ni Policeman's murder won't deter fight against crime says Superintendent Nicholson By jamaica-star.com Published On :: Mon, 11 Nov 2024 12:52:26 -0500 A police sergeant who was shot and injured at his home in Portmore, St Catherine, on Thursday night succumbed to his injuries on Monday morning. Full Article
ni ARID4B is critical for mouse embryonic stem cell differentiation towards mesoderm and endoderm, linking epigenetics to pluripotency exit [Developmental Biology] By www.jbc.org Published On :: 2020-12-18T00:06:18-08:00 Distinct cell types emerge from embryonic stem cells through a precise and coordinated execution of gene expression programs during lineage commitment. This is established by the action of lineage specific transcription factors along with chromatin complexes. Numerous studies have focused on epigenetic factors that affect embryonic stem cells (ESC) self-renewal and pluripotency. However, the contribution of chromatin to lineage decisions at the exit from pluripotency has not been as extensively studied. Using a pooled epigenetic shRNA screen strategy, we identified chromatin-related factors critical for differentiation toward mesodermal and endodermal lineages. Here we reveal a critical role for the chromatin protein, ARID4B. Arid4b-deficient mESCs are similar to WT mESCs in the expression of pluripotency factors and their self-renewal. However, ARID4B loss results in defects in up-regulation of the meso/endodermal gene expression program. It was previously shown that Arid4b resides in a complex with SIN3A and HDACS 1 and 2. We identified a physical and functional interaction of ARID4B with HDAC1 rather than HDAC2, suggesting functionally distinct Sin3a subcomplexes might regulate cell fate decisions Finally, we observed that ARID4B deficiency leads to increased H3K27me3 and a reduced H3K27Ac level in key developmental gene loci, whereas a subset of genomic regions gain H3K27Ac marks. Our results demonstrate that epigenetic control through ARID4B plays a key role in the execution of lineage-specific gene expression programs at pluripotency exit. Full Article
ni 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
ni 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
ni 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
ni Hydrogen/deuterium exchange memory NMR reveals structural epitopes involved in IgE cross-reactivity of allergenic lipid transfer proteins [Protein Structure and Folding] By www.jbc.org Published On :: 2020-12-18T00:06:18-08:00 Identification of antibody-binding epitopes is crucial to understand immunological mechanisms. It is of particular interest for allergenic proteins with high cross-reactivity as observed in the lipid transfer protein (LTP) syndrome, which is characterized by severe allergic reactions. Art v 3, a pollen LTP from mugwort, is frequently involved in this cross-reactivity, but no antibody-binding epitopes have been determined so far. To reveal human IgE-binding regions of Art v 3, we produced three murine high-affinity mAbs, which showed 70–90% coverage of the allergenic epitopes from mugwort pollen–allergic patients. As reliable methods to determine structural epitopes with tightly interacting intact antibodies under native conditions are lacking, we developed a straightforward NMR approach termed hydrogen/deuterium exchange memory (HDXMEM). It relies on the slow exchange between the invisible antigen-mAb complex and the free 15N-labeled antigen whose 1H-15N correlations are detected. Due to a memory effect, changes of NH protection during antibody binding are measured. Differences in H/D exchange rates and analyses of mAb reactivity to homologous LTPs revealed three structural epitopes: two partially cross-reactive regions around α-helices 2 and 4 as well as a novel Art v 3–specific epitope at the C terminus. Protein variants with exchanged epitope residues confirmed the antibody-binding sites and revealed strongly reduced IgE reactivity. Using the novel HDXMEM for NMR epitope mapping allowed identification of the first structural epitopes of an allergenic pollen LTP. This knowledge enables improved cross-reactivity prediction for patients suffering from LTP allergy and facilitates design of therapeutics. Full Article
ni Unique active-site and subsite features in the arabinogalactan-degrading GH43 exo-{beta}-1,3-galactanase from Phanerochaete chrysosporium [Enzymology] By www.jbc.org Published On :: 2020-12-25T00:06:31-08:00 Arabinogalactan proteins (AGPs) are plant proteoglycans with functions in growth and development. However, these functions are largely unexplored, mainly because of the complexity of the sugar moieties. These carbohydrate sequences are generally analyzed with the aid of glycoside hydrolases. The exo-β-1,3-galactanase is a glycoside hydrolase from the basidiomycete Phanerochaete chrysosporium (Pc1,3Gal43A), which specifically cleaves AGPs. However, its structure is not known in relation to its mechanism bypassing side chains. In this study, we solved the apo and liganded structures of Pc1,3Gal43A, which reveal a glycoside hydrolase family 43 subfamily 24 (GH43_sub24) catalytic domain together with a carbohydrate-binding module family 35 (CBM35) binding domain. GH43_sub24 is known to lack the catalytic base Asp conserved among other GH43 subfamilies. Our structure in combination with kinetic analyses reveals that the tautomerized imidic acid group of Gln263 serves as the catalytic base residue instead. Pc1,3Gal43A has three subsites that continue from the bottom of the catalytic pocket to the solvent. Subsite −1 contains a space that can accommodate the C-6 methylol of Gal, enabling the enzyme to bypass the β-1,6–linked galactan side chains of AGPs. Furthermore, the galactan-binding domain in CBM35 has a different ligand interaction mechanism from other sugar-binding CBM35s, including those that bind galactomannan. Specifically, we noted a Gly → Trp substitution, which affects pyranose stacking, and an Asp → Asn substitution in the binding pocket, which recognizes β-linked rather than α-linked Gal residues. These findings should facilitate further structural analysis of AGPs and may also be helpful in engineering designer enzymes for efficient biomass utilization. Full Article
ni Determinants of replication protein A subunit interactions revealed using a phosphomimetic peptide [Molecular Biophysics] By www.jbc.org Published On :: 2020-12-25T00:06:31-08:00 Replication protein A (RPA) is a eukaryotic ssDNA-binding protein and contains three subunits: RPA70, RPA32, and RPA14. Phosphorylation of the N-terminal region of the RPA32 subunit plays an essential role in DNA metabolism in processes such as replication and damage response. Phosphorylated RPA32 (pRPA32) binds to RPA70 and possibly regulates the transient RPA70-Bloom syndrome helicase (BLM) interaction to inhibit DNA resection. However, the structural details and determinants of the phosphorylated RPA32–RPA70 interaction are still unknown. In this study, we provide molecular details of the interaction between RPA70 and a mimic of phosphorylated RPA32 (pmRPA32) using fluorescence polarization and NMR analysis. We show that the N-terminal domain of RPA70 (RPA70N) specifically participates in pmRPA32 binding, whereas the unphosphorylated RPA32 does not bind to RPA70N. Our NMR data revealed that RPA70N binds pmRPA32 using a basic cleft region. We also show that at least 6 negatively charged residues of pmRPA32 are required for RPA70N binding. By introducing alanine mutations into hydrophobic positions of pmRPA32, we found potential points of contact between RPA70N and the N-terminal half of pmRPA32. We used this information to guide docking simulations that suggest the orientation of pmRPA32 in complex with RPA70N. Our study demonstrates detailed features of the domain-domain interaction between RPA70 and RPA32 upon phosphorylation. This result provides insight into how phosphorylation tunes transient bindings between RPA and its partners in DNA resection. Full Article
ni 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
