By Cynthia Farahat On Friday 27th, 2023 at 11:00 am EST, my sweet dear younger brother Amir Farahat passed away. Amir was the most loving father I have ever seen, a great brother, son, husband, and brother-in-law. My little Miró, my little prince, my soul is shattered by your loss. I will forever mourn your […]

January 12, 2022 (New York, NY) – The total value of residential mortgage debt in the US will continue to experience solid growth into 2022 and 2023. In our inaugural […]

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June 22, 2022 (New York, NY) – Will Apple’s entry into the buy now, pay later (BNPL) space upend the already competitive industry? That’s the question many are trying to […]

An important mechanism of resistance to β-lactam antibiotics is via their β-lactamase–catalyzed hydrolysis. Recent work has shown that, in addition to the established hydrolysis products, the reaction of the class D nucleophilic serine β-lactamases (SBLs) with carbapenems also produces β-lactones. We report studies on the factors determining β-lactone formation by class D SBLs. We show that variations in hydrophobic residues at the active site of class D SBLs (i.e. Trp105, Val120, and Leu158, using OXA-48 numbering) impact on the relative levels of β-lactones and hydrolysis products formed. Some variants, i.e. the OXA-48 V120L and OXA-23 V128L variants, catalyze increased β-lactone formation compared with the WT enzymes. The results of kinetic and product studies reveal that variations of residues other than those directly involved in catalysis, including those arising from clinically observed mutations, can alter the reaction outcome of class D SBL catalysis. NMR studies show that some class D SBL variants catalyze formation of β-lactones from all clinically relevant carbapenems regardless of the presence or absence of a 1β-methyl substituent. Analysis of reported crystal structures for carbapenem-derived acyl-enzyme complexes reveals preferred conformations for hydrolysis and β-lactone formation. The observation of increased β-lactone formation by class D SBL variants, including the clinically observed carbapenemase OXA-48 V120L, supports the proposal that class D SBL-catalyzed rearrangement of β-lactams to β-lactones is important as a resistance mechanism.

Epoxide hydrolases (EHs) have been characterized and engineered as biocatalysts that convert epoxides to valuable chiral vicinal diol precursors of drugs and bioactive compounds. Nonetheless, the regioselectivity control of the epoxide ring opening by EHs remains challenging. Alp1U is an α/β-fold EH that exhibits poor regioselectivity in the epoxide hydrolysis of fluostatin C (compound 1) and produces a pair of stereoisomers. Herein, we established the absolute configuration of the two stereoisomeric products and determined the crystal structure of Alp1U. A Trp-186/Trp-187/Tyr-247 oxirane oxygen hole was identified in Alp1U that replaced the canonical Tyr/Tyr pair in α/β-EHs. Mutation of residues in the atypical oxirane oxygen hole of Alp1U improved the regioselectivity for epoxide hydrolysis on 1. The single site Y247F mutation led to highly regioselective (98%) attack at C-3 of 1, whereas the double mutation W187F/Y247F resulted in regioselective (94%) nucleophilic attack at C-2. Furthermore, single-crystal X-ray structures of the two regioselective Alp1U variants in complex with 1 were determined. These findings allowed insights into the reaction details of Alp1U and provided a new approach for engineering regioselective epoxide hydrolases.

