reg MANF Promotes Diabetic Corneal Epithelial Wound Healing and Nerve Regeneration by Attenuating Hyperglycemia-Induced Endoplasmic Reticulum Stress By diabetes.diabetesjournals.org Published On :: 2020-05-07T08:35:09-07:00 Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a neurotrophic factor widely expressed in mammalian tissues, and it exerts critical protective effects on neurons and other cell types in various disease models, such as those for diabetes. However, to date, the expression and roles of MANF in the cornea, with or without diabetic keratopathy (DK), remain unclear. Here, we demonstrate that MANF is abundantly expressed in normal corneal epithelial cells; however, MANF expression was significantly reduced in both unwounded and wounded corneal epithelium in streptozotocin-induced type 1 diabetic C57BL/6 mice. Recombinant human MANF significantly promoted normal and diabetic corneal epithelial wound healing and nerve regeneration. Furthermore, MANF inhibited hyperglycemia-induced endoplasmic reticulum (ER) stress and ER stress–mediated apoptosis. Attenuation of ER stress with 4-phenylbutyric acid (4-PBA) also ameliorated corneal epithelial closure and nerve regeneration. However, the beneficial effects of MANF and 4-PBA were abolished by an Akt inhibitor and Akt-specific small interfering RNA (siRNA). Finally, we reveal that the subconjunctival injection of MANF-specific siRNA prevents corneal epithelial wound healing and nerve regeneration. Our results provide important evidence that hyperglycemia-suppressed MANF expression may contribute to delayed corneal epithelial wound healing and impaired nerve regeneration by increasing ER stress, and MANF may be a useful therapeutic modality for treating DK. Full Article
reg Epigenetic Regulation of Hepatic Lipogenesis: Role in Hepatosteatosis and Diabetes By diabetes.diabetesjournals.org Published On :: 2020-03-20T11:50:28-07:00 Hepatosteatosis, which is frequently associated with development of metabolic syndrome and insulin resistance, manifests when triglyceride (TG) input in the liver is greater than TG output, resulting in the excess accumulation of TG. Dysregulation of lipogenesis therefore has the potential to increase lipid accumulation in the liver, leading to insulin resistance and type 2 diabetes. Recently, efforts have been made to examine the epigenetic regulation of metabolism by histone-modifying enzymes that alter chromatin accessibility for activation or repression of transcription. For regulation of lipogenic gene transcription, various known lipogenic transcription factors, such as USF1, ChREBP, and LXR, interact with and recruit specific histone modifiers, directing specificity toward lipogenesis. Alteration or impairment of the functions of these histone modifiers can lead to dysregulation of lipogenesis and thus hepatosteatosis leading to insulin resistance and type 2 diabetes. Full Article
reg Stress-Induced Translational Regulation Mediated by RNA Binding Proteins: Key Links to {beta}-Cell Failure in Diabetes By diabetes.diabetesjournals.org Published On :: 2020-03-20T11:50:28-07:00 In type 2 diabetes, β-cells endure various forms of cellular stress, including oxidative stress and endoplasmic reticulum stress, secondary to increased demand for insulin production and extracellular perturbations, including hyperglycemia. Chronic exposure to stress causes impaired insulin secretion, apoptosis, and loss of cell identity, and a combination of these processes leads to β-cell failure and severe hyperglycemia. Therefore, a better understanding of the molecular mechanisms underlying stress responses in β-cells promises to reveal new therapeutic opportunities for type 2 diabetes. In this perspective, we discuss posttranscriptional control of gene expression as a critical, but underappreciated, layer of regulation with broad importance during stress responses. Specifically, regulation of mRNA translation occurs pervasively during stress to activate gene expression programs; however, the convenience of RNA sequencing has caused translational regulation to be overlooked compared with transcriptional controls. We highlight the role of RNA binding proteins in shaping selective translational regulation during stress and the mechanisms underlying this level of regulation. A growing body of evidence indicates that RNA binding proteins control an array of processes in β-cells, including the synthesis and secretion of insulin. Therefore, systematic evaluations of translational regulation and the upstream factors shaping this level of regulation are critical areas of investigation to expand our understanding of β-cell failure in type 2 diabetes. Full Article
reg Cell-specific expression of the transcriptional regulator RHAMM provides a timing mechanism that controls appropriate wound re-epithelialization [Glycobiology and Extracellular Matrices] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 Prevention of aberrant cutaneous wound repair and appropriate regeneration of an intact and functional integument require the coordinated timing of fibroblast and keratinocyte migration. Here, we identified a mechanism whereby opposing cell-specific motogenic functions of a multifunctional intracellular and extracellular protein, the receptor for hyaluronan-mediated motility (RHAMM), coordinates fibroblast and keratinocyte migration speed and ensures appropriate timing of excisional wound closure. We found that, unlike in WT mice, in Rhamm-null mice, keratinocyte migration initiates prematurely in the excisional wounds, resulting in wounds that have re-surfaced before the formation of normal granulation tissue, leading to a defective epidermal architecture. We also noted aberrant keratinocyte and fibroblast migration in the Rhamm-null mice, indicating that RHAMM suppresses keratinocyte motility but increases fibroblast motility. This cell context–dependent effect resulted from cell-specific regulation of extracellular signal-regulated kinase 1/2 (ERK1/2) activation and expression of a RHAMM target gene encoding matrix metalloprotease 9 (MMP-9). In fibroblasts, RHAMM promoted ERK1/2 activation and MMP-9 expression, whereas in keratinocytes, RHAMM suppressed these activities. In keratinocytes, loss of RHAMM function or expression promoted epidermal growth factor receptor–regulated MMP-9 expression via ERK1/2, which resulted in cleavage of the ectodomain of the RHAMM partner protein CD44 and thereby increased keratinocyte motility. These results identify RHAMM as a key factor that integrates the timing of wound repair by controlling cell migration. Full Article
reg S-Palmitoylation of the sodium channel Nav1.6 regulates its activity and neuronal excitability [Cell Biology] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 S-Palmitoylation is a reversible post-translational lipid modification that dynamically regulates protein functions. Voltage-gated sodium channels are subjected to S-palmitoylation and exhibit altered functions in different S-palmitoylation states. Our aim was to investigate whether and how S-palmitoylation regulates Nav1.6 channel function and to identify S-palmitoylation sites that can potentially be pharmacologically targeted. Acyl-biotin exchange assay showed that Nav1.6 is modified by S-palmitoylation in the mouse brain and in a Nav1.6 stable HEK 293 cell line. Using whole-cell voltage clamp, we discovered that enhancing S-palmitoylation with palmitic acid increases Nav1.6 current, whereas blocking S-palmitoylation with 2-bromopalmitate reduces Nav1.6 current and shifts the steady-state inactivation in the hyperpolarizing direction. Three S-palmitoylation sites (Cys1169, Cys1170, and Cys1978) were identified. These sites differentially modulate distinct Nav1.6 properties. Interestingly, Cys1978 is exclusive to Nav1.6 among all Nav isoforms and is evolutionally conserved in Nav1.6 among most species. Cys1978 S-palmitoylation regulates current amplitude uniquely in Nav1.6. Furthermore, we showed that eliminating S-palmitoylation at specific sites alters Nav1.6-mediated excitability in dorsal root ganglion neurons. Therefore, our study reveals S-palmitoylation as a potential isoform-specific mechanism to modulate Nav activity and neuronal excitability in physiological and diseased conditions. Full Article
