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SUMOylation of the transcription factor ZFHX3 at Lys-2806 requires SAE1, UBC9, and PIAS2 and enhances its stability and function in cell proliferation [Protein Synthesis and Degradation]

SUMOylation is a posttranslational modification (PTM) at a lysine residue and is crucial for the proper functions of many proteins, particularly of transcription factors, in various biological processes. Zinc finger homeobox 3 (ZFHX3), also known as AT motif-binding factor 1 (ATBF1), is a large transcription factor that is active in multiple pathological processes, including atrial fibrillation and carcinogenesis, and in circadian regulation and development. We have previously demonstrated that ZFHX3 is SUMOylated at three or more lysine residues. Here, we investigated which enzymes regulate ZFHX3 SUMOylation and whether SUMOylation modulates ZFHX3 stability and function. We found that SUMO1, SUMO2, and SUMO3 each are conjugated to ZFHX3. Multiple lysine residues in ZFHX3 were SUMOylated, but Lys-2806 was the major SUMOylation site, and we also found that it is highly conserved among ZFHX3 orthologs from different animal species. Using molecular analyses, we identified the enzymes that mediate ZFHX3 SUMOylation; these included SUMO1-activating enzyme subunit 1 (SAE1), an E1-activating enzyme; SUMO-conjugating enzyme UBC9 (UBC9), an E2-conjugating enzyme; and protein inhibitor of activated STAT2 (PIAS2), an E3 ligase. Multiple analyses established that both SUMO-specific peptidase 1 (SENP1) and SENP2 deSUMOylate ZFHX3. SUMOylation at Lys-2806 enhanced ZFHX3 stability by interfering with its ubiquitination and proteasomal degradation. Functionally, Lys-2806 SUMOylation enabled ZFHX3-mediated cell proliferation and xenograft tumor growth of the MDA-MB-231 breast cancer cell line. These findings reveal the enzymes involved in, and the functional consequences of, ZFHX3 SUMOylation, insights that may help shed light on ZFHX3's roles in various cellular and pathophysiological processes.




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Inhibition of glycosphingolipid biosynthesis reverts multidrug resistance by differentially modulating ABC transporters in chronic myeloid leukemias [Cell Biology]

Multidrug resistance (MDR) in cancer arises from cross-resistance to structurally- and functionally-divergent chemotherapeutic drugs. In particular, MDR is characterized by increased expression and activity of ATP-binding cassette (ABC) superfamily transporters. Sphingolipids are substrates of ABC proteins in cell signaling, membrane biosynthesis, and inflammation, for example, and their products can favor cancer progression. Glucosylceramide (GlcCer) is a ubiquitous glycosphingolipid (GSL) generated by glucosylceramide synthase, a key regulatory enzyme encoded by the UDP-glucose ceramide glucosyltransferase (UGCG) gene. Stressed cells increase de novo biosynthesis of ceramides, which return to sub-toxic levels after UGCG mediates incorporation into GlcCer. Given that cancer cells seem to mobilize UGCG and have increased GSL content for ceramide clearance, which ultimately contributes to chemotherapy failure, here we investigated how inhibition of GSL biosynthesis affects the MDR phenotype of chronic myeloid leukemias. We found that MDR is associated with higher UGCG expression and with a complex GSL profile. UGCG inhibition with the ceramide analog d-threo-1-(3,4,-ethylenedioxy)phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol (EtDO-P4) greatly reduced GSL and monosialotetrahexosylganglioside levels, and co-treatment with standard chemotherapeutics sensitized cells to mitochondrial membrane potential loss and apoptosis. ABC subfamily B member 1 (ABCB1) expression was reduced, and ABCC-mediated efflux activity was modulated by competition with nonglycosylated ceramides. Consistently, inhibition of ABCC-mediated transport reduced the efflux of exogenous C6-ceramide. Overall, UGCG inhibition impaired the malignant glycophenotype of MDR leukemias, which typically overcomes drug resistance through distinct mechanisms. This work sheds light on the involvement of GSL in chemotherapy failure, and its findings suggest that targeted GSL modulation could help manage MDR leukemias.




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The heme-regulatory motifs of heme oxygenase-2 contribute to the transfer of heme to the catalytic site for degradation [Protein Structure and Folding]

Heme-regulatory motifs (HRMs) are present in many proteins that are involved in diverse biological functions. The C-terminal tail region of human heme oxygenase-2 (HO2) contains two HRMs whose cysteine residues form a disulfide bond; when reduced, these cysteines are available to bind Fe3+-heme. Heme binding to the HRMs occurs independently of the HO2 catalytic active site in the core of the protein, where heme binds with high affinity and is degraded to biliverdin. Here, we describe the reversible, protein-mediated transfer of heme between the HRMs and the HO2 core. Using hydrogen-deuterium exchange (HDX)-MS to monitor the dynamics of HO2 with and without Fe3+-heme bound to the HRMs and to the core, we detected conformational changes in the catalytic core only in one state of the catalytic cycle—when Fe3+-heme is bound to the HRMs and the core is in the apo state. These conformational changes were consistent with transfer of heme between binding sites. Indeed, we observed that HRM-bound Fe3+-heme is transferred to the apo-core either upon independent expression of the core and of a construct spanning the HRM-containing tail or after a single turnover of heme at the core. Moreover, we observed transfer of heme from the core to the HRMs and equilibration of heme between the core and HRMs. We therefore propose an Fe3+-heme transfer model in which HRM-bound heme is readily transferred to the catalytic site for degradation to facilitate turnover but can also equilibrate between the sites to maintain heme homeostasis.




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Structural basis of substrate recognition and catalysis by fucosyltransferase 8 [Protein Structure and Folding]

Fucosylation of the innermost GlcNAc of N-glycans by fucosyltransferase 8 (FUT8) is an important step in the maturation of complex and hybrid N-glycans. This simple modification can dramatically affect the activities and half-lives of glycoproteins, effects that are relevant to understanding the invasiveness of some cancers, development of mAb therapeutics, and the etiology of a congenital glycosylation disorder. The acceptor substrate preferences of FUT8 are well-characterized and provide a framework for understanding N-glycan maturation in the Golgi; however, the structural basis of these substrate preferences and the mechanism through which catalysis is achieved remain unknown. Here we describe several structures of mouse and human FUT8 in the apo state and in complex with GDP, a mimic of the donor substrate, and with a glycopeptide acceptor substrate at 1.80–2.50 Å resolution. These structures provide insights into a unique conformational change associated with donor substrate binding, common strategies employed by fucosyltransferases to coordinate GDP, features that define acceptor substrate preferences, and a likely mechanism for enzyme catalysis. Together with molecular dynamics simulations, the structures also revealed how FUT8 dimerization plays an important role in defining the acceptor substrate-binding site. Collectively, this information significantly builds on our understanding of the core fucosylation process.




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The Histone Methyltransferase MLL1 Directs Macrophage-Mediated Inflammation in Wound Healing and Is Altered in a Murine Model of Obesity and Type 2 Diabetes

Andrew S. Kimball
Sep 1, 2017; 66:2459-2471
Immunology and Transplantation




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Correction: Histone demethylase KDM6B promotes epithelial-mesenchymal transition. [Additions and Corrections]

VOLUME 287 (2012) PAGES 44508–44517In Fig. 1A, the wrong image for the control group was presented. The authors inadvertently cropped the control images in Fig. 1, A and E, from the same raw image. Fig. 1A has now been corrected and does not affect the results or conclusions of the work. The authors sincerely apologize for their mistake during figure preparation and for any inconvenience this may have caused readers.jbc;295/19/6781/F1F1F1Figure 1A.




