mo SUMOylation of the transcription factor ZFHX3 at Lys-2806 requires SAE1, UBC9, and PIAS2 and enhances its stability and function in cell proliferation [Protein Synthesis and Degradation] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 SUMOylation is a posttranslational modification (PTM) at a lysine residue and is crucial for the proper functions of many proteins, particularly of transcription factors, in various biological processes. Zinc finger homeobox 3 (ZFHX3), also known as AT motif-binding factor 1 (ATBF1), is a large transcription factor that is active in multiple pathological processes, including atrial fibrillation and carcinogenesis, and in circadian regulation and development. We have previously demonstrated that ZFHX3 is SUMOylated at three or more lysine residues. Here, we investigated which enzymes regulate ZFHX3 SUMOylation and whether SUMOylation modulates ZFHX3 stability and function. We found that SUMO1, SUMO2, and SUMO3 each are conjugated to ZFHX3. Multiple lysine residues in ZFHX3 were SUMOylated, but Lys-2806 was the major SUMOylation site, and we also found that it is highly conserved among ZFHX3 orthologs from different animal species. Using molecular analyses, we identified the enzymes that mediate ZFHX3 SUMOylation; these included SUMO1-activating enzyme subunit 1 (SAE1), an E1-activating enzyme; SUMO-conjugating enzyme UBC9 (UBC9), an E2-conjugating enzyme; and protein inhibitor of activated STAT2 (PIAS2), an E3 ligase. Multiple analyses established that both SUMO-specific peptidase 1 (SENP1) and SENP2 deSUMOylate ZFHX3. SUMOylation at Lys-2806 enhanced ZFHX3 stability by interfering with its ubiquitination and proteasomal degradation. Functionally, Lys-2806 SUMOylation enabled ZFHX3-mediated cell proliferation and xenograft tumor growth of the MDA-MB-231 breast cancer cell line. These findings reveal the enzymes involved in, and the functional consequences of, ZFHX3 SUMOylation, insights that may help shed light on ZFHX3's roles in various cellular and pathophysiological processes. Full Article
mo A flexible network of vimentin intermediate filaments promotes migration of amoeboid cancer cells through confined environments [Cell Biology] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Tumor cells can spread to distant sites through their ability to switch between mesenchymal and amoeboid (bleb-based) migration. Because of this difference, inhibitors of metastasis must account for each migration mode. However, the role of vimentin in amoeboid migration has not been determined. Because amoeboid leader bleb–based migration (LBBM) occurs in confined spaces and vimentin is known to strongly influence cell-mechanical properties, we hypothesized that a flexible vimentin network is required for fast amoeboid migration. To this end, here we determined the precise role of the vimentin intermediate filament system in regulating the migration of amoeboid human cancer cells. Vimentin is a classic marker of epithelial-to-mesenchymal transition and is therefore an ideal target for a metastasis inhibitor. Using a previously developed polydimethylsiloxane slab–based approach to confine cells, RNAi-based vimentin silencing, vimentin overexpression, pharmacological treatments, and measurements of cell stiffness, we found that RNAi-mediated depletion of vimentin increases LBBM by ∼50% compared with control cells and that vimentin overexpression and simvastatin-induced vimentin bundling inhibit fast amoeboid migration and proliferation. Importantly, these effects were independent of changes in actomyosin contractility. Our results indicate that a flexible vimentin intermediate filament network promotes LBBM of amoeboid cancer cells in confined environments and that vimentin bundling perturbs cell-mechanical properties and inhibits the invasive properties of cancer cells. Full Article
mo Inhibition of glycosphingolipid biosynthesis reverts multidrug resistance by differentially modulating ABC transporters in chronic myeloid leukemias [Cell Biology] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Multidrug resistance (MDR) in cancer arises from cross-resistance to structurally- and functionally-divergent chemotherapeutic drugs. In particular, MDR is characterized by increased expression and activity of ATP-binding cassette (ABC) superfamily transporters. Sphingolipids are substrates of ABC proteins in cell signaling, membrane biosynthesis, and inflammation, for example, and their products can favor cancer progression. Glucosylceramide (GlcCer) is a ubiquitous glycosphingolipid (GSL) generated by glucosylceramide synthase, a key regulatory enzyme encoded by the UDP-glucose ceramide glucosyltransferase (UGCG) gene. Stressed cells increase de novo biosynthesis of ceramides, which return to sub-toxic levels after UGCG mediates incorporation into GlcCer. Given that cancer cells seem to mobilize UGCG and have increased GSL content for ceramide clearance, which ultimately contributes to chemotherapy failure, here we investigated how inhibition of GSL biosynthesis affects the MDR phenotype of chronic myeloid leukemias. We found that MDR is associated with higher UGCG expression and with a complex GSL profile. UGCG inhibition with the ceramide analog d-threo-1-(3,4,-ethylenedioxy)phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol (EtDO-P4) greatly reduced GSL and monosialotetrahexosylganglioside levels, and co-treatment with standard chemotherapeutics sensitized cells to mitochondrial membrane potential loss and apoptosis. ABC subfamily B member 1 (ABCB1) expression was reduced, and ABCC-mediated efflux activity was modulated by competition with nonglycosylated ceramides. Consistently, inhibition of ABCC-mediated transport reduced the efflux of exogenous C6-ceramide. Overall, UGCG inhibition impaired the malignant glycophenotype of MDR leukemias, which typically overcomes drug resistance through distinct mechanisms. This work sheds light on the involvement of GSL in chemotherapy failure, and its findings suggest that targeted GSL modulation could help manage MDR leukemias. Full Article
mo Genetic lineage tracing with multiple DNA recombinases: A user's guide for conducting more precise cell fate mapping studies [Methods and Resources] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Site-specific recombinases, such as Cre, are a widely used tool for genetic lineage tracing in the fields of developmental biology, neural science, stem cell biology, and regenerative medicine. However, nonspecific cell labeling by some genetic Cre tools remains a technical limitation of this recombination system, which has resulted in data misinterpretation and led to many controversies in the scientific community. In the past decade, to enhance the specificity and precision of genetic targeting, researchers have used two or more orthogonal recombinases simultaneously for labeling cell lineages. Here, we review the history of cell-tracing strategies and then elaborate on the working principle and application of a recently developed dual genetic lineage-tracing approach for cell fate studies. We place an emphasis on discussing the technical strengths and caveats of different methods, with the goal to develop more specific and efficient tracing technologies for cell fate mapping. Our review also provides several examples for how to use different types of DNA recombinase–mediated lineage-tracing strategies to improve the resolution of the cell fate mapping in order to probe and explore cell fate–related biological phenomena in the life sciences. Full Article
mo The testis-specific LINC component SUN3 is essential for sperm head shaping during mouse spermiogenesis [Cell Biology] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Sperm head shaping is a key event in spermiogenesis and is tightly controlled via the acrosome–manchette network. Linker of nucleoskeleton and cytoskeleton (LINC) complexes consist of Sad1 and UNC84 domain–containing (SUN) and Klarsicht/ANC-1/Syne-1 homology (KASH) domain proteins and form conserved nuclear envelope bridges implicated in transducing mechanical forces from the manchette to sculpt sperm nuclei into a hook-like shape. However, the role of LINC complexes in sperm head shaping is still poorly understood. Here we assessed the role of SUN3, a testis-specific LINC component harboring a conserved SUN domain, in spermiogenesis. We show that CRISPR/Cas9-generated Sun3 knockout male mice are infertile, displaying drastically reduced sperm counts and a globozoospermia-like phenotype, including a missing, mislocalized, or fragmented acrosome, as well as multiple defects in sperm flagella. Further examination revealed that the sperm head abnormalities are apparent at step 9 and that the sperm nuclei fail to elongate because of the absence of manchette microtubules and perinuclear rings. These observations indicate that Sun3 deletion likely impairs the ability of the LINC complex to transduce the cytoskeletal force to the nuclear envelope, required for sperm head elongation. We also found that SUN3 interacts with SUN4 in mouse testes and that the level of SUN4 proteins is drastically reduced in Sun3-null mice. Altogether, our results indicate that SUN3 is essential for sperm head shaping and male fertility, providing molecular clues regarding the underlying pathology of the globozoospermia-like phenotype. Full Article
