A. V. Domrina
Trans. Moscow Math. Soc. 83 (), 201-215.
Abstract, references and article information

A. Kh. Khachatryan, Kh. A. Khachatryan and A. Zh. Narimanyan
Trans. Moscow Math. Soc. 83 (), 183-200.
Abstract, references and article information

Realizing the Potential of Extractives for Industrial and Economic Development 18 October 2018 — 5:30PM TO 7:00PM Anonymous (not verified) 3 October 2018 Chatham House | 10 St James's Square | London | SW1Y 4LE

Over the past two decades, the extractives industries have risen in importance for many low- and middle- income countries their prospects for economic development and poverty reduction. During a period of rising commodities prices, the development of extractives became increasingly attractive to both governments and companies. There was - and remains - much discussion about their potential to support inclusive development.

However, there are also risks and uncertainties associated with the extractives industries and many things can, and do, go wrong. Fluctuations in commodity prices can be hard to manage and can lead to considerable fiscal pressures. In the longer-term, climate change and the various policy responses to this, will profoundly affect the extractives sector as renewables replace fossil fuels in the global energy mix.

Managing the extractives sectors will therefore remain highly challenging especially in low-income countries where institutions are often weak. This roundtable will bring together some of the foremost academics and practitioners working in the extractives industries and also in economic development to discuss a major new UNU-WIDER study Extractive Industries: The Management of Resources as a Driver of Sustainable Development.

Attendance at this event is by invitation only.

Plant-based 'Meat' and Cultured Meat: Revolutionizing the Livestock Sector 10 April 2019 — 4:00PM TO 5:30PM Anonymous (not verified) 14 March 2019 Chatham House | 10 St James's Square | London | SW1Y 4LE

Consensus is building across the scientific, environmental and public health communities that a radical shift away from excessive meat-eating patterns is urgently needed to tackle the unsustainability of the livestock sector. Recognizing the scale of the challenge ahead, public policymakers, civil society and innovators have increasingly sought to prompt shifts in consumer food choices – away from the most resource-intensive meat products and towards more sustainable alternatives.

Meat analogues – plant-based ‘meat’ and cultured meat also known as ‘lab-grown’ meat – mark a departure from traditional meat alternatives. Both are intended to be indistinguishable from – and in the case of cultured meat biologically equivalent to – animal-derived meat and are marketed principally at meat-eaters. Innovation and investment in meat analogues have increased significantly, but the direction and pace of growth in the meat analogue industry will depend upon a multitude of factors, including public acceptance, civil society support and incumbent industry responses.

This event will explore the challenges of scaling up production and generating demand for meat alternatives. It will also look at the ways policymakers in the UK and EU can impact the direction of the industry while examining what factors will influence consumer acceptance of plant-based ‘meat’ and cultured meat as substitutes for animal-derived meat.

Driven to Extraction: Can Sand Mining be Sustainable? 5 June 2019 — 1:30PM TO 3:00PM Anonymous (not verified) 29 April 2019 Chatham House | 10 St James's Square | London | SW1Y 4LE

A deep dive into loss and damage solutions 8 February 2022 — 1:00PM TO 2:15PM Anonymous (not verified) 31 January 2022 Online

This second event of our loss and damage series cuts through polarized debate by bringing together international experts to discuss innovative legal and financial approaches.

This event will focus on a deep dive into constructive solutions and progress made to address loss and damage.

Following the first event of this two-part series, ‘Loss and Damage – where are we now and what happens next’, this event focuses on a deep dive into constructive solutions and progress made to address loss and damage.

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 second event convenes a deep dive into the progress and potential on loss and damage solutions, while also examining the hurdles that are still to overcome to make loss and damage support a reality.

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.

What to Know About Hong Kong’s Chief Executive Election Expert comment sysadmin 27 March 2017

Tim Summers looks at what we know about Carrie Lam, the territory’s new leader, and where Hong Kong politics goes from here.

Carrie Lam, formerly number two in the Hong Kong government, was selected as the Special Administrative Region’s new chief executive on 26 March. What does the process and her selection say about Hong Kong’s political future?

