS reveals that this approach can produce real results.

Europe or the Indo-Pacific

During this week’s Polish-British Belvedere Forum in Warsaw, one of the main Polish concerns was that this ‘tilt’ to the Indo-Pacific could overstretch Britain’s scarce resources when it should be focusing on Europe, where they are most needed.

But AUKUS does not over-extend Britain. There is no military commitment involved in the agreement. The UK also remains outside the Quad – made up of the US, India, Japan, and Australia. And the ongoing stately voyage of its new aircraft carrier from the Mediterranean into the South China Sea provides better insight into the substance of the UK’s Indo-Pacific tilt.

Much derided for not carrying enough of its own aircraft – and for depending on US and Dutch escort vessels – the UK has in fact managed to coalesce a flexible group of allies around the Queen Elizabeth while enabling it to fly the British flag in Asian waters and strengthening interoperability with its allies for future joint operations.

Despite the hype, Britain’s main defence investments and deployments remain firmly focused in Europe, as laid out by the recent Integrated Review. And the decision to draft a new NATO Strategic Concept – midwifed by Britain at the 70th anniversary NATO summit hosted in London in December 2019 and confirmed during Joe Biden’s visit to NATO headquarters in June – will give Britain’s role in European security a new purpose and focus in the coming years.

Alone on the strategic landscape

For France, of course, the cancellation of its submarine deal is a painful humiliation, and a severe blow to thousands of workers in its hi-tech defence industry. It also comes at a sensitive moment politically, with Emmanuel Macron keen to demonstrate his international standing ahead of the 2022 presidential election. Instead, France now looks rather lonely on the strategic landscape alongside the more homogeneous and collectively powerful AUKUS trio.

But, rather than take the high road, a furious French reaction has compared Biden to Donald Trump and argued that this defence industrial failure for France should drive an acceleration towards European – for which, read EU – strategic autonomy.

This implies France sees European strategic autonomy as protecting and extending its own sovereign power and industrial interests rather than as a process for EU members to achieve more together in security and foreign policy than they can alone – thereby undermining rather than enhancing its case.

The gap between European strategic rhetoric and practical action was further highlighted by the AUKUS partnership being announced the evening before the EU launched its own Indo-Pacific strategy, and on the same day as China refused to allow a German frigate its first planned port visit to Shanghai.

America is still back

There is still a long way to go before the new submarine deal becomes reality. Australia needs to extricate itself from the French deal, decide how to secure the highly enriched uranium to power its new nuclear submarines, decide with the US and UK the division of labour and technology transfer of production, and assuage the International Atomic Energy Agency’s concerns about the precedent this deal sets. The fruits of this dramatic announcement will, therefore, be a long time in coming.

But, however the details play out, 15 September 2021 was a consequential day. The AUKUS announcement showed that China’s growing hard power is now eliciting a genuinely tough and structural political-military reaction.

Across the Atlantic, it also allowed President Biden – flanked ‘virtually’ by the British and Australian prime ministers – to send the global message that America is indeed back, just three weeks after the ignominious retreat from Afghanistan and chaotic exit from Kabul. And it offered him the opportunity to remind the world that the Indo-Pacific is where the US will be putting its main effort in the future.

For many in China, AUKUS now confirms their belief that the US and its principal allies are determined to contain China’s rise in its own ‘backyard’, where it believes it has the right to flex its muscles. For others, it will confirm Xi Jinping has overreached and China is now paying the price of his more assertive strategy. Either way, the Chinese are on notice that the ambivalent nature of the Obama pivot to Asia has given way to a more determined pivot under Biden.

While the US is stepping up, the UK has shown it is in the mix, leveraging opportunities as they arise. For example, the goodwill the UK has generated in Tokyo with this new partnership with Australia could help its case as it pursues membership of the Transpacific Partnership trade area in 2022.

The EU looks like a bystander in comparison and ill-equipped for the geopolitical competition inherent in this new strategic context. It is essential, therefore, once the dust has settled from these fraught few days, that the US and UK reach out to find ways to involve France and its EU partners in a meaningful, shared transatlantic approach to the Indo-Pacific.

Chatham House appoints new director and chief executive News release jon.wallace 5 April 2022

Bronwen Maddox will take up the role at the end of August, succeeding Dr Robin Niblett CMG.

The Royal Institute of International Affairs (Chatham House) is delighted to announce that its new director and chief executive will be Bronwen Maddox, who joins from the Institute for Government.

Bronwen Maddox has been the director of the Institute for Government, an independent think tank based in London promoting better government, since September 2016. 

She joined the institute from the current affairs magazine Prospect, where she spent six years as editor and CEO.

Bronwen was previously foreign editor, chief foreign commentator and US editor at The Times, and before that, she ran award-winning investigations and wrote economics editorials for the Financial Times, after a career as an investment analyst in the City. She writes frequent op-ed columns for the Financial Times and broadcasts widely.

