cr Conflict and the Water Crisis in Iraq By feedproxy.google.com Published On :: Mon, 24 Feb 2020 13:15:01 +0000 Invitation Only Research Event 9 March 2020 - 9:00am to 10:30am Chatham House | 10 St James's Square | London | SW1Y 4LE Event participants Dr Azzam Alwash, Founder & CEO, Nature IraqPeter Schwartzstein, Independent Journalist; Non-Resident Fellow, Centre for Climate SecurityDiscussant: Dr Jehan Baban, Founder & President, The Iraqi Environment and Health Society-UKChair: Dr Glada Lahn, Senior Research Fellow, Energy, Environment and Resources Department, Chatham House Water is a critical issue for Iraq’s future stability and prosperity. Only a few decades ago, the country was one of the most fertile in the region, with two major rivers flowing through it. Today, national and transboundary pollution, mismanagement, and debilitating cycles of conflict have contributed to a situation where only half of current water needs are being met, and where an 80% reduction in the flow of water down the Tigris and Euphrates rivers has led to the loss of millions of acres of formerly productive land and the displacement of rural communities.Water scarcity can be a driver of violence and conflict. Tribal conflicts over water sources have erupted sporadically in the south and the contamination of municipal water which led to the hospitalization of some 118,000 citizens was a trigger for the large-scale protests in Basra in late 2018. Without concerted action by national and local governments, companies and international agencies, the situation will only worsen as higher temperatures and reduced rainfall drive rural-to-urban migration and increase the risk of drought, food insecurity and water-related diseases.At this roundtable, part of the Chatham House Iraq Initiative, experts will discuss the domestic, regional and international factors that continue to exacerbate the water crisis in Iraq, and propose solutions, including technical innovation, public sector capacity-building and greater international cooperation, that might contribute to effective state-building, build resilience to the effects of climate change and reduce the risk of further conflict. Event attributes Chatham House Rule Department/project Middle East and North Africa Programme, Iraq Initiative Georgia Cooke Project Manager, Middle East and North Africa Programme +44 (0)20 7957 5740 Email Full Article
cr Webinar: The Environmental Crisis in the MENA Region – Impacts and Mitigation By feedproxy.google.com Published On :: Thu, 02 Apr 2020 13:40:01 +0000 Research Event 16 April 2020 - 11:30am to 12:30pm Chatham House | 10 St James's Square | London | SW1Y 4LE Event participants Glada Lahn, Senior Research Fellow, Energy, Environment and Resources Programme, Chatham HouseGreg Shapland, Associate Fellow, Middle East and North Africa Programme, Chatham House Moderator: Sanam Vakil, Deputy Director and Senior Research Fellow, Middle East and North Africa Programme, Chatham House The event will be livestreamed on the MENA Programme Facebook page.Climate and environmental issues have largely been marginalized in discussions about the Middle East and North Africa region and yet are critical to peace and security. In this webinar, experts will explore mounting pressures including those related to water (reduced, less reliable and more polluted sources), extreme temperatures, air pollution, land degradation and sea-level rise. Panelists will discuss the potential impact of worsening environmental conditions and what the region's governments can do to protect the health and livelihoods of their peoples.This webinar is part of the Chatham House MENA Programme's Online Event Series and will be held on the record. Department/project Middle East and North Africa Programme 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
cr Can Morocco Effectively Handle the COVID-19 Crisis? By feedproxy.google.com Published On :: Mon, 06 Apr 2020 09:10:24 +0000 6 April 2020 Dr Mohammed Masbah Associate Fellow, Middle East and North Africa Programme @MasbahMohammed LinkedIn Google Scholar Anna Jacobs Senior Research Assistant, Brookings Doha Center The Moroccan government is capitalizing on a burst of unity, social solidarity and public support in the face of a crisis. However, if it fails to effectively mitigate the public health and economic impacts of the COVID-19 pandemic, this spirit of solidarity and cooperation will not last long. GettyImages-1208907580.jpg A general view of empty stores during curfew as a precaution against the new type of coronavirus (COVID-19) in Rabat, Morocco on 1 April 2020. Photo by Jalal Morchidi/Anadolu Agency via Getty Images. In Morocco, the COVID-19 pandemic has increased public trust in government, but people still have doubts about the effectiveness of the healthcare system. According to a recent study conducted by the Moroccan Institute for Policy Analysis (MIPA), the majority of Moroccans surveyed are generally satisfied with the measures taken by the government to battle the coronavirus. However, the same survey also shows that Moroccans do not have confidence in the healthcare sector’s ability to respond to this pandemic.The positive perceptions of the government’s response can be explained by the swift and strict measures enacted. King Mohammed VI held a high-level meeting with the prime minister, the minister of health, and top security officials on 17 March and a few days later, on 20 March, the Moroccan government declared a state of health emergency and began to implement aggressive measures to contain the virus.This has included closing airports, schools, mosques, cafés and shops – with the exception of food markets – preventing large gatherings, as well as strict guidelines to ensure social distancing. As of 2 April, nearly 5000 people have been arrested for violating the state of health emergency.In order to address urgent medical needs and to mitigate the economic impact of the pandemic, the King ordered the creation of an emergency fund, raising more than 32.7 billion Moroccan Dirhams ($3.2 billion). The Ministry of Finance will begin to make cash transfers to vulnerable citizens, and especially those who have lost their jobs. However, the stipulations surrounding these cash transfers will be decided in the coming weeks.Updates about the virus are communicated daily by the Ministry of Health, despite growing criticism of its communication strategy. As of 4 April, Moroccan authorities have confirmed 883 cases and 58 deaths.Call for national unityIn times like these, there is a call for unity in the face of a national and global crisis, and opposition groups such as Adl wal Ihssan and Rif activists have expressed their support for government measures and have encouraged people to follow the new guidelines and restrictions. However, despite calls to release political prisoners, Moroccan authorities have not indicated that they will do so. This is a missed opportunity vis-à-vis the opposition because it could have served as a way to further strengthen national unity during the crisis.These are all promising signs and point to what is likely to be a short-term burst in unity and institutional trust. However, the institutional weaknesses in governance and the healthcare system have not disappeared, which is why this increase in institutional trust should be taken with a grain of salt.Public trust issuesThis pandemic poses tremendous challenges for governments across the globe, and this holds especially true for states in the Middle East and North Africa region, where citizens do not approve of government performance and do not trust key state institutions. The 2019 Arab Barometer survey found that Moroccans do not trust most of the country’s political institutions (notably the parliament and the Council of Ministers) and the level of satisfaction with the government’s performance remains extremely low.On the public health front, as shown in two of MIPA’s recent surveys, trust in the healthcare system is also very low. Around three-quarters of those surveyed do not trust Moroccan hospitals, highlighting the acute structural problems in the healthcare system. In fact, there is a stark divide between private and public healthcare, as well as a huge gap in access to healthcare facilities between urban and rural areas. Most of the country’s hospitals and doctors are located in major urban areas and the only three laboratories with capabilities for COVID-19 testing are located in Rabat and Casablanca, but even there, testing capacity is very limited.Similar to other countries, there could be a major shortage of doctors and medical equipment throughout Morocco. So far, the Ministry of Finance has said that 2 billion dirhams of the emergency fund will go towards purchasing medical equipment such as beds, ventilators, tests, prevention kits and radiology equipment, but the timeline remains unclear.A vulnerable economyThere is significant concern about the medium- and long-term economic impact of the virus. Two of the country’s key economic sectors have already been hit hard: agriculture and tourism. The agricultural sector was already struggling due to the impact of drought, while the coronavirus pandemic is likely to impact Morocco’s tourism industry not just this year, but well into 2021. In terms of government response, the emergency fund is a strong start, but questions surrounding the management of these funds have already been raised.The most vulnerable parts of the population have been affected by the economic crisis because of the country’s bulging informal sector – in which most people work - and a very weak private sector. In fact, two-thirds of the workforce are not covered by a pension plan, almost half of the working population does not currently benefit from medical coverage and there is no social care system for vulnerable parts of the population. As of 1 April, more than 700,000 workers have lost their jobs.Moving forward?Even if public perceptions of the government’s response are positive at the moment, this is most likely a short-term surge that should not be taken for granted. Despite the efforts made by the government, Morocco’s health system is not equipped to handle this crisis. Even with the new measures that have been implemented, if the spread of the virus gets out of control, more funds, more doctors, and more equipment will be needed. Given the structural weaknesses of the healthcare system, this will be an uphill battle.Moreover, even if the government manages to mitigate the public health impact, the economic consequences will be dire—especially in the tourism industry—and will severely hurt those workers in the informal sector who are living without a safety net. In Morocco, this category represents most of the working population.This crisis highlights that the Moroccan government must urgently tackle its large portfolio of unfinished reforms, notably in healthcare, the economy, and labour rights. So far, the government is capitalizing on the spirit of unity, social solidarity and public support. The future trajectory of the pandemic and the effectiveness of governance will determine if this spirit of solidarity will last. If the government fails to effectively mitigate the public health and economic impacts of this pandemic, this solidarity and cooperation will not last long. Full Article
cr Same Old Politics Will Not Solve Iraq Water Crisis By feedproxy.google.com Published On :: Wed, 15 Apr 2020 15:36:21 +0000 15 April 2020 Georgia Cooke Project Manager, Middle East and North Africa Programme Dr Renad Mansour Senior Research Fellow, Middle East and North Africa Programme; Project Director, Iraq Initiative @renadmansour Glada Lahn Senior Research Fellow, Energy, Environment and Resources Programme @Glada_Lahn Addressing Iraq’s water crisis should be a priority for any incoming prime minister as it is damaging the country’s attempts to rebuild. But successive governments have allowed the problem to fester. 2020-04-15-Iraq-Water Punting in the marshes south of the Iraqi city of Ammarah. Photo by Ghaith Abdul-Ahad/Getty Images. Historically, Iraq lay claim to one of the most abundant water supplies in the Middle East. But the flow of the Tigris and Euphrates rivers has reduced by up to 40% since the 1970s, due in part to the actions of neighbouring countries, in particular Turkey, upstream.Rising temperatures and reduced rainfall due to climate change are also negatively impacting Iraq’s water reserves. Evaporation from dams and reservoirs is estimated to lose the country up to 8 billion cubic metres of water every year.A threat to peace and stabilityShortages have dried up previously fertile land, increasing poverty in agricultural areas. Shortages have also served to fuel conflict: communities faced with successive droughts and government inertia proved to be easy targets for ISIS recruiters, who lured farmers into joining them by offering money and food to feed their families. Economic hardship for those whose livelihoods relied upon river water has also driven rural to urban migration, putting significant strain on already over-populated towns and cities, exacerbating housing, job and electricity shortages, and widening the gap between haves and have-nots.But scarcity isn’t the most crucial element of Iraq’s water crisis – contamination is. Decades of local government mismanagement, corrupt practices and a lack of regulation of dumping (it is estimated up to 70% of Iraq’s industrial waste is dumped directly into water) has left approximately three in every five citizens without a reliable source of potable water.In 2018, 118,000 residents of Basra province were hospitalised with symptoms brought on by drinking contaminated water, which not only put a spotlight on the inadequacies of a crumbling healthcare system but sparked mass protests and a subsequent violent crackdown.The water crisis is also undermining the stability of the country’s federal governance model, by occasionally sparking disputes between Baghdad and the Kurdistan Regional Government, as well as between governorates in the south.The crisis is both a symptom and a cause of poor governance. Iraq is stuck in a cycle whereby government inaction causes shortages and contamination, which result in economic losses, reduced food supply, increased prices and widespread poor health. This in turn leads to increasing levels of poverty, higher demand on services and civil unrest, increasing the pressure on a weak, dysfunctional system of government.What can be done?The first priority should be modernising existing water-management infrastructure - a relic of a time when the problem was an excess rather than a shortage of water (the last time Iraq’s flood defences were required was 1968). Bureaucratic hurdles, widespread corruption and an endless cycle of other crises taking precedent prevent good initiatives from being implemented or scaled up.Diversifying energy sources to improve provision is crucial. Baghdad has a sewage treatment plant that originally ran on its own electricity source, but this capacity was destroyed in 1991 and was never replaced. The city continues to suffer from dangerous levels of water pollution because the electricity supply from the grid is insufficient to power the plant. Solar energy has great potential in sun-drenched Iraq to bridge the gaping hole in energy provision, but successive governments have chosen to focus on fossil fuels rather than promoting investment to grow the renewables sector.Heightened tension with upstream Turkey could turn water into another cause of regional conflict. But, if approached differently, collaboration between Iraq and its neighbour could foster regional harmony.Turkey’s elevated geography and cooler climate mean its water reserves suffer 75% less evaporation than Iraq’s. Given that Turkey’s top energy priority is the diversification of its supply of imported hydrocarbons, a win-win deal could see Turkey exchange access to its water-management infrastructure for delivery of reduced cost energy supplies from Iraq.German-French cooperation on coal and steel in the 1950s and the evolution of economic integration that followed might provide a model for how bilateral cooperation over one issue could result in cooperation with other regional players (in this case Iran and Syria) on a range of other issues. This kind of model would need to consider the future of energy, whereby oil and gas would be replaced by solar-power exports.These solutions have been open to policymakers for years and yet they have taken little tangible action. While there are leaders and bureaucrats with the will to act, effective action is invariably blocked by a complex and opaque political system replete with vested interests in maintaining power and wealth via a weak state and limited services from central government.Breaking the cycleTo break this cycle, Iraq needs a group of professional and able actors outside of government to work with willing elements of the state bureaucracy as a taskforce to pressure for action and accountability. Publishing the recommendations from a hitherto withheld report produced in the aftermath of Basra’s 2018 heath crisis would be a great start.In time, this taskforce could champion the prioritisation of water on the national agenda, the implementation of infrastructure upgrades, and hold more productive conversations with neighbour states.With such a high degree of state fragmentation and dysfunction in Iraq, looking to the central government to provide leadership will not yield results. Engagement with a coalition of non-state actors can begin to address the water crisis and also open a dialogue around new models of governance for other critical issues. This might even be a starting point for rewriting the tattered social contract in Iraq.This piece is based on insights and discussion at a roundtable event, Conflict and the Water Crisis in Iraq, held at Chatham House on March 9 as part of the Iraq Initiative. Full Article