1. Elections for Hong Kong’s top job are still within Beijing’s control. Due to the failure of political reform proposals in 2015, Lam was elected on the basis of 777 votes from the 1,194 members of the Chief Executive Election Committee. This ‘small-circle’ process was essentially the same as that used since 1997 (the only change being the expansion of the committee from its initial size of 800). The design of the process favours Beijing, and indeed Lam was the favoured candidate of the central government and many of its supporters in Hong Kong.
2. But the influence of the central government has limits. The second-ranked candidate, former finance minister John Tsang (365 votes), had not been encouraged to stand by Beijing, and a fourth candidate, Regina Ip (who did not obtain enough nominations to join the vote), reportedly also rejected suggestions from Beijing that she should not put herself forward. The Committee itself contained 325 individuals affiliated to or sympathetic to opposition parties and around 100 establishment figures who did not support Lam – most of whom voted for Tsang. Although Lam gained more votes than her predecessor, CY Leung, in 2012 (he obtained 689 votes after a controversial campaign when scandals undermined his main opponent), Beijing appears to have expended substantial political capital in securing her victory.
3. Despite the closed process, public opinion matters. The campaign saw all the candidates actively seek not only the votes of committee members, but also wider popular support. This highlights the need for broader legitimacy, and the fact that public participation and media debate are central factors in Hong Kong’s open political culture. A number of opinion polls showed Lam to have notably lower levels of popular support than Tsang. This will constrain her ability to govern effectively and she will not be cut much slack by the Hong Kong population. There were protests at the election venue calling for ‘genuine universal suffrage’.
4. The new chief executive is an economic interventionist. The two main candidates – Lam and Tsang – have different policy approaches. Tsang’s was a more liberal ‘laissez faire’ one. Lam is likely to continue the somewhat more interventionist approach of CY Leung, who intervened more than previous governments to try to stabilize property prices and make more land available for housing, as well as reinstating policies targeting poverty and agreeing measures to limit the social impact of rising numbers of visitors and money from mainland China.
5. Political reform seems very far off. The third candidate, former judge Woo Kwok-hing, had the clearest position on the thorny issue of political reform. Many of the government’s critics see less prospect for progress here under Lam, who fronted the government’s consultation processes during the 2013–15 debates over political reform. Lam gave some conflicting signals during the campaign, and it remains to be seen whether she tries to restart the process. But given rising populism, the growing fragmentation and polarization of Hong Kong politics, and entrenched positions from both Beijing and the opposition, it will be even more difficult to obtain consensus on a way forward than when the last failed attempt at reform took place – a key indicator will be whether all political parties are willing to discuss compromises.
6. July’s anniversary will be contentious. Following formal appointment by the central government, Lam’s term will begin on 1 July. This will also mark the 20th anniversary of the handover of Hong Kong to Chinese sovereignty in 1997, which will coincide with a planned visit by President Xi Jinping. This will no doubt spark protests; for many, the 20th anniversary of the handover will therefore be less a time for celebration than an opportunity for many to highlight concerns about the future of the former British colony.

Putting the Hong Kong Crisis into Historical and Comparative Perspective 14 November 2019 — 8:30AM TO 9:30AM Anonymous (not verified) 17 October 2019 Chatham House | 10 St James's Square | London | SW1Y 4LE

This roundtable will focus on current events unfolding in Hong Kong, where the territory has been convulsed with protests for several months.

The speakers will examine how class, race and poverty play into the conflict. Taking a comparative approach, they will examine the generational divide, looking at the ideological gulf between the older, more conservative and pro-Beijing population versus the younger, more pro-democracy protesters. The discussion will also draw upon the erosion of trust between police and the wider public.

While acknowledging the unique features of this wave of unrest, the speakers will draw parallels, placing the current crisis in Hong Kong beside events that have occurred in other periods and other places.

Parallels to be explored include those with Shanghai struggles of the 1910s through 1980s and upheavals and crackdowns in the former Soviet bloc during the Cold War.

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

Pierre Lairez, Eric Pichon-Pharabod and Pierre Vanhove
Math. Comp. 93 (), 2985-3025.
Abstract, references and article information

Ran Gu and Bing Gao
Math. Comp. 93 (), 2837-2860.
Abstract, references and article information

Tsz-Kiu Aaron Chow and Yangyang Li
Trans. Amer. Math. Soc. 377 (), 5993-6020.
Abstract, references and article information

Ning Jiang, Yi-Long Luo and Shaojun Tang
Trans. Amer. Math. Soc. 377 (), 5323-5359.
Abstract, references and article information

Simone Cecchini and Rudolf Zeidler
Trans. Amer. Math. Soc. 377 (), 5271-5288.
Abstract, references and article information

Abdessamad Dehaj and Mohamed Guessous
Theor. Probability and Math. Statist. 111 (), 1-8.
Abstract, references and article information

Luiz Ricardo Abreu Melo
Proc. Amer. Math. Soc. 152 (), 5373-5380.
Abstract, references and article information

Bo Shan Deval, Xabier García-Martínez and Tim Van der Linden
Proc. Amer. Math. Soc. 152 (), 5039-5053.
Abstract, references and article information

Ana Caraiani, Royal Society University Research Fellow and professor of pure mathematics, Imperial College London, has been awarded the 2025 Ruth Lyttle Satter Prize in Mathematics by the American Mathematical Society (AMS). She has been honored for contributions to arithmetic geometry and number theory: in particular, the Langlands program.

