Kir2.1, a strong inward rectifier potassium channel encoded by the KCNJ2 gene, is a key regulator of the resting membrane potential of the cardiomyocyte and plays an important role in controlling ventricular excitation and action potential duration in the human heart. Mutations in KCNJ2 result in inheritable cardiac diseases in humans, e.g. the type-1 Andersen-Tawil syndrome (ATS1). Understanding the molecular mechanisms that govern the regulation of inward rectifier potassium currents by Kir2.1 in both normal and disease contexts should help uncover novel targets for therapeutic intervention in ATS1 and other Kir2.1-associated channelopathies. The information available to date on protein-protein interactions involving Kir2.1 channels remains limited. Additional efforts are necessary to provide a comprehensive map of the Kir2.1 interactome. Here we describe the generation of a comprehensive map of the Kir2.1 interactome using the proximity-labeling approach BioID. Most of the 218 high-confidence Kir2.1 channel interactions we identified are novel and encompass various molecular mechanisms of Kir2.1 function, ranging from intracellular trafficking to cross-talk with the insulin-like growth factor receptor signaling pathway, as well as lysosomal degradation. Our map also explores the variations in the interactome profiles of Kir2.1^WT versus Kir2.1^314-315, a trafficking deficient ATS1 mutant, thus uncovering molecular mechanisms whose malfunctions may underlie ATS1 disease. Finally, using patch-clamp analysis, we validate the functional relevance of PKP4, one of our top BioID interactors, to the modulation of Kir2.1-controlled inward rectifier potassium currents. Our results validate the power of our BioID approach in identifying functionally relevant Kir2.1 interactors and underline the value of our Kir2.1 interactome as a repository for numerous novel biological hypotheses on Kir2.1 and Kir2.1-associated diseases.

After ejaculation, mammalian spermatozoa must undergo a process known as capacitation in order to successfully fertilize the oocyte. Several post-translational modifications occur during capacitation, including sialylation, which despite being limited to a few proteins, seems to be essential for proper sperm-oocyte interaction. Regardless of its importance, to date, no single study has ever identified nor quantified which glycoproteins bearing terminal sialic acid (Sia) are altered during capacitation. Here we characterize sialylation during mouse sperm capacitation. Using tandem MS coupled with liquid chromatography (LC–MS/MS), we found 142 nonreductant peptides, with 9 of them showing potential modifications on their sialylated oligosaccharides during capacitation. As such, N-linked sialoglycopeptides from C4b-binding protein, endothelial lipase (EL), serine proteases 39 and 52, testis-expressed protein 101 and zonadhesin were reduced following capacitation. In contrast, mitochondrial aconitate hydratase (aconitase; ACO2), a TCA cycle enzyme, was the only protein to show an increase in Sia content during capacitation. Interestingly, although the loss of Sia within EL (N62) was accompanied by a reduction in its phospholipase A₁ activity, a decrease in the activity of ACO2 (i.e. stereospecific isomerization of citrate to isocitrate) occurred when sialylation increased (N612). The latter was confirmed by N612D recombinant protein tagged with both His and GFP. The replacement of Sia for the negatively charged Aspartic acid in the N612D mutant caused complete loss of aconitase activity compared with the WT. Computer modeling show that N612 sits atop the catalytic site of ACO2. The introduction of Sia causes a large conformational change in the alpha helix, essentially, distorting the active site, leading to complete loss of function. These findings suggest that the switch from oxidative phosphorylation, over to glycolysis that occurs during capacitation may come about through sialylation of ACO2.

Coronavirus disease 2019 (COVID-19) is a highly contagious infection and threating the human lives in the world. The elevation of cytokines in blood is crucial to induce cytokine storm and immunosuppression in the transition of severity in COVID-19 patients. However, the comprehensive changes of serum proteins in COVID-19 patients throughout the SARS-CoV-2 infection is unknown. In this work, we developed a high-density antibody microarray and performed an in-depth proteomics analysis of serum samples collected from early COVID-19 (n = 15) and influenza (n = 13) patients. We identified a large set of differentially expressed proteins (n = 132) that participate in a landscape of inflammation and immune signaling related to the SARS-CoV-2 infection. Furthermore, the significant correlations of neutrophil and lymphocyte with the CCL2 and CXCL10 mediated cytokine signaling pathways was identified. These information are valuable for the understanding of COVID-19 pathogenesis, identification of biomarkers and development of the optimal anti-inflammation therapy.

Over the past decade, modern methods of MS (MS) have emerged that allow reliable, fast and cost-effective identification of pathogenic microorganisms. Although MALDI-TOF MS has already revolutionized the way microorganisms are identified, recent years have witnessed also substantial progress in the development of liquid chromatography (LC)-MS based proteomics for microbiological applications. For example, LC-tandem MS (LC-MS²) has been proposed for microbial characterization by means of multiple discriminative peptides that enable identification at the species, or sometimes at the strain level. However, such investigations can be laborious and time-consuming, especially if the experimental LC-MS² data are tested against sequence databases covering a broad panel of different microbiological taxa. In this proof of concept study, we present an alternative bottom-up proteomics method for microbial identification. The proposed approach involves efficient extraction of proteins from cultivated microbial cells, digestion by trypsin and LC–MS measurements. Peptide masses are then extracted from MS¹ data and systematically tested against an in silico library of all possible peptide mass data compiled in-house. The library has been computed from the UniProt Knowledgebase covering Swiss-Prot and TrEMBL databases and comprises more than 12,000 strain-specific in silico profiles, each containing tens of thousands of peptide mass entries. Identification analysis involves computation of score values derived from correlation coefficients between experimental and strain-specific in silico peptide mass profiles and compilation of score ranking lists. The taxonomic positions of the microbial samples are then determined by using the best-matching database entries. The suggested method is computationally efficient – less than 2 mins per sample - and has been successfully tested by a test set of 39 LC-MS¹ peak lists obtained from 19 different microbial pathogens. The proposed method is rapid, simple and automatable and we foresee wide application potential for future microbiological applications.

