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Police make arrest relating to bags of cash that allegedly fell from Beryllium vehicle

The police have arrested an individual in the probe surrounding two bags of cash that allegedly fell from a Beryllium security vehicle en route to the Norman Manley International Airport in Kingston last week. 




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Man leaving home to live in cemetery

With tears streaming down his face and his voice trembling, a windshield wiper made a declaration that he would rather live in the cemetery than with his relatives. "A the cemetery me ago live. Unnu wicked to me," Ramarieo Bailey declared. Bailey...




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Manchester man charged with smoking ganja in public

Twenty-eight-year-old labourer Michael Ennis, of Manning's Hill district in Manchester, has been charged with smoking ganja in a public place following an incident in May Pen, Clarendon on Monday.




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Landscaper charged for allegedly stealing oranges

The Clarendon police have arrested and charged 25-year-old landscaper Anthony Marshall, of Lamparth district, Trout Hall in the parish for allegedly stealing oranges from a property in his community on Sunday.




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SAS Notes for SAS®9 - 66492: FILENAME FTP(FTP/TLS) fails with "ERROR: The connection was reset by a peer" due to using implicit FTP/TLS

If you connect to a FTP/TLS server that is configured to use implicit FTP/TLS, FILENAME FTP/TLS might fail with the following error:


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Biochemical transformation of bacterial lipopolysaccharides by acyloxyacyl hydrolase reduces host injury and promotes recovery [Enzymology]

Animals can sense the presence of microbes in their tissues and mobilize their own defenses by recognizing and responding to conserved microbial structures (often called microbe-associated molecular patterns (MAMPs)). Successful host defenses may kill the invaders, yet the host animal may fail to restore homeostasis if the stimulatory microbial structures are not silenced. Although mice have many mechanisms for limiting their responses to lipopolysaccharide (LPS), a major Gram-negative bacterial MAMP, a highly conserved host lipase is required to extinguish LPS sensing in tissues and restore homeostasis. We review recent progress in understanding how this enzyme, acyloxyacyl hydrolase (AOAH), transforms LPS from stimulus to inhibitor, reduces tissue injury and death from infection, prevents prolonged post-infection immunosuppression, and keeps stimulatory LPS from entering the bloodstream. We also discuss how AOAH may increase sensitivity to pulmonary allergens. Better appreciation of how host enzymes modify LPS and other MAMPs may help prevent tissue injury and hasten recovery from infection.




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Development of a novel mammalian display system for selection of antibodies against membrane proteins [Immunology]

Reliable, specific polyclonal and monoclonal antibodies are important tools in research and medicine. However, the discovery of antibodies against their targets in their native forms is difficult. Here, we present a novel method for discovery of antibodies against membrane proteins in their native configuration in mammalian cells. The method involves the co-expression of an antibody library in a population of mammalian cells that express the target polypeptide within a natural membrane environment on the cell surface. Cells that secrete a single-chain fragment variable (scFv) that binds to the target membrane protein thereby become self-labeled, enabling enrichment and isolation by magnetic sorting and FRET-based flow sorting. Library sizes of up to 109 variants can be screened, thus allowing campaigns of naïve scFv libraries to be selected against membrane protein antigens in a Chinese hamster ovary cell system. We validate this method by screening a synthetic naïve human scFv library against Chinese hamster ovary cells expressing the oncogenic target epithelial cell adhesion molecule and identify a panel of three novel binders to this membrane protein, one with a dissociation constant (KD) as low as 0.8 nm. We further demonstrate that the identified antibodies have utility for killing epithelial cell adhesion molecule–positive cells when used as a targeting domain on chimeric antigen receptor T cells. Thus, we provide a new tool for identifying novel antibodies that act against membrane proteins, which could catalyze the discovery of new candidates for antibody-based therapies.




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ARID4B is critical for mouse embryonic stem cell differentiation towards mesoderm and endoderm, linking epigenetics to pluripotency exit [Developmental Biology]

Distinct cell types emerge from embryonic stem cells through a precise and coordinated execution of gene expression programs during lineage commitment. This is established by the action of lineage specific transcription factors along with chromatin complexes. Numerous studies have focused on epigenetic factors that affect embryonic stem cells (ESC) self-renewal and pluripotency. However, the contribution of chromatin to lineage decisions at the exit from pluripotency has not been as extensively studied. Using a pooled epigenetic shRNA screen strategy, we identified chromatin-related factors critical for differentiation toward mesodermal and endodermal lineages. Here we reveal a critical role for the chromatin protein, ARID4B. Arid4b-deficient mESCs are similar to WT mESCs in the expression of pluripotency factors and their self-renewal. However, ARID4B loss results in defects in up-regulation of the meso/endodermal gene expression program. It was previously shown that Arid4b resides in a complex with SIN3A and HDACS 1 and 2. We identified a physical and functional interaction of ARID4B with HDAC1 rather than HDAC2, suggesting functionally distinct Sin3a subcomplexes might regulate cell fate decisions Finally, we observed that ARID4B deficiency leads to increased H3K27me3 and a reduced H3K27Ac level in key developmental gene loci, whereas a subset of genomic regions gain H3K27Ac marks. Our results demonstrate that epigenetic control through ARID4B plays a key role in the execution of lineage-specific gene expression programs at pluripotency exit.




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Importance of endothelial Hey1 expression for thoracic great vessel development and its distal enhancer for Notch-dependent endothelial transcription [Gene Regulation]

Thoracic great vessels such as the aorta and subclavian arteries are formed through dynamic remodeling of embryonic pharyngeal arch arteries (PAAs). Previous work has shown that loss of a basic helix-loop-helix transcription factor Hey1 in mice causes abnormal fourth PAA development and lethal great vessel anomalies resembling congenital malformations in humans. However, how Hey1 mediates vascular formation remains unclear. In this study, we revealed that Hey1 in vascular endothelial cells, but not in smooth muscle cells, played essential roles for PAA development and great vessel morphogenesis in mouse embryos. Tek-Cre–mediated Hey1 deletion in endothelial cells affected endothelial tube formation and smooth muscle differentiation in embryonic fourth PAAs and resulted in interruption of the aortic arch and other great vessel malformations. Cell specificity and signal responsiveness of Hey1 expression were controlled through multiple cis-regulatory regions. We found two distal genomic regions that had enhancer activity in endothelial cells and in the pharyngeal epithelium and somites, respectively. The novel endothelial enhancer was conserved across species and was specific to large-caliber arteries. Its transcriptional activity was regulated by Notch signaling in vitro and in vivo, but not by ALK1 signaling and other transcription factors implicated in endothelial cell specificity. The distal endothelial enhancer was not essential for basal Hey1 expression in mouse embryos but may likely serve for Notch-dependent transcriptional control in endothelial cells together with the proximal regulatory region. These findings help in understanding the significance and regulation of endothelial Hey1 as a mediator of multiple signaling pathways in embryonic vascular formation.




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N-acetylglucosamine drives myelination by triggering oligodendrocyte precursor cell differentiation [Molecular Bases of Disease]

Myelination plays an important role in cognitive development and in demyelinating diseases like multiple sclerosis (MS), where failure of remyelination promotes permanent neuro-axonal damage. Modification of cell surface receptors with branched N-glycans coordinates cell growth and differentiation by controlling glycoprotein clustering, signaling, and endocytosis. GlcNAc is a rate-limiting metabolite for N-glycan branching. Here we report that GlcNAc and N-glycan branching trigger oligodendrogenesis from precursor cells by inhibiting platelet-derived growth factor receptor-α cell endocytosis. Supplying oral GlcNAc to lactating mice drives primary myelination in newborn pups via secretion in breast milk, whereas genetically blocking N-glycan branching markedly inhibits primary myelination. In adult mice with toxin (cuprizone)-induced demyelination, oral GlcNAc prevents neuro-axonal damage by driving myelin repair. In MS patients, endogenous serum GlcNAc levels inversely correlated with imaging measures of demyelination and microstructural damage. Our data identify N-glycan branching and GlcNAc as critical regulators of primary myelination and myelin repair and suggest that oral GlcNAc may be neuroprotective in demyelinating diseases like MS.




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Ischemic stroke disrupts the endothelial glycocalyx through activation of proHPSE via acrolein exposure [Molecular Bases of Disease]

Infiltration of peripheral immune cells after blood-brain barrier dysfunction causes severe inflammation after a stroke. Although the endothelial glycocalyx, a network of membrane-bound glycoproteins and proteoglycans that covers the lumen of endothelial cells, functions as a barrier to circulating cells, the relationship between stroke severity and glycocalyx dysfunction remains unclear. In this study, glycosaminoglycans, a component of the endothelial glycocalyx, were studied in the context of ischemic stroke using a photochemically induced thrombosis mouse model. Decreased levels of heparan sulfate and chondroitin sulfate and increased activity of hyaluronidase 1 and heparanase (HPSE) were observed in ischemic brain tissues. HPSE expression in cerebral vessels increased after stroke onset and infarct volume greatly decreased after co-administration of N-acetylcysteine + glycosaminoglycan oligosaccharides as compared with N-acetylcysteine administration alone. These results suggest that the endothelial glycocalyx was injured after the onset of stroke. Interestingly, scission activity of proHPSE produced by immortalized endothelial cells and HEK293 cells transfected with hHPSE1 cDNA were activated by acrolein (ACR) exposure. We identified the ACR-modified amino acid residues of proHPSE using nano LC–MS/MS, suggesting that ACR modification of Lys139 (6-kDa linker), Lys107, and Lys161, located in the immediate vicinity of the 6-kDa linker, at least in part is attributed to the activation of proHPSE. Because proHPSE, but not HPSE, localizes outside cells by binding with heparan sulfate proteoglycans, ACR-modified proHPSE represents a promising target to protect the endothelial glycocalyx.




