India-China relations: Is the Quad the answer? Interview NCapeling 28 March 2023

The threat of China’s military aggression is being felt across the world, but this is a phenomenon India has been contending with for decades.

India’s border with China became the site of tense conflict in 2020, which led to India reinvesting in the Quad. Arzan Tarapore discusses key issues from his International Affairs article, such as how India is responding to increased aggression at the border and how a reinvigorated Quad may hold answers to balancing China in the Indo-Pacific.

What have India-China relations been like in the past?

Relations between India and China have varied over the decades. In the years following World War Two there was some hope they would find common cause in their international outlooks but that was quite quickly extinguished with their border war of 1962.

Since then, the two countries have oscillated between detente and tension. It took decades for them to normalize their relations and slowly build trust through several confidence-building agreements.

More recently it seemed the two countries were both willing to set aside their border dispute in order to profit from their burgeoning economic relationship – as, for both, there is no question development and economic growth is the primary national objective.

The question has been the extent to which their unresolved sovereignty and security issues undermine those goals as, at the same time, they both began paying more attention to the security of their territorial claims.

China in particular matched its explosive economic growth with startling military modernization and assertiveness. Its long-standing military doctrine and terrain advantages means it relies heavily on quality military infrastructure on the Tibetan plateau and it has accelerated the pace of those infrastructure upgrades and expansion.

In the 2010s, India belatedly began to improve its own transport infrastructure near the border, which threatened to reduce China’s military advantages. The earlier quiet on the border began to crack and China began launching border incursions with increasing frequency and scale.

This was a dynamic, iterative process, with incursions prompting India to accelerate its infrastructure development, which in turn probably prompted more incursions by China.

What happened around 2020 to change their relationship?

The cycle of competitive security policies on the border reached a tipping point in 2020 with Chinese incursions at multiple points simultaneously in Ladakh, apparently designed to establish a new status quo on the Line of Actual Control (LAC) separating Indian and Chinese-controlled territory.

The Indian political leadership played down the incursions but both Indian and Chinese militaries rushed to reinforce their positions near the border. They held multiple rounds of military talks which made halting progress.

On 15 June 2020, a skirmish resulted in the loss of 20 Indian troops, and an unknown number of Chinese troops. In the weeks that followed, both sides further reinforced their positions in a scramble to gain positional advantage.

How has India responded to China’s increasing military might?

The Indian government’s response to the Chinese landgrab was to threaten the entire bilateral relationship. In a reversal of decades of policy, it argued China had demolished the painstakingly constructed confidence-building measures on the border, and so the relationship could not continue as normal until the border crisis was resolved.

It imposed new restrictions on Chinese investment in India – even as overall trade continued to increase – and adopted a more assertive diplomatic posture.

Strategically, the 2020 border crisis had two major effects. First, it reinforced the Indian proclivity to see its northern borders as the primary threat to Indian national security.

India has heavily reinforced the border, reassigning some major formations and making numerous new investments in military capability to manage the threat. The significance of this however is that, in the context of budget scarcity, these military improvements come at the cost of potential increases in India’s capability in the Indian Ocean region – ultimately a more consequential zone of competition in the Indo-Pacific.

The Indian government may yet change course and reallocate resources for power projection but, at this stage, I see no evidence of that.

The second major strategic effect of the crisis was to unleash Indian cooperation with its partners, especially the US and the reinvigorated Quad grouping of Australia, India, Japan and the US.

India has generally avoided formal international alliances, and the Quad was in hiatus for years – why has India invested in it now?

India had always been mindful not to embrace external partners too closely so as to maintain its freedom of action and to not provoke a Chinese reaction. But since the Ladakh crisis, New Delhi has a newfound willingness to work more closely with the US, Japan, and Australia – because it calculates correctly that these partnerships enhance its freedom to act, and that China has already adopted the aggressive posture India feared.

It is important to note however that the border crisis was not the only driver of India’s strategic adjustment. The crisis coincided with the COVID-19 pandemic which highlighted to India the ineffectiveness of existing international institutional arrangements.

For New Delhi, then, the twin crises of Ladakh and the pandemic stressed the need for new international arrangements, and the Quad offered the best combination of agility and capability to meet the most pressing challenges of the Indo-Pacific region.

What do the Quad partners hope to achieve in their renewed partnership?

Beginning in 2021, the Quad assumed far greater significance. The first national leader summits happened – which have since continued at regular intervals – and its members have all agreed to a continually expanding agenda of work.

It seeks to provide international public goods, and everything from climate action to telecommunications regulations. Critically, it has limited its security role to some niche and relatively unprovocative areas, such as humanitarian assistance and maritime domain awareness – issues which benefit the Indo-Pacific as a whole and do not intensify security competition. It has certainly eschewed military cooperation.

Interestingly, the four Quad countries have also separately accelerated their military cooperation, bilaterally, trilaterally, and even quadrilaterally. But that cooperation lies outside the formal mechanisms of the Quad.

