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ADAM10 and ADAM17 proteases mediate proinflammatory cytokine-induced and constitutive cleavage of endomucin from the endothelial surface [Membrane Biology]

Contact between inflammatory cells and endothelial cells (ECs) is a crucial step in vascular inflammation. Recently, we demonstrated that the cell-surface level of endomucin (EMCN), a heavily O-glycosylated single-transmembrane sialomucin, interferes with the interactions between inflammatory cells and ECs. We have also shown that, in response to an inflammatory stimulus, EMCN is cleared from the cell surface by an unknown mechanism. In this study, using adenovirus-mediated overexpression of a tagged EMCN in human umbilical vein ECs, we found that treatment with tumor necrosis factor α (TNF-α) or the strong oxidant pervanadate leads to loss of cell-surface EMCN and increases the levels of the C-terminal fragment of EMCN 3- to 4-fold. Furthermore, treatment with the broad-spectrum matrix metalloproteinase inhibitor batimastat (BB94) or inhibition of ADAM metallopeptidase domain 10 (ADAM10) and ADAM17 with two small-molecule inhibitors, GW280264X and GI254023X, or with siRNA significantly reduced basal and TNFα-induced cell-surface EMCN cleavage. Release of the C-terminal fragment of EMCN by TNF-α treatment was blocked by chemical inhibition of ADAM10 alone or in combination with ADAM17. These results indicate that cell-surface EMCN undergoes constitutive cleavage and that TNF-α treatment dramatically increases this cleavage, which is mediated predominantly by ADAM10 and ADAM17. As endothelial cell-surface EMCN attenuates leukocyte–EC interactions during inflammation, we propose that EMCN is a potential therapeutic target to manage vascular inflammation.




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Excitotoxicity and Overnutrition Additively Impair Metabolic Function and Identity of Pancreatic {beta}-cells

A sustained increase in intracellular Ca2+ concentration (referred to herein as excitotoxicity), brought on by chronic metabolic stress, may contribute to pancreatic β-cell failure. To determine the additive effects of excitotoxicity and overnutrition on β-cell function and gene expression, we analyzed the impact of a high fat diet (HFD) on Abcc8 knock-out mice. Excitotoxicity caused β-cells to be more susceptible to HFD-induced impairment of glucose homeostasis, and these effects were mitigated by verapamil, a Ca2+ channel blocker. Excitotoxicity, overnutrition and the combination of both stresses caused similar but distinct alterations in the β-cell transcriptome, including additive increases in genes associated with mitochondrial energy metabolism, fatty acid β-oxidation and mitochondrial biogenesis, and their key regulator Ppargc1a. Overnutrition worsened excitotoxicity-induced mitochondrial dysfunction, increasing metabolic inflexibility and mitochondrial damage. In addition, excitotoxicity and overnutrition, individually and together, impaired both β-cell function and identity by reducing expression of genes important for insulin secretion, cell polarity, cell junction, cilia, cytoskeleton, vesicular trafficking, and regulation of β-cell epigenetic and transcriptional program. Sex had an impact on all β-cell responses, with male animals exhibiting greater metabolic stress-induced impairments than females. Together, these findings indicate that a sustained increase in intracellular Ca2+, by altering mitochondrial function and impairing β-cell identity, augments overnutrition-induced β-cell failure.




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Revisiting Proinsulin Processing: Evidence That Human {beta}-Cells Process Proinsulin With Prohormone Convertase (PC) 1/3 But Not PC2

Insulin is first produced in pancreatic β-cells as the precursor prohormone proinsulin. Defective proinsulin processing has been implicated in the pathogenesis of both type 1 and type 2 diabetes. Though there is substantial evidence that mouse β-cells process proinsulin using prohormone convertase 1/3 (PC1/3) then prohormone convertase 2 (PC2), this finding has not been verified in human β-cells. Immunofluorescence with validated antibodies reveals that there was no detectable PC2 immunoreactivity in human β-cells and little PCSK2 mRNA by in situ hybridization. Similarly, rat β-cells were not immunoreactive for PC2. In all histological experiments, PC2 immunoreactivity in neighbouring α-cells acts as a positive control. In donors with type 2 diabetes, β-cells had elevated PC2 immunoreactivity, suggesting that aberrant PC2 expression may contribute to impaired proinsulin processing in β-cells of patients with diabetes. To support histological findings using a biochemical approach, human islets were used for pulse-chase experiments. Despite inhibition of PC2 function by temperature blockade, brefeldin-A, chloroquine, and multiple inhibitors that blocked production of mature glucagon from proglucagon, β-cells retained the ability to produce mature insulin. Conversely, suppression of PC1/3 blocked processing of proinsulin but not proglucagon. By demonstrating that healthy human β-cells process proinsulin by PC1/3 but not PC2 we suggest that there is a need to revise the longstanding theory of proinsulin processing.




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Elevated First-Trimester Neutrophil Count Is Closely Associated with the Development of Maternal Gestational Diabetes Mellitus and Adverse Pregnancy Outcomes

Chronic low-grade inflammation plays a central role in the pathophysiology of gestational diabetes mellitus (GDM). In order to investigate the ability of different inflammatory blood cell parameters in predicting the development of GDM and pregnancy outcomes, 258 women with GDM and 1154 women without were included in this retrospective study. First-trimester neutrophil count outperformed white blood cell (WBC) count, and neutrophil-to-lymphocyte ratio (NLR) in the predictability for GDM. Subjects were grouped based on tertiles of neutrophil count during their first-trimester pregnancy. The results showed that as the neutrophil count increased, there was a step-wise increase in GDM incidence, as well as glucose and glycosylated hemoglobin (HbA1c) level, Homeostasis Model Assessment for Insulin Resistance (HOMA-IR), macrosomia incidence and newborn weight. Neutrophil count was positively associated with pre-pregnancy Body Mass Index (BMI), HOMA-IR and newborn weight. Additionally, neutrophil count was an independent risk factor for the development of GDM, regardless of the history of GDM. Spline regression showed that there was a significant linear association between GDM incidence and continuous neutrophil count when it exceeded 5.0 x 109/L. This work suggested that first-trimester neutrophil count is closely associated with the development of GDM and adverse pregnancy outcomes.




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Acute Hyperglycemia Increases Brain Pregenual Anterior Cingulate Cortex Glutamate Concentrations in Type 1 Diabetes Mellitus

The brain mechanisms underlying the association of hyperglycemia with depressive symptoms are unknown. We hypothesized that disrupted glutamate metabolism in pregenual anterior cingulate cortex (ACC) in type 1 diabetes (T1D) without depression affects emotional processing. Using proton magnetic resonance spectroscopy (MRS), we measured glutamate concentrations in ACC and occipital cortex (OCC) in 13 T1D without major depression (HbA1c=7.1±0.7% [54±7mmol/mol]) and 11 healthy non-diabetic controls (HbA1c=5.5±0.2% [37±3mmol/mol]) during fasting euglycemia (EU) followed by a 60-minute +5.5mmol/l hyperglycemic clamp (HG). Intrinsic neuronal activity was assessed using resting-state blood oxygen level dependent functional MRI to measure the fractional amplitude of low frequency fluctuations in slow-band 4 (fALFF4). Emotional processing and depressive symptoms were assessed using emotional tasks (Emotional-Stroop, Self-Referent-Encoding-Task SRET) and clinical ratings (HAM-D, SCL-90-R), respectively. During HG, ACC glutamate increased (1.2mmol/kg, +10%, p=0.014) while ACC fALFF4 was unchanged (-0.007, -2%, p=0.449) in T1D; in contrast, glutamate was unchanged (-0.2mmol/kg, -2%, p=0.578) while fALFF4 decreased (-0.05, -13%, p=0.002) in controls. OCC glutamate and fALFF4 were unchanged in both groups. T1D had longer SRET negative-word response-times (p=0.017) and higher depression-rating scores (HAM-D p=0.020; SCL-90-R-depression p=0.008). Higher glutamate change tended to associate with longer Emotional-Stroop response-times in T1D only. Brain glutamate must be tightly controlled during hyperglycemia due to the risk for neurotoxicity with excessive levels. Results suggest that ACC glutamate control mechanisms are disrupted in T1D, which affects glutamatergic neurotransmission related to emotional or cognitive processing. Increased prefrontal glutamate during acute hyperglycemic episodes could explain our previous findings of associations between chronic hyperglycemia, cortical thinning and depressive symptoms in T1D.




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Cardiac Magnetic Resonance Myocardial Feature Tracking for Optimized Risk Assessment after Acute Myocardial Infarction in Patients with Type 2 Diabetes

Type 2 diabetes mellitus predicts outcome following acute myocardial infarction (AMI). Since underlying mechanics are incompletely understood, we investigated left ventricular (LV) and atrial (LA) pathophysiological changes and their prognostic implications using cardiovascular magnetic resonance (CMR). Consecutive patients (n=1147, n=265 diabetic; n=882 non-diabetic) underwent CMR 3 days after AMI. Analyses included LV ejection fraction (LVEF), global longitudinal, circumferential and radial strains (GLS, GCS and GRS), LA reservoir, conduit and booster pump strains, as well as infarct size, edema and microvascular obstruction. Predefined endpoints were major adverse cardiovascular events (MACE) within 12 months. Diabetic patients had impaired LA reservoir (19.8 vs. 21.2%, p<0.01) and conduit strains (7.6 vs. 9.0%, p<0.01) but not ventricular function or myocardial damage. They were at higher risk of MACE than non-diabetic patients (10.2% vs. 5.8%, p<0.01) with most MACE occurring in patients with LVEF≥35%. Whilst LVEF (p=0.045) and atrial reservoir strain (p=0.024) were independent predictors of MACE in non-diabetic patients, GLS was in diabetic patients (p=0.010). Considering patients with diabetes and LVEF≥35% (n=237), GLS and LA reservoir strain below median were significantly associated with MACE. In conclusion, in patients with diabetes, LA and LV longitudinal strain permit optimized risk assessment early after reperfused AMI with incremental prognostic value over and above LVEF.