mo Targeting the polyamine pathway—“a means” to overcome chemoresistance in triple-negative breast cancer [Cell Biology] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Triple-negative breast cancer (TNBC) is characterized by its aggressive biology, early metastatic spread, and poor survival outcomes. TNBC lacks expression of the targetable receptors found in other breast cancer subtypes, mandating use of cytotoxic chemotherapy. However, resistance to chemotherapy is a significant problem, encountered in about two-thirds of TNBC patients, and new strategies are needed to mitigate resistance. In this issue of the Journal of Biological Chemistry, Geck et al. report that TNBC cells are highly sensitive to inhibition of the de novo polyamine synthesis pathway and that inhibition of this pathway sensitizes cells to TNBC-relevant chemotherapy, uncovering new opportunities for addressing chemoresistance. Full Article
mo Structural basis of specific inhibition of extracellular activation of pro- or latent myostatin by the monoclonal antibody SRK-015 [Molecular Biophysics] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 Myostatin (or growth/differentiation factor 8 (GDF8)) is a member of the transforming growth factor β superfamily of growth factors and negatively regulates skeletal muscle growth. Its dysregulation is implicated in muscle wasting diseases. SRK-015 is a clinical-stage mAb that prevents extracellular proteolytic activation of pro- and latent myostatin. Here we used integrated structural and biochemical approaches to elucidate the molecular mechanism of antibody-mediated neutralization of pro-myostatin activation. The crystal structure of pro-myostatin in complex with 29H4-16 Fab, a high-affinity variant of SRK-015, at 2.79 Å resolution revealed that the antibody binds to a conformational epitope in the arm region of the prodomain distant from the proteolytic cleavage sites. This epitope is highly sequence-divergent, having only limited similarity to other closely related members of the transforming growth factor β superfamily. Hydrogen/deuterium exchange MS experiments indicated that antibody binding induces conformational changes in pro- and latent myostatin that span the arm region, the loops contiguous to the protease cleavage sites, and the latency-associated structural elements. Moreover, negative-stain EM with full-length antibodies disclosed a stable, ring-like antigen–antibody structure in which the two Fab arms of a single antibody occupy the two arm regions of the prodomain in the pro- and latent myostatin homodimers, suggesting a 1:1 (antibody:myostatin homodimer) binding stoichiometry. These results suggest that SRK-015 binding stabilizes the latent conformation and limits the accessibility of protease cleavage sites within the prodomain. These findings shed light on approaches that specifically block the extracellular activation of growth factors by targeting their precursor forms. Full Article
mo Structures of the MHC-I molecule BF2*1501 disclose the preferred presentation of an H5N1 virus-derived epitope [Protein Structure and Folding] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 Lethal infections by strains of the highly-pathogenic avian influenza virus (HPAIV) H5N1 pose serious threats to both the poultry industry and public health worldwide. A lack of confirmed HPAIV epitopes recognized by cytotoxic T lymphocytes (CTLs) has hindered the utilization of CD8+ T-cell–mediated immunity and has precluded the development of effectively diversified epitope-based vaccination approaches. In particular, an HPAIV H5N1 CTL-recognized epitope based on the peptide MHC-I–β2m (pMHC-I) complex has not yet been designed. Here, screening a collection of selected peptides of several HPAIV strains against a specific pathogen-free pMHC-I (pBF2*1501), we identified a highly-conserved HPAIV H5N1 CTL epitope, named HPAIV–PA123–130. We determined the structure of the BF2*1501–PA123–130 complex at 2.1 Å resolution to elucidate the molecular mechanisms of a preferential presentation of the highly-conserved PA123–130 epitope in the chicken B15 lineage. Conformational characteristics of the PA123–130 epitope with a protruding Tyr-7 residue indicated that this epitope has great potential to be recognized by specific TCRs. Moreover, significantly increased numbers of CD8+ T cells specific for the HPAIV–PA123–130 epitope in peptide-immunized chickens indicated that a repertoire of CD8+ T cells can specifically respond to this epitope. We anticipate that the identification and structural characterization of the PA123–130 epitope reported here could enable further studies of CTL immunity against HPAIV H5N1. Such studies may aid in the development of vaccine development strategies using well-conserved internal viral antigens in chickens. Full Article
mo The heme-regulatory motifs of heme oxygenase-2 contribute to the transfer of heme to the catalytic site for degradation [Protein Structure and Folding] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 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. Full Article
mo Structural basis of cell-surface signaling by a conserved sigma regulator in Gram-negative bacteria [Molecular Biophysics] By feedproxy.google.com Published On :: 2020-04-24T06:08:45-07:00 Cell-surface signaling (CSS) in Gram-negative bacteria involves highly conserved regulatory pathways that optimize gene expression by transducing extracellular environmental signals to the cytoplasm via inner-membrane sigma regulators. The molecular details of ferric siderophore-mediated activation of the iron import machinery through a sigma regulator are unclear. Here, we present the 1.56 Å resolution structure of the periplasmic complex of the C-terminal CSS domain (CCSSD) of PupR, the sigma regulator in the Pseudomonas capeferrum pseudobactin BN7/8 transport system, and the N-terminal signaling domain (NTSD) of PupB, an outer-membrane TonB-dependent transducer. The structure revealed that the CCSSD consists of two subdomains: a juxta-membrane subdomain, which has a novel all-β-fold, followed by a secretin/TonB, short N-terminal subdomain at the C terminus of the CCSSD, a previously unobserved topological arrangement of this domain. Using affinity pulldown assays, isothermal titration calorimetry, and thermal denaturation CD spectroscopy, we show that both subdomains are required for binding the NTSD with micromolar affinity and that NTSD binding improves CCSSD stability. Our findings prompt us to present a revised model of CSS wherein the CCSSD:NTSD complex forms prior to ferric-siderophore binding. Upon siderophore binding, conformational changes in the CCSSD enable regulated intramembrane proteolysis of the sigma regulator, ultimately resulting in transcriptional regulation. Full Article
mo Structural and mutational analyses of the bifunctional arginine dihydrolase and ornithine cyclodeaminase AgrE from the cyanobacterium Anabaena [Enzymology] By feedproxy.google.com Published On :: 2020-04-24T06:08:45-07:00 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. Full Article
mo Glycation-mediated inter-protein cross-linking is promoted by chaperone-client complexes of {alpha}-crystallin: Implications for lens aging and presbyopia [Glycobiology and Extracellular Matrices] By feedproxy.google.com Published On :: 2020-04-24T06:08:45-07:00 Lens proteins become increasingly cross-linked through nondisulfide linkages during aging and cataract formation. One mechanism that has been implicated in this cross-linking is glycation through formation of advanced glycation end products (AGEs). Here, we found an age-associated increase in stiffness in human lenses that was directly correlated with levels of protein–cross-linking AGEs. α-Crystallin in the lens binds to other proteins and prevents their denaturation and aggregation through its chaperone-like activity. Using a FRET-based assay, we examined the stability of the αA-crystallin–γD-crystallin complex for up to 12 days and observed that this complex is stable in PBS and upon incubation with human lens–epithelial cell lysate or lens homogenate. Addition of 2 mm ATP to the lysate or homogenate did not decrease the stability of the complex. We also generated complexes of human αA-crystallin or αB-crystallin with alcohol dehydrogenase or citrate synthase by applying thermal stress. Upon glycation under physiological conditions, the chaperone–client complexes underwent greater extents of cross-linking than did uncomplexed protein mixtures. LC-MS/MS analyses revealed that the levels of cross-linking AGEs were significantly higher in the glycated chaperone–client complexes than in glycated but uncomplexed protein mixtures. Mouse lenses subjected to thermal stress followed by glycation lost resilience more extensively than lenses subjected to thermal stress or glycation alone, and this loss was accompanied by higher protein cross-linking and higher cross-linking AGE levels. These results uncover a protein cross-linking mechanism in the lens and suggest that AGE-mediated cross-linking of α-crystallin–client complexes could contribute to lens aging and presbyopia. Full Article
