ed Delineating an extracellular redox-sensitive module in T-type Ca2+ channels [Membrane Biology] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 T-type (Cav3) Ca2+ channels are important regulators of excitability and rhythmic activity of excitable cells. Among other voltage-gated Ca2+ channels, Cav3 channels are uniquely sensitive to oxidation and zinc. Using recombinant protein expression in HEK293 cells, patch clamp electrophysiology, site-directed mutagenesis, and homology modeling, we report here that modulation of Cav3.2 by redox agents and zinc is mediated by a unique extracellular module containing a high-affinity metal-binding site formed by the extracellular IS1–IS2 and IS3–IS4 loops of domain I and a cluster of extracellular cysteines in the IS1–IS2 loop. Patch clamp recording of recombinant Cav3.2 currents revealed that two cysteine-modifying agents, sodium (2-sulfonatoethyl) methanethiosulfonate (MTSES) and N-ethylmaleimide, as well as a reactive oxygen species–producing neuropeptide, substance P (SP), inhibit Cav3.2 current to similar degrees and that this inhibition is reversed by a reducing agent and a zinc chelator. Pre-application of MTSES prevented further SP-mediated current inhibition. Substitution of the zinc-binding residue His191 in Cav3.2 reduced the channel's sensitivity to MTSES, and introduction of the corresponding histidine into Cav3.1 sensitized it to MTSES. Removal of extracellular cysteines from the IS1–IS2 loop of Cav3.2 reduced its sensitivity to MTSES and SP. We hypothesize that oxidative modification of IS1–IS2 loop cysteines induces allosteric changes in the zinc-binding site of Cav3.2 so that it becomes sensitive to ambient zinc. Full Article
ed Atomic force microscopy-based characterization of the interaction of PriA helicase with stalled DNA replication forks [DNA and Chromosomes] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 In bacteria, the restart of stalled DNA replication forks requires the DNA helicase PriA. PriA can recognize and remodel abandoned DNA replication forks, unwind DNA in the 3'-to-5' direction, and facilitate the loading of the helicase DnaB onto the DNA to restart replication. Single-stranded DNA–binding protein (SSB) is typically present at the abandoned forks, but it is unclear how SSB and PriA interact, although it has been shown that the two proteins interact both physically and functionally. Here, we used atomic force microscopy to visualize the interaction of PriA with DNA substrates with or without SSB. These experiments were done in the absence of ATP to delineate the substrate recognition pattern of PriA before its ATP-catalyzed DNA-unwinding reaction. These analyses revealed that in the absence of SSB, PriA binds preferentially to a fork substrate with a gap in the leading strand. Such a preference has not been observed for 5'- and 3'-tailed duplexes, suggesting that it is the fork structure that plays an essential role in PriA's selection of DNA substrates. Furthermore, we found that in the absence of SSB, PriA binds exclusively to the fork regions of the DNA substrates. In contrast, fork-bound SSB loads PriA onto the duplex DNA arms of forks, suggesting a remodeling of PriA by SSB. We also demonstrate that the remodeling of PriA requires a functional C-terminal domain of SSB. In summary, our atomic force microscopy analyses reveal key details in the interactions between PriA and stalled DNA replication forks with or without SSB. Full Article
ed Structure-based discovery of a small-molecule inhibitor of methicillin-resistant Staphylococcus aureus virulence [Molecular Biophysics] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 The rapid emergence and dissemination of methicillin-resistant Staphylococcus aureus (MRSA) strains poses a major threat to public health. MRSA possesses an arsenal of secreted host-damaging virulence factors that mediate pathogenicity and blunt immune defenses. Panton–Valentine leukocidin (PVL) and α-toxin are exotoxins that create lytic pores in the host cell membrane. They are recognized as being important for the development of invasive MRSA infections and are thus potential targets for antivirulence therapies. Here, we report the high-resolution X-ray crystal structures of both PVL and α-toxin in their soluble, monomeric, and oligomeric membrane-inserted pore states in complex with n-tetradecylphosphocholine (C14PC). The structures revealed two evolutionarily conserved phosphatidylcholine-binding mechanisms and their roles in modulating host cell attachment, oligomer assembly, and membrane perforation. Moreover, we demonstrate that the soluble C14PC compound protects primary human immune cells in vitro against cytolysis by PVL and α-toxin and hence may serve as the basis for the development of an antivirulence agent for managing MRSA infections. Full Article
ed Tracking isotopically labeled oxidants using boronate-based redox probes [Methods and Resources] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Reactive oxygen and nitrogen species have been implicated in many biological processes and diseases, including immune responses, cardiovascular dysfunction, neurodegeneration, and cancer. These chemical species are short-lived in biological settings, and detecting them in these conditions and diseases requires the use of molecular probes that form stable, easily detectable, products. The chemical mechanisms and limitations of many of the currently used probes are not well-understood, hampering their effective applications. Boronates have emerged as a class of probes for the detection of nucleophilic two-electron oxidants. Here, we report the results of an oxygen-18–labeling MS study to identify the origin of oxygen atoms in the oxidation products of phenylboronate targeted to mitochondria. We demonstrate that boronate oxidation by hydrogen peroxide, peroxymonocarbonate, hypochlorite, or peroxynitrite involves the incorporation of oxygen atoms from these oxidants. We therefore conclude that boronates can be used as probes to track isotopically labeled oxidants. This suggests that the detection of specific products formed from these redox probes could enable precise identification of oxidants formed in biological systems. We discuss the implications of these results for understanding the mechanism of conversion of the boronate-based redox probes to oxidant-specific products. Full Article
ed Templated folding of intrinsically disordered proteins [Molecular Biophysics] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Much of our current knowledge of biological chemistry is founded in the structure-function relationship, whereby sequence determines structure that determines function. Thus, the discovery that a large fraction of the proteome is intrinsically disordered, while being functional, has revolutionized our understanding of proteins and raised new and interesting questions. Many intrinsically disordered proteins (IDPs) have been determined to undergo a disorder-to-order transition when recognizing their physiological partners, suggesting that their mechanisms of folding are intrinsically different from those observed in globular proteins. However, IDPs also follow some of the classic paradigms established for globular proteins, pointing to important similarities in their behavior. In this review, we compare and contrast the folding mechanisms of globular proteins with the emerging features of binding-induced folding of intrinsically disordered proteins. Specifically, whereas disorder-to-order transitions of intrinsically disordered proteins appear to follow rules of globular protein folding, such as the cooperative nature of the reaction, their folding pathways are remarkably more malleable, due to the heterogeneous nature of their folding nuclei, as probed by analysis of linear free-energy relationship plots. These insights have led to a new model for the disorder-to-order transition in IDPs termed “templated folding,” whereby the binding partner dictates distinct structural transitions en route to product, while ensuring a cooperative folding. Full Article