cr COVID-19 Crisis – Business as Usual for Gaza? By feedproxy.google.com Published On :: Wed, 06 May 2020 14:48:14 +0000 6 May 2020 Mohammed Abdalfatah Asfari Foundation Academy Fellow @mhalabi258 LinkedIn The COVID-19 pandemic has brought unprecedented challenges, economic collapse and strict lockdowns in many parts of the world. For the people of Gaza, this reality is nothing new. 2020-05-06-covid-19-gaza.jpg Palestinians light fireworks above the rubble during the Muslim holy month of Ramadan amid concerns about the spread of the coronavirus disease (COVID-19), in Gaza City , 30 April 2020. Photo by Majdi Fathi/NurPhoto via Getty Images. In August 2012, when the UN released its report Gaza in 2020: A liveable place?, they could not have imagined what the world would look like in 2020: cities under lockdown, restrictions on movement, border closures, widespread unemployment, economic collapse, fear and anxiety and, above all, uncertainty about what the future holds.For Gaza’s population of 2 million people this reality is nothing new. The conditions that the rest of the world are currently experiencing as a result of the COVID-19 pandemic is similar to the tight blockade Gaza has been living under ever since Hamas took over in 2007. Israel has imposed severe restrictions on the movement of people and goods, youth unemployment has reached 60 per cent, and over 80 per cent of Gaza’s population are now dependent on international aid.The people of Gaza are having to face the COVID-19 crisis already at a disadvantage, with poor infrastructure, limited resources and a shortage of the most basic services, such as water and power supply. It also has a fragile health system, with hospitals lacking essential medical supplies and equipment, as well as the capacity to deal with the outbreak as there are only 84 ICU beds and ventilators available. Meanwhile, intra-Palestinian divisions have persisted and were evident in the initial reaction to the pandemic. When President Mahmoud Abbas announced a state of emergency, it took two days for the Hamas-led government in Gaza to follow suit and shut down schools and universities. They later made a separate emergency appeal to address the crisis and prepare for a COVID-19 response in Gaza. This lack of coordination is typical of the way the Palestinian Authority and Hamas approach crisis situations.After the initial uncoordinated response, Hamas, as the de-facto ruler of Gaza, has asserted its ability to control Gaza’s borders by putting in place quarantine measures for everyone who enters the strip, whether through the Erez checkpoint with Israel or the Rafah border with Egypt. They have also assigned 21 hospitals, hotels, and schools as compulsory quarantine centres for all arrivals from abroad, who have to stay in quarantine for 21 days. In comparison, there are 20 quarantine centres in the West Bank. These strict measures have prevented the spread of the virus in the community and confined it to the quarantine centres, with only 20 confirmed cases of COVID-19 as of 6 May. Gaza’s de-facto authorities have also been able to monitor markets and prices to ensure the availability of essential goods.Faced with a major crisis, Al-Qassam Brigades – the armed wing of Hamas – have tried to play the role of a national army by participating in efforts to fight the pandemic. They have relatively good logistical capacity and have contributed to the construction of two quarantine facilities with a total capacity of 1,000 units to prepare for more arrivals into Gaza. At the local level, municipalities have been disinfecting public spaces and facilities in addition to disseminating information about the virus and related preventative and protective measures. Other precautionary measures put in place include closing the weekly open markets, and restricting social gatherings like weddings and funerals.Despite COVID-19, it’s business as usual when it comes to international dealings with Gaza. The key parties in the conflict – Israel, Hamas and the Palestinian Authority – along with the main external actors – Egypt, the United Nations and Qatar – have continued to stick to their policies aimed at keeping the security situation under control and preventing further escalation. Although Israel has allowed entry of pharmaceutical supplies and medical equipment into Gaza during the pandemic, it has kept its restrictions on the movement of goods and people in place, while keeping a close eye on the development of the COVID-19 outbreak in Gaza – a major outbreak here would be a nightmare scenario for Israel.Meanwhile, Qatar has continued to address the humanitarian and economic needs of Gaza in an attempt to ease the pressure and prevent further escalation. It has pledged $150 million over the next six months to help families in Gaza from poorer backgrounds. Gaza has also been discussed by the Middle East Quartet, as Nickolay Mladenov, the UN special coordinator for the Middle East Peace Process, expressed his concern about the risk of a disease outbreak in Gaza during a call with the members of the Quartet.Amid the pandemic, threats are still being exchanged between Israel and Hamas. The Israeli defence minister, Naftali Bennett, requested that in return for providing humanitarian aid to Gaza, Hamas agrees to return the remains of two Israeli soldiers killed in the 2014 war. While openly rejecting Bennett's statement, the leader of Hamas in Gaza, Yahya Sinwar, has offered to move forward with a prisoner swap deal if Israel agrees to release elderly prisoners and detainees in addition to detained women and children. Though dealing with its own COVID-19 outbreak, Egypt has started to mediate between the two parties in an attempt to stabilize the situation and reach a prisoner swap deal.In the wake of this pandemic, lessons should be learned and policies should be examined, by all parties. Firstly, Israel should re-evaluate its security measures towards Gaza by easing restrictions on movement and trade which would have a positive impact on living conditions for Gaza’s population. The current measures have proven to be unsustainable and have contributed to the endless cycle of violence. Secondly, the intra-Palestinian division should end, to save Palestinians from contradictory policies and insufficient capacity on both sides. In fact, all previous attempts have failed to end this self-destructive division and this is due to the absence of political will on both sides. Elections seem to be the only viable path towards unity. Finally, efforts by the international community should go beyond stabilizing the security situation and ongoing crisis inside Gaza, where disruption of normal life is the norm.While the world has reacted to this pandemic with a whole host of new policies and emergency measures, it has remained business as usual when dealing with Gaza. Should COVID-19 spread in Gaza, its people – who have already paid the price of a continuous blockade and intra-Palestinian division for 13 years – will pay a heavy price yet again. However, this time it is not a crisis that they alone will have to face. Full Article
cr Three distinct glycosylation pathways are involved in the decoration of Lactococcus lactis cell wall glycopolymers [Microbiology] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 Extracytoplasmic sugar decoration of glycopolymer components of the bacterial cell wall contributes to their structural diversity. Typically, the molecular mechanism that underpins such a decoration process involves a three-component glycosylation system (TGS) represented by an undecaprenyl-phosphate (Und-P) sugar-activating glycosyltransferase (Und-P GT), a flippase, and a polytopic glycosyltransferase (PolM GT) dedicated to attaching sugar residues to a specific glycopolymer. Here, using bioinformatic analyses, CRISPR-assisted recombineering, structural analysis of cell wall–associated polysaccharides (CWPS) through MALDI-TOF MS and methylation analysis, we report on three such systems in the bacterium Lactococcus lactis. On the basis of sequence similarities, we first identified three gene pairs, csdAB, csdCD, and csdEF, each encoding an Und-P GT and a PolM GT, as potential TGS component candidates. Our experimental results show that csdAB and csdCD are involved in Glc side-chain addition on the CWPS components rhamnan and polysaccharide pellicle (PSP), respectively, whereas csdEF plays a role in galactosylation of lipoteichoic acid (LTA). We also identified a potential flippase encoded in the L. lactis genome (llnz_02975, cflA) and confirmed that it participates in the glycosylation of the three cell wall glycopolymers rhamnan, PSP, and LTA, thus indicating that its function is shared by the three TGSs. Finally, we observed that glucosylation of both rhamnan and PSP can increase resistance to bacteriophage predation and that LTA galactosylation alters L. lactis resistance to bacteriocin. Full Article
cr The transcriptional regulator IscR integrates host-derived nitrosative stress and iron starvation in activation of the vvhBA operon in Vibrio vulnificus [Gene Regulation] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 For successful infection of their hosts, pathogenic bacteria recognize host-derived signals that induce the expression of virulence factors in a spatiotemporal manner. The fulminating food-borne pathogen Vibrio vulnificus produces a cytolysin/hemolysin protein encoded by the vvhBA operon, which is a virulence factor preferentially expressed upon exposure to murine blood and macrophages. The Fe-S cluster containing transcriptional regulator IscR activates the vvhBA operon in response to nitrosative stress and iron starvation, during which the cellular IscR protein level increases. Here, electrophoretic mobility shift and DNase I protection assays revealed that IscR directly binds downstream of the vvhBA promoter PvvhBA, which is unusual for a positive regulator. We found that in addition to IscR, the transcriptional regulator HlyU activates vvhBA transcription by directly binding upstream of PvvhBA, whereas the histone-like nucleoid-structuring protein (H-NS) represses vvhBA by extensively binding to both downstream and upstream regions of its promoter. Of note, the binding sites of IscR and HlyU overlapped with those of H-NS. We further substantiated that IscR and HlyU outcompete H-NS for binding to the PvvhBA regulatory region, resulting in the release of H-NS repression and vvhBA induction. We conclude that concurrent antirepression by IscR and HlyU at regions both downstream and upstream of PvvhBA provides V. vulnificus with the means of integrating host-derived signal(s) such as nitrosative stress and iron starvation for precise regulation of vvhBA transcription, thereby enabling successful host infection. Full Article
cr Substrate recognition and ATPase activity of the E. coli cysteine/cystine ABC transporter YecSC-FliY [Microbiology] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 Sulfur is essential for biological processes such as amino acid biogenesis, iron–sulfur cluster formation, and redox homeostasis. To acquire sulfur-containing compounds from the environment, bacteria have evolved high-affinity uptake systems, predominant among which is the ABC transporter family. Theses membrane-embedded enzymes use the energy of ATP hydrolysis for transmembrane transport of a wide range of biomolecules against concentration gradients. Three distinct bacterial ABC import systems of sulfur-containing compounds have been identified, but the molecular details of their transport mechanism remain poorly characterized. Here we provide results from a biochemical analysis of the purified Escherichia coli YecSC-FliY cysteine/cystine import system. We found that the substrate-binding protein FliY binds l-cystine, l-cysteine, and d-cysteine with micromolar affinities. However, binding of the l- and d-enantiomers induced different conformational changes of FliY, where the l- enantiomer–substrate-binding protein complex interacted more efficiently with the YecSC transporter. YecSC had low basal ATPase activity that was moderately stimulated by apo FliY, more strongly by d-cysteine–bound FliY, and maximally by l-cysteine– or l-cystine–bound FliY. However, at high FliY concentrations, YecSC reached maximal ATPase rates independent of the presence or nature of the substrate. These results suggest that FliY exists in a conformational equilibrium between an open, unliganded form that does not bind to the YecSC transporter and closed, unliganded and closed, liganded forms that bind this transporter with variable affinities but equally stimulate its ATPase activity. These findings differ from previous observations for similar ABC transporters, highlighting the extent of mechanistic diversity in this large protein family. Full Article
cr NAD+ biosynthesis in bacteria is controlled by global carbon/nitrogen levels via PII signaling [Microbiology] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 NAD+ is a central metabolite participating in core metabolic redox reactions. The prokaryotic NAD synthetase enzyme NadE catalyzes the last step of NAD+ biosynthesis, converting nicotinic acid adenine dinucleotide (NaAD) to NAD+. Some members of the NadE family use l-glutamine as a nitrogen donor and are named NadEGln. Previous gene neighborhood analysis has indicated that the bacterial nadE gene is frequently clustered with the gene encoding the regulatory signal transduction protein PII, suggesting a functional relationship between these proteins in response to the nutritional status and the carbon/nitrogen ratio of the bacterial cell. Here, using affinity chromatography, bioinformatics analyses, NAD synthetase activity, and biolayer interferometry assays, we show that PII and NadEGln physically interact in vitro, that this complex relieves NadEGln negative feedback inhibition by NAD+. This mechanism is conserved in distantly related bacteria. Of note, the PII protein allosteric effector and cellular nitrogen level indicator 2-oxoglutarate (2-OG) inhibited the formation of the PII-NadEGln complex within a physiological range. These results indicate an interplay between the levels of ATP, ADP, 2-OG, PII-sensed glutamine, and NAD+, representing a metabolic hub that may balance the levels of core nitrogen and carbon metabolites. Our findings support the notion that PII proteins act as a dissociable regulatory subunit of NadEGln, thereby enabling the control of NAD+ biosynthesis according to the nutritional status of the bacterial cell. Full Article
