Gijs den Besten
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Michael Dean
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Dawn L. Brasaemle
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Supporting Next Generation of Leaders in Sustainability News Release NCapeling 28 January 2021

A new programme offering paid internships for young people who are passionate about social, economic, and environmental sustainability has been launched.

Deplatforming Trump puts big tech under fresh scrutiny Expert comment NCapeling 22 January 2021

The response of digital platforms to the US Capitol riots raises questions about online content governance. The EU and UK are starting to come up with answers.

The ‘deplatforming’ of Donald Trump – including Twitter’s announcement that it has permanently banned him due to ‘the risk of further incitement of violence’ after the riots in the US – shows once more not only the sheer power of online platforms but also the lack of a coherent and consistent framework for online content governance.

Taking the megaphone away from Trump during the Capitol riots seems sensible, but was it necessary or proportionate to ban him from the platform permanently? Or consistent with the treatment of other ‘strongmen’ world leaders such as Modi, Duterte and Ayatollah Ali Khamenei who have overseen nationalistic violence but whose accounts remain intact?

Such complex decisions on online expression should not made unilaterally by powerful and unregulated tech actors, but instead should be subject to democratic oversight and grounded in the obligations of states and responsibilities of companies under international human rights law.

The speed and scale of digital information has left governments across the world struggling with how to tackle online harms such as hate speech, extremist content and disinformation since the emergence of mass social media 15 years ago.

The US’s hallowed approach to the First Amendment, under which speech on public issues – even hate speech – occupies the highest rank and is entitled to special protection, has contributed to a reluctance to regulate Silicon Valley’s digital platforms. But the irony is that by not regulating them, the government harmed freedom of expression by leaving complex speech decisions in the hands of private actors.

Meanwhile at the other extreme is the growing number of illiberal and authoritarian governments using a combination of vague laws, censorship, propaganda, and internet blackouts to severely restrict online freedom of expression, control the narrative and, in some cases, incite atrocities.

Regulation is on the way

The happy medium – flexible online content regulation providing clarity, predictability, transparency, and accountability – has until now been elusive. But even before the deplatforming of Trump, 2021 was set to be the year when this approach finally gained some traction, at least in Europe.

The EU’s recently-published draft Digital Services Act puts obligations on dominant social media platforms to manage ‘systemic risks’, for example through requirements for greater transparency about their content decisions, algorithms used for recommendations, and online advertising systems.

The UK will shortly publish its Online Safety Bill, which will establish a new regulatory framework for tackling online harms, including the imposition of a duty of care and codes of conduct on Big Tech, to be overseen by an independent regulator (Ofcom).

Both proposals are based on a ‘co-regulatory’ model under which the regulator sets out a framework substantiated with rules by the private sector, with the regulator performing a monitoring function to ensure the rules are complied with.

Both also draw on international human rights standards and the work of civil society in applying these standards in relation to the online public square, with the aim of increasing control for users over what they see online, requiring transparency about tech companies’ policies in a number of areas, and strengthening the accountability of platforms when they fall foul of the regulation.

The procedure for both proposals has also been inclusive, involving extensive multi-stakeholder consultations with civil society organizations and Big Tech, and the proposals will be subject to scrutiny in 2021, notably from the EU and UK parliaments.

Both proposals are at an early stage, and it remains to be seen whether they go far enough – or indeed will have a chilling effect on online platforms. But as an attempt to initiate a dialogue on globally coherent principles, they are positive first steps. They also provide food for thought for the new Joe Biden administration in the US as it turns its attention to the regulation of Big Tech.

For some time civil society – most prominently David Kaye, the former UN Special Rapporteur on freedom of expression and opinion – have called for content regulation to be informed by universal international human rights law standards.

The EU and UK are peculiarly well-placed to take the lead in this area because European countries have for decades been on the receiving end of judgments from the European Court of Human Rights on the appropriate limits to freedom of expression in cases brought under the European Convention on Human Rights.

In deciding these cases, the court has to balance the right to freedom of expression against the restrictions imposed – for example in the context of incitement to violence, political debate, and satire. Deciding where to draw the line on what can and cannot be expressed in a civilised society which prizes freedom of expression is inevitably a difficult exercise.

International human rights law provides a methodology that inquires whether the interference to freedom of expression was prescribed by law and pursues a legitimate aim, and also whether it was necessary in a democratic society to achieve those aims – including whether the interference was necessary and proportionate (as for example in Delfi AS v Estonia, which involved a news portal failing to take down unlawful hate speech).

To be effective, online content regulation has to bite on tech companies, which is a challenge given the internet is global but domestic law normally applies territorially. The EU’s proposals have an extraterritorial element as they apply to any online platforms providing services in the EU regardless of where the platform is headquartered.

