Lawrence E. Ostrowski
Jun 1, 2002; 1:451-465
Research

Sebastian A. Wagner
Oct 1, 2011; 10:M111.013284-M111.013284
Research

Christian Tagwerker
Apr 1, 2006; 5:737-748
Research

Ignat V. Shilov
Sep 1, 2007; 6:1638-1655
Technology

Martin R. Larsen
Jul 1, 2005; 4:873-886
Technology

Yasushi Ishihama
Sep 1, 2005; 4:1265-1272
Research

Linn Fagerberg
Feb 1, 2014; 13:397-406
Research

Jürgen Cox
Sep 1, 2014; 13:2513-2526
Technological Innovation and Resources

Despite its major importance in human health, the metabolic potential of the human gut microbiota is still poorly understood. We have recently shown that biosynthesis of Ruminococcin C (RumC), a novel ribosomally synthesized and posttranslationally modified peptide (RiPP) produced by the commensal bacterium Ruminococcus gnavus, requires two radical SAM enzymes (RumMC1 and RumMC2) catalyzing the formation of four Cα-thioether bridges. These bridges, which are essential for RumC's antibiotic properties against human pathogens such as Clostridium perfringens, define two hairpin domains giving this sactipeptide (sulfur-to-α-carbon thioether–containing peptide) an unusual architecture among natural products. We report here the biochemical and spectroscopic characterizations of RumMC2. EPR spectroscopy and mutagenesis data support that RumMC2 is a member of the large family of SPASM domain radical SAM enzymes characterized by the presence of three [4Fe-4S] clusters. We also demonstrate that this enzyme initiates its reaction by Cα H-atom abstraction and is able to catalyze the formation of nonnatural thioether bonds in engineered peptide substrates. Unexpectedly, our data support the formation of a ketoimine rather than an α,β-dehydro-amino acid intermediate during Cα-thioether bridge LC–MS/MS fragmentation. Finally, we explored the roles of the leader peptide and of the RiPP precursor peptide recognition element, present in myriad RiPP-modifying enzymes. Collectively, our data support a more complex role for the peptide recognition element and the core peptide for the installation of posttranslational modifications in RiPPs than previously anticipated and suggest a possible reaction intermediate for thioether bond formation.

Leukocidin ED (LukED) is a pore-forming toxin produced by Staphylococcus aureus, which lyses host cells and promotes virulence of the bacteria. LukED enables S. aureus to acquire iron by lysing erythrocytes, which depends on targeting the host receptor Duffy antigen receptor for chemokines (DARC). The toxin also targets DARC on the endothelium, contributing to the lethality observed during bloodstream infection in mice. LukED is comprised of two monomers: LukE and LukD. LukE binds to DARC and facilitates hemolysis, but the closely related Panton–Valentine leukocidin S (LukS-PV) does not bind to DARC and is not hemolytic. The interaction of LukE with DARC and the role this plays in hemolysis are incompletely characterized. To determine the domain(s) of LukE that are critical for DARC binding, we studied the hemolytic function of LukE–LukS-PV chimeras, in which areas of sequence divergence (divergence regions, or DRs) were swapped between the toxins. We found that two regions of LukE's rim domain contribute to hemolysis, namely residues 57–75 (DR1) and residues 182–196 (DR4). Interestingly, LukE DR1 is sufficient to render LukS-PV capable of DARC binding and hemolysis. Further, LukE, by binding DARC through DR1, promotes the recruitment of LukD to erythrocytes, likely by facilitating LukED oligomer formation. Finally, we show that LukE targets murine Darc through DR1 in vivo to cause host lethality. These findings expand our biochemical understanding of the LukE–DARC interaction and the role that this toxin-receptor pair plays in S. aureus pathophysiology.

Alright! The Muses sing, drawing you to the desk, pump your veins with hot blood and fill your mind with combustible imagination. You’re on fire and ready to write. The idea once tumbling in your mind is bucking with life and wants to breath words on your screen. It’s awesome. You’re awesome. All is good.

Then the passions temper under the cool, steady light of your computer screen. The process of fleshing out your idea with words demands time. So much so, you feel the vibrant energy of your story suffocate under the process. Now you’re using the logical, analytical side of your brain. Each scene or circumstance demands continuity and must fit into the internal logic of your world. Everything must make sense; else the reader will dismiss this pile of junk for amateur hubris.

With logic comes the questions. A train of them, each rumbling down the tracks uncaring of the idea which once bucked in the stables of your mind, eager for freedom, now tied to the rails. All of the doubts can easily be summarized into “Can I?”

Of course, this isn’t the real question haunting the halls of your mind.