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Re: Reducing risks from coronavirus transmission in the home—the role of viral load




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Transparency and independence in the vetting and recommendation of vaccine products




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A Transatlantic Partnership for WTO Reform in the Age of Coronavirus

Webinar Research Event

28 April 2020 - 2:00pm to 3:00pm

Event participants

Ignacio Garcia Bercero, Director, Directorate General for Trade of the European Commission; European Union Visiting Fellow, Oxford University
Jennifer Hillman, Senior Fellow for Trade and International Political Economy, Council on Foreign Relations; Member, WTO Appellate Body, 2007 - 11
Chair: Marianne Schneider-Petsinger, Senior Research Fellow, US and Americas Programme, Chatham House

Global trade and the WTO – which has been at the heart of the rules-based international trade system since its creation in 1995 – faced a critical moment even before COVID-19. The Appellate Body’s demise in December 2019 led to a renewed focus on the future of the WTO. But the challenges facing the WTO run deeper than that – the organization has lost relevance as a negotiation forum, resulting in the global trade rules not having kept pace with changes in technology and the rise of China. While the WTO provides a forum for international cooperation to address the trade fallout from COVID-19, what implications will the pandemic have for the long-term reform of the global trade system?

Both the US and EU have proposed various WTO reform strategies and taken steps towards collaboration, but is a transatlantic partnership for WTO reform feasible? Do the US and EU believe that a rules-based international trade system is in their interest – especially in light of COVID-19? What are the biggest issues dividing the US and EU on reforming the WTO, and is there a common assessment of the key problems? What steps can the US and EU take to address the dispute settlement function of the WTO and to modernize the trade rules? Are there broader issues, such as environmental and social sustainability, that should be included in a transatlantic agenda for WTO reform?

This event is  part of the Chatham House Global Trade Policy Forum and will take place virtually only.

We would like to take this opportunity to thank founding partner AIG and supporting partners Clifford Chance LLP, Diageo plc, and EY for their generous support of the Chatham House Global Trade Policy Forum.




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Kazakhstan: Tested by Transition

Invitation Only Research Event

28 November 2019 - 1:30pm to 3:30pm

Chatham House | 10 St James's Square | London | SW1Y 4LE

Event participants

Annette Bohr, Associate Fellow, Russia and Eurasia Programme, Chatham House
Kassymkhan Kapparov, Founder, Economist.kz
Joanna Lillis, Reporter, The Guardian, The Economist and The Independent
Kate Mallinson, Associate Fellow, Russia and Eurasia Programme, Chatham House
Dossym Satpayev, Director, Kazakhstan Risk Assessment Group; Member of the Presidium, Kazakhstan Council on International Relations
Chair: James Nixey, Head, Russia and Eurasia Programme, Chatham House

At face value at least, Central Asia’s wealthiest state has embarked on a bold experiment following the March 2019 decision by its founding father and long-standing ruler, Nursultan Nazarbayev, to resign from the presidency and initiate a managed political succession. A generational transition of this nature, untried in other former Soviet republics, brings with it high stakes.
 
As well as seeking to secure his own legacy, having dominated the country since before independence in 1991, Nazarbayev wants to ensure Kazakhstan does not depart from the course he has set while safeguarding Kazakhstan’s stability in the context of multiple and evolving domestic and international challenges. But this is easier said than done. Is Kazakhstan ready for the challenges of the future?
 
This event marks the launch of Chatham House’s major report Kazakhstan: Tested by Transition.

Department/project

Anna Morgan

Administrator, Ukraine Forum
+44 (0)20 7389 3274




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Kazakhstan: Tested by Transition

27 November 2019

A partial handover of political power through an orchestrated transition takes Kazakhstan into uncharted territory. Will it be able to pursue modernization and reform, and break from its authoritarian past?

Annette Bohr

Associate Fellow, Russia and Eurasia Programme

Dr Nigel Gould-Davies

Associate Fellow, Russia and Eurasia Programme, Chatham House

Kate Mallinson

Associate Fellow, Russia and Eurasia Programme

James Nixey

Director, Russia and Eurasia Programme

Birgit Brauer

Analyst, Writer and Journalist Covering Central Asia

Nargis Kassenova

Senior Fellow, Davis Center for Russian and Eurasian Studies, Harvard University

Joanna Lillis

Kazakhstan-Based Journalist Reporting on Central Asia

Dosym Satpayev

Independent Political Analyst and the Director of the Kazakhstan Risks Assessment Group

Kazakhstan is at a turning point in its history. At face value, at least, Central Asia’s wealthiest state has embarked on a bold experiment following the March 2019 decision by its founding father and long-standing ruler, Nursultan Nazarbayev, to resign from the presidency and initiate a managed political succession. A generational transition of this nature, untried in other former Soviet republics, brings with it high stakes. As well as looking to secure his own legacy, having dominated the country since before independence in 1991, Nazarbayev seeks to ensure Kazakhstan does not depart from the course he has set, while safeguarding regime stability in the context of multiple and evolving domestic and international challenges. This is easier said than done.

The uncertainty around this project is substantial, especially considering a ‘rowback’ decree just seven months after Nazarbayev’s resignation, limiting the powers of his anointed successor, Kassym-Jomart Tokayev. How long can Tokayev credibly remain president considering such a transparent undermining of his authority? Is Nazarbayev, in fact, grooming his daughter, Dariga Nazarbayeva, another relative or a power player from outside the family for the leadership in the longer term? Will the ‘Kazakh tandem’ of Nazarbayev and Tokayev function effectively, or will tensions and conflicts arise between them as many claim is happening already? How will the leadership cope with the protest mood now manifest on the streets of Kazakhstan, and address the political and socio-economic grievances fuelling this discontent? How might the political transition play out if Nazarbayev were to suddenly exit the political scene altogether?And what is the long-term transition plan for the time when Nazarbayev has departed, and how effective will it be?

As Kazakhstan enters uncharted territory, the purpose of this report is twofold. First, to make the case for the West to devote more attention to Kazakhstan. The country’s relative importance in Central Asia, and as the constant focus of intense attention from China and Russia, suggests that the West is wrong to direct so little time and diplomatic effort and so few resources towards it. This is not so much a miscalculation (that would be to assume there had been a calculation in the first place) as a misstep through neglect, presupposing that the future will resemble the present – with Kazakhstan remaining stable internally, relatively inconsequential geopolitically but nevertheless a friendly ally to the West. In fact, the country’s trajectory over the next few years is of potentially strategic import. This is because even its political semi-transition presents the West with a rare opportunity to push back against the global rise of authoritarianism, in a state that is open to rational argument and economic logic.

The second function of the report is to serve as a well-intentioned message to the leadership of Kazakhstan. The research undertaken by the report’s eight authors shows that Kazakhstan is at risk of failing to achieve the goals its leadership has set for the country. As significant as it has been, the partial stepping aside of Nazarbayev by no means guarantees the modernization and renewal that he and his successor have promised. Far deeper political, economic and social reforms will be needed if Kazakhstan is to meet the growing challenges to its stability, prosperity and development. Street protests since Nazarbayev’s resignation have demonstrated a level of popular disaffection far higher than the authorities acknowledge. The leadership needs to bridge the disconnect between the rulers and the ruled and start listening to its people.