Endometrial carcinoma (EC) is the most common gynecologic malignancy in the United States, with limited effective targeted therapies. Endometrial tumors exhibit frequent alterations in protein kinases, yet only a small fraction of the kinome has been therapeutically explored. To identify kinase therapeutic avenues for EC, we profiled the kinome of endometrial tumors and normal endometrial tissues using Multiplexed Inhibitor Beads and Mass Spectrometry (MIB-MS). Our proteomics analysis identified a network of kinases overexpressed in tumors, including Serine/Arginine-Rich Splicing Factor Kinase 1 (SRPK1). Immunohistochemical (IHC) analysis of endometrial tumors confirmed MIB-MS findings and showed SRPK1 protein levels were highly expressed in endometrioid and uterine serous cancer (USC) histological subtypes. Moreover, querying large-scale genomics studies of EC tumors revealed high expression of SRPK1 correlated with poor survival. Loss-of-function studies targeting SRPK1 in an established USC cell line demonstrated SRPK1 was integral for RNA splicing, as well as cell cycle progression and survival under nutrient deficient conditions. Profiling of USC cells identified a compensatory response to SRPK1 inhibition that involved EGFR and the up-regulation of IGF1R and downstream AKT signaling. Co-targeting SRPK1 and EGFR or IGF1R synergistically enhanced growth inhibition in serous and endometrioid cell lines, representing a promising combination therapy for EC.

Specific E3 ligases target tumor suppressors for degradation. Inhibition of such E3 ligases may be an important approach to cancer treatment. RNF146 is a RING domain and PARylation-dependent E3 ligase that functions as an activator of the β-catenin/Wnt and YAP/Hippo pathways by targeting the degradation of several tumor suppressors. Tankyrases 1 and 2 (TNKS1/2) are the only known poly-ADP-ribosyltransferases that require RNF146 to degrade their substrates. However, systematic identification of RNF146 substrates have not yet been performed. To uncover substrates of RNF146 that are targeted for degradation, we generated RNF146 knockout cells and TNKS1/2-double knockout cells and performed proteome profiling with label-free quantification as well as transcriptome analysis. We identified 160 potential substrates of RNF146, which included many known substrates of RNF146 and TNKS1/2 and 122 potential TNKS-independent substrates of RNF146. In addition, we validated OTU domain-containing protein 5 and Protein mono-ADP-ribosyltransferase PARP10 as TNKS1/2-independent substrates of RNF146 and SARDH as a novel substrate of TNKS1/2 and RNF146. Our study is the first proteome-wide analysis of potential RNF146 substrates. Together, these findings not only demonstrate that proteome profiling can be a useful general approach for the systemic identification of substrates of E3 ligases but also reveal new substrates of RNF146, which provides a resource for further functional studies.

Le ventre est l’une des parties du corps où il est plus difficile de perdre de la graisse. Souvent, la meilleure solution pour arriver à perdre de la graisse à cet endroit précis du corps consiste à manger sainement et équilibré. Cependant, quels sont les aliments qui brûlent les graisses du ventre sans danger pour la […]

L’article Quels sont les aliments qui brûlent rapidement les graisses du ventre ? est apparu en premier sur Ortho Doc France.

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Ankylosing Spondylitis (AS) is a common, inflammatory rheumatic disease, which primarily affects the axial skeleton and is associated with sacroiliitis, uveitis and enthesitis. Unlike other autoimmune rheumatic diseases, such as rheumatoid arthritis or systemic lupus erythematosus, autoantibodies have not yet been reported to be a feature of AS. We therefore wished to determine if plasma from patients with AS contained autoantibodies and if so, characterize and quantify this response in comparison to patients with Rheumatoid Arthritis (RA) and healthy controls. Two high-density nucleic acid programmable protein arrays expressing a total of 3498 proteins were screened with plasma from 25 patients with AS, 17 with RA and 25 healthy controls. Autoantigens identified were subjected to Ingenuity Pathway Analysis in order to determine patterns of signalling cascades or tissue origin. 44% of patients with Ankylosing Spondylitis demonstrated a broad autoantibody response, as compared to 33% of patients with RA and only 8% of healthy controls. Individuals with AS demonstrated autoantibody responses to shared autoantigens, and 60% of autoantigens identified in the AS cohort were restricted to that group. The AS patients autoantibody responses were targeted towards connective, skeletal and muscular tissue, unlike those of RA patients or healthy controls. Thus, patients with AS show evidence of systemic humoral autoimmunity and multispecific autoantibody production. Nucleic Acid Programmable Protein Arrays constitute a powerful tool to study autoimmune diseases.

Colorectal cancer (CRC) arises as the consequence of progressive changes from normal epithelial cells through polyp to tumor, and thus is an useful model for studying metabolic shift. In the present study, we studied the metabolomic profiles using high analyte specific gas chromatography/mass spectrometry (GC/MS) and liquid chromatography tandem mass spectrometry (LC/MS/MS) to attain a systems-level view of the shift in metabolism in cells progressing along the path to CRC. Colonic tissues including tumor, polyps and adjacent matched normal mucosa from 26 patients with sporadic CRC from freshly isolated resections were used for this study. The metabolic profiles were obtained using GC/MS and LC/MS/MS. Our data suggest there was a distinct profile change of a wide range of metabolites from mucosa to tumor tissues. Various amino acids and lipids in the polyps and tumors were elevated, suggesting higher energy needs for increased cellular proliferation. In contrast, significant depletion of glucose and inositol in polyps revealed that glycolysis may be critical in early tumorigenesis. In addition, the accumulation of hypoxanthine and xanthine, and the decrease of uric acid concentration, suggest that the purine biosynthesis pathway could have been substituted by the salvage pathway in CRC. Further, there was a step-wise reduction of deoxycholic acid concentration from mucosa to tumors. It appears that to gain a growth advantage, cancer cells may adopt alternate metabolic pathways in tumorigenesis and this flexibility allows them to adapt and thrive in harsh environment.

This article has been withdrawn by the authors. We discovered an error after this manuscript was published as a Paper in Press. Specifically, we learned that the structures of glycans presented for the PD-L1 peptide were drawn and labeled incorrectly. We wish to withdraw this article and submit a corrected version for review.

