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

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

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

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

Please join us for this critical session to discuss:

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

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

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

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

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.

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).

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.

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.

Reflections on Iraq since 2003 6 March 2023 — 11:00AM TO 12:15PM Anonymous (not verified) 20 February 2023 Chatham House

This event reflects on the legacy of the invasion and occupation for Iraq, the Middle East, and the West.

When a US-led coalition invaded Iraq and overthrew the Saddam Hussein regime 20 years ago, many Iraqis hoped that a more democratic, prosperous future lay ahead.

But in reality, their lives have been marred by different forms of violent conflict, fuelled by a corrupt system through which a new class of leaders gutted state finances and enriched themselves at the expense of the people.

Today, almost two-thirds of the Iraqi population are under 25 and have no memory of life under Saddam Hussein. For many, the legacy of the war is only a failed political system that kills every day by means of corruption and neglect.

At this roundtable, part of the Iraq Initiative, Chatham House welcomes journalist and author Ghaith Abdul-Ahad to discuss his book on this subject, called A Stranger in Your Own City: Travels in the Middle East’s Long War, alongside a panel of experts who will explore the profound legacy of the war for the Iraqi people.

This marks the first in a series of Chatham House Iraq Initiative events and analysis reflecting on the legacy of the invasion and occupation for Iraq, the Middle East and the West.

Yue Chen
May 1, 2007; 6:812-819
Research

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

Yi Zhang
Sep 1, 2005; 4:1240-1250
Research

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

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

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

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

How Beijing is closing surveillance gaps in the South China Sea The World Today iallan.drupal 15 October 2024

The discovery of a new radar system on China’s Triton Island military base shows that Beijing is rapidly developing its intelligence capacities in contested waters, write John Pollock and Damien Symon.

New satellite images reveal how the Chinese military is dramatically expanding its capabilities on Triton Island, which looks set to become a one of Beijing’s key signal intelligence bases in the South China Sea.

Once completed, the radar system would significantly increase China’s signals intercept and electronic warfare capabilities across the disputed Paracel Islands archipelago and add to a wider surveillance network spanning much of the South China Sea.

The enhanced facility on Triton is likely to offer a challenge to China’s competitors in the region and internationally.

China seized control of the Paracels from Vietnam in a 1974 naval battle, and competition for access to it waters has intensified since the recent discovery of oil and gas reserves. Chinese and Vietnamese maritime militia clashed off the coast of Triton in 2014.

In addition, American, British and Australian naval forces have for the past decade patrolled the waters to collectively challenge China’s contested ‘nine-dash-line’ claim to large stretches of the South China Sea. 

Overlapping anti-stealth network

A year after work was first identified on Triton, satellite images from Maxar have helped build a clearer picture of Beijing’s efforts to defend this strategic waterway.

The most striking development is the construction of a new radar system, known as SIAR – synthetic impulse and aperture radar – which purportedly detects stealth aircraft. The counter-stealth radar on Triton is characterized by its distinctive octagonal structure, which resembles another SIAR system built by China on Subi Reef in the Spratly Islands, south of the Paracels, in 2017. A half-completed tower also sits near the SIAR radar on Triton, which is likely to be the operations centre.

Once completed, the radar on Triton will form what is believed to be a wider network of at least three overlapping counter-stealth radars built across Chinese bases in the South China Sea over the past decade, including on Hainan Island, home to several Chinese naval bases. 

The positioning of the radar on Triton, 320km south of Hainan, is telling, says J. Michael Dahm, Senior Resident Fellow for Aerospace and China Studies at the Mitchell Institute. 

‘SIAR radars cannot see over the curve of the Earth, which means there is a gap in China’s air surveillance coverage between Subi Reef and Hainan Island. The Triton Island site will help close that gap’, said Dahm.

The aim, he suggests, is to give China contiguous counter-stealth radar coverage of the South China Sea.

More construction underway

The satellite images reveal other building projects on Triton. One is a large pad at the end of the road network which will probably be used as a launching point for a mobile anti-ship missile battery. The building at the northeast end of the road is probably a storage building for missile transport vehicles. 

Diminishing Vietnam’s options

The development of a new counter-stealth radar system and other suspected signals intercept structures on Triton represents a notable increase in China’s intelligence capabilities in the Paracels. The Chinese Communist Party has not disclosed the purpose of the building work on Triton, but its effects on regional and global competitors are likely to be wide ranging.

