Mitochondria are specialized compartments that produce requisite ATP to fuel cellular functions and serve as centers of metabolite processing, cellular signaling, and apoptosis. To accomplish these roles, mitochondria rely on the genetic information in their small genome (mitochondrial DNA) and the nucleus. A growing appreciation for mitochondria's role in a myriad of human diseases, including inherited genetic disorders, degenerative diseases, inflammation, and cancer, has fueled the study of biochemical mechanisms that control mitochondrial function. The mitochondrial transcriptional machinery is different from nuclear machinery. The in vitro re-constituted transcriptional complexes of Saccharomyces cerevisiae (yeast) and humans, aided with high-resolution structures and biochemical characterizations, have provided a deeper understanding of the mechanism and regulation of mitochondrial DNA transcription. In this review, we will discuss recent advances in the structure and mechanism of mitochondrial transcription initiation. We will follow up with recent discoveries and formative findings regarding the regulatory events that control mitochondrial DNA transcription, focusing on those involved in cross-talk between the mitochondria and nucleus.

Business Briefing: Assessing the geopolitical implications of EU AI regulation 17 September 2024 — 4:00PM TO 5:00PM Anonymous (not verified) 8 August 2024 Chatham House

Join us for this critical discussion of how the EU AI Act will shape the world’s approach to the technology.

Join us for this critical discussion of how the EU AI Act will shape the world’s approach to the technology

Governments, technology companies and civil society groups across the world are now advocating firmer AI regulation. Machine learning algorithms have changed the way we interact with technology and powered much of our online lives for decades: why has this pendulum swung back so far toward greater control, and why now?

In 2023 the UK government seized the initiative with its Bletchley AI Safety Summit. The event attempted to address the so called ‘frontier risks’ associated with AI development. Global competition on AI is reflected in AI governance efforts in China, US, the Gulf and beyond. But to date, it is the EU that has led the West in passing AI legislation. The EU AI Act, has separated AI systems into graded risk categories carrying different regulatory requirements, and it remains to be seen whether global AI will feel the Brussels effect.

This conversation will cover the following questions:

• Critics have painted regulation including the AI Act as anti-innovation. Is this a fair assessment?
• What lessons can we learn from the successes and shortcomings of GDPR?
• How do we tackle the challenge of low public trust in AI and low public trust in government technology projects, particularly in Western democracies?
• Does the proliferation of safety institutes, and the AI office, point to the emergence of a new type of technical governance institution? What is its future?

30 Years of Non-Maghreb: What next for Algeria-Morocco relations? 10 September 2024 — 2:00PM TO 3:15PM Anonymous (not verified) 13 August 2024 Online

Experts discuss Algeria-Morocco relations and implications for regional actors.

In 1989, the establishment of the Arab Maghreb Union (UMA) brought a promise of economic integration and strengthening of ties between Algeria, Libya, Mauritania, Morocco and Tunisia for the benefit and prosperity of their societies.

Decades on, very little has been accomplished in developing the Maghreb project, and the region remains one of the least integrated in the world, despite significant social and cultural similarities between member countries. The last time the full UMA leadership met was back in 1994, with August 2024 marking 30 years of closed borders between Algeria and Morocco.

Relations between the two largest Maghreb countries have deteriorated further since 2020 due to disagreements over issues of Western Sahara, and, most recently, the Abraham Accords, with Algeria cutting diplomatic ties with Morocco in 2021.

In this webinar, experts will discuss:

• Which primary obstacles are hindering Maghreb integration and Algeria-Morocco relations?
• What are the costs and implications for regional countries?
• What are the positions of Libya, Tunisia, and Mauritania?
• What is required for a rapprochement and how can external partners support this? 

What is the future of cross-border data flows? 16 September 2024 — 6:00PM TO 7:00PM Anonymous (not verified) 15 August 2024 Chatham House and Online

Navigating long-standing tensions and newfound difficulties for unlocking shared prosperity among modern, digital economies.

Cross-border data flows can unlock shared prosperity among digital economies, advance international security, and address cybercrime and global crises. But ensuring the free flow of data across borders involves navigating complex regulatory, security, trust, political, and technical challenges. Developing effective frameworks and agreements to support data flows is a significant undertaking.

Recent bilateral and multilateral agreements and initiatives have advanced data-sharing, respecting the right to privacy and upholding notions of sovereignty. This has contributed to clearer rules and (potentially) better solutions such as the OECD declaration on government access to data held by companies. Further progress, supportive of public safety and national security, is on the horizon, like G7 support for data free flow with trust and industry-led, trusted cloud principles on protecting human rights and competitiveness.

More work is needed to operationalize commitments and advance ongoing negotiations, like US–EU negotiations on e-evidence in criminal proceedings. This is key for ensuring ‘hard’ legal and regulatory mechanisms complement OECD principles. Stakeholders from law enforcement, national security, data protection and industry must confront tensions between sovereign prerogatives and cooperation. They must also overcome traditional silos between law enforcement and national security work. On the horizon are newfound challenges (for example, in harmonizing legal frameworks and responding to advances in technology). All the while, stakeholders must work together to promote economic interests, data protection, privacy and cybersecurity.

This expert panel discusses the future of cross-border data-sharing, raising questions including:

• What value does cross-border data-sharing bring and where are its current ‘pain points’?
• To enable data free flows, how should principles complement ‘hard’ legal and regulatory mechanisms?
• Beyond states, law enforcement, major industry players and international organizations, what roles should SMEs, the technical community and civil society stakeholders play in shaping and operationalizing principles?
• Looking ahead, where is progress in data-sharing principles and arrangements expected or possible?

A drinks reception follows the event.

This event is supported by Microsoft as part of a project on data sharing. The project has benefited greatly from the insights of a multi-stakeholder taskforce and concludes with an open-access special issue of the Journal of Cyber Policy.

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

How are migration and global megatrends shaping international labour?

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

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

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

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

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

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

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

Making the circular economy work for global development: how the UN Summit of the Future can deliver 23 September 2024 — 6:15PM TO 9:00PM Anonymous (not verified) 5 September 2024 Online

This policy roundtable focusses on how to advance implementation of a global approach and collaboration to an inclusive circular economy for an updated post-2030 SDG framework.

As the world looks beyond the Sustainable Development Goals (SDGs) towards the post-2030 era, integrating the principles of the circular economy into the future global development agenda becomes imperative.  

