id

Does He Have It?: Sensitivity, Specificity, and COVID-19 Testing




id

Pooling strategies for COVID-19 testing




id

Am I really uninfected? COVID-19 and rapid testing




id

Up to US to decide what to do with decommissioned HAWK missiles, Taiwan says




id

Analysis-India's middle class tightens its belt, squeezed by food inflation




id

COMAC says Air China is the first customer for C929 widebody jet




id

Doctor’s ‘pizza topping’ trick to tell the difference between hemorrhoids and a sign of colon cancer




id

This powerful, quiet, exhaust-free generator is almost 55% off ahead of Black Friday




id

North Ridgeville schools employee arrested, on leave




id

China reveals reusable cargo shuttle design for Tiangong space station (video)




id

Vietnam Airlines to request bids for 50 narrowbody jets next year




id

King tides, 28-foot waves to swamp the Oregon Coast this week




id

Northern California man goes missing after Uber ride from Bay Area to Placer County




id

Dubbi gaining traction with ‘Side Chick’

UK-based, Jamaica-born dancehall artiste Dubbi believes latest single, ' Side Chick' is a bona fide hit as its popularity has surged on the dancehall scene in the United Kingdom. "It is also streaming well in France and seems to be a real hit on...




id

Bridge over troubled water - Bushy Park residents construct new walkway after floodwaters sweep away old one

After parking his taxi cab along the sidewalk, Leon Thompson exited his vehicle and held on tightly to the tiny hands of his four small passengers. They all walked towards a makeshift bridge, and Thompson lifted each child, making four trips,...




id

St Thomas residents plan proper funeral for Donovan

In a touching display of compassion and solidarity, a group of St Thomas residents has come together to organise the funeral of a a well-known and beloved man with intellectual challenges. For years, Donovan Sinclair was a familiar face in the...




id

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

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




id

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

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




id

Peptidoglycan analysis reveals that synergistic deacetylase activity in vegetative Clostridium difficile impacts the host response [Glycobiology and Extracellular Matrices]

Clostridium difficile is an anaerobic and spore-forming bacterium responsible for 15–25% of postantibiotic diarrhea and 95% of pseudomembranous colitis. Peptidoglycan is a crucial element of the bacterial cell wall that is exposed to the host, making it an important target for the innate immune system. The C. difficile peptidoglycan is largely N-deacetylated on its glucosamine (93% of muropeptides) through the activity of enzymes known as N-deacetylases, and this N-deacetylation modulates host–pathogen interactions, such as resistance to the bacteriolytic activity of lysozyme, virulence, and host innate immune responses. C. difficile genome analysis showed that 12 genes potentially encode N-deacetylases; however, which of these N-deacetylases are involved in peptidoglycan N-deacetylation remains unknown. Here, we report the enzymes responsible for peptidoglycan N-deacetylation and their respective regulation. Through peptidoglycan analysis of several mutants, we found that the N-deacetylases PdaV and PgdA act in synergy. Together they are responsible for the high level of peptidoglycan N-deacetylation in C. difficile and the consequent resistance to lysozyme. We also characterized a third enzyme, PgdB, as a glucosamine N-deacetylase. However, its impact on N-deacetylation and lysozyme resistance is limited, and its physiological role remains to be dissected. Finally, given the influence of peptidoglycan N-deacetylation on host defense against pathogens, we investigated the virulence and colonization ability of the mutants. Unlike what has been shown in other pathogenic bacteria, a lack of N-deacetylation in C. difficile is not linked to a decrease in virulence.




id

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

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




id

Structural and biochemical characteristics of two Staphylococcus epidermidis RNase J paralogs RNase J1 and RNase J2 [Protein Structure and Folding]

RNase J enzymes are metallohydrolases that are involved in RNA maturation and RNA recycling, govern gene expression in bacteria, and catalyze both exonuclease and endonuclease activity. The catalytic activity of RNase J is regulated by multiple mechanisms which include oligomerization, conformational changes to aid substrate recognition, and the metal cofactor at the active site. However, little is known of how RNase J paralogs differ in expression and activity. Here we describe structural and biochemical features of two Staphylococcus epidermidis RNase J paralogs, RNase J1 and RNase J2. RNase J1 is a homodimer with exonuclease activity aided by two metal cofactors at the active site. RNase J2, on the other hand, has endonuclease activity and one metal ion at the active site and is predominantly a monomer. We note that the expression levels of these enzymes vary across Staphylococcal strains. Together, these observations suggest that multiple interacting RNase J paralogs could provide a strategy for functional improvisation utilizing differences in intracellular concentration, quaternary structure, and distinct active site architecture despite overall structural similarity.




id

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

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




id

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

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




id

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

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




id

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

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




id

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

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




id

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

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




id

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

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




id

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

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




id

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

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




id

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

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




id

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

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




id

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

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




id

Is Evaluating COVID-19 About the WHO or Country Responses?