The QT interval is a recording of cardiac electrical activity. Previous genome-wide association studies identified genetic variants that modify the QT interval upstream of LITAF (lipopolysaccharide-induced tumor necrosis factor-α factor), a protein encoding a regulator of endosomal trafficking. However, it was not clear how LITAF might impact cardiac excitation. We investigated the effect of LITAF on the voltage-gated sodium channel Nav1.5, which is critical for cardiac depolarization. We show that overexpressed LITAF resulted in a significant increase in the density of Nav1.5-generated voltage-gated sodium current INa and Nav1.5 surface protein levels in rabbit cardiomyocytes and in HEK cells stably expressing Nav1.5. Proximity ligation assays showed co-localization of endogenous LITAF and Nav1.5 in cardiomyocytes, whereas co-immunoprecipitations confirmed they are in the same complex when overexpressed in HEK cells. In vitro data suggest that LITAF interacts with the ubiquitin ligase NEDD4-2, a regulator of Nav1.5. LITAF overexpression down-regulated NEDD4-2 in cardiomyocytes and HEK cells. In HEK cells, LITAF increased ubiquitination and proteasomal degradation of co-expressed NEDD4-2 and significantly blunted the negative effect of NEDD4-2 on INa. We conclude that LITAF controls cardiac excitability by promoting degradation of NEDD4-2, which is essential for removal of surface Nav1.5. LITAF-knockout zebrafish showed increased variation in and a nonsignificant 15% prolongation of action potential duration. Computer simulations using a rabbit-cardiomyocyte model demonstrated that changes in Ca2+ and Na+ homeostasis are responsible for the surprisingly modest action potential duration shortening. These computational data thus corroborate findings from several genome-wide association studies that associated LITAF with QT interval variation.

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

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

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

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

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

This conversation will cover the following questions:

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

Islamic radicalisation in Central Asia 18 September 2024 — 10:00AM TO 11:30AM Anonymous (not verified) 20 August 2024 Chatham House and Online

Experts analyse rising foreign recruitment, current counter-radicalisation efforts and challenge past Chatham House predictions made of the Central Asia region.

In 2014, Chatham House released a report titled The Myth of Post-Soviet Muslim Radicalisation in the Central Asian Republics. At that time, a significant, Western-funded counter-radicalisation industry was addressing what was believed to be a major issue of Islamic violent extremism in the region.

Over the past decade, two key developments have occurred. First, Western interest in the region has declined in favour of traditional geopolitical concerns. Second, while violent extremism incidents within Central Asia remain rare, there has been a notable recruitment of Central Asians by foreign groups, with several attacks carried out by Central Asians overseas.

In this event, the original report’s authors, John Heathershaw and David Montgomery, will discuss whether the report’s arguments are still valid and how we might answer these questions today.

This raises several questions:

• What did the report accurately predict, and where did it fall short?
• How can we explain the lack of violent extremist organisations (VEOs) within Central Asia but the presence of Central Asians in VEOs abroad?
• Could repression by Central Asian states both domestically and transnationally have contributed to this issue?
• What, if anything, can the counter-radicalisation industry do today to address this problem more effectively?

Please note that in-person places are limited. Please wait for confirmation before participating. 

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

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

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

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

Please join us for this critical conversation covering:

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

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

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

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

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

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

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

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

In conversation with Valerii Zaluzhnyi, Ukrainian Ambassador to the UK 17 October 2024 — 10:00AM TO 11:00AM Anonymous (not verified) 16 September 2024 Chatham House and Online

The former Commander-in-Chief of the Armed Forces of Ukraine offers insight into the evolution of Russia’s war against his country, and what to expect next.

More than two and a half years since Russia launched its full-scale invasion, Ukraine has consistently adapted to Moscow’s advances by implementing new strategies.

Ukraine’s recent incursion into Russia’s Kursk region demonstrated operational tactical ingenuity, surprising both Russia and Ukraine’s Western supporters. Success against the Russian Black Sea Fleet has already showcased how Ukraine can skilfully beat back Russian aggression. And increasing numbers of targeted strikes on Russian supply depots and airfields are disrupting Russian operations behind the front lines.

Critical Western supplies continue to resource Ukraine’s military. But questions linger over the quantity and sustainability of these supplies. Kyiv will be watching the US presidential election in November as its biggest backer goes to the polls with the possibility of an outcome that could seriously affect the war. Meanwhile, Russian forces continue to edge forward in Donbas, despite heavy casualties, and strike at Ukrainian towns and cities from the air, demonstrating that President Putin has no intention of relinquishing the fight.

