Announcing Design Resonance in an Age of Crisis News Release sysadmin 1 June 2020

London Design Biennale and Chatham House announce Design Resonance in an Age of Crisis, which calls for action by designers around the world to create radical design solutions to critical problems across four key areas: Health, Environment, Society and Work.

Design In An Age of Crisis - Open Call News Release sysadmin 21 July 2020

Chatham House and London Design Biennale announce full details of 'Design In An Age of Crisis,' a global Open Call for radical design thinking.

Design in an Age of Crisis Launches News Release jon.wallace 13 January 2021

Design open call receives 500 submissions from over 50 countries across six continents.

Persuasion or manipulation? Limiting campaigning online Expert comment NCapeling 15 February 2021

To tackle online disinformation and manipulation effectively, regulators must clarify the dividing line between legitimate and illegitimate campaign practices.

Democracy is at risk, not only from disinformation but from systemic manipulation of public debate online. Evidence shows social media drives control of narratives, polarization, and division on issues of politics and identity. We are now seeing regulators turn their attention to protecting democracy from disinformation and manipulation. But how should they distinguish between legitimate and illegitimate online information practices, between persuasive and manipulative campaigning?

Unregulated, the tactics of disinformation and manipulation have spread far and wide. They are no longer the preserve merely of disaffected individuals, hostile international actors, and authoritarian regimes. Facebook’s periodic reporting on coordinated inauthentic behaviour and Twitter’s on foreign information operations reveal that militaries, governments, and political campaigners in a wide range of countries, including parts of Europe and America, have engaged in manipulative or deceptive information campaigns.

For example, in September 2019, Twitter removed 259 accounts it says were ‘falsely boosting’ public sentiment online that it found to be operated by Spain’s conservative and Christian-democratic political party Partido Popular. In October 2020, Facebook removed accounts with around 400,000 followers linked to Rally Forge, a US marketing firm which Facebook claims was working on behalf of right-wing organisations Turning Point USA and Inclusive Conservation Group. And in December 2020, Facebook took down a network of accounts with more than 6,000 followers, targeting audiences in Francophone Africa and focusing on France’s policies there, finding it linked with individuals associated with the French military.

Public influence on a global scale

Even more revealingly, in its 2020 Global Inventory of Organized Social Media Manipulation, the Oxford Internet Institute (OII) found that in 81 countries, government agencies and/or political parties are using ‘computational propaganda’ in social media to shape public attitudes.

These 81 countries span the world and include not only authoritarian and less democratic regimes but also developed democracies such as many EU member states. OII found that countries with the largest capacity for computational propaganda – which include the UK, US, and Australia – have permanent teams devoted to shaping the online space overseas and at home.

OII categorizes computational propaganda as four types of communication strategy – the creation of disinformation or manipulated content such as doctored images and videos; the use of personal data to target specific segments of the population with disinformation or other false narratives; trolling, doxing or online harassment of political opponents, activists or journalists; and mass-reporting of content or accounts posted or run by opponents as part of gaming the platforms’ automated flagging, demotion, and take-down systems.

Doubtless some of the governments included within OII’s statistics argue their behaviour is legitimate and appropriate, either to disseminate information important to the public interest or to wrestle control of the narrative away from hostile actors. Similarly, no doubt some political campaigners removed by the platforms for alleged engagement in ‘inauthentic behaviour’ or ‘manipulation’ would defend the legitimacy of their conduct.

The fact is that clear limits of acceptable propaganda and information influence operations online do not exist. Platforms still share little information overall about what information operations they see being conducted online. Applicable legal principles such as international human rights law have not yet crystallised into clear rules. As information operations are rarely exposed to public view – with notable exceptions such as the Cambridge Analytica scandal – there is relatively little constraint in media and public scrutiny or censure.

OII’s annual reports and the platforms’ periodic reports demonstrate a continual expansion of deceptive and manipulative practices since 2016, and increasing involvement of private commercial companies in their deployment. Given the power of political influence as a driver, this absence of clear limits may result in ever more sophisticated techniques being deployed in the search for maximal influence.