ni Nitro-fatty acids as activators of hSIRT6 deacetylase activity [Protein Structure and Folding] By www.jbc.org Published On :: 2020-12-25T00:06:31-08:00 Sirtuin 6, SIRT6, is critical for both glucose and lipid homeostasis and is involved in maintaining genomic stability under conditions of oxidative DNA damage such as those observed in age-related diseases. There is an intense search for modulators of SIRT6 activity, however, not many specific activators have been reported. Long acyl-chain fatty acids have been shown to increase the weak in vitro deacetylase activity of SIRT6 but this effect is modest at best. Herein we report that electrophilic nitro-fatty acids (nitro-oleic acid and nitro-conjugated linoleic acid) potently activate SIRT6. Binding of the nitro-fatty acid to the hydrophobic crevice of the SIRT6 active site exerted a moderate activation (2-fold at 20 μm), similar to that previously reported for non-nitrated fatty acids. However, covalent Michael adduct formation with Cys-18, a residue present at the N terminus of SIRT6 but absent from other isoforms, induced a conformational change that resulted in a much stronger activation (40-fold at 20 μm). Molecular modeling of the resulting Michael adduct suggested stabilization of the co-substrate and acyl-binding loops as a possible additional mechanism of SIRT6 activation by the nitro-fatty acid. Importantly, treatment of cells with nitro-oleic acid promoted H3K9 deacetylation, whereas oleic acid had no effect. Altogether, our results show that nitrated fatty acids can be considered a valuable tool for specific SIRT6 activation, and that SIRT6 should be considered as a molecular target for in vivo actions of these anti-inflammatory nitro-lipids. Full Article
ni Humanin selectively prevents the activation of pro-apoptotic protein BID by sequestering it into fibers [Protein Structure and Folding] By www.jbc.org Published On :: 2020-12-25T00:06:31-08:00 Members of the B-cell lymphoma (BCL-2) protein family regulate mitochondrial outer membrane permeabilization (MOMP), a phenomenon in which mitochondria become porous and release death-propagating complexes during the early stages of apoptosis. Pro-apoptotic BCL-2 proteins oligomerize at the mitochondrial outer membrane during MOMP, inducing pore formation. Of current interest are endogenous factors that can inhibit pro-apoptotic BCL-2 mitochondrial outer membrane translocation and oligomerization. A mitochondrial-derived peptide, Humanin (HN), was reported being expressed from an alternate ORF in the mitochondrial genome and inhibiting apoptosis through interactions with the pro-apoptotic BCL-2 proteins. Specifically, it is known to complex with BAX and BID. We recently reported the fibrillation of HN and BAX into β-sheets. Here, we detail the fibrillation between HN and BID. These fibers were characterized using several spectroscopic techniques, protease fragmentation with mass analysis, and EM. Enhanced fibrillation rates were detected with rising temperatures or pH values and the presence of a detergent. BID fibers are similar to those produced using BAX; however, the structures differ in final conformations of the BCL-2 proteins. BID fibers display both types of secondary structure in the fiber, whereas BAX was converted entirely to β-sheets. The data show that two distinct segments of BID are incorporated into the fiber structure, whereas other portions of BID remain solvent-exposed and retain helical structure. Similar analyses show that anti-apoptotic BCL-xL does not form fibers with humanin. These results support a general mechanism of sequestration of pro-apoptotic BCL-2 proteins into fibers by HN to inhibit MOMP. Full Article
ni A combinatorial native MS and LC-MS/MS approach reveals high intrinsic phosphorylation of human Tau but minimal levels of other key modifications [Neurobiology] By www.jbc.org Published On :: 2020-12-25T00:06:31-08:00 Abnormal changes of neuronal Tau protein, such as phosphorylation and aggregation, are considered hallmarks of cognitive deficits in Alzheimer's disease. Abnormal phosphorylation is thought to precede aggregation and therefore to promote aggregation, but the nature and extent of phosphorylation remain ill-defined. Tau contains ∼85 potential phosphorylation sites, which can be phosphorylated by various kinases because the unfolded structure of Tau makes them accessible. However, methodological limitations (e.g. in MS of phosphopeptides, or antibodies against phosphoepitopes) led to conflicting results regarding the extent of Tau phosphorylation in cells. Here we present results from a new approach based on native MS of intact Tau expressed in eukaryotic cells (Sf9). The extent of phosphorylation is heterogeneous, up to ∼20 phosphates per molecule distributed over 51 sites. The medium phosphorylated fraction Pm showed overall occupancies of ∼8 Pi (± 5) with a bell-shaped distribution; the highly phosphorylated fraction Ph had 14 Pi (± 6). The distribution of sites was highly asymmetric (with 71% of all P-sites in the C-terminal half of Tau). All sites were on Ser or Thr residues, but none were on Tyr. Other known posttranslational modifications were near or below our detection limit (e.g. acetylation, ubiquitination). These findings suggest that normal cellular Tau shows a remarkably high extent of phosphorylation, whereas other modifications are nearly absent. This implies that abnormal phosphorylations at certain sites may not affect the extent of phosphorylation significantly and do not represent hyperphosphorylation. By implication, the pathological aggregation of Tau is not likely a consequence of high phosphorylation. Full Article
ni Clearer Role for Business Regulators Needed in Monitoring Trade Agreements By www.chathamhouse.org Published On :: Mon, 06 Jul 2020 17:23:33 +0000 6 July 2020 Dr Jennifer Ann Zerk Associate Fellow, International Law Programme As the economic recovery from coronavirus is worked through, careful steps are needed to ensure actions to enforce human rights commitments in trade agreements do not worsen human rights impacts. 2020-07-06-Cambodia-Workers-Rights Garment workers hold stickers bearing US$177 during a demonstration to demand an increase of their minimum salary in Phnom Penh, Cambodia. Photo by Omar Havana/Getty Images. Trade policy is a blunt instrument for realizing human rights. Although many trade agreements now include commitments on human rights-related issues - particularly labour rights - not everyone agrees that linking trade to compliance with human rights norms is appropriate, let alone effective.Sceptics point out that such provisions may become an excuse for interference or ‘disguised protectionism’ and admittedly anyone would be hard-pressed to identify many concrete improvements which can be directly attributed to social and human rights clauses in trade agreements.This lack of discernible impact has a lot to do with weak monitoring and enforcement. A more fundamental problem is the tendency of trading partners to gloss over – both in the way that commitments are framed and in subsequent monitoring efforts – significant implementation gaps between the standards states sign up to, and the reality.Working from ‘baseline’ international standards and treating each state’s human rights treaty ratification record as an indicator of compliance does offer objective verifiability. But it also means underlying economic, structural, cultural, social, and other problems, often go unidentified and unaddressed in the trading relationship.Regulatory failings of trading partnersThose with sufficient leverage can use dispute resolution or enforcement proceedings to signal displeasure at the regulatory failings of their trading partners, as recently shown by the European Commission (EC) in relation to labour violations by trading partners – against South Korea under the 2011 EU-South Korea Free Trade Agreement (FTA) and Cambodia under the EU’s Generalised Scheme of Preferences (GSP) scheme.These actions do show a more proactive and rigorous EU approach to monitoring and enforcement and have been largely welcomed – especially by trade unions – as a necessary political response to persistent failings by the states to address violations of fundamental labour rights. However, claiming any major victories on behalf of the workers who produce the goods being traded seems premature.The ‘implementation gaps’ - between human rights commitments made in a state-to-state context and the reality of the human rights situation on the ground - mean there may be cases where enforcement action under a trading arrangement, such as the removal of trade preferences, may actually make things worse. Some local unions have expressed concern that the EU action against Cambodia may be detrimental to vulnerable migrant women factory workers, especially in the context of a worsening economic situation due to the pandemic.Making stakeholder voices heardThere are routes through which people with first-hand knowledge of human rights-related problems arising from trading relationships – such as labour rights abuses in global supply chains – can make their voices heard. Unions have used consultative bodies set up under trade agreements to highlight labour abuses in trading partner countries - this helped to shift the Commission’s strategy towards South Korea.But the rather vague and open-ended mandates of these consultative bodies, and their reliance on cash-strapped civil society organisations to do much of the heavy lifting, means they are not a solid basis for systematic follow-up of