Further, both the EU and UK want to give the regulator strong enforcement powers – it is proposed for example that Ofcom will have powers to fine platforms up to ten per cent of their turnover for breaches.

Although the proposals would not apply directly to the deplatforming of Trump which occurred in the US, the philosophy behind the EU and UK approach is likely to have an impact beyond European shores in promoting a co-regulatory model that some of the bigger tech companies have been inviting for some time, reluctant as they are to ‘play God’ on content moderation decisions without reference to any regulatory framework.

In the absence of regulation, the standards of tech platforms such as Facebook and Twitter have already evolved over time in response to pressure from civil rights groups, users, and advertisers, including updated policies on protecting civic conversation and hate speech.

Facebook has also set up an independent Oversight Board, whose members include leading human rights lawyers, to review decisions on content including – at its own request – the decision to indefinitely suspend Trump from Facebook and Instagram. Decisions on the Board’s first tranche of cases are expected imminently.

Gatekeeper status is key

Online content regulation also needs to address the role of Big Tech as the ‘digital gatekeepers’, because their monopoly power extends not just to editorial control of the news and information we consume, but also to market access.

The decision of Apple, Google, and Amazon to stop hosting right-wing social network Parler after it refused to combat calls for violence during the US Capitol riots was understandable in the circumstances, but also underlined the unilateral ability of Big Tech to decide the rules of the market.

Again, it is Europe where efforts are underway to tackle this issue: the EU’s draft Digital Market Act imposes obligations on online gatekeepers to avoid certain unfair practices, and the UK’s new Digital Markets Unit will have powers to write and enforce a new code of practice on those technology companies with ‘substantial and enduring’ market power.

In the US, Biden’s team will be following these developments with interest, given the growing bipartisan support for strengthening US antitrust rules and reviving antitrust enforcement. The EU’s recently published proposals for an EU-US tech agenda include a transatlantic dialogue on the responsibility of tech platforms and strengthened cooperation between antitrust authorities on digital markets.

Ultimately a consistent – and global – approach to online content is needed instead of fragmented approaches by different companies and governments. It is also important the framework is flexible so that it is capable of applying not only to major democracies but also to countries where too often sweeping state regulation has been used as a pretext to curtail online expression online.

The pursuit of a pluralistic framework tailored to different political and cultural contexts is challenging, and international human rights law cannot provide all the answers but, as a universal framework, it is a good place to start. The raft of regulatory measures from the EU and UK means that, regardless of whether Trump regains his online megaphone, 2021 is set to be a year of reckoning for Big Tech.

The UK's new Online Safety Bill 10 February 2021 — 3:00PM TO 3:45PM Anonymous (not verified) 26 January 2021 Online

Discussing the new proposals which include the establishment of a new ‘duty of care’ on companies to ensure they have robust systems in place to keep their users safe.

Governments, regulators and tech companies are currently grappling with the challenge of how to promote an open and vibrant internet at the same time as tackling harmful activity online, including the spread of hateful content, terrorist propaganda, and the conduct of cyberbullying, child sexual exploitation and abuse.

The UK government’s Online Harms proposals include the establishment of a new ‘duty of care’ on companies to ensure they have robust systems in place to keep their users safe. Compliance with this new duty will be overseen by an independent regulator.

On 15 December 2020, DCMS and the Home Office published the full UK government response, setting out the intended policy positions for the regulatory framework, and confirming Ofcom as the regulator.

With the legislation likely to be introduced early this year, the panel will discuss questions including:

• How to strike the balance between freedom of expression and protecting adults from harmful material?

• How to ensure the legislation’s approach to harm is sufficiently future-proofed so new trends and harms are covered as they emerge?

• What additional responsibilities will tech companies have under the new regulation?

• Will the regulator have sufficient powers to tackle the wide range of harms in question?

This event is invite-only for participants, but you can watch the livestream of the discussion on this page at 15.00 GMT on Wednesday 10 February.

New UK bill can fight fresh wave of online racist abuse Expert comment NCapeling 21 July 2021

The Euros final and Grand Prix put online abuse once more in the spotlight. The UK’s Online Safety Bill provides a strong framework for tackling the problem.

The ugly online abuse targeted at members of the England football team following the Euros final, and then at Lewis Hamilton after the British Grand Prix, was not only hateful to the individuals concerned, but divisive for the UK more broadly.

More needs to be done to regulate online platforms to avoid the spread of such abuse at scale. Online platforms are making increasing efforts to ‘self-regulate’ in order to tackle online abuse. Over the past year, Facebook and Twitter have strengthened their policies on hateful speech and conduct, such as Facebook’s policy banning Holocaust denial. Both have become more vigilant at deplatforming those who violate their terms of service, such as Donald Trump, and at removing online abuse using a combination of machines and humans.

