N-acylethanolamines (NAEs) are endogenous lipid-signaling molecules derived from fatty acids that regulate numerous biological functions, including in the brain. Interestingly, NAEs are elevated in the absence of fatty acid amide hydrolase (FAAH) and following CO₂-induced ischemia/hypercapnia, suggesting a neuroprotective response. Tetracosahexaenoic acid (THA) is a product and precursor to DHA; however, the NAE product, tetracosahexaenoylethanolamide (THEA), has never been reported. Presently, THEA was chemically synthesized as an authentic standard to confirm THEA presence in biological tissues. Whole brains were collected and analyzed for unesterified THA, total THA, and THEA in wild-type and FAAH-KO mice that were euthanized by either head-focused microwave fixation, CO₂ + microwave, or CO₂ only. PPAR activity by transient transfection assay and ex vivo neuronal output in medium spiny neurons (MSNs) of the nucleus accumbens by patch clamp electrophysiology were determined following THEA exposure. THEA in the wild-type mice was nearly doubled (P < 0.05) following ischemia/hypercapnia (CO₂ euthanization) and up to 12 times higher (P < 0.001) in the FAAH-KO compared with wild-type. THEA did not increase (P > 0.05) transcriptional activity of PPARs relative to control, but 100 nM of THEA increased (P < 0.001) neuronal output in MSNs of the nucleus accumbens. Here were identify a novel NAE, THEA, in the brain that is elevated upon ischemia/hypercapnia and by KO of the FAAH enzyme. While THEA did not activate PPAR, it augmented the excitability of MSNs in the nucleus accumbens. Overall, our results suggest that THEA is a novel NAE that is produced in the brain upon ischemia/hypercapnia and regulates neuronal excitation.

Adaptive thermogenesis is highly dependent on uncoupling protein 1 (UCP1), a protein expressed by thermogenic adipocytes present in brown adipose tissue (BAT) and white adipose tissue (WAT). Thermogenic capacity of human and mouse BAT can be measured by positron emission tomography-computed tomography quantifying the uptake of ¹⁸F-fluodeoxyglucose or lipid tracers. BAT activation is typically studied in response to cold exposure or treatment with β-3-adrenergic receptor agonists such as CL316,243 (CL). Currently, it is unknown whether cold-stimulated uptake of glucose or lipid tracers is a good surrogate marker of UCP1-mediated thermogenesis. In metabolic studies using radiolabeled tracers, we found that glucose uptake is increased in mildly cold-activated BAT of Ucp1^–/– versus WT mice kept at subthermoneutral temperature. Conversely, lower glucose disposal was detected after full thermogenic activation achieved by sustained cold exposure or CL treatment. In contrast, uptake of lipoprotein-derived fatty acids into chronically activated thermogenic adipose tissues was substantially increased in UCP1-deficient mice. This effect is linked to higher sympathetic tone in adipose tissues of Ucp1^–/– mice, as indicated by elevated levels of thermogenic genes in BAT and WAT. Thus, glucose and lipoprotein handling does not necessarily reflect UCP1-dependent thermogenic activity, but especially lipid uptake rather mirrors sympathetic activation of adipose tissues.

Of the known regulators of atherosclerosis, miRNAs have been demonstrated to play critical roles in lipoprotein homeostasis and plaque formation. Here, we generated a novel animal model of atherosclerosis by knocking in LDLR^W483X in C57BL/6 mice, as the W483X mutation in LDLR is considered the most common newly identified pathogenic mutation in Chinese familial hypercholesterolemia (FH) individuals. Using the new in vivo mouse model combined with a well-established atherosclerotic in vitro human cell model, we identified a novel atherosclerosis-related miRNA, miR-23a-3p, by microarray analysis of mouse aortic tissue specimens and human aortic endothelial cells (HAECs). miR-23a-3p was consistently downregulated in both models, which was confirmed by qPCR. Bioinformatics analysis and further validation experiments revealed that the TNFα-induced protein 3 (TNFAIP3) gene was the key target of miR-23a-3p. The miR-23a-3p-related functional pathways were then analyzed in HAECs. Collectively, the present results suggest that miR-23a-3p regulates inflammatory and apoptotic pathways in atherogenesis by targeting TNFAIP3 through the NF-B and p38/MAPK signaling pathways.

Phosphatidate phosphatase (PAP) catalyzes the penultimate step in the synthesis of triacylglycerol and regulates the synthesis of membrane phospholipids. There is much interest in this enzyme because it controls the cellular levels of its substrate, phosphatidate (PA), and product, DAG; defects in the metabolism of these lipid intermediates are the basis for lipid-based diseases such as obesity, lipodystrophy, and inflammation. The measurement of PAP activity is required for studies aimed at understanding its mechanisms of action, how it is regulated, and for screening its activators and/or inhibitors. Enzyme activity is determined through the use of radioactive and nonradioactive assays that measure the product, DAG, or P_i. However, sensitivity and ease of use are variable across these methods. This review summarizes approaches to synthesize radioactive PA, to analyze radioactive and nonradioactive products, DAG and P_i, and discusses the advantages and disadvantages of each PAP assay.