human rights problems.And yet, every country is likely to have a number of agencies with interests and expertise in these issues. Beyond labour inspectorates, this could include environmental regulators, licensing bodies, ombudsmen, national healthcare bodies, special-purpose commissions, ‘responsible business’ oversight and certification bodies, local government authorities and national human rights institutions.At present these groups are barely mentioned in trade agreements with monitoring frameworks for human rights. And if they do feature, there tends to be little in the agreement terms to guarantee their participation.To seriously address implementation gaps, there needs to be much greater and more systematic use of these domestic regulatory bodies in human rights monitoring and enforcement activities. These bodies are potentially vital sources of information and analysis about the many different social, economic, environmental and human rights consequences of trade, and can also contribute to designing and delivering ‘flanking measures’ needed to assist with the mitigation of human rights-related risks or adverse impacts which have been detected.Looking further ahead, monitoring practitioners may find - as those involved in the EU GSP+ scheme have already noticed - that close and visible engagement with domestic regulatory bodies helps strengthen a regulator in getting clearer political support and better resources. It can also help with greater ‘buy-in’ to human rights reform agendas, creating conditions for a positive legacy in the form of more confident, committed, and capable domestic regulatory bodies.Paying more attention to synergies that exist between the work of domestic regulatory bodies and the principles and objectives which cause states to seek human rights commitments from their trading partners is a vital contribution to the concept of ‘building back better’ from the present crisis.The goal should be to move from the present system – which veers between largely ineffective consultative arrangements and adversarial, often high stakes, dispute resolution – to more cooperative and collaborative systems which draw more proactively from the knowledge and expertise of domestic regulatory bodies, not only in the identification and monitoring of risks, but also in the delivery of jointly agreed strategies to address them.This article is part of the Chatham House Global Trade Policy Forum, promoting research and policy recommendations on the future of global trade. Full Article
ni Flaring in MENA: The Multibillion Dollar Decarbonization Lever By www.chathamhouse.org Published On :: Wed, 15 Jul 2020 12:05:58 +0000 15 July 2020 Adel Hamaizia Associate Fellow, Middle East and North Africa Programme Dr Mark Davis CEO, Capterio The climate crisis and ‘energy transition’ is driving a response from the oil and gas industry to decarbonize, with flaring – the deliberate combustion of gas associated with oil production – as a critical lever, especially in the Middle East and North Africa, write Adel Hamaizia and Mark Davis. 2020-07-15-Flare-Oil-Iraq Iraqi Southern Oil Company engineers look towards the flares in the Zubair oil field in southern Iraq. Photo by ESSAM -AL-SUDANI/AFP via Getty Images. Flaring is a significant source of economic and environmental waste. Except when safety-related, flared gas can often be captured and monetised using low-cost proven solutions.In doing so, governments can improve health and safety, reduce emissions (of carbon dioxide, methane, and particulates) and add value by driving up revenue, increasing reserves and production, creating jobs and improving the industry’s ‘social license to operate’.Flare capture also helps countries to deliver on the Paris Agreement and the UN’s Sustainable Development Goal #13 while, for example, providing affordable alternatives for heating and cooking.The Middle East and North Africa (MENA) region accounts for 40% of the world’s flaring. In the region, flaring has increased year-on-year - apart from 2018 - to almost six billion cubic feet of gas per day, generating up to 300-500 million tonnes of CO2-equivalent emissions per year.These emissions result not only from the combustion of gas, but also from the venting, from inefficient flares, of un-combusted methane, a more potent greenhouse gas. Yet much of this is avoidable.There are many commercially attractive options to reduce flaring in MENA. The key is to use the right proven technology and to be agile in commercial structuring. And the prize could be a boost to MENA’s annual revenues by up to $200 per second (up to $6.4 billion per year) by delivering wasted gas to market by pipeline, as power or in liquid form.The chart highlights the abundance of flaring across the MENA region, and in many cases, their proximity to population centres. While Iran, Iraq, and Algeria generate 75% of MENA’s flaring, Saudi Arabia, Kuwait, UAE and Qatar are notable for their relatively low ‘flaring intensity’ i.e. flaring normalized to oil production.In today’s world of lower energy prices, it makes sense to monetise every molecule. Even more so for national oil companies, which are responsible for most of the flaring, since they are not only the custodians of their countries’ natural resources, but they also generate a dominant source of government revenue.Most oil producers in MENA have already made commitments to the World Bank’s flaring-reduction initiatives (e.g. ‘Zero Routine Flaring by 2030’), but to date, delivery is mostly lacking. Three main issues have hindered progress.Firstly, operators, regulators, and governments highlight that flaring is often not ‘sufficiently on the radar’. Flaring is often underreported if not ignored or denied - although satellite detection gives unavoidable transparency. In MENA alone, more than 1,700 flare clusters are visible every day from space.Secondly, flare capture is sometimes not perceived to be economically viable due to costs, taxes, or inappropriate technology. Thirdly, there are often issues around resources, especially concerning management bandwidth, delivery capabilities or financing.Yet these issues can be solved if the right proven technologies are combined with the right commercial structures. To accelerate flare capture projects, stakeholders in the MENA hydrocarbons sector must consider several complementary, action-oriented initiatives.In particular, they should:Promote transparency and disclosure to drive greater awareness of flaring. Governments, regulators and operators must understand the real scale of their gas flaring opportunity and be capable of acting, as a recent report for the EBRD on Egypt highlighted. Compliance with clear standards for measuring, monitoring and verification is critical.Advance policies and incentives which encourage action. Better commercial terms will incentivise and accelerate flare investments. Stronger penalties will help, but independent and capable regulators must actually enforce these penalties. Through the use of such clear anti-flaring policies, Norway’s flaring intensity is almost 20 times lower than the MENA region.Improve the investment climate, beyond economics and open access to a broader range of players. Local market failures can be avoided by reducing the complexity and cost of in-country operations and by removing excessive, rigid, or redundant regulations. By enabling greater ‘third-party’ access to gas and power projects and infrastructure, new players can accelerate change by deploying new technologies and new operating models. Better third-party access will also unlock ideas, capital, skills and project-specific financing options. Algeria is making steps towards such liberalisation through its new 2019 Hydrocarbon Law.Reduce subsidies and improve energy efficiency and reduce demand, increase gas exports and boost national revenues. Countries with large subsidies on transport fuels and power, such as Algeria and Iraq, stand to gain the most.Encourage collaboration between stakeholders in industry and government by creating working groups to radiate best practices, build capacity, deploy technology and local content, such as the flare minimization programme in Saudi Arabia or Iraq’s major flare-to-power project operated by the Basrah Gas Company.The industry needs to prepare for a greener world after COVID-19 and investors and consumers are demanding cleaner fuels. Since gas is widely viewed as a transition fuel, MENA governments and stakeholders must work to eliminate its wastage and seize the revenue, production and environmental opportunities that flare capture projects offer.There is much new leadership in the region in government and critical institutions with new mandates for change. The time to act is now. Full Article
