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Antibiotic binding releases autoinhibition of the TipA multidrug-resistance transcriptional regulator [Gene Regulation]

Investigations of bacterial resistance strategies can aid in the development of new antimicrobial drugs as a countermeasure to the increasing worldwide prevalence of bacterial antibiotic resistance. One such strategy involves the TipA class of transcription factors, which constitute minimal autoregulated multidrug resistance (MDR) systems against diverse antibiotics. However, we have insufficient information regarding how antibiotic binding induces transcriptional activation to design molecules that could interfere with this process. To learn more, we determined the crystal structure of SkgA from Caulobacter crescentus as a representative TipA protein. We identified an unexpected spatial orientation and location of the antibiotic-binding TipAS effector domain in the apo state. We observed that the α6–α7 region of the TipAS domain, which is canonically responsible for forming the lid of antibiotic-binding cleft to tightly enclose the bound antibiotic, is involved in the dimeric interface and stabilized via interaction with the DNA-binding domain in the apo state. Further structural and biochemical analyses demonstrated that the unliganded TipAS domain sterically hinders promoter DNA binding but undergoes a remarkable conformational shift upon antibiotic binding to release this autoinhibition via a switch of its α6–α7 region. Hence, the promoters for MDR genes including tipA and RNA polymerases become available for transcription, enabling efficient antibiotic resistance. These insights into the molecular mechanism of activation of TipA proteins advance our understanding of TipA proteins, as well as bacterial MDR systems, and may provide important clues to block bacterial resistance.




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Identification and biochemical characterization of Asp t 36, a new fungal allergen from Aspergillus terreus [Protein Structure and Folding]

Aspergillus terreus is an allergenic fungus, in addition to causing infections in both humans and plants. However, the allergens in this fungus are still unknown, limiting the development of diagnostic and therapeutic strategies. We used a proteomic approach to search for allergens, identifying 16 allergens based on two-dimensional immunoblotting with A. terreus susceptible patient sera. We further characterized triose-phosphate isomerase (Asp t 36), one of the dominant IgE (IgE)-reactive proteins. The gene was cloned and expressed in Escherichia coli. Phylogenetic analysis showed Asp t 36 to be highly conserved with close similarity to the triose-phosphate isomerase protein sequence from Dermatophagoides farinae, an allergenic dust mite. We identified four immunodominant epitopes using synthetic peptides, and mapped them on a homology-based model of the tertiary structure of Asp t 36. Among these, two were found to create a continuous surface patch on the 3D structure, rendering it an IgE-binding hotspot. Biophysical analysis indicated that Asp t 36 shows similar secondary structure content and temperature sensitivity with other reported triose-phosphate isomerase allergens. In vivo studies using a murine model displayed that the recombinant Asp t 36 was able to stimulate airway inflammation, as demonstrated by an influx of eosinophils, goblet cell hyperplasia, elevated serum Igs, and induction of Th2 cytokines. Collectively, our results reveal the immunogenic property of Asp t 36, a major allergen from A. terreus, and define a new fungal allergen more broadly. This allergen could serve as a potent candidate for investigating component resolved diagnosis and immunotherapy.




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The C-terminal region of the plasmid partitioning protein TubY is a tetramer that can bind membranes and DNA [Protein Structure and Folding]

Bacterial low-copy-number plasmids require partition (par) systems to ensure their stable inheritance by daughter cells. In general, these systems consist of three components: a centromeric DNA sequence, a centromere-binding protein and a nucleotide hydrolase that polymerizes and functions as a motor. Type III systems, however, segregate plasmids using three proteins: the FtsZ/tubulin-like GTPase TubZ, the centromere-binding protein TubR and the MerR-like transcriptional regulator TubY. Although the TubZ filament is sufficient to transport the TubR-centromere complex in vitro, TubY is still necessary for the stable maintenance of the plasmid. TubY contains an N-terminal DNA-binding helix-turn-helix motif and a C-terminal coiled-coil followed by a cluster of lysine residues. This study determined the crystal structure of the C-terminal domain of TubY from the Bacillus cereus pXO1-like plasmid and showed that it forms a tetrameric parallel four-helix bundle that differs from the typical MerR family proteins with a dimeric anti-parallel coiled-coil. Biochemical analyses revealed that the C-terminal tail with the conserved lysine cluster helps TubY to stably associate with the TubR-centromere complex as well as to nonspecifically bind DNA. Furthermore, this C-terminal tail forms an amphipathic helix in the presence of lipids but must oligomerize to localize the protein to the membrane in vivo. Taken together, these data suggest that TubY is a component of the nucleoprotein complex within the partitioning machinery, and that lipid membranes act as mediators of type III systems.




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A structural and kinetic survey of GH5_4 endoglucanases reveals determinants of broad substrate specificity and opportunities for biomass hydrolysis [Protein Structure and Folding]

Broad-specificity glycoside hydrolases (GHs) contribute to plant biomass hydrolysis by degrading a diverse range of polysaccharides, making them useful catalysts for renewable energy and biocommodity production. Discovery of new GHs with improved kinetic parameters or more tolerant substrate-binding sites could increase the efficiency of renewable bioenergy production even further. GH5 has over 50 subfamilies exhibiting selectivities for reaction with β-(1,4)–linked oligo- and polysaccharides. Among these, subfamily 4 (GH5_4) contains numerous broad-selectivity endoglucanases that hydrolyze cellulose, xyloglucan, and mixed-linkage glucans. We previously surveyed the whole subfamily and found over 100 new broad-specificity endoglucanases, although the structural origins of broad specificity remained unclear. A mechanistic understanding of GH5_4 substrate specificity would help inform the best protein design strategies and the most appropriate industrial application of broad-specificity endoglucanases. Here we report structures of 10 new GH5_4 enzymes from cellulolytic microbes and characterize their substrate selectivity using normalized reducing sugar assays and MS. We found that GH5_4 enzymes have the highest catalytic efficiency for hydrolysis of xyloglucan, glucomannan, and soluble β-glucans, with opportunistic secondary reactions on cellulose, mannan, and xylan. The positions of key aromatic residues determine the overall reaction rate and breadth of substrate tolerance, and they contribute to differences in oligosaccharide cleavage patterns. Our new composite model identifies several critical structural features that confer broad specificity and may be readily engineered into existing industrial enzymes. We demonstrate that GH5_4 endoglucanases can have broad specificity without sacrificing high activity, making them a valuable addition to the biomass deconstruction toolset.




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Snapshots during the catalytic cycle of a histidine acid phytase reveal an induced-fit structural mechanism [Protein Structure and Folding]

Highly engineered phytases, which sequentially hydrolyze the hexakisphosphate ester of inositol known as phytic acid, are routinely added to the feeds of monogastric animals to improve phosphate bioavailability. New phytases are sought as starting points to further optimize the rate and extent of dephosphorylation of phytate in the animal digestive tract. Multiple inositol polyphosphate phosphatases (MINPPs) are clade 2 histidine phosphatases (HP2P) able to carry out the stepwise hydrolysis of phytate. MINPPs are not restricted by a strong positional specificity making them attractive targets for development as feed enzymes. Here, we describe the characterization of a MINPP from the Gram-positive bacterium Bifidobacterium longum (BlMINPP). BlMINPP has a typical HP2P-fold but, unusually, possesses a large α-domain polypeptide insertion relative to other MINPPs. This insertion, termed the U-loop, spans the active site and contributes to substrate specificity pockets underpopulated in other HP2Ps. Mutagenesis of U-loop residues reveals its contribution to enzyme kinetics and thermostability. Moreover, four crystal structures of the protein along the catalytic cycle capture, for the first time in an HP2P, a large ligand-driven α-domain motion essential to allow substrate access to the active site. This motion recruits residues both downstream of a molecular hinge and on the U-loop to participate in specificity subsites, and mutagenesis identified a mobile lysine residue as a key determinant of positional specificity of the enzyme. Taken together, these data provide important new insights to the factors determining stability, substrate recognition, and the structural mechanism of hydrolysis in this industrially important group of enzymes.




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Mapping the transition state for a binding reaction between ancient intrinsically disordered proteins [Molecular Biophysics]

Intrinsically disordered protein domains often have multiple binding partners. It is plausible that the strength of pairing with specific partners evolves from an initial low affinity to a higher affinity. However, little is known about the molecular changes in the binding mechanism that would facilitate such a transition. We previously showed that the interaction between two intrinsically disordered domains, NCBD and CID, likely emerged in an ancestral deuterostome organism as a low-affinity interaction that subsequently evolved into a higher-affinity interaction before the radiation of modern vertebrate groups. Here we map native contacts in the transition states of the low-affinity ancestral and high-affinity human NCBD/CID interactions. We show that the coupled binding and folding mechanism is overall similar but with a higher degree of native hydrophobic contact formation in the transition state of the ancestral complex and more heterogeneous transient interactions, including electrostatic pairings, and an increased disorder for the human complex. Adaptation to new binding partners may be facilitated by this ability to exploit multiple alternative transient interactions while retaining the overall binding and folding pathway.




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Bacterial iron detoxification at the molecular level [Protein Structure and Folding]

Iron is an essential micronutrient, and, in the case of bacteria, its availability is commonly a growth-limiting factor. However, correct functioning of cells requires that the labile pool of chelatable “free” iron be tightly regulated. Correct metalation of proteins requiring iron as a cofactor demands that such a readily accessible source of iron exist, but overaccumulation results in an oxidative burden that, if unchecked, would lead to cell death. The toxicity of iron stems from its potential to catalyze formation of reactive oxygen species that, in addition to causing damage to biological molecules, can also lead to the formation of reactive nitrogen species. To avoid iron-mediated oxidative stress, bacteria utilize iron-dependent global regulators to sense the iron status of the cell and regulate the expression of proteins involved in the acquisition, storage, and efflux of iron accordingly. Here, we survey the current understanding of the structure and mechanism of the important members of each of these classes of protein. Diversity in the details of iron homeostasis mechanisms reflect the differing nutritional stresses resulting from the wide variety of ecological niches that bacteria inhabit. However, in this review, we seek to highlight the similarities of iron homeostasis between different bacteria, while acknowledging important variations. In this way, we hope to illustrate how bacteria have evolved common approaches to overcome the dual problems of the insolubility and potential toxicity of iron.




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Evolving the naturally compromised chorismate mutase from Mycobacterium tuberculosis to top performance [Protein Structure and Folding]

Chorismate mutase (CM), an essential enzyme at the branch-point of the shikimate pathway, is required for the biosynthesis of phenylalanine and tyrosine in bacteria, archaea, plants, and fungi. MtCM, the CM from Mycobacterium tuberculosis, has less than 1% of the catalytic efficiency of a typical natural CM and requires complex formation with 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase for high activity. To explore the full potential of MtCM for catalyzing its native reaction, we applied diverse iterative cycles of mutagenesis and selection, thereby raising kcat/Km 270-fold to 5 × 105 m−1s−1, which is even higher than for the complex. Moreover, the evolutionarily optimized autonomous MtCM, which had 11 of its 90 amino acids exchanged, was stabilized compared with its progenitor, as indicated by a 9 °C increase in melting temperature. The 1.5 Å crystal structure of the top-evolved MtCM variant reveals the molecular underpinnings of this activity boost. Some acquired residues (e.g. Pro52 and Asp55) are conserved in naturally efficient CMs, but most of them lie beyond the active site. Our evolutionary trajectories reached a plateau at the level of the best natural enzymes, suggesting that we have exhausted the potential of MtCM. Taken together, these findings show that the scaffold of MtCM, which naturally evolved for mediocrity to enable inter-enzyme allosteric regulation of the shikimate pathway, is inherently capable of high activity.




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Hydrogen/deuterium exchange memory NMR reveals structural epitopes involved in IgE cross-reactivity of allergenic lipid transfer proteins [Protein Structure and Folding]

Identification of antibody-binding epitopes is crucial to understand immunological mechanisms. It is of particular interest for allergenic proteins with high cross-reactivity as observed in the lipid transfer protein (LTP) syndrome, which is characterized by severe allergic reactions. Art v 3, a pollen LTP from mugwort, is frequently involved in this cross-reactivity, but no antibody-binding epitopes have been determined so far. To reveal human IgE-binding regions of Art v 3, we produced three murine high-affinity mAbs, which showed 70–90% coverage of the allergenic epitopes from mugwort pollen–allergic patients. As reliable methods to determine structural epitopes with tightly interacting intact antibodies under native conditions are lacking, we developed a straightforward NMR approach termed hydrogen/deuterium exchange memory (HDXMEM). It relies on the slow exchange between the invisible antigen-mAb complex and the free 15N-labeled antigen whose 1H-15N correlations are detected. Due to a memory effect, changes of NH protection during antibody binding are measured. Differences in H/D exchange rates and analyses of mAb reactivity to homologous LTPs revealed three structural epitopes: two partially cross-reactive regions around α-helices 2 and 4 as well as a novel Art v 3–specific epitope at the C terminus. Protein variants with exchanged epitope residues confirmed the antibody-binding sites and revealed strongly reduced IgE reactivity. Using the novel HDXMEM for NMR epitope mapping allowed identification of the first structural epitopes of an allergenic pollen LTP. This knowledge enables improved cross-reactivity prediction for patients suffering from LTP allergy and facilitates design of therapeutics.




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Unique active-site and subsite features in the arabinogalactan-degrading GH43 exo-{beta}-1,3-galactanase from Phanerochaete chrysosporium [Enzymology]

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




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Seeded fibrils of the germline variant of human {lambda}-III immunoglobulin light chain FOR005 have a similar core as patient fibrils with reduced stability [Molecular Biophysics]

Systemic antibody light chains (AL) amyloidosis is characterized by deposition of amyloid fibrils derived from a particular antibody light chain. Cardiac involvement is a major risk factor for mortality. Using MAS solid-state NMR, we studied the fibril structure of a recombinant light chain fragment corresponding to the fibril protein from patient FOR005, together with fibrils formed by protein sequence variants that are derived from the closest germline (GL) sequence. Both analyzed fibril structures were seeded with ex-vivo amyloid fibrils purified from the explanted heart of this patient. We find that residues 11-42 and 69-102 adopt β-sheet conformation in patient protein fibrils. We identify arginine-49 as a key residue that forms a salt bridge to aspartate-25 in the patient protein fibril structure. In the germline sequence, this residue is replaced by a glycine. Fibrils from the GL protein and from the patient protein harboring the single point mutation R49G can be both heterologously seeded using patient ex-vivo fibrils. Seeded R49G fibrils show an increased heterogeneity in the C-terminal residues 80-102, which is reflected by the disappearance of all resonances of these residues. By contrast, residues 11-42 and 69-77, which are visible in the MAS solid-state NMR spectra, show 13Cα chemical shifts that are highly like patient fibrils. The mutation R49G thus induces a conformational heterogeneity at the C terminus in the fibril state, whereas the overall fibril topology is retained. These findings imply that patient mutations in FOR005 can stabilize the fibril structure.




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Determinants of replication protein A subunit interactions revealed using a phosphomimetic peptide [Molecular Biophysics]

Replication protein A (RPA) is a eukaryotic ssDNA-binding protein and contains three subunits: RPA70, RPA32, and RPA14. Phosphorylation of the N-terminal region of the RPA32 subunit plays an essential role in DNA metabolism in processes such as replication and damage response. Phosphorylated RPA32 (pRPA32) binds to RPA70 and possibly regulates the transient RPA70-Bloom syndrome helicase (BLM) interaction to inhibit DNA resection. However, the structural details and determinants of the phosphorylated RPA32–RPA70 interaction are still unknown. In this study, we provide molecular details of the interaction between RPA70 and a mimic of phosphorylated RPA32 (pmRPA32) using fluorescence polarization and NMR analysis. We show that the N-terminal domain of RPA70 (RPA70N) specifically participates in pmRPA32 binding, whereas the unphosphorylated RPA32 does not bind to RPA70N. Our NMR data revealed that RPA70N binds pmRPA32 using a basic cleft region. We also show that at least 6 negatively charged residues of pmRPA32 are required for RPA70N binding. By introducing alanine mutations into hydrophobic positions of pmRPA32, we found potential points of contact between RPA70N and the N-terminal half of pmRPA32. We used this information to guide docking simulations that suggest the orientation of pmRPA32 in complex with RPA70N. Our study demonstrates detailed features of the domain-domain interaction between RPA70 and RPA32 upon phosphorylation. This result provides insight into how phosphorylation tunes transient bindings between RPA and its partners in DNA resection.




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A highly potent CD73 biparatopic antibody blocks organization of the enzyme active site through dual mechanisms [Methods and Resources]

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




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Nitro-fatty acids as activators of hSIRT6 deacetylase activity [Protein Structure and Folding]

Sirtuin 6, SIRT6, is critical for both glucose and lipid homeostasis and is involved in maintaining genomic stability under conditions of oxidative DNA damage such as those observed in age-related diseases. There is an intense search for modulators of SIRT6 activity, however, not many specific activators have been reported. Long acyl-chain fatty acids have been shown to increase the weak in vitro deacetylase activity of SIRT6 but this effect is modest at best. Herein we report that electrophilic nitro-fatty acids (nitro-oleic acid and nitro-conjugated linoleic acid) potently activate SIRT6. Binding of the nitro-fatty acid to the hydrophobic crevice of the SIRT6 active site exerted a moderate activation (2-fold at 20 μm), similar to that previously reported for non-nitrated fatty acids. However, covalent Michael adduct formation with Cys-18, a residue present at the N terminus of SIRT6 but absent from other isoforms, induced a conformational change that resulted in a much stronger activation (40-fold at 20 μm). Molecular modeling of the resulting Michael adduct suggested stabilization of the co-substrate and acyl-binding loops as a possible additional mechanism of SIRT6 activation by the nitro-fatty acid. Importantly, treatment of cells with nitro-oleic acid promoted H3K9 deacetylation, whereas oleic acid had no effect. Altogether, our results show that nitrated fatty acids can be considered a valuable tool for specific SIRT6 activation, and that SIRT6 should be considered as a molecular target for in vivo actions of these anti-inflammatory nitro-lipids.




