ge Inhibition of the erythropoietin-producing receptor EPHB4 antagonizes androgen receptor overexpression and reduces enzalutamide resistance [Molecular Bases of Disease] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 Prostate cancer (PCa) cells heavily rely on an active androgen receptor (AR) pathway for their survival. Enzalutamide (MDV3100) is a second-generation antiandrogenic drug that was approved by the Food and Drug Administration in 2012 to treat patients with castration-resistant prostate cancer (CRPC). However, emergence of resistance against this drug is inevitable, and it has been a major challenge to develop interventions that help manage enzalutamide-resistant CRPC. Erythropoietin-producing human hepatocellular (Eph) receptors are targeted by ephrin protein ligands and have a broad range of functions. Increasing evidence indicates that this signaling pathway plays an important role in tumorigenesis. Overexpression of EPH receptor B4 (EPHB4) has been observed in multiple types of cancer, being closely associated with proliferation, invasion, and metastasis of tumors. Here, using RNA-Seq analyses of clinical and preclinical samples, along with several biochemical and molecular methods, we report that enzalutamide-resistant PCa requires an active EPHB4 pathway that supports drug resistance of this tumor type. Using a small kinase inhibitor and RNAi-based gene silencing to disrupt EPHB4 activity, we found that these disruptions re-sensitize enzalutamide-resistant PCa to the drug both in vitro and in vivo. Mechanistically, we found that EPHB4 stimulates the AR by inducing proto-oncogene c-Myc (c-Myc) expression. Taken together, these results provide critical insight into the mechanism of enzalutamide resistance in PCa, potentially offering a therapeutic avenue for enhancing the efficacy of enzalutamide to better manage this common malignancy. Full Article
ge Heterotrimeric Gq proteins as therapeutic targets? [Molecular Bases of Disease] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 Heterotrimeric G proteins are the core upstream elements that transduce and amplify the cellular signals from G protein–coupled receptors (GPCRs) to intracellular effectors. GPCRs are the largest family of membrane proteins encoded in the human genome and are the targets of about one-third of prescription medicines. However, to date, no single therapeutic agent exerts its effects via perturbing heterotrimeric G protein function, despite a plethora of evidence linking G protein malfunction to human disease. Several recent studies have brought to light that the Gq family–specific inhibitor FR900359 (FR) is unexpectedly efficacious in silencing the signaling of Gq oncoproteins, mutant Gq variants that mostly exist in the active state. These data not only raise the hope that researchers working in drug discovery may be able to potentially strike Gq oncoproteins from the list of undruggable targets, but also raise questions as to how FR achieves its therapeutic effect. Here, we place emphasis on these recent studies and explain why they expand our pharmacological armamentarium for targeting Gq protein oncogenes as well as broaden our mechanistic understanding of Gq protein oncogene function. We also highlight how this novel insight impacts the significance and utility of using G(q) proteins as targets in drug discovery efforts. Full Article
ge {alpha}-Synuclein filaments from transgenic mouse and human synucleinopathy-containing brains are maȷor seed-competent species [Molecular Bases of Disease] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Assembled α-synuclein in nerve cells and glial cells is the defining pathological feature of neurodegenerative diseases called synucleinopathies. Seeds of α-synuclein can induce the assembly of monomeric protein. Here, we used sucrose gradient centrifugation and transiently transfected HEK 293T cells to identify the species of α-synuclein from the brains of homozygous, symptomatic mice transgenic for human mutant A53T α-synuclein (line M83) that seed aggregation. The most potent fractions contained Sarkosyl-insoluble assemblies enriched in filaments. We also analyzed six cases of idiopathic Parkinson's disease (PD), one case of familial PD, and six cases of multiple system atrophy (MSA) for their ability to induce α-synuclein aggregation. The MSA samples were more potent than those of idiopathic PD in seeding aggregation. We found that following sucrose gradient centrifugation, the most seed-competent fractions from PD and MSA brains are those that contain Sarkosyl-insoluble α-synuclein. The fractions differed between PD and MSA, consistent with the presence of distinct conformers of assembled α-synuclein in these different samples. We conclude that α-synuclein filaments are the main driving force for amplification and propagation of pathology in synucleinopathies. Full Article
ge Reactive dicarbonyl compounds cause Calcitonin Gene-Related Peptide release and synergize with inflammatory conditions in mouse skin and peritoneum [Molecular Bases of Disease] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 The plasmas of diabetic or uremic patients and of those receiving peritoneal dialysis treatment have increased levels of the glucose-derived dicarbonyl metabolites like methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG). The elevated dicarbonyl levels can contribute to the development of painful neuropathies. Here, we used stimulated immunoreactive Calcitonin Gene–Related Peptide (iCGRP) release as a measure of nociceptor activation, and we found that each dicarbonyl metabolite induces a concentration-, TRPA1-, and Ca2+-dependent iCGRP release. MGO, GO, and 3-DG were about equally potent in the millimolar range. We hypothesized that another dicarbonyl, 3,4-dideoxyglucosone-3-ene (3,4-DGE), which is present in peritoneal dialysis (PD) solutions after heat sterilization, activates nociceptors. We also showed that at body temperatures 3,4-DGE is formed from 3-DG and that concentrations of 3,4-DGE in the micromolar range effectively induced iCGRP release from isolated murine skin. In a novel preparation of the isolated parietal peritoneum PD fluid or 3,4-DGE alone, at concentrations found in PD solutions, stimulated iCGRP release. We also tested whether inflammatory tissue conditions synergize with dicarbonyls to induce iCGRP release from isolated skin. Application of MGO together with bradykinin or prostaglandin E2 resulted in an overadditive effect on iCGRP release, whereas MGO applied at a pH of 5.2 resulted in reduced release, probably due to an MGO-mediated inhibition of transient receptor potential (TRP) V1 receptors. These results indicate that several reactive dicarbonyls activate nociceptors and potentiate inflammatory mediators. Our findings underline the roles of dicarbonyls and TRPA1 receptors in causing pain during diabetes or renal disease. Full Article
ge COVID-19 Impact on Refugees is Also Political By feedproxy.google.com Published On :: Tue, 31 Mar 2020 10:53:27 +0000 31 March 2020 Dr Lina Khatib Director, Middle East and North Africa Programme @LinaKhatibUK The spread of coronavirus in the Levant puts Syrian as well as other refugees and internally displaced people at particular risk because of the policies and practices of the authorities. 