Independent Thinking: UK Integrated Review, Georgia protests Audio NCapeling 16 March 2023

Episode 19 of our weekly podcast examines the AUKUS deal, UK defence priorities, and the state of Georgia’s democracy following anti-government protests.

The UK and Australia will soon be building nuclear submarines together, but is the UK’s tilt to the Indo-Pacific sustainable? Two years on from the last Integrated Review, has the UK finally clarified its foreign policy priorities on Russia, China, and on defence? And is the money there to do it all?

Also on the show, the panel discusses Georgia following recent anti-government protests in Tbilisi. Following the Rose revolution in 2003, Georgia seemed to be on a path towards closer ties with NATO and the European Union (EU). But the country’s government has recently moved closer to Russia and Vladimir Putin. What is the state of Georgia’s democracy and where is the country heading?

Joining Bronwen Maddox from Chatham House is Creon Butler, director of our Global Economy and Finance programme, Professor Andrew Dorman, editor of the International Affairs journal, and Alice Billon-Galland, research fellow in our Europe Programme.

They are joined by Natia Seskuria, associate fellow with the Royal United Services Institute (RUSI) and Arthur Snell, former diplomat and host of the podcast Doomsday Watch.

About Independent Thinking

A weekly podcast hosted by Chatham House director Bronwen Maddox, in conversation with leading policymakers, journalists, and Chatham House experts providing insight on the latest international issues.

Independent Thinking: Consequences of the Iraq war Audio NCapeling 23 March 2023

Episode 20 of our weekly podcast marks 20 years since the invasion of Iraq, with special guest Clare Short who resigned from the UK government over the issue.

Launched amid fears that Saddam Hussein was acquiring weapons of mass destruction, the Iraq war changed the Middle East and inflicted huge damage with effects that persist today.

This week’s panel examines the war from the perspective of those in power in London when the decision was made to commit UK forces to the invasion, and with those in Iraq who lived with the consequences.   

Joining Bronwen Maddox is special guest Clare Short, former Secretary of State for International Development, who served in the UK cabinet and resigned after the invasion began, becoming one of the best-known critics of prime minister Tony Blair’s approach to the war.

On the panel from Chatham House is Dr Patricia Lewis, director of the International Security programme, and three members of the Middle East and North Africa programme; the director Dr Lina Khatib, senior research fellow Dr Renad Mansour who is also project director of the Iraq Initiative, and research associate Hayder Al-Shakeri.

About Independent Thinking

A weekly podcast hosted by Chatham House director Bronwen Maddox, in conversation with leading policymakers, journalists, and Chatham House experts providing insight on the latest international issues.

India–Russia relations Explainer LToremark 14 October 2024

Explaining the history and current state of the relationship between India and Russia, its geopolitical significance, the importance of trade and defence cooperation, and the impact of the war in Ukraine.

What is the history of India’s relationship with Russia? 

The two countries established diplomatic relations in April 1947, shortly before India gained independence. India was on a quest to achieve economic self-sufficiency, so the then-Soviet Union was an important partner in terms of providing support for the country’s heavy industry, with investment in mining, energy and steel production. India’s economic planning model was also based on the Soviet five-year plan.

There is a high degree of historical affinity towards Russia in India, particularly among the older generation of policy elites. This is because the Soviet Union supported India during the Cold War, notably during the 1971 war between India and Pakistan, in which the US and China sided with Pakistan. This was arguably the peak of the Indo–Soviet relationship and also the year that the two countries signed a treaty of friendship and cooperation.

But even before that, the Soviet Union had supported India. During the 1965 war between India and Pakistan, the USSR played a mediating role and hosted the so-called Tashkent summit in 1966 where a peace treaty was signed.

The Soviet Union also used its UN Security Council veto several times in support of India, half a dozen times between 1957 and 1971. This was usually on the issue of Kashmir and once with respect to India’s military intervention in Goa to end Portuguese rule. It was also routine for the Indian prime minister to stop over in Moscow on the way back from Washington.

The relationship has continued into the post-Cold War period. Annual summits have been held since 2000, when a strategic partnership was signed (and subsequently upgraded in 2010). India and Russia have also been holding so-called 2+2 meetings – joint meetings with foreign and defence ministers – since 2021.

India’s External Affairs Minister Subrahmanyam Jaishankar has referred to the India–Russia relationship as the one constant in global politics over the last half century.

What is the current relationship between India and Russia? 

Russia remains a key strategic partner for India for both practical and ideological reasons. On the practical side, India benefits significantly from access to discounted Russian crude oil, which has increased from less than 2 per cent of India’s total imports before the Russian invasion of Ukraine to over 40 per cent in June 2024. Indian companies have also benefitted from exporting refined Russian oil products, some of which have found their way onto Western markets.

But energy cooperation is not confined to oil. It also includes cooperation in the nuclear space, where there is a strong historical foundation. When India conducted its first nuclear test in 1974, the Soviet Union did not shun cooperation with India – unlike the US. Compared to the US, Russia has also been able to better navigate India’s civil nuclear liability law, which was put in place in 2010. In February 2024, India and Russia upgraded an agreement to build six civil nuclear power plants in the Indian state of Tamil Nadu.

The other area of practical cooperation is defence. Russia accounts for over 50 per cent of India’s in-service military platforms. India is also the largest recipient of Russian arms exports, including the S400 missile defence system. There has been joint production of several platforms, such as the Brahmos supersonic cruise missile, which has been exported to third countries, starting with the Philippines. 

Russia has been a preferred arms supplier for India for many years because it provides arms at reasonable prices without end user constraints, and is often able to supply sensitive technologies, which other countries are not.

There is also a long-standing economic relationship. India and Russia aim to increase bilateral trade from $68 billion to $100 billion by the end of this decade. Connectivity initiatives include the Chennai-Vladivostok maritime corridor and the International North-South Transport Corridor.

There are regular interactions between the leaders of the two countries. Prime Minister Narendra Modi and President Vladimir Putin have met 17 times in the last decade and have held annual summits since 2000, with a few exceptions – and a notable gap following Russia’s invasion of Ukraine.

There is also a push to try and negotiate bilateral visa free access for Indians to increase people-to-people and tourism exchanges between the two countries.

There is also an ideological component to the relationship, which is often overlooked. One aspect is that India has a long-standing commitment to strategic autonomy in its foreign policy, which means engaging all major poles of influence in the international system – including Russia. There is also the aforementioned historical affinity due to Soviet support for India during the Cold War.

But the relationship is undergoing a managed decline. It does not have the same level of strategic importance as it did during the Cold War.

Although India still depends on Russia for a large proportion of its military hardware, since the 1990s there has been a push to diversify. As part of the ‘Make in India’ campaign, there is an attempt to strengthen domestic defence production as well as diversify to other countries. Between 2009 and 2013, 76 per cent of India’s arms imports were from Russia, but this has dropped to 36 per cent between 2019 and 2023 according to SIPRI.

While this trend predates the war in Ukraine, it has been accelerated by the war. There has been a delay in the delivery of several defence platforms, most notably the S400 missile defence system, as well as spare parts for fighter jets. The prolonged war of attrition in Ukraine has also undermined Indian confidence in some Russian military hardware.