cr Modification of a PE/PPE substrate pair reroutes an Esx substrate pair from the mycobacterial ESX-1 type VII secretion system to the ESX-5 system [Molecular Bases of Disease] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 Bacterial type VII secretion systems secrete a wide range of extracellular proteins that play important roles in bacterial viability and in interactions of pathogenic mycobacteria with their hosts. Mycobacterial type VII secretion systems consist of five subtypes, ESX-1–5, and have four substrate classes, namely, Esx, PE, PPE, and Esp proteins. At least some of these substrates are secreted as heterodimers. Each ESX system mediates the secretion of a specific set of Esx, PE, and PPE proteins, raising the question of how these substrates are recognized in a system-specific fashion. For the PE/PPE heterodimers, it has been shown that they interact with their cognate EspG chaperone and that this chaperone determines the designated secretion pathway. However, both structural and pulldown analyses have suggested that EspG cannot interact with the Esx proteins. Therefore, the determining factor for system specificity of the Esx proteins remains unknown. Here, we investigated the secretion specificity of the ESX-1 substrate pair EsxB_1/EsxA_1 in Mycobacterium marinum. Although this substrate pair was hardly secreted when homologously expressed, it was secreted when co-expressed together with the PE35/PPE68_1 pair, indicating that this pair could stimulate secretion of the EsxB_1/EsxA_1 pair. Surprisingly, co-expression of EsxB_1/EsxA_1 with a modified PE35/PPE68_1 version that carried the EspG5 chaperone-binding domain, previously shown to redirect this substrate pair to the ESX-5 system, also resulted in redirection and co-secretion of the Esx pair via ESX-5. Our results suggest a secretion model in which PE35/PPE68_1 determines the system-specific secretion of EsxB_1/EsxA_1. Full Article
cr 5-Ethynyl-2'-deoxycytidine and 5-ethynyl-2'-deoxyuridine are differentially incorporated in cells infected with HSV-1, HCMV, and KSHV viruses [Microbiology] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 Nucleoside analogues are a valuable experimental tool. Incorporation of these molecules into newly synthesized DNA (i.e. pulse-labeling) is used to monitor cell proliferation or to isolate nascent DNA. Some of the most common nucleoside analogues used for pulse-labeling of DNA in cells are the deoxypyrimidine analogues 5-ethynyl-2'-deoxyuridine (EdU) and 5-ethynyl-2'-deoxycytidine (EdC). Click chemistry enables conjugation of an azide molecule tagged with a fluorescent dye or biotin to the alkyne of the analog, which can then be used to detect incorporation of EdU and EdC into DNA. The use of EdC is often recommended because of the potential cytotoxicity associated with EdU during longer incubations. Here, by comparing the relative incorporation efficiencies of EdU and EdC during short 30-min pulses, we demonstrate significantly lower incorporation of EdC than of EdU in noninfected human fibroblast cells or in cells infected with either human cytomegalovirus or Kaposi's sarcoma-associated herpesvirus. Interestingly, cells infected with herpes simplex virus type-1 (HSV-1) incorporated EdC and EdU at similar levels during short pulses. Of note, exogenous expression of HSV-1 thymidine kinase increased the incorporation efficiency of EdC. These results highlight the limitations when using substituted pyrimidine analogues in pulse-labeling and suggest that EdU is the preferable nucleoside analogue for short pulse-labeling experiments, resulting in increased recovery and sensitivity for downstream applications. This is an important discovery that may help to better characterize the biochemical properties of different nucleoside analogues with a given kinase, ultimately leading to significant differences in labeling efficiency of nascent DNA. Full Article
cr The streptococcal multidomain fibrillar adhesin CshA has an elongated polymeric architecture [Microbiology] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 The cell surfaces of many bacteria carry filamentous polypeptides termed adhesins that enable binding to both biotic and abiotic surfaces. Surface adherence is facilitated by the exquisite selectivity of the adhesins for their cognate ligands or receptors and is a key step in niche or host colonization and pathogenicity. Streptococcus gordonii is a primary colonizer of the human oral cavity and an opportunistic pathogen, as well as a leading cause of infective endocarditis in humans. The fibrillar adhesin CshA is an important determinant of S. gordonii adherence, forming peritrichous fibrils on its surface that bind host cells and other microorganisms. CshA possesses a distinctive multidomain architecture comprising an N-terminal target-binding region fused to 17 repeat domains (RDs) that are each ∼100 amino acids long. Here, using structural and biophysical methods, we demonstrate that the intact CshA repeat region (CshA_RD1–17, domains 1–17) forms an extended polymeric monomer in solution. We recombinantly produced a subset of CshA RDs and found that they differ in stability and unfolding behavior. The NMR structure of CshA_RD13 revealed a hitherto unreported all β-fold, flanked by disordered interdomain linkers. These findings, in tandem with complementary hydrodynamic studies of CshA_RD1–17, indicate that this polypeptide possesses a highly unusual dynamic transitory structure characterized by alternating regions of order and disorder. This architecture provides flexibility for the adhesive tip of the CshA fibril to maintain bacterial attachment that withstands shear forces within the human host. It may also help mitigate deleterious folding events between neighboring RDs that share significant structural identity without compromising mechanical stability. Full Article
cr Pro-515 of the dynamin-like GTPase MxB contributes to HIV-1 inhibition by regulating MxB oligomerization and binding to HIV-1 capsid [Microbiology] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Interferon-regulated myxovirus resistance protein B (MxB) is an interferon-induced GTPase belonging to the dynamin superfamily. It inhibits infection with a wide range of different viruses, including HIV-1, by impairing viral DNA entry into the nucleus. Unlike the related antiviral GTPase MxA, MxB possesses an N-terminal region that contains a nuclear localization signal and is crucial for inhibiting HIV-1. Because MxB previously has been shown to reside in both the nuclear envelope and the cytoplasm, here we used bioinformatics and biochemical approaches to identify a nuclear export signal (NES) responsible for MxB's cytoplasmic location. Using the online computational tool LocNES (Locating Nuclear Export Signals or NESs), we identified five putative NES candidates in MxB and investigated whether their deletion caused nuclear localization of MxB. Our results revealed that none of the five deletion variants relocates to the nucleus, suggesting that these five predicted NES sequences do not confer NES activity. Interestingly, deletion of one sequence, encompassing amino acids 505–527, abrogated the anti-HIV-1 activity of MxB. Further mutation experiments disclosed that amino acids 515–519, and Pro-515 in particular, regulate MxB oligomerization and its binding to HIV-1 capsid, thereby playing an important role in MxB-mediated restriction of HIV-1 infection. In summary, our results indicate that none of the five predicted NES sequences in MxB appears to be required for its nuclear export. Our findings also reveal several residues in MxB, including Pro-515, critical for its oligomerization and anti-HIV-1 function. Full Article
cr Radical new business model for pharmaceutical industry needed to avert antibiotic resistance crisis By feedproxy.google.com Published On :: Mon, 12 Oct 2015 09:19:24 +0000 7 October 2015 20151009Antibiotics.jpg High-level complex of physiologically active antibiotic substance extracted from blastema at the Arctic Innovation Center (AIC) of Ammosov, North-Eastern Federal University (NEFU) in Yakutsk. Photo: Yuri Smityuk/ITAR-TASS Photo/Corbis. Revenues for pharmaceutical companies need to be 'delinked' from sales of antibiotics to avoid their over-use and avert a public health crisis, says a new report from the think-tank Chatham House.Over-use of antibiotics is contributing to the growing resistance of potentially deadly bacteria to existing drugs, threatening a public health crisis in the near future. The report notes that, by 2050, failing to tackle antibiotic resistance could result in 10 million premature deaths per year. Novel antibiotics to combat resistant pathogens are thus desperately needed, but market incentives are exacerbating the problem. Towards a New Global Business Model for Antibiotics: Delinking Revenues from Sales states that, 'The current business model requires high levels of antibiotic use in order to recover the costs of R&D. But mitigating the spread of resistance demands just the opposite: restrictions on the use of antibiotics.' To tackle this catch-22 problem, the Centre on Global Health Security at Chatham House recommends the establishment of a global body to implement a radical new business model for the industry, which would encourage investment and promote global access to - and conservation of - antibiotics. The current business model has several perverse effects. As R&D is an inherently risky and costly endeavour, the industry is chronically under-investing in new treatments. Today, few large pharmaceutical companies retain active antibacterial drug discovery programmes. Re-stoking the industry's interest in antibiotics would be one of the primary roles of the new body. Secondly, the need to recover sunk cost under the current business model encourages both high prices and over-marketing of successful drugs, making potentially life-saving treatments unaffordable to many in developing countries, while simultaneously encouraging over-use in developed markets and increasing resistance. The new global body would address these challenges by ‘delinking’ pharmaceutical revenues from sales of antibiotics. It would do this by directly financing the research and development of new drugs, which it would then acquire at a price based on production costs rather than the recovery of R&D expenses. Acquisition could take the form of procurement contracts with companies, the purchase of full IP rights or other licensing mechanisms. This would enable it to promote global access to antibiotics while simultaneously restricting over-use. Conservation would be promoted through education, regulation and good clinical practice, with the report recommending that 'proven conservation methods such as antibiotic stewardship programmes… be incentivized and implemented immediately.'Priorities for R&D financing would be based on a comprehensive assessment of threats arising from resistance. Antibiotics would qualify for the highest level of financial incentives if they combat resistant pathogens posing a serious threat to human health. Finance for the new body would come from individual nation states, with the report noting that this could 'begin with a core group of countries with significant research activity and large antibiotic markets, (though) it is envisaged that all high income countries should make an appropriate financial contribution.' It is not yet clear exactly how much funding would be necessary to combat resistance, but with inaction expected to cost $100 trillion in cumulative economic damage, the report argues that 'an additional global investment of up to $3.5 billion a year (about 10 per cent of the current value of global sales of antibiotics) would be a bargain.' Editor's notes Towards a New Global Business Model for Antibiotics: Delinking Revenues from Sales, is a Chatham House report edited by Charles Clift, Unni Gopinathan, Chantal Morel, Kevin Outterson, John-Arne Røttingen and Anthony So.The report is embargoed until 00.01 GMT Friday 9 October.For more information, or to request an interview with the editors, contact the press office. Contacts Press Office +44 (0)20 7957 5739 Email Full Article
cr Reducing meat consumption critical to achieving global climate goal By feedproxy.google.com Published On :: Tue, 24 Nov 2015 16:35:54 +0000 18 November 2015 20151124DietClimateChange.jpg Grand Central Market in Los Angeles, California, October 2015. Photo: Getty Images. In the week before governments assemble in Paris to agree a global climate deal, a new report from Chatham House shows that a worldwide shift to healthier diets could help close the gap between current emissions reduction plans and what is needed to prevent dangerous climate change.Pledges from countries attending the 21st UNFCCC Conference of the Parties put the world on track for around 3 degrees of warming by 2100, leaving governments with much more still to do. Changing diets to healthy levels of meat consumption could generate a quarter of the remaining emission reductions needed to keep warming below the ‘danger level’ of 2 degrees Celsius – the main goal of the climate negotiations.Changing Climate, Changing Diets: Pathways to Lower Meat Consumption by Laura Wellesley, Catherine Happer and Antony Froggatt argues that, ultimately, dietary change is fundamental to achieving the 2 degrees goal. The livestock sector is already responsible for 15 per cent of global greenhouse gas emissions. Unless strong demand growth for meat is curtailed, livestock sector emissions will increase to the point where dangerous climate change is unavoidable.Dietary change would also have major health benefits. Global per capita meat consumption is already above healthy levels, and double the recommended amount in industrialized countries. Too much red and processed meat is associated with an increased risk of non-communicable diseases, in particular cancer, as found most recently by the World Health Organization.'Reducing meat consumption is a real win-win for health and for the climate,' says report author Laura Wellesley. 'As governments look for strategies to close the Paris emissions gap quickly and cheaply, dietary change should be high on the list.'However, the report finds that governments are ignoring the opportunity. Reducing meat consumption does not feature in a single national emissions reduction plan submitted in advance of the Paris meeting. Governments are afraid to interfere in lifestyle choices for fear of public backlash.But new research undertaken for the report, including an innovative public survey in 12 countries and focus groups in Brazil, China, the United Kingdom, and the United States shows that government fears are exaggerated. Once aware of the link between meat and climate change, consumers accept the need for government action. Even unpopular interventions to make meat more expensive, for example through a carbon tax, would face diminishing resistance as publics come to understand the rationale behind intervention.To build support for government action, the report recommends initiatives to raise public awareness of the climate and health impacts of excessive meat consumption. Governments should pursue comprehensive strategies to shift diets, including policies on labelling, public procurement, regulation and pricing.'Raising awareness about the health and environmental impacts of meat is an important first step, but on its own it will not lead to significant behaviour change. Governments must do more to influence diets,' added Wellesley. Editor's notes Read Changing Climate, Changing Diets: Pathways to Lower Meat Consumption by Laura Wellesley, Catherine Happer and Antony Froggatt.This report is embargoed until 00:01 GMT on Tuesday 24 November. To arrange an interview with the authors please contact the press office.This research project was carried out in conjunction with Glasgow University Media Group. Further research findings:Meat consumption has already reached excessive levels in many Western countries: in industrialized countries, it is around twice the amount deemed healthy by experts. And with the rise of new meat-eating middle classes in developing countries, global meat consumption is set to increase by 76 per cent by 2050.Action on diets could also lower the costs of climate action across the rest of the economy by 50 per cent, while presenting a win-win strategy for policy-makers in terms of public health benefits.In the UK and US, men are more likely to want to eat more meat than women.In China, the desire to eat meat increases in line with income, while in the US and UK, wealthier people are less likely to say they want to eat more meat.In the UK and US, climate change is a more politicized and divisive issue, and people are more sceptical about the science.The US respondents remained most sceptical about the data presented to them.In the UK and US, people were reluctant to take personal responsibility for climate change, seeing it as something those in public roles were responsible for.The highest levels of concern around food safety and animal welfare associated with meat production were found among US respondents. People in the UK were most likely to eat less meat for health reasons.In the UK and US, meat was associated positively with nutrition and fulfilment, but negatively with health and food safety.The executive summary of the report is available in Mandarin and Portuguese. Read the International Agency for Research on Cancer/World Health Organization monographs evaluation on consumption of red meat and processed meat, 26 October 2015. Contacts Press Office +44 (0)20 7957 5739 Email Full Article