Twitter announced in the 24 hours following the Euros final that it had removed more than 1,000 tweets, and permanently suspended several accounts, for violating its rules. But inevitably not all abusive posts are picked up given the scale of the issue and, once the post has been seen, arguably the damage is done.

Platforms have also partnered with NGOs on initiatives to counter hate speech and have launched initiatives to tackle the rise in coordinated inauthentic behaviour and information operations that seek to sow distrust and division. But while these efforts are all laudable, they are not enough.

The root of the problem is not the content but a business model in which platforms’ revenue from advertising is directly linked to engagement. This encourages the use of ‘recommender’ algorithms which amplify divisive content by microtargeting users based on previous behaviour, as seen not just with racist abuse but also other toxic content such as anti-vaccination campaigns. Abusers can also remain anonymous, giving them protection from consequences.

Creating a legal duty of care

The UK government’s Online Safety Bill, published in May 2021, aims to tackle harmful content online by placing a duty of care on online platforms to keep users safe and imposing obligations tailored to the size, functionality, and features of the service.

Social media companies will be expected to comply with their duties by carrying out risk assessments for specified categories of harm, guided by codes of practice published by the independent regulator, OFCOM. The bill gives OFCOM the power to fine platforms up to £18 million or ten per cent of global turnover, whichever is higher, for failure to comply.

Following the Euros final, the UK government spoke of referring some racist messages and conduct online to the police. But only a small proportion of it can be prosecuted given the scale of the abuse and the fact only a minority constitutes criminal activity. The majority is ‘lawful but harmful’ content – toxic and dangerous but not technically falling foul of any law.

When addressing ‘lawful but harmful’ material, it is crucial that regulation negotiates the tension between tackling the abuse and preserving freedom of expression. The scale at which such expression can spread online is key here – freedom of speech should not automatically mean freedom of reach. But it is equally important that regulation does not have a chilling effect on free speech, as with the creeping digital authoritarianism in much of the world.

The Online Safety Bill’s co-regulatory approach aims to address these tensions by requiring platforms within the scope of the bill to specify in their terms and conditions how they deal with content on their services that is legal but harmful to adults, and by giving the regulator powers to police how platforms enforce them. Platforms such as Facebook and Twitter may already have strong policies on hate speech – now there will be a regulator to hold them to account.

Devil is in the detail

How successful OFCOM is in doing so will depend on the precise powers bestowed on it in the bill, and how OFCOM chooses to use them. It’s still early days - the bill will be scrutinized this autumn by a committee of MPs before being introduced to parliament. This committee stage will provide an opportunity for consideration of how the bill may need to evolve to get to grips with online abuse.

These latest two divisive and toxic episodes in UK sport are only likely to increase pressure from the public, parliament, and politicians for the bill to reserve robust powers for OFCOM in this area. If companies do not improve at dealing with online abuse, then OFCOM should have the power to force platforms to take more robust action, including by conducting an audit of platforms’ algorithms, enabling it to establish the extent to which their ‘recommender’ settings play a part in spreading hateful content.

Currently, the bill’s definition of harm is confined to harm to individuals, and the government has stated it does not intend this bill to tackle harm to society more broadly. But if racist abuse of individuals provokes racist attacks more widely, as has happened, the regulator should be able to take that wider context into account in its investigation and response.

Responses to the draft bill so far indicate challenges ahead. Some argue the bill does not go far enough to tackle online abuse, especially on the issue of users’ anonymity, while others fear the bill goes too far in stifling freedom of expression, labelling it a recipe for censorship.

Parliamentary scrutiny will need to take into account issues of identity, trust, and authenticity in social networks. While some call for a ban on the cloak of anonymity behind which racist abusers can hide online, anonymity does have benefits for those in vulnerable groups trying to expose hate.

An alternative approach gaining attention is each citizen being designated a secure digital identity, which would both provide users with greater control over what they can see online and enable social media platforms to verify specific accounts. Instituted with appropriate privacy and security safeguards, a secure digital ID would have benefits beyond social media, particularly in an online COVID-19 era.

The online public square is global so countries other than the UK and international organizations must also take measures. It is encouraging to see synergies between the UK’s Online Safety Bill and the EU’s Digital Services Act, published in draft form in December 2020, which also adopts a risk-based, co-regulatory approach to tackling harmful online content. And the UK is using its G7 presidency to work with allies to forge a more coherent response to internet regulation at the international level, at least among democratic states.

Addressing the scourge of online hate speech is challenging so the UK’s Online Safety Bill will not satisfy everyone. But it can give the public, parliament, and politicians a structure to debate these crucial issues and, ultimately, achieve more effective ways of tackling them.

Geopolitical corporate responsibility can drive change Expert comment NCapeling 26 July 2022

Russia’s long invasion of Ukraine is testing the commitment of business, but this could see the emergence of a new pillar of support for the rules-based international order.