As the COVID-19 pandemic continues to spread, thousands of scientists around the globe have changed research direction to understand better how the virus works and to find out how it may be tackled. The number of manuscripts on preprint servers is soaring and peer-reviewed publications using MS-based proteomics are beginning to emerge. To facilitate proteomic research on SARS-CoV-2, the virus that causes COVID-19, this report presents deep-scale proteomes (10,000 proteins; >130,000 peptides) of common cell line models, notably Vero E6, Calu-3, Caco-2, and ACE2-A549 that characterize their protein expression profiles including viral entry factors such as ACE2 or TMPRSS2. Using the 9 kDa protein SRP9 and the breast cancer oncogene BRCA1 as examples, we show how the proteome expression data can be used to refine the annotation of protein-coding regions of the African green monkey and the Vero cell line genomes. Monitoring changes of the proteome on viral infection revealed widespread expression changes including transcriptional regulators, protease inhibitors, and proteins involved in innate immunity. Based on a library of 98 stable-isotope labeled synthetic peptides representing 11 SARS-CoV-2 proteins, we developed PRM (parallel reaction monitoring) assays for nano-flow and micro-flow LC–MS/MS. We assessed the merits of these PRM assays using supernatants of virus-infected Vero E6 cells and challenged the assays by analyzing two diagnostic cohorts of 24 (+30) SARS-CoV-2 positive and 28 (+9) negative cases. In light of the results obtained and including recent publications or manuscripts on preprint servers, we critically discuss the merits of MS-based proteomics for SARS-CoV-2 research and testing.

Recent efforts in gut microbiome studies have highlighted the importance of explicitly describing the ecological processes beyond correlative analysis. However, we are still at the early stage of understanding the organizational principles of the gut ecosystem, partially because of the limited information provided by currently used analytical tools in ecological modeling practices. Proteomics and metaproteomics can provide a number of insights for ecological studies, including biomass, matter and energy flow, and functional diversity. In this Mini Review, we discuss proteomics and metaproteomics-based experimental strategies that can contribute to studying the ecology, in particular at the mucosal-luminal interface (MLI) where the direct host-microbiome interaction happens. These strategies include isolation protocols for different MLI components, enrichment methods to obtain designated array of proteins, probing for specific pathways, and isotopic labeling for tracking nutrient flow. Integration of these technologies can generate spatiotemporal and site-specific biological information that supports mathematical modeling of the ecosystem at the MLI.

Natural compounds that can stimulate salivary secretion are of interest in developing treatments for xerostomia, the perception of a dry mouth, that affects between 10 and 30% of the adult and elderly population. Chemesthetic transient receptor potential (TRP) channels are expressed in the surface of the oral mucosa. The TRPV1 agonists capsaicin and piperine have been shown to increase salivary flow when introduced into the oral cavity but the sialogogic properties of other TRP channel agonists have not been investigated. In this study we have determined the influence of different TRP channel agonists on the flow and protein composition of saliva. Mouth rinsing with the TRPV1 agonist nonivamide or menthol, a TRPM8 agonist, increased whole mouth saliva (WMS) flow and total protein secretion compared with unstimulated saliva, the vehicle control mouth rinse or cinnamaldehyde, a TRPA1 agonist. Nonivamide also increased the flow of labial minor gland saliva but parotid saliva flow rate was not increased. The influence of TRP channel agonists on the composition and function of the salivary proteome was investigated using a multi-batch quantitative MS method novel to salivary proteomics. Inter-personal and inter-mouth rinse variation was observed in the secreted proteomes and, using a novel bioinformatics method, inter-day variation was identified with some of the mouth rinses. Significant changes in specific salivary proteins were identified after all mouth rinses. In the case of nonivamide, these changes were attributed to functional shifts in the WMS secreted, primarily the over representation of salivary and nonsalivary cystatins which was confirmed by immunoassay. This study provides new evidence of the impact of TRP channel agonists on the salivary proteome and the stimulation of salivary secretion by a TRPM8 channel agonist, which suggests that TRP channel agonists are potential candidates for developing treatments for sufferers of xerostomia.

Studies in the yeast Saccharomyces cerevisiae have helped define mechanisms underlying the activity of the ubiquitin–proteasome system (UPS), uncover the proteasome assembly pathway, and link the UPS to the maintenance of cellular homeostasis. However, the spectrum of UPS substrates is incompletely defined, even though multiple techniques—including MS—have been used. Therefore, we developed a substrate trapping proteomics workflow to identify previously unknown UPS substrates. We first generated a yeast strain with an epitope tagged proteasome subunit to which a proteasome inhibitor could be applied. Parallel experiments utilized inhibitor insensitive strains or strains lacking the tagged subunit. After affinity isolation, enriched proteins were resolved, in-gel digested, and analyzed by high resolution liquid chromatography-tandem MS. A total of 149 proteasome partners were identified, including all 33 proteasome subunits. When we next compared data between inhibitor sensitive and resistant cells, 27 proteasome partners were significantly enriched. Among these proteins were known UPS substrates and proteins that escort ubiquitinated substrates to the proteasome. We also detected Erg25 as a high-confidence partner. Erg25 is a methyl oxidase that converts dimethylzymosterol to zymosterol, a precursor of the plasma membrane sterol, ergosterol. Because Erg25 is a resident of the endoplasmic reticulum (ER) and had not previously been directly characterized as a UPS substrate, we asked whether Erg25 is a target of the ER associated degradation (ERAD) pathway, which most commonly mediates proteasome-dependent destruction of aberrant proteins. As anticipated, Erg25 was ubiquitinated and associated with stalled proteasomes. Further, Erg25 degradation depended on ERAD-associated ubiquitin ligases and was regulated by sterol synthesis. These data expand the cohort of lipid biosynthetic enzymes targeted for ERAD, highlight the role of the UPS in maintaining ER function, and provide a novel tool to uncover other UPS substrates via manipulations of our engineered strain.