cr The refugee crisis: A European call for action By feedproxy.google.com Published On :: Fri, 18 Mar 2016 10:02:48 +0000 18 March 2016 Open Letter by the conveners of the Vision Europe Summit regarding the refugee crisis in Europe and the necessity to act now. European leaders need to implement common European solutions to the refugee crisis. Only joint solutions can credibly and effectively reduce the growing human suffering and social and political turmoil.The refugee crisis poses a serious challenge, both to the welfare of refugees and to European societies. In 2015, more than 1.5 million migrants crossed into the European Union. From Italy to Poland, and from Greece to Germany, countries face immense challenges in responding to requests for humanitarian aid, asylum, and integration. The associated integration challenges in housing, language, work and welfare are already formidable. Failing to manage them properly poses serious threats to social cohesion and political stability.European countries have had sufficient time to analyse and assess the long-standing challenges which created the current crisis. Now it is time to act – not individually and at the expense of others, but jointly and in a spirit of European solidarity. This is why Vision Europe – a partnership between seven leading think tanks and foundations in Europe – will in 2016 focus its efforts on providing practical solutions to the current refugee crisis, and its root causes. We, the seven signatories, writing in an individual capacity, see an urgent need for a common European approach, to compliment local and national efforts.At present, there is no consensus among member states on how to respond to the crisis, neither on the objectives to be achieved or the methods to be used. But disagreements on substance must be overcome now. Building on current discussions, we propose a comprehensive agenda at the EU level, with five major dimensions.First, it is important to control the EU’s external borders so that only refugees fleeing war and persecution, who have a legitimate right to seek asylum, can enter and potentially remain in the EU. The porous nature of the EU’s external borders has meant an unacceptable loss of control in the eyes of many EU citizens and has raised false hopes for irregular migrants trying to enter the Union. The control of the borders of the Schengen Area should be a collective effort of the EU and all Member States, coordinated by European Institutions with professional staff and with financial support provided to Member States at the EU’s periphery. Regaining control of the EU’s external borders is essential to preserve open internal borders.Second, beyond implementing the already agreed upon relocation of 160,000 refugees from Greece and Italy, the EU should develop a system which distributes a much larger number of refugees across the Union, directly from the hotspots in the EU and the neighbouring counties such as Turkey, Jordan or Lebanon. Member States not willing to host refugees themselves could choose to make a primarily financial contribution to the system. A Migration Solidarity Fund should be created to manage this compensatory system. Turkey’s efforts to reduce the crossings in the Aegean Sea should be matched by a willingness among EU Member States to take in refugees in an orderly manner. The Conclusions from the European Council seem to move in the right direction in this regard.The third measure should be to improve, standardize and speed up the processes to determine asylum applications. The sooner refugees know whether they can stay, the more energy can be invested in their integration into host countries’ societies and in family reunions. The sooner a decision is taken, the fairer and more feasible it is to send back those whose requests are refused in full respect of international law and human rights. And EU members cannot afford to have vastly different standards in granting asylum status. Under international law, there can be no limit set on the number of those eligible to request asylum.As a fourth measure, we recommend expanding efforts at the EU level to improve the living conditions of refugees staying in countries close to their countries of origin. Many refugees want to return to their homes as soon as the situation becomes safe again. They should not be driven to start the hazardous journey to the European Union only because of unbearable conditions in the countries where they are currently sheltering.Last but not least, the EU and its Member States should work vigorously towards ending the violent conflicts that are the principal causes of the crisis. Europe must invest heavily in the Syria peace process, in particular. The EU must also raise the ambition and resources of its Neighbourhood Policy, with a focus on helping to stabilise the region and on improving the living conditions and economic opportunities in the Southern neighbourhood.But action is also required at the national level, especially in the EU countries where significant numbers of refugees have received or are expected to receive asylum. The distribution of refugees across municipalities and regions should be fair and should come with adequate support and resources from the national level, emphasising education and language training. The recognition of professional competences and support to enter the labour market should be available at a very early stage. Within our societies, we need a dialogue between refugees and the host society. It should be made clear that respect for human rights, democratic values and cultural norms is indispensable for a prolonged stay in the respective European host country.Coming from seven European countries, with different national policies and approaches to the refugee crisis, the foundations and think tanks of Vision Europe are working together to advance new ideas, to frame an informed debate and to emphasize the benefits of common European solutions to Europe-wide problems. Europe is strong enough to manage the migration challenges, but only if political leaders act now, act responsibly and use the resources at their disposal, including support for civil society working in this area. We must not leave the public space to populists and nationalists offering false promises. Only a European solution will be workable and sustainable. Aart de GeusChairman and Chief Executive Officer, Bertelsmann Stiftung, GermanyArtur Santos SilvaPresident, Fundação Calouste Gulbenkian, PortugalGuntram WolffDirector, Bruegel, BelgiumMikko KosonenPresident, Finnish Innovation Fund Sitra, FinlandPiero GastaldoSecretary General, Compagnia di San Paolo, ItalyRobin NiblettDirector, Chatham House, United KingdomYves BertonciniDirector, Jacques Delors Institute, FranceEmbed this image <img src="https://www.chathamhouse.org/sites/default/files/images/2016-03-18-VisionEurope.jpg" alt="" title="" /> Full Article
cr TTIP will create new risks for the West whether it succeeds or fails By feedproxy.google.com Published On :: Thu, 14 Jul 2016 11:23:12 +0000 14 July 2016 A new paper by Chatham House argues that failure of the negotiations could signal the demise of the Western-led international order, particularly now the UK has decided to leave the EU, while success would also bring risks from the response to TTIP by economic and geopolitical rivals. 2016-07-14-ttip.jpg The container ship Osaka Express, operated by Hapag-Lloyd AG, leaves the container terminal at the port in Southampton, UK, on 2 October 2015. Photo: Getty Images. The Transatlantic Trade and Investment Partnership (TTIP) currently being negotiated between the European Union (EU) and the United States has been sold by politicians on both sides as a strategic opportunity to shape globalization to the benefit of both parties. But a new research paper from Chatham House finds that the risks of such an ambitious project are significant – whether or not the current deadlock in negotiations can be overcome – and the UK vote for Brexit increases those risks.The primary strategic benefit of TTIP would be to enable the United States and the EU to set the ‘rules of the road’ for international trade in the 21st century. TTIP’s backers hope that if the EU and the United States can agree on a new set of standards, the power of their combined markets will lead other countries to adopt the same rules. According to Realizing TTIP’s Strategic Potential one of the risks of agreeing such far-reaching rules is that they set the bar too high for other countries to accept. By imposing restrictive rules unilaterally on, for example, state-owned enterprises, TTIP could provoke retaliation and encourage other countries to establish alternative rules.TTIP also has the potential to attract other countries to align themselves economically and politically with the EU and the United States due to their ‘soft-power’. But this benefit will only materialise if strategically important countries, such as Turkey, are able to join. The research finds that the demands placed on Turkey may be too high for this to be a realistic prospect in the near future. Ukraine is another strategic country that could be targeted for expansion of TTIP, but extending membership to Ukraine would be regarded by Russia as a 'serious escalation' by the West in their confrontation.The paper argues there would be benefits to the UK, the EU and the United States if the UK were to join TTIP after the UK leaves the EU. For the UK it could provide the only real prospect of being able to influence international standards and a relatively quick means to conclude a comprehensive trade deal with the United States. For the EU and the United States, it would ensure the scale and attractiveness of TTIP is not reduced by the loss of one of the major European economies. It would also provide an immediate opportunity to establish TTIP as a plurilateral deal that is open to new members. The process would be made easier if the UK were to maintain an active role in the development of the EU position on TTIP, while the UK is still a member of the EU. This would mean that the UK would be in a position to accept the terms required to join TTIP relatively quickly upon exiting the EU. There will inevitably be sensitivities in the UK, other EU member states and the EU institutions about this, but it is in the strategic interests of all parties.The most immediate risk for TTIP, however, is of failure. Despite 14 rounds of negotiations so far there is still disagreement over what should be included in the scope of the negotiations, including issues such as financial services regulation, which the United States is determined to exclude, and how to handle politically sensitive questions such as investor-state dispute settlement, which has become a hot-button issue in the EU. Even if an agreement is reached it must then be ratified by a sceptical US Congress, where there are challenges on both sides of the aisle, and by EU institutions and member states. The hostility to TTIP in many parts of Europe, especially in Germany, is not encouraging.If the negotiations break down, or a deal is reached that falls short of the ambition set for it, this would send a damaging signal to the rest of the world about the ability of the EU and the United States to work together. It could also hasten the demise of their influence. For the EU, the stakes are greater now that the UK has decided to leave the EU.The paper notes that the EU-US trade relationship is still the largest bilateral relationship in the world 'for now', but that in most sectors the lead over China is decreasing. If they miss this opportunity, the United States and the EU may not get another chance to set the standards that will govern the global trading order in the 21st century.Report author, Gregor Irwin, said:'TTIP negotiations are hanging in the balance. If they succeed TTIP has the potential to shape the next generation of trade rules and ensure a transatlantic vision for the international trading system prevails. 'For now, both sides are facing off against each other in the negotiations and failing to focus enough on the strategic risks and opportunities from TTIP. If the full strategic potential from TTIP is to be realized they must pay more attention to how other countries are likely to respond.'The UK’s decision to leave to leave the EU should sharpen the incentives that both sides have to conclude a deal. It is in everyone’s interest to ensure that the UK is able to join TTIP once the UK leaves the EU.'Further opening up TTIP to include Turkey could create an alternative anchor for its economic and political relationship with the EU, short of EU membership. It could transform Turkey’s relationship with the EU, just as the North American Free Trade Agreement (NAFTA) has transformed Mexico’s relationship with the US.' Editor's notes Read Realizing TTIP’s Strategic Potential here.This research paper is authored by Gregor Irwin, Chief Economist of the strategic advisory firm Global Counsel and former Chief Economist of the Foreign and Commonwealth Office.Gregor Irwin is available for interview. For interview requests please contact the press office. Full Article
cr Chatham House Commission on Democracy and Technology in Europe By feedproxy.google.com Published On :: Thu, 25 Jul 2019 14:47:34 +0000 25 July 2019 Our project on Democracy and Technology in Europe is now entering its final phase. Now we want your help in shaping the final report. Commission-DemTech.jpg Commission on Democracy and Technology in Europe For the past few months, users have been sharing their thoughts on our website on the future of democracy and the role of technology in it. Many have shared concerns about the effects of technological change: Social media may be undermining the historic role of politicians to speak on behalf of their constituencies.Twitter favours brief writing and hence brief thinking, which may be leading to a deterioriation in democratic debates.The risk that the so-called 'echo chamber effect' undermines balanced and reasoned public debate.But there have also been lots of ideas about how technology can help European democracies become more responsive and dynamic such as:The use of technology to better inform citizens and include civil society in decision-making.Sybil-proof identity verification for social network accounts operated by local municipalities.The development of non-profit personal data cooperatives as a response to the domination of Big Tech.Now we want users help in shaping the final report. What do you think should be included?We are opening up the report writing process and inviting you to take part and feed in your views. Work with us on a collaborative draft in Google Docs – comment, edit and get an insight into the black box of think tank research.We’ll also be incorporating the most interesting submissions from the previous phase. If you'd like to make a submission, you can still do so here. How To JoinTo access the documents, you will need a Gmail account and to be registered as a user on demtech.chathamhouse.org. Each research question has its own working document, accessed via the Research Questions page.The process is open to everyone. We look forward to working with you!Join the project now Full Article