There is decline on the ideological side too. India is trying to project a world view that is non-Western but not explicitly anti-Western. This puts it out of sync with Russia’s world view, and that of countries like China and Iran. 

India is increasingly aloof or estranged from forums where Russia plays a prominent role, such as the Shanghai Cooperation Organization (SCO). Modi did not attend the July 2024 SCO summit. When India held the presidency of the SCO in 2023 it was a low-profile presidency and there was a virtual summit. In contrast, India’s high-profile G20 presidency in 2023 was framed as the country’s ‘coming out party’.

While Modi and Putin met in July 2024, it was the first time that they had met since September 2022, a significant gap.

What is more, their economic interactions are highly skewed. There is roughly $68 billion in trade between the two countries but $60 billion of that is oil imports. India’s large share of Russian crude imports also means that Russia holds a surplus of Indian rupees, which has caused some friction in terms of rouble-rupee trade.

On the Indian side, there have also been concerns about a number of Indian nationals that have been duped into fighting for Russia in the Ukraine conflict.

But although the relationship is not what it once was, Russia will remain a key strategic partner for India for the foreseeable future.

Does India support Russia’s war on Ukraine? 

India has neither condoned nor condemned Russia’s actions. The Indian government has been vocal in expressing its displeasure of the war and Modi has said that now is ‘not an era of war’. He has also expressed sorrow for the bombing of a children’s hospital, hit by Russian airstrikes in July 2024. During his August 2024 visit to Ukraine, Modi said that India’s position is not neutral, but that it stands on the side of peace.

But there is a gap between rhetoric and reality. India in fact maintains quite a neutral position. It has abstained in UN General Assembly resolutions condemning Russia’s actions. It did not endorse the joint communique produced at a peace conference in Switzerland in June 2024, which Modi also did not attend. And the G20 leaders’ declaration that was concluded under India’s G20 presidency had no mention of Russian actions in Ukraine.

India has also emerged as the second-biggest supplier of restricted critical technologies to Russia (behind China), helping to fuel Russia’s war machine.

This reflects India’s practical or pragmatic considerations, including its dependence on Russian military hardware and access to discounted Russian crude. But there is also a degree of sympathy in New Delhi for the Russian narrative of the war, that Moscow’s actions were sparked by NATO expansion into Russia’s self-perceived sphere of influence.

In theory, India is well positioned to play the role of a potential mediator. It maintains close ties with both Moscow and Washington, unlike other countries that have close relations with Russia, such as China, Iran or North Korea. The West has been understanding of India’s strategic constraints in terms of its dependence on Russian military hardware and its energy needs. But so far, India’s actions have been largely driven by self-interest. Despite its statements, it has not made any peace proposals like those of Turkey or China.

Indian symbolism over substance was also clear in Modi’s summer 2024 meetings with Putin and Zelenskyy.

Modi visited Putin in July 2024 – a visit that coincided with Russian airstrikes in Ukraine. Zelenskyy called the meeting a devastating blow to peace efforts. And the optics of Modi hugging Putin while a Ukrainian children’s hospital was bombed prompted a degree of damage control by New Delhi, leading to Modi’s visit to Ukraine in August 2024.

His visit to Ukraine was an attempt to reaffirm India’s position of neutrality on the war and its long-standing position of strategic autonomy. It was also an attempt at a course correction in India’s relationship with Ukraine. Modi was the first Indian prime minister to visit Ukraine since the two countries established diplomatic relations in 1993.

How does China impact India–Russia relations? 

China is an important consideration in terms of India’s strategic calculations towards Russia. One of the reasons New Delhi is eager to maintain engagement with Russia is fears that Moscow is becoming increasingly beholden to Beijing following its invasion of Ukraine. India wants to provide Russia with strategic options as it becomes increasingly isolated and wants to deter it from becoming a client state of China. In parts of the West, that is already seen as a foregone conclusion, but Russia is not yet seen as a lost cause in India.

The other point to keep in mind is that China and India largely see eye to eye on the Ukraine war. Neither see their close relationship with Moscow as translating into overt support for Russian actions in Ukraine. Both countries believe they are playing a constructive role through their purchase of discounted Russian crude, which is helping to control global energy prices.

But a key watch point is what would Russia’s position be on possible future hostilities between China and India. Historically, Moscow has played a relatively neutral position and has occasionally offered to play a mediating role. It has even leaned in India’s favour on occasion and has provided it with more advanced military platforms than it has provided China. 

The fear in New Delhi is that this could be shifting and in the future Moscow could side with China in a potential conflict or tensions with India. That would be a game changer for India and would prompt it to rethink its relationship with Russia.

Independent Thinking: How can France survive its budget crisis? Audio john.pollock 17 October 2024

Sophie Pedder and Shahin Vallée join the podcast to discuss France’s contentious budget and political drama, and the potential impact on Europe and beyond.

On this episode

France is facing political turmoil. The survival of Michel Barnier’s new government rests on whether he can pass a controversial budget intended to rescue the country from its huge fiscal deficit. Bronwen Maddox is joined by Sophie Pedder, the Paris bureau chief of The Economist, Shahin Vallée, a former adviser to Emmanuel Macron and Armida van Rij, the head of our Europe Programme.

About Independent Thinking

Independent Thinking is a weekly international affairs podcast hosted by our director Bronwen Maddox, in conversation with leading policymakers, journalists, and Chatham House experts providing insight on the latest international issues.

More ways to listen: Apple Podcasts, Spotify.

Egypt’s purchase of a Chinese fighter jet is a reminder Cold War tactics are back in the Middle East Expert comment LJefferson 18 October 2024

The Egyptian army is a formidable force lacking air superiority capabilities to match its size and ambitions. China understood this predicament and offered to help.

The reported agreement for Egypt to buy the Chinese Chengdu J-10C 4.5 generation fighter jets is part of a broader shift from focusing on modernizing ground troops to bolstering the air force. The details of the deal have not yet been published. Nonetheless, it reveals Egypt has two motivations beyond backing its arsenal with another fighter jet.

Elusive Western technology

The most important motivation for Egypt’s military diversification strategy (and the biggest source of frustration) is the perceived Western technology starvation.
   
A quick examination of the map around Egypt shows that the most significant perceived threats to its national security are located in remote places where Egypt doesn’t traditionally enjoy ground troops’ presence. These include Ethiopia, the Southern Red Sea, Libya and the vulnerability a potential Israel–Iran regional war would create. From the generals’ perspective in Cairo, this list is more than a catalyst to build a modern and capable long arm.

The race started in 2015 after the Obama administration paused an arms transfer to Cairo in 2013 that included four F-16C Block 52 fighter jets amid toppling the Muslim Brotherhood government. The psychological effect of Washington’s decision in Cairo increased Egypt’s risk tolerance towards challenging its military ties with the US by diversifying away from it. 

Egypt ordered the MiG-29M2 fighter jets from Russia and the French Rafales this same year. In 2018, Egypt negotiated a $2 billion deal with Russia to purchase the Su-35 fighter jet, seen in Washington as crossing a red line and triggering a warning to Egypt that it would impose sanctions under the Countering America’s Adversaries Through Sanctions Act (CAATSA). This caused the deal to collapse.