The massive exit of more than 1,000 international companies from Russia has surpassed – by a factor of nearly ten in merely four months – the number which pulled out of apartheid-led South Africa over an entire decade.

These company exits extend beyond those industries targeted for sanctions – oil and gas, banks and financial services, aerospace, and certain technology sectors – to include hundreds in consumer products ranging from Levi’s and H&M clothing to Coca-Cola and McDonalds. Many of these companies may wish to return to a post-conflict – or post-Putin – Russia, while a few have already sold their Russian operations, as McDonald’s has to an existing Siberian licensee.

Both reputational and operational factors are driving the huge exodus: reputational as companies have chosen to disassociate themselves from Putin’s regime; operational as transportation routes and supply chains have been interrupted.

Few of these companies have made explicit the principles at stake, while many still face ‘tricky legal, operational and ethical considerations’ and some have kept operations in place. But the collective impact of the exit in response to Russia’s affront to international law has sent shockwaves around the world.

Current issues and future implications

Minds now turn to whether this exodus sets a blueprint for the future, and how companies having to make complex and sensitive risk assessments and global business planning decisions can address both current issues as well as similar future challenges.

The new Declaration from the Business for Ukraine Coalition – an international civil society initiative of organizations and individuals – encourages companies to reinforce ‘responsible exit’ from Russia ‘in response to its unprovoked, full-scale war on Ukraine’.

The declaration’s objective is to ‘block access to the economic and financial resources enabling Russian aggression’ and it urgently calls on companies that have terminated or suspended their business operations and relationships to ‘stand by those commitments until the territorial sovereignty of Ukraine within internationally recognized borders is restored.’

It also states companies yet to terminate or suspend operations in Russia should do so unless they can demonstrate through due diligence that their provision of ‘essential’ services or products – such as medicines – meet critical humanitarian needs.

The 2022 Edelman Trust Barometer Special Report: The Geopolitical Business suggests Ukraine represents an inflection point posing ‘a new test’ for business. According to an online survey of 14,000 respondents in 14 countries, including employees, NGOs, and other stakeholders, there is a ‘rising call’ for business to be more engaged in geopolitics, with CEOs ‘expected to shape policy’ on societal and geopolitical issues.

Such expectations have been intensifying with the impetus of the combined stakeholder capitalism and corporate purpose agenda, even as a political backlash in the US against the environmental, social, and governance (ESG) movement linking institutional investors and multinational corporations gains momentum.

The emergence of corporate activism is a further development – partly driven by employees and accelerated during the pandemic – on issues of economic inequality, racial injustice, and gender equality, as well as the climate crisis.

When considering what broader purpose should drive this corporate geopolitical engagement, the Business for Ukraine Declaration offers an answer, calling Russia’s aggression ‘an attack on the rules-based international order which must be protected to ‘safeguard the international community and the global economy.’

This points to broader interests and values at stake in the Russian war on Ukraine because supporting the rules-based international order can become the basis of a new geopolitical corporate responsibility. Business, especially multinational corporations and institutional investors, fundamentally depend on and have enormously benefitted from this order.

Economic development needs a stable rules-based international order

Trade and investment, entrepreneurship, and innovation – the sinews of economic development – depend on predictable, rational behaviour by states at home and abroad. Individual companies and entire industries share a stake in upholding this order at a time when its stability and even legitimacy is undergoing a severe challenge.

The rules-based international order has evolved since the adoption of the UN Charter in 1945, the Universal Declaration of Human Rights in 1948, and the establishment of the standards, norms and institutions that reflect and reinforce these lodestars. It defines the international community, the rule of law, accountable governance, civic freedoms, and human rights within nations. It also supports national self-determination, sovereignty, and the disavowal of the use of force to alter borders among nations, and it provides accountability for genocide, crimes against humanity, and war crimes.

Business has a fundamental stake in the international order as the framework for stability, prosperity, open societies, and markets.

A new geopolitical corporate responsibility does not need to become a doctrine but can instead be an agenda to support the international rules-based order under stress. Such an agenda may help multinationals deal with expectations they already face, such as:

Avoiding situations where they cause, contribute, or are directly linked to human rights abuses. This objective is enshrined in the UN Guiding Principles on Business and Human Rights and companies can be further informed by the new UN Guide to Heightened Human Rights Due Diligence for Business in Conflict-Affected Contexts.

Committing to the ‘shared space’ of the rule of law, accountable governance, civic freedoms, and human rights. These are both the enablers of civil society and the underpinning of sustainable and profitable business and investment environments. The Chatham House synthesis paper The role of the private sector in protecting civic space sets forth the rationale for companies to defend these vital elements.

Supporting peace, justice, and strong institutions both within nations and across the international community as set forth by UN Sustainable Development Goal 16. The SDG 16 Business Framework: Inspiring Transformational Governance shows how companies, as well as national governments and international institutions, can contribute to these building blocks of stability and prosperity.