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The structure of a family 110 glycoside hydrolase provides insight into the hydrolysis of {alpha}-1,3-galactosidic linkages in {lambda}-carrageenan and blood group antigens [Enzymology]

α-Linked galactose is a common carbohydrate motif in nature that is processed by a variety of glycoside hydrolases from different families. Terminal Galα1–3Gal motifs are found as a defining feature of different blood group and tissue antigens, as well as the building block of the marine algal galactan λ-carrageenan. The blood group B antigen and linear α-Gal epitope can be processed by glycoside hydrolases in family GH110, whereas the presence of genes encoding GH110 enzymes in polysaccharide utilization loci from marine bacteria suggests a role in processing λ-carrageenan. However, the structure–function relationships underpinning the α-1,3-galactosidase activity within family GH110 remain unknown. Here we focus on a GH110 enzyme (PdGH110B) from the carrageenolytic marine bacterium Pseudoalteromonas distincta U2A. We showed that the enzyme was active on Galα1–3Gal but not the blood group B antigen. X-ray crystal structures in complex with galactose and unhydrolyzed Galα1–3Gal revealed the parallel β-helix fold of the enzyme and the structural basis of its inverting catalytic mechanism. Moreover, an examination of the active site reveals likely adaptations that allow accommodation of fucose in blood group B active GH110 enzymes or, in the case of PdGH110, accommodation of the sulfate groups found on λ-carrageenan. Overall, this work provides insight into the first member of a predominantly marine clade of GH110 enzymes while also illuminating the structural basis of α-1,3-galactoside processing by the family as a whole.




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Slices template

Slices template

Lorem ipsum dolor sit amet, consectetur adipiscing elit, sed do eiusmod tempor incididunt ut labore et dolore magna aliqua.

nfaulds-adams… 11 September 2020

Lorem ipsum dolor sit amet, consectetur adipiscing elit, sed do eiusmod tempor incididunt ut labore et dolore magna aliqua. Ut enim ad minim veniam, quis nostrud exercitation ullamco laboris nisi ut aliquip ex ea commodo consequat. Duis aute irure dolor in reprehenderit in voluptate velit esse cillum dolore eu fugiat nulla pariatur. Excepteur sint occaecat cupidatat non proident, sunt in culpa qui officia deserunt mollit anim id est laborum.




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Calreticulin enhances the secretory trafficking of a misfolded {alpha}-1-antitrypsin [Protein Structure and Folding]

α1-antitrypsin (AAT) regulates the activity of multiple proteases in the lungs and liver. A mutant of AAT (E342K) called ATZ forms polymers that are present at only low levels in the serum and induce intracellular protein inclusions, causing lung emphysema and liver cirrhosis. An understanding of factors that can reduce the intracellular accumulation of ATZ is of great interest. We now show that calreticulin (CRT), an endoplasmic reticulum (ER) glycoprotein chaperone, promotes the secretory trafficking of ATZ, enhancing the media:cell ratio. This effect is more pronounced for ATZ than with AAT and is only partially dependent on the glycan-binding site of CRT, which is generally relevant to substrate recruitment and folding by CRT. The CRT-related chaperone calnexin does not enhance ATZ secretory trafficking, despite the higher cellular abundance of calnexin-ATZ complexes. CRT deficiency alters the distributions of ATZ-ER chaperone complexes, increasing ATZ-BiP binding and inclusion body formation and reducing ATZ interactions with components required for ER-Golgi trafficking, coincident with reduced levels of the protein transport protein Sec31A in CRT-deficient cells. These findings indicate a novel role for CRT in promoting the secretory trafficking of a protein that forms polymers and large intracellular inclusions. Inefficient secretory trafficking of ATZ in the absence of CRT is coincident with enhanced accumulation of ER-derived ATZ inclusion bodies. Further understanding of the factors that control the secretory trafficking of ATZ and their regulation by CRT could lead to new therapies for lung and liver diseases linked to AAT deficiency.




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{alpha}2-Macroglobulin-like protein 1 can conȷugate and inhibit proteases through their hydroxyl groups, because of an enhanced reactivity of its thiol ester [Protein Structure and Folding]

Proteins in the α-macroglobulin (αM) superfamily use thiol esters to form covalent conjugation products upon their proteolytic activation. αM protease inhibitors use theirs to conjugate proteases and preferentially react with primary amines (e.g. on lysine side chains), whereas those of αM complement components C3 and C4B have an increased hydroxyl reactivity that is conveyed by a conserved histidine residue and allows conjugation to cell surface glycans. Human α2-macroglobulin–like protein 1 (A2ML1) is a monomeric protease inhibitor but has the hydroxyl reactivity–conveying histidine residue. Here, we have investigated the role of hydroxyl reactivity in a protease inhibitor by comparing recombinant WT A2ML1 and the A2ML1 H1084N mutant in which this histidine is removed. Both of A2ML1s' thiol esters were reactive toward the amine substrate glycine, but only WT A2ML1 reacted with the hydroxyl substrate glycerol, demonstrating that His-1084 increases the hydroxyl reactivity of A2ML1's thiol ester. Although both A2ML1s conjugated and inhibited thermolysin, His-1084 was required for the conjugation and inhibition of acetylated thermolysin, which lacks primary amines. Using MS, we identified an ester bond formed between a thermolysin serine residue and the A2ML1 thiol ester. These results demonstrate that a histidine-enhanced hydroxyl reactivity can contribute to protease inhibition by an αM protein. His-1084 did not improve A2ML1's protease inhibition at pH 5, indicating that A2ML1's hydroxyl reactivity is not an adaption to its acidic epidermal environment.




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The cation diffusion facilitator protein MamM's cytoplasmic domain exhibits metal-type dependent binding modes and discriminates against Mn2+ [Molecular Biophysics]

Cation diffusion facilitator (CDF) proteins are a conserved family of divalent transition metal cation transporters. CDF proteins are usually composed of two domains: the transmembrane domain, in which the metal cations are transported through, and a regulatory cytoplasmic C-terminal domain (CTD). Each CDF protein transports either one specific metal or multiple metals from the cytoplasm, and it is not known whether the CTD takes an active regulatory role in metal recognition and discrimination during cation transport. Here, the model CDF protein MamM, an iron transporter from magnetotactic bacteria, was used to probe the role of the CTD in metal recognition and selectivity. Using a combination of biophysical and structural approaches, the binding of different metals to MamM CTD was characterized. Results reveal that different metals bind distinctively to MamM CTD in terms of their binding sites, thermodynamics, and binding-dependent conformations, both in crystal form and in solution, which suggests a varying level of functional discrimination between CDF domains. Furthermore, these results provide the first direct evidence that CDF CTDs play a role in metal selectivity. We demonstrate that MamM's CTD can discriminate against Mn2+, supporting its postulated role in preventing magnetite formation poisoning in magnetotactic bacteria via Mn2+ incorporation.




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Representative cancer-associated U2AF2 mutations alter RNA interactions and splicing [Molecular Bases of Disease]

High-throughput sequencing of hematologic malignancies and other cancers has revealed recurrent mis-sense mutations of genes encoding pre-mRNA splicing factors. The essential splicing factor U2AF2 recognizes a polypyrimidine-tract splice-site signal and initiates spliceosome assembly. Here, we investigate representative, acquired U2AF2 mutations, namely N196K or G301D amino acid substitutions associated with leukemia or solid tumors, respectively. We determined crystal structures of the wild-type (WT) compared with N196K- or G301D-substituted U2AF2 proteins, each bound to a prototypical AdML polypyrimidine tract, at 1.5, 1.4, or 1.7 Å resolutions. The N196K residue appears to stabilize the open conformation of U2AF2 with an inter-RNA recognition motif hydrogen bond, in agreement with an increased apparent RNA-binding affinity of the N196K-substituted protein. The G301D residue remains in a similar position as the WT residue, where unfavorable proximity to the RNA phosphodiester could explain the decreased RNA-binding affinity of the G301D-substituted protein. We found that expression of the G301D-substituted U2AF2 protein reduces splicing of a minigene transcript carrying prototypical splice sites. We further show that expression of either N196K- or G301D-substituted U2AF2 can subtly alter splicing of representative endogenous transcripts, despite the presence of endogenous, WT U2AF2 such as would be present in cancer cells. Altogether, our results demonstrate that acquired U2AF2 mutations such as N196K and G301D are capable of dysregulating gene expression for neoplastic transformation.




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The heptameric structure of the flagellar regulatory protein FlrC is indispensable for ATPase activity and disassembled by cyclic-di-GMP [Protein Structure and Folding]

The bacterial enhancer-binding protein (bEBP) FlrC, controls motility and colonization of Vibrio cholerae by regulating the transcription of class-III flagellar genes in σ54-dependent manner. However, the mechanism by which FlrC regulates transcription is not fully elucidated. Although, most bEBPs require nucleotides to stimulate the oligomerization necessary for function, our previous study showed that the central domain of FlrC (FlrCC) forms heptamer in a nucleotide-independent manner. Furthermore, heptameric FlrCC binds ATP in “cis-mediated” style without any contribution from sensor I motif 285REDXXYR291 of the trans protomer. This atypical ATP binding raises the question of whether heptamerization of FlrC is solely required for transcription regulation, or if it is also critical for ATPase activity. ATPase assays and size exclusion chromatography of the trans-variants FlrCC-Y290A and FlrCC-R291A showed destabilization of heptameric assembly with concomitant abrogation of ATPase activity. Crystal structures showed that in the cis-variant FlrCC-R349A drastic shift of Walker A encroached ATP-binding site, whereas the site remained occupied by ADP in FlrCC-Y290A. We postulated that FlrCC heptamerizes through concentration-dependent cooperativity for maximal ATPase activity and upon heptamerization, packing of trans-acting Tyr290 against cis-acting Arg349 compels Arg349 to maintain proper conformation of Walker A. Finally, a Trp quenching study revealed binding of cyclic-di-GMP with FlrCC. Excess cyclic-di-GMP repressed ATPase activity of FlrCC through destabilization of heptameric assembly, especially at low concentration of protein. Systematic phylogenetic analysis allowed us to propose similar regulatory mechanisms for FlrCs of several Vibrio species and a set of monotrichous Gram-negative bacteria.




