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.

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.   

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.

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.

Shaping modern Britain: the role of African and Caribbean communities 24 October 2024 — 5:00PM TO 6:00PM Anonymous (not verified) 3 October 2024 Chatham House and Online

As part of Black History Month, this event celebrates the enduring contributions of African and Caribbean communities to the UK.

When British colonial rule ended, newly independent countries in Africa and the Caribbean retained influences such as the English language and governance systems modelled on that of the UK. Initially, these post-independence relations were largely marked by the UK’s soft power, shaping the nation-building processes in these regions.

Over time, however, this influence has become a two-way exchange. African and Caribbean cultures have profoundly shaped modern Britain – from music and food to sports, arts, literature and beyond. These evolving dynamics have not only enriched the UK’s cultural landscape but also provided significant benefits for diaspora communities, fostering a sense of belonging and promoting cultural exchange. Diaspora groups and civil society organizations have adeptly utilised these connections to advocate for their communities and advance their interests.

At this event, speakers will explore how African and Caribbean influences rose to prominence in the UK and how this cultural momentum can be harnessed to build stronger, forward-looking partnerships. By highlighting the shared histories and more vibrant present-day exchanges, this event will explore how these ties can be used to break down stereotypes, promote social cohesion, and contribute to a more inclusive future.

This event forms part of our series of events celebrating Black History Month, including a photo exhibition and drinks reception.

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.

Belt and Road Is Not a (Completely) Closed Shop Expert comment sysadmin 22 March 2018

Though the infrastructure initiative will continue to be led in many places by Chinese investment, where there are benefits of scale, effectiveness and risk management, outside participation will be welcome.

First announced in 2013, President Xi Jinping’s Belt and Road Initiative promises, at a minimum, to improve infrastructure and connectivity between China and the rest of Eurasia. Any bold plan to finance infrastructure on a large-scale across so many low-income economies deserves a sympathetic ear and a positive reception. But many wonder how large the role can be for non-Chinese players in what is clearly an initiative of the Chinese government.

So far, Chinese state and policy banks account for the overwhelming majority of the financing – and this money then flows to Chinese enterprises, mainly state-owned. One study found that 89% of the work went to Chinese contractors on China-funded projects.

Yet, recently in Paris, Chinese Foreign Minister Wang Yi said the Belt and Road was a ‘sunshine initiative’ that was open and for all to benefit from. He declared that there were to be ‘no backroom deals. There is openness and transparency.’ The Belt and Road Initiative will ‘respect international rules’ and ‘will run according to market rules’.

There are some notable instances of Belt and Road projects changing to conform more to international rules as they develop. For example, work on the Belgrade–Budapest high speed rail link originally ran into problems. Contracts were allegedly awarded to Chinese companies without following the EU-mandated competitive procurement processes. Now, the most recent round of contracts is to be awarded by tender.

Such a switch perhaps does not herald the unrestricted ‘market rules’ that Wang speaks of, but it does highlight that China is willing to turn Belt and Road towards openness in certain instances. These will be cases where it clearly brings benefits for China – but also where private sector players can be convinced of good commercial returns. These benefits are most likely to lie in three areas: scale and access, effectiveness and risk management.

Mutual benefits

Firstly, scale and access. Belt and Road can achieve greater scale if additional financing comes in alongside the current Chinese state and policy bank lending. This can come both by working together with multilateral institutions and with private sector institutions. This will in turn require defining projects or structuring financing with attractive risk-return trade-offs. In some cases, this will be feasible – in others not.

Getting bigger also necessitates initiating meaningful Belt and Road activity in more countries. As the Belgrade–Budapest rail experience has shown, approaches vary in terms of competitive tendering requirements and consideration of non-Chinese bidders. An approach that works in, say, Tajikistan, may not be effective in Poland. This is a pragmatic recognition of context that is quite separate from debates on what the ‘right’ approach to these standards should be. Both these elements suggest that a more open Belt and Road will be a larger and more far-reaching one.

Secondly, effectiveness. Despite extensive experience building infrastructure within China, many Chinese companies are much less familiar operating outside of China. Western, Japanese and Korean companies can bring their own experience to the table and help the success of these projects. By doing so, they also put competitive pressure on Chinese companies to improve and upgrade, while providing opportunities to learn. This in turn creates a stronger, more productive Chinese economy.