From the citation

Ana Caraiani’s work is characterized by a combination of novel ideas and a fearlessness in the face of technical obstacles that would daunt almost any other researcher. This has enabled her to prove several fundamental theorems in the Langlands program.

In the joint paper with Scholze, titled “On the generic part of the cohomology of non-compact unitary Shimura varieties” (Annals of Math., 2024), Caraiani proved very general results about the torsion cohomology classes in non-compact Shimura varieties, strengthening the early results in their 2017 paper in the compact case. The proof is a tour de force, combining perfectoid spaces, a mastery of the trace formula, and a new theory of perverse sheaves in p-adic geometry. These results are of intrinsic interest (for example, they give the first indications of a characteristic p version of Arthur’s conjectures), but they also have many applications throughout the Langlands program. One spectacular application of these results is in her joint paper, “Potential automorphy over CM fields” (with Allen, Calegari, Gee, Helm, Le Hung, Newton, Scholze, Taylor, and Thorne, Annals of Math., 2023), which among other results proves the Ramanujan conjecture for Bianchi modular forms, a problem that had been thought of as being completely out of reach.

The Ramanujan conjecture is of analytic nature, asserting a bound on the eigenvalue of a certain differential operator, but the only way in which cases of it have been proved is via algebraic geometry. In particular, the original Ramanujan conjecture for modular forms was proved by Deligne in the 1970s, as a consequence of his proof of the Weil conjectures. However, in the case of Bianchi modular forms there is no direct relationship with algebraic geometry, and it seems to be impossible to make any direct deductions from the Weil conjectures. Langlands (also in the 1970s) suggested a strategy for proving the Ramanujan conjecture as a consequence of his functoriality conjecture. Caraiani and her coauthors’ proof of the Ramanujan conjecture for Bianchi modular forms proceeds via a variant of Langlands’ strategy, and in particular does not use the Weil conjectures.

Most recently with James Newton, in the paper “On the modularity of elliptic curves over imaginary quadratic fields” (arXiv: 2301.10509), Caraiani has improved upon these results and applied them to the modularity of elliptic curves over imaginary quadratic fields. They come close to completely solving it, with only a small number of exceptions (which constitute 0% of cases).

Response of Ana Caraiani

First, I would like to thank Joan Birman and the AMS for establishing an award that recognizes research contributions by women mathematicians. This is particularly meaningful to me because I looked to many of the previous recipients of the Satter Prize for inspiration at challenging moments in my career. It is a great honour to be selected as a recipient!

I am indebted to my many collaborators, mentors and colleagues who have generously shared their mathematical ideas with me over the years and supported me in different but crucial ways. Special thanks go to Peter Scholze for the wonderful opportunity to collaborate with him on understanding a part of the geometry and cohomology of Shimura varieties, to Richard Taylor for initiating the "ten author" collaboration, which was much more successful than we had originally expected, and to James Newton for our joyful exploration of elliptic curves over imaginary quadratic fields. I also particularly want to acknowledge Jessica Fintzen and Toby Gee for their longstanding friendship and moral support.

Finally, I want to thank my family, especially my husband, Steven, my mother, Zoe, and my daughter, Nadia.

Biographical sketch of Ana Caraiani

Ana Caraiani was born in Bucharest, Romania, in 1984. She received a bachelor's degree in mathematics from Princeton University in 2007 and completed her PhD at Harvard University in 2012. After temporary positions at the University of Chicago, Princeton and the Institute for Advanced Study (IAS), and the University of Bonn, she moved to Imperial College London in 2017, where she is currently a Royal Society University Research Fellow and Professor of Pure Mathematics. She is a Fellow of the AMS, a recipient of an EMS Prize and a New Horizons Prize in Mathematics and was an invited speaker at the 2022 ICM. 

