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The Challenge of Classifying Metastatic Cell Properties by Molecular Profiling Exemplified with Cutaneous Melanoma Cells and Their Cerebral Metastasis from Patient Derived Mouse Xenografts [Research]

The prediction of metastatic properties from molecular analyses still poses a major challenge. Here we aimed at the classification of metastasis-related cell properties by proteome profiling making use of cutaneous and brain-metastasizing variants from single melanomas sharing the same genetic ancestry. Previous experiments demonstrated that cultured cells derived from these xenografted variants maintain a stable phenotype associated with a differential metastatic behavior: The brain metastasizing variants produce more spontaneous micro-metastases than the corresponding cutaneous variants. Four corresponding pairs of cutaneous and metastatic cells were obtained from four individual patients, resulting in eight cell-lines presently investigated. Label free proteome profiling revealed significant differences between corresponding pairs of cutaneous and cerebellar metastases from the same patient. Indeed, each brain metastasizing variant expressed several apparently metastasis-associated proteomic alterations as compared with the corresponding cutaneous variant. Among the differentially expressed proteins we identified cell adhesion molecules, immune regulators, epithelial to mesenchymal transition markers, stem cell markers, redox regulators and cytokines. Similar results were observed regarding eicosanoids, considered relevant for metastasis, such as PGE2 and 12-HETE. Multiparametric morphological analysis of cells also revealed no characteristic alterations associated with the cutaneous and brain metastasis variants. However, no correct classification regarding metastatic potential was yet possible with the present data. We thus concluded that molecular profiling is able to classify cells according to known functional categories but is not yet able to predict relevant cell properties emerging from networks consisting of many interconnected molecules. The presently observed broad diversity of molecular patterns, irrespective of restricting to one tumor type and two main classes of metastasis, highlights the important need to develop meta-analysis strategies to predict cell properties from molecular profiling data. Such base knowledge will greatly support future individualized precision medicine approaches.




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Genetic Profile and Functional Proteomics of Anal Squamous Cell Carcinoma: Proposal for a Molecular Classification [Research]

Anal squamous cell carcinoma is a rare tumor. Chemo-radiotherapy yields a 50% 3-year relapse-free survival rate in advanced anal cancer, so improved predictive markers and therapeutic options are needed. High-throughput proteomics and whole-exome sequencing were performed in 46 paraffin samples from anal squamous cell carcinoma patients. Hierarchical clustering was used to establish groups de novo. Then, probabilistic graphical models were used to study the differences between groups of patients at the biological process level. A molecular classification into two groups of patients was established, one group with increased expression of proteins related to adhesion, T lymphocytes and glycolysis; and the other group with increased expression of proteins related to translation and ribosomes. The functional analysis by the probabilistic graphical model showed that these two groups presented differences in metabolism, mitochondria, translation, splicing and adhesion processes. Additionally, these groups showed different frequencies of genetic variants in some genes, such as ATM, SLFN11 and DST. Finally, genetic and proteomic characteristics of these groups suggested the use of some possible targeted therapies, such as PARP inhibitors or immunotherapy.




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Biosynthesis of depsipeptides with a 3-hydroxybenzoate moiety and selective anticancer activities involves a chorismatase [Metabolism]

Neoantimycins are anticancer compounds of 15-membered ring antimycin-type depsipeptides. They are biosynthesized by a hybrid multimodular protein complex of nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS), typically from the starting precursor 3-formamidosalicylate. Examining fermentation extracts of Streptomyces conglobatus, here we discovered four new neoantimycin analogs, unantimycins B–E, in which 3-formamidosalicylates are replaced by an unusual 3-hydroxybenzoate (3-HBA) moiety. Unantimycins B–E exhibited levels of anticancer activities similar to those of the chemotherapeutic drug cisplatin in human lung cancer, colorectal cancer, and melanoma cells. Notably, they mostly displayed no significant toxicity toward noncancerous cells, unlike the serious toxicities generally reported for antimycin-type natural products. Using site-directed mutagenesis and heterologous expression, we found that unantimycin productions are correlated with the activity of a chorismatase homolog, the nat-hyg5 gene, from a type I PKS gene cluster. Biochemical analysis confirmed that the catalytic activity of Nat-hyg5 generates 3-HBA from chorismate. Finally, we achieved selective production of unantimycins B and C by engineering a chassis host. On the basis of these findings, we propose that unantimycin biosynthesis is directed by the neoantimycin-producing NRPS–PKS complex and initiated with the starter unit of 3-HBA. The elucidation of the biosynthetic unantimycin pathway reported here paves the way to improve the yield of these compounds for evaluation in oncotherapeutic applications.




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Repression of sphingosine kinase (SK)-interacting protein (SKIP) in acute myeloid leukemia diminishes SK activity and its re-expression restores SK function [Molecular Bases of Disease]

Previous studies have shown that sphingosine kinase interacting protein (SKIP) inhibits sphingosine kinase (SK) function in fibroblasts. SK phosphorylates sphingosine producing the potent signaling molecule sphingosine-1-phosphate (S1P). SKIP gene (SPHKAP) expression is silenced by hypermethylation of its promoter in acute myeloid leukemia (AML). However, why SKIP activity is silenced in primary AML cells is unclear. Here, we investigated the consequences of SKIP down-regulation in AML primary cells and the effects of SKIP re-expression in leukemic cell lines. Using targeted ultra-HPLC-tandem MS (UPLC-MS/MS), we measured sphingolipids (including S1P and ceramides) in AML and control cells. Primary AML cells had significantly lower SK activity and intracellular S1P concentrations than control cells, and SKIP-transfected leukemia cell lines exhibited increased SK activity. These findings show that SKIP re-expression enhances SK activity in leukemia cells. Furthermore, other bioactive sphingolipids such as ceramide were also down-regulated in primary AML cells. Of note, SKIP re-expression in leukemia cells increased ceramide levels 2-fold, inactivated the key signaling protein extracellular signal-regulated kinase, and increased apoptosis following serum deprivation or chemotherapy. These results indicate that SKIP down-regulation in AML reduces SK activity and ceramide levels, an effect that ultimately inhibits apoptosis in leukemia cells. The findings of our study contrast with previous results indicating that SKIP inhibits SK function in fibroblasts and therefore challenge the notion that SKIP always inhibits SK activity.




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Inhibition of the polyamine synthesis enzyme ornithine decarboxylase sensitizes triple-negative breast cancer cells to cytotoxic chemotherapy [Molecular Bases of Disease]

Treatment of patients with triple-negative breast cancer (TNBC) is limited by a lack of effective molecular therapies targeting this disease. Recent studies have identified metabolic alterations in cancer cells that can be targeted to improve responses to standard-of-care chemotherapy regimens. Using MDA-MB-468 and SUM-159PT TNBC cells, along with LC-MS/MS and HPLC metabolomics profiling, we found here that exposure of TNBC cells to the cytotoxic chemotherapy drugs cisplatin and doxorubicin alter arginine and polyamine metabolites. This alteration was because of a reduction in the levels and activity of a rate-limiting polyamine biosynthetic enzyme, ornithine decarboxylase (ODC). Using gene silencing and inhibitor treatments, we determined that the reduction in ODC was mediated by its negative regulator antizyme, targeting ODC to the proteasome for degradation. Treatment with the ODC inhibitor difluoromethylornithine (DFMO) sensitized TNBC cells to chemotherapy, but this was not observed in receptor-positive breast cancer cells. Moreover, TNBC cell lines had greater sensitivity to single-agent DFMO, and ODC levels were elevated in TNBC patient samples. The alterations in polyamine metabolism in response to chemotherapy, as well as DFMO-induced preferential sensitization of TNBC cells to chemotherapy, reported here suggest that ODC may be a targetable metabolic vulnerability in TNBC.




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Intellectual Breakdown Has Led to Political Turmoil

3 October 2019

Jim O'Neill

Chair, Chatham House
At the root of growing discontent is a clear problem: the international capitalist model has stopped functioning as it should.

2019-10-03-GJ.jpg

Gilets jaunes protestors march through the Place de la Concorde in Paris in November 2018. Photo: Getty Images.

As the chair of the Royal Institute of International Affairs, I recently hosted an offsite event with some of the organization’s strongest supporters, research staff, and other leaders. I left with a clearer view of three of the biggest issues of our time: slowing productivity growth, anti-establishment politics, and the rise of China.

Generally speaking, the reason that we have so many 'issues' is that the international capitalist model has stopped functioning as it should, particularly in the years since the 2008 financial crisis. This has become increasingly apparent to many Western voters, even as experts have struggled to understand the precise nature of the economic and political shifts underway.

According to the economic textbooks that I grew up with in the 1970s, successful businesses within a market-based system should deliver profits to their equity owners, which in turn should lead to stronger investment and rising wages. At the same time, the potential for profits should attract new market entrants, which in turn should erode the incumbents’ profitability, fuel competition, and spur innovation.

This pattern no longer holds. Incumbents’ reported profits seem to rise persistently – often with the help of extremely efficient balance-sheet and financial management – but there is scarce evidence of rising investment or wages. As a result, productivity across many advanced economies appears to be trending lower.

In these circumstances, it is little wonder that Western voters have been attracted to anti-establishment political parties. But this does not mean that liberal democracy is breaking down, as one often hears. In fact, a forthcoming Chatham House report casts substantial doubt on the credibility of that alarmist claim.

Between the 1970s and the start of the new millennium, politics in many Western countries moved rightward – a trend epitomized by New Labour in the United Kingdom and the Democratic Leadership Council in the United States. For a while, this mode of politics seemed to work fine. Under conditions of persistent growth, low inflation, and a rising tide that lifted all (or most) boats, a neoliberal consensus crystallized, and alternative views were marginalized.

