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

RecQ family helicases are highly conserved from bacteria to humans and have essential roles in maintaining genome stability. Mutations in three human RecQ helicases cause severe diseases with the main features of premature aging and cancer predisposition. Most RecQ helicases shared a conserved domain arrangement which comprises a helicase core, an RecQ C-terminal domain, and an auxiliary element helicase and RNaseD C-terminal (HRDC) domain, the functions of which are poorly understood. In this study, we systematically characterized the roles of the HRDC domain in E. coli RecQ in various DNA transactions by single-molecule FRET. We found that RecQ repetitively unwinds the 3'-partial duplex and fork DNA with a moderate processivity and periodically patrols on the ssDNA in the 5'-partial duplex by translocation. The HRDC domain significantly suppresses RecQ activities in the above transactions. In sharp contrast, the HRDC domain is essential for the deep and long-time unfolding of the G4 DNA structure by RecQ. Based on the observations that the HRDC domain dynamically switches between RecA core- and ssDNA-binding modes after RecQ association with DNA, we proposed a model to explain the modulation mechanism of the HRDC domain. Our findings not only provide new insights into the activities of RecQ on different substrates but also highlight the novel functions of the HRDC domain in DNA metabolisms.

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.

Myosins generate force and motion by precisely coordinating their mechanical and chemical cycles, but the nature and timing of this coordination remains controversial. We utilized a FRET approach to examine the kinetics of structural changes in the force-generating lever arm in myosin V. We directly compared the FRET results with single-molecule mechanical events examined by optical trapping. We introduced a mutation (S217A) in the conserved switch I region of the active site to examine how myosin couples structural changes in the actin- and nucleotide-binding regions with force generation. Specifically, S217A enhanced the maximum rate of lever arm priming (recovery stroke) while slowing ATP hydrolysis, demonstrating that it uncouples these two steps. We determined that the mutation dramatically slows both actin-induced rotation of the lever arm (power stroke) and phosphate release (≥10-fold), whereas our simulations suggest that the maximum rate of both steps is unchanged by the mutation. Time-resolved FRET revealed that the structure of the pre– and post–power stroke conformations and mole fractions of these conformations were not altered by the mutation. Optical trapping results demonstrated that S217A does not dramatically alter unitary displacements or slow the working stroke rate constant, consistent with the mutation disrupting an actin-induced conformational change prior to the power stroke. We propose that communication between the actin- and nucleotide-binding regions of myosin assures a proper actin-binding interface and active site have formed before producing a power stroke. Variability in this coupling is likely crucial for mediating motor-based functions such as muscle contraction and intracellular transport.

E. A. Rakhmanov and S. P. Suetin
Trans. Moscow Math. Soc. 83 (), 269-290.
Abstract, references and article information

L. Oeding
Trans. Moscow Math. Soc. 83 (), 227-250.
Abstract, references and article information

Sino-Russian Gas Cooperation: Power of Siberia I and II and Implications for Global LNG Supplies 27 November 2019 — 8:30AM TO 9:30AM Anonymous (not verified) 19 November 2019 Chatham House | 10 St James's Square | London | SW1Y 4LE

In a new event in the Sustainable Transitions series, the speaker will present an update of Sino-Russian gas cooperation.

To give a comprehensive account of their impact on global liquefied natural gas (LNG) supplies, he will discuss the following points:

• Gas is scheduled to start flowing from the Power of Siberia I (POS) on 2 December 2019. But what is the background of development of POS 1 and what is its current status and prospects?
• What are the chances of exporting gas through the proposed Altai pipeline? Why is the Mongolia export route so significant? And how will it affect the Central Asian Republics and in particular Turkmenistan’s gas export to China?
• What are the implications of both POS I and Altai gas via Mongolia route in the context of global LNG supply?
• What are the prospects for multilateral pipeline gas cooperation in northeast Asia?
• What are the implications for other Arctic onshore LNG supply, in particular, for Novatek’s Yamal LNG and Arctic LNG 1 and 2 to China on top of POS 1 and Altai gas?

Attendance at this event is by invitation only.

What's next for environmental peacebuilding? Lessons learned and opportunities from conflict-affected states 17 February 2021 — 3:00PM TO 4:00PM Anonymous (not verified) 8 February 2021 Online

 This event explores lessons and opportunities from conflict-affected states.