reg DHHC7-mediated palmitoylation of the accessory protein barttin critically regulates the functions of ClC-K chloride channels [Cell Biology] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 Barttin is the accessory subunit of the human ClC-K chloride channels, which are expressed in both the kidney and inner ear. Barttin promotes trafficking of the complex it forms with ClC-K to the plasma membrane and is involved in activating this channel. Barttin undergoes post-translational palmitoylation that is essential for its functions, but the enzyme(s) catalyzing this post-translational modification is unknown. Here, we identified zinc finger DHHC-type containing 7 (DHHC7) protein as an important barttin palmitoyl acyltransferase, whose depletion affected barttin palmitoylation and ClC-K-barttin channel activation. We investigated the functional role of barttin palmitoylation in vivo in Zdhhc7−/− mice. Although palmitoylation of barttin in kidneys of Zdhhc7−/− animals was significantly decreased, it did not pathologically alter kidney structure and functions under physiological conditions. However, when Zdhhc7−/− mice were fed a low-salt diet, they developed hyponatremia and mild metabolic alkalosis, symptoms characteristic of human Bartter syndrome (BS) type IV. Of note, we also observed decreased palmitoylation of the disease-causing R8L barttin variant associated with human BS type IV. Our results indicate that dysregulated DHHC7-mediated barttin palmitoylation appears to play an important role in chloride channel dysfunction in certain BS variants, suggesting that targeting DHHC7 activity may offer a potential therapeutic strategy for reducing hypertension. Full Article
reg 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
reg 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
reg Insulin Regulates Brain Function, but How Does It Get There? By diabetes.diabetesjournals.org Published On :: 2014-12-01 Sarah M. GrayDec 1, 2014; 63:3992-3997Perspectives in Diabetes Full Article
reg Intense Exercise Has Unique Effects on Both Insulin Release and Its Roles in Glucoregulation: Implications for Diabetes By diabetes.diabetesjournals.org Published On :: 2002-02-01 Errol B. MarlissFeb 1, 2002; 51:S271-S283Section 6: Pusatile and Phasic Insulin Release in Normal and Diabetic Men Full Article
reg Don’t Overstretch on Regional Integration By feedproxy.google.com Published On :: Thu, 23 May 2019 11:39:22 +0000 12 June 2019 Hans Kundnani Senior Research Fellow, Europe Programme @hanskundnani How the European Union took the idea of a ‘rules-based order’ too far – and how it can regain legitimacy. Young woman at the March for Europe in May 2018 Young woman at the March for Europe in May 2018. Photo by Emanuele Cremaschi/Getty Images The European Union is the ultimate ‘rules-based order’. Since the end of the Cold War, the world has become increasingly integrated, in a process that Dani Rodrik has called ‘hyper-globalization’ to distinguish this from the more moderate form of globalization that occurred during the Cold War period.But Europe, which was already more integrated than the rest of the world, has gone even further in removing barriers to the internal movement of capital, goods and people. The consequence of this has been the need for a more developed system of rules to govern this deep integration.For much of this period, many Europeans – and also many outside Europe who had a liberal view of international politics – believed that the EU was a kind of blueprint for global governance.They believed that the rest of the world would simply catch up with the enlightened and apparently successful approach that Europeans had taken. In short, Europeans were showing the way forward for the world.However, after a decade of crisis, it now seems as if Europe may have overreached. In particular with the creation of the single currency, European rules increasingly extended into areas of life in which member states had previously had relative autonomy.Since the beginning of the euro crisis in 2010, there has been a backlash against EU rules, which has raised the difficult question of whether international rule-making can go too far.What makes international rules problematic is that they depoliticize – that is, they take the policy areas they cover out of the realm of democratic contestation. This can be a good thing when applied to policy areas that we think should be non-negotiable, like human rights.But since the 1980s, and especially since the end of the Cold War, international rules have increasingly applied to areas of policy that not only should be contested but that should be at the centre of contestation – in particular, economic policy areas that have distributional consequences (that is, they create winners and losers).The EU’s rules constrain its member states even more than global rules – for example, those of the World Trade Organization (WTO) – or rules associated with other regional integration projects constrain nation states elsewhere in the world. In particular, the EU’s fiscal rules – created along with the euro – set strict limits on the ability of member states to run budget deficits and accumulate debt.Since the beginning of the euro crisis, these fiscal rules have been further tightened, which in turn has magnified the political backlash against the EU system and fuelled tensions between member states.In democratic nation states, rules are made through a process that gives them what is sometimes called ‘input legitimacy’. International rule-making, by contrast, is essentially the product of power relations between states and therefore lacks this specific kind of legitimacy.Supporters of European integration as currently constituted – whom one might term ‘pro-Europeans’ – would argue that EU rules are more like domestic rules than international rules: after all, they are agreed through a process involving democratic institutions such as the European Parliament. But even within the EU, power matters – as notably illustrated by Germany’s prominent (and controversial) role in driving the development of fiscal rules since the beginning of the euro crisis.In addition, because European integration is meant to be an irreversible process, it is extremely difficult to change or abolish rules that have already been agreed. To do so would be ‘disintegration’ in the sense that powers would be returned to member states.For example, there are good economic and political arguments for abolishing the ‘debt brake’, based on a German model, that EU member states agreed to incorporate into their national constitutions as part of the Fiscal Compact in 2011. But anyone making those arguments is labelled as Eurosceptic or ‘anti-European’.There is also insufficient differentiation between EU rules. Any decision taken at a European level – even those decisions, such as on the Fiscal Compact, that are outside the EU treaties – becomes part of the EU’s system of rules. To challenge such a decision is therefore to violate the rule of law and therefore the EU’s ‘values’.As Dieter Grimm has shown, legislation that would normally have the status of secondary law in a nation state has constitutional status in EU law and is therefore ‘immunized against political correction’.[1]Though European leaders still often speak of the EU as a model for the rest of the world, the reality is that it now illustrates what other regional integration projects should avoid as much as what they should emulate. Even before the euro crisis, few other regions were thinking of creating a common currency.But they will now think even more carefully about how far to follow Europe down the route of economic integration it has taken – and in particular will be unlikely to introduce EU-style fiscal rules.The difficult question is where exactly the limits of international rule-making should be set. The European experience in the past decade suggests that rules on economic policy are particularly problematic because of the distributional consequences they have.But European integration focused on economic policy from its beginnings with the European Coal and Steel Community in the 1950s. Moreover, because globalization is to a large extent an economic phenomenon, economic policy is precisely where international rules are needed.A good place to start in thinking about where to set the limits of international rule-making may be in terms of the objectives of rules. During the early phase of European integration and the more moderate phase of globalization in the 30 years after the end of the Second World War, integration strengthened nation states – indeed, Alan Milward argued that integration ‘rescued’ the nation state in Europe.[2]But since the end of the Cold War, rules at both the global level and a European level have been driven by the maximization of economic efficiency. This has undermined the nation state. As Rodrik has argued, a reprioritization is now needed – rules should be made above all with their impact on democracy in mind.[3]In order to regain legitimacy, Europe should apply this idea of democracy-enhancing rules to its own approach to integration. It should begin by differentiating more clearly between rules that are fundamental to the European project and those about which Europeans can – and should – disagree.The consequence of thinking of rules above all in terms of legitimacy may be that in some policy areas, particularly those with distributive consequences, rules should be abolished and power returned to member states.