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MMP activation-associated aminopeptidase N reveals a bivalent 14-3-3 binding motif [Protein Structure and Folding]

Aminopeptidase N (APN, CD13) is a transmembrane ectopeptidase involved in many crucial cellular functions. Besides its role as a peptidase, APN also mediates signal transduction and is involved in the activation of matrix metalloproteinases (MMPs). MMPs function in tissue remodeling within the extracellular space and are therefore involved in many human diseases, such as fibrosis, rheumatoid arthritis, tumor angiogenesis, and metastasis, as well as viral infections. However, the exact mechanism that leads to APN-driven MMP activation is unclear. It was previously shown that extracellular 14-3-3 adapter proteins bind to APN and thereby induce the transcription of MMPs. As a first step, we sought to identify potential 14-3-3–binding sites in the APN sequence. We constructed a set of phosphorylated peptides derived from APN to probe for interactions. We identified and characterized a canonical 14-3-3–binding site (site 1) within the flexible, structurally unresolved N-terminal APN region using direct binding fluorescence polarization assays and thermodynamic analysis. In addition, we identified a secondary, noncanonical binding site (site 2), which enhances the binding affinity in combination with site 1 by many orders of magnitude. Finally, we solved crystal structures of 14-3-3σ bound to mono- and bis-phosphorylated APN-derived peptides, which revealed atomic details of the binding mode of mono- and bivalent 14-3-3 interactions. Therefore, our findings shed some light on the first steps of APN-mediated MMP activation and open the field for further investigation of this important signaling pathway.




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Humanin selectively prevents the activation of pro-apoptotic protein BID by sequestering it into fibers [Protein Structure and Folding]

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




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A combinatorial native MS and LC-MS/MS approach reveals high intrinsic phosphorylation of human Tau but minimal levels of other key modifications [Neurobiology]

Abnormal changes of neuronal Tau protein, such as phosphorylation and aggregation, are considered hallmarks of cognitive deficits in Alzheimer's disease. Abnormal phosphorylation is thought to precede aggregation and therefore to promote aggregation, but the nature and extent of phosphorylation remain ill-defined. Tau contains ∼85 potential phosphorylation sites, which can be phosphorylated by various kinases because the unfolded structure of Tau makes them accessible. However, methodological limitations (e.g. in MS of phosphopeptides, or antibodies against phosphoepitopes) led to conflicting results regarding the extent of Tau phosphorylation in cells. Here we present results from a new approach based on native MS of intact Tau expressed in eukaryotic cells (Sf9). The extent of phosphorylation is heterogeneous, up to ∼20 phosphates per molecule distributed over 51 sites. The medium phosphorylated fraction Pm showed overall occupancies of ∼8 Pi (± 5) with a bell-shaped distribution; the highly phosphorylated fraction Ph had 14 Pi (± 6). The distribution of sites was highly asymmetric (with 71% of all P-sites in the C-terminal half of Tau). All sites were on Ser or Thr residues, but none were on Tyr. Other known posttranslational modifications were near or below our detection limit (e.g. acetylation, ubiquitination). These findings suggest that normal cellular Tau shows a remarkably high extent of phosphorylation, whereas other modifications are nearly absent. This implies that abnormal phosphorylations at certain sites may not affect the extent of phosphorylation significantly and do not represent hyperphosphorylation. By implication, the pathological aggregation of Tau is not likely a consequence of high phosphorylation.




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Structural transitions in Orb2 prion-like domain relevant for functional aggregation in memory consolidation [Molecular Biophysics]

The recent structural elucidation of ex vivo Drosophila Orb2 fibrils revealed a novel amyloid formed by interdigitated Gln and His residue side chains belonging to the prion-like domain. However, atomic-level details on the conformational transitions associated with memory consolidation remain unknown. Here, we have characterized the nascent conformation and dynamics of the prion-like domain (PLD) of Orb2A using a nonconventional liquid-state NMR spectroscopy strategy based on 13C detection to afford an essentially complete set of 13Cα, 13Cβ, 1Hα, and backbone 13CO and 15N assignments. At pH 4, where His residues are protonated, the PLD is disordered and flexible, except for a partially populated α-helix spanning residues 55–60, and binds RNA oligos, but not divalent cations. At pH 7, in contrast, His residues are predominantly neutral, and the Q/H segments adopt minor populations of helical structure, show decreased mobility and start to self-associate. At pH 7, the His residues do not bind RNA or Ca2+, but do bind Zn2+, which promotes further association. These findings represent a remarkable case of structural plasticity, based on which an updated model for Orb2A functional amyloidogenesis is suggested.




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Molecular characterization of the RNA-protein complex directing -2/-1 programmed ribosomal frameshifting during arterivirus replicase expression [Protein Structure and Folding]

Programmed ribosomal frameshifting (PRF) is a mechanism used by arteriviruses like porcine reproductive and respiratory syndrome virus (PRRSV) to generate multiple proteins from overlapping reading frames within its RNA genome. PRRSV employs −1 PRF directed by RNA secondary and tertiary structures within its viral genome (canonical PRF), as well as a noncanonical −1 and −2 PRF that are stimulated by the interactions of PRRSV nonstructural protein 1β (nsp1β) and host protein poly(C)-binding protein (PCBP) 1 or 2 with the viral genome. Together, nsp1β and one of the PCBPs act as transactivators that bind a C-rich motif near the shift site to stimulate −1 and −2 PRF, thereby enabling the ribosome to generate two frameshift products that are implicated in viral immune evasion. How nsp1β and PCBP associate with the viral RNA genome remains unclear. Here, we describe the purification of the nsp1β:PCBP2:viral RNA complex on a scale sufficient for structural analysis using small-angle X-ray scattering and stochiometric analysis by analytical ultracentrifugation. The proteins associate with the RNA C-rich motif as a 1:1:1 complex. The monomeric form of nsp1β within the complex differs from previously reported homodimer identified by X-ray crystallography. Functional analysis of the complex via mutational analysis combined with RNA-binding assays and cell-based frameshifting reporter assays reveal a number of key residues within nsp1β and PCBP2 that are involved in complex formation and function. Our results suggest that nsp1β and PCBP2 both interact directly with viral RNA during formation of the complex to coordinate this unusual PRF mechanism.




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Role of phospholipid synthesis in the development and differentiation of malaria parasites in the blood [Microbiology]

The life cycle of malaria parasites in both their mammalian host and mosquito vector consists of multiple developmental stages that ensure proper replication and progeny survival. The transition between these stages is fueled by nutrients scavenged from the host and fed into specialized metabolic pathways of the parasite. One such pathway is used by Plasmodium falciparum, which causes the most severe form of human malaria, to synthesize its major phospholipids, phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine. Much is known about the enzymes involved in the synthesis of these phospholipids, and recent advances in genetic engineering, single-cell RNA-Seq analyses, and drug screening have provided new perspectives on the importance of some of these enzymes in parasite development and sexual differentiation and have identified targets for the development of new antimalarial drugs. This Minireview focuses on two phospholipid biosynthesis enzymes of P. falciparum that catalyze phosphoethanolamine transmethylation (PfPMT) and phosphatidylserine decarboxylation (PfPSD) during the blood stages of the parasite. We also discuss our current understanding of the biochemical, structural, and biological functions of these enzymes and highlight efforts to use them as antimalarial drug targets.




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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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Malawi’s Re-Run Election is Lesson for African Opposition

1 July 2020

Fergus Kell

Projects Assistant, Africa Programme
The overturning of the result in the fresh presidential contest sets a bold precedent for the continent, as a process built upon the resilience of democratic institutions and the collective spirit of opposition.

2020-07-01-Malawi-Chakwera-Election

Lazarus Chakwera, leader of the Malawi Congress Party (MCP) arriving at the Mtandire suburb of the capital Lilongwe for an election rally. Photo by AMOS GUMULIRA/AFP via Getty Images.

Malawi is only the second African country to annul a presidential election, after Kenya in 2017. It is the first in which the opposition has won the re-run.

The initial May 2019 vote had narrowly returned incumbent Peter Mutharika to the presidency. But in February 2020 a landmark ruling by Malawi’s constitutional court annulled the result citing ‘widespread, systematic and grave’ irregularities, including the now-infamous use of corrective fluid in vote tallying, and the Malawi Electoral Commission’s (MEC) failure to address complaints before announcing results. New elections were ordered within 150 days.

In a decisive contrast with the previous year, the fresh polls on 23 June saw the coming together of Lazarus Chakwera of the Malawi Congress Party (MCP) and running mate Saulos Chilima of the United Transformation Movement (UTM) to head a coalition of nine opposition parties - having fiercely competed as the leading challengers previously.

The constitutional court ruling had also changed Malawi’s electoral system, replacing a first-past-the-post model with one demanding an outright majority, which further encouraged the regional power bases of Malawi’s opposition to cast ego aside and work in alliance with each other.

In tandem with a slick digital campaign, the new alliance travelled widely to hold rallies across what is one of the world’s youngest countries, while the elderly Mutharika remained largely confined to the capital. It would be a strategy that ultimately delivered Chakwera to the presidency, polling 58 per cent of votes to Mutharika’s 39.

Political opposition elsewhere in Africa should take note from Malawi’s coalition - dialogue, not division, can offer a genuine path to change, especially in those countries with less favourable institutional conditions. Neighbouring Zambia would certainly do well to heed this example ahead of a pivotal election of its own in 2021.

A victory built on institutional precedent

Yet the story here is not only about throwing out an incumbent: Malawians had already done so twice before, rejecting sitting presidents at the polls in 1994 and 2014. It is also not unfamiliar to see public opinion and the judiciary work in parallel to uphold the constitution: former president Bakili Muluzi was twice blocked from abolishing term limits by popular demonstration during his second term, and again prevented from running for a third time in 2009 by the constitutional court.

The new result did not arise as the foregone conclusion of a judicial miracle. Rather, throughout the re-run process Malawi has had to repeatedly draw upon the strength of its broad-based institutional foundations. The image of the constitutional court judges arriving to deliver their annulment verdict in February wearing bulletproof vests under their robes was a stark reminder that this was never the easy route to take.

In contrast to many other African states, Mutharika was unable to call upon military support as the Malawi Defence Forces (MDF) had moved to shield protesting citizens and protect the judiciary since the 2019 election. The MDF also had previous form in this respect, having defended then-vice president Joyce Banda’s constitutional right to assume the presidency after the incumbent’s death in 2012.

And this institutional resilience from the army would facilitate a smooth and mostly peaceful election process during the re-run, despite Mutharika attempts to intervene by replacing the MDF’s commander and his deputy in March 2020.

Just ten days before the fresh vote the Mutharika government switched focus back to the country’s legal system by attempting to enforce the premature retirement of Malawi’s chief justice, only to be blocked by the high court. Even as unofficial tallies trickled in, Mutharika’s Democratic Progressive Party (DPP) demanded the MEC annul the result: claiming their monitors were intimidated in MCP strongholds, and requesting unlawful access to scrutinise null and void votes.

Headed by a new chairperson, this time the MEC displayed enormous patience in the verification process and openly tackled complaints, now mainly from the DPP. On social media, Malawians celebrated the contrast between images of tally sheets from 2019 and the re-run.

Writing a new chapter

There are lessons here too for international partners. UK diplomacy played a subtle role in encouraging Mutharika to accept the legal process - he was invited to appear at the UK-Africa Investment Summit in January - while also helping promoting early dialogue among opposition parties.

At a time of pressure for UK engagement to offer clear strategic value, the impact of less easily quantifiable forms of influence should not be overlooked, especially as international observer missions effectively went missing in the discredited 2019 election. Preliminary statements back then from the Commonwealth, European Union, African Union and Southern African Development Community (SADC) struck a mostly congratulatory tone and were non-committal on the issues that would prove decisive in the court ruling. None went on to release their final reports.

Malawi must now start to move beyond election mode. Though COVID-19 cases remain low by global standards, a budget already heavily dependent on foreign aid and hampered by 18 months of political uncertainty will be slashed further by the pandemic’s impact. The IMF has predicted GDP growth of just 1% in 2020, down from a pre-coronavirus projection of 5%.

As it inherits a major balance of payments crisis, mounting debt and with no tourism revenue to fall back on, the new government will need to use its political capital to push for immediate reform. But it must not forget the core tenet of its campaign. The coalition that defeated Mutharika united the MCP’s rural support base with the middle-class urban following of the UTM. This spirit of unity and inclusion must be expanded and focus on long-term recovery. On this undertaking – unlike the polls – there will be no opportunity for a re-run.




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Economy Must Not Get Stuck Between Lockdown and Recovery

2 July 2020

Creon Butler

Research Director, Trade, Investment & New Governance Models: Director, Global Economy and Finance Programme
Despite recent outbreaks in several countries which had appeared to be close to excluding the virus, focusing on suppression and elimination is the best economic as well as health strategy.

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An almost empty British Airways passenger plane flies from Milan to London. Photo by Laurel Chor/Getty Images.

Lockdowns are being eased in many countries, but from different starting points in terms of prevalence of the virus, and with different near-term trade-offs between protecting life and easing constraints on economic activity.

The pressure to ease is understandable. The IMF estimates $10tn has been spent so far on official support measures worldwide, and forecasts global GDP will contract by an unprecedented 4.9% in 2020.

However, the WHO director general, Dr Tedros Adhanom Ghebreyesus, recently insisted that there is an ‘urgent responsibility to do everything we can with the tools we have now to suppress transmission and save lives’, even as research into vaccines and therapeutics continues.

Focusing on suppressing and eliminating the virus as quickly as possible is not just the best strategy for saving life, it also makes most sense in terms of minimising the long-term economic damage from the pandemic.

The alternatives remain uncertain

Neither a vaccine nor improved treatment are currently sufficiently certain to be the focal point for an economic recovery strategy. Despite optimism about vaccine development, there is no certainty of a decisive outcome by a given date. And, even if a vaccine proved effective, manufacturing and distributing it to 8bn people will present an unprecedented set of logistical and economic challenges and take many months, if not years.

In the meantime, although substantial progress has been made in reducing loss of life among those made seriously ill by the virus - and who have access to advanced medical facilities - it remains highly dangerous for a significant proportion of the population - around 20% in advanced economies.

An alternative containment strategy based on gradually reducing the prevalence of the virus in the population by maintaining an “R” number (replication coefficient) just below one will be both economically costly and highly risky when compared with a decisive push to eliminate the virus quickly.

With an R number just below one it is true the virus may eventually disappear, but only over a lengthy period, during which economically damaging social distancing measures will have to stay in place, dragging out the impact on both demand and supply.

Wage support measures to limit ‘economic scarring’ will have to be maintained, and kickstarting the economy with a conventional fiscal stimulus will be difficult, if not impossible, especially when the ability - or willingness - of consumers to spend is still heavily constrained either by social distancing measures or a lack of confidence.

There is also a major risk when the R number is close to one that the virus could suddenly take off again, leading to a complete failure of the strategy.

Benefits of suppress and eliminate

A successful policy focused on suppressing and eliminating the virus offers much better prospects. First, the government can then protect the vast bulk of the economy within its territory, even if it means continuing travel restrictions for some time vis-a-vis countries that are less committed to or less successful in eliminating the virus.

Some sectors - particularly long-haul air transport - will be hard hit, but other critical high value or employment intensive sectors - such as domestic hospitality, leisure and the arts - will be able to make a substantial recovery. To put it bluntly, the authorities may have to hold back some sectors to save others. Such a strategy would also ensure an economy can participate sustainably in free travel zones with other countries.

Second, a drive to suppress and eliminate the virus in the shortest possible timeframe, and then maintain that status, will help authorities communicate clearly to the public the overarching framework guiding the application of social distancing measures, and the nature of the ‘new normal’ economy that can be expected to emerge over the medium to long-term.

Achieving such clarity will enhance the public’s trust in the government’s strategy and hence responsiveness to government instructions. It will also minimise unnecessary and costly adaptations by business and increase its ability to target new opportunities arising from the genuine long-term changes brought about by the crisis.

In addition, a suppress and eliminate strategy is the only sure way to address the disproportionate impact of the virus on ethnic minorities and the poor, and to put an end to the isolation of the millions who currently have to shield themselves.

We know that suppressing the virus almost completely within a given territory is possible because some countries have already done it - notably New Zealand, South Korea, and Taiwan. Some which started with a serious epidemic, such as China, Spain and Italy, have also managed to reach a point where almost complete elimination within their territory can be envisaged.

Renewed outbreaks are likely to happen, particularly while the virus remains in active circulation globally. But this does not invalidate the underlying suppress and eliminate strategy.

Key policies to suppress and eliminate the virus include: a rapid and decisive national lockdown to reduce the disease to levels low enough for test, trace and quarantine systems to identify and suppress local outbreaks; social distancing measures for a limited period or in a specific locality to limit spread while, as far as possible, minimising economic impact; and effective quarantine and track systems applied at borders to prevent the disease from being re-introduced by non-essential travellers and returning nationals.

The precise form of these policies is evolving rapidly as we learn more about the virus. For example, if there is a need today to stop a rapidly escalating epidemic in a given territory, it won’t necessarily mean adopting exactly the same package of lock down measures across the board as were applied three months ago. Several activities had to cease then simply because the virus was spreading so fast there was no time to put in place effective mitigation measures. This does not have to be repeated.

In addition, the benefits of the widespread use of face masks are now much better understood. As is the value of deploying a battery of measures, each one only partially effective on its own but, in combination, with a decisive impact. Financial support measures may need to be adjusted or extended to underpin local lockdowns and, at any given point, the authorities will need to work within an overall budget for relaxation measures and prioritise - getting pupils back in school may mean holding back easing of restrictions elsewhere.

Choosing an effective strategy inevitably means making tough choices. Delaying short-term recovery measures, even by a matter of weeks in whole economies or specific localities, can make a decisive difference to delivering a long-term sustainable economic outcome. The authorities may also be forced to hold back some economic sectors, possibly even leading to permanent damage, as the price of a general recovery. But if we are not ready to make these choices, the economy may become permanently stuck in a halfway house between lockdown and recovery.




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Europe’s Clean Energy Future: Shared Challenges for Norway and the UK

3 July 2020

Antony Froggatt

Senior Research Fellow and Deputy Director, Energy, Environment and Resources Programme

Professor Paul Stevens

Distinguished Fellow, Energy, Environment and Resources Programme

Siân Bradley

Senior Research Fellow, Energy, Environment and Resources Programme
European oil and gas producers, such as Norway and the UK, face serious challenges in terms of the direction their energy sectors should take. There is an opportunity for both countries to place an accelerated energy transition at the heart of their post-pandemic economic recovery.

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Students gather to protest inaction on climate change in front of the parliament building in Oslo, Norway on 22 March 2019. Photo: Getty Images.

Even before the COVID-19 pandemic, it was clear that the world is undergoing a transition away from fossil fuels and carbon-intensive sectors, towards renewable energy and clean growth. The collapse of oil demand and prices have simply compounded the challenges that oil and gas producers already faced.

What happens next will have significant implications for Norway, as one of the world’s largest exporters of both energy and capital, and for the UK, as it plans its recovery and looks ahead to its hosting of the next major climate change summit in 2021 - COP26.

While the speed and scale of the transition has always been uncertain and contested, an accelerated transition with deep implications for future oil and gas demand looks plausible.