Ambiguity over reasonable limits on manipulation plays into the hands of governments which regulate ostensibly in the name of combating disinformation, but actually in the interests of maintaining their own control of the narrative and in disregard of the human right to freedom of expression. Following Singapore’s 2019 prohibition of online untruths, 17 governments ranging from Bolivia to Vietnam to Hungary passed regulations during 2020 criminalising ‘fake news’ on COVID-19 while many other governments are alleged to censor opposition arguments or criticisms of official state narratives.

Clear limits are needed. Facebook itself has been calling for societal discussion about the limits of acceptable online behaviour for some time and has issued recommendations of its own.

The European Democracy Action Plan: Aiming to protect pluralism and vigour in democracy

The European Democracy Action Plan (EDAP), which complements the European Commission’s Digital Services Act and Digital Markets Act proposals, is a welcome step. It is ground-breaking in its efforts to protect the pluralism and vigour of European democracies by tackling all forms of online manipulation, while respecting human rights.

While the EDAP tackles disinformation, it also condemns two categories of online manipulation – information influence operations which EDAP describes as ‘coordinated efforts by either domestic or foreign actors to influence a target audience using a range of deceptive means’ and foreign interference, described as ‘coercive and deceptive efforts to disrupt the free formation and expression of individuals’ political will by a foreign state actor or its agents’. These categories include influence operations such as harnessing fake accounts or gaming algorithms, and the suppression of independent information sources through censorship or mass reporting.

But the categories are so broad they risk capturing disinformation practices not only of rogue actors, but also of governments and political campaigners both outside and within the EU. The European Commission plans to work towards refined definitions. Its discussions with member states and other stakeholders should start to determine which practices ought to be tackled as manipulative, and which ought to be tolerated as legitimate campaigning or public information practices.

The extent of the EDAP proposals on disinformation demonstrates the EU’s determination to tackle online manipulation. The EDAP calls for improved practical measures building on the Commission’s 2020 acceleration of effort in the face of COVID-19 disinformation. The Commission is considering how best to impose costs on perpetrators of disinformation, such as by disrupting financial incentives or even imposing sanctions for repeated offences.

Beyond the regulatory and risk management framework proposed by the Digital Services Act (DSA), the Commission says it will issue guidance for platforms and other stakeholders to strengthen their measures against disinformation, building on the existing EU Code of Practice on Disinformation and eventually leading to a strengthened Code with more robust monitoring requirements. These are elements of a broader package of measures in the EDAP to preserve democracy in Europe.

Until there are clear limits, manipulative practices will continue to develop and to spread. More actors will resort to them in order not to be outgunned by opponents. It is hoped forthcoming European discussions – involving EU member state governments, the European Parliament, civil society, academia and the online platforms – will begin to shape at least a European and maybe a global consensus on the limits of information influence, publicly condemning unacceptable practices while safeguarding freedom of expression.

Most importantly, following the example of the EDAP, the preservation of democracy and human rights – rather than the promotion of political or commercial interest – should be the lodestar for those discussions.

Re-imagining trade for domestic and foreign policy Expert comment NCapeling 7 December 2021

Exploring future trade policy through issues such as the green transition, labour standards, human rights, the role of the WTO, and non-trade policy objectives.

Balancing trade and non-trade policy objectives

Marianne Schneider-Petsinger

The supply chain disruptions stemming from the COVID-19 pandemic highlight trade cannot be taken for granted, and economic interdependencies have both benefits and costs. As international commerce rebounds and trade policy is increasingly seen through the prism of enhancing resilience, the moment is ripe to redefine and reimagine trade.

The goal of trade policy has never been to increase trade for trade’s sake, so a new narrative and framework for global trade requires striking a careful balance between pursuing trade and non-trade policy objectives.

Protecting the environment, strengthening labour standards, and upholding human rights have long been goals for which trade policy is used as a lever, and the interaction of trade and national security interests as well as the links between trade and competition policy are not new issues either.

All these non-trade policy aspects have come to the forefront as the geopolitical context has shifted and the transition to green and digital economies has gathered force – and, at times, these different non-trade policy goals clash.

The US and European Union (EU) are promoting solar energy to fight climate change but supply chains for solar panels are heavily reliant on forced labour from Xinjiang, and hence it is not yet certain whether environmental or human rights concerns will prevail. However, it is clear trade policy tools can be part of a comprehensive solution which manages inherent tensions while still advancing both objectives.