About the prize

Awarded every two years, the Ruth Lyttle Satter Prize in Mathematics recognizes an outstanding contribution to mathematics research by a woman in the previous six years. The prize was established by Joan Birman in honor of her sister, Ruth. The 2025 prize will be recognized during the 2025 Joint Mathematics Meetings in January in Seattle.

Read more and see the list of past recipients.

Contact: AMS Communications

* * * * *

The American Mathematical Society is dedicated to advancing research and connecting the diverse global mathematical community through our publications, meetings and conferences, MathSciNet, professional services, advocacy, and awareness programs.

Kenta Suzuki of the Massachusetts Institute of Technology (MIT) is awarded the 2025 American Mathematical Society (AMS)-Mathematical Association of America (MAA)-Society for Industrial and Applied Mathematics (SIAM) Frank and Brennie Morgan Prize for his extraordinary research in the representation theory of $p$-adic groups. His papers, including two solo works, represent significant progress in different areas of the field.

From the citation

Suzuki worked on deep problems in representation theory, and he has authored and coauthored six research papers. In particular, he has made important contributions to the representation theory of $p$-adic groups. His results include asymptotics for the dimension of spaces fixed by a congruence subgroup in an admissible representation of $GL(n).$ His joint works include working out the local Langlands correspondence for several rank two $p$-adic groups, and the determination of canonical bases in the subregular quotient of the affine Hecke algebra and its antispherical module, along with their “coherent” categorifications.

Response of Kenta Suzuki

It is an honor for me to receive the Frank and Brennie Morgan Prize. I thank the Morgan family and the AMS, MAA, and SIAM for their generosity. I thank my mentors throughout the years, Toshihiko Nakazawa, Li Li, Michael Zieve, and Colin Hinde, for kindling my interest in mathematics. Toshihiko Nakazawa patiently explored mathematics with me from a young age and continues to inspire me with his insights. I thank Roman Bezrukavnikov, Wei Zhang, Zhiwei Yun, Ivan Losev, Vasily Krylov, and Calder Morton-Ferguson for further stimulating my interest in mathematics at MIT and introducing me to the many wonders of representation theory. Wei Zhang’s unwavering support has motivated me to explore many areas of mathematics. I leave every conversation with Roman Bezrukavnikov with new ideas, and he has helped me grow as a researcher by encouraging me to pursue even my most ambitious ideas. The mathematical community at MIT and Harvard have been supportive and taught me so much, both mathematical and nonmathematical. Finally, I thank my parents, particularly my mother, for supporting me throughout my journey in every possible way. She has been my role model and is one of the most intelligent and charismatic people I know.

Biographical sketch of Kenta Suzuki

Kenta Suzuki is a fourth-year undergraduate at MIT from Tokyo, Japan, and Plymouth, Michigan. Suzuki’s work focuses on the representation theory of $p$-adic groups and geometric representation theory. Suzuki is particularly interested in applying geometric methods to solve problems of representation theory. In his free time, he runs, reads, and is (slowly) learning how to cook.

About the prize

The AMS-MAA-SIAM Frank and Brennie Morgan Prize for Outstanding Research in Mathematics by an Undergraduate Student is awarded annually to an undergraduate (or students for joint work) for outstanding research in mathematics. The prize recipient's research can include more than one paper, however, the paper or papers to be considered for the prize must be completed while the student is an undergraduate. Publication of research is not required.

Established in 1995, the prize is entirely endowed by a gift from Mrs. Frank (Brennie) Morgan. The current prize amount is $1,200.

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

Learn more about the prize and previous recipients.

Contact: AMS Communications

*****

The American Mathematical Society is dedicated to advancing research and connecting the diverse global mathematical community through our publications, meetings and conferences, MathSciNet, professional services, advocacy, and awareness programs.

Forty-six mathematical scientists have been named recipients of AMS-Simons Research Enhancement Grants for Primarily Undergraduate Institution (PUI) Faculty. Each awardee will receive $3,000 per year for three years. 

The grants foster and support research collaboration by full-time mid-career mathematicians at US institutions that do not offer a mathematics doctoral degree.

This year’s grant recipients hail from 42 institutions across 21 US states. The grants will support their research in several different areas, from number theory to applied mathematics.

This is the grant program’s second cohort, said Sarah Bryant, associate vice president of programs. “Over the first two years, we’ve worked with faculty from 75 different institutions, including 19 minority-serving institutions, which shows just how much this program is expanding and making an impact,” Bryant said. She noted that “in the first year, the grants supported 87 trips, helped produce 70 publications and preprints, and gave awardees the resources needed to collaborate and advance their work.”