mo Structure of an ancestral mammalian family 1B1 cytochrome P450 with increased thermostability [Enzymology] By feedproxy.google.com Published On :: 2020-04-24T06:08:45-07:00 Mammalian cytochrome P450 enzymes often metabolize many pharmaceuticals and other xenobiotics, a feature that is valuable in a biotechnology setting. However, extant P450 enzymes are typically relatively unstable, with T50 values of ∼30–40 °C. Reconstructed ancestral cytochrome P450 enzymes tend to have variable substrate selectivity compared with related extant forms, but they also have higher thermostability and therefore may be excellent tools for commercial biosynthesis of important intermediates, final drug molecules, or drug metabolites. The mammalian ancestor of the cytochrome P450 1B subfamily was herein characterized structurally and functionally, revealing differences from the extant human CYP1B1 in ligand binding, metabolism, and potential molecular contributors to its thermostability. Whereas extant human CYP1B1 has one molecule of α-naphthoflavone in a closed active site, we observed that subtle amino acid substitutions outside the active site in the ancestor CYP1B enzyme yielded an open active site with four ligand copies. A structure of the ancestor with 17β-estradiol revealed only one molecule in the active site, which still had the same open conformation. Detailed comparisons between the extant and ancestor forms revealed increases in electrostatic and aromatic interactions between distinct secondary structure elements in the ancestral forms that may contribute to their thermostability. To the best of our knowledge, this represents the first structural evaluation of a reconstructed ancestral cytochrome P450, revealing key features that appear to contribute to its thermostability. Full Article
mo A Legionella effector kinase is activated by host inositol hexakisphosphate [Enzymology] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 The transfer of a phosphate from ATP to a protein substrate, a modification known as protein phosphorylation, is catalyzed by protein kinases. Protein kinases play a crucial role in virtually every cellular activity. Recent studies of atypical protein kinases have highlighted the structural similarity of the kinase superfamily despite notable differences in primary amino acid sequence. Here, using a bioinformatics screen, we searched for putative protein kinases in the intracellular bacterial pathogen Legionella pneumophila and identified the type 4 secretion system effector Lpg2603 as a remote member of the protein kinase superfamily. Employing an array of biochemical and structural biology approaches, including in vitro kinase assays and isothermal titration calorimetry, we show that Lpg2603 is an active protein kinase with several atypical structural features. Importantly, we found that the eukaryote-specific host signaling molecule inositol hexakisphosphate (IP6) is required for Lpg2603 kinase activity. Crystal structures of Lpg2603 in the apo-form and when bound to IP6 revealed an active-site rearrangement that allows for ATP binding and catalysis. Our results on the structure and activity of Lpg2603 reveal a unique mode of regulation of a protein kinase, provide the first example of a bacterial kinase that requires IP6 for its activation, and may aid future work on the function of this effector during Legionella pathogenesis. Full Article
mo Affinity maturation, humanization, and co-crystallization of a rabbit anti-human ROR2 monoclonal antibody for therapeutic applications [Immunology] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 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. Full Article
mo Zinc promotes liquid-liquid phase separation of tau protein [Protein Structure and Folding] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 Tau is a microtubule-associated protein that plays a major role in Alzheimer's disease (AD) and other tauopathies. Recent reports indicate that, in the presence of crowding agents, tau can undergo liquid–liquid phase separation (LLPS), forming highly dynamic liquid droplets. Here, using recombinantly expressed proteins, turbidimetry, fluorescence microscopy imaging, and fluorescence recovery after photobleaching (FRAP) assays, we show that the divalent transition metal zinc strongly promotes this process, shifting the equilibrium phase boundary to lower protein or crowding agent concentrations. We observed no tau LLPS-promoting effect for any other divalent transition metal ions tested, including Mn2+, Fe2+, Co2+, Ni2+, and Cu2+. We also demonstrate that multiple zinc-binding sites on tau are involved in the LLPS-promoting effect and provide insights into the mechanism of this process. Zinc concentration is highly elevated in AD brains, and this metal ion is believed to be an important player in the pathogenesis of this disease. Thus, the present findings bring a new dimension to understanding the relationship between zinc homeostasis and the pathogenic process in AD and related neurodegenerative disorders. Full Article
mo Templated folding of intrinsically disordered proteins [Molecular Biophysics] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Much of our current knowledge of biological chemistry is founded in the structure-function relationship, whereby sequence determines structure that determines function. Thus, the discovery that a large fraction of the proteome is intrinsically disordered, while being functional, has revolutionized our understanding of proteins and raised new and interesting questions. Many intrinsically disordered proteins (IDPs) have been determined to undergo a disorder-to-order transition when recognizing their physiological partners, suggesting that their mechanisms of folding are intrinsically different from those observed in globular proteins. However, IDPs also follow some of the classic paradigms established for globular proteins, pointing to important similarities in their behavior. In this review, we compare and contrast the folding mechanisms of globular proteins with the emerging features of binding-induced folding of intrinsically disordered proteins. Specifically, whereas disorder-to-order transitions of intrinsically disordered proteins appear to follow rules of globular protein folding, such as the cooperative nature of the reaction, their folding pathways are remarkably more malleable, due to the heterogeneous nature of their folding nuclei, as probed by analysis of linear free-energy relationship plots. These insights have led to a new model for the disorder-to-order transition in IDPs termed “templated folding,” whereby the binding partner dictates distinct structural transitions en route to product, while ensuring a cooperative folding. Full Article
mo The Histone Methyltransferase MLL1 Directs Macrophage-Mediated Inflammation in Wound Healing and Is Altered in a Murine Model of Obesity and Type 2 Diabetes By diabetes.diabetesjournals.org Published On :: 2017-09-01 Andrew S. KimballSep 1, 2017; 66:2459-2471Immunology and Transplantation Full Article
mo The High-Fat Diet-Fed Mouse: A Model for Studying Mechanisms and Treatment of Impaired Glucose Tolerance and Type 2 Diabetes By diabetes.diabetesjournals.org Published On :: 2004-12-01 Maria Sörhede WinzellDec 1, 2004; 53:S215-S219Section V: The Incretin Pathway Full Article
mo Nicotine and Insulin Resistance: When the Smoke Clears By diabetes.diabetesjournals.org Published On :: 2012-12-01 Mandeep BajajDec 1, 2012; 61:3078-3080Commentary Full Article
mo Pancreas Pathology of Latent Autoimmune Diabetes in Adults (LADA) in Patients and in a LADA Rat Model Compared With Type 1 Diabetes By diabetes.diabetesjournals.org Published On :: 2020-04-01 Anne JörnsApr 1, 2020; 69:624-633Islet Studies Full Article
mo The Incretin Approach for Diabetes Treatment: Modulation of Islet Hormone Release by GLP-1 Agonism By diabetes.diabetesjournals.org Published On :: 2004-12-01 Jens Juul HolstDec 1, 2004; 53:S197-S204Section V: The Incretin Pathway Full Article
mo PPARA Polymorphism Influences the Cardiovascular Benefit of Fenofibrate in Type 2 Diabetes: Findings From ACCORD-Lipid By diabetes.diabetesjournals.org Published On :: 2020-04-01 Mario Luca MorieriApr 1, 2020; 69:771-783Genetics/Genomes/Proteomics/Metabolomics Full Article
mo The cGAS-cGAMP-STING Pathway: A Molecular Link Between Immunity and Metabolism By diabetes.diabetesjournals.org Published On :: 2019-06-01 Juli BaiJun 1, 2019; 68:1099-1108Perspectives in Diabetes Full Article
mo A Polymorphism in the Glucocorticoid Receptor Gene, Which Decreases Sensitivity to Glucocorticoids In Vivo, Is Associated With Low Insulin and Cholesterol Levels By diabetes.diabetesjournals.org Published On :: 2002-10-01 Elisabeth F.C. van RossumOct 1, 2002; 51:3128-3134Genetics Full Article