Co-fractionation MS (CF-MS) is a technique with potential to characterize endogenous and unmanipulated protein complexes on an unprecedented scale. However this potential has been offset by a lack of guidelines for best-practice CF-MS data collection and analysis. To obtain such guidelines, this study thoroughly evaluates novel and published Saccharomyces cerevisiae CF-MS data sets using very high proteome coverage libraries of yeast gold standard complexes. A new method for identifying gold standard complexes in CF-MS data, Reference Complex Profiling, and the Extending 'Guilt-by-Association' by Degree (EGAD) R package are used for these evaluations, which are verified with concurrent analyses of published human data. By evaluating data collection designs, which involve fractionation of cell lysates, it is found that near-maximum recall of complexes can be achieved with fewer samples than published studies. Distributing sample collection across orthogonal fractionation methods, rather than a single high resolution data set, leads to particularly efficient recall. By evaluating 17 different similarity scoring metrics, which are central to CF-MS data analysis, it is found that two metrics rarely used in past CF-MS studies – Spearman and Kendall correlations – and the recently introduced Co-apex metric frequently maximize recall, whereas a popular metric—Euclidean distance—delivers poor recall. The common practice of integrating external genomic data into CF-MS data analysis is also evaluated, revealing that this practice may improve the precision and recall of known complexes but is generally unsuitable for predicting novel complexes in model organisms. If studying nonmodel organisms using orthologous genomic data, it is found that particular subsets of fractionation profiles (e.g. the lowest abundance quartile) should be excluded to minimize false discovery. These assessments are summarized in a series of universally applicable guidelines for precise, sensitive and efficient CF-MS studies of known complexes, and effective predictions of novel complexes for orthogonal experimental validation.

High-speed analysis of large (prote)omics sample sets at the rate of thousands or millions of samples per day on a single platform has been a challenge since the beginning of proteomics. For many years, ESI-based MS methods have dominated proteomics because of their high sensitivity and great depth in analyzing complex proteomes. However, despite improvements in speed, ESI-based MS methods are fundamentally limited by their sample introduction, which excludes off-line sample preparation/fractionation because of the time required to switch between individual samples/sample fractions, and therefore being dependent on the speed of on-line sample preparation methods such as liquid chromatography. Laser-based ionization methods have the advantage of moving from one sample to the next without these limitations, being mainly restricted by the speed of modern sample stages, i.e. 10 ms or less between samples. This speed matches the data acquisition speed of modern high-performing mass spectrometers whereas the pulse repetition rate of the lasers (>1 kHz) provides a sufficient number of desorption/ionization events for successful ion signal detection from each sample at the above speed of the sample stages. Other advantages of laser-based ionization methods include the generally higher tolerance to sample additives and contamination compared with ESI MS, and the contact-less and pulsed nature of the laser used for desorption, reducing the risk of cross-contamination. Furthermore, new developments in MALDI have expanded its analytical capabilities, now being able to fully exploit high-performing hybrid mass analyzers and their strengths in sensitivity and MS/MS analysis by generating an ESI-like stable yield of multiply charged analyte ions. Thus, these new developments and the intrinsically high speed of laser-based methods now provide a good basis for tackling extreme sample analysis speed in the omics.

Pathway analyses are key methods to analyze 'omics experiments. Nevertheless, integrating data from different 'omics technologies and different species still requires considerable bioinformatics knowledge.

Here we present the novel ReactomeGSA resource for comparative pathway analyses of multi-omics datasets. ReactomeGSA can be used through Reactome's existing web interface and the novel ReactomeGSA R Bioconductor package with explicit support for scRNA-seq data. Data from different species is automatically mapped to a common pathway space. Public data from ExpressionAtlas and Single Cell ExpressionAtlas can be directly integrated in the analysis. ReactomeGSA greatly reduces the technical barrier for multi-omics, cross-species, comparative pathway analyses.

We used ReactomeGSA to characterize the role of B cells in anti-tumor immunity. We compared B cell rich and poor human cancer samples from five of the Cancer Genome Atlas (TCGA) transcriptomics and two of the Clinical Proteomic Tumor Analysis Consortium (CPTAC) proteomics studies. B cell-rich lung adenocarcinoma samples lacked the otherwise present activation through NFkappaB. This may be linked to the presence of a specific subset of tumor associated IgG+ plasma cells that lack NFkappaB activation in scRNA-seq data from human melanoma. This showcases how ReactomeGSA can derive novel biomedical insights by integrating large multi-omics datasets.

L’utilisation du féminin dans les titres de professions dans le domaine de la santé a beaucoup évolué ces dernières années. Cela reflète une prise de conscience croissante de certaines réalités des métiers de la santé et la reconnaissance de la présence de plus en plus importante des femmes dans le domaine. Vous demandez-vous quand mettre les professions au féminin […]

L’article Quand mettre les professions au féminin dans le domaine de la santé ? est apparu en premier sur Ortho Doc France.

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Protein tyrosine kinases (PTKs) play key roles in cellular signal transduction, cell cycle regulation, cell division, and cell differentiation. Dysregulation of PTK-activated pathways, often by receptor overexpression, gene amplification, or genetic mutation, is a causal factor underlying numerous cancers. In this study, we have developed a parallel reaction monitoring (PRM)-based assay for quantitative profiling of 83 PTKs. The assay detects 308 proteotypic peptides from 54 receptor tyrosine kinases and 29 nonreceptor tyrosine kinases in a single run. Quantitative comparisons were based on the labeled reference peptide method. We implemented the assay in four cell models: 1) a comparison of proliferating versus epidermal growth factor (EGF)-stimulated A431 cells, 2) a comparison of SW480Null (mutant APC) and SW480APC (APC restored) colon tumor cell lines, and 3) a comparison of 10 colorectal cancer cell lines with different genomic abnormalities, and 4) lung cancer cell lines with either susceptibility (11-18) or acquired resistance (11-18R) to the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib. We observed distinct PTK expression changes that were induced by stimuli, genomic features or drug resistance, which were consistent with previous reports. However, most of the measured expression differences were novel observations. For example, acquired resistance to erlotinib in the 11-18 cell model was associated not only with previously reported upregulation of MET, but also with upregulation of FLK2 and downregulation of LYN and PTK7. Immunoblot analyses and shotgun proteomics data were highly consistent with PRM data. Multiplexed PRM assays provide a targeted, systems-level profiling approach to evaluate cancer-related proteotypes and adaptations. Data are available through Proteome eXchange Accession PXD002706.