Beyond physical hardware, the ‘software’ is also critical to success. Again foreign companies have much to contribute. Areas such as maintenance, training, legal and accounting services are all in demand. Indeed, many such British and other companies are already actively engaged in working on projects with Chinese companies to help in these areas.

Finally, risk management. Beyond the usual project management risk of large projects, Belt and Road brings additional challenges. Many countries have weak governance, internal divisions and security issues, all within distinctively different cultures and traditions. Chinese companies with little experience of local conditions will struggle. Going it alone may provide what is an illusion of control, but exposure to social and political dynamics can rebound on China in unexpected ways.

Cooperating with others who have a history of in-country experience is a way to manage these risks. Examples would include British and Chinese cooperation both at company and governmental level in engaging in particular African countries, in partnership with the relevant country government.

Mixed system

Mechanisms that encourage competitive choices and restrain corruption are positive, but mechanisms that slow decision-making to a crawl also prevent countries from getting benefits of infrastructure projects. Conversely, continuing along the current path of Chinese-led investment does have some clear attractions in certain settings, at least to those directly involved. It combines the ability of Chinese policy banks to provide large-scale funding in even high-risk environments with the relevant experience and production capacity of Chinese state-owned businesses. It allows for government-to-government deals, pragmatic negotiations and all-encompassing accords, at times out of the public eye. In many cases, it is hard to make a commercial case for the investments.

But in cases where there is mutual benefit, engagement and will, there will be a role for international partnerships.

Lars Jønson
May 1, 2007; 6:798-811
Research

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

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

Sean R. Collins
Mar 1, 2007; 6:439-450
Research

Lawrence E. Ostrowski
Jun 1, 2002; 1:451-465
Research

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

William M. Old
Oct 1, 2005; 4:1487-1502
Research

Europe should become the top priority for Liz Truss Expert comment NCapeling 3 September 2022

Liz Truss has the chance to be a better prime minister than Boris Johnson was, not least in the UK’s foreign policy.

For all the smoke-and-mirrors talk now commonplace about Brexit opportunities, there is real potential that Liz Truss could extract from the aftermath of that upheaval as well as from the turmoil in the world.

But the approach and priorities she revealed during her one year as a better UK foreign secretary than Boris Johnson was – although he did set a low bar – as well as the past three months campaigning for the leadership of her party contain a warning.

She has shown a willingness to aggravate relationships with allies in pursuit of the support of her party faithful, and of a vision of British independence as well as a tendency to dismiss economic analysis when it inconveniently questions her assertions about favoured policies.

At the heart of her political identity is a notion which is both a strength and a potentially calamitous weakness – a love of the notion of being a disrupter which injects a deliberate unpredictability into her approach towards a world in extreme flux.

If she indulges this without good judgment, she could do real damage to Britain’s prospects and standing in the world.

Ukraine and the energy crisis

In foreign policy, Europe should be her starting point and the opportunity here for the UK is clear. The war in Ukraine and crisis in the cost of energy gives it a role – despite having left the European Union (EU) – in talking to EU governments about the future of the continent on many fronts.

Johnson’s emphatic support of President Zelensky gave the UK a position of moral and strategic clarity which Truss can build on through what will be an exceptionally difficult winter for Europe’s governments.

She is in a position to persuade European leaders to remain united in Ukraine’s support while planning better how they are going to source energy. She could expand on that to help the EU find a way through its many other problems, such as upholding democratic values throughout the bloc or finding a response to migration.

There is also a chance for the UK to shape Europe’s thinking on the development and regulation of digital technology and medicine, energy, and the environment.

Truss’s declaration that the UK should now spend three per cent of its GDP on defence could help her in taking that kind of role. However this campaign declaration is not yet credible, given the pressures on the national finances and her silence so far on support for households on energy costs.

But that is the opportunity in theory and the signs are this is not her approach to Europe. Her provocative and opportunistic comment that the ‘jury’s out’ on whether President Macron (and France) was a friend or foe shocked both Britain’s allies and opponents.

For those keen to see divisions among democracies, it gave unexpected, heady encouragement, and to those within those countries, it injected a doubt about shared values which was deeply damaging. The chilly poise of Macron’s response – that the UK and France would always be allies – showed how far she had departed from normal protocol.

The episode encapsulated one of the sources of unease about the Truss style – improvisation under the banner of ‘disruption’ without thought of consequences.