In the field of peacebuilding, scholars and policymakers increasingly recognize the importance of environmental restoration, afforestation and infrastructural renewal for creating the sustainable livelihoods necessary for successful peacebuilding efforts.

Featuring academics writing for International Affairs on environmental peacebuilding in Colombia, Yemen and the Sahel, this webinar discusses the policy implications of the turn to environmental peacebuilding.

This event is part of the Chatham House’s Environment and Society Discussion Series in which the Energy Environment and Resources Programme brings together leading academics and policymakers to discuss key issues in environmental policy.

In particular, this event focuses on the role of environmental peacebuilding in creating sustainable livelihoods. From the impact the destruction of infrastructure can have on poverty as a driver of conflict, to the role environmental peacebuilding can play in bringing communities together by creating sustainable shared spaces of employment, the importance of the environmental livelihood creation is difficult to overstate.

Panellists focus on how policymakers can best encourage inclusive and sustainable livelihood creation and on addressing the key challenges such approaches face in the context of environmental peacebuilding efforts.

Loss and damage: Where are we now and what happens next? 25 January 2022 — 1:00PM TO 2:00PM Anonymous (not verified) 17 January 2022 Online

This event discusses the progress of the loss and damage agenda within climate negotiations. 

Loss and damage refers to harms and destruction caused by climate change impacts that cannot be avoided through mitigation or adaptation.

While it has gained increasing recognition in international climate change negotiations, turning the concept of loss and damage into tangible action for climate-vulnerable countries has been contentious.

Loss and damage is interwoven with issues of fairness and equity. The issue is highly disputed due to its connection with the historical responsibility of developed countries in causing climate change, as well as associated calls for compensation from developing countries.

At COP26, Scotland became the first government to pledge funds for loss and damage for countries in the Global South. However, most climate-vulnerable countries left disappointed by the failure of the Glasgow Climate Pact to secure the establishment of a dedicated loss and damage financing facility.

Developing countries have made it clear that they will continue to push for a new financing facility in the Glasgow Dialogue, a set of international discussions on loss and damage kicking off in June.

The Environment and Society Discussion Series is hosting two events on loss and damage ahead of that date. This first event outlines the key debates and discuss what progress has been made on advancing the loss and damage agenda within climate negotiations to date.

The second event focuses on solutions and possible ways forward, looking ahead to the COP27 negotiations in Egypt later in 2022, where loss and damage is expected to be a high-profile agenda item.

What happened at COP27? 23 November 2022 — 12:00PM TO 1:00PM Anonymous (not verified) 14 November 2022 Online

Is the world getting back on track for staying within a 1.5°C temperature rise?

The COP27 summit closes out another year marked by record-breaking floods, deadly heatwaves and other extreme weather events, on top of global energy and food shortages and a cost-of-living crisis.

Remarkable geopolitical shifts including Russia’s invasion of Ukraine have weakened commitments to climate goals and led many to worry that governments are backtracking on their climate pledges.

UN officials have urged countries to show up to COP27 with greater ambition but instead of new pledges, the focus is expected to be on whether countries are following through on commitments made at COP26.

This event explored whether COP27 has met the challenge of truly moving the needle, and whether the world is getting back on track for staying within the 1.5°C temperature rise, or for loss and damage and climate justice.

Our expert panel discusses the summit’s overall success and impact on delivering in key areas: climate finance, mitigation, adaptation, loss and damage, nature and biodiversity and the just transition.

This event is part of the Waddesdon Club Webinar Series. The Waddesdon Club is a Chatham House initiative to encourage climate leadership in financial and economic policymaking. Since 2016, it has proved a highly successful forum for convening senior policymakers and leading climate scientists with future leaders in finance ministries, central banks and other public sector economic and financial organizations from around the world.

The initiative is supported by Ikea Foundation, KR Foundation and the Rothschild Foundation.

Duterte’s Victory Is Cry for Help From Those Left Behind in Philippines Expert comment sysadmin 12 May 2016

But large support for mainstream parties and a mature democratic system should keep the country from slipping back towards authoritarianism.

The victory of political outsider Rodrigo Duterte in the 2016 Philippines’ elections is proof that a significant minority of the country’s population feels left behind by its recent economic success and estranged from its political elite. However the results of the elections as a whole suggest that most voters opted for a continuation of the current government’s policies.