Demonstrating corporate responsibility at the national and geopolitical levels to enhance equity, transparency, and accountability. Multinationals are already challenged to accept minimum corporate taxation within and across jurisdictions, curb excessive executive compensation, endorse mandatory disclosure of environmental and human rights due diligence, and strengthen corporate governance of ESG risks and responsibilities, including with respect to human rights.

Diminishing inequality by tackling poverty and ensuring sustainability by arresting the climate crisis. Alongside governments and international institutions, the business community already faces increasing pressure to improve its efforts in these areas.

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

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

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

The molecular mechanisms of reduced frataxin (FXN) expression in Friedreich's ataxia (FRDA) are linked to epigenetic modification of the FXN locus caused by the disease-associated GAA expansion. Here, we identify that SUV4-20 histone methyltransferases, specifically SUV4-20 H1, play an important role in the regulation of FXN expression and represent a novel therapeutic target. Using a human FXN–GAA–Luciferase repeat expansion genomic DNA reporter model of FRDA, we screened the Structural Genomics Consortium epigenetic probe collection. We found that pharmacological inhibition of the SUV4-20 methyltransferases by the tool compound A-196 increased the expression of FXN by ∼1.5-fold in the reporter cell line. In several FRDA cell lines and patient-derived primary peripheral blood mononuclear cells, A-196 increased FXN expression by up to 2-fold, an effect not seen in WT cells. SUV4-20 inhibition was accompanied by a reduction in H4K20me2 and H4K20me3 and an increase in H4K20me1, but only modest (1.4–7.8%) perturbation in genome-wide expression was observed. Finally, based on the structural activity relationship and crystal structure of A-196, novel small molecule A-196 analogs were synthesized and shown to give a 20-fold increase in potency for increasing FXN expression. Overall, our results suggest that histone methylation is important in the regulation of FXN expression and highlight SUV4-20 H1 as a potential novel therapeutic target for FRDA.

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Phospholipase Cε (PLCε) is activated downstream of G protein–coupled receptors and receptor tyrosine kinases through direct interactions with small GTPases, including Rap1A and Ras. Although Ras has been reported to allosterically activate the lipase, it is not known whether Rap1A has the same ability or what its molecular mechanism might be. Rap1A activates PLCε in response to the stimulation of β-adrenergic receptors, translocating the complex to the perinuclear membrane. Because the C-terminal Ras association (RA2) domain of PLCε was proposed to the primary binding site for Rap1A, we first confirmed using purified proteins that the RA2 domain is indeed essential for activation by Rap1A. However, we also showed that the PLCε pleckstrin homology (PH) domain and first two EF hands (EF1/2) are required for Rap1A activation and identified hydrophobic residues on the surface of the RA2 domain that are also necessary. Small-angle X-ray scattering showed that Rap1A binding induces and stabilizes discrete conformational states in PLCε variants that can be activated by the GTPase. These data, together with the recent structure of a catalytically active fragment of PLCε, provide the first evidence that Rap1A, and by extension Ras, allosterically activate the lipase by promoting and stabilizing interactions between the RA2 domain and the PLCε core.

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

DNA polymerases are today used throughout scientific research, biotechnology, and medicine, in part for their ability to interact with unnatural forms of DNA created by synthetic biologists. Here especially, natural DNA polymerases often do not have the “performance specifications” needed for transformative technologies. This creates a need for science-guided rational (or semi-rational) engineering to identify variants that replicate unnatural base pairs (UBPs), unnatural backbones, tags, or other evolutionarily novel features of unnatural DNA. In this review, we provide a brief overview of the chemistry and properties of replicative DNA polymerases and their evolved variants, focusing on the Klenow fragment of Taq DNA polymerase (Klentaq). We describe comparative structural, enzymatic, and molecular dynamics studies of WT and Klentaq variants, complexed with natural or noncanonical substrates. Combining these methods provides insight into how specific amino acid substitutions distant from the active site in a Klentaq DNA polymerase variant (ZP Klentaq) contribute to its ability to replicate UBPs with improved efficiency compared with Klentaq. This approach can therefore serve to guide any future rational engineering of replicative DNA polymerases.

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.