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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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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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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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Tackling Malnutrition: Harnessing the Power of Business

8 July 2020

Simon Pringle

Associate Fellow, Energy, Environment and Resources Programme
Malnutrition negatively impacts individuals, families, societies and economies around the world. Now is the time to align corporate, government and third sector efforts to relegate it to the past.

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A view of a market area in Goma, Democratic Republic of Congo on 10 October 2019. Congo is among the countries with the highest number of acutely malnourished people on a global level. Photo by JC Wenga/Anadolu Agency via Getty Images.

Many people are aware that the scourge of malnutrition affects a vast number of individuals and communities around the world. However, most tend to view it as a problem to be addressed by governments, charities or donors, rather than the corporate sector.

Certainly, when considered at a societal scale, malnutrition makes the complexities of delivering inclusive growth all the harder. It ratchets up the public health burden while restricting the potential for at-risk populations to take part in productive employment.  Economies are hindered, lives are blighted and the potential for people to reach their full potential can be severely limited.

A number of upcoming summits represent a window of opportunity to address nutrition in the context of resilience, particularly in the wake of COVID-19 and the much-referenced ambition for governments to ‘build back better’. The opportunity is there to foster a true partnership between governments, third sector organizations and businesses of all sizes, sectors and geographies to work for the betterment of society and deliver benefits to all participants in such a partnership. 

So what is the role of business in relation to nutrition - where does it sit on their list of priorities and why should it matter to them? A new Chatham House report represents an important contribution to the discussion about the role of business in addressing malnutrition. Through thorough research and direct engagement with businesses, it seeks to find out if malnutrition is on the corporate radar and the extent to which it is considered a material issue.

Surprisingly, whilst many large corporates recognize malnutrition as a matter for concern, this is typically defined only in the context of CSR programmes or related ambitions. These types of commitments have their limitations though; most notably the fact that the communities more severely affected by malnutrition typically sit outside of the sphere of influence of the multi-national companies with the greatest ability to mobilize resources and make an impact. Where populations are marginalized, operating within the informal economy and living in settings that are too fragile for large-scale business investment, corporate CSR programmes are unlikely to have a meaningful impact.

Report Launch: The Business Case for Investment in Nutrition

As COVID-19 pushes UN targets to end global hunger and malnutrition even further off-course, now is the time for businesses to step up and improve nutrition in their workforce and beyond.

The report also asked businesses whether they considered malnutrition to have a material impact on their ability to create value, protect value and manage risk. In the majority of instances the answer was no. This may be surprising, particularly given the evidence provided by new modelling – done for this report using a purpose-built model by Vivid Economics – that illustrates the costs posed to business by malnutrition within a population. On an immediate and direct level, the impacts can be considerable due to lost or reduced productivity from the employee base. However, if even that immediate impact is addressed, the externalities associated with malnutrition can come back and have a negative effect on businesses and investors alike.

When reflecting on externalities and the landscape of risk within which business operates, it is worth considering climate change by way of comparison. Climate change is well embedded in the risk profiling of most progressive and well-managed corporates – although in some instances meaningful action may be well overdue. That said, it is recognized that the direct and indirect impacts have the potential to conspire and permanently reduce shareholder, stakeholder and societal value. 

Similarly, if left unchecked, the externalities associated with malnutrition will undoubtedly contribute to an increased level of risk in terms of both operating and investment environments. This is both an issue of social equity and enlightened self-interest given that good nutrition is key to the success of many of the Sustainable Development Goals (SDGs), and is essential to driving sustainable economic growth. One of the lessons of the COVID-19 pandemic is the manner in which widespread malnutrition can significantly reduce the resilience of populations to external risks, including the outbreaks of infectious disease. We need only to look at the impact of climate stress and related events to understand how closely linked malnutrition is – or may become – to the incidence of social unrest and armed conflict in low-income countries.

Progressive companies and investors have already identified the ability to drive inclusive and sustainable growth as a compelling imperative for investment. In this context, the potential for improved nutrition – both in the workforce and amongst the communities upon which the firms depend – should be a true priority. As fund managers seek increasingly meaningful insight into the way that companies within their portfolio(s) create value, protect value and manage risk, the scope of environmental and social governance is expanding. Many recognize the link between delivering on the SDG agenda and protecting or enhancing shareholder value into the longer term. This is a powerful lever for change, particularly when considering that good nutrition is integral to the success of the ambitions laid out by the various SDGs. Successfully delivering against nutrition-focused targets could unlock growth in developing markets and create an enabling environment for achieving the broader SDG agenda. This may in turn help companies to deliver enduring shareholder value in a way that does not undermine their corporate sustainability commitments.

So, given the insights provided by this report, what can businesses do that have the potential to make a practical and effective impact? There are three main action points around which the private sector can galvanize its efforts and work in partnership to deliver a meaningful impact. 

The first action point is a basic requirement to be proactive and make supportive interventions with existing and future workforces, ensuring that staff are well fed and have appropriate facilities for breastfeeding and childcare. Beyond that foundational commitment, the second action point is to work to build impactful and well-governed partnerships to work within local communities and deliver outcomes at an appropriate scale. The third and final action point sets out the importance of reporting. Businesses should thoroughly assess the impacts of their operations, investments and influence. They should be transparent about those impacts and report both on the current situation and the commitments made to deliver on measurable targets.

Malnutrition is a scourge; it negatively impacts individuals, families, societies and economies. Now is the time to align corporate, government and third sector efforts to consign it to the past. We just need leaders to be bold enough to seize the opportunity.




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Flaring in MENA: The Multibillion Dollar Decarbonization Lever

15 July 2020

Adel Hamaizia

Associate Fellow, Middle East and North Africa Programme

Dr Mark Davis

CEO, Capterio
The climate crisis and ‘energy transition’ is driving a response from the oil and gas industry to decarbonize, with flaring – the deliberate combustion of gas associated with oil production – as a critical lever, especially in the Middle East and North Africa, write Adel Hamaizia and Mark Davis.

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Iraqi Southern Oil Company engineers look towards the flares in the Zubair oil field in southern Iraq. Photo by ESSAM -AL-SUDANI/AFP via Getty Images.

Flaring is a significant source of economic and environmental waste. Except when safety-related, flared gas can often be captured and monetised using low-cost proven solutions.

In doing so, governments can improve health and safety, reduce emissions (of carbon dioxide, methane, and particulates) and add value by driving up revenue, increasing reserves and production, creating jobs and improving the industry’s ‘social license to operate’.

Flare capture also helps countries to deliver on the Paris Agreement and the UN’s Sustainable Development Goal #13 while, for example, providing affordable alternatives for heating and cooking.

The Middle East and North Africa (MENA) region accounts for 40% of the world’s flaring. In the region, flaring has increased year-on-year - apart from 2018 - to almost six billion cubic feet of gas per day, generating up to 300-500 million tonnes of CO2-equivalent emissions per year.

These emissions result not only from the combustion of gas, but also from the venting, from inefficient flares, of un-combusted methane, a more potent greenhouse gas. Yet much of this is avoidable.

There are many commercially attractive options to reduce flaring in MENA. The key is to use the right proven technology and to be agile in commercial structuring. And the prize could be a boost to MENA’s annual revenues by up to $200 per second (up to $6.4 billion per year) by delivering wasted gas to market by pipeline, as power or in liquid form.

The chart highlights the abundance of flaring across the MENA region, and in many cases, their proximity to population centres. While Iran, Iraq, and Algeria generate 75% of MENA’s flaring, Saudi Arabia, Kuwait, UAE and Qatar are notable for their relatively low ‘flaring intensity’ i.e. flaring normalized to oil production.

In today’s world of lower energy prices, it makes sense to monetise every molecule. Even more so for national oil companies, which are responsible for most of the flaring, since they are not only the custodians of their countries’ natural resources, but they also generate a dominant source of government revenue.

Most oil producers in MENA have already made commitments to the World Bank’s flaring-reduction initiatives (e.g. ‘Zero Routine Flaring by 2030’), but to date, delivery is mostly lacking. Three main issues have hindered progress.

Firstly, operators, regulators, and governments highlight that flaring is often not ‘sufficiently on the radar’. Flaring is often underreported if not ignored or denied - although satellite detection gives unavoidable transparency. In MENA alone, more than 1,700 flare clusters are visible every day from space.

Secondly, flare capture is sometimes not perceived to be economically viable due to costs, taxes, or inappropriate technology. Thirdly, there are often issues around resources, especially concerning management bandwidth, delivery capabilities or financing.

Yet these issues can be solved if the right proven technologies are combined with the right commercial structures. To accelerate flare capture projects, stakeholders in the MENA hydrocarbons sector must consider several complementary, action-oriented initiatives.