A new Chatham House research paper about the role of the circular economy for the SDGs and their possible extension into the post-2030 development agenda will be launched in September 2024 during the UN Summit of the Future and the New York Climate Week. The paper outlines the rationale for the integration of circular economy goals into for the next crucial phase of international development and how to meet net-zero 2050 targets. It provides actionable recommendations on international cooperation mechanisms for policymakers and stakeholders at the UN Summit for the Future in 2024 and beyond.

The aim of the roundtable is to bring together stakeholders and leaders from intergovernmental organisations, business, governments and civil society. The focus of the roundtable meeting is: 

• Reflections on the Summit of the Future and the role of circularity for an updated post-2030 SDG framework.
• Discussion on key aspects of the institutional arrangements and international coordination that are needed for a globally coordinated approach to achieve an inclusive circular economy that supports SDG implementation. 
• Development of joint strategies on how to advance implementation of a global approach and collaboration to an inclusive circular economy as a follow-up from the Summit of the Future.

The objective is to emerge from the roundtable with a clearer roadmap for translating the recommendations for international coordination into concrete actions, with a shared commitment to driving meaningful change on the international level.

The event is co-hosted by Chatham House and partners from the Global Circular Economy Roadmap initiative including the African Circular Economy Network, the African Development Bank, Circular Change, Circular Innovation Lab, Circle Economy, EU CE Stakeholder Platform, Hanns Seidel Foundation, Institute of Global Environmental Strategies, Sitra, UNIDO, World Business Council on Sustainable Development, World Economic Forum and the Wyss Academy for Nature.

Further background information is available on the initiative website.

More speakers to be announced.

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.

The human cardiovascular system has adapted to function optimally in Earth's 1G gravity, and microgravity conditions cause myocardial abnormalities, including atrophy and dysfunction. However, the underlying mechanisms linking microgravity and cardiac anomalies are incompletely understood. In this study, we investigated whether and how calpain activation promotes myocardial abnormalities under simulated microgravity conditions. Simulated microgravity was induced by tail suspension in mice with cardiomyocyte-specific deletion of Capns1, which disrupts activity and stability of calpain-1 and calpain-2, and their WT littermates. Tail suspension time-dependently reduced cardiomyocyte size, heart weight, and myocardial function in WT mice, and these changes were accompanied by calpain activation, NADPH oxidase activation, and oxidative stress in heart tissues. The effects of tail suspension were attenuated by deletion of Capns1. Notably, the protective effects of Capns1 deletion were associated with the prevention of phosphorylation of Ser-345 on p47phox and attenuation of ERK1/2 and p38 activation in hearts of tail-suspended mice. Using a rotary cell culture system, we simulated microgravity in cultured neonatal mouse cardiomyocytes and observed decreased total protein/DNA ratio and induced calpain activation, phosphorylation of Ser-345 on p47phox, and activation of ERK1/2 and p38, all of which were prevented by calpain inhibitor-III. Furthermore, inhibition of ERK1/2 or p38 attenuated phosphorylation of Ser-345 on p47phox in cardiomyocytes under simulated microgravity. This study demonstrates for the first time that calpain promotes NADPH oxidase activation and myocardial abnormalities under microgravity by facilitating p47phox phosphorylation via ERK1/2 and p38 pathways. Thus, calpain inhibition may be an effective therapeutic approach to reduce microgravity-induced myocardial abnormalities.

The cystic fibrosis transmembrane conductance regulator (CFTR) is a plasma membrane anion channel that plays a key role in controlling transepithelial fluid movement. Excessive activation results in intestinal fluid loss during secretory diarrheas, whereas CFTR mutations underlie cystic fibrosis (CF). Anion permeability depends both on how well CFTR channels work (permeation/gating) and on how many are present at the membrane. Recently, treatments with two drug classes targeting CFTR—one boosting ion-channel function (potentiators) and the other increasing plasma membrane density (correctors)—have provided significant health benefits to CF patients. Here, we present an image-based fluorescence assay that can rapidly and simultaneously estimate both CFTR ion-channel function and the protein's proximity to the membrane. We monitor F508del-CFTR, the most common CF-causing variant, and confirm rescue by low temperature, CFTR-targeting drugs and second-site revertant mutation R1070W. In addition, we characterize a panel of 62 CF-causing mutations. Our measurements correlate well with published data (electrophysiology and biochemistry), further confirming validity of the assay. Finally, we profile effects of acute treatment with approved potentiator drug VX-770 on the rare-mutation panel. Mapping the potentiation profile on CFTR structures raises mechanistic hypotheses on drug action, suggesting that VX-770 might allow an open-channel conformation with an alternative arrangement of domain interfaces. The assay is a valuable tool for investigation of CFTR molecular mechanisms, allowing accurate inferences on gating/permeation. In addition, by providing a two-dimensional characterization of the CFTR protein, it could better inform development of single-drug and precision therapies addressing the root cause of CF disease.

The main protease (3CL Mpro) from SARS–CoV-2, the etiological agent of COVID-19, is an essential enzyme for viral replication. 3CL Mpro possesses an unusual catalytic dyad composed of Cys145 and His41 residues. A critical question in the field has been what the protonation states of the ionizable residues in the substrate-binding active-site cavity are; resolving this point would help understand the catalytic details of the enzyme and inform rational drug development against this pernicious virus. Here, we present the room-temperature neutron structure of 3CL Mpro, which allowed direct determination of hydrogen atom positions and, hence, protonation states in the protease. We observe that the catalytic site natively adopts a zwitterionic reactive form in which Cys145 is in the negatively charged thiolate state and His41 is doubly protonated and positively charged, instead of the neutral unreactive state usually envisaged. The neutron structure also identified the protonation states, and thus electrical charges, of all other amino acid residues and revealed intricate hydrogen-bonding networks in the active-site cavity and at the dimer interface. The fine atomic details present in this structure were made possible by the unique scattering properties of the neutron, which is an ideal probe for locating hydrogen positions and experimentally determining protonation states at near-physiological temperature. Our observations provide critical information for structure-assisted and computational drug design, allowing precise tailoring of inhibitors to the enzyme's electrostatic environment.