ni New Fighting Brings Three-year Armenian-Azerbaijani Truce to an End By www.chathamhouse.org Published On :: Thu, 16 Jul 2020 22:17:03 +0000 16 July 2020 Laurence Broers Associate Fellow, Russia and Eurasia Programme @LaurenceBroers Deadly clashes at the border between Armenia and Azerbaijan have followed renewed disappointment in the peace process, and cast a new shadow over its future. 2020-07-16-Armenia-Shrapnel-Conflict A man shows a piece of shrapnel after attacks carried out by the Armenian army at Dondar Kuscu village near Tovuz, Azerbaijan. Photo by Aziz Karimov/Getty Images. Although the Armenian-Azerbaijani conflict is focused on the Line of Contact around Nagorny Karabakh, a new - and significant - outbreak of violence has happened some 300 kilometres away on high ground along the de jure Armenia-Azerbaijan border.Although not a first, violence in this area has generally been contained by the proximity of major transport and infrastructure arteries, and of civilian populations on both sides of the border. Plus, unlike in Nagorny Karabakh, the extended deterrents conferred by Armenia’s membership of the Collective Security Treaty Organization (CSTO) and bilateral agreements with Russia are also – theoretically at least – in force.Despite this, battlespaces opened rapidly, with bombardment of civilian homes, drone strikes and cyberattacks on government and other sites being widely reported by both sides. At the time of writing, combined reported casualties were already at least 16, the highest for a single incident since April 2016’s ‘four-day war’.Most are known to be Azerbaijani combatants, including the highest-ranking Azerbaijani serviceman to be killed in action since the 1990s – the respected Major General Polad Hashimov. And, although rumoured to be removed soon anyway following a campaign of negative briefing, Azerbaijani foreign minister Elmar Mammadyarov was publicly blamed in the immediate aftermath for ‘meaningless’ diplomacy and dismissed. He was replaced by education minister Jeyhun Bayramov.Origins of the clashesHow the fighting began remains unclear. The escalation did not appear to result from a coordinated offensive operation of the kind that led to the four-day war, nor are there obvious strategic goals for either side in terms of the international border. There does appear to have been an element of surprise as an Azerbaijani vehicle unexpectedly encountered a new Armenian post, triggering deadly artillery exchanges.Unclear boundaries in highland terrain may have played a role. Although referred to as the international border, the de jure boundary between Armenia and Azerbaijan - previously an inconsequential internal administrative boundary in the Soviet Union - is not clearly demarcated in many areas and does not coincide with lines of actual control.Here, as in Nakhichevan - Azerbaijan’s exclave bordering Armenia and Iran - Armenian and Azerbaijani forces have been engaged in long-term, incremental competition for tactical advantage by claiming higher ground in ‘no man’s lands’. But in remote and cartographically ambiguous areas, the precise location of borders - and even place-names - are unclear, and rival forces can unexpectedly meet their adversaries.Although clear strategic objectives appear absent, what might then have been a lesser incident escalated purposefully into a crisis – suggesting a political rationale.A missed opportunity for a negotiations resetBoth Armenia and Azerbaijan began 2020 with unfinished consolidations of domestic power - whether bottom-up in the case of Armenia’s ‘Velvet Revolution’, or top-down in the case of Azerbaijan elite renewal. COVID-19 then added further challenges, with the government of Armenia facing significant domestic criticism for its handling of the pandemic, while numerous opposition activists in Azerbaijan were arrested, and the country’s economic vulnerability to external shocks was highlighted.But throughout this, the frontlines did remain calm - as they generally have since the three-year period from 2014-2017 which witnessed regular skirmishes, use of heavy weaponry and four days of intensive combat in April 2016. In January 2019, the OSCE Minsk Group made the often-cited announcement that the foreign ministers of Armenia and Azerbaijan had agreed on the necessity of ‘preparing their populations for peace’.Although the quietest year on the frontline since the 1990s then followed, neither side invested seriously in a peace strategy. After a reasonable start and moves towards humanitarian cooperation, relations between President Ilham Aliyev and Prime Minister Nikol Pashinyan eventually visibly soured.Several moves, such as the go-ahead for new infrastructure in the occupied territories and Pashinyan’s attendance at de facto leader Arayik Harutyunyan’s inauguration in Nagorny Karabakh, were received in Azerbaijan as evidence of Armenian insincerity towards the peace process.More inflammatory rhetoric then resumed, leading the OSCE Minsk Group to call for calm at the end of June. As recently as July 7, President Aliyev expressed public criticism of the peace process and emphasised the validity of Azerbaijan’s right to use force.Each new round of Armenian-Azerbaijani fighting serves as an audit of the various restraining factors preventing a larger war. A Russian-Euro-Atlantic-Iranian consensus on proactively containing any new Armenian-Azerbaijani war appears to still hold, although senior-level attention from US secretary of state Mike Pompeo trailed that of his counterparts.Russia acted quickly to offer mediation, reflecting the reality that any large-scale Armenia-Azerbaijan war would test Russia’s extended deterrence guarantees to Armenia. As in April 2016, Turkey has been vigorous in its support of Azerbaijan, raising concerns in Armenia and drawing oblique warnings from Russia. On the other hand, the CSTO - much to Armenian chagrin - dithered, initially calling then postponing a meeting citing the need for more time to study the situation.Unprecedented spontaneous demonstrations in Baku called for war with Armenia, broke into the Azerbaijani parliament and, in some cases, articulated anti-government slogans. In the absence of reliable polling, such protests cannot be taken as evidence of a popular consensus in favour of war.But they do underline the importance of the conflict as the one issue in Azerbaijan where open protest is accepted as legitimate and cannot easily be dispersed. As losses over the past week are counted, the dismissal of the foreign minister may not be sufficient to quell public anger.Prospects are now real of a return to the dynamics in 2014-15: recursive low-level violence aimed at influencing the diplomatic calendar and public opinion while remaining below the deterrence threshold for triggering active external involvement. Full Article
ni UK Should Focus on Better Defining Objectives in the Sahel By www.chathamhouse.org Published On :: Fri, 24 Jul 2020 11:19:46 +0000 22 July 2020 Dr Alex Vines OBE Managing Director, Ethics, Risk & Resilience; Director, Africa Programme The Sahel is one of Africa’s poorest and most fragile regions witnessing an escalation in jihadist activity and illegal migration, writes Alex Vines. GettyImages-1204470166.jpg Pictured is a Nigerian refugee living in the Awaradi settlement that houses some 9,000 displaced people fleeing violence from Boko Haram. Image: Getty Images. The UK has been redeploying diplomatic, defence and development capabilities towards the Sahel since 2018 – a strategic pivot intended to deliver development impact, address long term security threats to UK interests and support alliances with international partners.The Sahel is one of Africa’s poorest and most fragile regions and has witnessed an escalation in jihadist activity, illegal migration and trafficking since a security crisis erupted in Mali in 2012.The crisis spread to Niger and Burkina Faso and may now spill over into Côte d’Ivoire, Ghana and Senegal. With Nigeria also facing insurgency in the Lake Chad basin, all major regional security and economic anchors in the region are under threat including key UK partners. Reviewing the Sahel pivotThis pivot has already resulted in the expanding of UK embassies in Senegal, Mauritania and Mali and public commitments to opening new ones in Chad and Niger.Back in London, there has also been a large uplift of staff including the setting up of a cross-Whitehall Joint Sahel Department in late 2018 and plans for more UK civil servants to have placements with the French government on the Sahel.Yet in light of looming economic shocks from Brexit and Covid-19, there has been a lively debate in Whitehall on whether this is stretching UK resources too thin in an area of Africa that does not have close ties with the UK.UK ministers are this week reviewing the Sahel pivot and will decide if it continues or grinds to