In particular, they should:

  • Promote transparency and disclosure to drive greater awareness of flaring. Governments, regulators and operators must understand the real scale of their gas flaring opportunity and be capable of acting, as a recent report for the EBRD on Egypt highlighted. Compliance with clear standards for measuring, monitoring and verification is critical.
  • Advance policies and incentives which encourage action. Better commercial terms will incentivise and accelerate flare investments. Stronger penalties will help, but independent and capable regulators must actually enforce these penalties. Through the use of such clear anti-flaring policies, Norway’s flaring intensity is almost 20 times lower than the MENA region.
  • Improve the investment climate, beyond economics and open access to a broader range of players. Local market failures can be avoided by reducing the complexity and cost of in-country operations and by removing excessive, rigid, or redundant regulations. By enabling greater ‘third-party’ access to gas and power projects and infrastructure, new players can accelerate change by deploying new technologies and new operating models. Better third-party access will also unlock ideas, capital, skills and project-specific financing options. Algeria is making steps towards such liberalisation through its new 2019 Hydrocarbon Law.
  • Reduce subsidies and improve energy efficiency and reduce demand, increase gas exports and boost national revenues. Countries with large subsidies on transport fuels and power, such as Algeria and Iraq, stand to gain the most.
  • Encourage collaboration between stakeholders in industry and government by creating working groups to radiate best practices, build capacity, deploy technology and local content, such as the flare minimization programme in Saudi Arabia or Iraq’s major flare-to-power project operated by the Basrah Gas Company.

The industry needs to prepare for a greener world after COVID-19 and investors and consumers are demanding cleaner fuels. Since gas is widely viewed as a transition fuel, MENA governments and stakeholders must work to eliminate its wastage and seize the revenue, production and environmental opportunities that flare capture projects offer.

There is much new leadership in the region in government and critical institutions with new mandates for change. The time to act is now.




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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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Belarus Policy: Time to Play Hardball

12 August 2020

James Nixey

Director, Russia-Eurasia and Europe Programmes
Predictably, Aliaksandr Lukashenka’s regime has betrayed its people and the West’s trust yet again. A new, tougher approach is now the only option, and sanctions are only one of several actions that should be taken.

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Women take part in an event in support of detained and injured participants in mass protests against the results of the 2020 Belarusian presidential election. Photo by Natalia FedosenkoTASS via Getty Images.

Aliaksandr Lukashenka’s 26-year rule — one of the world’s longest — is itself testament to his regime’s unwillingness to change. Most of Belarus’s immediate neighbours — particularly Lithuania, Latvia, and Poland — are far more prosperous. Now, with the farce of last week’s vote and the subsequent renewed violence that Minsk is willing to use on its citizens, Belarus finds itself at the very bottom of the post-Soviet legitimacy league table. But others share a portion of blame for this saga. The West — and the EU in particular — have failed the people of Belarus.

Russia — as ever in its relationships with the Soviet Union’s other successor states — has much to answer for. Like a drug pusher, it made a loss-leading investment in getting Belarus hooked on subsidised energy with meaningless security guarantees thrown in. Lukashenka may not have been the most compliant of post-Soviet leaders — especially recently — but he is still preferred by the Kremlin over any other potential contender, especially the reforming ones currently at the fore. ‘A son-of-a-bitch, but our son-of-a-bitch’ is Russia’s take.

But if Russia is the pusher, Western countries have been the enablers. Lukashenka has played them — and played them off against Russia — by frequently rejecting the offers of one and getting closer to the other, then switching and doing the same. The inability or unwillingness to recognize — and act on — evidence of the regime’s insincerity and its propensity to inflict harm on its own citizens has encouraged Minsk’s worst excesses. At the time of writing, more than 3,000 are reported to have been arrested and many tortured.

The EU bears special responsibility for this enabling. Ever since Belarus’s independence almost 30 years ago, it has offered plenty of carrots but few meaningful sticks. President of the European Commission Ursula von der Leyen said that ‘harassment & violent repression of peaceful protesters has no place in Europe’, but statements alone are inadequate. The Belarusian people are risking their freedoms and their lives on the streets of Minsk while the EU simply ‘calls on’ the Belarusian authorities to respect the democratic process.

Never too late

There is plenty that can be done. Sanctions are a much-touted first step and they have been proven to change the calculus, if not the character, of a regime. The EU, the UK and the US should act decisively and in unison to impose them immediately. Included in this would be the immediate halting of direct EU support to state entities.

But — as with Russia — it is lazy to limit responses to sanctions alone. Expulsion from international groups and values-based organizations should also be expedited. The EU’s Eastern Partnership (EaP) project with Belarus and five other countries is a prime example of supposedly conditional offers of financial assistance having been accepted, claimed and then defaulted on, time and again. It is time to make an example of Belarus and expel it from the EaP since it is abundantly clear it has no intention of adopting the values demanded of it.

The OSCE (Organization for Security and Co-operation in Europe) was invited by the Belarusian authorities too late to observe last Sunday’s vote-rigging, so why, in the face of such obvious obstruction, is Belarus even a member? The OSCE often claims its strength is its inclusivity, but this has rarely stood up to scrutiny. Inclusivity may have advantages, but one should also acknowledge its propensity to dilute effectiveness. Belarus should be expelled from here too.

The same goes for the IMF, the World Bank group, and its WTO observer status. It is time to make an example of this regime.

There should be less diplomatic nicety. It is natural that foreign service officials are hard-wired to want to make things better through their undoubted skills of sensitivity and tact, and sometimes this is the right answer. But not always. It would be better in some instances, such as this one, to give a tougher message — making it clear this regime is no longer seen as legitimate and that, where possible, western countries will seek relationships with more representative figures. This is neither easy nor especially pleasant, but it is not the same as breaking off diplomatic relations entirely, which is not wise as sometimes the organs of power must be dealt with.

And in terms of immediate practical help, the EU has an obligation to open its borders to Belarusian refugees who will surely come its way as conditions deteriorate. Lithuania is already showing the way in this regard.

Belarus is not one of the more difficult countries. It has no influence, no natural resources and therefore no leverage. It could resort to even more brutal repression of its citizens, but it should be made clear that such a desperate move by the authorities would entail even greater sanction. A common argument against a tougher approach is that it will drive Belarus into the arms of Russia. But this is to fall into the same trap — blackmail in reality — that we have seen for 20 years. In fact, it would be a good litmus test for a similar policy towards other ‘abuser countries’, such as Hungary.

Russia is certainly watching closely right now, and the last thing it wants is another colour revolution. The probability is that it will get this wish for now, as the demonstrations will surely cool off and key opposition figures not already in jail have been forced to flee. But western quiescence, as it always does, encourages Russia to act with further impunity. No invasion needed this time though if it already has most of what it wants — Union State notwithstanding — and the West stands aside.

A Chinese proverb maintains that ‘the best time to plant a tree was 20 years ago. The second-best time is now’. This holds true for dealing with Belarus. It is not too late to act decisively and play hardball. In doing so, the EU would help repair its reputation for hand-wringing and the people of Belarus might look at the EU with a respect they have lost.




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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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Why the Mali Coup Should Matter to the UK

20 August 2020

Dr Alex Vines OBE

Managing Director, Ethics, Risk & Resilience; Director, Africa Programme
This coup was not unexpected as it followed months of mass protests against alleged corruption, a worsening economy and disputed elections.

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Press conference in Kati after the military arrested Malian president Ibrahim Boubacar Keita and he officially resigned. Photo by ANNIE RISEMBERG / AFP via Getty Images.

The coup in Mali is not a putsch by disgruntled soldiers in a distant land. It is an extended European neighbourhood and matters to Britain. The UK already has three Chinook helicopters deployed in country and 250 British troops are scheduled to take up UN peacekeeping duties in December in what could be the ministry of defence’s most dangerous deployment since Afghanistan.

This coup was not unexpected as it followed months of mass protests against alleged corruption, a worsening economy, disputed legislative election results and deteriorating security in this West African country. Mali’s military is struggling to stop the insurgents, some of them now also affiliated with the ISIL (ISIS) armed group, despite UN, EU, French and regional military support.

The departure of Mali's President Ibrahim Boubacar Keita was met with jubilation by anti-government demonstrators in Bamako and the leaders of the military coup say they would enact a political transition and stage elections within a 'reasonable time'.

Coups, followed by transitional arrangements and then new elections, are not rare in this region and have happened before in Mali when Keita’s predecessor Amadou Toumani Toure was overthrown by the military in 2012. The current cycle of insecurity followed despite a significant military intervention by France to restore elected government and stop the spread of Islamic extremist insurgency.

This is a reminder of how fragile the Sahel regon is and the importance of seeking stability and state building in a region of spreading Islamic extremist insurgency and rapidly-eroding state legitimacy.

The regional bloc ECOWAS (Economic Community of West African States) has denounced the coup and ordered the closing of regional borders with Mali as well as the suspension of all financial flows between Mali and its 15 members states. What follows now will be negotiations over the transitional arrangements and the timetable for new elections.

This will not be straightforward. Although the opposition was united in their demand for Keita's resignation there is little consensus on what to do next, while the UN Security Council and ECOWAS are divided on how to respond beyond initial condemnation.

It is urgent that three UK cabinet ministers, led by the first secretary of state Dominic Raab, who are currently reviewing the UK’s Sahel strategy complete this and decide upon its future direction.

The UK government needs crystal clarity on its Mali objectives as the clock ticks down to the deployment of British troops there. Increasingly this UN duty looks to become more peacemaking than peacekeeping.

This article was originally published in The Telegraph.




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By Inventing Military Threats, Lukashenka Is Playing with Fire

20 August 2020

Keir Giles

Senior Consulting Fellow, Russia and Eurasia Programme
In a bid to reassert control in Belarus, Aliaksandr Lukashenka is trying to stir the worst fears of his supporters by playing the war card. But overplaying his hand could prove disastrous if it leads to confrontation with either Russia or NATO.

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A mass rally in Grodno, Belarus where factory workers went on strike in protest against the election results and actions of law enforcement officers. Photo by Viktor DrachevTASS via Getty Images.

