is N-acetylglucosamine drives myelination by triggering oligodendrocyte precursor cell differentiation [Molecular Bases of Disease] By www.jbc.org Published On :: 2020-12-18T00:06:18-08:00 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. Full Article
is Ischemic stroke disrupts the endothelial glycocalyx through activation of proHPSE via acrolein exposure [Molecular Bases of Disease] By www.jbc.org Published On :: 2020-12-25T00:06:31-08:00 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. Full Article
is 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] By www.jbc.org Published On :: 2020-12-25T00:06:31-08:00 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. Full Article
is 12th International Forum on Illegal, Unreported and Unregulated Fishing By www.chathamhouse.org Published On :: Fri, 27 Sep 2019 09:15:01 +0000 12th International Forum on Illegal, Unreported and Unregulated Fishing 18 May 2020 TO 22 May 2020 — 2:00PM TO 3:30PM Anonymous (not verified) 27 September 2019 The Chatham House 12th International Forum on Illegal, Unreported and Unregulated (IUU) Fishing took place over the week of 18–22 May 2020. Due to COVID-19, it took the form of a series of daily webinars. The digital conference, which comprised six sessions and three keynote speeches, brought together more than 750 representatives of international organizations, governments, civil society organizations, businesses and academia – from 87 different countries – to discuss the latest initiatives, regulations and research in the areas of fisheries governance and trade in illegal fish products. Full Article
is Structural and biochemical characteristics of two Staphylococcus epidermidis RNase J paralogs RNase J1 and RNase J2 [Protein Structure and Folding] By www.jbc.org Published On :: 2020-12-04T00:06:06-08:00 RNase J enzymes are metallohydrolases that are involved in RNA maturation and RNA recycling, govern gene expression in bacteria, and catalyze both exonuclease and endonuclease activity. The catalytic activity of RNase J is regulated by multiple mechanisms which include oligomerization, conformational changes to aid substrate recognition, and the metal cofactor at the active site. However, little is known of how RNase J paralogs differ in expression and activity. Here we describe structural and biochemical features of two Staphylococcus epidermidis RNase J paralogs, RNase J1 and RNase J2. RNase J1 is a homodimer with exonuclease activity aided by two metal cofactors at the active site. RNase J2, on the other hand, has endonuclease activity and one metal ion at the active site and is predominantly a monomer. We note that the expression levels of these enzymes vary across Staphylococcal strains. Together, these observations suggest that multiple interacting RNase J paralogs could provide a strategy for functional improvisation utilizing differences in intracellular concentration, quaternary structure, and distinct active site architecture despite overall structural similarity. Full Article
is Calreticulin enhances the secretory trafficking of a misfolded {alpha}-1-antitrypsin [Protein Structure and Folding] By www.jbc.org Published On :: 2020-12-04T00:06:05-08:00 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. Full Article
is The cation diffusion facilitator protein MamM's cytoplasmic domain exhibits metal-type dependent binding modes and discriminates against Mn2+ [Molecular Biophysics] By www.jbc.org Published On :: 2020-12-04T00:06:05-08:00 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. Full Article
is Polydisperse molecular architecture of connexin 26/30 heteromeric hemichannels revealed by atomic force microscopy imaging [Protein Structure and Folding] By www.jbc.org Published On :: 2020-12-04T00:06:05-08:00 Connexin (Cx) protein forms hemichannels and gap junctional channels, which play diverse and profound roles in human physiology and diseases. Gap junctions are arrays of intercellular channels formed by the docking of two hemichannels from adjacent cells. Each hexameric hemichannel contains the same or different Cx isoform. Although homomeric Cxs forms have been largely described functionally and structurally, the stoichiometry and arrangement of heteromeric Cx channels remain unknown. The latter, however, are widely expressed in human tissues and variation might have important implications on channel function. Investigating properties of heteromeric Cx channels is challenging considering the high number of potential subunit arrangements and stoichiometries, even when only combining two Cx isoforms. To tackle this problem, we engineered an HA tag onto Cx26 or Cx30 subunits and imaged hemichannels that were liganded by Fab-epitope antibody fragments via atomic force microscopy. For Cx26-HA/Cx30 or Cx30-HA/Cx26 heteromeric channels, the Fab-HA binding distribution was binomial with a maximum of three Fab-HA bound. Furthermore, imaged Cx26/Cx30-HA triple liganded by Fab-HA showed multiple arrangements that can be derived from the law of total probabilities. Atomic force microscopy imaging of ringlike structures of Cx26/Cx30-HA hemichannels confirmed these findings and also detected a polydisperse distribution of stoichiometries. Our results indicate a dominant subunit stoichiometry of 3Cx26:3Cx30 with the most abundant subunit arrangement of Cx26-Cx26-Cx30-Cx26-Cx30-Cx30. To our knowledge, this is the first time that the molecular architecture of heteromeric Cx channels has been revealed, thus providing the basis to explore the functional effect of these channels in biology. Full Article
is Heme oxygenase-2 is post-translationally regulated by heme occupancy in the catalytic site [Protein Structure and Folding] By www.jbc.org Published On :: 2020-12-11T00:06:20-08:00 Heme oxygenase-2 (HO2) and -1 (HO1) catalyze heme degradation to biliverdin, CO, and iron, forming an essential link in the heme metabolism network. Tight regulation of the cellular levels and catalytic activities of HO1 and HO2 is important for maintaining heme homeostasis. HO1 expression is transcriptionally regulated; however, HO2 expression is constitutive. How the cellular levels and activity of HO2 are regulated remains unclear. Here, we elucidate the mechanism of post-translational regulation of cellular HO2 levels by heme. We find that, under heme-deficient conditions, HO2 is destabilized and targeted for degradation, suggesting that heme plays a direct role in HO2 regulation. HO2 has three heme binding sites: one at its catalytic site and the others at its two heme regulatory motifs (HRMs). We report that, in contrast to other HRM-containing proteins, the cellular protein level and degradation rate of HO2 are independent of heme binding to the HRMs. Rather, under heme deficiency, loss of heme binding to the catalytic site destabilizes HO2. Consistently, an HO2 catalytic site variant that is unable to bind heme exhibits a constant low protein level and an enhanced protein degradation rate compared with the WT HO2. Finally, HO2 is degraded by the lysosome through chaperone-mediated autophagy, distinct from other HRM-containing proteins and HO1, which are degraded by the proteasome. These results reveal a novel aspect of HO2 regulation and deepen our understanding of HO2's role in maintaining heme homeostasis, paving the way for future investigation into HO2's pathophysiological role in heme deficiency response. Full Article
is Representative cancer-associated U2AF2 mutations alter RNA interactions and splicing [Molecular Bases of Disease] By www.jbc.org Published On :: 2020-12-11T00:06:20-08:00 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. Full Article
is The heptameric structure of the flagellar regulatory protein FlrC is indispensable for ATPase activity and disassembled by cyclic-di-GMP [Protein Structure and Folding] By www.jbc.org Published On :: 2020-12-11T00:06:20-08:00 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. Full Article
is Cholesterol sensing by CD81 is important for hepatitis C virus entry [Protein Structure and Folding] By www.jbc.org Published On :: 2020-12-11T00:06:20-08:00 CD81 plays a central role in a variety of physiological and pathological processes. Recent structural analysis of CD81 indicates that it contains an intramembrane cholesterol-binding pocket and that interaction with cholesterol may regulate a conformational switch in the large extracellular domain of CD81. Therefore, CD81 possesses a potential cholesterol-sensing mechanism; however, its relevance for protein function is thus far unknown. In this study we investigate CD81 cholesterol sensing in the context of its activity as a receptor for hepatitis C virus (HCV). Structure-led mutagenesis of the cholesterol-binding pocket reduced CD81–cholesterol association but had disparate effects on HCV entry, both reducing and enhancing CD81 receptor activity. We reasoned that this could be explained by alterations in the consequences of cholesterol binding. To investigate this further we performed molecular dynamic simulations of CD81 with and without cholesterol; this identified a potential allosteric mechanism by which cholesterol binding regulates the conformation of CD81. To test this, we designed further mutations to force CD81 into either the open (cholesterol-unbound) or closed (cholesterol-bound) conformation. The open mutant of CD81 exhibited reduced HCV receptor activity, whereas the closed mutant enhanced activity. These data are consistent with cholesterol sensing switching CD81 between a receptor active and inactive state. CD81 interactome analysis also suggests that conformational switching may modulate the assembly of CD81–partner protein networks. This work furthers our understanding of the molecular mechanism of CD81 cholesterol sensing, how this relates to HCV entry, and CD81's function as a molecular scaffold; these insights are relevant to CD81's varied roles in both health and disease. Full Article
is Antibiotic binding releases autoinhibition of the TipA multidrug-resistance transcriptional regulator [Gene Regulation] By www.jbc.org Published On :: 2020-12-18T00:06:18-08:00 Investigations of bacterial resistance strategies can aid in the development of new antimicrobial drugs as a countermeasure to the increasing worldwide prevalence of bacterial antibiotic resistance. One such strategy involves the TipA class of transcription factors, which constitute minimal autoregulated multidrug resistance (MDR) systems against diverse antibiotics. However, we have insufficient information regarding how antibiotic binding induces transcriptional activation to design molecules that could interfere with this process. To learn more, we determined the crystal structure of SkgA from Caulobacter crescentus as a representative TipA protein. We identified an unexpected spatial orientation and location of the antibiotic-binding TipAS effector domain in the apo state. We observed that the α6–α7 region of the TipAS domain, which is canonically responsible for forming the lid of antibiotic-binding cleft to tightly enclose the bound antibiotic, is involved in the dimeric interface and stabilized via interaction with the DNA-binding domain in the apo state. Further structural and biochemical analyses demonstrated that the unliganded TipAS domain sterically hinders promoter DNA binding but undergoes a remarkable conformational shift upon antibiotic binding to release this autoinhibition via a switch of its α6–α7 region. Hence, the promoters for MDR genes including tipA and RNA polymerases become available for transcription, enabling efficient antibiotic resistance. These insights into the molecular mechanism of activation of TipA proteins advance our understanding of TipA proteins, as well as bacterial MDR systems, and may provide important clues to block bacterial resistance. Full Article
is The C-terminal region of the plasmid partitioning protein TubY is a tetramer that can bind membranes and DNA [Protein Structure and Folding] By www.jbc.org Published On :: 2020-12-18T00:06:18-08:00 Bacterial low-copy-number plasmids require partition (par) systems to ensure their stable inheritance by daughter cells. In general, these systems consist of three components: a centromeric DNA sequence, a centromere-binding protein and a nucleotide hydrolase that polymerizes and functions as a motor. Type III systems, however, segregate plasmids using three proteins: the FtsZ/tubulin-like GTPase TubZ, the centromere-binding protein TubR and the MerR-like transcriptional regulator TubY. Although the TubZ filament is sufficient to transport the TubR-centromere complex in vitro, TubY is still necessary for the stable maintenance of the plasmid. TubY contains an N-terminal DNA-binding helix-turn-helix motif and a C-terminal coiled-coil followed by a cluster of lysine residues. This study determined the crystal structure of the C-terminal domain of TubY from the Bacillus cereus pXO1-like plasmid and showed that it forms a tetrameric parallel four-helix bundle that differs from the typical MerR family proteins with a dimeric anti-parallel coiled-coil. Biochemical analyses revealed that the C-terminal tail with the conserved lysine cluster helps TubY to stably associate with the TubR-centromere complex as well as to nonspecifically bind DNA. Furthermore, this C-terminal tail forms an amphipathic helix in the presence of lipids but must oligomerize to localize the protein to the membrane in vivo. Taken together, these data suggest that TubY is a component of the nucleoprotein complex within the partitioning machinery, and that lipid membranes act as mediators of type III systems. Full Article
is A structural and kinetic survey of GH5_4 endoglucanases reveals determinants of broad substrate specificity and opportunities for biomass hydrolysis [Protein Structure and Folding] By www.jbc.org Published On :: 2020-12-18T00:06:18-08:00 Broad-specificity glycoside hydrolases (GHs) contribute to plant biomass hydrolysis by degrading a diverse range of polysaccharides, making them useful catalysts for renewable energy and biocommodity production. Discovery of new GHs with improved kinetic parameters or more tolerant substrate-binding sites could increase the efficiency of renewable bioenergy production even further. GH5 has over 50 subfamilies exhibiting selectivities for reaction with β-(1,4)–linked oligo- and polysaccharides. Among these, subfamily 4 (GH5_4) contains numerous broad-selectivity endoglucanases that hydrolyze cellulose, xyloglucan, and mixed-linkage glucans. We previously surveyed the whole subfamily and found over 100 new broad-specificity endoglucanases, although the structural origins of broad specificity remained unclear. A mechanistic understanding of GH5_4 substrate specificity would help inform the best protein design strategies and the most appropriate industrial application of broad-specificity endoglucanases. Here we report structures of 10 new GH5_4 enzymes from cellulolytic microbes and characterize their substrate selectivity using normalized reducing sugar assays and MS. We found that GH5_4 enzymes have the highest catalytic efficiency for hydrolysis of xyloglucan, glucomannan, and soluble β-glucans, with opportunistic secondary reactions on cellulose, mannan, and xylan. The positions of key aromatic residues determine the overall reaction rate and breadth of substrate tolerance, and they contribute to differences in oligosaccharide cleavage patterns. Our new composite model identifies several critical structural features that confer broad specificity and may be readily engineered into existing industrial enzymes. We demonstrate that GH5_4 endoglucanases can have broad specificity without sacrificing high activity, making them a valuable addition to the biomass deconstruction toolset. Full Article