2020-03-31-Covid19-lebanon The word Corona written in the sand on the beach in Lebanon's southern city of Saida. amid the spread of coronavirus in the country. Photo by MAHMOUD ZAYYAT/AFP via Getty Images. As Lebanon strains to contain COVID-19, it is not clear which governmental public health policies apply to refugees. The government announced free testing for coronavirus in the public Rafiq Hariri University Hospital in Beirut but has not mentioned if refugees are eligible.Lebanon’s coronavirus containment strategy is based on self-reporting and, given incidents of forced deportation and harassment of Syrian refugees from both the authorities and local communities, it is certainly less likely refugees would present themselves to the health authorities for fear of deportation.Despite agreeing a Lebanon Crisis Response Plan with the UN for refugees, different ministries were left to implement it without coordination, just as Lebanese politicians from all sides started trying to rally popular support for ridding Lebanon from refugees - in particular from Syria, who Lebanese leaders say are causing a strain on the country’s already weak infrastructure.This finger pointing is coupled with the leaders’ own complete disregard for the rampant corruption and lack of accountability within Lebanon’s political class, which contribute to the weakening of the country’s infrastructure.For refugees who do find themselves back in Syria, there are different challenges according to which area they are in. In the north-east, the WHO and international NGOs (INGOs) negotiate with both Kurdish authorities as well as the government - each presenting its own hurdles.Kurdish authorities in northeast Syria have closed the Semalka border with Iraqi Kurdistan, posing a serious dilemma for INGOs offering services in north-east Syria but concerned about their staff safety whose movement is now curtailed.The government of Syria has stipulated all emergency response must go through its ministries. But this limits what the WHO can do in the country and gives Syrian authorities the ability to block ‘cross-line aid’ which goes from government-controlled to non-government areas.Despite reports that doctors raised the alarm about suspected cases well before patient zero was confirmed, the government appears to be either covering up the actual extent of the spread of COVID-19 or failing to respond. Some limited testing kits have arrived but testing has barely started.The WHO’s Syria plan is divided into three regions (north-west, north-east, and areas under government control). But concerns remain as to how workable such a decentralized plan is because of the government’s practices. In January, the UN Security Council did not renew the cross-border response resolution for the Yaroubiye border crossing between Syria and Iraq that the WHO was using to send medical supplies into north-east Syria.Syrian authorities do not permit recently authorized ‘cross-line’ responders to engage with non-government authorities in areas outside regime control. This essentially voids the authorization to work cross-line as it is practically impossible to implement programs. The WHO has sought approval from the Syrian Ministry of Foreign Affairs to move medical supplies by land to north-east Syria.While promising facilitation, the Ministry’s reply comes with conditions of seeking detailed approval for every shipment. When Eastern Ghouta was under siege, similar conditions led to certain supplies being removed from UN/ICRC convoys to Eastern Ghouta, and there is no guarantee this will not happen again.Due to lack of capacity in north-east Syria, coronavirus tests conducted by the WHO there must be processed through the Central Public Health Laboratory in Damascus. Samples are transported twice a week from Qamishli to Damascus but no results were ever received from Damascus for those tests.While the WHO is able to coordinate access to north-west Syria with the Turkish authorities, the prospective coronavirus testing capacity in the Idlib region is low – despite claims that thousands of kits are arriving, a lack of resource on the ground means potentially only 20 tests per day could be done in an area inhabited by an estimated three million people.Following the recently announced ceasefire in the area, many internally displaced people are returning from the Turkish border to their homes in the north-west, but such mass movement increases the risk of coronavirus spreading. People also continue to move between Syria, Iraq, Turkey and Lebanon, posing a challenge to the WHO’s COVID-19 response in the Levant, as the WHO has distinct response plans for each country in the region and it is difficult to coordinate across these plans.Challenges face refugees even if they head towards Europe due to the potential for conflation between migration control and coronavirus outbreak control. Aurelie Ponthieu, Coordinator for Forced Migration at Médecins Sans Frontières (MSF) says there is a risk some countries could use COVID-19 to impose draconian measures towards asylum seekers.The crisis has also put a halt to search and rescue operations in the Mediterranean because European countries are not allowing boats carrying migrants to disembark under the pretext of limiting the spread of coronavirus. And for migrants who already made it - such as in Greece - they are now being put in collective quarantines in asylum centers, often with poor medical facilities.Ponthieu also reports that migrants being quarantined on overcrowded navy ships docked in Greek ports, making social distancing impossible. And she is concerned the Greek authorities are imposing a curfew on asylum seekers but not on the local population.UNHCR is stressing that people’s right of asylum must not be overruled by concerns about the spread of coronavirus, while local and international NGOs across the Levant are trying to coordinate their advocacy on lifting restrictions on freedom of movement for humanitarian workers and on other policies and practices by authorities in the region which are adversely affecting refugee and other vulnerable communities.The international community must not lose sight of the impact of the crisis on refugees and migrants. It is not enough simply to supply humanitarian and medical assistance without paying attention to the policies and practices of the different authorities who have direct control over the fate of vulnerable communities.The author would like to thank Aurelie Ponthieu and the two INGO field workers who all agreed to be interviewed to inform this analysis piece. Full Article
ge Webinar: Can the Justice and Development Party Still Absorb Popular Anger in Morocco? By feedproxy.google.com Published On :: Tue, 31 Mar 2020 13:50:01 +0000 Webinar Research Event 8 April 2020 - 1:00pm to 2:00pm Event participants Mohammed Masbah, Director, Moroccan Institute for Policy Analysis; Associate Fellow, MENA Programme, Chatham HouseModerator: Lina Khatib, Director, MENA Programme, Chatham House Ever since independence, the Moroccan monarchy has used political parties to legitimize the country’s authoritarian political process and structure, and to absorb social and political anger. The palace puts successive governments and other elected institutions, such as local and regional councils, at the frontline of public blame, and replaces them once they fail this function.In a recent article, MENA Programme Associate Fellow, Mohammed Masbah, examines how the Moroccan monarchy has used this strategy with the ruling Justice and Development Party (PJD) so that the palace remains the centre of political power, while the PJD – and other political parties before it– takes responsibility for coping with the mounting socio-economic crisis.In this webinar, part of the Chatham House project on The Future of the State in the Middle East and North Africa, the article’s author will discuss the risks this approach presents for the long-term stability of Morocco and what reforms are needed to increase citizens’ dwindling confidence in the political process.You can express your interest in attending by following this link. You will receive a Zoom confirmation email should your registration be successful. Department/project Middle East and North Africa Programme, The Future of the State in the Middle East Full Article