Many cell surface and secreted proteins are modified by the covalent addition of glycans that play an important role in the development of multicellular organisms. These glycan modifications enable communication between cells and the extracellular matrix via interactions with specific glycan-binding lectins and the regulation of receptor-mediated signaling. Aberrant protein glycosylation has been associated with the development of several muscular diseases suggesting essential glycan- and lectin-mediated functions in myogenesis and muscle development but our molecular understanding of the precise glycans, catalytic enzymes and lectins involved remain only partially understood. Here, we quantified dynamic remodeling of the membrane-associated proteome during a time-course of myogenesis in cell culture. We observed wide-spread changes in the abundance of several important lectins and enzymes facilitating glycan biosynthesis. Glycomics-based quantification of released N-linked glycans confirmed remodeling of the glycome consistent with the regulation of glycosyltransferases and glycosidases responsible for their formation including a previously unknown di-galactose-to-sialic acid switch supporting a functional role of these glycoepitopes in myogenesis. Furthermore, dynamic quantitative glycoproteomic analysis with multiplexed stable isotope labelling and analysis of enriched glycopeptides with multiple fragmentation approaches identified glycoproteins modified by these regulated glycans including several integrins and growth factor receptors. Myogenesis was also associated with the regulation of several lectins most notably the up-regulation of galectin-1 (LGALS1). CRISPR/Cas9-mediated deletion of Lgals1 inhibited differentiation and myotube formation suggesting an early functional role of galectin-1 in the myogenic program. Importantly, similar changes in N-glycosylation and the up-regulation of galectin-1 during postnatal skeletal muscle development were observed in mice. Treatment of new-born mice with recombinant adeno-associated viruses to overexpress galectin-1 in the musculature resulted in enhanced muscle mass. Our data form a valuable resource to further understand the glycobiology of myogenesis and will aid the development of intervention strategies to promote healthy muscle development or regeneration.

Gonadal soma-derived factor (gsdf) has been demonstrated to be essential for testicular differentiation in medaka (Oryzias latipes). To understand the protein dynamics of Gsdf in spermatogenesis regulation, we used a His-tag "pull-down" assay coupled with shotgun LC-MS/MS to identify a group of potential interacting partners for Gsdf, which included cytoplasmic dynein light chain 2, eukaryotic polypeptide elongation factor 1 alpha (eEF1α), and actin filaments in mature medaka testis. As for the interaction with TGFβ-dynein being critical for spermatogonial division in Drosophila melanogaster, the physical interactions of Gsdf-dynein and Gsdf-eEF1α were identified through a yeast 2-hybrid (Y2H) screening of an adult testis cDNA library using Gsdf as bait, which were verified by a paired Y2H assay. Co-immunoprecipitation of Gsdf and eEF1α was defined in adult testes as supporting the requirement of a Gsdf and eEF1α interaction in testis development. Proteomics analysis (data are available via ProteomeXchange with identifier PXD022153) and ultrastrutural observations showed that Gsdf deficiency activated eEF1α-mediated protein synthesis and ribosomal biogenesis, which in turn led to the differentiation of undifferentiated germ cells. Thus, our results provide a framework and new insight into the coordination of a Gsdf (TGFβ and eEF1α complex in the basic processes of germ cell proliferation, transcriptional and translational control of sexual RNA which may be fundamentally conserved across phyla during sexual differentiation.

Staphylococcus aureus is a major cause of infections worldwide and infection results in a variety of diseases. As of no surprise, protein phosphorylation is an important game player in signaling cascades and has been shown to be involved in S. aureus virulence. Albeit long neglected, eukaryotic-type serine/threonine kinases in S. aureus have been implicated in this complex signaling cascades. Due to the sub-stoichiometric nature of protein phosphorylation and a lack of suitable analysis tools, the knowledge of these cascades is however, to date, still limited.

Here, were apply an optimized protocol for efficient phosphopeptide enrichment via Fe3+-IMAC followed by LC-MS/MS to get a better understanding of the impact of protein phosphorylation on the complex signaling networks involved in pathogenicity. By profiling a serine/threonine kinase and phosphatase mutant from a methicillin-resistant S. aureus mutant library, we generated the most comprehensive phosphoproteome dataset of S. aureus to date, aiding a better understanding of signaling in bacteria. With the identification of 3800 class I p-sites we were able to increase the number of identifications by more than 21 times compared to recent literature. In addition, we were able to identify 74 downstream targets of the only reported eukaryotic-type Ser/Thr kinase of the S. aureus strain USA300, Stk1. This work allowed an extensive analysis of the bacterial phosphoproteome and indicates that Ser/Thr kinase signaling is far more abundant than previously anticipated in S. aureus.

Alpha-1-acid glycoprotein (AGP) is an acute phase glycoprotein in blood, which is primarily synthetized in the liver and whose biological role is not completely understood. It consists of 45% carbohydrates that are present in the form of five N-linked complex glycans. AGP N-glycosylation was shown to be changed in many different diseases and some changes appear to be disease-specific, thus it has a great diagnostic and prognostic potential. However, AGP glycosylation was mainly analyzed in small cohorts and without detailed site-specific glycan information. Here, we developed a cost-effective method for a high-throughput and site-specific N-glycosylation LC-MS analysis of AGP which can be applied on large cohorts, aid in search for novel disease biomarkers and enable better understanding of AGP’s role and function in health and disease. The method does not require isolation of AGP with antibodies and affinity chromatography, but AGP is enriched by acid precipitation from 5 μl of bloodplasma in a 96 well format. After trypsinization, AGP glycopeptides are purified using a hydrophilic interaction chromatography based solid-phase extraction and analyzed by RP-LC-ESI-MS. We used our method to show for the first time that AGP N-glycan profile is stable in healthy individuals (14 individuals in 3 time points), which is a requirement for evaluation of its diagnostic potential. Furthermore, we tested our method on a population including individuals with registered hyperglycemia in critical illness (59 cases and 49 controls), which represents a significantly increased risk of developing type 2 diabetes. Individuals at higher risk of diabetes presented increased N-glycan branching on AGP’s second glycosylation site and lower sialylation of N-glycans on AGP’s third and AGP1’s fourth glycosylation site. Although this should be confirmed on a larger prospective cohort, it indicates that site-specific AGP N-glycan profile could help distinguish individuals who are at risk of type 2 diabetes.

Annual Review 2017-18 Other resource sysadmin 18 July 2018

Explore the institute’s output, activities and achievements from the past year examining how to make the world more secure in uncertain times; new thinking on how societies can flourish and be prosperous; and how to contribute to a more just society.