There has long been a debate over when global demand will peak, but what happens after demand has peaked is perhaps the more critical question. Now there is the additional uncertainty of how this post-peak demand might be affected by an oncoming global recession and potentially by the greening of recovery measures implemented in response to it. Will there be an extended plateau, a gentle decline or a sudden collapse?

The post-peak trend will impact oil producers and exporters to varying degrees, in terms of their vulnerability to reduced volumes and lower prices, and their ability to compete in a shrinking market. There is also growing scepticism over whether natural gas can act as a bridge between coal-fired power and renewables, as increasingly, renewables directly replace coal.  There is also significant uncertainty over extent to which hydrogen, either produced from fossil fuels or renewable energy, will play a significant role in a decarbonizing energy sector.

Even before the pandemic, there was growing public and political pressure in most EU member states for more ambitious action on climate change. More challenging climate targets now look certain as a growing number of governments and companies commit to becoming carbon-neutral by ever-earlier dates.

While market developments, such as the rate of change and the costs of technologies such as renewable energy and electric vehicles will heavily influence their deployment rates, policy interventions and large-scale investment in core infrastructure are still crucial to their scaling up. We are now seeing the EU refocus its Green Deal in support of post-COVID recovery, and scale its support for transition in coal-dependent and carbon-intensive regions with its €100bn Just Transition Mechanism.  

These developments have significant implications for fossil fuel producers and energy consumers both inside and outside the EU. It will particularly affect Norway, not only as a significant supplier of energy to the EU, but as a member of the European Economic Area, with likely pressure to adopt similarly binding domestic carbon reduction legislation. Similarly, as the UK forges new post-Brexit trading and regulatory relationships, it will need to align with European policies for efficiency.

As the host of the critical COP26 UN Climate Change Summit in Glasgow next year, the UK will also need to at least match the EU in terms of its ambition on national emissions reductions, and in placing decarbonization and sustainability at the heart of COVID-19 recovery measures. However, unfortunately, the early indications are that 'Project Speed' will focus on traditional infrastructure projects are less than promising.    

The UK and Norway face similar challenges, as oil and gas producers that recognize the importance of climate change, and will rightly face scrutiny where they reinvest in their oil and gas sectors. They are both outside, yet highly dependent on developments within the EU. However, they are also both, somewhat surprisingly, world leaders in different aspects of decarbonization, such as off-shore wind or electric vehicle deployment, in part due their offshore capabilities and advanced manufacturing capabilities. This presents an opportunity for both countries and their industries to place an accelerated energy transition at the heart of their economic recovery and their relationship with the EU.

There will of course be different opinions on how to do this. A new Chatham House paper – Expert Perspectives on Norway’s Energy Future – explores these issues in the Norwegian context, and draws upon the views of 15 international experts on energy transition and climate change, each interviewed in depth. While unsurprisingly there is little consensus, these views provide valuable background from which to consider the future of future of energy for Norway, and for its partners including the UK and the EU.




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West Bank Annexation: International Rhetoric vs. Action

14 July 2020

Reni Zhelyazkova

Programme Coordinator, Middle East and North Africa Programme

Professor Yossi Mekelberg

Senior Consulting Research Fellow, Middle East and North Africa Programme
Israel may have delayed announcing its plans to annex West Bank lands but the international community now needs to transform its rhetoric into action if there is to be a lasting solution to the Israel-Palestine conflict, argue Reni Zhelyazkova and Yossi Mekelberg.

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Houses are pictured in the Maale Adumim settlement in the West Bank east of Jerusalem. The Israeli government has delayed plans to annex Jewish settlements in the West Bank and in the Jordan Valley. Photo: Getty Images

Observers of the Israel-Palestine conflict have been anticipating Israeli Prime Minister, Benjamin Netanyahu’s, announcement to annex parts of the West Bank. It has been a tumultuous year for Israeli politics which has seen three inconclusive elections and resulted in a sharing of power between Netanyahu and Benny Gantz of the Blue and White party. However, since the coalition government was sworn in, Netanyahu has appeared to not lose any time in moving forward with his plans.

Annexation has long been Netanyahu’s political aspiration and was part of his recent re-election platform but the anticipated announcement from the Israeli government didn’t come straight away. The determining factor in the delay was the inability to reach an agreement with Washington about the scope of the annexation while divisions within the Israeli government itself, in addition to international condemnation from the region and beyond, has also played a part.

Discussions around annexation have so far yielded one major outcome: it has introduced a different rhetoric by the Trump-Netanyahu axis even though things on the ground don’t necessarily follow. Ever since President Donald Trump took office in 2016, there has been a marked change in Washington’s language around the Israel-Palestine conflict. It has shifted towards legitimizing Israel’s expansionist ambitions in the West Bank while marginalizing, and considerably weakening, the Palestinian Authority (PA) through a series of punitive measures.

This has further damaged relations between Israel and Palestine and has resulted in a fundamental change in the public discourse around the conflict, from emphasizing a just solution based on self-determination for both sides, to focusing on a de-facto one-state solution.

But how has the discourse shifted so dramatically in less than four years? First came the announcement of the US embassy move to Jerusalem, and with it, recognition of the city as Israel’s capital. In his statement, President Trump avoided recognizing Palestinian claims over Jerusalem and did not acknowledge their historical connection with the city. When the PA rejected the move, the US administration then retaliated by cutting aid and development funding and closing the PLO mission in Washington stating: ‘We have permitted the PLO office to conduct operations that support the objective of achieving a lasting...peace between Israelis and the Palestinians … However, the PLO has not taken steps to advance the start of...meaningful negotiations with Israel.’

On the question of Israel’s settlements in the West Bank, the current US administration has shied away from calling them ‘illegal’ despite being deemed illegitimate under international law and condemned on numerous occasions by the UN Security Council, the UN General Assembly, the EU, the Arab League and the Palestinians themselves. US Secretary of State, Mike Pompeo, has even gone as far as saying that the establishment of Israeli settlements in the West Bank is not inconsistent with international law.

The culmination of US discourse in recent months has been the unveiling of the ‘Peace to Prosperity’ plan. The language of the proposal, once again, has shown partiality towards Israel by not mentioning the illegality of Israel’s occupation of the West Bank, or that of settlements, and entirely ignoring previous Palestinian positions or acknowledging their sensitivities. There is little doubt that the current US administration understands the power of rhetoric and has been using it to change the trajectory of discussions away from a two-state solution towards an outcome that would only serve Israeli interests.

Indeed, US rhetoric has empowered Netanyahu immensely too, ushering in a new reality that has rendered a Palestinian state nothing more than a hypothetical option. The language, combined with a multitude of unilateral actions, is helping to dismantle any efforts towards a two-state solution and the upholding of previous international agreements.

Many European and regional governments have condemned any move towards annexation. Indeed, 1,000 European parliamentarians from across political lines have urged Israel to abandon its plans. This has notably included, German Foreign Minister, Heiko Mass, whose first overseas visit during the coronavirus crisis was to Israel to reinforce Germany’s position against unilateral action.

But actions speak louder than words, and in the case of the US, its rhetoric has been matched by action unlike its EU counterparts whose statements of condemnation have rarely been followed by concrete action. For instance, the EU ratified a landmark aviation agreement with Israel just days before 1 July and economic, technological and scientific cooperation between Israel and Europe has never been stronger casting doubt on the strength of political will among EU countries to take action against Israel.

In the Middle East, the United Arab Emirates has been the most vociferous in disapproving Israel’s annexation plans. However, again, it is important to look beyond the rhetoric. Cooperation between the UAE and Israel has in fact increased in recent years mainly due to common opposition to Iran’s regional influence but also due to shared interests. In May, for instance, the first publicly acknowledged commercial flight between the UAE and Israel landed at Ben Gurion airport carrying aid aimed at mitigating the effects of COVID-19 in the Palestinian territories. But, to many, it looked like a stepping-stone towards a normalization of relations between Abu Dhabi and Jerusalem.

Similarly, Jordan and Egypt have also expressed their concern but it is difficult to imagine a scenario where either country would go as far as abrogating peace agreements that they currently have in place with Israel.

In spite of this, the global response has overwhelmingly been critical of Israel’s plans to annex parts of the West Bank. This has demonstrated some level of unity among world leaders which has not been seen for some time and may have played a significant role in delaying the Israeli government’s plans. In parallel, united international condemnation has also prevented the US from dominating the Israeli-Palestinian conflict entirely.

While the US approach has played a key role in the Israel-Palestine conflict so far, it remains to be seen how the international community will translate its voice into action to prevent the annexation of occupied Palestinian land.




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The Folly and Risk of Lopez Obrador’s Washington Trip

15 July 2020

Arturo Sarukhan

Associate Fellow, US and the Americas Programme (based in the US)
President Andres Manuel Lopez Obrador’s decision to travel to the US was met with concern and incredulity in Mexico and bafflement among many Democrats in the US. Being seen as a close ally to Donald Trump could be detrimental to the future of bilateral relations.

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Demo against Donald Trump's migration policies at the San Ysidro port of entry in Tijuana, Baja California state, Mexico. Photo by GUILLERMO ARIAS/AFP via Getty Images.

For a leader who had not travelled abroad since his inauguration – skipping G20 and APEC summits and the UN General Assembly – and who is probably one of the most intellectually incurious and disinterested Mexican presidents of the modern era when it comes to global issues, President Andres Manuel Lopez Obrador could have certainly waited until after the US elections in November to travel to Washington and personally engage with President Donald Trump .

Instead, Lopez Obrador – who has sought at all cost to avoid conflict with his US counterpart, having decided that bending the knee was a better option than standing his ground with Trump – waded straight into electoral politics in the US, despite his repeated assurances to the contrary.

The decision to travel now to Washington was fraught with political and diplomatic challenges, not least the fact that President Trump will use President Lopez Obrador as an electoral prop.

To American audiences, at a time when the US is riven by social and political convulsion unseen in 50 years since the Vietnam War and the civil rights movement, meeting with Trump in Washington just before the general campaign starts was seen by many as a pat on the back for a polarizing and unpopular president.

In Mexico, most discussion has been about the merits and timing of the visit, with one El Financiero newspaper poll conducted a week before showing public support (59%) for the trip, while a post-visit Reforma newspaper survey showed that a substantial majority of those polled (69%) believe a Biden victory in November is a better outcome for Mexico.

While it’s true that Lopez Obrador returned to Mexico unscathed, his visit – and his baffling Rose Garden remarks stating that Trump (the most anti-Mexican US president in modern history) has shown respect to Mexico and Mexicans – is certainly a slap in the face to migrants in the US, 11 million of whom are Mexicans, to American NGOs and activists that defend the rights of migrants and enlightened immigration and asylum policies, and a boon to Trump’s dog-whistle xenophobia and chauvinism.

Lopez Obrador’s words added insult to injury by asserting the US president has never imposed anything on Mexico, blithely ignoring Trump’s March 2019 threat to impose punitive tariffs on Mexico unless the country deterred and stopped Central American transmigration flows through Mexico on their way to the US.

Certainly if the purpose of the visit was to celebrate the July 1 entry into force of the USMCA – a spin made even more hollow by the fact that Canadian Prime minister Justin Trudeau decided to skip the event – then Lopez Obrador should have been reaching out to the Speaker Nancy Pelosi and the Democratic leadership to meet and thank them too, given the important role they played in supporting the revamping of NAFTA and the ratification of the USMCA.

The best-case scenario is that the meeting between the presidents will be leveraged by both governments to address looming hurdles with the entry into force of the USMCA.

But Trump still seems intent on wielding punitive tariffs and mercantilist measures to extract concessions from either Canada or Mexico. And across the border, the Lopez Obrador government – and his party in Congress – continue enacting abrupt policy shifts and changes to the rules across different sectors of the economy that bode ill for the level playing field required under the USMCA.

What could have easily been achieved via a virtual event has now morphed into a second successive Mexican government jumping on the Trump electoral bandwagon, after Enrique Peña Nieto’s ill-advised invitation to then-candidate Trump to travel to Mexico, and a new opportunity for the US president to ‘pimp’ Mexico for his campaign purposes. Perceptions have certainly deepened among Democrats that Lopez Obrador prefers to see Trump re-elected.

Although Lopez Obrador’s aim was to buy Mexico time between now and January of next year by hoping this visit will contain Trump’s anti-Mexican tirades on the campaign trail, whether or not Trump stops using Mexico as a political-electoral piñata is yet to be seen. I would not hold my breath.

Moreover, for a leader whose default position is ‘the best foreign policy is domestic policy’, the trip lays bare a paradox in Lopez Obrador’s mantra. It is precisely Mexico’s domestic weaknesses and failings that create foreign policy vulnerabilities, particularly vis-à-vis the Trump administration. And it is likely these will be used in the coming weeks and months to once again to pressure Mexico in what has become Trump’s ‘Sinatra Policy’ towards his southern neighbour: 'My Way'.

Perception is indeed reality, and Lopez Obrador – and more importantly Mexico – can ill-afford to be perceived as Trump’s patsies at this juncture of American history. As many expected, it only took four hours after President Lopez Obrador’s White House remarks for Trump-supporting Hispanic-outreach social media accounts to start piggybacking on them. Campaign officials have also specifically said they will likely use his quotes in TV ads aimed at Hispanic voters later this year.

In addition, there is a potentially bumpy road ahead for Mexico’s relationship with the Democratic Party. The statements and tweets issued by former vice-president Joe Biden, Biden campaign surrogates and officials, prominent Hispanic Democrats in Congress, and the Democratic National Chair signal as such, as does a letter sent the same day of the visit by Democratic representatives regarding outstanding labour issues in Mexico related to USMCA compliance and enforcement.

This trip could have a long-standing impact for Mexico’s relationship with the US – and US society – and the voters that will determine the future of this country in the decades to come. Lopez Obrador’s meeting with Trump could well become a ‘travel now, pay later’ moment in Mexico-US relations.




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New Fighting Brings Three-year Armenian-Azerbaijani Truce to an End

16 July 2020

Laurence Broers

Associate Fellow, Russia and Eurasia Programme
Deadly clashes at the border between Armenia and Azerbaijan have followed renewed disappointment in the peace process, and cast a new shadow over its future.

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A man shows a piece of shrapnel after attacks carried out by the Armenian army at Dondar Kuscu village near Tovuz, Azerbaijan. Photo by Aziz Karimov/Getty Images.

Although the Armenian-Azerbaijani conflict is focused on the Line of Contact around Nagorny Karabakh, a new - and significant - outbreak of violence has happened some 300 kilometres away on high ground along the de jure Armenia-Azerbaijan border.

Although not a first, violence in this area has generally been contained by the proximity of major transport and infrastructure arteries, and of civilian populations on both sides of the border. Plus, unlike in Nagorny Karabakh, the extended deterrents conferred by Armenia’s membership of the Collective Security Treaty Organization (CSTO) and bilateral agreements with Russia are also – theoretically at least – in force.

Despite this, battlespaces opened rapidly, with bombardment of civilian homes, drone strikes and cyberattacks on government and other sites being widely reported by both sides. At the time of writing, combined reported casualties were already at least 16, the highest for a single incident since April 2016’s ‘four-day war’.

Most are known to be Azerbaijani combatants, including the highest-ranking Azerbaijani serviceman to be killed in action since the 1990s – the respected Major General Polad Hashimov. And, although rumoured to be removed soon anyway following a campaign of negative briefing, Azerbaijani foreign minister Elmar Mammadyarov was publicly blamed in the immediate aftermath for ‘meaningless’ diplomacy and dismissed. He was replaced by education minister Jeyhun Bayramov.

Origins of the clashes

How the fighting began remains unclear. The escalation did not appear to result from a coordinated offensive operation of the kind that led to the four-day war, nor are there obvious strategic goals for either side in terms of the international border. There does appear to have been an element of surprise as an Azerbaijani vehicle unexpectedly encountered a new Armenian post, triggering deadly artillery exchanges.

Unclear boundaries in highland terrain may have played a role. Although referred to as the international border, the de jure boundary between Armenia and Azerbaijan - previously an inconsequential internal administrative boundary in the Soviet Union - is not clearly demarcated in many areas and does not coincide with lines of actual control.

Here, as in Nakhichevan - Azerbaijan’s exclave bordering Armenia and Iran - Armenian and Azerbaijani forces have been engaged in long-term, incremental competition for tactical advantage by claiming higher ground in ‘no man’s lands’. But in remote and cartographically ambiguous areas, the precise location of borders - and even place-names - are unclear, and rival forces can unexpectedly meet their adversaries.

Although clear strategic objectives appear absent, what might then have been a lesser incident escalated purposefully into a crisis – suggesting a political rationale.

A missed opportunity for a negotiations reset

Both Armenia and Azerbaijan began 2020 with unfinished consolidations of domestic power - whether bottom-up in the case of Armenia’s ‘Velvet Revolution’, or top-down in the case of Azerbaijan elite renewal. COVID-19 then added further challenges, with the government of Armenia facing significant domestic criticism for its handling of the pandemic, while numerous opposition activists in Azerbaijan were arrested, and the country’s economic vulnerability to external shocks was highlighted.

But throughout this, the frontlines did remain calm - as they generally have since the three-year period from 2014-2017 which witnessed regular skirmishes, use of heavy weaponry and four days of intensive combat in April 2016. In January 2019, the OSCE Minsk Group made the often-cited announcement that the foreign ministers of Armenia and Azerbaijan had agreed on the necessity of ‘preparing their populations for peace’.

Although the quietest year on the frontline since the 1990s then followed, neither side invested seriously in a peace strategy. After a reasonable start and moves towards humanitarian cooperation, relations between President Ilham Aliyev and Prime Minister Nikol Pashinyan eventually visibly soured.

Several moves, such as the go-ahead for new infrastructure in the occupied territories and Pashinyan’s attendance at de facto leader Arayik Harutyunyan’s inauguration in Nagorny Karabakh, were received in Azerbaijan as evidence of Armenian insincerity towards the peace process.

More inflammatory rhetoric then resumed, leading the OSCE Minsk Group to call for calm at the end of June. As recently as July 7, President Aliyev expressed public criticism of the peace process and emphasised the validity of Azerbaijan’s right to use force.

Each new round of Armenian-Azerbaijani fighting serves as an audit of the various restraining factors preventing a larger war. A Russian-Euro-Atlantic-Iranian consensus on proactively containing any new Armenian-Azerbaijani war appears to still hold, although senior-level attention from US secretary of state Mike Pompeo trailed that of his counterparts.

Russia acted quickly to offer mediation, reflecting the reality that any large-scale Armenia-Azerbaijan war would test Russia’s extended deterrence guarantees to Armenia. As in April 2016, Turkey has been vigorous in its support of Azerbaijan, raising concerns in Armenia and drawing oblique warnings from Russia. On the other hand, the CSTO - much to Armenian chagrin - dithered, initially calling then postponing a meeting citing the need for more time to study the situation.