ge Can Protest Movements in the MENA Region Turn COVID-19 Into an Opportunity for Change? By feedproxy.google.com Published On :: Tue, 28 Apr 2020 14:07:38 +0000 29 April 2020 Dr Georges Fahmi Associate Fellow, Middle East and North Africa Programme @GeorgesFahmi The COVID-19 pandemic will not in itself result in political change in the MENA region, that depends on the ability of both governments and protest movements to capitalize on this moment. After all, crises do not change the world - people do. 2020-04-28-covid-19-protest-movement-mena.jpg An aerial view shows the Lebanese capital Beirut's Martyrs Square that was until recent months the gathering place of anti-government demonstrators, almost deserted during the novel coronavirus crisis, on 26 March 2020. Photo by -/AFP via Getty Images. COVID-19 has offered regimes in the region the opportunity to end popular protest. The squares of Algiers, Baghdad, and Beirut – all packed with protesters over the past few months – are now empty due to the pandemic, and political gatherings have also been suspended. In Algeria, Iraq and Lebanon, COVID-19 has achieved what snipers, pro-regime propaganda, and even the economic crisis, could not.Moreover, political regimes have taken advantage of the crisis to expand their control over the political sphere by arresting their opponents, such as in Algeria where the authorities have cracked down on a number of active voices of the Hirak movement. Similarly, in Lebanon, security forces have used the pandemic as an excuse to crush sit-ins held in Martyr’s Square in Beirut and Nour Square in Tripoli.However, despite the challenges that the pandemic has brought, it also offers opportunities for protest movements in the region. While the crisis has put an end to popular mobilization in the streets, it has created new forms of activism in the shape of solidarity initiatives to help those affected by its consequences.In Iraq, for example, protest groups have directed their work towards awareness-raising and sharing essential food to help mitigate the problem of food shortages and rising prices across the country. In Algeria, Hirak activists have run online campaigns to raise awareness about the virus and have encouraged people to stay at home. Others have been cleaning and disinfecting public spaces. These initiatives increase the legitimacy of the protest movement, and if coupled with political messages, could offer these movements an important chance to expand their base of popular support.Exposes economic vulnerabilityEconomic grievances, corruption and poor provision of public services have been among the main concerns of this recent wave of protests. This pandemic only further exposes the levels of economic vulnerability in the region. COVID-19 is laying bare the socio-economic inequalities in MENA countries; this is particularly evident in the numbers of people engaged in the informal economy with no access to social security, including health insurance and pensions.Informal employment, approximately calculated by the share of the labour force not contributing to social security, is estimated to amount to 65.5% of total employment in Lebanon, 64.4% in Iraq, and 63.3% in Algeria. The crisis has underscored the vulnerability of this large percentage of the labour force who have been unable to afford the economic repercussions of following state orders to stay at home.The situation has also called attention to the vital need for efficient public services and healthcare systems. According to the fifth wave of the Arab Barometer, 74.4% of people in Lebanon are dissatisfied with their country’s healthcare services, as are 67.8% of people in Algeria and 66.5% in Iraq.Meanwhile, 66.2% of people in Lebanon believe it is necessary to pay a bribe in order to receive better healthcare, as do 56.2% of people in Iraq and 55.9% in Algeria. The COVID-19 crisis has highlighted the need for more government investment in public healthcare systems to render them more efficient and less corrupt, strengthening the protesters’ case for the need for radical socio-economic reforms.On the geopolitical level, the crisis puts into question the stability-focused approach of Western powers towards the region. For years, Western powers have directed their aid towards security forces in the interests of combating terrorism but COVID-19 has proved itself to be a much more lethal challenge to both the region and the West.Facing this new challenge requires international actors to reconsider their approach to include supporting health and education initiatives, as well as freedom of expression and transparency. As argued by Western policymakers themselves, it was China’s lack of transparency and slow response that enabled the proliferation of the virus, when it could have been contained in Wuhan back in December 2019.This crisis therefore offers regional protest movements the opportunity to capitalize on this moment and push back against the policies of Western powers that have invested in regional stability only to the extent of combating Islamic jihad. But crises do not change the world, people do. The COVID-19 pandemic will not in itself result in political change in the MENA region. Rather, it brings opportunities and risks that, when exploited, will allow political actors to advance their own agendas. While the crisis has put an end to popular mobilization and allowed regimes to tighten their grip over the political sphere, behind these challenges lie real opportunities for protest movements.The current situation represents a possibility for them to expand their popular base through solidarity initiatives and has exposed more widely the importance of addressing socio-economic inequalities. Finally, it offers the chance to challenge the stability-focused approach of Western powers towards the region which until now has predominantly focused on combating terrorism. Full Article
ge 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
ge 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
ge The hibernating 100S complex is a target of ribosome-recycling factor and elongation factor G in Staphylococcus aureus [Protein Synthesis and Degradation] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 The formation of translationally inactive 70S dimers (called 100S ribosomes) by hibernation-promoting factor is a widespread survival strategy among bacteria. Ribosome dimerization is thought to be reversible, with the dissociation of the 100S complexes enabling ribosome recycling for participation in new rounds of translation. The precise pathway of 100S ribosome recycling has been unclear. We previously found that the heat-shock GTPase HflX in the human pathogen Staphylococcus aureus is a minor disassembly factor. Cells lacking hflX do not accumulate 100S ribosomes unless they are subjected to heat exposure, suggesting the existence of an alternative pathway during nonstressed conditions. Here, we provide biochemical and genetic evidence that two essential translation factors, ribosome-recycling factor (RRF) and GTPase elongation factor G (EF-G), synergistically split 100S ribosomes in a GTP-dependent but tRNA translocation-independent manner. We found that although HflX and the RRF/EF-G pair are functionally interchangeable, HflX is expressed at low levels and is dispensable under normal growth conditions. The bacterial RRF/EF-G pair was previously known to target only the post-termination 70S complexes; our results reveal a new role in the reversal of ribosome hibernation that is intimately linked to bacterial pathogenesis, persister formation, stress responses, and ribosome integrity. Full Article
ge Significant political change is coming to the Gulf By feedproxy.google.com Published On :: Thu, 19 Feb 2015 10:31:55 +0000 19 February 2015 20150212GCCKinninmont.jpg Photo by ArabianEye / Getty Images Significant political change is coming to the Gulf monarchies, often seen in the West as bastions of stability, argues a new Chatham House report entitled Future Trends in the Gulf.The Gulf states are already undergoing dramatic demographic and economic changes – changes which are being accelerated by lower oil prices.The current political systems in the Gulf have been defined by the oil era, enabling governments to provide extensive economic benefits and no taxation, while maintaining a monopoly over political power. As the economic role of the state changes, its political role will change too.Even at a time of plenty, pressures for political change have been rising. Significant changes in the availability of information, the surge in social media and women’s education are driving new demands for transparency.Political protests have been most visible in Bahrain, but calls for change and reform have been growing in all of the Gulf countries. Raif Badawi, the blogger recently flogged in Saudi Arabia, is hardly an isolated case: campaigners for constitutional monarchies and elected parliaments have been facing severe punishments for years. The report author, Jane Kinninmont, says:'The US and UK underestimate the significant leverage that they still have in the Gulf compared with most other countries, even if it is less than in the 20th century. As much as Asian countries are strengthening their trade links with the Gulf, they are reluctant to step forward as the security allies that the Gulf countries need.' Combating instability, extremism and