ed A neuroglobin-based high-affinity ligand trap reverses carbon monoxide-induced mitochondrial poisoning [Molecular Biophysics] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Carbon monoxide (CO) remains the most common cause of human poisoning. The consequences of CO poisoning include cardiac dysfunction, brain injury, and death. CO causes toxicity by binding to hemoglobin and by inhibiting mitochondrial cytochrome c oxidase (CcO), thereby decreasing oxygen delivery and inhibiting oxidative phosphorylation. We have recently developed a CO antidote based on human neuroglobin (Ngb-H64Q-CCC). This molecule enhances clearance of CO from red blood cells in vitro and in vivo. Herein, we tested whether Ngb-H64Q-CCC can also scavenge CO from CcO and attenuate CO-induced inhibition of mitochondrial respiration. Heart tissue from mice exposed to 3% CO exhibited a 42 ± 19% reduction in tissue respiration rate and a 33 ± 38% reduction in CcO activity compared with unexposed mice. Intravenous infusion of Ngb-H64Q-CCC restored respiration rates to that of control mice correlating with higher electron transport chain CcO activity in Ngb-H64Q-CCC–treated compared with PBS-treated, CO-poisoned mice. Further, using a Clark-type oxygen electrode, we measured isolated rat liver mitochondrial respiration in the presence and absence of saturating solutions of CO (160 μm) and nitric oxide (100 μm). Both CO and NO inhibited respiration, and treatment with Ngb-H64Q-CCC (100 and 50 μm, respectively) significantly reversed this inhibition. These results suggest that Ngb-H64Q-CCC mitigates CO toxicity by scavenging CO from carboxyhemoglobin, improving systemic oxygen delivery and reversing the inhibitory effects of CO on mitochondria. We conclude that Ngb-H64Q-CCC or other CO scavengers demonstrate potential as antidotes that reverse the clinical and molecular effects of CO poisoning. Full Article
ed Protecting the Environment in Areas Affected by Armed Conflict By feedproxy.google.com Published On :: Fri, 27 Sep 2019 13:10:01 +0000 Members Event 15 October 2019 - 6:00pm to 7:00pm Chatham House | 10 St James's Square | London | SW1Y 4LE Event participants Dr Marja Lehto, Special Rapporteur, International Law Commission, UNDoug Weir, Research and Policy Director, The Conflict and Environment ObservatoryChair: Elizabeth Wilmshurst CMG, Distinguished Fellow, International Law Programme, Chatham House In 2011, the UN’s International Law Commission first included the ‘protection of the environment in relation to armed conflicts’ in its programme of work. Earlier this year, the Drafting Committee provisionally endorsed 28 legal principles intended to mitigate environmental degradation before, during and after conflicts. These addressed issues ranging from the pillage of natural resources to corporate environmental conduct and the environmental stress caused by population displacement. Special Rapporteur Dr Marja Lehto and a panel of experts will discuss some of the environmental issues arising from armed conflict and how these can be tackled. What are the International Law Commission’s recommendations and to what extent are stakeholders engaging with the work? In what sense are parties to the conflict, including governments, rebel groups and civil society, accountable for environmental devastation?And, looking beyond the environmental consequences of war, what is the role of climate change in driving insecurity and triggering conflict in the first place? Members Events Team Email Full Article
ed Breaking the Habit: Why Major Oil Companies Are Not ‘Paris-Aligned’ By feedproxy.google.com Published On :: Mon, 07 Oct 2019 14:50:01 +0000 Invitation Only Research Event 23 October 2019 - 8:30am to 10:00am Chatham House | 10 St James's Square | London | SW1Y 4LE Event participants Andrew Grant, Carbon Tracker InitiativeChair: Siân Bradley, Research Fellow, Energy, Environment and Resources, Chatham House The investment community is increasingly seeking to assess the alignment of their portfolios with the Paris Agreement. In a recent update to their Two Degrees of Separation report, Carbon Tracker assessed the capital expenditure of listed oil and gas producers against ‘well below’ 2C targets, and for the first time, against short-term actions at the project level.The speaker will present the key findings of the report and will argue that every oil major is betting heavily against a low-carbon world by investing in projects that are contrary to the Paris goals.This roundtable discussion will further explore the report findings and consider what investors, regulators and oil and gas companies can do to encourage alignment with the Paris Agreement ahead of 2020. Attendance at this event is by invitation only. Event attributes Chatham House Rule Department/project Energy, Environment and Resources Programme Full Article
ed How Qatar’s Food System Has Adapted to the Blockade By feedproxy.google.com Published On :: Thu, 14 Nov 2019 14:43:46 +0000 14 November 2019 Laura Wellesley Research Fellow, Energy, Environment and Resources Programme @laurawellesley 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. Full Article
ed Maintaining Connections: How Might the UK Remain Engaged in the EU's Climate and Energy Strategies? By feedproxy.google.com Published On :: Thu, 23 Jan 2020 10:35:01 +0000 Invitation Only Research Event 3 March 2020 - 10:30am to 12:00pm Chatham House | 10 St James's Square | London | SW1Y 4LE As the UK leaves the EU and the formal negotiations on the future relationship begins, this workshop will discuss any immediate changes and review the short and medium term impacts of Brexit on the energy sector. The workshop will look to cover:The implications for UK business and system operations of the UK leaving the Internal Energy Market.Current and future investment trends in the UK energy system.The trade of electricity and gas over inter-connectors.The need for the development of a new EU-UK operational framework mechanism.The UK's EU withdrawal agreement and the operation of the Single Electricity Market (SEM) across Ireland. Options for the UK outside of the EU Emissions Trading System (ETS) and the impact on carbon prices.This workshop is part of a programme funded by the UK Energy Research Centre on Brexit and the UK’s Net Zero Energy Policy being run by the University of Warwick and Chatham House.Attendance at this event is by invitation only. Event attributes Chatham House Rule Department/project Energy, Environment and Resources Programme Chloé Prendleloup Email Full Article
ed The prospects of carbon dioxide removal in climate policymaking within the United States By feedproxy.google.com Published On :: Fri, 14 Feb 2020 10:40:01 +0000 Research Event 19 November 2019 - 9:00am to 5:00pm School of Law, University of California, Davis Agendapdf | 158.8 KB Meeting Summarypdf | 207.92 KB This meeting formed part of a programme of work which investigates the role of negative emissions technologies (NETs) in achieving the Paris Agreement climate targets. Previous meetings held in London and Brussels have looked at integrating negative emissions into EU policy-making, the implications and degree to which NETs, and in particular bioenergy with carbon capture storage (BECCS), can be an effective climate mitigation tool. This meeting focused on the possible deployment pathways of NETs and alternatives to BECCS for the US in particular, in the context of geographical constraints and socioenvironmental implications, the role of the private sector, and appropriate governance and finance mechanisms. Department/project Energy, Environment and Resources Programme, Bioenergy, Carbon Capture and Storage (BECCS) Melissa MacEwen Project Manager, Energy, Environment and Resources Programme Email Full Article
ed Global aid and faith actors: the case for an actor-orientated approach to the ‘turn to religion’ By feedproxy.google.com Published On :: Wed, 04 Mar 2020 13:00:22 +0000 4 March 2020 , Volume 96, Number 2 Emma Tomalin Read Online In this article, drawing on the work of the development sociologist Norman Long, I make the case for an actor-oriented approach to understanding the ‘turn to religion’ by global aid actors over the past couple of decades. I ask, is the ‘turn to religion’ evidence of the emergence of post-secular partnerships or are faith actors being instrumentalized to serve neo-liberal development goals? I argue that neither option captures the whole story and advocate that the study of religion and development needs to move beyond a binary between the ‘turn to religion’ as either evidence of post-secular partnerships or of the ‘instrumentalization’ of religion by the secular global aid business, and instead to think about how faith actors themselves encounter and shape development discourses and frameworks, translate them into relevant formats and strategically employ them. Alongside the adoption of an actor-orientated approach, I build on the work of Lewis and Mosse, Olivier de Sardan and Bierschenk to view international faith-based organizations (IFBOs) as development brokers and translators. This approach allows me to articulate the distinctive role that many members of IFBOs report they play as intermediaries who shift register between the secular development language and the faith-inspired language of their local faith partners. I take the engagement of faith actors with the new Sustainable Development Goals framework as a case-study to explore this. Full Article
