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Phenotypic Adaption of Pseudomonas aeruginosa by Hacking Siderophores Produced by Other Microorganisms

Quentin Perraud
Apr 1, 2020; 19:589-607
Research




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Tandem Mass Tag Approach Utilizing Pervanadate BOOST Channels Delivers Deeper Quantitative Characterization of the Tyrosine Phosphoproteome

Xien Yu Chua
Apr 1, 2020; 19:730-743
Technological Innovation and Resources




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Immediate adaptation analysis implicates BCL6 as an EGFR-TKI combination therapy target in NSCLC

Yan Zhou Tran
Mar 31, 2020; 0:RA120.002036v1-mcp.RA120.002036
Research




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Characterization of signaling pathways associated with pancreatic {beta}-cell adaptive flexibility in compensation of obesity-linked diabetes in db/db mice

Taewook Kang
Apr 7, 2020; 0:RA119.001882v1-mcp.RA119.001882
Research




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Proximity Dependent Biotinylation: Key Enzymes and Adaptation to Proteomics Approaches

Payman Samavarchi-Tehrani
May 1, 2020; 19:757-773
Review




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The Smart Peace Initiative: An Integrated and Adaptive Approach to Building Peace

Invitation Only Research Event

12 May 2020 - 10:00am to 11:30am
Add to Calendar

Smart Peace brings together global expertise in conflict analysis and research, peacebuilding and mediation programming, and behavioural science and evaluation. Together, Smart Peace partners are developing integrated and adaptive peace initiatives, working with local partners to prevent and resolve complex and intractable conflicts in Central African Republic, Myanmar and northern Nigeria.
 
This roundtable is an opportunity for Smart Peace partners to share the Smart Peace concept, approach and objectives, and experiences of the first phases of programme implementation. Roundtable discussions among participants from policy, practice and research communities will inform future priorities and planning for Smart Peace learning, advocacy and communication.
 
Smart Peace partners include Conciliation Resources, Behavioural Insights Team, The Centre for Humanitarian Dialogue, Chatham House, ETH Zurich, International Crisis Group and The Asia Foundation.

Nilza Amaral

Project Manager, International Security Programme




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Tandem Mass Tag Approach Utilizing Pervanadate BOOST Channels Delivers Deeper Quantitative Characterization of the Tyrosine Phosphoproteome [Technological Innovation and Resources]

Dynamic tyrosine phosphorylation is fundamental to a myriad of cellular processes. However, the inherently low abundance of tyrosine phosphorylation in the proteome and the inefficient enrichment of phosphotyrosine(pTyr)-containing peptides has led to poor pTyr peptide identification and quantitation, critically hindering researchers' ability to elucidate signaling pathways regulated by tyrosine phosphorylation in systems where cellular material is limited. The most popular approaches to wide-scale characterization of the tyrosine phosphoproteome use pTyr enrichment with pan-specific, anti-pTyr antibodies from a large amount of starting material. Methods that decrease the amount of starting material and increase the characterization depth of the tyrosine phosphoproteome while maintaining quantitative accuracy and precision would enable the discovery of tyrosine phosphorylation networks in rarer cell populations. To achieve these goals, the BOOST (Broad-spectrum Optimization Of Selective Triggering) method leveraging the multiplexing capability of tandem mass tags (TMT) and the use of pervanadate (PV) boost channels (cells treated with the broad-spectrum tyrosine phosphatase inhibitor PV) selectively increased the relative abundance of pTyr-containing peptides. After PV boost channels facilitated selective fragmentation of pTyr-containing peptides, TMT reporter ions delivered accurate quantitation of each peptide for the experimental samples while the quantitation from PV boost channels was ignored. This method yielded up to 6.3-fold boost in pTyr quantification depth of statistically significant data derived from contrived ratios, compared with TMT without PV boost channels or intensity-based label-free (LF) quantitation while maintaining quantitative accuracy and precision, allowing quantitation of over 2300 unique pTyr peptides from only 1 mg of T cell receptor-stimulated Jurkat T cells. The BOOST strategy can potentially be applied in analyses of other post-translational modifications where treatments that broadly elevate the levels of those modifications across the proteome are available.




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Phenotypic Adaption of Pseudomonas aeruginosa by Hacking Siderophores Produced by Other Microorganisms [Research]

Bacteria secrete siderophores to access iron, a key nutrient poorly bioavailable and the source of strong competition between microorganisms in most biotopes. Many bacteria also use siderophores produced by other microorganisms (exosiderophores) in a piracy strategy. Pseudomonas aeruginosa, an opportunistic pathogen, produces two siderophores, pyoverdine and pyochelin, and is also able to use a panel of exosiderophores. We first investigated expression of the various iron-uptake pathways of P. aeruginosa in three different growth media using proteomic and RT-qPCR approaches and observed three different phenotypic patterns, indicating complex phenotypic plasticity in the expression of the various iron-uptake pathways. We then investigated the phenotypic plasticity of iron-uptake pathway expression in the presence of various exosiderophores (present individually or as a mixture) under planktonic growth conditions, as well as in an epithelial cell infection assay. In all growth conditions tested, catechol-type exosiderophores were clearly more efficient in inducing the expression of their corresponding transporters than the others, showing that bacteria opt for the use of catechol siderophores to access iron when they are present in the environment. In parallel, expression of the proteins of the pyochelin pathway was significantly repressed under most conditions tested, as well as that of proteins of the pyoverdine pathway, but to a lesser extent. There was no effect on the expression of the heme and ferrous uptake pathways. Overall, these data provide precise insights on how P. aeruginosa adjusts the expression of its various iron-uptake pathways (phenotypic plasticity and switching) to match varying levels of iron and competition.




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Proteomic Analysis of Salmonella-modified Membranes Reveals Adaptations to Macrophage Hosts [Research]

Systemic infection and proliferation of intracellular pathogens require the biogenesis of a growth-stimulating compartment. The gastrointestinal pathogen Salmonella enterica commonly forms highly dynamic and extensive tubular membrane compartments built from Salmonella-modified membranes (SMMs) in diverse host cells. Although the general mechanism involved in the formation of replication-permissive compartments of S. enterica is well researched, much less is known regarding specific adaptations to different host cell types. Using an affinity-based proteome approach, we explored the composition of SMMs in murine macrophages. The systematic characterization provides a broader landscape of host players to the maturation of Salmonella-containing compartments and reveals core host elements targeted by Salmonella in macrophages as well as epithelial cells. However, we also identified subtle host specific adaptations. Some of these observations, such as the differential involvement of the COPII system, Rab GTPases 2A, 8B, 11 and ER transport proteins Sec61 and Sec22B may explain cell line-dependent variations in the pathophysiology of Salmonella infections. In summary, our system-wide approach demonstrates a hitherto underappreciated impact of the host cell type in the formation of intracellular compartments by Salmonella.