Everything changed after 2008. Over the past decade, markets seemed to have stopped delivering widely shared growth, and mainstream parties have not come up with any new ideas. Voters have thus turned to the once-sidelined voices on the left and right.

The far-left policies being proposed by UK Labour leader Jeremy Corbyn almost certainly would not work. But that is beside the point. What matters to disadvantaged voters is that Corbyn’s proposals seem to offer something that the current system does not. Similarly, those on the right are unlikely to deliver greater prosperity, but their ideas have the virtue of sounding different. Blaming immigration, 'globalists', and China for everything can make for a powerful sales pitch.

In order to offer voters a better choice, the centre must do much more to ensure that market forces are delivering the same results as they did in previous decades. And here, throwing around sweeping accusations of 'populism' and the end of democracy won’t help.

In trying to explain the current moment, too many of my liberal colleagues are relying on a mistaken narrative. The problem is not that scary new populist forces are destroying the post-war economic model; rather, it is the other way around. The rise of new political movements is the logical result of the earlier period of neoliberal consolidation, and of the failure of centrist thinking to deliver the same results it once did.

To be sure, there is some merit to the argument that social media have facilitated the spread of heterodox – and sometimes toxic – points of view. The leading social-media companies clearly have not spent enough on protecting their users from sophisticated propaganda, scams, and the like. But the real question is why those messages have found so many receptive ears. After all, the same technologies that allow marginal voices to reach a much larger audience are also available to centrists. Barack Obama’s 2008 US presidential campaign harnessed the power of these platforms to great effect.

Finally, the Sino-American dispute over trade and technology may be more dramatic for involving a non-liberal, non-Western rising power. But the essence of the conflict is economic. Within the next decade or so, China’s economy will likely surpass that of the US as the largest in the world.

To my mind, Western policymakers should be countering Sinophobia and encouraging their societies to live comfortably with China. Economic progress in China will not prevent America’s 327 million people from becoming individually wealthier themselves. If the West adopts sensible policies, its own firms and consumers stand to benefit substantially from China’s growth.

As for think tanks like Chatham House, it is clear that we must play a more active role in setting the facts straight on all of these issues. It would be a tragedy to sacrifice our collective prosperity as a result of unclear thinking.

This article was originally published by Project Syndicate.




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UK General Election 2019: What the Political Party Manifestos Imply for Future UK Trade

Research Event

4 December 2019 - 12:30pm to 1:30pm

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

Event participants

Michael Gasiorek, Professor of Economics, University of Sussex; Director, Interanalysis; Fellow, UK Trade Policy Observatory, University of Sussex
Julia Magntorn Garrett, Research Officer, UK Trade Policy Observatory, University of Sussex
Prof Jim Rollo, Deputy Director, UK Trade Policy Observatory, University of Sussex; Associate Fellow, Global Economy and Finance Department, Chatham House
Nicolo Tamberi, Research Officer in the Economics of Brexit, University of Sussex
L. Alan Winters, Professor of Economics, Director, UK Trade Policy Observatory, University of Sussex

The upcoming UK general election is arguably a 'Brexit election', and as such, whoever wins the election will have little time to get their strategy for Brexit up and running to meet the new Brexit deadline of 31 January 2020. But what are the political parties’ policies for the UK's future trade? This event will present and discuss what the five main parties’ manifestos imply for future UK trade. Each manifesto will be presented and analysed by a fellow of the UK Trade Policy Observatory (UKTPO) and will be followed by a Q&A session. 

Michela Gariboldi

Research Assistant, Global Economy and Finance Programme
02073143692




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Characterization of the small molecule ARC39, a direct and specific inhibitor of acid sphingomyelinase in vitro

Eyad Naser
Mar 10, 2020; 0:jlr.RA120000682v1-jlr.RA120000682
Research Articles




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Lipid-tuned Zinc Transport Activity of Human ZnT8 Protein Correlates with Risk for Type-2 Diabetes [Molecular Bases of Disease]

Zinc is a critical element for insulin storage in the secretory granules of pancreatic beta cells. The islet-specific zinc transporter ZnT8 mediates granular sequestration of zinc ions. A genetic variant of human ZnT8 arising from a single nonsynonymous nucleotide change contributes to increased susceptibility to type-2 diabetes (T2D), but it remains unclear how the high risk variant (Arg-325), which is also a higher frequency (>50%) allele, is correlated with zinc transport activity. Here, we compared the activity of Arg-325 with that of a low risk ZnT8 variant (Trp-325). The Arg-325 variant was found to be more active than the Trp-325 form following induced expression in HEK293 cells. We further examined the functional consequences of changing lipid conditions to mimic the impact of lipid remodeling on ZnT8 activity during insulin granule biogenesis. Purified ZnT8 variants in proteoliposomes exhibited more than 4-fold functional tunability by the anionic phospholipids, lysophosphatidylcholine and cholesterol. Over a broad range of permissive lipid compositions, the Arg-325 variant consistently exhibited accelerated zinc transport kinetics versus the Trp-form. In agreement with the human genetic finding that rare loss-of-function mutations in ZnT8 are associated with reduced T2D risk, our results suggested that the common high risk Arg-325 variant is hyperactive, and thus may be targeted for inhibition to reduce T2D risk in the general populations.




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Episode 32 - The Internet of Natural Selection (IoNS)

In episode 32, Techworld's Scott Carey looks at Amazon's Echo and finds a dystopian future world in which our household appliances listen to us and talk back. Digital Arts editor Neil Bennett (15:06) explains why Tesla now has to design products for stupid people, and Macworld's David Price explains why mums don't like Apple's iOS 10 (28:00). We also discuss the beauty and lyricism of the German language.  


See acast.com/privacy for privacy and opt-out information.




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Episode 73 - The Internet of Electric Sheep (IoES) Facebook's blunder, the new Kindle and Blade Runner 2049

Episode 73 sees David Price lead Scott Carey, Miriam Harris and Henry Burrell into a critique of Mark Zuckerberg's decision to go into a VR tour of Puerto Rico. Disaster tourism at its finest/worst.


Henry then discusses the new Kindle Oasis, which for the firs time is waterproof - but very expensive and quietly released.


Finally we all chip in to ask why Blade Runner 2049 is quite so overtly sexist in its portrayal of women. There be spoilers.

 

See acast.com/privacy for privacy and opt-out information.




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Characterization of the small molecule ARC39, a direct and specific inhibitor of acid sphingomyelinase in vitro [Research Articles]

Inhibition of acid sphingomyelinase (ASM), a lysosomal enzyme that catalyzes the hydrolysis of sphingomyelin into ceramide and phosphorylcholine, may serve as an investigational tool or a therapeutic intervention to control many diseases. Specific ASM inhibitors are currently not sufficiently characterized. Here, we found that 1-aminodecylidene bis-phosphonic acid (ARC39) specifically and efficiently (>90%) inhibits both lysosomal and secretory ASM in vitro. Results from investigating sphingomyelin phosphodiesterase 1 (SMPD1/Smpd1) mRNA and ASM protein levels suggested that ARC39 directly inhibits ASM’s catalytic activity in cultured cells, a mechanism which differs from that of functional inhibitors of ASM (FIASMAs). We further provide evidence that ARC39 dose- and time-dependently inhibits lysosomal ASM in intact cells, and we show that ARC39 also reduces platelet- and ASMpromoted adhesion of tumor cells. The observed toxicity of ARC39 is low at concentrations relevant for ASM inhibition in vitro, and it does not strongly alter the lysosomal compartment or induce phospholipidosis in vitro. When applied intraperitoneally in vivo, even subtoxic high doses administered short-term induced sphingomyelin accumulation only locally in the peritoneal lavage without significant accumulation in plasma, liver, spleen or brain. These findings require further investigation with other possible chemical modifications. In conclusion, our results indicate that ARC39 potently and selectively inhibits ASM in vitro and highlight the need for developing compounds that can reach tissue concentrations sufficient for ASM inhibition in vivo.




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COVID-19: America's Looming Election Crisis

8 April 2020

Dr Lindsay Newman

Senior Research Fellow, US and the Americas Programme
Planning now is essential to ensure the legitimacy of November’s elections is not impacted by COVID-19, as vulnerabilities are becoming ever more apparent if voting in person is restricted.

2020-04-08-COVID-US-election

Roadside voting in Madison, Wisconsin in April 2020. Because of coronavirus, the number of polling places was drastically reduced. Photo by Andy Manis/Getty Images.

The COVID-19 epidemic has hit every aspect of American life. The upcoming November general elections will not be immune to the virus’ impact and may be scheduled to happen while the pandemic remains active, or has returned.

There is a danger the epidemic forces change to the way voting takes place this fall, amplifying risks around election security and voter suppression that ultimately undermine the integrity of the elections.

This is further highlighted by the US Supreme Court’s last-minute ruling along ideological lines to restrict an extension on the absentee voting period in the Wisconsin Democratic presidential primary despite the level of infections in the state, forcing voters into a trade-off between their health and their right to vote. The US could be thrown into a political crisis in addition to the health and economic crises it already faces.

Bipartisan sentiment

While France, Chile and Bolivia have already postponed elections in the wake of COVID-19, there is a bipartisan sentiment that the US elections should be held as scheduled on the Tuesday after the first Monday in November. This is enshrined not only in America’s sense of itself – having weathered elections during a civil war, a world war and heightened terrorist alert before – but also in its federal law since 1845.