ed Why an Inclusive Circular Economy is Needed to Prepare for Future Global Crises By feedproxy.google.com Published On :: Wed, 15 Apr 2020 13:23:01 +0000 15 April 2020 Patrick Schröder Senior Research Fellow, Energy, Environment and Resources Programme @patricks_CH Google Scholar The risks associated with existing production and consumption systems have been harshly exposed amid the current global health crisis but an inclusive circular economy could ensure both short-term and long-term resilience for future challenges. 2020-04-15-Waste-Collection-Peru.jpg Lima city employees picking up garbage during lockdown measures in Peru amid the COVID-19 crisis. Photo: Getty Images. The world is currently witnessing how vulnerable existing production and consumption systems are, with the current global health crisis harshly exposing the magnitude of the risks associated with the global economy in its current form, grounded, as it is, in a linear system that uses a ‘take–make–throw away’ approach.These ‘linear risks’ associated with the existing global supply chain system are extremely high for national economies overly dependent on natural resource extraction and exports of commodities like minerals and metals. Equally vulnerable are countries with large manufacturing sectors of ready-made garments and non-repairable consumer goods for western markets. Furthermore, workers and communities working in these sectors are vulnerable to these changes as a result of disruptive technologies and reduced demand.In a recently published Chatham House research paper, ‘Promoting a Just Transition to an Inclusive Circular Economy’, we highlight why a circular economy approach presents the world with a solution to old and new global risks – from marine plastic pollution to climate change and resource scarcity.Taking the long viewSo far, action to transition to a circular economy has been slow compared to the current crisis which has mobilized rapid global action. For proponents of transitioning to a circular economy, this requires taking the long view. The pandemic has shown us that global emergencies can fast-forward processes that otherwise might take years, even decades, to play out or reverse achievements which have taken years to accomplish.In this vein, there are three striking points of convergence between the COVID-19 pandemic and the need to transition to an inclusive circular economy.Firstly, the current crisis is a stark reminder that the circular economy is not only necessary to ensure long-term resource security but also short-term supplies of important materials. In many cities across the US, the UK and Europe, councils have suspended recycling to focus on essential waste collection services. The UK Recycling Association, for example, has warned about carboard shortages due to disrupted recycling operations with possible shortages for food and medicine packaging on the horizon.Similarly, in China, most recycling sites were shut during the country’s lockdown presenting implications for global recycling markets with additional concerns that there will be a fibre shortage across Europe and possibly around the world.Furthermore, worldwide COVID-19 lockdowns are resulting in a resurgence in the use of single-use packaging creating a new wave of plastic waste especially from food deliveries – already seen in China – with illegal waste fly-tipping dramatically increasing in the UK since the lockdown.In this vein, concerns over the current global health crisis is reversing previous positive trends where many cities had established recycling schemes and companies and consumers had switched to reusable alternatives.Secondly, the need to improve the working conditions of the people working in the informal circular economy, such as waste pickers and recyclers, is imperative. Many waste materials and recyclables that are being handled and collected may be contaminated as a result of being mixed with medical waste.Now, more than ever, key workers in waste management, collection and recycling require personal protective equipment and social protection to ensure their safety as well as the continuation of essential waste collection so as not to increase the potential for new risks associated with additional infectious diseases.In India, almost 450 million workers including construction workers, street vendors and landless agricultural labourers, work in the informal sector. In the current climate, the poorest who are unable to work pose a great risk to the Indian economy which could find itself having to shut down.Moreover, many informal workers live in make-shift settlements areas such as Asia’s largest slum, Dharavi in Mumbai, where health authorities are now facing serious challenges to contain the spread of the disease. Lack of access to handwashing and sanitation facilities, however, further increase these risks but circular, decentralized solutions could make important contributions to sustainable sanitation, health and improved community resilience.Thirdly, it is anticipated that in the long term several global supply chains will be radically changed as a result of transformed demand patterns and the increase in circular practices such as urban mining for the recovery and recycling of metals or the reuse and recycling of textile fibres and localized additive manufacturing (e.g. 3D printing).Many of these supply chains and trade flows have now been already severely disrupted due to the COVID-19 pandemic. For example, the global garment industry has been particularly hard-hit due to the closure of outlets amid falling demand for apparel.It is important to note, workers at the bottom of these garment supply chains are among the most vulnerable and most affected by the crisis as global fashion brands, for example, have been cancelling orders – in the order of $6 billion in the case of Bangladesh alone. Only after intense negotiations are some brands assuming financial responsibility in the form of compensation wage funds to help suppliers in Myanmar, Cambodia and Bangladesh to pay workers during the ongoing crisis.In addition, the current pandemic is damaging demand for raw materials thereby affecting mining countries. Demand for Africa’s commodities in China, for example, has declined significantly, with the impact on African economies expected to be serious, with 15 per cent of the world’s copper and 20 per cent of the world’s zinc mines currently going offline. A further threat is expected to come from falling commodity prices as a result of the curtailment of manufacturing activity in China particularly for crude oil, copper, iron ore and other industrial commodities which, in these cases, will have direct impacts on the Australian and Canadian mining sectors.This is all being compounded by an associated decline in consumer demand worldwide. For example, many South African mining companies – leading producers of metals and minerals – have started closing their mining operations following the government’s announcement of a lockdown in order to prevent the transmission of the virus among miners who often work in confined spaces and in close proximity with one another. As workers are laid off due to COVID-19, there are indications that the mining industry will see fast-tracking towards automated mining operations. All of these linear risks that have been exposed through the COVID-19 pandemic reinforce the need for a just transition to a circular economy. But while the reduction in the consumption of resources is necessary to achieve sustainability, the social impacts on low- and middle- income countries and their workers requires international support mechanisms.In addition, the current situation also highlights the need to find a new approach to globalized retail chains and a balance between local and global trade based on international cooperation across global value chains rather than implementation of trade protectionist measures.In this vein, all of the recovery plans from the global COVID-19 pandemic need to be aligned with the principles of an inclusive circular economy in order to ensure both short-term and long-term resilience and preparedness for future challenges and disruptions. Full Article