Continue reading Can I? When Doubt Kills Your Ideas at Mythic Scribes.

Helen Clark elected president of Chatham House News release jon.wallace 23 July 2021

The former New Zealand prime minister and Head of UN Development Programme has been elected president of Chatham House.

Former New Zealand prime minister and Head of the United Nations Development Programme, Helen Clark, has been elected president of Chatham House.

Ms Clark will replace former United Kingdom Prime Minister, Sir John Major, who is retiring from the role. She will join Baroness Eliza Manningham-Buller and Lord Darling as one of the institute’s three serving presidents.

Helen Clark was prime minister of New Zealand from 1999-2008. She then became the 8th and first female administrator of the UN Development Programme, completing two terms from 2009-2017.  

She is actively engaged in important international issues that are central to the institute’s priorities. She is currently chairing the Independent Panel for Pandemic Preparedness and Response with former president of Liberia, Ellen Johnson Sirleaf, which was convened by the World Health Organization last year and has just completed its main report. Her expertise extends to sustainable development, tackling climate change and developments in the Asia-Pacific.

Chatham House Director Robin Niblett welcomed the appointment:

‘We are excited to have found someone with the high-level political experience and who shares the strong reputation for integrity that Sir John enjoys. Helen Clark is highly regarded around the world for her past and current endeavours. Her election also underscores the institute’s global outlook and priorities, which she is so well qualified to help guide.’

Ms Clark was elected at the Annual General Meeting of Chatham House on 20 July which also marked the last official engagement for Lord O’Neill, who has now handed over to Sir Nigel Sheinwald as Chair of the institute.

Chatham House is delighted that Sir John Major will remain affiliated with the institute as president emeritus, and that Lord O’Neill will become a member of the institute’s panel of senior advisers.

Cross-border conflict, evidence, policy and trends (XCEPT)

This five-year policy-focused research programme seeks to respond to the challenges of long-term cross-border conflicts by exploring the drivers behind them.

Protracted conflicts in the Middle East and North Africa, Horn of Africa and parts of Asia, although usually arising from intra-state disputes, rarely remain contained within national borders. Their effects reverberate outward and external actors are drawn in.

The longer these wars last, the more difficult they are to resolve as the interests of international actors collide and the web of economic and political interactions which sustain violence and connect conflict across borders expand and deepen.

The Cross-border conflict, evidence, policy and trends (XCEPT) research programme brings together world-leading experts to examine conflict-affected borderlands, how conflicts connect across borders, and the drivers of violent and peaceful behaviour.

Chatham House provides research leadership to the programme, as part of the wider consortium, and our research explores:

• the intersection of conflict supply chains which sustain and embed violence
• coping supply chains for survival-based economic activity which occurs in the context of violence

Three geographic case studies will be supported by cross-cutting workstreams on gender and social inclusion, livelihoods, and border security. Each will produce analysis and recommendations to inform international policy responses to conflict across borders.

These case studies will focus on:

• armed actors and financial flows through Iraq and the Levant
• human smuggling across Libya, East and West Africa
• gold mining and weapons flows across Sudanese borderlands

The consortium is made up of a range of other organizations, including the Asia Foundation, the Malcolm H. Kerr Carnegie Middle East Center, the Rift Valley Institute, Chemonics UK and King’s College London.

XCEPT is funded by UK Aid from the UK government.

Independent Thinking: Biden and the Republicans, AUKUS Audio NCapeling 9 February 2023

Episode 14 of our weekly podcast examines the Chinese balloon saga, the State of the Union address, and updates on the AUKUS deal 18 months after it was signed.

This week saw US president Joe Biden address an unruly joint session of Congress, during which he discussed America’s place in the world, China, Ukraine, and the state of the US economy.

As a new presidential cycle begins at the mid-point of Biden’s presidency, the panel analyses how Biden is doing and the challenges that lie ahead for him.

Also it is now 18 months since the announcement of the AUKUS partnership between the UK, US and Australia to develop nuclear hunter killer submarines. What does AUKUS mean for Australia, non-proliferation, and the Indo-Pacific more broadly?

Finally, the panel discusses China’s balloon over Montana in the US. Was it a signal from Beijing and what was it trying to photograph?

Joining guest host John Kampfner this week from Chatham House are Dr Leslie Vinjamuri, director of the US and the Americas programme and Dr Patricia Lewis, director of the International Security programme. They are joined by Dr Euan Graham, Shangri-La Dialogue senior fellow for defence and strategy at the International Institute for Strategic Studies (IISS).