‘Pro-Europeans’ should be open to this kind of ‘disintegration’ as a way to help the EU regain legitimacy and thus be sustainable in the medium term. It is also only by successfully recalibrating the balance between rules and democracy that the EU will once again be seen as a model for regional integration projects in the rest of the world, and for global governance more generally.What needs to happenThe EU offers a cautionary tale on the limits of regional integration, with its status as a model for international governance eroded by a decade of crisis.In certain areas, notably fiscal policy, democratically contested decision-making has been subordinated to ‘depoliticized’ supranational rules. The crisis over the single currency exemplifies the tensions between autonomy and integration.To restore its legitimacy, the EU needs to recalibrate the balance between rules and democracy. Policymakers should ensure that laws are made with their impact on democracy in mind.Politicians and policymakers should differentiate more clearly between rules that are fundamental to the European project and those about which Europeans can – and should – disagree.In some policy areas, this could include returning powers to member states. Though politically challenging, this will require ‘pro-Europeans’ to tolerate some ‘disintegration’ as the price of ensuring the future stability of the EU.Notes[1] Grimm, D. (2015), ‘The Democratic Costs of Constitutionalisation: The European Case’, European Law Journal, Volume 21, Issue 4, July 2015, https://onlinelibrary.wiley.com/doi/abs/10.1111/eulj.12139.[2] Milward, A. (1999), The European Rescue of the Nation State, London: Routledge.[3] Rodrik, D. (2006), ‘Put Globalization to Work for Democracies’, New York Times, 17 September 2006, https://www.nytimes.com/2016/09/18/opinion/sunday/put-globalization-to-work-for-democracies.html.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
reg Power Politics Could Impede Progress on Responsible Regulation of Cyberspace By feedproxy.google.com Published On :: Tue, 03 Dec 2019 14:34:13 +0000 3 December 2019 Harriet Moynihan Senior Research Fellow, International Law Programme @HarrietMoyniha9 A new Chatham House paper examines the prospects of countries reaching agreement on issues of sovereignty and non-intervention in cyberspace in the face of persistent, low-level, state-to-state cyber attacks. 2019-11-29-Intl-Law-Cyberattacks.jpg A computer hacked by a virus known as Petya. The Petya ransomware cyberattack hit computers of Russian and Ukrainian companies on 27 June 2017. Photo: Getty Images. In discussions to date about how international law applies in cyberspace, commentators have tended to focus their attention on how the rules on the use of force, or the law of armed conflict, apply to cyber activities conducted by states that give rise to physical damage, injury or death.But in practice, the vast majority of state cyberattacks fall below this threshold. Far more common are persistent, low-level attacks that may leave no physical trace but that are capable of doing significant damage to a state’s ability to control its systems, often at serious economic cost.Such cyber incursions might include network disruptions in the operation of another government’s websites; tampering with electoral infrastructure to change or undermine the result; or using cyber means to destabilize another state’s financial sector.For these kinds of cyber operation, the principle of sovereignty, and the principle of non-intervention in another state’s internal affairs, are the starting point.A UN Group of Government Experts (GGE) agreed in 2013 and 2015 that the principles in the UN Charter, including sovereignty and the prohibition on intervention in another state’s affairs, apply to states’ activities in cyberspace. The 2015 GGE also recommended eleven (non-binding) norms of responsible state behaviour in cyberspace.However, states have not yet reached agreement on how to apply these principles. Until recently, there has also been very little knowledge of what states actually do in cyberspace, as they usually conduct cyber operations covertly and have been reluctant to put their views on record.A new Chatham House research paper analyses the application of the principles of sovereignty and non-intervention to state cyberattacks that fall below the principle of use of force. As well as analysing the application of the law in this area, the paper also makes recommendations to governments on how they might best make progress in reaching agreement in this area.Existing rules or new rules?As the research paper makes clear, there is currently some debate, principally between countries in the West, about the extent to which sovereignty is a legally binding rule in the context of cyberspace and, if so, how it and the principle of non-intervention might apply in practice.In the last few years, certain states have put on record how they consider international law to apply to states’ activities in cyberspace, namely the UK, Australia, France and the Netherlands. While there may be some differences in their approaches, which are discussed in the paper, there also remains important common ground: namely, that existing international law already provides a solid framework for regulating states’ cyber activities, as it regulates every other domain of state-to-state activity.There is also an emerging trend for states to work together when attributing cyberattacks to hostile states, enabling them to call out malign cyber activity when it violates international law. (See, for example, the joint statements made in relation to the NotPetya cyber attack and malicious cyber activity attributed to the Russian government).However, other countries have questioned whether existing international law as it stands is capable of regulating states’ cyber interactions and have called for ‘new legal instruments’ in this area.This includes a proposal by the Shanghai Cooperation Organization (led by Russia and China) for an International Code of Conduct on Information Security, a draft of which was submitted to the UN in 2011 and 2015, without success. The UN has also formed a new Open-Ended Working Group (OEWG) under a resolution proposed by Russia to consider how international law applies to states’ activities in cyberspace.The resolution establishing the OEWG, which began work earlier this year, includes the possibility of the group ‘introducing changes to the rules, norms and principles of responsible behaviour of States’ agreed in the 2013 and 2015 GGE reports. In the OEWG discussions at the UN in September, several countries claimed that a new legal instrument was needed to fill the ‘legal vacuum’ (Cuba) or ‘the gap of ungoverned areas’ (Indonesia).It would be concerning if the hard-won consensus on the application of international law to cyberspace that has been reached at past GGEs started to unravel. In contrast to 2013 and 2015, the 2017 meeting failed to reach an agreement.On 9 December, a renewed GGE will meet in New York, but the existence of the OEWG exploring the same issues in a separate process reflects the fact that cyber norms have become an area of geopolitical rivalry.Aside from the application of international law, states are also adopting divergent approaches to the domestic regulation of cyberspace within their own territory. The emerging trend towards a ‘splinternet’ – i.e. between states that believe the internet should be global and open on the hand, and those that favour a ‘sovereignty and control’ model on the other – is also likely to make discussions at the GGE more challenging.Distinct from the international law concept of sovereignty is the notion of ‘cybersovereignty’, a term coined by China to describe the wide-ranging powers it assumes under domestic law to regulate its citizens’ access to the internet and personal data within its territory. This approach is catching on (as reflected in Russia’s recently enacted ‘Sovereign Internet Law’), with other authoritarian states likely to follow suit.The importance of non-state actorsIn parallel with regional and UN discussions on how international law applies, a number of initiatives by non-state actors have also sought to establish voluntary principles about responsible state behaviour in cyberspace.The Global Commission on the Stability of Cyberspace, a multi-stakeholder body that has proposed principles, norms and recommendations to guide responsible behaviour by all parties in cyberspace, recently published its final report. The Cybersecurity Tech Accord aims to promote collaboration between tech companies on stability and resilience in cyberspace. President Macron’s ‘Paris Call for Trust and Security in Cyberspace’ has to date received the backing of 67 states, 139 international and civil society organizations, and 358 private-sector organizations.It remains to be seen in the long term whether the parallel processes at the UN will work constructively together or be competitive. But notwithstanding the challenging geopolitical backdrop, the UN GGE meeting next week at the least offers states the opportunity to consolidate and build on the results of past meetings; to increase knowledge and discussion about how international law might apply; and to encourage more states to put their own views of these issues on the record. Full Article