Unprecedented spontaneous demonstrations in Baku called for war with Armenia, broke into the Azerbaijani parliament and, in some cases, articulated anti-government slogans. In the absence of reliable polling, such protests cannot be taken as evidence of a popular consensus in favour of war.

But they do underline the importance of the conflict as the one issue in Azerbaijan where open protest is accepted as legitimate and cannot easily be dispersed. As losses over the past week are counted, the dismissal of the foreign minister may not be sufficient to quell public anger.

Prospects are now real of a return to the dynamics in 2014-15: recursive low-level violence aimed at influencing the diplomatic calendar and public opinion while remaining below the deterrence threshold for triggering active external involvement.




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Domestic Violence in Russia: The Impact of the COVID-19 Pandemic

20 July 2020

Ekaterina Aleynikova

Research Assistant, Russia and Eurasia Programme
The COVID-19 pandemic has made Russia’s domestic violence problem more visible, with shifting public opinion potentially incentivizing the government to change its approach, argues Ekaterina Aleynikova.

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Campaigners during a rally held in 2019 in support of a Russian law on domestic violence. Photo: Getty Images

Russia is one of the few countries in the region to have no legal definition of domestic violence and, as a result, there are no protective measures specific to domestic violence such as restraining orders or compulsory anger management training for abusers. In fact, the government has taken steps in recent years to remove any legal distinction between assault happening in one’s home, and elsewhere, with battery among family or household members for first-time offences decriminalized in 2017.

The Russian Ministry of Justice explicitly defended this position in its response to an enquiry into Russian domestic violence cases by the European Court of Human Rights (ECtHR) in November 2019. The ministry claimed existing legislation adequately protects citizens from domestic violence, ‘even though it has never been considered a separate offence’, reiterating that there is ‘no need’ for adopting specific legislation.

However, the four cases that led to the ECtHR’s enquiry demonstrate that current legislation is not sufficient. The most prominent case is that of Margarita Gracheva whose ex-husband severed her hands in 2017 despite her having made multiple complaints to the police ahead of the act being committed. If Russian legislation had mechanisms in place to isolate victims from their abusers, then Gracheva could have been protected by the law.

Instead, systemic impunity for abusers is supported by statements from people in power excusing domestic violence. The most recent of such statements came from the head of the Chechen Republic, Ramzan Kadyrov, in June 2020. When meeting with the family of a young woman allegedly murdered by her husband, Chechnya’s leader said, husbands beating their wives ‘happens’ and that the young woman should have tried harder to hold on to her marriage. These statements send clear signals to abusers that their actions are justified, and to the victims, that they won’t be protected if they were to come forward.

Similarly, to other parts of the world, civil society organizations in Russia have reported an increase in the number of cases of domestic violence during the COVID-19 pandemic. On a personal level, the pandemic has often exacerbated many of the factors that can lead to domestic violence such as stress, economic anxiety or social isolation.

On a systemic level, many of the provisions intended to protect victims of violence, which were already ineffective in Russia, have been worsened during the lockdown. Where police may not have rapidly responded to reports of domestic violence previously, under lockdown, they have become focused on  other priorities and, where shelters and support networks for the victims may have been scarce in the past, they have been further constrained.

Unsurprisingly, the strategy of the Russian state so far has been to deny that there is a problem of domestic violence, with the Ministry of Interior reporting that, according to their statistics, the number of domestic violence cases have gone down during the lockdown. Indeed, Chairwoman of the Federation Council, Valentina Matvienko, has said she does not believe lockdown has increased domestic violence because, on the contrary, families have been  ‘brought together’, reflecting wishful thinking at best and negligence at worst.

The pandemic has also been used as an excuse to postpone discussion of a federal law on domestic violence, drafted by civil society, that was submitted for review by the Duma last year. This bill would have introduced different types of domestic violence such as psychological and economic violence and transferred domestic violence offences from private to public prosecutions to make it easier for victims to seek justice.

The government’s disregard for domestic violence reflects, in part, the patriarchal mindsets of those in power but perhaps, more significantly, the Kremlin’s belief that conservative social groups constitute its main support base. This has been made evident by the politicization of Russia’s ‘traditional’ values in recent years which was vigorously deployed throughout the constitutional amendments campaign. While it is clear that the true purpose of amending the constitution has always been to allow Vladimir Putin to stay in power beyond 2024, amendments relating to this were absent from the government’s campaign. Instead, Russians were encouraged to vote by populist socially-conservative messages, hence why respect for traditional values has been added to the constitution.

Despite this, attitudes in Russian society are changing. A February 2020 survey by the Levada Centre showed that 61 per cent of Russians – and 74 per cent of Russian women – think domestic violence is a serious problem.

Moreover, the survey shows that women are much more aware of domestic violence than men – with every third woman in Russia admits being aware of domestic violence in their social circles while only every fifth man admits the same. This could be a sign that Russian men and women, on average, have a different understanding of what constitutes domestic violence. If so, adopting a law that defines domestic violence and holding a public awareness campaign is of paramount importance to eliminate any misunderstanding.

The difference could also be a sign that victims of domestic violence are more likely to confide in women hence making domestic violence less visible to men. This awareness gap perhaps explains the difference between men’s and women’s assessments of how serious the issue in Russia is.

The pandemic has provoked a new wave of discussions of domestic violence among Russia’s population with stories and statistics widely shared in the media and on the internet. As domestic violence becomes more visible, public perceptions are likely to shift further towards recognizing, and hopefully condemning, it. But, while legislation is crucial, the experience of other countries in the region, such as Armenia or Kazakhstan, shows that adopting laws on domestic violence is not enough. Measures are needed to ensure implementation of the law including training police officers and state officials and instituting disciplinary action for negligence of victims’ complaints.

Nevertheless, admitting there is a problem with domestic violence in Russia, and introducing laws, are an essential first step. The Russian government seems to have placed its bet on the support of conservative social groups but changing public opinion may prove this strategy unsustainable.




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Unrest Threatens Ethiopia’s Transition Under Abiy Ahmed

24 July 2020

Abel Abate Demissie

Associate Fellow, Africa Programme

Ahmed Soliman

Research Fellow, Horn of Africa, Africa Programme
Ethiopia is experiencing a turbulent transition. The uncompromising approach of political forces threatens to tear the country apart and reverse the hard-won gains made in recent years.

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Burned buildings which were set on fire during the violence after the assassination of Oromo's pop singer Hachalu Hundessa are seen in Shashamene, Ethiopia on 12 July 2020. Photo: Getty Images.

Violent unrest in Addis Ababa and the surrounding Oromia region has led to the loss of over 177 lives, with the detention of thousands and widespread destruction to property. The rise of identity-based conflict and related political tension is the most severe test of Prime Minister Abiy Ahmed’s leadership since he came to power two years ago.

Protests erupted after the assassination on the 29th of June of Hachalu Hundessa, a prominent Oromo singer and activist. They spiralled into widespread rioting, looting and arson which devastated some towns. Targeted attacks and killings, particularly against ethnic minorities in Oromia, have damaged communities’ social fabric and heightened regional tensions.

The motives behind Hachalu’s murder are not fully understood. Suspects linked to a militant faction of the Oromo Liberation Front (OLF) have been arrested, while the government has blamed the Tigray People’s Liberation Front (TPLF) and certain prominent activist-politicians for inciting ethnic violence and attempting to derail Ethiopia’s fragile political liberalization. With investigations not yet concluded, any exploitation of this tragedy for political gain and without adequate due process is likely to further erode trust in the government and public institutions. 

Ethiopia’s progress halting under Abiy Ahmed

The prime minister came to power with a vision of national unity – encapsulated in his ideology of Medemer – and implemented a raft of reforms aimed at strengthening institutions and increasing political space, inclusivity and freedoms. Abiy was awarded the 2019 Nobel Peace Prize for Ethiopia’s rapprochement with Eritrea, alongside domestic progress. He was lauded for mediating within the region, including in Sudan following the ouster of Omar al-Bashir.

However, Ethiopia’s simmering ethnic and political divisions have deep roots, with structural problems that have been insufficiently addressed under Abiy’s helm. These include conflicting narratives about Ethiopia’s history, an unfinished federal project and tensions over the division of power between the centre and the regions.

There is also the desire for better representation from various ethnic groups, linked to the pursuit of greater autonomy in many places, notably in the ethnically diverse southern region. Reforms have increased expectations among competing constituencies, heightening tensions further.

There are signs that Ethiopia is sliding dangerously backwards, particularly on security and democracy. The country has seen worsening levels of militant ethno-nationalism and inter-communal violence, a dangerous standoff between the federal government and Tigray region, and an increase in politically motivated deaths.

This has been compounded by the government turning to familiar, heavy-handed and securitized responses to law and order challenges, including intimidation and mass arrests of civilians, opposition politicians and journalists, and shutting off the internet. The Ethiopian Human Rights Commission called for security forces to refrain from punitive measures and pursue conciliatory approaches in implementing the state of emergency measures brought in to deal with COVID-19.

The country is also facing a triple economic shock caused by the pandemic, renewed instability and devastating desert locust swarms. The IMF recently reduced Ethiopia’s GDP growth projections for 2019/2020 to 3.2 percent down from 6.2 percent and the country has estimated that 1.4 million workers will be affected by the pandemic, particularly in the service and manufacturing sectors.

The impact on agriculture, which accounts for a third of GDP and on which most Ethiopian’s depend for their livelihoods, is expected to be severe. In addition to shaking investor confidence, the likely impact on livelihoods, food security and poverty levels makes it harder for the government to maintain public support and could add to instability.

Political turmoil caused by election delay

The situation has been exacerbated by the indefinite postponement of elections that were due in August 2020, as a result of COVID-19.

Efforts to avoid a crisis of legitimacy for the government caused by the end of parliament’s term in October 2020, led to a decision on the way forward being taken by the Council of Constitutional Inquiry (CCI). This group of legal experts led by the President of the Supreme Court, gave the ruling Prosperity Party (PP) an open-ended extension of their term, rubberstamped by the House of Federation, with no limits set on their powers during the interim period.

This decision sets a dangerous precedent and is a missed opportunity to achieve compromise and advance the democratic process. The lack of inclusion has angered opposition groups, with whom the government has had little genuine dialogue. Many in the opposition had advocated for a transitional or technocratic government during the interim, despite risks of further divisions and a vacuum of authority, and accuse the PP of manipulating institutions to stay in power.

Furthermore, the TPLF, the ruling party in the Tigray region and formerly the dominant national political force, is pushing forward with its intention to hold unilateral regional elections. It formed a new regional electoral commission, in spite of objections from the national electoral board and the government, which has implied it could use force to stop the elections. This rising enmity between the PP and the TPLF is extremely worrying and requires immediate de-escalation.

A pathway to genuine dialogue and reconciliation

Ethiopia’s problems can only be resolved through dialogue, compromise and reconciliation. Escalating tensions, particularly between the federal government, Tigray and Oromo opposition groups risk furthering instability and fragmentation. One way to establish confidence would be for a group of respected Ethiopian personalities (elders and religious leaders) to lead a political dialogue, with actors carefully chosen and vetted to ensure the buy-in of government, opposition parties and the public, and supported by Ethiopia’s regional and international partners.

Once established, an initial goal of such a platform would be to induce elites, populist leaders, activists and influential regional media to stop exploiting division and violence for narrow gain. Priority agenda issues include the election timetable and required institutional and legal reforms, the role of the opposition during the interim period, strengthening reconciliation efforts, and the need to carefully manage autonomous security forces within regional states.

The prime minister can still weather the storm and implement his vision of a unified multinational Ethiopia based on the values of democracy, rule of law and justice, but only if the government and other stakeholders do all they can to reduce tensions and preserve peace at this critical juncture. COVID-19 and the associated economic impacts have deepened the country’s multifaceted problems, which can only be resolved by political actors committing themselves towards inclusive dialogue and reconciliation, as they seek to forge a shared common future.




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COVID-19 Teaches Resilience and the ‘Vulnerability Paradox’

7 August 2020

Dr Gareth Price

Senior Research Fellow, Asia-Pacific Programme

Christopher Vandome

Research Fellow, Africa Programme
Humility from decision-makers, building trust in leaders and institutions, and learning from international experience are critical if countries are to better prepare for the next global crisis.

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An information poster on preventing the spread of COVID-19 in Hanoi, Vietnam. Photo by MANAN VATSYAYANA/AFP via Getty Images.

While we must wait for the final reckoning of most successful national coronavirus responses, it does still appear those countries with memories of MERS and SARS - such as Singapore, Taiwan, Hong-Kong, and South Korea – led the way in being best prepared for COVID-19, with strong contract tracing and isolation measures.

Experience of previous outbreaks informed the containment strategies adopted by countries in East Asia in response to COVID-19. Vietnam reported its first case of COVID-19 in January but, over the following four months with rapid targeted testing, contact tracing and successful containment, only around 300 additional cases with no deaths were confirmed.

These countries learned to be flexible fast when new transmissions occurred, establishing quick lockdown measures targeted at key groups such as Singapore’s schools or South Korea’s night clubs and religious centres. In stark contrast, most European countries were overwhelmed by the pandemic despite enjoying world-class health systems, predictive models, scientific expertise, wealth, and resources.

Asia may have suffered first from coronavirus, but there is no ‘first mover advantage’ in dealing with a pandemic. The more resilient a society, the better placed it is to cope with a variety of risks and challenges. But to become resilient, a society needs to have faced setbacks and learned from them. And to remain resilient, it needs to stay aware of its own vulnerabilities and avoid complacency.

Prior experience of crises and disturbances, coupled with a ‘trial and error’ process of learning to deal with them, makes a society more resilient, whereas high levels of economic welfare and relative lack of recent crises leave some societies less prepared to face shocks. This is known as the ‘vulnerability paradox’.

Within Europe, it has actually been the Greek handling of COVID-19 that so far appears more successful than others. Greece is a country which has suffered a decade of austerity leading to a weakened healthcare system. And with one of Europe’s oldest populations, the Greek government was keenly aware of its own vulnerabilities. This prompted an early lockdown and a rapid increase in intensive care beds.

Although better state capacity and health system capability are clearly positives for mitigating disasters, citizens do tend to be less familiar with risk preparedness. This lack of experience can then breed complacency which threatens societies where risks are often complex, numerous, transboundary and inter-related.

Conversely, the absence of systemic resilience at a national level often puts the onus on family units or local communities – creating resilience as a necessary response to weak government capacity. There is little choice but to learn to look after yourself and your community.

However, although the vulnerability paradox helps explain why prior experience makes a system more resilient, societies need to stay aware of their own vulnerabilities and avoid complacency if they are to continually remain resilient.

Complacency coupled with a belief in the virtues of the free market has left some countries hit harder than others by the pandemic. In normal times, ‘just in time’ business models can be highly efficient compared to holding vast stocks. But it does not require hindsight to know that a global health crisis will see demand for protective equipment soar and these business models severely challenged.

Several societies have also witnessed a decline in trust towards institutions, especially politicians or the media. The deployment of science as justification for political decisions around coronavirus was presumably intended to help garner trust in those decisions. But when the science itself is inexact because of inadequate or emerging knowledge, this strategy is hardly fail-safe.

COVID-19 does provide an opportunity to rebuild trust by rethinking the relationship between the state and its citizens, to engage people more directly in a discussion about societal resilience with empowered citizens, and to rebuild a social contract between state and society in the context of recent significant changes and further potential threats.

It should also provide a salutary wake-up call to a range of ‘strongmen’ leaders prone to portraying issues rather simplistically. Although COVID-19 may be one of the few complex problems to which simplistic measures do apply - such as wearing a mask and using social distancing – these do not provide the whole solution.

Generally, declining trust in politicians reflects the ongoing inability of current politics to deal with a range of societal challenges. COVID-19 is certainly the most sudden and presents the biggest immediate economic shock of recent times, but it is just the latest in a long line of examples of political failure, such as conflict in the Middle East, climate change, terrorism, and cyber-attacks.

Along with the growth of automation and digitization which provide opportunities at the macro-level but threats at a more micro-level, what most of these issues have in common is that national responses are likely to fail. Restoring trust requires re-energized global governance, and this means compromise and humility – qualities which appear in short supply to many current politicians.

But, regardless of political will, building resilience to tackle ongoing or rapidly forthcoming challenges also rubs up against free market beliefs, because building resilience is a long-term investment and comes at a price. But by acknowledging vulnerabilities, avoiding complacency, implementing lessons from past experiences, and learning from others, policymakers will be better prepared for the next crisis.

Reconstructing societies through the prism of resilience creates fundamentally different outcomes to global challenges, and can build trust between elected representatives and the wider population. Accepting the vulnerability paradox and acknowledging that those generally less prone to disasters are actually less able to cope when change happens creates a powerful argument for this new approach.




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Why the Corrupt President of Belarus Deserves Sanctions

10 August 2020

Ryhor Astapenia

Robert Bosch Stiftung Academy Fellow, Russia and Eurasia Programme
Sanctions would be a wake-up call for those who oversaw this brutal and dirty election campaign.

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People protest at a rally of solidarity with political prisoners in Belarus. Photo by Beata Zawrzel/NurPhoto via Getty Images.

Belarusian president Aliaksandr Lukashenka deserves sanctions. This election campaign in Belarus, which culminated in a vote on Sunday is the most brutal and dirty in its history. But, so far, the EU, the UK and the US have only issued familiar-sounding and futile appeals to the Belarusian authorities condemning their actions. Not imposing sanctions is a de facto licence to continue with repression.

Despite all this, the West is unlikely to impose significant sanctions afterwards. There are several questionable reasons for this. First, Western policymakers fear sanctions against Lukashenko will make him more likely to genuflect to Russia. However, relations with Russia have already deteriorated as Belarus accuses Russia of trying to interfere with its domestic affairs.

Sanctions serve as a wake-up call. The Belarusian authorities then might seek - once again - to repair relations with the West and reduce repression for greater assistance in any direct confrontation with Russia.

Second, the West is reluctant to implement sanctions because it has already invested somewhat in warming relations with Belarusian authorities. Punishing Lukashenko could mean burying the - admittedly modest - achievements of a Belarus-West dialogue that started in 2014 after the conflict in Ukraine began.

Even US secretary of state Mike Pompeo met with Lukashenko in Minsk this year, after which Belarus replaced a small but symbolic amount of Russian oil for American. All the same, the West has its conscience to answer to if dialogue is won but repressions continue.