sectarianism in the wider region requires looking hard at the pressures for change and insecurities inside the Gulf states. These help explain, for instance, why Qatar and the UAE have backed different sides in the intensifying civil conflict in Egypt.The report, based on three years of research, argues that: It is time for the GCC countries to seize the opportunity to carry out gradual and consensual political and social reforms towards more constitutional forms of monarchy. Western countries, especially the US and UK, need to diversify the base of relations with the Gulf beyond the existing elite – and reach out to a broader base among the increasingly well-educated and aspirational new generation.Defence cooperation with the Gulf needs to be placed in a wider political context, where respect for human rights is not seen as being at odds with security imperatives, but as part of ensuring sustainable security. The UK and US policy of expanding their military bases in Bahrain has sent a strong signal that political reform is not their priority. A fresh discourse on Gulf security needs to take account of the need for people to feel secure vis-à-vis their own governments, for instance by ensuring the police are held accountable by independent judiciaries, and ending lengthy detention without trial.In partnering with Gulf countries against extremism, Western allies need to broach sensitive issues such as religious education in Saudi Arabia, or the impact on Western publics and Muslim communities outside the region of flogging a blogger for insulting Islam. Editor's notes Read the report Future Trends in the Gulf by Jane Kinninmont, MENA Programme. Embargoed until Thursday 19 February, 00:01 GMT. Read the executive summary here. When linking to this report, please use this link, which will go live when the embargo is lifted. This report will be launched at an event at Chatham House on 19 February. For all enquiries, please contact the press office. To contact the author directly, please use:Email: jkinninmont@chathamhouse.orgPhone: +44 (0)7967 325 993Twitter: @janekinninmont Full Article
ge The Russian challenge demands a more robust Western strategy By feedproxy.google.com Published On :: Fri, 10 Jul 2015 09:23:28 +0000 4 June 2015 20150515RussianChallenge.jpg Photo: AP Photo/Alexander Zemlianichenko It is now clear that President Putin’s ‘new model Russia’ cannot be constructively accommodated into the international system. The war in Ukraine, in part the result of the West's laissez-faire approach to Russia, demonstrates the need for a new Western strategy towards Russia.The Russian Challenge - a major new report by six authors from the Russia and Eurasia Programme at Chatham House - argues that a new strategy must recognise that: The decline of the Russian economy, the costs of confrontation and the rise of China mean that the Putin regime is now facing the most serious challenge of its 15 years in power. The West has neither the wish nor the means to promote regime change in Russia. But Western countries need to consider the possible consequences of a chaotic end to the Putin system. A critical element in the new geo-economic competition between the West and Russia is the extent of Western support for Ukraine, whose reconstruction as an effective sovereign state, capable of standing up for itself, is crucial. This will require much greater resources than have been invested up until now. Russia has rapidly developed its armed forces and information warfare capabilities since the war in Georgia in 2008. The West must invest in defensive strategic communications and media support to counter the Kremlin’s false narratives and restore its conventional deterrent capabilities as a matter of urgency. In particular, NATO needs to demonstrate that the response to ‘ambiguous’ or ‘hybrid’ war will be robust. Sanctions are exerting economic pressure on the Russian leadership and should remain in place until Ukraine’s territorial integrity is properly restored. In particular, it is self-defeating to link the lifting of sanctions solely to implementation of the poorly crafted and inherently fragile Minsk accords. While deterrence and constraint are essential in the short term, the West must also prepare for an eventual change of leadership in Russia. There is a reasonable chance that current pressures will incline a future Russian leadership to want to re-engage with the West.James Nixey, Head of the Russia and Eurasia Programme at Chatham House, said: 'Pursuing these goals and achieving these objectives will ensure that the West is better prepared for any further deterioration in relations with Russia. The events of the last 18 months have demonstrated conclusively that when dealing with Russia, optimism is not a strategy.' Editor's notes Read the report The Russian Challenge from the Russia and Eurasia Programme, Chatham House.Embargoed until Thursday 4 June, 00:01 BST.This report will be launched at an event at Chatham House on Friday 5 June.For all enquiries, please contact the press office. Contacts Press Office +44 (0)20 7957 5739 Email Full Article
ge First ever global analysis of refugees’ energy use: High costs and poor supply undermine humanitarian assistance By feedproxy.google.com Published On :: Tue, 17 Nov 2015 11:50:49 +0000 11 November 2015 20151119MovingEnergyInitiative.jpg A migrant girl looks at a light illuminating a camp site of refugees and migrants on the Greek island of Lesbos, 4 October 2015. Photo: Getty Images. About 90 per cent of refugees living in camps have no access to electricity and many lack any form of lighting at night, says a Chatham House report for the Moving Energy Initiative. Energy poverty in refugee settlements is not on the radar of international initiatives and humanitarian agencies are ill-equipped to deal with the scale of need. Heat Light and Power for Refugees: Saving Lives, Reducing Costs zooms in on the energy needs of refugees and displaced people worldwide, and presents the first ever estimates of the volume and costs of what they use.'The problem goes beyond electricity. 80 per cent of those in camps rely on firewood for cooking and, as a result, we estimate that some 20,000 people die prematurely each year due to the pollution from indoor fires. Exposure to extremes of cold and heat are also killers for people living in flimsy, temporary shelter,' says Glada Lahn, senior research fellow at Chatham House. 'The current lack of provision for energy undermines the fundamental aims of humanitarian assistance,' she adds.There are nearly 60 million forcibly displaced people in the world, and they pay staggering costs for energy. The 83,277 households living in Dadaab in Kenya, the world’s largest refugee settlement, spent an estimated $6.2 million on firewood last year, which accounts for approximately 24 per cent of their overall household income. (The average UK household spent 4 per cent of its income on energy in 2011.) In Uganda, almost half of refugee households surveyed by the UNHCR skip meals because they do not have enough fuel to cook with.'The imperative is to find humane, creative and cost-effective ways to respond to the needs of so many individuals, most of whom are women and children. Improving access to clean, safe and sustainable energy offers a promising way forward,' says Kofi Annan in the report’s foreword.The report calls for an overhaul in the way that heat, light and power are delivered in humanitarian crises. It makes the case for new partnerships between humanitarian agencies and private providers to increase clean energy access in refugee settlements. Investment in energy infrastructure will also benefit host communities in some of the world’s poorest countries.'As refugee households spend approximately $2.1 billion on energy each year, developing local markets for energy services could be part of a mix of solutions,' adds Lahn. 