Director’s statement

I wrote a year ago that the world has entered one of the most politically turbulent periods in the modern era. This rings even more true now, as relations have seriously deteriorated between the US administration and its European allies, while instability persists across the Middle East, and China and Russia increase their strategic influence.

Over the past year, Chatham House has assessed these changes and proposed ways to manage the associated risks, while seeking out opportunities to expand prosperity and security across the world. Adam Ward, our deputy director, led the publication of the first Chatham House Expert Perspectives report on risks and opportunities in international affairs, to coincide with our fifth annual London Conference on 21–22 June 2018. The conference was attended by over 450 participants from 71 countries.

Furthermore, using our new simulation centre on the Stavros Niarchos Foundation (SNF) Floor, our research teams are ‘stress-testing’ their ideas in exercises involving both practitioners and experts. For example, in June 2017 the Centre on Global Health Security and the Africa Programme hosted our first scenario exercise, which explored how to respond to a humanitarian emergency that required landmine clearance. Since then, we have hosted other simulation and scenario planning exercises, including on cyberattacks, Brexit ‘futures’ and the rise of the populist parties in Europe.

We have also used the new facilities to host events supported by modern audiovisual systems; to stress-test our own communications strategy; and even to conduct a round of scenario-based interactive job interviews. The new media studio and editing facilities have led us to create more multimedia content, which has, in turn, enabled us to reach expanded and more diverse audiences for our work. The new SNF Floor has also provided staff with an open, multifunctional meeting area and has alleviated some of the space pressures which had been created by our growing staff numbers.

As you will read in the following pages, our research is currently centred around three themes: making the world more secure in uncertain times; offering new ideas on how societies can flourish and be prosperous; and contributing to a more just society. A growing number of cross-cutting projects enable us to address topics within each of these themes, including cyberthreats, transatlantic relations, the future of the EU–China economic relationship, regulating data, vulnerabilities in global food trade and implementing universal health coverage.

Our ability to do so has been enhanced by the appointment of several new senior research staff: Hans Kundnani as senior fellow in the Europe Programme; Champa Patel as head of the Asia- Pacific Programme; and Leslie Vinjamuri as head of the US and the Americas Programme and dean of the Queen Elizabeth II Academy for Leadership in International Affairs. In addition, Bernice Lee will take over as the new research director of our Global Economy and Finance Department, alongside her continuing role as executive director of the Hoffmann Centre for Sustainable Resource Economy.

During the coming months, we will lay the foundations to mark the institute’s centenary in the summer of 2020. In doing so, we will draw on our archives to acknowledge the institute’s unique achievements over the past 100 years, recognize those many individuals who have supported us along the way, and set out our objectives for the future. In preparation, we have already launched a series of members’ events with a historical focus, examining how the lessons from the past can inform international affairs and policy thinking today.

In closing, I would like to pay tribute and offer my sincere thanks to Stuart Popham, who steps down this year after six years as chair of the institute and 13 years between 2005 and 2018 as a member of Council. Stuart has been a tremendous support and guide to me, and to the institute as a whole, during this period. His measured advice to management and collegiate leadership of Council have been invaluable during a period in which the institute has more than doubled in size, and in which it has thrived despite the increasingly competitive environment for policy convening, analysis and ideas. We look forward to welcoming Stuart back to Chatham House as a highly engaged individual member, and wish him all the best for the future.

Robin Niblett CMG

Annual Review 2018-19 Other resource sysadmin 24 July 2019

Explore the institute’s output, activities and achievements from the past year examining how to make the world more stable in uncertain times, new thinking on how societies can promote prosperity, and how to contribute to a more just society.

Chair’s statement

I was delighted to be elected chair of Chatham House last year. It is an honour to lead such a remarkable institution and to have the opportunity to build on the legacy left by Stuart Popham, who stepped down last year as chair and whom I thank and pay tribute to.

My ambition is to ensure that the institute has an even better future than its illustrious past. We are living in unpredictable times, and I want us to be at the centre of the drive to guide the world to a healthier place both politically and economically.

Chatham House possesses world-leading convening power, which – when combined with our capacity to deliver leading, cross-cutting research – gives us a unique advantage in the field of international relations. I want us to harness these assets and better combine the strengths of our research teams so that we can address the big global challenges around economic growth; avoiding geopolitical tensions; and developing new governance systems (as outlined on page 7). This will enable us to improve our impact and effect more policy change.

I also want Chatham House to be an exciting place that attracts younger, more diverse, international audiences. We need to drive more engagement with the next generation of members and others to draw on their enthusiasm, energy and ideas. Our Common Futures Conversations project, for example, is engaging young people from 13 countries across Africa and Europe to identify their shared concerns, and is enabling them to work together to identify solutions via online communities.

This initiative, and indeed all of our activities, would not be possible without funding and support. As noted in more detail in the Honorary Treasurer’s report (page 32), 2018/19 was a challenging year financially, with income totalling £16,381,000, slightly below the level recorded in 2017/18.

Although total net assets at 31 March 2019 were 3 per cent down year on year, the balance sheet remain strong and there was an inflow of cash, with the level of forward income received and pledged increasing significantly.

In this context, I am delighted to note the award of the transformational £10 million grant to facilitate the creation of the Stavros Niarchos Foundation Wing, which will help facilitate research, host our Queen Elizabeth II Academy for Leadership in International Affairs and establish a new collaboration space – the ‘CoLab’ – for engaging our new audiences. All of Chatham House’s supporters, and not least our members, remain indispensable to our success. Without their engagement, enthusiasm and input, the institute could not fulfil its mission.

I am indebted to my colleagues on Council for their support, engagement and expertise. I can say with confidence that they are actively involved in their governance responsibilities at this time when the operational, as well as financial, pressures on all charitable institutions are more intense than ever.

I would like to pay tribute to Alistair Burnett, Martin Fraenkel and Barbara Ridpath, who step down from Council this year after a total of 15 years’ service. I would also like to thank and acknowledge Robin Niblett and his team for their dedication and hard work. Some of the outcomes of their labours are highlighted on the following pages.

Lord Jim O’Neill

Belarusians’ views on the political crisis - April 2021 Other resource NCapeling 11 June 2021

Results of a public opinion poll conducted between 20 and 30 April 2021.