What impact will these Quad actions have on Chinese aggression and the Indo-Pacific region?

This Quad approach, which I call ‘zone balancing’ in my article, is specifically designed to build the capacity and resilience of regional states, and to not inflame dyadic security competition.

The relatively uncompetitive character of these activities helps to deflate Chinese claims that the Quad is an antagonistic new bloc, and to ameliorate southeast Asian states’ concerns over the potential intensification of strategic competition.

But the Quad’s agenda is not fixed and not bounded. It has expanded year on year and may continue to extend into new areas. This gives it a degree of flexibility and coercive leverage as Beijing cannot be confident about the Quad’s future direction.

This slate of activities has a lot of utility in building the Quad’s regional legitimacy and habits of cooperation among its members. But it conspicuously does not address the region’s most pressing security challenges.

It is not, in its current form, equipped to manage the challenge of territorial disputes or aggression. So the Quad will not address India’s unresolved border dispute with China, potential crises over Taiwan, or the South China Sea.

I would argue, however, that the four members of the Quad have unparalleled advantages of capacity and geography. With further military cooperation, even outside the formal structures of the Quad, they have the potential to deter Chinese aggression, but that remains subject to their political preferences.

Will other countries in different parts of the world adopt similar balancing strategies?

Zone balancing could be an attractive strategy for other countries which want to either avoid the costs of hard military balancing, or to not provoke their rivals.

It has been used in the past – such as the Marshall Plan during the early Cold War – and I would not be surprised if other countries competing with China, or even China itself, use it.

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

Numerous iron-sulfur (Fe-S) proteins with diverse functions are present in the matrix and respiratory chain complexes of mitochondria. Although [4Fe-4S] clusters are the most common type of Fe-S cluster in mitochondria, the molecular mechanism of [4Fe-4S] cluster assembly and insertion into target proteins by the mitochondrial iron-sulfur cluster (ISC) maturation system is not well-understood. Here we report a detailed characterization of two late-acting Fe-S cluster-carrier proteins from Arabidopsis thaliana, NFU4 and NFU5. Yeast two-hybrid and bimolecular fluorescence complementation studies demonstrated interaction of both the NFU4 and NFU5 proteins with the ISCA class of Fe-S carrier proteins. Recombinant NFU4 and NFU5 were purified as apo-proteins after expression in Escherichia coli. In vitro Fe-S cluster reconstitution led to the insertion of one [4Fe-4S]2+ cluster per homodimer as determined by UV-visible absorption/CD, resonance Raman and EPR spectroscopy, and analytical studies. Cluster transfer reactions, monitored by UV-visible absorption and CD spectroscopy, showed that a [4Fe-4S]2+ cluster-bound ISCA1a/2 heterodimer is effective in transferring [4Fe-4S]2+ clusters to both NFU4 and NFU5 with negligible back reaction. In addition, [4Fe-4S]2+ cluster-bound ISCA1a/2, NFU4, and NFU5 were all found to be effective [4Fe-4S]2+ cluster donors for maturation of the mitochondrial apo-aconitase 2 as assessed by enzyme activity measurements. The results demonstrate rapid, unidirectional, and quantitative [4Fe-4S]2+ cluster transfer from ISCA1a/2 to NFU4 or NFU5 that further delineates their respective positions in the plant ISC machinery and their contributions to the maturation of client [4Fe-4S] cluster-containing proteins.

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

A Digital India Must Embrace the Circular Economy Expert comment sysadmin 15 January 2018

A growing amount of e-waste should draw attention to the broader sustainability of a digital society.

The latest Global E-Waste Monitor places India as one of the highest contributors to global e-waste, generating over 2 million metric tonnes in 2016. Posing serious health and environmental risks, growing e-waste represents the hidden cost of increasingly digital lives in an information society.

With just 33 per cent of the population owning a smart phone, India already has the second largest number of smart phone users in the world, nearly 4 times that of the United States. The amount of e-waste generated will exponentially increase in the coming decade as the cost of consumer electronics decline, middle-class incomes rise, and the frequency at which devices are discarded increases.

As governance instruments are increasingly digitized and industry re-repositions itself to leverage Industry 4.0 solutions, the generation of e-waste will become a byproduct of institutional choices rather than consumer consumption and behaviour alone.

India is already a leader in the management and recycling of e-waste. But over 90 per cent is managed in the unorganized sector by small businesses and individual entrepreneurs, typically from low-income marginalized communities, and often women. E-waste contains various toxic substances such as mercury and lead, prolonged exposure to which can lead to major health problems.

Almost 80 per cent of e-waste workers in India suffer from respiratory ailments due to improper standards and nearly 500,000 children are engaged in e-waste collection without adequate protection and safeguards. The bulk of the dirty and dangerous work supporting India’s march towards an increasingly digital society is done by those who have the least access to technology gains. Government regulations for the management of e-waste, on the other hand, are becoming more relaxed, presumably as a result of industry pressure. To streamline e-waste management, the government notified Electronic Waste Rules in 2011, based on the concept of extended producer responsibility (EPR).