'Using green, culturally appropriate technologies could save lives, reduce CO2 emissions by 11 million tonnes per year and radically improve living standards. Introducing even the most basic solutions, such as improved cookstoves and basic solar lanterns, could save $323 million a year in fuel costs.' Other findings include:Rape and violence against women is common in many unlit camps. Only 4 per cent of women and girls in households in the Goudoubo camp in Burkina Faso would go out after dark due to the lack of streetlights.Wood equalling around 49,000 football pitches worth of forest (64,700 acres) is burned by displaced families living in camps each year, mainly in countries suffering severe deforestation, because they have no alternative sources of energy.Firewood consumption emits nearly twice as much CO2 as liquid petroleum gas and produces little energy in comparison to its carbon intensity.International Development Minister Grant Shapps said:‘Across sub-Saharan Africa, hundreds of millions of people still do not have access to electricity. Women and girls are at risk of violence after dark, families are forced to inhale toxic kerosene fumes, and energy remains unaffordable for many.‘With the technology in place and investors coming on board, the time to act is now. The UK's Energy Africa campaign is already kick-starting a solar revolution across the continent.‘Supporting the Moving Energy Initiative is another way Britain can help boost access to clean, reliable and affordable energy. This will transform people’s lives and help achieve the UN’s goal of universal energy access by 2030.’ Editor's notes Read Heat Light and Power for Refugees: Saving Lives, Reducing Costs by Glada Lahn and Owen Grafham.To link back to the report in an article, please use this landing page for the final report.The Moving Energy Initiative (MEI) is a collaboration between GVEP International, Chatham House, Practical Action Consulting, the Norwegian Refugee Council (NRC) and the United Nations High Commissioner for Refugees (UNHCR). The report is supported by the UK Department for International Development through the Humanitarian Innovation and Evidence Programme.The number of refugee households in Dadaab, Kenya is as of May 2015.Chatham House will host a press briefing with MEI programme board member Michael Keating and authors Glada Lahn and Owen Grafham on Thursday 12 November at 10:30-11:30 GMT. To register, or for interview requests, please contact the press office.All figures are original and based on estimations and calculations prepared for the Moving Energy Initiative. Chatham House designed a model offering the first estimates of the scale and cost of energy use and CO2 emissions among forcibly displaced households worldwide, not including people affected by natural disasters. For more details on the populations considered in the report and used in the model, contact the authors.The authors are available to answer questions from the media. Please contact the press office. Contacts Press Office +44 (0)20 7957 5739 Email Full Article
ge By enabling formal trade, Nigeria can unleash its vast potential By feedproxy.google.com Published On :: Mon, 07 Dec 2015 16:18:19 +0000 3 December 2015 20151207Nigeriabooming.jpg Nigeria’s booming informal trade is costly for society, business and government, yet a critical opportunity exists to formalize such trade and drive more sustainable and less volatile growth, argues a new report from Chatham House.According to one estimate, informal activity accounts for up to 64 per cent of Nigeria’s GDP. Nigeria's Booming Borders: The Drivers and Consequences of Unrecorded Trade finds that this is a result of obstacles that impede trading through formal channels. These drivers include bureaucratic burdens and other factors, such as:The need for Nigerian businesses to produce at least nine documents in order to send an export shipment and at least 13 in order to bring in an import consignment.Rigid and dysfunctional foreign-exchange regulations that push most smaller traders into the incompletely regulated parallel exchange market.Corruption and unofficial ‘taxation’, especially on major border highways, which delegitimize formal channels and encourage the use of smuggling routes.As a result, the state loses direct tax revenues that would be generated by formal cross-border trade. This is not just siphoned into the informal economy; some is lost entirely. For example, many shippers opt to dock in neighbouring countries rather than deal with the expense and difficulty of using Nigeria’s ports.Informal trade also undermines the social contract between the private sector and government. The state lacks tax revenues to pay its officials, improve infrastructure or implement reforms, while traders feel the government provides no services in return for any taxes they might pay.‘Every day tens of thousands of unofficial payments are made, none destined for the government. Policy-makers need to create an environment that encourages trade to flow through formal channels and capture lost revenue’, says co-author Leena Koni Hoffmann.‘Formalization would assist Nigeria to pursue more high-quality, high-tech economic activity at a time when rising labour costs in Asia are creating scope for Nigerian manufacturers to compete’, she adds.The report makes a number of recommendations for how Nigeria could encourage more formal trade, including:Strengthening the resources and capacity of the Federal Ministry of Industry, Trade and Investment to coordinate action across key government ministries, departments and agencies, as well as public and private stakeholders.Prioritizing engagement in the development of Economic Community of West African States (ECOWAS) trade policies and fully implementing the ECOWAS Protocol on Free Movement of Persons to reduce harassment at borders.Allowing banks to operate simple services for small and medium-sized businesses to make trade payments directly from Nigerian naira to CFA francs and vice versa.Improving basic facilities that support traders, including improving the efficiency of border posts, installing truck parks and all-weather surfacing on market access roads, and introducing online booking for trucks to enter ports.Separating responsibilities for assessing duty and tariff liabilities from revenue collection in order to reduce opportunities for corruption, an approach already tested with success by the Lagos State Internal Revenue Service.Increasing funding and technical support for the National Bureau of Statistics, which has a significant role to play in measuring and capturing more of Nigeria’s external trade.Interviews conducted for the report reveal that business people would welcome the opportunity to pay taxes, but only if they received assurance that these payments would represent a contract with government guaranteeing that conditions for business would be improved.‘As Africa’s largest economy, formalizing external trade would allow Nigeria to fulfil its potential as the trading engine of the West and Central African economy and shape the business landscape across the region,’ says co-author Paul Melly. Editor's notes Read Nigeria's Booming Borders: the Drivers and Consequences of Unrecorded Trade (embargoed until 17:00 GMT on Monday 7 December).To request an interview with the authors, contact the press office.Nigeria’s recorded external trade for 2014 was $135.8 billion.Estimate of informal activity as a percentage of GDP from Jonathan Emenike Ogbuabor and Victor A. Malaolu, ‘Size and Causes of the Informal Sector of the Nigerian Economy: Evidence from Error Correction Mimic Model’, Journal of Economics and Sustainable Development, Vol. 4, No. 1, 2013. Contacts Press Office +44 (0)20 7957 5739 Email Full Article
ge 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