The third reason why the West may not resort to targeted economic sanctions and visa restrictions is a latent concern whether such measures have any effect on democratization processes at all. They may be appropriate punishment, but there is little evidence they ever change the nature of a regime.

According to this logic, if the West imposes sanctions, the Belarusian authorities will continue to crack down with repression because they will have nothing to lose. That said, in previous years, the Belarusian authorities have released political prisoners in response to sticks and carrots brandished by the West. If Belarusian political prisoners did not have a price tag, the authorities would most likely keep everyone in jail.

To be fair, there are reasonable arguments in favour of and against sanctions. But if the West fails to impose them - be it through lack of political will or out of genuine concern about their effectiveness - at least it should focus on helping ordinary Belarusians withstand Lukashenko’s repressions. After the vote, arrested and jailed Belarusian citizens might lack money for lawyers and arbitrarily imposed fines.

If repression spreads further, independent media and human rights organizations will need funds to keep their structures running in the heat of the crackdown. Many entrepreneurs might lose their companies for openly supporting free elections. Thus, if the West will not sanction Lukashenko, it should at least show solidarity with these Belarusians in peril.

This article was originally published in The Telegraph.




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International Donors Can End Lebanon's Corruption

10 August 2020

Dr Lina Khatib

Director, Middle East and North Africa Programme
Change must come from within Lebanon, but Emmanuel Macron and others can help by ending their patronage of a disastrous regime.

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An anti-government protester in Beirut puts up a poster accusing corruption in Lebanon's state judiciary. Photo by Sam Tarling/Getty Images.

In the aftermath of the devastating Beirut port explosion last week, it is not just the role of the Lebanese political class that has come under scrutiny, but that of their international peers too.

Sunday’s international donor conference led by the French president, Emmanuel Macron, raised €253m (£228m) in relief funds, but it also signalled an important change in rhetoric. For the first time, donors affirmed that relief funds would directly go to the Lebanese people, and that longer-term economic assistance would be dependent on Lebanon implementing structural reforms.

This affirmation came hot on the heels of growing international attention on rampant corruption among Lebanon’s ruling political class, which is widely blamed for the port explosion. It sends the message to Lebanon’s rulers that, while their country desperately needs foreign assistance to stand on its feet, no one can help Lebanon if it does not also help itself.

But the communique issued following the conference glossed over the international community’s own role in sustaining Lebanon’s corrupt political class over a period of decades. At the aid conference, Macron said that Lebanon’s future is at stake. What donors need to recognise is that this future is a shared responsibility for them and Lebanon’s leaders alike.

With Lebanon’s debt greater than 170% of its GDP, and with the port explosion costing an estimated $15bn of damage, Lebanon needs foreign assistance to prevent it becoming a failed state. But what it needs even more desperately are reforms that would counter the corruption and lack of accountability that led it to this sorry state of affairs in the first place.

It is Lebanon’s existing political system – a power-sharing pact between different sects rather than a system of governance on the basis of competence – that facilitates its leaders’ reckless behaviour.

The international community is partly responsible for sustaining this system through cascading patronage. For decades, Lebanese leaders grew accustomed to neglecting the national interest and eventually being bailed out by international assistance. Dollar deposits would land in the central bank from Gulf donors, loans would be offered by European countries and foreign aid packages would flow to Lebanese state institutions – only for the majority of this money to end up lining the pockets of the country’s rulers, who frequently overcame their political differences to share state resources between them. The Lebanese state came to exist as a shell in the eyes of its citizens.

Lebanon’s rulers benefited from citizens’ low expectations from the state and the lack of measures ensuring transparency and accountability in the country. They brokered a social contract that cast the leaders as patrons and the people as clients rather than citizens. Foreign powers were well aware of this dynamic but they often turned a blind eye to it, and even nurtured it, because they believed the Lebanese political system brought stability and predictability following the tumultuous civil war.

With time the leaders’ greed grew, and with that the economic situation worsened. Leaders who behaved as de facto local authorities, granting constituents civil service jobs or minor privileges, provided them less and less. There was some international recognition that this dynamic was becoming unsustainable – international donors pledged $11bn during the CEDRE conference of 2018 on condition that Lebanon implemented structural reforms.

And in the wake of Lebanon’s recent economic deterioration, the International Monetary Fund said in April that any discussion of a loan to Lebanon would be subject to more reforms. On both occasions, Lebanon’s rulers ignored the calls for reform, counting on foreign support eventually coming in unconditionally as it used to in the past. International donor follow-up was sluggish.

The port explosion needs to be a wake-up call for any international entity seeking a stable Lebanon. The blast is ultimately the result of the decades during which political classes in Lebanon and outside it fostered the country’s dysfunctional political system. No long-term assistance should flow into Lebanon without strong conditions on transparency and accountability in how this assistance would be employed.

Foreign support is not the problem per se, but rather when it is handed on a plate unconditionally, maintaining the patronage cascade, exacerbating the weakness of state institutions, and further impoverishing Lebanese citizens.

With Lebanon’s economy almost crumbling in the aftermath of the explosion, there is an opportunity for the international community to exert leverage over Lebanese leaders – whose personal wealth grew partially from legal and illegal transactions through the devastated port – so that necessary reforms are implemented. Such leverage would not remove Lebanon’s defective political system, but would pressure its leaders to accept at least some basic reforms.

But for Lebanon to really turn a new page, it needs a new social contract and a new political system based on fairness, transparency and accountability. This is a change that can only start from within Lebanon, but it also depends on the international community abandoning their tacit support of a disastrous political status quo.

This article was originally published in The Guardian.




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Watching Belarus Means Watching Russia Too

13 August 2020

Keir Giles

Senior Consulting Fellow, Russia and Eurasia Programme
Protesters in Belarus face a dilemma, as being too successful in confronting the Belarusian regime could mean they end up having to reckon with Russian forces as well.

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Russian president Vladimir Putin and Belarus president Aliaksandr Lukashenka skiing in the Black Sea resort of Sochi, Russia. Photo by SERGEI CHIRIKOV/AFP via Getty Images.

Amid outrage and revulsion at Belarus’s fraudulent election and the subsequent savage repression of protests, Western responses must be planned with half an eye on Russia. Not just for what is often described as the risk of ‘driving Belarus into Russia’s arms’ but also for the danger of unilateral Russian action, with or without Belarusian acquiescence.

In the past six years, there have been endless discussions of what might prompt another Russian military intervention in Europe after Ukraine. In many of these scenarios, it is precisely the situation currently unfolding in Belarus that has been top of the list, with all the wide-ranging implications for security of the continent as a whole that would follow.

Just as with Ukraine, Russia is considered likely to intervene if it seemed to Moscow there was a danger of ‘losing’ Belarus to the West. If the situation in Belarus becomes more unstable and unpredictable, assertive Russian action could aim to assert control by different possible means - either propping up Lukashenka as a paper-thin proxy for Russian power, or installing a different, more compliant leadership as a pretence at legitimacy.

New facts on the ground

Leadership and support for a Western response to events in Belarus might previously have been expected from the United States which, like the UK, had been actively pushing forward relations with Belarus. But besides its preoccupation with internal affairs, US criticism of the election and ‘detentions of peaceful protesters and journalists’ looks tenuous in the light of the current administration’s behaviour over its own recent domestic issues.

Nevertheless, for NATO and for the United States as its primary guarantor, what happens in Belarus remains critically important precisely because of the possible response by Russia. Unpredictability increases the risk of Russia declaring it has received a ‘request for assistance from the legitimate government of Belarus’ and moving military forces into the country.

Once the immediate challenge of suppressing dissent had been dealt with, the presence of Russian forces in Belarus – along with the air and missile forces they could be expected to bring with them - would substantially alter the security situation for a wide area of central Europe. Popular scenarios for Russian military adventures such as a move on the Suwałki gap - the strip of Polish-Lithuanian border separating the exclave of Kaliningrad from the rest of Russia - would no longer be several geopolitical steps away.

Ukraine would be forced to rapidly re-orient its defence posture to face a new threat from the north, while Belarus’s other neighbours would need to adjust to having effectively a direct border with Russia. In particular, NATO’s enhanced forward presence (eFP) contingents in Poland and Lithuania would become the focus of intense political attention, facing calls both for their rapid expansion, and their complete removal as destabilizing factors.

Examining Russia's options

NATO and the US’s European Command must now be watching Russia just as intently as Russia is watching Belarus. For now, Russia may be reassured by what it has seen. While the protests in Belarus are far more widespread than those in Ukraine which led to its former president Viktor Yanukovych fleeing the country, Aliaksandr Lukashenka is showing no signs of similarly losing his nerve.

The viciousness of the repression combined with more or less effective suppression of communications over the internet may mean unrest will soon be subdued. Even if there were a transfer of power, the current Belarusian opposition has not declared a policy of greater integration with the West - and Russia might feel it could constrain the options available to any replacement as effectively as it has done Lukashenka’s.

Perversely, continued international apathy could even work to Belarus’s benefit by providing reassurance to Russia. If a palpable lack of interest helps the Kremlin believe the discontent in Belarus is purely organic and spontaneous, and is not other countries ‘mobilizing the protest potential of the population’ in order to bring about a ‘colour revolution’, this would be a strong argument against a need to act in order to head off Western encroachment.

But the options facing ordinary Belarusians do remain bleak. Passivity means acceptance of continuing stagnation under Lukashenka, with his rule extended indefinitely. Active opposition means a very real risk of arrest with the possibility of serious injury. Unsuccessful protest means the cause may once again soon be forgotten by the outside world. Successful protest carries the ever-present risk of Russia stepping in with an offer of ‘fraternal assistance’ and Belarus becoming effectively a province of Russia rather than an independent country with – in the long term - the opportunity to choose its own future.




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Nigeria’s Recovery Means Rethinking Economic Diversification

14 August 2020

Iseoluwa Akintunde

Mo Ibrahim Foundation Academy Fellow, Energy, Environment and Resources Programme
With more than half its revenue derived from oil exports, Nigeria’s economic fortunes are tied to the boom and bust cycles of the oil market. Those fortunes have waned way below expectations this year and, with more than one-quarter of its labour force jobless, it is time to question the country’s economic pathway.

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Yahaya Musa, 19-year old local mason, inspects a wall of a 'plastic bottle house' in Sabongarin Yelwa village, near Kaduna, Nigeria. Photo by AMINU ABUBAKAR/AFP via Getty Images.

For decades, the mantra of ‘economic diversification’ characterized attempts to reverse Nigeria’s dependence on oil with little real progress. Despite numerous reforms, international loans and restructuring programmes, 85 million Nigerians live in deteriorating conditions of poverty. The current coronavirus pandemic combined with mounting debt obligations and declining GDP gives new urgency to this issue.

The fall in international oil prices, which led government to slash its oil benchmark price from $57 to $30 a barrel and cut 20% of the capital budget, worsens these problems, but it is far from the only factor. Biomass, which drives household pollution and contributed to the death of 114,000 people in Nigeria in 2017, is the most dominant source of energy in Nigeria, amounting to more than 80% of the total energy mix, followed by fossil fuels (18%), and a negligible amount of renewable energy.

Although a diversified energy sector with a strong emphasis on renewables is known to reduce health and economic risks of combustion, there has been little emphasis on the role a diversified energy mix could play in ensuring sustainable development – even though the estimated potential of 427,000MW of solar power and photovoltaic generation means Nigeria has enormous renewable energy opportunities.

The global economy is also undergoing tectonic structural changes that will affect demand for Nigeria’s oil, leaving a fossil fuel-dependent economy more vulnerable. Improvements in global fuel efficiency, the ascent of electricity as a substitute for oil in the transport sector, and the falling prices of renewables and storage technologies all lead to a reduction in demand for fossil fuel products.

Creating structures for transition

This is not a ‘get out of oil’ prescription, and energy transition is complex. But it is inevitable. There are no universal strategies applicable to all countries; local contexts and political realities inform what is possible. Nigeria can take advantage of its abundant natural gas deposit as a ‘transition fuel’ to buy it time for putting the appropriate transition structures in place. The country has made progress in reducing the amount of gas flared, but much remains to be done for Nigeria to meet the 2030 global deadline to end flaring, after failing to meet its 2020 national target.

The first step to proper transition is to align Nigeria’s international obligations with its domestic policies and legislations - the distance between words and action must be bridged and the institutional capacity to implement raised. And, while they contain symbolic green gestures, the economic recovery and growth plan developed in response to the 2016 recession, and the post-COVID-19 economic sustainability plan, do not espouse green growth as a fundamental objective.

Nigeria must start looking inwards, investing its resources in designing and funding a green transition strategy. Its leadership role in floating Africa’s first Sovereign Green Bonds should be followed with non-debt funding options. Faced with a pandemic that has shattered the boundaries of what is politically possible, the Buhari government has overcome initial inertia to announce a halt in oil subsidy payments, although whether it will see through that policy is yet to be seen.

If it does, how it uses the savings will be significant. The money could provide support for Nigeria’s renewable sector to counteract the price disparity with fossil fuels and encourage rapid research and development. The Nigerian Ecological Fund — which is 3% of the Federation Account — should be reformed and expanded beyond its current scope of addressing ‘serious ecological problems’ to cover climate change with a strong emphasis on mitigation and resilience. That would increase Nigeria’s climate finance and minimize reliance on multilateral climate funds.

Beyond public investments in green infrastructure, the government can also incentivize the private sector to drive a green economy. As the largest purchaser of goods and services in the country, it can leverage purchasing power to green the procurement process. With the release of about $421 million to the Ministry of Works, the 2020 budgetary allocation for road projects has been fully disbursed to the Ministry, making procurement in the construction sector ripe for green reforms. The application of sustainable building techniques and materials could reduce Nigeria’s 17 million housing deficit and create more jobs.

But the task of greening the Nigerian economy is too important to be left to the federal government alone. It also requires mainstreaming climate change and sustainable development into the operations, governance, and budgets of government ministries, departments, and private entities at the sub-national and national levels.

There has been much focus on reviving agriculture, which is laudable, but agrarian practices have radically changed from the 1970s when the sector accounted for 57% of Nigeria’s GDP and generated 64.5% of export earnings. Beset by a loss of biodiversity, drought, and desertification, extreme weather events, rise in sea levels and variable rainfall, it is no longer smart for Nigeria to invest in this area without due regard for the significant climate risks. Any effort to revive agriculture and its export potential must be green-centred and integrate regenerative and climate-smart practices.

The right policy mix combined with aggressive funding can position the country as a renewable energy leader, both on the African continent and globally. And it will reap the benefits in technology development, foreign investment, decreased emissions, poverty reduction, and energy for the 80 million people currently without access to the national grid – all of which could ripple into millions of clean energy jobs in manufacturing and installation across the country.

The road to a green future must be paved with deliberate and consistent policies. Reforms hatched because oil prices have plunged should not be ditched when there is a boom. On the brink of a second recession in four years, Nigeria has learnt that the economic turmoil caused by COVID-19 is only the latest warning that pinning economic growth on a boom-bust market and the generosity of foreign donors and creditors is a failing strategy. There is another way and there is an opportunity for Nigeria to lead.




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Conflict-Related Sexual Violence in Ukraine: An Opportunity for Gender-Sensitive Policymaking?

18 August 2020

Kateryna Busol

Robert Bosch Stiftung Academy Fellow, Russia and Eurasia Programme
Meaningful change is needed in Ukraine’s response to the conflict-related sexual violence, which affects both women and men.

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Ukrainian feminists and human rights activists carry posters at an International Women's Day protest in Kyiv, Ukraine on 8 March 2019. Photo: Getty Images.

The virus of violence

According to the UN (para. 7) and the International Criminal Court (ICC, para. 279), conflict-related sexual violence (CRSV) is quite prevalent in hostilities-affected eastern Ukraine. Both sexes are subjected to sexualized torture, rape, forced nudity, prolonged detention in unsanitary conditions with members of the other sex and threats of sexual violence towards detainees or their relatives to force confessions. Men are castrated. Women additionally suffer from sexual slavery, enforced and survival prostitution, and other forms of sexual abuse. Women are more exposed to CRSV: in the hostilities-affected area, every third woman has experienced or witnessed CRSV as opposed to every fourth man.

COVID-19 has redirected funding priorities, affecting the availability of medical and psychological help for CRSV survivors worldwide. In Ukraine, the very reporting of such violence, stigmatized even before the pandemic, has been further undermined by the country-wide quarantine-induced restrictions on movement and the closure of checkpoints between the government-controlled and temporarily uncontrolled areas.

Addressing CRSV in Ukraine

The stigma of CRSV, the patchy domestic legislation, and the unpreparedness of the criminal justice system to deal with such cases prevent the authorities from properly helping those harmed in the ongoing Russia-Ukraine armed conflict.

CRSV is equally traumatizing yet different in nuance for men and women. Female victims often choose not to report the violence. Women avoid protracted proceedings likely to cause re-traumatization and the disclosure of their experience, which could be particularly excruciating in small communities where everybody knows everyone.

Men also struggle to provide their accounts of CRSV. Their suppressed pain and shame of genital mutilation and other CRSV result in sexual and other health disfunctions. Combined with the post-conflict mental health struggles, this has been shown to lead to increased domestic violence and even suicide.

The very investigation of CRSV in Ukraine is challenging. Certain tests and examinations need to be done straight after an assault, which in the context of detention and grey zones of hostilities is often impossible. Specialized medical and psychological support is lacking. Investigators and prosecutors are hardly trained to deal with CRSV to the point that they do not ask questions about it during the interviews. Burdened by trauma and stigma, survivors are inclined to report torture or inhuman treatment, but not the sexualized aspects thereof.

Seven years into the conflict, the state still has not criminalized the full spectrum of CRSV in its domestic law. Ukraine’s Criminal Code contains a brief list of the violations of the rules and customs of warfare in article 438. It prohibits the inhuman treatment of civilians and POWs but does not list any types of CRSV.

The article has an open-ended reference to Ukraine’s ratified international treaties, from which the responsibility for other armed conflict violations may be derived. For the more detailed norms on CRSV, Ukraine should refer at least to Geneva Convention IV protecting civilians and two additional protocols to the Geneva Conventions, to which it is a party.

However, the novelty of the war context for Ukrainian investigators, prosecutors and judges and their overcautiousness about the direct application of international conventions mean that in practice, observing the treaty or jurisprudential instruction on CRSV has been slow.

Use of the Criminal Code’s articles on sexual violence not related to an armed conflict is not viable. Such provisions fail to reflect the horrible variety and complexity of CRSV committed in hostilities. They also envisage lesser punishment than a war crime of sexual violence would entail. Cumulatively, this fails to account for the intention of a perpetrator, the gravity of the crime and the trauma of its victims.