11 July 2020

Dr Charles Clift

Senior Consulting Fellow, Global Health Programme
Striking the right balance in membership and terms of reference is challenging for the evaluation panel set up to examine the coordinated international health response to coronavirus.

2020-07-11-WHO-Data-Coronavirus-Tedros

Examining the global response of indivudual countries and the World Health Organization (WHO) to coronavirus. Photo Illustration by Rafael Henrique/SOPA Images/LightRocket via Getty Images.

When the resolution was passed by World Health Organization (WHO) member states at the World Health Assembly (WHA) in May requesting an evaluation ‘at the earliest appropriate moment’ of lessons learned from the WHO-coordinated international health response to COVID-19, it was generally thought the appropriate moment would be when the pandemic was on the wane.

Yet the Independent Panel for Pandemic Preparedness and Response has actually been established at a time when - as noted by WHO director-general Dr Tedros Adhanom Ghebreyesus in his announcement of the panel - the pandemic is still accelerating.

In most of the world the virus is not under control, and cases have actually doubled in the last six weeks. So why now?

Emphasis on global solidarity

Throughout the pandemic so far, Dr Tedros has emphasised two main points – the need for urgent action by countries, and the imperative need for global solidarity. In announcing the panel, he said this is the ‘defining crisis of our age’ and that ‘we cannot defeat this pandemic as a divided world … the COVID-19 pandemic is a test of global solidarity and global leadership’.

He may well see establishing the panel now - when the pandemic still has a long way to run - as an opportunity to reinforce messages which have hitherto seemed to fall on deaf ears, notably saying ‘we are in the midst of the battle of our lives, and we have to do better’. And he has also said that we should learn lessons now that will be useful in the continuing fight against the pandemic.

Establishing both the membership of the panel and its terms of reference has been left largely in the hands of the co-chairs – distinguished ex-politicians Helen Clark of New Zealand and Ellen Johnson Sirleaf of Liberia. But they will have to construct the panel in close consultation with member states on the basis of their proposals for membership – a process that will likely be fraught by the divisive politics which have already so upset Dr Tedros.

In addition, embedded in the mandate from the WHA resolution is the phrase ‘WHO-coordinated international health response’ – negotiated language which is intentionally ambiguous and reveals an unresolved tension.

Does it mean the panel should principally focus on WHO’s performance, which is what several countries – including the US – want to see? Or should it give at least equal weight to the way countries have responded individually and collectively, as Dr Tedros and the WHO may want to see?

These different interpretations mean both the construction of the panel and its terms of reference could be highly contentious. Most countries, including China and the US but also others, will not want their responses to be subjected to independent investigation. Nor will they want to include panel members likely to be critical of their responses. This suggests the possibility that there will be political pressure to focus the enquiry principally on the performance of WHO rather than that of countries – an outcome Dr Tedros would not welcome.

It remains to be seen how the co-chairs will manage these highly political issues, and avoid the panel becoming an extension of ‘pandemic politics’ by other means. Can it come to definitive conclusions in the midst of a pandemic and, if so, how likely are they to be heeded?

It is also highly likely that several other reviews will be launched, wholly independently of oversight by WHO and its member states, as happened following the 2014 Ebola outbreak. This provides opportunities for a variety of perspectives on both the performance of WHO, and of individual countries.

Already, The Lancet has announced its own Commission on COVID-19 with a broad mandate covering both the health and economic responses to the pandemic. Both this and the Independent Panel for Pandemic Preparedness and Response are likely to be only the first of many COVID-19 reviews.




id

COVID-19: The Hidden Majority in India's Migration Crisis

13 July 2020

Dr Champa Patel

Director, Asia-Pacific Programme
While the social and economic costs of coronavirus lockdowns, travel bans and social distancing initially focused on international migrants, there has been increasing attention paid to the plight of internal migrants.