is Snapshots during the catalytic cycle of a histidine acid phytase reveal an induced-fit structural mechanism [Protein Structure and Folding] By www.jbc.org Published On :: 2020-12-18T00:06:18-08:00 Highly engineered phytases, which sequentially hydrolyze the hexakisphosphate ester of inositol known as phytic acid, are routinely added to the feeds of monogastric animals to improve phosphate bioavailability. New phytases are sought as starting points to further optimize the rate and extent of dephosphorylation of phytate in the animal digestive tract. Multiple inositol polyphosphate phosphatases (MINPPs) are clade 2 histidine phosphatases (HP2P) able to carry out the stepwise hydrolysis of phytate. MINPPs are not restricted by a strong positional specificity making them attractive targets for development as feed enzymes. Here, we describe the characterization of a MINPP from the Gram-positive bacterium Bifidobacterium longum (BlMINPP). BlMINPP has a typical HP2P-fold but, unusually, possesses a large α-domain polypeptide insertion relative to other MINPPs. This insertion, termed the U-loop, spans the active site and contributes to substrate specificity pockets underpopulated in other HP2Ps. Mutagenesis of U-loop residues reveals its contribution to enzyme kinetics and thermostability. Moreover, four crystal structures of the protein along the catalytic cycle capture, for the first time in an HP2P, a large ligand-driven α-domain motion essential to allow substrate access to the active site. This motion recruits residues both downstream of a molecular hinge and on the U-loop to participate in specificity subsites, and mutagenesis identified a mobile lysine residue as a key determinant of positional specificity of the enzyme. Taken together, these data provide important new insights to the factors determining stability, substrate recognition, and the structural mechanism of hydrolysis in this industrially important group of enzymes. Full Article
is Mapping the transition state for a binding reaction between ancient intrinsically disordered proteins [Molecular Biophysics] By www.jbc.org Published On :: 2020-12-18T00:06:18-08:00 Intrinsically disordered protein domains often have multiple binding partners. It is plausible that the strength of pairing with specific partners evolves from an initial low affinity to a higher affinity. However, little is known about the molecular changes in the binding mechanism that would facilitate such a transition. We previously showed that the interaction between two intrinsically disordered domains, NCBD and CID, likely emerged in an ancestral deuterostome organism as a low-affinity interaction that subsequently evolved into a higher-affinity interaction before the radiation of modern vertebrate groups. Here we map native contacts in the transition states of the low-affinity ancestral and high-affinity human NCBD/CID interactions. We show that the coupled binding and folding mechanism is overall similar but with a higher degree of native hydrophobic contact formation in the transition state of the ancestral complex and more heterogeneous transient interactions, including electrostatic pairings, and an increased disorder for the human complex. Adaptation to new binding partners may be facilitated by this ability to exploit multiple alternative transient interactions while retaining the overall binding and folding pathway. Full Article
is Evolving the naturally compromised chorismate mutase from Mycobacterium tuberculosis to top performance [Protein Structure and Folding] By www.jbc.org Published On :: 2020-12-18T00:06:18-08:00 Chorismate mutase (CM), an essential enzyme at the branch-point of the shikimate pathway, is required for the biosynthesis of phenylalanine and tyrosine in bacteria, archaea, plants, and fungi. MtCM, the CM from Mycobacterium tuberculosis, has less than 1% of the catalytic efficiency of a typical natural CM and requires complex formation with 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase for high activity. To explore the full potential of MtCM for catalyzing its native reaction, we applied diverse iterative cycles of mutagenesis and selection, thereby raising kcat/Km 270-fold to 5 × 105 m−1s−1, which is even higher than for the complex. Moreover, the evolutionarily optimized autonomous MtCM, which had 11 of its 90 amino acids exchanged, was stabilized compared with its progenitor, as indicated by a 9 °C increase in melting temperature. The 1.5 Å crystal structure of the top-evolved MtCM variant reveals the molecular underpinnings of this activity boost. Some acquired residues (e.g. Pro52 and Asp55) are conserved in naturally efficient CMs, but most of them lie beyond the active site. Our evolutionary trajectories reached a plateau at the level of the best natural enzymes, suggesting that we have exhausted the potential of MtCM. Taken together, these findings show that the scaffold of MtCM, which naturally evolved for mediocrity to enable inter-enzyme allosteric regulation of the shikimate pathway, is inherently capable of high activity. Full Article
is A highly potent CD73 biparatopic antibody blocks organization of the enzyme active site through dual mechanisms [Methods and Resources] By www.jbc.org Published On :: 2020-12-25T00:06:31-08:00 The dimeric ectonucleotidase CD73 catalyzes the hydrolysis of AMP at the cell surface to form adenosine, a potent suppressor of the immune response. Blocking CD73 activity in the tumor microenvironment can have a beneficial effect on tumor eradication and is a promising approach for cancer therapy. Biparatopic antibodies binding different regions of CD73 may be a means to antagonize its enzymatic activity. A panel of biparatopic antibodies representing the pairwise combination of 11 parental monoclonal antibodies against CD73 was generated by Fab-arm exchange. Nine variants vastly exceeded the potency of their parental antibodies with ≥90% inhibition of activity and subnanomolar EC50 values. Pairing the Fabs of parents with nonoverlapping epitopes was both sufficient and necessary whereas monovalent antibodies were poor inhibitors. Some parental antibodies yielded potent biparatopics with multiple partners, one of which (TB19) producing the most potent. The structure of the TB19 Fab with CD73 reveals that it blocks alignment of the N- and C-terminal CD73 domains necessary for catalysis. A separate structure of CD73 with a Fab (TB38) which complements TB19 in a particularly potent biparatopic shows its binding to a nonoverlapping site on the CD73 N-terminal domain. Structural modeling demonstrates a TB19/TB38 biparatopic antibody would be unable to bind the CD73 dimer in a bivalent manner, implicating crosslinking of separate CD73 dimers in its mechanism of action. This ability of a biparatopic antibody to both crosslink CD73 dimers and fix them in an inactive conformation thus represents a highly effective mechanism for the inhibition of CD73 activity. Full Article
is Role of phospholipid synthesis in the development and differentiation of malaria parasites in the blood [Microbiology] By www.jbc.org Published On :: 2018-11-09T03:40:54-08:00 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. Full Article
is Lipid-tuned Zinc Transport Activity of Human ZnT8 Protein Correlates with Risk for Type-2 Diabetes [Molecular Bases of Disease] By www.jbc.org Published On :: 2016-12-30T00:06:37-08:00 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. Full Article
is Malawi’s Re-Run Election is Lesson for African Opposition By www.chathamhouse.org Published On :: Wed, 01 Jul 2020 19:53:16 +0000 1 July 2020 Fergus Kell Projects Assistant, Africa Programme LinkedIn The overturning of the result in the fresh presidential contest sets a bold precedent for the continent, as a process built upon the resilience of democratic institutions and the collective spirit of opposition. 2020-07-01-Malawi-Chakwera-Election Lazarus Chakwera, leader of the Malawi Congress Party (MCP) arriving at the Mtandire suburb of the capital Lilongwe for an election rally. Photo by AMOS GUMULIRA/AFP via Getty Images. Malawi is only the second African country to annul a presidential election, after Kenya in 2017. It is the first in which the opposition has won the re-run.The initial May 2019 vote had narrowly returned incumbent Peter Mutharika to the presidency. But in February 2020 a landmark ruling by Malawi’s constitutional court annulled the result citing ‘widespread, systematic and grave’ irregularities, including the now-infamous use of corrective fluid in vote tallying, and the Malawi Electoral Commission’s (MEC) failure to address complaints before announcing results. New elections were ordered within 150 days.In a decisive contrast with the previous year, the fresh polls on 23 June saw the coming together of Lazarus Chakwera of the Malawi Congress Party (MCP) and running mate Saulos Chilima of the United Transformation Movement (UTM) to head a coalition of nine opposition parties - having fiercely competed as the leading challengers previously.The constitutional court ruling had also changed Malawi’s electoral system, replacing a first-past-the-post model with one demanding an outright majority, which further encouraged the regional power bases of Malawi’s opposition to cast ego aside and work in alliance with each other.In tandem with a slick digital campaign, the new alliance travelled widely to hold rallies across what is one of the world’s youngest countries, while the elderly Mutharika remained largely confined to the capital. It would be a strategy that ultimately delivered Chakwera to the presidency, polling 58 per cent of votes to Mutharika’s 39.Political opposition elsewhere in Africa should take note from Malawi’s coalition - dialogue, not division, can offer a genuine path to change, especially in those countries with less favourable institutional conditions. Neighbouring Zambia would certainly do well to heed this example ahead of a pivotal election of its own in 2021.A victory built on institutional precedentYet the story here is not only about throwing out an incumbent: Malawians had already done so twice before, rejecting sitting presidents at the polls in 1994 and 2014. It is also not unfamiliar to see public opinion and the judiciary work in parallel to uphold the constitution: former president Bakili Muluzi was twice blocked from abolishing term limits by popular demonstration during his second term, and again prevented from running for a third time in 2009 by the constitutional court.The new result did not arise as the foregone conclusion of a judicial miracle. Rather, throughout the re-run process Malawi has had to repeatedly draw upon the strength of its broad-based institutional foundations. The image of the constitutional court judges arriving to deliver their annulment verdict in February wearing bulletproof vests under their robes was a stark reminder that this was never the easy route to take.In contrast to many other African states, Mutharika was unable to call upon military support as the Malawi Defence Forces (MDF) had moved to shield protesting citizens and protect the judiciary since the 2019 election. The MDF also had previous form in this respect, having defended then-vice president Joyce Banda’s constitutional right to assume the presidency after the incumbent’s death in 2012.And this institutional resilience from the army would facilitate a smooth and mostly peaceful election process during the re-run, despite Mutharika attempts to intervene by replacing the MDF’s commander and his deputy in March 2020.Just ten days before the fresh vote the Mutharika government switched focus back to the country’s legal system by attempting to enforce the premature retirement of Malawi’s chief justice, only to be blocked by the high court. Even as unofficial tallies trickled in, Mutharika’s Democratic Progressive Party (DPP) demanded the MEC annul the result: claiming their monitors were intimidated in MCP strongholds, and requesting unlawful access to scrutinise null and void votes.Headed by a new chairperson, this time the MEC displayed enormous patience in the verification process and openly tackled complaints, now mainly from the DPP. On social media, Malawians celebrated the contrast between images of tally sheets from 2019 and the re-run.Writing a new chapterThere are lessons here too for international partners. UK diplomacy played a subtle role in encouraging Mutharika to accept the legal process - he was invited to appear at the UK-Africa Investment Summit in January - while also helping promoting early dialogue among opposition parties.At a time of pressure for UK engagement to offer clear strategic value, the impact of less easily quantifiable forms of influence should not be overlooked, especially as international observer missions effectively went missing in the discredited 2019 election. Preliminary statements back then from the Commonwealth, European Union, African Union and Southern African Development Community (SADC) struck a mostly congratulatory tone and were non-committal on the issues that would prove decisive in the court ruling. None went on to release their final reports.Malawi must now start to move beyond election mode. Though COVID-19 cases remain low by global standards, a budget already heavily dependent on foreign aid and hampered by 18 months of political uncertainty will be slashed further by the pandemic’s impact. The IMF has predicted GDP growth of just 1% in 2020, down from a pre-coronavirus projection of 5%.As it inherits a major balance of payments crisis, mounting debt and with no tourism revenue to fall back on, the new government will need to use its political capital to push for immediate reform. But it must not forget the core tenet of its campaign. The coalition that defeated Mutharika united the MCP’s rural support base with the middle-class urban following of the UTM. This spirit of unity and inclusion must be expanded and focus on long-term recovery. On this undertaking – unlike the polls – there will be no opportunity for a re-run. Full Article