Dilated cardiomyopathy (DCM) is associated with mutations in cardiomyocyte sarcomeric proteins, including α-tropomyosin. In conjunction with troponin, tropomyosin shifts to regulate actomyosin interactions. Tropomyosin molecules overlap via tropomyosin–tropomyosin head-to-tail associations, forming a continuous strand along the thin filament. These associations are critical for propagation of tropomyosin's reconfiguration along the thin filament and key for the cooperative switching between heart muscle contraction and relaxation. Here, we tested perturbations in tropomyosin structure, biochemistry, and function caused by the DCM-linked mutation, M8R, which is located at the overlap junction. Localized and nonlocalized structural effects of the mutation were found in tropomyosin that ultimately perturb its thin filament regulatory function. Comparison of mutant and WT α-tropomyosin was carried out using in vitro motility assays, CD, actin co-sedimentation, and molecular dynamics simulations. Regulated thin filament velocity measurements showed that the presence of M8R tropomyosin decreased calcium sensitivity and thin filament cooperativity. The co-sedimentation of actin and tropomyosin showed weakening of actin-mutant tropomyosin binding. The binding of troponin T's N terminus to the actin-mutant tropomyosin complex was also weakened. CD and molecular dynamics indicate that the M8R mutation disrupts the four-helix bundle at the head-to-tail junction, leading to weaker tropomyosin–tropomyosin binding and weaker tropomyosin–actin binding. Molecular dynamics revealed that altered end-to-end bond formation has effects extending toward the central region of the tropomyosin molecule, which alter the azimuthal position of tropomyosin, likely disrupting the mutant thin filament response to calcium. These results demonstrate that mutation-induced alterations in tropomyosin–thin filament interactions underlie the altered regulatory phenotype and ultimately the pathogenesis of DCM.

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).

Heterotrimeric G-proteins are signaling switches broadly divided into four families based on the sequence and functional similarity of their Gα subunits: Gs, Gi/o, Gq/11, and G12/13. Artificial mutations that activate Gα subunits of each of these families have long been known to induce oncogenic transformation in experimental systems. With the advent of next-generation sequencing, activating hotspot mutations in Gs, Gi/o, or Gq/11 proteins have also been identified in patient tumor samples. In contrast, patient tumor-associated G12/13 mutations characterized to date lead to inactivation rather than activation. By using bioinformatic pathway analysis and signaling assays, here we identified cancer-associated hotspot mutations in Arg-200 of Gα13 (encoded by GNA13) as potent activators of oncogenic signaling. First, we found that components of a G12/13-dependent signaling cascade that culminates in activation of the Hippo pathway effectors YAP and TAZ is frequently altered in bladder cancer. Up-regulation of this signaling cascade correlates with increased YAP/TAZ activation transcriptional signatures in this cancer type. Among the G12/13 pathway alterations were mutations in Arg-200 of Gα13, which we validated to promote YAP/TAZ-dependent (TEAD) and MRTF-A/B-dependent (SRE.L) transcriptional activity. We further showed that this mechanism relies on the same RhoGEF-RhoGTPase cascade components that are up-regulated in bladder cancers. Moreover, Gα13 Arg-200 mutants induced oncogenic transformation in vitro as determined by focus formation assays. In summary, our findings on Gα13 mutants establish that naturally occurring hotspot mutations in Gα subunits of any of the four families of heterotrimeric G-proteins are putative cancer drivers.

G protein–coupled receptors (GPCRs) initiate signaling cascades via G-proteins and beta-arrestins (βarr). βarr-dependent actions begin with recruitment of βarr to the phosphorylated receptor tail and are followed by engagement with the receptor core. βarrs are known to act as adaptor proteins binding receptors and various effectors, but it is unclear whether in addition to the scaffolding role βarrs can allosterically activate their downstream targets. Here we demonstrate the direct allosteric activation of proto-oncogene kinase Src by GPCR–βarr complexes in vitro and establish the conformational basis of the activation. Whereas free βarr1 had no effect on Src activity, βarr1 in complex with M2 muscarinic or β2-adrenergic receptors reconstituted in lipid nanodiscs activate Src by reducing the lag phase in Src autophosphorylation. Interestingly, receptor–βarr1 complexes formed with a βarr1 mutant, in which the finger-loop, required to interact with the receptor core, has been deleted, fully retain the ability to activate Src. Similarly, βarr1 in complex with only a phosphorylated C-terminal tail of the vasopressin 2 receptor activates Src as efficiently as GPCR–βarr complexes. In contrast, βarr1 and chimeric M2 receptor with nonphosphorylated C-terminal tail failed to activate Src. Taken together, these data demonstrate that the phosphorylated GPCR tail interaction with βarr1 is necessary and sufficient to empower it to allosterically activate Src. Our findings may have implications for understanding more broadly the mechanisms of allosteric activation of downstream targets by βarrs.

The amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)–linked RNA-binding protein called FUS (fused in sarcoma) has been implicated in several aspects of RNA regulation, including mRNA translation. The mechanism by which FUS affects the translation of polyribosomes has not been established. Here we show that FUS can associate with stalled polyribosomes and that this association is sensitive to mTOR (mammalian target of rapamycin) kinase activity. Specifically, we show that FUS association with polyribosomes is increased by Torin1 treatment or when cells are cultured in nutrient-deficient media, but not when cells are treated with rapamycin, the allosteric inhibitor of mTORC1. Moreover, we report that FUS is necessary for efficient stalling of translation because deficient cells are refractory to the inhibition of mTOR-dependent signaling by Torin1. We also show that ALS-linked FUS mutants R521G and P525L associate abundantly with polyribosomes and decrease global protein synthesis. Importantly, the inhibitory effect on translation by FUS is impaired by mutations that reduce its RNA-binding affinity. These findings demonstrate that FUS is an important RNA-binding protein that mediates translational repression through mTOR-dependent signaling and that ALS-linked FUS mutants can cause a toxic gain of function in the cytoplasm by repressing the translation of mRNA at polyribosomes.

The inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs), which form tetrameric channels, play pivotal roles in regulating the spatiotemporal patterns of intracellular calcium signals. Mutations in IP3Rs have been increasingly associated with many debilitating human diseases such as ataxia, Gillespie syndrome, and generalized anhidrosis. However, how these mutations affect IP3R function, and how the perturbation of as-sociated calcium signals contribute to the pathogenesis and severity of these diseases remains largely uncharacterized. Moreover, many of these diseases occur as the result of autosomal dominant inheritance, suggesting that WT and mutant subunits associate in heterotetrameric channels. How the in-corporation of different numbers of mutant subunits within the tetrameric channels affects its activities and results in different disease phenotypes is also unclear. In this report, we investigated representative disease-associated missense mutations to determine their effects on IP3R channel activity. Additionally, we designed concatenated IP3R constructs to create tetrameric channels with a predefined subunit composition to explore the functionality of heteromeric channels. Using calcium imaging techniques to assess IP3R channel function, we observed that all the mutations studied resulted in severely attenuated Ca2+ release when expressed as homotetramers. However, some heterotetramers retained varied degrees of function dependent on the composition of the tetramer. Our findings suggest that the effect of mutations depends on the location of the mutation in the IP3R structure, as well as on the stoichiometry of mutant subunits assembled within the tetrameric channel. These studies provide insight into the pathogenesis and penetrance of these devastating human diseases.

IQGAP1 is a key scaffold protein that regulates numerous cellular processes and signaling pathways. Analogous to many other cellular proteins, IQGAP1 undergoes post-translational modifications, including phosphorylation. Nevertheless, very little is known about the specific sites of phosphorylation or the effects on IQGAP1 function. Here, using several approaches, including MS, site-directed mutagenesis, siRNA-mediated gene silencing, and chemical inhibitors, we identified the specific tyrosine residues that are phosphorylated on IQGAP1 and evaluated the effect on function. Tyr-172, Tyr-654, Tyr-855, and Tyr-1510 were phosphorylated on IQGAP1 when phosphotyrosine phosphatase activity was inhibited in cells. IQGAP1 was phosphorylated exclusively on Tyr-1510 under conditions with enhanced MET or c-Src signaling, including in human lung cancer cell lines. This phosphorylation was significantly reduced by chemical inhibitors of MET or c-Src or by siRNA-mediated knockdown of MET. To investigate the biological sequelae of phosphorylation, we generated a nonphosphorylatable IQGAP1 construct by replacing Tyr-1510 with alanine. The ability of hepatocyte growth factor, the ligand for MET, to promote AKT activation and cell migration was significantly greater when IQGAP1-null cells were reconstituted with IQGAP1 Y1510A than when cells were reconstituted with WT IQGAP1. Collectively, our data suggest that phosphorylation of Tyr-1510 of IQGAP1 alters cell function. Because increased MET signaling is implicated in the development and progression of several types of carcinoma, IQGAP1 may be a potential therapeutic target in selected malignancies.

China: End of the Reform Era 20 July 2018 — 12:30PM TO 1:30PM Anonymous (not verified) 30 May 2018 Chatham House, London

The speaker will argue that China’s reform era is ending, and that core factors which characterized it - including political stability, ideological openness and rapid economic growth - are unravelling.

Since the 1990s, Beijing’s leaders have firmly rejected any fundamental reform of their authoritarian one-party political system, even as a decades-long boom has reshaped China’s economy and society. On the surface, their efforts have been a success, but Carl Minzner says a closer look at China’s reform era reveals a different truth.

He outlines how over the past three decades, a frozen political system has fuelled both the rise of entrenched interests within the Communist Party and the systematic underdevelopment of institutions of governance among state and society at large. Economic gaps have widened, social unrest has worsened and ideological polarization has deepened.

The speaker will discuss how China’s leaders are attempting to address these looming challenges, including institutional reforms and a shift back towards single-man rule. The speaker will also consider the question of regime stability given that China’s era of ‘reform and opening up’ is ending and there is now a renewed uncertainty over Beijing’s future.

THIS EVENT IS NOW FULL AND REGISTRATION HAS CLOSED.

Mobile Ecosystems as a Driver of Innovation and Growth in the Asia-Pacific 19 September 2018 — 12:30PM TO 3:00PM Anonymous (not verified) 18 September 2018 Chatham House, London

Development Prospects in the Asia-Pacific: The Role of the Asian Development Bank 25 September 2019 — 12:30PM TO 1:30PM Anonymous (not verified) 4 September 2019 Chatham House | 10 St James's Square | London | SW1Y 4LE

The speaker will discuss development prospects in the Asia-Pacific and their implications for Europe and the UK. He will outline prospects for the region’s growth, the impact of the current US-China trade conflict as well as other challenges faced by the region. He will also discuss the future role of the Asian Development Bank and how it plans to support the further development of the region.

Network Power in the Asia-Pacific: Making Sense of the New Regionalism and Opportunities for Cooperation 7 February 2020 — 9:45AM TO 5:30PM Anonymous (not verified) 17 January 2020 Chatham House | 10 St James's Square | London | SW1Y 4LE

The Asia-Pacific region continues to increase in geopolitical and geoeconomic importance. The rise of China and tensions with the US are affecting bilateral relationships and traditional alliances in the region. Whether seen from the perspective of the Quad – Australia, India, Japan and the US – or the Indo-Pacific concept embraced by a wide range of countries but with no shared consensus on scope and objectives or with ASEAN who insists on the importance of its own centrality, the region is redefining and reconceptualising itself.

With a diverse range of initiatives – including the Regional Comprehensive Economic Partnership (RCEP) and Comprehensive and Progressive Agreement for Trans-Pacific Partnership (CPTPP) – there are a plethora of regional agreements and institutional groupings that add further complexity.

As the Bretton Woods architecture continues to be dominated by Western powers, China is also spearheading parallel governance initiatives such as the Asian Infrastructure Investment Bank (AIIB), the Belt and Road Initiative and the Shanghai Cooperation Organization (SCO) as a means of enhancing its geopolitical and geoeconomic influence.

This one-day conference will focus on how such networks and alliances have been built, and sustained, in the Asia-Pacific region. In order to understand how new regional initiatives might open up opportunities for new forms of international cooperation, the conference will focus on the themes of cyber-technology and innovation, sustainable development and mitigating the impacts of climate change and new infrastructure initiatives. It will assess whether there is a zero-sum conflict between competing networks and agendas or whether a common approach can be developed.

Virtual Roundtable: The Economic Implications of COVID-19 on Asia 2 April 2020 — 11:00AM TO 12:00PM Anonymous (not verified) 27 March 2020 Chatham House | 10 St James's Square | London | SW1Y 4LE

The COVID-19 pandemic is likely to have a damaging economic impact on Asia, potentially the most serious since the financial crisis two decades ago. While early estimates suggest that a recession is inevitable, differing countries in Asia are generally deploying modest fiscal and monetary measures. This is true even in China, compared with the ‘whatever it takes’ approach pursued by Europe and America.