2020-07-13-India-Farming-Migration

Migrant workers plant paddy in a field at Jhandi village in Patiala, India. Photo by Bharat Bhushan/Hindustan Times via Getty Images.

The World Bank estimates that the magnitude of internal migration is about two‐and‐a‐half times that of international migration. Within India, an estimated 40 million internal migrant workers, largely in the informal economy, were severely impacted by the government’s COVID-19 lockdown.

With transportation systems initially shut down, many had no recourse to travel options back to homes and villages, resulting in harrowing journeys home. Those who were able to make it home found, in some instances, villages refusing entry because of fears of transmission.

The shocking images of migrants forced to walk in desperation showed the enormity of the crisis as well as some of the challenges posed by an extended lockdown in India where so many people live hand to mouth and cannot afford not to work.

Migrant workers and the informal economy

The complete failure of the government to anticipate the needs of this group, and the subsequent distress caused, has made visible a large workforce who experience precarity of work and often live hand to mouth.

One key challenge is the lack of robust data on the scale of internal migration. While estimates abound, there is no proper data collection system in place to accurately record temporary, seasonal and circular migration patterns. However, it is estimated that more than 90% of working people in India are engaged in the informal economy, with states such as Uttar Pradesh and Bihar accounting for more than 80% of workers in this sector.

A recent government labour force survey estimated that more than 71% of people with a regular salary working in non-agricultural industries had no written job contract. Nearly half of workers are not eligible for social security benefits.

Daily-wage workers are particularly vulnerable, with limited or no access to social security and most living in poverty. Living hand to mouth, their loss of livelihoods has led to a lack of money to pay rents or pay for food. Women are impacted whether because of their gender, responsibilities as caregivers, or as members of disadvantaged castes and communities.

COVID-19 has massively impacted this group of workers. Stranded Workers Action Network found that 50% of workers had rations left for less than one day; 74% had less than half their daily wages remaining to survive for the rest of the lockdown period; and 89% had not been paid by their employers at all during the lockdown.

According to Supreme Court proceedings, relief camps are housing some 660,000 workers; some 2.2 million people also rely on emergency food supplies. Job losses, and home and food insecurity have left this group highly vulnerable.

In March 2020, in response to COVID-19, the Indian government instituted the Pradhan Mantri Garib Kalyan Package (PMGKB), a $22.6 billion relief package. The World Bank announced $1 billion funding to accelerate social protection support, in part through the PMGKB.

This support would work alongside pre-existing initiatives such as the Public Distribution System (PDS), which covers 800 million people, and Direct Benefit Transfers (DBT). This cash injection could help address one of the key challenges facing India’s piecemeal and uneven social protection programmes – inadequate funding. India’s spending on public social protection excluding health is just 1.3% of the GDP.

However, there are still other challenges to overcome. One is how to ensure coordination and coverage within, and across, differing states. The second is how to transition multiple schemes into one integrated system that can be accessed anywhere within the country, particularly important when many workers are on the move. There is an urgent need for a comprehensive system, which is adaptive and flexible to needs and provides adequate social and income support.

Another coverage issue relates to the use of direct cash transfers (DCTs) to support people impacted by the loss of livelihoods, where funds are deposited within bank accounts. Such measures fail to consider the significant numbers of people who do not have access to banks and will not be able to access this support.

Wider impact on livelihoods and remittances

​There is a risk, with extended lockdown and risks of further waves of infection, that labour shortages could negatively impact the economy. There is a wider need to support re-entry back into the workforce and support livelihoods. National Survey Sample data shows that between 2007 and 2008, internal remittances amounted to US$10 billion. These domestic transfers financed over 30% of all household consumption in remittance-receiving households.

But future migration for work is likely to be severely impacted. As restrictions begin to ease, employers and businesses cannot necessarily rely on cheap available labour. Having faced destitution and hardship, many may wish to stay closer to families and local support networks.

As Irudaya Rajan notes in The New Humanitarian, it is likely ‘there will be a reduction in long-distance migration in India after this’, as many migrants will be wary of being stranded again. This would be hugely detrimental to stimulating the economy as reverse migration could push down wages and subsequently demand.

Another issue may be returning migrant workers, who have been working overseas, over half of whom work in the Gulf. It is unclear if, or when, migrants will be able to return to work, with the World Bank estimating that remittances from this group could fall by about 23%.

However, what is striking has been India’s support for this group - the Vande Bharat Mission has deployed flights and naval ships to help return migrant workers, especially vulnerable groups - in marked contrast to the lack of preparation and care for internal migrants.