a standstill including whether full embassies are opened in Niger and Chad.This debate is not new. The UK has opened and closed its diplomatic missions in the Sahel in fits and starts since the early 1960s. More recently, MI6 pushed the re-opening of the embassy in Bamako in 2010 foreseeing Mali’s fragility before the current crisis started.Partnering with the FrenchBut though the Sahel is likely to dominate the Africa peace and security agenda for decades to come, the UK’s serious engagement in the region is not just about strategic foresight.It also fulfils two other objectives: of partnership with two key bilateral allies, particularly France, and authority and leverage in multilateral fora such as the United Nations, African Union and the EU.Partnering with the French in the Sahel has become even more important due to Brexit and the need to reinforce relationships with key European partners.In 2012, David Cameron concluded that the rapid French response to stop a jihadist advance on the Malian capital Bamako was 'in our interests' and authorized the deployment of 330 UK military personnel, two cargo aircraft and a surveillance plane.In July 2018, the UK announced further support to French led Opération Barkhane sending three Royal Air Force Chinook helicopters – supported by almost 100 personnel – which remain in theatre to this day.UN commitmentDemonstrating the UK’s commitment to UN peacekeeping has also resulted in the deployment of 250 troops to join a UN peacekeeping mission to Mali later this year.Based in Gao, these troops will form a long-range reconnaissance capability providing threat awareness, contributing to the protection of civilians and helping to prevent conflict from spilling over to neighbouring states.This represents one of the biggest British peacekeeping deployments since Bosnia and it will be the most dangerous mission for British forces since Afghanistan.The UK is also one of the largest humanitarian donors to the region and has contributed over £500 million in bilateral development and humanitarian assistance since 2015.With COVID-19 now an additional challenge in the Sahel, a significant part of the UK’s £764 million contribution to the global COVID-19 effort will be channelled to the region.New embassies are 'global Britain' strategy pillarsKeeping an eye on the impact of these initiatives requires a meaningful UK diplomatic network on the ground.New embassies in the Sahel cost a fraction of maintaining three Chinook helicopters in the region providing the government real time insight in the post-Brexit absence of a regular supply of country analysis from the European External Action Service and support for the UK’s international relationships.It also underlines the UK’s commitment to UN peacekeeping and standing as a permanent member of the UN Security Council in light of regular discussions of the Sahel.The tripartite ministerial review of the Sahel pivot by the secretaries of state for foreign affairs, international development and defence that is underway should not penny pinch by reversing the opening of small embassies in Niger and Chad nor threaten the overall strategic focus on the Sahel – most recently welcomed by the House of Lord’s Select Committee on International Relations and Defence in its July report on UK Africa policy.Instead, UK ministers should focus on better defining what the UK’s specific objectives are in the Sahel and particularly what the UK plans to do about Burkina Faso whose rapidly deteriorating security threatens to over-spill into key UK partner Ghana.This article was first published in the Daily Telegraph. 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ni 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
ni 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. 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ni Nigeria’s Recovery Means Rethinking Economic Diversification By www.chathamhouse.org Published On :: Fri, 14 Aug 2020 15:17:01 +0000 14 August 2020 Iseoluwa Akintunde Mo Ibrahim Foundation Academy Fellow, Energy, Environment and Resources Programme @Ise0luwa LinkedIn With more than half its revenue derived from oil exports, Nigeria’s economic fortunes are tied to the boom and bust cycles of the oil market. Those fortunes have waned way below expectations this year and, with more than one-quarter of its labour force jobless, it is time to question the country’s economic pathway. 2020-08-14-Nigeria-Bottles-Building Yahaya Musa, 19-year old local mason, inspects a wall of a 'plastic bottle house' in Sabongarin Yelwa village, near Kaduna, Nigeria. Photo by AMINU ABUBAKAR/AFP via Getty Images. For decades, the mantra of ‘economic diversification’ characterized attempts to reverse Nigeria’s dependence on oil with little real progress. Despite numerous reforms, international loans and restructuring programmes, 85 million Nigerians live in deteriorating conditions of poverty. The current coronavirus pandemic combined with mounting debt obligations and declining GDP gives new urgency to this issue.The fall in international oil prices, which led government to slash its oil benchmark price from $57 to $30 a barrel and cut 20% of the capital budget, worsens these problems, but it is far from the only factor. Biomass, which drives household pollution and contributed to the death of 114,000 people in Nigeria in 2017, is the most dominant source of energy in Nigeria, amounting to more than 80% of the total energy mix, followed by fossil fuels (18%), and a negligible amount of renewable energy.Although a diversified energy sector with a strong emphasis on renewables is known to reduce health and economic risks of combustion, there has been little emphasis on the role a diversified energy mix could play in ensuring sustainable development – even though the estimated potential of 427,000MW of solar power and photovoltaic generation means Nigeria has enormous renewable energy opportunities.The global economy is also undergoing tectonic structural changes that will affect demand for Nigeria’s oil, leaving a fossil fuel-dependent economy more vulnerable. Improvements in global fuel efficiency, the ascent of electricity as a substitute for oil in the transport sector, and the falling prices of renewables and storage technologies all lead to a reduction in demand for fossil fuel products.Creating structures for transitionThis is not a ‘get out of oil’ prescription, and energy transition is complex. But it is inevitable. There are no universal strategies applicable to all countries; local contexts and political realities inform what is possible. Nigeria can take advantage of its abundant natural gas deposit as a ‘transition fuel’ to buy it time for putting the appropriate transition structures in place. The country has made progress in reducing the amount of gas flared, but much remains to be done for Nigeria to meet the 2030 global deadline to end flaring, after failing to meet its 2020 national target.The first step to proper transition is to align Nigeria’s international obligations with its domestic policies and legislations - the distance between words and action must be bridged and the institutional capacity to implement raised. And, while they contain symbolic green gestures, the economic recovery and growth plan developed in response to the 2016 recession, and the post-COVID-19 economic sustainability plan, do not espouse green growth as a fundamental objective.Nigeria must start looking inwards, investing its resources in designing and funding a green transition strategy. Its leadership role in floating Africa’s first Sovereign Green Bonds should be followed with non-debt funding options. Faced with a pandemic that has shattered the boundaries of what is politically possible, the Buhari government has overcome initial inertia to announce a halt in oil subsidy payments, although whether it will see through that policy is yet to be seen.If it does, how it uses the savings will be significant. The money could provide support for Nigeria’s renewable sector to counteract the price disparity with fossil fuels and encourage rapid research and development. The Nigerian Ecological Fund — which is 3% of the Federation Account — should be reformed and expanded beyond its current scope of addressing ‘serious ecological problems’ to cover climate change with a strong emphasis on mitigation and resilience. That would increase Nigeria’s climate finance and minimize reliance on multilateral climate funds.Beyond public investments in green infrastructure, the government can also incentivize the private sector to drive a green economy. As the largest purchaser of goods and services in the country, it can leverage purchasing power to green the procurement process. With the release of about $421 million to the Ministry of Works, the 2020 budgetary