reg The EU Cannot Build a Foreign Policy on Regulatory Power Alone By feedproxy.google.com Published On :: Tue, 11 Feb 2020 16:33:26 +0000 11 February 2020 Alan Beattie Associate Fellow, Global Economy and Finance Programme and Europe Programme @alanbeattie LinkedIn Brussels will find its much-vaunted heft in setting standards cannot help it advance its geopolitical interests. 2020-02-11-Leyen.jpg EU Commission President Ursula von der Leyen speaks at the European Parliament in Strasbourg in February. Photo: Getty Images. There are two well-established ideas in trade. Individually, they are correct. Combined, they can lead to a conclusion that is unfortunately wrong.The first idea is that, across a range of economic sectors, the EU and the US have been engaged in a battle to have their model of regulation accepted as the global one, and that the EU is generally winning.The second is that governments can use their regulatory power to extend strategic and foreign policy influence.The conclusion would seem to be that the EU, which has for decades tried to develop a foreign policy, should be able to use its superpower status in regulation and trade to project its interests and its values abroad.That’s the theory. It’s a proposition much welcomed by EU policymakers, who know they are highly unlikely any time soon to acquire any of the tools usually required to run an effective foreign policy.The EU doesn’t have an army it can send into a shooting war, enough military or political aid to prop up or dispense of governments abroad, or a centralized intelligence service. Commission President Ursula von der Leyen has declared her outfit to be a ‘geopolitical commission’, and is casting about for any means of making that real.Through the ‘Brussels effect’ whereby European rules and standards are exported via both companies and governments, the EU has indeed won many regulatory battles with the US.Its cars, chemicals and product safety regulations are more widely adopted round the world than their American counterparts. In the absence of any coherent US offering, bar some varied state-level systems, the General Data Protection Regulation (GDPR) is the closest thing the world has to a single model for data privacy, and variants of it are being adopted by dozens of countries.The problem is this. Those parts of global economic governance where the US is dominant – particularly the dollar payments system – are highly conducive to projecting US power abroad. The extraterritorial reach of secondary sanctions, plus the widespread reliance of banks and companies worldwide on dollar funding – and hence the American financial system – means that the US can precisely target its influence.The EU can enforce trade sanctions, but not in such a powerful and discriminatory way, and it will always be outgunned by the US. Donald Trump could in effect force European companies to join in his sanctions on Iran when he pulled out of the nuclear deal, despite EU legislation designed to prevent their businesses being bullied. He can go after the chief financial officer of Huawei for allegedly breaching those sanctions.By contrast, the widespread adoption of GDPR or data protection regimes inspired by it may give the EU a warm glow of satisfaction, but it cannot be turned into a geopolitical tool in the same way.Nor, necessarily, does it particularly benefit the EU economy. Europe’s undersized tech sector seems unlikely to unduly benefit from the fact that data protection rules were written in the EU. Indeed, one common criticism of the regulations is that they entrench the power of incumbent tech giants like Google.There is a similar pattern at work in the adoption of new technologies such as artificial intelligence and the Internet of Things. In that field, the EU and its member states are also facing determined competition from China, which has been pushing its technologies and standards through forums such as the International Telecommunication Union.The EU has been attempting to write international rules for the use of AI which it hopes to be widely adopted. But again, these are a constraint on the use of new technologies largely developed by others, not the control of innovation.By contrast, China has created a vast domestic market in technologies like facial recognition and unleashed its own companies on it. The resulting surveillance kit can then be marketed to emerging market governments as part of China’s enduring foreign policy campaign to build up supporters in the developing world.If it genuinely wants to turn its economic power into geopolitical influence – and it’s not entirely clear what it would do with it if it did – the EU needs to recognize that not all forms of regulatory and trading dominance are the same.Providing public goods to the world economy is all very well. But unless they are so particular in nature that they project uniquely European values and interests, that makes the EU a supplier of useful plumbing but not a global architect of power.On the other hand, it could content itself with its position for the moment. It could recognize that not until enough hard power – guns, intelligence, money – is transferred from the member states to the centre, or until the member states start acting collectively, will the EU genuinely become a geopolitical force. Speaking loudly and carrying a stick of foam rubber is rarely a way to gain credibility in international relations.This article is part of a series of publications and roundtable discussions in the Chatham House Global Trade Policy Forum. Full Article
reg Russia’s Uncertain Regime Transformation By feedproxy.google.com Published On :: Wed, 11 Mar 2020 15:47:58 +0000 11 March 2020 Professor Nikolai Petrov Senior Research Fellow, Russia and Eurasia Programme, Chatham House Google Scholar Dr Ben Noble Lecturer in Russian Politics, University College London; Senior Research Fellow, HSE, Moscow Despite the drama, Vladimir Putin’s announcement endorsing a constitutional change allowing him to remain president from 2024 does surprisingly little to change the status quo. 2020-03-11-Putin-Constitution.jpg Russian President Vladimir Putin addresses lawmakers debating on the second reading of the constitutional reform bill during a session of the State Duma, Russia's lower house of parliament March 10, 2020. Photo by ALEXANDER NEMENOV/AFP via Getty Images. With Putin’s current term as head of state due to run out in 2024, the question everybody has been asking is what he will do to remain in power. The Russian president’s recent speech, made in person in the State Duma during the second reading of his own constitutional reform bill, has been interpreted by many as a clear answer. Summaries such as “Putin forever” and “perpetual Putin” abound. But the reality is not so clear.Putin has not committed to standing for re-election in 2024, never mind staying in power until 2036, when two additional six-year terms from 2024 would run out. What he has done is provide the constitutional grounds to retain power as president. It creates a highly credible option without committing him to it.And the uncertainty matters. Because as long as members of the elite are unsure whether Putin will take up the option to remain president, they are kept in check.Broader constitutional reformWith the flurry of interest around Putin’s announcement, we should not lose sight of his moves to further strengthen the presidency. As part of the broader constitutional reform package, Russia’s existing “super-presidency” will gain additional powers, such as the authority to fire top-tier judges and to block legislation when the legislature has overridden a presidential veto (in other words, a “super-veto”).The proposals also put the autonomy of local self-government at risk, with Moscow and regional executives gaining the constitutional power to hire and fire officials who are not even technically part of the state. And the president now has a formalised role as “general leader” of the government. Putin is creating the “Great Presidency”.However, the majority of constitutional changes do not relate to the presidency – they have different purposes. Firstly, to revitalise support for the regime which took a hit following unpopular pension reforms in 2018. Secondly, to distract or appease those worried by Putin remaining in a strengthened presidency. And perhaps most significantly, to boost turnout in the nationwide vote on reforms.This desire to re-energise popular support becomes apparent as the changes – some of which will have to be inserted rather awkwardly into the constitution’s structure – focus on three elements aimed squarely at improving the regime’s appeal: increased material support from the state for citizens, including indexing state pensions; an emphasis on “traditional