One factor for this may be the volume of remittances these migrant workers bring to the Indian economy, but it overlooks the contribution of internal remittances, on which there is far less robust data.

But the current challenges can also be an opportunity. The scale of the migrant crisis has made visible an often-overlooked population of workers. With political will, and investment at federal and state levels, this could be an opportunity to transform livelihoods.

As thoughts will turn to how to stimulate economies and get people back to work, it is imperative that those in authority turn their minds to how to create a more just society, that invests in healthcare, and has a social protection system that supports the most vulnerable in society.

Migrants are not just objects of charity that need support. Internal migrants are key income generators that play a vital role in Indian society and should never be overlooked again.

This article was originally published in Routed Magazine.




id

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

20 July 2020

Ekaterina Aleynikova

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

GettyImages-1159506648 (1).jpg

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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




id

Domestic Violence in Ukraine: Lessons from COVID-19

23 July 2020

Kateryna Busol

Robert Bosch Stiftung Academy Fellow, Russia and Eurasia Programme
The pandemic has shed light on domestic violence in Ukraine, mobilizing civil society to demand more nuanced policy on the issue.

2020-07-23-UkraineIWD.jpg

A protester chants slogans on a megaphone during an International Women's Day protest on 8 March 2019 in Kyiv, Ukraine. Photo: Getty Images.

The virus of violence

During quarantine, the greater economic vulnerability of Ukrainian women has locked many of them with abusive partners. The uncertainty of personal finances, health and security in confinement has exacerbated domestic violence against women, in certain cases aggravated by the perpetrator’s war-related post-traumatic stress disorder (PTSD).

In pre- pandemic times, only one third of domestic violence victims, 78% of whom are women, reported the abuse. During the pandemic, the calls to domestic violence helplines increased by 50% in the Donbas war zone and by 35% in other regions of Ukraine.

However, more precise estimates are hard to make. This is largely because some fractions of Ukrainian society still see domestic violence as a private family matter, which will get little assistance from the police. Also, reporting from a small confinement place permanently shared with a perpetrator during the lockdown can trigger more abuse.

The COVID-19-tested legal framework

The spike in domestic violence during lockdown has intensified the debate about the inadequacy of Ukraine’s approach.

Ukraine adopted the law on domestic violence in 2017 and made such behaviour punishable under administrative and criminal law. Importantly, the law does not limit domestic violence to physical abuse, but recognizes its sexual, psychological and economic variations. Domestic violence is further not limited to a married couple or close family members, but can be perpetrated against a distant relative or a cohabiting partner.

The extended definition of rape now includes rape of a spouse or a family member as an aggravating circumstance. A special police unit has been designated to deal with domestic abuse cases. Police can now issue protection orders in prompt reaction to an offence and immediately distance a perpetrator from a victim.

The victim can also spend time in a shelter - a system which the Ukrainian government has promised to create. A special registry of domestic violence cases has been set up for the exclusive use by the designated law enforcement and social security authorities to help them be more holistically informed in building a response.

However important, the introduced legal and institutional infrastructure was slow in proving its efficiency pre-COVID-19. It is struggling even more to stand the test of the coronavirus.

Changing the established mindset takes time. 38% of Ukraine’s judges and 39% of prosecutors still struggle to see domestic violence not as a household issue. Even though the police are becoming more reactive to home abuse complaints, getting emergency protection orders is still difficult. The court restraining orders are more effective, however they require the unnecessarily protracted and humiliating procedures of proving one’s own victimhood to different state authorities.

In response to the challenges of coronavirus for women, the police spread information posters and created a special chat-bot about the available help. However, while the domestic violence helplines of La Strada and other human rights NGOs are busier than ever, the police statistics suggest that the lockdown has not catalyzed home abuse.

This could indicate a higher trust to non-state institutions and the inability of a considerable group of women to use more sophisticated communication means such as chat-bots when they cannot call the police in the presence of an abuser. This problem is exacerbated by a current  lack of shelters in rural areas, as most are located in urban settings. Overcrowded in ordinary times, the shelters’ capacity to accept survivors during the lockdown is further limited by the social distancing rules.