For Vietnam, which is rapidly expanding its own bases in the South China Sea, the intelligence structures on Triton would significantly diminish its capacity to operate undetected in the area. Alongside existing radar on Triton which can detect sea-going vessels, Beijing now has the potential to track Vietnamese air movements and gain forewarning of Hanoi’s manoeuvres in the area, including efforts to access oil and gas deposits.

The desire to strengthen control over these resources may explain why China is fortifying Triton Island, says Bill Hayton, Associate Fellow in the Asia-Pacific Programme, Chatham House. ‘The developments might be a warning that China is planning to mount another drilling expedition’, he suggests.

Addressing Russia’s use of forced displacement in Ukraine 7 November 2024 — 12:30PM TO 2:00PM Anonymous (not verified) 17 October 2024 Chatham House and Online

Experts consider the role international law could play in responding to Russia’s forcible movement of people during its war against Ukraine.

In the two and a half years since its full-scale invasion of Ukraine, evidence has emerged of Russia’s use of forced deportation and forcible transfer. Russia has also employed arbitrary detention as a tool of war and occupation.

Much attention has been on the International Criminal Court’s arrest warrants against Russian President Vladimir Putin and his children’s commissioner Maria Alekseyevna Lvova-Belova. These warrants were issued in relation to the alleged war crimes concerning the unlawful deportation of children from Ukraine to Russia and the unlawful transfer of thousands of children from occupied areas of Ukraine.

Meanwhile, Ukrainian citizens are being arrested and sent to Russia to serve prison sentences. They are often detained without charge and conviction.

This panel discussion explores:

• What evidence is emerging of Russia using unlawful deportation and transfer of children, and the arbitrary detention of civilians?
• What is the role and significance of international law on these issues?
• What challenges might these practices create for later peace negotiations, as well as the securing of justice?
• What is the process of releasing illegally detained Ukrainians, and Ukrainian children in particular, and reuniting them with their families? How do Russian volunteers inside Russia cooperate with Ukrainian NGOs to facilitate family reunification?

The event includes a screening of part of the documentary After the Rain: Putin’s Stolen Children. 

The institute occupies a position of respect and trust, and is committed to fostering inclusive dialogue at all events. Event attendees are expected to uphold this by adhering to our code of conduct.

The killing of Yahya Sinwar won’t change the course of the Gaza war Expert comment jon.wallace 18 October 2024

Israel has larger ambitions for Gaza beyond the Hamas leader’s death and the armed group is still asserting its influence despite its degradation.

After a year of being hunted as one of the most wanted men in the Middle East, Hamas leader Yahya Sinwar was killed by Israeli forces on 17 October, in the city of Rafah in the Gaza Strip.

Hailing from Khan Younis refugee camp, Sinwar was imprisoned in Israel in 1989 for the abduction and killing of two Israeli soldiers. He was freed alongside 1,000 other prisoners during a major 2011 exchange, gradually building a notorious reputation as an intelligent and ruthless political figure.

As Hamas’ Gaza chief since 2017, Sinwar oversaw the consolidation of the movement’s authoritarian rule in the Strip and co-directed its military confrontations with Israel. He is regarded as a chief architect of Hamas’ deadly assault of 7 October, which killed 1,200 Israelis, mostly civilians, in southern communities.

Many world leaders and pundits were quick to embrace Sinwar’s death as an opportunity to press for a ceasefire in Gaza and secure the release of roughly 100 Israeli hostages still held by Hamas and other groups. It is too early to know the full repercussions of this development, but these hopes are largely misplaced – and reflect a reluctance to confront the larger obstacles and motivations that are preventing an end to the war.

Morale amid aimlessness

For Israelis, Sinwar’s death is undoubtedly a morale booster. It is a symbolic victory over a man deemed responsible for the 7 October massacres, and a tactical success that rids Israel of a formidable foe – one who was also an invested ally of Iran and the Axis of Resistance. Israeli politicians and generals will relish the news as another step towards restoring their reputations after their failure to prevent the 7 October attack.

Yet contrary to some wishful thinking, Sinwar’s death is unlikely to change Israel’s calculus in Gaza. Prime Minister Benjamin Netanyahu, whose popularity has been slowly recovering in recent months, described the news as ‘the beginning of the end’ but warned that ‘the task before us is not yet complete’.