Despite increasing appetite for federal elections to go ahead in November, there are serious vulnerabilities, which are already becoming visible as connections are drawn between mail-in voting and voter fraud, greater voter access and disadvantages for the Republican party, and city polling closures and Democratic voter suppression.

Concerns around voting access have gained the most attention. If voting in-person is untenable or risky (especially for vulnerable health populations), voters must have alternative means to cast ballots.

During negotiations for the Coronavirus Aid, Relief, and Economic Security (CARES) Act, the Democratic caucus in the House of Representatives proposed $4 billion in state election grants and a nationally-mandated period for early voting and no-excuse absentee voting.

But the final CARES Act sidestepped the access question and stripped funding to $400 million for election security grants to ‘prevent, prepare for, and respond to coronavirus, domestically or internationally, for the 2020 Federal election cycle’. Without knowing exactly what is in store from a cyber-threat perspective, the actual cost for basic election security upgrades is estimated to be $2.1billion. And that is a pre-COVID-19 calculation.

With social-distanced voters likely to be getting more election information than ever from social media, information security is critical to prevent influence from untrustworthy sources. And opportunities for cyber intrusions are likely to increase as states transition to greater virtual registration, plus absentee and mail-in balloting.

This will open new doors on well-documented, existing voter suppression efforts. With the Supreme Court clawing back the Voting Rights Act in 2013 - allowing certain states to make changes to election and voting laws without federal pre-clearance - heightened election security requirements, such as exact match campaigns and voter purges, have been used to justify voter suppression.

As more vote remotely in the remaining primaries (many now rescheduled for 2 June) and the November general elections, the added burden on states around verification will only increase temptation to set aside ‘non-compliant’ ballots. Especially as some in the Republican Party, including Donald Trump, have advocated a contested view that higher turnout favours the Democratic Party.

A fundamental principle of US democracy is that losers of elections respect the result, but history shows that election results have been contested. In 2000, it took weeks for a result to be confirmed in the presidential election. More recently, in the 2018 race for governor in Georgia, allegations of voter suppression raised questions about the validity of the eventual result.

Without proper access, security, and verification the electoral process – whenever it takes place – will become vulnerable to questions of integrity. The federal response to the initial spread of COVID-19 saw costly delays which pushed the US into a public health crisis and economic contraction.

Any narrative thread of election illegitimacy with November’s elections will further pull apart the fabric of a country already frayed by coronavirus. Federal and state authorities must start planning now for how the US will hold elections in the midst - or immediate aftermath - of COVID-19.




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Principles of electrospray ionization [Biophysical Methods]

Electrospray ionization is today the most widely used ionization technique in chemical and bio-chemical analysis. Interfaced with a mass spectrometer it allows to investigate the molecular composition of liquid samples. With electrospray a large variety of chemical substances can be ionized. There is no limitation in mass which enables even the investigation of large non-covalent protein complexes. Its high ionization efficiency profoundly changed bio-molecular sciences because proteins can be identified and quantified on trace amounts in a high throughput fashion. This review article focusses mainly on the exploration of the underlying ionization mechanism. Some ionization characteristics are discussed which are related to this mechanism. Typical spectra of peptides, proteins and non-covalent complexes are shown and the quantitative character of spectra is highlighted. Finally the possibilities and limitations in measuring the association constant of bivalent non-covalent complexes are described.




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Selection of features with consistent profiles improves relative protein quantification in mass spectrometry experiments [Research]

In bottom-up mass spectrometry-based proteomics, relative protein quantification is often achieved with data-dependent acquisition (DDA), data-independent acquisition (DIA), or selected reaction monitoring (SRM). These workflows quantify proteins by summarizing the abundances of all the spectral features of the protein (e.g., precursor ions, transitions or fragments) in a single value per protein per run. When abundances of some features are inconsistent with the overall protein profile (for technological reasons such as interferences, or for biological reasons such as post-translational modifications), the protein-level summaries and the downstream conclusions are undermined. We propose a statistical approach that automatically detects spectral features with such inconsistent patterns. The detected features can be separately investigated, and if necessary removed from the dataset. We evaluated the proposed approach on a series of benchmark controlled mixtures and biological investigations with DDA, DIA and SRM data acquisitions. The results demonstrated that it can facilitate and complement manual curation of the data. Moreover, it can improve the estimation accuracy, sensitivity and specificity of detecting differentially abundant proteins, and reproducibility of conclusions across different data processing tools. The approach is implemented as an option in the open-source R-based software MSstats.




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Quantitative proteomics of human heart samples collected in vivo reveal the remodeled protein landscape of dilated left atrium without atrial fibrillation [Research]

Genetic and genomic research has greatly advanced our understanding of heart disease. Yet, comprehensive, in-depth, quantitative maps of protein expression in hearts of living humans are still lacking. Using samples obtained during valve replacement surgery in patients with mitral valve prolapse (MVP), we set out to define inter-chamber differences, the intersect of proteomic data with genetic or genomic datasets, and the impact of left atrial dilation on the proteome of patients with no history of atrial fibrillation (AF).  We collected biopsies from right atria (RA), left atria (LA) and left ventricle (LV) of seven male patients with mitral valve regurgitation with dilated LA but no history of AF. Biopsy samples were analyzed by high-resolution mass spectrometry (MS), where peptides were pre-fractionated by reverse phase high-pressure liquid chromatography prior to MS measurement on a Q-Exactive-HF Orbitrap instrument. We identified 7,314 proteins based on 130,728 peptides. Results were confirmed in an independent set of biopsies collected from three additional individuals. Comparative analysis against data from post-mortem samples showed enhanced quantitative power and confidence level in samples collected from living hearts. Our analysis, combined with data from genome wide association studies suggested candidate gene associations to MVP, identified higher abundance in ventricle for proteins associated with cardiomyopathies and revealed the dilated LA proteome, demonstrating differential representation of molecules previously associated with AF, in non-AF hearts. This is the largest dataset of cardiac protein expression from human samples collected in vivo. It provides a comprehensive resource that allows insight into molecular fingerprints of MVP and facilitates novel inferences between genomic data and disease mechanisms. We propose that over-representation of proteins in ventricle is consequent not to redundancy but to functional need, and conclude that changes in abundance of proteins known to associate with AF are not sufficient for arrhythmogenesis.




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Perlecan knockdown significantly alters extracellular matrix composition and organization during cartilage development [Research]

Perlecan is a critical proteoglycan found in the extracellular matrix (ECM) of cartilage. In healthy cartilage, perlecan regulates cartilage biomechanics and we previously demonstrated perlecan deficiency leads to reduced cellular and ECM stiffness in vivo. This change in mechanics may lead to the early onset osteoarthritis seen in disorders resulting from perlecan knockdown such as Schwartz-Jampel syndrome (SJS). To identify how perlecan knockdown affects the material properties of developing cartilage, we used imaging and liquid chromatography–tandem mass spectrometry (LC-MS/MS) to study the ECM in a murine model of SJS, Hspg2C1532Y-Neo. Perlecan knockdown led to defective pericellular matrix formation, whereas the abundance of bulk ECM proteins, including many collagens, increased. Post-translational modifications and ultrastructure of collagens were not significantly different; however, LC-MS/MS analysis showed more protein was secreted by Hspg2C1532Y-Neo cartilage in vitro, suggesting that the incorporation of newly synthesized ECM was impaired. In addition, glycosaminoglycan deposition was atypical, which may explain the previously observed decrease in mechanics. Overall, these findings provide insight into the influence of perlecan on functional cartilage assembly and the progression of osteoarthritis in SJS.




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Molecular & Cellular Proteomics




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Nigerian Elections: Big Men and Ballot Boxes

1 March 2007 , Number 6

The minister paused, leaned forward and fiddled with his cufflinks, ‘It wasn’t about whether the election was rigged or not,’ he said. ‘The truth is, everybody rigged it. We just rigged it better than them.’ Does the next Nigerian presidential election in April promise anything different?

Sola Tayo

Journalist, HARDtalk, BBC News

GettyImages-73130322.jpg

Supporters of the ruling Peoples Democratic Party wave banners and posters




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Three Takeaways From the Belarusian Parliamentary Elections

28 November 2019

Ryhor Astapenia

Robert Bosch Stiftung Academy Fellow, Russia and Eurasia Programme
Lukashenka’s domestic support is waning and he is not willing to make concessions to the West. Instead, he is trying to appease the ruling cadre.

2019-11-28-Luk.jpg

Alexander Lukashenka leaves a voting booth on 17 November. Photo: Getty Images.

Belarus’s parliamentary elections, held on 17 November, were predictably non-transparent, with numerous violations. The regime of Alexander Lukasheka allowed no opposition candidates as members of parliament – in contrast to the previous parliament, in which there were two opposition MPs. While this might seem to be a return to ‘business as usual’, three key takeaways from the elections highlight a shifting political and social landscape.

1. Lukashenka is appeasing his ruling cadre by promising to increase their role in the political system.

With several influential officials becoming new MPs, it is more likely that parliament will be more involved in any forthcoming discussion of a new constitution. Lukashenka has been promising constitutional reform for several years; he has said publicly that it will lead to an increased significance of government agencies as well as parliament. The aim of this is to keep them more engaged and on Lukashenka’s side.

In terms of the composition of the new parliament itself, there are some key differences with previous years. It is no longer a comfortable place for officials to while away their pre-retirement: many MPs are now in their fifties or younger, and have plans for careers beyond parliament.