mo Correction: A dual druggable genome-wide siRNA and compound library screening approach identifies modulators of parkin recruitment to mitochondria. [Additions and Corrections] By feedproxy.google.com Published On :: 2020-04-24T06:08:45-07:00 VOLUME 295 (2020) PAGES 3285–3300An incorrect graph was used in Fig. 5C. This error has now been corrected. Additionally, some of the statistics reported in the legend and text referring to Fig. 5C were incorrect. The F statistics for Fig. 5C should state Fken(3,16) = 7.454, p < 0.01; FCCCP(1,16) = 102.9, p < 0.0001; Finteraction(3,16) = 7.480, p < 0.01. This correction does not affect the results or conclusions of this work.jbc;295/17/5835/F5F1F5Figure 5C. Full Article
mo Correction: Comparative structure-function analysis of bromodomain and extraterminal motif (BET) proteins in a gene-complementation system. [Additions and Corrections] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 VOLUME 295 (2020) PAGES 1898–1914Yichen Zhong's name was misspelled. The correct spelling is shown above. Full Article
mo Correction: Histone demethylase KDM6B promotes epithelial-mesenchymal transition. [Additions and Corrections] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 VOLUME 287 (2012) PAGES 44508–44517In Fig. 1A, the wrong image for the control group was presented. The authors inadvertently cropped the control images in Fig. 1, A and E, from the same raw image. Fig. 1A has now been corrected and does not affect the results or conclusions of the work. The authors sincerely apologize for their mistake during figure preparation and for any inconvenience this may have caused readers.jbc;295/19/6781/F1F1F1Figure 1A. Full Article
mo Combination upstream and downstream treatment modalities for RECOVERY from COVID-19 By feeds.bmj.com Published On :: Friday, May 8, 2020 - 11:27 Full Article
mo How changes to drug prohibition could be good for the UK—an essay by Molly Meacher and Nick Clegg By feeds.bmj.com Published On :: Monday, November 14, 2016 - 23:30 Full Article
mo US adults are more likely to have poor health than those in 10 similar countries, survey finds By feeds.bmj.com Published On :: Wednesday, November 16, 2016 - 22:00 Full Article
mo Supervised physiotherapy for mild or moderate ankle sprain By feeds.bmj.com Published On :: Wednesday, November 16, 2016 - 23:31 Full Article
mo US must address addiction as an illness, not as a moral failing, Surgeon General says By feeds.bmj.com Published On :: Tuesday, November 22, 2016 - 11:25 Full Article
mo NHS spent 8% more on medicines last year By feeds.bmj.com Published On :: Wednesday, November 23, 2016 - 06:30 Full Article
mo Trial of novel leukaemia drug is stopped for second time after two more deaths By feeds.bmj.com Published On :: Friday, November 25, 2016 - 10:46 Full Article
mo Chemoprevention of colorectal cancer in individuals with previous colorectal neoplasia: systematic review and network meta-analysis By feeds.bmj.com Published On :: Monday, December 5, 2016 - 14:46 Full Article
mo Melding the best of two worlds: Cecil Pickett's work on cellular oxidative stress and in drug discovery and development [Molecular Bases of Disease] By feedproxy.google.com Published On :: 2020-03-20T00:06:23-07:00 Many chemicals and cellular processes cause oxidative stress that can damage lipids, proteins, or DNA (1). To quickly sense and respond to this ubiquitous threat, organisms have evolved enzymes that neutralize harmful oxidants such as reactive oxygen species and electrophilic compounds (including xenobiotics and their breakdown products) in cells.These antioxidant enzymes include GSH S-transferase (GST),2 NADPH:quinone oxidoreductase 1, thioredoxin, hemeoxygenase-1, and others (2, 3). Many of these proteins are commonly expressed in cells exposed to oxidative stress.The antioxidant response element (ARE) is a major regulatory component of this cellular stress response. The ARE is a conserved, 11-nucleotide-long DNA motif present in the 5'-flanking regions of many genes encoding antioxidant proteins. The laboratory of Cecil Pickett (Fig. 1) at the Merck Frosst Centre for Therapeutic Research in Quebec discovered ARE, a finding reported in the early 1990s in two JBC papers recognized as Classics here (4, 5).jbc;295/12/3929/F1F1F1Figure 1.Cecil Pickett (pictured) and colleagues first described the ARE motif, present in the 5' regions of many genes whose expression is up-regulated by oxidative stress and xenobiotics. Photo courtesy of Cecil Pickett.ARE's discovery was spurred in large part by Pickett's career choice. After completing a PhD in biology and a 2-year postdoc at UCLA in the mid-1970s, he began to work in the pharmaceutical industry.Recruited to Merck in 1978 by its then head of research and development (and later CEO), Roy Vagelos, “I became interested in how drug-metabolizing enzymes were induced by various xenobiotics,” Pickett says.According to Pickett, Vagelos encouraged researchers at the company... Full Article
mo Democratize Trade Policymaking to Better Protect Human Rights By feedproxy.google.com Published On :: Thu, 06 Jun 2019 12:11:18 +0000 12 June 2019 Dr Jennifer Ann Zerk Associate Fellow, International Law Programme There is growing interest in the use of human rights impact assessment to screen proposed trade agreements for human rights risks, and to ensure appropriate risk mitigation steps are taken. 2019-02-15-HumanRightsTradeAgreements-Smaller.jpg Tea pickers walk at dawn through the tea plantations of Munnar, Kerala, on 7 May 2017. Copyright: Pardeep Singh Gill/Getty Images With international trade discourse taking an increasingly transactional and sometimes belligerent tone, it would be easy to overlook the quiet revolution currently under way to bring new voices into trade policy development and monitoring. The traditional division of responsibilities between the executive and legislature – whereby treaties are negotiated and signed by the executive, and the legislature does what is necessary to implement them – may be undergoing some change.Growing awareness of the implications of trade and investment treaties for many aspects of day-to-day life – food standards, employment opportunities, environmental quality, availability of medicines and data protection, just to name a few – is fuelling demands by people and businesses for more of a say in the way these rules are formulated and developed.Various options for enhancing public and parliamentary scrutiny of trading proposals have recently been examined by two UK parliamentary select committees.[1] The reason for this interest is obviously Brexit, which has presented UK civil servants and parliamentarians with the unusual (some would say exciting) opportunity to design an approval and scrutiny process for trade agreements from scratch.Doubtless, EU authorization, liaison and approval procedures (which include a scrutinizing role for the European Parliament) will be influential,[2] as will the European Commission’s experience with stakeholder engagement on trade issues.[3] The recommendations of both UK select committees to include human rights impact assessment processes as part of pre-negotiation preparations[4] echo calls from UN agencies and NGOs for more rigorous and timely analysis of the human rights risks that may be posed by new trading relationships.[5] Again, EU practice with what it terms ‘sustainability impact assessment’ of future trade agreements provides a potential model to draw from.[6] However, process is no substitute for action. Human rights impact assessment is never an end in itself; rather, it is a means to a positive end, in this case a trade agreement which is aligned with the trading partners’ respective human rights obligations and aspirations. It bears remembering, though, that the idea of assessing trade proposals for future human rights risks is a relatively recent one. Do we have the tools and resources to make sure that this is a meaningful compliance and risk management exercise?Thus far there is little evidence that human rights impact assessment and stakeholder engagement exercises are having any real impact on the content of trade agreements.[7] This is the case even in the EU, where practice in these areas is the most advanced and systematic.[8]There are several possible reasons for this. First, the methodological challenges are enormous. Aside from the crystal-ball gazing needed to forecast the social, economic and environmental effects of a trade intervention well into the future, demonstrating causal links between a trade agreement and a predicted adverse impact is often highly problematic given the number of other economic and political factors that may be in play.[9]Secondly, there are many challenges around the need to engage with affected people and listen to their views.[10] The sheer number of possible impacts of a trade agreement on different individuals and communities, as well as the range of rights potentially engaged, makes this a difficult (some would say impossible) task. Some prioritization is always necessary.This makes for difficult decisions about who to engage with and how. Perceived bias or an apparent lack of even-handedness – favouring business compared to civil society, for instance – can sow mistrust about the true aims of such a process, undermining its future effectiveness as participants begin to question whether it is genuine or worthwhile.