To avoid slipping into decline, and to resist external pressures and geopolitical overtures that could diminish the sovereignty that its leadership is so determined to safeguard, Kazakhstan needs new faces – innovators and reformers – throughout every level of the administration, as well as new ideas. This report is intended to help with the ‘ideas’ part of that proposition. It also includes a series of recommendations for Western governments and institutions and for the Kazakhstan government. 




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POSTPONED: Transitional Justice in Ukraine: What Might it Look Like?

Invitation Only Research Event

17 March 2020 - 9:30am to 1:00pm

Chatham House | 10 St James's Square | London | SW1Y 4LE

Event participants

Kirsty Brimelow QC, Barrister, Doughty Street Chambers
Miles Jackson, Associate Professor of Law, University of Oxford
Anton Korynevych, Representative of the President of Ukraine for Crimea
Oleksandra Matviychuk, Head of the Board, Centre for Civil Liberties
Taras Tsymbrivksyy, Head, USAID Human Rights in Action Program; Ukrainian Helsinki Human Rights Union

Still grappling with the war in the east and the occupation of Crimea, Ukraine’s new leadership has announced its intention to develop its transitional justice infrastructure to respond to the human rights violations arising from Russia’s aggression. 

Numerous reports (not least ones by the UN Human Rights Monitoring Mission in Ukraine) list persecutions, illegal detentions, enforced disappearances, torture and killings among the crimes perpetrated in Crimea and parts of occupied Donbas. 

As Ukraine has only just started developing its transitional justice roadmap, this event will seek to discuss viable initial approaches, such as a ‘truth-telling commission’ or amnesties. 

The panellists will also discuss the role for civil society and those directly affected by hostilities in the transitional justice process.  

PLEASE NOTE THIS EVENT IS POSTPONED UNTIL FURTHER NOTICE.

Event attributes

Chatham House Rule

Anna Morgan

Administrator, Ukraine Forum
+44 (0)20 7389 3274




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Russia’s Uncertain Regime Transformation

11 March 2020

Professor Nikolai Petrov

Senior Research Fellow, Russia and Eurasia Programme, Chatham House

Dr Ben Noble

Lecturer in Russian Politics, University College London; Senior Research Fellow, HSE, Moscow
Despite the drama, Vladimir Putin’s announcement endorsing a constitutional change allowing him to remain president from 2024 does surprisingly little to change the status quo.

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Russian President Vladimir Putin addresses lawmakers debating on the second reading of the constitutional reform bill during a session of the State Duma, Russia's lower house of parliament March 10, 2020. Photo by ALEXANDER NEMENOV/AFP via Getty Images.

With Putin’s current term as head of state due to run out in 2024, the question everybody has been asking is what he will do to remain in power. The Russian president’s recent speech, made in person in the State Duma during the second reading of his own constitutional reform bill, has been interpreted by many as a clear answer. Summaries such as “Putin forever” and “perpetual Putin” abound. But the reality is not so clear.

Putin has not committed to standing for re-election in 2024, never mind staying in power until 2036, when two additional six-year terms from 2024 would run out. What he has done is provide the constitutional grounds to retain power as president. It creates a highly credible option without committing him to it.

And the uncertainty matters. Because as long as members of the elite are unsure whether Putin will take up the option to remain president, they are kept in check.

Broader constitutional reform

With the flurry of interest around Putin’s announcement, we should not lose sight of his moves to further strengthen the presidency. As part of the broader constitutional reform package, Russia’s existing “super-presidency” will gain additional powers, such as the authority to fire top-tier judges and to block legislation when the legislature has overridden a presidential veto (in other words, a “super-veto”).

The proposals also put the autonomy of local self-government at risk, with Moscow and regional executives gaining the constitutional power to hire and fire officials who are not even technically part of the state. And the president now has a formalised role as “general leader” of the government. Putin is creating the “Great Presidency”.

However, the majority of constitutional changes do not relate to the presidency – they have different purposes. Firstly, to revitalise support for the regime which took a hit following unpopular pension reforms in 2018. Secondly, to distract or appease those worried by Putin remaining in a strengthened presidency. And perhaps most significantly, to boost turnout in the nationwide vote on reforms.

This desire to re-energise popular support becomes apparent as the changes – some of which will have to be inserted rather awkwardly into the constitution’s structure – focus on three elements aimed squarely at improving the regime’s appeal: increased material support from the state for citizens, including indexing state pensions; an emphasis on “traditional values”, including a declaration that marriage can only be a union between a man and a woman; and increased Russian sovereignty, including a “nationalisation” of the elite, with a constitutional ban on top-level officials having bank accounts abroad. 

Constitutional reform is, moreover, the most visible part of a broader political transformation already underway, including a major propaganda drive. Putin has promised a significant increase in resources for its “maternity capital” programme, putting more money in the pockets of young Russian families.

And he has instructed Prime Minister Mikhail Mishustin’s government to focus on delivering his “national projects” – goals aimed at improving Russians’ lives across a range of areas, from infrastructure to education and healthcare.

Taking advantage of several imminent historical milestones is also on the cards. It has been reported Putin will sign the constitutional reform bill on March 18 – the anniversary of Russia’s annexation of Crimea. And May 9 is the 75th anniversary of the end of the Great Patriotic War (the Russian term for the Second World War), with foreign dignitaries invited to attend events in Moscow.

Putin has also been filling the airwaves with a high-production-values series called “20 Questions for Vladimir Putin”, as well as holding public meetings with citizens in provinces such as Cherepovets and Ivanovo. There is a clear aim to demonstrate the president is not only still in control, but also concerned with the well-being of everyday Russians.

With parliamentary elections scheduled for September 2021 the Kremlin knows that, to maintain its control of a super-majority of seats in the State Duma, its ratings-raising drive has to work – even if it does always have the option of using manifestly authoritarian methods for realising desired election results. A proposal to call early State Duma elections was made during the second reading of Putin’s reform bill, but was quickly withdrawn after Putin spoke out against the idea.

Russia’s complex architecture of “power”

Throughout this transformation, maintaining control of the elite – particularly of the siloviki – is key for Putin. A reshuffling and removal of senior officials in the Procuracy has seen Yury Chaika replaced as general prosecutor by Ivan Krasnov, previously a deputy chair of the Investigative Committee, which is widely seen as a rival structure in Russia’s complex architecture of “power” bodies.

When considered alongside the constitutional changes giving the president broader powers in appointing regional prosecutors, this is textbook “divide and rule”. Power balancing is also on display with the Security Council, as the job description for Dmitry Medvedev’s new role as its deputy chair could provide fertile ground for clashes with the body’s secretary, Nikolai Patrushev.

Pitting rival patronal networks against each other means Putin can keep rivals in check within the broader structure of the “Great Presidency”, while staying firmly in control himself.

The prospect of Putin remaining president is unlikely to be popular. According to data from independent Russian polling agency the Levada Centre, only 27 per cent of Russians want Putin to stay in the post after 2024. This figure could, of course, change in either direction as the prospect becomes more real for Russians. But if Putin’s announcement galvanises mass opposition, the authorities may well use responses to the COVID-19 outbreak to keep protesters at bay – something already on display in Moscow.