is Chatham House History: Five Key Moments on Africa By www.chathamhouse.org Published On :: Thu, 09 Jul 2020 15:47:08 +0000 9 July 2020 Christopher Vandome Research Fellow, Africa Programme LinkedIn To mark the centenary of Chatham House, the Africa programme curated an exhibition of archive material which charts how the institute has been both a major forum for discussion on Africa, and an important platform for African leaders to engage in international affairs. Mandela1a.jpg President Nelson Mandela of South Africa addresses an audience at an event co-hosted by Chatham House, the CBI and COSAT on July 10, 1996. As with any history, Chatham House has a long and complex one. Progress has come in fits and starts, sometimes driven by wider social change, but often led by individuals within the institute. When examining the institute's work on Africa, five seminal moments from the history really stood out.The FoundersLionel Curtis is credited as the founder of the institute, having proposed the idea at a meeting at the Hotel Majestic while attending the Treaty of Versailles talks.Curtis served in South Africa during the Second Boer war and subsequent period of unification. He was one of the cohort of officials that served under Lord Milner, later dubbed ‘Milner’s Kindergarten’. Several of this group were involved in the foundation of the institute. A Century of Supporting African Engagement in International Affairs A short presentation highlighting how Chatham House has been both a major forum for discussion on Africa, and an important platform for African leaders. His experiences in South Africa undoubtedly informed his political philosophy - a strong belief in liberal imperialism. This is captured in the emblems of empire inlaid into the roundtable which is still in the Chatham House library, given to Curtis as a wedding gift.But more importantly than his political philosophy, Curtis was an astute social networker and fundraiser who unlocked the finance required to establish the institute. Curtis’s papers in the Chatham House archives depict his almost obsessive following of the career of the South African diamond tycoon Sir Abe Bailey that eventually led to the first significant endowment to the institute - after the building. South African Prime Minister Jan Smuts, a friend of Curtis and early champion of the institute, spoke at a dinner in honour of Bailey’s contribution.Curtis’s connections meant much of the early finance came from South Africa, including from Otto Beit and Percy Molteno, who was also an early financer of the African National Congress (ANC).Hailey’s Africa SurveyIn 1938, Chatham House published Lord Hailey’s monumental Africa Survey. Its detailed 1,837 pages of study came to represent a seismic shift in attitudes towards the continent. Lord Lothian’s foreword emphasises that it grew from an idea of Smuts from 1929, although these origins remain disputed.What is known is that Oxford University had submitted a proposal for a study of the continent to an American foundation which rejected it on the grounds that they didn’t want American money to be used to expand Smut’s doctrine of dominion. The group then merged their own plan into an emerging study by progressive missionary Joseph Oldham.Curtis brought in his friend Lord Hailey to lead the initiative. Hailey was a distinguished civil servant who served in India but never in Africa. The project moved to Chatham House and received a substantial grant from the Carnegie Foundation. Having been originally conceived as a study to reinforce segregationist ideas, the final survey was groundbreaking. Its underlying assumption of basic racial equality debunked the premises of segregation and re-set British attitudes towards Africa.This shift in mindset was hugely significant at the time, but the work would later be criticized for not including any African voices. And, despite carrying his name, Lord Lothian wrote very little of the text. He fell ill, in part due to the pressure of the four-year project, and the work was largely written by notable Africanists Lucy Mair, Charlotte Leubuscher, and Margery Perham. The Africa Survey was updated and reprinted in 1956, including a pull-out map depicting newly-independent Sudan. A sign of real change.Independence and National LiberationThe 1960s was a decade of transformation both on the continent and at Chatham House. The institute became an important conduit for newly-independent African states to engage in international affairs, hosting several independence presidents, including Prime Minister Modibo Keita of Mali, President Léopold Senghor of Senegal, and President Julius Nyerere of Tanzania. Many of these speeches were republished in the Institute’s journal, International Affairs.In January 1962, the Nigerian government invited Chatham House to host a conference in Lagos on the external international relations of the newly-independent African states. But it wasn’t just presidents that were offered a platform. Liberation leaders were also invited to speak as well as conduct research. African Liberation – The Historical and Contemporary Significance of Re-discovered Nationalist Speeches at Chatham House of Dr Eduardo Mondlane and Oliver Tambo Two speeches at Chatham House in 1968 and 1985 by African nationalist leaders Dr Eduardo Mondlane and Oliver Tambo at key moments of their liberation struggle for majority rule are re-examined for their significance. Dr Bernard Chidzero, a later finance minister in independent Zimbabwe, wrote on African nationalism in International Affairs in 1960, and conducted a multi-year study at the institute resulting in the publication of a book. In 1968, Eduardo Mondlane, founding president of FRELIMO, made an important speech on the nationalist fight for independence in Mozambique.In 1961, Kenneth Younger, a new director of the institute, increased its research capacity on Africa through significant new hires. Catherine Hoskyns’s 1965 book on the Congo crisis became the seminal study on the topic. Dennis Austin, who had experience in West Africa, wrote the definitive work on Ghana’s transition to independence in 1964.African InstitutesChatham House has also been involved in the establishment of think-tanks across the world, including three in Africa.The South African Institute of International Affairs (SAIIA) was founded in 1934, in response to proposals made by Chatham House the previous year at the inaugural British Commonwealth Relations Conference. An East African Institute of International Affairs was also established in Nairobi but did not survive. The Nigerian Institute of International Affairs (NIIA) was formed in 1961 in Lagos. Its founding director general Dr L A Fabunmi, said ‘the main task of the Nigerian Institute of International Affairs will be to create, develop, and sustain an African perspective in world affairs’.Chatham House has maintained a good working relationship with its sister institutes. In 2005 a special edition of International Affairs was launched at NIIA, the first time in the journal’s history it was launched outside the UK. And SAIIA staff and leaders are regular contributors to Chatham House events and research, including a partnership on the study of Central and Eastern European relations with Africa.The Africa ProgrammeCreated in 2002. this was the first time Chatham House had a dedicated research team working on Africa, producing a sustained and balanced assessment of events on the continent. Throughout the 1980s and 1990s, work on Africa had been conducted by regionally-focused study groups, and the personal interests of the director for studies, Dr Jack Spence – a leading authority on South African foreign policy. An earlier attempt to create a more formal programme in the late 1990s fell victim to staff turnover.In 1998, the British Angola Forum (BAF) was formed and found a home at Chatham House. It marked a departure from the institute’s focus on post-colonial 'Anglophone Africa'. At the end of Angola's civil war in 2002, under the leadership of Dr Alex Vines, the BAF morphed into a continent-wide programme.Since then, the Africa Programme has produced more than 160 original research publications, and organizes between 120-140 events on Africa every year. The Africa Programme is marking the centenary of the institute with a major research theme on Foreign Relations and African Agency in International Relations.Chatham House’s work on Africa has its roots in the liberal imperialism of the post war leaders. But throughout the last 100 years, it has been a platform for progress, playing a vital role in informing policymakers and facilitating debate on African affairs, as well as highlighting African perspectives on global issues.The exhibition on the History of Africa at Chatham House was first displayed at the world-renowned fine art auctioneers and valuers Bonham’s in London for a reception in February 2020 marking the centenary of the Institute. It was curated by Christopher Vandome with the assistance of the Chatham House Library, and digitized with the help of the Institute’s communications department. Please contact the Library team for further information regarding the archive.Chatham House Centenary:Throughout our centenary year in 2020, Chatham House marks a century of influence, independent analysis and trusted dialogue with a number of exciting initiatives. Throughout the year, we explore key political moments from the institute's history and reflect on how Chatham House and other think-tanks should approach the future. Full Article
is Is Evaluating COVID-19 About the WHO or Country Responses? By www.chathamhouse.org Published On :: Sat, 11 Jul 2020 13:23:41 +0000 11 July 2020 Dr Charles Clift Senior Consulting Fellow, Global Health Programme @CliftWorks Striking the right balance in membership and terms of reference is challenging for the evaluation panel set up to examine the coordinated international health response to coronavirus. 2020-07-11-WHO-Data-Coronavirus-Tedros Examining the global response of indivudual countries and the World Health Organization (WHO) to coronavirus. Photo Illustration by Rafael Henrique/SOPA Images/LightRocket via Getty Images. When the resolution was passed by World Health Organization (WHO) member states at the World Health Assembly (WHA) in May requesting an evaluation ‘at the earliest appropriate moment’ of lessons learned from the WHO-coordinated international health response to COVID-19, it was generally thought the appropriate moment would be when the pandemic was on the wane.Yet the Independent Panel for Pandemic Preparedness and Response has actually been established at a time when - as noted by WHO director-general Dr Tedros Adhanom Ghebreyesus in his announcement of the panel - the pandemic is still accelerating.In most of the world the virus is not under control, and cases have actually doubled in the last six weeks. So why now?Emphasis on global solidarityThroughout the pandemic so far, Dr Tedros has emphasised two main points – the need for urgent action by countries, and the imperative need for global solidarity. In announcing the panel, he said this is the ‘defining crisis of our age’ and that ‘we cannot defeat this pandemic as a divided world … the COVID-19 pandemic is a test of global solidarity and global leadership’.He may well see establishing the panel now - when the pandemic still has a long way to run - as an opportunity to reinforce messages which have hitherto seemed to fall on deaf ears, notably saying ‘we are in the midst of the battle of our lives, and we have to do better’. And he has also said that we should learn lessons now that will be useful in the continuing fight against the pandemic.Establishing both the membership of the panel and its terms of reference has been left largely in the hands of the co-chairs – distinguished ex-politicians Helen Clark of New Zealand and Ellen Johnson Sirleaf of Liberia. But they will have to construct the panel in close consultation with member states on the basis of their proposals for membership – a process that will likely be fraught by the divisive politics which have already so upset Dr Tedros.In addition, embedded in the mandate from the WHA resolution is the phrase ‘WHO-coordinated international health response’ – negotiated language which is intentionally ambiguous and reveals an unresolved tension.Does it mean the panel should principally focus on WHO’s performance, which is what several countries – including the US – want to see? Or should it give at least equal weight to the way countries have responded individually and collectively, as Dr Tedros and the WHO may want to see?These different interpretations mean both the construction of the panel and its terms of reference could be highly contentious. Most countries, including China and the US but also others, will not want their responses to be subjected to independent investigation. Nor will they want to include panel members likely to be critical of their responses. This suggests the possibility that there will be political pressure to focus the enquiry principally on the performance of WHO rather than that of countries – an outcome Dr Tedros would not welcome.It remains to be seen how the co-chairs will manage these highly political issues, and avoid the panel becoming an extension of ‘pandemic politics’ by other means. Can it come to definitive conclusions in the midst of a pandemic and, if so, how likely are they to be heeded?It is also highly likely that several other reviews will be launched, wholly independently of oversight by WHO and its member states, as happened following the 2014 Ebola outbreak. This provides opportunities for a variety of perspectives on both the performance of WHO, and of individual countries.Already, The Lancet has announced its own Commission on COVID-19 with a broad mandate covering both the health and economic responses to the pandemic. Both this and the Independent Panel for Pandemic Preparedness and Response are likely to be only the first of many COVID-19 reviews. Full Article