EPR makes manufacturers of electronic products responsible for the end-of-life management of their products, including setting up collection centres. By shifting the burden to manufacturers, the EPR framework, in theory, creates incentives for more environmentally friendly design. But the impact of EPR rules on manufacturers has been minimal, at best. The recently released Draft Notification (2017) by the Ministry of Environment, Forest and Climate Change further relaxes the EPR rule by reducing the e-waste collection targets for industries.

While the efficiency and productivity gains of Digital India are to be welcomed, growing e-waste should draw attention to the broader sustainability of a digital society. Data centres, for example, are one the largest contributors to global warming, contributing a similar amount to global greenhouse emissions as the aviation industry.

This amount is expected to triple in the next decade. In many ways, the sustainability challenge is a ‘wicked problem’ – where possible solutions create a new set of additional challenges and the choice between available alternatives is largely about competing values.

For example, data centres powered by renewable sources of energy such as solar provide a greener alternative, but will also create new forms of e-waste in the form of photovoltaic cells and panels. An unverified estimate suggests that India’s projected solar capacity of 100 gigawatts by 2022 will create 7.76 million tonnes of e-waste. Without adequate and preemptive consideration of how this waste should be disposed and recycled, renewable energy solutions can create new negative externalities.

For Digital India to be sustainable, we need to develop anticipatory knowledge for preemptive solutions. It is an opportune moment to think of the broader architecture of a digital society, one that avoids getting locked into unsustainable models of production and consumption, as is the case with many industrialized economies.

The argument that such considerations are premature for India, given high levels of poverty and unemployment, are misplaced. Enquiries into the sustainability of Digital India are no less urgent than the need for sustained job-creating economic growth. These issues should not be addressed in a sequential or linear manner, but in parallel, or else we will be only partially aware of available choices and their consequences, creating new forms of technological and economic lock-ins.

The value-based choice demanded by the ‘wicked problem’ at hand is one that embraces the idea of a circular economy — one that departs from the linear economic growth model predicated on ‘take, make, dispose’ to embrace a growth model based on creating closed loops of production, consumption and re-use. A circular economy model is built on the idea of designing out waste and pollution; keeping products and materials in use; and regenerating natural systems. In many ways, India is already a leader in the circular economy.

Alongside, the management of e-waste and other forms of recycling, high levels of repair and reuse are distinctly observable. A number of reports note that the informal waste management sector in India works better than systems in many industrialized economies.

A circular economy vision for Digital India would include organizing informal waste management systems, including safety and social protection initiatives for workers; revising and tightening existent e-waste rules for increased accountability by manufacturers both in terms of durable design and responsible disposal; green data centres; and building future smart cities with a view towards energy and water efficiency, among others.

A recent report by the Ellen McArthur Foundation and the World Economic Forum also estimates that a circular economy path to development could bring India annual benefits of $624 billion by 2050. Greenhouse gas emissions could also be 44 per cent lower in 2050, compared with current development path.

Unsurprisingly, Nordic countries are leading the way in promoting the idea of a circular economy. Sweden recently announced tax breaks for repair related activities and Finland hosted the first global conference on the circular economy earlier this year. The circular economy provides an opportunity for India to capitalize and leverage an already existing culture of circular activities, and promote it as a policy agenda that will create new forms of employment while facilitating sustainable environmental management.

This article was originally published in the Indian Express.

India Budget 2018: Who are the Biggest Winners and Losers? Expert comment sysadmin 2 February 2018

Any claims to boost farmers’ prospects will inevitably be seen as political, coming ahead of a series of key elections. But this budget recognises India’s most pressing concerns - and seeks to address them.

In 2016 India’s prime minister, Narendra Modi, pledged to double farmers’ incomes by 2022. While the pledge may have been aspirational, reliant on good weather as much as government policy, the 2018/19 budget demonstrates the depth of the government’s commitment to the agriculture sector.

There’s clearly a political edge to any moves to bolster agriculture: any solace to rural India will be described as political opportunism until most people in India are not engaged directly or indirectly in the agricultural sector.

And with a number of state elections coming up this year and a general election next – suggestions that it will be brought forward have increased in volume since the budget – a politically-astute budget is unsurprising. At the same time, there is a real sense of crisis in Indian agriculture which the budget is attempting to ameliorate.

Significant hike in infrastructure spending

The budget – which has Keynesian undertones – announces both direct and indirect support for rural India; it increases significantly the price at which the government purchases agricultural produce, and offers a range of further support through initiatives in areas such as irrigation. Furthermore, there is a significant hike in spending on infrastructure – roads, railways, ports and waterways – with a major allocation for rural infrastructure.