The grant allows for any activities that will further the awardee’s research program. Expenses include but are not limited to conference participation, institute visits, collaboration travel (awardee or collaborator), computer equipment or software, family-care expenses, and teaching assistants.

Administration of the award by the grantee’s institution is required; annual discretionary funds for a grantee’s department and administrative funds for a grantee's institution will be available at the end of each grant year.

The grants are made possible through funding from the Simons Foundation and the American Mathematical Society (AMS), as well as Eve, Kirsten, Lenore, and Ada of the Menger family.

Applications for the next cohort are anticipated to open on MathPrograms.org on January 9, 2025. Visit the AMS website to view an informational PowerPoint or sign up to receive email updates about the program. Faculty who applied for but did not receive the 2023 or 2024 awards are encouraged to reapply if they are still eligible for the grant. 

Robert McCann, University of Toronto, will receive the 2025 American Mathematical Society (AMS) - Society for Industrial and Applied Mathematics (SIAM) Norbert Wiener Prize in Applied Mathematics “in recognition of his groundbreaking contributions to optimal transport theory, and for pioneering deep applications to economics and physics,” according to the citation. McCann holds a Canada Research Chair in Mathematics, Economics, and Physics.

From the citation

Robert McCann has made fundamental contributions to optimal transport theory, reflecting remarkable technical abilities and amazing conceptual creativity. His discovery of displacement convexity and his solution to Monge’s (1746-1818) problem for different transportation costs were early, foundational advances that preceded by nearly 30 years the current enormous attention bestowed on optimal transport theory and its applications. Beyond these, McCann produced many important, unexpected results, linking optimal transport to new areas of application within and outside mathematics: different notions of curvature, new and hidden convexities in the economics of information, and a non-smooth theory of gravity based on the interaction of entropy with the Einstein field equation.

Response of Robert McCann

I am honored and humbled to have my work on optimal transportation and its applications to economics and physics recognized by the AMS-SIAM 2025 Norbert Wiener Prize (endowed by MIT). I think the whole optimal transport community can join me in taking pride in this acknowledgement of the impact and success of our efforts and can view this award as an incentive to further achievements. After singling out my PhD advisor, Elliott Lieb, who first taught me about the mines and the factories, I'd like to thank the many other mentors, collaborators, colleagues, and students – too numerous to name – who shared in my mathematical, physical, and economic adventures (and those who wrote letters to document!). Our interactions inspire and sustain me on my scientific journey; I could not have achieved these results without you, and my life is enriched by your presence. I try to pass it forward by giving as good as I got, and I encourage you to do the same. I also thank my family for their love and support, and their willingness to share me by putting up with my long hours of distraction and frequent travels. I hope this recognition helps to reassure them that their sacrifices are not for nought.

Biographical sketch of Robert McCann

Robert McCann studied engineering and physics before graduating with a degree in mathematics from Queen's University at Kingston, Ontario, and a doctorate from Princeton University. Following a Tamarkin appointment at Brown University and a postdoctoral fellowship at Institut des Hautes Études Scientifiques (IHES), he became a professor of mathematics at the University of Toronto, where he now holds a Canada Research Chair in Mathematics, Economics, and Physics. He is an authority on optimal transportation and has played a pioneering role in its rapid development since the 1990s. In particular, the notion of displacement convexity introduced in his 1994 PhD thesis lies behind many of the area's myriad applications. He serves on the editorial board of various journals, and as editor-in-chief of the Canadian Journal of Mathematics since 2007 (with a hiatus from 2017-21). His research has been recognized by awards such as an invitation to lecture at the 2014 International Congress of Mathematicians in Seoul; election to the Royal Society of Canada in 2014; the 2017 Jeffery-Williams Prize of the Canadian Mathematical Society; and the 2023 W.T. and Idalia Reid Prize of the Society for Industrial and Applied Mathematics (SIAM).

About the prize

The AMS-SIAM Norbert Wiener Prize in Applied Mathematics is awarded every three years for an outstanding contribution to applied mathematics in the highest and broadest sense.The American Mathematical Society (AMS) and the Society for Industrial and Applied Mathematics (SIAM) award the prize jointly. Recipients must be a member of one of these societies. 

This prize was established in 1967 in honor of Professor Norbert Wiener and was endowed by a fund from the Department of Mathematics of the Massachusetts Institute of Technology. The endowment was supplemented further by a generous donor. The current award is $5,000.