Amid these complexities, Ambassador Zaluzhnyi will discuss how the war is changing both sides, advances on the battlefield, and what dangers lie ahead for Ukraine in the coming months. Other key questions include:

• What kind of enemy is Russia today and how to secure its strategic defeat in Ukraine;
• How have new strategies, such as the recent incursion into the Kursk region, affected the state of play on the battlefield?
• What technologies and armaments does Ukraine need from its Western allies in both the short and long term?

Individual membership provides you with the complete Chatham House experience, connecting you with a unique global policy community. Find out more about membership.

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.

Hdac3 is a lysine deacetylase that removes acetyl groups from histones and additional proteins. Although Hdac3 functions within mesenchymal lineage skeletal cells are defined, little is known about Hdac3 activities in bone-resorbing osteoclasts. In this study we conditionally deleted Hdac3 within Ctsk-expressing cells and examined the effects on bone modeling and osteoclast differentiation in mice. Hdac3 deficiency reduced femur and tibia periosteal circumference and increased cortical periosteal osteoclast number. Trabecular bone was likewise reduced and was accompanied by increased osteoclast number per trabecular bone surface. We previously showed that Hdac3 deacetylates the p65 subunit of the NF-κB transcriptional complex to decrease DNA-binding and transcriptional activity. Hdac3-deficient osteoclasts demonstrate increased K310 NF-κB acetylation and NF-κB transcriptional activity. Hdac3-deficient osteoclast lineage cells were hyper-responsive to RANKL and showed elevated ex vivo osteoclast number and size and enhanced bone resorption in pit formation assays. Osteoclast-directed Hdac3 deficiency decreased cortical and trabecular bone mass parameters, suggesting that Hdac3 regulates coupling of bone resorption and bone formation. We surveyed a panel of osteoclast-derived coupling factors and found that Hdac3 suppression diminished sphingosine-1-phosphate production. Osteoclast-derived sphingosine-1-phosphate acts in paracrine to promote bone mineralization. Mineralization of WT bone marrow stromal cells cultured with conditioned medium from Hdac3-deficient osteoclasts was markedly reduced. Expression of alkaline phosphatase, type 1a1 collagen, and osteocalcin was also suppressed, but no change in Runx2 expression was observed. Our results demonstrate that Hdac3 controls bone modeling by suppressing osteoclast lineage cell responsiveness to RANKL and coupling to bone formation.

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

The 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.

Water, Ecosystems and Energy in South Asia: Making Cross-Border Collaboration Work Research paper sysadmin 29 June 2016

A new paper sets out the factors that have made previous cross-border projects in South Asia successful, arguing that cooperation around water is feasible despite the region’s political differences and economic assymetries.

• The countries of South Asia share some of the world’s major river basins – the Ganga (or Ganges), the Brahmaputra and the Indus. These rivers and their tributaries flow through seven countries, support more than 1 billion people, irrigate millions of hectares of land and are of cultural importance to many of those who rely on them.
• River management presents common challenges across the region. These include physical factors such as droughts, flooding, cyclones and climate change, as well political and institutional factors impeding the development of solutions and policies to improve resource management and reduce vulnerability. Water is increasingly seen as a source of competition, with population growth, industrialization and urbanization exacerbating the pressures on supply.
• Although South Asian examples of regional cooperation in general are limited, there is a clear positive trend. In areas such as disaster response and cross-border power trading, regional and bilateral engagement is beginning to take place. Multilateral official arrangements exist for trade and other economic issues, but there is none on water or ecosystems. However, as the benefits from cooperation become proven, its desirability is likely to gradually enter mainstream policy thinking on water issues.
• This research paper sets out the factors that have enabled cooperation, and the processes adopted, in previous successful cross-border projects. It focuses on four categories of cooperation: development of early-warning systems for natural disasters, in particular floods; protection of cross-border ecosystems; sharing of learning, through the showcasing of innovative approaches in one country that can be adopted by others; and power trading, in particular the development of hydropower in Bhutan and its export to India.
• The paper argues that cooperation around water in South Asia is feasible despite political differences and economic asymmetries. Different forms of collective action, and common understanding of both the threats and the shared benefits from cooperation, are required to foster more partnerships within the river basin states.

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.