Having failed to swiftly translate popular support into tangible political achievements, there are signs the protests against the fraudulent presidential election in Belarus may be losing momentum in the face of the state’s resilience and still-confident security and enforcement apparatus.

Attempts to blame the unrest on the West have focused on groups Lukashenka and Russia can both call enemies. And now Aliaksandr Lukashenka is not only inventing anti-Russian policies supposedly held by the opposition, such as suppressing the Russian language and closing the border with Russia, but also a supposed military threat from NATO.

Border movements

Increased military activity inside Belarus does give Lukashenka a wider range of options. Unscheduled activation of military units includes airspace defence practice with missiles and aircraft, electronic warfare (EW) units put on round-the-clock alert, and a number of infantry brigades preparing for live firing exercises.

Lukashenka is drawing attention to the north-west corner of Belarus, singling out the city of Grodno near the border with Poland and Lithuania as a supposed target for Western efforts at destabilization. Grodno is also the destination for an airborne brigade moving from the east to the west of the country and the focus of military exercises under way on the country’s western borders.

All this feeds Lukashenka’s narrative that Belarus is in danger from NATO and the West who are supposedly both stirring up the protests and seeking to exploit disorder - and that this danger extends to possible military clashes.

The Belarusian exercises are over the border from where NATO troops - including elements of the Light Dragoons, a British reconnaissance unit - have been in place in Poland as part of NATO's enhanced forward presence (eFP) since 2017. Pointing to NATO activity in Poland and Lithuania, Lukashenka said on Wednesday ‘we have to follow their movements and plans’ and that ‘they will answer for it if something happens’.

The danger is that having invented a tense situation in Grodno, Lukashenka may now need to be proved right. There may be staged incidents or ‘provocations’ against Belarus military forces, either supposedly instigated by protesters or even by NATO forces on the border - all aimed at bolstering the narrative that NATO, the EU, and the West in general are hostile to Belarus and that more drastic measures are necessary for protection.

Russia’s options still open

Although initial fears of a Russian move into Belarus have receded, Lukashenka’s complaints about NATO also bolster the case for Moscow to intervene. The military exercises fit the narrative that Belarus is under threat from the West - which is exactly the pretext Russia would need.

If this is believed in Moscow, where foreign minister Sergey Lavrov has already described events in Belarus as part of a ‘struggle for the post-Soviet space’, this makes a Russian intervention more likely. Moving forces away from their base near the border with Russia to the other end of the country near Poland and Lithuania also means any Russian entry into Belarus could go more smoothly, with fewer wild cards of possible Belarusian opposition to consider.

There are plenty of sensible, rational, logical reasons why a Russian military intervention in Belarus would be disastrous and counter-productive. But what seems sensible and rational in Europe and North America does not always carry weight in Moscow, which may see the situation completely differently and measure options by completely different standards.

One key area of doubt is the sympathies of the Belarus armed forces. Although some elements of the Belarusian army - particularly airborne and special forces - work closely with their Russian counterparts, more general suggestions that the Belarusian military is merely an extension of Russia’s and is not capable of taking decisions for itself are an over-simplification.

The Belarus armed forces do know that hosting Russian ground troops, airbases or air defence systems would fatally undermine the country’s hopes of avoiding being caught up in any confrontation between Russia and NATO.

And although the great majority of Belarusian officers are Russian-speaking and many have been trained and educated in Russia, there may be sufficient pride in national identity and resentment at heavy-handed treatment by Russia to lead to substantial obstruction of Russian initiatives.

The Belarus General Staff has already refused permission for a Russian aircraft carrying 155 personnel from the Rosgvardiya militarized security force and three tonnes of cargo ‘for the Belarusian interior ministry’ to land in Belarus. This could indicate not only tension between Russia and Belarus, but even between ministries within Belarus itself.

Like Russia, Lukashenka has plenty of options in reserve if his situation deteriorates further. Announcing a state of emergency would allow the Belarusian army to support the security forces in dealing with protests. If the army is on the move with their equipment they are better prepared to be brought into action if needed, but testing the loyalty of the armed forces could prove dangerous if the sympathies of army units turn out to lie more with civilians than with their oppressors from the interior ministry.

The military preparations against fictitious threats and a patiently-waiting Russia is a toxic mix and Belarus’s friends abroad must tread carefully. A key task for the European Union (EU) is to help the Belarusian people without providing a pretext for further violence and Russian intervention.

The right level of engagement needs to be carefully calibrated, avoiding disasters of strategic communication such as European Commissioner Thierry Breton being translated into English as saying Belarus is not part of Europe – with the lack of EU interest that that implies. Although the EU statement promising sanctions and offering funds received a mixed reception, at least it cannot be used by Lukashenka and Vladimir Putin as evidence that their warnings of a Western military threat are genuine.




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Rage Against the Algorithm: the Risks of Overestimating Military Artificial Intelligence

27 August 2020

Yasmin Afina

Research Assistant, International Security Programme
Increasing dependency on artificial intelligence (AI) for military technologies is inevitable and efforts to develop these technologies to use in the battlefield is proceeding apace, however, developers and end-users must ensure the reliability of these technologies, writes Yasmin Afina.

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F-16 SimuSphere HD flight simulator at Link Simulation in Arlington, Texas, US. Photo: Getty Images.

AI holds the potential to replace humans for tactical tasks in military operations beyond current applications such as navigation assistance. For example, in the US, the Defense Advanced Research Projects Agency (DARPA) recently held the final round of its AlphaDogfight Trials where an algorithm controlling a simulated F-16 fighter was pitted against an Air Force pilot in virtual aerial combat. The algorithm won by 5-0. So what does this mean for the future of military operations?

The agency’s deputy director remarked that these tools are now ‘ready for weapons systems designers to be in the toolbox’. At first glance, the dogfight shows that an AI-enabled air combat would provide tremendous military advantage including the lack of survival instincts inherent to humans, the ability to consistently operate with high acceleration stress beyond the limitations of the human body and high targeting precision.

The outcome of these trials, however, does not mean that this technology is ready for deployment in the battlefield. In fact, an array of considerations must be taken into account prior to their deployment and use – namely the ability to adapt in real-life combat situations, physical limitations and legal compliance.

Testing environment versus real-life applications

First, as with all technologies, the performance of an algorithm in its testing environment is bound to differ from real-life applications such as in the case of cluster munitions. For instance, Google Health developed an algorithm to help with diabetic retinopathy screening. While the algorithm’s accuracy rate in the lab was over 90 per cent, it did not perform well out of the lab because the algorithm was used to high-quality scans in its training, it rejected more than a fifth of the real-life scans which were deemed as being below the quality threshold required. As a result, the process ended up being as time-consuming and costly – if not more so – than traditional screening.

Similarly, virtual environments akin to the AlphaDogfight Trials do not reflect the extent of risks, hazards and unpredictability of real-life combat. In the dogfight exercise, for example, the algorithm had full situational awareness and was repeatedly trained to the rules, parameters and limitations of its operating environment. But, in a real-life dynamic and battlefield, the list of variables is long and will inevitably fluctuate: visibility may be poor, extreme weather could affect operations and the performance of aircraft and the behaviour and actions of adversaries will be unpredictable.

Every single eventuality would need to be programmed in line with the commander’s intent in an ever-changing situation or it would drastically affect the performance of algorithms including in target identification and firing precision.

Hardware limitations

Another consideration relates to the limitations of the hardware that AI systems depend on. Algorithms depend on hardware to operate equipment such as sensors and computer systems – each of which are constrained by physical limitations. These can be targeted by an adversary, for example, through electronic interference to disrupt the functioning of the computer systems which the algorithms are operating from.

Hardware may also be affected involuntarily. For instance, a ‘pilotless’ aircraft controlled by an algorithm can indeed undergo higher accelerations, and thus, higher g-force than the human body can endure. However, the aircraft in itself is also subject to physical limitations such as acceleration limits beyond which parts of the aircraft, such as its sensors, may be severely damaged which in turn affects the algorithm’s performance and, ultimately, mission success. It is critical that these physical limitations are factored into the equation when deploying these machines especially when they so heavily rely on sensors.

Legal compliance

Another major, and perhaps the greatest, consideration relates to the ability to rely on machines for legal compliance. The DARPA dogfight exclusively focused on the algorithm’s ability to successfully control the aircraft and counter the adversary, however, nothing indicates its ability to ensure that strikes remain within the boundaries of the law.

In an armed conflict, the deployment and use of such systems in the battlefield are not exempt from international humanitarian law (IHL) and most notably its customary principles of distinction, proportionality and precautions in attack. It would need to be able to differentiate between civilians, combatants and military objectives, calculate whether its attacks will be proportionate against the set military objective and live collateral damage estimates and take the necessary precautions to ensure the attacks remain within the boundaries of the law – including the ability to abort if necessary. This would also require the machine to have the ability to stay within the rules of engagement for that particular operation.

It is therefore critical to incorporate IHL considerations from the conception and throughout the development and testing phases of algorithms to ensure the machines are sufficiently reliable for legal compliance purposes.

It is also important that developers address the 'black box' issue whereby the algorithm’s calculations are so complex that it is impossible for humans to understand how it came to its results. It is not only necessary to address the algorithm’s opacity to improve the algorithm’s performance over time, it is also key for accountability and investigation purposes in cases of incidents and suspected violations of applicable laws.

Reliability, testing and experimentation

Algorithms are becoming increasingly powerful and there is no doubt that they will confer tremendous advantages to the military. Over-hype, however, must be avoided at the expense of the machine’s reliability on the technical front as well as for legal compliance purposes.

The testing and experimentation phases are key during which developers will have the ability to fine-tune the algorithms. Developers must, therefore, be held accountable for ensuring the reliability of machines by incorporating considerations pertaining to performance and accuracy, hardware limitations as well as legal compliance. This could help prevent incidents in real life that result from overestimating of the capabilities of AI in military operations. 