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

*****

The American Mathematical Society is dedicated to advancing research and connecting the diverse global mathematical community through our publications, meetings and conferences, MathSciNet, professional services, advocacy, and awareness programs.

In 2020, when Anthony Parker, known to his fans as DJ Specs, decided to trade his textbooks for turntables, he didn't just pivot his career -- he pivoted his entire life. At just 25 years old, this Kingston-born DJ has already carved out a space...

Earlier this month when Alicea Samaru-Brown walked across the stage at The University of the West Indies (UWI) graduation, she beamed with pride. Her husband, Dennis Brown, and her son, Orlando Brown, cheered the loudest from the audience and this...

With tears streaming down his face and his voice trembling, a windshield wiper made a declaration that he would rather live in the cemetery than with his relatives. "A the cemetery me ago live. Unnu wicked to me," Ramarieo Bailey declared. Bailey...

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

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

Clostridium difficile is an anaerobic and spore-forming bacterium responsible for 15–25% of postantibiotic diarrhea and 95% of pseudomembranous colitis. Peptidoglycan is a crucial element of the bacterial cell wall that is exposed to the host, making it an important target for the innate immune system. The C. difficile peptidoglycan is largely N-deacetylated on its glucosamine (93% of muropeptides) through the activity of enzymes known as N-deacetylases, and this N-deacetylation modulates host–pathogen interactions, such as resistance to the bacteriolytic activity of lysozyme, virulence, and host innate immune responses. C. difficile genome analysis showed that 12 genes potentially encode N-deacetylases; however, which of these N-deacetylases are involved in peptidoglycan N-deacetylation remains unknown. Here, we report the enzymes responsible for peptidoglycan N-deacetylation and their respective regulation. Through peptidoglycan analysis of several mutants, we found that the N-deacetylases PdaV and PgdA act in synergy. Together they are responsible for the high level of peptidoglycan N-deacetylation in C. difficile and the consequent resistance to lysozyme. We also characterized a third enzyme, PgdB, as a glucosamine N-deacetylase. However, its impact on N-deacetylation and lysozyme resistance is limited, and its physiological role remains to be dissected. Finally, given the influence of peptidoglycan N-deacetylation on host defense against pathogens, we investigated the virulence and colonization ability of the mutants. Unlike what has been shown in other pathogenic bacteria, a lack of N-deacetylation in C. difficile is not linked to a decrease in virulence.

Myelination plays an important role in cognitive development and in demyelinating diseases like multiple sclerosis (MS), where failure of remyelination promotes permanent neuro-axonal damage. Modification of cell surface receptors with branched N-glycans coordinates cell growth and differentiation by controlling glycoprotein clustering, signaling, and endocytosis. GlcNAc is a rate-limiting metabolite for N-glycan branching. Here we report that GlcNAc and N-glycan branching trigger oligodendrogenesis from precursor cells by inhibiting platelet-derived growth factor receptor-α cell endocytosis. Supplying oral GlcNAc to lactating mice drives primary myelination in newborn pups via secretion in breast milk, whereas genetically blocking N-glycan branching markedly inhibits primary myelination. In adult mice with toxin (cuprizone)-induced demyelination, oral GlcNAc prevents neuro-axonal damage by driving myelin repair. In MS patients, endogenous serum GlcNAc levels inversely correlated with imaging measures of demyelination and microstructural damage. Our data identify N-glycan branching and GlcNAc as critical regulators of primary myelination and myelin repair and suggest that oral GlcNAc may be neuroprotective in demyelinating diseases like MS.

High-throughput sequencing of hematologic malignancies and other cancers has revealed recurrent mis-sense mutations of genes encoding pre-mRNA splicing factors. The essential splicing factor U2AF2 recognizes a polypyrimidine-tract splice-site signal and initiates spliceosome assembly. Here, we investigate representative, acquired U2AF2 mutations, namely N196K or G301D amino acid substitutions associated with leukemia or solid tumors, respectively. We determined crystal structures of the wild-type (WT) compared with N196K- or G301D-substituted U2AF2 proteins, each bound to a prototypical AdML polypyrimidine tract, at 1.5, 1.4, or 1.7 Å resolutions. The N196K residue appears to stabilize the open conformation of U2AF2 with an inter-RNA recognition motif hydrogen bond, in agreement with an increased apparent RNA-binding affinity of the N196K-substituted protein. The G301D residue remains in a similar position as the WT residue, where unfavorable proximity to the RNA phosphodiester could explain the decreased RNA-binding affinity of the G301D-substituted protein. We found that expression of the G301D-substituted U2AF2 protein reduces splicing of a minigene transcript carrying prototypical splice sites. We further show that expression of either N196K- or G301D-substituted U2AF2 can subtly alter splicing of representative endogenous transcripts, despite the presence of endogenous, WT U2AF2 such as would be present in cancer cells. Altogether, our results demonstrate that acquired U2AF2 mutations such as N196K and G301D are capable of dysregulating gene expression for neoplastic transformation.