Duterte looks almost certain to be inaugurated as the next president of the Philippines on 30 June. The country’s presidential voting system – a single round, first-past-the-post election – delivered victory to a populist outsider with 39 per cent support. Two candidates advocating a continuation of the current government’s policies − the Liberal Party’s Mar Roxas and independent Grace Poe − polled a combined 45 per cent. The long-standing factionalism within Philippines elite politics split the ‘anti-Duterte’ vote.

Changing the conversation

The contrast between Duterte and Roxas could hardly be greater. Mar Roxas is the grandson of the first president of an independent Philippines, a graduate of Wharton Business School and a former investment banker in the US. Rodrigo Duterte is a political outsider with an electoral base geographically almost as far from Manila as is possible to get in the Philippines: the city of Davao on the island of Mindanao.

The story of Duterte’s victory is the story of how ‘Duterte managed to change the national conversation from poverty towards crime and corruption,’ says Marites Vitug, editor-at-large of one of the Philippines’ most popular online news sites, Rappler. In January, Duterte was running fourth in opinion polls but a strategy that positioned him as the only opponent to the Manila elite gave him victory. This is the first time a provincial official has made it to the top job.

The headline figures tell us that the Philippines’ economy has done very well under President Benigno Aquino. Between 2010 and 2014, growth averaged 6.3 per cent per year. That fell to a still-impressive 5.8 per cent last year but is expected to pick up this year and next, according to the Asian Development Bank. Growth in agriculture, however, is significantly slower and rural areas feel left behind. While economic growth is benefiting the majority, inequality is worsening and resentment rising in poor villages. The contrast between the metropolitan sophistication of the Makati district in Manila and life in faraway provinces such as Duterte’s Mindanao is widening.

Ironically the Philippines’ economic success is a part of the explanation for the defeat of the ‘mainstream’ presidential candidates. Crime and corruption may have become more important issues simply because more voters have become better off and therefore more likely to be concerned about crime and corruption than before. It’s also undeniable that Duterte has a record for getting things done. Human rights groups rightly criticize his (at best) tolerance of the extra-judicial killing of alleged criminals but his repeated re-election as mayor demonstrates that many citizens are prepared to accept that in exchange for improved personal security. A surprising number of Manila residents have actually moved to Davao because of its better quality of life.

Traditional power bases

However, the results as a whole suggest a narrow majority in favour of current policies. In the vice-presidential race, the Liberal Party candidate Leni Robredo is narrowly ahead of Ferdinand ‘Bongbong’ Marcos, the son of the eponymous former president. Like Duterte she is regarded as a successful mayor of a well-run city, Albay. Duterte’s running mate Alan Cayetano received just 14 per cent of the vote.

In the senate election, Liberals won five of the 12 seats being contested, with a party- backed independent winning a sixth. The opposition, even with boxing champion and national idol Manny Pacquiao running for the United Nationalist Alliance, won four.

Taken as a whole, the results show the enduring nature of traditional Philippines power bases. The country’s many islands and distinct linguistic and cultural regions are virtual fiefs in which families and big bosses can wield almost total power through control of local authorities, businesses, the courts and security forces.

Threat to democracy?

It’s easy to forget that the election of Ferdinand Marcos in 1965 was originally welcomed as a challenge to the traditional elites of Philippine politics. The same accolades are currently greeting Duterte. Could they presage a return to the Philippines’ bad old days?

This seems less likely. Philippine democracy has matured considerably since Marcos declared martial law in 1972. There is a substantial, and vocal, middle class with experience of mobilizing against ‘bad’ presidents. There will also be pressures from international investors and the Philippines’ treaty ally, the United States, for better governance.

The Philippines will chair the Association of Southeast Asian Nations next year. That will put Duterte in the international spotlight as host of several international meetings – including the East Asia Summit attended by, among others, the presidents of China, Russia and the US. Since his victory Duterte has promised to act with decorum in office and declared that his election campaign antics were just a ploy to attract attention. Some leaders in Southeast Asia will use his victory to buttress their arguments against allowing their people to freely vote. It’s up to Duterte to decide whether he wants to be an advertisement for – or an argument against – democracy.

To comment on this article, please contact Chatham House Feedback

Artificial Intelligence Apps Risk Entrenching India’s Socio-economic Inequities Expert comment sysadmin 14 March 2018

Artificial intelligence applications will not be a panacea for addressing India’s grand challenges. Data bias and unequal access to technology gains will entrench existing socio-economic fissures.