How effective will these measures be in reviving growth and in easing the pain, particularly on the poor in developing countries in Asia? Is Asia witnessing a sudden but temporary halt in economic activity rather than a prolonged slowdown? At this virtual roundtable, the speakers will consider the likelihood of a recovery for trade in the region and will explore what lessons can be learned from countries like Singapore, who seem to be successfully managing the health and economic aspects of COVID-19.

This event is online only. After registering, you will receive a follow-up confirmation email with details of how to join the webinar.

What are the lasting impacts of the AUKUS agreement? Interview LJefferson 15 August 2022

Drawing on their International Affairs article, Jamal Barnes and Samuel Makinda outline the effect of AUKUS on Australia-France relations and the liberal order.

Almost a year after the surprise announcement of the AUKUS treaty, its full diplomatic implications are still being understood. The security cooperation agreement between Australia, the US and the UK caused outrage in France and was a notable source of discord between states that see themselves as defenders of the liberal international order.

In this interview Jamal Barnes and Samuel Makinda discuss their recent article in International Affairs and assess the effect of the agreement on relationships between its signatories and France and the EU, the potential for reconciliation in the treaty’s aftermath, as well as the implications it has for trust in world politics.  

What was the AUKUS treaty and why did Australia sign it?

The AUKUS treaty is an agreement between Australia, the US and the UK. Signed in 2021, it facilitates cooperation on security issues in the Indo-Pacific between the three countries – specifically, it concerns the sharing of ‘military capabilities and critical technologies, such as cyber, artificial intelligence, quantum technologies, and undersea domains’.

A key aspect is that Australia will purchase nuclear-fuelled submarines from either the US or UK. Australia decided to purchase nuclear-powered submarines – and reneged on its 2016 agreement to purchase French-built diesel-propelled submarines – because it believed that the French-made submarines were no longer fit for purpose.

However, the agreement is about more than submarines. Although Australia, the UK and US argue that AUKUS is designed to defend the rules-based international order and help ‘preserve security and stability in the Indo-Pacific’, AUKUS has been largely seen as a response to the rise of China and its military activities in the region. The AUKUS agreement reflects the increased attention that the US, UK and Australia are paying to the Indo-Pacific and their commitment to constraining China’s exercise of power in the region.

What were the effects of the AUKUS treaty on relations between Australia and France?

It led to a serious diplomatic rift. Australian officials, including former Prime Minister Morrison, had visited President Macron in France and told him nothing about AUKUS. Morrison had assured Macron in June 2021 while former Australian foreign and defence ministers had assured their French counterparts that Australia was fully committed to the purchase of French submarines just two weeks before the announcement of AUKUS.

When French officials found out about AUKUS on the day it was announced on 15 September 2021, they declared publicly that they had been betrayed and stabbed in the back. Not only had France built its relationship with Australia on trust, but its relationship was more than just about submarines. It was designed to be central to France’s 50-year engagement strategy in the Indo-Pacific. However, France was not only left out of talks but was also betrayed by a country it considered a close ally.

France responded by temporarily recalling its ambassador and stated that it would ‘redefine’ its relationship with Australia. It did not say that it would not work with Australia, but rather downgraded its relationship to one where it would only do so on a case-by-case basis.

In your article you mention that the AUKUS treaty was seen as a betrayal of trust by France in particular. Why use the word ‘betrayal’?

The word betrayal is accurate because Australia’s actions went beyond simply cancelling a business contract. Australia breached France’s trust. Not all agreements involve trust. Some are driven by self-interest while others are simply legal contracts. When these agreements are broken, the usual response is feelings of disappointment and a belief that one party is unreliable and has not lived up to its end of the agreement.

However, when diplomatic partnerships involve trust, they often contain an emotional element. A key element of trust is that one party makes itself vulnerable to another in the expectation that neither party will take advantage. When that trust is breached, the response is different from a breach of contract.

It involves feelings of betrayal as deeper emotional factors are involved. This could be seen in President Macron’s anger, and his and other French officials’ willingness to publicly call Prime Minister Morrison a liar who had stabbed France in the back. If the previous France-Australia agreement was simply a legal contract, it would have been difficult to explain the emotional element of this diplomatic fallout.

How did the signing of the AUKUS treaty affect wider relations between members of AUKUS and EU member states?

The EU, like France, felt betrayed by the AUKUS announcement. Despite being a key ally of the US, Australia, and the UK, it was left out of AUKUS discussions, and was not aware of the agreement until it was announced in the media.

What made this worse was that the EU was in the process of announcing its Indo-Pacific strategy, which was characterized as ‘maybe one of the [EU’s] most important geopolitical documents’ by High Representative for Foreign and Security Affairs, Josep Borrell. For the EU, this was the latest in a long line of recent policy betrayals that had left it uncertain if it could trust key allies on important issues. The result was greater calls from within the EU to more forcefully pursue ‘strategic autonomy’, meaning a more assertive and independent EU foreign policy.

Do betrayals of trust affect the health of the liberal international order?

Yes, they can. While it is common for leaders in liberal democracies to lie to their own people, lying to the leaders of other countries can have serious repercussions for the norms, rules and institutions of international society. A key aspect of international society is the ‘presumption of trust’ that facilitates legal compliance and diplomatic cooperation.

Without this presumption it is difficult for states to engage in long term partnerships or have confidence that diplomatic agreements will be upheld. In our article, we highlight how Australia’s violation of a particular norm, that agreements must be kept, has undermined this presumption of trust. This norm not only helps build trust between states, but also contributes to the maintenance of international order by helping to support the presumption of trust in international society.

Critical elections and the future of American politics 14 December 2022 — 9:00AM TO 10:15AM Anonymous (not verified) 8 December 2022 Chatham House

This event explores whether the United States is undergoing a critical change in the composition of the Republican and Democratic parties.

Drawing on current and historical events, Paul E. Peterson joins us to examine whether the United States is undergoing a critical change in the composition of the Republican and Democratic parties.

Key questions to consider include:

• What factors might be driving such an evolution within both parties?

• How could these dynamics affect the balance of power in Washington and in states?

This event is co-hosted with the Centre on US Politics at UCL, and the US and Americas programme at Chatham House would like to thank the British Association for American Studies for their generous support of this event.

The near death and uncertain future of the US National Security Council 27 January 2023 — 9:00AM TO 10:00AM Anonymous (not verified) 9 January 2023 Chatham House

What role should the US National Security Council play in an era of great power competition?