Istanbul Convention – The bigger picture

Ukraine failed to ratify the Council of Europe Convention on preventing and combating violence against women, better known as the Istanbul Convention, largely due to the opposition of religious organizations. Concerned that the treaty’s terms ‘gender’ and ‘sexual orientation’ would contribute to the promotion of same-sex relationships in Ukraine, they argued that Ukraine’s current legislation provides adequate protection against domestic violence. However, this is not the case.

The Istanbul Convention does not ‘promote’ same-sex relationships, it only mentions sexual orientation among the non-exhaustive list of prohibited discrimination grounds. Remarkably, Ukraine’s domestic violence law itself is against such discrimination.

The Convention defines ‘gender’ as the socially constructed roles a society attributes to women and men. Ukraine’s overcautiousness about the term is ironic at least in two dimensions.

First, the 2017 domestic violence law restates its aim to eliminate discriminating beliefs about the social roles of each ‘sex’. In doing so, the law supports the rationale of what the Istanbul Convention denotes as ‘gender’ without using the term itself.

Second,  it is exactly the constraints of the rigidly defined niches for both sexes in Ukraine that have substantially contributed to the intensified domestic violence, whether it be  war or  coronavirus-related. The lack of sustainable psychological support for traumatized veterans and the stigma of mental health struggles, especially among men, mars their reintegration to peaceful life. This often results in alcohol abuse or even suicide.

As the economic uncertainty of the war and the virus prevents some men from fully living up to their traditional socially - and self-imposed - breadwinner role, this increases the risk of problematic behaviour and domestic violence.

By diverting the focus of the debate  to the term ‘gender’ used in the Istanbul Convention, conservative groups have ignored the fact that it describes the priority already enshrined in Ukraine’s 2017 law - to eliminate discriminatory beliefs about the socially constructed roles of men and women. This has drawn away time and resources needed to protect those vulnerable to domestic abuse.

Ukraine has not addressed the pigeonholing of women and men into gendered stereotypes. This has harmed men while further victimizing women and children, especially during the lockdown. Ironically, this is leading to the undermining of the very traditional family values certain opponents of the Istanbul Convention appealed to.

Fortunately, Ukraine’s ever-vigilant civil society,  dismayed at the wave of the lockdown domestic violence, petitioned President Zelenskyy to ratify the Convention. With a new draft law on ratification, the ball is now in the parliament’s court. It remains to be seen whether Ukraine’s policymakers will be up to the task.            




id

Elections in Côte d’Ivoire: President Ouattara’s Dilemma

28 July 2020

Paul Melly

Consulting Fellow, Africa Programme
After the sudden death of Côte d’Ivoire’s Prime Minister Amadou Gon Coulibaly, President Ouattara is now deciding whether to stand for a third term. However, such a move would face challenges internationally, and particularly in West Africa.

GettyImages-1227751629.jpg

President of Ivory Coast Alassane Ouattara arrives in Bamako on 23 July 2020, where West African leaders gathered in a push to end an escalating political crisis in Mali. Photo: Getty Images.

Gon Coulibaly, an economic technocrat and Ouattara loyalist since the 1990s, was earmarked in March as the candidate for the ruling Rassemblement des Houphouëtistes pour la Démocratie et la Paix (RHDP) party in the elections due in October, and represented a handpicked heir, trusted to sustain the strategy established during Ouattara’s nine years in power.

Many RDHP parliamentarians and local mayors are now pressing the 78-year-old Ouattara to run again. This was not what he had planned. He hoped to go out on a high – ‘par la grande porte’ – and set a statesmanlike example of retirement by choice, making way for the next generation. His leadership of reform of the regional currency that will see the end of the West African CFA franc would have been the crowning achievement of a presidency that had taken his country from post-war stagnation to sustained growth GDP growth rates around seven per cent before COVID-19 forced a slowdown, as it has worldwide.

A profound strategic dilemma

Gon Coulibaly had undergone a heart transplant in 2012, and when he hurried to Paris in early May and was fitted with a stent, some wondered whether he would have the energy required for an election campaign. Yet he returned home on 2 July, with his formal nomination by the RHDP pencilled in for early the next month. His sudden death on 8 July, at the age of just 61, was a terrible personal blow for Ouattara, who had regarded him almost as a son, and much more than a purely political protégé. But it also left the president facing a profound strategic dilemma.

Names of alternative potential RHDP candidates have been floated – notably the defence minister, and now interim premier, Hamed Bakayoko and the secretary general of the presidency Patrick Achi. Both have solid electoral track records and ample experience of government. But over recent days the impression has grown that they do not command the ultimate confidence of Alassane Ouattara to take on the leadership of the nation.