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Longitudinal Analysis of Serum Cytokine Levels and Gut Microbial Abundance Links IL-17/IL-22 with Clostridia and Insulin Sensitivity in Humans

Recent studies using mouse models suggest that interaction between the gut microbiome and IL-17/IL-22 producing cells plays a role in the development of metabolic diseases. We investigated this relationship in humans using data from the prediabetes study of the Integrated Human Microbiome Project (iHMP). Specifically, we addressed the hypothesis that early in the onset of metabolic diseases there is a decline in serum levels of IL-17/IL-22, with concomitant changes in the gut microbiome. Clustering iHMP study participants on the basis of longitudinal IL-17/IL-22 profiles identified discrete groups. Individuals distinguished by low levels of IL-17/IL-22 were linked to established markers of metabolic disease, including insulin sensitivity. These individuals also displayed gut microbiome dysbiosis, characterized by decreased diversity, and IL-17/IL-22-related declines in the phylum Firmicutes, class Clostridia, and order Clostridiales. This ancillary analysis of the iHMP data therefore supports a link between the gut microbiome, IL-17/IL-22 and the onset of metabolic diseases. This raises the possibility for novel, microbiome-related therapeutic targets that may effectively alleviate metabolic diseases in humans as they do in animal models.




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Maintaining Myocardial Glucose Utilization in Diabetic Cardiomyopathy Accelerates Mitochondrial Dysfunction

Cardiac glucose uptake and oxidation are reduced in diabetes despite hyperglycemia. Mitochondrial dysfunction contributes to heart failure in diabetes. It is unclear if these changes are adaptive or maladaptive. To directly evaluate the relationship between glucose delivery and mitochondrial dysfunction in diabetic cardiomyopathy we generated transgenic mice with inducible cardiomyocyte-specific expression of the glucose transporter (GLUT4). We examined mice rendered hyperglycemic following low-dose streptozotocin prior to increasing cardiomyocyte glucose uptake by transgene induction. Enhanced myocardial glucose in non-diabetic mice decreased mitochondrial ATP generation and was associated with echocardiographic evidence of diastolic dysfunction. Increasing myocardial glucose delivery after short-term diabetes onset, exacerbated mitochondrial oxidative dysfunction. Transcriptomic analysis revealed that the largest changes, driven by glucose and diabetes, were in genes involved in mitochondrial function. This glucose-dependent transcriptional repression was in part mediated by O-GlcNAcylation of the transcription factor Sp1. Increased glucose uptake induced direct O-GlcNAcylation of many electron transport chain subunits and other mitochondrial proteins. These findings identify mitochondria as a major target of glucotoxicity. They also suggest reduced glucose utilization in diabetic cardiomyopathy might defend against glucotoxicity and caution that restoring glucose delivery to the heart in the context of diabetes could accelerate mitochondrial dysfunction by disrupting protective metabolic adaptations.




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Dextran Sulfate Protects Pancreatic {beta}-Cells, Reduces Autoimmunity and Ameliorates Type 1 Diabetes

A failure in self-tolerance leads to autoimmune destruction of pancreatic β-cells and type 1 diabetes (T1D). Low molecular weight dextran sulfate (DS) is a sulfated semi-synthetic polysaccharide with demonstrated cytoprotective and immunomodulatory properties in vitro. However, whether DS can protect pancreatic β-cells, reduce autoimmunity and ameliorate T1D is unknown. Here we report that DS, but not dextran, protects human β-cells against cytokine-mediated cytotoxicity in vitro. DS also protects mitochondrial function and glucose-stimulated insulin secretion and reduces chemokine expression in human islets in a pro-inflammatory environment. Interestingly, daily treatment with DS significantly reduces diabetes incidence in pre-diabetic non-obese diabetic (NOD) mice, and most importantly, reverses diabetes in early-onset diabetic NOD mice. DS decreases β-cell death, enhances islet heparan sulfate (HS)/heparan sulfate proteoglycan (HSPG) expression and preserves β-cell mass and plasma insulin in these mice. DS administration also increases the expression of the inhibitory co-stimulatory molecule programmed death-1 (PD-1) in T-cells, reduces interferon-+ CD4+ and CD8+ T-cells and enhances the number of FoxP3+ cells. Collectively, these studies demonstrate that the action of one single molecule, DS, on β-cell protection, extracellular matrix preservation and immunomodulation can reverse diabetes in NOD mice highlighting its therapeutic potential for the treatment of T1D.




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Nutrient-Induced Metabolic Stress, Adaptation, Detoxification, and Toxicity in the Pancreatic {beta}-Cell

Paraphrasing the Swiss physician and father of toxicology Paracelsus (1493–1541) on chemical agents used as therapeutics, "the dose makes the poison," it is now realized that this aptly applies to the calorigenic nutrients. The case here is the pancreatic islet β-cell presented with excessive levels of nutrients such as glucose, lipids, and amino acids. The short-term effects these nutrients exert on the β-cell are enhanced insulin biosynthesis and secretion and changes in glucose sensitivity. However, chronic fuel surfeit triggers additional compensatory and adaptive mechanisms by β-cells to cope with the increased insulin demand or to protect itself. When these mechanisms fail, toxicity due to the nutrient surplus ensues, leading to β-cell dysfunction, dedifferentiation, and apoptosis. The terms glucotoxicity, lipotoxicity, and glucolipotoxicity have been widely used, but there is some confusion as to what they mean precisely and which is most appropriate for a given situation. Here we address the gluco-, lipo-, and glucolipo-toxicities in β-cells by assessing the evidence both for and against each of them. We also discuss potential mechanisms and defend the view that many of the identified "toxic" effects of nutrient excess, which may also include amino acids, are in fact beneficial adaptive processes. In addition, candidate fuel-excess detoxification pathways are evaluated. Finally, we propose that a more general term should be used for the in vivo situation of overweight-associated type 2 diabetes reflecting both the adaptive and toxic processes to mixed calorigenic nutrients excess: "nutrient-induced metabolic stress" or, in brief, "nutri-stress."




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The FKH domain in FOXP3 mRNA frequently contains mutations in hepatocellular carcinoma that influence the subcellular localization and functions of FOXP3 [Molecular Bases of Disease]

The transcription factor forkhead box P3 (FOXP3) is a biomarker for regulatory T cells and can also be expressed in cancer cells, but its function in cancer appears to be divergent. The role of hepatocyte-expressed FOXP3 in hepatocellular carcinoma (HCC) is unknown. Here, we collected tumor samples and clinical information from 115 HCC patients and used five human cancer cell lines. We examined FOXP3 mRNA sequences for mutations, used a luciferase assay to assess promoter activities of FOXP3's target genes, and employed mouse tumor models to confirm in vitro results. We detected mutations in the FKH domain of FOXP3 mRNAs in 33% of the HCC tumor tissues, but in none of the adjacent nontumor tissues. None of the mutations occurred at high frequency, indicating that they occurred randomly. Notably, the mutations were not detected in the corresponding regions of FOXP3 genomic DNA, and many of them resulted in amino acid substitutions in the FKH region, altering FOXP3's subcellular localization. FOXP3 delocalization from the nucleus to the cytoplasm caused loss of transcriptional regulation of its target genes, inactivated its tumor-inhibitory capability, and changed cellular responses to histone deacetylase (HDAC) inhibitors. More complex FKH mutations appeared to be associated with worse prognosis in HCC patients. We conclude that mutations in the FKH domain of FOXP3 mRNA frequently occur in HCC and that these mutations are caused by errors in transcription and are not derived from genomic DNA mutations. Our results suggest that transcriptional mutagenesis of FOXP3 plays a role in HCC.




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Inhibition of the erythropoietin-producing receptor EPHB4 antagonizes androgen receptor overexpression and reduces enzalutamide resistance [Molecular Bases of Disease]

Prostate cancer (PCa) cells heavily rely on an active androgen receptor (AR) pathway for their survival. Enzalutamide (MDV3100) is a second-generation antiandrogenic drug that was approved by the Food and Drug Administration in 2012 to treat patients with castration-resistant prostate cancer (CRPC). However, emergence of resistance against this drug is inevitable, and it has been a major challenge to develop interventions that help manage enzalutamide-resistant CRPC. Erythropoietin-producing human hepatocellular (Eph) receptors are targeted by ephrin protein ligands and have a broad range of functions. Increasing evidence indicates that this signaling pathway plays an important role in tumorigenesis. Overexpression of EPH receptor B4 (EPHB4) has been observed in multiple types of cancer, being closely associated with proliferation, invasion, and metastasis of tumors. Here, using RNA-Seq analyses of clinical and preclinical samples, along with several biochemical and molecular methods, we report that enzalutamide-resistant PCa requires an active EPHB4 pathway that supports drug resistance of this tumor type. Using a small kinase inhibitor and RNAi-based gene silencing to disrupt EPHB4 activity, we found that these disruptions re-sensitize enzalutamide-resistant PCa to the drug both in vitro and in vivo. Mechanistically, we found that EPHB4 stimulates the AR by inducing proto-oncogene c-Myc (c-Myc) expression. Taken together, these results provide critical insight into the mechanism of enzalutamide resistance in PCa, potentially offering a therapeutic avenue for enhancing the efficacy of enzalutamide to better manage this common malignancy.