It also looks as if small steps are being taken towards the emergence of a party system in Belarus. The leader of Belaya Rus, a pro-government association of Belarusian officials, got a seat in parliament for the first time, increasing the likelihood of it becoming a political party. The number of MPs from different parties has increased to 21 (out of 110 in total). Although these still all broadly support Lukashenka, they can differ from the president in policy positions. For example, the Labour and Justice Party, with 6 seats in parliament, supported the annexation of Crimea in 2014. Change, of course, may not necessarily be in a pro-Western direction.

Moreover, the newly elected members of parliament look more like real politicians. They go to debates, speak to independent journalists and have their own social media channels. Some have even felt able to criticize the actions of the authorities.

Similar changes have been taking place in other institutions in Belarus. The government is now more competent than it has ever been. The National Bank has managed to carry out macroeconomic stabilization on one of the most unstable currencies in Europe, while the ministries responsible for the economic development have implemented certain small-scale reforms. The Minister of the Interior has even acknowledged mistakes made by his department (under his predecessor), and undertaken to make improvements.

This has resulted in a near-comical situation, whereby the Belarusian non-state media outlets have an increasingly positive view of some state officials, such as Prime Minister Siarhei Rumas, while the state media has been scaling back its coverage of him to ensure he does not become too popular.

2. Belarus has less need for the West and is reluctant to make even small concessions.

Since the slight warming of Belarusian relations with the West in 2014, Lukashenka has been having more meetings with prominent Western officials. Western institutions began trying to cooperate more closely with Belarus, but soon saw that it was not very interested. In 2018, the European Bank of Reconstruction and Development allocated €360 million to Belarus. However, it is now considering a reduction, as reforms in Belarus have not, in its view, gone far enough. The European Union has also committed considerable time and money to regional authorities, but this has not brought any significant changes to Belarusian local government.

The absence of opposition candidates also demonstrates that the Belarusian authorities are prepared for a new deterioration of relations with the West. The authorities could certainly have afforded some opposition in parliament, especially since they themselves choose whom to appoint. Given that they did not, they either do not consider worsened relations a problem or are confident that the West will continue to cooperate with Belarus in order to limit Russian power, regardless of its violations of the rule of law.

3. There is growing popular dissatisfaction with the current regime, but the state has no good plan for how to deal with it.

Parliamentary election campaigns in Belarus are traditionally low-key, but this year they were particularly muted. The authorities tried to ensure that people knew as little about the election as possible. Campaign posters appeared on the streets just two weeks before polling day. It seems the authorities were reluctant to politicize society, as further resentment at autocratic rule is brewing.

Many Belarusians who previously supported Lukashenka now have a very critical opinion of him. Take political blogging: the most popular political blogger in Belarus is a 22-year-old man who goes by the name of NEXTA. He produces low-quality videos which are highly critical of the authorities. A film by him about Lukashenka, released a month ago, has already received 1.8 million views, even though there are only 9.5 million people in Belarus.

The authorities are not in a concessionary mood. The presidential elections in 2020 will also likely be a sham. If the authorities’ grip over the country is weakened, they will fear an outbreak of anger, resulting in widespread protests which the regime might once again have to meet with violence.




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Problem Notes for SAS®9 - 65295: The order of columns is not maintained when you select columns for output in the Business Rules transformation

In SAS Data Integration Studio, the columns that you select to include in the target table in a Business Rules transformation appear in the Selected columns area in a random order. Th




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Problem Notes for SAS®9 - 34294: A missing discrete dependent variable in the selection model together with a OUTPUT statement might cause an Access Violation error

If the following conditions are met in PROC QLIM: the SELECT option and DISCRETE option are specified in the same MODEL statement or ENDOGENOUS statement the same dependent variable with S




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Problem Notes for SAS®9 - 65597: An SQL procedure query with a WHERE clause that contains multiple subselects might return incorrect results

An issue occurs when code contains a complex SQL procedure query with a WHERE clause that contains multiple subselects. Incorrect results might be returned. Click the Hot Fix tab in this note to




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ER stress increases store-operated Ca2+ entry (SOCE) and augments basal insulin secretion in pancreatic beta cells [Molecular Bases of Disease]

Type 2 diabetes mellitus (T2DM) is characterized by impaired glucose-stimulated insulin secretion and increased peripheral insulin resistance. Unremitting endoplasmic reticulum (ER) stress can lead to beta-cell apoptosis and has been linked to type 2 diabetes. Although many studies have attempted to link ER stress and T2DM, the specific effects of ER stress on beta-cell function remain incompletely understood. To determine the interrelationship between ER stress and beta-cell function, here we treated insulin-secreting INS-1(832/13) cells or isolated mouse islets with the ER stress–inducer tunicamycin (TM). TM induced ER stress as expected, as evidenced by activation of the unfolded protein response. Beta cells treated with TM also exhibited concomitant alterations in their electrical activity and cytosolic free Ca2+ oscillations. As ER stress is known to reduce ER Ca2+ levels, we tested the hypothesis that the observed increase in Ca2+ oscillations occurred because of reduced ER Ca2+ levels and, in turn, increased store-operated Ca2+ entry. TM-induced cytosolic Ca2+ and membrane electrical oscillations were acutely inhibited by YM58483, which blocks store-operated Ca2+ channels. Significantly, TM-treated cells secreted increased insulin under conditions normally associated with only minimal release, e.g. 5 mm glucose, and YM58483 blocked this secretion. Taken together, these results support a critical role for ER Ca2+ depletion–activated Ca2+ current in mediating Ca2+-induced insulin secretion in response to ER stress.




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The FKH domain in FOXP3 mRNA frequently contains mutations in hepatocellular carcinoma that influence the subcellular localization and functions of FOXP3 [Molecular Bases of Disease]

The transcription factor forkhead box P3 (FOXP3) is a biomarker for regulatory T cells and can also be expressed in cancer cells, but its function in cancer appears to be divergent. The role of hepatocyte-expressed FOXP3 in hepatocellular carcinoma (HCC) is unknown. Here, we collected tumor samples and clinical information from 115 HCC patients and used five human cancer cell lines. We examined FOXP3 mRNA sequences for mutations, used a luciferase assay to assess promoter activities of FOXP3's target genes, and employed mouse tumor models to confirm in vitro results. We detected mutations in the FKH domain of FOXP3 mRNAs in 33% of the HCC tumor tissues, but in none of the adjacent nontumor tissues. None of the mutations occurred at high frequency, indicating that they occurred randomly. Notably, the mutations were not detected in the corresponding regions of FOXP3 genomic DNA, and many of them resulted in amino acid substitutions in the FKH region, altering FOXP3's subcellular localization. FOXP3 delocalization from the nucleus to the cytoplasm caused loss of transcriptional regulation of its target genes, inactivated its tumor-inhibitory capability, and changed cellular responses to histone deacetylase (HDAC) inhibitors. More complex FKH mutations appeared to be associated with worse prognosis in HCC patients. We conclude that mutations in the FKH domain of FOXP3 mRNA frequently occur in HCC and that these mutations are caused by errors in transcription and are not derived from genomic DNA mutations. Our results suggest that transcriptional mutagenesis of FOXP3 plays a role in HCC.




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Inhibition of the erythropoietin-producing receptor EPHB4 antagonizes androgen receptor overexpression and reduces enzalutamide resistance [Molecular Bases of Disease]

Prostate cancer (PCa) cells heavily rely on an active androgen receptor (AR) pathway for their survival. Enzalutamide (MDV3100) is a second-generation antiandrogenic drug that was approved by the Food and Drug Administration in 2012 to treat patients with castration-resistant prostate cancer (CRPC). However, emergence of resistance against this drug is inevitable, and it has been a major challenge to develop interventions that help manage enzalutamide-resistant CRPC. Erythropoietin-producing human hepatocellular (Eph) receptors are targeted by ephrin protein ligands and have a broad range of functions. Increasing evidence indicates that this signaling pathway plays an important role in tumorigenesis. Overexpression of EPH receptor B4 (EPHB4) has been observed in multiple types of cancer, being closely associated with proliferation, invasion, and metastasis of tumors. Here, using RNA-Seq analyses of clinical and preclinical samples, along with several biochemical and molecular methods, we report that enzalutamide-resistant PCa requires an active EPHB4 pathway that supports drug resistance of this tumor type. Using a small kinase inhibitor and RNAi-based gene silencing to disrupt EPHB4 activity, we found that these disruptions re-sensitize enzalutamide-resistant PCa to the drug both in vitro and in vivo. Mechanistically, we found that EPHB4 stimulates the AR by inducing proto-oncogene c-Myc (c-Myc) expression. Taken together, these results provide critical insight into the mechanism of enzalutamide resistance in PCa, potentially offering a therapeutic avenue for enhancing the efficacy of enzalutamide to better manage this common malignancy.




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Structural basis of specific inhibition of extracellular activation of pro- or latent myostatin by the monoclonal antibody SRK-015 [Molecular Biophysics]

Myostatin (or growth/differentiation factor 8 (GDF8)) is a member of the transforming growth factor β superfamily of growth factors and negatively regulates skeletal muscle growth. Its dysregulation is implicated in muscle wasting diseases. SRK-015 is a clinical-stage mAb that prevents extracellular proteolytic activation of pro- and latent myostatin. Here we used integrated structural and biochemical approaches to elucidate the molecular mechanism of antibody-mediated neutralization of pro-myostatin activation. The crystal structure of pro-myostatin in complex with 29H4-16 Fab, a high-affinity variant of SRK-015, at 2.79 Å resolution revealed that the antibody binds to a conformational epitope in the arm region of the prodomain distant from the proteolytic cleavage sites. This epitope is highly sequence-divergent, having only limited similarity to other closely related members of the transforming growth factor β superfamily. Hydrogen/deuterium exchange MS experiments indicated that antibody binding induces conformational changes in pro- and latent myostatin that span the arm region, the loops contiguous to the protease cleavage sites, and the latency-associated structural elements. Moreover, negative-stain EM with full-length antibodies disclosed a stable, ring-like antigen–antibody structure in which the two Fab arms of a single antibody occupy the two arm regions of the prodomain in the pro- and latent myostatin homodimers, suggesting a 1:1 (antibody:myostatin homodimer) binding stoichiometry. These results suggest that SRK-015 binding stabilizes the latent conformation and limits the accessibility of protease cleavage sites within the prodomain. These findings shed light on approaches that specifically block the extracellular activation of growth factors by targeting their precursor forms.