Trade policy is also not just a foreign policy instrument but links closely to domestic policy – the populist backlash against globalization in much of the developed world, especially the US and Europe, was in part driven by anti-trade sentiment.

While American attitudes towards trade improved after the 2016 election of Donald Trump, positive views towards trade dropped sharply in 2021. The Biden administration’s worker-centred trade policy aims to address distributional effects of international economic integration which is a long-standing challenge. Thus, tackling non-trade policy issues without losing sight of this unresolved core issue requires careful calibration.

Trade policy is being pulled in many different directions at the same time as the core institution governing global trade – the World Trade Organization (WTO) – is in crisis, and it is uncertain how much of the non-trade policy agenda the WTO can handle. If the linkage to non-trade policy becomes too strong, this could be the straw that breaks the WTO’s back, but if it is too weak, the WTO risks becoming irrelevant in efforts to tackle key global challenges.

But if its 164 members can generate trade-oriented solutions to non-trade issues, they can revive the organization and mobilize domestic support for global trade at the same time. This balancing act in managing the tensions between trade and non-trade policy objectives lies at the centre of future-proofing trade policy and global trade governance.

Developing countries must be part of green trade revolution

Carolyn Deere Birkbeck

The biggest challenge in taking environmental efforts forward within the multilateral context is to successfully combine environmental ambition with an approach which engages developing countries as partners, reflects their environment-related trade priorities, and addresses their sustainable development interests.

The importance of engaging developing countries must not be underestimated because it is vital a global green economy does not leave the poorest behind, or becomes two-tier where green trade happens only between certain countries and the essential task of incentivizing and supporting sustainable production and consumption patterns in all countries is neglected.

The new member-led initiatives at the WTO do signal that, while the rulemaking and negotiating functions remain central to the global trade body, governments recognize the need for enhanced, transparent, and inclusive policy dialogue as well as problem-solving on sectoral issues and specific trade-related challenges.

Given the well-documented challenges of achieving multilateral consensus at the WTO, governments are exploring new ways to work within multilateral frameworks and to redefine what progress and successful outcomes should look like.

Therefore, there is a need for best practices, voluntary action, pledges, and guidelines to both sustain the relevance of the multilateral trading system and support policy action at the national level for trade which underpins environmental and wider sustainable goals.

Making progress on an environmental agenda which reflects sustainable development concerns requires stronger leadership, engagement, and advocacy from business, civil society, and research communities in both developing and developed countries, as well as economies in transition.

Meaningful, inclusive dialogue and action at the WTO also requires deeper efforts to build policy coherence among environment, development, and trade policymaking at home, with environmental ministries having a key role to play in bringing expertise to bear and ensuring strong regulatory environments and institutions for the implementation of national, regional, and international environmental commitments.

But at the domestic level, many countries still have to overcome complex politics and diverse interests as they work to transform their economies toward greater sustainability and tackle the costs of transition.

Social preparation holds the key to trade transitions

Bernice Lee 

Trade being often depicted as the mother of all ills should not come as a surprise, as politicians are only too happy to put the blame on trade when all sorts of exogenous shocks, such as technological change, could actually be the trigger which fires the bullet into local industries or jobs.

Admittedly trade does have a way of breaking the seams in the social fabric but the fact politicians often ignore negative impacts of trade means its benefits can be likened to Schrodinger’s cat, both real and illusive. But trade being mainly depicted as a ‘zero-sum’ pursuit and trade deals as the result of swashbuckling duels belie the reality that the real business of trade is often boring, bureaucratic, but necessary.

This is particularly true when trade provides access to a much larger variety of necessary products, such as medicine, food, and minerals, which can be expensive to make domestically. Selling products and services abroad also brings in the hard currency needed to buy these goods or to spend on trips abroad.

This does not take away the fact trade is extremely disruptive but, as a result of all the theorizing and understandable rants about trade, large swathes of the international community have effectively foregone it as a force for good or as an instrument which – while not the answer to all problems – can help smooth the path to well-being through efficiency gains and income growth, as well as putting to work the theory of comparative advantage as promised by the textbooks.