Artificial intelligence (AI) is high on the Indian government’s agenda. Some days ago, Prime Minister Narendra Modi inaugurated the Wadhwani Institute for Artificial Intelligence, reportedly India’s first research institute focused on AI solutions for social good. In the same week, Niti Aayog CEO Amitabh Kant argued that AI could potentially add $957 billion to the economy and outlined ways in which AI could be a ‘game changer’.

During his budget speech, Finance Minister Arun Jaitley announced that Niti Aayog would spearhead a national programme on AI; with the near doubling of the Digital India budget, the IT ministry also announced the setting up of four committees for AI-related research. An industrial policy for AI is also in the pipeline, expected to provide incentives to businesses for creating a globally competitive Indian AI industry.

Narratives on the emerging digital economy often suffer from technological determinism — assuming that the march of technological transformation has an inner logic, independent of social choice and capable of automatically delivering positive social change. However, technological trajectories can and must be steered by social choice and aligned with societal objectives. Modi’s address hit all the right notes, as he argued that the ‘road ahead for AI depends on and will be driven by human intentions’. Emphasising the need to direct AI technologies towards solutions for the poor, he called upon students and teachers to identify ‘the grand challenges facing India’ – to ‘Make AI in India and for India’.

To do so, will undoubtedly require substantial investments in R&D, digital infrastructure and education and re-skilling. But, two other critical issues must be simultaneously addressed: data bias and access to technology gains.

While computers have been mimicking human intelligence for some decades now, a massive increase in computational power and the quantity of available data are enabling a process of ‘machine learning.’ Instead of coding software with specific instructions to accomplish a set task, machine learning involves training an algorithm on large quantities of data to enable it to self-learn; refining and improving its results through multiple iterations of the same task. The quality of data sets used to train machines is thus a critical concern in building AI applications.

Much recent research shows that applications based on machine learning reflect existing social biases and prejudice. Such bias can occur if the data set the algorithm is trained on is unrepresentative of the reality it seeks to represent. If for example, a system is trained on photos of people that are predominantly white, it will have a harder time recognizing non-white people. This is what led a recent Google application to tag black people as gorillas.

Alternatively, bias can also occur if the data set itself reflects existing discriminatory or exclusionary practices. A recent study by ProPublica found for example that software that was being used to assess the risk of recidivism in criminals in the United States was twice as likely to mistakenly flag black defendants as being at higher risk of committing future crimes.

The impact of such data bias can be seriously damaging in India, particularly at a time of growing social fragmentation. It can contribute to the entrenchment of social bias and discriminatory practices, while rendering both invisible and pervasive the processes through which discrimination occurs. Women are 34 per cent less likely to own a mobile phone than men – manifested in only 14 per cent of women in rural India owning a mobile phone, while only 30 per cent of India’s internet users are women.

Women’s participation in the labour force, currently at around 27 per cent, is also declining, and is one of the lowest in South Asia. Data sets used for machine learning are thus likely to have a marked gender bias. The same observations are likely to hold true for other marginalized groups as well.

Accorded to a 2014 report, Muslims, Dalits and tribals make up 53 per cent of all prisoners in India; National Crime Records Bureau data from 2016 shows in some states, the percentage of Muslims in the incarcerated population was almost three times the percentage of Muslims in the overall population. If AI applications for law and order are built on this data, it is not unlikely that it will be prejudiced against these groups.

(It is worth pointing out that the recently set-up national AI task force is comprised of mostly Hindu men – only two women are on the task force, and no Muslims or Christians. A recent article in the New York Times talked about AI’s ‘white guy problem’; will India suffer from a ‘Hindu male bias’?)

Yet, improving the quality, or diversity, of data sets may not be able to solve the problem. The processes of machine learning and reasoning involve a quagmire of mathematical functions, variables and permutations, the logic of which are not readily traceable or predictable. The dazzle of AI-enabled efficiency gains must not blind us to the fact that while AI systems are being integrated into key socio-economic systems, their accuracy and logic of reasoning have not been fully understood or studied.