[11]The challenges are even more acute where impact assessment practitioners are tasked with investigating potential human rights impacts in other countries. Even if it is possible to get past the inevitable political sensitivities,[12] the sort of in-depth consultations required will be beyond the budget and time constraints of most assignments.[13]There are good reasons why trade policy should be subject to greater public and parliamentary scrutiny, and why there should be more opportunities for public participation in the formation of new trading regimes. By building more opportunities for stakeholder consultation at these stages, we can acquire perspectives on trade that are not available from other forms of assessment and analysis.However, policymakers should be wary of overstating the benefits of existing procedural models. Human rights impact assessment processes are still struggling to provide compelling analyses of the relationships between trade agreements and the enjoyment of human rights, let alone a roadmap for policymakers and trade negotiators as to what should be done.[14]And financial and practical barriers to participation in stakeholder engagement exercises mean that, at best, these will provide only a partial picture of stakeholder impacts and views.Experiences with human rights impact assessment of trade agreements so far demonstrate the need for realism about two things: first, the extent to which one can sensibly anticipate and analyse human rights-related risks and opportunities in the preparation stages for a new trading agreement; and, second, the extent to which problems identified in this way can be headed off with the right form of words in the treaty itself.Both recent UK select committee reports place considerable faith in the ability of pre-project transparency and scrutiny processes to flush out potential problems and prescribe solutions. Of course, there may be cases where frontloading the analysis in this way could be useful, for instance where the human rights implications are so clear that they can readily be addressed through upfront commitments by the parties concerned, whether by bespoke or standardized approaches.More often, though, for a trade agreement running many years into the future, human rights impacts and implications will take time to emerge, suggesting the need for robust monitoring and mitigation frameworks designed with longevity in mind. Ideally, pre-signing approval and assessment processes would lay the groundwork for future action by both trading partners, either jointly or separately (though preferably both).To this end, as well as developing ideas for more robust substantive provisions on human rights, policymakers should consider the institutional arrangements required – whether pursuant to the trade agreement or by complementary processes – to ensure that human rights-related risks identified during the planning stages are properly and proactively followed up, that emerging risks are tackled in a timely fashion, and that there are opportunities for meaningful stakeholder contributions to these processes.What needs to happenTrade policymakers can use human rights impact assessment to screen proposed trade treaties for human rights-related risks and to identify possible ways of mitigating those risks, whether through the terms of the agreement itself, domestic law reform or flanking measures.Building more opportunities for stakeholder consultations can enable perspectives on trade to be highlighted that are not available from other forms of assessment.Assessment is complicated, however, by methodological challenges and the difficulties of forecasting a trade agreement’s future impacts. Policymakers need to be realistic about the risks that can be anticipated, and the extent to which many of those identified can be addressed upfront in trade agreements’ terms.These inherent limitations may be overcome to some extent by better ongoing monitoring. Future trade agreements should include more robust human rights risk monitoring and mitigation frameworks, designed with longevity in mind.Notes[1] UK Joint Committee on Human Rights (2019), ‘Human Rights Protections in International Agreements, Seventeenth Report of Session 2017–19’, HC 1833 HL paper 310, 12 March 2019, https://publications.parliament.uk/pa/jt201719/jtselect/jtrights/1833/1833.pdf; and House of Commons International Trade Committee (2018), ‘UK Trade Policy Transparency and Scrutiny, Sixth Report of Session 2017-2019’, HC 1043, 29 December 2018.[2] European Parliament and Directorate General for External Policies (2019), Parliamentary scrutiny of trade policies across the western world, study paper, March 2019, http://www.europarl.europa.eu/RegData/etudes/STUD/2019/603477/EXPO_STU(2019)603477_EN.pdf.[3] European Commission (2019), ‘Trade policy and you’, http://ec.europa.eu/trade/trade-policy-and-you/index_en.htm.[4] See UK Joint Committee on Human Rights (2019), ‘Human Rights Protections in International Agreements’, para 12; and House of Commons International Trade Committee (2018), ‘UK Trade Policy Transparency and Scrutiny’, paras 124–34.[5] OHCHR (2003), Report of the High Commissioner for Human Rights on Human Rights, Trade and Investment, 2 July 2003, E/CN.4/Sub.2/2003/9, Annex, at para 63; UN Economic and Social Council (2017), ‘General Comment No 24 (2017) of the Committee on Economic, Social and Cultural Rights on State obligations under the International Covenant on Economic, Social and Cultural Rights in the context of business activities’, UN Doc. E/C.12/GC/24, 10 August 2017, para 13; and UN General Assembly (2011), ‘Guiding principles on human rights impact assessment of trade and investment agreements’, Report of the Special Rapporteur on the Right to Food, Olivier De Schutter, UN Doc. A/HRC/19/59/Add.5, 19 December 2011.[6] European Commission (2016), Handbook for Sustainability Impact Assessment (2nd ed.), Brussels: European Union, http://trade.ec.europa.eu/doclib/docs/2016/april/tradoc_154464.PDF.[7] Zerk, J. (2019), Human Rights Impact Assessment of Trade Agreements, Chatham House Research Paper, London: Royal Institute of International Affairs, https://www.chathamhouse.org/publication/human-rights-impact-assessment-trade-agreements.[8] Ibid., pp. 11–13. For a detailed explanation of the EU’s approach to human rights impact assessment, see European Commission (2016), Handbook for Sustainability Impact Assessment.[9] Zerk (2019), Human Rights Impact Assessment of Trade Agreements, pp. 14–21.[10] Ibid., pp. 21–22.[11] Ergon Associates (2011), Trade and Labour: Making effective use of trade sustainability impact assessments and monitoring mechanisms, Final Report to DG Employment, Social Affairs and Inclusion European Commission, September 2011; and Gammage, C. (2010), ‘A Sustainability Impact Assessment of the Economic Partnership Agreements: Challenging the Participatory Process’, Law and Development Review, 3(1): pp. 107–34. For a civil society view, see Trade Justice Movement (undated), ‘Trade Justice Movement submission to the International Trade Committee inquiry into UK Trade Policy Transparency and Scrutiny’, https://www.tjm.org.uk/resources/briefings/tjm-submission-to-the-international-trade-committee-inquiry-into-uk-trade-policy-transparency-and-scrutiny, esp. paras 23–32.[12] Zerk (2019), Human Rights Impact Assessment of Trade Agreements, pp. 20–21.[13] Ibid., pp. 21–22.[14] Ibid.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. Full Article
mo The Morass of Central American Migration: Dynamics, Dilemmas and Policy Alternatives By feedproxy.google.com Published On :: Mon, 11 Nov 2019 16:10:01 +0000 Invitation Only Research Event 22 November 2019 - 8:15am to 9:30am Chatham House | 10 St James's Square | London | SW1Y 4LE Event participants Anita Isaacs, Professor of Political Science, Haverford College; Co-Director, Migration Encounters ProjectJuan Ricardo Ortega, Principal Advisor for Central America, Inter-American Development BankChair: Amy Pope, Associate Fellow, Chatham House; US Deputy Homeland Security Adviser for the Obama Administration (2015-17) 2019 has seen a record number of people migrating from Central America’s Northern Triangle – an area that covers El Salvador, Guatemala and Honduras. Estimates from June 2019 have placed the number of migrants at nearly double of what they were in 2018 with the increase in numbers stemming from a lack of economic opportunity combined with a rise in crime and insecurity in the region. The impacts of migration can already be felt within the affected states as the exodus has played a significant role in weakening labour markets and contributing to a ‘brain drain’ in the region. It has also played an increasingly active role in the upcoming US presidential election with some calling for more security on the border to curb immigration while others argue that a more effective strategy is needed to address the sources of migration. What are the core causes of Central American migration and how have the US, Central American and now also Mexican governments facilitated and deterred migration from the region? Can institutions be strengthened to alleviate the causes of migration? And what possible policy alternatives and solutions are there that could alleviate the pressures individuals and communities feel to migrate? Anita Isaacs, professor of Political Science at Haverford College and co-director of the Migration Encounters Project, and Juan Ricard Ortega, principal advisor for Central America at the Inter-American Development Bank, will join us for a discussion on the core drivers of migration within and across Central America.Attendance at this event is by invitation only. Event attributes Chatham House Rule Department/project US and the Americas Programme US and Americas Programme Email Full Article