Alas, what the textbooks do not clearly spell out – until recently – is that trade brings positive benefits only if a society is ready for trade, which often means having the cushion for social protection such as healthcare, unemployment benefits, and opportunities for training and reskilling.

The ‘China shock’ literature vividly depicts how workers rarely seamlessly move from one job or sector to another and so, without adequate social protection, trade not only magnifies existing fractures, it also exacerbates inequality. As the aftershock lingers for decades, the lesson learned is the importance of social readiness for trade, especially the role played by governments in providing support for workers as part of the adjustment to trade and globalization.

Authors of this China shock literature recently suggested the next shock will be the transition from fossil fuel production, but the good news is this so-called ‘just transition’ challenge is one which proponents of green energy are well aware of.

But ultimately the China shock could be the dry run for the advent of machine intelligence, meaning better preparation is needed with solid social policies, investment in institutional readiness, and social preparedness to ensure the machines only take on monotonous and unsafe work – not our livelihoods and communities.

Trading partners must move to creating human rights impact

Dr Jennifer Zerk

The question of whether, and how, trade policy should be used as a way of addressing human rights concerns remains controversial and attempts to link the two still attract accusations of ‘protectionism’ and ‘neo-colonialism’.

Momentum appears to be behind those arguing for greater alignment between trade policy and human rights objectives – a trend which is most noticeable in the increasing willingness of trade partners to reference human rights standards in their trade agreements and in the growth of complementary activities such as human rights impact assessment and monitoring.

Evidence that these are having an impact ‘on the ground’ remains elusive. Nevertheless, efforts to enhance scrutiny of trade agreements from a human rights perspective, and to signal the importance of respect for human rights to a trading relationship, can still have value.

Even if causal relationships between trading arrangements and human rights impacts are difficult to establish conclusively, human rights impact assessment and subsequent monitoring activities provide valuable opportunities for stakeholders to weigh in on aspects of trade policy which are of concern.

Such processes not only help governments to realize rights of public participation, they also contribute to good governance by making it more likely that potential human rights problems will be recognized and addressed.

Turning to the agreements themselves, various ideas have been put forward on how to make these more responsive to human rights concerns.

Options mooted by EU institutions in recent years include an enhanced monitoring and enforcement role for consultative bodies established under specialized ‘trade and sustainable development’ chapters, and better mainstreaming of human rights commitments in sector-specific chapters.

However, given the political and resource-related difficulties in developing credible monitoring systems for human rights-related issues, and the unlikelihood of actual enforcement, many view this as little more than window-dressing.

For governments wanting to see real impact, ‘supply chain due diligence’ regimes pioneered by the EU in relation to timber and conflict minerals present a promising regulatory model.

These regimes seek to curb trade in products derived from, or which aggravate, human rights abuses as well as aiming to promote more responsible sourcing of products by EU importers. They create powerful incentives within partner countries to crack down on harmful practices by producers, which are bolstered further by regulations that demand more proactive human rights risk management by EU operators throughout their supply chains. Capacity-building and aid packages have been deployed to help speed up the necessary reforms.

New regulatory measures imposing mandatory human rights due diligence obligations on companies operating in a much broader range of sectors are now under consideration by the European Commission. While the role of trade-related measures in the enforcement of this new regime is still unclear, trading partners should be sure to preserve the regulatory space for sector-level and company-level initiatives such as these in future agreements.

Understanding the impact of NTPOs on investment

Professor Michael Gasiorek

Increasingly, trade policy is not just all about achieving trade-related outcomes as international trade, by definition, involves interaction with partner countries and therefore trade policy with regard to those partner countries can be used as a means to achieve ‘non-trade policy objectives’ (NTPOs).

In turn this means trade policy is also no longer just about the domestic economy but also about policies and economies in other countries – such as poorer countries achieving sustainable development goals (SDGs), concerns about practices in other countries in areas such as governance or corruption, or a desire to address broader challenges such as climate change.

But the inclusion of NTPOs in trade policy arrangements between countries also creates possible impacts on investment flows between countries. Stronger NTPO commitments could have a negative impact both on foreign direct investment (FDI) and domestic investment because the commitments increase costs for the companies involved which makes the investment less attractive.