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Two- and three-color STORM analysis reveals higher-order assembly of leukotriene synthetic complexes on the nuclear envelope of murine neutrophils [Computational Biology]

Over the last several years it has become clear that higher order assemblies on membranes, exemplified by signalosomes, are a paradigm for the regulation of many membrane signaling processes. We have recently combined two-color direct stochastic optical reconstruction microscopy (dSTORM) with the (Clus-DoC) algorithm that combines cluster detection and colocalization analysis to observe the organization of 5-lipoxygenase (5-LO) and 5-lipoxygenase–activating protein (FLAP) into higher order assemblies on the nuclear envelope of mast cells; these assemblies were linked to leukotriene (LT) C4 production. In this study we investigated whether higher order assemblies of 5-LO and FLAP included cytosolic phospholipase A2 (cPLA2) and were linked to LTB4 production in murine neutrophils. Using two- and three-color dSTORM supported by fluorescence lifetime imaging microscopy we identified higher order assemblies containing 40 molecules (median) (IQR: 23, 87) of 5-LO, and 53 molecules (62, 156) of FLAP monomer. 98 (18, 154) molecules of cPLA2 were clustered with 5-LO, and 77 (33, 114) molecules of cPLA2 were associated with FLAP. These assemblies were tightly linked to LTB4 formation. The activation-dependent close associations of cPLA2, FLAP, and 5-LO in higher order assemblies on the nuclear envelope support a model in which arachidonic acid is generated by cPLA2 in apposition to FLAP, facilitating its transfer to 5-LO to initiate LT synthesis.




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Catabolic degradation of endothelial VEGFA via autophagy [Glycobiology and Extracellular Matrices]

Extracellular matrix-evoked angiostasis and autophagy within the tumor microenvironment represent two critical, but unconnected, functions of the small leucine-rich proteoglycan, decorin. Acting as a partial agonist of vascular endothelial growth factor 2 (VEGFR2), soluble decorin signals via the energy sensing protein, AMP-activated protein kinase (AMPK), in the autophagic degradation of intracellular vascular endothelial growth factor A (VEGFA). Here, we discovered that soluble decorin evokes intracellular catabolism of endothelial VEGFA that is mechanistically independent of mTOR, but requires an autophagic regulator, paternally expressed gene 3 (PEG3). We found that administration of autophagic inhibitors such as chloroquine or bafilomycin A1, or depletion of autophagy-related 5 (ATG5), results in accumulation of intracellular VEGFA, indicating that VEGFA is a basal autophagic substrate. Mechanistically, decorin increased the VEGFA clearance rate by augmenting autophagic flux, a process that required RAB24 member RAS oncogene family (RAB24), a small GTPase that facilitates the disposal of autophagic compartments. We validated these findings by demonstrating the physiological relevance of this process in vivo. Mice starved for 48 h exhibited a sharp decrease in overall cardiac and aortic VEGFA that could be blocked by systemic chloroquine treatment. Thus, our findings reveal a unified mechanism for the metabolic control of endothelial VEGFA for autophagic clearance in response to decorin and canonical pro-autophagic stimuli. We posit that the VEGFR2/AMPK/PEG3 axis integrates the anti-angiogenic and pro-autophagic bioactivities of decorin as the molecular basis for tumorigenic suppression. These results support future therapeutic use of decorin as a next-generation protein therapy to combat cancer.




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Prominins control ciliary length throughout the animal kingdom: New lessons from human prominin-1 and zebrafish prominin-3 [Cell Biology]

Prominins (proms) are transmembrane glycoproteins conserved throughout the animal kingdom. They are associated with plasma membrane protrusions, such as primary cilia, as well as extracellular vesicles derived thereof. Primary cilia host numerous signaling pathways affected in diseases known as ciliopathies. Human PROM1 (CD133) is detected in both somatic and cancer stem cells and is also expressed in terminally differentiated epithelial and photoreceptor cells. Genetic mutations in the PROM1 gene result in retinal degeneration by impairing the proper formation of the outer segment of photoreceptors, a modified cilium. Here, we investigated the impact of proms on two distinct examples of ciliogenesis. First, we demonstrate that the overexpression of a dominant-negative mutant variant of human PROM1 (i.e. mutation Y819F/Y828F) significantly decreases ciliary length in Madin–Darby canine kidney cells. These results contrast strongly to the previously observed enhancing effect of WT PROM1 on ciliary length. Mechanistically, the mutation impeded the interaction of PROM1 with ADP-ribosylation factor–like protein 13B, a key regulator of ciliary length. Second, we observed that in vivo knockdown of prom3 in zebrafish alters the number and length of monocilia in the Kupffer's vesicle, resulting in molecular and anatomical defects in the left-right asymmetry. These distinct loss-of-function approaches in two biological systems reveal that prom proteins are critical for the integrity and function of cilia. Our data provide new insights into ciliogenesis and might be of particular interest for investigations of the etiologies of ciliopathies.




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The cytochrome P450 enzyme CYP24A1 increases proliferation of mutant KRAS-dependent lung adenocarcinoma independent of its catalytic activity [Cell Biology]

We previously reported that overexpression of cytochrome P450 family 24 subfamily A member 1 (CYP24A1) increases lung cancer cell proliferation by activating RAS signaling and that CYP24A1 knockdown inhibits tumor growth. However, the mechanism of CYP24A1-mediated cancer cell proliferation remains unclear. Here, we conducted cell synchronization and biochemical experiments in lung adenocarcinoma cells, revealing a link between CYP24A1 and anaphase-promoting complex (APC), a key cell cycle regulator. We demonstrate that CYP24A1 expression is cell cycle–dependent; it was higher in the G2-M phase and diminished upon G1 entry. CYP24A1 has a functional destruction box (D-box) motif that allows binding with two APC adaptors, CDC20-homologue 1 (CDH1) and cell division cycle 20 (CDC20). Unlike other APC substrates, however, CYP24A1 acted as a pseudo-substrate, inhibiting CDH1 activity and promoting mitotic progression. Conversely, overexpression of a CYP24A1 D-box mutant compromised CDH1 binding, allowing CDH1 hyperactivation, thereby hastening degradation of its substrates cyclin B1 and CDC20, and accumulation of the CDC20 substrate p21, prolonging mitotic exit. These activities also occurred with a CYP24A1 isoform 2 lacking the catalytic cysteine (Cys-462), suggesting that CYP24A1's oncogenic potential is independent of its catalytic activity. CYP24A1 degradation reduced clonogenic survival of mutant KRAS-driven lung cancer cells, and calcitriol treatment increased CYP24A1 levels and tumor burden in Lsl-KRASG12D mice. These results disclose a catalytic activity-independent growth-promoting role of CYP24A1 in mutant KRAS-driven lung cancer. This suggests that CYP24A1 could be therapeutically targeted in lung cancers in which its expression is high.




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The heme-regulatory motifs of heme oxygenase-2 contribute to the transfer of heme to the catalytic site for degradation [Protein Structure and Folding]

Heme-regulatory motifs (HRMs) are present in many proteins that are involved in diverse biological functions. The C-terminal tail region of human heme oxygenase-2 (HO2) contains two HRMs whose cysteine residues form a disulfide bond; when reduced, these cysteines are available to bind Fe3+-heme. Heme binding to the HRMs occurs independently of the HO2 catalytic active site in the core of the protein, where heme binds with high affinity and is degraded to biliverdin. Here, we describe the reversible, protein-mediated transfer of heme between the HRMs and the HO2 core. Using hydrogen-deuterium exchange (HDX)-MS to monitor the dynamics of HO2 with and without Fe3+-heme bound to the HRMs and to the core, we detected conformational changes in the catalytic core only in one state of the catalytic cycle—when Fe3+-heme is bound to the HRMs and the core is in the apo state. These conformational changes were consistent with transfer of heme between binding sites. Indeed, we observed that HRM-bound Fe3+-heme is transferred to the apo-core either upon independent expression of the core and of a construct spanning the HRM-containing tail or after a single turnover of heme at the core. Moreover, we observed transfer of heme from the core to the HRMs and equilibration of heme between the core and HRMs. We therefore propose an Fe3+-heme transfer model in which HRM-bound heme is readily transferred to the catalytic site for degradation to facilitate turnover but can also equilibrate between the sites to maintain heme homeostasis.