The intensification of Israel’s war with Hezbollah – including a ground invasion of Lebanon, airstrikes across the country, and the displacement of over 1 million people – has shifted Israelis’ focus away from Gaza over the past month, especially as Hezbollah rockets disrupt life in Israel’s central cities as well as the north.

During that time, the Israeli army has begun a major offensive in the northern part of the Strip, implementing what appears to be the first part of the so-called ‘General’s Plan’ – an operation to besiege and force out roughly 300,000 Palestinian civilians who remain in the area. It could also pave the way for Israel’s absorption of part of the territory. (Israel’s military has denied pursuing the plan).

As such, the Israeli government has relegated the importance of the hostages. Netanyahu is eager to divert the public’s frustration with his months-long sabotage of a deal, while the military – despite its clashes with the prime minister – is seizing the chance to redraw Israel’s geopolitical environment. Even if a deal is struck in the wake of Sinwar’s death, Israel’s bombing and carving-up of Gaza and south Lebanon will likely continue.

Dynamic but degraded

For Hamas, the killing of its fiery politburo chief – just over two months after the assassination of his predecessor Ismail Haniyeh in Tehran – is certainly a blow to its leadership and internal stability. But the Islamist movement’s dynamism has not changed. Hamas’s decision-making processes are not pegged to specific individuals, and other figures, whether in Gaza or in exile, will be rotated into senior positions.

It is unclear whether Hamas will promote a leader who shares Sinwar’s hardline orientation, or drift back to a more moderate figure similar to Haniyeh. Regardless, Hamas’s core demands in any ceasefire and hostage negotiations are unlikely to shift significantly. The movement is still seeking a permanent end to the war, and Israel is still refusing to grant it.

Hamas’s military capacity has been severely degraded by the Israeli offensive, not least by the fact that much of Gaza has been made unliveable and ungovernable. But the movement is far from destroyed. Its militants continue to fight a guerrilla war to undermine Israel’s foothold in Gaza, while trying to reassert Hamas control over public order, the war economy, and the distribution of aid.

Moreover, as the history of movements like Hamas and Hezbollah shows, the devastating nature of Israel’s campaigns and occupations are planting the seeds for further militancy among Palestinians, whether organized under Hamas or smaller, decentralized groups. The war has brutally decimated Gaza’s society, and the notion that killing figures like Sinwar will dissuade future recruits to fight Israel is fanciful.

On the Palestinian political level, Hamas and Fatah are still in talks about forming a unity agreement, though negotiations have so far remained fruitless. Even if a pact is made, Israel’s relentless targeting of Hamas personnel, the perception of the Fatah-led Palestinian Authority (PA) as feckless collaborators, and Palestinians’ feeling of total abandonment raise doubts about the parties’ ability to regain popular support or legitimacy – whether to lead an interim government or the wider national movement.

The gravest threat

The killing of Sinwar is a significant marker in the Gaza war, with important ramifications for the movement he led and the conflict he seismically shaped. Israel will portray his death as validation of its aggressive military approach, and a further step in the erosion of Iran’s regional influence – an agenda the US has actively supported.

Sinwar’s death does not make Hamas–Fatah reconciliation more likely, whoever his successor may be Expert comment jon.wallace 22 October 2024

The killing may aid Hamas recruitment – but it will not make agreement with Fatah any easier to achieve.

Western political leaders were quick to argue that Israel’s killing of Hamas leader Yahya Sinwar on 17 October presented an opportunity for a ceasefire in Gaza and the return of Israeli hostages.

US President Joe Biden immediately called on Israeli prime minister Benjamin Netanyahu to seize the moment to negotiate, now that Israel has achieved one of its war aims.

However, that ‘moment’ has already passed. Israel’s military assault on Gaza has intensified since Sinwar was killed, leading UN Peace Process Co-ordinator Tor Wennesland to say that ‘nowhere is safe in Gaza’. It is abundantly clear Netanyahu is intent on further degrading Hamas, resetting a new ‘power balance’ and carving out a buffer zone, no matter the cost in Palestinian lives or Israeli hostages. 

But there are other implications of Sinwar’s assassination beyond the zero-sum analysis of will there or won’t there be a ceasefire.

Hamas’s ability to fight

At present, everyone has an opinion on how Sinwar’s killing will affect Hamas and its ability to resist and respond to Israel’s military. His death will have been a major blow – symbolically, operationally, and psychologically. Hamas has been downgraded and its capacity to respond compromised.