mo Democrats Have Set Themselves Up to Fail in November's Election By feedproxy.google.com Published On :: Fri, 21 Feb 2020 09:45:27 +0000 21 February 2020 Dr Lindsay Newman Senior Research Fellow, US and the Americas Programme @lindsayrsnewman LinkedIn Debates and caucuses are proving that the party took the wrong lesson from the midterms. They're now applying that lesson to 2020 with potentially disastrous results. 2020-02-21-DemDebate.jpg 2020 Democratic presidential candidates at the debate in Las Vegas on 19 February. Photo: Getty Images. The Democratic Party’s struggle for its future policy direction is evident this election season. The primary results in Iowa and New Hampshire, narrow first- and second-place finishes for Senator Bernie Sanders (a progressive) and former South Bend mayor Pete Buttigieg (a moderate), were just two indicators. During Wednesday night’s debate in Las Vegas, the split became even more obvious.The six candidates onstage clashed on ideology (socialism and capitalism, progressivism and centrism) as well as policy (healthcare, climate change, fossil fuels, criminal justice, China). Buttigieg made plain the stakes for Democrats, saying, 'We’ve got to wake up as a party.'If a Democratic candidate is elected to be the United States’ 46th president on 3 November, it will be despite this unresolved intra-party struggle.One lesson the Democratic Party has taken from the 2018 midterm elections is that running candidates across the ideological spectrum is a winning formula.It is easy to see how they came to this conclusion following the 2016 presidential and 2018 Congressional election experiences. In 2016, the favoured candidate status of former secretary of state Hillary Clinton deterred other aspirants from entering the Democratic primary ahead of a general election she went on to lose to Republican Donald Trump. In 2018, progressive and moderate centrist candidates, both first-timers and incumbents, ran and Democrats retook leadership in the House of Representatives with a 235-seat majority.But what if this conclusion was noise and not the signal?The Democratic National Committee (DNC) set the rules for the 2020 election based on the theory that by allowing an inclusive field (more than two dozen candidates entered the presidential race) the campaign processes, including debates, caucuses and primaries, would ultimately identify the most robust, representative candidate to go up against Donald Trump. Perhaps, and somewhat ironically, the 2016 Republican primary process, which involved a wide field culled by Trump’s unexpected success, informed the DNC’s reforms. And while very nice as a hypothesis of Bayesian updating, what has unfolded instead is a scattershot four-way — at times even five-way — race.In the midst of this party divide, whoever ends up being the Democratic nominee will likely not represent the views of some meaningful proportion of the Democratic base. While healthcare remains the top issue across the Democratic electorate, there are those (candidates and voters) who want a single-payer option for all without a private insurance option and those who want to expand healthcare access while maintaining private insurers. Likewise, on foreign policy, there are those who link US trade policy with protecting American workers and who would therefore continue to use tariffs as a key trade policy, as well as those critical of Trump’s reliance on tariffs.Compare that with the current state of the Republican Party. Trump’s approval with Republicans is in the high 80s, sometimes even low 90s, and after all but one Republican senator voted to acquit him in the Senate impeachment trial, the party is undeniably Trump’s. A sure sign is the historic turnout for Trump in his essentially uncontested Iowa and New Hampshire primaries.Their own divisions pose a number of risks, then, for Democrats heading into November’s general election. The first one relates to vulnerabilities arising out of the primary process itself. If the fractures emerging from Iowa and New Hampshire persist, the likelihood of a quick wrap-up of the Democratic primary by April reduces, and the possibility of a contested Democratic convention in July increases (even if from a low base). While exciting television and Twitter fodder, a lengthy primary positions Democrats to go into the fall facing questions of party disunity behind the eventual nominee.Although complicated to demonstrate empirically, some work has been done to understand whether the protracted 2016 Democratic primary and Sanders’ slow support for Democratic nominee Clinton in 2016 played a part in her defeat and Trump’s electoral success. A delayed general election campaign for the eventual Democratic nominee in 2020 almost certainly advantages President Trump’s money machine, which reportedly has more than twice as much on hand as then-president Barack Obama had going into his 2012 re-election. Further, unlike 2016, which was an open-seat election for the presidency, in 2020 Trump will have a demonstrated incumbent advantage.The Democratic Party’s succession battle also raises risks around general election turnout. If Sanders is the party’s nominee, Biden or Buttigieg’s constituency may not come out to vote for him. More worrisome for Democrats, if Sanders is the party’s nominee then centrist voters, including those representing the finance industry, may peel off and vote for Trump, who has overseen economic expansion and record unemployment rates following the 2017 tax overhaul and various deregulations.Alternatively, if Biden, Buttigieg or former mayor Michael Bloomberg become the nominee, Sanders’ many loyal supporters are likely to feel their policy priorities are not represented. And if those voters stay home because the Democratic nominee is not promising a political revolution, evidence suggests that depressed turnout levels may favour Republicans.A third political peril relates to the business of legislating after the election. If despite the potential pitfalls a Democratic candidate manoeuvres and manages to build a winning coalition on 3 November, they will face the reality of legislative politics, which over the last 10 years have been defined by policy gridlock. Obama managed to get Obamacare through both Democratic-majority congressional chambers, but presided over divided chambers for the remainder of his term. Similarly, Trump’s major legislative accomplishment — the 2017 tax overhaul — was a result of Republican control in both the House of Representatives and the Senate.A Democratic president will have to make progress on his or her agenda given not only the typical Republican-Democrat divide in Congress, but also facing potential raw divisions within the Democratic Party itself. In such a scenario, a Democratic administration may be tempted to take an expansive view of the president’s authority as we have seen under Trump, including relying on executive actions (tariffs and sanctions) on foreign policy.The Democratic National Convention in Milwaukee, Wisconsin, beginning 13 July, and the party platform crafted over those four days present an essential opportunity to resolve the party’s divisions before November. If left unchecked, the party might find that its ex ante strategy for the 2020 Democratic primary ends in Trump’s re-election.This article was originally published in the Independent. Full Article