The lack of public debate and state action on CRSV understates its magnitude. Ukraine should break its silence about CRSV in Donbas and make addressing this violence part of its actionable agenda - in law and in implementation.

Ukraine should incorporate all war crimes and crimes against humanity of CRSV in its domestic legislation; ensure a more gendered psychological and medical support for both sexes; establish rehabilitation and compensation programmes for CRSV survivors; create special victims and witness protection schemes; consider the different stigmatizing effects of CRSV on men and women in criminal proceedings and engage the professionals of the same sex as the victim; map CRSV in the bigger picture of other crimes in Donbas to better understand the motives of the perpetrators; submit more information about CRSV to the ICC and educate the public to destigmatize the CRSV survivors.

The drafters of Ukraine’s transitional justice roadmap should ensure that it highlights CRSV, adopts a gendered approach to it and endorses female participation as a crucial component of reconciliation and broader policymaking.

Embracive policymaking

Although ‘the discriminatory line almost inevitably hurts women,’ 'every gender discrimination is a two-edged sword’, Ruth Bader Ginsburg famously argued before the US Supreme Court. This could not be more relevant for Ukraine. The conflict - and lockdown-related violence has reverberated deeper within Ukrainian society, raising fundamental questions about the roles of both sexes and gender equality.

The failure to address CRSV and its different stigmas for both sexes mirrors the general lack of sustainable gender lenses in Ukraine's policymaking. It is no coincidence that a June 2020 proposal for gender parity in political parties coincided with another spike of sexist remarks by top officials. While women get access to more positions in the army, sexual harassment in the military is investigated slowly. Despite all the impressive female professionals, no woman made it to the first four-member consultative civic group in the Minsk process. Such lack of diversity sends an unfortunate message that women are not important for Ukraine’s peace process.

Ginsburg said, ‘women belong in all places where decisions are being made.’ CRSV against either sex won’t be addressed properly until both sexes contribute with their talents and their grievances to all pillars of Ukraine’s state governance and strategy. Ukraine should look to engage professional women - and there are plenty - to join its public service not just in numbers, but as the indispensable equal voices of a powerful choir.




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Balancing Demands on the World’s Forests

19 August 2020

Alison Hoare

Senior Research Fellow, Energy, Environment and Resources Programme
Finding equitable solutions to balancing the myriad demands on forests requires meaningful engagement with local actors, writes Alison Hoare.

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An aerial view of forest area in the Ternei District in Primorye Territory in the far east of Russia located along the country's border with Asia. Photo: Getty Images.

Healthy forests have always been a vital resource for the communities living in, and around, them. Offering food, clothing, fuel and medicine, forests also stabilize the water table and guard against soil erosion. Timber from forests also serves local, national and international markets, generates jobs and is an important revenue stream for many governments around the world.

Forests have also increasingly been tasked with combatting the double threats of climate change and biodiversity loss. Furthermore, the COVID-19 pandemic has put a spotlight on the role of forests in preventing diseases which has further added to the need to preserve the world’s forest area.

However, at the same time, pressure on forest lands is increasing, particularly for agriculture and also for mining, infrastructure and urbanization. But, with myriad demands placed on forests, and impacts that transcend political boundaries, achieving a balance requires a reckoning of local and global priorities.

International forest initiatives until now have, quite rationally, prioritized a globalized conceptualization of forests – privileging their place in global supply chains and global crises. International regulations around timber, for instance, are primarily aimed at securing a long-term source of timber by reducing illegality in the system while national plans under the Paris Agreement focus on forests primarily as a global carbon sink.

Within these initiatives, local impacts are often dealt with as flanking measures. Community benefit-sharing agreements, compensation schemes and incentive programmes are aimed at mitigating impacts and modifying behaviour at the local level so that these align with international goals.

Meanwhile, and despite intense international attention, it has been found that globally natural forest cover declined in the six years since the New York Declaration of Forests set a goal to halve deforestation. Greenhouse gas emissions have continued to rise and, although there have been successes, illegal timber continues to be traded internationally.

To halt these trends, it is important to reflect on the demands being placed on forests and to achieve a better balance between them. But this will require radical change. That’s why, in July, Chatham House convened an online Global Forum on Forest Governance at which these issues were explored.

One issue that was discussed is why it remains vital to listen to, and learn from, a wide range of voices. Single perspectives fail to acknowledge or respond to the full range of pressures exerted on forests therefore it is important to have a range of perspectives including those from the global north and south, economists and agronomists, social scientists and climate scientists.

But beyond the research community, all those who have a stake in forests must be included in the discussion too: women and men, young and old people, those living in urban and rural areas as well as people from the government and private sectors.

This lesson has often been repeated but rarely enacted perhaps because it is not easy to do and takes time. Nevertheless, broadening participation can help deliver the deep-rooted changes that are needed to the way forests are governed and managed.

Considerable evidence exists to show that improvements to governance can facilitate a more equitable approach to forests that better balances the needs and priorities of these different groups. Legal and institutional reforms, for example, that are sensitive to the needs of local populations have precipitated change. Successes in improving transparency have also been a key factor in holding both the private sector and governments to account.

Thus, creating radical change may not mean brand new ideas. Lessons can be learnt from the successes and failures of the past. It will be important that, as new and increasing demands are placed on already overburdened forests, these lessons are not forgotten and previous mistakes are not repeated.

What will matter over the next few years will be which ideas are acted upon and who gets to decide. As more than 100 countries announce plans to increase the ambition of their nationally determined contributions on emission reductions, and as the EU and the US move forward with plans to legislate deforestation out of commodity supply chains, a clear message that has emerged is that local actors need to be in the driving seat. This needs to go beyond listening and consultation to meaningful engagement that gives due weight to local priorities, perspectives and experience.




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US-Cuba Sanctions: Are They Working Yet?

20 August 2020

Dr Christopher Sabatini

Senior Research Fellow for Latin America, US and the Americas Programme
The recent spate of sanctions limiting US travel to Cuba announced by the White House and the news that the Cuban regime has re-opened US dollar stores have sharpened the question: do sanctions work and when? Central to that question is how would they work?

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A taxi driver wears a face mask while driving tourists around Havana on 19 March 2020. Photo: Getty Images.

It’s easy to take a look at the array of economic and diplomatic punitive policies that the sanctions-happy Trump administration has slapped on individuals and countries from Argentina to Iran and conclude that they have failed to achieve their objectives. With US oil sanctions on Venezuela, trade sanctions on select Argentine, Brazilian and Canadian exports and the tightening of the US embargo on Cuba, sanctions have become a go-to tool of the current administration.

Have they worked so far? Some have. Some haven’t. All of this leads to a legitimate question: when do they? The most extreme example, the US embargo on Cuba – first imposed by executive order under the Trading with the Enemy Act in 1961 and then codified into law by the Cuba Democracy Act (1992) and Libertad Act (1996) passed by Congress – has failed miserably, but remains an article of faith among its advocates, the bulk of them in southern Florida. The 1992 Democracy Act and 1996 Libertad Act have failed to produce either democracy or liberty in Cuba… yet their potential efficacy persists in the collective imaginations of their supporters. Why?

Conditions on Cuba

Any policy needs to have an explicit goal and with it an implicit or explicit theory of change. Whether it’s advertising that smoking kills on cigarette packages or trade negotiations, these efforts have behind them an explicit idea of the change they seek to foster and the causal relationships to achieve them. These are testable and, in theory, subject to course correction if they are not meeting their intended goals. Has advertising reduced the incidence of smoking?  Are workers better paid and receiving better health benefits and labour protections under the trade agreement several years on?

None of those has applied on the US’s embargo on Cuba. First, the policy goals have changed. In some cases, it has been stated that the limitations on US commerce and travel to the island is to reduce the regime’s international support for autocratic regimes. But Cuba’s to-the-death support of the Nicolas Maduro government in Venezuela has demonstrated this isn’t working. 

Arguably it has had the opposite effect: by impoverishing the state-centered Cuban economy, the embargo has made the regime more dependent on the decreasing oil that Venezuela supplies the island nation. In other cases, the stated goal has been regime change as the titles of the 1992 and 1996 act titles reveal.

The latter even lays out a set of conditions that must be present in Cuba before the Congress can lift the trade and diplomatic isolation the US has imposed on the island unilaterally. Those include the release of political prisoners, the absence of any Castro family members from decision-making, and credible steps toward free and fair elections. 24 years after the passage of the Libertad Act, Cuba is no closer to achieving not just one but any of those goals despite the putative incentive of a full and complete lifting of the embargo.   

The question here is the implicit theory of change for the embargo. Here, embargo supporters have never been clear about this link. First, there is the implied hope that sanctions will impose such costs and suffering on the general population that the masses will rise up and shake off autocratic rule of their overlords.

There are several problems with this. One is that general sanctions that reduce access to foodstuffs and finances – as has been the case in the US embargo on Cuba and sanctions on Venezuela – lowers the incentives for protest. It concentrates the government’s political and economic control over the population rather than weakening it. More, people who are hungry living under a repressive government simply aren’t that likely to rise up; they are often more concerned with the day-to-day struggles of getting by.

Second, there is a naïve notion that either those in power or those around them will see the light of day and decide to step down. Promoters of sanctions often have a cold-eyed reality of the nature of evil of autocratic governments. So why do they believe in some hidden decency among its inner circles? In truth, the purveyors of this view deny the basic and laudable basis for their hatred of autocrats: their bottomless cruelty and disregard for their own people. 

Do sanctions work? 

There is also a growing body of research on the efficacy of sanctions. Comparative research has revealed a number of conclusions, none of which appear to have been considered by current policymakers in the White House or State Department.  

The first of these is that sanctions work when they are implemented broadly by a wide coalition of governments. Most of the sanctions that have succeeded in their intentions have been along those lines including the UN sanctions on Iran to push the country to a nuclear deal.  

The second is that the goals of sanctions should be narrow and clearly defined. Successful cases, as Daniel Drezner who wrote a book on the topic has detailed, have been tied to specific goals. Regime change is not one of those. It is too broad and amorphous – though as I say above also unrealistic in its logic between intended effect and the targeted individual. 

A third element of successful sanctions is keeping them flexible and credible. As detailed in a Council on Foreign Relations backgrounder ‘the target must believe that sanctions will be increased or reduced based on its behaviour.’ 

That’s never been the case with Cuba sanctions under the Democracy or Libertad acts. Instead, sanctions relief is presented as a binary choice: democracy or nothing. There are no provisions for intermediate steps that could potentially incentivize changes of behaviour toward loosening state control and reducing human rights abuses.  

The recent tightening of the US embargo that included restrictions on US travel to Cuba and financial transactions under the Trump White House has been disconnected from any specific policy changes in the island. In this case, human rights conditions that the changes were linked to or intended to punish had not taken a dramatic turn for the worse. They were instead intended to simply ratchet up pressure for an embargo which advocates felt was too leaky and hope for a collapse that would weaken the Maduro regime.

That is precisely the problem for many of the most strident advocates of the US-Cuba embargo: the policy has become the objective, divorced from on-the-ground realities and incentives to move them forward.  There is the legitimate concern that the sanctions hurt the very people that the policy claims to defend. They also serve as a rallying point for the Castro regime and a way to cover up for its own economic failures.  But the most damning indictment of the embargo is that in its almost 50-year history it has failed to achieve its objectives.

If the matter is the efficacy of sanctions, then the US embargo on Cuba does not meet the test. It’s not limited to Cuba. None of the cases of regime change that many of the embargo advocates love to cite, communist Eastern Europe, the Soviet Union and South Africa had embargos as tight or isolating as those imposed on Cuba for nearly half a century. There’s a reason for that. It’s basic logic.

A version of this article will also appear in Spanish in the journal Foro Cubano in September.  




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Lessons from COVID-19: A Catalyst for Improving Sanctions?

26 August 2020

Emanuela-Chiara Gillard

Associate Fellow, International Law Programme
As the COVID-19 pandemic continues, efforts by states and humanitarian actors to stop its spread and to treat the sick are being hindered by existing sanctions and counterterrorism measures.

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Syrians walk past a mural painted as part of an awareness campaign by UNICEF and WHO, bearing instructions on protection from COVID-19, in the Kurdish-majority city of Qamishli, Syria, on 16 August 2020. Photo by Delil Souleiman/AFP via Getty Images.

If sanctions imposed by the UN Security Council, the EU, or states unilaterally, are not sufficiently targeted, and do not include adequate safeguards for humanitarian action, they can adversely affect the very populations for whose well-being they were imposed in the first place.  This is not a new concern, but one brought starkly to the fore by their impact on responses to COVID-19.

The detrimental impact of sanctions, which can prevent the supply of medical or personal protective equipment (PPE), or the provision of technical support or training to local health authorities is evident. Sanctions can also affect remote learning if support cannot be provided to local education authorities, export licences cannot be obtained for the necessary equipment and software, or if the companies providing reliable internet coverage are designated under the sanctions.

A comparison of US and EU sanctions on Syria reveals key challenges, but also opportunities for improving current arrangements for the imposition and implementation of sanctions so as to minimize adverse consequences in Syria and more generally.

The US has imposed broad sanctions, such as restrictions on the provision of funds, goods or services – even charitable contributions – to the Syrian government, including the health and education ministries, now playing a central role in the COVID-19 response.

UN agencies are exempted from these restrictions. A general license authorizes NGOs to conduct activities to meet basic needs, but it excludes those involving the government. So NGOs wishing to provide medical devices, PPE, training or other support to ministry of health staff have to apply for a specific licence.

But procedures for applying for licences are complicated, and the approval process notoriously slow.  No accommodation has been made to facilitate the COVID-19 response: no interpretative guidance – that would be valuable for all NGOs – has been issued, and no procedures established for reviewing applications more quickly.  There is no statement of policy indicating the circumstances under which specific licences might be granted.

Transactions with designated entities other than the government, such as internet providers whose services are necessary for remote learning, remain prohibited, and regulations expressly preclude applying for specific licences.

US sanctions frequently have a broad scope, both in direct and indirect application.  NGOs registered in the US, and staff who are US nationals, are directly bound by them, and grant agreements between the US government and non-US NGOs require the latter to comply with US sanctions.

This leaves the non-US NGOs in a Catch-22 situation – as they are not ‘US persons’ they cannot apply for specific licenses, but if they operate without such licences they may be violating grant requirements. This lack of clarity contributes to banks’ unwillingness to provide services, and may lead NGOs to curtail their activities.  This situation is regrettable in Syria, where the US is the first donor to humanitarian action, and also arises in other contexts where the US has imposed similar sanctions.

The EU’s sanctions for Syria are far more targeted. Of relevance to the COVID-19 response, they do not include prohibitions on the provision of support to the government that could impede assistance in the medical field.  There are, however, restrictions on the provision of certain types of PPE or substances used for disinfection, and also on transactions with designated telecommunications providers that affect continuity of education during lockdowns.  Although not prohibited, these activities must be authorized by member states’ competent authorities. Similar concerns arise about the complexity and delays of the processes.

The EU sanctions framework is complex, so the recent European Commission Guidance Note on Syria providing official clarification of how it applies to humanitarian action is welcome.  Although the note only explains the existing rules rather than amending them to facilitate the COVID-19 response, it does include a number of important elements relevant not just to Syria, but to the interplay between sanctions and humanitarian action more broadly.

First, it notes that ‘in accordance with International Humanitarian Law where no other option is available, the provision of humanitarian aid should not be prevented by EU restrictive measures’.  This recognizes that humanitarian assistance takes priority over any inconsistent restrictions in sanctions, and it also applies both to UN sanctions and unilateral measures. It is a starting premise that is frequently overlooked in discussions of whether sanctions should include exceptions for humanitarian action.  Its reaffirmation is timely, and it must guide states in drawing up future sanctions.

Second, the note states that sanctions do not require the screening of final beneficiaries of humanitarian programmes.  This means that once someone has been identified as an individual in need on the basis of humanitarian principles, no further screening is required.  This is extremely important to COVID-19 responses as it reflects a foundational principle of IHL that, to the fullest extent practicable, everyone is entitled to the medical care required by their condition without distinction.

Third, while responsibility for the implementation of sanctions, including the granting of authorizations, lies with member states, the note nudges them to adopt a number of measures to expedite and streamline such processes.  These include the suggestion that states could issue a single authorization for the provision of humanitarian aid in response to the pandemic.

The European Commission is to be commended for this initiative, which should be replicated for other contexts where the COVID-19 response may be undermined by sanctions.  These include Gaza, where it would be important to highlight that the designation of Hamas under EU counterterrorism sanctions must not prevent the provision of assistance to relevant ministries.

Failing to draw a distinction between the designated political party and the structures of civil administration risks turning targeted financial sanctions into measures akin to comprehensive sanctions.

The pandemic should serve as a catalyst for improving the system for the adoption and implementation of sanctions by the UN, the EU and individual states, including the UK as it elaborates its sanctions policy post-Brexit. The principles are clear: without prejudicing the aims for which sanctions have been imposed, humanitarian needs must always be prioritized, and met.




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Can the International Criminal Court Help Belarus?

26 August 2020

Kateryna Busol

Robert Bosch Stiftung Academy Fellow, Russia and Eurasia Programme
A referral of election violence in Belarus to the International Criminal Court could enhance the support for the Belarusian people at other crucial platforms.

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A protester carries a former Belarusian flag during an opposition rally by the Minsk Hero City Obelisk. Photo by Valery SharifulinTASS via Getty Images.

Making the case

The recent election results in Belarus have triggered revolution in yet another post-Soviet country and Aliaksandr Lukashenka’s response has been devastatingly brutal. However, the Belarusian people’s resilience and Western sanctionsadopted on 14 August – have proved effective. As some of the 6,700 jailed protesters were released, accounts of horrific treatment by law enforcement emerged: overcrowded cells, no food, torture, forced confessions, severe beatings , and threats of rape.

With reports of mounting violence, Polish MEP Radosław Sikorski warned Lukashenka to expect not just sanctions but also the possible intervention of the International Criminal Court (ICC), an idea supported by the opposition-led Belarus’ National Salvation. While there are significant impediments to the Court’s involvement, the impact of such an initiative could be ground-breaking.

Legal framework

The ICC considers criminal responsibility of top civilian or military leaders for only the most serious atrocities - war crimes, genocide, crimes against humanity and, in certain cases, the crime of aggression. In the context of Belarus, the Court’s jurisdiction over crimes against humanity might be relevant. According to the Rome Statute, the ICC’s founding treaty, crimes against humanity include widespread or systematic abuses directed against a civilian population. Atrocities relevant to Belarus include arbitrary imprisonment, torture, inhuman treatment, sexual violence, and enforced disappearances.

