JM Dietschy
Oct 1, 1993; 34:1637-1659
Reviews

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

Ronald M. Krauss
Jan 1, 1982; 23:97-104
Articles

Weerapan Khovidhunkit
Jul 1, 2004; 45:1169-1196
Thematic Reviews

DL Brasaemle
Nov 1, 1997; 38:2249-2263
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AR Tall
Aug 1, 1993; 34:1255-1274
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Dawn L. Brasaemle
Dec 1, 2007; 48:2547-2559
Thematic Reviews

RK Tangirala
Nov 1, 1995; 36:2320-2328
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Robert W. Mahley
Jan 1, 1999; 40:1-16
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Jason M. Ridlon
Feb 1, 2006; 47:241-259
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IJ Goldberg
Apr 1, 1996; 37:693-707
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JP Segrest
Feb 1, 1992; 33:141-166
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JE Hixson
Mar 1, 1990; 31:545-548
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The Committee to Protect Journalists named winner of the Chatham House Prize 2018 News Release sysadmin 5 October 2018

The Committee to Protect Journalists (CPJ) has been voted the winner of this year’s Chatham House Prize.

Digital governance must not marginalize smaller states Expert comment LToremark 19 May 2021

For effective and inclusive digital governance, multi-stakeholderism must raise its game.

Last month, the G7 announced it is to work towards a trusted, values-driven digital ecosystem. While this is commendable, the G7 must recognize that key international digital governance decisions should involve all states whose populations will be affected. Not doing so is to deny the legitimate interests of those populations and may cause a lack of trust in international digital governance that embeds longer-term instability.

While a multi-stakeholder approach to digital governance is important, it must be structured in a way that allows for meaningful representation of states’ interests and ensures their representatives have the opportunity and capacity to take part. As the internet becomes fundamental to life in every country of the world, international digital governance is increasingly important to all governments and excluding some states’ perspectives may engender wider risks to international security and governance.

The ‘glitter ball’ of digital governance

International digital governance is playing catch-up with the digital sphere it needs to govern. Its starting point is a ‘glitter ball’ of governance initiatives: a large number of complex facets with overlapping impacts – and an almost impenetrable core. Governance initiatives (see infographic) include governance of the internet itself and its uses, international cybersecurity, international human rights, data management, as well as the impact of digital developments in areas such as armed conflict, trade and health.

Many of the bodies involved – such as the Internet Governance Forum, the Internet Corporation for Assigned Names and Numbers (ICANN) and technical standards bodies – include a wide range of stakeholders, yet there is no one accessible, central body. Furthermore, certain key issues, such as the role and responsibilities of tech platforms, are barely touched upon by international governance mechanisms. There is also currently only a limited role for traditional UN multilateral decision-making, a process which builds in a role for smaller states.

The sheer number of forums involved, each with a different set of working methods and rules on participation, makes it difficult to fully grasp what digital governance looks like as a whole. The UN secretary-general’s High-level Panel on Digital Cooperation recognized the complexity of digital cooperation arrangements and the barriers to inclusion facing small and developing countries as well as under-represented groups. In response, the June 2020 UN Roadmap on Digital Cooperation accepts the need to streamline digital governance while ensuring marginalized voices are heard.

The UN is considering potential models for future governance, each of which would – reassuringly – involve multi-stakeholder participation, dedicated funds to boost participation, consolidation of discussions currently split between different forums and a minor coordinating role for the UN.  

Building in roles for smaller states

As the UN designs new digital governance architecture, it is particularly important to build in roles for small and medium states. Core constituencies affected by decisions should be at the centre and governments – as guardians of public interest – should have a key say in the decision-making process. The distrust generated by built-in power imbalances needs to be addressed, as does the dominance of voices from the Global North in bodies such as ICANN.   

There has been some progress made to increase participation. For example, the Freedom Online Coalition includes a number of developing countries and the 2020 Internet Governance Forum included input from 175 states.

However, participation is not only a matter of having a seat at the table. As discussed at the March 2021 UN Open-ended Working Group on ICTs in the context of international security, capacity-building is vital. The group’s conclusions include the suggested development of a global cyber capacity-building agenda with information sharing and norms guidance under the auspices of the UN. Representatives of small and medium states need a roadmap to understand in which forums they can defend and pursue their interests, and the financial help to do so if necessary.

Managing multi-stakeholder participation

A multi-stakeholder approach has been fundamental to digital governance from the start and has played a vital role in helping to secure the openness and universality of the internet. This approach is rightly seen as essential to effective governance because it introduces diverse expertise, allows the interests of all impacted sectors to be taken into account and helps ensure decisions are accepted by those affected.

However, as identified in a Chatham House report on inclusive global governance, multi-stakeholderism needs to raise its game. One of its downsides is that in the cacophony some important voices may not be heard because they lack resource or capacity to speak up. There is a perennial risk of debate and decision-making being captured by the wealthiest companies or the most powerful states. At present, small and medium states are under-represented in multi-stakeholder forums and it is important that those managing such forums seek to identify and include previously excluded voices.

Multi-stakeholderism should not come at the expense of efficiency. While it does not have to mean huge, inefficient meetings or endless discussion, it should also not mean that smaller, less well-funded voices are not heard. Instead, such processes should enable representation of appropriate interest groups, complemented by wider meetings (such as regional meetings, or sector-specific meetings) as needed. While inclusivity and transparency are key, synergies between regional and global forums can work well –  for example, some countries have adopted national versions of the Internet Governance Forum –  and so too can hybrid models such as the Freedom Online Coalition, which meets both as government members and for regular multi-stakeholder dialogue.