About Independent Thinking

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

What are the top economic priorities for the new US President? 19 November 2024 — 8:00AM TO 9:15AM Anonymous (not verified) 15 October 2024 Chatham House

A post-US election discussion on the outlook for US economic policy and implications for the global economy.

A fortnight on from the US Presidential and Congressional elections, this expert panel, organised by Chatham House’s Global Economy and Finance Programme in collaboration with the Society of Professional Economists, will consider the outlook for US economic policy and implications for the global economy.

Questions for discussion will include:

• What will the economic priorities of the new President be? What will be the role of industrial strategy/green transition, regulation, trade, migration and fiscal policy?
• How far will the President be constrained by other branches of the US government, including Congress, the courts and state governments?
• What will the implications be for the global economy broadly and through the specific channels of trade, investment, monetary policy and debt?
• How will the new President handle economic and financial relations with the US’s traditional G7 allies, China and the Global South?

The institute occupies a position of respect and trust, and is committed to fostering inclusive dialogue at all events. Event attendees are expected to uphold this by adhering to our code of conduct.

Will the next US president invest in Middle East stability or walk away? Expert comment LToremark 17 October 2024

Harris and Trump look set to continue US deprioritization of the region, but they would do better to enlist the support of their partners.

When stability in the Middle East feels so distant, it is much to the dismay of America’s partners that conflict management in the region has fallen down the list of US priorities. As Israel’s war in Gaza has reached its tragic one-year milestone, a new front has opened in Lebanon and further direct escalation between Israel and Iran seems imminent, it is hoped that the next US president will take a bolder role.

Namely, leaders in the UK, Europe and the Middle East are looking to whoever is in the White House to do more to restrain Israel, deliver self-determination – if not a peace process – for Palestine, and contain Iran’s interventionist regional role and nuclear programme.

While it is naive to expect either Kamala Harris or Donald Trump to prioritize conflict management in the Middle East above immigration, the economy, the war in Ukraine or competition with China, the past year has shown the danger of ignoring or sidestepping cascading and glaring regional challenges. 

For Harris or Trump to have a more sustainable impact in the region, they must enlist the support of European, British and Middle Eastern partners and work collectively to build multilateral processes that can set a stronger foundation for regional stability.

Repercussions of deprioritization

The Abraham Accords, which normalized relations between Israel, the UAE and Bahrain, led many to believe that a new era of integration was possible in the Middle East. To some, it also vindicated the US decision to deprioritize the region that had started with Barack Obama’s presidency and his drawing down from ‘forever wars’ in Iraq and Afghanistan. Presidents Trump and Biden continued that approach, encouraging America’s partners in the Middle East to assume greater responsibility for regional stability. Notably, neither renewed negotiations with Iran despite both committing to deliver a stronger deal with Tehran.

The shock of the 7 October attacks shattered that view, and the longer overhang of the US decision to deprioritize the region has visibly played out over the past twelve months. 

While the Biden administration marshalled full political and military support for Israel and there is not – yet – a direct regional war with Iran, the US has been unsuccessful in multiple areas: delivering a ceasefire agreement, securing the release of hostages, maintaining regular humanitarian relief and producing a so-called ‘day after’ plan of action.  

Moreover, the US temporary arrangement with Iran to prevent nuclear acceleration in exchange for marginal sanctions relief has also shown the limits of compartmentalization when managing a portfolio of issues with Tehran.  

No new approach

Trump and Harris’s policy approaches to conflict in the region further show their limited intent to change course on the Middle East. Both leaders are aware that Middle East politics, particularly on Israel–Palestine and Iran – the key issues requiring urgent attention – has become a US partisan minefield that could alienate voters. Despite their different plans, with Trump inclined to be more unilateral, they will both continue the trend of gradually deprioritizing conflict management in favour of greater burden sharing by those in the region.  

President Trump has promised a tougher approach aimed at curtailing conflict and advancing US interests. On Iran, Trump has made clear that he would return to a policy of maximum pressure on the Islamic Republic, perhaps to come to new agreement with Tehran or alternatively to constrain Iran even further.  He has championed his administration’s withdrawal from the 2015 Joint Comprehensive Plan of Action (JCPOA), also known as the Iran nuclear deal. Trump has argued that this approach put economic strain on Iran and reduced its ability to fund proxy groups. 

His advisers have also indicated that they would extend this pressure campaign and provide maximum support to the Iranian opposition and activists. Yet without clear goals or a willingness to negotiate with Tehran to contain further nuclear advancements, the result may well be another round of instability.  

Should he return to office, Trump has indicated that he would immediately put an end to the war in Gaza, though how remains unclear. More broadly, he would likely double down on the agreements to promote Israeli–Saudi normalization and attempt to bypass the Palestinian leadership, focusing on broader regional normalization. But sidestepping Palestinian self-determination, which since 7 October has been the condition for broader Arab normalization, will be difficult for Saudi Arabia to sell to its broader, now politicized, public.  