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Structural and mutational analyses of the bifunctional arginine dihydrolase and ornithine cyclodeaminase AgrE from the cyanobacterium Anabaena [Enzymology]

In cyanobacteria, metabolic pathways that use the nitrogen-rich amino acid arginine play a pivotal role in nitrogen storage and mobilization. The N-terminal domains of two recently identified bacterial enzymes: ArgZ from Synechocystis and AgrE from Anabaena, have been found to contain an arginine dihydrolase. This enzyme provides catabolic activity that converts arginine to ornithine, resulting in concomitant release of CO2 and ammonia. In Synechocystis, the ArgZ-mediated ornithine–ammonia cycle plays a central role in nitrogen storage and remobilization. The C-terminal domain of AgrE contains an ornithine cyclodeaminase responsible for the formation of proline from ornithine and ammonia production, indicating that AgrE is a bifunctional enzyme catalyzing two sequential reactions in arginine catabolism. Here, the crystal structures of AgrE in three different ligation states revealed that it has a tetrameric conformation, possesses a binding site for the arginine dihydrolase substrate l-arginine and product l-ornithine, and contains a binding site for the coenzyme NAD(H) required for ornithine cyclodeaminase activity. Structure–function analyses indicated that the structure and catalytic mechanism of arginine dihydrolase in AgrE are highly homologous with those of a known bacterial arginine hydrolase. We found that in addition to other active-site residues, Asn-71 is essential for AgrE's dihydrolase activity. Further analysis suggested the presence of a passage for substrate channeling between the two distinct AgrE active sites, which are situated ∼45 Å apart. These results provide structural and functional insights into the bifunctional arginine dihydrolase–ornithine cyclodeaminase enzyme AgrE required for arginine catabolism in Anabaena.




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Affinity maturation, humanization, and co-crystallization of a rabbit anti-human ROR2 monoclonal antibody for therapeutic applications [Immunology]

Antibodies are widely used as cancer therapeutics, but their current use is limited by the low number of antigens restricted to cancer cells. A receptor tyrosine kinase, receptor tyrosine kinase-like orphan receptor 2 (ROR2), is normally expressed only during embryogenesis and is tightly down-regulated in postnatal healthy tissues. However, it is up-regulated in a diverse set of hematologic and solid malignancies, thus ROR2 represents a candidate antigen for antibody-based cancer therapy. Here we describe the affinity maturation and humanization of a rabbit mAb that binds human and mouse ROR2 but not human ROR1 or other human cell-surface antigens. Co-crystallization of the parental rabbit mAb in complex with the human ROR2 kringle domain (hROR2-Kr) guided affinity maturation by heavy-chain complementarity-determining region 3 (HCDR3)-focused mutagenesis and selection. The affinity-matured rabbit mAb was then humanized by complementarity-determining region (CDR) grafting and framework fine tuning and again co-crystallized with hROR2-Kr. We show that the affinity-matured and humanized mAb retains strong affinity and specificity to ROR2 and, following conversion to a T cell–engaging bispecific antibody, has potent cytotoxicity toward ROR2-expressing cells. We anticipate that this humanized affinity-matured mAb will find application for antibody-based cancer therapy of ROR2-expressing neoplasms.




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Risk Factors for Diabetic Peripheral Neuropathy and Cardiovascular Autonomic Neuropathy in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study

Barbara H. Braffett
May 1, 2020; 69:1000-1010
Complications




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Pancreas Pathology of Latent Autoimmune Diabetes in Adults (LADA) in Patients and in a LADA Rat Model Compared With Type 1 Diabetes

Anne Jörns
Apr 1, 2020; 69:624-633
Islet Studies




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Insulin Regulates Brain Function, but How Does It Get There?

Sarah M. Gray
Dec 1, 2014; 63:3992-3997
Perspectives in Diabetes




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Changes in Gut Microbiota Control Metabolic Endotoxemia-Induced Inflammation in High-Fat Diet-Induced Obesity and Diabetes in Mice

Patrice D. Cani
Jun 1, 2008; 57:1470-1481
Metabolism




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Autoantibodies in Diabetes

Catherine Pihoker
Dec 1, 2005; 54:S52-S61
Section II: Type 1-Related Forms of Diabetes




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Diabetes in China: Epidemiology and Genetic Risk Factors and Their Clinical Utility in Personalized Medication

Cheng Hu
Jan 1, 2018; 67:3-11
Perspectives in Diabetes




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Latent Autoimmune Diabetes in Adults: Definition, Prevalence, {beta}-Cell Function, and Treatment

Gunnar Stenström
Dec 1, 2005; 54:S68-S72
Section II: Type 1-Related Forms of Diabetes




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Zaidi: 'Mutual interest' between Giants, Harper

Giants president of baseball operations Farhan Zaidi would prefer to stay mum when it comes to his forays into the free-agent market, but he realized there was no use in attempting to obscure the club's meeting with superstar Bryce Harper in Las Vegas earlier this week.




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Sources: Giants add Parra to outfield mix

As they continue to await a resolution to the Bryce Harper sweepstakes, the Giants augmented their outfield depth by signing veteran Gerardo Parra to a Minor League deal Tuesday, sources confirmed to MLB.com's Jon Paul Morosi and Mark Feinsand.




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Risks of duloxetine for stress incontinence outweigh benefits, say researchers




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Close cousins in protection: the evolution of two norms

2 May 2019 , Volume 95, Number 3

Emily Paddon Rhoads and Jennifer Welsh

The Protection of Civilians (PoC) in peacekeeping and the Responsibility to Protect (R2P) populations from atrocity crimes are two norms that emerged at the turn of the new millennium with the aim of protecting vulnerable peoples from mass violence and/or systematic and widespread violations of human rights. To date, most scholars have analysed the discourses over the status, strength and robustness of both norms separately. And yet, the distinction between the two has at times been exceptionally fine. In this article, we analyse the constitutive relationship between PoC and R2P, and the impact of discursive and behavioural contestation on their joint evolution within the UN system and state practice over three phases (1999–2005; 2006–10; 2011–18). In so doing, we contribute to the International Relations literature on norms by illuminating ideational interplay in the dynamics of norm evolution and contestation. More specifically, we illustrate how actors may seek to strengthen support for one norm, or dimension of a norm, by contrasting it or linking it with another. Our analysis also reveals that while the two norms of R2P and PoC were initially debated and implemented through different institutional paths and policy frameworks, discursive and behavioural contestation has in more recent years brought them closer together in one important respect. The meaning ascribed to both norms—by representatives of states and institutions such as the United Nations—has become more state-centric, with an emphasis on building and strengthening the capacity of national authorities to protect populations. This meaning contrasts with the more cosmopolitan origins of R2P and PoC, and arguably limits possibilities for the external enforcement of both norms through any form of international authority that stands above or outside sovereign states. This article forms part of the special section of the May 2019 issue of International Affairs on ‘The dynamics of dissent’, guest-edited by Anette Stimmer and Lea Wisken.




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Engage China to Uphold Multilateralism – But Not at Any Cost

12 June 2019

Harriet Moynihan

Senior Research Fellow, International Law Programme
Where China’s interests align with those of the international community, there are opportunities for the country’s influence and economic power to strengthen the rules-based international order. Where they do not, states that traditionally support that order should join together to push back.

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Students holding Chinese national flags watch the live broadcast of the 40th anniversary celebration of China's reform and opening-up at Huaibei Normal University on 18 December. Photo: Getty Images.

China’s adherence to the rules-based international system is selective, prioritizing certain rules in favour of others. States supportive of that ‘system’ – or, as some argue, systems[1] – should identify areas of mutual strategic interest so that they can draw China further into the global rules-based order and leverage China as a constructive player that potentially also contributes to improvements in such areas. This is particularly apposite at a time when the US is in retreat from multilateralism and Russia seems bent on disrupting the rules-based international order.

Supportive player

There are many reasons for actively engaging with China on mutual areas of interest. China is a committed multilateralist in many areas, recognizing that often international cooperation and frameworks hold the key to its domestic problems, for example in the fields of environmental sustainability and financial regulation.

China’s economic power is valuable in upholding international institutions: China is the UN’s third-largest donor (after the US and Japan) at a time when the UN is facing budgetary shortfalls. China is also the second-highest contributor to the UN peacekeeping budget, and the largest contributor of peacekeeping forces among the five permanent members of the UN Security Council.

China also has a valuable role to play in the settlement of international disputes over trade and investment. China is a big supporter of the World Trade Organization (WTO)’s dispute settlement mechanism, and one of its most active participants;[2] China is currently playing an active role in negotiations to save the WTO’s appellate mechanism from folding in the wake of the US’s refusal to nominate new judges.

The last 15 years have also seen a major shift in Chinese attitudes to investment arbitration, from a general suspicion and limitation of arbitration rights to broad acceptance and incorporation of such rights in China’s trade and investment treaties. China is actively engaged in multilateral negotiations through the UN Commission on International Trade Law (UNCITRAL) on reforms to investor–state dispute settlement.

China has shown leadership on global climate change diplomacy, urging nations to remain committed to the Paris Agreement in the wake of the US decision to pull out, and has been an important interlocutor with the UK and the EU on these issues. As a strong supporter of the Paris Agreement, but also as the world’s top emitter of carbon dioxide, China has a crucial role to play in pushing forward implementation of the Paris targets. Despite its high emissions, China remains one of the few major economies on track to meet its targets,[3] giving it greater leverage to peer review other parties’ efforts.

A recent report by the UK parliament’s Foreign Affairs Committee (FAC), on China and the rules-based international order, noted that where a body of trust and goodwill is developed with China, there is the possibility of discovering interests that coincide and the ability to work together on issues mutually regarded as of global importance. The report refers to a number of success stories from UK partnership with China in multilateral forums, including in counterproliferation and global health.[4]

Developing areas of global governance

As well as working with the current system, China is increasingly involved in the shaping of newer areas of international law – whether it be submissions to the International Tribunal for the Law of the Sea (ITLOS) on procedural rules for the emerging deep-sea mining regime or pitching for a greater role in Arctic governance.[5]

This enthusiasm should be harnessed to promote the international rule of law, but at the same time there needs to be recognition of the strategic goals that drive China’s engagement. China’s interest in the Arctic, while including the desire to protect its ecology and environment, is also about access to marine resources, as well as about the Arctic’s strategic potential for China’s military.