is COVID-19: The Hidden Majority in India's Migration Crisis By www.chathamhouse.org Published On :: Mon, 13 Jul 2020 12:58:13 +0000 13 July 2020 Dr Champa Patel Director, Asia-Pacific Programme @patel_champa While the social and economic costs of coronavirus lockdowns, travel bans and social distancing initially focused on international migrants, there has been increasing attention paid to the plight of internal migrants. 2020-07-13-India-Farming-Migration Migrant workers plant paddy in a field at Jhandi village in Patiala, India. Photo by Bharat Bhushan/Hindustan Times via Getty Images. The World Bank estimates that the magnitude of internal migration is about two‐and‐a‐half times that of international migration. Within India, an estimated 40 million internal migrant workers, largely in the informal economy, were severely impacted by the government’s COVID-19 lockdown.With transportation systems initially shut down, many had no recourse to travel options back to homes and villages, resulting in harrowing journeys home. Those who were able to make it home found, in some instances, villages refusing entry because of fears of transmission.The shocking images of migrants forced to walk in desperation showed the enormity of the crisis as well as some of the challenges posed by an extended lockdown in India where so many people live hand to mouth and cannot afford not to work.Migrant workers and the informal economyThe complete failure of the government to anticipate the needs of this group, and the subsequent distress caused, has made visible a large workforce who experience precarity of work and often live hand to mouth.One key challenge is the lack of robust data on the scale of internal migration. While estimates abound, there is no proper data collection system in place to accurately record temporary, seasonal and circular migration patterns. However, it is estimated that more than 90% of working people in India are engaged in the informal economy, with states such as Uttar Pradesh and Bihar accounting for more than 80% of workers in this sector.A recent government labour force survey estimated that more than 71% of people with a regular salary working in non-agricultural industries had no written job contract. Nearly half of workers are not eligible for social security benefits.Daily-wage workers are particularly vulnerable, with limited or no access to social security and most living in poverty. Living hand to mouth, their loss of livelihoods has led to a lack of money to pay rents or pay for food. Women are impacted whether because of their gender, responsibilities as caregivers, or as members of disadvantaged castes and communities.COVID-19 has massively impacted this group of workers. Stranded Workers Action Network found that 50% of workers had rations left for less than one day; 74% had less than half their daily wages remaining to survive for the rest of the lockdown period; and 89% had not been paid by their employers at all during the lockdown.According to Supreme Court proceedings, relief camps are housing some 660,000 workers; some 2.2 million people also rely on emergency food supplies. Job losses, and home and food insecurity have left this group highly vulnerable.In March 2020, in response to COVID-19, the Indian government instituted the Pradhan Mantri Garib Kalyan Package (PMGKB), a $22.6 billion relief package. The World Bank announced $1 billion funding to accelerate social protection support, in part through the PMGKB.This support would work alongside pre-existing initiatives such as the Public Distribution System (PDS), which covers 800 million people, and Direct Benefit Transfers (DBT). This cash injection could help address one of the key challenges facing India’s piecemeal and uneven social protection programmes – inadequate funding. India’s spending on public social protection excluding health is just 1.3% of the GDP.However, there are still other challenges to overcome. One is how to ensure coordination and coverage within, and across, differing states. The second is how to transition multiple schemes into one integrated system that can be accessed anywhere within the country, particularly important when many workers are on the move. There is an urgent need for a comprehensive system, which is adaptive and flexible to needs and provides adequate social and income support.Another coverage issue relates to the use of direct cash transfers (DCTs) to support people impacted by the loss of livelihoods, where funds are deposited within bank accounts. Such measures fail to consider the significant numbers of people who do not have access to banks and will not be able to access this support.Wider impact on livelihoods and remittancesThere is a risk, with extended lockdown and risks of further waves of infection, that labour shortages could negatively impact the economy. There is a wider need to support re-entry back into the workforce and support livelihoods. National Survey Sample data shows that between 2007 and 2008, internal remittances amounted to US$10 billion. These domestic transfers financed over 30% of all household consumption in remittance-receiving households.But future migration for work is likely to be severely impacted. As restrictions begin to ease, employers and businesses cannot necessarily rely on cheap available labour. Having faced destitution and hardship, many may wish to stay closer to families and local support networks.As Irudaya Rajan notes in The New Humanitarian, it is likely ‘there will be a reduction in long-distance migration in India after this’, as many migrants will be wary of being stranded again. This would be hugely detrimental to stimulating the economy as reverse migration could push down wages and subsequently demand.Another issue may be returning migrant workers, who have been working overseas, over half of whom work in the Gulf. It is unclear if, or when, migrants will be able to return to work, with the World Bank estimating that remittances from this group could fall by about 23%.However, what is striking has been India’s support for this group - the Vande Bharat Mission has deployed flights and naval ships to help return migrant workers, especially vulnerable groups - in marked contrast to the lack of preparation and care for internal migrants.One factor for this may be the volume of remittances these migrant workers bring to the Indian economy, but it overlooks the contribution of internal remittances, on which there is far less robust data.But the current challenges can also be an opportunity. The scale of the migrant crisis has made visible an often-overlooked population of workers. With political will, and investment at federal and state levels, this could be an opportunity to transform livelihoods.As thoughts will turn to how to stimulate economies and get people back to work, it is imperative that those in authority turn their minds to how to create a more just society, that invests in healthcare, and has a social protection system that supports the most vulnerable in society.Migrants are not just objects of charity that need support. Internal migrants are key income generators that play a vital role in Indian society and should never be overlooked again.This article was originally published in Routed Magazine. Full Article
is The Folly and Risk of Lopez Obrador’s Washington Trip By www.chathamhouse.org Published On :: Wed, 15 Jul 2020 16:34:54 +0000 15 July 2020 Arturo Sarukhan Associate Fellow, US and the Americas Programme (based in the US) @Arturo_Sarukhan LinkedIn President Andres Manuel Lopez Obrador’s decision to travel to the US was met with concern and incredulity in Mexico and bafflement among many Democrats in the US. Being seen as a close ally to Donald Trump could be detrimental to the future of bilateral relations. 2020-07-15-Mexico-Protest-US-Migration Demo against Donald Trump's migration policies at the San Ysidro port of entry in Tijuana, Baja California state, Mexico. Photo by GUILLERMO ARIAS/AFP via Getty Images. For a leader who had not travelled abroad since his inauguration – skipping G20 and APEC summits and the UN General Assembly – and who is probably one of the most intellectually incurious and disinterested Mexican presidents of the modern era when it comes to global issues, President Andres Manuel Lopez Obrador could have certainly waited until after the US elections in November to travel to Washington and personally engage with President Donald Trump .Instead, Lopez Obrador – who has sought at all cost to avoid conflict with his US counterpart, having decided that bending the knee was a better option than standing his ground with Trump – waded straight into electoral politics in the US, despite his repeated assurances to the contrary.The decision to travel now to Washington was fraught with political and diplomatic challenges, not least the fact that President Trump will use President Lopez Obrador as an electoral prop.To American audiences, at a time when the US is riven by social and political convulsion unseen in 50 years since the Vietnam War and the civil rights movement, meeting with Trump in Washington just before the general campaign starts was seen by many as a pat on the back for a polarizing and unpopular president.In Mexico, most discussion has been about the merits and timing of the visit, with one El Financiero newspaper poll conducted a week before showing public support (59%) for the trip, while a post-visit Reforma newspaper survey showed that a substantial majority of those polled (69%) believe a Biden victory in November is a better outcome for Mexico.While it’s true that Lopez Obrador returned to Mexico unscathed, his visit – and his baffling Rose Garden remarks stating that Trump (the most anti-Mexican US president in modern history) has shown respect to Mexico and Mexicans – is certainly a slap in the face to migrants in the US, 11 million of whom are Mexicans, to American NGOs and activists that defend the rights of migrants and enlightened immigration and asylum policies, and a boon to Trump’s dog-whistle xenophobia and chauvinism.Lopez Obrador’s words added insult to injury by asserting the US president has never imposed anything on Mexico, blithely ignoring Trump’s March 2019 threat to impose punitive tariffs on Mexico unless the country deterred and stopped Central American transmigration flows through Mexico on their way to the US.Certainly if the purpose of the visit was to celebrate the July 1 entry into force of the USMCA – a spin made even more hollow by the fact that Canadian Prime minister Justin Trudeau decided to skip the event – then Lopez Obrador should have been reaching out to the Speaker Nancy Pelosi and the Democratic leadership to meet and thank them too, given the important role they played in supporting the revamping of NAFTA and the ratification of the USMCA.The best-case scenario is that the meeting between the presidents will be leveraged by both governments to address looming hurdles with the entry into force of the USMCA.But Trump still seems intent on wielding punitive tariffs and mercantilist measures to extract concessions from either Canada or Mexico. And across the border, the Lopez Obrador government – and his party in Congress – continue enacting abrupt policy shifts and changes to the rules across different sectors of the economy that bode ill for the level playing field required under the USMCA.What could have easily been achieved via a virtual event has now morphed into a second successive Mexican government jumping on the Trump electoral bandwagon, after Enrique Peña Nieto’s ill-advised invitation to then-candidate Trump to travel to Mexico, and a new opportunity for the US president to ‘pimp’ Mexico for his campaign purposes. Perceptions have certainly deepened among Democrats that Lopez Obrador prefers to see Trump re-elected.Although Lopez Obrador’s aim was to buy Mexico time between now and January of next year by hoping this visit will contain Trump’s anti-Mexican tirades on the campaign trail, whether or not Trump stops using Mexico as a political-electoral piñata is yet to be seen. I would not hold my breath.Moreover, for a leader whose default position is ‘the best foreign policy is domestic policy’, the trip lays bare a paradox in Lopez Obrador’s mantra. It is precisely Mexico’s domestic weaknesses and failings that create foreign policy vulnerabilities, particularly vis-à-vis the Trump administration. And it is likely these will be used in the coming weeks and months to once again to pressure Mexico in what has become Trump’s ‘Sinatra Policy’ towards his southern neighbour: 'My Way'.Perception is indeed reality, and Lopez Obrador – and more importantly Mexico – can ill-afford to be perceived as Trump’s patsies at this juncture of American history. As many expected, it only took four hours after President Lopez Obrador’s White House remarks for Trump-supporting Hispanic-outreach social media accounts to start piggybacking on them. Campaign officials have also specifically said they will likely use his quotes in TV ads aimed at Hispanic voters later this year.In addition, there is a potentially bumpy road ahead for Mexico’s relationship with the Democratic Party. The statements and tweets issued by former vice-president Joe Biden, Biden campaign surrogates and officials, prominent Hispanic Democrats in Congress, and the Democratic National Chair signal as such, as does a letter sent the same day of the visit by Democratic representatives regarding outstanding labour issues in Mexico related to USMCA compliance and enforcement.This trip could have a long-standing impact for Mexico’s relationship with the US – and US society – and the voters that will determine the future of this country in the decades to come. Lopez Obrador’s meeting with Trump could well become a ‘travel now, pay later’ moment in Mexico-US relations. Full Article
is Emerging Economies: Where is the Debt Problem? By www.chathamhouse.org Published On :: Thu, 16 Jul 2020 20:21:38 +0000 16 July 2020 David Lubin Associate Fellow, Global Economy and Finance Programme @davidlubin Just two months ago it appeared self-evident that emerging economies faced a devastating inability to service their foreign debt, mostly denominated in dollars. That has turned out to be wrong, for now at least. 