Pyruvate kinase muscle isoform 2 (PKM2) is a key glycolytic enzyme and transcriptional coactivator and is critical for tumor metabolism. In cancer cells, native tetrameric PKM2 is phosphorylated or acetylated, which initiates a switch to a dimeric/monomeric form that translocates into the nucleus, causing oncogene transcription. However, it is not known how these post-translational modifications (PTMs) disrupt the oligomeric state of PKM2. We explored this question via crystallographic and biophysical analyses of PKM2 mutants containing residues that mimic phosphorylation and acetylation. We find that the PTMs elicit major structural reorganization of the fructose 1,6-bisphosphate (FBP), an allosteric activator, binding site, impacting the interaction with FBP and causing a disruption in oligomerization. To gain insight into how these modifications might cause unique outcomes in cancer cells, we examined the impact of increasing the intracellular pH (pHi) from ∼7.1 (in normal cells) to ∼7.5 (in cancer cells). Biochemical studies of WT PKM2 (wtPKM2) and the two mimetic variants demonstrated that the activity decreases as the pH is increased from 7.0 to 8.0, and wtPKM2 is optimally active and amenable to FBP-mediated allosteric regulation at pHi 7.5. However, the PTM mimetics exist as a mixture of tetramer and dimer, indicating that physiologically dimeric fraction is important and might be necessary for the modified PKM2 to translocate into the nucleus. Thus, our findings provide insight into how PTMs and pH regulate PKM2 and offer a broader understanding of its intricate allosteric regulation mechanism by phosphorylation or acetylation.

Defining discontinuous antigenic epitopes remains a substantial challenge, as exemplified by the case of lipid transfer polyproteins, which are common pollen allergens. Hydrogen/deuterium exchange monitored by NMR can be used to map epitopes onto folded protein surfaces, but only if the complex rapidly dissociates. Modifying the standard NMR-exchange measurement to detect substoichiometric complexes overcomes this time scale limitation and provides new insights into recognition of lipid transfer polyprotein by antibodies. In the future, this new and exciting development should see broad application to a range of tight macromolecular interactions.

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.

Net Zero and Beyond: What Role for Bioenergy with Carbon Capture and Storage? 23 January 2020 — 8:30AM TO 10:00AM Anonymous (not verified) 6 January 2020 Chatham House | 10 St James's Square | London | SW1Y 4LE

In the context of the feasibility of reducing greenhouse gas emissions to net zero, policymakers are beginning to pay more attention to options for removing carbon dioxide from the atmosphere. A wide range of potential carbon dioxide removal (CDR) options are currently being discussed and modelled though the most prominent among them are bioenergy with carbon capture and storage (BECCS) and afforestation and reforestation.

There are many reasons to question the reliance on BECCS assumed in the models including the carbon balances achievable, its substantial needs for land, water and other inputs and technically and economically viable carbon capture and storage technologies.

This meeting will examine the potentials and challenges of BECCS in the context of other CDR and emissions abatement options. It will discuss the requisite policy and regulatory frameworks to minimize sustainability and socio-political risks of CDR approaches while also avoiding overshooting climate goals.

Attendance at this event is by invitation only.

Cities as climate leaders: Progress and ambition 1 December 2021 — 12:00PM TO 1:00PM Anonymous (not verified) 16 November 2021 Online

This panel discusses the progress cities have already made, whether progress at COP26 was enough, and what more needs to be done to scale action and ambition internationally.

Cities are critical to tackling the pressing environmental challenges of our time. While they now account for an estimated 75 per cent of global CO2 emissions, cities also offer a unique opportunity for devolved leadership on climate action. At the recent COP26, some significant progress was made in elevating cities’ position on climate action with a flurry of announcements and commitments.

For example, more than 1,000 cities are now committed to the Cities Race to Zero and C40’s Clean Construction Declaration saw multiple cities committing to at least halving emissions from initial construction of buildings by 2030. A raft of financing commitments were also made to improve urban resilience in the face of climate change.

This builds on existing momentum before COP26. Over 50 world cities are now on track to meet Paris Agreement and the Marrakech Partnership is further enabling collaboration between governments and cities within the UNFCCC processes.

Therefore, how we design, build, govern and use our urban places will be a key factor for decarbonization and climate change adaptation.

On the back of COP26, this panel brings together leaders from across urban development sectors to discuss the progress cities have already made, whether progress at COP26 was enough, and what more needs to be done to scale action and ambition internationally. 

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.

Webinar: Hong Kong: Dissent in the Age of Coronavirus 17 April 2020 — 12:00PM TO 1:00PM Anonymous (not verified) 8 April 2020

Street protests demanding greater autonomy and democratization in Hong Kong upended the city for seven months last year. However, with the outbreak of the coronavirus in China in late January, the protests quickly died out. What does this mean for the city’s protest movement?

The speaker will argue that, despite the lack of high-profile street rallies, protest in the city is continuing. It is building on and evolving from last year’s protest movement albeit in different forms. At the same time, the Hong Kong authorities, emboldened by a hard line from Beijing, have begun cracking down on activists and protesters in the city as they seek to put a lid on dissent ahead of important Legislative Council elections scheduled for this September.

In this webinar, the speaker will look at the current state of dissent in Hong Kong and prospects for Hong Kong’s future.

This event will be held on the record.