Chatham House surveyed a total of 937 respondents between 20 and 30 April 2021. Our survey sample corresponds to the general structure of Belarus’s urban population and is corrected and weighted by gender, age, size of respondents’ town of residence and education level.

Summary

• After Lukashenka, the most known political figures in Belarus are pro-protest politicians: Tsikhanouskaya, Babaryka, Tsikhanouski, Kalesnikava, Tsapkala and Latushka. Viktar Babaryka is the most popular presidential candidate among Belarusian urban citizens, and Lukashenka comes second to him.
• State organizations and bodies are still mistrusted by more than half the population, while the army is slightly more popular than other bodies. Independent media, labour unions and human rights organizations are trusted far more than state ones.
• Russia leads when it comes to positive attitudes to foreign states: one in three Belarusians feel very positive about their neighbour and 79 per cent feel positive in general. 71 per cent Belarusians feel positive about China, which is the next highest indicator. Despite propaganda efforts, Ukraine, Lithuania, Poland and EU states in general are still perceived positively by more than 60 per cent of Belarusians, with fewer than 20 per cent feeling negative about them.
• The position on Russian interference in the Belarusian political crisis is consolidated enough: 58 per cent think that Russia should remain neutral. The rest are almost equally divided between those who think Russia should support the protest movement (19 per cent) and those who think Russia should support Lukashenka (23 per cent).
• 40 per cent have changed their attitude to the Russian government since it supported Lukashenka in the crisis, and 73 per cent are sure that Russia is his sole support.
• While 32 per cent of Belarusians see union with Russia as the most appropriate foreign policy, 46 per cent would like to be in a union with both Russia and the EU simultaneously.
• Almost half the population thinks that Belarusian foreign policy in the event of a pro-protest government coming to power would be oriented toward friendship and cooperation with both Russia and the West, which correlates with how the majority thinks it should be. Although 42 per cent expect foreign policy would lean toward the EU in that situation, which is less acceptable: only 25 per cent think it ‘should’.
• The proportion of respondents who think Belarus should remain in the Collective Security Treaty Organization is 58 per cent, while 35 per cent would like to see Belarus not belonging to any military bloc and a small share (seven per cent) would prefer Belarus to join NATO.
• Almost half of the population considers Lukashenka to be the major obstacle for political stability and economic development and is sure he does not care about, and in fact is a threat to, independence.
• In general, most Belarusians have a consolidated opinion that the authorities should start negotiating with opponents and free all political prisoners.
• More than half of Belarusians think that Lukashenka must leave immediately or before the end of 2021, while 27 per cent think he should leave when his term ends in 2025. The opinion that Lukashenka should rule for another term beginning in 2025 is marginal – only ten per cent support this.
• Expectations are not so optimistic though: only 26 per cent believe he will leave office this year. One in three thinks he will leave in 2025; a further 19 per cent say that he will stay on for further terms in office.
• If Lukashenka doesn’t leave, people expect an increase in emigration and unemployment, the continuation of repression in all areas of life, falling exchange rates and the tightening of dependency on Russia.
• Opinion on abortions is still consolidated, with only 19 per cent thinking they should be banned in most or all cases. The same applies to Lukashenka’s infamous statement that society in Belarus is not ready to have a female president: only 20 per cent agree with the opinion.
• 52 per cent don’t think there is a problem of wage inequality between men and women in Belarus, while 37 per cent do see an issue.

Download a presentation of the survey’s main findings

Impact report 2020–21 Other resource dora.popova 14 July 2021

Explore our policy impact in the past year, including through our research, convening and next generation initiatives, in a revised format annual review.

Chair’s statement

It has been an extraordinary year of change for us all. The COVID-19 pandemic is the greatest challenge to the world for generations. Millions have lost their lives or suffered devastating impacts on their health, both from COVID-19 itself and because health systems have been unable to deliver treatments for other conditions. The pandemic has also caused the greatest shock to the global economy since the 1930s, setting back the progress of recent years in eliminating poverty, getting more children into education and improving global health.

This means Chatham House is needed more than ever. Our world-leading convening and cutting-edge research on the major challenges facing the world, from building more sustainable economic growth and tackling climate change to easing geopolitical tensions, has continued despite the challenges of lockdown. For that I pay tribute to the resilience and ingenuity of the staff who have found innovative solutions to the obstacles presented by the pandemic, all while working largely from home.

This year I am also delighted to note the exceptional gift of £10 million from the MAVA Foundation to enable us to launch the Sustainability Accelerator. This initiative builds on the Hoffmann Centre’s last five years of innovative convening and activity. And it puts sustainability at the core of the institute’s work in this critical year for addressing climate change and biodiversity.

So, as I prepare to step down from my three years as chair of the institute, I would like to thank my fellow Council members and Robin Niblett and his team for their hard work and ambition to deliver on Chatham House’s mission. I have also been especially pleased to see how we are engaging younger, more diverse audiences through the next generation initiatives, including our Panel of Young Advisers, the Common Futures Conversations project, the QEII Academy Ambassadors, our Internship Programme and the Chatham House-SNF CoLab.

I am particularly pleased about the Chatham House Summer School, where 16–18-year-olds can now engage with experts on international affairs and get an insight into careers within the charity and not-for-profit sector.

It has been an honour to lead this extraordinary institution and I look forward to continuing my involvement with Chatham House in new ways.

Lord Jim O’Neill

Belarusians’ views on the political crisis - Nov 2021 Other resource NCapeling 20 January 2022

Results of a public opinion poll conducted between 1 and 10 November 2021.

Chatham House surveyed a total of 767 respondents between 1 and 10 November 2021. Our survey sample corresponds to the general structure of Belarus’s urban population and is adjusted by gender, age, education level and the size of respondents’ place of residence.