A multi-stakeholder approach should also not lose sight of the key role of states – and where mandated, sub-state entities – in making public policy decisions.

An important role for the UN

For 75 years, the UN has acted as a bulwark of international security and shared values, and a promoter of economic and social development. If misused, technology has the potential to undermine this bulwark, to facilitate conflict, erode rights and undermine development. The UN must encourage the harnessing of technology for society’s benefit, while leading a collective effort to guard against the risks through the retention and growth of a universal, open internet – particularly in the face of growing digital authoritarianism exacerbated by COVID-19.

The UN can also help protect against a commercial culture that threatens to trample fundamental freedoms of privacy and autonomy in its pursuit of wealth and to widen economic and social gulfs by leaving large swathes of the world behind. If the UN is to play this role effectively – and for the benefit of all its members ­– it requires the active participation of all states, large and small.

Why the next generation is key to protecting human rights Expert comment LToremark 23 June 2021

Strengthening youth participation in public affairs is essential to building inclusive and democratic societies that respect human rights.

Young people have always been drivers of social and economic reform, and today’s global youth population is more numerous and interconnected than ever before. While they have been at the forefront of civic rights movements in recent years, young people are largely excluded from discussions around human rights norms and how to monitor their protection and defence.

Young people are consistently underrepresented in intergovernmental mechanisms and national dialogues, which not only squanders their potential to contribute to effective solutions but also risks disengagement and disillusionment with multilateralism more broadly, at a time when many are already warning of the fraying of the international liberal order. Although there are actors and initiatives working to lift barriers to youth participation in governance – such as the UN Secretary-General’s Envoy on Youth, Jayathma Wickramanayake, or the UN 2016 Not Too Young To Run campaign – these efforts tend to fall short in effecting real change and rarely translate into institutionalized procedures.

While ‘the youth’ is a heterogenous group, comprising different ages, ethnicities, national identities and interests, their participation in realizing human rights is essential to addressing the current challenges and possibilities of human rights for future generations. This will help foster more effective solutions to rights-related challenges, re-build trust in the international human rights framework among younger demographics and broaden and deepen commitments to human rights across generations.

Human rights policies and the online environment

Young people tend to be more technologically literate than their predecessors and also represent the majority of internet users and social media consumers in many countries. They can therefore play a key role in innovating and imagining rights-based solutions to emerging problems for the human rights framework, such as illegitimate collection of data by governments and companies, microtargeting by online platforms, and the sharing of harmful content online. In many cases, international human rights practices have failed to keep pace with these changes and the challenges they bring.

Younger demographics may also approach these novel human rights issues from different starting points. For example, a UK study found that 30 per cent of 18-24 year-olds were ‘unconcerned’ about data privacy compared with only 12 per cent of those aged 55-64, and it has been shown that younger people tend to be more discerning of fake news compared to older generations. There may be a need for human rights institutions and practitioners to acknowledge and bridge these gaps in perspective and understanding to ensure long-term support for proposed solutions.

International cooperation for human rights protection

It has been suggested that young people have reaped the benefits of previous human rights-based policy reforms and have a strong sense of what rights they are entitled to and why these need to be protected through an international framework. Young people are also generally more supportive of multilateralism compared to their older counterparts, as demonstrated by a 2020 survey by Pew Research Center on global attitudes, which showed that 72 per cent of respondents aged 18-29 stated they have a favourable view of the UN, compared with 58 per cent of respondents aged 50 and older.

At a recent Chatham House workshop, young participants from countries as diverse as Lebanon, Kenya and the United States expressed concern that growing hostility towards globalization threatens to undo progress in human rights standards and multilateralism more broadly, progress that they have seen and benefitted from. The rise of nationalist and populist parties has also seen countries shift their attention inwards, as evidenced by former president Trump’s decision to withdraw the US from the Paris Agreement on climate change, and threats by Brazil’s president, Jair Bolsonaro, to follow suit.

Engaging more actively with younger individuals on global human rights reform will help ensure the long-term relevance of multilateral cooperation as well as domestic buy-in of human rights commitments.

Awareness of the interconnectivity of global problems

Young people’s proficiency on online platforms has enabled greater coordination and knowledge sharing without geographical constraints, allowing young activists – like Greta Thunberg – to inspire global movements and foster online discussions about intersectional solutions to modern-day challenges.

This intersectional and transnational lens will be a vital component of building solutions to politically or historically complex issues and can be leveraged to foster better understanding of competing human rights claims relating to issues such as land re-distribution in South Africa or limitations on freedom of movement during the COVID-19 pandemic. These democratic forums and platforms will ultimately help build a global community committed to and engaged with human rights.

Capturing the next generation’s potential

With these concerns and areas of potential in mind, how can human rights institutions and mechanisms create more meaningful avenues for youth input? 

Recent Chatham House research has suggested that multilateral institutions’ efforts to engage youth has often taken the form of ‘superficial listening’, for example inviting a high-profile youth actor to a one-off event or appointing youth delegates who are not able to participate in formal discussions or mainstream governance forums. While encouraging youth participation in meetings focused on human rights can lead to positive change, tokenism can discourage future engagement and dilute the effectiveness of the forums in question.

Capitalizing on the potential of the next generation can be achieved through integrating youth councils and advisers into national and international human rights policy processes, as well as human rights institutions. A few replicable models are already operational, such as the Y7 and the Y20 delegations – the official youth engagement groups for the G7 and G20 – that advance evidence-based proposals to world leaders ahead of the G7 and G20 summits.