While government spending on infrastructure had been growing, the 2018/19 budget appears to accept that innovative funding models to fund rural projects are unlikely to work – instead, rural highways will have to be funded from overall taxation, as is generally the norm.

The other bold initiative focuses on healthcare. One hundred million poor families (so around half a billion Indians in total) will receive up to Rs500,000 for medical care under a health insurance programme. Given the correlation between ill health and poverty, this should have implications for the economy as well as healthcare itself. At the moment poverty effectively excludes many Indians from private healthcare.

Education too received a boost, with several proposals including teacher training. There have long been concerns over the quality of Indian education. In particular, even where schools exist physically, teachers themselves are absent.

As is often the case with India, the question will be in the implementation. While there are bound to be hiccups, the current Indian government does appear to realise the need for on-the-ground, visible change.

The recent state election in Gujarat demonstrated that while the ruling Bharatiya Janata Party (BJP) is clearly favourite to win another term, it is not invulnerable. If the changes do not reach the “last mile”, then they will accrue neither the economic nor the political benefits.

The downsides? Increased taxes will raise inflation, potentially exacerbated by sustained government borrowing; a 20% rise in customs duty will affect imports of mobile phones (though benefit domestic producers and encourage other foreign firms to set up manufacturing plants in India) and some of the revenue projections appear optimistic.

On balance though, this is a budget that recognises the most pressing challenges which India faces, and attempts to provide solutions to them.

This article was originally published in The Independent.

International Arbitration: Exploring India’s Potential 15 November 2019 — 9:30AM TO 5:30PM Anonymous (not verified) 17 October 2019 Chatham House | 10 St James's Square | London | SW1Y 4LE

As India’s economic clout grows, so does its aspiration to become a favoured arbitration destination in a globalized world dominated by foreign investments flows and cross border transactions. India’s bid to enhance its status as an arbitration destination depends largely on the suitability of its legal environment in meeting the demands of an increasingly sophisticated approach to disputed resolution. This conference will assess these, and other related, issues.

To register your interest in attending this event, please contact Nisha Ramdas by phone +91 9650977833 or by e-mail nisha@globaldialoguereview.com.

N. Leigh Anderson
Nov 1, 2002; 1:845-867
Reviews/Perspectives

SNF Dialogues: Social media, social movements and political change 6 July 2022 — 2:30PM TO 3:45PM Anonymous (not verified) 15 June 2022 Online

Experts and activists explore how the digital world has changed the nature of social movements and the impact this has on policymaking.

From Extinction Rebellion to Black Lives Matter, social movements are increasingly harnessing social media to project their calls for action. This event, convened in partnership with the SNF Dialogues series, will reflect on the value of social media to social movements and the effects of such digital movements on policymakers. Experts and activists from around the world will explore whether social media is an effective tool for social movements or a distraction, the extent to which digital forms of protest incite social change, and finally if this change has an impact on policy decisions.

The SNF Dialogues, an initiative of the Stavros Niarchos Foundation (SNF), are a series of monthly discussions whose goal is to foster the exchange of ideas, inspire a new way of thinking and acting, and encourage and elevate public discourse across geographic boundaries. The Dialogues discussions are free and open to the public, aiming to bring to light timely questions and developments, share informed reflections and concerns, highlight new data and angles, and present fascinating people, projects and ideas.

The Dialogues are curated and moderated by Anna-Kynthia Bousdoukou and are facilitated by the non-profit journalism organization iMEdD (incubator for Media Education and Development).

The discussion will be conducted in English with simultaneous interpretation into Greek. If you wish to watch the discussion in Greek, tune in here.

Independent Thinking: India, International Women's Day Audio NCapeling 9 March 2023

Episode 18 of our weekly podcast examines issues for women working in international affairs, and tackles India’s domestic politics and international standing.

Our panel this week discuss their experiences working professionally in global affairs and what advice they have for other women wanting to work in public policy.

India is also under discussion as Chatham House hosted Rahul Gandhi, leading Indian politician and former president of the Indian National Congress (INC). The panel considers his remarks about India’s internal quandaries and international perceptions of the country, almost a decade on from the 2014 election which brought Narendra Modi and the BJP to power.

Joining Bronwen Maddox from Chatham House are Rashmin Sagoo, director of the International Law programme, Anna Aberg from the Environment and Society programme, Armida van Rij from the International Security programme, and Isabella Wilkinson, research associate on cybersecurity. They are joined by Dr Mukulika Banerjee, who was until recently the director of the LSE South Asia Centre.

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.

JF Oram
Dec 1, 1996; 37:2473-2491
Reviews

K Schoonjans
May 1, 1996; 37:907-925
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.

Expert

Expert

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.

Selim Esedoḡlu, Jiajia Guo and David Li
Math. Comp. 93 (), 2679-2710.
Abstract, references and article information

Bero Roos
Theor. Probability and Math. Statist. 111 (), 137-151.
Abstract, references and article information

TODAY KINGSTON...