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Has the Dollar Started Its Long Decline?

28 August 2020

Jim O'Neill

Chair, Chatham House
Ultimately, the dollar’s dominance cannot persistently outweigh the relative decline of the US economy in the world. At some point, it will start to be replaced by something else. But don’t confuse that with where the dollar’s price is heading against other currencies.

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A statue of George Washington is pictured in front of the New York Stock Exchange (NYSE) on 16 March 2020, at Wall Street in New York City. Photo by JOHANNES EISELE/AFP via Getty Images.

One of the features of financial markets since early summer has been a decline in the value of the dollar against many currencies, and with it, an especially interesting acceleration in the price of gold. In addition to the usual professional market analysis about the dollar’s movement, this has led to speculation that it might be the beginning of the end of the dollar’s pre-eminence.

Having spent far too much of my professional life as a supposed currency expert, I reiterate something I learnt early on: the foreign exchange business sometimes grants an analyst their 15 minutes of fame, but no expert is a match for the millions who participate in this huge global market all day long. But I spent over 30 years in the financial markets, the vast majority in the hubbub of the forex market. And along the journey, I think I learnt a few tricks of the trade.

At the core of trying to answer questions about the dollar, I learnt a long time ago that there are two entirely separate questions, one of which has two subsections, about the dollar. Firstly, there is the question about the use of the dollar. Will it continue to dominate the world’s financial system as the most widely accepted medium of exchange?

This is not at all the same issue as the dollar’s day-to-day performance against other currencies. This is the second question, which is almost definitely the most pertinent one to what has happened during the summer. How the dollar’s value moves against other currencies is driven by a structural, or a valuation component, and a cyclical component. Each can be analysed separately, and if you were daft enough to devote the years I did to the process, you can combine the two, to have a dynamically adjusted fair value, persuading yourself at least that such an approach combines all available information at any point in time.

In terms of valuation, the most common approach is so-called purchasing power parity, which holds that a currency, in equilibrium, will ultimately reflect the difference in prices between two countries. If inflation is persistently higher in the US than in the eurozone, then the equilibrium value of the dollar will decline over time. I developed my own version of equilibrium currency rates, as it seemed to me in the real world, that the real inflation adjusted value of a currency was not stable, and that it moved over time. This was a reflection of productivity differentials between two countries. I christened it GSDEER: 'the Goldman Sachs Dynamic Equilibrium Real Exchange Rate' when I joined the firm in 1995.

What I learned is that when a currency is more than two standard deviations away from its fair value, it makes a huge amount of sense to watch closely, and when the momentum changes, it is worth going with this trend reversal. The momentum can change based on a change in the forces that have driven the currency away from its fair value, although it can be often easier to detect simply by watching the change in price.

One of the things that has frustrated currency participants over the past decade, with the exception of the Swiss franc and the pound, is that other major currencies have not been that far away from their fair value against the dollar or each other. Even during the dollar’s rise in recent years, including the period up to the summer, while it had clearly become overvalued, with the possible exception of the pound, it hadn’t become more than two standard deviations above its own fair value. In this regard, I have believed that one might be on the lookout for a chance to buy the pound against the dollar, and perhaps against the yen.

The cyclical component of a currency’s movement around its conceptual equilibrium can perhaps best be captured in the nominal interest rate adjusted for inflation expectations. I persuaded myself that the actual spot exchange rate of the dollar on any one day should be close to the adjusted GSDEER, and if it was not, then it would be useful for traders.

The dollar had become more interesting pre-COVID, as it appeared to have risen notably against many currencies, including the euro. And in this regard, the dollar was highly susceptible, and has turned out to be actually vulnerable, to a change in the state of the US and euro area economies. Now that the Federal Reserve has returned to extremely expansive monetary policy, and with it, lower real interest rates, a dollar decline seemed pretty inevitable.

At current prices, on 26 August, the dollar still seems modestly expensive compared to dynamically adjusted fair value. The dollar decline could persist. In the late 1980s and mid 1990s, the dollar fell to very low levels and became very undervalued — this tended to coincide with widespread talk about the dollar’s preeminence, which turned out to be, at least for that era, wrong. And I do share the views of some people who believe, as a result of US policies, conditions are more conducive to a sustained period of dollar weakness. This requires strong ongoing evidence that Europe, China and much of the rest of Asia continue to manage COVID-19 better than the US, and that their cyclical recoveries from the pandemic continue to surprise relative to the US.

Now as for the first question, about the demise of the dollar’s dominance, let me repeat that this is largely a separate issue, but I encourage any reader to be careful about getting sucked into this belief in making an investment or hedging decision.

It is quite possible that the use of the dollar can decline, and start off a systematic decline even when its value is strong. Indeed, in the past couple of years when its value was largely rising, decisions made by US policymakers to use the dollar’s dominance as a way of penalising other countries has resulted in those countries reducing their share of dollar currency reserves. Russia is a particular example, and there is some modest evidence that China is doing likewise.

And the opposite can also be true.

Ultimately, the dollar’s dominance cannot persistently outweigh the relative decline of the US economy in the world, which has been occurring now for 20 years. At some point, it will start to be replaced by something else. Whether that is, the renminbi, the euro, Bitcoin, the return of gold — all are conceivable, and may happen. It might be starting now. But don’t confuse that with where the dollar’s price is heading against other currencies in coming days, weeks, or in 2021.

This article was originally published in The Article.




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US Electorate Shows Distrust of the Realities of Foreign Policy

4 September 2020

Bruce Stokes

Associate Fellow, US and the Americas Programme (based in the US)
The identity of the next US president is yet to be determined, but the foreign policy views of the American public are already clear. In principle, Americans support US engagement in the world but, in practice, they worry other countries take advantage of the United States.

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A poll station official holding "I Voted" stickers in South Carolina. Photo by Mark Makela/Getty Images.

Whoever occupies the White House after the election, it is evident the emphasis will be on ‘America First’, and that only characteristics and approaches will differ. If Donald Trump is re-elected, his electoral base will support a continuation of isolationist, protectionist policies. If Joe Biden becomes president, he will enjoy some limited popular backing for international re-engagement, but his voters still clearly want him to prioritize domestic issues.

Implications for the foreign policy of the next US administration are evident. America may have a long history of isolationism, but that should not be confused with ignorance of the growing interconnectedness of today’s world. However, Americans are struggling to find a new equilibrium for their country’s role in the world.

Around seven-in-ten hold the view that the United States should take a leading or major role in international affairs, and the same number acknowledge that international events affect their daily life. But Americans remain reticent about global engagement, and half of registered voters believe other countries take unfair advantage of the United States.

This clear contradiction is mirrored in what can be expected from the election victor, with a Joe Biden administration likely to speak for those who want America to lead, while a second Donald Trump administration is expected to continue complaining about US victimization by an ungrateful world.

A majority (57%) of Americans say foreign policy is 'very important' to them as they decide who to vote for in the 2020 election. This may seem like a high priority, but American polls often show many issues are 'very important' to voters. What matters is relative importance and foreign policy pales in comparison with the significance the public accords to the economy (79%) or healthcare (68%). Immigration (52%) and climate change (42%) are of even less relative importance to voters.

Notably, despite the deep partisanship in American politics today, there is no difference between Republican and Democrat voters on the low priority they accord foreign policy. And barely one-third (35%) of the public give top priority to working with allies and international institutions to confront global challenges such as climate change, poverty and disease — in fact only 31% say improving relations with allies should be a top foreign policy priority over the next five years.

However, despite this apparent lack of support for international relations, a rising majority of Americans believe international trade is good for the economy — running contrary to many international assumptions that Americans are inherently protectionist. But this increased interest may not amount to much in reality. Americans also believe trade destroys jobs and lowers wages. Trump is clearly wedded to a protectionist worldview and may continue to try dismantling the World Trade Organization (WTO). Biden is unlikely to initiate any new trade liberalizing negotiations given what would be, at best, a slim Democratic majority in the Senate and anti-trade views held by many unions and blue-collar voters among his constituency. Any political capital he commits to trade is likely to focus on reforming the WTO, but privately his advisers admit they are not optimistic.

In addition, both Biden and Trump face strong public support for ratcheting up pressure on China, although their lines of attack may differ, with Trump likely to double down on tariffs while Biden would work closely with Europe on both trade and human rights issues. More broadly, almost three-quarters (73%) of Americans now express an unfavourable view of China, up 18 points since the last presidential election. One-quarter of Americans classify Beijing as an ‘enemy’ with almost half saying the US should get tougher with China on economic issues, although attitudes do divide along partisan lines, with Republicans generally more critical of Beijing, but Democrats are tougher on human rights.

On immigration, Trump’s policies are out of step with the public. Six-in-ten Americans oppose expanding the border wall with Mexico, 74% support legal status for immigrants illegally brought to the United States as children — including a majority of Republicans (54%) — and as many Americans favour increasing immigration as support decreasing it. But Trump has already promised to double down on limiting immigration if he wins because it is what his Republican electoral base wants and, as with trade, this is one of his long-expressed personal beliefs. If he wins, expect more mass roundups of undocumented people, completion of his border wall and stricter limitations on legal immigration.

In contrast, Biden is likely to loosen constraints on immigration because he believes immigration has been good for the economy and the Democratic party is increasingly dependent on Hispanic and Asian voters, the two fastest growing portions of the population. However, open borders are not a Biden option. The US foreign-born population is at near-record levels and, every time in American history the portion of foreign born has come close to being 14% of the total population — in the 1880s, the 1920s and now — there has been a populist backlash. Democrats cannot risk that again.