Please plan to arrive at Chatham House from 08:45 GMT as the event will begin promptly at 09:00 GMT

Over the last three years, the US National Security Council (NSC) has gone from being neglected to necessary again, in Washington.

After former US President Donald Trump ignored and then tried to dismantle the NSC, current US President Joe Biden has restored the body but chosen not to reform it.

Born in the days before the Cold War and empowered during the War on Terror, what role should the NSC play in an era of great power competition?

Plus, how must it, and the rest of Washington, evolve to meet the challenges and opportunities that remain in the 21st century?

State of the Union has lessons for transatlantic unity Expert comment NCapeling 8 February 2023

Analysing key foreign policy aspects of President Joe Biden’s annual address, and what it means for the upcoming Munich Security Conference and the year ahead.

Trade and economics are key areas to watch

Daniel W. Drezner

Russia’s absence from the Munich Security Conference will allow US and European policymakers to brag about their flourishing partnership. The past year has seen repeated predictions of a fracturing transatlantic relationship – only to see repeated agreement on how to sanction Russia and which arms to ship to Ukraine.

Putin invaded because he thought the West was divided. Events have proven him wrong. When one takes a step back, however, and examines the Biden administration’s embrace of geoeconomics, Putin’s assumption becomes easier to comprehend.

The strongest throughline between the Trump and Biden administrations has been their shared mindset on weaponized interdependence. Both administrations have been wary of US interdependence with an increasingly autocratic China.

The primary difference has been that, while the Trump administration talked a good game, the Biden administration has passed laws and issued executive orders making the pivot away from trade liberalization a reality.

The passage of the CHIPS and Science Act, Bipartisan Infrastructure Law, and the Inflation Reduction Act (IRA) amount to the most ambitious US attempt at industrial policy in decades, accompanied by multiple executive orders examining US supply chain resilience and imposing unprecedented export controls targeting China.

The Biden administration’s restrictions on exchange with China’s semiconductors includes the use of the ‘foreign direct product rule’, essentially a means of applying US export controls in an extraterritorial manner.

The Biden administration’s angry response to the WTO panel ruling against US steel and aluminum tariffs makes it clear the US will apply an expanded definition of national security to restrict trade. In many ways, the sanctions on Russia are a continuation of a US foreign economic policy grounded in geoeconomics.

Several of these measures have rankled European officials. The IRA massively subsidizes the North American production of environmentally-friendly cars, discriminating against European producers. And continued US hostility to the WTO leaves European officials wondering if they are the last bastion of multilateralism left in the world. In Washington and Davos last month, European policymakers made their displeasure clear.

The sanctions against Russia and export controls against China threaten to be additional sore subjects. During the strategic embargo of the Soviet Union, US officials wanted to maximize restrictions while European allies wanted more trade opportunities. Since then, Europeans have suspected that the US uses multilateral export controls regimes to advance its commercial interests, while Americans worry Europe underestimates the risks of business-as-usual with China.

The Biden administration has tried to finesse these trade tensions, and was successful at persuading the Netherlands to join the US in the export controls on China. More generally, Biden officials talk about ‘friendshoring’ and propose mechanisms for greater policy coordination, such as the US-EU Trade and Technology Council. But even in these gestures, US officials have taken greater market access off the table.

In the State of the Union address, Biden bragged about how the US ‘came together to defend a stronger and safer Europe’ as well as defending his ‘buy American’ plans and pledging to make sure the ‘supply chain for America begins in America’. At the upcoming Munich Security Conference, attention should be on how much officials talk about trade and economic issues. The more that topic comes up, the clearer it will be that both sides are subtweeting each other about the future of the transatlantic economic relationship.

Division on China now would bring a high price

Dr Leslie Vinjamuri

President Biden has made unity his guiding principle and chief objective, but it is a tall order. His State of the Union address touted past bipartisan backing for investments in infrastructure, climate-friendly technologies, and semiconductor chips, along with a focus on creating jobs for working-class Americans, especially in manufacturing.

Little was said that was explicitly about China, but the Biden administration has said that China is its pacing challenge, and competing with China has shaped the ambition behind these legislative successes.

In fact, the hallmark of the address was its foreign policy minimalism. Biden hailed unity in the US defence of democracy in Ukraine in the face of Russia’s aggression. And in defending US sovereignty in the face of China’s violations, this time with a balloon.

But the presidents temporary minimalism on foreign policy will be short-lived. And unity with America’s partners and allies will continue to be at the centre of Biden’s strategy. In the past 12 months, it is the yardstick by which he has measured America’s success with respect to Ukraine.

Russia’s invasion of Ukraine has so far served as a lubricant for the NATO alliance, and for the US relationship with its non-NATO allies.

This has not automatically sprung from the well of Russia’s aggression. NATO’s success, and transatlantic unity, has been achieved through the sheer force of diplomatic effort, not least by the US.

Now Biden is looking for unity on China. His administration has identified China as its pacing threat. While Ukraine will continue to demand and deserve attention, the US will be looking beyond the urgent to focus on other less urgent but crucially important challenges. That means China.

China’s balloon helps ensure unity will be an easy victory at home. For several days, the balloon floated across the US, captivating the American public, seizing the headlines, and hardening US attitudes towards its only peer competitor.

Republican leaders in Congress are determined to scrutinize US policy to ensure it is tough on China, especially on technology and deterrence. This intense domestic focus on China could put Biden in a bind as he seeks to resume diplomacy. It also explains why he was careful not to inflate the China threat in his address. Secretary Blinken’s visit to Beijing has already been postponed.

As the Munich Security Conference approaches, the president’s unity agenda will turn to Europe, but the timing is difficult. China is opening and a charm offensive across Europe is likely. Europe is vulnerable as it seeks to recover its economies, continue to hold Russia back, and inhibit greater alignment between Russia and China.

The risk for the US is that domestic pressure to take a harder line on China escalates and Europe refuses to keep up. But dividing on China would come at a high price, both for Europe and the US, so to avoid this, they should take a pragmatic and sequenced approach to cooperation.

The goal for now should be policy coordination, as success is vital to momentum and managing expectations in the current environment is critical. Alignment may be possible with discrete partners on specific topics. But the perfect should not be the enemy of the good.

The US has postponed, not cancelled, Blinken’s trip while Europe is preparing to ramp up its diplomacy with China. A collective but temporary and shared transatlantic pause on diplomacy would offer low hanging fruit to give momentum to transatlantic cooperation.