ed Privileging Local Food is Flawed Solution to Reduce Emissions By feedproxy.google.com Published On :: Thu, 23 Apr 2020 13:59:11 +0000 23 April 2020 Christophe Bellmann Associate Fellow, Hoffmann Centre for Sustainable Resource Economy LinkedIn The COVID-19 pandemic has brought food security and food imports to the forefront again. Some fear that the crisis could quickly strain global food supply chains as countries adopt new trade restrictions to avoid domestic food shortages. 2020-04-23-Trade-Food-Apples Apples being picked before going into cold storage so they can be bought up until Christmas. Photo by Suzanne Kreiter/The Boston Globe via Getty Images. The pressure of the coronavirus pandemic is adding to a widely held misconception that trade in food products is bad for the environment due to the associated ‘food miles’ – the carbon footprint of agricultural products transported over long distances.This concept, developed by large retailers a decade ago, is often invoked as a rationale for restricting trade and choosing locally-produced food over imports. Consuming local food may seem sensible at first glance as it reduces the carbon footprint of goods and generates local employment. However, this assumption ignores the emissions produced during the production, processing or storage stages which often dwarf transport emissions. Other avenues to address the climate change impact of trade are more promising.Demystifying food emissionsIn the US, for example, food items travel more than 8,000 km on average before reaching the consumer. Yet transport only accounts for 11 per cent of total emissions with 83 per cent – mostly nitrous oxide (N2O) and methane (CH4) emissions – occurring at the production stage.US Department of Agriculture data on energy use in the American food system echoes this finding, showing that processing, packaging, and selling of food represent ten times the energy used to transport food.In practice, it may be preferable from an environmental perspective to consume lamb, onion or dairy products transported by sea because the lower emissions generated at the production stage offset those resulting from transport. Similarly, growing tomatoes under heated greenhouses in Sweden is often more emissions-intensive than importing open-grown ones from Southern Europe.Seasonality also matters. British apples placed in storage for ten months leads to twice the level of emissions as that of South American apples sea-freighted to the UK. And the type of transport is also important as, overall, maritime transport generates 25 to 250 times less emissions than trucks, and air freight generates on average five times more emissions than road transport.Therefore, air-freighted Kenyan beans have a much larger carbon footprint than those produced in the UK, but crossing Europe by truck to import Italian wine might generate more emissions than transatlantic shipments.Finally, one should take into account the last leg of transport. A consumer driving more than 10 km to purchase 1 kg of fresh produce will generate proportionately more greenhouse gas (GHG) emissions than air-freighting 1 kg of produce from Kenya.Shifting consumption towards local foods may reduce GHG emissions in sectors with relatively low emissions intensities but, when non-carbon dioxide emissions are taken into account, this is more often the exception than the rule.Under these circumstances, preventing trade is an inefficient and expensive way of reducing GHG emissions. Bureau et al. for example, calculate that a global tariff maintaining the volume of trade at current levels until 2030 may reduce global carbon dioxide emissions by 3.5 per cent. However, this would be roughly seven times less than the full implementation of the Paris Agreement and cost equivalent to the current GDP of Brazil or 1.8 per cent of world GDP.By preventing an efficient use of resources, such restrictions would also undermine the role of trade in offsetting possible climate-induced production shortfalls in some parts of the world and allowing people to access food when they can’t produce it themselves.Reducing the climate footprint of tradeThis is not to say that nothing should be done to tackle transport emissions. The OECD estimates that international trade-related freight accounted for over 5 per cent of total global fuel emissions with shipping representing roughly half of it, trucks 40 per cent, air 6 per cent and rail 2 per cent. With the projected tripling of freight transport by 2050, emissions from shipping are expected to rise between 50 and 250 per cent.Furthermore, because of their international nature, these emissions are not covered by the Paris Agreement. Instead the two UN agencies regulating these sectors – the International Civil Aviation Organization and the International Maritime Organization – are responsible for reducing these emissions and, so far, significant progress has proven elusive.Regional or bilateral free trade agreements to further stimulate trade could address this problem by exploiting comparative advantages. Impact assessments of those agreements often point towards increases in GHG emissions due to a boost in trade flows. In the future, such agreements could incorporate – or develop in parallel – initiatives to ensure carbon neutrality by connecting carbon markets among contracting parties or by taxing international maritime and air transport emissions.Such initiatives could be combined with providing additional preferences in the form of enhanced market access to low-carbon food and healthier food. The EU, as one of the chief proponents of bilateral and regional trade agreements and a leader in promoting a transition to a low-carbon economy could champion such an approach.This article is part of a series from the Chatham House Global Trade Policy Forum, designed to promote research and policy recommendations on the future of global trade. It is adapted from the research paper, Delivering Sustainable Food and Land Use Systems: The Role of International Trade, authored by Christophe Bellmann, Bernice Lee and Jonathan Hepburn. Full Article
ed Episode 19: Django Unchained By feedproxy.google.com Published On :: Fri, 04 Jan 2013 05:17:00 +0000 Django Unchained ReviewDiscussion on Tarantino: The DirectorWhat We Watched: Not MuchWhat Game Jason Loves? A: Tokyo JungleYou can listen or download the episode here. (Right click to save) Email us at thefilmclubpodcast@gmail.com or leave us a voicemail at 773-245-3476. Full Article
ed Episode 21: Zero Dark Thirty & Most Anticipated of 2013 By feedproxy.google.com Published On :: Fri, 18 Jan 2013 19:17:00 +0000 Zero Dark Thirty ReviewOur Top 10 Most Anticipated Films of 2013What We Watched: Jiro: Dreams of Sushi, Take This Waltz, Futurama, The Great Happiness Space, Indie Game: The Movie, Somewhere Between, Lincoln & Chasing GhostsYou can listen to or download our episode here. (right click to save) Next Episode: Reviews of Mama and The Last StandThanks again to Jim and Patrick from The Director's Club Podcast for their support.If you'd like to check out their podcast go here: http://directorsclubpodcast.comIf you would like to read Jim's awesome blog on why he loves movie podcasts, go here: http://instantjim.com/post/40536863106/moviepodcasts2012 Full Article
ed Towards an Outcome-Oriented Food and Agricultural Aid and Development System By feedproxy.google.com Published On :: Mon, 29 Jul 2019 12:35:02 +0000 Invitation Only Research Event 21 May 2019 - 9:00am to 24 May 2019 - 5:00pm The Rockefeller Foundation, Bellagio Center, Italy Chatham House, in partnership with the European Centre for Development Policy Management (ECDPM), convened leading experts and key stakeholders to consider how the system of global institutions that provide aid and finance, global public goods and technical assistance to low-income countries can be better aligned to support the realization of SDG 2 in the context of those countries’ own efforts with a focus on SDGs 2.3 and 2.4.This meeting aimed to contribute to an outcome-oriented food and agricultural aid development system; create greater understanding of the comparative advantages of key institutions, areas of duplication or inefficiency and gaps; identify topics for further research and analysis; and identify key near-term political moments to focus the community and catalyze steps towards change. Event attributes Chatham House Rule Department/project Global Health Programme Alexandra Squires McCarthy Programme Coordinator, Global Health Programme +44 (0)207 314 2789 Email Full Article
ed Reviewing Antimicrobial Resistance: Where Are We Now and What Needs to Be Done? By feedproxy.google.com Published On :: Fri, 30 Aug 2019 14:55:01 +0000 Research Event 8 October 2019 - 10:30am to 12:00pm RSA House, 8 John Adam Street, London, WC2N 6EZ Event participants Tim Jinks, Head of Drug-Resistant Infections Programme, WellcomeJim O’Neill, Chair, Review on Antimicrobial Resistance; Chair, Chatham HouseHaileyesus Getahun, Director of Global Coordination and Partnership on Antimicrobial Resistance, World Health Organization Juan Lubroth, Chief Veterinary Officer, Food and Agriculture Organization (Videolink)Jyoti Joshi, Head, South Asia, Center for Disease Dynamics, Economics & PolicyEstelle Mbadiwe, Coordinator-Nigeria, Global Antibiotic Resistance PartnershipCharles Clift, Senior Consulting Fellow, Chatham House; Report Author The Review on Antimicrobial Resistance, chaired by Jim O’Neill, was commissioned by former UK prime minister, David Cameron, in July 2014. Supported by the UK government and the Wellcome Trust, the final report of the review was published in May 2016 and has had a global impact in terms of motivating political leaders and decision-makers to take more seriously the threat posed by antimicrobial resistance.Yet there is now a perception that the political momentum to address the issue is waning and needs to be reinvigorated.In a further report produced by Chatham House, the progress of the recommendations of the review is assessed and the key ways to move forward are identified.Panellists at this event, where highlights of the report are presented, provide their assessment of the progress so far and discuss priorities for future action.The report was funded by Wellcome. Department/project Global Health Programme, Antimicrobial Resistance Alexandra Squires McCarthy Programme Coordinator, Global Health Programme +44 (0)207 314 2789 Email Full Article