But it will recover, regenerate and retaliate in time – and Sinwar’s death will have been no surprise to Palestinians in Gaza or elsewhere. Hamas is accustomed to seeing its leaders assassinated. Since its formation in 1987, it has been ‘decapitated’ many times, only to continue with its mission to ‘liberate Palestine’.

Hamas’s portrayal of Sinwar dying in his fatigues, head wrapped in a keffiyeh and resisting until the end will persuade many young Palestinians that he died as a martyr serving the Palestinian cause. Many will be inspired to join and fortify the ranks of Hamas as a result.

The IDF’s release of drone footage showing Sinwar’s last moments will have done nothing to undermine his credibility. 

On the contrary, it will serve as a rallying call to disaffected and disenfranchised young Palestinians horrified by Israel’s bombing of civilian targets in Gaza and disaffected with Fatah’s inability to prevent Israeli settler expansion and violence in the West Bank.

Reconciliation

Some hope that if Sinwar is replaced by a more ‘moderate’ leader, his killing may smooth the path to Hamas–Fatah reconciliation – and that this could provide a foundation for a patchwork political solution when Israel and Gaza arrive at the ‘day after.’  

But the idea that a downgraded and ‘leaderless’ Hamas will be susceptible to international pressure to reconcile with Fatah is divorced from reality.  

Prospective new Hamas leaders such as Khaled al Meshaal and Khalil al-Hayya are based in Qatar. 

They may be more pliable to external pressure to reconcile with Fatah in search of a political outcome, but their ability to influence events on the ground in Gaza will be limited. That was demonstrated by the Sinwar-orchestrated attacks on 7 October 2023, which took place without the blessing of the exiled leadership in Doha.

Hamas has long gone to ground in Gaza and become far more decentralized than it was before 7 October. It is now more typical of an insurgency, where Hamas cadres exercise a great degree of operational autonomy.

In other words, the disconnect between Hamas in Gaza and its political leadership in Qatar has only grown wider since this round of conflict started.

International efforts

That will undermine international efforts made by Qatar, Egypt, Saudi Arabia, China, Russia and others to bring about a reconciliation. Moscow and Beijing already hosted reconciliation talks in February and April early this year but made no progress in closing the chasm between the two parties. Saudi Arabia has also hosted talks.

The three Arab states, none of which have so far commented publicly on Sinwar’s killing, will likely view his death as an opportunity to bolster the political wing of Hamas – backing it with pledges of political, diplomatic and financial support.

Saudi Arabia and Egypt will have next to no influence over the succession process, but Qatar’s long-established relationship with the political wing of Hamas affords it leverage over the organization, albeit limited. They may be able to strengthen the hand of those based in Doha by promising to work harder at securing a ceasefire, guaranteeing the provision of humanitarian relief, and working towards a political solution.

The MENA uprisings: Five years on, what role is civil society playing? 31 October 2024 — 2:00PM TO 3:00PM Anonymous (not verified) 23 October 2024 Online

Panellists examine the protest movements’ legacies in different context and how civil society continues to work towards positive change.

Five years after nation-wide protests in Algeria, Iraq, Lebanon, and Sudan demanded systemic changes and political reforms, the situation remains largely unchanged. In some cases, it has deteriorated. Sudan is facing a humanitarian catastrophe amidst an ongoing civil war. Lebanon is dealing with Israeli aggression amidst a severe economic crisis with little response from the caretaker government. In Iraq and Algeria, relative stability masks the reality of increased suppression of dissent. This preservation of the status quo supports the entrenched political structures that strive to uphold it.

The current absence of large-scale street protests in these countries should not be taken as an indication that populations are content with the status quo. The issues that ignited the initial uprisings remain and in many cases have worsened. Despite enormous challenges, activists continue to navigate their systems to survive and instigate change. In the face of increasing difficulties, they are raising awareness of their countries’ predicaments and are finding alternative economic solutions. Additionally they are mobilizing community support, and pushing to voice their disillusionment. All these efforts aim at actively participating in shaping decisions that determines their future.

This webinar explores:

• What has been the impact of the uprisings in Algeria, Iraq, Lebanon, and Sudan?
• How are civil society and activists contributing to change within their communities?
• What is the current landscape for civic engagement within the politics, society and economy in these countries?
• What prospects are there for solidarity and cooperation among civil society actors across these regions and beyond?