Summary

• After Aliaksandr Lukashenka, the most well-known political figures in Belarus are the protest leaders: Sviatlana Tsikhanouskaya, Viktar Babaryka, Siarhei Tsikhanouski, Valery Tsapkala, Marya Kalesnikava and Pavel Latushka.
• Lukashenka and Babaryka have the highest popularity ratings among Belarus’s urban population. At the same time, Lukashenka has a high negative rating: half of the city residents surveyed say that they would never vote for him. Babaryka has one of the lowest negative ratings in the country.
• The popularity ratings of pro-government politicians are low, and their negative ratings remain extremely high, although the latter have decreased slightly in comparison with July 2021. The popularity ratings of protest leaders are significantly higher than those of politicians who support the current government.
• Trust in state and independent organizations is polarized along political lines. Thus, respondents classed as hardcore protesters do not trust state structures and do trust independent ones, while Lukashenka’s supporters hold the opposite positions.
• Belarusians’ geopolitical orientations remain stable. The most widely preferred option for a geopolitical union is simultaneous integration with the EU and Russia.
• Belarusians have become increasingly negative about the possibility that Russian airbases could be established on Belarusian territory (48 per cent in November 2021, compared to 39 per cent in July 2021).
• Belarusians are now feeling more strongly that the situation concerning the COVID-19 pandemic has worsened: in November, more than half were beginning to respond that Belarus is unable to cope with the spread of coronavirus.
• Sanctions against Lukashenka and those around him are supported more widely than sanctions against state enterprises.
• Belarusians feel there is acute social tension in their country: almost everyone surveyed states that social tension exists, while one in every five respondents considers the situation catastrophic. A perception that there is social tension is closely related to many factors, with the strongest of all being a sense of a lack of personal safety.
• Only one-third of Belarusians are prepared to call the state built under Lukashenka their own. Most of the survey respondents do not trust this state to some degree, and do not believe that the state protects the interests of Belarusian citizens.

Download a presentation of the survey’s main findings

• Belarusians’ views on the political crisis (PDF)

• Взгляды белорусов на политический кризис (PDF)

Annual Review 2021–22 Other resource NCapeling 11 July 2022

Explore highlights from our work over the past year, including research, events, and next generation initiatives.

Chair’s statement

The past 12 months have seen new levels of instability injected into international affairs. The consequences of the COVID-19 pandemic, the continued fracturing of the international system and Russia’s war on Ukraine, which triggered the largest movement of refugees since the Second World War, have had severe impacts on trade, prices and people around the world.

Chatham House’s Russia and Eurasia Programme and its Ukraine Forum have advised allied governments on their response to the war on Ukraine, and secured the participation of Ukrainian president Volodymyr Zelenskyy in the most watched event of the institute’s history.

The challenge now is to ensure Chatham House can bring together its diverse areas of research and offer influential ideas on how to respond to the uncertain future. Council has supported the push to define clear priorities for the institute’s work, and the launch of two new research centres covering sustainability and global governance.

Drawing out the best from the institute’s expertise in the changed geopolitical landscape will be a top priority for Bronwen Maddox when she takes over as director at the end of August. Council is delighted to have found such a worthy successor to Robin Niblett. Robin’s 15 years of inspiring leadership have seen the institute more than triple in size of staff and budget. New areas of research under his tenure include cyber policy, digital governance, global health, the US and the Americas, and the UK in the world post-Brexit.

Robin also launched the Queen Elizabeth II Academy for Leadership in International Affairs, providing the base for many initiatives to engage the next generation. He also leaves the institute with a rebuilt balance sheet after securing some major long-term gifts; expanded and renovated premises; and a strong communications and digital infrastructure that has raised the profile of Chatham House with our audiences.

Council places on record the institute’s debt to Robin and to his wife, Trisha de Borchgrave. Chatham House’s supporters around the world were delighted to see Robin awarded a knighthood in HM The Queen’s Birthday Honours 2022.

I pay tribute also to my predecessor, Jim O’Neill, and I am grateful to Simon Fraser, deputy chair, and to the other four retiring members of Council (Mimi Ajibadé, Heide Baumann, Kenneth Cukier and Tim Willasey-Wilsey) for their dedication and counsel.

Council will continue to focus on strengthening the impact of the institute’s work and on improving governance, as well as providing continuity during the leadership transition. We will act as a strategic partner for Bronwen as she takes Chatham House forward. Central to this will be implementing the institute’s plan to strengthen equality, diversity and inclusion across the board. Finally, I thank the staff for their commitment through this period of transformation.

Sir Nigel Sheinwald GCMG

100 years of International Affairs Other resource dora.popova 1 March 2023

Charting a century of key moments in international relations and International Affairs.

International Affairs was created to be a record of speeches given by visiting dignitaries at Chatham House. Over the last 100 years, the journal has evolved into an independent academic journal publishing work of the highest quality.

On the fringes of the Paris peace conference Lionel Curtis called for an organization whose purpose would be to foster mutual understanding of and between nations. Chatham House was established in 1920 and for much of the time since, International Affairs has been a central part of the institute’s publishing output.

As such, for most of its history, contributions to the journal have reflected the prevailing attitudes of the time, both in terms of who was published and the content of their work. Perhaps the most important change over the last century has been the increasing diversity of voices and perspectives published in IA’s pages. Today, as the journal enters its second century, it publishes authors from across the globe. Yet the editorial team is all too aware there is still much to do.

Keep reading to explore the journal’s history and to find out more about our second century.

The drawings in this timeline were commissioned by the International Affairs team from Sequential Potential Comics.

In nucleotide excision repair, bulky DNA lesions such as UV-induced cyclobutane pyrimidine dimers are removed from the genome by concerted dual incisions bracketing the lesion, followed by gap filling and ligation. So far, two dual-incision patterns have been discovered: the prokaryotic type, which removes the damage in 11–13-nucleotide-long oligomers, and the eukaryotic type, which removes the damage in 24–32-nucleotide-long oligomers. However, a recent study reported that the UvrC protein of Mycobacterium tuberculosis removes damage in a manner analogous to yeast and humans in a 25-mer oligonucleotide arising from incisions at 15 nt from the 3´ end and 9 nt from the 5´ end flanking the damage. To test this model, we used the in vivo excision assay and the excision repair sequencing genome-wide repair mapping method developed in our laboratory to determine the repair pattern and genome-wide repair map of Mycobacterium smegmatis. We find that M. smegmatis, which possesses homologs of the Escherichia coli uvrA, uvrB, and uvrC genes, removes cyclobutane pyrimidine dimers from the genome in a manner identical to the prokaryotic pattern by incising 7 nt 5´ and 3 or 4 nt 3´ to the photoproduct, and performs transcription-coupled repair in a manner similar to E. coli.