The main factor of the US military sales in the Middle East is the upholding of the Israel Military Qualitative Edge principle over its neighbours. This principle requires the US to ensure Israel is superior over other regional countries’ strategic military capabilities, especially in air power.

For Egypt, this has long been a strategic vulnerability. The US turned down multiple requests by Egypt to purchase the active radar long-range AIM-120 AMRAAM fire-and-forget missile that can be launched from the F-16 fighter jets, the main striking force in Egypt’s arsenal. 

Unlike the Gulf and other states (such as Jordan and Turkey), Egypt was only allowed the old AIM-7 Sparrow and the AIM-9 Sidewinders, which are shorter in range and technologically inferior. Israel also allegedly pressured the Trump administration to refuse Egypt’s request to buy the F-35 stealth fight jets in 2019.

The US and Israel reportedly pressured France to not sell to Egypt the MBDA’s Meteor 100 km air-to-air missile with the Rafale fighters. Instead, Egypt received the 80 km MICA missile as part of the deal to buy 30 Rafales in 2021. Acquiring this advanced radar system and long-range missiles was likely behind Cairo’s deal to purchase 24 Eurofighter Typhoon aircraft from Italy in 2022. However, it is unlikely that they will come with the full package.

Egypt thought the Chinese J-10C Vigorous Dragon fighter may solve this predicament. The Chinese fighter has a beyond-visual range AESA radar and can carry the PL-15 200 km air-to-air missile, similar to the Rafale’s Meteor. The J-10C’s price tag is attractive for Egypt at $40-50 million, much less than the F-16 and Rafales.

The Chinese fighters are also a hedge against Russia’s sanctioned fighter jets, traditionally a second choice for the Egyptian air force.

Risky manoeuvres 

This doesn’t mean Egypt is on a path to abandon its weapons purchases from its Western partners. Egyptian weapons procurement policy is not only motivated by technical considerations. It also serves political objectives. Egypt still receives $1.3 billion every year in military and economic aid from Washington. Regime security and backing are two objectives that will likely encourage Cairo to rely on Western weapons systems for decades. 

However, from Egypt’s military perspective, the time may have come to resort to the Cold War tactics of diversification and counterbalancing. Being forced to accept old technology during the significant modernization of its air force creates a technical and operational necessity to seek this technology elsewhere. 

The regional uncertainty since Hamas’s 7 October attack on Israel and the war that followed in Gaza, southern Lebanon, and Israel’s intermittent confrontations with Iran makes make it imperative for the Egyptian strategic planners to take risky manoeuvres while targeting specific capabilities they seem desperate to acquire. 

The threat to deploy CAATSA sanctions against Egypt in 2019 makes the J-10C deal with China an interesting case study for all Middle Eastern allies of the West. It shows an uptick in Egypt’s risk tolerance to overcome its technological dilemma. It allows other countries considering the Chinese fighters (mainly Saudi Arabia) to gauge Washington’s reaction and design their future approach accordingly.   

Another motivation is to pressure the US, UK, and their allies to reconsider their implicit embargo on certain advanced technology by showing that Cairo now has alternatives. This tactic seems to work. General Frank McKenzie, the former head of US Central Command, said during a congressional hearing in 2022 that Washington will finally provide Egypt with the F-15 heavy-weight air superiority fighter, a longstanding demand by Cairo.

Building favours

The J-10C fighter jet ticks all the boxes: It satisfies Cairo’s diversity strategy and technological needs. It is under the sanctions threshold since it is less technologically savvy than the most controversial J-20 5th generation fighters, the equivalent to Russia’s SU-35. And it takes Egypt’s military partnership with China to a new level.

The rumour that the Chinese fighters are bought to replace the ageing versions of Egypt’s significant F-16 fleet is a source of pride for Beijing since its military technology started to be seen as a competitor to Western technology. A heavyweight military power like Egypt relying on Chinese fighters would almost certainly boost China’s share in the regional weapons market, just like Cairo’s purchase of the Rafale boosted its popularity globally.

Independent Thinking: Will debt constrain Western foreign policy? Audio john.pollock 24 October 2024

Patrick Wintour and Ranil Dissanayake join the podcast ahead of the UK Budget to discuss the high debt facing G7 economies and its impact on foreign, defence and development policies.

On this episode

Ahead of a crucial Budget by Chancellor Rachel Reeves, UK national debt is at almost 100 per cent of GDP – and it’s not alone. Many G7 economies face massive debt levels, restricting ambitions when it comes to foreign policy and global engagement. 

Bronwen Maddox is joined by Patrick Wintour, the Guardian’s diplomatic editor and Ranil Dissanayake, a senior research fellow at the Centre for Global Development. With them are Olivia O’Sullivan and David Lubin from Chatham House.

About Independent Thinking

Independent Thinking is a weekly international affairs podcast hosted by our director Bronwen Maddox, in conversation with leading policymakers, journalists, and Chatham House experts providing insight on the latest international issues.

More ways to listen: Apple Podcasts, Spotify.

Independent Thinking: Why is North Korea sending troops to Russia? Audio john.pollock 31 October 2024

Orysia Lutsevych, Edward Howell and Yossi Mekelberg discuss North Korean troops fighting with Russian forces against Ukraine, as well as the issue of military conscription.

On this episode

North Korea is sending troops to Russia, but what is Kim Jong-Un hoping to get from Vladmir Putin for this military assistance against Ukraine? The panel also discuss the role military conscription plays in Israel, South Korea and Ukraine’s defence.

Bronwen Maddox is joined by Edward Howell, the Korea Foundation fellow at Chatham House, Orysia Lutsevych, the head of our Ukraine Forum and Yossi Mekelberg, a senior consulting fellow with our Middle East and North Africa Programme.

About Independent Thinking

Independent Thinking is a weekly international affairs podcast hosted by our director Bronwen Maddox, in conversation with leading policymakers, journalists, and Chatham House experts providing insight on the latest international issues.

More ways to listen: Apple Podcasts, Spotify.

Independent Thinking: What does Donald Trump’s re-election mean for the world? Audio john.pollock 8 November 2024

Edward Luce, Leslie Vinjamuri and Gerald Seib join the podcast this week to discuss Donald Trump’s victory over Kamala Harris in the US presidential election.

On this episode

Donald Trump has decisively defeated Kamala Harris in the US presidential election. What does his return to the White House mean for America and the world? 

Bronwen Maddox is joined by Edward Luce, the FT’s North America editor, Gerald Seib, the former Washington bureau chief of The Wall Street Journal and Leslie Vinjamuri, the head of our US and Americas programme.

About Independent Thinking

Independent Thinking is a weekly international affairs podcast hosted by our director Bronwen Maddox, in conversation with leading policymakers, journalists, and Chatham House experts providing insight on the latest international issues.

More ways to listen: Apple Podcasts, Spotify.