However, NTPOs bringing progress on governance, or strengthening institutions, or giving more clarity on environmental regulations could signal a more stable and safe business environment, with production standards which create increased market access for exports – all of which may lead to increased incentives to invest.

A third possibility is that NTPOs do not have much effect either way because, although trade agreement increasingly include provisions on economic and social rights, or civil and political rights, or environmental protection – these are typically ‘best endeavour’ clauses which are frequently not binding or subject to dispute settlement, making them less likely to be implemented.

Transatlantic Tech Talks: Cooperation or sovereignty? Audio bhorton.drupal 15 December 2021

A new mini-series from Undercurrents explores international cooperation on regulating the tech sector.

Transatlantic Tech Talks is a three part mini-series on the Undercurrents podcast feed, produced with the support of Microsoft, which explores the state of international cooperation on digital governance between the United States, the UK and Europe.

As technological innovation accelerates, and new digital tools and business models arise, governments are working to develop a framework of regulations to safeguard the rights and interests of their citizens. Not all stakeholders agree, however, on the best way to achieve this. While some advocate a ‘digital cooperation’ approach based on transparency and data-sharing, others are more concerned with maintaining ‘digital sovereignty’.

In the first episode of this series, Ben is joined by Casper Klynge, Harriet Moynihan and Marianne Schneider-Petsinger, who set out the broad context for these debates. They assess where the major government, private sector and civil society actors stand on the question of digital governance, and how they are approaching the international negotiations.

CARM1 is a protein arginine methyltransferase (PRMT) that acts as a coactivator in a number of transcriptional programs. CARM1 orchestrates this coactivator activity in part by depositing the H3R17me2a histone mark in the vicinity of gene promoters that it regulates. However, the gross levels of H3R17me2a in CARM1 KO mice did not significantly decrease, indicating that other PRMT(s) may compensate for this loss. We thus performed a screen of type I PRMTs, which revealed that PRMT6 can also deposit the H3R17me2a mark in vitro. CARM1 knockout mice are perinatally lethal and display a reduced fetal size, whereas PRMT6 null mice are viable, which permits the generation of double knockouts. Embryos that are null for both CARM1 and PRMT6 are noticeably smaller than CARM1 null embryos, providing in vivo evidence of redundancy. Mouse embryonic fibroblasts (MEFs) from the double knockout embryos display an absence of the H3R17me2a mark during mitosis and increased signs of DNA damage. Moreover, using the combination of CARM1 and PRMT6 inhibitors suppresses the cell proliferation of WT MEFs, suggesting a synergistic effect between CARM1 and PRMT6 inhibitions. These studies provide direct evidence that PRMT6 also deposits the H3R17me2a mark and acts redundantly with CARM1.

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

Expert

The functional mechanisms of multidomain proteins often exploit interdomain interactions, or “cross-talk.” An example is human Pin1, an essential mitotic regulator consisting of a Trp–Trp (WW) domain flexibly tethered to a peptidyl-prolyl isomerase (PPIase) domain, resulting in interdomain interactions important for Pin1 function. Substrate binding to the WW domain alters its transient contacts with the PPIase domain via means that are only partially understood. Accordingly, we have investigated Pin1 interdomain interactions using NMR paramagnetic relaxation enhancement (PRE) and molecular dynamics (MD) simulations. The PREs show that apo-Pin1 samples interdomain contacts beyond the range suggested by previous structural studies. They further show that substrate binding to the WW domain simultaneously alters interdomain separation and the internal conformation of the WW domain. A 4.5-μs all-atom MD simulation of apo-Pin1 suggests that the fluctuations of interdomain distances are correlated with fluctuations of WW domain interresidue contacts involved in substrate binding. Thus, the interdomain/WW domain conformations sampled by apo-Pin1 may already include a range of conformations appropriate for binding Pin1's numerous substrates. The proposed coupling between intra-/interdomain conformational fluctuations is a consequence of the dynamic modular architecture of Pin1. Such modular architecture is common among cell-cycle proteins; thus, the WW–PPIase domain cross-talk mechanisms of Pin1 may be relevant for their mechanisms as well.

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.

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.

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.