cr Creon Butler appointed to lead Global Economy and Finance Programme By feedproxy.google.com Published On :: Tue, 22 Oct 2019 10:22:32 +0000 22 October 2019 Creon Butler has been appointed to lead the Global Economy and Finance programme at Chatham House, joining the institute at the beginning of December. He will also form part of the institute’s senior leadership team. Creon will join Chatham House from the Cabinet Office where he served as director for international economic affairs in the National Security Secretariat and G7/G20 ‘sous sherpa’, advising on global policy issues such as climate change, natural resource security, global health threats and the future of the international economic architecture.Creon first joined the Cabinet Office in 2013 as director in the European and Global Issues Secretariat, advising prime minister David Cameron on international economic and financial issues, ranging from country-specific developments in China and Germany to global challenges such as antimicrobial resistance and anticorruption. He designed and organized the UK’s global Anti-Corruption Summit in May 2016. Earlier in his career, he served in the Bank of England, HM Treasury and in the Foreign and Commonwealth Office, where he was director for economic policy and chief economic adviser. He was also deputy high commissioner in New Delhi from 2006 to 2009.Robin Niblett, director of Chatham House, said: 'We are delighted that Creon Butler will join Chatham House at such an important moment, when geoeconomic competition and technological disruption are changing the structure of the global economy, and as governments and societies across the world must develop more sustainable pathways to economic growth. Creon brings precisely the right combination of knowledge and experience to enable Chatham House to conceive inclusive solutions for the future.'Creon Butler said: “Chatham House’s high quality, independent and focused policy research has never been more important in helping policy makers to chart the best path given today’s extraordinary economic and political uncertainties. I am very pleased to have the opportunity to lead the institute’s Global Economy and Finance programme at this critical time.' Full Article
cr Supporting the US Economy by Improving the Mobility of High-skilled Labour Across the Atlantic By feedproxy.google.com Published On :: Wed, 20 Sep 2017 10:33:17 +0000 27 September 2017 US policymakers should give special consideration to a more open immigration policy for highly skilled professionals from the EU. This would ultimately benefit the US economy. Read online Download PDF Marianne Schneider-Petsinger Senior Research Fellow, US and the Americas Programme @mpetsinger 2017-09-25-labour-mobility-us-economy.jpg Businessman on bicycle passing skyline of La Defense business district in Paris, France. Photo: Getty Images. SummaryThe United States and the European Union are deeply integrated economically in terms of movement of goods, services and capital across the Atlantic, but this is not matched by the mobility of labour. Freer movement of high-skilled workers across the Atlantic has a potentially critical role to play in maintaining and strengthening the bilateral economic relationship.Both the US and EU seek to attract high-skilled labour through the use of temporary visa programmes. Various routes are available for highly skilled workers from the EU to temporarily work in the US (for instance, through the H-1B visa for foreign nationals in ‘specialty occupations’, as well as other visa categories for treaty traders and investors, intra-company transferees, and international students seeking work authorization in the US before or after graduation). The main ways for highly skilled workers from the US to temporarily work in EU member states are through EU-wide schemes that apply in 25 out of the 28 member states (for holders of EU Blue Cards or intra-company transferees); or via member states’ parallel national schemes.The experiences of US and EU employers and workers under the US H-1B programme and the EU’s Blue Card scheme differ greatly. The EU Blue Card scheme avoids many of the drawbacks of the H-1B visa. It does not have an annual cap on the number of visas issued. It also grants greater autonomy to the worker by not requiring the employer to sponsor long-term residence, by providing greater flexibility to switch employment, and by having a longer grace period for visa-holders to find new employment after dismissal.The US visa system hampers America’s economic growth. Restrictive policies such as an annual limit on the number of H-1B visas issued, and the associated uncertainty for employees and employers, hinder the ability of US companies to expand and innovate. The complex and costly visa application process is a particular burden for small and medium-sized enterprises. Problems around the timely availability of visas frustrate investors both from the US and from abroad (including from the EU). European firms face difficulties in acquiring visas for intra-company transferees, and not all EU member states have access to the treaty trader and treaty investor visa categories. At times, this impedes foreign direct investment and restricts US job creation. In addition, current policies hinder the economy’s retention of EU and other graduates of US universities. This is of particular concern given that skilled graduates have a critical role to play in addressing the US’s growing shortage of workers in the science, technology, engineering and mathematics (STEM) fields.Given the comparability of US and EU wages and labour markets, US concerns about foreign workers ‘stealing’ their jobs or depressing wages generally do not apply to EU citizens. On the contrary, a more open immigration policy for high-skilled workers – in particular for EU citizens – would benefit the US economy.Efforts to reform visa systems for high-skilled labour are under way in both the US and EU. In order to facilitate the movement of highly skilled workers across the Atlantic, this research paper recommends (1) creating a special visa for highly skilled EU citizens to work temporarily in the US; (2) extending the availability of treaty trader and investor visas to all EU member states; and (3) increasing efforts to eliminate fraud and abuse in the H-1B system. These measures could potentially help to create more investment, jobs and economic growth in the US. Department/project International Security Programme, US and the Americas Programme Full Article
cr Screening Room: For Sama By feedproxy.google.com Published On :: Thu, 29 Aug 2019 16:40:01 +0000 Members Event Screening Room 1 October 2019 - 6:00pm to 8:15pm Chatham House | 10 St James's Square | London | SW1Y 4LE Event participants Dr Hamza Al Kateab, Director, AlQudes Hospital, Aleppo (2012-16); Operation Manager, HuozhiRita Dayoub, Academy Associate, Centre on Global Health Security, Chatham House; Founder, Health Workers at the Frontline InitiativeDr Husam Taha El-mugamar, Vice President, Sudan Doctors’ Union UKChair: Elham Saudi, Director, Lawyers for Justice in Libya For Sama tells the story of a young woman living in Aleppo during a five year period of armed conflict. From 2011 to 2016, Waad al-Kateab documents her personal experience of the war in Syria as she joins the uprising against the Assad regime, falls in love and gives birth to her daughter while living in AlQudes Hospital, run by her husband Hamza and under attack by Syrian and Russian forces.The screening will be followed by a panel discussion exploring the impact of attacks on healthcare institutions in conflict zones. To what extent are attacks on healthcare services used in contemporary warfare? How do these attacks affect health workers in regions facing armed conflict or political unrest? And what is the role of the international community in ensuring the protection of healthcare delivery in conflict zones?Running time: 95 minsThis event is open to Chatham House Members only. Not a member? Find out more.For further information on the different types of Chatham House events, visit Our Events Explained. Members Events Team Email Full Article
cr 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
cr Biosecurity: Preparing for the Aftermath of Global Health Crises By feedproxy.google.com Published On :: Thu, 09 Jan 2020 14:16:59 +0000 9 January 2020 Professor David R Harper CBE Senior Consulting Fellow, Global Health Programme @DavidRossHarper Benjamin Wakefield Research Associate, Global Health Programme @BCWakefield LinkedIn The Ebola outbreak in the Democratic Republic of the Congo is a reminder that the security of samples taken during global health emergencies is a vital part of safeguarding biosecurity. 2020-01-09-DRC.jpg A nurse prepares a vaccine against Ebola in Goma in August 2019. Photo: Getty Images. The world’s second-largest Ebola outbreak is ongoing in the Democratic Republic of the Congo (DRC) and experts from around the world have been parachuted in to support the country’s operation to stamp out the outbreak. The signs are encouraging, but we need to remain cautious.In such emergencies, little thought is usually given to what happens to the body-fluid samples taken during the course of the outbreak after the crisis is over. What gets left behind has considerable implications for global biosecurity.Having unsecured samples poses the obvious risk of accidental exposures to people who might come into contact with them, but what of the risk of malicious use? Bioterrorists would have ready access to materials that have the characteristics essential to their purpose: the potential to cause disease that is transmissible from person to person, the capacity to result in high fatality rates and, importantly, the ability to cause panic and social disruption at the very mention of them.Comparisons can be drawn with the significant international impact of the anthrax attacks in the US in 2001. Not only was there a direct effect in the US with five deaths and a further 17 people infected, but there was a paralysis of public health systems in other countries involved in the testing of countless samples from the so-called ‘white-powder incidents’ that followed.Many laboratory tests were done purely on a precautionary basis to eliminate any possibility of a risk, no matter how remote. However, the UK was also hit when a hoaxer sent envelopes of white powder labelled as anthrax to 15 MPs.The threat of the pathogen alone resulted in widespread fear, the deployment of officers trained in response to chemical, biological, radiological and nuclear incidents and the evacuation of a hospital emergency department.We learned from the 2014–16 West Africa Ebola outbreaks that during the emergency, the future biosecurity implications of the many thousands of samples taken from people were given very little consideration. It is impossible to be sure where they all are and whether they have been secured.It is widely recognized that the systems needed at the time for tracking and monitoring resources, including those necessary for samples, were weak or absent, and this has to be addressed urgently along with other capacity-building initiatives.In Sierra Leone, for example, the remaining biosecurity risk is only being addressed after the fact. To help achieve this, the government of Canada is in the process of providing a secure biobank in the Sierra Leonean capital of Freetown. The aim is to provide the proper means of storage for these hazardous samples and to allow them to remain in-country, with Sierra Leonean ownership.However, it is already more three years since the emergency was declared over by the then director-general of the World Health Organization (WHO), Margaret Chan, and the biobank and its associated laboratory are yet to be fully operational.There are many understandable reasons for this delay, including the critical issue of how best to ensure the sustainability of any new facility. But what is clear is that these solutions take time to implement and must be planned for in advance.The difficulties of responding to an outbreak in a conflict zone have been well documented, and the frequent violence in DRC has undoubtedly caused delays in controlling the outbreak. According to figures from WHO, during 2019 approximately 390 attacks on health facilities in DRC killed 11 and injured 83 healthcare workers and patients.Not only does the conflict inhibit the response, but it could also increase the risk posed by unsecured samples. There are two main potential concerns.First is the risk of accidental release during an attack on a health facility, under which circumstances sample containers may be compromised or destroyed. Second is that the samples may be stolen for malicious use or to sell them to a third-party for malicious use. It is very important in all outbreaks to ensure the necessary measures are in place to secure samples; in conflict-affected areas, this is particularly challenging.The sooner the samples in the DRC are secured, the sooner this risk to global biosecurity is reduced. And preparations for the next emergency must be made without further delay.The following steps need to be taken:Affected countries must ‘own’ the problem, with clear national government commitment to take the required actions.Funding partners must coordinate their actions and work closely with the countries to find the best solutions.If samples are to be kept in-country, secure biobanks must be established to contain them.Sustainable infrastructure must be built for samples to be kept secure into the future.An international agreement should be reached on the best approach to take to prepare for the aftermath of global health emergencies. Full Article
cr 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
cr Legal Provision for Crisis Preparedness: Foresight not Hindsight By feedproxy.google.com Published On :: Tue, 21 Apr 2020 17:03:31 +0000 21 April 2020 Dr Patricia Lewis Research Director, Conflict, Science & Transformation; Director, International Security Programme @PatriciaMary COVID-19 is proving to be a grave threat to humanity. But this is not a one-off, there will be future crises, and we can be better prepared to mitigate them. 2020-04-21-Nurse-COVID-Test Examining a patient while testing for COVID-19 at the Velocity Urgent Care in Woodbridge, Virginia. Photo by Chip Somodevilla/Getty Images. A controversial debate during COVID-19 is the state of readiness within governments and health systems for a pandemic, with lines of the debate drawn on the issues of testing provision, personal protective equipment (PPE), and the speed of decision-making.President Macron in a speech to the nation admitted French medical workers did not have enough PPE and that mistakes had been made: ‘Were we prepared for this crisis? We have to say that no, we weren’t, but we have to admit our errors … and we will learn from this’.In reality few governments were fully prepared. In years to come, all will ask: ‘how could we have been better prepared, what did we do wrong, and what can we learn?’