Webinar: On the Front Line: The Impact of COVID-19 on Asia's Migrant Workers 21 May 2020 — 2:00PM TO 2:45PM Anonymous (not verified) 15 May 2020

Asia’s army of migrant workers are on the frontline in confronting the health and economic effects of COVID-19. Lacking formal safety nets, health care access, and facing social dislocation, hundreds of millions across the region are bearing the brunt of the coronavirus lockdown. Asian governments have scrambled to come up with an effective health and humanitarian response, exposing public apathy and significant shortcomings in public policy.

Is better regional coordination necessary to mitigate the impact of the COVID-19 on migrant labourers? Is the private sector in Asia part of the problem or part of the solution?

In this webinar, the speakers will discuss the likely implications of lasting economic damage on the livelihoods of Asia’s migrant workers, as well as responses and measures to effectively mitigate the impact.

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

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

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

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

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

Math is often described as the science of patterns, which makes it a natural subject to help in the study of the underlying causes of patterns found in nature, for example, bands of vegetation that often occur on gently sloped terrains in certain near-desert ecosystems worldwide. We are starting to learn more about these bands' common properties by using mathematical models built on data, such as rainfall totals and the curvature of the terrain. Mary Silber talks about these mathematical models of vegetation bands.

Tim Chumley explains the connections between random billiards and the science of heat and energy transfer. If you've ever played billiards or pool, you've used your intuition and some mental geometry to plan your shots. Mathematicians have gone a step further, using these games as inspiration for new mathematical problems. Starting from the simple theoretical setup of a single ball bouncing around in an enclosed region, the possibilities are endless. For instance, if the region is shaped like a stadium (a rectangle with semicircles on opposite sides), and several balls start moving with nearly the same velocity and position, their paths in the region soon differ wildly: chaos. Mathematical billiards even have connections to thermodynamics, the branch of physics dealing with heat, temperature, and energy transfer.

Otto Overkamp
Trans. Amer. Math. Soc. 377 (), 5863-5903.
Abstract, references and article information

Anne-Miek Bibbe posted a photo:

JOEPIE: I'm almost there! I wish Uncle Jeroen was here, I'm a little, really just a little bit afraid of the dark.
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JOEPIE: Ik ben bijna bij Peter! Ik wou dat oom Jeroen hier was, ik ben een beetje, echt maar een héél klein beetje bang in het donker.

Christian Weiss
Theor. Probability and Math. Statist. 111 (), 199-209.
Abstract, references and article information

Claudio Macci and Barbara Pacchiarotti
Theor. Probability and Math. Statist. 111 (), 21-43.
Abstract, references and article information

Frederic Heihoff
Proc. Amer. Math. Soc. 152 (), 5229-5247.
Abstract, references and article information

Jian Li
Proc. Amer. Math. Soc. 152 (), 5207-5217.
Abstract, references and article information

Sophie Morier-Genoud of the University of Reims Champagne-Ardenne and Valentin Ovsienko of the Centre National de la Recherche Scientifique, Reims, are awarded the 2025 AMS David P. Robbins Prize for their paper “$q$-deformed rationals and $q$-continued fractions,” published in Forum of Mathematics, Sigma.

“In this groundbreaking work .. it is shown that the new concept has striking connections and applications to a wide range of mathematical areas,” according to the prize citation. “The paper has subsequently inspired a profusion of significant further research developments.”

From the citation

The David P. Robbins Prize is awarded to Sophie Morier-Genoud and Valentin Ovsienko for their paper “$q$-deformed rationals and $q$-continued fractions,” published in Forum of Mathematics, Sigma, in 2020.

The authors provide an entirely novel and natural definition of a $q$-analog of the rational numbers. Although a $q$-analog of the integers has been used extensively since the work of Euler, a satisfactory and meaningful $q$-analog of the rationals had remained elusive until this paper. The definition also leads to a natural $q$-analog of the real numbers and has a wide range of fascinating and far-reaching applications.

A $q$-analog of a mathematical concept is a generalization of the concept which depends on a new parameter $q$ in such a way that the original concept is recovered when $q$ is set to 1, and various interesting or useful properties also arise.

Response of Sophie Morier-Genoud

I am thrilled and honored to receive the 2025 David P. Robbins Prize. This is a fantastic recognition and a great encouragement to keep doing what I like to do. I always had a lot of fun doing mathematics and I feel privileged to do it as a profession. 

I am grateful to everyone who helped me in making this path possible. 

I would like to thank all my collaborators and colleagues in the Math Department at the University of Reims and also everywhere in the world who show interest in the math we are doing and contribute to enrich the theory of $q$-numbers.

Response of Valentin Ovsienko

I am deeply moved to receive this prize, named in honor of David P. Robbins, the creator of mathematical concepts that will forever remain among the most beautiful.