Michael Dean
Jul 1, 2001; 42:1007-1017
Thematic Reviews

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

Reactive oxygen species (ROS) are an unavoidable host environmental cue for intracellular pathogens such as Mycobacterium tuberculosis and Mycobacterium bovis; however, the signaling pathway in mycobacteria for sensing and responding to environmental stress remains largely unclear. Here, we characterize a novel CmtR-Zur-ESX3-Zn2+ regulatory pathway in M. bovis that aids mycobacterial survival under oxidative stress. We demonstrate that CmtR functions as a novel redox sensor and that its expression can be significantly induced under H2O2 stress. CmtR can physically interact with the negative regulator Zur and de-represses the expression of the esx-3 operon, which leads to Zn2+ accumulation and promotion of reactive oxygen species detoxication in mycobacterial cells. Zn2+ can also act as an effector molecule of the CmtR regulator, using which the latter can de-repress its own expression for further inducing bacterial antioxidant adaptation. Consistently, CmtR can induce the expression of EsxH, a component of esx-3 operon involved in Zn2+ transportation that has been reported earlier, and inhibit phagosome maturation in macrophages. Lastly, CmtR significantly contributes to bacterial survival in macrophages and in the lungs of infected mice. Our findings reveal the existence of an antioxidant regulatory pathway in mycobacteria and provide novel information on stress-triggered gene regulation and its association with host–pathogen interaction.

Hepatocyte nuclear factor-1β (HNF-1β) is a tissue-specific transcription factor that is required for normal kidney development and renal epithelial differentiation. Mutations of HNF-1β produce congenital kidney abnormalities and inherited renal tubulopathies. Here, we show that ablation of HNF-1β in mIMCD3 renal epithelial cells results in activation of β-catenin and increased expression of lymphoid enhancer–binding factor 1 (LEF1), a downstream effector in the canonical Wnt signaling pathway. Increased expression and nuclear localization of LEF1 are also observed in cystic kidneys from Hnf1b mutant mice. Expression of dominant-negative mutant HNF-1β in mIMCD3 cells produces hyperresponsiveness to exogenous Wnt ligands, which is inhibited by siRNA-mediated knockdown of Lef1. WT HNF-1β binds to two evolutionarily conserved sites located 94 and 30 kb from the mouse Lef1 promoter. Ablation of HNF-1β decreases H3K27 trimethylation repressive marks and increases β-catenin occupancy at a site 4 kb upstream to Lef1. Mechanistically, WT HNF-1β recruits the polycomb-repressive complex 2 that catalyzes H3K27 trimethylation. Deletion of the β-catenin–binding domain of LEF1 in HNF-1β–deficient cells abolishes the increase in Lef1 transcription and decreases the expression of downstream Wnt target genes. The canonical Wnt target gene, Axin2, is also a direct transcriptional target of HNF-1β through binding to negative regulatory elements in the gene promoter. These findings demonstrate that HNF-1β regulates canonical Wnt target genes through long-range effects on histone methylation at Wnt enhancers and reveal a new mode of active transcriptional repression by HNF-1β.

Evolving evidence suggests that nicotine may contribute to impaired asthma control by stimulating expression of nerve growth factor (NGF), a neurotrophin associated with airway remodeling and airway hyperresponsiveness. We explored the hypothesis that nicotine increases NGF by reducing lung fibroblast (LF) microRNA-98 (miR-98) and PPARγ levels, thus promoting airway remodeling. Levels of NGF, miR-98, PPARγ, fibronectin 1 (FN1), endothelin-1 (EDN1, herein referred to as ET-1), and collagen (COL1A1 and COL3A1) were measured in human LFs isolated from smoking donors, in mouse primary LFs exposed to nicotine (50 μg/ml), and in whole lung homogenates from mice chronically exposed to nicotine (100 μg/ml) in the drinking water. In selected studies, these pathways were manipulated in LFs with miR-98 inhibitor (anti-miR-98), miR-98 overexpression (miR-98 mimic), or the PPARγ agonist rosiglitazone. Compared with unexposed controls, nicotine increased NGF, FN1, ET-1, COL1A1, and COL3A1 expression in human and mouse LFs and mouse lung homogenates. In contrast, nicotine reduced miR-98 levels in LFs in vitro and in lung homogenates in vivo. Treatment with anti-miR-98 alone was sufficient to recapitulate increases in NGF, FN1, and ET-1, whereas treatment with a miR-98 mimic significantly suppressed luciferase expression in cells transfected with a luciferase reporter linked to the putative seed sequence in the NGF 3'UTR and also abrogated nicotine-induced increases in NGF, FN1, and ET-1 in LFs. Similarly, rosiglitazone increased miR-98 and reversed nicotine-induced increases in NGF, FN1, and ET-1. Taken together, these findings demonstrate that nicotine-induced increases in NGF and other markers of airway remodeling are negatively regulated by miR-98.

Expert

Expert

Histone recognition by “reader” modules serves as a fundamental mechanism in epigenetic regulation. Previous studies have shown that Spindlin1 is a reader of histone H3K4me3 as well as “K4me3-R8me2a” and promotes transcription of rDNA or Wnt/TCF4 target genes. Here we show that Spindlin1 also acts as a potent reader of histone H3 “K4me3-K9me3/2” bivalent methylation pattern. Calorimetric titration revealed a binding affinity of 16 nm between Spindlin1 and H3 “K4me3-K9me3” peptide, which is one to three orders of magnitude stronger than most other histone readout events at peptide level. Structural studies revealed concurrent recognition of H3K4me3 and H3K9me3/2 by aromatic pockets 2 and 1 of Spindlin1, respectively. Epigenomic profiling studies showed that Spindlin1 colocalizes with both H3K4me3 and H3K9me3 peaks in a subset of genes enriched in biological processes of transcription and its regulation. Moreover, the distribution of Spindlin1 peaks is primarily associated with H3K4me3 but not H3K9me3, which suggests that Spindlin1 is a downstream effector of H3K4me3 generated in heterochromatic regions. Collectively, our work calls attention to an intriguing function of Spindlin1 as a potent H3 “K4me3-K9me3/2” bivalent mark reader, thereby balancing gene expression and silencing in H3K9me3/2-enriched regions.

RecQ family helicases are highly conserved from bacteria to humans and have essential roles in maintaining genome stability. Mutations in three human RecQ helicases cause severe diseases with the main features of premature aging and cancer predisposition. Most RecQ helicases shared a conserved domain arrangement which comprises a helicase core, an RecQ C-terminal domain, and an auxiliary element helicase and RNaseD C-terminal (HRDC) domain, the functions of which are poorly understood. In this study, we systematically characterized the roles of the HRDC domain in E. coli RecQ in various DNA transactions by single-molecule FRET. We found that RecQ repetitively unwinds the 3'-partial duplex and fork DNA with a moderate processivity and periodically patrols on the ssDNA in the 5'-partial duplex by translocation. The HRDC domain significantly suppresses RecQ activities in the above transactions. In sharp contrast, the HRDC domain is essential for the deep and long-time unfolding of the G4 DNA structure by RecQ. Based on the observations that the HRDC domain dynamically switches between RecA core- and ssDNA-binding modes after RecQ association with DNA, we proposed a model to explain the modulation mechanism of the HRDC domain. Our findings not only provide new insights into the activities of RecQ on different substrates but also highlight the novel functions of the HRDC domain in DNA metabolisms.

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.