TODAY KINGSTON...

Zinc is a critical element for insulin storage in the secretory granules of pancreatic beta cells. The islet-specific zinc transporter ZnT8 mediates granular sequestration of zinc ions. A genetic variant of human ZnT8 arising from a single nonsynonymous nucleotide change contributes to increased susceptibility to type-2 diabetes (T2D), but it remains unclear how the high risk variant (Arg-325), which is also a higher frequency (>50%) allele, is correlated with zinc transport activity. Here, we compared the activity of Arg-325 with that of a low risk ZnT8 variant (Trp-325). The Arg-325 variant was found to be more active than the Trp-325 form following induced expression in HEK293 cells. We further examined the functional consequences of changing lipid conditions to mimic the impact of lipid remodeling on ZnT8 activity during insulin granule biogenesis. Purified ZnT8 variants in proteoliposomes exhibited more than 4-fold functional tunability by the anionic phospholipids, lysophosphatidylcholine and cholesterol. Over a broad range of permissive lipid compositions, the Arg-325 variant consistently exhibited accelerated zinc transport kinetics versus the Trp-form. In agreement with the human genetic finding that rare loss-of-function mutations in ZnT8 are associated with reduced T2D risk, our results suggested that the common high risk Arg-325 variant is hyperactive, and thus may be targeted for inhibition to reduce T2D risk in the general populations.

13 July 2020

Viral infection is one environmental factor that may contribute to the initiation of pancreatic β-cell destruction during the development of autoimmune diabetes. Picornaviruses, such as encephalomyocarditis virus (EMCV), induce a pro-inflammatory response in islets leading to local production of cytokines, such as IL-1, by resident islet leukocytes. Furthermore, IL-1 is known to stimulate β-cell expression of iNOS and production of the free radical nitric oxide. The purpose of this study was to determine whether nitric oxide contributes to the β-cell response to viral infection. We show that nitric oxide protects β-cells against virally mediated lysis by limiting EMCV replication. This protection requires low micromolar, or iNOS-derived, levels of nitric oxide. At these concentrations nitric oxide inhibits the Krebs enzyme aconitase and complex IV of the electron transport chain. Like nitric oxide, pharmacological inhibition of mitochondrial oxidative metabolism attenuates EMCV-mediated β-cell lysis by inhibiting viral replication. These findings provide novel evidence that cytokine signaling in β-cells functions to limit viral replication and subsequent β-cell lysis by attenuating mitochondrial oxidative metabolism in a nitric oxide–dependent manner.

Priorities for implementing Ethiopia's national dialogue 11 May 2022 — 1:00PM TO 3:00PM Anonymous (not verified) 3 May 2022 Online

Experts discuss challenges and priorities in shaping an inclusive and effective national dialogue in Ethiopia.

Ethiopia is grappling with numerous contentious national issues – not least persistent conflict in several parts of the country – which underscore the need for large-scale dialogue and reconciliation efforts to address the country’s deep-rooted societal and political divisions. Ethiopia’s newly established National Dialogue Commission – whose 11 commissioners were appointed in February 2022 – has begun a four-phased process of preparations for a dialogue, with its initial stage focused on stakeholder engagement and local knowledge mobilization.

There are major challenges, however, in ensuring inclusivity amidst ongoing conflict and questions on how a country-wide process will sit alongside local dialogue initiatives and wider mediation and peacebuilding efforts. Linking the process to constitutional bodies will also be an important priority to ensure dialogue outcomes are effectively implemented.

At this public event, panellists will exchange perspectives on how to shape an effective national dialogue in Ethiopia, including priorities for building a credible National Dialogue Commission and the roles and responsibilities of other national, regional and local-level actors. They will also discuss key implementation mechanisms and long-term priorities for trust-building and cultivating a conducive environment for inclusive dialogue.

This webinar is part of a series of events and outputs on Ethiopia’s political transition.

This event will also be broadcast live on the Chatham House Africa Programme’s Facebook page.

The online media changing African news The World Today mhiggins.drupal 2 August 2022

Africa’s news sites are gripping audiences with digital innovation and bold directions. Helen Fitzwilliam talks to editors at three platforms.

Lydia Namubiru
News editor of ‘The Continent’ (South Africa)

At the start of the pandemic, we realized a lot of fake news was being shared on WhatsApp. So, The Continent chose to launch on that platform to insert some real journalism in a way that could easily be shared. We now have about 100,000 readers across Africa and the rest of the world, but we had to dramatically change the way we write and edit stories: to compete with the likes of Twitter and Instagram, we try to keep stories tight at 300 words. 

There’s a real variety. We can run an investigation into corruption in the Democratic Republic of the Congo a week after a front page on the fashion designer who dresses Africa’s ‘big men’ [powerful leaders]. We cover feminist issues, the backlash against LGBT people in Ghana; we’ve had the Namibian first lady talking to us about misogyny. These are not the sort of topics a typical African newspaper is going to lead with.