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Proximity Dependent Biotinylation: Key Enzymes and Adaptation to Proteomics Approaches [Reviews]

The study of protein subcellular distribution, their assembly into complexes and the set of proteins with which they interact with is essential to our understanding of fundamental biological processes. Complementary to traditional assays, proximity-dependent biotinylation (PDB) approaches coupled with mass spectrometry (such as BioID or APEX) have emerged as powerful techniques to study proximal protein interactions and the subcellular proteome in the context of living cells and organisms. Since their introduction in 2012, PDB approaches have been used in an increasing number of studies and the enzymes themselves have been subjected to intensive optimization. How these enzymes have been optimized and considerations for their use in proteomics experiments are important questions. Here, we review the structural diversity and mechanisms of the two main classes of PDB enzymes: the biotin protein ligases (BioID) and the peroxidases (APEX). We describe the engineering of these enzymes for PDB and review emerging applications, including the development of PDB for coincidence detection (split-PDB). Lastly, we briefly review enzyme selection and experimental design guidelines and reflect on the labeling chemistries and their implication for data interpretation.




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ACT government defends seeking access to Canberrans' metadata

The ACT government has defended its right to seek access to Canberrans' private phone and internet records without a warrant.




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Ricochet uses power of the dark web to help journalists, sources dodge metadata laws

A new internet messaging tool that sidesteps the federal government's metadata collection regime to help journalists protect whistle blowers and assists human rights activists has received a tick of approval from security experts.




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Schnyder corneal dystrophy-associated UBIAD1 is defective in MK-4 synthesis and resists autophagy-mediated degradation

Dong-Jae Jun
May 1, 2020; 61:746-757
Research Articles




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Episode 15 - The Internet of ill Advised Man Buns (IoIAMB) Google I/O and terrible film adaptations

Host Matt Egan is joined by producer Chris to talk about the raft of announcements coming out of the Google I/O developer conference this week, including Android N, Google assistant and Allo. Techworld.com editor Charlotte Jee joins in to discuss driverless cars (17:00) following the Queen's speech this week. Finally, acting editor at Macworld.co.uk David Price talks about terrible film adaptations of video games, from Angry Birds to World of Warcraft (29:00). Don't forget to like, share and tell your friends!  


See acast.com/privacy for privacy and opt-out information.




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Immediate adaptation analysis implicates BCL6 as an EGFR-TKI combination therapy target in NSCLC [Research]

Drug resistance is a major obstacle to curative cancer therapies, and increased understanding of the molecular events contributing to resistance would enable better prediction of therapy response, as well as contribute to new targets for combination therapy. Here we have analyzed the early molecular response to epidermal growth factor receptor (EGFR) inhibition using RNA sequencing data covering 13 486 genes and mass spectrometry data covering 10 138 proteins. This analysis revealed a massive response to EGFR inhibition already within the first 24 hours, including significant regulation of hundreds of genes known to control downstream signaling, such as transcription factors, kinases, phosphatases and ubiquitin E3-ligases. Importantly, this response included upregulation of key genes in multiple oncogenic signaling pathways that promote proliferation and survival, such as ERBB3, FGFR2, JAK3 and BCL6, indicating an early adaptive response to EGFR inhibition. Using a library of more than 500 approved and experimental compounds in a combination therapy screen, we could show that several kinase inhibitors with targets including JAK3 and FGFR2 increased the response to EGFR inhibitors. Further, we investigated the functional impact of BCL6 upregulation in response to EGFR inhibition using siRNA-based silencing of BCL6. Proteomics profiling revealed that BCL6 inhibited transcription of multiple target genes including p53, resulting in reduced apoptosis which implicates BCL6 upregulation as a new EGFR inhibitor treatment escape mechanism. Finally, we demonstrate that combined treatment targeting both EGFR and BCL6 act synergistically in killing lung cancer cells. In conclusion, or data indicates that multiple different adaptive mechanisms may act in concert to blunt the cellular impact of EGFR inhibition, and we suggest BCL6 as a potential target for EGFR inhibitor-based combination therapy.




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Characterization of signaling pathways associated with pancreatic {beta}-cell adaptive flexibility in compensation of obesity-linked diabetes in db/db mice [Research]

The onset of obesity-linked type 2 diabetes (T2D) is marked by an eventual failure in pancreatic β-cell function and mass that is no longer able to compensate for the inherent insulin resistance and increased metabolic load intrinsic to obesity. However, in a commonly used model of T2D, the db/db mouse, β-cells have an inbuilt adaptive flexibility enabling them to effectively adjust insulin production rates relative to the metabolic demand. Pancreatic β-cells from these animals have markedly reduced intracellular insulin stores, yet high rates of (pro)insulin secretion, together with a substantial increase in proinsulin biosynthesis highlighted by expanded rough endoplasmic reticulum and Golgi apparatus. However, when the metabolic overload and/or hyperglycemia is normalized, β-cells from db/db mice quickly restore their insulin stores and normalize secretory function. This demonstrates the β-cell’s adaptive flexibility and indicates that therapeutic approaches applied to encourage β-cell rest are capable of restoring endogenous β-cell function. However, mechanisms that regulate β-cell adaptive flexibility are essentially unknown. To gain deeper mechanistic insight into the molecular events underlying β-cell adaptive flexibility in db/db β-cells, we conducted a combined proteomic and post-translational modification specific proteomic (PTMomics) approach on islets from db/db mice and wild-type controls (WT) with or without prior exposure to normal glucose levels. We identified differential modifications of proteins involved in redox homeostasis, protein refolding, K48-linked deubiquitination, mRNA/protein export, focal adhesion, ERK1/2 signaling, and renin-angiotensin-aldosterone signaling, as well as sialyltransferase activity, associated with β-cell adaptive flexibility. These proteins are all related to proinsulin biosynthesis and processing, maturation of insulin secretory granules, and vesicular trafficking—core pathways involved in the adaptation of insulin production to meet metabolic demand. Collectively, this study outlines a novel and comprehensive global PTMome signaling map that highlights important molecular mechanisms related to the adaptive flexibility of β-cell function, providing improved insight into disease pathogenesis of T2D.