However, she has shown consistency over the Northern Ireland Protocol with little sign of compromise, and that alone could cause much unnecessary damage to UK interests. It also puts her on a collision course with the EU and the UK House of Lords, due to consider controversial legislation again in early October after the Conservative party conference.

There is huge opposition in the Lords to two aspects of the legislation. The first target is the intention of the Johnson government – likely to be repeated by a Truss government – to use the bill to jettison aspects of the protocol, which many argue breaks international law. The second is the delegated power the bill would give ministers.

The cost of a new, serious clash – or worse, a full trade war – with the EU is high. There is the loss of trade, the increase in friction for business, which is consistently underestimated by the UK government, and the loss of scientific and research partnerships.

More than that, though, there is the weakening of ties to a set of allies with common values sharing an increasingly troubled neighbourhood.

US, China, and others remain important

And to say Europe should come first is not to dismiss other claims on the UK’s foreign policy. Her instinctive liking for the US will help Truss in relations with Washington at a difficult time, and her apparent intention to designate China as ‘a threat’ will support that relationship too.

Redefine the Commonwealth now to safeguard its future Expert comment NCapeling 6 October 2022

Although seen as one of the Queen’s greatest legacies, the Commonwealth must provide tangible benefits to its citizens in an era of geopolitical competition.

The Commonwealth’s breadth allows a wide diversity of countries of different sizes, geographies, cultures, and values to be members – it is both rich and poor, north and south, and ethnically diverse. This makes it more interesting than many other multilateral institutions such as the G7, NATO, and the European Union (EU).

But it suffers from an unclear purpose. Since its inception, successive UK governments have grappled with its role – whether it is a preferential trading bloc or merely a source of most of Britain’s post-war immigration.

This lack of purpose – and structure – has left the Commonwealth impotent in dealing with a host of bilateral difficulties between the UK, its overseas territories, and Commonwealth partners in recent years.

Brexit could induce Britain to re-prioritize the Commonwealth, but so far the UK has only signed two new trade deals with Commonwealth members – Australia and New Zealand – while development aid, one of the most tangible ways the UK worked with many Commonwealth countries, has been cut and the UK’s defence focus has pivoted towards the Indo-Pacific and Europe’s Eastern front.

The UK also suffered embarrassing and overwhelming defeats in both the UN General Assembly (UNGA) and the International Court of Justice (ICJ) on the legality of its continued occupation of the Chagos Islands and has avoided directly challenging India’s tacit support for Russia’s invasion of Ukraine in the hope of securing a trade deal.

At the recent Commonwealth Heads of Government Meeting (CHOGM), Boris Johnson reportedly attempted to depose Baroness Scotland, the Commonwealth’s Secretary General, but suffered a humiliating defeat in a vote of Commonwealth members.

These challenges are likely to continue, especially in the wake of the death of HM The Queen which could be seen by republican movements as an opportune time to rally support. Australia and New Zealand’s leaders, both republicans, downplayed the idea of a poll on the monarchy immediately after the Queen’s death, but it would be a mistake to assume this has gone quiet forever. Antigua and Barbuda’s prime minister has already said there will be a referendum on becoming a republic within three years.

Defining a new vision for the future

A concrete vision for the Commonwealth is long overdue and there is no better time to cast one than now. HM The Queen was more than just a figurehead for the Commonwealth and it remains unknown exactly what role King Charles III will see for himself.

But, unlike his mother who was a young, modern Queen heralding a post-imperial future, Charles takes the throne at a later age and at a time when important questions need to be addressed in an increasingly fractured world.

Most importantly the UK should avoid the temptation to define the Commonwealth in terms of shared principles and values. India, Pakistan, and Bangladesh all abstained on the United Nations (UN) motion condemning Russia’s invasion of Ukraine, and Commonwealth members are likely to be similarly divided over China’s territorial claims, the US-China conflict, the net-zero agenda, and nuclear non-proliferation.

The Commonwealth’s breadth – its greatest strength – means consensus is often impossible, and so should not be the goal. Instead the Commonwealth should focus on tangible areas of cooperation where there is mutual interest such as trade, aid, and migration.