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Structures of the MHC-I molecule BF2*1501 disclose the preferred presentation of an H5N1 virus-derived epitope [Protein Structure and Folding]

Lethal infections by strains of the highly-pathogenic avian influenza virus (HPAIV) H5N1 pose serious threats to both the poultry industry and public health worldwide. A lack of confirmed HPAIV epitopes recognized by cytotoxic T lymphocytes (CTLs) has hindered the utilization of CD8+ T-cell–mediated immunity and has precluded the development of effectively diversified epitope-based vaccination approaches. In particular, an HPAIV H5N1 CTL-recognized epitope based on the peptide MHC-I–β2m (pMHC-I) complex has not yet been designed. Here, screening a collection of selected peptides of several HPAIV strains against a specific pathogen-free pMHC-I (pBF2*1501), we identified a highly-conserved HPAIV H5N1 CTL epitope, named HPAIV–PA123–130. We determined the structure of the BF2*1501–PA123–130 complex at 2.1 Å resolution to elucidate the molecular mechanisms of a preferential presentation of the highly-conserved PA123–130 epitope in the chicken B15 lineage. Conformational characteristics of the PA123–130 epitope with a protruding Tyr-7 residue indicated that this epitope has great potential to be recognized by specific TCRs. Moreover, significantly increased numbers of CD8+ T cells specific for the HPAIV–PA123–130 epitope in peptide-immunized chickens indicated that a repertoire of CD8+ T cells can specifically respond to this epitope. We anticipate that the identification and structural characterization of the PA123–130 epitope reported here could enable further studies of CTL immunity against HPAIV H5N1. Such studies may aid in the development of vaccine development strategies using well-conserved internal viral antigens in chickens.




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Structural insight into the recognition of pathogen-derived phosphoglycolipids by C-type lectin receptor DCAR [Protein Structure and Folding]

The C-type lectin receptors (CLRs) form a family of pattern recognition receptors that recognize numerous pathogens, such as bacteria and fungi, and trigger innate immune responses. The extracellular carbohydrate-recognition domain (CRD) of CLRs forms a globular structure that can coordinate a Ca2+ ion, allowing receptor interactions with sugar-containing ligands. Although well-conserved, the CRD fold can also display differences that directly affect the specificity of the receptors for their ligands. Here, we report crystal structures at 1.8–2.3 Å resolutions of the CRD of murine dendritic cell-immunoactivating receptor (DCAR, or Clec4b1), the CLR that binds phosphoglycolipids such as acylated phosphatidyl-myo-inositol mannosides (AcPIMs) of mycobacteria. Using mutagenesis analysis, we identified critical residues, Ala136 and Gln198, on the surface surrounding the ligand-binding site of DCAR, as well as an atypical Ca2+-binding motif (Glu-Pro-Ser/EPS168–170). By chemically synthesizing a water-soluble ligand analog, inositol-monophosphate dimannose (IPM2), we confirmed the direct interaction of DCAR with the polar moiety of AcPIMs by biolayer interferometry and co-crystallization approaches. We also observed a hydrophobic groove extending from the ligand-binding site that is in a suitable position to interact with the lipid portion of whole AcPIMs. These results suggest that the hydroxyl group-binding ability and hydrophobic groove of DCAR mediate its specific binding to pathogen-derived phosphoglycolipids such as mycobacterial AcPIMs.




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Structural basis of cell-surface signaling by a conserved sigma regulator in Gram-negative bacteria [Molecular Biophysics]

Cell-surface signaling (CSS) in Gram-negative bacteria involves highly conserved regulatory pathways that optimize gene expression by transducing extracellular environmental signals to the cytoplasm via inner-membrane sigma regulators. The molecular details of ferric siderophore-mediated activation of the iron import machinery through a sigma regulator are unclear. Here, we present the 1.56 Å resolution structure of the periplasmic complex of the C-terminal CSS domain (CCSSD) of PupR, the sigma regulator in the Pseudomonas capeferrum pseudobactin BN7/8 transport system, and the N-terminal signaling domain (NTSD) of PupB, an outer-membrane TonB-dependent transducer. The structure revealed that the CCSSD consists of two subdomains: a juxta-membrane subdomain, which has a novel all-β-fold, followed by a secretin/TonB, short N-terminal subdomain at the C terminus of the CCSSD, a previously unobserved topological arrangement of this domain. Using affinity pulldown assays, isothermal titration calorimetry, and thermal denaturation CD spectroscopy, we show that both subdomains are required for binding the NTSD with micromolar affinity and that NTSD binding improves CCSSD stability. Our findings prompt us to present a revised model of CSS wherein the CCSSD:NTSD complex forms prior to ferric-siderophore binding. Upon siderophore binding, conformational changes in the CCSSD enable regulated intramembrane proteolysis of the sigma regulator, ultimately resulting in transcriptional regulation.




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Templated folding of intrinsically disordered proteins [Molecular Biophysics]

Much of our current knowledge of biological chemistry is founded in the structure-function relationship, whereby sequence determines structure that determines function. Thus, the discovery that a large fraction of the proteome is intrinsically disordered, while being functional, has revolutionized our understanding of proteins and raised new and interesting questions. Many intrinsically disordered proteins (IDPs) have been determined to undergo a disorder-to-order transition when recognizing their physiological partners, suggesting that their mechanisms of folding are intrinsically different from those observed in globular proteins. However, IDPs also follow some of the classic paradigms established for globular proteins, pointing to important similarities in their behavior. In this review, we compare and contrast the folding mechanisms of globular proteins with the emerging features of binding-induced folding of intrinsically disordered proteins. Specifically, whereas disorder-to-order transitions of intrinsically disordered proteins appear to follow rules of globular protein folding, such as the cooperative nature of the reaction, their folding pathways are remarkably more malleable, due to the heterogeneous nature of their folding nuclei, as probed by analysis of linear free-energy relationship plots. These insights have led to a new model for the disorder-to-order transition in IDPs termed “templated folding,” whereby the binding partner dictates distinct structural transitions en route to product, while ensuring a cooperative folding.




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The cGAS-cGAMP-STING Pathway: A Molecular Link Between Immunity and Metabolism

Juli Bai
Jun 1, 2019; 68:1099-1108
Perspectives in Diabetes




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Melding the best of two worlds: Cecil Pickett's work on cellular oxidative stress and in drug discovery and development [Molecular Bases of Disease]

Many chemicals and cellular processes cause oxidative stress that can damage lipids, proteins, or DNA (1). To quickly sense and respond to this ubiquitous threat, organisms have evolved enzymes that neutralize harmful oxidants such as reactive oxygen species and electrophilic compounds (including xenobiotics and their breakdown products) in cells.These antioxidant enzymes include GSH S-transferase (GST),2 NADPH:quinone oxidoreductase 1, thioredoxin, hemeoxygenase-1, and others (2, 3). Many of these proteins are commonly expressed in cells exposed to oxidative stress.The antioxidant response element (ARE) is a major regulatory component of this cellular stress response. The ARE is a conserved, 11-nucleotide-long DNA motif present in the 5'-flanking regions of many genes encoding antioxidant proteins. The laboratory of Cecil Pickett (Fig. 1) at the Merck Frosst Centre for Therapeutic Research in Quebec discovered ARE, a finding reported in the early 1990s in two JBC papers recognized as Classics here (4, 5).jbc;295/12/3929/F1F1F1Figure 1.Cecil Pickett (pictured) and colleagues first described the ARE motif, present in the 5' regions of many genes whose expression is up-regulated by oxidative stress and xenobiotics. Photo courtesy of Cecil Pickett.ARE's discovery was spurred in large part by Pickett's career choice. After completing a PhD in biology and a 2-year postdoc at UCLA in the mid-1970s, he began to work in the pharmaceutical industry.Recruited to Merck in 1978 by its then head of research and development (and later CEO), Roy Vagelos, “I became interested in how drug-metabolizing enzymes were induced by various xenobiotics,” Pickett says.According to Pickett, Vagelos encouraged researchers at the company...




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Tackling Cyber Disinformation in Elections: Applying International Human Rights Law

Research Event

6 November 2019 - 5:30pm to 7:00pm

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

Event participants

Susie Alegre, Barrister and Associate Tenant, Doughty Street Chambers
Evelyn Aswad, Professor of Law and the Herman G. Kaiser Chair in International Law, University of Oklahoma
Barbora Bukovská, Senior Director for Law and Policy, Article 19
Kate Jones, Director, Diplomatic Studies Programme, University of Oxford
Chair: Harriet Moynihan, Associate Fellow, International Law Programme, Chatham House

Cyber operations are increasingly used by political parties, their supporters and foreign states to influence electorates – from algorithms promoting specific messages to micro-targeting based on personal data and the creation of filter bubbles.
 