. But after every crisis, governments ask these same questions.Most countries have put in place national risk assessments and established processes and systems to monitor and stress-test crisis-preparedness. So why have some countries been seemingly better prepared?Comparing different approachesSome have had more time and been able to watch the spread of the disease and learn from those countries that had it first. Others have taken their own routes, and there will be much to learn from comparing these different approaches in the longer run.Governments in Asia have been strongly influenced by the experience of the SARS epidemic in 2002-3 and - South Korea in particular - the MERS-CoV outbreak in 2015 which was the largest outside the Middle East. Several carried out preparatory work in terms of risk assessment, preparedness measures and resilience planning for a wide range of threats.Case Study of Preparedness: South KoreaBy 2007, South Korea had established the Division of Public Health Crisis Response in Korea Centers for Disease Control and Prevention (KCDC) and, in 2016, the KCDC Center for Public Health Emergency Preparedness and Response had established a round-the-clock Emergency Operations Center with rapid response teams.KCDC is responsible for the distribution of antiviral stockpiles to 16 cities and provinces that are required by law to hold and manage antiviral stockpiles.And, at the international level, there are frameworks for preparedness for pandemics. The International Health Regulations (IHR) - adopted at the 2005 World Health Assembly and binding on member states - require countries to report certain disease outbreaks and public health events to the World Health Organization (WHO) and ‘prevent, protect against, control and provide a public health response to the international spread of disease in ways that are commensurate with and restricted to public health risks, and which avoid unnecessary interference with international traffic and trade’.Under IHR, governments committed to a programme of building core capacities including coordination, surveillance, response and preparedness. The UN Sendai Framework for Disaster Risk highlights disaster preparedness for effective response as one of its main purposes and has already incorporated these measures into the Sustainable Development Goals (SDGs) and other Agenda 2030 initiatives. UN Secretary-General António Guterres has said COVID-19 ‘poses a significant threat to the maintenance of international peace and security’ and that ‘a signal of unity and resolve from the Council would count for a lot at this anxious time’.Case Study of Preparedness: United StatesThe National Institutes of Health (NIH) and the Center for Disease Control (CDC) established PERRC – the Preparedness for Emergency Response Research Centers - as a requirement of the 2006 Pandemic and All-Hazards Preparedness Act, which required research to ‘improve federal, state, local, and tribal public health preparedness and response systems’.The 2006 Act has since been supplanted by the 2019 Pandemic and All-Hazards Preparedness and Advancing Innovation Act. This created the post of Assistant Secretary for Preparedness and Response (ASPR) in the Department for Health and Human Services (HHS) and authorised the development and acquisitions of medical countermeasures and a quadrennial National Health Security Strategy.The 2019 Act also set in place a number of measures including the requirement for the US government to re-evaluate several important metrics of the Public Health Emergency Preparedness cooperative agreement and the Hospital Preparedness Program, and a requirement for a report on the states of preparedness and response in US healthcare facilities.This pandemic looks set to continue to be a grave threat to humanity. But there will also be future pandemics – whether another type of coronavirus or a new influenza virus – and our species will be threatened again, we just don’t know when.Other disasters too will befall us – we already see the impacts of climate change arriving on our doorsteps characterised by increased numbers and intensity of floods, hurricanes, fires, crop failure and other manifestations of a warming, increasingly turbulent atmosphere and we will continue to suffer major volcanic eruptions, earthquakes and tsunamis. All high impact, unknown probability events.Preparedness for an unknown future is expensive and requires a great deal of effort for events that may not happen within the preparers’ lifetimes. It is hard to imagine now, but people will forget this crisis, and revert to their imagined projections of the future where crises don’t occur, and progress follows progress. But history shows us otherwise.Preparations for future crises always fall prey to financial cuts and austerity measures in lean times unless there is a mechanism to prevent that. Cost-benefit analyses will understandably tend to prioritise the urgent over the long-term. So governments should put in place legislation – or strengthen existing legislation – now to ensure their countries are as prepared as possible for whatever crisis is coming.Such a legal requirement would require governments to report back to parliament every year on the state of their national preparations detailing such measures as:The exact levels of stocks of essential materials (including medical equipment)The ability of hospitals to cope with large influx of patientsHow many drills, exercises and simulations had been organised – and their findingsWhat was being done to implement lessons learned & improve preparednessIn addition, further actions should be taken:Parliamentary committees such as the UK Joint Committee on the National Security Strategy should scrutinise the government’s readiness for the potential threats outlined in the National Risk register for Civil Emergencies in-depth on an annual basis.Parliamentarians, including ministers, with responsibility for national security and resilience should participate in drills, table-top exercises and simulations to see for themselves the problems inherent with dealing with crises.All governments should have a minister (or equivalent) with the sole responsibility for national crisis preparedness and resilience. The Minister would be empowered to liaise internationally and coordinate local responses such as local resilience groups.There should be ring-fenced budget lines in annual budgets specifically for preparedness and resilience measures, annually reported on and assessed by parliaments as part of the due diligence process.And at the international level:The UN Security Council should establish a Crisis Preparedness Committee to bolster the ability of United Nations Member States to respond to international crisis such as pandemics, within their borders and across regions. The Committee would function in a similar fashion as the Counter Terrorism Committee that was established following the 9/11 terrorist attacks in the United States.States should present reports on their level of preparedness to the UN Security Council. The Crisis Preparedness Committee could establish a group of experts who would conduct expert assessments of each member state’s risks and preparedness and facilitate technical assistance as required.Regional bodies such as the OSCE, ASEAN and ARF, the AU, the OAS, the PIF etc could also request national reports on crisis preparedness for discussion and cooperation at the regional level.COVID-19 has been referred to as the 9/11 of crisis preparedness and response. Just as that shocking terrorist attack shifted the world and created a series of measures to address terrorism, we now recognise our security frameworks need far more emphasis on being prepared and being resilient. Whatever has been done in the past, it is clear that was nowhere near enough and that has to change.Case Study of Preparedness: The UKThe National Risk Register was first published in 2008 as part of the undertakings laid out in the National Security Strategy (the UK also published the Biological Security Strategy in July 2018). Now entitled the National Risk Register for Civil Emergencies it has been updated regularly to analyse the risks of major emergencies that could affect the UK in the next five years and provide resilience advice and guidance.The latest edition - produced in 2017 when the UK had a Minister for Government Resilience and Efficiency - placed the risk of a pandemic influenza in the ‘highly likely and most severe’ category. It stood out from all the other identified risks, whereas an emerging disease (such as COVID-19) was identified as ‘highly likely but with moderate impact’.However, much preparatory work for an influenza pandemic is the same as for COVID-19, particularly in prepositioning large stocks of PPE, readiness within large hospitals, and the creation of new hospitals and facilities.One key issue is that the 2017 NHS Operating Framework for Managing the Response to Pandemic Influenza was dependent on pre-positioned ’just in case’ stockpiles of PPE. But as it became clear the PPE stocks were not adequate for the pandemic, it was reported that recommendations about the stockpile by NERVTAG (the New and Emerging Respiratory Virus Threats Advisory Group which advises the government on the threat posed by new and emerging respiratory viruses) had been subjected to an ‘economic assessment’ and decisions reversed on, for example, eye protection.The UK chief medical officer Dame Sally Davies, when speaking at the World Health Organization about Operation Cygnus – a 2016 three-day exercise on a flu pandemic in the UK – reportedly said the UK was not ready for a severe flu attack and ‘a lot of things need improving’.Aware of the significance of the situation, the UK Parliamentary Joint Committee on the National Security Strategy launched an inquiry in 2019 on ‘Biosecurity and human health: preparing for emerging infectious diseases and bioweapons’ which intended to coordinate a cross-government approach to biosecurity threats. But the inquiry had to postpone its oral hearings scheduled for late October 2019 and, because of the general election in December 2019, the committee was obliged to close the inquiry. Full Article
cr Webinar: Coronavirus Crisis – Implications for an Evolving Cybersecurity Landscape By feedproxy.google.com Published On :: Thu, 23 Apr 2020 11:25:01 +0000 Corporate Members Event Webinar 7 May 2020 - 1:00pm to 2:00pm Event participants Neil Walsh, Chief, Cybercrime and Anti-Money Laundering Department, UN Office of Drugs and CrimeLisa Quest, Head, Public Sector, UK & Ireland, Oliver WymanChair: Joyce Hakmeh, Senior Research Fellow, International Security Programme; Co-Editor, Journal of Cyber Policy, Chatham HouseFurther speakers to be announced. The COVID-19 pandemic is having a profound impact on the cybersecurity landscape - both amplifying already-existing cyber threats and creating new vulnerabilities for state and non-state actors. The crisis has highlighted the importance of protecting key national and international infrastructures, with the World Health Organization, US Department of Health and Human Services and hospitals across Europe suffering cyber-attacks, undermining their ability to tackle the coronavirus outbreak. Changing patterns of work resulting from widespread lockdowns are also creating new vulnerabilities for organizations with many employees now working from home and using personal devices to work remotely.In light of these developments, the panellists will discuss the evolving cyber threats resulting from the pandemic. How are they impacting ongoing conversations around cybersecurity? How can governments, private sector and civil society organizations work together to effectively mitigate and respond to them? And what could the implications of such cooperation be beyond the crisis? This event is part of a fortnightly series of 'Business in Focus' webinars reflecting on the impact of COVID-19 on areas of particular professional interest for our corporate members and giving circles.Not a corporate member? Find out more. Full Article
cr Coronavirus Risks Worsening a Food Crisis in the Sahel and West Africa By feedproxy.google.com Published On :: Fri, 01 May 2020 14:20:52 +0000 1 May 2020 Dr Leena Koni Hoffmann Associate Fellow, Africa Programme @leenahoffmann LinkedIn Paul Melly Consulting Fellow, Africa Programme @paulmelly2 In responding to the spread of the coronavirus, the governments of the Sahel and West Africa will need to draw on their collective experience of strategic coordination in emergency planning, and work together to prioritize the flow of food across borders. 2020-05-01-Africa-Market-Virus An informal market in the Anyama district of Abidjan, Côte d’Ivoire, is sanitized against the coronavirus. Photo by SIA KAMBOU/AFP via Getty Images. The COVID-19 pandemic has struck the Sahel and West Africa at a time when the region is already under severe pressure from violent insecurity and the effects of climate change on its land, food and water resources.By the end of April, there had been 9,513 confirmed coronavirus cases across the 17 countries of the region, and some 231 deaths, with the highest overall numbers recorded in Nigeria, Ghana, Guinea, Côte d’Ivoire, Senegal, Niger and Burkina Faso. Low testing rates mean than these numbers give only a partial picture.The Food Crisis Prevention Network (RPCA) forecast in early April that almost 17 million people in the Sahel and West Africa (7.1 million in Nigeria alone) will need food and nutritional assistance during the coming lean season in June–August, more than double the number in an average year. The combined impact of violent insecurity and COVID-19 could put more than 50 million other people across the region at risk of food and nutrition crisis.Rippling across the regionThe effects of the collapse in global commodity prices, currency depreciations, rising costs of consumer goods and disruptions to supply chains are rippling across the region. And for major oil-exporting countries such as Nigeria, Ghana, Chad and Cameroon, the wipe-out of foreign currency earnings will hammer government revenues just as the cost of food and other critical imports goes up. It is likely that the number of people who suffer the direct health impact of the coronavirus will be far outstripped by the number for whom there will be harsh social and economic costs.In recent years, valuable protocols and capacities have been put in place by governments in West and Central Africa in response to Ebola and other infectious disease outbreaks.But inadequate healthcare funding and infrastructure across this region compound the challenge of responding to the spread of the COVID-19 infection – which is testing the resources of even the world’s best-funded public health systems.Over many years, however, the region has steadily built up structures to tackle humanitarian and development challenges, particularly as regards food security. It has an established system for assessing the risk of food crisis annually and coordinating emergency support to vulnerable communities. Each country monitors climate and weather patterns, transhumance, market systems and agricultural statistics, and terrorist disruption of agricultural productivity, from local community to national and regional level.The system is coordinated and quality-controlled, using common technical data standards, by the Permanent Interstate Committee for Drought Control in the Sahel (CILSS), a regional intergovernmental body established in 1973 in response to a devastating drought. Collective risk assessments allow emergency support to be mobilized through the RPCA.For almost three months already, countries in Sahelian West Africa have been working with the World Health Organization to prepare national COVID-19 response strategies and strengthen health controls at their borders. Almost all governments have also opted for domestic curfews, and variations of lockdown and market restrictions.Senegal has been a leader in rapidly developing Africa’s diagnostic capacity, and plans are under way to speed up production of test kits. Niger was swift to develop a national response strategy, to which donors have pledged €194.5 million. While the IMF has agreed emergency financial assistance to help countries address the urgent balance-of-payments, health and social programme needs linked to the COVID-19 pandemic, signing off $3.4 billion for Nigeria, $442 million for Senegal and $130 million for Mauritania.Steps are also now being taken towards the formulation of a more joined-up regional approach. Notably, Nigeria’s President Muhammadu Buhari has been chosen by an extraordinary session of the Economic Community of West African States to coordinate the regional response to COVID-19. As Africa’s biggest economy and home to its largest population, Nigeria is a critical hub for transnational flows of goods and people. Its controversial August 2019 land border closure, in a bid to address smuggling, has already painfully disrupted regional agri-food trade and value chains. The active engagement of the Buhari administration will thus be crucial to the success of a multifaceted regional response.One of the first tough questions the region’s governments must collectively address is how long to maintain the border shutdowns that were imposed as an initial measure to curb the spread of the virus. Closed borders are detrimental to food security, and disruptive to supply chains and the livelihoods of micro, small and medium-sized entrepreneurs that rely on cross-border trade. The impact of prolonged closures will be all the more profound in a region where welfare systems are largely non-existent or, at best, highly precarious.Nigeria, in particular, with more than 95 million people already living in extreme poverty, might do well to explore measures to avoid putting food further beyond the reach of people who are seeing their purchasing power evaporate.In taking further actions to control the spread of the coronavirus, the region’s governments will need to show faith in the system that they have painstakingly developed to monitor and respond to the annual risk of food crisis across the Sahel. This system, and the critical data it offers, will be vital to informing interventions to strengthen the four components of food security – availability, access, stability and utilization – in the context of COVID-19, and for charting a post-pandemic path of recovery.Above all, careful steps will need to be put in place to ensure that preventing the spread of the coronavirus does not come at the cost of even greater food insecurity for the people of the Sahel and West Africa. The region’s governments must prioritize the flow of food across borders and renew their commitment to strategic coordination and alignment. Full Article