The other big challenge stems from the distribution of AI-led technology gains. Even if estimates of AI contribution to GDP are correct, the adoption of these technologies is likely to be in niches within the organized sector. These industries are likely to be capital- rather than labour-intensive, and thus unlikely to contribute to large-scale job creation.

At the same time, AI applications can most readily replace low- to medium-skilled jobs within the organized sector. This is already being witnessed in the outsourcing sector – where basic call and chat tasks are now automated. Re-skilling will be important, but it is unlikely that those who lose their jobs will also be those who are being re-skilled – the long arch of technological change and societal adaptation is longer than that of people’s lives. The contractualization of work, already on the rise, is likely to further increase as large industries prefer to have a flexible workforce to adapt to technological change. A shift from formal employment to contractual work can imply a loss of access to formal social protection mechanisms, increasing the precariousness of work for workers.

The adoption of AI technologies is also unlikely in the short- to medium-term in the unorganized sector, which engages more than 80 per cent of India’s labor force. The cost of developing and deploying AI applications, particularly in relation to the cost of labour, will inhibit adoption. Moreover, most enterprises within the unorganized sector still have limited access to basic, older technologies – two-thirds of the workforce are employed in enterprises without electricity. Eco-system upgrades will be important but incremental. Given the high costs of developing AI-based applications, most start-ups are unlikely to be working towards creating bottom-of-the-pyramid solutions.

Access to AI-led technology gains is thus likely to be heavily differentiated – a few high-growth industries can be expected, but these will not necessarily result in the welfare of labour. Studies show that labour share of national income, especially routine labour, has been declining steadily across developing countries.

We should be clear that new technological applications themselves are not going to transform or disrupt this trend – rather, without adequate policy steering, these trends will be exacerbated.

Policy debates about AI applications in India need to take these two issues seriously. AI applications will not be a panacea for addressing ‘India’s grand challenges’. Data bias and unequal access to technology gains will entrench existing socio-economic fissures, even making them technologically binding.

In addition to developing AI applications and creating a skilled workforce, the government needs to prioritize research that examines the complex social, ethical and governance challenges associated with the spread of AI-driven technologies. Blind technological optimism might entrench rather than alleviate the grand Indian challenge of inequity and growth.

This article was originally published in the Indian Express.

Rethinking European and Afghan policy approaches to migration 9 February 2021 — 12:30PM TO 1:30PM Anonymous (not verified) 19 January 2021 Online

Speakers argue for a more multidimensional approach to migration, and for a nuanced reassessment of policy.

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

Afghanistan is a key country of origin for asylum seekers in Europe, and the prime global recipient of EU development assistance. It was one of the first nations to conclude a migration partnership agreement with the EU, in 2016.

Implementation has been thwarted, however, by war and violence, limited state capacity, entrenched economic deprivation, internal displacement and the unfolding impact of COVID-19.

The speakers argue for a more multidimensional approach to migration, and for a nuanced reassessment of policy. They underscore the strength of Afghanistan’s responses to migration, returns, reintegration, security and peace, and point to the need for synchronizing the EU’s policy approaches.

They argue that effective policy must consider the historical significance of mobility for Afghanistan and the need for coherent regional responses to migration.

This event launches the publication The EU and the Politics of Migration Management in Afghanistan.

Martin Ehler and Karlheinz Gröchenig
Math. Comp. 93 (), 2885-2919.
Abstract, references and article information

Haiyong Wang
Math. Comp. 93 (), 2861-2884.
Abstract, references and article information

Katherine Baker, Lehel Banjai and Mariya Ptashnyk
Math. Comp. 93 (), 2711-2743.
Abstract, references and article information

T. De Ryck and S. Mishra
Math. Comp. 93 (), 2643-2677.
Abstract, references and article information

Stacey Finley from University of Southern California discusses how mathematical models support the research of cancer biology. Cancer research is a crucial job, but a difficult one. Tumors growing inside the human body are affected by all kinds of factors. These conditions are difficult (if not impossible) to recreate in the lab, and using real patients as subjects can be painful and invasive. Mathematical models give cancer researchers the ability to run experiments virtually, testing the effects of any number of factors on tumor growth and other processes — all with far less money and time than an experiment on human subjects or in the lab would use.