What this all means for Russia is that, despite the drama, considerable uncertainty remains following Putin’s announcement. What we can say for certain, however, is that it dashes hopes of serious political change any time soon.




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"What's the point in living, in a body I don't want" - how the NHS treats trans people

James Barrett, president of the British Association of Gender Identity Specialists, and Nina, a trans woman, join us to discuss how difficult it can be for trans people to access gender clinics, and what barriers are faced by the community after their transition has been completed. Read James Barrett's personal...




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Caring for renal transplant patients

Renal transplantation improves quantity and quality of life compared with chronic dialysis. A UK general practice with 8000 patients will have around four patients with a functioning renal transplant, one patient on the transplant waiting list, and several under consideration for transplantation. Many medical problems in renal transplant...




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Don't save on transport at the cost of the NHS

Last week we heard about how evidence in policy making is imperilled - but today we’re hearing about a plan to make evidence about health central to all aspects of government. Laura Webber, director of public health modelling at the UK Health Forum, Susie Morrow, chair of the Wandsworth Living Streets Group and Brian Ferguson, chief economist at...




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Talk evidence - smoking, gloves and transparency

This month we have some more feedback from our listeners (2.20) Carl says it's time to start smoking cessation (or stop the reduction in funding for smoking reduction) (11.40) and marvels at how pretty Richard Doll's seminal smoking paper is. It's gloves off for infection control (22.20) Andrew George, a non-executive director of the Health...




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How Blockchain could improve clinical trial transparency

Blockchain is the digital technology that underpins cryptocurrencies such as bitcoin, and has been proposed as the digital panacea of our times. But Leeza Osipenko, from the London School of Economics, has thought about how it could actually be used in clinical trials, and what else would need to change in our regulatory environment to make that...




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Talk Evidence covid-19 update - lack of testing transparency, how to give good debate

For the next few months Talk Evidence is going to focus on the new corona virus pandemic. There is an enormous amount of uncertainty about the disease, what the symptoms are, fatality rate, treatment options, things we shouldn't be doing. We're going to try to get away from the headlines and talk about what we need to know - to hopefully give you...




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5' AMP-activated protein kinase activation causes GLUT4 translocation in skeletal muscle

EJ Kurth-Kraczek
Aug 1, 1999; 48:1667-1671
Articles




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Evidence for 5'AMP-Activated Protein Kinase Mediation of the Effect of Muscle Contraction on Glucose Transport

Tatsuya Hayashi
Aug 1, 1998; 47:1369-1373
Rapid Publications




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De Novo Mutations in EIF2B1 Affecting eIF2 Signaling Cause Neonatal/Early-Onset Diabetes and Transient Hepatic Dysfunction

Permanent neonatal diabetes mellitus (PNDM) is caused by reduced β-cell number or impaired β-cell function. Understanding of the genetic basis of this disorder highlights fundamental β-cell mechanisms. We performed trio genome sequencing for 44 patients with PNDM and their unaffected parents to identify causative de novo variants. Replication studies were performed in 188 patients diagnosed with diabetes before 2 years of age without a genetic diagnosis. EIF2B1 (encoding the eIF2B complex α subunit) was the only gene with novel de novo variants (all missense) in at least three patients. Replication studies identified two further patients with de novo EIF2B1 variants. In addition to having diabetes, four of five patients had hepatitis-like episodes in childhood. The EIF2B1 de novo mutations were found to map to the same protein surface. We propose that these variants render the eIF2B complex insensitive to eIF2 phosphorylation, which occurs under stress conditions and triggers expression of stress response genes. Failure of eIF2B to sense eIF2 phosphorylation likely leads to unregulated unfolded protein response and cell death. Our results establish de novo EIF2B1 mutations as a novel cause of permanent diabetes and liver dysfunction. These findings confirm the importance of cell stress regulation for β-cells and highlight EIF2B1’s fundamental role within this pathway.




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Transatlantic Dialogue on Reducing Deforestation in Supply Chains of Agricultural Commodities

Invitation Only Research Event

23 October 2014 - 9:00am to 24 October 2014 - 5:00pm

Pew Charitable Trust Center, Washington DC

This transatlantic dialogue will bring together a number of stakeholders, focused on options for reducing deforestation in agricultural supply chains. Key questions will be asked such as: What are the current and projected patterns of supply and demand for key commodities, and their impacts on forests? Who are the key producers and what is their relative impact on forests? How are these patterns likely to change in the future? What are the key points of leverage in these supply chains? What is the scope of potential action by the US, the EU, and its member states?

The current status and future trends in the global production and trade in major agricultural commodities will also be examined, along with the key leverage points for influence. Global forest footprint of major agricultural commodities and deforestation hotspots will be discussed and key drivers of deforestation will be examined. Finally, the potential roles of government in reducing commodity-driven deforestation will be analysed to gain a better understanding of the potential for state action in the EU and the US contexts.

Attendance at this event is by invitation only.

Event attributes

External event




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Marte confident transition to CF will be smooth

Ketel Marte does not lack for confidence when it comes to switching from second base/shortstop to center field, which is where he's expected to see a lot of time this season.




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Adil El-Tayar: renowned NHS transplant surgeon who died from covid-19

bmj;369/may07_6/m1803/FAF1faPhoto credit: Abbas GhazanfarOn 25 March Adil El-Tayar, a renowned organ transplantation specialist, became the first working NHS surgeon to die from covid-19 in hospital...




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Myocardial Blood Flow and Myocardial Flow Reserve After Cardiac Transplantation: Mistakes in Diagnostic Value and Prognosis




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Reply: Clarifying the Utility of Myocardial Blood Flow and Myocardial Flow Reserve After Cardiac Transplantation




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{beta}-Cell Stress Shapes CTL Immune Recognition of Preproinsulin Signal Peptide by Posttranscriptional Regulation of Endoplasmic Reticulum Aminopeptidase 1

The signal peptide of preproinsulin is a major source for HLA class I autoantigen epitopes implicated in CD8 T cell (CTL)–mediated β-cell destruction in type 1 diabetes (T1D). Among them, the 10-mer epitope located at the C-terminal end of the signal peptide was found to be the most prevalent in patients with recent-onset T1D. While the combined action of signal peptide peptidase and endoplasmic reticulum (ER) aminopeptidase 1 (ERAP1) is required for processing of the signal peptide, the mechanisms controlling signal peptide trimming and the contribution of the T1D inflammatory milieu on these mechanisms are unknown. Here, we show in human β-cells that ER stress regulates ERAP1 gene expression at posttranscriptional level via the IRE1α/miR-17-5p axis and demonstrate that inhibition of the IRE1α activity impairs processing of preproinsulin signal peptide antigen and its recognition by specific autoreactive CTLs during inflammation. These results underscore the impact of ER stress in the increased visibility of β-cells to the immune system and position the IRE1α/miR-17 pathway as a central component in β-cell destruction processes and as a potential target for the treatment of autoimmune T1D.




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Use of sodium-glucose co-transporter 2 inhibitors and risk of serious renal events: Scandinavian cohort study




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Transatlantic Dialogue on China

A joint Chatham House-RUSI project that focuses on strengthening common understanding across the Atlantic and develop new ideas for how the US and Europe can better engage with and respond to China’s rise.