2020-07-16-India-Banking Yes Bank branch of Malcha Marg, in New Delhi, India. Photo by Vipin Kumar/Hindustan Times via Getty Images. Back in April, nervousness about external debts reached its peak when highly-respected economists Carmen Reinhart and Kenneth Rogoff suggested emerging economies with less than a AAA credit rating be offered a moratorium on all their external debt service payments.Although such a proposal might make sense if emerging economies were actually facing any serious shortage of access to foreign exchange, it is a difficult case to make. What we should worry about is not the external debt of emerging economies, but rather the large increases in government debts denominated in their own currencies.In the first six months of 2020, borrowers from emerging economies issued more than $400 billion of Eurobonds to international investors, up by one-fifth over the same period in 2019. Most of these bonds were sold by borrowers with relatively high credit ratings, but many of the poorest countries do not fear for their access to international capital markets - largely because the US Federal Reserve increased global supply of dollars to a point where their availability is beyond question.Much of the panic about emerging economies’ external debt comes from ‘sticker shock’ - the bald fact that developing countries’ external debt rose by $4.1 trillion in the decade to 2018 generates much hand-wringing.But the increase in gross external debt of developing countries looks a lot scarier than the net increase in debt, which sets off a country’s foreign assets - mostly foreign exchange reserves - against its liabilities. And it is net that counts.At the end of 2018, foreign exchange reserves covered 70% of the external debt of low and middle income developing countries - much lower than a decade ago, when that coverage was above 100%. But in the 1980s and 1990s – two decades of financial instability largely because of excessive foreign debt – the coverage was 15%. By that measure, we are far from crisis territory.Complacency about the external debt burden of developing countries is quite wrong. But, if complacency is misplaced, so is panic.The debt growing most worryingly is the domestic debt of governments. There are large, systemically important emerging economies who will suffer eye-watering increases in public debt this year thanks to a combination of collapsing GDP and the fiscal effort needed to save lives.In Brazil, public debt is rising from 75% GDP last year to a level that could top 100% in 2020. South African public debt is rising from just over 60% last year to something close to 80% GDP. These are truly unprecedented levels of debt.So why worry about a government’s domestic debt? These are debts which are denominated in these countries’ own currency. So surely the central bank can just print the currency needed to repay their obligations if more conventional solutions – such as tax increases – will not work.But it is one thing for the US Federal Reserve to increase supply of dollars on a massive scale, since the world is hungry for them - it is quite another thing if emerging economies do the same with their currencies which almost entirely lack the many attractions of the dollar. That remains the currency of the pre-eminent global superpower whose capital markets offer legal certainty and depth of liquidity. And other highly developed economies have a similar privilege.And yet printing money – in effect, asking the central bank to finance budget deficits – does seem as though it could become a more attractive option for many emerging countries. Importantly, international fund managers have lost interest in buying bonds issued by emerging economy governments in their local currencies. Just a few years ago, foreign investors owned more than 40% of South Africa’s public debt. That has fallen sharply to 30% and is unlikely to rise.Monetising budget deficits was once anathema, since it was routinely associated with uncontrolled rates of inflation - bad news not only for firms trying to decide whether to invest but also for the poor, who suffer disproportionately when inflation accelerates.Right now there are emerging economies – such as Indonesia – whose central banks lend directly to the government, and the sky has not fallen in. The rupiah has been remarkably stable this year. However, there are other examples – Argentina, Turkey – where central bank financing of government deficits has been associated with uncomfortably high inflation rates.This needs careful watching. The biggest risk is the accumulation of public debt threatening longer-term growth. If firms stop investing because they worry about the risks to the value of their currency as domestic public debt explodes, emerging economies will have a tough time growing their way out of these debts.It could be this, rather than the external debt of emerging economies, that is the biggest risk to the post-coronavirus economic environment in the developing world. Full Article
is The UK’s Huawei Decision: Why the West is Losing the Tech Race By www.chathamhouse.org Published On :: Fri, 17 Jul 2020 16:36:31 +0000 17 July 2020 Dr Yu Jie Senior Research Fellow on China, Asia-Pacific Programme @yu_jiec LinkedIn Joyce Hakmeh Senior Research Fellow, International Security Programme; Co-Editor, Journal of Cyber Policy @joycehakmeh LinkedIn On 5G and the technological race, the answer is a visionary rather than a reactive approach and, so far, the West has opted for the latter. GettyImages-1140107267.jpg A pedestrian walks past a Huawei product stand at a telecommunications shop in central London on 29 April 2019. Photo: Getty Images. The UK’s decision to ban its mobile providers from buying new Huawei 5G equipment after December 2020 and removing all the company’s 5G kit from their networks by 2027 is a blow to Huawei and China, but it is one battle in a long war that the West is currently losing.5G’s significance for the next generation of technology is indisputable and so is its critical role in helping countries achieve digital transformation and economic success. Not only does it offer faster and better connection speeds and greater capacity, it also transforms the way people interact with online services. And it will allow industry to automate and optimize processes that are not possible today.Due to its transformative importance, what is in essence a technological issue has turned into a contest over global technological leadership that extends beyond the US-China rivalry and has created tensions between the US and its long-time allies. Yet 5G is just one key technology in a more expansive landscape that will underpin the future of the world’s critical infrastructure, including in areas such as quantum computing, biotechnology, artificial intelligence, the internet of things and big data.To achieve technological leadership in these domains requires governments to invest in a long-term, strategic and agile vision that is able to encompass the interdependencies between these areas and then leverage the resulting technological advances for economic progress. It also requires governments working with each other and with the private sector to support research and development and to create companies with leading-edge technologies that can compete globally.China understands this and has a national and international vision to establish itself as a technological superpower. Re-balancing from a hub of labour-intensive manufacturing to a global innovation powerhouse is the absolute priority of the ruling Chinese Communist Party.China’s state-led approachIn the earlier part of this journey, commercial espionage and IP theft of western R&D were at the heart of the Chinese way of competing. Now, Beijing is cultivating national champions that can drive China’s technological innovation, with the goal of using domestic suppliers to reduce reliance on foreign technology at home as well as extending its international outreach. In the 5G area, Beijing has introduced domestically the so-called ‘New Infrastructure Investments Fund’, which earmarks special loans to boost 5G technology applications in medical devices, electric vehicles and communication platforms. This Fund constitutes a major part of the stimulus package for China’s post-COVID economic recovery.Apart from 5G, China's recent launch of a second state-funded semiconductor development fund valued at $29 billion, following an earlier $20 billion fund for the same purpose, shows the extent to which state financial resources are being utilized in China’s quest to become technologically self-sufficient.It is too early to know if the Chinese government’s industrial policies will eventually achieve the technological self-sufficiency Beijing has long desired. But its growing national capabilities have stoked serious concerns across the West and led to the current US administration’s determined effort to dismantle Chinese high-tech companies.China’s approach to macroeconomic management diverges significantly from that of the US and other market economies, particularly in its policy towards driving innovation. Due to the legacy of a state-planned economy, China is certain that simply relying on market forces is insufficient.While Beijing financially supports government-controlled technological enterprises, Washington takes a laissez-faire, light-touch approach by the state to the business sector. The US believes that a politicized process of distributing public money is inherently susceptible to rent-seeking and corruption, and gets in the way of competitive innovation. In line with most liberal economists, many Western governments believe the government should refrain from market intervention. For its part, Beijing stresses a state-dominated economy as a necessary precondition both to the future growth of the Chinese economy and to the legitimization of one-party rule. If the pro-market economists’ view is correct, the US should have little to fear from Chinese industrial innovation policy in the long-term. Let Beijing waste money and distort resource allocation, while Washington follows its private sector-led principles, confident that this approach will produce a more competitive economy in the long run.Using the leverage of technical standardsBut one area that should concern the US and that illustrates the Chinese vision for global technological dominance is technical standard setting. Technical standards determine how technologies work with each other, enabling their interoperability around the world, meaning they can function irrespective of where they are being used.The Chinese leadership has long understood the relationship between technical standards and economic power. Standards help to monetize technological innovation and research and can help shape new technologies. China has therefore been playing an increasingly active role in international standards organizations to legitimize Chinese technologies, whereas the US, which historically has been highly influential in this area, has not been participating as much or as effectively.China has also been using its Belt and Road Initiative (BRI) as an opportunity to internationalize the distribution of its standards to countries signed up to the BRI. The so-called Digital Silk Road, which has been described as China’s most important global governance initiative, acts as a route to accelerate this process. Later this year, China is expected to launch its new ‘China Standards 2035’ plan, which aims to shape how the next generation of technologies will work together.China’s preferred model and its recent actions have given Western leaders much to worry about. But standing up to China’s growing global influence in high technology and re-establishing the West’s desired technological edge will take much more than achieving a common front on excluding China from their 5G networks. It requires a long-term vision built on the power of competitive markets, backed by solid investment in the next generation of technology. This will require, in turn, much greater cooperation between Western governments and between them and their private sectors.And, whilst recent protective steps taken in Washington and other Western capitals may slow down China’s trailblazing in the technology sphere, it will only hasten China's determination to become tech self-sufficient in the long term. This will increase the probability of a splintered internet, which will have negative repercussions for all. Full Article
is Russia’s Behaviour Risks Weaponizing Outer Space By www.chathamhouse.org Published On :: Mon, 27 Jul 2020 14:19:39 +0000 27 July 2020 Dr Beyza Unal Deputy Director, International Security Programme @beyzaunal Google Scholar Mathieu Boulègue Research Fellow, Russia and Eurasia Programme @matboulegue LinkedIn Google Scholar With negotiations in Vienna between the US and Russia hoping to prevent the weaponization of space, how much do Russia’s satellites pose a threat to the peaceful use of outer space, ask Beyza Unal and Mathieu Boulègue? GettyImages-1209576417.jpg Russia's President, Vladimir Putin, during a video link with cosmonauts on the International Space Station (ISS). Photo: Getty Images. Days before the publication of last week’s report into Russian activity in the UK, and the subsequent call from several UK parliamentarians for a swift response to the ‘Russian threat’, Russia tested a new anti-satellite weapon capability releasing a small projectile from its Kosmos-2543 sub-satellite.Kosmos-2543, a small satellite contained inside a larger satellite, Kosmos-2542, and 'birthed’ into orbit in late 2019, recently came under scrutiny in January 2020 when it was reportedly caught ‘buzzing’ US spy satellites in Low Earth Orbit.By releasing a small projectile from the Kosmos-2543 sub-satellite, the US claims that Russia has launched a new projectile into orbit with relatively high speed – estimated at around 500 km per hour – leading to concerns about the potential of Russia to develop this technology as a weapon to target foreign satellites.It is not the first time Moscow has relied on a Russian doll – or matryoshka – approach to launching satellites into outer space. In October 2017, a sub-satellite, Kosmos-2521, was ejected from its main satellite, Kosmos-2519, into a high-speed object in low orbit.The Russian Ministry of Defence has declared that its latest activity is just for ‘routine’ inspections and surveillance of Russia’s other space assets, with the government’s official statement avoiding recognizing the existence of the new object while, at the same time, Kremlin spokesperson, Dmitry Peskov, recalling Russia’s commitment for the ‘complete demilitarization’ of space.While it is possible that Russia’s matryoshka satellites have indeed been developed to carry out routine repairs of Russia’s space fleet, they also have the potential to interfere with, and destroy, other satellites with such action needing to be considered a threat until Russia demonstrates otherwise.Russia’s use of outer spaceRussia is not the only state investigating anti-satellite weaponry capabilities. There is a wider trend (e.g. China, India, US) to demonstrate advanced space capabilities with nefarious, if not directly offensive, intent. But, for the past few years, Russia in particular, has been provocative in testing its space weapon capabilities. For example, in April 2020, Russia launched and tested into low orbit the PL-19 Nudol direct-ascent anti-satellite (DA-ASAT) interceptor missile system from the Plesetsk Cosmodrome demonstrating its space assets with potential offensive capabilities, in particular, Russia’s capacity to destroy satellites in Low Earth Orbit.In addition, the satellites, Kosmos-2535 and Kosmos-2536, launched in July 2019, are also suspected to be operating beyond their official mission of studying Russian orbital assets. It is reported that these satellites conducted a close proximity activity, coming within one kilometre from each other, which led to the creation of orbital debris.Russia’s space strategyBy exploiting asymmetric advantages in space, Russia seeks to leverage its capabilities against competitors in space and in other domains, falling in line with its wider military strategy as well as its current Federal Space Programme for 2016 to 2025.Russian space activities also have a cyber and electronic warfare angle. With the help of remote-sensing capabilities, Russian spy satellites potentially seek to disrupt military and civilian satellite communications and navigation systems. Indeed, in 2018, French authorities publicly accused Russia of seeking to intercept communication satellites for French and Italian armed forces putting data transmission through Western civilian and military satellites at risk of interception.Furthermore, earlier this year, both Kosmos-2542 and 2543 came within 160 kilometres of a US spy satellite, US