On climate change, there is strong evidence the American public is increasingly worried, and likely to support rejoining the Paris Agreement if Biden is elected and increases US commitments to cut carbon emissions. But the public also appears unlikely to punish Trump if, as promised, he leaves that accord, and he is almost certain to continue denying climate science in the interest of the coal, oil, and gas industries.

The public’s concern about global warming does not necessarily translate into support for taking substantive action. There is a huge partisan divide between the number of Democrats (68%) and Republicans (11%) who say climate change is a very important issue in the 2020 election. When pressed on what action they want on climate change, and who they trust to do it, Americans are less likely than Europeans to accept paying higher prices. A carbon tax stands no chance of passing the Senate, thanks to moderate Democrats from fossil-fuel states, and America’s love affair with large, CO²-emitting vehicles shows no signs of ebbing.

The outcome of the 2020 US election will almost certainly not be determined by foreign concerns, although an international crisis — a terrorist incident, a military confrontation with China or North Korea — could impact voting in an unforeseen way. But given the mood of the American electorate, if Trump is re-elected, there will be scant public pressure for a more activist, collaborative US foreign policy, beyond support for a tough line on China, while a win for Biden will give more room for some international initiatives.

But public opinion data is clear. Voters want the next US president to focus first on domestic issues — overcoming the pandemic, digging the country out of a deep economic hole, calming racial tensions, and reversing inequality. The outcome of the election may end America’s recently antagonistic foreign policy and halt the deterioration of its international role. But dramatic American re-engagement appears unlikely as the public’s priorities lie elsewhere.




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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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Picking Up the Broken Pieces of UK Foreign Policy

14 September 2020

Sir Simon Fraser

Deputy Chairman, Chatham House; Senior Adviser, Europe Programme
The challenge is to define a credible new role for a medium-sized international power.

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US president Donald Trump (right) is welcomed by British prime minister Boris Johnson (centre) and NATO secretary-general Jens Stoltenberg during the NATO Summit in London, December 2019. Photo by Mustafa Kamaci/Anadolu Agency via Getty Images.

Does the UK have a foreign policy? The failures in Iraq and Afghanistan curbed our Blairite appetite for intervention. Then the Brexit referendum and the advent of Donald Trump as US president upended the European and Atlantic pillars of our strategy. The UK has been outflanked by Russian opportunism, and on China it is confused about the balance of security risk and economic opportunity. Meanwhile, the world is accelerating into a dangerous, bipolar era of geopolitics.

The claim that leaving the EU would open a highway to British global influence was always hollow. Since 2016, the UK’s influence has declined; our forces are barely present in international theatres of conflict and, as recent days have again shown, the Brexit soap opera undermines our diplomacy and soft power. So far, there are only glimmers of a new direction.

On issues such as Iran, climate change and excluding Russia from the G7, the UK has stayed close to EU positions. Elsewhere, it has taken a tougher stance on China and Hong Kong that is aligned more closely with the US and the Five Eyes intelligence community, which includes Australia, Canada and New Zealand. There is also a renewed focus on human rights.

However, this does not add up to a coherent strategy. Getting it to do so is the job of this autumn’s 'integrated review' of security, defence, development and foreign policy. The timing is driven by the government’s comprehensive spending review, which — bizarrely — means they will reach conclusions without knowing what sort of deal, if any, we will strike with the EU, or who will be the next US president.

The challenge is to define a credible and distinctive role for a freestanding medium power with strong traditions of diplomacy, defence, intelligence, trade and aid. Not everything has changed; although unmoored from the EU, the UK remains a significant player in Nato, the UN Security Council and other international organisations. 

The review needs to start by deciding what matters most. A sensible list would include avoiding conflict between the US and China, maintaining global prosperity, preventing nuclear proliferation, addressing environmental damage and climate change, and shoring up a multilateral system of international rules. There will always be urgent problems, and it matters how we respond to them. But a foreign policy should be geared to enduring aims.

On each priority, the review must examine how the UK, outside the EU, can make a difference. Sometimes it may find a specific national role, such as convening next year’s COP26 climate conference. Nine times out of 10, however, the route to our national goals will lie, as before, through leveraging relationships with others.

Three relationships matter most. We need a plan for the US, whoever wins the election. If Boris Johnson is the European leader closest to Donald Trump, how will the British prime minister turn that to his advantage if Trump wins? On the other hand, a Joe Biden victory would better serve our wider interest in a reinvigorated Euro-Atlantic community — although, under this government, that would also weaken our hand in Washington compared with Berlin and Paris. What is the plan to counter that?

Second, we need clear thinking on China. In the new bipolar geopolitics, the UK should stand firmly with the US — although not to the extent of allowing Washington to dictate our policy, or of cutting necessary and useful links with China. We need to decide on a strategic objective. Are we preparing for lasting great-power confrontation or even conflict; or are we working for a more sophisticated global equilibrium? In either case, who will be our best international partners?

Evidently, this requires a constructive relationship with Europe, with which the UK has the most obvious shared interests. Bilateral relationships will be valuable, as will the E3 group of the UK, France and Germany. But our reluctance to negotiate a foreign policy relationship with the EU collectively is an error.

When the brainy Whitehall strategists have put down their pens, the review will then, as always, descend into a hard-nosed haggle over money. There are already large holes in Ministry of Defence procurement budgets; the COVID-induced recession will make things worse. With new priorities to fund, such as cybersecurity, the argument will be less about spending more than gouging out savings to redistribute.

Finally, the review must look at delivery. As Downing Street has disempowered ministries, Whitehall’s foreign policy machinery has become over-centralized. Trade and economic considerations should have more weight. Delivery of the new strategy should also be led by a reformed and renamed Department for International Affairs that has leadership on foreign, development and trade policy, oversees external intelligence and works closely with the Ministry of Defence.

Only with such clarity on priorities, relationships and resources can we craft the coherent foreign policy post-Brexit Britain needs. The task will be easier if the UK and EU reach a deal in December.

This article was originally published in the Financial Times.




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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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CDKN2A/p16INK4a suppresses hepatic fatty acid oxidation through the AMPK{alpha}2-SIRT1-PPAR{alpha} signaling pathway [Metabolism]

In addition to their well-known role in the control of cellular proliferation and cancer, cell cycle regulators are increasingly identified as important metabolic modulators. Several GWAS have identified SNPs near CDKN2A, the locus encoding for p16INK4a (p16), associated with elevated risk for cardiovascular diseases and type-2 diabetes development, two pathologies associated with impaired hepatic lipid metabolism. Although p16 was recently shown to control hepatic glucose homeostasis, it is unknown whether p16 also controls hepatic lipid metabolism. Using a combination of in vivo and in vitro approaches, we found that p16 modulates fasting-induced hepatic fatty acid oxidation (FAO) and lipid droplet accumulation. In primary hepatocytes, p16-deficiency was associated with elevated expression of genes involved in fatty acid catabolism. These transcriptional changes led to increased FAO and were associated with enhanced activation of PPARα through a mechanism requiring the catalytic AMPKα2 subunit and SIRT1, two known activators of PPARα. By contrast, p16 overexpression was associated with triglyceride accumulation and increased lipid droplet numbers in vitro, and decreased ketogenesis and hepatic mitochondrial activity in vivo. Finally, gene expression analysis of liver samples from obese patients revealed a negative correlation between CDKN2A expression and PPARA and its target genes. Our findings demonstrate that p16 represses hepatic lipid catabolism during fasting and may thus participate in the preservation of metabolic flexibility.




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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.




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Methylated PP2A stabilizes Gcn4 to enable a methionine-induced anabolic program [Metabolism]

Methionine, through S-adenosylmethionine, activates a multifaceted growth program in which ribosome biogenesis, carbon metabolism, and amino acid and nucleotide biosynthesis are induced. This growth program requires the activity of the Gcn4 transcription factor (called ATF4 in mammals), which facilitates the supply of metabolic precursors that are essential for anabolism. However, how Gcn4 itself is regulated in the presence of methionine is unknown. Here, we discover that Gcn4 protein levels are increased by methionine, despite conditions of high cell growth and translation (in which the roles of Gcn4 are not well-studied). We demonstrate that this mechanism of Gcn4 induction is independent of transcription, as well as the conventional Gcn2/eIF2α-mediated increased translation of Gcn4. Instead, when methionine is abundant, Gcn4 phosphorylation is decreased, which reduces its ubiquitination and therefore degradation. Gcn4 is dephosphorylated by the protein phosphatase 2A (PP2A); our data show that when methionine is abundant, the conserved methyltransferase Ppm1 methylates and alters the activity of the catalytic subunit of PP2A, shifting the balance of Gcn4 toward a dephosphorylated, stable state. The absence of Ppm1 or the loss of the PP2A methylation destabilizes Gcn4 even when methionine is abundant, leading to collapse of the Gcn4-dependent anabolic program. These findings reveal a novel, methionine-dependent signaling and regulatory axis. Here methionine directs the conserved methyltransferase Ppm1 via its target phosphatase PP2A to selectively stabilize Gcn4. Through this, cells conditionally modify a major phosphatase to stabilize a metabolic master regulator and drive anabolism.