The UK and its allies may find that diplomatic efforts – such as condemning China or Russia for human rights abuses – are more successful if they have listened to and acted on fellow Commonwealth countries’ concerns, from post-COVID vaccine provision to climate financing. Boosting the aid budget and opening borders may prove more important in engaging developing country partners than traditional diplomatic avenues.

Liz Truss’s British International Investment project could be a valuable vehicle for financing, especially if it leverages private sector funding, but many Commonwealth countries are feeling the more immediate impact of the UK’s aid cuts. In these circumstances many have already turned to Chinese infrastructure financing.

This is where the Commonwealth could be valuable. In the Pacific, it links certain island nations to the UK, Australia, and New Zealand at a time of renewed geopolitical competition with China in the Pacific. The fact the Commonwealth is not explicitly about promoting a particular ideology or countering China is helpful.

Commonwealth should be less UK-centric

There is also no reason why all the Commonwealth operations need to be based in London, which is not only expensive but also reinforces an approach to governance that assumes everything must be decided by civil servants in London. As the world’s largest democracy, India is an obvious alternative candidate although its reluctance to condemn Russia’s invasion and its domestic political tensions may count against it.

It is also important the Commonwealth’s wealthier members – the UK, Canada, and Australia – provide financing for countries such as India to take on extra responsibilities. The Commonwealth Games is a good place to start – despite having 72 competing nations and territories, the games have only been held three times outside the UK, Canada, Australia, and New Zealand.

The Commonwealth also needs to be forward-looking and one of its most exciting assets is its demographic youthfulness. Europe, China, and the US have ageing populations whereas Nigeria, India, and Bangladesh have some of the world’s largest young populations.

Synapse loss is associated with motor and cognitive decline in multiple neurodegenerative disorders, and the cellular redistribution of tau is related to synaptic impairment in tauopathies, such as Alzheimer's disease and frontotemporal dementia. Here, we examined the cellular distribution of tau protein species in human tau overexpressing line 66 mice, a transgenic mouse model akin to genetic variants of frontotemporal dementia. Line 66 mice express intracellular tau aggregates in multiple brain regions and exhibit sensorimotor and motor learning deficiencies. Using a series of anti-tau antibodies, we observed, histologically, that nonphosphorylated transgenic human tau is enriched in synapses, whereas phosphorylated tau accumulates predominantly in cell bodies and axons. Subcellular fractionation confirmed that human tau is highly enriched in insoluble cytosolic and synaptosomal fractions, whereas endogenous mouse tau is virtually absent from synapses. Cytosolic tau was resistant to solubilization with urea and Triton X-100, indicating the formation of larger tau aggregates. By contrast, synaptic tau was partially soluble after Triton X-100 treatment and most likely represents aggregates of smaller size. MS corroborated that synaptosomal tau is nonphosphorylated. Tau enriched in the synapse of line 66 mice, therefore, appears to be in an oligomeric and nonphosphorylated state, and one that could have a direct impact on cognitive function.

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.

Chatham House welcomes 2024 interns News release jon.wallace 25 October 2024

An internship at Chatham House offers an invaluable learning experience through a six-month placement in one of our teams.

Chatham House is excited to welcome the 2024 cohort to the Molchanov Sustainability Internship Programme. 

Introduced in January 2021, the programme has been made possible following the gift of Pavel Molchanov, to support the next generation of leaders in sustainability. 

The internships grant practical learning opportunities at a world-famous think-tank, helping a new generation of policymakers understand how to shape policy, influence debate, and create meaningful change towards a sustainable future. 

This autumn, Chatham House staff in six departments are delighted to welcome interns to their teams: 

Aisha Abdirahman will work with the Environment and Society Centre, Kendall Spence with the Africa Programme, Matthew Harris with the International Affairs journal, Noor Elgallal with the Middle East and North Africa Programme, Phoebe Hardingham with the Russia and Eurasia Programme, and Thomas Maddock with the Europe Programme.

For more information about the internships, please contact the Academy team.

M el-Saadani
Apr 1, 1989; 30:627-630
Articles

The Committee to Protect Journalists named winner of the Chatham House Prize 2018 News Release sysadmin 5 October 2018

The Committee to Protect Journalists (CPJ) has been voted the winner of this year’s Chatham House Prize.

Chatham House Commission on Democracy and Technology in Europe News Release sysadmin 25 July 2019

Our project on Democracy and Technology in Europe is now entering its final phase. Now we want your help in shaping the final report.