allocation for road projects has been fully disbursed to the Ministry, making procurement in the construction sector ripe for green reforms. The application of sustainable building techniques and materials could reduce Nigeria’s 17 million housing deficit and create more jobs.But the task of greening the Nigerian economy is too important to be left to the federal government alone. It also requires mainstreaming climate change and sustainable development into the operations, governance, and budgets of government ministries, departments, and private entities at the sub-national and national levels.There has been much focus on reviving agriculture, which is laudable, but agrarian practices have radically changed from the 1970s when the sector accounted for 57% of Nigeria’s GDP and generated 64.5% of export earnings. Beset by a loss of biodiversity, drought, and desertification, extreme weather events, rise in sea levels and variable rainfall, it is no longer smart for Nigeria to invest in this area without due regard for the significant climate risks. Any effort to revive agriculture and its export potential must be green-centred and integrate regenerative and climate-smart practices.The right policy mix combined with aggressive funding can position the country as a renewable energy leader, both on the African continent and globally. And it will reap the benefits in technology development, foreign investment, decreased emissions, poverty reduction, and energy for the 80 million people currently without access to the national grid – all of which could ripple into millions of clean energy jobs in manufacturing and installation across the country.The road to a green future must be paved with deliberate and consistent policies. Reforms hatched because oil prices have plunged should not be ditched when there is a boom. On the brink of a second recession in four years, Nigeria has learnt that the economic turmoil caused by COVID-19 is only the latest warning that pinning economic growth on a boom-bust market and the generosity of foreign donors and creditors is a failing strategy. There is another way and there is an opportunity for Nigeria to lead. Full Article
ni Conflict-Related Sexual Violence in Ukraine: An Opportunity for Gender-Sensitive Policymaking? By www.chathamhouse.org Published On :: Mon, 17 Aug 2020 23:55:05 +0000 18 August 2020 Kateryna Busol Robert Bosch Stiftung Academy Fellow, Russia and Eurasia Programme @KaterynaBusol LinkedIn Meaningful change is needed in Ukraine’s response to the conflict-related sexual violence, which affects both women and men. 2020-08-18-Ukraine-Intl-Womens-Day.jpg Ukrainian feminists and human rights activists carry posters at an International Women's Day protest in Kyiv, Ukraine on 8 March 2019. Photo: Getty Images. The virus of violenceAccording to the UN (para. 7) and the International Criminal Court (ICC, para. 279), conflict-related sexual violence (CRSV) is quite prevalent in hostilities-affected eastern Ukraine. Both sexes are subjected to sexualized torture, rape, forced nudity, prolonged detention in unsanitary conditions with members of the other sex and threats of sexual violence towards detainees or their relatives to force confessions. Men are castrated. Women additionally suffer from sexual slavery, enforced and survival prostitution, and other forms of sexual abuse. Women are more exposed to CRSV: in the hostilities-affected area, every third woman has experienced or witnessed CRSV as opposed to every fourth man.COVID-19 has redirected funding priorities, affecting the availability of medical and psychological help for CRSV survivors worldwide. In Ukraine, the very reporting of such violence, stigmatized even before the pandemic, has been further undermined by the country-wide quarantine-induced restrictions on movement and the closure of checkpoints between the government-controlled and temporarily uncontrolled areas.Addressing CRSV in UkraineThe stigma of CRSV, the patchy domestic legislation, and the unpreparedness of the criminal justice system to deal with such cases prevent the authorities from properly helping those harmed in the ongoing Russia-Ukraine armed conflict.CRSV is equally traumatizing yet different in nuance for men and women. Female victims often choose not to report the violence. Women avoid protracted proceedings likely to cause re-traumatization and the disclosure of their experience, which could be particularly excruciating in small communities where everybody knows everyone.Men also struggle to provide their accounts of CRSV. Their suppressed pain and shame of genital mutilation and other CRSV result in sexual and other health disfunctions. Combined with the post-conflict mental health struggles, this has been shown to lead to increased domestic violence and even suicide.The very investigation of CRSV in Ukraine is challenging. Certain tests and examinations need to be done straight after an assault, which in the context of detention and grey zones of hostilities is often impossible. Specialized medical and psychological support is lacking. Investigators and prosecutors are hardly trained to deal with CRSV to the point that they do not ask questions about it during the interviews. Burdened by trauma and stigma, survivors are inclined to report torture or inhuman treatment, but not the sexualized aspects thereof.Seven years into the conflict, the state still has not criminalized the full spectrum of CRSV in its domestic law. Ukraine’s Criminal Code contains a brief list of the violations of the rules and customs of warfare in article 438. It prohibits the inhuman treatment of civilians and POWs but does not list any types of CRSV.The article has an open-ended reference to Ukraine’s ratified international treaties, from which the responsibility for other armed conflict violations may be derived. For the more detailed norms on CRSV, Ukraine should refer at least to Geneva Convention IV protecting civilians and two additional protocols to the Geneva Conventions, to which it is a party.However, the novelty of the war context for Ukrainian investigators, prosecutors and judges and their overcautiousness about the direct application of international conventions mean that in practice, observing the treaty or jurisprudential instruction on CRSV has been slow.Use of the Criminal Code’s articles on sexual violence not related to an armed conflict is not viable. Such provisions fail to reflect the horrible variety and complexity of CRSV committed in hostilities. They also envisage lesser punishment than a war crime of sexual violence would entail. Cumulatively, this fails to account for the intention of a perpetrator, the gravity of the crime and the trauma of its victims.The lack of public debate and state action on CRSV understates its magnitude. Ukraine should break its silence about CRSV in Donbas and make addressing this violence part of its actionable agenda - in law and in implementation.Ukraine should incorporate all war crimes and crimes against humanity of CRSV in its domestic legislation; ensure a more gendered psychological and medical support for both sexes; establish rehabilitation and compensation programmes for CRSV survivors; create special victims and witness protection schemes; consider the different stigmatizing effects of CRSV on men and women in criminal proceedings and engage the professionals of the same sex as the victim; map CRSV in the bigger picture of other crimes in Donbas to better understand the motives of the perpetrators; submit more information about CRSV to the ICC and educate the public to destigmatize the CRSV survivors.The drafters of Ukraine’s transitional justice roadmap should ensure that it highlights CRSV, adopts a gendered approach to it and endorses female participation as a crucial component of reconciliation and broader policymaking.Embracive policymakingAlthough ‘the discriminatory line almost inevitably hurts women,’ 'every gender discrimination is a two-edged sword’, Ruth Bader Ginsburg famously argued before the US Supreme Court. This could not be more relevant for Ukraine. The conflict - and lockdown-related violence has reverberated deeper within Ukrainian society, raising fundamental questions about the roles of both sexes and gender equality.The failure to address CRSV and its different stigmas for both sexes mirrors the general lack of sustainable gender lenses in Ukraine's policymaking. It is no coincidence that a June 2020 proposal for gender parity in political parties coincided with another spike of sexist remarks by top officials. While women get access to more positions in the army, sexual harassment in the military is investigated slowly. Despite all the impressive female professionals, no woman made it to the first four-member consultative civic group in the Minsk process. Such lack of diversity sends an unfortunate message that women are not important for Ukraine’s peace process.Ginsburg said, ‘women belong in all places where decisions are being made.’ CRSV against either sex won’t be addressed properly until both sexes contribute with their talents and their grievances to all pillars of Ukraine’s state governance and strategy. Ukraine should look to engage professional women - and there are plenty - to join its public service not just in numbers, but as the indispensable equal voices of a powerful choir. Full Article