Dancehall powerhouse Tommy Lee Sparta has been revealed as one of the headliners for Sting 2024, with promoters promising an electrifying show on Boxing Day at JamWorld, Portmore, St Catherine. The announcement has already set fans buzzing with...

Programmed cell death protein 1 (PD-1) is a critical inhibitory receptor that limits excessive T cell responses. Cancer cells have evolved to evade these immunoregulatory mechanisms by upregulating PD-1 ligands and preventing T cell–mediated anti-tumor responses. Consequently, therapeutic blockade of PD-1 enhances T cell–mediated anti-tumor immunity, but many patients do not respond and a significant proportion develop inflammatory toxicities. To improve anti-cancer therapy, it is critical to reveal the mechanisms by which PD-1 regulates T cell responses. We performed global quantitative phosphoproteomic interrogation of PD-1 signaling in T cells. By complementing our analysis with functional validation assays, we show that PD-1 targets tyrosine phosphosites that mediate proximal T cell receptor signaling, cytoskeletal organization, and immune synapse formation. PD-1 ligation also led to differential phosphorylation of serine and threonine sites within proteins regulating T cell activation, gene expression, and protein translation. In silico predictions revealed that kinase/substrate relationships engaged downstream of PD-1 ligation. These insights uncover the phosphoproteomic landscape of PD-1–triggered pathways and reveal novel PD-1 substrates that modulate diverse T cell functions and may serve as future therapeutic targets. These data are a useful resource in the design of future PD-1–targeting therapeutic approaches.

4 September 2020

14 September 2020

In addition to their well-known role in the control of cellular proliferation and cancer, cell cycle regulators are increasingly identified as important metabolic modulators. Several GWAS have identified SNPs near CDKN2A, the locus encoding for p16INK4a (p16), associated with elevated risk for cardiovascular diseases and type-2 diabetes development, two pathologies associated with impaired hepatic lipid metabolism. Although p16 was recently shown to control hepatic glucose homeostasis, it is unknown whether p16 also controls hepatic lipid metabolism. Using a combination of in vivo and in vitro approaches, we found that p16 modulates fasting-induced hepatic fatty acid oxidation (FAO) and lipid droplet accumulation. In primary hepatocytes, p16-deficiency was associated with elevated expression of genes involved in fatty acid catabolism. These transcriptional changes led to increased FAO and were associated with enhanced activation of PPARα through a mechanism requiring the catalytic AMPKα2 subunit and SIRT1, two known activators of PPARα. By contrast, p16 overexpression was associated with triglyceride accumulation and increased lipid droplet numbers in vitro, and decreased ketogenesis and hepatic mitochondrial activity in vivo. Finally, gene expression analysis of liver samples from obese patients revealed a negative correlation between CDKN2A expression and PPARA and its target genes. Our findings demonstrate that p16 represses hepatic lipid catabolism during fasting and may thus participate in the preservation of metabolic flexibility.

Sophos X-Ops unveils five-year investigation tracking China-based groups targeting perimeter devices

The Internet is full of cats—and in this case, malware-delivering fake cat websites used for very targeted search engine optimization.

David Durán
Nov 19, 2020; 0:RA120.002276v1-mcp.RA120.002276
Research

Sean A Burnap
Dec 7, 2020; 0:RA120.002305v1-mcp.RA120.002305
Research

Ka-Won Kang
Nov 30, 2020; 0:RA120.002169v1-mcp.RA120.002169
Research

Tirsa L. E. van Westering
Dec 1, 2020; 19:2047-2067
Research

Adult progenitor cell populations typically exist in a quiescent state within a controlled niche environment. However, various stresses or forms of damage can disrupt this state, which often leads to dysfunction and aging. We built a glucocorticoid (GC)-induced liver damage model of mice, found that GC stress induced liver damage, leading to consequences for progenitor cells expansion. However, the mechanisms by which niche factors cause progenitor cells proliferation are largely unknown. We demonstrate that, within the liver progenitor cells niche, Galectin-3 (Gal-3) is responsible for driving a subset of progenitor cells to break quiescence. We show that GC stress causes aging of the niche, which induces the up-regulation of Gal-3. The increased Gal-3 population increasingly interacts with the progenitor cell marker CD133, which triggers focal adhesion kinase (FAK)/AMP-activated kinase (AMPK) signaling. This results in the loss of quiescence and leads to the eventual stemness exhaustion of progenitor cells. Conversely, blocking Gal-3 with the inhibitor TD139 prevents the loss of stemness and improves liver function. These experiments identify a stress-dependent change in progenitor cell niche that directly influence liver progenitor cell quiescence and function.