Mass spectrometry-based glycoproteomics has gone through some incredible developments over the last few years. Technological advances in glycopeptide enrichment, fragmentation methods, and data analysis workflows have enabled the transition of glycoproteomics from a niche application, mainly focused on the characterization of isolated glycoproteins, to a mature technology capable of profiling thousands of intact glycopeptides at once. In addition to numerous biological discoveries catalyzed by the technology, we are also observing an increase in studies focusing on global protein glycosylation and the relationship between multiple glycosylation sites on the same protein. It has become apparent that just describing protein glycosylation in terms of micro- and macro-heterogeneity, respectively the variation and occupancy of glycans at a given site, is not sufficient to describe the observed interactions between sites. In this perspective we propose a new term, meta-heterogeneity, to describe a higher level of glycan regulation: the variation in glycosylation across multiple sites of a given protein. We provide literature examples of extensive meta-heterogeneity on relevant proteins such as antibodies, erythropoietin, myeloperoxidase and a number of serum and plasma proteins. Furthermore, we postulate on the possible biological reasons and causes behind the intriguing meta-heterogeneity observed in glycoproteins.

This review covers recent developments in glycosaminoglycan (GAG) analysis via mass spectrometry (MS). GAGs participate in a variety of biological functions, including cellular communication, wound healing, and anticoagulation, and are important targets for structural characterization. GAGs exhibit a diverse range of structural features due to the variety of O- and N-sulfation modifications and uronic acid C-5 epimerization that can occur, making their analysis a challenging target. Mass spectrometry approaches to the structure assignment of GAGs have been widely investigated, and new methodologies remain the subject of development. Advances in sample preparation, tandem MS techniques (MS/MS), on-line separations and automated analysis software have advanced the field of GAG analysis. These recent developments have led to remarkable improvements in the precision and time efficiency for the structural characterization of GAGs.

O-GlcNAcylation, the addition of a single N-acetylglucosamine residue to serine and threonine residues of cytoplasmic, nuclear, or mitochondrial proteins, is a widespread regulatory post-translational modification. It is involved in response to nutritional status and stress and its dysregulation is associated with diseases ranging from Alzheimer’s to diabetes.  While the modification was first detected over thirty-five years ago, research into the function of O-GlcNAcylation has accelerated dramatically in the last ten years due to the development of new enrichment and mass spectrometry techniques that facilitate its analysis.  This article summarizes methods for O-GlcNAc enrichment, key mass spectrometry instrumentation advancements, particularly those that allow modification site localization, and software tools that allow analysis of data from O-GlcNAc modified peptides.

The glycoprotein spike (S) on the surface of SARS-CoV-2 is a determinant for viral invasion and host immune response. Herein, we characterized the site-specific N-glycosylation of S protein at the level of intact glycopeptides. All 22 potential N-glycosites were identified in the S-protein protomer and were found to be preserved among the 753 SARS-CoV-2 genome sequences. The glycosites exhibited glycoform heterogeneity as expected for a human cell-expressed protein subunit. We identified masses that correspond to 157 N-glycans, primarily of the complex type. In contrast, the insect cell-expressed S protein contained 38 N-glycans, completely of the high-mannose type. Our results revealed that the glycan types were highly determined by the differential processing of N-glycans among human and insect cells, regardless of the glycosites’ location. Moreover, the N-glycan compositions were conserved among different sizes of subunits. Our study indicate that the S protein N-glycosylation occurs regularly at each site, albeit the occupied N-glycans were diverse and heterogenous. This N-glycosylation landscape and the differential N-glycan patterns among distinct host cells are expected to shed light on the infection mechanism and present a positive view for the development of vaccines and targeted drugs.

The Rhizobium-legume symbiosis is a beneficial interaction in which the bacterium converts atmospheric nitrogen into ammonia and delivers it to the plant in exchange for carbon compounds. This symbiosis implies the adaptation of bacteria to live inside host plant cells. In this work we apply RP-LC-MS/MS and  iTRAQ techniques to study the proteomic profile of endosymbiotic cells (bacteroids) induced by Rhizobium leguminosarum bv viciae strain UPM791 in legume nodules. Nitrogenase subunits, tricarboxylic acid cycle enzymes, and stress response proteins are amongst the most abundant from over one thousand rhizobial proteins identified in pea (Pisum sativum) bacteroids. Comparative analysis of bacteroids induced in pea and in lentil (Lens culinaris)nodules revealed the existence of a significant host-specific differential response affecting dozens of bacterial proteins, including stress-related proteins, transcriptional regulators, and proteins involved in the carbon and nitrogen metabolisms. A mutant affected in one of these proteins, homologous to a GntR-like transcriptional regulator, showed a symbiotic performance significantly  impaired in symbiosis with pea, but not with lentil plants. Analysis of the proteomes of bacteroids isolated from both hosts also revealed the presence of different sets of plant-derived nodule-specific cysteine rich (NCR) peptides, indicating that the endosymbiotic bacteria find a host-specific cocktail of chemical stressors inside the nodule. By studying variations of the bacterial response to different plant cell environments we will be able to identify specific limitations imposed by the host that might give us clues for the improvement of rhizobial performance.