The risks of digital tools spreading disinformation and polarizing debate, as opposed to deepening democratic engagement, have been highlighted by concerns over cyber interference in the UK’s Brexit referendum, the 2016 US presidential elections and in Ukraine. 
 
While some governments are adopting legislation in an attempt to address some of these issues, for example Germany’s ‘NetzDG’ law and France’s ‘Law against the manipulation of information’, other countries have proposed an independent regulator as in the case of the UK’s Online Harms white paper. Meanwhile, the digital platforms, as the curators of content, are under increasing pressure to take their own measures to address data mining and manipulation in the context of elections. 

How do international human rights standards, for example on freedom of thought, expression and privacy, guide the use of digital technology in the electoral context? What practical steps can governments and technology actors take to ensure policies, laws and practices are in line with these fundamental standards? And with a general election looming in the UK, will these steps come soon enough?
 
This event brings together a wide range of stakeholders including civil society, the tech sector, legal experts and government, coincides with the publication of a Chatham House research paper on disinformation, elections and the human rights framework

Jacqueline Rowe

Programme Assistant, International Law Programme
020 7389 3287




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Iran Crisis Pushes Foreign Policy to Top of 2020 Election Debate

14 January 2020

Dr Lindsay Newman

Senior Research Fellow, US and the Americas Programme
Democrats would be wise to communicate a clear alternative to Trump’s ‘America First’ policy in the Middle East.

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Donald Trump speaks to the media in front of the White House on Monday. Photo: Getty Images.

Conventional wisdom says that foreign policy takes a backseat role in US elections. But last autumn’s Democratic primary debates suggest a potential shift is taking place in the conventional view. While healthcare dominated the discussion (Democrats attribute their 2018 midterm gains to the issue), through November foreign policy followed closely behind in second place in terms of minutes devoted to the discussion.

This trend is consistent with President Donald Trump’s America First approach to foreign policy, in which an eye is always kept on how decisions abroad play for the domestic audience. One former Trump administration official has called this dynamic the ‘recoupling’ of foreign policy with domestic policy.

The US–China trade conflict, which commanded headlines throughout 2019, is perhaps the best example of this recoupling, tying trade imbalances less with the geopolitical than with domestic impact on farmers. Immigration is another policy area in which Trump has linked domestic implications and indeed domestic opinion with foreign policy. It’s in the title: America First.

Now, for better or worse, the targeted killing of Qassem Soleimani, Iran’s response and the subsequent fallout may make US foreign policy towards Iran and the US role in the Middle East a central issue for the 2020 US elections. As it comes just ahead of the Democratic presidential primaries, voters will be looking to the candidates to differentiate their foreign policy experience and proposals for America’s Middle East policy.

To President Donald Trump, Soleimani’s assassination represents a campaign promise kept to confront Iran’s aggression.

The Trump administration initially justified the action by citing intelligence of an imminent threat to US personnel and targets, but after Defense Secretary Mark Esper called this into question, Trump tweeted that ‘it doesn’t really matter because of [Soleimani’s] horrible past’. Ultimately, Trump’s message, on the campaign trail and any general debate stage he agrees to be on, is that he has overseen a new national security strategy for Iran.

Soleimani’s removal from the Iranian calculus is just a part of this broader policy, which also includes neutralizing the Iranian government’s destabilizing influence in the Middle East, denying Iran and especially the Islamic Revolutionary Guard Corps’ access to funding for its malign activities, and rallying the international community against domestic human rights violations and unjust detentions.

To counter Trump, Democrats and democratic presidential candidates would be best-served by offering a simple argument that too links domestic interests and foreign policy: the killing of Soleimani and Trump’s national security strategy for Iran have not made the US or its interests safer.

Iran’s ballistic missile attack on US forces in Iraq, which Iran’s Supreme Leader Ayatollah Ali Khamenei called a ‘slap in the face’ for the US, makes the risks to US assets and personnel abundantly clear. Even if Iran reverts entirely to covert, proxy efforts to counter US interests, the current US–Iran tensions remain unresolved and will likely continue to persist through the 2020 elections in November.

As a matter of the first order, Soleimani was replaced by his deputy Brigadier General Esmail Ghaani within a day of the former’s death, with Khamenei saying that the Quds Force will be ‘unchanged’.

At the second order, Iraq’s parliament voted in favour of a nonbinding resolution to rescind the invitation to US forces, which led Trump to threaten sanctions and demands for reimbursement. Whether US troops will ultimately leave Iraq (following a ‘mistaken’ report that the US was preparing to depart) remains to be seen, but the destabilization of the US military presence in Iraq fulfils a key Iranian objective.

In the interim, the US-led coalition in Iraq and Syria fighting ISIS announced that it would at least temporarily cease its counterterrorism efforts to instead fortify its outposts and prepare for Iranian retaliation, opening a wider door for the resurgence of the terror group.

By arguing that the US, its troops and interest have not been made safer by Trump’s Middle East policy – from withdrawing from the Iran nuclear deal to the imposition of a ‘maximum pressure campaign’ to Soleimani’s killing – Democrats will be able to point to every post-Soleimani US injury, death, regional terrorism attack, asset compromise, cyberattack and shipping disruption as evidence.

Democratic presidential candidates also ought to be explicit about how they plan to manage tensions with Iran – strategic, diplomatic and military – particularly their position on the future of the nuclear deal.

Iran has made clear that the path to de-escalation is through sanctions relief. Asserting leverage need not always involve taking away all of your counterparty’s options (‘maximum pressure’). It also involves knowing what your adversary wants (sanctions relief) and showing a willingness to offer it (especially where it means less to you) in exchange for something of greater worth (avoiding war/a non-nuclear Iran).

Clarity around future policy of a potential Democratic president may bring de-escalation forward in a way that Trump’s statement of Iran standing down are unlikely to do.




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Chatham House US 2020 Election Series

A year-long project focused on what is at stake in the pivotal 2020 US presidential and congressional elections, considering the future of US policy on trade, global economy and technology, national security, transatlantic relations, climate, migration and Latin America.

As part of this initiative, we are launching the Chatham House US Foreign Policy Forum as an incubator for foreign policy dialogue and shared expertise outside of the Washington DC framework.

Meeting regularly, in its inaugural year the Forum will largely focus on the 2020 elections, facilitating discussions around developments in the election and critical policy insights.

These activities support the development of a multi-authored volume outlining the current state of play and potential priorities of a second Trump term, as well as a Democratic administration. The text will contribute to the public debate and research considering the resiliency of US institutions as well as the future of US policy engagement abroad.

Situated in London, this project leverages Chatham House’s world-leading, independent foreign policy institute and unparalleled experience in convening multi-stakeholder discussions to provide a unique, international perspective on the 2020 elections.




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Reflections from the Munich Security Conference on America’s Role in the World

Invitation Only Research Event

17 February 2020 - 8:00am to 9:15am

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

Event participants

Senator Chris Coons, United States Senator, Delaware
Chair: Dr Leslie Vinjamuri, Director, US and Americas Programme

In the aftermath of World War II, the United States cemented its role as the leader of a new global order, characterized by the creation of international institutions and treaties like the United Nations and North Atlantic Treaty Organization. More recently, however, the United States has appeared to take an inward turn, a trend which has been mirrored across the globe and has led to the international order being challenged more now than ever before.

As the Trump administration and US members of Congress attempt to address multiple challenges from a rising China and a disruptive Russia to a nuclear North Korea and shifting Middle East, Senator Chris Coons will offer his vision for restoring American leadership on the world stage.What is the role of Congress in setting and shaping US foreign policy?  How will the outcome of the consequential 2020 elections shape the future of America’s global role? Would a change in administration necessarily increase prospects of American reengagement, and if so, across which international spheres?

Event attributes

Chatham House Rule

Department/project

US and Americas Programme




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US 2020: Super Tuesday and Implications for the General Election

Invitation Only Research Event

5 March 2020 - 12:00pm to 1:30pm

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

Event participants

Dr Lindsay Newman, Senior Research Fellow, US and the Americas Programme, Chatham House
Professor Peter Trubowitz, Professor of International Relations, London School of Economics and Political Science; Associate Fellow, US and the Americas Programme, Chatham House
Amy Pope, Associate Fellow, US and the Americas Programme, Chatham House; Deputy Homeland Security Advisor, US National Security Council, 2015-17
Chair: Dr Leslie Vinjamuri, Director, US and the Americas Programme, Chatham House

The US 2020 election season enters a potentially decisive next phase with the Super Tuesday primaries on 3 March. With these fifteen, simultaneously-held state elections, the Democrats hope to have greater clarity about their party’s likely nominee for the general race against President Donald Trump in November. Concerns around intraparty divisions in the Democratic party between progressives (represented by Senators Elizabeth Warren and Bernie Sanders) and moderates (represented by former Vice President Joe Biden and former mayor Pete Buttigieg) have surrounded the primary races so far, and are unlikely to dissipate even if one candidate emerges from the field on 3 March.

Against this backdrop, Chatham House brings together a panel of experts to discuss the state of the Democratic primary race, implications for the general election, and the Trump campaign’s priorities ahead of its re-election bid. Will the Democratic party resolve its divisions and unite behind a progressive or moderate in light of the Super Tuesday election results? How is Trump positioned to fair against the Democratic candidates left in the race? Did Former Mayor of New York Michael Bloomberg’s primary gamble to focus on Super Tuesday pay off? And what policy priorities are likely to be pursued under either a Trump 2.0 or a Democratic administration?