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

Mining and the Circular Economy: Implications for the Minerals and Metals Industries 6 November 2017 — 4:00PM TO 5:30PM Anonymous (not verified) 31 October 2017 Chatham House, London

A New Era for China: Implications for the Global Mining and Metals Industries 18 June 2018 — 9:00AM TO 10:30AM Anonymous (not verified) 8 June 2018 Chatham House, London

Since the turn of the century, China’s demand for resources has dominated global headlines. It’s rapid demand growth through the early 2000s sparked the beginning of the commodities ‘super cycle’, and encouraged a growing Chinese presence in international mining, and in global metals and minerals markets. More recently, its transition toward the ‘new normal’ of slower but higher quality growth has underpinned the sudden slowdown in global commodities demand.

Drawing on China’s domestic ambitions, as set out in the 19th party congress, and on its wider strategic ambitions through the Belt and Road Initiative, the speaker will set out his thoughts on China’s next era of growth, and its likely implications for international mining investment and global metals and minerals markets.

Realizing the Potential of Extractives for Industrial and Economic Development 18 October 2018 — 5:30PM TO 7:00PM Anonymous (not verified) 3 October 2018 Chatham House | 10 St James's Square | London | SW1Y 4LE

Over the past two decades, the extractives industries have risen in importance for many low- and middle- income countries their prospects for economic development and poverty reduction. During a period of rising commodities prices, the development of extractives became increasingly attractive to both governments and companies. There was - and remains - much discussion about their potential to support inclusive development.

However, there are also risks and uncertainties associated with the extractives industries and many things can, and do, go wrong. Fluctuations in commodity prices can be hard to manage and can lead to considerable fiscal pressures. In the longer-term, climate change and the various policy responses to this, will profoundly affect the extractives sector as renewables replace fossil fuels in the global energy mix.

Managing the extractives sectors will therefore remain highly challenging especially in low-income countries where institutions are often weak. This roundtable will bring together some of the foremost academics and practitioners working in the extractives industries and also in economic development to discuss a major new UNU-WIDER study Extractive Industries: The Management of Resources as a Driver of Sustainable Development.

Attendance at this event is by invitation only.

The Electric Vehicle Revolution: Impacts on Oil Economies and Industry 24 January 2019 — 8:15AM TO 9:45AM Anonymous (not verified) 3 December 2018 Chatham House | 10 St James's Square | London | SW1Y 4LE

Electric vehicle (EV) deployment is gathering pace: the Norwegian government thinks that EV subsidies will be unnecessary by 2025 as they reach parity with diesel and petrol vehicles.

China has stipulated that EVs comprise 12 per cent of vehicle sales by 2020 while more governments are committing to banning diesel and petrol vehicles.

These developments are expected to be replicated as urban air pollution rises up the political agenda while technological developments and falling costs have given rise to ambitious forecasts on the increase in the deployment of EVs and the demise of the internal combustion engine.

Considering this, the presentations and initial discussion focus on:

• The influence of new technologies on the automotive landscape, including autonomous vehicles.
• How the automotive and oil companies are adjusting their business models to accommodate and encourage the rise in EVs.
• The risks and opportunities for the deployment of EVs for incumbents and new market actors.
• The role of government for example in public procurement and infrastructure development.
• The potential for modal shift and its impact on oil demand.

The discussion then seeks to explore the need for benchmarks of change including data and metrics to understand the changing risk landscape and the implications for different actors.

Finally, the discussion focuses on the speed of transformation and what this means for existing and new market actors.

Food system transformation: A blind spot for climate and biodiversity action? 20 October 2022 — 12:00PM TO 1:00PM Anonymous (not verified) 5 October 2022 Chatham House and Online

How can COP27 and COP15 accelerate the agenda for sustainable food systems and land use?

Tackling the dual crises of climate change and biodiversity loss requires extraordinary levels of action at an unprecedented speed. Agriculture is the biggest user of land, the biggest source of methane emissions, a major contributor to total greenhouse gas emissions and the leading driver of biodiversity loss.

Anything short of a food system transformation puts climate and biodiversity objectives in peril. However, governments have not yet produced credible pathways and strong policies for tackling our growing ‘foodprint’ – the negative impacts of what we grow and eat.

In advance of COP27 in Sharm El-Sheikh for climate and COP15 in Montreal for biodiversity, Chatham House has published a new briefing paper which examines aligning food systems with climate and biodiversity targets.

The paper reviews the climate and biodiversity policy landscape to 2030, with a focus on land-based aspects and the inclusion of food and agriculture. The paper highlights serious conflicts between the impacts of the food system and goals to protect and restore biodiversity and mitigate climate change.

In light of this, opportunities for joined-up action on food, climate and biodiversity are identified, including three key steps for countries to take this decade to produce suitably ambitious and effective policies across the climate–biodiversity–food nexus.

This event brings together leading voices from the international policy arenas for climate and biodiversity to react to the briefing paper and discuss how COP27 and COP15 can accelerate the agenda for sustainable food systems and land use.

Duterte’s Victory Is Cry for Help From Those Left Behind in Philippines Expert comment sysadmin 12 May 2016

But large support for mainstream parties and a mature democratic system should keep the country from slipping back towards authoritarianism.

The victory of political outsider Rodrigo Duterte in the 2016 Philippines’ elections is proof that a significant minority of the country’s population feels left behind by its recent economic success and estranged from its political elite. However the results of the elections as a whole suggest that most voters opted for a continuation of the current government’s policies.

Duterte looks almost certain to be inaugurated as the next president of the Philippines on 30 June. The country’s presidential voting system – a single round, first-past-the-post election – delivered victory to a populist outsider with 39 per cent support. Two candidates advocating a continuation of the current government’s policies − the Liberal Party’s Mar Roxas and independent Grace Poe − polled a combined 45 per cent. The long-standing factionalism within Philippines elite politics split the ‘anti-Duterte’ vote.

Changing the conversation

The contrast between Duterte and Roxas could hardly be greater. Mar Roxas is the grandson of the first president of an independent Philippines, a graduate of Wharton Business School and a former investment banker in the US. Rodrigo Duterte is a political outsider with an electoral base geographically almost as far from Manila as is possible to get in the Philippines: the city of Davao on the island of Mindanao.

The story of Duterte’s victory is the story of how ‘Duterte managed to change the national conversation from poverty towards crime and corruption,’ says Marites Vitug, editor-at-large of one of the Philippines’ most popular online news sites, Rappler. In January, Duterte was running fourth in opinion polls but a strategy that positioned him as the only opponent to the Manila elite gave him victory. This is the first time a provincial official has made it to the top job.

The headline figures tell us that the Philippines’ economy has done very well under President Benigno Aquino. Between 2010 and 2014, growth averaged 6.3 per cent per year. That fell to a still-impressive 5.8 per cent last year but is expected to pick up this year and next, according to the Asian Development Bank. Growth in agriculture, however, is significantly slower and rural areas feel left behind. While economic growth is benefiting the majority, inequality is worsening and resentment rising in poor villages. The contrast between the metropolitan sophistication of the Makati district in Manila and life in faraway provinces such as Duterte’s Mindanao is widening.