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.

The glucagon receptor (GCGR) activated by the peptide hormone glucagon is a seven-transmembrane G protein–coupled receptor (GPCR) that regulates blood glucose levels. Ubiquitination influences trafficking and signaling of many GPCRs, but its characterization for the GCGR is lacking. Using endocytic colocalization and ubiquitination assays, we have identified a correlation between the ubiquitination profile and recycling of the GCGR. Our experiments revealed that GCGRs are constitutively ubiquitinated at the cell surface. Glucagon stimulation not only promoted GCGR endocytic trafficking through Rab5a early endosomes and Rab4a recycling endosomes, but also induced rapid deubiquitination of GCGRs. Inhibiting GCGR internalization or disrupting endocytic trafficking prevented agonist-induced deubiquitination of the GCGR. Furthermore, a Rab4a dominant negative (DN) that blocks trafficking at recycling endosomes enabled GCGR deubiquitination, whereas a Rab5a DN that blocks trafficking at early endosomes eliminated agonist-induced GCGR deubiquitination. By down-regulating candidate deubiquitinases that are either linked with GPCR trafficking or localized on endosomes, we identified signal-transducing adaptor molecule–binding protein (STAMBP) and ubiquitin-specific protease 33 (USP33) as cognate deubiquitinases for the GCGR. Our data suggest that USP33 constitutively deubiquitinates the GCGR, whereas both STAMBP and USP33 deubiquitinate agonist-activated GCGRs at early endosomes. A mutant GCGR with all five intracellular lysines altered to arginines remains deubiquitinated and shows augmented trafficking to Rab4a recycling endosomes compared with the WT, thus affirming the role of deubiquitination in GCGR recycling. We conclude that the GCGRs are rapidly deubiquitinated after agonist-activation to facilitate Rab4a-dependent recycling and that USP33 and STAMBP activities are critical for the endocytic recycling of the GCGR.

Elevated levels of fasting insulin release and insufficient glucose-stimulated insulin secretion (GSIS) are hallmarks of diabetes. Studies have established cross-talk between integrin signaling and insulin activity, but more details of how integrin-dependent signaling impacts the pathophysiology of diabetes are needed. Here, we dissected integrin-dependent signaling pathways involved in the regulation of insulin secretion in β-cells and studied their link to the still debated autocrine regulation of insulin secretion by insulin/insulin-like growth factor (IGF) 2–AKT signaling. We observed for the first time a cooperation between different AKT isoforms and focal adhesion kinase (FAK)–dependent adhesion signaling, which either controlled GSIS or prevented insulin secretion under fasting conditions. Indeed, β-cells form integrin-containing adhesions, which provide anchorage to the pancreatic extracellular matrix and are the origin of intracellular signaling via FAK and paxillin. Under low-glucose conditions, β-cells adopt a starved adhesion phenotype consisting of actin stress fibers and large peripheral focal adhesion. In contrast, glucose stimulation induces cell spreading, actin remodeling, and point-like adhesions that contain phospho-FAK and phosphopaxillin, located in small protrusions. Rat primary β-cells and mouse insulinomas showed an adhesion remodeling during GSIS resulting from autocrine insulin/IGF2 and AKT1 signaling. However, under starving conditions, the maintenance of stress fibers and the large adhesion phenotype required autocrine IGF2-IGF1 receptor signaling mediated by AKT2 and elevated FAK-kinase activity and ROCK-RhoA levels but low levels of paxillin phosphorylation. This starved adhesion phenotype prevented excessive insulin granule release to maintain low insulin secretion during fasting. Thus, deregulation of the IGF2 and adhesion-mediated signaling may explain dysfunctions observed in diabetes.