values”, including a declaration that marriage can only be a union between a man and a woman; and increased Russian sovereignty, including a “nationalisation” of the elite, with a constitutional ban on top-level officials having bank accounts abroad. Constitutional reform is, moreover, the most visible part of a broader political transformation already underway, including a major propaganda drive. Putin has promised a significant increase in resources for its “maternity capital” programme, putting more money in the pockets of young Russian families.And he has instructed Prime Minister Mikhail Mishustin’s government to focus on delivering his “national projects” – goals aimed at improving Russians’ lives across a range of areas, from infrastructure to education and healthcare.Taking advantage of several imminent historical milestones is also on the cards. It has been reported Putin will sign the constitutional reform bill on March 18 – the anniversary of Russia’s annexation of Crimea. And May 9 is the 75th anniversary of the end of the Great Patriotic War (the Russian term for the Second World War), with foreign dignitaries invited to attend events in Moscow.Putin has also been filling the airwaves with a high-production-values series called “20 Questions for Vladimir Putin”, as well as holding public meetings with citizens in provinces such as Cherepovets and Ivanovo. There is a clear aim to demonstrate the president is not only still in control, but also concerned with the well-being of everyday Russians.With parliamentary elections scheduled for September 2021 the Kremlin knows that, to maintain its control of a super-majority of seats in the State Duma, its ratings-raising drive has to work – even if it does always have the option of using manifestly authoritarian methods for realising desired election results. A proposal to call early State Duma elections was made during the second reading of Putin’s reform bill, but was quickly withdrawn after Putin spoke out against the idea.Russia’s complex architecture of “power”Throughout this transformation, maintaining control of the elite – particularly of the siloviki – is key for Putin. A reshuffling and removal of senior officials in the Procuracy has seen Yury Chaika replaced as general prosecutor by Ivan Krasnov, previously a deputy chair of the Investigative Committee, which is widely seen as a rival structure in Russia’s complex architecture of “power” bodies.When considered alongside the constitutional changes giving the president broader powers in appointing regional prosecutors, this is textbook “divide and rule”. Power balancing is also on display with the Security Council, as the job description for Dmitry Medvedev’s new role as its deputy chair could provide fertile ground for clashes with the body’s secretary, Nikolai Patrushev.Pitting rival patronal networks against each other means Putin can keep rivals in check within the broader structure of the “Great Presidency”, while staying firmly in control himself.The prospect of Putin remaining president is unlikely to be popular. According to data from independent Russian polling agency the Levada Centre, only 27 per cent of Russians want Putin to stay in the post after 2024. This figure could, of course, change in either direction as the prospect becomes more real for Russians. But if Putin’s announcement galvanises mass opposition, the authorities may well use responses to the COVID-19 outbreak to keep protesters at bay – something already on display in Moscow.What this all means for Russia is that, despite the drama, considerable uncertainty remains following Putin’s announcement. What we can say for certain, however, is that it dashes hopes of serious political change any time soon. Full Article
reg Virtual Roundtable: The Impact of COVID-19 on the Wider FSU Region By feedproxy.google.com Published On :: Thu, 16 Apr 2020 13:40:02 +0000 Invitation Only Research Event 21 April 2020 - 10:00am to 11:30am Event participants Christopher Davis, Professorial Fellow, Institute of Population Ageing, University of OxfordNino Evgenidze, Executive Director, EPRCKatya Gorchinskaya, Journalist, former CEO of Hromadske.uaKonstantin Sokulskiy, Head of Governance, UNDP, KazakhstanChair: James Nixey, Programme Director, Russia and Eurasia, Chatham House COVID-19 has put a serious strain on healthcare and economic systems around the world. This virtual roundtable will explore its impact on Russia, Ukraine, Georgia and Kazakhstan. Through a comparative examination of government and society responses, this event will show how COVID-19 has laid bare the region’s broader social, economic and political challenges. Department/project Russia and Eurasia Programme Anna Morgan Administrator, Ukraine Forum +44 (0)20 7389 3274 Email Full Article
reg Pregnant in Dundee By kolembo.wordpress.com Published On :: Sun, 20 Jul 2014 15:23:57 +0000 How far would you travel from where you were born? She spends more on her dogs in one week, Than the government provides for those in trouble. She’s a naturally happy person. The mottled concrete walls of the council block she’s moved in to, Complement her pock-marked, pink skin. For a rich person, She’s ugly. […] Full Article Poetry charity generosity maternity poetry pregnancy women
reg Collab shows we are one Caribbean - ‘We Got This’ presents a united regional front against COVID-19 By jamaica-gleaner.com Published On :: Fri, 08 May 2020 00:08:53 -0500 WHAT STARTED as an idea of two Barbadians – Ian Webster and Cheyne Jones – transformed into We Got This, a song which proved enough to stir the collective imagination of 25 recording artistes from 14 countries across the region, disseminating the... Full Article
reg Serotonin Regulates Adult {beta}-Cell Mass by Stimulating Perinatal {beta}-Cell Proliferation By diabetes.diabetesjournals.org Published On :: 2020-01-20T12:00:26-08:00 A sufficient β-cell mass is crucial for preventing diabetes, and perinatal β-cell proliferation is important in determining the adult β-cell mass. However, it is not yet known how perinatal β-cell proliferation is regulated. Here, we report that serotonin regulates β-cell proliferation through serotonin receptor 2B (HTR2B) in an autocrine/paracrine manner during the perinatal period. In β-cell–specific Tph1 knockout (Tph1 βKO) mice, perinatal β-cell proliferation was reduced along with the loss of serotonin production in β-cells. Adult Tph1 βKO mice exhibited glucose intolerance with decreased β-cell mass. Disruption of Htr2b in β-cells also resulted in decreased perinatal β-cell proliferation and glucose intolerance in adulthood. Growth hormone (GH) was found to induce serotonin production in β-cells through activation of STAT5 during the perinatal period. Thus, our results indicate that GH-GH receptor-STAT5-serotonin-HTR2B signaling plays a critical role in determining the β-cell mass by regulating perinatal β-cell proliferation, and defects in this pathway affect metabolic phenotypes in adults. Full Article
reg Insulin-Deficient Diabetic Condition Upregulates the Insulin-Secreting Capacity of Human Induced Pluripotent Stem Cell-Derived Pancreatic Endocrine Progenitor Cells After Implantation in Mice By diabetes.diabetesjournals.org Published On :: 2020-03-20T11:50:28-07:00 The host environment is a crucial factor for considering the transplant of stem cell–derived immature pancreatic cells in patients with type 1 diabetes. Here, we investigated the effect of insulin (INS)-deficient diabetes on the fate of immature pancreatic endocrine cell grafts and the underlying mechanisms. Human induced pluripotent stem cell–derived pancreatic endocrine progenitor cells (EPCs), which contained a high proportion of chromogranin A+ NK6 homeobox 1+ cells and very few INS+ cells, were used. When the EPCs were implanted under the kidney capsule in immunodeficient mice, INS-deficient diabetes accelerated increase in plasma human C-peptide, a marker of graft-derived INS secretion. The acceleration was suppressed by INS infusion but not affected by partial attenuation of hyperglycemia by dapagliflozin, an INS-independent glucose-lowering agent. Immunohistochemical analyses indicated that the grafts from diabetic mice contained more endocrine cells including proliferative INS-producing cells compared with that from nondiabetic mice, despite no difference in whole graft mass between the two groups. These data suggest that INS-deficient diabetes upregulates the INS-secreting capacity of EPC grafts by increasing the number of endocrine cells including INS-producing cells without changing the graft mass. These findings provide useful insights into postoperative diabetic care for cell therapy using stem cell–derived pancreatic cells. Full Article
reg Bregman progressing from elbow surgery By mlb.mlb.com Published On :: Sat, 16 Feb 2019 16:25:12 EDT Astros third baseman Alex Bregman continues to progress from the arthroscopic elbow surgery he had a month to remove bone chips. Full Article