KH-11, similarly to Russia ‘buzzing’ around the British Isles or submarine surveillance that Norway and Sweden have been subjected to recently.Shadowing and tailing in space is regarded as spying and this recent anti-satellite weapon test is part of a trend which demonstrates Russia’s persistent space strategy for close-proximity operations with foreign countries.Orbital hypocrisyDespite Russia’s calls for a treaty to prevent the placement of weapons in outer space, there remains little international trust in Russia’s behaviour in space so far with a US-Russia Space Security Exchange meeting scheduled to take place in Vienna on 27 July to discuss outer space stability and security.This is amid a backdrop of bilateral nuclear arms control talks on the extension of the extant nuclear weapons reduction treaty, New START, which is scheduled to expire in February 2021. There is no guarantee, however, that the talks will achieve anything especially since the future of outer space requires a wider multilateral dialogue with all parties involved – including China.Anti-satellite tests (ASATs) are a particularly dangerous form of weapon. Not only do they create major vulnerabilities in a domain where so much of humanity depends on for navigation, communications and environmental monitoring, they are also primarily a target for destabilization and undermining global positioning information in times of crisis.And, perhaps most significantly, they possess the highly destructive potential to create even more space debris in Earth’s orbits that endanger the peaceful use of satellites and could do serious damage to large parts of the economies of developed and developing countries.Avoiding space warfareSpace is for all but there is a risk that it is being hijacked by a few. It is time to re-assert and reinforce the rules, principles and norms of responsible state behaviour in outer space enshrined in the 1967 Outer Space Treaty and its associated international agreements.And, because the treaty specifically prohibits stationing nuclear weapons and other weapons of mass destruction in orbit or on celestial bodies, it is necessary to build on it to ban other types of weapons in space.Space has been militarized since 1957 with the launch of Soviet satellite Sputnik. But the increasing weaponization of space adds more uncertainty, and unveils more vulnerabilities, that states need to address before space warfare becomes a reality. Full Article
is Nile Basin States Must Persist with Water Diplomacy By www.chathamhouse.org Published On :: Tue, 11 Aug 2020 14:03:31 +0000 11 August 2020 Owen Grafham Assistant Director, Energy, Environment and Resources Programme LinkedIn Google Scholar Ahmed Soliman Research Fellow, Horn of Africa, Africa Programme @AhmedSolHoA Dr Nouar Shamout Water Resources and Sustainability (Independent Researcher) After multiple failed negotiations, any serious breakdown in current talks mediated by the African Union would be dangerous for regional stability. The international community must ramp up its support for this crucial diplomacy to ensure that an agreement is reached. 2020-08-12-Dam-Nile-Ethiopia The Blue Nile river passes through the Grand Ethiopian Renaissance Dam (GERD) near Guba in Ethiopia. Photo by EDUARDO SOTERAS/AFP via Getty Images. Ongoing talks between Egypt, Ethiopia and Sudan attempting to find a diplomatic and peaceful solution to the dispute over the Blue Nile Basin offer a unique opportunity for trans-boundary cooperation and have huge significance for a region dealing with multiple complex issues.With trust clearly at a premium, the continuation of talks demonstrates good faith, but there is an urgent need to strengthen negotiations through all available diplomatic channels. The African Union (AU) is well-placed to continue mediating, but sustained high-level engagement is also needed from regional and international partners such as the EU and US, as well as multilateral support in terms of both financial and technical resources.A tense history to overcomeAt the heart of this dispute is the new Grand Ethiopian Renaissance Dam (GERD) – set to become Africa's biggest hydroelectric dam when complete. Egypt and Sudan, who lie downstream, fear that Ethiopia, as the dam builders, will effectively gain control of the flow of the Nile, a turn of events that radically changes the way that water resources have been shared in the region.Egypt - widely described as a ‘gift of the Nile’ - is almost entirely dependent on the Nile to meet its various water needs, and is the major beneficiary of the 1929 and 1959 agreements on using the shared river’s water. The 1959 agreement gives Egypt a share of 55.5 billion cubic meters (BCM) annually out of 74 billion available, and a veto right over projects being developed upstream, while Sudan is allocated 18.5 BCM.Crucially neither of these old agreements recognises the interests of other upstream countries on the Nile, some of which have asserted their own development ambitions on the river over the last two decades and pushed for a new agreement to enshrine equitable rights and harmonious use of the water.One such country is Ethiopia where the Blue Nile River originates. The GERD is a central part of Ethiopia’s ambitions for economic prosperity. The dam, which is largely self-financed, will have a capacity of 74 BCM when completed, enough to provide abundant cheap energy to power both national and regional developments. Currently, more than half Ethiopia’s 110 million people do not have access to electricity, but demand is increasing by 30 per cent annually.Unclear impactsThe unclear impact of the GERD – and lower volumes of water – on food security and agriculture complicate the negotiations. Egypt, Ethiopia and Sudan’s populations are set to increase significantly in the coming decades and each are already dealing with significant challenges around food insecurity and nutrition, which in Egypt and Sudan, are partly exacerbated by the colonial-era agricultural structures set up to exploit cash crops.Any change in water quality would have a huge impact on the 67% of Egyptian farm holdings considered as ‘small’ – the majority of which are on the banks of the Nile. And changes in water volumes might increase desertification and loss of livelihoods, potentially causing civil unrest if not addressed properly.The environmental impact of the GERD on the complex Nile River system also raises concerns about the river’s ecosystem, the surrounding environment, and the river’s downstream course. Despite talks in 2015 leading to an agreement on declaration of principles, thorough technical studies have not been implemented.Although there is little evidence that overall water levels in the Nile Basin have reduced in recent years, climate change is causing more variation in the Nile’s flow which increases the risk of flooding and extended droughts. Downstream states are also concerned about impacts from any breaches, damage or failure of the dam, including possible seismic activity.Of course, the GERD also offers some added value to the downstream states. The dam can help manage floods in Sudan, reduce the significant water loss to evaporation - as in the case of Lake Nasser - and lessen the effect of sediment on downstream dams. In Sudan, where less than one-quarter of the estimated 70 million hectares of arable land is currently cultivated, any reduction in seasonal flooding would boost agricultural output and aid economic recovery. The dam will offer Ethiopia significant opportunities for the trade of cheap renewable energy to Sudan and neighbouring states earning it a possible $1bn a year in revenues. And adopting a more ‘basin-integrated’ management approach can be a springboard for enhanced regional cooperation between the three states.But geopolitical tensions between the three have escalated since satellite imagery revealed apparent significant filling of the dam prior to reaching any agreement. Ethiopia has long said it would begin filling the dam during its rainy season, but insists the filling occurred naturally through June-July from rainfall and runoff and its first-year target of 4.9 BCM was reached without needing to close the dam gates. Egypt and Sudan have restated their calls for a binding legal agreement on the rules for filling and management of disputes.Security response not the answerInternal pressures are particularly acute, with all three countries experiencing public uprisings and regime change in the last decade, and current leaders are under pressure not to appear weak from influential sections of society pushing a hard nationalist line.Hawkish elements in Egypt have long supported a more securitized response to any potential threats from the GERD, and the recent request from President Sisi that Egyptian air forces be ready to handle targets inside and outside of the country was interpreted as a threat to Turkey in Libya, and Ethiopia.Egypt has also asked for the GERD to be discussed at the UN Security Council but Ethiopia’s Nobel peace prize-winning prime minister Abiy Ahmed, facing significant internal unrest himself, has made it clear that a costly confrontation is not in anyone’s interests. Meanwhile, Sudan’s transitional government - being jointly run by civilians and the military - is keen to assert its own interests on the Nile but has also played a conciliatory role with its neighbours. Increased engagement of Gulf states in the Horn of Africa and the impacts of conflicts in Libya, Yemen and Syria add more complexity to the overall regional picture.Certainly none of the major parties sharing the river would benefit from a hard security response to the dam. For Egypt, such a move would torpedo its re-engagement in Sub-Saharan Africa under President Sisi and likely lead to its expulsion from the AU. For Ethiopia, overt conflict would be a huge setback for its development and regional integration ambitions. And Sudan’s nascent transition can ill-afford to be part of another regional conflict.Thankfully, such an outcome is both highly unlikely and historically rare, and behind the scenes there has been significant progress. Some reports suggest a provisional agreement has been reached on the volume of filling required and the timeframe for the filling to happen. If so, most dispute now revolves around what to do in the event of a drought, provisions for information exchange, and how to translate all this into a binding agreement.A two-phase approach, consisting of a short-term deal on filling and operating the GERD followed by discussions on future developments and allocation, could be the best way to reach a lasting settlement and replace the extremely outdated existing water-sharing agreements.Reaching a successful deal between the three countries is not easy as it requires brave leadership and political goodwill, a de-escalation of long-standing rhetoric and brinkmanship, and a willingness to compromise on all sides to ensure the gaps between the countries' positions are significantly narrowed.What is required is a determined effort to keep the countries talking and provide the solutions which can bridge the parties’ differences, build confidence, and secure the vital diplomatic success so badly needed for wider stability and progress in the region. Full Article
is Choosing Kamala Harris Puts Identity at the Heart of Presidential Race By www.chathamhouse.org Published On :: Wed, 12 Aug 2020 10:06:36 +0000 12 August 2020 Dr Leslie Vinjamuri Director, US and the Americas Programme; Dean, Queen Elizabeth II Academy for Leadership in International Affairs @londonvinjamuri Google Scholar Joe Biden’s choice of Kamala Harris as his running mate will have a lasting impact on how Americans think about the presidential ticket, and confirms the violent killing of George Floyd unleashed a demand for racial equality that continues to have dramatic impact. 2020-08-12-Kamala-Harris Senator Kamala Harris speaks during a Senate Homeland Security and Governmental Affairs hearing. Photo by ALEXANDER DRAGO/POOL/AFP via Getty Images. Despite being such a historic selection, in certain aspects, Kamala Harris does not actually signal change. She is a moderate in the Democratic Party, an insider more than an outsider, and a highly experienced leader with national, state level and city level credentials. She worked as a district attorney in San Francisco for several years before being elected attorney general for the state of California, and then to the US Senate in 2016. Harris also stood as a candidate against Biden in the contest to become the Democratic Party's presidential candidate.Like Joe Biden, she is a highly experienced leader with strong credentials. But California is solidly blue, so she cannot deliver a new state for him. In many ways she is a safe choice and — at a time when Biden is far ahead of Donald Trump in the polls and America faces a lot of uncertainty — many leading political analysts say safe is exactly what the Democratic candidate needs. The 2020 US Presidential Elections and the State of the Nation Amy Walter and Adam Boulton discuss the current state of the nation and what this means for the US presidential election. But certainly as a signal to the American people, and the rest of the world, of what America is and what it stands for, the choice of Kamala Harris is truly historic. The senator from California is the first African-American woman, and the first Asian-American woman, on the presidential ticket. If Biden wins in November, Harris becomes the first female vice-president.The historic aspects do not end there. Harris also represents a rapidly growing segment of the US population, but one that gets far less mention — multi-racial Americans. The exact size of America’s multi-racial population has been notoriously hard to measure, especially as it has only been 15 years since the US Census Bureau allowed Americans to choose more than one race when completing their census form. But America has long seen itself as a melting pot, so Harris’s place on the ballot underscores a national narrative with a deep resonance across the country, not least among America’s schoolchildren.In recent weeks, it came to feel inevitable Biden would choose an African-American running mate. His selection comes at a time when more Americans than ever before have taken to the streets to protest the brutal killing of George Floyd and racial injustice. And the demand for racial equality has been accelerated by the COVID-19 pandemic which has disproportionately affected African-Americans who are dying from the virus at around double the rate of their white American counterparts, while twice the number of black businesses are closing relative to their white counterparts.The choice of Harris also speaks to another fundamental aspect of the ‘American dream’. She is the daughter of two immigrant parents, her father being from Jamaica and her mother from India. Immigration has become one of the toughest issues in US politics, and immigrants have suffered repeated rhetorical attacks from Trump. One of Harris’s first stands in the US Senate was against President Trump’s entry ban to the US on several countries with majority Muslim populations.When it comes to questions of identity, the choices that the US electorate now face in November could not be more stark. President Trump used the opportunity of the July 4 weekend to deliver a speech at Mount Rushmore which appeared to actively seek division and to ignite America’s cultural wars.By choosing Kamala Harris, Biden also continues to signal that he will lead from the moderate wing of the Democratic Party.Harris may be left of Biden, but she is far to the right of other well-known progressive candidates, especially Elizabeth Warren. She has not, for example, supported more far-reaching measures to redistribute wealth, especially the proposal for a wealth tax. And she has a track record of being tough on crime during her years as a prosecutor. Although she played an active role in recent protests and signalled her commitment to police reform and anti-lynching laws, not all young or progressive protesters will be easily persuaded by her credentials.However, for voters who hoped for a more progressive candidate, two factors play to the advantage of the Biden-Harris ticket. This election still looks set to be a referendum on President Trump and — especially now — his ability to manage the public health and economic crises at home. And Biden has continued to include the progressive side of the Democratic Party in his plans, giving Bernie Sanders and Alexandria Ocasio-Cortez key roles in developing climate proposals, and establishing a series of Unity task forces to bring the party together.There are also other more conventional factors at play. Biden has relied on the support of African-American and also female voters. While Harris may not broaden this support, it should help ensure these voters turn out — if primarily via their postal box — to vote for Biden. His choice of Kamala Harris answers the one big outstanding question facing his candidacy and signals the true beginning of the race to the White House. Full Article