Event attributes

Chatham House Rule

US and Americas Programme




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Democrats Have Set Themselves Up to Fail in November's Election

21 February 2020

Dr Lindsay Newman

Senior Research Fellow, US and the Americas Programme
Debates and caucuses are proving that the party took the wrong lesson from the midterms. They're now applying that lesson to 2020 with potentially disastrous results.

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2020 Democratic presidential candidates at the debate in Las Vegas on 19 February. Photo: Getty Images.

The Democratic Party’s struggle for its future policy direction is evident this election season. The primary results in Iowa and New Hampshire, narrow first- and second-place finishes for Senator Bernie Sanders (a progressive) and former South Bend mayor Pete Buttigieg (a moderate), were just two indicators. During Wednesday night’s debate in Las Vegas, the split became even more obvious.

The six candidates onstage clashed on ideology (socialism and capitalism, progressivism and centrism) as well as policy (healthcare, climate change, fossil fuels, criminal justice, China). Buttigieg made plain the stakes for Democrats, saying, 'We’ve got to wake up as a party.'

If a Democratic candidate is elected to be the United States’ 46th president on 3 November, it will be despite this unresolved intra-party struggle.

One lesson the Democratic Party has taken from the 2018 midterm elections is that running candidates across the ideological spectrum is a winning formula.

It is easy to see how they came to this conclusion following the 2016 presidential and 2018 Congressional election experiences. In 2016, the favoured candidate status of former secretary of state Hillary Clinton deterred other aspirants from entering the Democratic primary ahead of a general election she went on to lose to Republican Donald Trump. In 2018, progressive and moderate centrist candidates, both first-timers and incumbents, ran and Democrats retook leadership in the House of Representatives with a 235-seat majority.

But what if this conclusion was noise and not the signal?

The Democratic National Committee (DNC) set the rules for the 2020 election based on the theory that by allowing an inclusive field (more than two dozen candidates entered the presidential race) the campaign processes, including debates, caucuses and primaries, would ultimately identify the most robust, representative candidate to go up against Donald Trump. Perhaps, and somewhat ironically, the 2016 Republican primary process, which involved a wide field culled by Trump’s unexpected success, informed the DNC’s reforms. And while very nice as a hypothesis of Bayesian updating, what has unfolded instead is a scattershot four-way — at times even five-way — race.

In the midst of this party divide, whoever ends up being the Democratic nominee will likely not represent the views of some meaningful proportion of the Democratic base. While healthcare remains the top issue across the Democratic electorate, there are those (candidates and voters) who want a single-payer option for all without a private insurance option and those who want to expand healthcare access while maintaining private insurers. Likewise, on foreign policy, there are those who link US trade policy with protecting American workers and who would therefore continue to use tariffs as a key trade policy, as well as those critical of Trump’s reliance on tariffs.

Compare that with the current state of the Republican Party. Trump’s approval with Republicans is in the high 80s, sometimes even low 90s, and after all but one Republican senator voted to acquit him in the Senate impeachment trial, the party is undeniably Trump’s. A sure sign is the historic turnout for Trump in his essentially uncontested Iowa and New Hampshire primaries.

Their own divisions pose a number of risks, then, for Democrats heading into November’s general election. The first one relates to vulnerabilities arising out of the primary process itself. If the fractures emerging from Iowa and New Hampshire persist, the likelihood of a quick wrap-up of the Democratic primary by April reduces, and the possibility of a contested Democratic convention in July increases (even if from a low base). While exciting television and Twitter fodder, a lengthy primary positions Democrats to go into the fall facing questions of party disunity behind the eventual nominee.

Although complicated to demonstrate empirically, some work has been done to understand whether the protracted 2016 Democratic primary and Sanders’ slow support for Democratic nominee Clinton in 2016 played a part in her defeat and Trump’s electoral success. A delayed general election campaign for the eventual Democratic nominee in 2020 almost certainly advantages President Trump’s money machine, which reportedly has more than twice as much on hand as then-president Barack Obama had going into his 2012 re-election. Further, unlike 2016, which was an open-seat election for the presidency, in 2020 Trump will have a demonstrated incumbent advantage.

The Democratic Party’s succession battle also raises risks around general election turnout. If Sanders is the party’s nominee, Biden or Buttigieg’s constituency may not come out to vote for him. More worrisome for Democrats, if Sanders is the party’s nominee then centrist voters, including those representing the finance industry, may peel off and vote for Trump, who has overseen economic expansion and record unemployment rates following the 2017 tax overhaul and various deregulations.

Alternatively, if Biden, Buttigieg or former mayor Michael Bloomberg become the nominee, Sanders’ many loyal supporters are likely to feel their policy priorities are not represented. And if those voters stay home because the Democratic nominee is not promising a political revolution, evidence suggests that depressed turnout levels may favour Republicans.

A third political peril relates to the business of legislating after the election. If despite the potential pitfalls a Democratic candidate manoeuvres and manages to build a winning coalition on 3 November, they will face the reality of legislative politics, which over the last 10 years have been defined by policy gridlock. Obama managed to get Obamacare through both Democratic-majority congressional chambers, but presided over divided chambers for the remainder of his term. Similarly, Trump’s major legislative accomplishment — the 2017 tax overhaul — was a result of Republican control in both the House of Representatives and the Senate.

A Democratic president will have to make progress on his or her agenda given not only the typical Republican-Democrat divide in Congress, but also facing potential raw divisions within the Democratic Party itself. In such a scenario, a Democratic administration may be tempted to take an expansive view of the president’s authority as we have seen under Trump, including relying on executive actions (tariffs and sanctions) on foreign policy.

The Democratic National Convention in Milwaukee, Wisconsin, beginning 13 July, and the party platform crafted over those four days present an essential opportunity to resolve the party’s divisions before November. If left unchecked, the party might find that its ex ante strategy for the 2020 Democratic primary ends in Trump’s re-election.

This article was originally published in the Independent.




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COVID-19: America's Looming Election Crisis

8 April 2020

Dr Lindsay Newman

Senior Research Fellow, US and the Americas Programme
Planning now is essential to ensure the legitimacy of November’s elections is not impacted by COVID-19, as vulnerabilities are becoming ever more apparent if voting in person is restricted.

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Roadside voting in Madison, Wisconsin in April 2020. Because of coronavirus, the number of polling places was drastically reduced. Photo by Andy Manis/Getty Images.

The COVID-19 epidemic has hit every aspect of American life. The upcoming November general elections will not be immune to the virus’ impact and may be scheduled to happen while the pandemic remains active, or has returned.

There is a danger the epidemic forces change to the way voting takes place this fall, amplifying risks around election security and voter suppression that ultimately undermine the integrity of the elections.

This is further highlighted by the US Supreme Court’s last-minute ruling along ideological lines to restrict an extension on the absentee voting period in the Wisconsin Democratic presidential primary despite the level of infections in the state, forcing voters into a trade-off between their health and their right to vote. The US could be thrown into a political crisis in addition to the health and economic crises it already faces.

Bipartisan sentiment

While France, Chile and Bolivia have already postponed elections in the wake of COVID-19, there is a bipartisan sentiment that the US elections should be held as scheduled on the Tuesday after the first Monday in November. This is enshrined not only in America’s sense of itself – having weathered elections during a civil war, a world war and heightened terrorist alert before – but also in its federal law since 1845.

Despite increasing appetite for federal elections to go ahead in November, there are serious vulnerabilities, which are already becoming visible as connections are drawn between mail-in voting and voter fraud, greater voter access and disadvantages for the Republican party, and city polling closures and Democratic voter suppression.

Concerns around voting access have gained the most attention. If voting in-person is untenable or risky (especially for vulnerable health populations), voters must have alternative means to cast ballots.

During negotiations for the Coronavirus Aid, Relief, and Economic Security (CARES) Act, the Democratic caucus in the House of Representatives proposed $4 billion in state election grants and a nationally-mandated period for early voting and no-excuse absentee voting.

But the final CARES Act sidestepped the access question and stripped funding to $400 million for election security grants to ‘prevent, prepare for, and respond to coronavirus, domestically or internationally, for the 2020 Federal election cycle’. Without knowing exactly what is in store from a cyber-threat perspective, the actual cost for basic election security upgrades is estimated to be $2.1billion. And that is a pre-COVID-19 calculation.

With social-distanced voters likely to be getting more election information than ever from social media, information security is critical to prevent influence from untrustworthy sources. And opportunities for cyber intrusions are likely to increase as states transition to greater virtual registration, plus absentee and mail-in balloting.

This will open new doors on well-documented, existing voter suppression efforts. With the Supreme Court clawing back the Voting Rights Act in 2013 - allowing certain states to make changes to election and voting laws without federal pre-clearance - heightened election security requirements, such as exact match campaigns and voter purges, have been used to justify voter suppression.

As more vote remotely in the remaining primaries (many now rescheduled for 2 June) and the November general elections, the added burden on states around verification will only increase temptation to set aside ‘non-compliant’ ballots. Especially as some in the Republican Party, including Donald Trump, have advocated a contested view that higher turnout favours the Democratic Party.

A fundamental principle of US democracy is that losers of elections respect the result, but history shows that election results have been contested. In 2000, it took weeks for a result to be confirmed in the presidential election. More recently, in the 2018 race for governor in Georgia, allegations of voter suppression raised questions about the validity of the eventual result.

Without proper access, security, and verification the electoral process – whenever it takes place – will become vulnerable to questions of integrity. The federal response to the initial spread of COVID-19 saw costly delays which pushed the US into a public health crisis and economic contraction.

Any narrative thread of election illegitimacy with November’s elections will further pull apart the fabric of a country already frayed by coronavirus. Federal and state authorities must start planning now for how the US will hold elections in the midst - or immediate aftermath - of COVID-19.