At the domestic level, grassroots youth-led movements can help bridge the gap between local constituencies and international policymakers, with youth activists on the ground helping to implement human rights standards and fighting against the spread of misinformation. Strong local networks and civic spaces are essential for pushing back against human rights abuses, and youth activists should be mobilized to connect the efforts of domestic and international bodies to the real issues on the ground; for example, canvassing grassroots youth networks on domestic and traditional customs before implementing development agendas around women’s rights.

As well as providing insertion points for youth policy actors, human rights institutions must communicate their goals more effectively to younger generations and promote intergenerational and inclusive dialogue, for example by holding virtual consultations that  give access to individuals from different backgrounds. Similarly, they should ask young people about their priorities for human rights reform using regular and accessible surveys or by sharing information on online platforms regularly used by this demographic. This will ensure lasting buy-in from the next generation, essential for the relevance and sustainability of the human rights framework in the years to come.

This piece draws upon insights gathered at a workshop hosted by Chatham House in March 2021, which brought together the Institute’s networks of next generation groups including representatives of the QEII Academy Ambassadors, the Panel of Young Advisers, and the Common Futures Conversations community, as well as young members from the South African Institute of International Affairs.

Protecting universal human rights: Imagine a better world Explainer Video NCapeling 19 November 2021

Short animation examining why protecting and defending human rights ensures an equitable response to humanitarian crises and addresses economic inequality.

Human rights are not policies that can be overturned, they are not granted by governments. They belong to everyone as human beings.

For the most part, states are meeting their commitments to defend and protect universal human rights. But increasingly some governments are beginning to shy away from their obligations, and some are even actively seeking to subvert human rights.

And the regional and international bodies created and charged with defending these rights are being challenged by the rise of new powers and political movements.

Chatham House is built on big ideas. Help us imagine a better world.

Our researchers develop positive solutions to global challenges, working with governments, charities, businesses and society to build a better future.

SNF CoLab is our project supported by the Stavros Niarchos Foundation (SNF) to share our ideas in experimental, collaborative ways – and to learn about designing a better future.

Why the private sector should protect civic society Explainer Video NCapeling 10 December 2021

A short animation explaining the crucial role that the private sector can play in protecting and defending civic space.

This video explainer introduces a synthesis paper which analyses how the private sector can support the protection of civic society space.

The private sector is in a unique position to work with civil society organizations to uphold and defend civic freedoms and support sustainable and profitable business environments. Companies have the capacity, resources and expertise to enhance the protection of civic space.

By doing so, this helps create a society in which fundamental rights and the rule of law are respected and exercised by governments, private citizens, and all organizations which, in turn, is critical to a sustainable and profitable business environment.  

For more information, download the report.

Sanctions must not prevent humanitarian work in Ukraine Expert comment NCapeling 30 May 2022

Restrictions on supply of certain items and financial sanctions can impede vital relief unless adequate safeguards are put in place such as exceptions or general licences.

Sanctions play a major role in the response to Russia’s invasion of Ukraine. The United Nations (UN) has not imposed sanctions, but an important number of states have done so. They have imposed a wide array of restrictions and the number of targeted – or ‘designated’ – persons is unprecedented.

The public has been captivated by the freezing of oligarchs’ assets. There is ongoing discussion about seizing them to provide compensation for war damage. Debate continues about how far to ban oil and gas imports.

One aspect of the sanctions has received far less attention, even though it can exacerbate the effect of the conflict on civilians. Some of the trade restrictions and financial sanctions pose immediate and concrete challenges to the capacity of humanitarian organizations to work in Ukraine and in neighbouring states.

Trade sanctions imposed by the European Union (EU) and UK prohibit the export or supply of certain goods and technology in the transport, telecommunications, energy, and oil or mineral exploration sectors to non-government-controlled areas of the Donetsk or Luhansk oblasts, or for use there.

Restricted items include technical equipment which is necessary for humanitarian operations, such as water pumps and refrigerating equipment, but also far more mundane items such as vehicles for transport of persons and goods, and office equipment that are necessary for humanitarian organizations trying to work in the region.

Designations can reduce options for support

Financial sanctions also raise problems. Some are immediately apparent. Significantly for humanitarian operations, the two de facto republics of Donetsk and Luhansk are designated by the EU, the UK, and the US. Consequently, it is prohibited to make funds or assets available to them directly or indirectly.

This prohibition covers the payment of any taxes, licences, and other fees to these authorities, as well as the provision of assets to ministries under their control in the course of humanitarian operations, such as ministries of health and education.

Designations of other entities may also be relevant, such as Russian ‘state enterprises’ which operate in these areas and are the sole providers of commodities necessary for humanitarian response, such as heating fuel.

These are the designations which most obviously impact humanitarian response. However, more than 1,000 persons and entities have been designated and humanitarian organizations must avoid purchasing goods and services from them.

Risk-averse commercial partners

Commercial actors – such as banks, insurers, freight companies and commodity providers – whose services are required by humanitarian organizations must also comply with the sanctions. Experience shows that the due diligence measures adopted by humanitarian organizations do not always allay concerns of risk-averse sectors such as banks.

Fears of violating the sanctions, coupled with the fact humanitarian organizations are rarely profitable clients, have led them to severely restrict the services they provide.

This is not the first occasion the problem has arisen. What is different in relation to Ukraine is the number of designated persons and the ‘sanctions packages’ adopted in quick succession. As compliance officers struggle to keep abreast, their institutions become even more risk-averse.