is By Inventing Military Threats, Lukashenka Is Playing with Fire By www.chathamhouse.org Published On :: Thu, 20 Aug 2020 11:42:32 +0000 20 August 2020 Keir Giles Senior Consulting Fellow, Russia and Eurasia Programme @KeirGiles LinkedIn Google Scholar 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. 2020-08-20-Belarus-Protest-Election 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 movementsIncreased 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 openAlthough 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. Full Article
is Rage Against the Algorithm: the Risks of Overestimating Military Artificial Intelligence By www.chathamhouse.org Published On :: Thu, 27 Aug 2020 14:13:18 +0000 27 August 2020 Yasmin Afina Research Assistant, International Security Programme @afinayasmin LinkedIn 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. GettyImages-112897149.jpg 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 applicationsFirst, 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 limitationsAnother 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 complianceAnother 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 experimentationAlgorithms 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. Full Article
is US Electorate Shows Distrust of the Realities of Foreign Policy By www.chathamhouse.org Published On :: Fri, 04 Sep 2020 11:36:03 +0000 4 September 2020 Bruce Stokes Associate Fellow, US and the Americas Programme (based in the US) @bruceestokes 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. 2020-09-04-US-Election-Black-Voter 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. Full Article
is Is the Juba Peace Agreement a Turning Point for Sudan? By www.chathamhouse.org Published On :: Mon, 14 Sep 2020 13:34:19 +0000 14 September 2020 Dame Rosalind Marsden Associate Fellow, Africa Programme @MarsdenRosalind Sudan is looking towards a brighter future after the initialling of the Juba peace agreement on August 31, an important first step towards bringing peace to the conflict zones and laying the foundation for democratic transition and economic reform throughout the country. 2020-09-14-Sudan-Peace-Deal-Juba Chairman of Sudan’s Sovereign Council, Lt General Abdel Fattah al Burhan (left), South Sudan President Salva Kiir (centre) and the Sudanese Prime Minister Dr Abdalla Hamdok (right) greet people gathering during the initialling of the Sudan peace deal with the rebel groups in Juba, South Sudan. Photo by AKUOT CHOL/AFP via Getty Images. Although there is a long road ahead to achieve sustainable peace and formidable challenges remain, the hope is Sudan can turn the page on decades of war that has left hundreds of thousands dead and millions displaced, particularly in Darfur and the Two Areas (South Kordofan and Blue Nile).The peace agreement, between Sudan’s transitional government and the Sudan Revolutionary Front (SRF), a broad alliance of armed and other movements, and Minni Minawi’s Sudan Liberation Movement, is not yet comprehensive as it did not include two other important armed movements.Expected to be formally signed in early October, the deal has been hailed as a ’historic achievement’ by the UN secretary-general, and the international community also commended the government of South Sudan for its positive role as mediator and urged hold-out groups to join the peace process. Much does depend on delivering on the agreement, and the experience of implementing past peace accords in Sudan has been dismal, particularly when it comes to bringing tangible benefits to people on the ground.What potentially makes the Juba agreement different is that Sudan’s civilian-led transitional government aspires to deliver peace, justice and democracy in line with the goals of the revolution; that the agreement was negotiated between the Sudanese themselves, with a light touch from the South Sudanese mediation and low-key logistical and technical support from the international community; and that much of the negotiations were conducted between former comrades, in marked contrast to the confrontational atmosphere that prevailed during the Bashir era.As Prime Minister Abdalla Hamdok put it: ’This is a Sudanese peace, made with our own hands and by our own efforts’ and: ’This is not a paper agreement, but is a living organism that needs care, attention and political will from all of us’.Achievements of the agreementThe result of almost one year’s hard work in Juba, the agreement is comprehensive in scope and addresses the fundamental issues of Sudan’s crises in Darfur, the Two Areas and other marginalized regions, albeit in a mixture of regional and national protocols. It goes a long way to realizing the vision of a democratic ‘New Sudan’ based on respect for the diversity of the Sudanese people and equal citizenship without religious, ethnic, cultural or gender discrimination.There is a focus on the concerns of historically marginalized populations in Sudan’s conflict zones and disadvantaged areas, and it addresses root causes of conflict, such as issues of identity, marginalization, the relationship between religion and state, governance, resource-sharing, land issues, social justice, and equality at the national level.The deal also looks to resolve the consequences of conflict, such as humanitarian relief, the safe and voluntary return of IDPs and refugees to their original lands and compensation, eviction of illegal settlers and the development and reconstruction of the conflict-affected areas. It provides for significant devolution of power and resources to the regions, including autonomy for the Two Areas and restoration of a single Darfur region. On transitional justice, the government has committed to cooperate fully with the International Criminal Court (ICC) and ensure Bashir and others subject to arrest warrants will ‘appear before’ the ICC.This deal will change the face of the transitional government by bringing marginalized forces to the centre of the political process. The transitional period will extend to 2023, with the armed movements having three seats in the (currently 11-member) Sovereign Council and 25% of seats in the Cabinet and soon-to-be-formed Legislative Assembly.The power-sharing provisions have been criticized as disproportionate to the size of the movements’ political constituencies and military presence inside Sudan. But the movements argue significant representation in the government is necessary to support implementation and that their arrival in Khartoum will help to strengthen the transition to democracy.Establishing a single, national professional army, reflective of the diversity of Sudan and with a new military doctrine opens the way for much-needed comprehensive security sector reform. During the transition, this will include the creation of a 12,000 strong joint force between government security forces and the armed movements to help protect civilians in Darfur. Importantly, mechanisms allowing for civilian input on security reforms are also established.The deal also guarantees religious freedom and the separation of religion from politics. This ensures religion will not be exploited by state institutions as it was during the Bashir-era, provides for the constitution to be based on equal citizenship, and for the establishment of a National Commission for Religious Freedom to protect the rights of Christians and other minorities. In the Two Areas, the autonomous government will have special legislative powers to pass laws based on the secular 1973 Constitution.Increasing inclusivityKey to achieving inclusive and sustainable peace is ensuring popular ownership and finding ways to engage civil society stakeholders and marginalized communities such as nomads in dialogue, reconciliation and social peace initiatives. The negotiations were mainly a top-down elitist process. Although the UN brought IDPs, tribal leaders and women’s groups to Juba for short periods, there was limited participation by civil society. However, the agreement provides for a wider range of stakeholders to feed into a comprehensive peace through reconciliation and transitional justice mechanisms, follow-on conferences and an inclusive National Constitutional Conference.Achieving a comprehensive peace will also mean bringing other armed movements on board, particularly those led by Abdel Aziz Al Hilu and Abdel Wahid Al Nur, both of whom hold significant territory, forces and support (in the Two Areas and Darfur respectively). Negotiations in Juba with Abdel Aziz had stalled over his demands for a secular state or, failing that, the right to self-determination, but he has now reached a preliminary agreement with Prime Minister Hamdok on a way forward.Other challenges of implementing peaceTurning the peace agreement into reality on the ground will face many other challenges given the fragility of a civilian-military transitional government, distrust, and competition between the signatory movements and some political parties, as well as increasing insecurity in many parts of the country caused by armed militias, inter-tribal violence, the proliferation of weapons, and sabotage by elements of the former regime. There is also likely to be resistance from groups such as illegal settlers who see their interests being threatened.With its economy in meltdown because of economic mismanagement by the Bashir regime, COVID-19, and unprecedented floods, finding resources to implement the peace deal is far beyond the means of Sudan’s cash-strapped government. Implementation therefore requires sustained and generous support from its regional and international partners, including the country’s urgent removal from the US State Sponsors of Terrorism list, which is preventing debt relief, access to concessionary loans and large-scale foreign investment. With donor budgets under heavy pressure, raising money will be hard, but by continuing to support a nascent democracy in a strategically important but unstable region, Sudan’s allies will be safeguarding their long-term interests.If properly implemented, the Juba peace agreement is a major first step towards creating a ‘New Sudan’ based on peace, equal citizenship and social justice. Key tests of whether Sudan can finally turn the page are whether the signatory movements and other revolutionary forces can unite to deliver the dividends of peace for the victims of Sudan’s conflicts, and embrace inclusion rather than tribalism and narrow political affiliation; whether the remaining armed movements are ready to start serious negotiations for a comprehensive peace; and whether Sudan now receives the support and attention it deserves from the international community. Surely Sudan has already come too far for this historic opportunity to be lost. Full Article