She is also visiting professor in the Policy Institute at King’s College London, a non-executive board member of the Law Commission, and has just been appointed a council member of Research England, one of the research councils of UK Research & Innovation.

Ms Maddox succeeds Dr Robin Niblett CMG who is standing down in the summer after 15 years in the role. She will take up the role at the end of August.

Chair of Chatham House, Sir Nigel Sheinwald said:

‘This is an exciting appointment for the future of Chatham House and for London as a global hub. Russia’s invasion of Ukraine and the unprecedented response of the rest of the world reminds us that organizations like Chatham House, with its outstanding record of independent analysis and new ideas on how to build a secure and prosperous world, are needed more than ever.

‘Bronwen Maddox has an international reputation as a compelling commentator and analyst on world affairs, with a proven ability to spot emerging issues and frame them in ways which will provoke intelligent debate and fresh thinking. She has provided successful and innovative leadership at the IFG, Prospect and The Times, and is committed to continuing to broaden Chatham House’s diverse appeal and impact. She is the ideal person to lead the institute into the next stage of its development at this crucial time for the future of international relations.’

Bronwen Maddox said:

‘I am honoured and delighted to become Chatham House’s next director. It’s a momentous period in international affairs and Chatham House, with its reputation for rigour, independence and expert analysis, has a unique role to play in assessing these changes and prompting solutions to confront them – as it shows every day. I look forward to the privilege of working with its teams, and the many others who have come together to advance its work.’

Sir Nigel also paid tribute to Dr Niblett:

‘Robin Niblett has transformed Chatham House in his fifteen years as its head. The institute’s research, activities and impact have grown considerably in that time thanks to Robin’s own high-quality commentary, his productive relationships with our stakeholders, partners, supporters and members and his commitment to the institute’s staff. He leaves an institute which has a much wider and fresher appeal and has strengthened London’s standing as a great centre for international affairs.’

Dr Niblett said:

‘This appointment is excellent news for Chatham House. Bronwen Maddox is ideally placed to ensure the institute continues to play its part in helping governments, business and civil society tackle the serious challenges we face, not just from the return of geopolitical competition and interstate conflict, but also from climate change, unsustainable economic activity and growing inequality, priorities for the institute that have been underlined by the COVID-19 pandemic.’

Accumulation of the microtubule-associated protein tau is associated with Alzheimer's disease (AD). In AD brain, tau is abnormally phosphorylated at many sites, and phosphorylation at Ser-262 and Ser-356 plays critical roles in tau accumulation and toxicity. Microtubule affinity–regulating kinase 4 (MARK4) phosphorylates tau at those sites, and a double de novo mutation in the linker region of MARK4, ΔG316E317D, is associated with an elevated risk of AD. However, it remains unclear how this mutation affects phosphorylation, aggregation, and accumulation of tau and tau-induced neurodegeneration. Here, we report that MARK4ΔG316E317D increases the abundance of highly phosphorylated, insoluble tau species and exacerbates neurodegeneration via Ser-262/356–dependent and –independent mechanisms. Using transgenic Drosophila expressing human MARK4 (MARK4wt) or a mutant version of MARK4 (MARK4ΔG316E317D), we found that coexpression of MARK4wt and MARK4ΔG316E317D increased total tau levels and enhanced tau-induced neurodegeneration and that MARK4ΔG316E317D had more potent effects than MARK4wt. Interestingly, the in vitro kinase activities of MARK4wt and MARK4ΔG316E317D were similar. When tau phosphorylation at Ser-262 and Ser-356 was blocked by alanine substitutions, MARK4wt did not promote tau accumulation or exacerbate neurodegeneration, whereas coexpression of MARK4ΔG316E317D did. Both MARK4wt and MARK4ΔG316E317D increased the levels of oligomeric forms of tau; however, only MARK4ΔG316E317D further increased the detergent insolubility of tau in vivo. Together, these findings suggest that MARK4ΔG316E317D increases tau levels and exacerbates tau toxicity via a novel gain-of-function mechanism and that modification in this region of MARK4 may affect disease pathogenesis.

Alzheimer's disease (AD) is characterized by neuronal loss and accumulation of β-amyloid-protein (Aβ) in the brain parenchyma. Sleep impairment is associated with AD and affects about 25–40% of patients in the mild-to-moderate stages of the disease. Sleep deprivation leads to increased Aβ production; however, its mechanism remains largely unknown. We hypothesized that the increase in core body temperature induced by sleep deprivation may promote Aβ production. Here, we report temperature-dependent regulation of Aβ production. We found that an increase in temperature, from 37 °C to 39 °C, significantly increased Aβ production in amyloid precursor protein-overexpressing cells. We also found that high temperature (39 °C) significantly increased the expression levels of heat shock protein 90 (Hsp90) and the C-terminal fragment of presenilin 1 (PS1-CTF) and promoted γ-secretase complex formation. Interestingly, Hsp90 was associated with the components of the premature γ-secretase complex, anterior pharynx-defective-1 (APH-1), and nicastrin (NCT) but was not associated with PS1-CTF or presenilin enhancer-2. Hsp90 knockdown abolished the increased level of Aβ production and the increased formation of the γ-secretase complex at high temperature in culture. Furthermore, with in vivo experiments, we observed increases in the levels of Hsp90, PS1-CTF, NCT, and the γ-secretase complex in the cortex of mice housed at higher room temperature (30 °C) compared with those housed at standard room temperature (23 °C). Our results suggest that high temperature regulates Aβ production by modulating γ-secretase complex formation through the binding of Hsp90 to NCT/APH-1.