ed Strengthening National Accountability and Preparedness for Global Health Security (SNAP-GHS) By feedproxy.google.com Published On :: Thu, 19 Dec 2019 15:43:55 +0000 The project aims to identify the enablers and barriers to enhance data use by National Public Health Institutes (NPHIs), producing outputs that will facilitate strengthening of the role of NPHIs in monitoring potential public health threats, and in shaping and informing domestic policies on health security and preparedness. Global health security is underpinned by the actions taken at a national level to ensure capacities exist to sufficiently prepare for and respond to acute threats and crises. In many contexts, National Public Health Institutes (NPHIs) were first established because of, and in response to, specific public health challenges typically related to infectious diseases.The Strengthening National Accountability and Preparedness for Global Health Security (SNAP-GHS) project evolved from a series of roundtables and discussions hosted by the Centre on Global Health Security at Chatham House, in collaboration with the Graduate Institute of Geneva.The outcome of the project is a SNAP-GHS Toolkit to support NPHIs in better diagnosing and understanding the challenges to data use within their own institutes, as well as in relation to external stakeholders and agencies. The toolkit is intended to be used for further circulation and dissemination by the International Association of National Public Health Institutes (IANPHI).The project is led by the Centre on Global Health Security at Chatham House in collaboration with the Ethiopian Public Health Institute, the Nigeria Centre for Disease Control, and the National Institute for Health in Pakistan. Full Article
ed New Coronavirus Outbreak: Concern Is Warranted, Panic Is Not By feedproxy.google.com Published On :: Thu, 23 Jan 2020 12:03:21 +0000 23 January 2020 Professor David Heymann CBE Distinguished Fellow, Global Health Programme Lara Hollmann Research Assistant, Global Health Programme @lara_hollmann LinkedIn Whenever there is a new infection in humans, such as the novel coronavirus, it is appropriate to be concerned because we do not know enough about its potential. Explainer: Coronavirus - What You Need to Know World-renowned global health expert Professor David Heymann CBE explains the key facts and work being done on the Coronavirus outbreak. When it comes to emerging infectious diseases – those newly recognized in humans or in new locations – it is not only what we know that matters but also what we do not know.An outbreak of a new coronavirus first reported in Wuhan, China, which has so far led to more than 500 confirmed cases and multiple deaths across five countries (and two continents) has prompted the question from several corners of the world: Should we be worried?Although expert teams coordinated by the World Health Organization (WHO) are working on key questions to get answers as soon as possible, the level of uncertainty is still high.We do not yet know exactly how deadly the disease is, how best to treat those who get sick, precisely how it is spreading, nor how stable the virus is. It is thought that the virus spread from an animal source, but the exact source is yet to be confirmed and the disease is now in human populations and appears to be spreading from human to human.It is such uncertainty, inherent in emerging infectious disease outbreaks, that warrants concern. Until they are resolved, it is appropriate for the world to be concerned. It is useful to remember that most established scourges of humanity such as HIV, influenza and tuberculosis likely started as emerging infectious diseases that jumped the species barrier from animals to humans.Shortly after the Chinese authorities reported the first cases of ‘mystery pneumonia’ in Wuhan, China, to WHO, the virus causing the disease was isolated and identified as being part of the coronavirus family. It belongs to the same virus family as SARS, a highly contagious and life-threatening coronavirus that caused a nine-month epidemic in 2003 that affected 26 countries and resulted in more than 8,000 infections and nearly 800 deaths.A second novel coronavirus that emerged in 2012 and persists today – MERS, or Middle East Respiratory Syndrome – is less contagious (spread by close contact rather than coughing and sneezing).The differences between the SARS coronavirus and the MERS coronavirus highlight that, despite belonging to the same virus family, pathogens do not necessarily behave in the same way. It is as yet unknown whether the new virus is, or will turn out to be, more like SARS or MERS, or neither. Chinese authorities have confirmed that there is human-to-human transmission. However, it is not yet established whether it is sustained, which would make the outbreak more difficult to control. As of 23 January, the number of cases range from 500 confirmed cases up to an estimated 1,700 cases, according to a disease outbreak model by Imperial College London.Likewise, we do not know to what extent the virus is able to mutate and if so, how rapidly. Generally, coronaviruses are known to be able to mutate, with the risk that a less contagious form of the virus becomes highly contagious. This could have an impact not only on the transmission pattern and rate but also the death rate. The virus could change in either direction, to become either more or less of a threat.It is important to take a precautionary approach while uncertainty persists. It is also important not to overreact and for measures to be scientifically sound. Concern over this outbreak is due, but panic is not.Three virtual networks of experts supporting the response – one of virologists, one of epidemiologists and one of clinicians – are working on the key pieces of the jigsaw puzzle: watching the virus, watching the transmission patterns, and watching the people who have been infected. It is crucial to maintain the ongoing investigation of the disease, stay focused on the science and to keep sharing the necessary information. Full Article
ed The Hurdles to Developing a COVID-19 Vaccine: Why International Cooperation is Needed By feedproxy.google.com Published On :: Thu, 23 Apr 2020 09:26:36 +0000 23 April 2020 Professor David Salisbury CB Associate Fellow, Global Health Programme LinkedIn Dr Champa Patel Director, Asia-Pacific Programme @patel_champa While the world pins its hopes on vaccines to prevent COVID-19, there are scientific, regulatory and market hurdles to overcome. Furthermore, with geopolitical tensions and nationalistic approaches, there is a high risk that the most vulnerable will not get the life-saving interventions they need. 2020-04-23-Covid-Vaccine.jpg A biologist works on the virus inactivation process in Belo Horizonte, Brazil on 24 March 2020. The Brazilian Ministry of Health convened The Technological Vaccine Center to conduct research on COVID-19 in order to diagnose, test and develop a vaccine. Photo: Getty Images. On 10 January 2020, Chinese scientists released the sequence of the COVID-19 genome on the internet. This provided the starting gun for scientists around the world to start developing vaccines or therapies. With at least 80 different vaccines in development, many governments are pinning their hopes on a quick solution. However, there are many hurdles to overcome. Vaccine developmentFirstly, vaccine development is normally a very long process to ensure vaccines are safe and effective before they are used. Safety is not a given: a recent dengue vaccine caused heightened disease in vaccinated children when they later were exposed to dengue, while Respiratory Syncytial Virus vaccine caused the same problem. Nor is effectiveness a given. Candidate vaccines that use novel techniques where minute fragments of the viruses’ genetic code are either injected directly into humans or incorporated into a vaccine (as is being pursued, or could be pursued for COVID-19) have higher risks of failure simply because they haven’t worked before. For some vaccines, we know what levels of immunity post-vaccination are likely to