Urinary proteomics studies have primarily focused on identifying markers of chronic kidney disease (CKD) progression. Here, we aimed to determine urinary markers of CKD renal parenchymal injury through proteomics analysis in animal kidney tissues and cells and in the urine of patients with CKD. Label-free quantitative proteomics analysis based on liquid chromatography-tandem mass spectrometry was performed on urine samples obtained from 6 normal controls and 9, 11, and 10 patients with CKD stages 1, 3, and 5, respectively, and on kidney tissue samples from a rat CKD model by 5/6 nephrectomy. Tandem mass tag-based quantitative proteomics analysis was performed for primary cultured glomerular endothelial cells (GECs) and proximal tubular epithelial cells (PTECs) before and after inducing 24-h hypoxia injury. Upon hierarchical clustering, out of 858 differentially expressed proteins (DEPs) in the urine of CKD patients, the levels of 416 decreased and 403 increased sequentially according to the disease stage, respectively. Among 2965 DEPs across 5/6 nephrectomized and sham-operated rat kidney tissues, 86 DEPs showed same expression patterns in the urine and kidney tissue. After cross-validation with two external animal proteome datasets, 38 DEPs were organized; only 10 DEPs, including serotransferrin, gelsolin, poly ADP-ribose polymerase 1, neuroblast differentiation-associated protein AHNAK, microtubule-associated protein 4, galectin-1, protein S, thymosin beta-4, myristoylated alanine-rich C-kinase substrate, and vimentin were finalized by screening human GECs and PTECs data. Among these ten potential candidates for universal CKD marker, validation analyses for protein S and galectin-1 were conducted. Galectin-1 was observed to have a significant inverse correlation with renal function as well as higher expression in glomerulus with chronic injury than protein S. This constitutes the first multi-sample proteomics study for identifying key renal-expressed proteins associated with CKD progression. The discovered proteins represent potential markers of chronic renal cell and tissue damage and candidate contributors to CKD pathophysiology.

Nuclear Disarmament and the Protection of Cultural Heritage Research paper sysadmin 6 October 2017

States possessing nuclear weapons should be called upon to consider and publish the risks posed to cultural heritage, and their mitigation strategies, in their nuclear-weapons doctrines and policies.

Summary

• Renewed risk assessments for nuclear weapons and policies are taking place around the world in light of nuclear modernization and the changing geostrategic environment that is making the use of nuclear weapons more likely. As such the humanitarian impacts of nuclear weapons and tests have received increased attention. However, the effect on cultural heritage has so far been neglected.
• The potential for armed conflict to destroy cultural heritage has been recognized in international law since 1954. There is significant evidence on the impact of nuclear weapons on cultural heritage including the consequences of their use in Hiroshima and Nagasaki and the effect of nuclear-testing programmes in places of cultural significance since 1945. States that possess nuclear weapons have increased liabilities and responsibilities to protect cultural heritage and cultural rights. The need to protect cultural heritage should strengthen the case for reducing and eliminating nuclear weapons.
• Failure to take into account the protection of heritage in the development of nuclear weapons policies – including disarmament, non-proliferation and arms-control negotiations – significantly undermines states’ existing commitments to protecting heritage threatened by conflict.
• Risk assessments of the impact of nuclear weapons on cultural heritage and important cultural artefacts – and methods of preventing such catastrophic damage – should be part of protecting cultural heritage in every country and the subject of informed public debate. A new body of knowledge on the full range of nuclear weapons impacts would introduce a fresh perspective to inform decision-makers, international organizations and the public in thinking about nuclear weapons policies and practices.
• Risk and resilience frameworks, which provide sets of solutions for risk assessments, would allow assessments of nuclear weapons threats to heritage and highlight vulnerabilities that need to be addressed. Such frameworks would provide a basis for policymakers to identify the world’s cultural heritage most at risk and help develop mitigation strategies to ensure that it is protected. In particular, states possessing nuclear weapons should be called upon to consider and publish the risks posed to cultural heritage, and their mitigation strategies, in their nuclear weapons doctrines and policies, as a contribution to transparency and confidence-building, and as a responsibility to the world’s shared heritage. International organizations, such as the UN Educational, Scientific, and Cultural Organization (UNESCO), have a role to play in bridging security perspectives with protecting cultural heritage.

Exploring Transatlantic Responses to Far-right Populism in Europe: Simulation Exercise Research paper sysadmin 1 May 2018

A new paper summarizes the findings of a recent simulation exercise exploring how governments on both sides of the Atlantic might respond to a descent towards populist authoritarianism in an EU member state.

Summary

• To better understand how governments on both sides of the Atlantic might respond to a descent towards populist authoritarianism in an EU member state, Chatham House organized a simulation event involving a group of experts drawn from the public sector, academia and NGOs.
• Simulation exercises enable the testing and modelling of the responses of different actors when presented with specific situations; participants’ interactions in a given set of circumstances are explored, and patterns of negotiation are captured and analysed.
• In this simulation, European, US and multilateral representatives were given the task of managing relations with Baltia, a fictional Eastern European state on the verge of electing a far-right nationalist, Eurosceptic government. They were then challenged to manage their relationship with Baltia after it had elected such a government, which was pushing for a ‘leave’ vote in a planned referendum on the country’s continued EU membership.
• The simulation highlighted a number of issues:
  • Limited instruments are available to liberal democratic governments where there is cause for concern regarding the outcome of an election in an allied country. There are relatively few tools at the disposal of governments to support political allies, or to prevent outcomes that are perceived as threatening democratic norms. The simulation reinforced the view that interventionist moves, either from the European Commission or from individual national governments, would be more likely to come in response to an unfavourable development rather than pre-emptively.
  • The EU, and caucuses of European states, are the main international interlocutors in this type of political crisis involving an EU member state. The US opted to play a limited role in the negotiations; the same was largely true for NATO, aside from its action in sharing intelligence about a potential coup in Baltia. France and Germany formed a natural working partnership, taking meetings together and coordinating policies first before discussing them with a wider European circle, although their positions did not always align.
  • The UK’s capacity to shape the outcome of collective EU discussions appeared more restricted, while Brexit also seemed to shape the response of other EU states to the developing situation in Baltia. Although member states were undoubtedly reluctant to see another country go down this route, they were also resolute in demonstrating a unity of approach and limited flexibility in the face of the new populist government’s attempt to divide them.