Ironically the Philippines’ economic success is a part of the explanation for the defeat of the ‘mainstream’ presidential candidates. Crime and corruption may have become more important issues simply because more voters have become better off and therefore more likely to be concerned about crime and corruption than before. It’s also undeniable that Duterte has a record for getting things done. Human rights groups rightly criticize his (at best) tolerance of the extra-judicial killing of alleged criminals but his repeated re-election as mayor demonstrates that many citizens are prepared to accept that in exchange for improved personal security. A surprising number of Manila residents have actually moved to Davao because of its better quality of life.

Traditional power bases

However, the results as a whole suggest a narrow majority in favour of current policies. In the vice-presidential race, the Liberal Party candidate Leni Robredo is narrowly ahead of Ferdinand ‘Bongbong’ Marcos, the son of the eponymous former president. Like Duterte she is regarded as a successful mayor of a well-run city, Albay. Duterte’s running mate Alan Cayetano received just 14 per cent of the vote.

In the senate election, Liberals won five of the 12 seats being contested, with a party- backed independent winning a sixth. The opposition, even with boxing champion and national idol Manny Pacquiao running for the United Nationalist Alliance, won four.

Taken as a whole, the results show the enduring nature of traditional Philippines power bases. The country’s many islands and distinct linguistic and cultural regions are virtual fiefs in which families and big bosses can wield almost total power through control of local authorities, businesses, the courts and security forces.

Threat to democracy?

It’s easy to forget that the election of Ferdinand Marcos in 1965 was originally welcomed as a challenge to the traditional elites of Philippine politics. The same accolades are currently greeting Duterte. Could they presage a return to the Philippines’ bad old days?

This seems less likely. Philippine democracy has matured considerably since Marcos declared martial law in 1972. There is a substantial, and vocal, middle class with experience of mobilizing against ‘bad’ presidents. There will also be pressures from international investors and the Philippines’ treaty ally, the United States, for better governance.

The Philippines will chair the Association of Southeast Asian Nations next year. That will put Duterte in the international spotlight as host of several international meetings – including the East Asia Summit attended by, among others, the presidents of China, Russia and the US. Since his victory Duterte has promised to act with decorum in office and declared that his election campaign antics were just a ploy to attract attention. Some leaders in Southeast Asia will use his victory to buttress their arguments against allowing their people to freely vote. It’s up to Duterte to decide whether he wants to be an advertisement for – or an argument against – democracy.

To comment on this article, please contact Chatham House Feedback

Artificial Intelligence Apps Risk Entrenching India’s Socio-economic Inequities Expert comment sysadmin 14 March 2018

Artificial intelligence applications will not be a panacea for addressing India’s grand challenges. Data bias and unequal access to technology gains will entrench existing socio-economic fissures.

Artificial intelligence (AI) is high on the Indian government’s agenda. Some days ago, Prime Minister Narendra Modi inaugurated the Wadhwani Institute for Artificial Intelligence, reportedly India’s first research institute focused on AI solutions for social good. In the same week, Niti Aayog CEO Amitabh Kant argued that AI could potentially add $957 billion to the economy and outlined ways in which AI could be a ‘game changer’.

During his budget speech, Finance Minister Arun Jaitley announced that Niti Aayog would spearhead a national programme on AI; with the near doubling of the Digital India budget, the IT ministry also announced the setting up of four committees for AI-related research. An industrial policy for AI is also in the pipeline, expected to provide incentives to businesses for creating a globally competitive Indian AI industry.

Narratives on the emerging digital economy often suffer from technological determinism — assuming that the march of technological transformation has an inner logic, independent of social choice and capable of automatically delivering positive social change. However, technological trajectories can and must be steered by social choice and aligned with societal objectives. Modi’s address hit all the right notes, as he argued that the ‘road ahead for AI depends on and will be driven by human intentions’. Emphasising the need to direct AI technologies towards solutions for the poor, he called upon students and teachers to identify ‘the grand challenges facing India’ – to ‘Make AI in India and for India’.

To do so, will undoubtedly require substantial investments in R&D, digital infrastructure and education and re-skilling. But, two other critical issues must be simultaneously addressed: data bias and access to technology gains.

While computers have been mimicking human intelligence for some decades now, a massive increase in computational power and the quantity of available data are enabling a process of ‘machine learning.’ Instead of coding software with specific instructions to accomplish a set task, machine learning involves training an algorithm on large quantities of data to enable it to self-learn; refining and improving its results through multiple iterations of the same task. The quality of data sets used to train machines is thus a critical concern in building AI applications.

Much recent research shows that applications based on machine learning reflect existing social biases and prejudice. Such bias can occur if the data set the algorithm is trained on is unrepresentative of the reality it seeks to represent. If for example, a system is trained on photos of people that are predominantly white, it will have a harder time recognizing non-white people. This is what led a recent Google application to tag black people as gorillas.

Alternatively, bias can also occur if the data set itself reflects existing discriminatory or exclusionary practices. A recent study by ProPublica found for example that software that was being used to assess the risk of recidivism in criminals in the United States was twice as likely to mistakenly flag black defendants as being at higher risk of committing future crimes.

The impact of such data bias can be seriously damaging in India, particularly at a time of growing social fragmentation. It can contribute to the entrenchment of social bias and discriminatory practices, while rendering both invisible and pervasive the processes through which discrimination occurs. Women are 34 per cent less likely to own a mobile phone than men – manifested in only 14 per cent of women in rural India owning a mobile phone, while only 30 per cent of India’s internet users are women.

Women’s participation in the labour force, currently at around 27 per cent, is also declining, and is one of the lowest in South Asia. Data sets used for machine learning are thus likely to have a marked gender bias. The same observations are likely to hold true for other marginalized groups as well.

Accorded to a 2014 report, Muslims, Dalits and tribals make up 53 per cent of all prisoners in India; National Crime Records Bureau data from 2016 shows in some states, the percentage of Muslims in the incarcerated population was almost three times the percentage of Muslims in the overall population. If AI applications for law and order are built on this data, it is not unlikely that it will be prejudiced against these groups.

(It is worth pointing out that the recently set-up national AI task force is comprised of mostly Hindu men – only two women are on the task force, and no Muslims or Christians. A recent article in the New York Times talked about AI’s ‘white guy problem’; will India suffer from a ‘Hindu male bias’?)

Yet, improving the quality, or diversity, of data sets may not be able to solve the problem. The processes of machine learning and reasoning involve a quagmire of mathematical functions, variables and permutations, the logic of which are not readily traceable or predictable. The dazzle of AI-enabled efficiency gains must not blind us to the fact that while AI systems are being integrated into key socio-economic systems, their accuracy and logic of reasoning have not been fully understood or studied.

The other big challenge stems from the distribution of AI-led technology gains. Even if estimates of AI contribution to GDP are correct, the adoption of these technologies is likely to be in niches within the organized sector. These industries are likely to be capital- rather than labour-intensive, and thus unlikely to contribute to large-scale job creation.

At the same time, AI applications can most readily replace low- to medium-skilled jobs within the organized sector. This is already being witnessed in the outsourcing sector – where basic call and chat tasks are now automated. Re-skilling will be important, but it is unlikely that those who lose their jobs will also be those who are being re-skilled – the long arch of technological change and societal adaptation is longer than that of people’s lives. The contractualization of work, already on the rise, is likely to further increase as large industries prefer to have a flexible workforce to adapt to technological change. A shift from formal employment to contractual work can imply a loss of access to formal social protection mechanisms, increasing the precariousness of work for workers.