ni 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
ni 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
ni 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
ni 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
ni 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
ni 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
ni 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
ni Review: Decolonization and its discontents By www.chathamhouse.org Published On :: Mon, 01 Aug 2022 08:27:03 +0000 Review: Decolonization and its discontents The World Today mhiggins.drupal 1 August 2022 Jenna Marshall on a lively if flawed argument to find a way forward in a debate that has descended ‘into acrimony’. Against Decolonization: Taking African Agency SeriouslyOlufemi Taiwo, Hurst, £14.99 Decolonization was once heralded as a moment of potential and possibility for the formerly imperial world to chart a new way forward no longer tied to the apparatus of empire. It marked a period of transition to nation states – and an expansion of a rights-based international community that would dispense with the morally bankrupt regime of racism, dispossession and subjugation that characterized colonialism. The descent of the decolonization debate Half a century later, the debate surrounding decolonization has descended into acrimony. Some factions cast the issue of decolonization as a sustained attack on British and western culture writ large; other disparate voices coalesce around related social justice issues such as inequality, climate change and education. Decolonization has become ubiquitous in the public domain – and its ubiquity is the problem Decolonization has become ubiquitous in the public domain – and its ubiquity is the problem. In Against Decolonization, Olufemi Taiwo renounces a concept he conceives as having been emptied of serious study and analytical purchase; one incapable of addressing the complexities of modern global politics and more importantly, Africa’s place in it. Although the book attacks the inexhaustible ways in which the ‘trope of decolonization’ has been deployed, Taiwo is less bothered by the purported failures of scholars he deems ‘decolonizers’ and focuses his attention instead on the political landscape of African countries, past and present. Central to the book’s argument are two distinct scholarly strands on decolonization. The first, legal focus, centres on the political and economic forces of state-building. The second essays an ‘ideology’ of decolonization that rests on ‘forcing an ex-colony to forswear on pain of being forever under the yoke of colonization any and every cultural, political, intellectual, social and linguistic artefact, idea, process, institution and practice that retains even the slightest whiff of the colonial past’. Whether one should characterize the latter as simply a field of study or a potential set of policy arrangements remains unclear – yet what is certain is that it is too nebulous, too elastic, too open-ended to offer any substantive model or mechanism to understand postcolonial Africa. Correcting Eurocentric narcissism The decolonization research agenda in Africa came to prominence during the Cold War period of national liberation struggles. The intellectual project that followed centred on dismantling Eurocentrism as colonial subjugation through its promotion of the West as the crucible of legitimate and scientific knowledge. Since then, scholars have argued that decolonization itself has become compromised by its enduringly Eurocentric gaze at the expense of the agency of African thinkers, creatives and statesmen and women. Taiwo seeks to correct this narcissism – and the omissions left in its wake – by introducing lesser-known Africans and pan-African scholars and cultural figures. These voices, he hopes, will illuminate issues often ignored by ‘decolonizers’ and spark a ‘renewed interest in an appreciation of the many different ways in which African thinkers have responded to the colonial experience’. The decolonization of language Taiwo challenges the decolonization of language as an oversold promise. Romanticizing an imagined, pristine African pre-colonial past, he says, ultimately leads to nativism and atavism. As a case in point, Taiwo highlights bureaucratic instances of ‘language policy planning’ to deploy African languages in places such as Niger, Mali, Cameroon, Senegal and Nigeria that were hindered by multilingualism, education and high rates of illiteracy. The abstract language of decolonization allows western scholars to engage with the concept without considering their own complicity in upholding systems of exclusion The author goes on to confront the abstract language of decolonization, which, he says, allows western scholars to unproblematically engage with the concept without any serious consideration of their own complicity in upholding systems of exclusion. It entrenches their own institutional power within the academy, amplifies their perspectives at the expense of others, and limits the possibilities for understanding the problems of world politics with deleterious effects on policy. It is a serious claim, but there are issues to be addressed: Taiwo assumes there is coherence among scholars of decolonization, which is not the case. When Taiwo approaches how to foster political systems that cater to the needs of their citizens he dismantles the binary of ‘West as modern’ v ‘Africa as traditional’. Chieftaincies as traditional African governance, he points out, were the product of colonial anthropology, not Africans themselves. From the Fanti Confederation of 1871 to the Egba United Government in what is now Nigeria, Taiwo demonstrates that there has been a sustained tradition towards demands for democratic values. As he concedes an intellectual neglect of African philosophers that underlies the design and operations of Africa’s political institutions, Taiwo’s initial dismissal of the significance of cultural decolonization deserves another look. How should political and economic drives toward self-determination be advanced in the absence of knowledge shaped and mediated through African lived experiences? In this respect, the tale of two decolonizations – the legal alongside the ideological – suggest an unhelpful, if not false, binary. The problem of reconciling modernity and colonialism What resonates throughout the book is the idea that Europe cannot profess to hold an exclusive intellectual claim to modernity. Its universal aspirations are open to all of humanity, allowing those who have historically been marginalized to be worldmakers. The idea that modernity and colonialism are irreconcilable is problematic. For instance, Taiwo argues that the curtailment of capitalism in Africa by restricting the growth of the middle classes while limiting competition between African capitalists and the metropole is the consequence of colonialism. Capitalism not only requires inequality for it to function but that race – as a mechanism for producing ‘difference’ – enshrines it Yet the celebrated cultural anthropologist Sidney Mintz established an understanding that the matter for debate is not whether non-westerners were part of the modern system, but how and to what degree they were included and able to actualise its ideals. The emerging capitalist world economy needed non-western lands and labour, and so they were conscripted to this end. Recent abolitionist and black radical scholarship has built on this argument to maintain that capitalism not only requires inequality for it to function but that race – as a mechanism for producing ‘difference’ – enshrines it. Acknowledging the unacknowledged In the end, Taiwo communicates a palpable frustration at the state of academic discourses on contemporary Africa under the guise of emancipatory and radical scholarship. He offers an alternative approach whereby African students might rid themselves of a faddism that is ‘at best unsatisfactory’ and at worst produces ‘confusion, obscurantism, if not outright distortion and falsification’. Yet out of this irritation, Taiwo’s greatest contribution in Against Decolonization might be to urge an acknowledgement of how and to what degree decolonization has become subdued and its political possibilities curtailed. He ultimately urges us to reconsider the purpose of the decolonization academic movement as an ethics to abide by rather than a social theory of the postcolonial world. This requires those ‘decolonizers’ on whose careers the term is built to adopt greater intellectual humility – to resist the posture of the anarchist radical scholar armed for the ‘good fight’. Instead, they should apply a scholarly curiosity to genuinely engage with those already on the battlefield, so to speak; those ‘doing the work’ in practice, but who have been unacknowledged until now. Full Article