Why burning biomass is not zero-carbon Explainer Video NCapeling 17 October 2022

Short animation explaining why burning biomass produces more carbon dioxide per unit of energy generated than almost all fossil fuels.

The climate emergency requires countries to transition away from fossil fuels, but it is important to be careful about the alternative energy sources chosen.

In particular, concern is growing over the use of biomass for energy, which is generated when wood or other plant material is burnt to generate heat and electricity. Many governments treat biomass energy as zero-carbon at the point of combustion, and subsidize it in the same way as renewables such as solar or wind, resulting in a large increase in the use of biomass for energy in the UK and the European Union (EU) over the past 15 years.

The treatment of biomass as zero-carbon in policy frameworks rests on the argument that biomass emissions will be reabsorbed by forest growth, particularly from trees planted to replace those cut down to burn.

But growing trees to maturity takes many years and, depending on the feedstock used, biomass burning increases global warming for decades to centuries. This is called the ‘carbon payback period’ – the time it takes for carbon dioxide levels to return to what they would have been if biomass had not been used.

New research from Chatham House and the Woodwell Climate Research Center calculated the real climate impact of burning US wood pellets in the UK and EU. In 2019, according to this analysis, US-sourced pellets burned for energy in the UK were responsible for between 13 million and 16 million tonnes of carbon dioxide, equivalent to the annual greenhouse gas emissions from 6-7 million passenger vehicles.

But because biomass is treated as zero-carbon, almost none of these emissions were included in the UK’s national greenhouse gas reports. And the removal of forest carbon from US forests is not included accurately in US reports, either.

Why technology does not make easy wars Interview LJefferson 28 November 2022

Stephanie Carvin explains why technology does not overcome the challenges of war.

The invasion of Ukraine has demonstrated that many of the assumptions held about the role of technology in contemporary warfare are flawed. The lesson that technology cannot overcome the challenges of warfare is one that the West has also yet to learn, despite a series of failed interventions since the end of the Cold War.

In a wide-ranging conversation, Isabel Muttreja sat down with Stephanie Carvin to talk about her contribution to the September 2022 issue of International Affairs on ‘how not to war’. They discuss the US’ over-reliance on technology and why ‘easy wars’ become ‘forever wars.’

You argue in your article that the US overly relies on technology in war. When did this start?

I don’t necessarily think the US is exceptional. I think all states have tried in some ways to use technologies. One of the key arguments in the article is that the US is an enlightenment country, and part of the enlightenment is a belief in rationality and science and that you can better things through the application of science.

I think that there is this particular scientific approach or embracing of technology, in the American and in fact larger Western tradition on technology as a way to save lives. There is a strange humanitarian impulse that often underlies this use of technology.

We are seeing a quest to try and get perfect information. The idea is that if you have perfect information, you are going to be able to dominate the battlefield, and that’s proven itself to be false. I’m not even sure you can ever get perfect information.

But it underlines this modern approach, that if you can have all the information that’s out there, crunch it into some kind of algorithm, that you can then target discriminately, proportionately, reduce the level of casualties, and reduce the level of unnecessary damage. And that’s a kind of liberal tradition. You are trying to have your cake and eat it too.

You talk about the US being an ultimately liberal state, but they have been involved in a lot of wars over the last 10–20 years. Is that a contradiction?

I hope it is. But I think it goes back to the enlightenment nature of the United States, which is that the US sees itself as a shining city on a hill that has to protect itself at all costs. Liberals abhor tyranny, and they abhor unnecessary deaths. But I think that the idea is that if you threaten us, we see ourselves as embodying these values, therefore, we have to protect ourselves.

There’s a tendency to not really recognize the kind of insurgencies that we’ve seen in Iraq and Afghanistan, or even Vietnam, as war. We don’t really see that as a kind of armed conflict, even though, arguably, that has been the dominant mode of conflict for some time. They even used to call it ‘military operations other than warfare’. We tend to still think of war as great power competition or as the Second World War.