mo Latin America’s COVID-19 Moment: Differences and Solidarity By feedproxy.google.com Published On :: Thu, 30 Apr 2020 11:37:25 +0000 30 April 2020 Dr Christopher Sabatini Senior Research Fellow for Latin America, US and the Americas Programme @ChrisSabatini LinkedIn There has been no better example of the political diversity in Latin America than the varying responses of governments to the coronavirus crisis. 2020-04-30-Chile-Covid.jpg A municipal cleaning worker disinfects the central market in Santiago, Chile on 7 April 2020 amid the coronavirus pandemic. Photo: Getty Images. Differing approaches across the hemisphere have had different impacts on presidential popularity and, at least in one case, on democratic institutions and human rights. Yet, even within that diversity, South America’s Southern Cone countries (Argentina, Chile, Paraguay and Uruguay) have shown a sign of solidarity: protecting and facilitating trade flows, sponsoring cross-border research and ensuring citizens’ return to their home countries. The response from populist leadersOn the extreme have been the responses of presidents of Brazil, Nicaragua and Mexico, all of whom have ignored the science of the virus and of experts and refused to implement isolation policies. President Jair Bolsonaro of Brazil fired his health minister, Luis Henrique Mandetta on 16 April for contradicting him and earlier had claimed that the pandemic was a hoax or little more than a ‘measly cold.' Meanwhile, Nicaraguan president Daniel Ortega has resisted closing businesses and schools. After a mysterious 34-day absence, Ortega appeared on television on 15 April reinforcing his refusal to close businesses saying that Nicaraguans must work or they will die and claiming that the virus was ‘imported.’ Mexico’s Andres Manuel Lopez Obrador (AMLO) has also resisted the call for strict stay-at-home policies, though with his Deputy Health Minister, Hugo López-Gatell, has closed schools – recently extending the closure to the 1st of June and urging non-essential businesses to close – but focusing primarily on social distancing. In contrast to his deputy health minister and Foreign Minister Marcelo Ebrard – who had declared the situation a health emergency on 30th March, later than many neighbouring countries – AMLO has largely attempted to avoid discussion of the pandemic, claiming that in his case he has lucky charms that prevent him from contracting the virus. And both Bolsonaro and AMLO have participated in large public rallies, doing all the things that politicians love, shaking hands and hugging babies, and in the case of the former even wiping his nose before embracing an elderly woman.The Nicaraguan, Brazilian and Mexican presidents make an odd grouping since one (Bosonaro) is considered of the extreme populist right and the others (Ortega and AMLO) of the populist left. What unites them is good old-fashioned populism, a belief in a leader who represents the amorphous popular will and should be unfettered by checks and balances on his power, including something like… science. An eclectic groupAt the other extreme have been the quick responses by governments in Peru, Argentina, Chile, El Salvador and Colombia which put quarantine measures in place in mid-March. In these cases, governments have even banned outdoor activities and in the case of Peru and Colombia (in the large cities) have imposed alternating days for when women and men can leave the house so as to better control outside movement. This too, though, is an eclectic group. It includes a Peronist president Alberto Fernández in Argentina, conservative presidents Sebastian Piñera in Chile and Ivan Duque in Colombia, interim president and relative political neophyte Martin Vizcarra in Peru and outsider president Nayib Bukele in El Salvador. El Salvador’s strict quarantine measures have led to rising concerns that Bukele is using the crisis to consolidate personal power, using the national police and the armed forces to enforce the quarantine and ignoring three rulings by the Supreme Court urging the president to end the abuses. In Argentina, Peronist Fernández has shown a surprising commitment to containment even as it hurts his party’s working-class base, not something typically expected of the populist Peronist Party. In all of these cases, the quick, strong responses by the presidents shored up their popularity. Peru’s Vizcarra saw his popularity shoot up 35 points in a week to 82 per cent according to surveys taken in March. In late March 2020, Fernández in Argentina saw his approval ratings swell to 79.2 per cent with 94.7 percent of citizens approving of the government’s strict shelter-at-home policies. Even presidents Piñera and Duque who had struggled with low approval ratings throughout 2019 and saw those numbers sink even lower after the social protests that ended the year have seen their numbers rise. According to an 20th April poll, Piñera’s popular approval rating swelled from 13 percent in March 18th at the start of the crisis to 25 per cent by 20th April; while hardly a sweeping popular mandate, even that level was unthinkable only a few months ago when administration was battered by social protests. In Colombia, after a series of political missteps and the popular protests, Duque’s popular approval rating had slumped to 26 per cent; by April 2nd, 62 percent of Colombians supported the once-beleaguered president. (No recent surveys were available for Bukele in El Salvador.)In contrast, Bolsonaro’s in Brazil has only nudged up. Before the crisis hit, the president’s popularity had been in steady decline from a high of 49 per cent in January 2019 to 30 per cent by early December 2019. But by the first week in April, in the midst of a crisis in which other presidents saw their approval ratings increase by double digits, after his public disagreements with the health minister, Bolsonaro’s had sunk to 33 per cent while the soon-to-be-fired Mandetta’s stood at 76 per cent. AMLO in Mexico has fared no better. The populist leftist scored a high 86 per cent approval rating in February 1, 2019. By March 28, 2020 with concerns over his weak and flippant COVID-19 response and a severe contraction in economic growth, AMLO’s approval rating had sunk 26 points to 60 per cent and his disapproval stood at 37 per cent. In the midst of disharmony, coordinationDespite these differences, many countries in the region have shown the solidarity they often speak of but rarely follow in policy or practice. Peru, Chile and other countries have collaborated in repatriating citizens back to their home countries in the midst of the crisis. Even the countries of the Southern Cone common market, MERCOSUR, have pulled together on a number of fronts. The trade bloc had effectively been ruled a dead-man-walking after its failed efforts to integrate Venezuela into the bloc, lowering its standards to let in the petroleum dependent semi-authoritarian government of then President Hugo Chávez. Even on the basics of internal cooperation, the block was struggling, unable to coordinate monetary policies and non-tariff trade barriers between the original founding member states, Argentina, Brazil, Paraguay and Uruguay.The 35-year-old customs union seemed to get a breath a new life with the announcement that it had concluded 20-year-long negotiations with the EU for a free trade deal. Ratification of that deal, however, ran aground on the political differences between the recently elected governments of Bolsonaro in Brazil and the Peronist Fernández in Argentina. Bolsonaro refused to attend the Fernández December 2019 inauguration, in protest of the newly elected president’s leftist leanings. And this was well before their sharply divergent reactions to the COVID-19 virus. How surprising then that Mercosur has served as an effective coordination mechanism for these different and once opposed governments. The trade body is collaborating among member states to ensure the repatriation of citizens and has agreed to coordinate to ensure that trade flows, especially of medical supplies, are not interrupted by shutdown measures. Mercosur has even gone one step further than several other bodies have failed to take. In early April the bloc’s governing body, based in Montevideo, Uruguay created a $16 million (12 million pound) fund to augment country research and assist in the purchase of supplies needed to combat the virus. Now if Brazil, Argentina and the others could only coordinate their domestic coronavirus responses and economic policy. In late March Fernández announced he was pulling Argentina out of a possible Mercosur-EU trade deal. Full Article
mo NICE recommends implantable monitor to identify atrial fibrillation after stroke By feeds.bmj.com Published On :: Tuesday, January 14, 2020 - 00:30 Full Article
mo Covid-19: Projections of mortality in the US rise as states open up By feeds.bmj.com Published On :: Wednesday, May 6, 2020 - 12:26 Full Article
mo More changes announced to court operations By jamaica-gleaner.com Published On :: Fri, 08 May 2020 13:19:10 -0500 Additional changes have been made to the operations of the island's courts in light of COVID-19. Changes below: Criminal Cases All hearings in the Home Circuit Court Division of the Gun Court, the High Court Division of the Gun Court, the... Full Article
mo UTech community in mourning over passing of lecturer By jamaica-gleaner.com Published On :: Fri, 08 May 2020 13:49:03 -0500 The University of Technology, Jamaica (UTech) fraternity has been plunged into mourning following the death of lecturer Jamar Thelwell. The 34-year-old passed away yesterday from cancer. His colleague Jerome Shepherd said Thelwell’s death has... Full Article
mo ‘Buffalo Soldiers’: Jamaican ice hockey team to be memorialised in Canadian sports yearbook By jamaica-gleaner.com Published On :: Sat, 09 May 2020 00:11:59 -0500 Jamaica’s senior men’s ice hockey team’s historic championship win at last year’s Amerigol LATAM Cup is memorialised in a Canadian sports yearbook published earlier this year. The team copped the championship in its first international outing... Full Article
mo Businesses hope to get some action for Mother’s Day By jamaica-gleaner.com Published On :: Sat, 09 May 2020 00:09:50 -0500 Just last year, one could find a variety of deals and promotions for Mother’s Day with ease, but for 2020, the opposite is true. This change could be connected with the coronavirus pandemic and a number of businesses having to close their doors for... Full Article