For UK banks, the situation is exacerbated by the adoption of the Economic Crime (Transparency and Enforcement) Act 2022. This amends existing rules by removing the requirement for the UK Treasury to prove knowledge or reasonable cause to suspect that a transaction violated sanctions, imposing strict liability for sanctions violations.

Time for the UK to follow others

The EU, the US, Switzerland, and other states which have imposed sanctions have sought to mitigate their adverse effects by including safeguards for humanitarian action. Although the UK has largely replicated the measures adopted by the EU in terms of restrictions and designations, it lags behind in including such safeguards.

The UK trade restrictions and financial sanctions do not include exceptions for humanitarian action. While several general licences have been issued, none relate to humanitarian operations.

Instead, the UK measures foresee only the possibility of applying for specific licences – from the Treasury in the case of financial sanctions and the Department of International Trade for trade restrictions. But obtaining specific licences is a time-consuming process which is simply not appropriate for emergency response.

If the UK is to show it is serious about responding to the immense needs caused by the invasion it must introduce appropriate safeguards in its sanctions – either in the form of exceptions or general licences.

What matters is they cover all key humanitarian organizations responding to the Ukraine crisis that are subject to UK sanctions – either because they are UK persons or because their funding agreements with the UK government require them to comply with UK measures.

These include UN agencies, funds and programmes, components of the International Red Cross and Red Crescent Movement, and non-governmental organizations (NGOs) responding to the crisis in Ukraine and neighbouring states. The provision must also clearly extend to commercial entities which provide necessary services for humanitarian operations.

Given the UK recently adopted an exception along similar lines in relation to the Afghanistan sanctions, there is a valuable precedent for Ukraine.

The UK must not sleepwalk into leaving the ECHR Expert comment NCapeling 17 March 2023

Talk of the UK leaving the European Convention on Human Rights (ECHR) keeps rearing its head with little thought for the real impact.

Withdrawal from the European Convention on Human Rights (ECHR) has not been firmly ruled out as a potential UK government policy option to allow easier implementation of its controversial new measures to deport asylum seekers to Rwanda. This, in the context of a UK general election looming and tackling the ‘small boats problem’ being one of the five priorities of UK prime minister Rishi Sunak.

In recent months, ECHR withdrawal has come up in relation to the UK’s controversial draft Illegal Migration Bill, the (now shelved) bill of rights, and – perhaps most significantly – the Northern Ireland Protocol deal with implications for the Good Friday Agreement. But leaving the ECHR – and likely the Council of Europe – would be counterproductive for the UK’s global leadership.

UK values and priorities will be undermined

The only other countries in the region outside of the Council of Europe, Russia and Belarus, both had sanctions imposed on them by the UK for their human rights record. Russia was expelled from the Council of Europe in 2022 due to its aggression in Ukraine and, although the UK would be deciding to remove itself from Europe’s oldest and largest intergovernmental human rights body, the optics would not be good.

This is especially true considering the UK’s vocal support for Ukraine in international forums, including its intervention in Ukraine’s case against Russia before the International Court of Justice and, potentially, in a separate case against Russia before the European Court of Human Rights itself.

More significantly and closer to home, the ECHR is a fundamental part of the Good Friday Agreement. It is difficult to argue UK withdrawal would not breach the agreement. As well as risking damage to intercommunal relations, such a breach is likely to significantly harm strategic relations with the US – and President Biden is set to visit Northern Ireland and the Republic of Ireland to mark the 25th anniversary of the Good Friday Agreement.

It would also damage relations with the UK’s closest neighbours, Ireland, and the European Union (EU), with whom the prime minister has only recently scored credits for securing the Northern Ireland Protocol deal. If the UK withdraws from the ECHR, the EU would be entitled to terminate important provisions concerning international law enforcement and judicial cooperation in criminal justice matters under Article 692 of the UK-EU Trade and Cooperation Agreement, further isolating the UK from allies who share its legal and other values.

Withdrawal would be in the name of sovereignty but with little thought to the practical implications on rights and few perceived gains from doing so. But the idea could easily gain traction by erroneously conflating the Strasbourg court and Council of Europe (of which the UK is a member) with the European Union (which the UK has left).

This means leaving the ECHR could easily be confused as a post-Brexit ‘tidy up’ exercise of taking back control from the EU when the reality is the UK would be withdrawing from a completely different regional body.

It would also be at odds with the UK’s Integrated Review Refresh which, reassuringly, contains references to the UK’s commitment to the rule of law, ‘respect for the fundamental principles of the UN Charter and international law’, and ‘universal human rights that underpins our democracy’. This would make the UK far less able to champion international law and influence states with long records of human rights violations, and run contrary to UK strategic priorities such as tackling aggression from Russia and China, its support for multilateralism, and its global legal leadership.

All this loss would come for little gain. Before going down this path, there must be a clearer understanding about exactly what concerns there are about the ECHR, and whether they stand up to scrutiny. Are they about UK sovereignty, specific issues about the European Court of Human Rights, or about the rights and obligations contained in the Convention?

The latter would raise a far bigger question on the UK’s commitment to other international treaties, such as the International Covenant on Civil and Political Rights and the UN Convention on Rights of the Child, as many ECHR obligations also exist elsewhere in both common law and international law.

The need for cool heads and a long-term view

The significant concerns surrounding proposals in the Illegal Migration bill have been well-documented, including in relation to obligations under the ECHR and UN Refugee Convention.

There are many reasons beyond simply human rights concerns which are preventing migrants being deported to Rwanda, including the fact there are insufficient countries with which the UK has agreements to allow for deportation.