The ICC is a last resort. It can intervene only if states are unable or unwilling to properly investigate and prosecute serious crimes themselves. Although Belarus’s Criminal Code punishes crimes against humanity, as Lukashenka himself is implicated, impartial trials in the country are impossible while he is still in power. Other countries may investigate specific atrocities in Belarus under the universal jurisdiction principle. Universal jurisdiction greenlights investigations into the most serious crimes regardless of where they are perpetrated. German, Swedish and French proceedings on Syria are illustrative examples of this. Protesters may also file individual complaints of abuse to UN bodies under the protocols of the International Covenant on Civil and Political Rights and the Convention on the Elimination of All Forms of Discrimination against Women. The European Court of Human Rights is not an option for the protesters because Belarus is not a member of the Council of Europe.

As the UN mechanisms are yet to be triggered and there has not yet been any talk of universal jurisdiction proceedings, the question of recourse to the ICC remains. But as Belarus is not party to the Rome Statute, the only way to trigger the Court’s jurisdiction is a referral by the UN Security Council (UNSC). Even though it would be vetoed by Russia –  and, almost certainly, China – it could be worth pursuing.

The importance of symbolism

So far, the UNSC has referred to the ICC two situations in non-party states – Sudan and Libya. But for cases that do not end up being referred to the Court, the UNSC debates are as significant for what they manage to agree upon as they are for what they do not. Regarding Belarus, two impeded UNSC accountability initiatives are relevant: on Syria and MH17.

In 2014, Russia and China vetoed the referral of cases of violence in Syria to the ICC. In 2015, Russia was the only country to block the creation by the UNSC of a special tribunal to investigate Malaysian Airlines flight MH17, downed by a Russian missile over war-affected eastern Ukraine. In both cases, the vetoes delayed justice, but they did not prevent it. For Syria, special independent mechanisms to collect evidence for adjudication were developed. Although justice has yet to be done, except in states like Germany, the evidence is ready for any future court. For MH17, a proceeding at a domestic Dutch court became an alternative. Parallel to that, new evidence of Russia’s role in both Syria and the downing of MH17 emerged - contextualising its UNSC vetoes.

Russia’s stakes in the Belarusian elections are probably even higher: the victory of democracy in Belarus will deprive it of one of its closest and most dependent post-Soviet allies.

Even if Russia destroys any chance of Belarusian citizens using the ICC, the attempted ICC-Belarus discussion will not have been in vain. Russia’s opposition to the respective UNSC resolution would be a self-defeating validation of Lukashenka’s atrocities against his own people, unashamedly restated at one of the world’s top diplomatic negotiation tables. Similar to Syria and MH17, the UNSC would reconfirm its self-imposed impotency to defend basic human rights amid political conjuncture. This would bring more attention to the issue and catalyse action through other platforms, including the discussions across UN bodies and the consideration of Belarusians’ individual complaints of abuse, and could lead to tougher sanctions. It could also further make the case for universal jurisdiction proceedings in other countries.      

Supporting civil society

Belarusian civil society will need stronger support from democratic governments and human rights organizations in reporting and documenting the crimes. Other countries, neighbouring states in particular, should be ready to welcome Belarusian protesters through refugee schemes, so they are able to continue their activities from abroad.

When nationwide strikes enveloped Belarus, singers from the Minsk Opera supported protesters by singing Va, pensiero, the famed chorus of the Hebrew slaves from Verdi’s Nabucco – and a symbol of united Italy’s revival. The people of Belarus also want to live in a democratic state ‘where the mind is without fear and the head is held high’. And they deserve all the support they can get. The inevitable fall of Lukashenka’s regime might take time but it should not take more lives.




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Formal Representation for Young People Enhances Politics for All

10 September 2020

Ben Horton

Communications Manager, Communications and Publishing

Michel Alimasi

Member, Common Futures Conversations, Italy

Gift Jedida

Member, Common Futures Conversations, Kenya

Sanne Thijssen

Member, Common Futures Conversations, Netherlands

Mondher Tounsi

Member, Common Futures Conversations, Tunisia
Despite grassroots associations, community organizing and online groups offering pathways for political engagement, the room for youth representation in international politics remains narrow, with many young people still left feeling they are passive participants in policymaking.

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Youth protests at Parliament square against a new exam rating system which has been introduced in British education system - London, England on August 16, 2020. Photo by Dominika Zarzycka/NurPhoto via Getty Images.

According to UN Youth, people aged 15-24 make up one-sixth of the world’s population but, in roughly one-third of countries, the eligibility for parliamentarians begins at 25 years old and only 1.6% of parliamentarians are in their twenties. Young people are largely being excluded and overlooked, both as political candidates and even as participants in political processes, giving them limited political control over their own futures. 

If politics continues to be regarded as a space for older, more politically experienced individuals from particular backgrounds, young people will continue to be left systematically marginalized, and overall disengagement with politics within societies will continue to grow. Global leaders may increasingly point out the importance of youth representation in national and international fora, but the reality is their real policymaking impact still comes mainly from self-organized and informal activities.

And yet, despite this continued exclusion, huge numbers of young people are interested in political and civic engagement, and they have been driven to create new spaces. Youth networks, movements, and constituencies have emerged which provide the opportunity for younger voices to express political stances, and thus enhance the diversity and inclusivity of political debate. 

From the global Extinction Rebellion protests, to the student-led Rhodes Must Fall movement in South Africa and the UK, there are numerous examples of the power of informal youth networks and movements pushing for change. In certain cases, such as Sudan’s political revolution in 2019, we can see how direct action by young people creates major impact, but unfortunately these successes are few as most informal initiatives remain overlooked and undervalued. 

Putting youth representation into government

Creating diverse representation requires the linking of vital informal networks to formal political processes. In response to a recent Common Futures Conversations challenge, one mechanism with the potential to achieve this aim that emerged is creating dedicated youth representatives within government departments, so that qualified young people with relevant expertise are formally appointed to act as the link between government and informal youth movements. 

These individuals should be hired as employees rather than volunteers and take up the responsibilities of a government employee, supported by a large network of youth-led movements and initiatives as well as a smaller, voluntary advisory board of young people. 

This network then acts as a sounding board for the representative, gathering the opinions in their local communities and bringing forward crucial concerns so the youth representatives can confidently feed into policymaking processes with a clear sense of the substance of youth opinion. Alongside the network, a voluntary board of young people could provide additional support to the representatives when required to consult a broader range of youth organizations.

Both in the youth network and the board, a key priority is to involve different movements and initiatives reflecting diversities such as geographic spread, people who are marginalized due to ethnicity, gender or sexuality, educational and professional backgrounds, and other factors. 

Implementing such a structure would ensure more diversity in youth representation, something which is missing in many existing youth participation and formal political structures. Representation needs to move away from only highly-educated youth living in cities to ensure more influence for those young people usually left on the sidelines. 

Youth involvement in politics leads to better civic engagement overall. It improves the influence and access of young people, and supports governments becoming more inclusive and responsive to the plurality of voices they are representing. It also has the potential of encouraging millions more people to become properly engaged with politics. 

In order to gain support from parliamentarians and policymakers, it is crucial to highlight these benefits and demonstrate how the support of young people helps shift the political landscape for the better. All the necessary parties already exist in most countries, so all that is required is to drive a collective initiative and for both governments and the youth to take responsibility for making it work.

As the former president of Ireland Mary Robinson said during a recent Chatham House Centenary event: ‘We need to make space for young people so we can hear their voices, their imagination, their commitment to question and speak truth to power. We need young people to feel that they are part of the solution.’ 

Building formal structures is a necessary step to achieving this vision, as it provides practical solutions to realize a more diverse, inclusive and meaningful participation of the youth in politics, and also creates more representative and responsive governments.




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Seven Ways the West Can Help Belarus

10 September 2020

Ryhor Astapenia

Robert Bosch Stiftung Academy Fellow, Russia and Eurasia Programme
Outlining the key steps that government, international institutions, and NGOs can take to bring an end to the suffering of the Belarus people.

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Opposition supporters hold white-red-white flags at a Minsk protest in support of Belarusian opposition activist Maria Kolesnikova. Photo by Natalia FedosenkoTASS via Getty Images.

1. Acknowledge the new reality

A huge number of Belarusians across all levels of society simply no longer recognize Lukashenka as their legitimate president. The unprecedented size and persistence of protests against his regime and the sheer scale of reports of repressive actions, torture, and even murder, mean Belarus will never be the same again.

However, current paralysis in EU policy and the absence of a comprehensive US policy are both serving as a de facto licence for Lukashenka to deepen the political crisis. The sooner policymakers realize this and act with more responsibility and confidence, the quicker the increasing repression can be reversed.

2. Do not recognize Lukashenka as president

If the international community stops recognizing Lukashenka as president, it makes him more toxic to others, including Russia and China, both of which will be reluctant to waste resources on someone who is seen as the main cause of Belarusian instability. Even if Russia still decides to save Lukashenka and financially support him, ignoring Lukashenka decreases the legitimacy of any agreements he signs with the Kremlin on collaboration or integration.

Demanding a re-run of the presidential election should also remain firmly on the agenda as functionaries within Lukashenka's system should know this international pressure is not going away until a truly transparent vote takes place.

3. Be present on the ground

In order to curb repression and establish ties with actors within Belarus, a monitoring group should be organized under the auspices of the UN, the OSCE or other international organizations to establish a presence on the ground, and to stay in the country as long as it is needed, and is possible. Governments and parliaments can send their own missions, while staff from international media and NGOs should be encouraged to report on what is actually happening inside the country.

The bigger the visible presence of the international community is in Belarus, the less brutal Lukashenka’s agencies can be in persecuting protestors, which in turn would then allow more substantial negotiations to take place between the democratic movement and Lukashenka.

4. Announce a package of economic support for a democratic Belarus

The Belarusian economy was already in bad shape before the election, but the situation is going to get much worse. The only way out is support from the international community with a ‘Marshall Plan for a democratic Belarus’. States and international financial institutions should declare they will provide significant financial assistance through grants or low-interest loans, but only if there is democratic change first.

It is essential to make this economic package conditional on democratic reform, but also that it will have no geopolitical strings attached. If a democratically-elected government decides it wants to improve relations with Russia, it should still be able to count on an assistance package.

This would send a strong signal to economic reformers who remain inside Lukashenka's system, giving them a genuine choice between a functioning Belarusian economy or sticking with Lukashenka, whose leadership is seen by many as to be responsible for ruining the country’s economy.

5. Introduce targeted political and economic sanctions

The Lukashenka regime deserves tough sanctions internationally, but so far only selective visa restrictions or account freezes have been imposed, which have little to no effect on what is actually happening on the ground. Visa sanction lists need to be expanded but, more importantly, there should be increased economic pressure on the regime. Companies which are the most important to Lukashenka's business interests should be identified and targeted with sanctions, all their trading activity halted, and all their accounts abroad frozen.

Governments should also persuade their own country’s large companies to reconsider working with Belarusian producers. It is shameful that international corporations continue to advertise in media controlled by Lukashenka and appear to be ignoring the reports of human rights violations at Belarusian companies they do business with.

Moreover, there should be a deadline set to halt all repression, or broader economic sanctions will be imposed. This would send a strong message to Lukashenka and also his entourage, many of whom would then become more convinced he has to go.

6. Support NGOs to investigate allegations of torture

There are few legal mechanisms to prosecute those thought to be involved in election fraud and acts of brutality. Nevertheless, all reports of torture and falsifications should be properly documented by human rights defenders, including identifying those alleged to have taken part. Gathering evidence now prepares the ground for investigations, targeted sanctions, and leverage on law enforcement officials in the future.

But, given that such an investigation is not possible in Belarus right now, international human rights activists should be enabled to start the process outside the country with support from Belarusian NGOs.

7. Support known victims of the regime

Even with an unprecedented campaign of solidarity among Belarusians, many people need support, especially those alleged to have suffered torture. Some media outlets claim to have lost a significant amount of revenue because advertisers were forced to pull out, and journalists arrested. Human rights defenders need funds to keep organizations running in the heat of this crackdown.

Supporting all these people and organizations will cost tens of millions of euros, but it would significantly ease the huge financial burden facing those who have opposed the regime.




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Is the Juba Peace Agreement a Turning Point for Sudan?

14 September 2020

Dame Rosalind Marsden

Associate Fellow, Africa Programme
Sudan is looking towards a brighter future after the initialling of the Juba peace agreement on August 31, an important first step towards bringing peace to the conflict zones and laying the foundation for democratic transition and economic reform throughout the country.

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Chairman of Sudan’s Sovereign Council, Lt General Abdel Fattah al Burhan (left), South Sudan President Salva Kiir (centre) and the Sudanese Prime Minister Dr Abdalla Hamdok (right) greet people gathering during the initialling of the Sudan peace deal with the rebel groups in Juba, South Sudan. Photo by AKUOT CHOL/AFP via Getty Images.

Although there is a long road ahead to achieve sustainable peace and formidable challenges remain, the hope is Sudan can turn the page on decades of war that has left hundreds of thousands dead and millions displaced, particularly in Darfur and the Two Areas (South Kordofan and Blue Nile).

The peace agreement, between Sudan’s transitional government and the Sudan Revolutionary Front (SRF), a broad alliance of armed and other movements, and Minni Minawi’s Sudan Liberation Movement, is not yet comprehensive as it did not include two other important armed movements.

Expected to be formally signed in early October, the deal has been hailed as a ’historic achievement’ by the UN secretary-general, and the international community also commended the government of South Sudan for its positive role as mediator and urged hold-out groups to join the peace process. Much does depend on delivering on the agreement, and the experience of implementing past peace accords in Sudan has been dismal, particularly when it comes to bringing tangible benefits to people on the ground.

What potentially makes the Juba agreement different is that Sudan’s civilian-led transitional government aspires to deliver peace, justice and democracy in line with the goals of the revolution; that the agreement was negotiated between the Sudanese themselves, with a light touch from the South Sudanese mediation and low-key logistical and technical support from the international community; and that much of the negotiations were conducted between former comrades, in marked contrast to the confrontational atmosphere that prevailed during the Bashir era.

As Prime Minister Abdalla Hamdok put it: ’This is a Sudanese peace, made with our own hands and by our own efforts’ and: ’This is not a paper agreement, but is a living organism that needs care, attention and political will from all of us’.

Achievements of the agreement

The result of almost one year’s hard work in Juba, the agreement is comprehensive in scope and addresses the fundamental issues of Sudan’s crises in Darfur, the Two Areas and other marginalized regions, albeit in a mixture of regional and national protocols. It goes a long way to realizing the vision of a democratic ‘New Sudan’ based on respect for the diversity of the Sudanese people and equal citizenship without religious, ethnic, cultural or gender discrimination.

There is a focus on the concerns of historically marginalized populations in Sudan’s conflict zones and disadvantaged areas, and it addresses root causes of conflict, such as issues of identity, marginalization, the relationship between religion and state, governance, resource-sharing, land issues, social justice, and equality at the national level.

The deal also looks to resolve the consequences of conflict, such as humanitarian relief, the safe and voluntary return of IDPs and refugees to their original lands and compensation, eviction of illegal settlers and the development and reconstruction of the conflict-affected areas. It provides for significant devolution of power and resources to the regions, including autonomy for the Two Areas and restoration of a single Darfur region. On transitional justice, the government has committed to cooperate fully with the International Criminal Court (ICC) and ensure Bashir and others subject to arrest warrants will ‘appear before’ the ICC.

This deal will change the face of the transitional government by bringing marginalized forces to the centre of the political process. The transitional period will extend to 2023, with the armed movements having three seats in the (currently 11-member) Sovereign Council and 25% of seats in the Cabinet and soon-to-be-formed Legislative Assembly.

The power-sharing provisions have been criticized as disproportionate to the size of the movements’ political constituencies and military presence inside Sudan. But the movements argue significant representation in the government is necessary to support implementation and that their arrival in Khartoum will help to strengthen the transition to democracy.

Establishing a single, national professional army, reflective of the diversity of Sudan and with a new military doctrine opens the way for much-needed comprehensive security sector reform. During the transition, this will include the creation of a 12,000 strong joint force between government security forces and the armed movements to help protect civilians in Darfur. Importantly, mechanisms allowing for civilian input on security reforms are also established.

The deal also guarantees religious freedom and the separation of religion from politics. This ensures religion will not be exploited by state institutions as it was during the Bashir-era, provides for the constitution to be based on equal citizenship, and for the establishment of a National Commission for Religious Freedom to protect the rights of Christians and other minorities. In the Two Areas, the autonomous government will have special legislative powers to pass laws based on the secular 1973 Constitution.

Increasing inclusivity

Key to achieving inclusive and sustainable peace is ensuring popular ownership and finding ways to engage civil society stakeholders and marginalized communities such as nomads in dialogue, reconciliation and social peace initiatives. The negotiations were mainly a top-down elitist process. Although the UN brought IDPs, tribal leaders and women’s groups to Juba for short periods, there was limited participation by civil society. However, the agreement provides for a wider range of stakeholders to feed into a comprehensive peace through reconciliation and transitional justice mechanisms, follow-on conferences and an inclusive National Constitutional Conference.

Achieving a comprehensive peace will also mean bringing other armed movements on board, particularly those led by Abdel Aziz Al Hilu and Abdel Wahid Al Nur, both of whom hold significant territory, forces and support (in the Two Areas and Darfur respectively). Negotiations in Juba with Abdel Aziz had stalled over his demands for a secular state or, failing that, the right to self-determination, but he has now reached a preliminary agreement with Prime Minister Hamdok on a way forward.

Other challenges of implementing peace

Turning the peace agreement into reality on the ground will face many other challenges given the fragility of a civilian-military transitional government, distrust, and competition between the signatory movements and some political parties, as well as increasing insecurity in many parts of the country caused by armed militias, inter-tribal violence, the proliferation of weapons, and sabotage by elements of the former regime. There is also likely to be resistance from groups such as illegal settlers who see their interests being threatened.

With its economy in meltdown because of economic mismanagement by the Bashir regime, COVID-19, and unprecedented floods, finding resources to implement the peace deal is far beyond the means of Sudan’s cash-strapped government. Implementation therefore requires sustained and generous support from its regional and international partners, including the country’s urgent removal from the US State Sponsors of Terrorism list, which is preventing debt relief, access to concessionary loans and large-scale foreign investment. With donor budgets under heavy pressure, raising money will be hard, but by continuing to support a nascent democracy in a strategically important but unstable region, Sudan’s allies will be safeguarding their long-term interests.

If properly implemented, the Juba peace agreement is a major first step towards creating a ‘New Sudan’ based on peace, equal citizenship and social justice. Key tests of whether Sudan can finally turn the page are whether the signatory movements and other revolutionary forces can unite to deliver the dividends of peace for the victims of Sudan’s conflicts, and embrace inclusion rather than tribalism and narrow political affiliation; whether the remaining armed movements are ready to start serious negotiations for a comprehensive peace; and whether Sudan now receives the support and attention it deserves from the international community. Surely Sudan has already come too far for this historic opportunity to be lost.