mo Political Will Was Not Enough for Justice Reform in Moldova By feedproxy.google.com Published On :: Tue, 26 Nov 2019 15:51:37 +0000 27 November 2019 Cristina Gherasimov Former Academy Associate, Russia and Eurasia Programme @cgherasimov The pro-reform Sandu government had the will to dismantle oligarchic power structures, but was taken down by limited political experience. 2019-11-26-Sandu.jpg Maia Sandu in Germany in July. Photo: Getty Images. The lack of political will to carry out rule of law reforms is frequently the reason why reforms are not fully implemented. The case of Moldova proves that in societies where strong vested interests still persist, political savviness is equally as important as political will.Old and new political power brokers in Moldova struck a fragile pact in June to oust Vladimir Plahotniuc. Plahotniuc had built a network of corruption and patronage with the help of the Democratic Party, which he treated as a personal vehicle and which allowed him and a small economic elite circle to enrich themselves off of government institutions and state-owned enterprises, to the detriment of Moldovan citizens and the health of their political process.Maia Sandu, co-leader of the pro-reform ACUM electoral bloc, then formed a technocratic government with a remit to implement Moldova’s lagging reform agenda. Though made up of ministers with the integrity and political will to implement difficult transformational reforms, its biggest weakness was its coalition partner – the pro-Russian Socialists’ Party and its informal leader, Igor Dodon, the president of Moldova.Now the Socialists – threatened by how key reforms to the justice system would impact their interests – have joined forces with Plahotniuc’s former allies, the Democratic Party, to oust ACUM, exploiting the party’s lack of political savviness. Reform interruptedIt was always clear the coalition would be short-lived. President Dodon and the co-ruling Socialists joined to buy themselves time, with the hope that they could restrict the most far-reaching reforms and tie the hands of ACUM ministers. In less than five months, however, the Sandu government initiated key reforms in the judicial system, aimed at dismantling Plahotniuc’s networks of patronage but also impacting the Socialists, who to a large degree also profited from the previous status quo.The red line came over a last-minute change in the selection process of the prosecutor general proposed by Sandu on 6 November, which the Socialists claimed was unconstitutional and gave them the justification to put forward a motion of no confidence in the Sandu government. This was conveniently supported by the Democratic Party, who appeared threatened by an independent prosecutor’s office and saw an opportunity to return to power.Thus, the political will to reform proved insufficient in the absence of a clear strategy on how to address the concerns of the old regime that they would be prosecuted and their vested interests threatened. Here, ACUM’s lack of political experience let them down. With their hands tied from the beginning in a fragile coalition with the Socialists, ACUM were unable to prevent sabotage from within state institutions and their own coalition, and could not find consensus to proceed with more radical methods to tackle corruption.Less than two days after the Sandu government was out, a new government was sworn in on 14 November. Prime Minister Ion Chicu was an adviser to President Dodon before taking office and former minister of finance under the Plahotniuc-backed government of Pavel Filip, as part of a cabinet of ministers consisting largely of other presidential advisers and former high-level bureaucrats and ministers from the Plahotniuc era. The new governmentA top priority for the Chicu government is to convince the international community that it is independent from President Dodon, and that its ‘technocrats’ will keep the course of reforms of the Sandu government. This is critical to preserving the financial assistance of Western partners, which the Moldovan government heavily relies on, particularly with a presidential election campaign next year, when they will likely want to create fiscal space for various giveaways to voters.But within its first week in office, Chicu appears incapable of walking this line. Reverting to the initially proposed pre-selection process of prosecutor general signals that the post could be filled by a loyal appointee of President Dodon. Moreover, Chicu’s first visit abroad was to Russia, allegedly a major financial contributor of the Socialists’ Party. With the Socialists now holding the presidency, government, Chisinau mayoralty, and the parliament speaker’s seat, the danger of an increased Russian influence on key political decisions is very real.A government steered by President Dodon risks bringing Moldova back to where it was before June, with a political elite mimicking reforms while misusing power for private gains. The biggest danger is that instead of continuing the reform process to bring Moldova back on its European integration path, the new government may focus on strengthening the old patronage system, this time with President Dodon at the top of the pyramid.LessonsThis new minority government, supported by the Democrats, is a more natural one for President Dodon and therefore has more chances to survive, at least until presidential elections in autumn of 2020. Both the Socialists and the Democrats will likely seek to use this time to rebuild their own methods of capturing state resources. But with the Socialists relying on the Democrats’ votes in parliament, this is a recipe for further political instability.Similar to Moldova, several other states across the post-Soviet space such as Ukraine and Armenia have had new political forces come to power with the political will and mandate to carry out difficult reforms to strengthen rule of law and fight systemic corruption in their countries. What they all have in common is the lack of political experience of how to create change, while old elites, used to thinking on their feet to defend their vested interests, retain their connections and economic and political influence.Moldova is a good example of why political will needs to be backed up by clear strategy on how to deal with threatened vested interests in order for new political forces to be able to maintain themselves in power and reforms to be sustainable. When the chance comes again for fresh leaders to come to power, it is importantthey are politically prepared to use it swiftly and wisely. Full Article
mo Moldova in 2020 and Beyond: Challenges Ahead By feedproxy.google.com Published On :: Mon, 17 Feb 2020 10:00:02 +0000 Invitation Only Research Event 5 March 2020 - 2:00pm to 3:30pm Chatham House | 10 St James's Square | London | SW1Y 4LE Event participants Maia Sandu, President, Action and Solidarity Party; Prime Minister of Moldova (June-November 2019)Chair: Cristina Gherasimov, Research Fellow, German Council on Foreign Relations; Academy Associate, Russia and Eurasia Programme, Chatham House After a tumultuous 2019 when Moldova witnessed the end of the Plahotniuc era, the country seems bound for an equally difficult year ahead. Increasing international isolation, a temporary working coalition between the Socialists and the Democrats, concentration of power and resources in the hands of President Igor Dodon, and presidential elections in autumn are among the ordeals to be discussed at this event. Ms Sandu will assess how Moldova can move beyond these challenges and return to a path for sustainable democratic reform. Department/project Russia and Eurasia Programme Anna Morgan Administrator, Ukraine Forum +44 (0)20 7389 3274 Email Full Article
mo Webinar: Russian Disinformation's Golden Moment: Challenges and Responses in the COVID-19 Era By feedproxy.google.com Published On :: Tue, 21 Apr 2020 23:55:01 +0000 Invitation Only Research Event 7 May 2020 - 3:00pm to 4:30pm Event participants Anneli Ahonen, Head, StratCom East Task Force, European External Action ServiceKeir Giles, Senior Consulting Fellow, Russia and Eurasia Programme, Chatham HouseThomas Kent, Adjunct Associate Professor, Harriman Institute, Columbia University; Senior Fellow, the Jamestown FoundationChairs:James Nixey, Programme Director, Russia and Eurasia, Chatham HouseGlen Howard, President, The Jamestown Foundation The COVID-19 pandemic provides the ideal environment for malign influence to thrive as it feeds on fear and a vacuum of authoritative information. What are the current challenges posed by Russian disinformation, and how should Western nations be responding? In this discussion, jointly hosted by the Jamestown Foundation and the Chatham House Russia and Eurasia Programme, the speakers will consider what best practice looks like in safeguarding Western societies against the pernicious effects of disinformation. This event will be held on the record. Department/project Russia and Eurasia Programme, Russia's Domestic Politics Anna Morgan Administrator, Ukraine Forum +44 (0)20 7389 3274 Email Full Article