Zika virus (ZIKV) is a neurotropic flavivirus that causes several diseases including birth defects such as microcephaly. Intrinsic immunity is known to be a frontline defense against viruses through host anti-viral restriction factors. Limited knowledge is available on intrinsic immunity against ZIKV in brains. Amyloid precursor protein (APP) is predominantly expressed in brains and implicated in the pathogenesis of Alzheimer's diseases. We have found that ZIKV interacts with APP, and viral infection increases APP expression via enhancing protein stability. Moreover, we identified the viral peptide, HGSQHSGMIVNDTGHETDENRAKVEITPNSPRAEATLGGFGSLGL, which is capable of en-hancing APP expression. We observed that aging brain tissues with APP had protective effects on ZIKV infection by reducing the availability of the viruses. Also, knockdown of APP expression or blocking ZIKV-APP interactions enhanced ZIKV replication in human neural progenitor/stem cells. Finally, intracranial infection of ZIKV in APP-null neonatal mice resulted in higher mortality and viral yields. Taken together, these findings suggest that APP is a restriction factor that protects against ZIKV by serving as a decoy receptor, and plays a protective role in ZIKV-mediated brain injuries.

Stop codon read-through (SCR) is a process of continuation of translation beyond a stop codon. This phenomenon, which occurs only in certain mRNAs under specific conditions, leads to a longer isoform with properties different from that of the canonical isoform. MTCH2, which encodes a mitochondrial protein that regulates mitochondrial metabolism, was selected as a potential read-through candidate based on evolutionary conservation observed in the proximal region of its 3' UTR. Here, we demonstrate translational read-through across two evolutionarily conserved, in-frame stop codons of MTCH2 using luminescence- and fluorescence-based assays, and by analyzing ribosome-profiling and mass spectrometry (MS) data. This phenomenon generates two isoforms, MTCH2x and MTCH2xx (single- and double-SCR products, respectively), in addition to the canonical isoform MTCH2, from the same mRNA. Our experiments revealed that a cis-acting 12-nucleotide sequence in the proximal 3' UTR of MTCH2 is the necessary signal for SCR. Functional characterization showed that MTCH2 and MTCH2x were localized to mitochondria with a long t1/2 (>36 h). However, MTCH2xx was found predominantly in the cytoplasm. This mislocalization and its unique C terminus led to increased degradation, as shown by greatly reduced t1/2 (<1 h). MTCH2 read-through–deficient cells, generated using CRISPR-Cas9, showed increased MTCH2 expression and, consistent with this, decreased mitochondrial membrane potential. Thus, double-SCR of MTCH2 regulates its own expression levels contributing toward the maintenance of normal mitochondrial membrane potential.

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

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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.

RNA-protein interfaces control key replication events during the HIV-1 life cycle. The viral trans-activator of transcription (Tat) protein uses an archetypal arginine-rich motif (ARM) to recruit the host positive transcription elongation factor b (pTEFb) complex onto the viral trans-activation response (TAR) RNA, leading to activation of HIV transcription. Efforts to block this interaction have stimulated production of biologics designed to disrupt this essential RNA-protein interface. Here, we present four co-crystal structures of lab-evolved TAR-binding proteins (TBPs) in complex with HIV-1 TAR. Our results reveal that high-affinity binding requires a distinct sequence and spacing of arginines within a specific β2-β3 hairpin loop that arose during selection. Although loops with as many as five arginines were analyzed, only three arginines could bind simultaneously with major-groove guanines. Amino acids that promote backbone interactions within the β2-β3 loop were also observed to be important for high-affinity interactions. Based on structural and affinity analyses, we designed two cyclic peptide mimics of the TAR-binding β2-β3 loop sequences present in two high-affinity TBPs (KD values of 4.2 ± 0.3 and 3.0 ± 0.3 nm). Our efforts yielded low-molecular weight compounds that bind TAR with low micromolar affinity (KD values ranging from 3.6 to 22 μm). Significantly, one cyclic compound within this series blocked binding of the Tat-ARM peptide to TAR in solution assays, whereas its linear counterpart did not. Overall, this work provides insight into protein-mediated TAR recognition and lays the ground for the development of cyclic peptide inhibitors of a vital HIV-1 RNA-protein interaction.

Erythromycin-resistance methyltransferases are SAM dependent Rossmann fold methyltransferases that convert A2058 of 23S rRNA to m6 2A2058. This modification sterically blocks binding of several classes of antibiotics to 23S rRNA, resulting in a multidrug-resistant phenotype in bacteria expressing the enzyme. ErmC is an erythromycin resistance methyltransferase found in many Gram-positive pathogens, whereas ErmE is found in the soil bacterium that biosynthesizes erythromycin. Whether ErmC and ErmE, which possess only 24% sequence identity, use similar structural elements for rRNA substrate recognition and positioning is not known. To investigate this question, we used structural data from related proteins to guide site-saturation mutagenesis of key residues and characterized selected variants by antibiotic susceptibility testing, single turnover kinetics, and RNA affinity–binding assays. We demonstrate that residues in α4, α5, and the α5-α6 linker are essential for methyltransferase function, including an aromatic residue on α4 that likely forms stacking interactions with the substrate adenosine and basic residues in α5 and the α5-α6 linker that likely mediate conformational rearrangements in the protein and cognate rRNA upon interaction. The functional studies led us to a new structural model for the ErmC or ErmE-rRNA complex.

A. I. Aptekarev and M. L. Yattselev
Trans. Moscow Math. Soc. 83 (), 251-268.
Abstract, references and article information

Z. A. Kasumov and N. R. Akhmedzade
Trans. Moscow Math. Soc. 83 (), 67-74.
Abstract, references and article information

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.