China’s economic policy pendulum has swung towards stimulus – but keep expectations low Expert comment jon.wallace 14 October 2024

Beijing historically swings between stimulus and frugality. But Xi Jinping’s ambition for self-reliance will constrain any new efforts to boost the economy.

Policymakers in Beijing have spent the past three weeks trying to convince the world that they are determined to deliver meaningful support to China’s sagging economy. 

Since late September statements have come from the central bank, which promised to cut interest rates, release liquidity, and provide funding to securities firms; from the politburo, which said it wanted to stabilize the real estate market, boost the capital market and shift towards looser fiscal and monetary policy; from the government’s main planning body, which promised a package of policies to support domestic demand; and from the finance minister himself, who at the weekend committed to issue more debt to recapitalize banks, support local governments and aid unhappy consumers.

Though details have been scant, the Chinese stock market has responded enthusiastically to this flurry of rhetoric. But the bigger question for the global economy is whether a boost in Chinese demand can return the country to its former status as a reliable destination for global exports and capital.

With that measure of success in mind, it is worth keeping expectations low. For the past 15 years, Chinese authorities have been wrestling with two conflicting objectives: to grow the economy, and to minimize the risk of financial instability. Those goals sit uneasily with each other because the effort to boost growth has relied on borrowing; and yet a rise in debt can increase the risk of a debt crisis.  

Chinese policymaking has responded to this dilemma by taking on a pendulum-like quality. Sometimes the authorities boost the economy by funding more investment spending. At other times that stimulus gets reined back as policymakers worry about the economy’s indebtedness.

In the aftermath of the great financial crisis of 2008, for example, Beijing’s over-riding priority was to protect the Chinese economy from the risk of recession by implementing a huge credit-financed stimulus to spur investment in infrastructure and real estate. 

By 2012, though, concerns about over-indebtedness began to dominate, and a withdrawal of stimulus saw the Chinese economy sag. In late 2015,a new round of stimulus measures emerged, only to be withdrawn again around 2018.

With that pendulum in mind, the optimistic take on what policymakers have said in recent weeks is that we are now back in stimulus mode. That’s true in part, but three factors suggest that this time is a little different.

Different times

First, China’s rising debt burden increases authorities’ worries about financial stability. Data from the BIS show that China’s private sector debt almost doubled in the past 15 years to 200 per cent of GDP at the end of 2023. The comparable debt stock for the US and the Eurozone was much lower, at 150 per cent each.

Second, ideology is playing a growing role in shaping Chinese economic policy. The most visible effect has been to prioritize Chinese state-owned enterprises, at the expense of the private sector. This became especially visible in 2021 with a campaign against the ‘unrestrained expansion of capital’ – Beijing’s way of expressing its anxiety that China’s corporate sector was behaving in a manner inconsistent with Chinese Communist Party goals. 

Although that phrase is no longer current, entrepreneurs’ animal spirits remain in the doldrums. They are likely to stay there as long as President Xi Jinping’s preference is for ‘bigger, better, stronger’ state-owned enterprises, which use capital much less efficiently than private firms.

Third, today Chinese policy is shaped by Beijing’s perception of geopolitical risks that it faces. Those risks became starkly apparent in February 2022 after Russia’s invasion of Ukraine, when essentially every country that prints a reserve currency joined to freeze Russia’s access to its foreign exchange reserves. That enveloped the Russian economy in a network of sanctions that sharply constrained its access to a whole range of imports.

It is not difficult to consider a similar scenario confronting China. Beijing’s approach to economic policy is therefore heavily influenced by the need to insulate itself from that kind of risk (though Chinese policy had in any case been tilting in this direction for years).

‘Asymmetric decoupling’

This policy can be described as ‘asymmetric decoupling’: a simultaneous effort on the one hand to reduce China’s reliance on the rest of the world by substituting imports with domestic production; and, on the other hand, to increase the rest of the world’s reliance on China by establishing itself as a ‘zhizao qiangguo’, or manufacturing powerhouse.

This is the right context in which to understand a central economic goal of the authorities, which is to reduce the economy’s dependence on real estate investment. 

The intention is to allow capital and credit resources to migrate to new sectors of the economy that will help to build that manufacturing powerhouse: high-tech and green energy, in particular. What that means in practice is that any forthcoming support for the real estate sector will be rather limited.