Arabinogalactan proteins (AGPs) are plant proteoglycans with functions in growth and development. However, these functions are largely unexplored, mainly because of the complexity of the sugar moieties. These carbohydrate sequences are generally analyzed with the aid of glycoside hydrolases. The exo-β-1,3-galactanase is a glycoside hydrolase from the basidiomycete Phanerochaete chrysosporium (Pc1,3Gal43A), which specifically cleaves AGPs. However, its structure is not known in relation to its mechanism bypassing side chains. In this study, we solved the apo and liganded structures of Pc1,3Gal43A, which reveal a glycoside hydrolase family 43 subfamily 24 (GH43_sub24) catalytic domain together with a carbohydrate-binding module family 35 (CBM35) binding domain. GH43_sub24 is known to lack the catalytic base Asp conserved among other GH43 subfamilies. Our structure in combination with kinetic analyses reveals that the tautomerized imidic acid group of Gln263 serves as the catalytic base residue instead. Pc1,3Gal43A has three subsites that continue from the bottom of the catalytic pocket to the solvent. Subsite −1 contains a space that can accommodate the C-6 methylol of Gal, enabling the enzyme to bypass the β-1,6–linked galactan side chains of AGPs. Furthermore, the galactan-binding domain in CBM35 has a different ligand interaction mechanism from other sugar-binding CBM35s, including those that bind galactomannan. Specifically, we noted a Gly → Trp substitution, which affects pyranose stacking, and an Asp → Asn substitution in the binding pocket, which recognizes β-linked rather than α-linked Gal residues. These findings should facilitate further structural analysis of AGPs and may also be helpful in engineering designer enzymes for efficient biomass utilization.

The dimeric ectonucleotidase CD73 catalyzes the hydrolysis of AMP at the cell surface to form adenosine, a potent suppressor of the immune response. Blocking CD73 activity in the tumor microenvironment can have a beneficial effect on tumor eradication and is a promising approach for cancer therapy. Biparatopic antibodies binding different regions of CD73 may be a means to antagonize its enzymatic activity. A panel of biparatopic antibodies representing the pairwise combination of 11 parental monoclonal antibodies against CD73 was generated by Fab-arm exchange. Nine variants vastly exceeded the potency of their parental antibodies with ≥90% inhibition of activity and subnanomolar EC50 values. Pairing the Fabs of parents with nonoverlapping epitopes was both sufficient and necessary whereas monovalent antibodies were poor inhibitors. Some parental antibodies yielded potent biparatopics with multiple partners, one of which (TB19) producing the most potent. The structure of the TB19 Fab with CD73 reveals that it blocks alignment of the N- and C-terminal CD73 domains necessary for catalysis. A separate structure of CD73 with a Fab (TB38) which complements TB19 in a particularly potent biparatopic shows its binding to a nonoverlapping site on the CD73 N-terminal domain. Structural modeling demonstrates a TB19/TB38 biparatopic antibody would be unable to bind the CD73 dimer in a bivalent manner, implicating crosslinking of separate CD73 dimers in its mechanism of action. This ability of a biparatopic antibody to both crosslink CD73 dimers and fix them in an inactive conformation thus represents a highly effective mechanism for the inhibition of CD73 activity.

Members of the B-cell lymphoma (BCL-2) protein family regulate mitochondrial outer membrane permeabilization (MOMP), a phenomenon in which mitochondria become porous and release death-propagating complexes during the early stages of apoptosis. Pro-apoptotic BCL-2 proteins oligomerize at the mitochondrial outer membrane during MOMP, inducing pore formation. Of current interest are endogenous factors that can inhibit pro-apoptotic BCL-2 mitochondrial outer membrane translocation and oligomerization. A mitochondrial-derived peptide, Humanin (HN), was reported being expressed from an alternate ORF in the mitochondrial genome and inhibiting apoptosis through interactions with the pro-apoptotic BCL-2 proteins. Specifically, it is known to complex with BAX and BID. We recently reported the fibrillation of HN and BAX into β-sheets. Here, we detail the fibrillation between HN and BID. These fibers were characterized using several spectroscopic techniques, protease fragmentation with mass analysis, and EM. Enhanced fibrillation rates were detected with rising temperatures or pH values and the presence of a detergent. BID fibers are similar to those produced using BAX; however, the structures differ in final conformations of the BCL-2 proteins. BID fibers display both types of secondary structure in the fiber, whereas BAX was converted entirely to β-sheets. The data show that two distinct segments of BID are incorporated into the fiber structure, whereas other portions of BID remain solvent-exposed and retain helical structure. Similar analyses show that anti-apoptotic BCL-xL does not form fibers with humanin. These results support a general mechanism of sequestration of pro-apoptotic BCL-2 proteins into fibers by HN to inhibit MOMP.