reg 'Great swing': Bregman tweet thrills young fan By mlb.mlb.com Published On :: Tue, 19 Feb 2019 10:51:45 EDT It took only two words for Alex Bregman to send 9-year-old Jax Nystrom into a frenzy, but this kind of reaction -- young people freaking out at the slightest bit of attention from him -- has become commonplace for the Astros' All-Star third baseman. Full Article
reg Samuda to make strong push for regional pro football league By jamaica-gleaner.com Published On :: Wed, 06 May 2020 00:14:35 -0500 JAMAICA OLYMPIC Association (JOA) President Christopher Samuda believes that his sports administration experience will aid him in helping to finally shape a professional football league in the Caribbean. Concacaf announced Samuda’s appointment to... Full Article
reg Deepening the pool - Western Jamaican swim clubs seek government development and new pool in region to foster training By jamaica-gleaner.com Published On :: Wed, 06 May 2020 23:18:02 -0500 Western Bureau: A number of swimming officials in western Jamaica say that the region’s struggles with underdevelopment will continue even if the COVID-19 pandemic is brought under control. They say this is because they still lack proper pools to... Full Article
reg Sarah Wollaston - obesity, not a sugary drinks tax, is regressive By feeds.bmj.com Published On :: Wed, 02 Dec 2015 11:28:11 +0000 The UK Parliament's Health Select Committee's recent report on childhood obesity says 1 in 5 children are obese by the time they leave school. The committee calls for legislation to turn the tide by taxing sugary drinks, a pre-watershed ban on junk food advertising, and investment in public health. We joined Sarah Wollaston, conservative MP for... Full Article
reg Identifying a viral rash in pregnancy By feeds.bmj.com Published On :: Fri, 17 Mar 2017 15:33:02 +0000 Viral exanthema can cause rash in a pregnant woman and should be considered even in countries that have comprehensive vaccination programmes. Measles and rubella can cause intrauterine death. Intrauterine infection with rubella can lead to congenital rubella syndrome in the liveborn baby. In this podcast, Jack Carruthers, honorary clinical... Full Article
reg HIV in pregnancy - "without the big picture, people aren't going to be able to take the medication" By feeds.bmj.com Published On :: Fri, 15 Sep 2017 17:11:27 +0000 A new Rapid Recommendation from The BMJ suggests that for pregnant women, they may wish to avoid certain antiviral treatments for HIV. This recommendation differs from the WHO's, and to discuss why that is, and what makes that difference important, we're joined by Reed Siemieniuk, a physician and methodologist from McMaster University, and Alice... Full Article
reg Can we regulate intellectual interests like financial ones? By feeds.bmj.com Published On :: Fri, 13 Apr 2018 19:07:09 +0000 We talk about financial conflicts of interest a lot atThe BMJ - and have take taken the decision that our educational content should be without them. We also talk a lot about non-financial conflicts of interest, but the choppy waters of those are much more difficult to navigate. In this podcast, we discuss whether we should, or if we could even... Full Article
reg Fertility awareness based methods for pregnancy prevention By feeds.bmj.com Published On :: Sat, 13 Jul 2019 17:38:01 +0000 Fertility awareness based methods of contraception are increasingly being used for pregnancy prevention. In the US, the proportion of contraceptive users who choose such methods has grown from 1% in 2008 to approximately 3% in 2014. Relative to other methods of pregnancy prevention, however, substantial misinformation exists around fertility... Full Article
reg Cancer drug trials used for regulatory approval are at risk of bias By feeds.bmj.com Published On :: Thu, 19 Sep 2019 14:09:14 +0000 Around half of trials that supported new cancer drug approvals in Europe between 2014 and 2016 were judged to be at high risk of bias, in a new study. Huseyin Naci,assistant professor of health policy a the London School of Economics joins us to talk about why potential bias may mean potential exaggeration of treatment effects, and could be... Full Article
reg A Lesson in Metabolic Regulation Inspired by the Glucokinase Glucose Sensor Paradigm By diabetes.diabetesjournals.org Published On :: 1996-02-01 Franz M MatschinskyFeb 1, 1996; 45:223-241Banting Lecture 1995 Full Article
reg Banting Lecture 2001: Dysregulation of Fatty Acid Metabolism in the Etiology of Type 2 Diabetes By diabetes.diabetesjournals.org Published On :: 2002-01-01 J. Denis McGarryJan 1, 2002; 51:7-18Banting Lecture 2001 Full Article
reg Triggering and amplifying pathways of regulation of insulin secretion by glucose By diabetes.diabetesjournals.org Published On :: 2000-11-01 JC HenquinNov 1, 2000; 49:1751-1760Articles Full Article
reg PPAR-gamma: adipogenic regulator and thiazolidinedione receptor By diabetes.diabetesjournals.org Published On :: 1998-04-01 BM SpiegelmanApr 1, 1998; 47:507-514Articles Full Article
reg Interplay of Placental DNA Methylation and Maternal Insulin Sensitivity in Pregnancy By diabetes.diabetesjournals.org Published On :: 2020-02-20T11:55:30-08:00 The placenta participates in maternal insulin sensitivity changes during pregnancy; however, mechanisms remain unclear. We investigated associations between maternal insulin sensitivity and placental DNA methylation markers across the genome. We analyzed data from 430 mother-offspring dyads in the Gen3G cohort. All women underwent 75-g oral glucose tolerance tests at ~26 weeks of gestation; we used glucose and insulin measures to estimate insulin sensitivity (Matsuda index). At delivery, we collected samples from placenta (fetal side) and measured DNA methylation using Illumina EPIC arrays. Using linear regression models to quantify associations at 720,077 cytosine-guanine dinucleotides (CpGs), with adjustment for maternal age, gravidity, smoking, BMI, child sex, and gestational age at delivery, we identified 188 CpG sites where placental DNA methylation was associated with Matsuda index (P < 6.94 x 10–8). Among genes annotated to these 188 CpGs, we found enrichment in targets for miRNAs, in histone modifications, and in parent-of-origin DNA methylation including the H19/MIR675 locus (paternally imprinted). We identified 12 known placenta imprinted genes, including KCNQ1. Mendelian randomization analyses revealed five loci where placenta DNA methylation may causally influence maternal insulin sensitivity, including the maternally imprinted gene DLGAP2. Our results suggest that placental DNA methylation is fundamentally linked to the regulation of maternal insulin sensitivity in pregnancy. Full Article
reg Why can’t vehicle registration be renewed online? By jamaica-gleaner.com Published On :: Tue, 05 May 2020 00:10:48 -0500 THE EDITOR, Madam: I arrived at the Constant Spring tax office at 6:05 a.m. on Monday, May 4 to renew my vehicle registration. At that hour, there were already 30 persons ahead of me. Persons related horror stories of spending up to five hours in... Full Article
reg Re-registration process for persons with disabilities cumbersome By jamaica-gleaner.com Published On :: Wed, 06 May 2020 23:05:41 -0500 THE EDITOR, Madam: THE JAMAICA Council for Persons with Disabilities (JCPD) – an agency of the Ministry of Labour... Full Article
reg Mitochondrial Proton Leak Regulated by Cyclophilin D Elevates Insulin Secretion in Islets at Nonstimulatory Glucose Levels By diabetes.diabetesjournals.org Published On :: 2020-01-20T12:00:25-08:00 Fasting hyperinsulinemia precedes the development of type 2 diabetes. However, it is unclear whether fasting insulin hypersecretion is a primary driver of insulin resistance or a consequence of the progressive increase in fasting glycemia induced by insulin resistance in the prediabetic state. Herein, we have discovered a mechanism that specifically regulates non–glucose-stimulated insulin secretion (NGSIS) in pancreatic islets that is activated by nonesterified free fatty acids, the major fuel used by β-cells during fasting. We show that the mitochondrial permeability transition pore regulator cyclophilin D (CypD) promotes NGSIS, but not glucose-stimulated insulin secretion, by increasing mitochondrial proton leak. Islets from prediabetic obese mice show significantly higher CypD-dependent proton leak and NGSIS compared with lean mice. Proton leak–mediated NGSIS is conserved in human islets and is stimulated by exposure to nonesterified free fatty acids at concentrations observed in obese subjects. Mechanistically, proton leak activates islet NGSIS independently of mitochondrial ATP synthesis but ultimately requires closure of the KATP channel. In summary, we have described a novel nonesterified free fatty acid–stimulated pathway that selectively drives pancreatic islet NGSIS, which may be therapeutically exploited as an alternative way to halt fasting hyperinsulinemia and the progression of type 2 diabetes. Full Article