be protective. This is not the case for coronavirus. Clinical trials will have to be done for efficacy. This is not optional – regulators will need to know extensive testing has taken place before licencing any vaccine. Even if animal tests are done in parallel with early human tests, the remainder of the process is still lengthy. There is also great interest in the use of passive immunization, whereby antibodies to SARS-CoV-2 (collected from people who have recovered from infection or laboratory-created) are given to people who are currently ill. Antivirals may prove to be a quicker route than vaccine development, as the testing requirements would be shorter, manufacturing may be easier and only ill people would need to be treated, as opposed to all at-risk individuals being vaccinated.Vaccine manufacturingDevelopers, especially small biotechs, will have to make partnerships with large vaccine manufacturers in order to bring products to market. One notorious bottleneck in vaccine development is getting from proof-of-principle to commercial development: about 95 per cent of vaccines fail at this step. Another bottleneck is at the end of production. The final stages of vaccine production involve detailed testing to ensure that the vaccine meets the necessary criteria and there are always constraints on access to the technologies necessary to finalize the product. Only large vaccine manufacturers have these capacities. There is a graveyard of failed vaccine candidates that have not managed to pass through this development and manufacturing process.Another consideration is adverse or unintended consequences. Highly specialized scientists may have to defer their work on other new vaccines to work on COVID-19 products and production of existing products may have to be set aside, raising the possibility of shortages of other essential vaccines. Cost is another challenge. Vaccines for industrialized markets can be very lucrative for pharmaceutical companies, but many countries have price caps on vaccines. Important lessons have been learned from the 2009 H1N1 flu pandemic when industrialized countries took all the vaccines first. Supplies were made available to lower-income countries at a lower price but this was much later in the evolution of the pandemic. For the recent Ebola outbreaks, vaccines were made available at low or no cost. Geopolitics may also play a role. Should countries that manufacture a vaccine share it widely with other countries or prioritize their own populations first? It has been reported that President Trump attempted to purchase CureVac, a German company with a candidate vaccine. There are certainly precedents for countries prioritizing their own populations. With H1N1 flu in 2009, the Australian Government required a vaccine company to meet the needs of the Australian population first. Vaccine distributionGlobal leadership and a coordinated and coherent response will be needed to ensure that any vaccine is distributed equitably. There have been recent calls for a G20 on health, but existing global bodies such as the Coalition for Epidemic Preparedness Innovations (CEPI) and GAVI are working on vaccines and worldwide access to them. Any new bodies should seek to boost funding for these entities so they can ensure products reach the most disadvantaged. While countries that cannot afford vaccines may be priced out of markets, access for poor, vulnerable or marginalized peoples, whether in developed or developing countries, is of concern. Developing countries are at particular risk from the impacts of COVID-19. People living in conflict-affected and fragile states – whether they are refugees or asylum seekers, internally displaced or stateless, or in detention facilities – are at especially high risk of devastating impacts. Mature economies will also face challenges. Equitable access to COVID-19 vaccine will be challenging where inequalities and unequal access to essential services have been compromised within some political systems. The need for global leadership There is an urgent need for international coordination on COVID-19 vaccines. While the WHO provides technical support and UNICEF acts as a procurement agency, responding to coronavirus needs clarity of global leadership that arches over national interests and is capable of mobilizing resources at a time when economies are facing painful recessions. We see vaccines as a salvation but remain ill-equipped to accelerate their development.While everyone hopes for rapid availability of safe, effective and affordable vaccines that will be produced in sufficient quantities to meet everyone’s needs, realistically, we face huge hurdles. Full Article
ed Hepatic monoamine oxidase B is involved in endogenous geranylgeranoic acid synthesis in mammalian liver cells [Research Articles] By feedproxy.google.com Published On :: 2020-05-01T00:05:28-07:00 Geranylgeranoic acid (GGA) originally was identified in some animals and has been developed as an agent for preventing second primary hepatoma. We previously have also identified GGA as an acyclic diterpenoid in some medicinal herbs. Recently, we reported that in human hepatoma-derived HuH-7 cells, GGA is metabolically labeled from 13C-mevalonate. Several cell-free experiments have demonstrated that GGA is synthesized through geranylgeranial by oxygen-dependent oxidation of geranylgeraniol (GGOH), but the exact biochemical events giving rise to GGA in hepatoma cells remain unclear. Monoamine oxidase B (MOAB) has been suggested to be involved in GGOH oxidation. Here, using two human hepatoma cell lines, we investigated whether MAOB contributes to GGA biosynthesis. Using either HuH-7 cell lysates or recombinant human MAOB, we found that: 1) the MAO inhibitor tranylcypromine dose-dependently downregulates endogenous GGA levels in HuH-7 cells; and 2) siRNA-mediated MAOB silencing reduces intracellular GGA levels in HuH-7 and Hep3B cells. Unexpectedly, however, CRISPR/Cas9-generated MAOB-KO human hepatoma Hep3B cells had GGA levels similar to those in MAOB-WT cells. A sensitivity of GGA levels to siRNA-mediated MAOB downregulation was recovered when the MAOB-KO cells were transfected with a MAOB-expression plasmid, suggesting that MAOB is the enzyme primarily responsible for GGOH oxidation and that some other latent metabolic pathways may maintain endogenous GGA levels in the MAOB-KO hepatoma cells. Along with the previous findings, these results provide critical insights into the biological roles of human MAOB and provide evidence that hepatic MAOB is involved in endogenous GGA biosynthesis via GGOH oxidation. Full Article
ed A novel GPER antagonist protects against the formation of estrogen-induced cholesterol gallstones in female mice [Research Articles] By feedproxy.google.com Published On :: 2020-05-01T00:05:27-07:00 Many clinical studies and epidemiological investigations have clearly demonstrated that women are twice as likely to develop cholesterol gallstones as men, and oral contraceptives and other estrogen therapies dramatically increase that risk. Further, animal studies have revealed that estrogen promotes cholesterol gallstone formation through the estrogen receptor (ER) α, but not ERβ, pathway. More importantly, some genetic and pathophysiological studies have found that G protein-coupled estrogen receptor (GPER) 1 is a new gallstone gene, Lith18, on chromosome 5 in mice and produces additional lithogenic actions, working independently of ERα, to markedly increase cholelithogenesis in female mice. Based on computational modeling of GPER, a novel series of GPER-selective antagonists were designed, synthesized, and subsequently assessed for their therapeutic effects via calcium mobilization, cAMP, and ERα and ERβ fluorescence polarization binding assays. From this series of compounds, one new compound, 2-cyclohexyl-4-isopropyl-N-(4-methoxybenzyl)aniline (CIMBA), exhibits superior antagonism and selectivity exclusively for GPER. Furthermore, CIMBA reduces the formation of 17β-estradiol-induced gallstones in a dose-dependent manner in ovariectomized mice fed a lithogenic diet for 8 weeks. At 32 μg/day/kg CIMBA, no gallstones are found, even in ovariectomized ERα (–/–) mice treated with 6 μg/day 17β-estradiol and fed the lithogenic diet for 8 weeks. In conclusion, CIMBA treatment protects against the formation of estrogen-induced cholesterol gallstones by inhibiting the GPER signaling pathway in female mice. CIMBA may thus be a new agent for effectively treating cholesterol gallstone disease in women. Full Article