Assessing the trajectory of the Middle East conflict 4 November 2024 — 4:00PM TO 5:00PM Anonymous (not verified) 29 October 2024 Online

Experts examine how the conflict may develop and what we can expect from regional and international actors.

A year on, the war in Gaza has spilled beyond Israel and Palestine with escalation across the region intensifying.

Recent weeks have seen Israel deepening its military offensive on Lebanon and keeping the north of the Gaza strip under siege, while leaders of Hezbollah and Hamas have been successfully targeted by its forces. Israel also launched an unprecedented assault against Iran in response to Tehran’s missile attacks on Israeli territory earlier in October.

Against this backdrop, regional states, particularly in the Gulf, in line with their overall approach to the conflict, are prioritizing diplomacy over escalation. They maintain their neutrality on the hostility between Israel and Iran and its aligned groups from the axis of resistance.

The strength of old alliances is being tested while new alignments are uncovered that may reshape the geopolitical landscape of the region, particularly following the US presidential election.

In this webinar, experts will examine:

• What are Israel’s calculations at this stage and how have the domestic political dynamics changed over recent weeks?
• What are the impacts of the war on Iran and its aligned actors and what can we expect from Tehran and groups from the axis of resistance?
• How are the wars in Gaza and Lebanon connected and would ending one stop the other?
• What is the response from regional states, particularly in the Gulf, and what role can they play?
• What are the possible scenarios for a post-election US policy on Israel and the Middle East?

Addressing illegal gold mining: International policy priorities 18 November 2024 — 11:30AM TO 1:00PM Anonymous (not verified) 6 November 2024 Chatham House and Online

Held in partnership with the World Gold Council, this panel of experts examines the global Artisanal and Small-Scale Gold Mining (ASGM) landscape and propose policy priorities essential for fostering sector formalization.

In this panel discussion, held in partnership with the World Gold Council, experts will examine the global Artisanal and Small-Scale Gold Mining (ASGM) landscape and propose policy priorities essential for fostering sector formalization.

An estimated twenty million people worldwide are involved in the Artisanal and Small-Scale Gold Mining (ASGM) sector, which now accounts for around 20 percent of global gold output. However, 85 percent of this production occurs outside formal legal frameworks. While many in ASGM operate within informal economies or seek pathways to formalization, a significant portion is also vulnerable to criminal exploitation, involving organized crime and armed groups.

In Ethiopia, the sector’s informality is tied to the nation’s volatile security dynamics, with illicit gold mining proliferating as non-state actors compete for control in conflict-prone regions such as Tigray. Additionally, gold is increasingly trafficked through transnational illicit networks in the Sahel and Sudan fuelling instability. South America is also impacted, for example in Peru where the government’s response to illegal ASGM initially saw success in 2019 but has faced sustainability challenges, and environmental impact.

ASGM growth is driven by the rising value of gold, youth unemployment, weak law enforcement, climate impacts, and conflict. While formalization offers significant economic potential, robust international cooperation and industry commitment is required to address the human toll, environmental impact and support sustainable practices.

In this panel discussion, experts will focus on addressing the expansion of illicit control and exploitation within ASGM, highlighting the pathways for governments and large-scale mining companies to drive meaningful change.

This event is hosted in partnership with the World Gold Council. There will be a reception with light refreshments hosted at Chatham House following the event.

This event will be livestreamed via the Africa Programme Facebook page.

The institute occupies a position of respect and trust, and is committed to fostering inclusive dialogue at all events. Event attendees are expected to uphold this by adhering to our code of conduct.