It would also signal to China a unity that has a power of its own. A clear and coordinated signal, soon, that Europe and the US are moving forward with diplomacy is essential.

Munich can move the talk into action on Ukraine

James Nixey

Russia’s excommunication from this year’s Munich Security Conference is an opportunity. The principle of inclusivity may have pros and cons, but the cons have been evident since at least 2007 – its use as a platform for Russia’s leadership to launch broadsides about ‘western injustice’ and a reflexive default to increasingly inappropriate and harmful diplomatic courtesies and allowances.

Without the distraction of listening to Russian lies, there is at least now the remote possibility of a more unified West agreeing to specific action beyond the talk. As at the recent Ramstein talks, it is unlikely Munich will result in an agreement to send F-16 fighter jets to Ukraine. That may prove a step too far for the West or it will need further Russian atrocities inflicted upon Ukrainians on a scale horrendous enough to prick consciences once again.

However, although President Biden’s State of the Union address has promised nothing new or innovative regarding Ukraine or Russia, it did re-establish the fundamentals of US support and so can serve as a ‘pre-read’ for a newfound resolve.

Although some European countries are a lost cause, others – Germany for example – have proved able to be guilted into action. The key lesson for everyone to understand is that Ukraine is sovereign. Or at least ‘nothing about Ukraine, without Ukraine’. The difference is moot but, from these simple precepts, all else flows.

Ukrainians will be their impassioned selves at Munich. But although publicly gracious and thankful, privately they are distraught at the West’s collective failure to affirm these principles and back them with the necessary support, not just to force a stalemate or a ‘frozen conflict’ but to engineer victory.

Most Ukrainian officials would privately argue that the danger to their country comes more from the West and forums such as the Munich Security Conference than it does from Russia, which can be defeated with the requisite tangible assistance. In Munich, beyond fine words of support – watertight from some, ambiguous from others – there lurks the ever-present danger of the politician who simply wants it all to go away by offering Putin an off-ramp.

The irony of the host city of this forum is that many times over the past year compromise ‘solutions’ have been described as having ‘a whiff of Munich’ about them – a reference of course to appeasement in 1938, which still haunts.

As it should, because the failure to ensure Ukraine’s victory with an outcome the Ukrainian government and people are content with and which convinces Russia it was a disastrous mistake to escalate, will lead to a global security collapse too catastrophic to contemplate.

Middle East security challenges must be dealt with

Dr Sanam Vakil

A trifecta of security concerns – Iran’s advancing nuclear programme, the export of unmanned aerial vehicles (UAVs) to support Russia in the war in Ukraine, and a heavy-handed response towards protests in Iran – has raised alarm bells in Washington, Europe and the UK. These intersecting challenges lay bare the lack of a broader Iran strategy and the deprioritization of Middle East security among transatlantic partners.

This downgrading of the Middle East was evident in President Biden’s State of the Union speech as, for the first time in decades, the region was not even mentioned. The upcoming Munich Security conference provides a much needed opportunity for the transatlantic community to align on next steps and multilateral policy responses.

Transatlantic partners have long relied on the prism of the JCPOA negotiations as the pathway to both separate and manage nuclear tensions from broader regional challenges associated with Iran’s export of lethal aid and sponsorship of proxy groups.

Despite repeated negotiation efforts led by the Biden administration since April 2021, the JCPOA has languished due to Tehran’s fears over another US retreat. The promise of sanctions relief has also failed to incentivise Iran’s return to the deal. Tehran’s nuclear programme has accelerated without the consistent IAEA oversight which was part of the initial deal and is now at a level where it can produce enough uranium enrichment for four nuclear weapons.

Tehran’s decision to send drones to support Moscow’s war effort has further elevated transatlantic concerns, and reports have circulated that Tehran may also export its missile capabilities and build a drone factory in Russia. In tandem, the two sanctioned states have begun to strengthen their economic arrangements.

Offsetting the North Korean strategic challenge 16 March 2023 — 9:30AM TO 10:30AM Anonymous (not verified) 8 March 2023 Online

This event explores what balance between pressure and dialogue is most likely to incentivise North Korea to limit its provocations.

With North Korea having steadily increased its nuclear and conventional security capabilities over the course of recent months, the speakers explore practical options for lowering tensions on the Korean peninsula.

They consider how best to re-engage diplomatically with North Korea, including the role of key actors such as the US, South Korea, Japan, and European states, in advancing a constructive resolution of current tensions.

The discussion explores finding a balance between pressure and dialogue which is most likely to incentivise North Korea to limit its provocations, assess the risks of a possible seventh nuclear test, and consider the viability of multilateral cooperation in enhancing regional security in north-east Asia.

This event forms part of the Korea Foundation Korea Fellowship, funded by the Korea Foundation and Taejae Academy.

Ethics of dealing with authoritarians 28 March 2023 — 12:00PM TO 1:00PM Anonymous (not verified) 20 March 2023 Chatham House

How can democracies simultaneously defend human rights and promote open societies while still engaging with leaders from non-democratic states as strategic allies?

In 2022, the Biden administration called upon the world’s democracies to unite against a rising tide of autocracy. Through its messaging, conferences, and op-eds, the US and its allies presented the public with a binary choice: democracy or autocracy.

But in today’s world, and in the practice of international relations, the choice is rarely this simple.  

Joel Rosenthal, president of Carnegie Council, joins Chatham House to discuss how democracies and multilateral institutions can leverage ethics as a tool to assess concerns and trade-offs when engaging with illiberal actors.

Can democracies afford to be adversarial with certain countries or overly selective in cooperation when facing global-scale challenges such as climate change and the emergence of AI?

How can democracies simultaneously defend human rights and promote open societies while still engaging with leaders from non-democratic states as strategic allies?

The interconnected impacts of the Iraq war Expert comment LJefferson 22 March 2023

Relying on weak intelligence for invading Iraq has had a negative impact on US and UK credibility with several consequences that persist to this day.

20 years on from the fateful decision to invade Iraq, it is generally accepted that the US and UK governments overstated the evidence available for them to justify military action. The central claim to defend invading Iraq was that the country had continued its illicit nuclear weapons programme and had retained illegal stockpiles of biological and chemical weapons. None of these claims supported an imminent threat justification nor could any hidden caches of WMD be found by the US Iraq Survey Group after the invasion.  