ni Reflections at 100: Empire and decolonization By www.chathamhouse.org Published On :: Tue, 01 Nov 2022 10:02:20 +0000 Reflections at 100: Empire and decolonization Audio MVieira 1 November 2022 How did leading academics and policymakers think about and impact imperialism and decolonization from the 1920s to 1970s? This episode of Reflections at 100, marking the centenary of International Affairs, looks at how empire and decolonization have been discussed in the journal. Isabel and Krisztina speak to Meera Sabaratnam about how thinkers and policymakers from the 1920s to 1970s understood both empire and then decolonization. Meera highlights four tensions present within the discussions, and how these may impact the international order today. Inderjeet Parmar delves deeper into the influence of Chatham House at the time and situates these discussions in the broader think-tank and global context. Reflections at 100 is a mini-series accompanying the journal’s centenary Archive Collections. The collections bring together articles from our archive which speak to the past, present, and future of current affairs issues. In each podcast episode we speak to editors and contributors to the collection and explore what the research tells us about policymaking today. Explore the Archive Collection, free to access until mid-November 2022, including Meera’s introduction: 100 years of empire and decolonization. International Affairs was started at Chatham House in 1922 to communicate research to members who could not attend in person. Over the past 100 years it has transformed into a journal that publishes academically rigorous and policy relevant research. It is published for Chatham House by Oxford University Press. Read the latest issue here. Full Article
ni The Translation of Dosimetry into Clinical Practice: What It Takes to Make Dosimetry a Mandatory Part of Clinical Practice By jnm.snmjournals.org Published On :: 2024-09-05T07:37:49-07:00 Full Article
ni Challenges with 177Lu-PSMA-617 Radiopharmaceutical Therapy in Clinical Practice By jnm.snmjournals.org Published On :: 2024-09-19T06:38:07-07:00 Full Article
ni Theranostics for Meningioma on the Rise: New EANM/EANO/RANO/SNMMI Guidelines Pave the Way to Improved Patient Outcomes Using Radiolabeled Somatostatin Receptor Ligands By jnm.snmjournals.org Published On :: 2024-10-10T08:33:38-07:00 Full Article
ni Intraarterial Administration of Peptide Receptor Radionuclide Therapy in Patients with Advanced Meningioma: Initial Safety and Efficacy By jnm.snmjournals.org Published On :: 2024-10-24T11:58:49-07:00 Visual Abstract Full Article
ni Clinical, Pathologic, and Imaging Variables Associated with Prostate Cancer Detection by PSMA PET/CT and Multiparametric MRI By jnm.snmjournals.org Published On :: 2024-10-30T08:04:14-07:00 Visual Abstract Full Article
ni Oncologist, Business Leader, and Investor Arie S. Belldegrun Discusses a Career in Innovative Medical Entrepreneurship: A Conversation with Ken Herrmann and Johannes Czernin By jnm.snmjournals.org Published On :: 2024-10-30T08:04:15-07:00 Full Article
ni Feasibility, Tolerability, and Preliminary Clinical Response of Fractionated Radiopharmaceutical Therapy with 213Bi-FAPI-46: Pilot Experience in Patients with End-Stage, Progressive Metastatic Tumors By jnm.snmjournals.org Published On :: 2024-10-30T08:04:15-07:00 Visual Abstract Full Article
ni Feasibility of 177Lu-PSMA Administration as Outpatient Procedure for Prostate Cancer By jnm.snmjournals.org Published On :: 2024-11-07T04:28:31-08:00 Full Article
ni Sophos Firewall hardening best practices By news.sophos.com Published On :: Fri, 25 Oct 2024 12:41:06 +0000 Make the most of your Sophos Firewall. Full Article Products & Services Firewall network Pacific Rim Defense
ni Pacific Rim: Learning to eat soup with a knife By news.sophos.com Published On :: Thu, 31 Oct 2024 12:36:53 +0000 What our incident responders know from five years of fighting an octopus Full Article Security Operations Pacific Rim Pacific Rim Defense PSIRT Sophos X-Ops
ni "Questioning the Quantifiable: Are We Measuring What Matters in Heart Failure Care?" By www.bmj.com Published On :: Tuesday, November 12, 2024 - 10:10 Full Article
ni Addressing Climate Catastrophe Concerns in Asthma Medication Delivery: Rethinking Inhaler Use for Environmental and Clinical Efficacy By www.bmj.com Published On :: Tuesday, November 12, 2024 - 13:24 Full Article
ni Global lysine acetylation and 2-hydroxyisobutyrylation reveal the metabolism conversion mechanism in Giardia lamblia By www.mcponline.org Published On :: 2020-12-29 Wenhe ZhuDec 29, 2020; 0:RA120.002353v1-mcp.RA120.002353Research Full Article
ni Multi-sample mass spectrometry-based approach for discovering injury markers in chronic kidney disease By www.mcponline.org Published On :: 2020-12-20 Ji Eun KimDec 20, 2020; 0:RA120.002159v1-mcp.RA120.002159Research Full Article
ni A Novel Mechanism for NF-{kappa}B-activation via I{kappa}B-aggregation: Implications for Hepatic Mallory-Denk-Body Induced Inflammation By www.mcponline.org Published On :: 2020-12-01 Yi LiuDec 1, 2020; 19:1968-1985Research Full Article
ni Identification of Microorganisms by Liquid Chromatography-Mass Spectrometry (LC-MS1) and in Silico Peptide Mass Libraries By www.mcponline.org Published On :: 2020-12-01 Peter LaschDec 1, 2020; 19:2125-2138Technological Innovation and Resources Full Article
ni Proteome analysis reveals a significant host-specific response in Rhizobium leguminosarum bv viciae endosymbiotic cells By www.mcponline.org Published On :: 2020-11-19 David DuránNov 19, 2020; 0:RA120.002276v1-mcp.RA120.002276Research Full Article
ni Proteogenomic characterization of the pathogenic fungus Aspergillus flavus reveals novel genes involved in aflatoxin production By www.mcponline.org Published On :: 2020-11-24 Mingkun YangNov 24, 2020; 0:RA120.002144v1-mcp.RA120.002144Research Full Article
ni A proteomic approach to understand the clinical significance of acute myeloid leukemia-derived extracellular vesicles reflecting essential characteristics of leukemia By www.mcponline.org Published On :: 2020-11-30 Ka-Won KangNov 30, 2020; 0:RA120.002169v1-mcp.RA120.002169Research Full Article
ni The Mechanism of NEDD8 Activation of CUL5 Ubiquitin E3 Ligases By www.mcponline.org Published On :: 2020-12-02 Ryan J LumpkinDec 2, 2020; 0:RA120.002414v1-mcp.RA120.002414Research Full Article
ni Pluripotency of embryonic stem cells lacking clathrin-mediated endocytosis cannot be rescued by restoring cellular stiffness [Molecular Biophysics] By www.jbc.org Published On :: 2020-12-04T00:06:06-08:00 Mouse embryonic stem cells (mESCs) display unique mechanical properties, including low cellular stiffness in contrast to differentiated cells, which are stiffer. We have previously shown that mESCs lacking the clathrin heavy chain (Cltc), an essential component for clathrin-mediated endocytosis (CME), display a loss of pluripotency and an enhanced expression of differentiation markers. However, it is not known whether physical properties such as cellular stiffness also change upon loss of Cltc, similar to what is seen in differentiated cells, and if so, how these altered properties specifically impact pluripotency. Using atomic force microscopy (AFM), we demonstrate that mESCs lacking Cltc display higher Young's modulus, indicative of greater cellular stiffness, compared with WT mESCs. The increase in stiffness was accompanied by the presence of actin stress fibers and accumulation of the inactive, phosphorylated, actin-binding protein cofilin. Treatment of Cltc knockdown mESCs with actin polymerization inhibitors resulted in a decrease in the Young's modulus to values similar to those obtained with WT mESCs. However, a rescue in the expression profile of pluripotency factors was not obtained. Additionally, whereas WT mouse embryonic fibroblasts could be reprogrammed to a state of pluripotency, this was inhibited in the absence of Cltc. This indicates that the presence of active CME is essential for the pluripotency of embryonic stem cells. Additionally, whereas physical properties may serve as a simple readout of the cellular state, they may not always faithfully recapitulate the underlying molecular fate. Full Article