With a story such as Ukraine, the war’s impact on the cost of living has been the most obvious angle for us. It has driven countries such as Malawi into crisis, forcing a devaluation of the currency.
 
As for the future, we see two issues looming. Workers’ economic rights and their treatment by multinationals will be a big story. There are refugees in camps in Kenya working in data operations and being paid a pittance to help create huge, potentially multimillion-dollar systems for US companies. 

Second, Africa has the world’s youngest population and the oldest leaders, so this will likely lead to activism and protests. The young are exposed to the global village, so they want different things and have different values. They speak a completely different language their leaders do not understand. It will be an interesting conflict, but could lead to real violence. 

John Githongo
Editor of ‘The Elephant’ (Kenya)

We set up this platform four years ago. Due to political and commercial pressures, mainstream media wasn’t doing much critical reporting. We have between 30,000 and 80,000 readers a week, the majority of them in Africa. 

The digital space reaches a completely different demographic. When The Elephant started, it was 80 per cent male and over 40, but we have gained more younger people and more women. Now it is 60 per cent men, 40 per cent women and that is something we have been working at. 

Our editorial approach is that as long as a piece has a strong argument and fits into our pan-African brief, we will publish it – even if we don’t agree with it.

The conflicts in Ethiopia and parts of the Sahel make the war in Ukraine pale in comparison. So many people have died in Ethiopia or been displaced and now we have the onset of a famine after four years of failed rain. During the 1960s and 1970s, when the Cold War found its way on to African soil, millions of people died – so there is caution about getting involved in a European fight.

There is always a lot of fake news around during elections. But people are beginning to be more sceptical. We go after those who attempt to change the level of debate with reputation-laundering and try to expose their actions. 
 
The future of democracy is going to be a big issue. When Africans were watching the attack on the US Capitol last year, they were hoping it was not a Black Lives Matter protest, which could have resulted in a ‘blackbath’. As soon as they saw the white guys wearing horns, people laughed with relief. 

There is an ongoing recalibration of Africa’s geopolitical relations with the rest of the world. A poll released in June showed China has overtaken the United States as the foreign power having the biggest positive influence in Africa in the eyes of young people across the continent. The younger generation is writing its own narrative. 

Wale Lawal
Editor of ‘The Republic’ (Nigeria)

Nigerian audiences are increasingly online and tend to read both local and international publications. They also know that the issues they care about are either under-reported or reported at lower quality levels. 

At The Republic, we provide political journalism that tends to require high levels of expertise. Yet online audiences also prioritize engagement: it is not enough for an issue to be important, it also needs to be interesting.

Some topics we have covered that Western media tend not to include how people experience blackness in different parts of the world; the waves of mostly female-led and youth-led movements rising up against autocratic governments across Africa; and relationships between countries within Africa itself. In the early days of the pandemic, we launched a Covid-19 and Africa series, having noticed a glaring lack of African expert voices in global media.
 
We also cover Africa’s evolving relations with Russia. Whenever we encounter a story like Russia’s invasion of Ukraine, the first thing we always ask ourselves is what missing voice can we add to the current discussion? All we were reading about after the invasion was how neighbouring countries were opening their borders and their homes to Ukrainians. Most people saw only that. 

But we knew that around 15,000 Africans were studying in Ukraine, that Africans routinely face harsh treatment at international borders, and that clearly their voices were missing from the discussion.

With fake news and information gaps on social media, our usual approach is to develop expert-led columns and circulate these as widely as possible.

Our next mission is to think about the role that independent media can play in supporting democracies, such as by increasing voter turnout. During the last election in Nigeria, less than 35 per cent of those who registered to vote eventually did so.

Visual Abstract

Wenhe Zhu
Dec 29, 2020; 0:RA120.002353v1-mcp.RA120.002353
Research

Mouse embryonic stem cells (mESCs) display unique mechanical properties, including low cellular stiffness in contrast to differentiated cells, which are stiffer. We have previously shown that mESCs lacking the clathrin heavy chain (Cltc), an essential component for clathrin-mediated endocytosis (CME), display a loss of pluripotency and an enhanced expression of differentiation markers. However, it is not known whether physical properties such as cellular stiffness also change upon loss of Cltc, similar to what is seen in differentiated cells, and if so, how these altered properties specifically impact pluripotency. Using atomic force microscopy (AFM), we demonstrate that mESCs lacking Cltc display higher Young's modulus, indicative of greater cellular stiffness, compared with WT mESCs. The increase in stiffness was accompanied by the presence of actin stress fibers and accumulation of the inactive, phosphorylated, actin-binding protein cofilin. Treatment of Cltc knockdown mESCs with actin polymerization inhibitors resulted in a decrease in the Young's modulus to values similar to those obtained with WT mESCs. However, a rescue in the expression profile of pluripotency factors was not obtained. Additionally, whereas WT mouse embryonic fibroblasts could be reprogrammed to a state of pluripotency, this was inhibited in the absence of Cltc. This indicates that the presence of active CME is essential for the pluripotency of embryonic stem cells. Additionally, whereas physical properties may serve as a simple readout of the cellular state, they may not always faithfully recapitulate the underlying molecular fate.