Climate action and gender equality: Can we close the gap on one without the other? 8 March 2021 — 2:30PM TO 4:00PM Anonymous (not verified) 15 February 2021 Online

In partnership with the COP26 presidency, policymakers and experts examine the interrelationship between gender equality and climate action, and highlight innovative examples of policy and practice from around the world.

Marking International Women’s Day, this event organized by the COP26 presidency in partnership with Chatham House, will explore how gender equality and climate action go hand-in-hand. The agreement of the Gender Action Plan (GAP) at COP25 sent the message that the time for gender-responsive climate action is now.

This will be a unique opportunity to hear from policymakers and civil society leaders discussing whether enough is being done, as well as highlighting cutting-edge work around the world and suggesting what the future could hold.

The event will be livestreamed on this event page.

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.

‘Hong Kong is now in the hands of its people – they cannot rely on others to stick up for them now.’ Expert comment sysadmin 29 June 2017

Kerry Brown on ‘one country, two systems’, the UK’s diminishing influence and the territory’s future, 20 years after the handover.

1 July marks the 20th anniversary of the transfer of Hong Kong’s sovereignty from Britain to China. Kerry Brown speaks with Jason Naselli about what the future holds for the territory.

How sustainable is the ‘one country, two systems’ framework? Will the arrangement last the full 50 years (until 2047) as originally envisioned?

It is questionable whether the arrangement that exists today was the one envisioned in 1997 when the handover happened. It was always a very abstract, flexible system, granting Hong Kong a high degree of autonomy, meaning it could maintain its capitalist system. Of course, in the lead up to 1997 all these things were broadly seen as being in Beijing’s interests to preserve.

But these days, the one thing that few said in 1997 has come to pass – the People’s Republic has maintained one-party rule as a political system, but become one of the world’s great economies. It has been so far a huge success.

Hong Kong therefore has diminished in importance over the years to the point that maintaining at least some semblance of one country, two systems is almost like an act of charity. It has been nibbled at, compromised and seems to grow weaker by the day. Most in Hong Kong would say there is a system: one country, one system. That’s the deal.

The central government’s deepening involvement in the territory’s politics is a subject of growing controversy in Hong Kong. Does the Chinese government need to alter its approach?

Not particularly. It doesn’t want to see Hong Kong fail as an economy. That doesn’t suit its interests at all. But nor does it want a truculent, disobedient polity that is meant to be part of its sovereign territory.

So it has increasingly set political parameters. Hong Kong can have its unique system – as long as it is obedient. And on the whole, that is the deal that all of the city’s chief executives until now have internally understood perfectly.

As part of the 1997 handover, the UK has ‘a continuing moral and political obligation’ to Hong Kong. How will this relationship play out as Brexit shifts Britain’s place in the world?

The Foreign Office offers a six-monthly report to Parliament, updating on how the handover deal is going. As the years go on, however, it becomes increasingly illusive how the UK has any real locus to say much about the situation on Hong Kong. It did say, rightly, that the detainment of one of the booksellers taken in in 2015 was a violation of the treaty because he was British. This was the strongest wording that has ever appeared from an official British source. But with dependence on creating a new kind of relationship with China now foremost in people’s minds because of Brexit and other economic pressures, it is not surprising that the priority increasingly lies elsewhere.

With direct management of Hong Kong gone, the UK was always going to be more and more irrelevant. That has happened. And in any case, relations with China have had to become more complex and multifaceted. Hong Kong was always the tail wagging the dog for the UK relations with China. Now there has been a rebalancing, the calculation always has to be how much unilaterally supporting Hong Kong will damage relations with Beijing. This has become an increasingly asymmetrical question: in a playoff, preserving links with Beijing will always prevail. That’s just the reality of the new world we are seeing come into being.

Hong Kong has played an important financial role for China over the past 20 years, but where will it fit as markets and financial institutions on the mainland mature?

It maintains is role as a major RMB hub, and as a finance centre. But it is surrounded by competition. Singapore, and Sydney, and other places in the region have RMB deals. Shanghai and Tianjin aspire to be portals for entry to the domestic Chinese market. Hong Kong every day has to think of new ways to maintain its relevance and beat back competition. So far, it has done well. But this is an issue it can never be complacent about.

What has been the most significant change in Hong Kong society since 1997?

The rising cultural and linguistic influence of the mainland on Hong Kong. Hong Kong has maintained its difference – but it has had to change. It is clear that Hong Kong is now in the hands of Hong Kongese – they cannot rely on others to stick up for them now. The culture, identity and future of the territory are in their hands. In that sense, they have autonomy.

Root Causes of Rohingya Crisis Must Not be Ignored Expert comment sysadmin 28 September 2017

The focus on Aung San Suu Kyi masks the complete lack of an adequate response to the crisis in Myanmar, whether at the global or regional level.

Aung San Suu Kyi’s recent speech on the Rohingya crisis was - at best - light on details on how the current situation could be remedied and - at worst - full of easily disproven assertions.

While she does not directly control the military, it is her government that is blocking humanitarian access to the areas affected by the violence. And the Rohingya have faced systemic persecution and discrimination for decades.

Some may argue this is simply realpolitik and that any public support for the Rohingya could mean facing a backlash from the military and a large part of her support base. But arguably, she does have moral authority (which helped her in the past to stand up to the military generals) that is now being eroded by her ambivalence in speaking out.

However, the focus on Aung San Suu Kyi masks the complete lack of an adequate response to the crisis – whether at the global or regional level.