Many Middle East leaders, including those from the Arabian peninsula, might welcome the return of a Trump presidency, but Trump’s ‘America First’ policy did not provide Arab Gulf leaders, especially Riyadh, with protection from Iran’s attack on Saudi oil facilities seen in September 2019.  

Trump also promised without success to deliver a bigger, better Iran deal that would extend the JCPOA and include compromises on Tehran’s support for proxy groups and constraints on its missile programme. Rather than imposing his previous strategy, a second Trump presidency would be more effective if it worked collaboratively with transatlantic and regional partners on regional security issues pertaining to Israel–Palestine and Iran.  

Continuation and reinforcement?

Despite her recent tough talk on Iran, it is expected that Harris will reinforce the current wave of diplomatic efforts to deescalate and manage tensions with Tehran, rather than advocate for ‘maximum pressure’.  

Harris would likely build on efforts to revive a new paradigm that could contain Iran’s nuclear programme. She is expected to emphasize a strategy of engagement combined with pressure to prevent Iran from obtaining a nuclear weapon, while addressing its regional activities.   

Now that Iran has provided missiles and drones to Russia, it is clear that Tehran’s transfer of lethal aid needs an urgent response beyond continued reliance on sanctions. Harris’s team would be wise to pursue a multilateral negotiation process bringing together Europe and the UK, who are already discussing these issues, to collectively engage Tehran on a broader deal.

Moreover, winning support from Israel and the Gulf is a necessary condition to build a more sustainable Iranian agreement. 

In conversation with James Manyika, Senior Vice President of Research, Technology and Society at Google 12 December 2024 — 11:15AM TO 12:45PM Anonymous (not verified) 29 October 2024 Chatham House and Online

A conversation on AI’s global, societal and economic impacts.

2024 has been a landmark year for Artificial Intelligence (AI) development, deployment and use, with significant progress in AI-driven science, governance and cooperation. Looking ahead, AI continues to demonstrate economic promise and potential to expand on scientific breakthroughs in areas such as climate and health. This wave of innovation is occurring against a backdrop of geopolitical uncertainty and not all countries are fully able to participate. Heading into 2025, there are urgent questions about how best to maximise shared opportunities when it comes to AI and to advance global cooperation.

James Manyika, Senior Vice President of Research, Technology & Society at Google, will unpack what 2025 will bring for AI in science, economics, global governance and international cooperation. 

Key questions include:

• What will be AI’s global societal and economic impact in 2025 and beyond? 
• What are the ways AI could help increase economic growth and economy-wide productivity? What factors must be in place for this to happen?
• How best can we maximise shared opportunities and advance global cooperation when it comes to AI? Where can public-private partnerships unlock scientific breakthroughs for societal progress, combatting shared global challenges such as climate change and global health issues?  
• What are the principles of safe, responsible AI, and how should companies remain responsive to their evolution and integrate them into technology design and implementation? 
• What is the current – and ideal – role of technology companies in emerging mechanisms for global cooperation and national governance on AI?

This event is being held in partnership with Google.

You will receive notice by 13:00 on Wednesday 11 December if you have been successful in securing an in-person place.

The institute occupies a position of respect and trust, and is committed to fostering inclusive dialogue at all events. Event attendees are expected to uphold this by adhering to our code of conduct.

Harris and Trump's shared goal masks a fundamental AI policy divide Expert comment rgold.drupal 3 November 2024

Both presidential candidates will pursue US tech dominance but differ on the means to achieve it.

There remain some differences between the US presidential candidates’ positions on the governance of artificial intelligence and other emerging technology, notably around competition. 

But under either future administration, US decision-making looks set to be heavily influenced by growing securitization, the aims of the US technology industry and broader competition with China. 

‘Safe’ AI development 

Vice President Kamala Harris attended the inaugural Global AI Safety summit in the UK in 2023, where she announced President Joe Biden’s Executive Order on AI. This significant move by the federal government sought to define national and cyber security guidelines for AI developers and outline privacy and transparency guarantees. It also committed the federal government to a review of the National Security implications of this emerging technology, which was published last week.

In her remarks at the summit, Harris was clear that her definitions of safety extended beyond catastrophic risk mitigation to societal and personal harm. She noted the corrosive effects of some algorithmic decision-making and disinformation on democracy, appealing for AI that is developed ‘in the service of the public interest’.