ed Nanodomains can persist at physiologic temperature in plasma membrane vesicles and be modulated by altering cell lipids [Research Articles] By feedproxy.google.com Published On :: 2020-05-01T00:05:27-07:00 The formation and properties of liquid-ordered (Lo) lipid domains (rafts) in the plasma membrane are still poorly understood. This limits our ability to manipulate ordered lipid domain-dependent biological functions. Giant plasma membrane vesicles (GPMVs) undergo large-scale phase separations into coexisting Lo and liquid-disordered lipid domains. However, large-scale phase separation in GPMVs detected by light microscopy is observed only at low temperatures. Comparing Förster resonance energy transfer-detected versus light microscopy-detected domain formation, we found that nanodomains, domains of nanometer size, persist at temperatures up to 20°C higher than large-scale phases, up to physiologic temperature. The persistence of nanodomains at higher temperatures is consistent with previously reported theoretical calculations. To investigate the sensitivity of nanodomains to lipid composition, GPMVs were prepared from mammalian cells in which sterol, phospholipid, or sphingolipid composition in the plasma membrane outer leaflet had been altered by cyclodextrin-catalyzed lipid exchange. Lipid substitutions that stabilize or destabilize ordered domain formation in artificial lipid vesicles had a similar effect on the thermal stability of nanodomains and large-scale phase separation in GPMVs, with nanodomains persisting at higher temperatures than large-scale phases for a wide range of lipid compositions. This indicates that it is likely that plasma membrane nanodomains can form under physiologic conditions more readily than large-scale phase separation. We also conclude that membrane lipid substitutions carried out in intact cells are able to modulate the propensity of plasma membranes to form ordered domains. This implies lipid substitutions can be used to alter biological processes dependent upon ordered domains. Full Article
ed Schnyder corneal dystrophy-associated UBIAD1 is defective in MK-4 synthesis and resists autophagy-mediated degradation [Research Articles] By feedproxy.google.com Published On :: 2020-05-01T00:05:27-07:00 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. Full Article
ed Vitamin E does not prevent Western diet-induced NASH progression and increases metabolic flux dysregulation in mice [Research Articles] By feedproxy.google.com Published On :: 2020-05-01T00:05:27-07:00 Fatty liver involves ectopic lipid accumulation and dysregulated hepatic oxidative metabolism, which can progress to a state of elevated inflammation and fibrosis referred to as nonalcoholic steatohepatitis (NASH). The factors that control progression from simple steatosis to NASH are not fully known. Here, we tested the hypothesis that dietary vitamin E (VitE) supplementation would prevent NASH progression and associated metabolic alterations induced by a Western diet (WD). Hyperphagic melanocortin-4 receptor-deficient (MC4R–/–) mice were fed chow, chow+VitE, WD, or WD+VitE starting at 8 or 20 weeks of age. All groups exhibited extensive hepatic steatosis by the end of the study (28 weeks of age). WD feeding exacerbated liver disease severity without inducing proportional changes in liver triglycerides. Eight weeks of WD accelerated liver pyruvate cycling, and 20 weeks of WD extensively upregulated liver glucose and oxidative metabolism assessed by 2H/13C flux analysis. VitE supplementation failed to reduce the histological features of NASH. Rather, WD+VitE increased the abundance and saturation of liver ceramides and accelerated metabolic flux dysregulation compared with 8 weeks of WD alone. In summary, VitE did not limit NASH pathogenesis in genetically obese mice, but instead increased some indicators of metabolic dysfunction. Full Article
ed Hematopoiesis is regulated by cholesterol efflux pathways and lipid rafts: connections with cardiovascular diseases [Thematic Reviews] By feedproxy.google.com Published On :: 2020-05-01T00:05:27-07:00 Lipid rafts are highly ordered regions of the plasma membrane that are enriched in cholesterol and sphingolipids and play important roles in many cells. In hematopoietic stem and progenitor cells (HSPCs), lipid rafts house receptors critical for normal hematopoiesis. Lipid rafts also can bind and sequester kinases that induce negative feedback pathways to limit proliferative cytokine receptor cycling back to the cell membrane. Modulation of lipid rafts occurs through an array of mechanisms, with optimal cholesterol efflux one of the major regulators. As such, cholesterol homeostasis also regulates hematopoiesis. Increased lipid raft content, which occurs in response to changes in cholesterol efflux in the membrane, can result in prolonged receptor occupancy in the cell membrane and enhanced signaling. In addition, certain diseases, like diabetes, may contribute to lipid raft formation and affect cholesterol retention in rafts. In this review, we explore the role of lipid raft-related mechanisms in hematopoiesis and CVD (specifically, atherosclerosis) and discuss how defective cholesterol efflux pathways in HSPCs contribute to expansion of lipid rafts, thereby promoting myelopoiesis and thrombopoiesis. We also discuss the utility of cholesterol acceptors in contributing to lipid raft regulation and disruption, and highlight the potential to manipulate these pathways for therapeutic gain in CVD as well as other disorders with aberrant hematopoiesis. Full Article
ed GPIHBP1, a partner protein for lipoprotein lipase, is expressed only in capillary endothelial cells [Images In Lipid Research] By feedproxy.google.com Published On :: 2020-05-01T00:05:27-07:00 Full Article
ed Images in Lipid Research [Editorials] By feedproxy.google.com Published On :: 2020-05-01T00:05:27-07:00 Full Article
ed 5 things you need to know to understand the Iran-US crisis By feedproxy.google.com Published On :: Wed, 15 Jan 2020 12:28:24 +0000 Source CNN URL https://edition.cnn.com/2020/01/08/middleeast/trump-qasem-soleimani-iran-us-iraq... Release date 08 January 2020 Expert Dr Leslie Vinjamuri In the news type Op-ed Hide date on homepage Full Article
ed Bolivia’s Ousted President Is Not Done Fighting For His Job By feedproxy.google.com Published On :: Wed, 15 Jan 2020 12:30:32 +0000 Source VICE URL https://www.vice.com/en_us/article/9ke4bp/bolivias-ousted-president-is-not-done-... Release date 15 November 2019 Expert Dr Christopher Sabatini In the news type Op-ed Hide date on homepage Full Article
ed Why France is focused on fighting jihadists in Mali By feedproxy.google.com Published On :: Wed, 15 Jan 2020 12:34:51 +0000 Source BBC URL https://www.bbc.co.uk/news/world-africa-50558972 Release date 27 November 2019 Expert Paul Melly In the news type Op-ed Hide date on homepage Full Article
ed Russia and Turkey failed to mediate peace in Libya. What happens now? By feedproxy.google.com Published On :: Fri, 17 Jan 2020 16:04:19 +0000 Source The Washington Post URL https://www.washingtonpost.com/politics/2020/01/15/russia-turkey-failed-mediate-... Release date 15 January 2020 Expert Tim Eaton In the news type Op-ed Hide date on homepage Full Article
ed Why is the U.S. joining Venezuela and Nicaragua in discrediting a system to protect human rights? By feedproxy.google.com Published On :: Tue, 21 Jan 2020 14:24:06 +0000 Source The Washington Post URL https://www.washingtonpost.com/opinions/2020/01/17/why-is-us-joining-venezuela-n... Release date 17 January 2020 Expert Dr Christopher Sabatini In the news type Op-ed Hide date on homepage Full Article
ed China already leads 4 of the 15 U.N. specialized agencies — and is aiming for a 5th By feedproxy.google.com Published On :: Thu, 05 Mar 2020 10:58:21 +0000 Source The Washington Post URL https://www.washingtonpost.com/politics/2020/03/03/china-already-leads-4-15-un-s... Release date 03 March 2020 Expert Courtney J. Fung In the news type Op-ed Hide date on homepage Full Article
ed For China’s coronavirus diplomacy to succeed, Beijing must dial up generosity and downplay ideology By feedproxy.google.com Published On :: Wed, 06 May 2020 17:31:39 +0000 Source South China Morning Post URL https://www.scmp.com/comment/opinion/article/3079971/chinas-coronavirus-diplomac... Release date 16 April 2020 Expert Dr Yu Jie In the news type Op-ed Hide date on homepage Full Article
ed There are valid questions about how China handled coronavirus but advocating hostility won't help By feedproxy.google.com Published On :: Wed, 06 May 2020 17:36:29 +0000 Source The Independent URL https://www.independent.co.uk/independentpremium/voices/coronavirus-china-cases-... Release date 10 April 2020 Expert Dr Tim Summers In the news type Op-ed Hide date on homepage Full Article