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Schnyder corneal dystrophy-associated UBIAD1 is defective in MK-4 synthesis and resists autophagy-mediated degradation [Research Articles]

The autosomal dominant disorder Schnyder corneal dystrophy (SCD) is caused by mutations in UbiA prenyltransferase domain-containing protein-1 (UBIAD1), which uses geranylgeranyl pyrophosphate (GGpp) to synthesize the vitamin K2 subtype menaquinone-4 (MK-4). SCD is characterized by opacification of the cornea, owing to aberrant build-up of cholesterol in the tissue. We previously discovered that sterols stimulate association of UBIAD1 with ER-localized HMG-CoA reductase, which catalyzes a rate-limiting step in the synthesis of cholesterol and nonsterol isoprenoids, including GGpp. Binding to UBIAD1 inhibits sterol-accelerated ER-associated degradation (ERAD) of reductase and permits continued synthesis of GGpp in cholesterol-replete cells. GGpp disrupts UBIAD1-reductase binding and thereby allows for maximal ERAD of reductase as well as ER-to-Golgi translocation of UBIAD1. SCD-associated UBIAD1 is refractory to GGpp-mediated dissociation from reductase and remains sequestered in the ER to inhibit ERAD. Here, we report development of a biochemical assay for UBIAD1-mediated synthesis of MK-4 in isolated membranes and intact cells. Using this assay, we compared enzymatic activity of WT UBIAD1 with that of SCD-associated variants. Our studies revealed that SCD-associated UBIAD1 exhibited reduced MK-4 synthetic activity, which may result from its reduced affinity for GGpp. Sequestration in the ER protects SCD-associated UBIAD1 from autophagy and allows intracellular accumulation of the mutant protein, which amplifies the inhibitory effect on reductase ERAD. These findings have important implications not only for the understanding of SCD etiology but also for the efficacy of cholesterol-lowering statin therapy, which becomes limited, in part, because of UBIAD1-mediated inhibition of reductase ERAD.




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Problem Notes for SAS®9 - 65900: Registering an Oracle table to the metadata might fail and generate an error

When you register an Oracle table to the metadata, it might fail and generate an error similar to the following: "ERROR: An exception has been encountered...ERROR: Read Access Violation METALIB..."




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Problem Notes for SAS®9 - 65834: PROC METADATA returns various errors when the input contains certain multi-byte characters

The METADATA procedure might return an error similar to one of the following:

  • ERROR: Missing root element definition.
  • Full Article


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    Problem Notes for SAS®9 - 65031: Grid options set mappings are returned based on which option set is the first in the metadata search chain

    When users are defined in multiple groups associated with grid options set mappings, the first grid option set that is returned by the metadata search chain takes precedence. Only one grid options set mapping is used




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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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    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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    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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    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]

    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.




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    A kinesin adapter directly mediates dendritic mRNA localization during neural development in mice [Neurobiology]

    Motor protein-based active transport is essential for mRNA localization and local translation in animal cells, yet how mRNA granules interact with motor proteins remains poorly understood. Using an unbiased yeast two–hybrid screen for interactions between murine RNA-binding proteins (RBPs) and motor proteins, here we identified protein interaction with APP tail-1 (PAT1) as a potential direct adapter between zipcode-binding protein 1 (ZBP1, a β-actin RBP) and the kinesin-I motor complex. The amino acid sequence of mouse PAT1 is similar to that of the kinesin light chain (KLC), and we found that PAT1 binds to KLC directly. Studying PAT1 in mouse primary hippocampal neuronal cultures from both sexes and using structured illumination microscopic imaging of these neurons, we observed that brain-derived neurotrophic factor (BDNF) enhances co-localization of dendritic ZBP1 and PAT1 within granules that also contain kinesin-I. PAT1 is essential for BDNF-stimulated neuronal growth cone development and dendritic protrusion formation, and we noted that ZBP1 and PAT1 co-locate along with β-actin mRNA in actively transported granules in living neurons. Acute disruption of the PAT1–ZBP1 interaction in neurons with PAT1 siRNA or a dominant-negative ZBP1 construct diminished localization of β-actin mRNA but not of Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα) mRNA in dendrites. The aberrant β-actin mRNA localization resulted in abnormal dendritic protrusions and growth cone dynamics. These results suggest a critical role for PAT1 in BDNF-induced β-actin mRNA transport during postnatal development and reveal a new molecular mechanism for mRNA localization in vertebrates.




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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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    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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    Adapt or Die: The Need for Orders to Evolve

    12 June 2019

    Adam Ward

    Former Deputy Director, Chatham House
    Historically, efforts to build rules-based international orders have emerged out of conflict, only for each system to falter when a new crisis emerges. At issue today, with the post-1945 multilateral system under strain, is how to modernize the making and application of rules to break that cycle.

    2019-06-07-UN-protest.jpg

    School children hold a placard reading "CHANGE" during the Youth Climate Strike May 24, 2019 outside United Nations headquarters in New York City. Photo by Johannes EISELE/AFP/Getty Images.

    The most vexing, complicated and elusive question in international relations is how to achieve an order, based on rules, that enjoys legitimacy, rewards investments in cooperation, reconciles clashing interests and deters conflict. It is not a problem over which a magic wand can be waved. But in our own time, immense and patient efforts have been made towards that general goal, however imperfect the result.

    The concept of the ‘rules-based international order’ refers today in its most general sense to arrangements put into place to allow for cooperative efforts in addressing geopolitical, economic and other global challenges, and to arbitrate disputes. It is embodied in a variety of multilateral institutions, starting with the United Nations and running through various functional architectures such as the Bretton Woods system, the corpus of international law and other regimes and treaties, down to various regional instances where sovereignty is pooled or where powers have been delegated consensually by states on a particular issue.

    Some aspects of the rules-based order are heavily informed by distinct values, such as those contained in the Universal Declaration of Human Rights. But, more often than not, they simply prescribe a set of basic principles for how the business of international political and economic relations is to be transacted. The parameters of legitimate and illegitimate behaviour are specified. Compliance is incentivized, and some scope to sanction transgressors is provided for.