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

Expert

In animals, the response to chronic hypoxia is mediated by prolyl hydroxylases (PHDs) that regulate the levels of hypoxia-inducible transcription factor α (HIFα). PHD homologues exist in other types of eukaryotes and prokaryotes where they act on non HIF substrates. To gain insight into the factors underlying different PHD substrates and properties, we carried out biochemical and biophysical studies on PHD homologues from the cellular slime mold, Dictyostelium discoideum, and the protozoan parasite, Toxoplasma gondii, both lacking HIF. The respective prolyl-hydroxylases (DdPhyA and TgPhyA) catalyze prolyl-hydroxylation of S-phase kinase-associated protein 1 (Skp1), a reaction enabling adaptation to different dioxygen availability. Assays with full-length Skp1 substrates reveal substantial differences in the kinetic properties of DdPhyA and TgPhyA, both with respect to each other and compared with human PHD2; consistent with cellular studies, TgPhyA is more active at low dioxygen concentrations than DdPhyA. TgSkp1 is a DdPhyA substrate and DdSkp1 is a TgPhyA substrate. No cross-reactivity was detected between DdPhyA/TgPhyA substrates and human PHD2. The human Skp1 E147P variant is a DdPhyA and TgPhyA substrate, suggesting some retention of ancestral interactions. Crystallographic analysis of DdPhyA enables comparisons with homologues from humans, Trichoplax adhaerens, and prokaryotes, informing on differences in mobile elements involved in substrate binding and catalysis. In DdPhyA, two mobile loops that enclose substrates in the PHDs are conserved, but the C-terminal helix of the PHDs is strikingly absent. The combined results support the proposal that PHD homologues have evolved kinetic and structural features suited to their specific sensing roles.

Rhodopsin is a canonical class A photosensitive G protein–coupled receptor (GPCR), yet relatively few pharmaceutical agents targeting this visual receptor have been identified, in part due to the unique characteristics of its light-sensitive, covalently bound retinal ligands. Rhodopsin becomes activated when light isomerizes 11-cis-retinal into an agonist, all-trans-retinal (ATR), which enables the receptor to activate its G protein. We have previously demonstrated that, despite being covalently bound, ATR can display properties of equilibrium binding, yet how this is accomplished is unknown. Here, we describe a new approach for both identifying compounds that can activate and attenuate rhodopsin and testing the hypothesis that opsin binds retinal in equilibrium. Our method uses opsin-based fluorescent sensors, which directly report the formation of active receptor conformations by detecting the binding of G protein or arrestin fragments that have been fused onto the receptor's C terminus. We show that these biosensors can be used to monitor equilibrium binding of the agonist, ATR, as well as the noncovalent binding of β-ionone, an antagonist for G protein activation. Finally, we use these novel biosensors to observe ATR release from an activated, unlabeled receptor and its subsequent transfer to the sensor in real time. Taken together, these data support the retinal equilibrium binding hypothesis. The approach we describe should prove directly translatable to other GPCRs, providing a new tool for ligand discovery and mutant characterization.

Myosins generate force and motion by precisely coordinating their mechanical and chemical cycles, but the nature and timing of this coordination remains controversial. We utilized a FRET approach to examine the kinetics of structural changes in the force-generating lever arm in myosin V. We directly compared the FRET results with single-molecule mechanical events examined by optical trapping. We introduced a mutation (S217A) in the conserved switch I region of the active site to examine how myosin couples structural changes in the actin- and nucleotide-binding regions with force generation. Specifically, S217A enhanced the maximum rate of lever arm priming (recovery stroke) while slowing ATP hydrolysis, demonstrating that it uncouples these two steps. We determined that the mutation dramatically slows both actin-induced rotation of the lever arm (power stroke) and phosphate release (≥10-fold), whereas our simulations suggest that the maximum rate of both steps is unchanged by the mutation. Time-resolved FRET revealed that the structure of the pre– and post–power stroke conformations and mole fractions of these conformations were not altered by the mutation. Optical trapping results demonstrated that S217A does not dramatically alter unitary displacements or slow the working stroke rate constant, consistent with the mutation disrupting an actin-induced conformational change prior to the power stroke. We propose that communication between the actin- and nucleotide-binding regions of myosin assures a proper actin-binding interface and active site have formed before producing a power stroke. Variability in this coupling is likely crucial for mediating motor-based functions such as muscle contraction and intracellular transport.

Decarbonizing Heat: A New Frontier for Technologies and Business Models 27 February 2019 — 8:15AM TO 9:45AM Anonymous (not verified) 3 December 2018 Chatham House | 10 St James's Square | London | SW1Y 4LE

Building space and water heating accounts for over 35 percent of global energy consumption - nearly double that of transport. However, there has been limited progress in decarbonizing the sector to date. International cooperation is required to ensure harmonized policies drag low carbon heating technologies down the cost curve to the extent that low carbon heating is cost competitive and affordable. The initial presentations and discussion focus on:

• Demand reduction technologies and policies that speed up transformation of the sector.
• The different challenges for energy efficiency of retrofitting as opposed to new build.
• The impact of electrification on GHG emissions and the power sector.
• The comparative role of national and city level initiatives.