General Manager Matt Klentak discussed the Phillies' offseason in a press conference on Thursday in Clearwater, Fla. The Phillies remain in contact with the agents for Bryce Harper and Manny Machado. The belief is that the front office still prefers Machado over Harper because of Machado's combination of offense and defense.

Ramaphosa Has Won the Battle. But Can He Win the War? Expert comment sysadmin 21 December 2017

Cyril Ramaphosa is taking charge of South Africa’s ruling party, the ANC, at its weakest point in post-apartheid history. Expectations couldn’t be higher.

Ramaphosa ran for the leadership of the ANC on a platform of party renewal, economic recovery, and building the capacity of the state. But Jacob Zuma remains the President of South Africa and, under the constitution, can stay in office until elections in 2019. Therefore, meeting expectations on economic recovery will depend on Ramaphosa taking the presidency – and he has a number of political battles to face before that becomes reality.

To begin with, Ramaphosa and his supporters did not win a total victory at the elective conference. The presidency was only one position in the senior cadre – the co-called ‘top six’ – that was elected. This body is now split evenly between Ramaphosa and his allies, and those that supported his opponent Dr Nkosazana Dlamini-Zuma - Jacob Zuma’s preferred successor. This creates two centres of power in the ANC, limiting what Ramaphosa will be able to achieve from within the party.

Although there is significant pressure from the electorate to remove Zuma from national office, actually doing so will be difficult. Zuma’s predecessor Thabo Mbeki was removed from the national presidency before his term was up when the National Executive Committee (NEC) of the party recalled him from office following Zuma’s assumption of party leadership. But this option may not be available to Ramaphosa. The split within the ‘top six’ and new NEC will make it difficult to present an ultimatum to Zuma. His loyalists will not want a witch hunt within the party.

Corruption and elitism within the party

Much of the tension centres on questions of corruption, the dominant political issue in South Africa at the moment. In the build up to the elective conference Gwede Mantashe - now national chairperson - admitted that “The biggest challenge from where we’re sitting is the image and the reputation of the ANC. The ANC is seen as equal to corruption and looting.” Ramaphosa made anti-corruption initiatives a centrepiece of his campaign, including the establishment of a judicial commission and rapid action to investigate and prosecute the guilty.

But the split within the party may undermine the credibility of these promises. Ramaphosa’s problem is that some of the new ‘top six’ - including Deputy President David Mabuza, and Secretary General Ace Magashule – would be high on the list of those the electorate want to see investigated. Party resistance may restrict the extent to which Ramaphosa can demonstrate a comprehensive break from the past.

Corruption within the party goes far deeper than the headline cases of ‘state capture’ and expropriation. At a branch level, access to political power has become the primary means of access to economic resource. It is a process of selective patronage that differentiates between those who are ‘in’ from those who aren’t. At its broadest, this type of corruption has created a mistrust of the ANC and the new economic elite that the party has created around it – including Ramaphosa himself.

Having lost out to Mbeki in the fight to succeed Mandela despite being the favourite for the job, Ramaphosa spearheaded the ANC’s deployment of cadres in business. He has become one of the country’s richest men, and a highly sought after board member by South Africa’s largest companies across mining, telecoms, and logistics.

One of his biggest challenges will be to remove the perception of elitism as his senior position within the party and economy has given rise to mistrust from a grass roots level. The political tussle at the conference was also largely driven by a small number of the party elite being able to control large groups of delegate votes. The nature of political competition within the party is symptomatic of the ANCs electoral dominance in the early days of the nation’s democracy. But this support is now far less certain, and the party cannot afford to become complacent.

Resetting the relationship with business

Ramaphosa’s business dealings may mean he has to walk a fine line in censuring his colleagues for making money from politics. But it may also be a significant opportunity for the party to reset its relationship with the private sector. Under Mbeki, relations between the ANC and business were distant, but characterized by recognition of mutual dependence.

Under Zuma this relationship deteriorated, and the President demonstrated he was willing to make decisions to boost his political power irrespective of economic consequences. Ramaphosa could, for the first time, truly align the interests of business and government, without abandoning his transformative policy agenda.

At an ANC regional economic colloquium in Johannesburg in November Ramaphosa outlined his ten-point economic plan. It would deliver the party’s adopted mantra of ‘radical economic transformation’, but through broadly neo-liberal policies on private business development and state-owned enterprise reform to allow private capital to co-invest.

He took the ethos and principles of the Freedom Charter – the 1955 statement of core ANC principles – and applied them to a modernising economy. Talk of a ‘new deal’, productive partnerships in the mining sector, and an emphasis on job creation in manufacturing will woo investors. The rand surged upon his election.

But Ramaphosa will not be able to deliver on the economic demands of the country until he is in the office of the presidency - and Zuma still holds many of the cards. Ramaphosa can promise his followers potential power and government positions in future, but Zuma can still offer them now.

Removing Zuma will require skilful internal party politicking, and Ramaphosa will need to limit the fallout – he cannot afford to further damage the credibility of the party before it faces the electorate in 2019. He has won the battle, but the outcome of the war is far from certain.

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.

Ramaphosa Must Act Fast With New Mandate in South Africa Expert comment sysadmin 23 May 2019

In the wake of South Africa’s election, political constraints will ebb momentarily. The president should seize the opportunity to deliver meaningful change.

On 25 May, Cyril Ramaphosa will be inaugurated as president of South Africa, having dragged the African National Congress (ANC) over the line in the 8 May election. The ANC gained a 57 per cent majority, its lowest vote since 1994, its status as national liberator deeply eroded by successive corruption scandals. Only Ramaphosa’s personal popularity stopped it haemorrhaging more support.