The Wnt/β-catenin pathway is one of the major pathways that regulates embryonic development, adult homeostasis, and stem cell self-renewal. In this pathway, transcription factors T-cell factor and lymphoid enhancer factor (TCF/LEF) serve as a key switch to repress or activate Wnt target gene transcription by recruiting repressor molecules or interacting with the β-catenin effector, respectively. It has become evident that the protein stability of the TCF/LEF family members may play a critical role in controlling the activity of the Wnt/β-catenin signaling pathway. However, factors that regulate the stability of TCF/LEFs remain largely unknown. Here, we report that pVHL binding protein 1 (VBP1) regulates the Wnt/β-catenin signaling pathway by controlling the stability of TCF/LEFs. Surprisingly, we found that either overexpression or knockdown of VBP1 decreased Wnt/β-catenin signaling activity in both cultured cells and zebrafish embryos. Mechanistically, VBP1 directly binds to all four TCF/LEF family members and von Hippel-Lindau tumor-suppressor protein (pVHL). Either overexpression or knockdown of VBP1 increases the association between TCF/LEFs and pVHL and then decreases the protein levels of TCF/LEFs via proteasomal degradation. Together, our results provide mechanistic insights into the roles of VBP1 in controlling TCF/LEFs protein stability and regulating Wnt/β-catenin signaling pathway activity.

Protein biosynthesis is fundamental to cellular life and requires the efficient functioning of the translational machinery. At the center of this machinery is the ribosome, a ribonucleoprotein complex that depends heavily on Mg2+ for structure. Recent work has indicated that other metal cations can substitute for Mg2+, raising questions about the role different metals may play in the maintenance of the ribosome under oxidative stress conditions. Here, we assess ribosomal integrity following oxidative stress both in vitro and in cells to elucidate details of the interactions between Fe2+ and the ribosome and identify Mn2+ as a factor capable of attenuating oxidant-induced Fe2+-mediated degradation of rRNA. We report that Fe2+ promotes degradation of all rRNA species of the yeast ribosome and that it is bound directly to RNA molecules. Furthermore, we demonstrate that Mn2+ competes with Fe2+ for rRNA-binding sites and that protection of ribosomes from Fe2+-mediated rRNA hydrolysis correlates with the restoration of cell viability. Our data, therefore, suggest a relationship between these two transition metals in controlling ribosome stability under oxidative stress.

Kinases are critical components of intracellular signaling pathways and have been extensively investigated with regard to their roles in cancer. p21-activated kinase-1 (PAK1) is a serine/threonine kinase that has been previously implicated in numerous biological processes, such as cell migration, cell cycle progression, cell motility, invasion, and angiogenesis, in glioma and other cancers. However, the signaling network linked to PAK1 is not fully defined. We previously reported a large-scale yeast genetic interaction screen using toxicity as a readout to identify candidate PAK1 genetic interactions. En masse transformation of the PAK1 gene into 4,653 homozygous diploid Saccharomyces cerevisiae yeast deletion mutants identified ∼400 candidates that suppressed yeast toxicity. Here we selected 19 candidate PAK1 genetic interactions that had human orthologs and were expressed in glioma for further examination in mammalian cells, brain slice cultures, and orthotopic glioma models. RNAi and pharmacological inhibition of potential PAK1 interactors confirmed that DPP4, KIF11, mTOR, PKM2, SGPP1, TTK, and YWHAE regulate PAK1-induced cell migration and revealed the importance of genes related to the mitotic spindle, proteolysis, autophagy, and metabolism in PAK1-mediated glioma cell migration, drug resistance, and proliferation. AKT1 was further identified as a downstream mediator of the PAK1-TTK genetic interaction. Taken together, these data provide a global view of PAK1-mediated signal transduction pathways and point to potential new drug targets for glioma therapy.