The faithful segregation, or “partition,” of many low-copy number bacterial plasmids is driven by plasmid-encoded ATPases that are represented by the P1 plasmid ParA protein. ParA binds to the bacterial nucleoid via an ATP-dependent nonspecific DNA (nsDNA)-binding activity, which is essential for partition. ParA also has a site-specific DNA-binding activity to the par operator (parOP), which requires either ATP or ADP, and which is essential for it to act as a transcriptional repressor but is dispensable for partition. Here we examine how DNA binding by ParA contributes to the relative distribution of its plasmid partition and repressor activities, using a ParA with an alanine substitution at Arg351, a residue previously predicted to participate in site-specific DNA binding. In vivo, the parAR351A allele is compromised for partition, but its repressor activity is dramatically improved so that it behaves as a “super-repressor.” In vitro, ParAR351A binds and hydrolyzes ATP, and undergoes a specific conformational change required for nsDNA binding, but its nsDNA-binding activity is significantly damaged. This defect in turn significantly reduces the assembly and stability of partition complexes formed by the interaction of ParA with ParB, the centromere-binding protein, and DNA. In contrast, the R351A change shows only a mild defect in site-specific DNA binding. We conclude that the partition defect is due to altered nsDNA binding kinetics and affinity for the bacterial chromosome. Furthermore, the super-repressor phenotype is explained by an increased pool of non-nucleoid bound ParA that is competent to bind parOP and repress transcription.

Faithful replication of the mitochondrial genome is carried out by a set of key nuclear-encoded proteins. DNA polymerase γ is a core component of the mtDNA replisome and the only replicative DNA polymerase localized to mitochondria. The asynchronous mechanism of mtDNA replication predicts that the replication machinery encounters dsDNA and unique physical barriers such as structured genes, G-quadruplexes, and other obstacles. In vitro experiments here provide evidence that the polymerase γ heterotrimer is well-adapted to efficiently synthesize DNA, despite the presence of many naturally occurring roadblocks. However, we identified a specific G-quadruplex–forming sequence at the heavy-strand promoter (HSP1) that has the potential to cause significant stalling of mtDNA replication. Furthermore, this structured region of DNA corresponds to the break site for a large (3,895 bp) deletion observed in mitochondrial disease patients. The presence of this deletion in humans correlates with UV exposure, and we have found that efficiency of polymerase γ DNA synthesis is reduced after this quadruplex is exposed to UV in vitro.

All 30 Major League teams will wear special "MLB 150" patches on their uniforms for the entire 2019 season in honor of the 150th anniversary of the 1869 Cincinnati Red Stockings, the first openly all-salaried professional baseball team.

Odubel Herrera smiled and patted his stomach. The paunch that he carried into Spring Training 2018 is no longer there. Herrera has reported to camp leaner and, as he said Friday morning at Spectrum Field, motivated to bounce back from the worst season of his four-year career.

Spring Training is imminent, Opening Day is within sight and the big league season isn't complete for fans without a subscription to MLB.TV. The most comprehensive streaming service in professional sports is now available for the 2019 season.

MLB.com looked at each team's two highest-ranked position players in WAR, according to the Steamer projections. Here are the top 10, but keep in mind that things could change once Manny Machado and Bryce Harper find homes.

Since debuting in 2011, center fielder Mike Trout has been far and away the best player in the Majors, but the Angels have reached the postseason just once in his eight-year career.

All 30 Major League teams will wear special "MLB 150" patches on their uniforms for the entire 2019 season in honor of the 150th anniversary of the 1869 Cincinnati Red Stockings, the first openly all-salaried professional baseball team.

The 2019 MLB season feels so close now. Spring Training has begun. Players are taking the field. So it's time to rank the best of the best.

VOLUME 289 (2014) PAGES 6604–6618In Fig. 4G, in the foxi1 panel, the images in Fig. 4G, i and l, corresponding to “smad1 MO” and “smad5 MO + samd1/9 mRNA” samples, respectively, were inadvertently reused during figure preparation. This error has now been corrected using images pertaining to each treatment and sample. This correction does not affect the results or conclusions of the work.jbc;295/52/18650/F4F1F4Figure 4G.

Angola Forum 2018: 30th Anniversary of the Battle of Cuito Cuanavale 23 March 2018 — 10:00AM TO 2:30PM Anonymous (not verified) 8 March 2018 Chatham House, London

Reflections on Southern Africa’s Turning Point

23 March 2018 marks the 30th anniversary of the final assault of what became known as the Battle of Cuito Cuanavale.

The confrontation between the Angolan army, supported by Cuba and the Soviet Union, and the armed opposition UNITA, supported by the South African Defence Force, is the largest land battle to have taken place in Africa since World War Two.

The battle was a watershed in Angolan and southern African history, but its significance continues to be contested. Today, although the battlefield has a monument and museum, it remains one of the most landmine-contaminated parts of Angola and this hinders development plans for international tourism.

This event brings together veterans and experts to contribute towards developing a deeper understanding of the battle. Discussions will further focus on the significance of the wider events around the battle, its regional implications, as well as the legacy of the battlefield.

South Africa’s 2019 Election: Polling Data and Party Prospects 13 March 2019 — 12:30PM TO 1:30PM Anonymous (not verified) 7 March 2019 Chatham House, London

On 8 May 2019, South Africans will vote in their sixth national election. Incumbent President Cyril Ramaphosa is leading his ANC party campaign, which promises inclusive economic growth and social transformation, including through a sustainable land reform programme. However, public frustrations with the party’s record of service delivery and government corruption after 25 years in power could threaten the ANC’s electoral dominance especially in urban areas.

At this meeting, Professor David Everatt, head of the Wits School of Governance and political pollster, will present polling data and discuss the prospects and strategies of the main parties and their leaders ahead of the May election.

Attendance at this event is by invitation only.

COVID-19 in South Africa: Leadership, Resilience and Inequality Expert comment sysadmin 7 May 2020

In a world looking for leadership, South Africa’s president Cyril Ramaphosa has been remarkable. One year after he carried the time-worn ANC through a national election, South Africans are crying out for more.

In the COVID-19 crisis so far, Cyril Ramaphosa has been widely praised for displaying the decisive leadership so many hoped for when they cast their ballot for him in May 2019. Buttressed by others such as health minister Dr Zweli Mkhize, and on a simple objective to prevent transmission, South Africa has been a lesson to the world. Act fast. Act hard.