This will be done through examining transatlantic approaches and responses to China through the lens for four key themes (digital technology; trade and investment; governance of global commons; and climate change and the environment) that have been identified as crucial to developing effective policy responses and fostering collaboration.

The project will strengthen national, regional and international responses to the risks and opportunities posed by China’s changing role within the global economy and international rules-based order.

Department contact

Pepijn Bergsen

Research Fellow, Europe Programme
020 795 75748

More on Transatlantic Dialogue on China




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Britain Must Balance a Transatlantic Heart With a European Head

19 December 2019

Robin Niblett

Director and Chief Executive, Chatham House
Returning from an EU-rooted foreign and economic policy to one which is more international in outlook will be difficult, take time, and be more costly than the new UK government currently envisages.

GettyImages-1189074470.jpg

Boris Johnson chairs the first cabinet meeting after winning a majority of 80 seats in the 2019 UK general election. Photo by Matt Dunham – WPA Pool/Getty Images.

The convincing general election win for the Conservative Party and Boris Johnson opens a new chapter in British history. On 31 January 2020, Britain will withdraw from the EU and return to its historical position as a separate European power.

Recognising the strategic significance of this change, the Queen’s speech opening the new parliament stated that 'the government will undertake the deepest review of Britain's security, defence, and foreign policy since the end of the Cold War'. But in what context?

Prime Minister Boris Johnson and other Brexit supporters have yearned for Britain to return to its exceptional trajectory. In their view, Britain can once again become a trading nation - more global in outlook and ambition than its European neighbours, freed from the shackles of an ageing and fractured European continent and its deadening regulatory hand.

This imagery makes good copy. But the 21st century does not offer Britain the same opportunities as did the 18th, 19th or early 20th centuries. This is a different world, and Britain’s position in it needs to be crafted with a sharp eye to what is possible.

Geopolitics undergoing wrenching change

This is not declinism. The UK remains an economically strong and politically influential country by relative global standards – it is currently the fifth or sixth largest economy in the world, and the second largest donor of official development assistance. It has ubiquitous cultural brands from fashion and music to the royal family, and an eminent diplomatic and security position at the heart of all of the world’s major international institutions and alliances, from NATO and the UN security council to the IMF, G7, G20 and Commonwealth. 

But Britain leaves the EU just as the geopolitical landscape is undergoing wrenching change. The United States has turned inwards, closer to its own historic norm, and is undermining the international institutions which it created alongside Britain in the 1940s. China’s international influence is on the rise alongside its vast and still growing economy, challenging traditional norms of individual freedom and public transparency.

Russia is navigating the cracks and crevices of the fracturing rules-based international order with ruthless efficiency. Sensing the change in the wind, many governments are now back-tracking on their post-Cold War transitions to more open and democratic societies.

The implications of this new context have yet to be fully internalised by those who look forward to Britain’s future outside the EU. Britain will be negotiating new trade deals in an increasingly transactional, fragmented and protectionist international economic environment. It will be trying to sell its world-class services into markets where national control over finance, law, technology and media is increasingly prized.

Making new diplomatic inroads will be no easier. The government will face strong internal and external criticism if it lends security assistance to states that are simultaneously clamping down on their citizens’ rights. With the number of military personnel in decline and investment in new equipment stretched across multiple expensive platforms, the UK could struggle to project meaningful defence cooperation to new security partners in Asia at the same time as upholding its NATO commitments and its deployments in conflict zones around the world.

Britain also opens its new global chapter at a time when it is changing domestically. There is no over-riding reason for a missionary British foreign policy – neither the economic returns or image of national glory that drove Empire, nor the existential defence of its land, interests and freedom that drove it during the Cold War.

Stretching liberal interventionism to Iraq, as Tony Blair did when he was prime minister, and to Libya as David Cameron did in 2011, has injected a deep dose of popular scepticism to the idea that Britain - with or without allies - can or should help make the world in its own image.

This more defensive mindset – epitomised by parliament’s refusal to use military force to punish President Bashar al Assad’s regime for using chemical weapons against its citizens in 2013 – will not abate soon. Especially when the new government’s political bandwidth will be stretched by fiendishly complex trade-offs between its financial promises to support domestic renewal, the imperatives of striking and implementing a new free trade agreement with the EU, and the economic consequences of leaving the single market.

All this points to the fact that the most important step for Britain at the beginning of this new national chapter will be to establish an effective partnership with the EU and its member states. They face the same international risks as Britain and have as much to gain from the preservation of rules-based international behaviour. Recognising the continued interdependence between Britain and the EU will offer both sides greater leverage in a more competitive and hostile world.

A new transatlantic relationship

Once it has agreed its new relationship with the EU, Britain can turn to crafting its new relationship with the mighty United States. US-UK economic interdependence and close security ties should help discipline the bilateral economic relationship. The more difficult challenge will be for the UK to avoid falling into fissures between the US and the EU over how to manage bilateral relations with China and Russia, particularly if President Trump wins a second term.

Britain will have to get used to this difficult balancing act between its transatlantic heart and European head after Brexit. This makes it all the more important for the UK to develop new diplomatic and commercial initiatives with countries that are also struggling to cope with the current uncertain, transactional international environment.

Canada, Japan, South Korea, Australia and New Zealand can grow as bilateral economic partners and as allies in international institutions, such as the G7, OECD and WTO. They may even open a door to British engagement in regional trade arrangements such as the Comprehensive and Progressive Agreement for Trans-Pacific Partnership (CP-TPP), which do not require the same political commitments as EU membership.

Turning from an EU-rooted foreign and economic policy to one that is once again more international in outlook will be difficult, take time and be more costly than the government currently envisages. The irony is that for this to be successful requires sustained political investment by the Johnson government to build a strong relationship with the EU that it is focused on leaving.




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Chile’s Social Unrest: Why It’s Time to Get Serious about a ‘Just’ Transition

4 November 2019

Patrick Schröder

Senior Research Fellow, Energy, Environment and Resources Programme
President Sebastián Piñera’s decision to cancel the COP25 climate negotiations, which Chile was due to host in early December, shows the importance of ensuring the transition to a sustainable world is just.

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Demonstrators march in Santiago, Chile during street protests which erupted over a now suspended hike in metro ticket prices. Photo: Getty Images.

One year ago, during the last annual Conference of Parties (COP) held in Katowice, the Polish government launched a Solidarity and Just Transition Declaration, signed by 56 governments including the UK, making the case for why the green transition must be just.

Three years earlier in 2015, the landmark Paris Agreement also included provisions for a just transition where it stated that the decarbonization process should be ‘Taking into account the imperatives of a just transition of the workforce and the creation of decent work and quality jobs in accordance with nationally defined development priorities’. In practice, however, the concept of a just transition has not yet been implemented and has not been sufficiently considered by governments or corporations around the world.

The social unrest that has erupted in Chile’s capital Santiago over the past month, which has forced the Chilean government to ask to move this year’s COP to Madrid, is a case in point. This discontent clearly shows that climate action cannot be separated from social justice concerns. There has not been a real commitment by governments to ensure a just transition based on social dialogue from the local to the national level. This was seen in France with the gilets jaunes protests in November 2018 – one month after President Emmanuel Macron ended the so-called ‘fortune tax’ and instead introduced taxes on diesel fuel as part of an effort to transition to green energy – and the current situation in Chile has some striking parallels. 