Strengthening Our Commitment to the Next Generation News Release NCapeling 9 November 2020

Panel of Young Advisers and Queen Elizabeth II Academy Ambassadors underscore our drive to reach, engage and inspire young people to change their world.

How can companies defend civic space? 2 February 2021 — 4:00PM TO 5:00PM Anonymous (not verified) 19 January 2021 Online

Panellists discuss how companies can go beyond corporate social responsibility and philanthropy initiatives to protect and support civic freedoms around the world.

Please click on the below link to confirm your participation and receive your individual joining details from Zoom for this event. You will receive a confirmation email from Zoom, which contains the option to add the event to your calendar if you so wish.

There is increasing pressure on companies to use their power and profits to engage with social and political causes. In doing so, companies can help to support the ‘shared civic space’ that enables the private sector and civil society organizations to benefit from a society that respects the rule of law and human rights, at a time when many of these rights are under threat around the world.

Many companies have introduced CSR initiatives, due diligence mechanisms and corporate philanthropy. Over 11,000 companies are now signatories to the UN’s Global Compact for sustainable and socially responsible business worldwide.

But as demonstrated by misguided corporate responses to the Black Lives Matter protests this year, there is a danger of corporate activism being perceived as ‘lip service’ rather than genuinely addressing the negative impacts of business operations on civic space.

Recent Chatham House research indicates that meaningful engagement by businesses on such issues must be timely, contextually sensitive and industry-relevant. For example, in 2015, Tiffany & Co. worked with other companies to intervene on behalf of Rafael Marques after he was arrested for reporting on widespread human rights abuses in the Angolan diamond industry. During COVID-19, Microsoft offered free cybersecurity software to healthcare and human rights organizations at increased risk of hacking attacks.

This panel event will draw upon practical examples of private sector support for civic space across different sectors, geographies and political environments.

Why might companies step up to defend freedom of association, expression or political participation even where this comes at a financial or political cost? How can companies resist complicity with governments or regulation that threaten civic space? And what forums exist, or should exist, for developing tactical alliances between companies and civil society actors?

This event is also the launch of a new Chatham House resource, The Role of the Private Sector in Protecting Civic Space.

Learnings must become practice as the Taliban return Expert comment NCapeling 7 September 2021

There is greater awareness of the adverse impact of counterterrorism measures and sanctions on humanitarian action. It is time to apply lessons learned.

The 9/11 attacks prompted the international community to adopt a wide range of counterterrorism measures. Debate continues over their compliance with international humanitarian law (IHL) and human rights law, and their effectiveness.

What has become clear is that some of these measures have made it difficult for humanitarian assistance to be provided to the millions of people living in areas under the control of armed groups designated as terrorist, or where such groups have a significant presence.

These include Al-Qaeda in Yemen’s Arabian peninsula, ISIL affiliates in Syria, Al Shabaab in Somalia, Boko Haram in Nigeria, Hamas in Gaza, and various Al-Qaeda affiliates in the Sahel. The lessons painfully learned need to be applied to Afghanistan under Taliban rule.

Impeding humanitarian work

Traditionally, legal counterterrorism measures criminalized acts of violence but, in recent years, measures adopted by the UN Security Council, the European Union (EU), and some states unilaterally, have expanded to address broader forms of support for terrorist acts and to groups designated as terrorist.

When these measures apply in situations of armed conflict – and in the absence of adequate safeguards – they can impede humanitarian organizations from operating as foreseen by IHL and in accordance with humanitarian principles, which require life-saving assistance to be provided in an impartial manner. Restrictions in sanctions imposed for policy objectives other than counterterrorism create similar tensions.

Prohibitions on making funds or other assets available directly or indirectly to persons or groups designated as terrorist can capture incidental payments made during humanitarian operations and relief consignments which are diverted and end up in the hands of these designated groups.

The most extreme restrictions cover the provision of medical assistance, in violation of the foundational principle of IHL that everyone who is wounded and sick – civilian or fighter – is entitled to medical care without discrimination, and those who provide it must not be punished.

Humanitarian organizations have been highlighting these problems for more than a decade. Recent developments give cause for cautious optimism that a turning point has been reached, as the bodies imposing counterterrorism measures and sanctions internationally and domestically have begun to demand compliance with international law and IHL.