cr The transcriptional regulator MEIS2 sets up the ground state for palatal osteogenesis in mice [Gene Regulation] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 Haploinsufficiency of Meis homeobox 2 (MEIS2), encoding a transcriptional regulator, is associated with human cleft palate, and Meis2 inactivation leads to abnormal palate development in mice, implicating MEIS2 functions in palate development. However, its functional mechanisms remain unknown. Here we observed widespread MEIS2 expression in the developing palate in mice. Wnt1Cre-mediated Meis2 inactivation in cranial neural crest cells led to a secondary palate cleft. Importantly, about half of the Wnt1Cre;Meis2f/f mice exhibited a submucous cleft, providing a model for studying palatal bone formation and patterning. Consistent with complete absence of palatal bones, the results from integrative analyses of MEIS2 by ChIP sequencing, RNA-Seq, and an assay for transposase-accessible chromatin sequencing identified key osteogenic genes regulated directly by MEIS2, indicating that it plays a fundamental role in palatal osteogenesis. De novo motif analysis uncovered that the MEIS2-bound regions are highly enriched in binding motifs for several key osteogenic transcription factors, particularly short stature homeobox 2 (SHOX2). Comparative ChIP sequencing analyses revealed genome-wide co-occupancy of MEIS2 and SHOX2 in addition to their colocalization in the developing palate and physical interaction, suggesting that SHOX2 and MEIS2 functionally interact. However, although SHOX2 was required for proper palatal bone formation and was a direct downstream target of MEIS2, Shox2 overexpression failed to rescue the palatal bone defects in a Meis2-mutant background. These results, together with the fact that Meis2 expression is associated with high osteogenic potential and required for chromatin accessibility of osteogenic genes, support a vital function of MEIS2 in setting up a ground state for palatal osteogenesis. Full Article
cr The transcriptional regulator IscR integrates host-derived nitrosative stress and iron starvation in activation of the vvhBA operon in Vibrio vulnificus [Gene Regulation] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 For successful infection of their hosts, pathogenic bacteria recognize host-derived signals that induce the expression of virulence factors in a spatiotemporal manner. The fulminating food-borne pathogen Vibrio vulnificus produces a cytolysin/hemolysin protein encoded by the vvhBA operon, which is a virulence factor preferentially expressed upon exposure to murine blood and macrophages. The Fe-S cluster containing transcriptional regulator IscR activates the vvhBA operon in response to nitrosative stress and iron starvation, during which the cellular IscR protein level increases. Here, electrophoretic mobility shift and DNase I protection assays revealed that IscR directly binds downstream of the vvhBA promoter PvvhBA, which is unusual for a positive regulator. We found that in addition to IscR, the transcriptional regulator HlyU activates vvhBA transcription by directly binding upstream of PvvhBA, whereas the histone-like nucleoid-structuring protein (H-NS) represses vvhBA by extensively binding to both downstream and upstream regions of its promoter. Of note, the binding sites of IscR and HlyU overlapped with those of H-NS. We further substantiated that IscR and HlyU outcompete H-NS for binding to the PvvhBA regulatory region, resulting in the release of H-NS repression and vvhBA induction. We conclude that concurrent antirepression by IscR and HlyU at regions both downstream and upstream of PvvhBA provides V. vulnificus with the means of integrating host-derived signal(s) such as nitrosative stress and iron starvation for precise regulation of vvhBA transcription, thereby enabling successful host infection. Full Article
cr 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
cr The mRNA levels of heat shock factor 1 are regulated by thermogenic signals via the cAMP-dependent transcription factor ATF3 [Metabolism] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 Heat shock factor 1 (HSF1) regulates cellular adaptation to challenges such as heat shock and oxidative and proteotoxic stresses. We have recently reported a previously unappreciated role for HSF1 in the regulation of energy metabolism in fat tissues; however, whether HSF1 is differentially expressed in adipose depots and how its levels are regulated in fat tissues remain unclear. Here, we show that HSF1 levels are higher in brown and subcutaneous fat tissues than in those in the visceral depot and that HSF1 is more abundant in differentiated, thermogenic adipocytes. Gene expression experiments indicated that HSF1 is transcriptionally regulated in fat by agents that modulate cAMP levels, by cold exposure, and by pharmacological stimulation of β-adrenergic signaling. An in silico promoter analysis helped identify a putative response element for activating transcription factor 3 (ATF3) at −258 to −250 base pairs from the HSF1 transcriptional start site, and electrophoretic mobility shift and ChIP assays confirmed ATF3 binding to this sequence. Furthermore, functional assays disclosed that ATF3 is necessary and sufficient for HSF1 regulation. Detailed gene expression analysis revealed that ATF3 is one of the most highly induced ATFs in thermogenic tissues of mice exposed to cold temperatures or treated with the β-adrenergic receptor agonist CL316,243 and that its expression is induced by modulators of cAMP levels in isolated adipocytes. To the best of our knowledge, our results show for the first time that HSF1 is transcriptionally controlled by ATF3 in response to classic stimuli that promote heat generation in thermogenic tissues. Full Article
cr Inflammatory and mitogenic signals drive interleukin 23 subunit alpha (IL23A) secretion independent of IL12B in intestinal epithelial cells [Signal Transduction] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 The heterodimeric cytokine interleukin-23 (IL-23 or IL23A/IL12B) is produced by dendritic cells and macrophages and promotes the proinflammatory and regenerative activities of T helper 17 (Th17) and innate lymphoid cells. A recent study has reported that IL-23 is also secreted by lung adenoma cells and generates an inflammatory and immune-suppressed stroma. Here, we observed that proinflammatory tumor necrosis factor (TNF)/NF-κB and mitogen-activated protein kinase (MAPK) signaling strongly induce IL23A expression in intestinal epithelial cells. Moreover, we identified a strong crosstalk between the NF-κB and MAPK/ERK kinase (MEK) pathways, involving the formation of a transcriptional enhancer complex consisting of proto-oncogene c-Jun (c-Jun), RELA proto-oncogene NF-κB subunit (RelA), RUNX family transcription factor 1 (RUNX1), and RUNX3. Collectively, these proteins induced IL23A secretion, confirmed by immunoprecipitation of endogenous IL23A from activated human colorectal cancer (CRC) cell culture supernatants. Interestingly, IL23A was likely secreted in a noncanonical form, as it was not detected by an ELISA specific for heterodimeric IL-23 likely because IL12B expression is absent in CRC cells. Given recent evidence that IL23A promotes tumor formation, we evaluated the efficacy of MAPK/NF-κB inhibitors in attenuating IL23A expression and found that the MEK inhibitor trametinib and BAY 11–7082 (an IKKα/IκB inhibitor) effectively inhibited IL23A in a subset of human CRC lines with mutant KRAS or BRAFV600E mutations. Together, these results indicate that proinflammatory and mitogenic signals dynamically regulate IL23A in epithelial cells. They further reveal its secretion in a noncanonical form independent of IL12B and that small-molecule inhibitors can attenuate IL23A secretion. Full Article
cr 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
cr Extending the Limits of Quantitative Proteome Profiling with Data-Independent Acquisition and Application to Acetaminophen-Treated Three-Dimensional Liver Microtissues By feedproxy.google.com Published On :: 2015-05-01 Roland BrudererMay 1, 2015; 14:1400-1410Research Full Article
cr PaxDb, a Database of Protein Abundance Averages Across All Three Domains of Life By feedproxy.google.com Published On :: 2012-08-01 M. WangAug 1, 2012; 11:492-500Technological Innovation and Resources Full Article
cr Large Scale Screening for Novel Rab Effectors Reveals Unexpected Broad Rab Binding Specificity By feedproxy.google.com Published On :: 2008-06-01 Mitsunori FukudaJun 1, 2008; 7:1031-1042Research Full Article
cr Complementary Profiling of Gene Expression at the Transcriptome and Proteome Levels in Saccharomyces cerevisiae By feedproxy.google.com Published On :: 2002-04-01 Timothy J. GriffinApr 1, 2002; 1:323-333Research Full Article
cr A Tandem Affinity Tag for Two-step Purification under Fully Denaturing Conditions: Application in Ubiquitin Profiling and Protein Complex Identification Combined with in vivoCross-Linking By feedproxy.google.com Published On :: 2006-04-01 Christian TagwerkerApr 1, 2006; 5:737-748Research Full Article
cr Highly Selective Enrichment of Phosphorylated Peptides from Peptide Mixtures Using Titanium Dioxide Microcolumns By feedproxy.google.com Published On :: 2005-07-01 Martin R. LarsenJul 1, 2005; 4:873-886Technology Full Article
cr Analysis of the Human Tissue-specific Expression by Genome-wide Integration of Transcriptomics and Antibody-based Proteomics By feedproxy.google.com Published On :: 2014-02-01 Linn FagerbergFeb 1, 2014; 13:397-406Research Full Article
cr The cytochrome P450 enzyme CYP24A1 increases proliferation of mutant KRAS-dependent lung adenocarcinoma independent of its catalytic activity [Cell Biology] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 We previously reported that overexpression of cytochrome P450 family 24 subfamily A member 1 (CYP24A1) increases lung cancer cell proliferation by activating RAS signaling and that CYP24A1 knockdown inhibits tumor growth. However, the mechanism of CYP24A1-mediated cancer cell proliferation remains unclear. Here, we conducted cell synchronization and biochemical experiments in lung adenocarcinoma cells, revealing a link between CYP24A1 and anaphase-promoting complex (APC), a key cell cycle regulator. We demonstrate that CYP24A1 expression is cell cycle–dependent; it was higher in the G2-M phase and diminished upon G1 entry. CYP24A1 has a functional destruction box (D-box) motif that allows binding with two APC adaptors, CDC20-homologue 1 (CDH1) and cell division cycle 20 (CDC20). Unlike other APC substrates, however, CYP24A1 acted as a pseudo-substrate, inhibiting CDH1 activity and promoting mitotic progression. Conversely, overexpression of a CYP24A1 D-box mutant compromised CDH1 binding, allowing CDH1 hyperactivation, thereby hastening degradation of its substrates cyclin B1 and CDC20, and accumulation of the CDC20 substrate p21, prolonging mitotic exit. These activities also occurred with a CYP24A1 isoform 2 lacking the catalytic cysteine (Cys-462), suggesting that CYP24A1's oncogenic potential is independent of its catalytic activity. CYP24A1 degradation reduced clonogenic survival of mutant KRAS-driven lung cancer cells, and calcitriol treatment increased CYP24A1 levels and tumor burden in Lsl-KRASG12D mice. These results disclose a catalytic activity-independent growth-promoting role of CYP24A1 in mutant KRAS-driven lung cancer. This suggests that CYP24A1 could be therapeutically targeted in lung cancers in which its expression is high. Full Article
cr SUMOylation of the transcription factor ZFHX3 at Lys-2806 requires SAE1, UBC9, and PIAS2 and enhances its stability and function in cell proliferation [Protein Synthesis and Degradation] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 SUMOylation is a posttranslational modification (PTM) at a lysine residue and is crucial for the proper functions of many proteins, particularly of transcription factors, in various biological processes. Zinc finger homeobox 3 (ZFHX3), also known as AT motif-binding factor 1 (ATBF1), is a large transcription factor that is active in multiple pathological processes, including atrial fibrillation and carcinogenesis, and in circadian regulation and development. We have previously demonstrated that ZFHX3 is SUMOylated at three or more lysine residues. Here, we investigated which enzymes regulate ZFHX3 SUMOylation and whether SUMOylation modulates ZFHX3 stability and function. We found that SUMO1, SUMO2, and SUMO3 each are conjugated to ZFHX3. Multiple lysine residues in ZFHX3 were SUMOylated, but Lys-2806 was the major SUMOylation site, and we also found that it is highly conserved among ZFHX3 orthologs from different animal species. Using molecular analyses, we identified the enzymes that mediate ZFHX3 SUMOylation; these included SUMO1-activating enzyme subunit 1 (SAE1), an E1-activating enzyme; SUMO-conjugating enzyme UBC9 (UBC9), an E2-conjugating enzyme; and protein inhibitor of activated STAT2 (PIAS2), an E3 ligase. Multiple analyses established that both SUMO-specific peptidase 1 (SENP1) and SENP2 deSUMOylate ZFHX3. SUMOylation at Lys-2806 enhanced ZFHX3 stability by interfering with its ubiquitination and proteasomal degradation. Functionally, Lys-2806 SUMOylation enabled ZFHX3-mediated cell proliferation and xenograft tumor growth of the MDA-MB-231 breast cancer cell line. These findings reveal the enzymes involved in, and the functional consequences of, ZFHX3 SUMOylation, insights that may help shed light on ZFHX3's roles in various cellular and pathophysiological processes. Full Article
cr {gamma}-Hydroxybutyrate does not mediate glucose inhibition of glucagon secretion [Signal Transduction] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 Hypersecretion of glucagon from pancreatic α-cells strongly contributes to diabetic hyperglycemia. Moreover, failure of α-cells to increase glucagon secretion in response to falling blood glucose concentrations compromises the defense against hypoglycemia, a common complication in diabetes therapy. However, the mechanisms underlying glucose regulation of glucagon secretion are poorly understood and likely involve both α-cell–intrinsic and intraislet paracrine signaling. Among paracrine factors, glucose-stimulated release of the GABA metabolite γ-hydroxybutyric acid (GHB) from pancreatic β-cells might mediate glucose suppression of glucagon release via GHB receptors on α-cells. However, the direct effects of GHB on α-cell signaling and glucagon release have not been investigated. Here, we found that GHB (4–10 μm) lacked effects on the cytoplasmic concentrations of the secretion-regulating messengers Ca2+ and cAMP in mouse α-cells. Glucagon secretion from perifused mouse islets was also unaffected by GHB at both 1 and 7 mm glucose. The GHB receptor agonist 3-chloropropanoic acid and the antagonist NCS-382 had no effects on glucagon secretion and did not affect stimulation of secretion induced by a drop in glucose from 7 to 1 mm. Inhibition of endogenous GHB formation with the GABA transaminase inhibitor vigabatrin also failed to influence glucagon secretion at 1 mm glucose and did not prevent the suppressive effect of 7 mm glucose. In human islets, GHB tended to stimulate glucagon secretion at 1 mm glucose, an effect mimicked by 3-chloropropanoic acid. We conclude that GHB does not mediate the inhibitory effect of glucose on glucagon secretion. Full Article