ed X-ray structures of catalytic intermediates of cytochrome c oxidase provide insights into its O2 activation and unidirectional proton-pump mechanisms [Molecular Biophysics] By feedproxy.google.com Published On :: 2020-04-24T06:08:45-07:00 Cytochrome c oxidase (CcO) reduces O2 to water, coupled with a proton-pumping process. The structure of the O2-reduction site of CcO contains two reducing equivalents, Fea32+ and CuB1+, and suggests that a peroxide-bound state (Fea33+–O−–O−–CuB2+) rather than an O2-bound state (Fea32+–O2) is the initial catalytic intermediate. Unexpectedly, however, resonance Raman spectroscopy results have shown that the initial intermediate is Fea32+–O2, whereas Fea33+–O−–O−–CuB2+ is undetectable. Based on X-ray structures of static noncatalytic CcO forms and mutation analyses for bovine CcO, a proton-pumping mechanism has been proposed. It involves a proton-conducting pathway (the H-pathway) comprising a tandem hydrogen-bond network and a water channel located between the N- and P-side surfaces. However, a system for unidirectional proton-transport has not been experimentally identified. Here, an essentially identical X-ray structure for the two catalytic intermediates (P and F) of bovine CcO was determined at 1.8 Å resolution. A 1.70 Å Fe–O distance of the ferryl center could best be described as Fea34+ = O2−, not as Fea34+–OH−. The distance suggests an ∼800-cm−1 Raman stretching band. We found an interstitial water molecule that could trigger a rapid proton-coupled electron transfer from tyrosine-OH to the slowly forming Fea33+–O−–O−–CuB2+ state, preventing its detection, consistent with the unexpected Raman results. The H-pathway structures of both intermediates indicated that during proton-pumping from the hydrogen-bond network to the P-side, a transmembrane helix closes the water channel connecting the N-side with the hydrogen-bond network, facilitating unidirectional proton-pumping during the P-to-F transition. Full Article
ed Long noncoding RNA pncRNA-D reduces cyclin D1 gene expression and arrests cell cycle through RNA m6A modification [RNA] By feedproxy.google.com Published On :: 2020-04-24T06:08:45-07:00 pncRNA-D is an irradiation-induced 602-nt long noncoding RNA transcribed from the promoter region of the cyclin D1 (CCND1) gene. CCND1 expression is predicted to be inhibited through an interplay between pncRNA-D and RNA-binding protein TLS/FUS. Because the pncRNA-D–TLS interaction is essential for pncRNA-D–stimulated CCND1 inhibition, here we studied the possible role of RNA modification in this interaction in HeLa cells. We found that osmotic stress induces pncRNA-D by recruiting RNA polymerase II to its promoter. pncRNA-D was highly m6A-methylated in control cells, but osmotic stress reduced the methylation and also arginine methylation of TLS in the nucleus. Knockdown of the m6A modification enzyme methyltransferase-like 3 (METTL3) prolonged the half-life of pncRNA-D, and among the known m6A recognition proteins, YTH domain-containing 1 (YTHDC1) was responsible for binding m6A of pncRNA-D. Knockdown of METTL3 or YTHDC1 also enhanced the interaction of pncRNA-D with TLS, and results from RNA pulldown assays implicated YTHDC1 in the inhibitory effect on the TLS–pncRNA-D interaction. CRISPR/Cas9-mediated deletion of candidate m6A site decreased the m6A level in pncRNA-D and altered its interaction with the RNA-binding proteins. Of note, a reduction in the m6A modification arrested the cell cycle at the G0/G1 phase, and pncRNA-D knockdown partially reversed this arrest. Moreover, pncRNA-D induction in HeLa cells significantly suppressed cell growth. Collectively, these findings suggest that m6A modification of the long noncoding RNA pncRNA-D plays a role in the regulation of CCND1 gene expression and cell cycle progression. Full Article
ed RNA helicase-regulated processing of the Synechocystis rimO-crhR operon results in differential cistron expression and accumulation of two sRNAs [Gene Regulation] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 The arrangement of functionally-related genes in operons is a fundamental element of how genetic information is organized in prokaryotes. This organization ensures coordinated gene expression by co-transcription. Often, however, alternative genetic responses to specific stress conditions demand the discoordination of operon expression. During cold temperature stress, accumulation of the gene encoding the sole Asp–Glu–Ala–Asp (DEAD)-box RNA helicase in Synechocystis sp. PCC 6803, crhR (slr0083), increases 15-fold. Here, we show that crhR is expressed from a dicistronic operon with the methylthiotransferase rimO/miaB (slr0082) gene, followed by rapid processing of the operon transcript into two monocistronic mRNAs. This cleavage event is required for and results in destabilization of the rimO transcript. Results from secondary structure modeling and analysis of RNase E cleavage of the rimO–crhR transcript in vitro suggested that CrhR plays a role in enhancing the rate of the processing in an auto-regulatory manner. Moreover, two putative small RNAs are generated from additional processing, degradation, or both of the rimO transcript. These results suggest a role for the bacterial RNA helicase CrhR in RNase E-dependent mRNA processing in Synechocystis and expand the known range of organisms possessing small RNAs derived from processing of mRNA transcripts. Full Article
ed Unified approach to critical-contrast homogenisation with explicit links to time-dispersive media By www.ams.org Published On :: Fri, 10 Apr 2020 08:09 EDT K. D. Cherednichenko, Yu. Yu. Ershova, A. V. Kiselev and S. N. Naboko Trans. Moscow Math. Soc. 80 (2020), 251-294. Abstract, references and article information Full Article
ed On the existence of an operator group generated by the one-dimensional Dirac system By www.ams.org Published On :: Fri, 10 Apr 2020 08:09 EDT A. M. Savchuk and I. V. Sadovnichaya Trans. Moscow Math. Soc. 80 (2020), 235-250. Abstract, references and article information Full Article
ed An explicit form for extremal functions in the embedding constant problem for Sobolev spaces By www.ams.org Published On :: Fri, 10 Apr 2020 08:09 EDT I. A. Sheipak and T. A. Garmanova Trans. Moscow Math. Soc. 80 (2020), 189-210. Abstract, references and article information Full Article
ed The finiteness of the spectrum of boundary value problems defined on a geometric graph By www.ams.org Published On :: Fri, 10 Apr 2020 08:09 EDT V. A. Sadovnichii, Ya. T. Sultanaev and A. M. Akhtyamov Trans. Moscow Math. Soc. 80 (2020), 123-131. Abstract, references and article information Full Article
ed What happens to a fund that is listed pursuant to a product specific rule filing once the fund is eligible to operate under Rule 6c-11 and elects to list on Nasdaq under Rule 5704? By feedproxy.google.com Published On :: Publication Date: Apr 10 2020 The SEC will withdraw the existing approval order and the fund will become subject to the requirements of Rule 6c-11 and Nasdaq Rule 5704.... Full Article
ed What will an ETF listed under Nasdaq Rule 5704 need to submit to Nasdaq to evidence compliance with the continued listing standards? By feedproxy.google.com Published On :: Publication Date: Apr 10 2020 Funds listed under Nasdaq Rule 5704 are required to submit an annual certification regarding the funds compliance with Rule 6c-11 during the most recent fiscal year. The certification is required within 30 calendar days of a fund’s fiscal year end. The certification can be found here.... Full Article
ed What types of ETFs are eligible to be listed under Nasdaq Rule 5704? By feedproxy.google.com Published On :: Publication Date: Apr 10 2020 ETFs that meet the definition of “Exchange Traded Fund” in Nasdaq Rule 5704(a)(1)(A) are eligible to be considered for listing pursuant to Nasdaq Rule 5704. ETFs that are excluded from operating pursuant to Rule 6c-11 under the Investment Company Act of 1940 are not eligible to list under Nasdaq Rule 5704.... Full Article
ed What documentation is required in connection with listing an ETF under Nasdaq Rule 5704? By feedproxy.google.com Published On :: Publication Date: Apr 10 2020 New Fund Launches In addition to completing the Listing Application, new funds are required to complete a certification prior to receiving approval of an initial listing application. The certification can be found here. Listing Transfers In addition to completing the Listing Application, funds switching from another market to Nasdaq are required to complete a certification regarding compliance with SEC Rule 6c-11. The certification must be completed prior to... Full Article
ed GoDaddy – “unauthorized individual” had access to login info By feedproxy.google.com Published On :: Tue, 05 May 2020 15:53:59 +0000 Web hosting behemoth GoDaddy just filed a data breach notification with the US state of California. Full Article Data loss data breach GoDaddy
ed Firefox 76.0 released with critical security patches – update now By feedproxy.google.com Published On :: Wed, 06 May 2020 14:58:01 +0000 Firefox's latest version is out, with new password management features and a raft of security fixes. Full Article Firefox Mozilla Exploit Patches Tor update vulnerability