Former president Thabo Mbeki’s disastrous response to the HIV crisis cast a long shadow over his legacy, and Ramaphosa has taken note. South Africa has had one of the tightest lockdowns in the world. No exercise. No cigarettes. No alcohol.

The lockdown was imposed when the country had only around 1,000 recorded cases and just two deaths. As a result, transmission from returning travellers has not yet led to an exponential infection rate within the community. The government’s swift reaction has bought much needed time with the peak now seemingly delayed to September or October.

Continental and national leadership

Ramaphosa has also emerged as a key focal point for Africa-wide responses. As current chair of the African Union (AU) he leads the continental engagement with the World Health Organization (WHO), and the various international finance institutions, while South African officials are working with the AU and the United Nations Economic Commission for Africa (UNECA) on a push for African debt restructuring.

He has also been active in trouble shooting to unlock external assistance to the continent, including from China and Russia. Appointing special envoys is typical of his boardroom-honed leadership style.

International and regional partnerships are vital for resilience and the arrival of 217 Cuban doctors to South Africa is strongly reminiscent of the liberationist solidarity of the Cold War era. And regional economies remain dependent on South Africa to protect their own vulnerable citizens. Following the 2008 financial crisis, it was South Africa’s regional trading relationships that remained robust, while trade with its main global partners in China and the US dropped.

Despite the plaudits, Ramaphosa remains vulnerable to challenge at home, notably around his failure to stimulate South Africa’s moribund economy. On the eve of lockdown, Moody’s joined its peers Standard and Poor’s and Fitch in giving South Africa a below investment grade credit rating. The move was a long time coming. Long mooted economic reforms were slow to materialise, and South Africa had fallen into recession.

Ramaphosa depends on a small core of close advisors and allies, initially united in apparent opposition to the kleptocratic rule of President Jacob Zuma and the deep patronage networks he created within both the party and the state. But this allegiance is being tested by economic reality. Support within the party was already drifting prior to the crisis.

Disagreements are not just technocratic – there are big ideological questions in play around the role of the state in the economy, the level of intervention, and its affordability, with key government figures sceptical of rapid market reforms. Energy minister and former union stalwart Gwede Mantashe is wary of job losses, and minister of public enterprises Pravin Gordhan protective of state-owned enterprises (SOEs). Before coronavirus hit, Ramaphosa seemed content to allow these policy disputes to play themselves out with little decisive intervention.

Slow progress on reform, against worsening economic performance, left Ramaphosa and his allies exposed. In January the president missed the UK’s African Investment Summit in order to assert control over a party meeting at which it was expected his detractors would seek to remove Gordhan.

COVID-19 has sharpened thinking

As the independently assertive - and eminently quotable - pro-market reformist finance minister Tito Mboweni stated, ‘you can’t eat ideology’. Accelerated reform and restructuring is required if the government turns to the International Monetary Fund (IMF) for assistance.

For the first time, Gordhan has been forced to deny a bailout to beleaguered state airline South African Airways (SAA), and the government’s lockdown bailout of R500 billion has been applauded by business. Much like the fiscal stimulus and recovery plan of 2018, it relies on smart spending, targeting sectors with high multiplier effects. It also includes significant reserve bank loans.

But it has been criticised for not doing enough to help the most vulnerable. There is considerable fear of what could happen when the virus takes hold in South Africa’s townships and informal settlements where social distancing is almost impossible, basic toilet facilities are shared, and HIV and TB rates high.

There are mounting concerns of the humanitarian cost of a prolonged lockdown, and the government has been faster than others in implementing a tiered lockdown system, trying to get people back to work and keep the economy afloat.

South Africa has been criticized by the UN for the use of lethal force by security forces in enforcing lockdown and, in a society plagued by corruption, there are fears legislation to stop the spread of false information could be used to restrict legitimate reporting on the virus response or other issues.

COVID-19 shines a spotlight on societies’ fault-lines worldwide. South Africa is often touted as having one of the highest levels of inequality in the world but, in a globalized economy, these divisions are international as much as they are local.

Resilience comes from within, but also depends on regional and global trading and financial systems. South Africans and international partners have long recognised Ramaphosa’s leadership qualities as an impressive voice for the global south.

But he must also be an advocate for South Africa’s poor. This crisis could accelerate implementation of his landmark pro-poor National Health Insurance and Universal Health Care programmes. Or the hit of COVID-19 on top of South Africa’s existing economic woes could see them derailed entirely. Ramaphosa must push through economic reforms at the same time as managing COVID-19 and rebuilding trust in his government.

Webinar: South Africa's Economic Recovery Beyond COVID-19 27 May 2020 — 1:00PM TO 2:00PM Anonymous (not verified) 18 May 2020

Angola Forum 2021: Policy options to support economic recovery in Angola 7 October 2021 — 2:00PM TO 5:00PM Anonymous (not verified) 22 September 2021 Online

Speakers discuss policy options to support economic recovery in Angola as the country transitions away from a state-led oil economy to a private-sector-led growth model.

The government of Angola has made some progress on a range of policies targeting macroeconomic stability and structural reform. However, the country has been suffering from a recurring economic recession for six consecutive years, with the last positive annual GDP growth rate posted in 2015 at 0.9 per cent.

The national budget remains dependent on oil revenue, leaving the country highly exposed to volatile oil prices particularly during the COVID-19 pandemic. While revenues collapsed, increased spending was needed to respond to the health crisis and estimates of Angola’s debt spike range from 130 to 150 per cent of its GDP by the close of 2020.

At this virtual Angola Forum, speakers discuss policy options to support economic recovery in Angola as the country transitions away from a state-led oil economy to a private-sector-led growth model.

The Forum launches the English translation of the Angola Economic Report 2019-20 by the Centro de Estudos de Investigação (CEIC) of the Catholic University of Angola in partnership with the Konrad-Adenauer-Stiftung (KAS), and the findings of Afrobarometer’s first ever survey in Angola, Ovilongwa – Estudos de Opinião Pública, which interviewed 2,400 adult Angolans and sampled individual perceptions on democracy and economic reform in Angola.

This event will be held in English and Portuguese with simultaneous interpretation.

The Forum will also be broadcast live on the Africa Programme Facebook page.