ge Moving Energy Initiative Starts Clean Energy Projects for Refugees By feedproxy.google.com Published On :: Mon, 26 Jun 2017 12:25:21 +0000 26 June 2017 The Moving Energy Initiative starts four new clean energy projects for refugees. Combo_large_LCP (2).jpg Refugees in Burkina Faso, Kenya and Jordan will benefit from greater access to affordable, clean energy for domestic use and to power ‘microbusinesses’, following a grant scheme from the Moving Energy Initiative which launches today.The Moving Energy Initiative is supporting projects ranging from a solar-powered ICT hub in Kenya’s Kakuma camp and vegetable growing zones watered by solar-powered pumps in Burkina Faso’s Goudoubo camp, to reliable energy generation for north Jordan’s Al Mafraq hospital where Syrian refuges and local residents access health care.Embed this image <img src="https://www.chathamhouse.org/sites/default/files/images/Combo_large_LCP.jpg" alt="" title="" />In total, four projects will be implemented over the next 12 months, with all involving training for refugees and local staff to use and maintain the clean energy technologies. They aim to deliver tangible reductions in CO2 emissions whilst increasing access to vital services, saving costs and providing livelihood opportunities for local communities and refugees. The projects are also expected to fuel entrepreneurship, opening up the potential for setting up businesses, small shops and restaurants which can expand beyond this initial grant. Project partners were chosen through an open and competitive process kicked off in February 2017 in Burkina Faso, Kenya and Jordan. Bidders were asked to demonstrate their ability to provide solutions that reduce fossil fuel consumption and increase access to energy in camps. The successful projects were chosen on the basis of the applicants’ ability to innovate in a humanitarian setting, as well as their track record and their approach to sustainability.Find out more about why these projects are needed and the impact they aim to have by watching the video: Check out the Moving Energy Initiative website for more information.Keep updated on the progress of these projects as they develop by following us on Twitter @CH_EERD. Related contentMoving Energy Initiative: Sustainable Energy for Refugees and Displaced PeopleThe Moving Energy Initiative Expert WorkshopToolkits for the Moving Energy Initiative Full Article
ge The Transatlantic Business Response to Foreign Policy Challenges By feedproxy.google.com Published On :: Tue, 10 Jun 2014 15:00:02 +0000 Invitation Only Research Event 12 June 2014 - 8:00am to 9:15am Chatham House, London Meeting Notepdf | 97.01 KB Event participants Myron Brilliant, Executive Vice President and Head of International Affairs, US Chamber of CommerceChair: James Nixey, Head, Russia and Eurasia Programme, Chatham House The speaker will outline a number of foreign policy challenges facing transatlantic business, such as China’s increasing economic power, turmoil in the Middle East, and Russia’s recent actions in eastern Europe. He will examine how these issues can provide obstacles to cooperation and development, and restrict access to markets, and how they can be addressed. The event is part of our series on US and European Perspectives on Common Economic Challenges. Conducted with the support of Bank of America Merrill Lynch, this series examines some of the principal global challenges that we face today and the potentially differing perspectives from the US and across Europe. Attendance at this event is by invitation only. Department/project US and the Americas Programme, US Geoeconomic Trends and Challenges Rory Kinane +44 (0) 20 7314 3650 Email Full Article
ge Building Global Partnerships for Stronger Local Economies By feedproxy.google.com Published On :: Tue, 03 Feb 2015 14:45:01 +0000 Members Event 11 February 2015 - 6:00pm to 7:00pm Chatham House, London Transcriptpdf | 110.44 KB Transcript Q&Apdf | 173.45 KB Event participants Scott Walker, Governor, Wisconsin, United StatesChair: Justin Webb, Presenter, Today Programme, BBC Radio 4 Drawing on his experience as governor of Wisconsin, Scott Walker will outline the importance of forging strong global partnerships to fuel business growth and build prosperous local economies. Governor Walker will consider how mutually beneficial partnerships can be developed within the global community and the impact of these on local communities.LIVE STREAM: This event will be live streamed. The live stream will be made available at 18:00 GMT on Wednesday 11 February.ASK A QUESTION: Send questions for the speaker by email to questions@chathamhouse.org or using #CHEvents on Twitter. A selection will be put to him during the event. Event attributes Livestream Members Events Team Email Full Article
ge Review article: The 100 billion dollar brain: central intelligence machinery in the UK and the US By feedproxy.google.com Published On :: Thu, 12 Mar 2015 13:54:57 +0000 12 March 2015 , Volume 91, Number 2 Richard J. Aldrich Full Article
ge NATO Hopes to Assure Allies While Saving Refugees By feedproxy.google.com Published On :: Fri, 11 Mar 2016 10:05:37 +0000 11 March 2016 Dr Beyza Unal Senior Research Fellow, International Security Programme @beyzaunal Google Scholar NATO’s mission in the Aegean Sea seems aimed as much at deterring Russia as saving lives. It could lead to confrontation. 2016-03-11-BundesmarineB.jpg Early last month NATO launched a new maritime security mission, ostensibly to prevent people smuggling across the Aegean Sea. This mission, however, was not originally a reaction to the humanitarian catastrophe at sea. Instead, it was a response to growing Russian assertiveness.A maritime patrol unit was first discussed in the North Atlantic Council in December 2015, when the Alliance agreed to provide a ‘tailored package of assurances’ to Ankara in a period of heightened tensions after Turkey shot down a Russian jet. The package included measures such as early reconnaissance planes (AWACS), air policing, naval presence in the Eastern Mediterranean, provisions for Maritime Patrol Aircrafts (MPA) and Intelligence, Surveillance & Reconnaissance (ISR), and port visits. None of the discussion at the time linked it with protecting refugees. Now framing this decision in that light creates a new mission for NATO’s Maritime Command (MARCOM), a mission that it has never conducted before.Neither NATO’s founding documents or the most recent 2010 Strategic Concept provide for this type of mission, and NATO units are not trained to carry out an actual rescue mission. Protecting strategic assets and goods, such as oil tankers, escorting naval vessels providing food into conflict zones, deterring piracy and monitoring the Mediterranean for terrorist activity have been the main priorities for MARCOM in the post-Cold War period. These activities and maritime exercises were aimed at defence against non-state actors.The positioning of NATO’s maritime fleet in the Aegean Sea to save refugees, however, has the potential to be used as a deterrent against Russia’s Anti Access/Anti-Denial capacity in the eastern Mediterranean. Russia, meanwhile, has increased its naval presence at the Tartus naval base in Syria, which it has used to support its air campaigns in Syria. This level of reciprocated military build-up is hard to sustain in the long-run. NATO−Russia tensionsOver the past few years, Russia’s assertive policies – its multiple military operations, the continuing modernization of its army and ‘simulated attacks’ such as the one in 2013 that tested Sweden’s air defence response mechanisms − have increasingly worried the Alliance and its partners. Clashing interests over Syria’s future and Russia’s attacks against the Western-supported rebel groups have also served to increase tensions between NATO member states and Russia. Recent analysis logged 60 dangerous incidents in the Euro-Atlantic area between Russia and NATO counties in the period between March 2014 and March 2015. NATO’s preparedness has been severely tested by these incidents, and has led the alliance to strengthen its presence on Europe’s southern flank.Such increased tensions could create a situation whereby accidents and miscalculations lead to escalation. NATO forces and Russia are already engaged in further force posturing − the decision to accelerate Montenegro’s accession to NATO and the increased conduct of wartime exercises, such as NATO’s search for submarines in open waters (Dynamic Manta 2016), reconnaissance operations (Cold Operation 16) or Russia’s simulated exercises, for instance – which could undermine global stability. Three weeks after the Russian jet was shot down, a Russian patrol ship fired warning shots at a Turkish vessel to attract attention and avoid a collision. This event did not escalate but given the heightened tensions, similar events may spiral out of control. The tentative cease-fire in Syria is a confidence building measure that could normalize and rebuild relations. But further steps should be taken to establish political dialogue, open up the channels for potential meetings at the NATO−Russia Council, and increase transparency and risk mitigation in exercises and activities. The longer both sides wait, the more likely a confrontation will be.To comment on this article, please contact Chatham House Feedback Full Article