Speculation has grown that the president will conclude that he has no choice but to go back on his promise to retire and stand for yet another term. Although some respected legal experts disagree, he has always made a point of insisting that the constitutional reform of 2016 allows him to run again. And many influential voices within the RHDP are now pressing him to do so.

This is not ‘rentacrowd’ fawning. Many members of the governing party have always felt that Ouattara offers the strongest blend of political appeal, governing capability and international profile required to lead a country that likes to see itself as West Africa’s ‘elephant’.

A weak opposition, but third term challenges

In electoral terms, Ouattara’s greatest campaign asset might be the unconvincing state of the opposition figures who are actually free to stand, after the Ivorian authorities’ strong-armed the judicial system into blocking the hopes of the of the smooth-talking former parliamentary speaker Guillame Soro, who had great appeal for Cote D’Ivoire’s growing young population. Soro is now exiled in France after conviction in absentia for corruption. Ex-president Laurent Gbagbo remains in Brussels, while the International Criminal Court considers the prosecution appeal against his acquittal on charges of human rights crimes. He is now allowed to travel and has applied for a passport to come home, but it is unclear if this will be granted. That leaves another former head of state, the 86-year old Henri Konan Bédié, as the main opposition challenger.

However, even if the RHDP party machine delivers victory for Ouattara, a third term risks hard questions from those who dispute its legitimacy and it may generate other significant political challenges too. Some 60 per cent of Ivorians are under the age of 25, and many young people are impatient for leaders more in tune with their concerns and outlook. Some 51 per cent now live in towns and cities.

The sprawling Abidjan conurbation, in particular, weighs heavily in the political culture and national mood. Street protest and urban frustrations are a real factor, and something that fuels vocal grassroots support for both the Soro and Gbagbo camps.

Moreover, despite the government’s capable management, the COVID-19 crisis has struck a severe economic and social blow that is sure to impose painful legacy pressures. Even when real GDP was rising by seven per cent per annum, increasingly evident inequality was brewing popular resentment. Corruption appeared to be on the rise, and the obvious prosperity, construction and consumption in parts of Abidjan were not reflected nationwide nor in all sections of society.

In the latter years of his second term, Ouattara recognized this and launched an ambitious programme to broaden the reach of development and nudge growth towards a more ‘inclusive’ model. But selling this as the core of an election agenda would be harder for a political veteran who has been in power since 2011 and who now went back on his rhetoric about making way for a younger generation.

A third term Ouattara would also face challenges internationally, and particularly in West Africa. He has always presented himself as a statesmanlike figure with restraint and respect for institutional values, setting a tone that has helped in the management of numerous regional crises – exemplified by his participation in a five-president mission to Bamako last week, an effort to broker a solution to Mali’s political and protest deadlock. If a third term run sparks mass domestic protest or accusations of constitutional manipulation, the diplomatic standing and influence so associated with Ouattara will be jeopardized.

So Côte d’Ivoire’s president faces profoundly awkward questions as he ponders the third term bid that he had forsworn less than five months ago. And yet he may well conclude that, from his political perspective, there is no viable alternative.




id

COVID-19 Teaches Resilience and the ‘Vulnerability Paradox’

7 August 2020

Dr Gareth Price

Senior Research Fellow, Asia-Pacific Programme

Christopher Vandome

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

2020-08-07-Vietnam-Health-Virus-Art

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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




id

Why the Corrupt President of Belarus Deserves Sanctions

10 August 2020

Ryhor Astapenia

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

2020-08-10-Belarus-Protest-Election

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

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

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

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

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

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

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

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

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

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

This article was originally published in The Telegraph.




id

Choosing Kamala Harris Puts Identity at the Heart of Presidential Race

12 August 2020

Dr Leslie Vinjamuri

Director, US and the Americas Programme; Dean, Queen Elizabeth II Academy for Leadership in International Affairs
Joe Biden’s choice of Kamala Harris as his running mate will have a lasting impact on how Americans think about the presidential ticket, and confirms the violent killing of George Floyd unleashed a demand for racial equality that continues to have dramatic impact.

2020-08-12-Kamala-Harris

Senator Kamala Harris speaks during a Senate Homeland Security and Governmental Affairs hearing. Photo by ALEXANDER DRAGO/POOL/AFP via Getty Images.