In 2019 the UN Security Council unanimously issued a binding demand to member states to ensure all counterterrorism measures they adopt comply with obligations under international law, including IHL.

Recent renewals of UN country-specific sanctions have included similar demands with regards to measures taken by member states to give effect to them. Although this still falls short of an express exception for humanitarian action, it is a significant development, and a strong encouragement to include appropriate safeguards when implementing UN measures domestically.

Similar encouraging practice is discernible at EU level, and new domestic counterterrorism laws adopted by several states include safeguards for humanitarian action.

Applying lessons learned to Afghanistan

It is too soon to know what policies the Taliban will adopt, and the measures that the international community will take to promote compliance with IHL, human rights, and counterterrorism objectives. Nonetheless, policymakers implementing sanctions – and considering their expansion – cannot ignore their potential adverse impact on humanitarian action. They must bear in mind five key lessons.

First, there must be clarity on current legal restrictions, starting from who is designated under sanctions and counterterrorism measures. The UN Security Council has never designated the Taliban per se. Instead, it has listed ‘individuals, groups, undertakings and entities associated with the Taliban’. At present this list includes 135 individuals and five entities, four of which are ‘hawalas’ – money changers – the other being the Haqqani Network, a Sunni Islamist group.

UN financial sanctions require states to freeze the assets of designated persons and groups and ensure no funds, financial assets, or economic resources are made available to them, either directly or indirectly.

EU and UK sanctions simply replicate the restrictions and designations imposed by the UN, but the US has designated the Taliban as a ‘specially designated global terrorist’ which makes the Global Terrorism Sanctions Regulations applicable. These prohibit US nationals from making any contribution or provision of funds, goods, or services to, or for, the benefit of the Taliban.

Second, while listed individuals may play a role in the forthcoming Taliban administration, sanctions do not prohibit providing resources to a government department headed by a designated person.

There is a distinction between an individual and a department, and prohibitions in counterterrorism measures or sanctions on the provision of funds or other assets apply to the designated person, not to the department they may head.

Problems may arise if a designated person appropriates resources for personal benefit or to undermine policy objectives for which the sanctions were imposed. But this does not bring the department within the scope of the designation. Instead, the issue must be addressed from a prevention of diversion perspective.

Third, sanctions and counterterrorism measures must be designed so as to minimize their adverse impact on humanitarian action. One way of doing so is designating leadership figures rather than groups. The new US administration took this approach towards the Houthi in Yemen, with the designation of the group being revoked and new designations focusing on its leaders.

The chilling effect of sanctions is far broader than the actual restrictions they impose. Commercial actors in particular limit their activities in areas they perceive as high risk. In view of this, the effect of expanding existing designations to list the Taliban, now that it is in control of Afghanistan, would be to turn targeted sanctions into comprehensive ones.

In parallel, sanctions or counterterrorism measures should include express safeguards, which exclude funds, assets, and other support provided during humanitarian action from the restrictions – ideally in the form of exceptions or, if an option, general licences.

The adverse impact of the US Global Terrorism Sanctions has been limited until now, as only a small number of humanitarian actors subject to US measures operated in areas under Taliban control. This has now changed, and it is imperative the US issue a broad general licence to exclude assistance provided during humanitarian action from the sanctions.

Fourth, restrictions in funding agreements must not be more onerous than the underlying measures they aim to promote compliance with – in particular, they must not require screening or exclusion of final beneficiaries from the assistance they have been determined as requiring.

Finally, engagement with non-state armed groups for humanitarian purposes is essential for conducting operations effectively and safely, both for humanitarian organizations and the people they are trying to assist. Counterterrorism measures and sanctions do not prohibit such contact even when such groups or their members have been designated.

The past two decades have given states ample time to learn to avoid the adverse impact of sanctions and counterterrorism measures on humanitarian action. The people of Afghanistan deserve that these lessons now be applied.

Our research paper IHL and the humanitarian impact of counterterrorism measures and sanctions identifies the principal points of friction between these bodies of law, clarifies outstanding issues and misunderstandings, and offers practical recommendations for resolving tensions.

How can the investor community address the ‘S’ in ESG? – the role of social purpose values 16 November 2021 — 1:30PM TO 2:30PM Anonymous (not verified) 18 October 2021 Online

This webinar highlights the crucial relationship between an open civic space and a profitable business environment.