His sustained action against corrupt public servants and promises of job-creating economic growth has attracted support from beyond the ANC’s base, including a significant minority of white voters, and generated significant international goodwill. Ramaphosa now has a short window of opportunity to reset social democracy in South Africa before the political cycle of municipal, party and national elections from 2021 to 2024 forces his attention back to party politics.

Defining ‘Ramaphosa-ism’

But personal popularity is fickle, and goodwill alone will not turn around the ailing economy. To attract investment and keep the electorate on side, Ramaphosa’s government needs to move beyond pragmatic crisis responses and articulate a clear, shared vision for how market intervention can allow the economy to grow while simultaneously delivering social transformation.

Growth will be hard to achieve in the short term. The economy is expected to grow 1.2% in 2019 and 1.5% in 2020, according to the IMF. Consumer confidence remains subdued, and a decade of declining GDP per capita and increasing inequality has put a strain on households. A ‘fiscal stimulus’ in 2018 delivered very little new government spending, and over the past 10 years, the government wage bill has increased three times higher than the rate of inflation.

Eskom, the state electricity provider, has debts equating to the GDP of Latvia and is not the only state-owned enterprise (SOE) that has required bailing out by the government. There are plans to break up Eskom into three separate entities but calls for deeper reform – or even privatization – are growing.

The president’s responses to these challenges will go a long way to defining ‘Ramaphosa-ism’ and the role of government in pursuing equitable economy growth.

Economic expectations under Ramaphosa

Ramaphosa was a champion of the introduction of a minimum wage and a proponent of the National Development Plan, which relies on growth to drive job creation. His support for land reform is an individual conviction as much as it is a party line, although his views are softer than many in the party, with state-owned land being the initial target.

Investor uncertainty on land tenure and regulations in mining will need to be addressed through passing key pieces of legislation on land reform and the revised Mining and Petroleum Resources Development Act.

Where Ramaphosa differs from his predecessors is his links with business. Thabo Mbeki enjoyed a relationship of mutual respect with business; this disintegrated under Jacob Zuma. Ramaphosa, however, is part of South Africa’s business community, having founded the Shanduka Group, with investments in multiple sectors including retail, telecoms and extractives, and served as chairman of MTN and Bidvest. As president, he has surrounded himself with close economic advisers from business and banking.

In the short term, anti-corruption measures and competent appointments will ease investor woes. In the long term, there is a need to improve the ease of doing business, including labour market reforms, and to make South Africa a more competitive business environment by reducing the hold of large conglomerates on the economy. Ramaphosa may also make greater use of public-private partnerships for large projects.

Political constraints

Ramaphosa faces few immediate political challenges. The ANC is still deeply divided, but although Ramaphosa does not enjoy the ideological support of the entire party, his opponents are leaderless post-Zuma, and have been unable to offer a coherent alternative. ANC Secretary General Ace Magashule has fallen into the role of interim figurehead of this faction, and allegations of corruption would make it difficult for him to aspire to national leadership.

The need to avoid splits before the election meant Ramaphosa had to make concessions, and his first cabinet in February 2018 included opponents and those accused of corruption or incompetence, such as Malusi Gigaba and Bathabile Dlamini. Such concessions to political opponents are unlikely to continue after the election.

Meanwhile, opposition parties made some advances in the election, but where Zuma was an easy target, they are still grappling with how to confront Ramaphosa. The party with the biggest gains was the Economic Freedom Fighters, whose increase of just over 4 points from the last election gave it 11 per cent of the vote this time. They will likely continue to be an effective disruptor. Ramaphosa may also be challenged by trade unions on his reforms, notably over any break-up of SOEs.

But the biggest and most immediate external political challenge for Ramaphosa will be rebuilding trust between government and society, in a context where social protest has become an alternative form of political participation. A turnout of 65 per cent may be considered normal in Western democracies but is a notable drop for a country as politicized as South Africa, driven by frustration and a sense of exclusion as much as apathy. Turnout by young people was even lower.

Achieving the vision

South Africa has all the platforms it needs to project its renewal and attract vital external investment – it is a non-permanent member of the UN Security Council, it will take over as chair of the African Union in 2020, it is a member of BRICS and it is the only African member of the G20. But in the recent past, it has struggled to tell a coherent story about its vision for the future and offer to the world.

In the immediate wake of the election, internal and external political constraints will ebb. Ramaphosa must act fast to deliver results before the election cycle starts again. To attract much needed investment stimulus, he will not only need to articulate and market his vision for South Africa, but also outline how he plans to achieve it.

A new transatlantic relationship? 4 October 2022 — 6:30PM TO 7:30PM Anonymous (not verified) 22 September 2022 Chatham House and Online

US senator Jeanne Shaheen examines the implications of new UK leadership, the war in Ukraine, and NATO expansion for the US–UK relationship.

In recent weeks, the UK has ushered in a new prime minister and a new monarch. The US will hold potentially power-shifting mid-term elections in November after nearly two years of the Biden presidency that promised to bring the US ‘back’ as a global leader in international affairs.

These leadership changes come at a time when Europe is at war, NATO is expanding and US–China competition is re-ordering long-held alliances. Old assumptions about foreign policy are in flux in the midst of huge international challenges.

Democratic senator Shaheen, a senior member of the Senate Foreign Relations Committee, explores how these changes might influence the US–UK ‘special’ relationship.

• How will the trajectory of Russia’s war on Ukraine influence the bilateral relationship? What leadership is needed now?

• What does Russia’s war on Ukraine mean for NATO in responding to other pressing security challenges?

• What domestic constraints might limit the US’s power to reinsert itself as a global leader?

As with all Chatham House member events, questions from the members drive the conversation.

Read the transcript. 

The road to COP27: In conversation with US Special Presidential Envoy for Climate John Kerry 27 October 2022 — 3:00PM TO 4:00PM Anonymous (not verified) 20 October 2022 Chatham House and Online

What will progress on climate change look like at COP27?