Despite being such a historic selection, in certain aspects, Kamala Harris does not actually signal change. She is a moderate in the Democratic Party, an insider more than an outsider, and a highly experienced leader with national, state level and city level credentials. She worked as a district attorney in San Francisco for several years before being elected attorney general for the state of California, and then to the US Senate in 2016. Harris also stood as a candidate against Biden in the contest to become the Democratic Party's presidential candidate.

Like Joe Biden, she is a highly experienced leader with strong credentials. But California is solidly blue, so she cannot deliver a new state for him. In many ways she is a safe choice and — at a time when Biden is far ahead of Donald Trump in the polls and America faces a lot of uncertainty — many leading political analysts say safe is exactly what the Democratic candidate needs.

The 2020 US Presidential Elections and the State of the Nation

Amy Walter and Adam Boulton discuss the current state of the nation and what this means for the US presidential election.

But certainly as a signal to the American people, and the rest of the world, of what America is and what it stands for, the choice of Kamala Harris is truly historic. The senator from California is the first African-American woman, and the first Asian-American woman, on the presidential ticket. If Biden wins in November, Harris becomes the first female vice-president.

The historic aspects do not end there. Harris also represents a rapidly growing segment of the US population, but one that gets far less mention — multi-racial Americans. The exact size of America’s multi-racial population has been notoriously hard to measure, especially as it has only been 15 years since the US Census Bureau allowed Americans to choose more than one race when completing their census form. But America has long seen itself as a melting pot, so Harris’s place on the ballot underscores a national narrative with a deep resonance across the country, not least among America’s schoolchildren.

In recent weeks, it came to feel inevitable Biden would choose an African-American running mate. His selection comes at a time when more Americans than ever before have taken to the streets to protest the brutal killing of George Floyd and racial injustice. And the demand for racial equality has been accelerated by the COVID-19 pandemic which has disproportionately affected African-Americans who are dying from the virus at around double the rate of their white American counterparts, while twice the number of black businesses are closing relative to their white counterparts.

The choice of Harris also speaks to another fundamental aspect of the ‘American dream’. She is the daughter of two immigrant parents, her father being from Jamaica and her mother from India. Immigration has become one of the toughest issues in US politics, and immigrants have suffered repeated rhetorical attacks from Trump. One of Harris’s first stands in the US Senate was against President Trump’s entry ban to the US on several countries with majority Muslim populations.

When it comes to questions of identity, the choices that the US electorate now face in November could not be more stark. President Trump used the opportunity of the July 4 weekend to deliver a speech at Mount Rushmore which appeared to actively seek division and to ignite America’s cultural wars.

By choosing Kamala Harris, Biden also continues to signal that he will lead from the moderate wing of the Democratic Party.

Harris may be left of Biden, but she is far to the right of other well-known progressive candidates, especially Elizabeth Warren. She has not, for example, supported more far-reaching measures to redistribute wealth, especially the proposal for a wealth tax. And she has a track record of being tough on crime during her years as a prosecutor. Although she played an active role in recent protests and signalled her commitment to police reform and anti-lynching laws, not all young or progressive protesters will be easily persuaded by her credentials.

However, for voters who hoped for a more progressive candidate, two factors play to the advantage of the Biden-Harris ticket. This election still looks set to be a referendum on President Trump and — especially now — his ability to manage the public health and economic crises at home. And Biden has continued to include the progressive side of the Democratic Party in his plans, giving Bernie Sanders and Alexandria Ocasio-Cortez key roles in developing climate proposals, and establishing a series of Unity task forces to bring the party together.

There are also other more conventional factors at play. Biden has relied on the support of African-American and also female voters. While Harris may not broaden this support, it should help ensure these voters turn out — if primarily via their postal box — to vote for Biden. His choice of Kamala Harris answers the one big outstanding question facing his candidacy and signals the true beginning of the race to the White House.




id

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

26 August 2020

Emanuela-Chiara Gillard

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

2020-08-25-covid-sanctions.jpg

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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




id

First US Presidential Debate – Five Key Questions Answered

30 September 2020

Anar Bata

Coordinator, US and the Americas Programme

Dr Leslie Vinjamuri

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

Megan Greene

Dame DeAnne Julius Senior Academy Fellow in International Economics

Dr Christopher Sabatini

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

GettyImages-1228797368.jpg

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

How will this debate impact the rest of the race?

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

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




id

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

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




id

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

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




id

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

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




id

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

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




id

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

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




id

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

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