China’s submissions to ITLOS on the rules of procedure for deep-sea mining are constructive, but also reflect an ambition to secure first-mover advantage when commercial mining eventually takes place. Like other major powers working in this policy area, China’s actions are guided by self-interest, but that doesn’t mean its goals can’t be pursued through multilateral rules.

China is also interested in creating new international structures and instruments that further its strategic aims. For example, with Russia (through the Shanghai Cooperation Organisation) it has proposed an International Code of Conduct for Information Security in the UN.[6]

China is also pondering an array of options for dispute-resolution mechanisms for its Belt and Road projects, including the possibility of an Asian version of the international Convention on the Settlement of Investment Disputes, which might sit under the auspices of the Asian Infrastructure Investment Bank (AIIB).[7]

The creation of new instruments and institutions need not be a threat to the rules-based international order in itself. We have already seen a combination of the creation of parallel complementary regimes alongside the reform of existing institutions, for example in development financing through the AIIB or the New Development Bank (often referred to as the ‘BRICS Bank’); these two banks are relatively conventionally structured along the lines of Western-dominated institutions, albeit with greater Chinese control. Based on these examples, selective adaptation seems more likely than a hostile ‘Eastphalian’ takeover.[8]

Risks

There is, however, a real risk that in certain areas China may promote a rival authoritarian model of governance, assisted by an opportunistic convergence with Russia on issues such as human rights, development and internet governance. In areas where China’s core interests clash with those of the rules-based international order, China has shown itself to be unbending, as in its refusal to abide by the July 2016 decision of the Permanent Court of Arbitration in its dispute with the Philippines over the South China Sea.[9]

China is becoming more assertive at the UN, but while it seeks to project itself there as a responsible emerging global leader, it is promoting a vision that weakens international norms of human rights, transparency and accountability,[10] while also carrying out practices domestically that raise serious human rights concerns (not least the detention of hundreds of thousands of Uighurs in re-education camps in Xinjiang).[11]

China’s increased dominance geographically and geopolitically through its Belt and Road infrastructure projects carries with it a number of social and economic risks, including smaller states becoming trapped in unsustainable financial debts to China.

But at a recent Chatham House conference on Asia and international law, participants highlighted the limitations on how far China can shape an alternative governance model.[12] China currently lacks soft power, cultural power and language power, all of which are needed in order to embed an alternative model abroad. China also currently lacks capacity and confidence to build coalitions with other states in the UN.

Where it has tried to get buy-in from the international community for its new institutions, such as the China International Commercial Court (CICC) announced in July 2018, there has been scepticism about the standards to be applied.[13] Unless the court can demonstrate sufficient due process, international parties are likely to prefer other centres with a strong reputation for upholding the rule of law, such as those in London, Dubai and Singapore.

Where China does promote its own governance model at the expense of the rules-based international order, states are starting to push back, often in concert. EU member states so far have adopted a joined-up approach to the Belt and Road Initiative. With the exception of Italy, they have refused to sign a Memorandum of Understanding on participation unless China provides much greater transparency on its compliance with international standards.

The EU also recently presented a coordinated response to China on the situation in Xinjiang.[14] Similarly, members of the so-called ‘Five Eyes’ intelligence-sharing alliance (comprising Australia, Canada, New Zealand, the UK and the US) have acted together in relation to certain incidents of cyber interference attributed to China.[15]

There are also signs of pushback from smaller states closer to home in relation to challenges to national sovereignty, debt diplomacy and financial viability arising from Belt and Road projects. The Sri Lankan government recently reversed the award of a $300 million housing deal to China, instead opting for a joint venture with an Indian company.

China has been downscaling its investments as a way to counter some of the backlash it has received: the most recent Belt and Road summit put forward a more modest set of aspirations. This suggests that there is some scope for states to stand up to China and use leverage to secure better deals.

Many international institutions have been Western-dominated for years;[16] China, together with many emerging and middle powers, has felt for some time that the international architecture does not reflect the world we live in. Given that context, states that champion the rules-based international order should acknowledge China’s desire to update the international order to reflect greater multipolarity, globalization and technological change, while being clear-eyed about their engagement with China. This involves investing in a proper understanding of China and how it works.[17]

Where possible, cooperation with China should lead to outcomes that are backed up by international standards and transparency. The above-mentioned FAC report cites evidence that the UK’s support, and that of other developed countries, had a positive impact in shaping the governance and standards of the AIIB.[18] China has brought in international experts to advise on disputes before the CIIC, which may reassure would-be litigants.

China’s relationship with the rules-based international order needs to be assessed pragmatically and dynamically. China can be a valuable partner in many areas where its objectives are closely aligned with those of the international community – from trade to climate change to peacekeeping.

But where the country’s core interests are at odds with those of the wider international community, an increasingly confident China will strongly resist pressure, including on the South China Sea and human rights. In these areas, states supportive of international law can most powerfully push back through alliances and by ensuring that their own core values are not compromised in the interests of economic benefits.

What needs to happen

  • China’s rising power and selective commitment to multilateralism make it a potentially influential ally in modernizing international governance.
  • China is increasingly involved in shaping newer areas of international law. This enthusiasm could be harnessed in the service of institutional development and reform.
  • Other states should identify areas of mutual strategic interest where China may offer a constructive role, including dispute settlement, health and climate change.
  • However, engagement must not ignore the strategic calculations that drive China’s agenda, or its poor record on civil and political rights, transparency and accountability.
  • Cooperation with China should lead to outcomes that are backed up by international standards and transparency.
  • Where China’s actions undermine the rules-based international order, coordinated action by states supportive of that order is likely to be more effective than acting individually.

Notes

[1] Chalmers, M. (2019), Which Rules? Why There is No Single ‘Rules-Based International System’, RUSI Occasional Paper, April 2019, London: Royal United Services Institute, https://rusi.org/occasional-papers/Which-Rules-Why-There-Is-No-Single-Rules-Based-International-System.

[2] See, for example, Moynihan, H. (2017), China’s Evolving Approach to International Dispute Settlement, Briefing, London: Royal Institute of International Affairs, https://www.chathamhouse.org/publication/chinas-evolving-approach-international-dispute-settlement.

[3] UN Environment (2018), Emissions Gap Report 2018, p. XVII, https://www.unenvironment.org/resources/emissions-gap-report-2018.

[4] House of Commons Foreign Affairs Committee (2019), China and the Rules-Based International System: Sixteenth Report of Session 2017–19, p. 32, https://publications.parliament.uk/pa/cm201719/cmselect/cmfaff/612/612.pdf.

[5] Moynihan, H. (2018), ‘China Expands Its Global Governance Ambitions in the Arctic’, Expert Comment, 15 October 2018, https://www.chathamhouse.org/expert/comment/china-expands-its-global-governance-ambitions-arctic.

[6] Updated version proposed 9 January 2015.

[7] Moynihan, H. (2018), ‘Exploring Public International Law Issues with Chinese Scholars – Part Four’, Meeting Summary, 3 June 2018, https://www.chathamhouse.org/publication/exploring-public-international-law-issues-chinese-scholars-part-four.

[8] Chatham House (2019, forthcoming, ‘Security and Prosperity in the Asia-Pacific: The Role of International Law’, conference summary, https://www.chathamhouse.org/event/security-and-prosperity-asia-pacific-role-international-law.

[9] Permanent Court of Arbitration Case No. 2013-19 (Philippines v China), Award of 12 July 2016, https://pca-cpa.org/wp-content/uploads/sites/6/2016/07/PH-CN-20160712-Award.pdf.

[10] Piccone, T. (2018), China’s Long Game on Human Rights at the United Nations, Washington, DC: Brookings Institution, https://www.brookings.edu/wp-content/uploads/2018/09/FP_20181009_china_human_rights.pdf.

[11] Wye, R. (2018), ‘‘The entire Uyghur population is seemingly being treated as suspect’: China’s persecution of its Muslim minority’, LSE Religion and Global Society blog, 18 September 2018, https://blogs.lse.ac.uk/religionglobalsociety/2018/09/the-entire-uyghur-population-is-seemingly-being-treated-as-suspect-chinas-persecution-of-its-muslim-minority/.

[12] Chatham House (2019, forthcoming, ‘Security and Prosperity in the Asia-Pacific: The Role of International Law’.

[13] Walters, M. (2018), ‘Jury is out over China’s new commercial court, say lawyers’, Law Society Gazette, 1 November 2018, https://www.lawgazette.co.uk/law/jury-is-out-over-chinas-new-commercial-court-say-lawyers/5068125.article.

[14] The Economist (2019), ‘Hope remains for Western solidarity. Look at embassies in Beijing’, 17 April 2019, https://www.economist.com/china/2019/04/20/hope-remains-for-western-solidarity-look-at-embassies-in-beijing.

[15] In December 2018, the Five Eyes attributed the activities of a Chinese cyber espionage group targeting intellectual property and sensitive commercial property to China’s Ministry of State Security.

[16] Roberts, A. (2017), Is International Law International?, Oxford: Oxford University Press.

[17] Parton, C. (2019), China–UK Relations: Where to Draw the Border Between Influence and Interference?, RUSI Occasional Paper, February 2019, London: Royal United Services Institute, p. 30, https://rusi.org/publication/occasional-papers/china-uk-relations-where-draw-border-between-influence-and.

[18] House of Commons Foreign Affairs Committee (2019), China and the Rules-Based International System, p. 15.