reg Lipokine 5-PAHSA Is Regulated by Adipose Triglyceride Lipase and Primes Adipocytes for De Novo Lipogenesis in Mice By diabetes.diabetesjournals.org Published On :: 2020-02-20T11:55:30-08:00 Branched esters of palmitic acid and hydroxystearic acid (PAHSA) are anti-inflammatory and antidiabetic lipokines that connect glucose and lipid metabolism. We aimed to characterize involvement of the 5-PAHSA regioisomer in the adaptive metabolic response of white adipose tissue (WAT) to cold exposure (CE) in mice, exploring the cross talk between glucose utilization and lipid metabolism. CE promoted local production of 5- and 9-PAHSAs in WAT. Metabolic labeling of de novo lipogenesis (DNL) using 2H2O revealed that 5-PAHSA potentiated the effects of CE and stimulated triacylglycerol (TAG)/fatty acid (FA) cycling in WAT through impacting lipogenesis and lipolysis. Adipocyte lipolytic products were altered by 5-PAHSA through selective FA re-esterification. The impaired lipolysis in global adipose triglyceride lipase (ATGL) knockout mice reduced free PAHSA levels and uncovered a metabolite reservoir of TAG-bound PAHSAs (TAG estolides) in WAT. Utilization of 13C isotope tracers and dynamic metabolomics documented that 5-PAHSA primes adipocytes for glucose metabolism in a different way from insulin, promoting DNL and impeding TAG synthesis. In summary, our data reveal new cellular and physiological mechanisms underlying the beneficial effects of 5-PAHSA and its relation to insulin action in adipocytes and independently confirm a PAHSA metabolite reservoir linked to ATGL-mediated lipolysis. Full Article
reg Liver ChREBP Protects Against Fructose-Induced Glycogenic Hepatotoxicity by Regulating L-Type Pyruvate Kinase By diabetes.diabetesjournals.org Published On :: 2020-03-20T11:50:28-07:00 Excessive fructose consumption is closely linked to the pathogenesis of metabolic disease. Carbohydrate response element-binding protein (ChREBP) is a transcription factor essential for fructose tolerance in mice. However, the functional significance of liver ChREBP in fructose metabolism remains unclear. Here, we show that liver ChREBP protects mice against fructose-induced hepatotoxicity by regulating liver glycogen metabolism and ATP homeostasis. Liver-specific ablation of ChREBP did not compromise fructose tolerance, but rather caused severe transaminitis and hepatomegaly with massive glycogen overload in mice fed a high-fructose diet, while no obvious inflammation, cell death, or fibrosis was detected in the liver. In addition, liver ATP contents were significantly decreased by ChREBP deficiency in the fed state, which was rendered more pronounced by fructose feeding. Mechanistically, liver contents of glucose-6-phosphate (G6P), an allosteric activator of glycogen synthase, were markedly increased in the absence of liver ChREBP, while fasting-induced glycogen breakdown was not compromised. Furthermore, hepatic overexpression of LPK, a ChREBP target gene in glycolysis, could effectively rescue glycogen overload and ATP reduction, as well as mitigate fructose-induced hepatotoxicity in ChREBP-deficient mice. Taken together, our findings establish a critical role of liver ChREBP in coping with hepatic fructose stress and protecting from hepatotoxicity by regulating LPK. Full Article
reg Acyl-ghrelin Is Permissive for the Normal Counterregulatory Response to Insulin-Induced Hypoglycemia By diabetes.diabetesjournals.org Published On :: 2020-01-20T12:00:26-08:00 Insulin-induced hypoglycemia leads to far-ranging negative consequences in patients with diabetes. Components of the counterregulatory response (CRR) system that help minimize and reverse hypoglycemia and coordination between those components are well studied but not yet fully characterized. Here, we tested the hypothesis that acyl-ghrelin, a hormone that defends against hypoglycemia in a preclinical starvation model, is permissive for the normal CRR to insulin-induced hypoglycemia. Ghrelin knockout (KO) mice and wild-type (WT) littermates underwent an insulin bolus-induced hypoglycemia test and a low-dose hyperinsulinemic-hypoglycemic clamp procedure. Clamps also were performed in ghrelin-KO mice and C57BL/6N mice administered the growth hormone secretagogue receptor agonist HM01 or vehicle. Results show that hypoglycemia, as induced by an insulin bolus, was more pronounced and prolonged in ghrelin-KO mice, supporting previous studies suggesting increased insulin sensitivity upon ghrelin deletion. Furthermore, during hyperinsulinemic-hypoglycemic clamps, ghrelin-KO mice required a 10-fold higher glucose infusion rate (GIR) and exhibited less robust corticosterone and growth hormone responses. Conversely, HM01 administration, which reduced the GIR required by ghrelin-KO mice during the clamps, increased plasma corticosterone and growth hormone. Thus, our data suggest that endogenously produced acyl-ghrelin not only influences insulin sensitivity but also is permissive for the normal CRR to insulin-induced hypoglycemia. Full Article
reg Immunomodulation Followed by Antigen-Specific Treg Infusion Controls Islet Autoimmunity By diabetes.diabetesjournals.org Published On :: 2020-01-20T12:00:26-08:00 Optimal immune-based therapies for type 1 diabetes (T1D) should restore self-tolerance without inducing chronic immunosuppression. CD4+Foxp3+ regulatory T cells (Tregs) are a key cell population capable of facilitating durable immune tolerance. However, clinical trials with expanded Tregs in T1D and solid-organ transplant recipients are limited by poor Treg engraftment without host manipulation. We showed that Treg engraftment and therapeutic benefit in nonautoimmune models required ablative host conditioning. Here, we evaluated Treg engraftment and therapeutic efficacy in the nonobese diabetic (NOD) mouse model of autoimmune diabetes using nonablative, combinatorial regimens involving the anti-CD3 (αCD3), cyclophosphamide (CyP), and IAC (IL-2/JES6–1) antibody complex. We demonstrate that αCD3 alone induced substantial T-cell depletion, impacting both conventional T cells (Tconv) and Tregs, subsequently followed by more rapid rebound of Tregs. Despite robust depletion of host Tconv and host Tregs, donor Tregs failed to engraft even with interleukin-2 (IL-2) support. A single dose of CyP after αCD3 depleted rebounding host Tregs and resulted in a 43-fold increase in donor Treg engraftment, yet polyclonal donor Tregs failed to reverse diabetes. However, infusion of autoantigen-specific Tregs after αCD3 alone resulted in robust Treg engraftment within the islets and induced remission in all mice. This novel combinatorial therapy promotes engraftment of autoantigen-specific donor Tregs and controls islet autoimmunity without long-term immunosuppression. Full Article
reg {beta}-Cell Stress Shapes CTL Immune Recognition of Preproinsulin Signal Peptide by Posttranscriptional Regulation of Endoplasmic Reticulum Aminopeptidase 1 By diabetes.diabetesjournals.org Published On :: 2020-03-20T11:50:28-07:00 The signal peptide of preproinsulin is a major source for HLA class I autoantigen epitopes implicated in CD8 T cell (CTL)–mediated β-cell destruction in type 1 diabetes (T1D). Among them, the 10-mer epitope located at the C-terminal end of the signal peptide was found to be the most prevalent in patients with recent-onset T1D. While the combined action of signal peptide peptidase and endoplasmic reticulum (ER) aminopeptidase 1 (ERAP1) is required for processing of the signal peptide, the mechanisms controlling signal peptide trimming and the contribution of the T1D inflammatory milieu on these mechanisms are unknown. Here, we show in human β-cells that ER stress regulates ERAP1 gene expression at posttranscriptional level via the IRE1α/miR-17-5p axis and demonstrate that inhibition of the IRE1α activity impairs processing of preproinsulin signal peptide antigen and its recognition by specific autoreactive CTLs during inflammation. These results underscore the impact of ER stress in the increased visibility of β-cells to the immune system and position the IRE1α/miR-17 pathway as a central component in β-cell destruction processes and as a potential target for the treatment of autoimmune T1D. Full Article
reg Global, regional, and national burden of neck pain in the general population, 1990-2017: systematic analysis of the Global Burden of Disease Study 2017 By feeds.bmj.com Published On :: Thursday, March 26, 2020 - 19:10 Full Article
reg Association between maternal and paternal mental illness and risk of injuries in children and adolescents: nationwide register based cohort study in Sweden By feeds.bmj.com Published On :: Wednesday, April 8, 2020 - 22:31 Full Article
reg Prospective registration and reporting of trial number in randomised clinical trials: global cross sectional study of the adoption of ICMJE and Declaration of Helsinki recommendations By feeds.bmj.com Published On :: Tuesday, April 14, 2020 - 09:20 Full Article