Dr. Outi Tervo of Greenland Institute for Natural Resources, shares how mathematics helps recommend speed limits for marine vessels, which benefits narwhals and Inuit culture. Narwhals "can only be found in the Arctic," said Outi Tervo, a senior scientist at GINR. "These species are going to be threatened by climate change more than other species that can live in a bigger geographical area." The collaboration has already lobbied on behalf of the narwhals to reduce the level of sea traffic in their habitat, after using mathematical analysis to identify how noise from passing boats changes the narwhals' foraging behavior.

Yinji Li, Zhiwei Wang and Xiangyu Zhou
Trans. Amer. Math. Soc. 377 (), 5947-5992.
Abstract, references and article information

Christoforos Neofytidis
Trans. Amer. Math. Soc. 377 (), 5289-5321.
Abstract, references and article information

Ta Cong Son, Tran Manh Cuong, Le Quang Dung and Le Van Dung
Theor. Probability and Math. Statist. 111 (), 153-165.
Abstract, references and article information

T. A. Suslina
St. Petersburg Math. J. 35 (), 537-570.
Abstract, references and article information

Alin Bostan, Xavier Caruso and Julien Roques
Bull. Amer. Math. Soc. 61 (), 609-658.
Abstract, references and article information

When using the distinct count function in SAS Visual Analytics reports, you might find that a negative value is displayed instead of the actual distinct count: imgalt="distinct_count" src="{fusion_66562_1_disti

Broad-specificity glycoside hydrolases (GHs) contribute to plant biomass hydrolysis by degrading a diverse range of polysaccharides, making them useful catalysts for renewable energy and biocommodity production. Discovery of new GHs with improved kinetic parameters or more tolerant substrate-binding sites could increase the efficiency of renewable bioenergy production even further. GH5 has over 50 subfamilies exhibiting selectivities for reaction with β-(1,4)–linked oligo- and polysaccharides. Among these, subfamily 4 (GH5_4) contains numerous broad-selectivity endoglucanases that hydrolyze cellulose, xyloglucan, and mixed-linkage glucans. We previously surveyed the whole subfamily and found over 100 new broad-specificity endoglucanases, although the structural origins of broad specificity remained unclear. A mechanistic understanding of GH5_4 substrate specificity would help inform the best protein design strategies and the most appropriate industrial application of broad-specificity endoglucanases. Here we report structures of 10 new GH5_4 enzymes from cellulolytic microbes and characterize their substrate selectivity using normalized reducing sugar assays and MS. We found that GH5_4 enzymes have the highest catalytic efficiency for hydrolysis of xyloglucan, glucomannan, and soluble β-glucans, with opportunistic secondary reactions on cellulose, mannan, and xylan. The positions of key aromatic residues determine the overall reaction rate and breadth of substrate tolerance, and they contribute to differences in oligosaccharide cleavage patterns. Our new composite model identifies several critical structural features that confer broad specificity and may be readily engineered into existing industrial enzymes. We demonstrate that GH5_4 endoglucanases can have broad specificity without sacrificing high activity, making them a valuable addition to the biomass deconstruction toolset.

Intrinsically disordered protein domains often have multiple binding partners. It is plausible that the strength of pairing with specific partners evolves from an initial low affinity to a higher affinity. However, little is known about the molecular changes in the binding mechanism that would facilitate such a transition. We previously showed that the interaction between two intrinsically disordered domains, NCBD and CID, likely emerged in an ancestral deuterostome organism as a low-affinity interaction that subsequently evolved into a higher-affinity interaction before the radiation of modern vertebrate groups. Here we map native contacts in the transition states of the low-affinity ancestral and high-affinity human NCBD/CID interactions. We show that the coupled binding and folding mechanism is overall similar but with a higher degree of native hydrophobic contact formation in the transition state of the ancestral complex and more heterogeneous transient interactions, including electrostatic pairings, and an increased disorder for the human complex. Adaptation to new binding partners may be facilitated by this ability to exploit multiple alternative transient interactions while retaining the overall binding and folding pathway.