    For some, the rules-based international order is a politically highly charged concept. Indeed, the absence of a common standardized definition of it is perhaps a by-product of the controversy which the mere notion of a rules-based order often attracts – among those who had no or little part in its shaping; those who regard multilateralism as an infringement of sovereignty and a straitjacket on national ambitions; and those who sense in it a presumption of universal values and shared interests that jars with their own particular historical experience and political preferences. And in a world in which each country occupies its own place on the spectrum of attraction to, tolerance of and resistance to multilateralism, it is inevitable that the present system should be a patchy and incomplete one.

    If that patchiness seems increasingly apparent today, then this reflects the proliferation of problems on a truly global scale that multilateral initiatives have as yet failed to keep up with. This is partly because of the sheer pace of change and the deep complexity of problems, and partly because any significant programme of coordinated action requires a focus and consensus that today is in shrinking supply.

    More than that, some of the sharpest challenges – climate change; the lack or weakness of rules in the sea, space and cyber domains; the dilemmas thrown up by technological change – are problematic precisely because they are areas in and through which geopolitical competitions are being contested. The policy challenges may be new, but the pattern of behaviour currently surrounding them presents some dangerous echoes from the past.

    Throughout history, most attempts to form international orders have been conceived in a coercive way. From classical antiquity to the 20th century, the dominant form of order has been that imposed or attempted by successive territorial empires, or by predominant powers who made the rules by fiat and were deferred to by their neighbours and satellites.

    Significant attempts at more collaborative conceptions of order, aimed at coexistence and minimizing risk through rules and accepted conventions, have been far rarer. And the key point about them is that they have been attempted only after competition has spilled over in an uncontrolled, exhausting and ruinous conflict that has called for mechanisms and understandings to prevent a recurrence of disaster. That, in any case, has been the European experience, and subsequently the result of the engulfing crises that radiated out globally from Europe in the 20th century.

    Early efforts at order-building focused on mutual recognition and the management of what were felt to be inevitable rivalries. The Westphalian Peace of 1648 emerged from a 30-year period of religious war in Europe. It emphasized the sanctity of sovereignty and non-interference in the internal affairs of other states as a precondition for order, but relied on a jostling balance-of-power approach to the preservation of a basic stability.

    A tolerance of conflicts to correct imbalances was implicit to the scheme. But its acute sensitivity to shifts in alignments of power contributed to the later conflicts – from the wars of the Spanish Succession and Austrian Succession to the Seven Years’ War – that ravaged Europe in the 18th century and occurred in an increasingly global theatre of military operations, tracing the development of European imperial projects.

    Despite these shortcomings, the balance-of-power model was produced again as a remedy to uncontrolled conflict, at the Congress of Vienna in 1814–15, following more than 20 years of French Revolutionary and Napoleonic wars. A Concert of Europe, accommodating a rehabilitated France, was instituted to regulate the system and periodically decide major geopolitical issues. But it fell into disuse. And although Europe did not suffer a general war for the rest of the 19th century, the salient geopolitical facts were ones not of power balances but of the sharp relative decline of France and the vertiginous rise of Prussia, which defeated Austria and France on the path to German unification.

    These dynamics produced convoluted and ever-widening balancing manoeuvres that by the eve of the First World War in 1914 had congealed and hardened into the opposing Triple Alliance and Triple Entente systems, which trapped their respective members into tangled commitments to fight at the trigger of a crisis.

    The peacemaking efforts, in Paris in 1919, that followed the war entailed conscious efforts to overturn the balance-of-power model. The tone was set by US President Woodrow Wilson’s Fourteen Points, with their emphasis on transparency and openness, while the concepts of egalitarianism among states, the drive towards disarmament and the practice of collective security were central to the revolutionary creation of a League of Nations in 1920.

    But the peacemaking also included a punitive dimension – the designation of German culpability, the demand of economic reparations and territorial adjustments – imposed by victor on vanquished. To its critics, the international order being evolved, and the rules drafted to underpin it, had the attributes of an involuntary settlement more than those of a construct built by equals.

    Lacking a comprehensive membership – crucially, the US had demurred, while other major powers progressively withdrew or were thrown out – and the military means to impose itself, a divided and often circumspect League faltered in meeting a succession of international crises. It then collided fatally with the revanchism of Germany, Italy and Japan that produced the Second World War.

    The ambitiousness and eventual institutional intricacy of the UN system founded in 1945 marked a response to the scale of the ordeal through which the world had passed, and sought to correct the deficits of the League. The UN’s membership and the activity of its main organs and specialized agencies all grew prodigiously in succeeding decades, as did its efforts to advance the spirit and culture of multilateralism.

    But by giving special privileges to the victors, principally through veto rights held among a small group of permanent Security Council members, the UN reflected and perpetuated a certain historical circumstance: there was no formal institutional adaptation in its highest structures to account for a progressive redistribution of international power, the rehabilitation of defeated countries, the rise of the decolonized world or the desire of emerging powers to assume international responsibilities commensurate with their heft. Rather than a mechanism for international governance, it remained an intergovernmental body through which states pursued their specific or collective priorities.

    Indeed, the dominant questions around order in the first five decades of the UN’s existence were those posed by the Cold War conducted by the US and the Soviet Union and their respective allies and satellites, while the UN in effect was a prominent arena in which this global antagonism was carried out.

    The world order was bipolar in concentrating power in two camps, with a swath of neutrals, non-aligned and swing players in between; and bi-systemic in the complete contrast in the ideological affinities and economic models that were promoted. Nuclear weapons raised the stakes associated with direct conflict to an existential level, and so pushed armed contests to peripheral theatres or on to skirmishing proxies.

    The collapse of communism in the early 1990s ushered in a new dispensation. Those who divined the arrival of a ‘unipolar moment’ for the US were perhaps more accurate in their choice of epithet than they knew. At least on the surface, the US became by far the preponderant power. The decline and 1991 dissolution of the Soviet Union, in consequence of its economic decrepitude and strategic overstretch, not only removed the US’s peer competitor, but also opened up avenues for promoting economic liberalization and democratic government.

    This shift was manifest in particular in changing dynamics in Europe. The US had sponsored the reunification of Germany and was a patron of its subsequent embedding in an integrating, democratic and liberal region. Over time, this drew the former Warsaw Pact members into EU and NATO structures (albeit at a pace and with a completeness that Russia’s strategic calculations could not be accommodated to).