2020 was a tipping point for investors to think and act more responsibly, galvanized by catalysts like the killing of George Floyd and the pandemic. There is increasing investor support for social and environmental causes. Younger investors are placing increasing emphasis on values and social issues in their investment decisions.

The ‘S’ in the Environment Social and Governance (ESG) agenda is clearly gaining traction, but how far does it extend to civil and political liberties i.e. the right of citizens, NGOs and journalists to speak freely, assemble and associate which are increasingly shrinking around the world?

While there is increasing focus on human rights issues such as modern slavery and supply chains, civil society space issues often fall between the cracks when investors consider ESG.

This webinar also explores opportunities and challenges that arise for the investor community in terms of factoring civic space issues into their political risk and ESG analysis.

• To what extent are civic space issues being factored into ESG social purpose values, especially by younger investors?
• What is the best methodology for assessing these issues in order to ensure a common and coherent set of global standards in this area?
• And how can investors mitigate the risks of their activities to civic space in practice?

Chatham House welcomes 2022 interns News release jon.wallace 11 May 2022

Internships provide learning opportunities about shaping policy, influencing debate and creating real change.

Chatham House is excited to welcome the second cohort to the Molchanov Sustainability Internship Programme.

Introduced in January 2021, the programme has been made possible following the gift of Pavel Molchanov, to support the next generation of leaders in sustainability.

The internships grant invaluable, practical learning opportunities about shaping policy, influencing debate and creating real change towards a sustainable future.

Alis Martin, Internships and Outreach Manager at Chatham House, said:

‘We are delighted to welcome the second cohort to the Molchanov Sustainability Internship Programme. This cohort brings a diversity of new and invaluable perspectives and ideas to the work of our programmes.

‘Over the course of 12 weeks, interns will be working alongside internationally respected experts in Chatham House programmes, exploring issues of sustainability through the lenses of climate change, the circular economy, conflict prevention, emerging technology, global health, governance, human rights, security policy, sustainable cities and sustainable finance.

‘Fostering sustainable and equitable growth and engaging the next generation of policy leaders is central to Chatham House’s vision. We are committed to providing the best experience and opportunities to our interns who share an interest in pursuing a career in the field of sustainability.

‘It is crucial that we incorporate the views and knowledge of those who will be affected most in the future and I very much look forward to seeing the innovative and impactful ideas that will undoubtedly result from their work.’

Mr Molchanov said:

‘Recent headlines around the world underscore the importance of taking the broadest possible perspective on sustainability. Energy supply concerns, rising food prices, and continued pandemic pressure are all interconnected with climate issues. I look forward to hearing about the work in which this year’s internship participants engage.’

Jerome Puri, intern, Middle East and North Africa Programme, said:

‘I applied for this internship to gain a holistic insight into the coordination of a policy institute and to understand how Chatham House promotes international cooperation and accountable governance around the world.  Chatham House offers an unparalleled opportunity to contribute to projects on frontier issues facing the MENA region and develop a diverse range of skills ranging from project management and communications to policy-oriented research skills.’

Obioma Egemonye, intern, Africa Programme, said:

‘I was particularly interested in joining the Africa Programme at Chatham House after learning an immeasurable amount from their work on the Social Norms and Accountable Governance (SNAG) research for my undergraduate dissertation. I am most looking forward to attending the variety of events held by Chatham House and the Africa programme specifically.’

Valdone Sniukaite, intern, Europe Programme, said:

‘I am excited to be joining the Europe Programme team and getting exposure to the inner workings of a policy and research think tank. I’m mostly looking forward to building my organizational skill set by working on the Belvedere Forum and using the opportunity of being around experts in the field of international affairs to broaden my knowledge.’

Lucile de Laforcade, intern, Queen Elizabeth II Academy for Leadership in International Affairs, said:

‘As part of the Academy, I am able to work at the crossroads of research, leadership, international affairs and personal development. This makes the Academy a place of constant challenge to find innovative, sustainable solutions, and emulate new ideas. As an aspiring academic, this is particularly empowering! I am hoping to gain new skills, further develop independent thinking, and cultivate my own research interests in the vibrant environment of a leading policy institute.’

Katie McCann, intern, Communications and Publishing, said:

‘I’m really interested in youth engagement in international politics so I’m very excited to be working on the Common Futures Conversations platform which brings young people across Europe and Africa into the debate on the pressing global issues of our time. I hope my time at Chatham House will expose me to people of different backgrounds and beliefs which will encourage me to engage even more critically with international affairs.’