Sustainability transitions are a complex web of political choices and investment decisions which affect countries and societies in many different ways. Questions of social justice are everywhere, but in most cases, poorly understood by decision-makers. For example, although poverty has been reduced significantly over the last decade, Chile has one of the worst rates of inequality in Latin America and the highest Gini index in the OECD. The decisions taken in 2017 to power Metro de Santiago with solar photovoltaics and wind energy are commendable from a climate perspective, however, it led to students and young people protesting against rises in subway fares in October 2019.

They were joined by Chileans who are frustrated with rising living costs and by workers and trade unions struggling with low wages. As reported by the Chilean Human Rights Commission (INDH), so far more than 4,200 people have been arrested and more than 1,300 injured and hospitalized.

Climate negotiations beyond technicalities

This time there is also another important dimension to the protests: social unrest as a reaction to worsening inequality has the potential to derail multilateral cooperation on climate change and other global issues. Since tackling climate change is a race against the clock, the world faces the challenge of addressing both urgency and equity. The world cannot afford delays and needs to move fast but decision-makers need to take time for deliberation and civic participation to avoid rapid and ill-conceived transitions which eventually meet public resistance.

Many technical experts and negotiators, who often unintentionally divorce climate policy and technical discussions about emission reductions from social justice concerns, have been caught by surprise by the cancellation of the negotiations. For this year’s COP, one important focus of the official negotiations are the so-called 'Article 6 Rules' – the accounting mechanisms and modalities for a new form of international interaction on carbon markets and off-setting to ensure carbon markets can support countries in enhancing the ambitions of their stated climate action, known as Nationally Determined Contributions (NDCs). 

What is becoming much more obvious now is that just transitions are at least equally important for achieving NDCs and other long-term mitigation strategies.

In order to meet the 1.5 degree target, stated by the Intergovernmental Panel on Climate Change (IPCC), the world will have to invest an average of around $3 trillion a year over the next three decades in transforming its energy supply systems. But how can we ensure that these investments benefit low-income communities? Will they further increase everyday living costs? The climate finance related discussions focussing on commercially-oriented investments for low-carbon energy systems in most cases only consider the aspect of affordability, but not the other important principles of alternative ‘just’ energy finance, such as good governance, due process, intra-generational equity, spatial equity and financial resilience. Investments to support just transitions need to ensure investments, not only for large energy infrastructure, but also in the jobs, skills and work vital to both adaptation and mitigation.

Just transitions for a circular economy

The just transition concept is also the entry point to broader discussions about inclusive economic transformations, questioning the dominant paradigm of consumerism and ending the wasteful use of critical resources. The current linear economic model of take-make-throw away – in Chile epitomized by the linear extractive model of the mining sector that has contributed to widening inequality – the linear extractive model is not only destructive on the natural environment but also destructive for social cohesion.

In Chile, the commodity boom in copper production – the country accounts for about 30 per cent of the world’s output – and more recently lithium – which is used in batteries for mobile phones, laptops and electric cars – have generated enormous prosperity in Chile. But the wealth has been unequally distributed and has not been used to lay the foundation for raising the overall level of incomes.

A socially embedded and inclusive circular economy can, therefore, be a way forward from the current situation the Latin American country finds itself in. The circular economy was intended to feature prominently during the 25th COP and Chile’s policies – from the Ministry of Environment and Chile's Production Development Corporation (CORFO) – have played an important role in supporting the development of a circular economy, launching in 2018, the first public circular economy programme in Latin America

The government’s support for start-up companies and entrepreneurs to develop inclusive circular economy business models is the right approach to addressing the issues of waste, employment, services for low-income communities and local economic development. These are solutions that need to be scaled up having the potential to reduce Chile’s economic reliance on the dominant extractive model.

As a global community, it is necessary to address the environmental and social objectives equally as not addressing social objectives will become an obstacle in achieving climate mitigation and solving other environmental issues. 

The Chilean protests are a wake-up call and present an opportunity for the global climate change community – which includes governments – to ensure just transitions are implemented in practice.




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Climate Change, Energy Transition, and the Extractive Industries Transparency Initiative (EITI)

Invitation Only Research Event

17 January 2020 - 9:30am to 5:00pm

Chatham House | 10 St James's Square | London | SW1Y 4LE

Climate change and energy transition are re-shaping the extractive sectors, and the opportunities and risks they present for governments, companies and civil society. As the central governance standard in the extractives sector, the EITI has a critical role in supporting transparency in producer countries.

This workshop will bring together experts from the energy and extractives sectors, governance and transparency, and climate risk and financial disclosure initiatives to discuss the role of governance and transparency through the transition. It will consider the appropriate role for the EITI and potential entry points for policy and practice, and the potential for coordination with related transparency and disclosure initiatives. 

Please note attendance is by invitation only.




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Just Circular Economy Transitions in Latin America

Invitation Only Research Event

11 December 2019 - 9:00am to 12 December 2019 - 5:00pm

Montevideo, Uruguay

To identify and promote collaborative opportunities for an inclusive and sustainable circular economy transition at the international level, a clearer understanding and discussions of the potential winners and losers of such a transition is needed. In short, a ‘win-win-win’ vision for the environment, people and the economy, needs to be built and credible pathways to achieving this vision.

This research workshop, organized by Chatham House and UNIDO, will build on previous and ongoing research by Chatham House, and others, to drive forward an inclusive circular economy agenda and promote a just transition from linear to circular economic models. Chatham House, in collaboration with partners, aims to provide a strong evidence base of the opportunities and trade-offs in this transition from linear to circular models by robustly analysing the political economies in key regions in the developing world and engaging with leading stakeholders from governments, international organizations, civil society and the business community.

Latin America is an important geographical region for the circular economy especially in view of the circular bioeconomy and the agenda around inclusiveness. Several countries are beginning to embrace the circular economy concept and related policies. This workshop will bring together circular economy leaders from policy, business and civil society across Latin American countries to identify and discuss challenges, large-scale positive sum opportunities, investment needs, existing alliances and the potential to scale up circular economy practices. The second day of the workshop includes site visits to various circular economy projects in Uruguay.

Attendance at this event is by invitation only. 

Melissa MacEwen

Project Manager, Energy, Environment and Resources Programme




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Promoting a Just Transition to an Inclusive Circular Economy

1 April 2020

Considerations of justice and social equity are as important for the circular economy transition as they are in the contexts of low-carbon transitions and digitalization of the economy. This paper sets out the just transition approach, and its relevance in climate change and energy transition debates.

Patrick Schröder

Senior Research Fellow, Energy, Environment and Resources Programme

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Residents of Mount Ijen take sulphur at Ijen Crater, Banyuwangi, East Java, on 2 July 2018. Photo: Getty Images.