    And yet, despite these advances, in retrospect the chief development of the 20 years after the Cold War was a different one: globalization had at a gathering pace prompted a redistribution of political power, while its interlocking economic structures created a dense web of interests and dependencies that moved in all directions. It was likely in these circumstances that the appearance of any major emergency would produce insistent voices demanding what they saw as a more inclusive, legitimate and effective form of international order.

    Crises duly arrived, first in the shape of the 2003 US-led invasion of Iraq, which strained alliances and stirred controversial debates about the justice and permissibility of military interventions and the need for constraints on US power; and then in the form of the financial meltdown of 2008, seen by many as a principally Western debacle calling for new global economic governance structures as instanced in the improvised G20. Neither set of debates was conclusively resolved, but each persisted against the backdrop of quickening systemic change.

    The dilemmas about the shape and maintenance of a rules-based order with multilateralism at its core have since only deepened. The world is pulling in different directions. The ‘America First’ posture of the Trump administration has upturned the central feature of the system. It entails a distaste for multilateral agreements, a disavowal of traditional notions of US leadership, and an insistence on the unimpeded exercise of American power in pursuit of defined national interests.

    China asserts the centrality of multilateralism, and practises it selectively, but on the whole favours binary diplomatic transactions where it holds asymmetric advantages; it has used this approach in the construction of its Belt and Road Initiative, as well as on other fronts.

    Europe has created in its continent a rules-based order par excellence in the shape of the EU, but its energy has been sapped and its introversion fed by a succession of crises, of which the amputation of the Brexit-bound UK is simply one. The EU has yet to chart its future course or define a global strategy to uphold and advance the multilateralism which has been at its core.

    Russia unabashedly is subverting the rules-based order as part of a programme of aggrieved self-aggrandizement. Japan champions the principle of a rules-based system, but the country has been disoriented by its abrupt detachment on this issue from its traditional US partner; while Japan has sought to engage like-minded countries in the West, they have not forged a concerted practical plan of action together.

    Among other regional powers, Brazil has a populist government that echoes many of the Trump administration’s instincts, and India, whatever its preferences, has yet to acquire a foreign policy or presence on the global stage equal to its demographic weight and economic potential.

    Prominent points of risk in this fragmenting picture are the multilateral trade system, efforts to address climate change, and collective measures to deal with entrenched conflicts.

    One obvious consequence of the attrition of the rules-based system through the indifference or ambitions of the great powers is that it will leave smaller states much more exposed and hostage to the vagaries of geopolitical competition. A key question therefore is whether such states will choose and be able to defend a system which gives them a measure of protection.

    Over recent decades, a variety of regional groupings – ASEAN, the African Union, the Gulf Cooperation Council, the Organization of American States – have evolved as species of rules-based mechanisms and in order to gather their collective weight. They make a ready constituency for those who would build a coalition for multilateralism. But it is also clear that the support of smaller regional players for such an approach depends on a revision of the rule-making system towards greater inclusivity and a broader say as to the issues it should address.

    It is in the context of these trends and structural shifts that Chatham House Expert Perspectives 2019 offers ideas for how to modernize and adapt elements of the rules-based international order. As the title of this opening essay indicates, the imperative to ‘adapt’ reflects the gravity of contemporary challenges, and the inability of many existing structures to underpin ever-more-essential cooperation. Chatham House experts do not offer a master plan, but they attack the problem from a variety of indicative angles.

    Suggestions are offered as to where gaps in international rules – regarding economic governance, the global health architecture and in respect of under-regulated domains such as space, for example – need to be filled to address immediate problems and advertise the relevance of multilateralism.

    Other ideas demonstrate how logjams affecting some aspects of the system can be worked around; how key powers with scope to shape the system should be engaged; how a broader variety of actors beyond national governments need to be drawn into the effort; how rule-breakers might be tackled; and how imposing order on some chaotic situations requires the fundamental premises of existing policies to be rethought.

    Chatham House, which celebrates its centenary in 2020, is a child of efforts after the Great War to reconceive the conduct of international relations and fulfil a mission that is today defined as the creation of a ‘sustainably secure, prosperous and just world’. The historical record shows that international orders not built on these attributes will fail.

    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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    MEIZITANG OBAT PELANGSING BADAN HERBAL ALAMI - Rahasia Pria

    Meizitang Obat Pelangsing Badan Herbal Merupakan Suplemen Diet Herbal Berbentuk SOFTGEL Yang Sangat Berkhasiat Melangsingkan Tubuh Dengan Cepat Dan Aman,



    • Sports and Health

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    OBAT PELANGSING BADAN HERBAL FATLOSS DIET ALAMI - Rahasia Pria

    Obat Pelangsing Badan Herbal Fatloss Jimpness Beauty Penghilang Lemak Seketika Merupakan Obat Pelangsing Badan Yang Aman Dikonsumsi Untuk Pria Maupun Wanita



    • Sports and Health

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    Pelangsing Badan Herbal Lida Obat Diet Alami - Rahasia Pria

    Pelangsing Badan Herbal Lida Daidaihua Adalah Pelangsing Badan Yang Mengandung Bahan Herbal Yang Sangat Cepat Menurunkan Berat Badan, Aman Dan Cepat .



    • Sports and Health

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    Krim Pelangsing Badan Alami Geen Tea - Rahasia Pria

    Krim Pelangsing Badan Alami Green Tea adalah pelangsing herbal berbentuk krim berguna untuk melangsingkan dan mempercepat pembakaran lemak perut, lengan dl



    • Sports and Health

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    Trudeau Election Marks New Start for Canada

    22 October 2015

    Cleo Paskal

    Associate Fellow, Energy, Environment and Resources Programme and Asia-Pacific Programme
    Canada's partners are about to see a sea change in policy from the new Liberal government on a range of issues, especially relating to energy and the environment.

    20151022Trudeau.jpg

    Canadian Liberal Party leader Justin Trudeau arrives to give a press conference in Ottawa on 20 October 2015. Photo by Getty Images.

    The Liberal Party likes to think of itself as ‘Canada’s natural governing party’. Though they have been out of power for 10 years, and newly elected prime minister Justin Trudeau is relatively inexperienced, the party has deep and old networks across the country. The backroom is full of experienced old hands, including former prime ministers who have known Trudeau since he was a toddler. With a number of bold shifts promised in Canadian foreign policy, and a willingness to be fiscally expansive (Trudeau has said he is willing to run deficits for three years to implement their policies), the change is likely to be dramatic, fast and unrelenting.