reg Term complications and subsequent risk of preterm birth: registry based study By feeds.bmj.com Published On :: Wednesday, April 29, 2020 - 22:30 Full Article
reg Security Challenges in the Mediterranean Region By feedproxy.google.com Published On :: Mon, 20 Jan 2020 15:15:01 +0000 Members Event 5 March 2020 - 1:00pm to 2:00pm Chatham House | 10 St James's Square | London | SW1Y 4LE Event participants HE George Vella, President, Republic of MaltaChair: Dr Alex Vines OBE, Managing Director, Ethics, Risk & Resilience; Director, Africa Programme, Chatham House The president of Malta discusses the current security challenges in the Mediterranean region, reflecting on the role of international cooperation in addressing climate change, migration and refugee flows. Members Events Team Email Full Article
reg The EU Cannot Build a Foreign Policy on Regulatory Power Alone By feedproxy.google.com Published On :: Tue, 11 Feb 2020 16:33:26 +0000 11 February 2020 Alan Beattie Associate Fellow, Global Economy and Finance Programme and Europe Programme @alanbeattie LinkedIn Brussels will find its much-vaunted heft in setting standards cannot help it advance its geopolitical interests. 2020-02-11-Leyen.jpg EU Commission President Ursula von der Leyen speaks at the European Parliament in Strasbourg in February. Photo: Getty Images. There are two well-established ideas in trade. Individually, they are correct. Combined, they can lead to a conclusion that is unfortunately wrong.The first idea is that, across a range of economic sectors, the EU and the US have been engaged in a battle to have their model of regulation accepted as the global one, and that the EU is generally winning.The second is that governments can use their regulatory power to extend strategic and foreign policy influence.The conclusion would seem to be that the EU, which has for decades tried to develop a foreign policy, should be able to use its superpower status in regulation and trade to project its interests and its values abroad.That’s the theory. It’s a proposition much welcomed by EU policymakers, who know they are highly unlikely any time soon to acquire any of the tools usually required to run an effective foreign policy.The EU doesn’t have an army it can send into a shooting war, enough military or political aid to prop up or dispense of governments abroad, or a centralized intelligence service. Commission President Ursula von der Leyen has declared her outfit to be a ‘geopolitical commission’, and is casting about for any means of making that real.Through the ‘Brussels effect’ whereby European rules and standards are exported via both companies and governments, the EU has indeed won many regulatory battles with the US.Its cars, chemicals and product safety regulations are more widely adopted round the world than their American counterparts. In the absence of any coherent US offering, bar some varied state-level systems, the General Data Protection Regulation (GDPR) is the closest thing the world has to a single model for data privacy, and variants of it are being adopted by dozens of countries.The problem is this. Those parts of global economic governance where the US is dominant – particularly the dollar payments system – are highly conducive to projecting US power abroad. The extraterritorial reach of secondary sanctions, plus the widespread reliance of banks and companies worldwide on dollar funding – and hence the American financial system – means that the US can precisely target its influence.The EU can enforce trade sanctions, but not in such a powerful and discriminatory way, and it will always be outgunned by the US. Donald Trump could in effect force European companies to join in his sanctions on Iran when he pulled out of the nuclear deal, despite EU legislation designed to prevent their businesses being bullied. He can go after the chief financial officer of Huawei for allegedly breaching those sanctions.By contrast, the widespread adoption of GDPR or data protection regimes inspired by it may give the EU a warm glow of satisfaction, but it cannot be turned into a geopolitical tool in the same way.Nor, necessarily, does it particularly benefit the EU economy. Europe’s undersized tech sector seems unlikely to unduly benefit from the fact that data protection rules were written in the EU. Indeed, one common criticism of the regulations is that they entrench the power of incumbent tech giants like Google.There is a similar pattern at work in the adoption of new technologies such as artificial intelligence and the Internet of Things. In that field, the EU and its member states are also facing determined competition from China, which has been pushing its technologies and standards through forums such as the International Telecommunication Union.The EU has been attempting to write international rules for the use of AI which it hopes to be widely adopted. But again, these are a constraint on the use of new technologies largely developed by others, not the control of innovation.By contrast, China has created a vast domestic market in technologies like facial recognition and unleashed its own companies on it. The resulting surveillance kit can then be marketed to emerging market governments as part of China’s enduring foreign policy campaign to build up supporters in the developing world.If it genuinely wants to turn its economic power into geopolitical influence – and it’s not entirely clear what it would do with it if it did – the EU needs to recognize that not all forms of regulatory and trading dominance are the same.Providing public goods to the world economy is all very well. But unless they are so particular in nature that they project uniquely European values and interests, that makes the EU a supplier of useful plumbing but not a global architect of power.On the other hand, it could content itself with its position for the moment. It could recognize that not until enough hard power – guns, intelligence, money – is transferred from the member states to the centre, or until the member states start acting collectively, will the EU genuinely become a geopolitical force. Speaking loudly and carrying a stick of foam rubber is rarely a way to gain credibility in international relations.This article is part of a series of publications and roundtable discussions in the Chatham House Global Trade Policy Forum. Full Article
reg Iran Workshop Series: Domestic, Regional and International Outlook By feedproxy.google.com Published On :: Wed, 19 Feb 2020 15:05:01 +0000 Invitation Only Research Event 17 December 2019 - 10:00am to 3:30pm Chatham House | 10 St James's Square | London | SW1Y 4LE After a summer of regional tensions and continued uncertainty regarding the future of the JCPOA, the Chatham House MENA Programme held a closed workshop to examine the impact of the Trump administration’s maximum pressure campaign.Discussions focused on the domestic developments and challenges inside Iran, prospects for new negotiations with Iran, and the regional issues facing the country. Participants also considered the differences between American and European approaches towards Iran. Event attributes Chatham House Rule Department/project Middle East and North Africa Programme, Iran Forum Reni Zhelyazkova Programme Coordinator, Middle East and North Africa Programme +44 (0)20 7314 3624 Email Full Article
Reni Zhelyazkova Programme Coordinator, Middle East and North Africa Programme +44 (0)20 7314 3624 Email
reg 12th International Forum on Illegal, Unreported and Unregulated Fishing By feedproxy.google.com Published On :: Fri, 27 Sep 2019 09:15:01 +0000 Research Event 18 May 2020 - 2:00pm to 22 May 2020 - 3:30pmAdd to CalendariCalendar Outlook Google Yahoo The 12th International Forum on Illegal, Unreported and Unregulated Fishing was originally scheduled to take place 19-20 March 2020 at Chatham House in London, but was postponed due to COVID-19. We are excited to announce that we have decided to transform the 2020 conference into a series of webinars, delivering the forum discussions over the course of a week (18-22 May 2020). The foci of these exciting sessions include a discussion on the importance of international cooperation to end IUU fishing; the interplay between subsidies and IUU practices; the particular impact of IUU fishing on women and gender relations; transparency; new technologies, and a contextual exploration of IUU fishing in Southeast Asia. Many of the excellent panellists confirmed for the in-person event in March have agreed to participate in this digital version of the IUU Fishing Forum. The online format also provides new opportunities; we hope to reach new, larger and more geographically diverse audiences around the world. The agenda, along with the registration links for the sessions, will be published shortly. Anna Aberg Research Analyst, Energy, Environment and Resources Programme 020 7314 3629 Email Department/project Energy, Environment and Resources Programme, 12th International Forum on Illegal, Unreported and Unregulated Fishing Full Article