Abnormal changes of neuronal Tau protein, such as phosphorylation and aggregation, are considered hallmarks of cognitive deficits in Alzheimer's disease. Abnormal phosphorylation is thought to precede aggregation and therefore to promote aggregation, but the nature and extent of phosphorylation remain ill-defined. Tau contains ∼85 potential phosphorylation sites, which can be phosphorylated by various kinases because the unfolded structure of Tau makes them accessible. However, methodological limitations (e.g. in MS of phosphopeptides, or antibodies against phosphoepitopes) led to conflicting results regarding the extent of Tau phosphorylation in cells. Here we present results from a new approach based on native MS of intact Tau expressed in eukaryotic cells (Sf9). The extent of phosphorylation is heterogeneous, up to ∼20 phosphates per molecule distributed over 51 sites. The medium phosphorylated fraction Pm showed overall occupancies of ∼8 Pi (± 5) with a bell-shaped distribution; the highly phosphorylated fraction Ph had 14 Pi (± 6). The distribution of sites was highly asymmetric (with 71% of all P-sites in the C-terminal half of Tau). All sites were on Ser or Thr residues, but none were on Tyr. Other known posttranslational modifications were near or below our detection limit (e.g. acetylation, ubiquitination). These findings suggest that normal cellular Tau shows a remarkably high extent of phosphorylation, whereas other modifications are nearly absent. This implies that abnormal phosphorylations at certain sites may not affect the extent of phosphorylation significantly and do not represent hyperphosphorylation. By implication, the pathological aggregation of Tau is not likely a consequence of high phosphorylation.

1 July 2020

18 August 2020

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

Methionine, through S-adenosylmethionine, activates a multifaceted growth program in which ribosome biogenesis, carbon metabolism, and amino acid and nucleotide biosynthesis are induced. This growth program requires the activity of the Gcn4 transcription factor (called ATF4 in mammals), which facilitates the supply of metabolic precursors that are essential for anabolism. However, how Gcn4 itself is regulated in the presence of methionine is unknown. Here, we discover that Gcn4 protein levels are increased by methionine, despite conditions of high cell growth and translation (in which the roles of Gcn4 are not well-studied). We demonstrate that this mechanism of Gcn4 induction is independent of transcription, as well as the conventional Gcn2/eIF2α-mediated increased translation of Gcn4. Instead, when methionine is abundant, Gcn4 phosphorylation is decreased, which reduces its ubiquitination and therefore degradation. Gcn4 is dephosphorylated by the protein phosphatase 2A (PP2A); our data show that when methionine is abundant, the conserved methyltransferase Ppm1 methylates and alters the activity of the catalytic subunit of PP2A, shifting the balance of Gcn4 toward a dephosphorylated, stable state. The absence of Ppm1 or the loss of the PP2A methylation destabilizes Gcn4 even when methionine is abundant, leading to collapse of the Gcn4-dependent anabolic program. These findings reveal a novel, methionine-dependent signaling and regulatory axis. Here methionine directs the conserved methyltransferase Ppm1 via its target phosphatase PP2A to selectively stabilize Gcn4. Through this, cells conditionally modify a major phosphatase to stabilize a metabolic master regulator and drive anabolism.

Africa Aware: Supply chains, land contestation, conflict Audio NCapeling 30 March 2023

This episode examines relations between Ethiopia and Sudan as part of an XCEPT project mini-series.

The war in northern Ethiopia since November 2020, and subsequent conquest of disputed farmlands in Al-Fashaga by the Sudanese army on the Ethiopia-Sudan border, has brought into focus the importance of agricultural commodities such as sesame as a potential driver of land contestation and conflict. 

The panel discusses the interrelation of commodity and conflict supply chains, land contestation, and boundary disputes in the Horn of Africa, with a particular focus on the regions of Wolkait/Western Tigray in northwest Ethiopia and Al Fashaga in eastern Sudan.

This podcast was produced with support from the Cross-Border Conflict Evidence, Policy and Trends (XCEPT) project, funded by UK Aid from the UK government.

On October 24 and 25, SophosAI presents ideas on how to use models large and small—and defend against malignant ones.

Alba Simats
Dec 1, 2020; 19:1921-1935
Research

Ji Eun Kim
Dec 20, 2020; 0:RA120.002159v1-mcp.RA120.002159
Research

Yi Liu
Dec 1, 2020; 19:1968-1985
Research

Sylwia Struk
Dec 28, 2020; 0:RA119.001766v1-mcp.RA119.001766
Research

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

Alison B. Ross
Nov 30, 2020; 0:R120.002190v1-mcp.R120.002190
Review

Congcong Lu
Nov 17, 2020; 0:R120.002257v1-mcp.R120.002257
Review

Diana Samodova
Dec 1, 2020; 19:2139-2156
Technological Innovation and Resources