    International engagement

    The Liberals’ proposed new Canada has a hint of nostalgia for a time when Canadians thought of themselves as a force for good in the world. There is likely to be a large-scale reengagement with the international community, especially the United Nations, not only on climate policy, but also peacekeeping and disaster response. Canada’s French-speaking experts make it well placed to engage in crisis-hit French-speaking countries while carrying somewhat less colonial baggage. Meanwhile, the Liberals have promised to withdraw Canadian forces from the combat mission against ISIS in Iraq, pledging instead to reorient their focus towards aid.

    Science-based policies

    Trudeau has the backing of a very deep bench of experienced parliamentarians, some of whom have been waiting a long time to get back in the governing game. They include Stéphane Dion, the former environment minister who gained respect for his chairing of the 2005 UN climate change conference in Montreal, and Marc Garneau, former astronaut and president of the Canadian Space Agency. This will be a government that understands and values (and has promised to restore funding for) scientific research.

    This means more investment in climate resilience, renewables and other forward planning policies, but also a reexamination of some of Canada’s long-standing strengths, including Canada’s fisheries. Under the previous government, over half-a-dozen critical fisheries research libraries were shut down, in some cases with large-scale loss of data. A more science-based fisheries policy, combined with the promised funding to the Royal Canadian Navy, may result in a reinvigorated and coordinated Canadian fisheries policy. This would become particularly important in a time of global food constraints.

    ‘Nation-to-nation’

    Trudeau’s stated goal of establishing ‘nation-to-nation’ relations with Canada’s indigenous peoples has potentially global implications.

    Through treaties, Canada’s First Nations can stake a claim to about a third of Canada’s landmass, including resource rich areas. They own or control access to land that contains oil, gas, uranium, gold, diamonds and much more. China, for one, realized the potential power of First Nations as far back as 2008, when Beijing invited over two dozen indigenous leaders to China to talk business. During that trip, Peguis Chief Glenn Hudson explained that the trip was ‘an important step for us in moving forward. Our future is not only in Canada, but partnering with other countries.’

    Trudeau’s ‘nation-to-nation’ statement acknowledges the strengthening role of First Nations in Canada’s resource policy. Indigenous communities have been among the most adversely affected by oil sands development and, in other parts of Canada, have successfully blocked resources extraction or transit. For example, in May, the Lax Kw'alaams Band refused to allow a proposed multi-million dollar Petronas LNG project to be developed on their land over concerns it would affect their economically and culturally important salmon runs.

    Real First Nations engagement with resource management has the potential substantially change Canada’s energy, environment and resources profile. First Nations in eastern Canada have already blocked hydro development that could power much of the northeastern United States and, in a time of pipeline expansion, First Nations might become instrumental in deciding if more pipelines will run north-to-south, towards the border with the United States, or east-to-west, towards the Pacific and the markets in Asia.

    Energy sector

    At the same time, while Trudeau said he was against the Northern Gateway pipeline, in large part because of how it would affect the people of the Pacific coast, he backed Keystone XL. However, he is unlikely to push for it in the face of a veto by President Obama. Also, low fossil fuel prices contributed to the election in May of a left-leaning provincial government in the badly hit oil heartland of Alberta. If prices stay low, that could very well combine with Liberal campaign promises to put a coordinated national price on carbon and to phase out fossil fuel subsidies, additionally reshaping Canada’s energy landscape..

    Agriculture and the Trans-Pacific Partnership

    The Liberals also have a stated goal of investing in a more innovative and safe agricultural sector, while defending the interests of Canadian farmers. This dovetails with their promise to openly examine and discuss the Trans-Pacific Partnership (TPP) before ratification. Canadian dairy farmers in particular were concerned about some of the TPP provisions but, without access to the details of the text, it was difficult to estimate how the sector would be affected.

    One proposed agricultural policy that may have widespread economic implications is the legalization, regulation and taxation of marijuana. As some states in the United States have found, this has the potential to be economically beneficial and, for Canada, a possible major boon to cross-border tourism.

    In a myriad of small ways, and a few big ones, the new Liberal government plans to change Canada’s international role and domestic landscape. This is one to watch.

    To comment on this article, please contact Chatham House Feedback 




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    Lamin C Counteracts Glucose Intolerance in Aging, Obesity, and Diabetes Through {beta}-Cell Adaptation

    Aging-dependent changes in tissue function are associated with the development of metabolic diseases. However, the molecular connections linking aging, obesity, and diabetes remain unclear. Lamin A, lamin C, and progerin, products of the Lmna gene, have antagonistic functions on energy metabolism and life span. Lamin C, albeit promoting obesity, increases life span, suggesting that this isoform is crucial for maintaining healthy conditions under metabolic stresses. Because β-cell loss during obesity or aging leads to diabetes, we investigated the contribution of lamin C to β-cell function in physiopathological conditions. We demonstrate that aged lamin C only–expressing mice (LmnaLCS/LCS) become obese but remain glucose tolerant due to adaptive mechanisms including increased β-cell mass and insulin secretion. Triggering diabetes in young mice revealed that LmnaLCS/LCS animals normalize their fasting glycemia by both increasing insulin secretion and regenerating β-cells. Genome-wide analyses combined to functional analyses revealed an increase of mitochondrial biogenesis and global translational rate in LmnaLCS/LCS islets, two major processes involved in insulin secretion. Altogether, our results demonstrate for the first time that the sole expression of lamin C protects from glucose intolerance through a β-cell–adaptive transcriptional program during metabolic stresses, highlighting Lmna gene processing as a new therapeutic target for diabetes treatment.




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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

    Approximately 10% of patients with type 2 diabetes suffer from latent autoimmune diabetes in adults (LADA). This study provides a systematic assessment of the pathology of the endocrine pancreas of patients with LADA and for comparison in a first rat model mimicking the characteristics of patients with LADA. Islets in human and rat pancreases were analyzed by immunohistochemistry for immune cell infiltrate composition, by in situ RT-PCR and quantitative real-time PCR of laser microdissected islets for gene expression of proinflammatory cytokines, the proliferation marker proliferating cell nuclear antigen (PCNA), the anti-inflammatory cytokine interleukin (IL) 10, and the apoptosis markers caspase 3 and TUNEL as well as insulin. Human and rat LADA pancreases showed differences in areas of the pancreas with respect to immune cell infiltration and a changed ratio between the number of macrophages and CD8 T cells toward macrophages in the islet infiltrate. Gene expression analyses revealed a changed ratio due to an increase of IL-1β and a decrease of tumor necrosis factor-α. IL-10, PCNA, and insulin expression were increased in the LADA situation, whereas caspase 3 gene expression was reduced. The analyses into the underlying pathology in human as well as rat LADA pancreases provided identical results, allowing the conclusion that LADA is a milder form of autoimmune diabetes in patients of an advanced age.