My first book was on prisoners of war in the American tradition. What often determined the treatment of people as prisoners of war was if the United States recognized their form of warfare. There’s a racial element here too that I don’t want to dismiss.

So, for example, the US war in the Philippines at the start of the 20th century: They went in, won a very quick victory over the Spanish and effectively took over the Philippines. And then they had a long insurgency for two years with the native Filipinos who didn’t want US domination. While they gave the Spanish all the prisoner of war rights, they didn’t give them to the Filipinos.

This is because they recognized the form of conflict that the Spanish engaged in, but the Indigenous way of warfare was not recognized. The West has struggled to culturally understand the way other people fight. And that’s when the laws of war conventions have broken down between, say, the United States, the West, and other states.

You talk in your article about the US entering ‘easy wars’ and ending up with ‘forever wars’ – what does this mean?

There’s an allure to this high-tech version of warfare, that it can solve a lot of problems, but it’s an illusion. It is ultimately a bit of a false promise.

The idea that machines are going to replace humans is fundamentally untrue. We are seeing this to a certain extent right now, even in the Russia/Ukraine war. This is very much a battle of machines and soldiers. One of the themes of this issue of International Affairs is hubris. The idea that things that appear to be quick wins often tend to be long-term losses. And that’s exactly what this article is talking about.

‘Forever wars’ is not my favourite term, but it’s this concept that what was promised to be an easy war, a high technology-driven conflict, where you can go in, use some surgically precise weapons, take care of the problem, eliminate your opponent and then extract yourself from a situation, has actually turned into a quagmire.

The limits of technology become apparent within a few months as well as the fact of the messy business of state-building, or the fact that insurgencies and political movements don’t just disintegrate at the show of some high-tech, sophisticated weaponry. It just tends to mean that these wars do go on for a long time, and you have to eventually extricate yourself, but there’s no clean way to do this. We saw this of course with Afghanistan, and to a large extent Iraq.

We get distracted by the shiny object. We see this promise, we see this vision of a kind of warfare that for some may have great appeal.  There are new super weapons, whether it be cyber information warfare or artificial intelligence. Everyone wants to be ahead of the curve, right?

Are these lessons on technology and ‘easy wars’ applicable to other countries?

I think what we’ve learned about the Russian military is that there’s a lot more at the heart of it. Part of the problem Russia is experiencing is that its capabilities were not what it thought they were. It’s clear that Vladimir Putin was enamoured with a lot of the ideas, like that the Russian military was increasingly high-tech and that they had these hypersonic missiles.

They also had very powerful cyber weapons amongst other things. Putin, too, seems to have been caught up in this idea that he could have had a 72-hour special military operation, which would have taken Kyiv. Clearly, that hasn’t happened. Once again, we see the underestimation of the human factor.

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.

US and Europe Strategic Security Cooperation: The View from Washington 27 March 2023 — 9:00AM TO 10:00AM Anonymous (not verified) 9 March 2023 Chatham House

As the US prepares to enter the next presidential election cycle, can the transatlantic alliance stay the course, especially against a deepening Russia-China partnership?

Thank you for your interest in joining our event. Please plan to arrive at Chatham House from 08:45 GMT as the event will begin promptly at 09:00.

The Biden administration’s response to Russia’s war in Ukraine and the rise of a globally assertive China, as articulated in the 2022 US national strategy, is to ‘constrain Russia and out-compete China’. It needs Europe as a partner and ally for both – yet Europe is also an object and a battleground in this era of strategic competition.

As the US prepares to enter the next presidential election cycle, can the transatlantic alliance stay the course, especially against a deepening Russia-China partnership? Can Europeans, in particular, move from deepening dependency to greater agency and self-reliance? What is the role for Germany – and for the UK?

Alexander S. Hebert
Jan 1, 2014; 13:339-347
Technological Innovation and Resources

Steven A. Carr
Mar 1, 2014; 13:907-917
Technological Innovation and Resources

Michal Bassani-Sternberg
Mar 1, 2015; 14:658-673
Research

Ileana M. Cristea
Dec 1, 2005; 4:1933-1941
Research

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