This essay was produced for the 2019 edition of Chatham House Expert Perspectives – our annual survey of risks and opportunities in global affairs – in which our researchers identify areas where the current sets of rules, institutions and mechanisms for peaceful international cooperation are falling short, and present ideas for reform and modernization.




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The rule of law and maritime security: understanding lawfare in the South China Sea

4 September 2019 , Volume 95, Number 5

Douglas Guilfoyle

Does the rule of law matter to maritime security? One way into the question is to examine whether states show a discursive commitment that maritime security practices must comply with international law. International law thus provides tools for argument for or against the validity of certain practices. The proposition is thus not only that international law matters to maritime security, but legal argument does too. In this article, these claims will be explored in relation to the South China Sea dispute. The dispute involves Chinese claims to enjoy special rights within the ‘nine-dash line’ on official maps which appears to lay claim to much of the South China Sea. Within this area sovereignty remains disputed over numerous islands and other maritime features. Many of the claimant states have engaged in island-building activities, although none on the scale of China. Ideas matter in such contests, affecting perceptions of reality and of what is possible. International law provides one such set of ideas. Law may be a useful tool in consolidating gains or defeating a rival's claims. For China, law is a key domain in which it is seeking to consolidate control over the South China Sea. The article places the relevant Chinese legal arguments in the context of China's historic engagement with the law of the sea. It argues that the flaw in China's approach has been to underestimate the extent to which it impinges on other states' national interests in the maritime domain, interests they conceptualize in legal terms.




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In Judging Prorogation, UK Supreme Court Marks Evolution, Not Revolution, in Law

3 October 2019

Ruma Mandal

Director, International Law Programme
Despite the political significance, last week’s judgment does not signal a newly activist court.

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The Supreme Court building in Westminster. Photo: Getty Images.

The UK Supreme Court’s ruling last Wednesday has, at least temporarily, scuppered the prime minister’s plans to limit parliamentary debate before the looming Brexit deadline. Some of the prime minister’s allies have attacked the ruling as a ‘constitutional coup’. But a close reading reveals that the court has stayed within its remit to interpret, rather than make, the law.

In a carefully reasoned judgment, the court emphasized that the case was not about Brexit. But the judges certainly did not shy away from the extraordinary nature of the matters before it, noting that such factual situations have ‘never arisen before and are unlikely ever to arise again… But our law is used to rising to such challenges and supplies us with the legal tools to enable us to reason to a solution.’

The key question before the court was whether the prime minister’s decision to seek prorogation was ‘justiciable’ – i.e. amenable to being reviewed by a court. The English and Scottish courts earlier on in these proceedings had come, dramatically, to opposing views on this.

The Supreme Court was not dissuaded by the inherently political considerations involved in the prime minister’s decision, stating that while ‘courts cannot decide political questions, the fact that a legal dispute concerns the conduct of politicians, or arises from a matter of political controversy, has never been sufficient reason for the courts to refuse to consider it’.

The court went on to emphasize that the Crown’s remaining prerogative powers (exercised on the advice of the government or directly by ministers) have long been subject to judicial scrutiny; such oversight is essential to guarding the separation of powers underpinning the UK’s constitution.

So far, so conventional. The full bench of the Supreme Court was required to grapple, though, with a prerogative power that had never been tested before in the courts. And so they delved back to the 1611 Case of Proclamations: ‘the King hath no prerogative, but that which the law of the land allow him’. In the court’s view, the legal issue to be resolved was the scope of the power to prorogue (the existence of this particular prerogative not being in dispute).

With no case law available to provide direct guidance on this question, the court, instead, relied on two fundamental principles of the UK’s constitution – parliamentary sovereignty and parliamentary accountability. What would be the logical consequence of an unlimited power to prorogue? The ability to shut parliament permanently.

The conclusion: this particular prerogative power had limits. The court held that:

‘A decision to prorogue Parliament (or to advise the monarch to prorogue Parliament) will be unlawful if the prorogation has the effect of frustrating or preventing, without reasonable justification, the ability of Parliament to carry out its constitutional functions as a legislature and as the body responsible for the supervision of the executive. In such a situation, the court will intervene if the effect is sufficiently serious to justify such an exceptional course.’

Having come to this conclusion, the court was left to examine what justification had in fact been given, noting that the prime minister’s motives were irrelevant. It noted that no clear reason had been given – the relevant documents were all concerned with preparing for the Queen’s speech.

Noting evidence on normal practice for such preparations, including from a former prime minister, the court found it ‘impossible… to conclude…that there was any reason – let alone a good reason – to advise Her Majesty to prorogue Parliament for five weeks’.

The court’s decision was neither inevitable nor a radical departure from legal tradition. It represents the gradual evolution of the long-established legal principle that the crown’s powers are set by the law and supervised by the courts.

Courts have traditionally been reticent to rule on prerogative powers which are ‘high politics’ by nature – classic examples include declaring war and negotiating treaties. In recent years, though, the judiciary has shown a growing confidence to grapple with the contours of those prerogative powers that remain. Deference is still shown when looking at how those powers have been used as opposed to the limits of the prerogative in question.

The Supreme Court ruling won’t reassure those who worry about the emergence of an activist court willing to wade (improperly) into the political arena. Nor will it necessarily bring comfort to those anxious about an unwritten constitution in an era where political conventions are fast unravelling.

But divisive court rulings are nothing new, nor are ministerial outbursts about inconvenient judgments. In the current environment, politicians should take particular care not to send mixed messages which undermine the independence of the UK’s judiciary. Public trust in British institutions is dangerously low and the UK can ill-afford further damage to its reputation as a country steeped in democracy and the rule of law.




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War Crimes and Their Prosecution

Invitation Only Research Event

5 March 2020 - 9:00am to 10:30am

Chatham House | 10 St James's Square | London | SW1Y 4LE

Event participants

Michelle Butler, Barrister, Matrix Chambers
Charles Garraway, Visiting Fellow, Human Rights Centre, University of Essex
Chair: Elizabeth Wilmshurst, Distinguished Fellow, International Law Programme, Chatham House

 

The International Criminal Court cannot act when crimes are being genuinely prosecuted in a state. The meeting will discuss whether the ICC complementarity rules apply when a state puts restrictions on the prosecution of war crimes committed in particular circumstances or within a particular time period. In this context, the discussion will also cover the extent to which such restrictions are precluded by international obligations such as those in the Geneva Conventions with regard to the investigation and prosecution of war crimes.

Event attributes

Chatham House Rule

Jacqueline Rowe

Programme Assistant, International Law Programme
020 7389 3287




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Seventy Years of the Geneva Conventions: What of the Future?

24 March 2020

Seventy years after the adoption of the Geneva Conventions, there are challenges that remain to be addressed. This briefing takes three pertinent examples, and discusses possibilities for addressing them.

Emanuela-Chiara Gillard

Associate Fellow, International Law Programme

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Rescue of the wounded in Duma city by Syrian Red Crescent paramedics, 2 February 2018. Photo: Samer Bouidani/NurPhoto/Getty

Summary

  • The 70th anniversary of the adoption of the 1949 Geneva Conventions was commemorated in 2019. But violations of the Conventions and of the 1977 Additional Protocols are widespread.
  • Contemporary conflicts have been marked by violations of some of the foundational rules of international humanitarian law (IHL) relating to the protection of the wounded and sick and of providers of medical assistance.
  • A further area of IHL that has come under strain and scrutiny are the rules regulating humanitarian relief operations and their application to sieges and blockades.
  • War has a huge impact on children, and the treatment of children in armed conflict is another area of the law that requires further attention.
  • In the current political climate, it is unlikely that new treaties will be negotiated to address emerging issues or uncertainties in the law.
  • Other measures must be explored, including the adoption of domestic measures to implement existing law; support for processes that interpret the law; and initiatives to promote compliance with the law by organized armed groups.
  • One overarching challenge is the interplay between IHL and counterterrorism measures. It can undermine the protections set out in IHL, and hinder principled humanitarian action and activities to promote compliance with the law by organized armed groups.




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Iraq Tribunal: US Pulling Out

1 May 2008 , Number 3

Rowdy sessions of the Iraq High Tribunal attracted sensational daily news coverage while Saddam Hussein was being tried. However, following his grim execution in December 2006, coverage all but evaporated. The foreign press and most western monitors packed their bags and left, and television reporting in Iraq dwindled. Now even the United States Department of Justice, which initially provided key financial and political support, is quietly withdrawing its advisers. So what is happening at the Tribunal and why are the Americans pulling out?

Sonya Sceats

Associate Fellow, International Law Programme




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Accountability, denial and the future-proofing of British torture

7 May 2020 , Volume 96, Number 3

Ruth Blakeley and Sam Raphael

When powerful liberal democratic states are found to be complicit in extreme violations of human rights, how do they respond and why do they respond as they do? Drawing on the example of the United Kingdom's complicity in torture since 9/11, this article demonstrates how reluctant the UK has been to permit a full reckoning with its torturous past. We demonstrate that successive UK governments engaged in various forms of denial, obfuscation and attempts to obstruct investigation and avoid accountability. The net effect of their responses has been to deny the victims redress, through adequate judicial processes, and to deny the public adequate state accountability. These responses are not simply aimed at shielding from prosecution the perpetrators and those who have oversight of them, nor preventing political embarrassment. The various forms of denial and obstruction are also designed to ensure that collusion can continue uninterrupted. A core concern of intelligence officials and ministers has been to prevent any process that would lead to a comprehensive prohibition on involvement in operations where torture and cruel, inhuman and degrading treatment are a real possibility. The door remains wide open, and deliberately so, for British involvement in torture.