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    Nadal asks Djokovic to consider vaccines

    MADRID, Spain (AP): Rafael Nadal says Novak Djokovic will need to be vaccinated to keep playing if the governing bodies of tennis make coronavirus shots obligatory once they become available. Nadal told the Spanish newspaper La Voz de Galicia this...




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    A maladaptive pathway to drug approval

    The European Medicines Agency (EMA) has embraced a new model of drug testing and marketing called “adaptive pathways”, allowing new drugs for “unmet medical needs” to be launched on the market faster, on the basis of fewer data. While industry claims this is necessary, an analysis on thebmj.com looks at the assumptions underlying the new pathway,...




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    Big Metadata

    We’re in an era of big data - and hospitals and GPs are generating an inordinate amount of it that has potential to improve everyone’s health. But only if it’s used properly. New research published on www.bmj.com this week describes another set of information, about that data, that the authors believe could be just as important as the data...




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    How Qatar’s Food System Has Adapted to the Blockade

    14 November 2019

    Laura Wellesley

    Research Fellow, Energy, Environment and Resources Programme
    Two-and-a-half years on from the imposition of a trade blockade against Qatar by the Arab Quartet, Qatar’s food system has undergone a remarkable transformation – but it is one that brings new risks to Qatar’s future food and resource security.

    2019-11-14-QatarCows.jpg

    Cows are are fed at a dairy factory at Baladna farm in al-Khor, Qatar. Photo: Karim Jaafar/AFP via Getty Images.

    Earlier this month, Sheikh Tamim – the emir of Qatar – hailed the country’s success in overcoming the impacts of the embargo levied by the so-called Arab Quartet – Bahrain, Egypt, Saudi Arabia and the United Arab Emirates (UAE). Qatar will post a budget surplus for the first time in three years, and the country’s long-term plan for economic diversification has taken great strides, according to the emir. Key among the achievements cited was the advancement of Qatar’s domestic food industry.

    When the blockade was introduced in June 2017, it threw the vulnerability of Qatar’s domestic food supply to outside interruption into sharp relief. Qatar is poorly suited to growing food. The desert country ranks as the most water-stressed in the world. As one of the hottest, most arid countries in the world, trade is critical to feeding the nation; over 90 per cent of its food supply is imported.

    Most of Qatar’s cereal imports – including 80 per cent of its wheat supply – arrive by sea from exporters including India, Russia and Australia. Sitting on the eastern edge of the Persian Gulf, Qatar’s only maritime gateway to the world is the Strait of Hormuz. This narrow body of water can, as events this summer have shown, be disrupted by geopolitical events. But for 40 per cent of overall food imports, overland trade from Saudi Arabia was Qatar’s primary supply channel before June 2017 – particularly so for dairy products and fresh fruit and vegetables coming from the EU, Turkey and Jordan.

    The abrupt closure of Saudi Arabia’s borders prompted significant private investment in Qatar’s own food industry; domestic production has reportedly increased four-fold since the blockade was introduced. Prior to the blockade, Qatar imported 85 per cent of its vegetables; it now hopes to produce 60 per cent within the next three years. Perhaps even more remarkably, the country is now self-sufficient in dairy, having previously relied on imports for 72 per cent of its supply.

    This progress has come at a cost. Qatar’s booming domestic industry is highly resource-intensive. To fill the gap in the dairy sector, Baladna – the country’s principal dairy producer – imported around 18,000 Holstein dairy cows from the EU and US. The company is thriving; in June of this year, it made its first dairy exports.

    But the desert is not a natural environment for these cows; they must be kept indoors, at temperatures around 15°C cooler than the outside air, and misted with water to prevent overheating. The cooling systems are a huge drain on local resources. Each dairy cow requires an average of 185 gallons of water a day, almost twice the volume used by the average Qatari household. The majority of this water comes from oil- or gas-powered desalination plants; the cooling systems themselves run on gas-fired electricity.

    Qatar has traditionally invested in production overseas – particularly in Sudan and Tanzania – to secure its fodder supply, but the government has plans to become self-sufficient in fodder crops such as lucerne (alfalfa) and Rhodes grass. This will require irrigation on a vast scale. Qatar’s farmland is mostly located in the north of the country where it benefits from aquifers; fodder production already accounts for half of the groundwater extracted for use in agriculture.

    Despite commitments made under the National Food Security Programme to improving the water efficiency of Qatar’s food production, the rate of draw-down of these aquifers exceeds their recharge rates. Overexploitation has resulted in saline intrusion, threatening their long-term viability. With 92 per cent of all extracted groundwater given to farmers free of charge, there is little incentive for economizing on its use.

    Increasing production will also likely mean increasing fertilizer use; rates of fertilizer use in Qatar are among the highest in the world, second only to those in Singapore.

    Both government and industry are taking small steps to ‘green’ the country’s food production. Certain local authorities plan to ban the use of groundwater for fodder production by 2025, requiring producers to use treated sewage water instead and reserving the use of groundwater for crop production.

    A number of companies are also adopting so-called ‘circular’ practices to achieve more efficienct resource use; Agrico, a major vegetable producer, has expanded its organic hydroponics operations, a move the company reports has led to a 90 per cent reduction in water use. But, with a target to produce up to 50 per cent of Qatar’s fresh food supply domestically within just a few years, scattered examples of resource-saving strategies will not be enough to mitigate the rise in water demand.

    As Qatar looks to continue growing its food industry in the wake of the blockade, it is from Saudi Arabia – ironic though it may be – that Qatar stands to learn important lessons.

    Saudi Arabia’s scaling up of domestic wheat production – initially to achieve self-sufficiency and then to support a prosperous export industry – was ultimately a failed effort. The unsustainable extraction of groundwater – fuelled by generous subsidies for wheat producers and the nominal cost of diesel for pumping – brought the country’s water table to the brink of collapse, and the government was forced to make a dramatic U-turn, reducing then removing the subsidies and shrinking its wheat sector.