ge England and Australia Are Failing in Their Commitments to Refugee Health By feedproxy.google.com Published On :: Mon, 09 Sep 2019 12:50:31 +0000 10 September 2019 Alexandra Squires McCarthy Former Programme Coordinator, Global Health Programme Robert Verrecchia Both boast of universal health care but are neglecting the most vulnerable. 2019-09-09-Manus.jpg A room where refugees were once housed on Manus Island, Papua New Guinea. Photo: Getty Images. England and Australia are considered standard-bearers of universal access to health services, with the former’s National Health Service (NHS) recognized as a global brand and the latter’s Medicare seen as a leader in the Asia-Pacific region. However, through the exclusion of migrant and refugee groups, each is failing to deliver true universality in their health services. These exclusions breach both their own national policies and of international commitments they have made.While the marginalization of mobile populations is not a new phenomenon, in recent years there has been a global increase in anti-migrant rhetoric, and such health care exclusions reflect a global trend in which undocumented migrants, refugees and asylum seekers are denied rights.They are also increasingly excluded in the interpretation of phrases such as ‘leave no one behind’ and ‘universal health coverage’, commonly used by UN bodies and member states, despite explicit language in UN declarations that commits countries to include mobile groups.Giving all people – including undocumented migrants and asylum seekers – access to health care is essential not just for the health of the migrant groups but also the public health of the populations that host them. In a world with almost one billion people on the move, failing to take account of such mobility leaves services ill-equipped and will result in missed early and preventative treatment, an increased burden on services and a susceptibility to the spread of infectious disease.EnglandWhile in the three other nations of the UK, the health services are accountable to the devolved government, the central UK government is responsible for the NHS in England, where there are considerably greater restrictions in access.Undocumented migrants and refused asylum seekers are entitled to access all health care services if doctors deem it clinically urgent or immediately necessary to provide it. However, the Home Office’s ‘hostile environment’ policies towards undocumented migrants, implemented aggressively and without training for clinical staff, are leading to the inappropriate denial of urgent and clearly necessary care.One example is the case of Elfreda Spencer, whose treatment for myeloma was delayed for one year, allowing the disease to progress, resulting in her death.In England, these policies, which closely link health care and immigration enforcement, are also deterring people from seeking health care they are entitled to. For example, medical bills received by migrants contain threats to inform immigration enforcement of their details if balances are not cleared in a certain timeframe. Of particular concern, the NGO Maternity Action has demonstrated that such a link to immigration officials results in the deterrence of pregnant women from seeking care during their pregnancy.Almost all leading medical organizations in the United Kingdom have raised concerns about these policies, highlighting the negative impact on public health and the lack of financial justification for their implementation. Many have highlighted that undocument migrants use just and estimated 0.3% of the NHS budget and have pointed to international evidence that suggests that restrictive health care policies may cost the system more.AustraliaIn Australia, all people who seek refuge by boat are held, and have their cases processed offshore in Papua New Guinea (PNG) and Nauru, at a cost of almost A$5 billion between 2013 and 2017. Through this international agreement, in place since 2013, Australia has committed to arrange and pay for the care for the refugees, including health services ‘to a standard of care broadly comparable to that available to the general Australian community under the public health system’.However, the standard of care made available to the refugees is far from comparable to that available to the general population in Australia. Findings against the current care provision contractor on PNG, Pacific International Hospital, which took over in the last year, are particularly damning.For instance, an Australian coroner investigating the 2014 death from a treatable leg infection of an asylum seeker held in PNG concluded that the contractor lacked ‘necessary clinical skills’, and provided ‘inadequate’ care. The coroner’s report, issued in 2018, found the company had also, in other cases, denied care, withheld pain relief, distributed expired medication and had generally poor standards of care, with broken or missing equipment and medication, and services often closed when they were supposed to be open.This has also been reiterated by the Royal Australasian College of Physicians, which has appealed to the Australian government to end its policies of offshore processing immediately, due to health implications for asylum seekers. This echoes concerns of the medical community around the government’s ongoing attempts to repeal the ‘Medivac’ legislation, which enables emergency medical evacuation from PNG and Nauru.Bad policyBoth governments have signed up to UN Sustainable Development Goals commitment to ‘safe and orderly migration’, an essential component of which is access to health care. The vision for this was laid out in a global action plan on promoting the health of refugees and migrants, agreed by member states at the 2019 World Health Assembly.However, rather than allow national policies to be informed by such international plans and the evidence put forward by leading health professionals and medical organizations, the unsubstantiated framing of migrants as a security risk and economic burden has curtailed migrant and refugee access to health care.The inclusion of migrants and refugees within universal access to health services is not merely a matter of human rights. Despite being framed as a financial burden, ensuring access for all people may reduce costs on health services through prevention of costly later-stage medical complications, increased transmission of infections and inefficient administrative costs of determining eligibility.Thailand provides an example of a middle-income country that recognized this, successfully including all migrants and refugees in its health reforms in 2002. Alongside entitling all residents to join the universal coverage scheme, the country also ensured that services were ‘migrant friendly’, including through the provision of translators. A key justification for the approach was the economic benefit of ensuring a healthy migrant population, including the undocumented population.The denial of quality health services to refugees and undocumented migrants is a poor policy choice. Governments may find it tempting to gain political capital through excluding these groups, but providing adequate access to health services is part of both governments’ commitments made at the national and international levels. Not only are inclusive health services feasible to implement and good for the health of migrants and refugees, in the long term, they are safer for public health and may save money. Full Article