My scientific life has been spent trying to connect different topics in algebra, geometry, and mathematical physics. The $q$-numbers, which is a combinatorial notion, are the result of my journey with my younger and much smarter collaborator Sophie Morier-Genoud, following this route. We tried to better understand connections between cluster algebra, Coxeter friezes, Conway’s ideas, the Jones polynomial... We realized that it is impossible to $q$-deform a singular object, but only an infinite sequence of them! In order to $q$-deform rationals, one needs to count them all. We chose the way of counting determined by continued fractions and the action of the modular group.

Working on this subject has been and remains the happiest part of my scientific life. I was captivated by $q$-rationals and I was completely haunted by $q$-irrationals. This happiness, enhanced by interest of other researchers, in itself is reward enough. 

My collaboration with Sophie produced a variety of results, including two energetic children, Lisa and Anatole; the $q$-numbers are also little kids who need to grow up!

Biographical sketch of Sophie Morier-Genoud

Sophie Morier-Genoud is currently full professor at the University of Reims Champagne-Ardenne in France. She completed her PhD at the University of Lyon (2006) under the supervision of Philippe Caldero. She was T.H. Hildebrandt Assistant Professor at the University of Michigan (2006-2008), postdoctoral fellow of the Fondation Sciences Mathématiques de Paris (2008-2009) and associate professor at Sorbonne Université (2009-2021). Her research work is mainly related to algebraic combinatorics and representation theory. She currently serves as an editor for the column “Gems and Curiosities” of the Mathematical Intelligencer.

Biographical sketch of Valentin Ovsienko

Valentin Ovsienko was born in 1964 in the Soviet Union. He received his PhD in 1989 from Moscow State University under the supervision of Alexandre Kirillov. Ovsienko is currently in Reims, Champagne, as a senior researcher at the French Centre National de la Recherche Scientifique. He worked in projective differential geometry, infinite-dimensional Lie algebras, integrable systems, octonions, and, more recently, in combinatorics. Together with Sophie Morier-Genoud, he is the editor of the column “Gems and Curiosities” of the Mathematical Intelligencer, and he invites everyone to write beautiful articles for it.

About the prize

The David P. Robbins Prize is awarded every three years for a paper with the following characteristics: It reports on novel research in algebra, combinatorics, or discrete mathematics and has a significant experimental component; and it is on a topic which is broadly accessible and provides a simple statement of the problem and clear exposition of the work. Papers published within the six calendar years preceding the year in which the prize is awarded are eligible for consideration.

The 2025 prize will be presented at the 2025 Joint Mathematics Meetings in Seattle.

Learn more about the prize and previous recipients.

Contact: AMS Communications.

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Recent studies have suggested that innate immune responses exhibit characteristics associated with memory linked to modulations in both vertebrates and invertebrates. However, the diverse evolutionary paths taken, particularly within the invertebrate taxa, should lead to similarly diverse innate immunity memory processes. Our understanding of innate immune memory in invertebrates primarily comes from studies of the fruit fly Drosophila melanogaster, the generality of which is unclear. Caenorhabditis elegans typically inhabits soil harboring a variety of fatal microbial pathogens; for this invertebrate, the innate immune system and aversive behavior are the major defensive strategies against microbial infection. However, their characteristics of immunological memory remains infantile. Here we discovered an immunological memory that promoted avoidance and suppressed innate immunity during reinfection with bacteria, which we revealed to be specific to the previously exposed pathogens. During this trade-off switch of avoidance and innate immunity, the chemosensory neurons AWB and ADF modulated production of serotonin and dopamine, which in turn decreased expression of the innate immunity-associated genes and led to enhanced avoidance via the downstream insulin-like pathway. Therefore, our current study profiles the immune memories during C. elegans reinfected by pathogenic bacteria and further reveals that the chemosensory neurons, the neurotransmitter(s), and their associated molecular signaling pathways are responsible for a trade-off switch between the two immunological memories.

Animals can sense the presence of microbes in their tissues and mobilize their own defenses by recognizing and responding to conserved microbial structures (often called microbe-associated molecular patterns (MAMPs)). Successful host defenses may kill the invaders, yet the host animal may fail to restore homeostasis if the stimulatory microbial structures are not silenced. Although mice have many mechanisms for limiting their responses to lipopolysaccharide (LPS), a major Gram-negative bacterial MAMP, a highly conserved host lipase is required to extinguish LPS sensing in tissues and restore homeostasis. We review recent progress in understanding how this enzyme, acyloxyacyl hydrolase (AOAH), transforms LPS from stimulus to inhibitor, reduces tissue injury and death from infection, prevents prolonged post-infection immunosuppression, and keeps stimulatory LPS from entering the bloodstream. We also discuss how AOAH may increase sensitivity to pulmonary allergens. Better appreciation of how host enzymes modify LPS and other MAMPs may help prevent tissue injury and hasten recovery from infection.