Gα proteins promote dynamic adjustments of cell shape directed by actin-cytoskeleton reorganization via their respective RhoGEF effectors. For example, Gα13 binding to the RGS-homology (RH) domains of several RH-RhoGEFs allosterically activates these proteins, causing them to expose their catalytic Dbl-homology (DH)/pleckstrin-homology (PH) regions, which triggers downstream signals. However, whether additional Gα proteins might directly regulate the RH-RhoGEFs was not known. To explore this question, we first examined the morphological effects of expressing shortened RH-RhoGEF DH/PH constructs of p115RhoGEF/ARHGEF1, PDZ-RhoGEF (PRG)/ARHGEF11, and LARG/ARHGEF12. As expected, the three constructs promoted cell contraction and activated RhoA, known to be downstream of Gα13. Intriguingly, PRG DH/PH also induced filopodia-like cell protrusions and activated Cdc42. This pathway was stimulated by constitutively active Gαs (GαsQ227L), which enabled endogenous PRG to gain affinity for Cdc42. A chemogenetic approach revealed that signaling by Gs-coupled receptors, but not by those coupled to Gi or Gq, enabled PRG to bind Cdc42. This receptor-dependent effect, as well as CREB phosphorylation, was blocked by a construct derived from the PRG:Gαs-binding region, PRG-linker. Active Gαs interacted with isolated PRG DH and PH domains and their linker. In addition, this construct interfered with GαsQ227L's ability to guide PRG's interaction with Cdc42. Endogenous Gs-coupled prostaglandin receptors stimulated PRG binding to membrane fractions and activated signaling to PKA, and this canonical endogenous pathway was attenuated by PRG-linker. Altogether, our results demonstrate that active Gαs can recognize PRG as a novel effector directing its DH/PH catalytic module to gain affinity for Cdc42.

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.

RAS genes are the most commonly mutated in human cancers and play critical roles in tumor initiation, progression, and drug resistance. Identification of targets that block RAS signaling is pivotal to develop therapies for RAS-related cancer. As RAS translocation to the plasma membrane (PM) is essential for its effective signal transduction, we devised a high-content screening assay to search for genes regulating KRAS membrane association. We found that the tyrosine phosphatase PTPN2 regulates the plasma membrane localization of KRAS. Knockdown of PTPN2 reduced the proliferation and promoted apoptosis in KRAS-dependent cancer cells, but not in KRAS-independent cells. Mechanistically, PTPN2 negatively regulates tyrosine phosphorylation of KRAS, which, in turn, affects the activation KRAS and its downstream signaling. Consistently, analysis of the TCGA database demonstrates that high expression of PTPN2 is significantly associated with poor prognosis of patients with KRAS-mutant pancreatic adenocarcinoma. These results indicate that PTPN2 is a key regulator of KRAS and may serve as a new target for therapy of KRAS-driven cancer.

Bone morphogenetic protein-9 (BMP-9) is a circulating cytokine that is known to play an essential role in the endothelial homeostasis and the binding of BMP-9 to the receptor activin-like kinase 1 (ALK-1) promotes endothelial cell quiescence. Previously, using an unbiased screen, we identified ALK-1 as a high-capacity receptor for low-density lipoprotein (LDL) in endothelial cells that mediates its transcytosis in a nondegradative manner. Here we examine the crosstalk between BMP-9 and LDL and how it influences their interactions with ALK-1. Treatment of endothelial cells with BMP-9 triggers the extensive endocytosis of ALK-1, and it is mediated by caveolin-1 (CAV-1) and dynamin-2 (DNM2) but not clathrin heavy chain. Knockdown of CAV-1 reduces BMP-9–mediated internalization of ALK-1, BMP-9–dependent signaling and gene expression. Similarly, treatment of endothelial cells with LDL reduces BMP-9–induced SMAD1/5 phosphorylation and gene expression and silencing of CAV-1 and DNM2 diminishes LDL-mediated ALK-1 internalization. Interestingly, BMP-9–mediated ALK-1 internalization strongly re-duces LDL transcytosis to levels seen with ALK-1 deficiency. Thus, BMP-9 levels can control cell surface levels of ALK-1, via CAV-1, to regulate both BMP-9 signaling and LDL transcytosis.

Astrid M. Moerman
Dec 23, 2020; 0:jlr.RA120000974v1-jlr.RA120000974
Research Articles

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