With global attention zeroing in on COP27, policymakers and world leaders will meet in Egypt to take the next step in the fight against the climate crisis. The planet is on course to warm well beyond 1.5°C and climate hazards are increasing our exposure to climate risk. Violent and unpredictable weather events increasingly leave devastation among communities, particularly in vulnerable countries.

At the same time, the ripple effects of the conflict in Ukraine will have wide-ranging economic, social and geopolitical consequences for years to come. Whilst some finance is being made available, more is needed to properly address the damage caused by climate change and fund the transition to net zero worldwide. These challenges have become more acute as the world grapples with a growing energy crisis, the war in Ukraine and a troubling economic outlook.

Joined by US Special Presidential Envoy for Climate John Kerry, the following questions are considered:

• Is ‘1.5 degrees’ still on track?

• How can countries better collaborate to move to net zero faster?

• How can we achieve progress on adaptation, climate finance, and loss and damage?

As with all members events, questions from the audience drive the conversation.

Read the transcript. 

In conversation with Rahul Gandhi 6 March 2023 — 6:00PM TO 7:00PM Anonymous (not verified) 27 February 2023 Chatham House and Online

The former president of the Indian National Congress discusses how today’s world will set the path for the world’s biggest democracy.

Soon to be the world’s largest population, and with a rapidly growing economy and an increasing presence in global affairs, India’s place in the world is changing.

Hosting the G20 this year, the New Delhi summit in September 2023 is a symbol of India’s growing might, moving from emerging to prominent player on the world stage.

However, challenges faced by the country are substantial. Frosty relations with China, ongoing tension with Pakistan, climate catastrophe, and food insecurity all represent significant global concerns to India.

Internally, the hurdles are imposing. Millions still live below the poverty line and demographic instability poses risks to the country. The state of democracy across the country is consistently questioned.

At this event, Rahul Gandhi explores key questions including:

• How does India see the impact of the war in Ukraine?
• Will New Delhi be able to balance relations between the West and Russia?
• Can India offer an alternative vision for Asia that challenges China?
• Internally, to what extent is democracy in India under strain?
• Can India’s economy evolve to create a wide-reaching, prosperous nation in the coming years?

As with all member events, questions from the audience drive the conversation.

In conversation with Ehud Barak 27 March 2023 — 12:00PM TO 1:00PM Anonymous (not verified) 21 March 2023 Chatham House and Online

The former prime minister of Israel discusses his country’s political outlook and foreign policy priorities.

On the eve of its 75th independence anniversary, Israel is at a critical crossroads. Weeks of long, intense protests surrounding judicial reforms pursued by the current government have widened the debate over the role played by the, so far independent, judiciary, notably the Supreme Court.

Supporters on both sides of the argument are fighting over different visions of Israel – a true liberal-democracy, or a much-reduced version of a democratic system. Whichever side of the argument people fall, the debate symbolizes tension in Israel’s society and decline in trust of its political and constitutional institutions.

Abroad, the situation remains intricate. Israel-Iran relations remain on a knife edge while the Abraham Accords normalized relations with parts of the Gulf. Then there are the continual issues surrounding relations with the Palestinians and their right to self-determination and statehood.

Old international challenges are now rubbing up against the new. Israel is part of a changing power dynamic in the Middle East, the result of a much-reduced US footprint. Furthermore, it must now contend with the other global superpower in China and continue to work on its response to the war in Ukraine.

Amid its domestic struggle to maintain its democratic character, fast-moving regional and international developments are in need of addressing. Friends and allies are deeply concerned with the country’s constitutional crisis, potentially re-evaluating their relations with the Jewish state.

Former prime minister of Israel Ehud Barak lays out his views on the complexities of domestic and international challenges facing Israel today.

Questions covered include:

• What are the main root causes of the current constitutional crisis, and how could it be best resolved?
• Could the current situation lead to a breakdown of the political system, even widespread violence?
• How could the current circumstances in Israel and Palestine affect relations between the two and any prospect for peace negotiations?
• How will US-Israel relations stand up against China’s influence in the region?
• What is Israel’s interpretation of the war in Ukraine and how is the country affected?

As with all member events, questions from the audience drive the conversation.

Chatham House exhibition - In conversation with the future 19 April 2023 — 6:00PM TO 8:00PM Anonymous (not verified) 31 March 2023 Chatham House

Hear from the innovative leaders and companies driving change towards a more sustainable future.

This event is an opportunity to hear from the innovative leaders and companies driving change towards a more sustainable future.

The evening begins with a panel discussion then, over sustainably sourced drinks and canapés, you are invited to walk through Chatham House and explore the innovative and experimental ideas enabling radical shifts to allow us to prosper without exhausting our planet’s resources.

Our exhibiting partners include Earthshot Prize winner NotPla, Hawkins Brown, Polymateria, and BEEN London. 

Bronwen Maddox, director of Chatham House, opens the evening at 6pm and introduces our panel of experts, chaired by Ana Yang, head of Chatham House’s Sustainability Accelerator. 

Please note that this event is operating a ballot for in-person attendance. Your place will be confirmed by Wednesday 12 April if you are successful.

An employment judge has cleared the way for Farah Jameel, a former chair of the BMA’s General Practitioners Committee for England (GPCE), to go ahead with claims of discrimination and unfair dismissal against the association over her removal from the post during maternity leave.Jameel, who was elected the first female chair in November 2021, was put on temporary suspension in 2022 after complaints by BMA staff. The BMA told her in August 2023 that her contract was being terminated.The contract described her as a contractor providing consultancy services rather than an employee. But in a preliminary ruling the employment judge Natasha Joffe has held that Jameel was in reality an office holder and an employee, opening the way for her claims to proceed to a full hearing by an employment tribunal.The GPCE passed a vote of no confidence in Jameel in July 2023, as a means of electing a new...