The adoption of AI technologies is also unlikely in the short- to medium-term in the unorganized sector, which engages more than 80 per cent of India’s labor force. The cost of developing and deploying AI applications, particularly in relation to the cost of labour, will inhibit adoption. Moreover, most enterprises within the unorganized sector still have limited access to basic, older technologies – two-thirds of the workforce are employed in enterprises without electricity. Eco-system upgrades will be important but incremental. Given the high costs of developing AI-based applications, most start-ups are unlikely to be working towards creating bottom-of-the-pyramid solutions.

Access to AI-led technology gains is thus likely to be heavily differentiated – a few high-growth industries can be expected, but these will not necessarily result in the welfare of labour. Studies show that labour share of national income, especially routine labour, has been declining steadily across developing countries.

We should be clear that new technological applications themselves are not going to transform or disrupt this trend – rather, without adequate policy steering, these trends will be exacerbated.

Policy debates about AI applications in India need to take these two issues seriously. AI applications will not be a panacea for addressing ‘India’s grand challenges’. Data bias and unequal access to technology gains will entrench existing socio-economic fissures, even making them technologically binding.

In addition to developing AI applications and creating a skilled workforce, the government needs to prioritize research that examines the complex social, ethical and governance challenges associated with the spread of AI-driven technologies. Blind technological optimism might entrench rather than alleviate the grand Indian challenge of inequity and growth.

This article was originally published in the Indian Express.

India's Response to COVID-19: Political and Social Implications 12 May 2020 — 12:00PM TO 12:45PM Anonymous (not verified) 14 May 2020

On March 23rd, India’s Prime Minister Narendra Modi ordered the world’s largest lockdown on its population of 1.3 billion. The strict measures were praised by some for their success in slowing the spread of coronavirus but faced criticism for the lack of warning which led millions of migrant workers to return home without assistance. Recently the government has begun to lift restrictions in an attempt to revive the economy.

The Indian government has sought technological solutions to contain the pandemic and these have raised concerns around privacy, surveillance, equity and mass use. Furthermore, some low wage workers are forced to accept these solutions if they are to return to work, leaving them with little choice.

In this webinar, the speakers discuss the economic, political and healthcare implications of the coronavirus pandemic on India. Will India seek to rethink its strategy for leadership in the post-COVID-19 global order? Is it possible to develop technologies that can effectively limit the spread of the coronavirus and ensure privacy?

The speakers argue that careful consideration of the second and third-order effects of the pandemic, and the tools being used to contain it, are necessary to preserve rights, liberties, and even democracy.

Webinar: Gandhi's Vision for India 15 June 2020 — 12:00PM TO 12:45PM Anonymous (not verified) 9 June 2020

In 1931, Mahatma Gandhi visited Chatham House as part of his campaign for Indian independence. Addressing an overflowing hall, he described the poverty and the religious conflict that plagued India at the time.

Today, India is the world’s fifth largest economy and more than 270 million people have been lifted out of poverty in just a decade. But poverty in India remains widespread and the outbreak of the COVID-19 pandemic is only expected to exacerbate the situation. Meanwhile, the communal violence that erupted in Delhi earlier this year reflects intensifying religious tensions under Prime Minister Narendra Modi.

In this webinar, the speakers discuss Gandhi’s global legacy and to what extent we are seeing a re-awakening of his principles across modern India.

This event is part of a series, held in the context of the Chatham House Centenary in 2020, bringing together historians, practitioners and current policymakers to discuss contemporary problems of international relations.

Lasse L. Wolf and Hong-Wei Zhang
Proc. Amer. Math. Soc. 152 (), 5445-5453.
Abstract, references and article information

Knockout mouse models have been extensively used to study the antiviral activity of IFIT (interferon-induced protein with tetratricopeptide repeats). Human IFIT1 binds to cap0 (m7GpppN) RNA, which lacks methylation on the first and second cap-proximal nucleotides (cap1, m7GpppNm, and cap2, m7GpppNmNm, respectively). These modifications are signatures of “self” in higher eukaryotes, whereas unmodified cap0-RNA is recognized as foreign and, therefore, potentially harmful to the host cell. IFIT1 inhibits translation at the initiation stage by competing with the cap-binding initiation factor complex, eIF4F, restricting infection by certain viruses that possess “nonself” cap0-mRNAs. However, in mice and other rodents, the IFIT1 orthologue has been lost, and the closely related Ifit1b has been duplicated twice, yielding three paralogues: Ifit1, Ifit1b, and Ifit1c. Although murine Ifit1 is similar to human IFIT1 in its cap0-RNA–binding selectivity, the roles of Ifit1b and Ifit1c are unknown. Here, we found that Ifit1b preferentially binds to cap1-RNA, whereas binding is much weaker to cap0- and cap2-RNA. In murine cells, we show that Ifit1b can modulate host translation and restrict WT mouse coronavirus infection. We found that Ifit1c acts as a stimulatory cofactor for both Ifit1 and Ifit1b, promoting their translation inhibition. In this way, Ifit1c acts in an analogous fashion to human IFIT3, which is a cofactor to human IFIT1. This work clarifies similarities and differences between the human and murine IFIT families to facilitate better design and interpretation of mouse models of human infection and sheds light on the evolutionary plasticity of the IFIT family.

VAR2CSA is the placental-malaria–specific member of the antigenically variant Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family. It is expressed on the surface of Plasmodium falciparum-infected host red blood cells and binds to specific chondroitin-4-sulfate chains of the placental proteoglycan receptor. The functional ∼310 kDa ectodomain of VAR2CSA is a multidomain protein that requires a minimum 12-mer chondroitin-4-sulfate molecule for specific, high affinity receptor binding. However, it is not known how the individual domains are organized and interact to create the receptor-binding surface, limiting efforts to exploit its potential as an effective vaccine or drug target. Using small angle X-ray scattering and single particle reconstruction from negative-stained electron micrographs of the ectodomain and multidomain constructs, we have determined the structural architecture of VAR2CSA. The relative locations of the domains creates two distinct pores that can each accommodate the 12-mer of chondroitin-4-sulfate, suggesting a model for receptor binding. This model has important implications for understanding cytoadherence of infected red blood cells and potentially provides a starting point for developing novel strategies to prevent and/or treat placental malaria.

Cation diffusion facilitator (CDF) proteins are a conserved family of divalent transition metal cation transporters. CDF proteins are usually composed of two domains: the transmembrane domain, in which the metal cations are transported through, and a regulatory cytoplasmic C-terminal domain (CTD). Each CDF protein transports either one specific metal or multiple metals from the cytoplasm, and it is not known whether the CTD takes an active regulatory role in metal recognition and discrimination during cation transport. Here, the model CDF protein MamM, an iron transporter from magnetotactic bacteria, was used to probe the role of the CTD in metal recognition and selectivity. Using a combination of biophysical and structural approaches, the binding of different metals to MamM CTD was characterized. Results reveal that different metals bind distinctively to MamM CTD in terms of their binding sites, thermodynamics, and binding-dependent conformations, both in crystal form and in solution, which suggests a varying level of functional discrimination between CDF domains. Furthermore, these results provide the first direct evidence that CDF CTDs play a role in metal selectivity. We demonstrate that MamM's CTD can discriminate against Mn2+, supporting its postulated role in preventing magnetite formation poisoning in magnetotactic bacteria via Mn2+ incorporation.