    The UAE also provides an instructive example for how domestic food production may be supported – this time positive. This summer, the Department of Environment in Abu Dhabi announced its Recycled Water Policy, laying out a policy framework to promote and facilitate reused water across all major sectors, including agriculture.

    Back in 2014, the Ministry of Climate Change and Environment set hydroponics as a key priority, launching a 100 million Emirati dirham fund to incentivize and support farmers establishing hydroponic farms. And the International Center for Biosaline Agriculture, based in Dubai and supported by the UAE government, undertakes pioneering research into sustainable food production in saline environments.

    On the face of it, Qatar has indeed bounced back from the blockade. As and when cross-border trade is re-established with Saudi Arabia, Qatar will boast a more diverse – and more resilient – network of trade relationships than it did prior to June 2017.

    In addition to investment in domestic food production, the blockade also provoked a rapid recalibration of Qatar’s trade relationships. Allies in the region – most notably Turkey and Iran – were quick to come to Qatar’s assistance, delivering fresh produce by air. Since then, Qatar has scaled up its trading relationship with both countries.

    It has also leveraged its position as the world’s largest exporter of liquid natural gas to establish new maritime trade lines with major food exporters, including India. Should tensions spike again in the future, it will be in a stronger position to weather the storm.

    But, in the absence of a commitment to support the widespread adoption of circular agricultural technologies and practices, Qatar’s commitment to increasing its self-sufficiency and expanding its domestic production could ultimately undermine its long-term food security.

    Rising average temperatures and increasingly frequent extreme weather events – like the heatwave in 2010 when temperatures soared to over 50°C – will exacerbate already high resource stress in the country. Unsustainable exploitation of finite land, water and energy reserves will limit the country’s long-term capacity to produce food and weaken its ability to withstand future disruptions to regional and international supply channels.

    As Qatar continues in its efforts to secure a reliable food supply, it would do well to heed the experience of its neighbours, be they friend or foe.




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    The New Reality: Germany Adapts to Its Role as a Major Migrant Magnet

    Although long one of the world's top migrant destinations, only in the recent past has Germany come to acknowledge and adjust to its role as a country of immigration. Its welcoming approach—a relatively new development—has been put to the test amid massive humanitarian inflows beginning in 2015. This country profile examines Germany's history on immigration and highlights current and emerging debates.




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    Changing U.S. Policy and Safe-Third Country “Loophole” Drive Irregular Migration to Canada

    Nearly 50,000 asylum seekers have entered Canada irregularly via land crossing from the United States since spring 2017—contributing to a doubling in the overall number of asylum requests seen in 2016. Based on interviews with asylum claimants, this article analyzes their motivations for making the journey and the political implications of rising irregular migration to Canada.




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    Human Rights, Climate Change, Environmental Degradation and Migration: A New Paradigm

    Discussion at launch of this MPI-IOM Issue in Brief, Human Rights, Climate Change, Environmental Degradation and Migration: A New Paradigm, which focuses on the vulnerability of environmental migrants and how the international legal framework can better ensure their protection, particularly in the Asia-Pacific region.




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    Human Rights, Climate Change, Environmental Degradation and Migration: A New Paradigm

    This issue brief addresses the rights of migrants whose movement is induced by environmental degradation or climate change, particularly in the highly vulnerable Asia-Pacific region. The brief evaluates the current international legal framework, identifies gaps in the framework and its implementation, and reviews options available to the international community.




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    Human Rights, Climate Change, Environmental Degradation and Migration: A New Paradigm

    This MPI event, in partnership with the International Organization for Migration (IOM), discusses the critical issue of climate-related displacement in the Asia-Pacific region, focusing on the vulnerability of environmental migrants and how the international legal framework can better ensure their protection.




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    Watch: Large flock of migrating birds shows up on Florida weather radar

    A Florida TV station's weather radar detected a large mass between the state and Cuba that turned out to be something other than an unseasonable storm -- it was a flock of migrating birds.




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    2019 Update to: Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

    John B. Buse
    Feb 1, 2020; 43:487-493
    Consensus Report Update




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    Genetic Discrimination Between LADA and Childhood-Onset Type 1 Diabetes Within the MHC

    OBJECTIVE

    The MHC region harbors the strongest loci for latent autoimmune diabetes in adults (LADA); however, the strength of association is likely attenuated compared with that for childhood-onset type 1 diabetes. In this study, we recapitulate independent effects in the MHC class I region in a population with type 1 diabetes and then determine whether such conditioning in LADA yields potential genetic discriminators between the two subtypes within this region.

    RESEARCH DESIGN AND METHODS

    Chromosome 6 was imputed using SNP2HLA, with conditional analysis performed in type 1 diabetes case subjects (n = 1,985) and control subjects (n = 2,219). The same approach was applied to a LADA cohort (n = 1,428) using population-based control subjects (n = 2,850) and in a separate replication cohort (656 type 1 diabetes case, 823 LADA case, and 3,218 control subjects).

    RESULTS

    The strongest associations in the MHC class II region (rs3957146, β [SE] = 1.44 [0.05]), as well as the independent effect of MHC class I genes, on type 1 diabetes risk, particularly HLA-B*39 (β [SE] = 1.36 [0.17]), were confirmed. The conditional analysis in LADA versus control subjects showed significant association in the MHC class II region (rs3957146, β [SE] = 1.14 [0.06]); however, we did not observe significant independent effects of MHC class I alleles in LADA.

    CONCLUSIONS

    In LADA, the independent effects of MHC class I observed in type 1 diabetes were not observed after conditioning on the leading MHC class II associations, suggesting that the MHC class I association may be a genetic discriminator between LADA and childhood-onset type 1 diabetes.




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    ADA supports proposed rules to update federal Anti-Kickback Statute, Stark Law

    The American Dental Association supports a new safe harbor for cybersecurity technology and services and modifying the existing safe harbor for electronic health records to add protections for cybersecurity. This was in response to the Office of the Inspector General and Centers for Medicare & Medicaid Services’ proposed changes to the federal Anti-Kickback Statute and Stark Law exceptions.




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    New ADA standard, technical report available for comment by Feb. 17

    The American Dental Association Standards Committee on Dental Informatics has approved two documents for circulation and comment.




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    ADA Member Advantage ends two endorsements

    ADA Member Advantage announced Jan. 8 the end of its endorsement relationship with two companies.