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A short video about MathSciNet

There is a three-minute video about MathSciNet now available online on Vimeo. It is also available as part of a blog post from EBSCO, which mostly discusses Mathematics and Statistics Awareness Month and the really neat book Living Proof: Stories … Continue reading




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'The Truth is, Chile is Unequal': What's Behind Chile's Protests

18 December 2019

Dr Christopher Sabatini

Senior Research Fellow for Latin America, US and the Americas Programme

Lyndsey Jefferson

Digital Editor, Communications and Publishing Department
As part of a series on global protests, Dr Christopher Sabatini tells Lyndsey Jefferson why Chileans are taking to the streets.

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A demonstrator waves a Chilean flag during a protest in Santiago on 21 October 2019. Photo: Getty Images.

Why are these protests happening now?

The truth is, Chile is unequal, even though it actually reduced poverty from 1989, the time of the democratic transition, until today, from 40% to 16%.

There are a number of reasons for the protests. One is the most proximate cause, which is the increase in the subway fares, but that really doesn’t explain the underlying tensions.

One of those tensions is despite reductions in poverty, social mobility remains a large problem in Chile. It remains a very elitist country with limited social mobility. So, poverty may be reduced, but the likelihood that someone in the working middle class would reach the upper middle class has always been a stretch.

The second issue is a lack of political change. The last four presidents were the same two people.

Chile’s been governed, with the exception of Piñera, basically by the same political coalition, La Concertación, which is a combination of the Christian Democratic and Socialist parties. Piñera came from the right, an outside party, but even he has remained. There has been no renewal of the political leadership which again reinforces that lack of social mobility. 

Do the protesters have any other demands or grievances? 

The demands are amorphous and that’s part of the issue – they’re going to be difficult to meet. People are expressing a genuine desire for change but what would that change mean?

Chileans don’t necessarily want to change the economic model; they simply want more mobility. That’s difficult to do and these are untested demands. 

Chileans also want political reform. What Piñera offered is to rewrite the constitution, which was created under military government in 1980. Other than some changes here and there in terms of the electoral system and reduction of military power, it has pretty much remained intact.

Will constitutional change really address these demands? It’s simply a document that may create the rules for how power is allocated and conducted, but it’s not going to dramatically remake Chilean society.

You mentioned inequality as a key driver of the protests. Can you expand a bit more on the current economic situation of ordinary Chileans?

Chile is going to grow at only around 2-3%, but it was growing at around 4-5% earlier. A lot of those funds were ploughed into social programmes that have since been reduced. 

Chile’s economy really boomed in the early 2000s because of Chinese demands of Chilean imports. But as with any sort of commodities-based economy, the jobs it provides tend to be lower wage.

As a result, despite the fact that Chile tried to diversify its economy by investing in entrepreneurship and innovation, it hasn’t grown in a way that provides jobs that many associate with upward mobility. As Chile's economy cooled, its ability to lift people out of poverty lagged as well.

Demonstrators hold placards depicting eyes – in reference to police pellets hitting demonstrators' eyes – during a protest in Santiago on 10 December 2019. Photo: Getty Images.

Two major issues for the protesters are education and pensions – can you explain why this is?

These are two issues of the economic and social model that was held up at one time as being a model for the region, the neoliberal models that are really coming under question and are in some ways at the heart of this.

One is the privatized pension system which is failing to produce the returns that retirees need to survive. The second is the education system. Chile created a voucher system where parents can shop around and send their kids to the best schools. The idea was to create competition among schools to improve.

The problem was like any market, it created a certain amount of inequality among schools. There was a problem of some schools underperforming and being relegated poorer performing students, or students being forced to go to those schools because the more successful schools were already spoken for. 

At the end of October, the government announced a series of social reforms. Will this be enough to satisfy the protesters’ demands?

Social reforms may address some of the issues of insufficient pensions or lack of quality education, but it will take a while for them to have an effect.

The second thing is, social reforms don’t address the issues of power. At the heart of this is this idea of closed economic, political and social power. That comes about through economic growth and how you break up concentrations of wealth. Social reforms aren’t going to do that, although they’ll help on the margins. 

We’re seeing horrific scenes of police violence against protesters and dozens of people have died. Has this deterred the protesters in any way? 

No, in many ways it has sort of inspired them. It has, I think, sustained the protests.

We’re not talking massive repression and tanks rolling in like Tiananmen Square. We’re talking about tear gas, rubber bullets, some injuries and deaths, and even credible reports of torture.

It’s funny you should mention this – a class I’m teaching today is about social media and protests. One of the central arguments is that successful social protests need a martyr; they need a rallying cry.

The deaths and the repression sort of help sustain that, but moreover, social media helps communicate what’s happening through videos and pictures. It really helps maintain this sense of righteousness, disdain for the government, and this idea of the need to demand change.

Where do you see this going next?

I don’t think we know. In the 60s and 70s, the political scientist Samuel Huntington argued in Political Order in Changing Societies that as economies grow, political institutions often strain to contain and channel demands. I think we’re seeing this now.

This social ferment over political, economic and social demands is uncharted water. I don’t know where this will go, but I think we’ll see a change in the constitution. We’ve already seen a fragmenting of the party system, which I think will continue. Hopefully, that will lead to new leadership that can help reflect a change in Chile itself. 




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Iran Crisis: How Far Does Trump’s Authority Go?

10 January 2020

Dr Leslie Vinjamuri

Dean, Queen Elizabeth II Academy for Leadership in International Affairs; Director, US and the Americas Programme
The legal and political boundaries of presidential power are being redefined, but the president may still be attentive to some constraints.

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Donald Trump arrives for a rally in Toledo, Ohio on 9 January. Photo: Getty Images.

On Thursday, the US House of Representatives passed a resolution affirming its authority under the War Powers Resolution Act, and reminding the president, the American people and the world that when it comes to the use of military force, Congress must be taken into account. 

President Donald Trump replied by retweeting John Bolton, his former national security advisor, who tweeted that the War Powers Act was ‘unconstitutional’, effectively dismissing Congressional efforts to rein in the president.

This round of legal Twitter diplomacy came days after the president tweeted that ‘legal notice (to Congress) is not required, but it is given nevertheless’ and that ‘should Iran strike any US person or target, the United States will quickly and fully strike back, and perhaps in a disproportionate manner.’ 

President Trump’s overt attacks on Congressional authority and disregard for the law are not normal for a US president, but legal constraints over the president’s authority to use military force have been eroding for several years.

In 1973, Congress passed the War Powers Act, requiring the president to report to Congress and acquire Congressional approval for continued overseas troop deployments. But Congressional authority over the use of military force has continued to diminish, especially since the 9/11 attacks. 

Now, Congress is pushing back – a resolution similar to that passed by the House is likely to be voted on by the Senate soon. Given the intense frustration of some senators over the president’s handling of the current conflict, this resolution may pass, though the president is still likely to veto. 

The bigger problem, of which this is one part, is the expansion of executive authority, and it predates this presidency. Many argue that executive power is greatest on matters of foreign policy, and that in this domain the US president is unconstrained. As partisanship has increased and the demands on Congress have made it harder for its members to cultivate foreign policy expertise, the power of the president has grown.

So the fact that Congress is taking active steps to check the president’s power not only on the question of impeachment, but also on foreign policy, is significant, even if the law is not likely to restrain President Trump. But Congress is also playing a long game. And its growing determination to assert its authority matters not only for this presidency, but also for the future.

Political constraints

In the short term, other constraints matter more. Even if President Trump rejects legal restraints – and shuns diplomatic pressure that might have mattered to other presidents – he is not impervious to political restraint.

Already there are signs that Trump listens to his key Republican allies in Congress. When Senator Lindsay Graham pushed back against the president’s threat to attack cultural heritage sites in Iran, and the Pentagon failed to shore up the president’s threat, the president changed his position. The threats also provoked an overwhelming response in Europe, and across the Middle East, but the president has shown that he is willing to disregard international admonishment. Not so for domestic allies.

Nor is this the first time that Senator Graham’s views have mattered. When the president announced his decision to pull troops from northeast Syria, effectively abandoning the Kurds, a key partner to the US in its fight against ISIS, Senator Graham and Senator Mitch McConnell pushed back and it mattered. 

Public opinion also matters to the president, especially Republican public opinion, and this is likely to affect the president’s next steps. Recent polls suggest that Americans feel less safe as a result of the killing of General Qassem Soleimani by a considerable margin of 55% to 24%.

But the same survey also shows that a majority of Americans support the decision to kill Soleimani. Already Vice President Mike Pence has spoken at a rally in Ohio designed to bolster support for this Presidential action.  

So what might change public opinion and will this alter the president’s future steps?

Americans are very reluctant to support further deployments of troops overseas. President Trump knows this and he has consistently stated that he seeks to pull US troops out of the Middle East.

In fact, the opposite has happened. And once again, the decision to kill General Soleimani is pulling the US further into the Middle East and putting into stark light the inconsistency of Trump’s foreign policy ambitions. In recent days, the United States has committed to sending thousands of troops to the region.

Continued US troop deployments may not play well with Trump’s base, though they currently support his Iran policy. But absent an obvious justification, this could change, so it is not surprising that this has become a rallying point for Vice President Pence.