The bacterial enhancer-binding protein (bEBP) FlrC, controls motility and colonization of Vibrio cholerae by regulating the transcription of class-III flagellar genes in σ54-dependent manner. However, the mechanism by which FlrC regulates transcription is not fully elucidated. Although, most bEBPs require nucleotides to stimulate the oligomerization necessary for function, our previous study showed that the central domain of FlrC (FlrCC) forms heptamer in a nucleotide-independent manner. Furthermore, heptameric FlrCC binds ATP in “cis-mediated” style without any contribution from sensor I motif 285REDXXYR291 of the trans protomer. This atypical ATP binding raises the question of whether heptamerization of FlrC is solely required for transcription regulation, or if it is also critical for ATPase activity. ATPase assays and size exclusion chromatography of the trans-variants FlrCC-Y290A and FlrCC-R291A showed destabilization of heptameric assembly with concomitant abrogation of ATPase activity. Crystal structures showed that in the cis-variant FlrCC-R349A drastic shift of Walker A encroached ATP-binding site, whereas the site remained occupied by ADP in FlrCC-Y290A. We postulated that FlrCC heptamerizes through concentration-dependent cooperativity for maximal ATPase activity and upon heptamerization, packing of trans-acting Tyr290 against cis-acting Arg349 compels Arg349 to maintain proper conformation of Walker A. Finally, a Trp quenching study revealed binding of cyclic-di-GMP with FlrCC. Excess cyclic-di-GMP repressed ATPase activity of FlrCC through destabilization of heptameric assembly, especially at low concentration of protein. Systematic phylogenetic analysis allowed us to propose similar regulatory mechanisms for FlrCs of several Vibrio species and a set of monotrichous Gram-negative bacteria.

Investigations of bacterial resistance strategies can aid in the development of new antimicrobial drugs as a countermeasure to the increasing worldwide prevalence of bacterial antibiotic resistance. One such strategy involves the TipA class of transcription factors, which constitute minimal autoregulated multidrug resistance (MDR) systems against diverse antibiotics. However, we have insufficient information regarding how antibiotic binding induces transcriptional activation to design molecules that could interfere with this process. To learn more, we determined the crystal structure of SkgA from Caulobacter crescentus as a representative TipA protein. We identified an unexpected spatial orientation and location of the antibiotic-binding TipAS effector domain in the apo state. We observed that the α6–α7 region of the TipAS domain, which is canonically responsible for forming the lid of antibiotic-binding cleft to tightly enclose the bound antibiotic, is involved in the dimeric interface and stabilized via interaction with the DNA-binding domain in the apo state. Further structural and biochemical analyses demonstrated that the unliganded TipAS domain sterically hinders promoter DNA binding but undergoes a remarkable conformational shift upon antibiotic binding to release this autoinhibition via a switch of its α6–α7 region. Hence, the promoters for MDR genes including tipA and RNA polymerases become available for transcription, enabling efficient antibiotic resistance. These insights into the molecular mechanism of activation of TipA proteins advance our understanding of TipA proteins, as well as bacterial MDR systems, and may provide important clues to block bacterial resistance.

Bacterial low-copy-number plasmids require partition (par) systems to ensure their stable inheritance by daughter cells. In general, these systems consist of three components: a centromeric DNA sequence, a centromere-binding protein and a nucleotide hydrolase that polymerizes and functions as a motor. Type III systems, however, segregate plasmids using three proteins: the FtsZ/tubulin-like GTPase TubZ, the centromere-binding protein TubR and the MerR-like transcriptional regulator TubY. Although the TubZ filament is sufficient to transport the TubR-centromere complex in vitro, TubY is still necessary for the stable maintenance of the plasmid. TubY contains an N-terminal DNA-binding helix-turn-helix motif and a C-terminal coiled-coil followed by a cluster of lysine residues. This study determined the crystal structure of the C-terminal domain of TubY from the Bacillus cereus pXO1-like plasmid and showed that it forms a tetrameric parallel four-helix bundle that differs from the typical MerR family proteins with a dimeric anti-parallel coiled-coil. Biochemical analyses revealed that the C-terminal tail with the conserved lysine cluster helps TubY to stably associate with the TubR-centromere complex as well as to nonspecifically bind DNA. Furthermore, this C-terminal tail forms an amphipathic helix in the presence of lipids but must oligomerize to localize the protein to the membrane in vivo. Taken together, these data suggest that TubY is a component of the nucleoprotein complex within the partitioning machinery, and that lipid membranes act as mediators of type III systems.

Highly engineered phytases, which sequentially hydrolyze the hexakisphosphate ester of inositol known as phytic acid, are routinely added to the feeds of monogastric animals to improve phosphate bioavailability. New phytases are sought as starting points to further optimize the rate and extent of dephosphorylation of phytate in the animal digestive tract. Multiple inositol polyphosphate phosphatases (MINPPs) are clade 2 histidine phosphatases (HP2P) able to carry out the stepwise hydrolysis of phytate. MINPPs are not restricted by a strong positional specificity making them attractive targets for development as feed enzymes. Here, we describe the characterization of a MINPP from the Gram-positive bacterium Bifidobacterium longum (BlMINPP). BlMINPP has a typical HP2P-fold but, unusually, possesses a large α-domain polypeptide insertion relative to other MINPPs. This insertion, termed the U-loop, spans the active site and contributes to substrate specificity pockets underpopulated in other HP2Ps. Mutagenesis of U-loop residues reveals its contribution to enzyme kinetics and thermostability. Moreover, four crystal structures of the protein along the catalytic cycle capture, for the first time in an HP2P, a large ligand-driven α-domain motion essential to allow substrate access to the active site. This motion recruits residues both downstream of a molecular hinge and on the U-loop to participate in specificity subsites, and mutagenesis identified a mobile lysine residue as a key determinant of positional specificity of the enzyme. Taken together, these data provide important new insights to the factors determining stability, substrate recognition, and the structural mechanism of hydrolysis in this industrially important group of enzymes.

Intrinsically disordered protein domains often have multiple binding partners. It is plausible that the strength of pairing with specific partners evolves from an initial low affinity to a higher affinity. However, little is known about the molecular changes in the binding mechanism that would facilitate such a transition. We previously showed that the interaction between two intrinsically disordered domains, NCBD and CID, likely emerged in an ancestral deuterostome organism as a low-affinity interaction that subsequently evolved into a higher-affinity interaction before the radiation of modern vertebrate groups. Here we map native contacts in the transition states of the low-affinity ancestral and high-affinity human NCBD/CID interactions. We show that the coupled binding and folding mechanism is overall similar but with a higher degree of native hydrophobic contact formation in the transition state of the ancestral complex and more heterogeneous transient interactions, including electrostatic pairings, and an increased disorder for the human complex. Adaptation to new binding partners may be facilitated by this ability to exploit multiple alternative transient interactions while retaining the overall binding and folding pathway.