The meeting concludes by looking at the challenges and risks in accelerating the transformation of heating and the lessons that can be learned from other sectors.

Sino-Russian Gas Cooperation: Power of Siberia I and II and Implications for Global LNG Supplies 27 November 2019 — 8:30AM TO 9:30AM Anonymous (not verified) 19 November 2019 Chatham House | 10 St James's Square | London | SW1Y 4LE

In a new event in the Sustainable Transitions series, the speaker will present an update of Sino-Russian gas cooperation.

To give a comprehensive account of their impact on global liquefied natural gas (LNG) supplies, he will discuss the following points:

• Gas is scheduled to start flowing from the Power of Siberia I (POS) on 2 December 2019. But what is the background of development of POS 1 and what is its current status and prospects?
• What are the chances of exporting gas through the proposed Altai pipeline? Why is the Mongolia export route so significant? And how will it affect the Central Asian Republics and in particular Turkmenistan’s gas export to China?
• What are the implications of both POS I and Altai gas via Mongolia route in the context of global LNG supply?
• What are the prospects for multilateral pipeline gas cooperation in northeast Asia?
• What are the implications for other Arctic onshore LNG supply, in particular, for Novatek’s Yamal LNG and Arctic LNG 1 and 2 to China on top of POS 1 and Altai gas?

Attendance at this event is by invitation only.

Stacey Finley from University of Southern California discusses how mathematical models support the research of cancer biology. Cancer research is a crucial job, but a difficult one. Tumors growing inside the human body are affected by all kinds of factors. These conditions are difficult (if not impossible) to recreate in the lab, and using real patients as subjects can be painful and invasive. Mathematical models give cancer researchers the ability to run experiments virtually, testing the effects of any number of factors on tumor growth and other processes — all with far less money and time than an experiment on human subjects or in the lab would use.

Benjamin Jaye and Manasa N. Vempati
Proc. Amer. Math. Soc. 152 (), 5105-5116.
Abstract, references and article information

R. Gibara and D. Kinzebulatov
St. Petersburg Math. J. 35 (), 445-460.
Abstract, references and article information

Dynamic singer Tosh Alexander has been lighting up the music scene with her latest track, ' My Ting Different', a thrilling collaboration with American rapper and songwriter Lady London. The song fuses R...

Nigy Boy's management team was forced to put out a scam alert on Thursday as news surfaced that a promoter in the Turks and Caicos Islands, inadvertently wired thousands of US dollars to who he believed was the artiste's booking team as a deposit...

When a scuba diver comes up from the deep too quickly, the rapid decrease in pressure can give them a case of "the bends" or decompression sickness. It is caused by bubbles of gas building up in the body, causing pain. It can also be fatal....

If you connect to a FTP/TLS server that is configured to use implicit FTP/TLS, FILENAME FTP/TLS might fail with the following error:

Carnosine (β-alanyl-l-histidine) and anserine (β-alanyl-3-methyl-l-histidine) are abundant peptides in the nervous system and skeletal muscle of many vertebrates. Many in vitro and in vivo studies demonstrated that exogenously added carnosine can improve muscle contraction, has antioxidant activity, and can quench various reactive aldehydes. Some of these functions likely contribute to the proposed anti-aging activity of carnosine. However, the physiological role of carnosine and related histidine-containing dipeptides (HCDs) is not clear. In this study, we generated a mouse line deficient in carnosine synthase (Carns1). HCDs were undetectable in the primary olfactory system and skeletal muscle of Carns1-deficient mice. Skeletal muscle contraction in these mice, however, was unaltered, and there was no evidence for reduced pH-buffering capacity in the skeletal muscle. Olfactory tests did not reveal any deterioration in 8-month-old mice lacking carnosine. In contrast, aging (18–24-month-old) Carns1-deficient mice exhibited olfactory sensitivity impairments that correlated with an age-dependent reduction in the number of olfactory receptor neurons. Whereas we found no evidence for elevated levels of lipoxidation and glycation end products in the primary olfactory system, protein carbonylation was increased in the olfactory bulb of aged Carns1-deficient mice. Taken together, these results suggest that carnosine in the olfactory system is not essential for information processing in the olfactory signaling pathway but does have a role in the long-term protection of olfactory receptor neurons, possibly through its antioxidant activity.