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Novichok Poisons Germany's Relations with Russia

14 September 2020

John Lough

Associate Fellow, Russia and Eurasia Programme
The conclusion of a specialist German military laboratory that Alexey Navalny was poisoned with the nerve agent novichok has shocked Germany’s political class and is forcing the government to re-assess relations with Russia.

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A worker at the construction site of a section of the Nord Stream 2 natural gas pipeline near Kingisepp, Leningrad Region. Photo by Alexander DemianchukTASS via Getty Images.

When Chancellor Angela Merkel offered to provide medical care for Navalny in Germany after he fell ill from suspected poisoning in Russia, she could have hardly expected her humanitarian gesture would trigger a crisis in her country’s relations with Russia.

Merkel has used uncharacteristically blunt words to condemn the apparent attempt on Navalny’s life, saying the use of novichok raises serious questions that only the Russian government could answer. She described Navalny as being the ‘victim of a crime’ which was a violation of the ‘basic values and basic rights’ that Germany and its allies were committed to. Her tone and body language certainly showed how strongly she felt about the issue.

Germany’s Social Democrat foreign minister Heiko Maas then followed up by suggesting Russia’s response might force Germany to change its position on the construction of the Nord Stream 2 pipeline which aims to double Germany’s direct gas imports from Russia under the Baltic Sea.

This is a dramatic change of position since his party has been a staunch supporter of the controversial project. Two Christian Democrat candidates for the Chancellorship called for a stop to the pipeline together with representatives from the Greens, who could be part of a government coalition after the 2021 federal election.

Claims of hostile provocation

The Russian foreign ministry shot back with a statement condemning Berlin’s ‘unsubstantiated accusations and ultimatums’ and claiming Germany was using Navalny’s hospitalisation to discredit Russia internationally. It demanded Germany share data and test results with the Russian Prosecutor’s Office, saying any failure to comply would be ‘a crude hostile provocation against Russia’ that risked consequences for the bilateral relationship as well as ‘serious complications in the international situation’.

Such strong language from Moscow towards Germany has not been seen for over 30 years, and is all the more remarkable as Putin has personally invested heavily in the relationship with Germany in view of its economic and political importance, and its strong desire for constructive ties with Russia. Until 2014, Russian analysts viewed Germany as Russia’s ‘lobbyist’ in Europe.

Berlin is now trying to downplay the situation, claiming the Navalny poisoning is not actually a Germany-Russia matter and referring it to the Organisation for the Prohibition of Chemical Weapons. By consulting with its EU and NATO allies, Berlin is further internationalising the issue to reduce impact on the bilateral relationship.

Such a forceful reaction to the poisoning reflects Germany’s increasing frustration with the Kremlin. The murder in broad daylight in Berlin in August 2019 of a Chechen wanted by the Russian authorities has been traced to the FSB. And the publication of a report in May 2020 into the hacking of the German parliament in 2015, including Merkel’s parliamentary office, was a further reminder of how far Russia had deviated from the course of partnership that Berlin believed the two countries had established in the 1990s.

Merkel described the cyberattack as ‘monstrous’, saying it was part of a strategy of hybrid warfare that includes ‘disorientation’ and ‘manipulation of facts’. Further tension has been added since the recent Belarus election as Moscow is supporting Lukashenka’s presidency whereas the EU does not recognise him as the legitimate president.

This accumulation of events is forcing German policymakers to recognise the Russian leadership is a menace to its own citizens, its neighbours and to Germany itself. Although Berlin abandoned several of its illusions about partnership with Russia in 2014 when it led the EU response to Russia’s annexation of Ukraine and destabilization of south-eastern Ukraine, it still hoped that the Kremlin would see reason and adjust its policies.

It combined sectoral economic sanctions with continuing dialogue and a joint effort to help settle the conflict in Donbas despite the obvious fact that Russia was a party to the conflict. It still believed that Moscow had an interest in finding a compromise. Instead, experience so far suggests Russia has a greater interest in keeping the conflict ‘semi-frozen’ as a way of forcing Ukraine to compromise.

Controversially, Germany also saw the need to expand energy relations with Russia in a bid to stabilise ties and draw Russia closer to Europe. The Nord Stream 2 pipeline initiated in September 2015 by Gazprom and five European companies – two of them German – is a monument to this policy.

Even though this project lacked an overall economic rationale, the German government supported it – much to the consternation of the Baltic States, Poland and others who objected to what they saw as Berlin’s insistence on a ‘Russia-first’ policy that undercut the interests of Ukraine. This was because the pipeline’s purpose is to re-route gas flows away from Ukraine, depriving it of transit revenues and a lever of influence in its relations with Moscow.

It now appears the German government is finally waking up to the fact that its attempts to encourage better Russian behaviour have failed. Policy looks set to become tougher and a moratorium on Nord Stream 2 now appears a real possibility if Russia fails to investigate the Navalny poisoning and provide adequate answers.

However, sanctioning the new pipeline is likely to provoke counter-measures against German business interests in Russia. If Berlin is determined to pursue this tougher line, it could end up facing an uncomfortable dilemma and being forced to consider alternative ways to signal displeasure at Russia’s criminal actions.




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First US Presidential Debate – Five Key Questions Answered

30 September 2020

Anar Bata

Coordinator, US and the Americas Programme

Dr Leslie Vinjamuri

Director, US and the Americas Programme; Dean, Queen Elizabeth II Academy for Leadership in International Affairs

Megan Greene

Dame DeAnne Julius Senior Academy Fellow in International Economics

Dr Christopher Sabatini

Senior Research Fellow for Latin America, US and the Americas Programme
On 29 September, US president Donald Trump went head-to-head with Joe Biden in the first presidential debate of the 2020 US election. Anar Bata spoke with experts across Chatham House to get their views on the key debate moments and the implications for the US election.

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People watch the first presidential debate between US President Donald Trump and Former US Vice President Joe Biden on 29 September 2020 in Hoboken, New Jersey. Photo: Getty Images.

What role do the presidential debates serve in encouraging voter turnout?

Leslie Vinjamuri: Going into the debates, 74% of Americans were set to tune in and watch according to a new Monmouth Poll. This is striking since more than 90% have already decided who their candidate will be, and many have already cast their ballots. 

During President Donald Trump’s time in office, Americans have been far more politically engaged than in previous periods. A record 49.3% of the voting eligible population turned out to vote in the 2018 midterm elections, according to the United States Election Project. This was the highest voter turnout since 1914, and it also reversed a downward trend. 

Debates don’t change voters’ minds and last night’s debate, the first between Donald Trump and Joe Biden is unlikely to be an exception. But debates can shape public sentiment and enthusiasm, not least for voting.

Polling confirms that Trump trails Biden by an average of around 7% nationally, but also that his base is highly enthusiastic. The same is not true for Biden: the older voters that support him are far more enthusiastic than younger voters that do the same.

How credible are Trump's claims that the US economy is experiencing a V-shaped recovery and Biden's claims that there is a K-shaped recovery? 

Megan Greene: Off the back of an unprecedented lockdown in the US and a resultant short and sharp contraction of the economy, the immediate recovery was swift and V-shaped. This is partly a reflection of significant support to Americans in the form of unemployment benefit enhancements and to businesses in the form of Paycheck Protection Program (PPP) loans. But as the economy reopened, growth was always going to rebound and a short-term V-shaped recovery was always going to materialize.  

Don’t be fooled by Donald Trump’s assertion that a V-shaped recovery will persist though. Most of the support for workers and small businesses expired in late July or early August and people and firms have stayed afloat by dipping into their savings. In the absence of another fiscal stimulus package—very unlikely before the end of the year—this is completely unsustainable.  

The K-shaped recovery that Joe Biden has suggested is far more likely going forward. The lockdown revealed extraordinary inequality in the US economy. The death toll of the virus on black and Asian Americans was higher than on white Americans. Huge disparities were laid bare in the labour market as well.

It was precisely those hourly service workers who saw few wage gains since the last recession who were first to lose their jobs in this crisis. The service workers who kept their jobs were real heroes—delivering our food, teaching our kids over Zoom, removing our trash—and yet have not been remunerated accordingly. Unemployment for high-income workers is nearly back to January 2020 levels, but is still down by over 15% for low-income workers.  

This trend will only get worse as small businesses go under and large, superstar companies step in to fill the void. This increase in market concentration reduces the number of potential employers from which workers can choose and reduces workers’ wage negotiating power.  

Rising inequality in the US is by no means a new trend, but as with many things it has been accelerated by the coronavirus crisis. Inequality will continue to drag on the economy if it is left unaddressed.

Did either candidate refer to America’s role in the world?

Leslie Vinjamuri: This debate could only have hurt America’s global image. This comes in the midst of a pandemic, when the gravest problems are at home, and when America’s global leadership depends on getting its house in order. Rather than restoring confidence, Donald Trump used the debates to undermine confidence in the elections and to stoke fear of violence in America’s cities.

By design, most of the debate was focused on domestic issues. But the candidates did discuss climate science, the one issue touched on that matters most beyond America’s borders. The difference between Trump's and Biden’s plans was stark and the debates made clear that America’s global leadership on climate change hinges on these elections.

Biden articulated a clear plan to reduce carbon emissions, create green jobs and invest in green infrastructure. When it comes to global leadership, this would bring the United States back into a debate that China has been leading. Last week, President Xi Jinping committed China to achieving carbon neutrality by 2060; Biden has committed the US to achieving this goal by 2050.

But Trump repeatedly deflected the moderator’s question about whether he accepted climate science. And when asked about the link between climate change and forest fires, he launched a series of attacks on forest managers.

In addition to Trump's comments on China and COVID-19, the only reference made to foreign policy was Biden's comments that he would be tougher on Russia. Did this debate reaffirm the notion that the majority of Americans prefer less engagement with the world? 

Chris Sabatini: According to the themes set by the moderator Chris Wallace and the debate committee, foreign policy was not scheduled to be among the topics covered in the 29 September debates. That will come up later. When it did appear in the first debates it was around largely domestic topics: COVID-19, allegations of corruption, concerns about trade and manufacturing and suspicions of Russian influence shaping the US elections and US foreign policy. 

That foreign policy surfaced in this debate and around those specific, partisan issues demonstrates not a lack of interest by US voters in the world but the ways in which extra-national influence is seen by some (and played by the candidates) as damaging US politics, society and the economy. The problem is that such fears don't make for coherent or constructive foreign policies, but rather reinforce a perception of the US as a victim. Let's hope the issue of foreign policy comes up and is discussed more thoughtfully and positively in future debates when it is on the docket.

How will this debate impact the rest of the race?

Leslie Vinjamuri: For voters at home, the most disturbing part of tonight’s debates should be Donald Trump’s repeated attacks on the integrity of the electoral process.  This comes on the heels of the president’s failure last week to confirm that he would respect the outcome of the elections.

Trump used the debates as a platform to launch a series of attacks on mail-in ballots, casting them as fraudulent and saying that people should just turn up and vote. The recent debates confirmed that when it comes to the pandemic, the economy, and especially the environment, the alternatives are stark and there is a lot at stake. Whether this drives voters to the polls, or to switch off the television remains to be seen.




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Inhibition of mitochondrial oxidative metabolism attenuates EMCV replication and protects {beta}-cells from virally mediated lysis [Immunology]

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




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The glucose-sensing transcription factor ChREBP is targeted by proline hydroxylation [Metabolism]

Cellular energy demands are met by uptake and metabolism of nutrients like glucose. The principal transcriptional regulator for adapting glycolytic flux and downstream pathways like de novo lipogenesis to glucose availability in many cell types is carbohydrate response element–binding protein (ChREBP). ChREBP is activated by glucose metabolites and post-translational modifications, inducing nuclear accumulation and regulation of target genes. Here we report that ChREBP is modified by proline hydroxylation at several residues. Proline hydroxylation targets both ectopically expressed ChREBP in cells and endogenous ChREBP in mouse liver. Functionally, we found that specific hydroxylated prolines were dispensable for protein stability but required for the adequate activation of ChREBP upon exposure to high glucose. Accordingly, ChREBP target gene expression was rescued by re-expressing WT but not ChREBP that lacks hydroxylated prolines in ChREBP-deleted hepatocytes. Thus, proline hydroxylation of ChREBP is a novel post-translational modification that may allow for therapeutic interference in metabolic diseases.




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Post-translational control of the long and winding road to cholesterol [Lipids]

The synthesis of cholesterol requires more than 20 enzymes, many of which are intricately regulated. Post-translational control of these enzymes provides a rapid means for modifying flux through the pathway. So far, several enzymes have been shown to be rapidly degraded through the ubiquitin–proteasome pathway in response to cholesterol and other sterol intermediates. Additionally, several enzymes have their activity altered through phosphorylation mechanisms. Most work has focused on the two rate-limiting enzymes: 3-hydroxy-3-methylglutaryl CoA reductase and squalene monooxygenase. Here, we review current literature in the area to define some common themes in the regulation of the entire cholesterol synthesis pathway. We highlight the rich variety of inputs controlling each enzyme, discuss the interplay that exists between regulatory mechanisms, and summarize findings that reveal an intricately coordinated network of regulation along the cholesterol synthesis pathway. We provide a roadmap for future research into the post-translational control of cholesterol synthesis, and no doubt the road ahead will reveal further twists and turns for this fascinating pathway crucial for human health and disease.




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The role of uncoupling protein 2 in macrophages and its impact on obesity-induced adipose tissue inflammation and insulin resistance [Immunology]

The development of a chronic, low-grade inflammation originating from adipose tissue in obese subjects is widely recognized to induce insulin resistance, leading to the development of type 2 diabetes. The adipose tissue microenvironment drives specific metabolic reprogramming of adipose tissue macrophages, contributing to the induction of tissue inflammation. Uncoupling protein 2 (UCP2), a mitochondrial anion carrier, is thought to separately modulate inflammatory and metabolic processes in macrophages and is up-regulated in macrophages in the context of obesity and diabetes. Here, we investigate the role of UCP2 in macrophage activation in the context of obesity-induced adipose tissue inflammation and insulin resistance. Using a myeloid-specific knockout of UCP2 (Ucp2ΔLysM), we found that UCP2 deficiency significantly increases glycolysis and oxidative respiration, both unstimulated and after inflammatory conditions. Strikingly, fatty acid loading abolished the metabolic differences between Ucp2ΔLysM macrophages and their floxed controls. Furthermore, Ucp2ΔLysM macrophages show attenuated pro-inflammatory responses toward Toll-like receptor-2 and -4 stimulation. To test the relevance of macrophage-specific Ucp2 deletion in vivo, Ucp2ΔLysM and Ucp2fl/fl mice were rendered obese and insulin resistant through high-fat feeding. Although no differences in adipose tissue inflammation or insulin resistance was found between the two genotypes, adipose tissue macrophages isolated from diet-induced obese Ucp2ΔLysM mice showed decreased TNFα secretion after ex vivo lipopolysaccharide stimulation compared with their Ucp2fl/fl littermates. Together, these results demonstrate that although UCP2 regulates both metabolism and the inflammatory response of macrophages, its activity is not crucial in shaping macrophage activation in the adipose tissue during obesity-induced insulin resistance.




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Methylarginine metabolites are associated with attenuated muscle protein synthesis in cancer-associated muscle wasting [Protein Synthesis and Degradation]

Cancer cachexia is characterized by reductions in peripheral lean muscle mass. Prior studies have primarily focused on increased protein breakdown as the driver of cancer-associated muscle wasting. Therapeutic interventions targeting catabolic pathways have, however, largely failed to preserve muscle mass in cachexia, suggesting that other mechanisms might be involved. In pursuit of novel pathways, we used untargeted metabolomics to search for metabolite signatures that may be linked with muscle atrophy. We injected 7-week–old C57/BL6 mice with LLC1 tumor cells or vehicle. After 21 days, tumor-bearing mice exhibited reduced body and muscle mass and impaired grip strength compared with controls, which was accompanied by lower synthesis rates of mixed muscle protein and the myofibrillar and sarcoplasmic muscle fractions. Reductions in protein synthesis were accompanied by mitochondrial enlargement and reduced coupling efficiency in tumor-bearing mice. To generate mechanistic insights into impaired protein synthesis, we performed untargeted metabolomic analyses of plasma and muscle and found increased concentrations of two methylarginines, asymmetric dimethylarginine (ADMA) and NG-monomethyl-l-arginine, in tumor-bearing mice compared with control mice. Compared with healthy controls, human cancer patients were also found to have higher levels of ADMA in the skeletal muscle. Treatment of C2C12 myotubes with ADMA impaired protein synthesis and reduced mitochondrial protein quality. These results suggest that increased levels of ADMA and mitochondrial changes may contribute to impaired muscle protein synthesis in cancer cachexia and could point to novel therapeutic targets by which to mitigate cancer cachexia.




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Ascertaining the biochemical function of an essential pectin methylesterase in the gut microbe Bacteroides thetaiotaomicron [Metabolism]

Pectins are a major dietary nutrient source for the human gut microbiota. The prominent gut microbe Bacteroides thetaiotaomicron was recently shown to encode the founding member (BT1017) of a new family of pectin methylesterases essential for the metabolism of the complex pectin rhamnogalacturonan-II (RG-II). However, biochemical and structural knowledge of this family is lacking. Here, we showed that BT1017 is critical for the metabolism of an RG-II–derived oligosaccharide ΔBT1017oligoB generated by a BT1017 deletion mutant (ΔBT1017) during growth on carbohydrate extract from apple juice. Structural analyses of ΔBT1017oligoB using a combination of enzymatic, mass spectrometric, and NMR approaches revealed that it is a bimethylated nonaoligosaccharide (GlcA-β1,4-(2-O-Me-Xyl-α1,3)-Fuc-α1,4-(GalA-β1,3)-Rha-α1,3-Api-β1,2-(Araf-α1,3)-(GalA-α1,4)-GalA) containing components of the RG-II backbone and its side chains. We showed that the catalytic module of BT1017 adopts an α/β-hydrolase fold, consisting of a central twisted 10-stranded β-sheet sandwiched by several α-helices. This constitutes a new fold for pectin methylesterases, which are predominantly right-handed β-helical proteins. Bioinformatic analyses revealed that the family is dominated by sequences from prominent genera of the human gut microbiota, including Bacteroides and Prevotella. Our re-sults not only highlight the critical role played by this family of enzymes in pectin metabolism but also provide new insights into the molecular basis of the adaptation of B. thetaiotaomicron to the human gut.