In the US, President George W. Bush and Vice President Dick Cheney hinted at additional evidence which could not be shared publicly to suggest that if only people knew what the government knew, they would agree that Iraq posed a significant threat to the West and needed to be disarmed.

In the UK, the Blair government acted similarly, focusing on a narrow interpretation of the evidence provided by the intelligence services and ignoring many of the dire warnings offered by academics and other experts. The Chilcot Inquiry found that the Blair government greatly exaggerated the threat Iraq posed to the UK, and that government arguments were based on the prime minister’s personal beliefs, as well as his promise to President Bush to support the US invasion. 

Relying on inadequate information and a biased analysis for invading Iraq has had a negative impact on US and UK credibility in the international security policy environment and domestically with ramifications that persist to this day.  

Impacts on soft power and trust

The invasion had an impact on US and UK soft power due to negative perceptions of the decision to go to war and the competence of the UK and US: public opinion polling by the Pew Center showed that perceptions of the US declined significantly as a result of the invasion of Iraq, especially in the Middle East and Central Asia.

This is undoubtedly a challenge for the US, but arguably an even bigger challenge for the UK, which due to its size and power relies much more on diplomacy and coalition-building in order to achieve its goals within various international treaty frameworks.   

Over nearly two decades, the US and the UK no longer seemed to enjoy the same foundation of trust, even with close allies, as they did previously. This changed in February 2022.

Towards the end of 2021, both the US and the UK were sounding the alarm about an impending Russian invasion of Ukraine based on information and analysis from their intelligence services. Despite the amassing of Russian troops, tanks and artillery on the border clearly visible from the air and by satellite imagery, several allies remained unconvinced until the invasion happened.  

This was in part due to their own assessments which indicated that Russia would stop short of an invasion, and in part because allies were unwilling to take US and UK statements on faith, without being able to assess the information themselves.

US officials found this frustrating as it meant that NATO and the EU were slower off the mark with support for Ukraine than they might otherwise have been. However, the accuracy of the US/UK intelligence on Russia’s invasion, coupled with their sharing it openly, may well have restored faith in their capabilities and analysis.  

A more open approach to intelligence  

Over the last few years, there seems to have been a change in accepted practice regarding sharing and using intelligence. The UK Ministry of Defence has taken a much more open approach to intelligence in the war in Ukraine, sharing the most recent defence information publicly in order to counter Russian disinformation.  

This is a positive step to ensure that intelligence can be discussed and assessed critically. Being more open about secret intelligence may also be linked to the increasing capabilities of open-source intelligence (OSINT). Non-governmental and international organizations and the media all now have access to data from, for example, imaging satellites and can independently verify information coming from governments. 

Perceived double standards 

A reduction of trust in US and UK intelligence was not the only impact of the invasion of Iraq. Russia and China have repeatedly called out the US and UK for acting without a second UN Security Council mandate. Putin uses the decision to invade Iraq, as well as the NATO humanitarian intervention in Kosovo, to justify Russia’s actions in Crimea. He invokes parallel language to spread disinformation about a ‘responsibility to protect life’ of the (‘ethnically Russian’) Crimean population. Russia has also repeatedly used the WMD trope to create false narratives around Ukrainian biosecurity laboratories to justify Russian military actions against Ukraine.  

Deciding to invade Iraq under what turned out to be a false pretext has weakened the application of the international rule of law and has led to a perceived double standard whereby powerful states can use UN processes in their favour, or completely disregard them if they do not deliver their goals.

As the Chilcot Inquiry found, there was very little preparation for the post-invasion period either in the US or the UK. Confirmation bias led not only to trusting shaky intelligence but also to believing in a best-case scenario and a ‘relatively benign security environment’ once the invasion had prevailed. Mismanaging the country’s occupation afterwards also led to the perception that the UK and US are less competent than projected. 

Problems for the international order  

The Iraq War has left many smaller and medium-sized states outside Europe and North America with the impression that powerful states are not committed to an equitable international system and instead will bend the rules to suit them while nonetheless holding other states to account. This dynamic poses a serious problem for the international system. 

It opens the door to ‘whataboutism’ in Russia’s false justifications for invading Ukraine and undermines faith in international law, destabilizing the international order in the longer term. Beyond the immediate challenges of dealing with the war in Ukraine, reforming and strengthening the international order to make it more equitable will be one of the most significant challenges the US and UK will face over the next decade. 

A trust deficit  

Domestically, for already disappointed citizens, the deceit over intelligence it is yet another piece of evidence which suggests that their government is not trustworthy and may not have their best interests at heart. This has profound implications for US and UK democracies, making it harder for governments to counter citizens’ susceptibilities to disinformation campaigns. 

The evolution of the Pepe the Frog meme The World Today rescobales.drupal 29 March 2023

From laidback comic book character to alt-right villain and more, the Pepe the Frog meme is emblematic of the relationship between politics and online culture.

The evolution of the Pepe the Frog meme provides a case study of how online meme culture can appropriate non-political imagery, codify it and redeploy it, sometimes for extreme political purposes. American artist Matt Furie created Pepe the Frog, with his catchphrase ‘Feels good man’, for his comic series Boy’s Club in 2005.

The laidback character was quickly adapted as a meme on internet forums such as 4chan and Reddit. By 2014 and 2015 politicized Pepe memes began appearing against Furie’s wishes, notably from the emerging ‘alt-right’. Late in 2015, Donald Trump retweeted a caricature of himself as Pepe at a US presidential lectern.

A stream of racist and anti-semitic Pepe renderings led to the meme being added to the Anti-Defamation League’s database of hate symbols in 2016. Three years later, democracy activists in Hong Kong began using images of Pepe in protests.

In their book, Meme Wars: The Untold Story of the Online Battles Upending Democracy in America, the authors Joan Donovan, Emily Dreyfuss and Brian Friedberg chart how democracy disrupters and conspiracy theorists use memes such as Pepe the Frog as weapons of mass disinformation. Donovan charted this timeline of his evolution from comic strip good guy to Covid anti-vaxxer.

2005: Pepe the Frog

2012: Sad Pepe

 2014: Smug Pepe

 2014: Rage Pepe

2014 & 2015: Nazi Pepe

 2015: Donald Trump as Pepe

2017: Pepe and the alt-right

2017: Groyper and Kekistan

2019: QAnon Pepe

2020: Hong Kong Pepe

2020: Covid-19 Pepe

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