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.

9 July 2020

22 July 2020

14 August 2020

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30 September 2020

Viral infection is one environmental factor that may contribute to the initiation of pancreatic β-cell destruction during the development of autoimmune diabetes. Picornaviruses, such as encephalomyocarditis virus (EMCV), induce a pro-inflammatory response in islets leading to local production of cytokines, such as IL-1, by resident islet leukocytes. Furthermore, IL-1 is known to stimulate β-cell expression of iNOS and production of the free radical nitric oxide. The purpose of this study was to determine whether nitric oxide contributes to the β-cell response to viral infection. We show that nitric oxide protects β-cells against virally mediated lysis by limiting EMCV replication. This protection requires low micromolar, or iNOS-derived, levels of nitric oxide. At these concentrations nitric oxide inhibits the Krebs enzyme aconitase and complex IV of the electron transport chain. Like nitric oxide, pharmacological inhibition of mitochondrial oxidative metabolism attenuates EMCV-mediated β-cell lysis by inhibiting viral replication. These findings provide novel evidence that cytokine signaling in β-cells functions to limit viral replication and subsequent β-cell lysis by attenuating mitochondrial oxidative metabolism in a nitric oxide–dependent manner.

Oxygen regulates hypoxia-inducible factor (HIF) transcription factors to control cell metabolism, erythrogenesis, and angiogenesis. Whereas much has been elucidated about how oxygen regulates HIF, whether lipids affect HIF activity is un-known. Here, using cultured cells and two animal models, we demonstrate that lipoprotein-derived fatty acids are an independent regulator of HIF. Decreasing extracellular lipid supply inhibited HIF prolyl hydroxylation, leading to accumulation of the HIFα subunit of these heterodimeric transcription factors comparable with hypoxia with activation of downstream target genes. The addition of fatty acids to culture medium suppressed this signal, which required an intact mitochondrial respiratory chain. Mechanistically, fatty acids and oxygen are distinct signals integrated to control HIF activity. Finally, we observed lipid signaling to HIF and changes in target gene expression in developing zebrafish and adult mice, and this pathway operates in cancer cells from a range of tissues. This study identifies fatty acids as a physiological modulator of HIF, defining a mechanism for lipoprotein regulation that functions in parallel to oxygen.

Environmental factors, such as viral infection, are proposed to play a role in the initiation of autoimmune diabetes. In response to encephalomyocarditis virus (EMCV) infection, resident islet macrophages release the pro-inflammatory cytokine IL-1β, to levels that are sufficient to stimulate inducible nitric oxide synthase (iNOS) expression and production of micromolar levels of the free radical nitric oxide in neighboring β-cells. We have recently shown that nitric oxide inhibits EMCV replication and EMCV-mediated β-cell lysis and that this protection is associated with an inhibition of mitochondrial oxidative metabolism. Here we show that the protective actions of nitric oxide against EMCV infection are selective for β-cells and associated with the metabolic coupling of glycolysis and mitochondrial oxidation that is necessary for insulin secretion. Inhibitors of mitochondrial respiration attenuate EMCV replication in β-cells, and this inhibition is associated with a decrease in ATP levels. In mouse embryonic fibroblasts (MEFs), inhibition of mitochondrial metabolism does not modify EMCV replication or decrease ATP levels. Like most cell types, MEFs have the capacity to uncouple the glycolytic utilization of glucose from mitochondrial respiration, allowing for the maintenance of ATP levels under conditions of impaired mitochondrial respiration. It is only when MEFs are forced to use mitochondrial oxidative metabolism for ATP generation that mitochondrial inhibitors attenuate viral replication. In a β-cell selective manner, these findings indicate that nitric oxide targets the same metabolic pathways necessary for glucose stimulated insulin secretion for protection from viral lysis.

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