cr Cross-regulation between LUBAC and caspase-1 modulates cell death and inflammation [Signal Transduction] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 The linear ubiquitin assembly complex (LUBAC) is an essential component of the innate and adaptive immune system. Modification of cellular substrates with linear polyubiquitin chains is a key regulatory step in signal transduction that impacts cell death and inflammatory signaling downstream of various innate immunity receptors. Loss-of-function mutations in the LUBAC components HOIP and HOIL-1 yield a systemic autoinflammatory disease in humans, whereas their genetic ablation is embryonically lethal in mice. Deficiency of the LUBAC adaptor protein Sharpin results in a multi-organ inflammatory disease in mice characterized by chronic proliferative dermatitis (cpdm), which is propagated by TNFR1-induced and RIPK1-mediated keratinocyte cell death. We have previously shown that caspase-1 and -11 promoted the dermatitis pathology of cpdm mice and mediated cell death in the skin. Here, we describe a reciprocal regulation of caspase-1 and LUBAC activities in keratinocytes. We show that LUBAC interacted with caspase-1 via HOIP and modified its CARD domain with linear polyubiquitin and that depletion of HOIP or Sharpin resulted in heightened caspase-1 activation and cell death in response to inflammasome activation, unlike what is observed in macrophages. Reciprocally, caspase-1, as well as caspase-8, regulated LUBAC activity by proteolytically processing HOIP at Asp-348 and Asp-387 during the execution of cell death. HOIP processing impeded substrate ubiquitination in the NF-κB pathway and resulted in enhanced apoptosis. These results highlight a regulatory mechanism underlying efficient apoptosis in keratinocytes and provide further evidence of a cross-talk between inflammatory and cell death pathways. Full Article
cr NF-{kappa}B mediates lipopolysaccharide-induced alternative pre-mRNA splicing of MyD88 in mouse macrophages [Signal Transduction] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 Although a robust inflammatory response is needed to combat infection, this response must ultimately be terminated to prevent chronic inflammation. One mechanism that terminates inflammatory signaling is the production of alternative mRNA splice forms in the Toll-like receptor (TLR) signaling pathway. Whereas most genes in the TLR pathway encode positive mediators of inflammatory signaling, several, including that encoding the MyD88 signaling adaptor, also produce alternative spliced mRNA isoforms that encode dominant-negative inhibitors of the response. Production of these negatively acting alternatively spliced isoforms is induced by stimulation with the TLR4 agonist lipopolysaccharide (LPS); thus, this alternative pre-mRNA splicing represents a negative feedback loop that terminates TLR signaling and prevents chronic inflammation. In the current study, we investigated the mechanisms regulating the LPS-induced alternative pre-mRNA splicing of the MyD88 transcript in murine macrophages. We found that 1) the induction of the alternatively spliced MyD88 form is due to alternative pre-mRNA splicing and not caused by another RNA regulatory mechanism, 2) MyD88 splicing is regulated by both the MyD88- and TRIF-dependent arms of the TLR signaling pathway, 3) MyD88 splicing is regulated by the NF-κB transcription factor, and 4) NF-κB likely regulates MyD88 alternative pre-mRNA splicing per se rather than regulating splicing indirectly by altering MyD88 transcription. We conclude that alternative splicing of MyD88 may provide a sensitive mechanism that ensures robust termination of inflammation for tissue repair and restoration of normal tissue homeostasis once an infection is controlled. Full Article
cr 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
cr Phosphoproteomic characterization of the signaling network resulting from activation of the chemokine receptor CCR2 [Genomics and Proteomics] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Leukocyte recruitment is a universal feature of tissue inflammation and regulated by the interactions of chemokines with their G protein–coupled receptors. Activation of CC chemokine receptor 2 (CCR2) by its cognate chemokine ligands, including CC chemokine ligand 2 (CCL2), plays a central role in recruitment of monocytes in several inflammatory diseases. In this study, we used phosphoproteomics to conduct an unbiased characterization of the signaling network resulting from CCL2 activation of CCR2. Using data-independent acquisition MS analysis, we quantified both the proteome and phosphoproteome in FlpIn-HEK293T cells stably expressing CCR2 at six time points after activation with CCL2. Differential expression analysis identified 699 significantly regulated phosphorylation sites on 441 proteins. As expected, many of these proteins are known to participate in canonical signal transduction pathways and in the regulation of actin cytoskeleton dynamics, including numerous guanine nucleotide exchange factors and GTPase-activating proteins. Moreover, we identified regulated phosphorylation sites in numerous proteins that function in the nucleus, including several constituents of the nuclear pore complex. The results of this study provide an unprecedented level of detail of CCR2 signaling and identify potential targets for regulation of CCR2 function. Full Article
cr Inflammatory and mitogenic signals drive interleukin 23 subunit alpha (IL23A) secretion independent of IL12B in intestinal epithelial cells [Signal Transduction] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 The heterodimeric cytokine interleukin-23 (IL-23 or IL23A/IL12B) is produced by dendritic cells and macrophages and promotes the proinflammatory and regenerative activities of T helper 17 (Th17) and innate lymphoid cells. A recent study has reported that IL-23 is also secreted by lung adenoma cells and generates an inflammatory and immune-suppressed stroma. Here, we observed that proinflammatory tumor necrosis factor (TNF)/NF-κB and mitogen-activated protein kinase (MAPK) signaling strongly induce IL23A expression in intestinal epithelial cells. Moreover, we identified a strong crosstalk between the NF-κB and MAPK/ERK kinase (MEK) pathways, involving the formation of a transcriptional enhancer complex consisting of proto-oncogene c-Jun (c-Jun), RELA proto-oncogene NF-κB subunit (RelA), RUNX family transcription factor 1 (RUNX1), and RUNX3. Collectively, these proteins induced IL23A secretion, confirmed by immunoprecipitation of endogenous IL23A from activated human colorectal cancer (CRC) cell culture supernatants. Interestingly, IL23A was likely secreted in a noncanonical form, as it was not detected by an ELISA specific for heterodimeric IL-23 likely because IL12B expression is absent in CRC cells. Given recent evidence that IL23A promotes tumor formation, we evaluated the efficacy of MAPK/NF-κB inhibitors in attenuating IL23A expression and found that the MEK inhibitor trametinib and BAY 11–7082 (an IKKα/IκB inhibitor) effectively inhibited IL23A in a subset of human CRC lines with mutant KRAS or BRAFV600E mutations. Together, these results indicate that proinflammatory and mitogenic signals dynamically regulate IL23A in epithelial cells. They further reveal its secretion in a noncanonical form independent of IL12B and that small-molecule inhibitors can attenuate IL23A secretion. Full Article
cr A Credit-fuelled Economic Recovery Stores Up Trouble for Turkey By feedproxy.google.com Published On :: Mon, 17 Feb 2020 13:47:40 +0000 17 February 2020 Fadi Hakura Consulting Fellow, Europe Programme LinkedIn Turkey is repeating the mistakes that led to the 2018 lira crisis and another freefall for the currency may not be far off. 2020-02-17-TurCB.jpg Headquarters of the Central Bank of the Republic of Turkey. Photo: Getty Images. Since the 2018 economic crisis, when the value of the lira plummeted and borrowing costs soared, Turkey’s economy has achieved a miraculous ‘V-shaped’ economic recovery from a recession lasting three quarters to a return back to quarterly growth above 1 per cent in the first three months of 2019.But this quick turnaround has been built on vast amounts of cheap credit used to re-stimulate a consumption and construction boom. This so-called ‘triple C’ economy generated a rapid growth spurt akin to a modestly able professional sprinter injected with steroids.This has made the currency vulnerable. The lira has steadily depreciated by 11 per cent against the US dollar since the beginning of 2019 and crossed the rate of 6 lira versus the US dollar on 7 February. And there are further warning signs on the horizon.Credit bonanzaStatistics reveal that Turkish domestic credit grew by around 13 per cent on average throughout 2019. The credit bonanza is still ongoing. Mortgage-backed home sales jumped by a record high of 600 per cent last December alone and the 2019 budget deficit catapulted by 70 per cent due to higher government spending.Turkey’s central bank fuelled this credit expansion by cutting interest rates aggressively to below inflation and, since the start of this year, purchasing lira-denominated bonds equivalent to around one-third of total acquisitions last year to push yields lower.Equally, it has linked bank lending to reserve requirements – the money that banks have to keep at the central bank – to boost borrowings via state and private banks. Banks with a ‘real’ loan growth (including inflation) of between 5 and 15 per cent enjoy a 2 per cent reserve ratio on most lira deposits, which authorities adjusted from an earlier band of 10-20 per cent that did not consider double-digit inflation.Cumulatively, bond purchases (effectively quantitative easing) and reserve management policies have also contributed to eased credit conditions.Commercial banks have also reduced deposit rates on lira accounts to less than inflation to encourage consumption over saving. Together with low lending rates, the boost to the economy has flowed via mortgages, credit card loans, vehicle leasing transactions and general business borrowings.Accordingly, stimulus is at the forefront of the government’s economic approach, as it was in 2017 and 2018. It does not seem to be implementing structural change to re-orient growth away from consumption towards productivity. In addition, governance is, again, a central issue. President Recep Tayyip Erdogan’s near total monopolization of policymaking means he guides all domestic and external policies. He forced out the previous central bank governor, Murat Cetinkaya, in July 2019 because he did not share the president’s desire for an accelerated pace of interest rate reductions.New challengesDespite the similarities, the expected future financial turbulence will be materially different from its 2018 predecessor in four crucial respects. Firstly, foreign investors will only be marginally involved. Turkey has shut out foreign investors since 2018 from lira-denominated assets by restricting lira swap arrangements. Unsurprisingly, the non-resident holdings of lira bonds has plummeted from 20 per cent in 2018 to less than 10 per cent today.Secondly, the Turkish government has recently introduced indirect domestic capital controls by constraining most commercial transactions to the lira rather than to the US dollar or euro to reduce foreign currency demand in light of short-term external debt obligations of $191 billion.Thirdly, the Turkish state banks are intervening quite regularly to soften Lira volatility, thereby transitioning from a ‘free float’ to a ‘managed float’. So far, they have spent over $37 billion over the last two years in a futile effort to buttress the lira. This level of involvement in currency markets cannot be maintained.Fourthly, the Turkish state is being far more interventionist in the Turkish stock exchange and bond markets to keep asset prices elevated. Government-controlled local funds have participated in the Borsa Istanbul and state banks in sovereign debt to sustain rallies or reverse a bear market. All these measures have one running idea: exclude foreign investors and no crisis will recur. Yet, when the credit boom heads to a downturn sooner or later, Turks will probably escalate lira conversions to US dollars; 51 per cent of all Turkish bank deposits are already dollar-denominated and the figure is still rising.If Turkey’s limited foreign reserves cannot satisfy the domestic dollar demand, the government may have to impose comprehensive capital controls and allow for a double digit depreciation in the value of the lira to from its current level, with significant repercussions on Turkey’s political stability and economic climate.To avoid this scenario, it needs to restore fiscal and monetary prudence, deal the with the foreign debt overhang in the private sector and focus on productivity-improving economic and institutional reforms to gain the confidence of global financial markets and Turks alike. Full Article
cr The Future of Democracy in Europe: Technology and the Evolution of Representation By feedproxy.google.com Published On :: Tue, 25 Feb 2020 11:31:48 +0000 3 March 2020 To the extent that perceptions of a crisis in liberal democracy in Europe can be confirmed, this paper investigates the nature of the problem and its causes, and asks what part, if any, digital technology plays in it. Read online Download PDF Hans Kundnani Senior Research Fellow, Europe Programme @hanskundnani 2020-02-27-Irish-Referendum.jpg A woman writes a note on the Savita Halappanavar mural in Dublin on 26 May 2018, following a referendum on the 36th amendment to Ireland’s constitution. The referendum result was overwhelmingly in favour of removing the country’s previous near-universal ban on abortion. Photo: Getty Images. SummaryThere is a widespread sense that liberal democracy is in crisis, but little consensus exists on the specific nature and causes of the crisis. In particular, there are three prisms through which the crisis is usually seen: the rise of ‘populism’, ‘democratic deconsolidation’, and a ‘hollowing out’ of democracy. Each reflects normative assumptions about democracy.The exact role of digital technology in the crisis is disputed. Despite the widely held perception that social media is undermining democracy, the evidence for this is limited. Over the longer term, the further development of digital technology could undermine the fundamental preconditions for democracy – though the pace and breadth of technological change make predictions about its future impact difficult.Democracy functions in different ways in different European countries, with political systems on the continent ranging from ‘majoritarian democracies’ such as the UK to ‘consensual democracies’ such as Belgium and Switzerland. However, no type seems to be immune from the crisis. The political systems of EU member states also interact in diverse ways with the EU’s own structure, which is problematic for representative democracy as conventionally understood, but difficult to reform.Political parties, central to the model of representative democracy that emerged in the late 18th century, have long seemed to be in decline. Recently there have been some signs of a reversal of this trend, with the emergence of parties that have used digital technology in innovative ways to reconnect with citizens. Traditional parties can learn from these new ‘digital parties’.Recent years have also seen a proliferation of experiments in direct and deliberative democracy. There is a need for more experimentation in these alternative forms of democracy, and for further evaluation of how they can be integrated into the existing institutions and processes of representative democracy at the local, regional, national and EU levels.We should not think of democracy in a static way – that is, as a system that can be perfected once and for all and then simply maintained and defended against threats. Democracy has continually evolved and now needs to evolve further. The solution to the crisis will not be to attempt to limit democracy in response to pressure from ‘populism’ but to deepen it further as part of a ‘democratization of democracy’. Department/project Europe Programme, Commission on Democracy and Technology in Europe Full Article