Summary

  • Many social and political issues have so far been neglected in planning for the circular economy transition. This paper aims to redress this by considering how ‘just transition’ and social equity may be achieved through policy and practice.
  • The prevailing economic model is linear, in that resources are extracted, transformed into products, used, and finally discarded. In contrast, the circular economy recognizes that natural resources are finite, and aims to keep the materials in products in circulation for as long as possible: reusing, repairing, remanufacturing, sharing and recycling. While the concept of the circular economy is largely focused on developing new technologies and businesses to enable keeping materials in circulation, it also includes the notions of ‘designing out’ waste, substituting renewable materials for non-renewable ones, and restoring natural systems.
  • The UN 2030 Agenda demonstrates that environmental, social and economic sustainability objectives cannot be separated. As the links between the environmental issues of climate change, overconsumption of resources and waste generation, and social issues of inequality and the future of work become increasingly obvious, the urgency to connect environmental with social justice is gaining in significance. The language of ‘just transition’ – a transition that ensures environmental sustainability, decent work, social inclusion and poverty eradication – has started to penetrate debates and research on sustainability policy, particularly in the contexts of climate change and low-carbon energy transition.
  • A just transition framework for the circular economy can identify opportunities that reduce waste and stimulate product innovation, while at the same time contributing positively to sustainable human development. And a just transition is needed to reduce inequalities within and between countries, and to ensure that the commitment of the UN Sustainable Development Goals to leave no one behind is fulfilled.
  • It is important to identify the likely impacts on employment as a result of digitalization and industrial restructuring. Combining circular economy policies with social protection measures will be important in order to ensure that the burden of efforts to promote circularity will not fall on the poor through worsening working conditions and health impacts, reduced livelihoods, or job losses. Identifying potential winners and losers through participatory ‘roadmapping’ can help shape effective cooperation mechanisms and partnerships nationally and internationally.
  • Many low- and middle-income countries that rely heavily on ‘linear’ sectors such as mining, manufacturing of non-repairable fast-moving consumer goods, textiles and agriculture, and the export of these commodities to higher-income countries, are likely to be negatively affected by the shift to circularity. These countries will need support from the international community through targeted assistance programmes if international trade in established commodities and manufactures declines in the medium to long term. 
  • International cooperation to create effective and fair governance mechanisms, and policy coordination at regional, national and local levels will play an important role in shaping a just transition. Multilateral technical assistance programmes will need to be designed and implemented, in particular to support low- and middle-income countries.
  • Governments, international development finance institutions and banks are among the bodies beginning to establish circular economy investment funds and programmes. Just transition principles are yet to be applied to many of these new finance mechanisms, and will need to be integrated into development finance to support the circular economy transition.
  • New international cooperation programmes, and a global mechanism to mobilize dedicated support funds for countries in need, will be critical to successful implementation across global value chains. Transparent and accountable institutions will also be important in ensuring that just transition funds reach those affected as intended.




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Impact of 1,N6-ethenoadenosine, a damaged ribonucleotide in DNA, on translesion synthesis and repair [Enzymology]

Incorporation of ribonucleotides into DNA can severely diminish genome integrity. However, how ribonucleotides instigate DNA damage is poorly understood. In DNA, they can promote replication stress and genomic instability and have been implicated in several diseases. We report here the impact of the ribonucleotide rATP and of its naturally occurring damaged analog 1,N6-ethenoadenosine (1,N6-ϵrA) on translesion synthesis (TLS), mediated by human DNA polymerase η (hpol η), and on RNase H2–mediated incision. Mass spectral analysis revealed that 1,N6-ϵrA in DNA generates extensive frameshifts during TLS, which can lead to genomic instability. Moreover, steady-state kinetic analysis of the TLS process indicated that deoxypurines (i.e. dATP and dGTP) are inserted predominantly opposite 1,N6-ϵrA. We also show that hpol η acts as a reverse transcriptase in the presence of damaged ribonucleotide 1,N6-ϵrA but has poor RNA primer extension activities. Steady-state kinetic analysis of reverse transcription and RNA primer extension showed that hpol η favors the addition of dATP and dGTP opposite 1,N6-ϵrA. We also found that RNase H2 recognizes 1,N6-ϵrA but has limited incision activity across from this lesion, which can lead to the persistence of this detrimental DNA adduct. We conclude that the damaged and unrepaired ribonucleotide 1,N6-ϵrA in DNA exhibits mutagenic potential and can also alter the reading frame in an mRNA transcript because 1,N6-ϵrA is incompletely incised by RNase H2.




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Genetic evidence for reconfiguration of DNA polymerase {theta} active site for error-free translesion synthesis in human cells [DNA and Chromosomes]

The action mechanisms revealed by the biochemical and structural analyses of replicative and translesion synthesis (TLS) DNA polymerases (Pols) are retained in their cellular roles. In this regard, DNA polymerase θ differs from other Pols in that whereas purified Polθ misincorporates an A opposite 1,N6-ethenodeoxyadenosine (ϵdA) using an abasic-like mode, Polθ performs predominantly error-free TLS in human cells. To test the hypothesis that Polθ adopts a different mechanism for replicating through ϵdA in human cells than in the purified Pol, here we analyze the effects of mutations in the two highly conserved tyrosine residues, Tyr-2387 and Tyr-2391, in the Polθ active site. Our findings that these residues are indispensable for TLS by the purified Pol but are not required in human cells, as well as other findings, provide strong evidence that the Polθ active site is reconfigured in human cells to stabilize ϵdA in the syn conformation for Hoogsteen base pairing with the correct nucleotide. The evidence that a DNA polymerase can configure its active site entirely differently in human cells than in the purified Pol establishes a new paradigm for DNA polymerase function.




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Facts about English Learners and the NCLB/ESSA Transition in Select States

These fact sheets provide a sketch of key characteristics of the foreign-born and English Learner (EL) populations in select states. The fact sheets look at the demographics of these states, discuss EL student outcomes as measured by standardized tests, and conclude with an overview of state accountability mechanisms that affect ELs under relevant provisions of the Every Student Succeeds Act and predecessor No Child Left Behind Act.




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Revolution and Political Transition in Tunisia: A Migration Game Changer?

With a history of encouraging workers to emigrate to relieve unemployment at home, Tunisia now has 11 percent of its population living abroad. The factors underlying the 2011 revolution that sparked the Arab Spring have also fueled emigration desires for many Tunisians. This country profile explores historical and current trends in Tunisia from colonial settlement to the aftermath of the Arab Spring, and the new focus on migrant rights at home and abroad.




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Egypt: Migration and Diaspora Politics in an Emerging Transit Country

From being a source of labor emigration to the Gulf region to a destination for refugees from Syria, sub-Saharan Africa, and elsewhere, Egypt has long experienced different forms of mobility. This article, which profiles the trends and policies that have shaped Egypt's migration history, focuses on its long-standing use of migration as a soft-power tool to achieve its foreign policy aims and as a safety valve for political discontent.




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The Germany-Turkey Migration Corridor: Refitting Policies for a Transnational Age

This Transatlantic Council on Migration report describes how the migration of nationals between Germany and Turkey has developed over recent decades; examines the economic, social, and political factors behind this development; and discusses the policy implications and lessons that can be drawn.




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Superior Long-term Survival for Simultaneous Pancreas-Kidney Transplantation as Renal Replacement Therapy: 30-Year Follow-up of a Nationwide Cohort

OBJECTIVE

In patients with type 1 diabetes and end-stage renal disease, it is controversial whether a simultaneous pancreas-kidney (SPK) transplantation improves survival compared with kidney transplantation alone. We compared long-term survival in SPK and living- or deceased-donor kidney transplant recipients.