AMP-activated protein kinase (AMPK) is a key regulator of energy metabolism that phosphorylates a wide range of proteins to maintain cellular homeostasis. AMPK consists of three subunits: α, β, and γ. AMPKα and β are encoded by two genes, the γ subunit by three genes, all of which are expressed in a tissue-specific manner. It is not fully understood, whether individual isoforms have different functions. Using RNA-Seq technology, we provide evidence that the loss of AMPKβ1 and AMPKβ2 lead to different gene expression profiles in human induced pluripotent stem cells (hiPSCs), indicating isoform-specific function. The knockout of AMPKβ2 was associated with a higher number of differentially regulated genes than the deletion of AMPKβ1, suggesting that AMPKβ2 has a more comprehensive impact on the transcriptome. Bioinformatics analysis identified cell differentiation as one biological function being specifically associated with AMPKβ2. Correspondingly, the two isoforms differentially affected lineage decision toward a cardiac cell fate. Although the lack of PRKAB1 impacted differentiation into cardiomyocytes only at late stages of cardiac maturation, the availability of PRKAB2 was indispensable for mesoderm specification as shown by gene expression analysis and histochemical staining for cardiac lineage markers such as cTnT, GATA4, and NKX2.5. Ultimately, the lack of AMPKβ1 impairs, whereas deficiency of AMPKβ2 abrogates differentiation into cardiomyocytes. Finally, we demonstrate that AMPK affects cellular physiology by engaging in the regulation of hiPSC transcription in an isoform-specific manner, providing the basis for further investigations elucidating the role of dedicated AMPK subunits in the modulation of gene expression.

Acute lung injury (ALI), is a rapidly progressing heterogenous pulmonary disorder that possesses a high risk of mortality. Accumulating evidence has implicated the activation of the p65 subunit of NF-κB [NF-κB(p65)] activation in the pathological process of ALI. microRNAs (miRNAs), a group of small RNA molecules, have emerged as major governors due to their post-transcriptional regulation of gene expression in a wide array of pathological processes, including ALI. The dysregulation of miRNAs and NF-κB activation has been implicated in human diseases. In the current study, we set out to decipher the convergence of miR-99b and p65 NF-κB activation in ALI pathology. We measured the release of pro-inflammatory cytokines (IL-1β, IL-6, and TNFα) in bronchoalveolar lavage fluid using ELISA. MH-S cells were cultured and their viability were detected with cell counting kit 8 (CCK8) assays. The results showed that miR-99b was up-regulated, while PRDM1 was down-regulated in a lipopolysaccharide (LPS)-induced murine model of ALI. Mechanistic investigations showed that NF-κB(p65) was enriched at the miR-99b promoter region, and further promoted its transcriptional activity. Furthermore, miR-99b targeted PRDM1 by binding to its 3'UTR, causing its down-regulation. This in-creased lung injury, as evidenced by increased wet/dry ratio of mouse lung, myeloperoxidase activity and pro-inflammatory cytokine secretion, and enhanced infiltration of inflammatory cells in lung tissues. Together, our findings indicate that NF-κB(p65) promotion of miR-99b can aggravate ALI in mice by down-regulating the expression of PRDM1.

Type I and III interferons induce expression of the “myxovirus resistance proteins” MxA in human cells and its ortholog Mx1 in murine cells. Human MxA forms cytoplasmic structures, whereas murine Mx1 forms nuclear bodies. Whereas both HuMxA and MuMx1 are antiviral toward influenza A virus (FLUAV) (an orthomyxovirus), only HuMxA is considered antiviral toward vesicular stomatitis virus (VSV) (a rhabdovirus). We previously reported that the cytoplasmic human GFP-MxA structures were phase-separated membraneless organelles (“biomolecular condensates”). In the present study, we investigated whether nuclear murine Mx1 structures might also represent phase-separated biomolecular condensates. The transient expression of murine GFP-Mx1 in human Huh7 hepatoma, human Mich-2H6 melanoma, and murine NIH 3T3 cells led to the appearance of Mx1 nuclear bodies. These GFP-MuMx1 nuclear bodies were rapidly disassembled by exposing cells to 1,6-hexanediol (5%, w/v), or to hypotonic buffer (40–50 mosm), consistent with properties of membraneless phase-separated condensates. Fluorescence recovery after photobleaching (FRAP) assays revealed that the GFP-MuMx1 nuclear bodies upon photobleaching showed a slow partial recovery (mobile fraction: ∼18%) suggestive of a gel-like consistency. Surprisingly, expression of GFP-MuMx1 in Huh7 cells also led to the appearance of GFP-MuMx1 in 20–30% of transfected cells in a novel cytoplasmic giantin-based intermediate filament meshwork and in cytoplasmic bodies. Remarkably, Huh7 cells with cytoplasmic murine GFP-MuMx1 filaments, but not those with only nuclear bodies, showed antiviral activity toward VSV. Thus, GFP-MuMx1 nuclear bodies comprised phase-separated condensates. Unexpectedly, GFP-MuMx1 in Huh7 cells also associated with cytoplasmic giantin-based intermediate filaments, and such cells showed antiviral activity toward VSV.

Daphne E.C. Boer
Dec 23, 2020; 0:jlr.RA120001043v1-jlr.RA120001043
Research Articles

Natalie Bruiners
Dec 1, 2020; 61:1617-1628
Research Articles

Julia V Busik
Dec 23, 2020; 0:jlr.TR120000981v1-jlr.TR120000981
Thematic Reviews

Abudukadier Abulizi
Dec 1, 2020; 61:1565-1576
Research Articles