Undertaking dangerous and perilous journeys

Since the attacks on border and military posts by the armed group Arakan Rohingya Salvation Army (ARSA) in August 2017, there has been a strong military crackdown against the Rohingya in Rakhine state: a substantial number of Rohingya villages destroyed; close to half a million people Rohingya fleeing into Bangladesh and tens of thousands internally displaced within Myanmar.

Prince bin Ra’ad , UN High Commissioner for Human Rights, has called the crisis a “textbook example of ethnic cleansing” and tens of thousands of Rohingya are still undertaking dangerous and perilous journeys seeking sanctuary. In response, the UN and EU have focused on addressing the immediate humanitarian crisis in Bangladesh, which is already home to many formerly displaced Rohingya communities.

Within the region, Sheikh Hasina’s secular Awami League government in Bangladesh initially proposed joint military operations with Myanmar against the ARSA - in part because of concerns about the long standing relationship between Rohingya political or armed groups and the Jamaat-e-Islami, an ally of the main opposition Bangladesh Nationalist Party (BNP).

However, faced with massive refugee flows, Bangladesh turned its focus to the humanitarian crisis while stressing that Myanmar must allow the return of refugees. Bangladesh’s concern is partly motivated by internal security concerns. If the current situation becomes protracted, with no clear resolution in sight, frustration could create the conditions for further radicalisation within Rohingya communities.

The Association of South East Asian Nations (ASEAN) has yet to come to grips with the situation. Despite its mandate to ensure peace and stability within the region, its policy of non-interference and consensus trumps the need to secure and maintain stability. Instead countries have responded bilaterally - for example, Indonesia sent its foreign minister to both Myanmar and Bangladesh while Malaysia has been consistently vocal about its concerns.

So this raises broader questions on the effectiveness of ASEAN. Currently celebrating its 50th anniversary, ASEAN needs to decide how to mediate and resolve issues with regional implications as its principle of non-intervention effectively blocks any constructive discussion on the Rohingyas ongoing statelessness and impact of this on the region.

However, there is also an opportunity here for ASEAN to consider how mediation and negotiation could potentially manage such crises. And there is a historical precedent: the 1989 Comprehensive Plan of Action on Indo-Chinese refugees saw cooperation between recipient countries in the region and the international community on how to resettle Vietnamese refugees (although Cold War considerations did play a part in that specific crisis).

India and China have both backed Myanmar, reflecting their economic and security interests in the country but also motivated by each wanting to contain the influence of the other within Myanmar. Rakhine is important with its natural resources and coastal location and, as China is not directly affected by the refugee crisis, it has less to lose than others in standing by Aung San Suu Kyi and her government.

India is nearing completion of the Kaladan Multi-modal Transit Transport Project, connecting the Bay of Bengal with the northeast Indian state of Mizoram, and sees Myanmar as an important market for its regional ambitions. For parts of the Indian administration, the crisis plays to a domestic narrative that some of the Rohingya already settled in Jammu and Kashmir have links to armed groups in Pakistan and are an internal security concern.

So while India is providing humanitarian aid to Bangladesh, it is also threatening to deport almost 40,000 Rohingya. The case is currently being heard at the Indian Supreme Court, but given that the Rohingya lack citizenship in Myanmar, it is not clear to where they would be deported.

Myanmar, ASEAN and other affected countries need to show political will to find a solution to the Rohingya’s long-standing issue of statelessness - discrimination was legally formalised in a 1982 Burma Citizenship Law, which recognised 135 ethnicities for citizenship but excluded the Rohingya.

The root causes of this crisis – long standing discrimination, persecution and lack of citizenship – cannot be ignored. There is a need for a comprehensive peace process, which recognises the ethnic and religious diversity within Myanmar.

And incentives, such as improving infrastructure, access to services and livelihoods, may also be needed to ensure there is a lasting solution that allows the Rohingya return and thrive as part of Myanmar society.

Without such a response, it is difficult to see an end to the current impasse.

The Hard Truth Is Rohingya Refugees Are Not Going Home Expert comment sysadmin 6 October 2017

The only likely outcome of the crisis is the near-permanent presence of hundreds of thousands of Rohingya along the Bangladesh border.

The harrowing scenes of human suffering on the Myanmar–Bangladesh border have provoked outpourings of sympathy and some firm statements by international politicians. At least half a million people have been brutally expelled from their homes and are now living in miserable conditions in muddy refugee camps and storm-drenched shanty towns. As the international community debates how to respond, it needs to take a clear-eyed view of the situation and recognise a brutal truth: the refugees are almost certainly not going home.

Consequently, policymakers must not hide behind the fiction that Bangladesh is only temporarily hosting the refugees in preparation for their rapid return home. Over-optimistic assumptions now will lead to worse misery in the long term. Instead, the world needs to plan on the basis that Bangladesh will be hosting a very large and permanent refugee population.

The expulsion of the Rohingya Muslims from Rakhine State in northwestern Myanmar is the culmination of decades of discriminatory policies enacted by the country’s military rulers since 1962. In 1978, the Burmese military’s ‘Operation Dragon King’ pushed 200,000 Muslims into Bangladesh. International pressure forced the military to allow most of them to return. Then, in 1991–92, the military again expelled a quarter of a million people. Bangladesh forced some of them back over the border and eventually the military agreed to allow the United Nations High Commissioner for Refugees to manage the repatriation of most of the remainder.