Rachael Mullally, intern, International Law Programme, said:

‘What I admire most about the International Law Programme here is its position as a dependable yet experimental source on global governance debates. I am especially excited to get working on the Human Rights Pathways Project, focusing on tangible ideas as to how the human rights framework can evolve to meet power shifts between states and non-state actors.’

Elia Duran-Smith, intern, International Security Programme, said:

‘I was particularly drawn to this internship because of the thematic focuses of the programme around nuclear security and emerging technologies in the sector, which are fundamental to understanding the future of the global security environment. I am looking forward to learning more about these topics while developing and expanding my research and writing skills, as well as gaining an understanding of project management and how Chatham House engages with stakeholders on policy.’

Rory Selvey, intern, Sustainability Accelerator, said:

‘For me, speeding up the transition towards a fairer, low-carbon society is one of most important global challenges. I’m really excited to be an intern at the Sustainability Accelerator, collaborating with different teams and exploring innovation solutions to this challenge. Chatham House will help me develop vital knowledge and skills, acting as a fantastic springboard for a potential career in sustainable finance, macroeconomics, or international development.’

Bruna Miguel, intern, Environment and Society Programme, said:

‘Being an intern in the Environment and Society Programme will give me the opportunity to further investigate how these issues relate and how we can achieve true sustainability. I look forward to learning from the experts in the area that I will meet (and hopefully find a dissertation topic!).’

Ritvij Singh, intern, Global Health Programme, said:

‘My view of healthcare delivery is from the frontlines as a medical doctor. I applied to this internship to widen my perspective and get an insight into the institutions that will help facilitate universal health. I will use this experience to pursue a career in global health.’

For more information about the internships, please contact Alis Martin.

Mammalian circadian clocks are driven by transcription/translation feedback loops composed of positive transcriptional activators (BMAL1 and CLOCK) and negative repressors (CRYPTOCHROMEs (CRYs) and PERIODs (PERs)). CRYs, in complex with PERs, bind to the BMAL1/CLOCK complex and repress E-box–driven transcription of clock-associated genes. There are two individual CRYs, with CRY1 exhibiting higher affinity to the BMAL1/CLOCK complex than CRY2. It is known that this differential binding is regulated by a dynamic serine-rich loop adjacent to the secondary pocket of both CRYs, but the underlying features controlling loop dynamics are not known. Here we report that allosteric regulation of the serine-rich loop is mediated by Arg-293 of CRY1, identified as a rare CRY1 SNP in the Ensembl and 1000 Genomes databases. The p.Arg293His CRY1 variant caused a shortened circadian period in a Cry1−/−Cry2−/− double knockout mouse embryonic fibroblast cell line. Moreover, the variant displayed reduced repressor activity on BMAL1/CLOCK driven transcription, which is explained by reduced affinity to BMAL1/CLOCK in the absence of PER2 compared with CRY1. Molecular dynamics simulations revealed that the p.Arg293His CRY1 variant altered a communication pathway between Arg-293 and the serine loop by reducing its dynamicity. Collectively, this study provides direct evidence that allosterism in CRY1 is critical for the regulation of circadian rhythm.

Expert

Expert

Centrioles are key eukaryotic organelles that are responsible for the formation of cilia and flagella, and for organizing the microtubule network and the mitotic spindle in animals. Centriole assembly requires oligomerization of the essential protein spindle assembly abnormal 6 (SAS-6), which forms a structural scaffold templating the organization of further organelle components. A dimerization interaction between SAS-6 N-terminal “head” domains was previously shown to be essential for protein oligomerization in vitro and for function in centriole assembly. Here, we developed a pharmacophore model allowing us to assemble a library of low-molecular-weight ligands predicted to bind the SAS-6 head domain and inhibit protein oligomerization. We demonstrate using NMR spectroscopy that a ligand from this family binds at the head domain dimerization site of algae, nematode, and human SAS-6 variants, but also that another ligand specifically recognizes human SAS-6. Atomistic molecular dynamics simulations starting from SAS-6 head domain crystallographic structures, including that of the human head domain which we now resolve, suggest that ligand specificity derives from favorable Van der Waals interactions with a hydrophobic cavity at the dimerization site.