A number of initiatives developed during the Biden administration have attempted to steer emerging technology as it takes root in society. This includes the establishment of the US AI Safety Institute, various schemes on global AI governance and investment in Public AI projects like the National AI Research Resource (NAIRR).

The US public is largely supportive: polling by the AI Policy Institute (AIPI) points to a majority preference for safety standards governing the US effort to lead in AI, rather than pedal-to-the-metal development. Investment in public options on AI and the infrastructure required to develop and sustain it is a bold direction that the incoming administration should consider expanding.

Biden’s Executive Order on AI has come under fire by the Trump campaign. At a rally in Iowa, Trump explained that he would cancel the order ‘on day one’, echoing a Republican platform that described it as imposing ‘Radical Leftwing ideas’ . 

Trump does, however, have his own track record in technology policy. During his first presidency, his administration passed an Executive Order on AI, stressing that ‘continued American leadership in Artificial Intelligence is of paramount importance to maintaining the economic and national security of the United States’. The tools and institutions announced as part of the order – including AI research investment, national AI research institutes and AI regulatory guidance including on federal use of AI – echo those of the current administration. 

Four years is a long time in AI, however. As the power of this technology is revealed, talk of safety may give way to talk of security. While the candidates may disagree on the role of the federal government in setting standards, there will be close alignment on the central need for US supremacy in national security. Neither administration seems likely to erect barriers to securitization of AI should it emerge as a critical strategic asset.

AI regulation at home 

American industry will remain the pivotal force shaping the US AI ecosystem, particularly as America jostles for position as the maker of the global rules governing AI. A notable aspect of Biden’s AI Executive Order was where it staked responsibility. Reports by AI and Cloud companies on the safety of their tools and infrastructure are sent to the Department of Commerce.

Under Secretary Gina Raimondo, whose star continues to rise, the department has become significantly more engaged with technology companies. In the absence of any other legal authority, AI governance has therefore sat under the purview of a secretary who herself has noted that they are ‘not a regulator’. 

The trend of industry leaders driving the government agenda on AI is replicated in other departments. There was an outcry over the composition of the new Department of Homeland Security advisory panel, the Artificial Intelligence and Security Board, with civil society groups concerned about the preponderance of industry voices: the 22-member panel includes the CEOs of OpenAI, Anthropic, NVIDIA, IBM, AWS, Adobe, Microsoft and Alphabet.

Under a Harris presidency, these trends seem likely to continue. Plus with deadlock in Congress probable, establishing new legal authorities for emerging technology will be difficult. That will likely mean emerging tech governance remains heavily influenced by the Department for Commerce. 

Like Harris, Trump has his allies in industry. While the Biden administration has courted the CEOs of AI companies who have historically spoken out in favour of regulation, Trump’s allies tend towards a more deregulatory agenda. 

Silicon Valley billionaires Elon Musk and Marc Andreessen have backed Trump’s plans to minimize AI regulation, lauding his support for ‘little tech’. They have also backed reported plans for so-called ‘Manhattan Projects’ to develop military technology, stewarded by ‘industry-led’ agencies. Trump’s aversion to strong regulatory institutions may mean an end to Biden’s anti-trust efforts, benefitting the biggest voices in the room, though his VP pick may disagree. JD Vance has somewhat surprisingly come out strongly in defence of the current chair of the Federal Trade Commission, Lina Khan, and her anti-trust efforts targeting US big tech.

Regardless, business interests will likely shape either a Harris or Trump administration’s approach as the US grapples with balancing the ambitions of its industry with an increasingly protectionist stance towards its biggest import market, China.

Competition abroad

China looms large in the imaginations of both campaigns. 

The US has signalled to its allies that American AI standards should replace Chinese standards. Export controls on semiconductors were expanded in September this year, with key voices in the industry – notably the Netherlands, Japan and South Korea – describing the restrictions as ‘economically motivated’ despite nominally being tied to national security by the US. 

M el-Saadani
Apr 1, 1989; 30:627-630
Articles

M. Mahmood Hussain
Jan 1, 2003; 44:22-32
Reviews

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

George H. Rothblat
May 1, 1999; 40:781-796
Reviews

William R. Morrison
Oct 1, 1964; 5:600-608
Articles

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.

Expert

Expert

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.

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.

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

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

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

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

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

Gurmeet K. Bakshi, Jyoti Garg and Gabriela Olteanu
Math. Comp. 93 (), 3027-3058.
Abstract, references and article information

Ole Løseth Elvetun and Bjørn Fredrik Nielsen
Math. Comp. 93 (), 2811-2836.
Abstract, references and article information

Daniel López Neumann
Trans. Amer. Math. Soc. 377 (), 5361-5387.
Abstract, references and article information