State-sponsored abuses of the Rohingya and ethnic violence perpetrated against them by chauvinists among the ethnic Rakhine population have continued. The abuse became dramatically worse in 2012 when tens of thousands of Rohingya were forced to flee their homes, although most remained inside the country. This year, armed attacks by self-proclaimed defenders of the Rohingya, the Arakan Rohingya Salvation Army, gave the military an excuse to mount what the UN High Commissioner for Human Rights called ‘a textbook example of ethnic cleansing’.

It is tempting to believe that, as before, the Myanmar government will allow the expelled Rohingya to return after international pressure. However, recent geopolitical developments in southeast Asia and the election of a democratic government in Myanmar in 2015 make this much less likely.

Southeast Asia is now an arena of geopolitical competition between China and its rivals: mainly the United States, India and Japan. All are battling for influence. Both China and India have made public statements of support for Myanmar’s government in the current crisis. In that context, diplomatic pressure or economic sanctions imposed by Europe or the United States will only have one effect – to push Myanmar towards China.

Moreover, those in the EU and US who want to see democracy survive in Myanmar will be unwilling to push the elected government led by Aung San Suu Kyi too far. There is an extraordinary degree of hostility towards the Rohingya among the majority Bamar population. This has broken out into street violence on occasions but even where the situation is calm, anti-Muslim prejudice is easily awoken. The current government is very unlikely to challenge such sentiments at a time when it is trying to preserve its position against the military’s continuing domination of political and economic life.

Myanmar is one of the 10 members of the Association of Southeast Asian Nations but ASEAN is unlikely to impose any meaningful pressure. Only Malaysia has been publicly critical of Myanmar’s government. Indonesia has attempted to mediate – its foreign minister Retno Marsudi has held face-to-face meetings with Aung San Suu Kyi – but without apparent effect. Both countries have sent aid and volunteers to the Rohingya refugee camps but there is absolutely no talk of sanctions or other overt pressure.

The question then is: what will happen to the refugees? One option could be resettlement, but neither Bangladesh nor any of the other states in the region are willing to take them in. Malaysia already hosts 60,000 registered Rohingya refugees and probably another 150,000 unregistered ones. Unknown thousands of Rohingya have fled to Thailand and Indonesia by boat but have often fallen victim to unscrupulous human traffickers in cahoots with local officials. Thailand has already said it will refuse to allow new ‘boat people’ to land.

The only likely outcome therefore is the near-permanent presence of hundreds of thousands of Rohingya along the Bangladesh border. Delaying preparations for a permanent refugee population in the hope that they will be allowed to re-cross the border back into Myanmar will only make the situation worse. Seventy years ago, another ‘temporary’ movement of people into refugee camps created decades of instability around the Middle East. The world must remember the Palestinians as it plans for the future of the Rohingya.

The 2020 Inner Mongolia Language Protests: Wider Meanings for China and the Region 24 November 2020 — 3:00PM TO 4:00PM Anonymous (not verified) 12 November 2020 Online

Speakers discuss the historical roots of the language issue, as well as the wider significance of the protests in China.

Please note this is an online event. Please register on Zoom using the link below to secure your registration.

In September thousands of people protested in Inner Mongolia in opposition to a government move to replace Mongolian language with Standard Mandarin in three school subjects – history, politics and Chinese language.

Announced less than a week before the start of the new school year, the policy also requires schools to use new national textbooks in Chinese, instead of regional textbooks. The mass protests and classroom walk-outs reflect ethnic Mongolian’s anxiety that their native language may be eliminated. What has the government’s response to the protests been?

Gurmeet K. Bakshi, Jyoti Garg and Gabriela Olteanu
Math. Comp. 93 (), 3027-3058.
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Ole Løseth Elvetun and Bjørn Fredrik Nielsen
Math. Comp. 93 (), 2811-2836.
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Selim Esedoḡlu, Jiajia Guo and David Li
Math. Comp. 93 (), 2679-2710.
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Buyang Li, Zongze Yang and Zhi Zhou
Math. Comp. 93 (), 2557-2586.
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Ricardo Bermudez-Otero and Tobias Galla discuss the mathematics describing the evolution of human languages. The sounds and structures of the world's approximately 7,000 languages never stop changing. Just compare the English in Romeo and Juliet or the Spanish in Don Quixote to the modern forms. But historical records give an incomplete view of language evolution. Increasingly, linguists draw upon mathematical models to figure out which features of a language change often and which ones change more rarely over the course of thousands of years. A new model inspired by physics assigns a "temperature" to many sounds and grammatical structures. Features with higher temperatures are less stable, so they change more often as time goes on. The linguistic thermometer will help researchers reconstruct how our languages came to be, and how they might change in future generations.

Dr. Rekha Thomas from the University of Washington discusses three-dimensional image reconstructions from two-dimensional photos. The mathematics of image reconstruction is both simpler and more abstract than it seems. To reconstruct a 3D model based on photographic data, researchers and algorithms must solve a set of polynomial equations. Some solutions to these equations work mathematically, but correspond to an unrealistic scenario — for instance, a camera that took a photo backwards. Additional constraints help ensure this doesn't happen. Researchers are now investigating the mathematical structures underlying image reconstruction, and stumbling over unexpected links with geometry and algebra.

Alexandra Kjuchukova, Allison N. Miller, Arunima Ray and Sümeyra Sakallı
Trans. Amer. Math. Soc. 377 (), 5905-5946.
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Ming-Lun Hsieh and Shunsuke Yamana
Trans. Amer. Math. Soc. 377 (), 5617-5672.
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Jong In Han and Sijong Kwak
Trans. Amer. Math. Soc. 377 (), 5561-5581.
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