RESEARCH DESIGN AND METHODS

We included all 2,796 patients with type 1 diabetes in the Netherlands who started renal replacement therapy between 1986 and 2016. We used multivariable Cox regression analyses adjusted for recipient age and sex, dialysis modality and vintage, transplantation era, and donor age to compare all-cause mortality between deceased- or living-donor kidney and SPK transplant recipients. Separately, we analyzed mortality between regions where SPK transplant was the preferred intervention (80% SPK) versus regions where a kidney transplant alone was favored (30% SPK).

RESULTS

Of 996 transplanted patients, 42%, 16%, and 42% received a deceased- or living-donor kidney or SPK transplant, respectively. Mean (SD) age at transplantation was 50 (11), 48 (11), and 42 (8) years, respectively. Median (95% CI) survival time was 7.3 (6.2; 8.3), 10.5 (7.2; 13.7), and 16.5 (15.1; 17.9) years, respectively. SPK recipients with a functioning pancreas graft at 1 year (91%) had the highest survival (median 17.4 years). Compared with deceased-donor kidney transplant recipients, adjusted hazard ratios (95% CI) for 10- and 20-year all-cause mortality were 0.79 (0.49; 1.29) and 0.98 (0.69; 1.39) for living-donor kidney and 0.67 (0.46; 0.98) and 0.79 (0.60; 1.05) for SPK recipients, respectively. A treatment strategy favoring SPK over kidney transplantation alone showed 10- and 20-year mortality hazard ratios of 0.56 (0.40; 0.78) and 0.69 (0.52; 0.90), respectively.

CONCLUSIONS

Compared with living- or deceased-donor kidney transplantation, SPK transplant was associated with improved patient survival, especially in recipients with a long-term functioning pancreatic graft, and resulted in an almost twofold lower 10-year mortality rate.




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Targeting CXCR1/2 Does Not Improve Insulin Secretion After Pancreatic Islet Transplantation: A Phase 3, Double-Blind, Randomized, Placebo-Controlled Trial in Type 1 Diabetes

OBJECTIVE

Reparixin is an inhibitor of CXCR1/2 chemokine receptor shown to be an effective anti-inflammatory adjuvant in a pilot clinical trial in allotransplant recipients.

RESEARCH DESIGN AND METHODS

A phase 3, multicenter, randomized, double-blind, parallel-assignment study (NCT01817959) was conducted in recipients of islet allotransplants randomized (2:1) to reparixin or placebo in addition to immunosuppression. Primary outcome was the area under the curve (AUC) for C-peptide during the mixed-meal tolerance test at day 75 ± 5 after the first and day 365 ± 14 after the last transplant. Secondary end points included insulin independence and standard measures of glycemic control.

RESULTS

The intention-to-treat analysis did not show a significant difference in C-peptide AUC at both day 75 (27 on reparixin vs. 18 on placebo, P = 0.99) and day 365 (24 on reparixin vs. 15 on placebo, P = 0.71). There was no statistically significant difference between treatment groups at any time point for any secondary variable. Analysis of patient subsets showed a trend for a higher percentage of subjects retaining insulin independence for 1 year after a single islet infusion in patients receiving reparixin as compared with patients receiving placebo (26.7% vs. 0%, P = 0.09) when antithymocyte globulin was used as induction immunosuppression.

CONCLUSIONS

In this first double-blind randomized trial, islet transplantation data obtained with reparixin do not support a role of CXCR1/2 inhibition in preventing islet inflammation-mediated damage.




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Surprise! Transitioning to online teaching

 By Abbe Herzig, AMS Director of Education Many of us are experiencing stress as schools, colleges and universities move instruction out of the classroom. Fortunately, even if distance learning is new to you, it isn’t new, and there is a … Continue reading




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Kentucky Wildcats land star Wake Forest transfer Olivier Sarr

The University of Kentucky has landed a commitment from former Wake Forest big man Olivier Sarr, one of the top transfers ahead of the 2020 season.




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Phase 3 Trial of Transplantation of Human Islets in Type 1 Diabetes Complicated by Severe Hypoglycemia

Bernhard J. Hering
Jul 1, 2016; 39:1230-1240
Emerging Technologies and Therapeutics




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Efficacy and Safety of Canagliflozin, a Sodium-Glucose Cotransporter 2 Inhibitor, as Add-on to Insulin in Patients With Type 1 Diabetes

Robert R. Henry
Dec 1, 2015; 38:2258-2265
Special Article Collection: Insulin




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Sodium-Glucose Cotransporter 2 Inhibition and Glycemic Control in Type 1 Diabetes: Results of an 8-Week Open-Label Proof-of-Concept Trial

Bruce A. Perkins
May 1, 2014; 37:1480-1483
Novel Communications in Diabetes




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Improvement in Outcomes of Clinical Islet Transplantation: 1999-2010

Franca B. Barton
Jul 1, 2012; 35:1436-1445
Diabetes Care Symposium




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Effects of Gender-Affirming Hormone Therapy on Insulin Sensitivity and Incretin Responses in Transgender People

OBJECTIVE

The long-term influences of sex hormone administration on insulin sensitivity and incretin hormones are controversial. We investigated these effects in 35 transgender men (TM) and 55 transgender women (TW) from the European Network for the Investigation of Gender Incongruence (ENIGI) study.

RESEARCH DESIGN AND METHODS

Before and after 1 year of gender-affirming hormone therapy, body composition and oral glucose tolerance tests (OGTTs) were evaluated.

RESULTS

In TM, body weight (2.8 ± 1.0 kg; P < 0.01), fat-free mass (FFM) (3.1 ± 0.9 kg; P < 0.01), and waist-to-hip ratio (–0.03 ± 0.01; P < 0.01) increased. Fasting insulin (–1.4 ± 0.8 mU/L; P = 0.08) and HOMA of insulin resistance (HOMA-IR) (2.2 ± 0.3 vs. 1.8 ± 0.2; P = 0.06) tended to decrease, whereas fasting glucose (–1.6 ± 1.6 mg/dL), glucose-dependent insulinotropic polypeptide (GIP) (–1.8 ± 1.0 pmol/L), and glucagon-like peptide 1 (GLP-1) (–0.2 ± 1.1 pmol/L) were statistically unchanged. Post-OGTT areas under the curve (AUCs) for GIP (2,068 ± 1,134 vs. 2,645 ± 1,248 [pmol/L] x min; P < 0.01) and GLP-1 (2,352 ± 796 vs. 2,712 ± 1,015 [pmol/L] x min; P < 0.01) increased. In TW, body weight tended to increase (1.4 ± 0.8 kg; P = 0.07) with decreasing FFM (–2.3 ± 0.4 kg; P < 0.01) and waist-to-hip ratio (–0.03 ± 0.01; P < 0.01). Insulin (3.4 ± 0.8 mU/L; P < 0.01) and HOMA-IR (1.7 ± 0.1 vs. 2.4 ± 0.2; P < 0.01) rose, fasting GIP (–1.4 ± 0.8 pmol/L; P < 0.01) and AUC GIP dropped (2,524 ± 178 vs. 1,911 ± 162 [pmol/L] x min; P < 0.01), but fasting glucose (–0.3 ± 1.4 mg/dL), GLP-1 (1.3 ± 0.8 pmol/L), and AUC GLP-1 (2,956 ± 180 vs. 2,864 ± 93 [pmol/L] x min) remained unchanged.

CONCLUSIONS

In this cohort of transgender persons, insulin sensitivity but also post-OGTT incretin responses tend to increase with masculinization and to decrease with feminization.