is Novichok Poisons Germany's Relations with Russia By www.chathamhouse.org Published On :: Mon, 14 Sep 2020 15:47:16 +0000 14 September 2020 John Lough Associate Fellow, Russia and Eurasia Programme @JohnLough The conclusion of a specialist German military laboratory that Alexey Navalny was poisoned with the nerve agent novichok has shocked Germany’s political class and is forcing the government to re-assess relations with Russia. 2020-09-14-Nord-Stream-2-Pipe A worker at the construction site of a section of the Nord Stream 2 natural gas pipeline near Kingisepp, Leningrad Region. Photo by Alexander DemianchukTASS via Getty Images. When Chancellor Angela Merkel offered to provide medical care for Navalny in Germany after he fell ill from suspected poisoning in Russia, she could have hardly expected her humanitarian gesture would trigger a crisis in her country’s relations with Russia.Merkel has used uncharacteristically blunt words to condemn the apparent attempt on Navalny’s life, saying the use of novichok raises serious questions that only the Russian government could answer. She described Navalny as being the ‘victim of a crime’ which was a violation of the ‘basic values and basic rights’ that Germany and its allies were committed to. Her tone and body language certainly showed how strongly she felt about the issue.Germany’s Social Democrat foreign minister Heiko Maas then followed up by suggesting Russia’s response might force Germany to change its position on the construction of the Nord Stream 2 pipeline which aims to double Germany’s direct gas imports from Russia under the Baltic Sea.This is a dramatic change of position since his party has been a staunch supporter of the controversial project. Two Christian Democrat candidates for the Chancellorship called for a stop to the pipeline together with representatives from the Greens, who could be part of a government coalition after the 2021 federal election.Claims of hostile provocationThe Russian foreign ministry shot back with a statement condemning Berlin’s ‘unsubstantiated accusations and ultimatums’ and claiming Germany was using Navalny’s hospitalisation to discredit Russia internationally. It demanded Germany share data and test results with the Russian Prosecutor’s Office, saying any failure to comply would be ‘a crude hostile provocation against Russia’ that risked consequences for the bilateral relationship as well as ‘serious complications in the international situation’.Such strong language from Moscow towards Germany has not been seen for over 30 years, and is all the more remarkable as Putin has personally invested heavily in the relationship with Germany in view of its economic and political importance, and its strong desire for constructive ties with Russia. Until 2014, Russian analysts viewed Germany as Russia’s ‘lobbyist’ in Europe.Berlin is now trying to downplay the situation, claiming the Navalny poisoning is not actually a Germany-Russia matter and referring it to the Organisation for the Prohibition of Chemical Weapons. By consulting with its EU and NATO allies, Berlin is further internationalising the issue to reduce impact on the bilateral relationship.Such a forceful reaction to the poisoning reflects Germany’s increasing frustration with the Kremlin. The murder in broad daylight in Berlin in August 2019 of a Chechen wanted by the Russian authorities has been traced to the FSB. And the publication of a report in May 2020 into the hacking of the German parliament in 2015, including Merkel’s parliamentary office, was a further reminder of how far Russia had deviated from the course of partnership that Berlin believed the two countries had established in the 1990s.Merkel described the cyberattack as ‘monstrous’, saying it was part of a strategy of hybrid warfare that includes ‘disorientation’ and ‘manipulation of facts’. Further tension has been added since the recent Belarus election as Moscow is supporting Lukashenka’s presidency whereas the EU does not recognise him as the legitimate president.This accumulation of events is forcing German policymakers to recognise the Russian leadership is a menace to its own citizens, its neighbours and to Germany itself. Although Berlin abandoned several of its illusions about partnership with Russia in 2014 when it led the EU response to Russia’s annexation of Ukraine and destabilization of south-eastern Ukraine, it still hoped that the Kremlin would see reason and adjust its policies.It combined sectoral economic sanctions with continuing dialogue and a joint effort to help settle the conflict in Donbas despite the obvious fact that Russia was a party to the conflict. It still believed that Moscow had an interest in finding a compromise. Instead, experience so far suggests Russia has a greater interest in keeping the conflict ‘semi-frozen’ as a way of forcing Ukraine to compromise.Controversially, Germany also saw the need to expand energy relations with Russia in a bid to stabilise ties and draw Russia closer to Europe. The Nord Stream 2 pipeline initiated in September 2015 by Gazprom and five European companies – two of them German – is a monument to this policy.Even though this project lacked an overall economic rationale, the German government supported it – much to the consternation of the Baltic States, Poland and others who objected to what they saw as Berlin’s insistence on a ‘Russia-first’ policy that undercut the interests of Ukraine. This was because the pipeline’s purpose is to re-route gas flows away from Ukraine, depriving it of transit revenues and a lever of influence in its relations with Moscow.It now appears the German government is finally waking up to the fact that its attempts to encourage better Russian behaviour have failed. Policy looks set to become tougher and a moratorium on Nord Stream 2 now appears a real possibility if Russia fails to investigate the Navalny poisoning and provide adequate answers.However, sanctioning the new pipeline is likely to provoke counter-measures against German business interests in Russia. If Berlin is determined to pursue this tougher line, it could end up facing an uncomfortable dilemma and being forced to consider alternative ways to signal displeasure at Russia’s criminal actions. Full Article
is Inhibition of mitochondrial oxidative metabolism attenuates EMCV replication and protects {beta}-cells from virally mediated lysis [Immunology] By www.jbc.org Published On :: 2020-12-04T00:06:05-08:00 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. Full Article
is CDKN2A/p16INK4a suppresses hepatic fatty acid oxidation through the AMPK{alpha}2-SIRT1-PPAR{alpha} signaling pathway [Metabolism] By www.jbc.org Published On :: 2020-12-11T00:06:21-08:00 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. Full Article
is The glucose-sensing transcription factor ChREBP is targeted by proline hydroxylation [Metabolism] By www.jbc.org Published On :: 2020-12-11T00:06:20-08:00 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. Full Article
is The role of uncoupling protein 2 in macrophages and its impact on obesity-induced adipose tissue inflammation and insulin resistance [Immunology] By www.jbc.org Published On :: 2020-12-18T00:06:18-08:00 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. Full Article
is Methylarginine metabolites are associated with attenuated muscle protein synthesis in cancer-associated muscle wasting [Protein Synthesis and Degradation] By www.jbc.org Published On :: 2020-12-18T00:06:18-08:00 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. Full Article
is Ascertaining the biochemical function of an essential pectin methylesterase in the gut microbe Bacteroides thetaiotaomicron [Metabolism] By www.jbc.org Published On :: 2020-12-25T00:06:31-08:00 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. Full Article
is Methylated PP2A stabilizes Gcn4 to enable a methionine-induced anabolic program [Metabolism] By www.jbc.org Published On :: 2020-12-25T00:06:31-08:00 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. Full Article
is In crystallo screening for proline analog inhibitors of the proline cycle enzyme PYCR1 [Metabolism] By www.jbc.org Published On :: 2020-12-25T00:06:31-08:00 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. Full Article
is Serum lipoprotein-derived fatty acids regulate hypoxia-inducible factor [Metabolism] By www.jbc.org Published On :: 2020-12-25T00:06:31-08:00 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. Full Article
is The bacterial cell division protein fragment EFtsN binds to and activates the major peptidoglycan synthase PBP1b [Metabolism] By www.jbc.org Published On :: 2020-12-25T00:06:31-08:00 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. Full Article
is Inhibition of oxidative metabolism by nitric oxide restricts EMCV replication selectively in pancreatic beta-cells [Enzymology] By www.jbc.org Published On :: 2020-12-25T00:06:30-08:00 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. Full Article
is Coronavirus infection and PARP expression dysregulate the NAD metabolome: An actionable component of innate immunity [Molecular Bases of Disease] By www.jbc.org Published On :: 2020-12-25T00:06:30-08:00 Poly(ADP-ribose) polymerase (PARP) superfamily members covalently link either a single ADP-ribose (ADPR) or a chain of ADPR units to proteins using NAD as the source of ADPR. Although the well-known poly(ADP-ribosylating) (PARylating) PARPs primarily function in the DNA damage response, many noncanonical mono(ADP-ribosylating) (MARylating) PARPs are associated with cellular antiviral responses. We recently demonstrated robust up-regulation of several PARPs following infection with murine hepatitis virus (MHV), a model coronavirus. Here we show that SARS-CoV-2 infection strikingly up-regulates MARylating PARPs and induces the expression of genes encoding enzymes for salvage NAD synthesis from nicotinamide (NAM) and nicotinamide riboside (NR), while down-regulating other NAD biosynthetic pathways. We show that overexpression of PARP10 is sufficient to depress cellular NAD and that the activities of the transcriptionally induced enzymes PARP7, PARP10, PARP12 and PARP14 are limited by cellular NAD and can be enhanced by pharmacological activation of NAD synthesis. We further demonstrate that infection with MHV induces a severe attack on host cell NAD+ and NADP+. Finally, we show that NAMPT activation, NAM, and NR dramatically decrease the replication of an MHV that is sensitive to PARP activity. These data suggest that the antiviral activities of noncanonical PARP isozyme activities are limited by the availability of NAD and that nutritional and pharmacological interventions to enhance NAD levels may boost innate immunity to coronaviruses. Full Article
is How is the war in Ukraine affecting perceptions of Russia in Africa? By www.chathamhouse.org Published On :: Fri, 10 Jun 2022 08:23:56 +0000 How is the war in Ukraine affecting perceptions of Russia in Africa? Explainer Video NCapeling 10 June 2022 Aanu Adeoye outlines how the invasion of Ukraine is affecting perceptions of Russia across the Africa region. He says the voting patterns at the United Nations (UN) shows that the majority of African countries are unhappy about Russia’s actions, but there is not a united voice as there is in the European Union (EU) and North America. Certain countries are heavily influenced by historical ties with Russia going back to the Soviet era and their own struggles for liberation, while others tend to remain non-aligned whenever possible. Full Article
is Now is the moment to launch an African vaccine industry By www.chathamhouse.org Published On :: Sun, 31 Jul 2022 17:05:22 +0000 Now is the moment to launch an African vaccine industry The World Today mhiggins.drupal 31 July 2022 The continent plans to make 60 per cent of its vaccines by 2040. After the failure of the world to help in the pandemic, it’s high time, says Ngozi Erondu. The lack of an African vaccine industry has been a glaring concern for decades. Before the pandemic, 99 per cent of Africa’s vaccines were manufactured outside the continent. As well as endangering the lives of millions, this situation has inhibited social and economic progress on the continent. In response, the Africa Centres for Disease Control and Prevention (Africa CDC) has undertaken an ambitious plan, outlined in the Partnerships for African Vaccine Manufacturing (PAVM) Framework for Action, to develop the nascent African vaccine manufacturing sector into an end-to-end industry by 2040. The framework aims to raise the share of African-manufactured vaccines used across the continent to 60 per cent by 2040, or the equivalent to up to 1.7 billion doses annually. Seven of every 10 vaccines used in Africa are currently donated through Gavi, the Vaccine Alliance. Most are administered within childhood immunization programmes and are largely manufactured either in India, or by multinational vaccine manufacturers in North America or Japan. Vaccine donations have inhibited the development in Africa of vaccines and other countermeasures against diseases. Though the Ebola virus was discovered in Central Africa in 1976, vaccine development was not adequately funded until it emerged in Europe in 2014. Human monkeypox resurfaced in Nigeria in 2017, yet the global Coalition for Epidemic Preparedness Innovations only targeted it for vaccine development in July this year. The pandemic highlighted Africa’s fatal dependency on imported vaccines. Only 20 per cent of Africans are fully vaccinated against Covid-19, due to the failure of countries in the Global North to ensure the equitable distribution of vaccines via the COVAX facility to 40 per cent of the world’s most vulnerable people. The pandemic also confirmed that Africa could not rely on fellow states of the Global South. At the height of the Delta variant outbreak in early 2021, India halted vaccine exports to Africa, where only 1.5 per cent of the population had at that time received any vaccine doses. After decades of discussions, there are signs that Africa could soon succeed in creating its own vaccine industry. First, the 55-member African Union is in the process of establishing the African Medicines Agency, a regional regulatory body. ‘The new public health order’ Additionally, the African Export-Import Bank and African Development Bank (AfDB) have established a foundation to provide financial and strategic support for the development of the pharmaceutical industry and the consolidation of regional vaccination programmes in Africa (the foundation would potentially negotiate intellectual property rights and licensing issues but that remains to be seen). Second, studies show there is an emerging middle class in Africa. In a 2011 report by the AfDB, this was estimated at some 56 million households. Potentially, this means many people will be able to buy vaccines and medicines made in Africa. About a third of African countries currently pay for their vaccine needs. According to PAVM forecasts, the value of the total African market could reach between $3 billion and $17 billion by 2040. The recent entry into effect of the African Continental Free Trade Area should also prove conducive to African vaccine development. Through economic integration, free movement and harmonized regional standards, countries that invest in their biopharmaceutical and medical technology sectors may attract employees, regional and international businesses, and investment. Further, the pandemic has encouraged people to relocate to countries with, or planning for, universal healthcare. Building an African pharmaceutical industry from the ground up could take much longer than two decades and cost tens of billions of dollars. Nevertheless, the moment seems ripe, and timely support has been forthcoming from influential regional actors, including Rwandan President Paul Kagame, South Africa’s Cyril Ramaphosa, and private sector business executives, including the Zimbabwean-born billionaire Strive Masiyiwa. With a pandemic treaty embedding equity in prevention, preparedness and response some way off, and given the limitations surrounding the recent World Trade Organization compromise on the TRIPS waiver – which temporarily waives Covid-19 vaccine patent protections for poorer countries – it is doubly important for Africa to build up its own pharmaceutical industry and emergency systems. With a pandemic treaty some way off, it is important for Africa to build up its own pharmaceutical industry In 2021, John Nkengasong, then director of Africa CDC, wrote of the necessity of a post-pandemic ‘new public health order’ for Africa. Such a change may threaten the global health organizations, industries and institutes who derive payment from ‘saving Africa’ during emergencies. Additionally, through strengthening Africa CDC, other actors such as the World Health Organization may find that they have a diminished strategic role on the continent. While Africa should not dismiss these valuable and long-standing partnerships, it must take the opportunity to advance its interests and to assume leadership in this important area. Full Article