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In crystallo screening for proline analog inhibitors of the proline cycle enzyme PYCR1 [Metabolism]

Pyrroline-5-carboxylate reductase 1 (PYCR1) catalyzes the biosynthetic half-reaction of the proline cycle by reducing Δ1-pyrroline-5-carboxylate (P5C) to proline through the oxidation of NAD(P)H. Many cancers alter their proline metabolism by up-regulating the proline cycle and proline biosynthesis, and knockdowns of PYCR1 lead to decreased cell proliferation. Thus, evidence is growing for PYCR1 as a potential cancer therapy target. Inhibitors of cancer targets are useful as chemical probes for studying cancer mechanisms and starting compounds for drug discovery; however, there is a notable lack of validated inhibitors for PYCR1. To fill this gap, we performed a small-scale focused screen of proline analogs using X-ray crystallography. Five inhibitors of human PYCR1 were discovered: l-tetrahydro-2-furoic acid, cyclopentanecarboxylate, l-thiazolidine-4-carboxylate, l-thiazolidine-2-carboxylate, and N-formyl l-proline (NFLP). The most potent inhibitor was NFLP, which had a competitive (with P5C) inhibition constant of 100 μm. The structure of PYCR1 complexed with NFLP shows that inhibitor binding is accompanied by conformational changes in the active site, including the translation of an α-helix by 1 Å. These changes are unique to NFLP and enable additional hydrogen bonds with the enzyme. NFLP was also shown to phenocopy the PYCR1 knockdown in MCF10A H-RASV12 breast cancer cells by inhibiting de novo proline biosynthesis and impairing spheroidal growth. In summary, we generated the first validated chemical probe of PYCR1 and demonstrated proof-of-concept for screening proline analogs to discover inhibitors of the proline cycle.




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Serum lipoprotein-derived fatty acids regulate hypoxia-inducible factor [Metabolism]

Oxygen regulates hypoxia-inducible factor (HIF) transcription factors to control cell metabolism, erythrogenesis, and angiogenesis. Whereas much has been elucidated about how oxygen regulates HIF, whether lipids affect HIF activity is un-known. Here, using cultured cells and two animal models, we demonstrate that lipoprotein-derived fatty acids are an independent regulator of HIF. Decreasing extracellular lipid supply inhibited HIF prolyl hydroxylation, leading to accumulation of the HIFα subunit of these heterodimeric transcription factors comparable with hypoxia with activation of downstream target genes. The addition of fatty acids to culture medium suppressed this signal, which required an intact mitochondrial respiratory chain. Mechanistically, fatty acids and oxygen are distinct signals integrated to control HIF activity. Finally, we observed lipid signaling to HIF and changes in target gene expression in developing zebrafish and adult mice, and this pathway operates in cancer cells from a range of tissues. This study identifies fatty acids as a physiological modulator of HIF, defining a mechanism for lipoprotein regulation that functions in parallel to oxygen.




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The bacterial cell division protein fragment EFtsN binds to and activates the major peptidoglycan synthase PBP1b [Metabolism]

Peptidoglycan (PG) is an essential constituent of the bacterial cell wall. During cell division, the machinery responsible for PG synthesis localizes mid-cell, at the septum, under the control of a multiprotein complex called the divisome. In Escherichia coli, septal PG synthesis and cell constriction rely on the accumulation of FtsN at the division site. Interestingly, a short sequence of FtsN (Leu75–Gln93, known as EFtsN) was shown to be essential and sufficient for its functioning in vivo, but what exactly this sequence is doing remained unknown. Here, we show that EFtsN binds specifically to the major PG synthase PBP1b and is sufficient to stimulate its biosynthetic glycosyltransferase (GTase) activity. We also report the crystal structure of PBP1b in complex with EFtsN, which demonstrates that EFtsN binds at the junction between the GTase and UB2H domains of PBP1b. Interestingly, mutations to two residues (R141A/R397A) within the EFtsN-binding pocket reduced the activation of PBP1b by FtsN but not by the lipoprotein LpoB. This mutant was unable to rescue the ΔponB-ponAts strain, which lacks PBP1b and has a thermosensitive PBP1a, at nonpermissive temperature and induced a mild cell-chaining phenotype and cell lysis. Altogether, the results show that EFtsN interacts with PBP1b and that this interaction plays a role in the activation of its GTase activity by FtsN, which may contribute to the overall septal PG synthesis and regulation during cell division.




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Inhibition of oxidative metabolism by nitric oxide restricts EMCV replication selectively in pancreatic beta-cells [Enzymology]

Environmental factors, such as viral infection, are proposed to play a role in the initiation of autoimmune diabetes. In response to encephalomyocarditis virus (EMCV) infection, resident islet macrophages release the pro-inflammatory cytokine IL-1β, to levels that are sufficient to stimulate inducible nitric oxide synthase (iNOS) expression and production of micromolar levels of the free radical nitric oxide in neighboring β-cells. We have recently shown that nitric oxide inhibits EMCV replication and EMCV-mediated β-cell lysis and that this protection is associated with an inhibition of mitochondrial oxidative metabolism. Here we show that the protective actions of nitric oxide against EMCV infection are selective for β-cells and associated with the metabolic coupling of glycolysis and mitochondrial oxidation that is necessary for insulin secretion. Inhibitors of mitochondrial respiration attenuate EMCV replication in β-cells, and this inhibition is associated with a decrease in ATP levels. In mouse embryonic fibroblasts (MEFs), inhibition of mitochondrial metabolism does not modify EMCV replication or decrease ATP levels. Like most cell types, MEFs have the capacity to uncouple the glycolytic utilization of glucose from mitochondrial respiration, allowing for the maintenance of ATP levels under conditions of impaired mitochondrial respiration. It is only when MEFs are forced to use mitochondrial oxidative metabolism for ATP generation that mitochondrial inhibitors attenuate viral replication. In a β-cell selective manner, these findings indicate that nitric oxide targets the same metabolic pathways necessary for glucose stimulated insulin secretion for protection from viral lysis.




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Climate migration: Ways ahead from the next generation

Climate migration: Ways ahead from the next generation The World Today rsoppelsa.drupal 25 May 2022

Ella Dennis and Mike Higgins talk to young activists seeking solutions as global warming wreaks havoc in sub-Saharan Africa

Africa has the lowest carbon emissions per capita yet the highest rate of temperature increase in the world. Rising levels of desertification, drought and flooding are already forcing millions of Africans to relocate to find more stable livelihoods. 

The continent’s youth will bear the brunt of this climate migration problem. It is estimated that by 2050, Africa will be home to 86 million internal climate migrants.

How is climate migration already affecting sub-Saharan Africa and what frameworks could tackle it? To begin to answer those questions, five young activists from across the region, who are members of Chatham House’s Common Futures Conversations, took part in a panel discussion at the world’s first youth-led Conference on Climate Migration, convened in April by the Alliance for Citizen Engagement, a nonpartisan think tank based in the US. 

[Farmer-herder] conflicts will pose even larger security concerns as climate migration intensifies

Laura Mukhwana, Kenyan PhD candidate

The conversation and follow-up discussions focused on a common problem – climate migration brings people into conflict and puts pressure on infrastructure. 

In Kenya, droughts have left 3.5 million people hungry and the chronic flooding of several lakes in the Rift Valley has displaced hundreds of thousands, said Gerald Muchiri, 29, a social scientist from Kenya. One result has been outbreaks of violence between pastoralists such as the Orma people and the farmers of the Pokomo community, said Laura Mukhwana, 33, a PhD student in Kenya. She believes this violence is likely to worsen. ‘Inter-group conflicts will pose even larger security concerns for surrounding communities as climate migration intensifies,’ she said.

Suleman Nuhu, 24, a farmer and veterinary student from Nigeria, said farmer-herder conflicts were his country’s most significant climate-migration issue. The movement of nomadic tribes from the north had affected him personally: ‘Nomads have trespassed on [my family’s] farms many times while moving with their livestock, destroying our crops.’ 

Changes in climate also force people to move from rural to urban areas. Nigeria, for instance, struggles with the so-called ‘Lagos problem’, said Temiloluwa Lawal, 25, a lawyer and researcher from Nigeria. An estimated 22 million people, a number that is rising fast, are crammed into a city smaller than Greater London. While not on the same scale, Zimbabwe experiences comparable challenges, said Tinotenda Dube, 29, a Zimbabwean finance director. Thanks to drought, unemployed rural migrants arriving in cities ‘put excessive pressure on service delivery against a low tax base,’ he said. ‘People, including close family members of mine, are crowded in dilapidated homes because they cannot afford to pay rent for decent housing.’ 

But there is hope, say the activists. Dube believes that affordable housing is an ‘integral component of [tackling] the climate migration crisis’. 

In Zimbabwe, he has developed a low-cost home finance model that, he said, has helped more than 250 low-income households find good-quality accommodation. Alongside this initiative, Dube has co-founded a property and construction company, Solinfra Zimbabwe Private Ltd, to provide low-cost housing. 

Muchiri is taking action in Kenya, founding an NGO called Social Assistance Welfare to tackle public health issues, he said: ‘As climate migration becomes more intense, I expect preventable health issues to increase throughout the region, and thus see Social Assistance Welfare as an important mitigation.’

To mitigate food security problems, we must reduce reliance on rain-fed agriculture through irrigation schemes

Suleman Nuhu, farmer and veterinary student from Nigeria

In Nigeria, Nuhu noted that to help reduce conflict between farmers and herders social-media campaigns are encouraging pastoralists to move from nomadic livestock farming to more efficient intensive systems, using ranching and grazing reserves. ‘As for food security problems, the best mitigation is to reduce reliance on rain-fed agriculture through irrigation schemes,’ he said. 

All five agreed that, in their experience, the youth of sub-Saharan Africa could be better informed about climate migration. But they took encouragement from the fact the young are passionate about tackling issues arising from the broader climate crisis. 

In Kenya, Mukhwana pointed to successful youth projects around agro-forestry and tree-planting. She added that there is ‘a growing movement of urban youth who are advocating for climate justice, such as the Kenyan Youth Environmental Network and Fridays for the Future Kenya’. It was pleasing too, she said, that when the Kenyan government revised its contributions to the Paris Climate Accords it staged a week-long youth conference to include their opinions.

‘Overall, I am quite hopeful about how the youth are mobilizing themselves in Kenya,’ she added.

Find out more about Chatham House’s Common Futures Conversations