α1-antitrypsin (AAT) regulates the activity of multiple proteases in the lungs and liver. A mutant of AAT (E342K) called ATZ forms polymers that are present at only low levels in the serum and induce intracellular protein inclusions, causing lung emphysema and liver cirrhosis. An understanding of factors that can reduce the intracellular accumulation of ATZ is of great interest. We now show that calreticulin (CRT), an endoplasmic reticulum (ER) glycoprotein chaperone, promotes the secretory trafficking of ATZ, enhancing the media:cell ratio. This effect is more pronounced for ATZ than with AAT and is only partially dependent on the glycan-binding site of CRT, which is generally relevant to substrate recruitment and folding by CRT. The CRT-related chaperone calnexin does not enhance ATZ secretory trafficking, despite the higher cellular abundance of calnexin-ATZ complexes. CRT deficiency alters the distributions of ATZ-ER chaperone complexes, increasing ATZ-BiP binding and inclusion body formation and reducing ATZ interactions with components required for ER-Golgi trafficking, coincident with reduced levels of the protein transport protein Sec31A in CRT-deficient cells. These findings indicate a novel role for CRT in promoting the secretory trafficking of a protein that forms polymers and large intracellular inclusions. Inefficient secretory trafficking of ATZ in the absence of CRT is coincident with enhanced accumulation of ER-derived ATZ inclusion bodies. Further understanding of the factors that control the secretory trafficking of ATZ and their regulation by CRT could lead to new therapies for lung and liver diseases linked to AAT deficiency.

CD81 plays a central role in a variety of physiological and pathological processes. Recent structural analysis of CD81 indicates that it contains an intramembrane cholesterol-binding pocket and that interaction with cholesterol may regulate a conformational switch in the large extracellular domain of CD81. Therefore, CD81 possesses a potential cholesterol-sensing mechanism; however, its relevance for protein function is thus far unknown. In this study we investigate CD81 cholesterol sensing in the context of its activity as a receptor for hepatitis C virus (HCV). Structure-led mutagenesis of the cholesterol-binding pocket reduced CD81–cholesterol association but had disparate effects on HCV entry, both reducing and enhancing CD81 receptor activity. We reasoned that this could be explained by alterations in the consequences of cholesterol binding. To investigate this further we performed molecular dynamic simulations of CD81 with and without cholesterol; this identified a potential allosteric mechanism by which cholesterol binding regulates the conformation of CD81. To test this, we designed further mutations to force CD81 into either the open (cholesterol-unbound) or closed (cholesterol-bound) conformation. The open mutant of CD81 exhibited reduced HCV receptor activity, whereas the closed mutant enhanced activity. These data are consistent with cholesterol sensing switching CD81 between a receptor active and inactive state. CD81 interactome analysis also suggests that conformational switching may modulate the assembly of CD81–partner protein networks. This work furthers our understanding of the molecular mechanism of CD81 cholesterol sensing, how this relates to HCV entry, and CD81's function as a molecular scaffold; these insights are relevant to CD81's varied roles in both health and disease.

Replication protein A (RPA) is a eukaryotic ssDNA-binding protein and contains three subunits: RPA70, RPA32, and RPA14. Phosphorylation of the N-terminal region of the RPA32 subunit plays an essential role in DNA metabolism in processes such as replication and damage response. Phosphorylated RPA32 (pRPA32) binds to RPA70 and possibly regulates the transient RPA70-Bloom syndrome helicase (BLM) interaction to inhibit DNA resection. However, the structural details and determinants of the phosphorylated RPA32–RPA70 interaction are still unknown. In this study, we provide molecular details of the interaction between RPA70 and a mimic of phosphorylated RPA32 (pmRPA32) using fluorescence polarization and NMR analysis. We show that the N-terminal domain of RPA70 (RPA70N) specifically participates in pmRPA32 binding, whereas the unphosphorylated RPA32 does not bind to RPA70N. Our NMR data revealed that RPA70N binds pmRPA32 using a basic cleft region. We also show that at least 6 negatively charged residues of pmRPA32 are required for RPA70N binding. By introducing alanine mutations into hydrophobic positions of pmRPA32, we found potential points of contact between RPA70N and the N-terminal half of pmRPA32. We used this information to guide docking simulations that suggest the orientation of pmRPA32 in complex with RPA70N. Our study demonstrates detailed features of the domain-domain interaction between RPA70 and RPA32 upon phosphorylation. This result provides insight into how phosphorylation tunes transient bindings between RPA and its partners in DNA resection.

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