An even greater political risk, and one that will matter to the president, is the risk to US military personnel and civilians overseas. Public support for the killing of Soleimani and increased US presence in the region is bound to dissipate if Americans are killed.

But it isn’t clear how the president will respond, and already the death of one American in the militia attack on 27 December seems to have been a critical factor in Trump’s decision to authorize the assassination of General Soleimani.  

So far, Iran’s response appears to be calibrated to avoid this kind of public backlash, and keep the door open to some sort of managed resolution of the current crisis.

But the considerable risk of miscalculation and mistakes has already been born out. A week after the killing of Soleimani, the world is tuning in to the tragic news that a civilian airliner departing Iran for Ukraine appears to have been accidentally shot down by an Iranian missile, resulting in the deaths of all 176 people on board, including 82 Iranians and 63 Canadians.

Whether the US president is constrained is a critical question for Americans, for US democracy and for the rest of the world. Trump is different, but he is not unconstrained. Steps taken by Congress along with diplomatic and political pressure mean he is still operating within boundaries. But it is clear that these boundaries are being redefined.




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Virtual Roundtable: The Shock of Coronavirus – Hard Truths

Research Event

15 April 2020 - 3:00pm to 4:00pm

Event participants

Professor Adam Tooze, Kathryn and Shelby Cullom Davis Professor of History, Columbia University
Discussant: Megan Greene, Dame DeAnne Julius Senior Academy Fellow in International Economics, Chatham House; Senior Fellow, Harvard Kennedy School
Chair: Dr Leslie Vinjamuri, Director, US and the Americas Programme; Dean, Queen Elizabeth II Academy for Leadership in International Affairs, Chatham House

This event is part of the Inaugural Virtual Roundtable Series on the US, Americas and the State of the World and will take place virtually only.

Department/project

US and Americas Programme




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Privileging Local Food is Flawed Solution to Reduce Emissions

23 April 2020

Christophe Bellmann

Associate Fellow, Hoffmann Centre for Sustainable Resource Economy
The COVID-19 pandemic has brought food security and food imports to the forefront again. Some fear that the crisis could quickly strain global food supply chains as countries adopt new trade restrictions to avoid domestic food shortages.

2020-04-23-Trade-Food-Apples

Apples being picked before going into cold storage so they can be bought up until Christmas. Photo by Suzanne Kreiter/The Boston Globe via Getty Images.

The pressure of the coronavirus pandemic is adding to a widely held misconception that trade in food products is bad for the environment due to the associated ‘food miles’ – the carbon footprint of agricultural products transported over long distances.

This concept, developed by large retailers a decade ago, is often invoked as a rationale for restricting trade and choosing locally-produced food over imports. Consuming local food may seem sensible at first glance as it reduces the carbon footprint of goods and generates local employment. 

However, this assumption ignores the emissions produced during the production, processing or storage stages which often dwarf transport emissions. Other avenues to address the climate change impact of trade are more promising.

Demystifying food emissions

In the US, for example, food items travel more than 8,000 km on average before reaching the consumer. Yet transport only accounts for 11 per cent of total emissions with 83 per cent – mostly nitrous oxide (N2O) and methane (CH4) emissions – occurring at the production stage.

US Department of Agriculture data on energy use in the American food system echoes this finding, showing that processing, packaging, and selling of food represent ten times the energy used to transport food.

In practice, it may be preferable from an environmental perspective to consume lamb, onion or dairy products transported by sea because the lower emissions generated at the production stage offset those resulting from transport. Similarly, growing tomatoes under heated greenhouses in Sweden is often more emissions-intensive than importing open-grown ones from Southern Europe.

Seasonality also matters. British apples placed in storage for ten months leads to twice the level of emissions as that of South American apples sea-freighted to the UK. And the type of transport is also important as, overall, maritime transport generates 25 to 250 times less emissions than trucks, and air freight generates on average five times more emissions than road transport.

Therefore, air-freighted Kenyan beans have a much larger carbon footprint than those produced in the UK, but crossing Europe by truck to import Italian wine might generate more emissions than transatlantic shipments.

Finally, one should take into account the last leg of transport. A consumer driving more than 10 km to purchase 1 kg of fresh produce will generate proportionately more greenhouse gas (GHG) emissions than air-freighting 1 kg of produce from Kenya.

Shifting consumption towards local foods may reduce GHG emissions in sectors with relatively low emissions intensities but, when non-carbon dioxide emissions are taken into account, this is more often the exception than the rule.

Under these circumstances, preventing trade is an inefficient and expensive way of reducing GHG emissions. Bureau et al. for example, calculate that a global tariff maintaining the volume of trade at current levels until 2030 may reduce global carbon dioxide emissions by 3.5 per cent. However, this would be roughly seven times less than the full implementation of the Paris Agreement and cost equivalent to the current GDP of Brazil or 1.8 per cent of world GDP.

By preventing an efficient use of resources, such restrictions would also undermine the role of trade in offsetting possible climate-induced production shortfalls in some parts of the world and allowing people to access food when they can’t produce it themselves.

Reducing the climate footprint of trade

This is not to say that nothing should be done to tackle transport emissions. The OECD estimates that international trade-related freight accounted for over 5 per cent of total global fuel emissions with shipping representing roughly half of it, trucks 40 per cent, air 6 per cent and rail 2 per cent. With the projected tripling of freight transport by 2050, emissions from shipping are expected to rise between 50 and 250 per cent.

Furthermore, because of their international nature, these emissions are not covered by the Paris Agreement. Instead the two UN agencies regulating these sectors – the International Civil Aviation Organization and the International Maritime Organization – are responsible for reducing these emissions and, so far, significant progress has proven elusive.

Regional or bilateral free trade agreements to further stimulate trade could address this problem by exploiting comparative advantages. Impact assessments of those agreements often point towards increases in GHG emissions due to a boost in trade flows. In the future, such agreements could incorporate – or develop in parallel – initiatives to ensure carbon neutrality by connecting carbon markets among contracting parties or by taxing international maritime and air transport emissions.

Such initiatives could be combined with providing additional preferences in the form of enhanced market access to low-carbon food and healthier food. The EU, as one of the chief proponents of bilateral and regional trade agreements and a leader in promoting a transition to a low-carbon economy could champion such an approach.

This article is part of a series from the Chatham House Global Trade Policy Forum, designed to promote research and policy recommendations on the future of global trade. It is adapted from the research paper, Delivering Sustainable Food and Land Use Systems: The Role of International Trade, authored by Christophe Bellmann, Bernice Lee and Jonathan Hepburn.




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Diabetes Core Update: Therapeutic Inertia – April 2020

In this first episode of a three-part series on “Disrupting Therapeutic Inertia in Diabetes Management,” Drs. John Russell and Neil Skolnik examine a case study of a 55-year-old man with type 2 diabetes (3 years duration, A1C 8.2%). In so doing, they review six articles that define achievement gaps in reaching A1C goals and the reasons for why those gaps exist. In episodes 2 and 3 of this series, Drs. Russell and Skolnik we will look at additional causes of therapeutic inertia and solutions for overcoming it. This special three-part series on therapeutic inertia is supported by independent educational grant from Sanofi (https://www.sanofi.com).

This issue will review:

  1. Achievement of target therapeutic goals in persons with T2DM
  2. Achievement of therapeutic goals from 2005 – 2015
  3. Clinical Inertia in Newly Diagnosed Type 2 DM
  4. Clinical Inertia over Time in Type 2 DM
  5. Gap Between Efficacy in Randomized Controlled Trials and Effectiveness in Real-World Use
  6. Difference between Clinical Trial and Real-World Studies Achievement of Target A1C <7.0% in Patients Treated with Basal Insulin in RCTs and Clinical Practice

For more information about each of ADA’s science and medical journals, please visit www.diabetesjournals.org.

Presented by:

Neil Skolnik, M.D., Professor of Family and Community Medicine, Sidney Kimmel Medical College, Thomas Jefferson University; Associate Director, Family Medicine Residency Program, Abington Jefferson Health

John J. Russell, M.D., Professor of Family and Community Medicine, Sidney Kimmel Medical College, Thomas Jefferson University; Director, Family Medicine Residency Program, Chair-Department of Family Medicine, Abington Jefferson Health




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Diabetes Core Update: COVID-19 – Impact on Youth and their Families, May 2019

This special issue focuses on the impact COVID-19 is having on youth with diabetes and their families. 

Recorded April 30, 2020.

This is a part of the American Diabetes Associations ongoing project providing resources for practicing clinicians on the care of Diabetes during the Covid-19 pandemic.  Today’s discussion is an audio version of a webinar recorded on April 30, 2020.

Presented by:

Barry Conrad, MPH, RD, CDE
Stanford Children's Health

Tamara S. Hannon, MD, MS
Indiana University

Marisa Hilliard, PhD
Baylor College of Medicine and Texas Children's Hospital

Cynthia Munoz, PhD, MPH
President-Elect, Helath Care & Education, American Diabetes Association

Jennifer Raymond, MD, MCR
Children's Hospital Los Angelas

 




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Covid-19: Doctors face shortages of vital drugs, gases, and therapeutics, survey finds




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Trust boss gave misleading information to GMC about consultant who was unfairly dismissed




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Covid-19: South Korea relaxes social distancing after the number of new cases drops below 10 a day




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Covid-19: Lack of capacity led to halting of community testing in March, admits deputy chief medical officer




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Covid-19: Campaigner calls for national guidance to stop DNR orders being made without discussion with patients and families




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Covid-19: Nightingale hospitals set to shut down after seeing few patients