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Three Takeaways From the Belarusian Parliamentary Elections

28 November 2019

Ryhor Astapenia

Robert Bosch Stiftung Academy Fellow, Russia and Eurasia Programme
Lukashenka’s domestic support is waning and he is not willing to make concessions to the West. Instead, he is trying to appease the ruling cadre.

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Alexander Lukashenka leaves a voting booth on 17 November. Photo: Getty Images.

Belarus’s parliamentary elections, held on 17 November, were predictably non-transparent, with numerous violations. The regime of Alexander Lukasheka allowed no opposition candidates as members of parliament – in contrast to the previous parliament, in which there were two opposition MPs. While this might seem to be a return to ‘business as usual’, three key takeaways from the elections highlight a shifting political and social landscape.

1. Lukashenka is appeasing his ruling cadre by promising to increase their role in the political system.

With several influential officials becoming new MPs, it is more likely that parliament will be more involved in any forthcoming discussion of a new constitution. Lukashenka has been promising constitutional reform for several years; he has said publicly that it will lead to an increased significance of government agencies as well as parliament. The aim of this is to keep them more engaged and on Lukashenka’s side.

In terms of the composition of the new parliament itself, there are some key differences with previous years. It is no longer a comfortable place for officials to while away their pre-retirement: many MPs are now in their fifties or younger, and have plans for careers beyond parliament.

It also looks as if small steps are being taken towards the emergence of a party system in Belarus. The leader of Belaya Rus, a pro-government association of Belarusian officials, got a seat in parliament for the first time, increasing the likelihood of it becoming a political party. The number of MPs from different parties has increased to 21 (out of 110 in total). Although these still all broadly support Lukashenka, they can differ from the president in policy positions. For example, the Labour and Justice Party, with 6 seats in parliament, supported the annexation of Crimea in 2014. Change, of course, may not necessarily be in a pro-Western direction.

Moreover, the newly elected members of parliament look more like real politicians. They go to debates, speak to independent journalists and have their own social media channels. Some have even felt able to criticize the actions of the authorities.

Similar changes have been taking place in other institutions in Belarus. The government is now more competent than it has ever been. The National Bank has managed to carry out macroeconomic stabilization on one of the most unstable currencies in Europe, while the ministries responsible for the economic development have implemented certain small-scale reforms. The Minister of the Interior has even acknowledged mistakes made by his department (under his predecessor), and undertaken to make improvements.

This has resulted in a near-comical situation, whereby the Belarusian non-state media outlets have an increasingly positive view of some state officials, such as Prime Minister Siarhei Rumas, while the state media has been scaling back its coverage of him to ensure he does not become too popular.

2. Belarus has less need for the West and is reluctant to make even small concessions.

Since the slight warming of Belarusian relations with the West in 2014, Lukashenka has been having more meetings with prominent Western officials. Western institutions began trying to cooperate more closely with Belarus, but soon saw that it was not very interested. In 2018, the European Bank of Reconstruction and Development allocated €360 million to Belarus. However, it is now considering a reduction, as reforms in Belarus have not, in its view, gone far enough. The European Union has also committed considerable time and money to regional authorities, but this has not brought any significant changes to Belarusian local government.

The absence of opposition candidates also demonstrates that the Belarusian authorities are prepared for a new deterioration of relations with the West. The authorities could certainly have afforded some opposition in parliament, especially since they themselves choose whom to appoint. Given that they did not, they either do not consider worsened relations a problem or are confident that the West will continue to cooperate with Belarus in order to limit Russian power, regardless of its violations of the rule of law.

3. There is growing popular dissatisfaction with the current regime, but the state has no good plan for how to deal with it.

Parliamentary election campaigns in Belarus are traditionally low-key, but this year they were particularly muted. The authorities tried to ensure that people knew as little about the election as possible. Campaign posters appeared on the streets just two weeks before polling day. It seems the authorities were reluctant to politicize society, as further resentment at autocratic rule is brewing.

Many Belarusians who previously supported Lukashenka now have a very critical opinion of him. Take political blogging: the most popular political blogger in Belarus is a 22-year-old man who goes by the name of NEXTA. He produces low-quality videos which are highly critical of the authorities. A film by him about Lukashenka, released a month ago, has already received 1.8 million views, even though there are only 9.5 million people in Belarus.

The authorities are not in a concessionary mood. The presidential elections in 2020 will also likely be a sham. If the authorities’ grip over the country is weakened, they will fear an outbreak of anger, resulting in widespread protests which the regime might once again have to meet with violence.




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Trudeau Election Marks New Start for Canada

22 October 2015

Cleo Paskal

Associate Fellow, Energy, Environment and Resources Programme and Asia-Pacific Programme
Canada's partners are about to see a sea change in policy from the new Liberal government on a range of issues, especially relating to energy and the environment.

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Canadian Liberal Party leader Justin Trudeau arrives to give a press conference in Ottawa on 20 October 2015. Photo by Getty Images.

The Liberal Party likes to think of itself as ‘Canada’s natural governing party’. Though they have been out of power for 10 years, and newly elected prime minister Justin Trudeau is relatively inexperienced, the party has deep and old networks across the country. The backroom is full of experienced old hands, including former prime ministers who have known Trudeau since he was a toddler. With a number of bold shifts promised in Canadian foreign policy, and a willingness to be fiscally expansive (Trudeau has said he is willing to run deficits for three years to implement their policies), the change is likely to be dramatic, fast and unrelenting.

International engagement

The Liberals’ proposed new Canada has a hint of nostalgia for a time when Canadians thought of themselves as a force for good in the world. There is likely to be a large-scale reengagement with the international community, especially the United Nations, not only on climate policy, but also peacekeeping and disaster response. Canada’s French-speaking experts make it well placed to engage in crisis-hit French-speaking countries while carrying somewhat less colonial baggage. Meanwhile, the Liberals have promised to withdraw Canadian forces from the combat mission against ISIS in Iraq, pledging instead to reorient their focus towards aid.

Science-based policies

Trudeau has the backing of a very deep bench of experienced parliamentarians, some of whom have been waiting a long time to get back in the governing game. They include Stéphane Dion, the former environment minister who gained respect for his chairing of the 2005 UN climate change conference in Montreal, and Marc Garneau, former astronaut and president of the Canadian Space Agency. This will be a government that understands and values (and has promised to restore funding for) scientific research.

This means more investment in climate resilience, renewables and other forward planning policies, but also a reexamination of some of Canada’s long-standing strengths, including Canada’s fisheries. Under the previous government, over half-a-dozen critical fisheries research libraries were shut down, in some cases with large-scale loss of data. A more science-based fisheries policy, combined with the promised funding to the Royal Canadian Navy, may result in a reinvigorated and coordinated Canadian fisheries policy. This would become particularly important in a time of global food constraints.

‘Nation-to-nation’

Trudeau’s stated goal of establishing ‘nation-to-nation’ relations with Canada’s indigenous peoples has potentially global implications.

Through treaties, Canada’s First Nations can stake a claim to about a third of Canada’s landmass, including resource rich areas. They own or control access to land that contains oil, gas, uranium, gold, diamonds and much more. China, for one, realized the potential power of First Nations as far back as 2008, when Beijing invited over two dozen indigenous leaders to China to talk business. During that trip, Peguis Chief Glenn Hudson explained that the trip was ‘an important step for us in moving forward. Our future is not only in Canada, but partnering with other countries.’

Trudeau’s ‘nation-to-nation’ statement acknowledges the strengthening role of First Nations in Canada’s resource policy. Indigenous communities have been among the most adversely affected by oil sands development and, in other parts of Canada, have successfully blocked resources extraction or transit. For example, in May, the Lax Kw'alaams Band refused to allow a proposed multi-million dollar Petronas LNG project to be developed on their land over concerns it would affect their economically and culturally important salmon runs.

Real First Nations engagement with resource management has the potential substantially change Canada’s energy, environment and resources profile. First Nations in eastern Canada have already blocked hydro development that could power much of the northeastern United States and, in a time of pipeline expansion, First Nations might become instrumental in deciding if more pipelines will run north-to-south, towards the border with the United States, or east-to-west, towards the Pacific and the markets in Asia.

Energy sector

At the same time, while Trudeau said he was against the Northern Gateway pipeline, in large part because of how it would affect the people of the Pacific coast, he backed Keystone XL. However, he is unlikely to push for it in the face of a veto by President Obama. Also, low fossil fuel prices contributed to the election in May of a left-leaning provincial government in the badly hit oil heartland of Alberta. If prices stay low, that could very well combine with Liberal campaign promises to put a coordinated national price on carbon and to phase out fossil fuel subsidies, additionally reshaping Canada’s energy landscape..

Agriculture and the Trans-Pacific Partnership

The Liberals also have a stated goal of investing in a more innovative and safe agricultural sector, while defending the interests of Canadian farmers. This dovetails with their promise to openly examine and discuss the Trans-Pacific Partnership (TPP) before ratification. Canadian dairy farmers in particular were concerned about some of the TPP provisions but, without access to the details of the text, it was difficult to estimate how the sector would be affected.

One proposed agricultural policy that may have widespread economic implications is the legalization, regulation and taxation of marijuana. As some states in the United States have found, this has the potential to be economically beneficial and, for Canada, a possible major boon to cross-border tourism.

In a myriad of small ways, and a few big ones, the new Liberal government plans to change Canada’s international role and domestic landscape. This is one to watch.

To comment on this article, please contact Chatham House Feedback 




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