ge The Political Economy of Universal Health Coverage By feedproxy.google.com Published On :: Mon, 06 Jan 2020 13:35:01 +0000 Corporate Members Event Nominees Breakfast Briefing Partners and Major Corporates 22 January 2020 - 8:00am to 9:15am Chatham House | 10 St James's Square | London | SW1Y 4LE Event participants Robert Yates, Head, Centre on Global Health Security, Chatham HouseChair: Professor David R Harper, Senior Consulting Fellow, Centre on Global Health Security, Chatham House; Managing Director, Harper Public Health Consulting Limited At the United Nations General Assembly in September 2019, all governments re-committed their countries to achieving universal health coverage (UHC) whereby ‘all people obtain the health services they need without suffering financial hardship when paying for them’. To achieve UHC, governments will need to oversee health systems that are predominantly publicly financed although countries may use both private and public health providers of health services.Robert Yates will provide a review of recent transitions towards Universal Health Coverage, highlighting the importance of genuine political commitment by heads of state, and the potential benefits to corporate stakeholders in helping reach this sustainable development goal. What are the political, economic and health benefits of UHC? Why can only public financing mechanisms, rather than a free market in health services, deliver an equitable health system? And what is the role of the private sector within the political economy of UHC?This event is only open to Major Corporate Member and Partner organizations of Chatham House. If you would like to register your interest, please RSVP to Linda Bedford. We will contact you to confirm your attendance.To enable as open a debate as possible, this event will be held under the Chatham House Rule. Event attributes Chatham House Rule Members Events Team Email Full Article
ge Let's Emerge From COVID-19 with Stronger Health Systems By feedproxy.google.com Published On :: Thu, 26 Mar 2020 09:33:28 +0000 26 March 2020 Robert Yates Director, Global Health Programme; Executive Director, Centre for Universal Health @yates_rob Heads of state should grasp the opportunity to become universal health heroes to strengthen global health security 2020-03-26-Health-Protest A "Big Insurance: Sick of It" rally in New York City. Photo by Mario Tama/Getty Images. As the COVID-19 pandemic presents the greatest threat to human health in over a century, people turn to their states to resolve the crisis and protect their health, their livelihoods and their future well-being.How leaders perform and respond to the pandemic is likely to define their premiership - and this therefore presents a tremendous opportunity to write themselves into the history books as a great leader, rescuing their people from a crisis. Just as Winston Churchill did in World War Two.Following Churchill’s advice to “never let a good crisis go to waste”, if leaders take decisive action now, they may emerge from the COVID-19 crisis as a national hero. What leaders must do quickly is to mitigate the crisis in a way which has a demonstrable impact on people’s lives.Given the massive shock caused by the pandemic to economies across the world, it is not surprising that heads of state and treasury ministers have implemented enormous economic stimulus packages to protect businesses and jobs – this was to be expected and has been welcome.National heroes can be madeBut, in essence, this remains primarily a health crisis. And one obvious area for leaders to act rapidly is strengthening their nation’s health system to stop the spread of the virus and successfully treat those who have fallen sick. It is perhaps here that leaders have the most to gain - or lose - and where national heroes can be made.This is particularly the case in countries with weak and inequitable health systems, where the poor and vulnerable often fail to access the services they need. One major practical action that leaders can implement immediately is to launch truly universal, publicly-financed health reforms to cover their entire population – not only for COVID-19 services but for all services.This would cost around 1-2% GDP in the short-term but is perfectly affordable in the current economic climate, given some of the massive fiscal stimuluses already being planned (for example, the UK is spending 15% GDP to tackle COVID-19).Within one to two years, this financing would enable governments to implement radical supply side reforms including scaling up health workforces, increasing the supply of essential medicines, diagnostics and vaccines and building new infrastructure. It would also enable them to remove health service user fees which currently exclude hundreds of millions of people worldwide from essential healthcare. Worldwide these policies have proven to be effective, efficient, equitable and extremely popular.And there is plenty of precedent for such a move. Universal health reform is exactly what political leaders did in the UK, France and Japan as post-conflict states emerging from World War Two. It is also the policy President Kagame launched in the aftermath of the genocide in Rwanda, as did Prime Minister Thaksin in Thailand after the Asian Financial Crisis in 2002, and the Chinese leadership did following the SARS crisis, also in 2003.In China’s case, reform involved re-socialising the health financing system using around 2% GDP in tax financing to increase health insurance coverage from a low level of one-third right up to 96% of the population.All these universal health coverage (UHC) reforms delivered massive health and economic benefits to the people - just what is needed now to tackle COVID-19 - and tremendous political benefits to the leaders that implemented them.When considering the current COVID-19 crisis, this strategy would be particularly relevant for countries underperforming on health coverage and whose health systems are more likely to be overwhelmed if flooded with a surge of patients, such as India, Pakistan, Bangladesh, Myanmar, Indonesia and most of sub-Saharan Africa, where many governments spend less than 1% of their GDP on health and most people have to buy services over the counter.But also the two OECD countries without a universal health system – the United States and Ireland – are seeing the threat of COVID-19 already fuelling the debate about the need to create national, publicly-financed health system. And the presidents of South Africa, Kenya and Indonesia have already committed their governments to eventually reach full population coverage anyway, and so may use this crisis to accelerate their own universal reforms. Although difficult to predict which leaders are likely to grasp the opportunity, if some of these countries now fast-track nationwide UHC, at least something good will be coming from the crisis, something which will benefit their people forever. And ensuring everyone accesses the services they need, including public health and preventive services, also provides the best protection against any future outbreaks becoming epidemics.Every night large audiences are tuning in to press briefings fronted by their heads of state hungry for the latest update on the crisis and to get reassurance that their government’s strategy will bring the salvation they desperately need. To truly improve health security for people across the world, becoming UHC heroes could be the best strategic decision political leaders ever make. Full Article
ge Blaming China Is a Dangerous Distraction By feedproxy.google.com Published On :: Wed, 15 Apr 2020 10:50:59 +0000 15 April 2020 Jim O'Neill Chair, Chatham House Chinese officials' initial effort to cover up the coronavirus outbreak was appallingly misguided. But anyone still focusing on China's failings instead of working toward a solution is essentially making the same mistake. 2020-04-15-China-coronavirus-health Medical staff on their rounds at a quarantine zone in Wuhan, China. Photo by STR/AFP via Getty Images. As the COVID-19 crisis roars on, so have debates about China’s role in it. Based on what is known, it is clear that some Chinese officials made a major error in late December and early January, when they tried to prevent disclosures of the coronavirus outbreak in Wuhan, even silencing healthcare workers who tried to sound the alarm.China’s leaders will have to live with these mistakes, even if they succeed in resolving the crisis and adopting adequate measures to prevent a future outbreak. What is less clear is why other countries think it is in their interest to keep referring to China’s initial errors, rather than working toward solutions.For many governments, naming and shaming China appears to be a ploy to divert attention from their own lack of preparedness. Equally concerning is the growing criticism of the World Health Organization (WHO), not least by Donald Trump who has attacked the organization - and threatens to withdraw US funding - for supposedly failing to hold the Chinese government to account. Unhelpful and dangerousAt a time when the top global priority should be to organize a comprehensive coordinated response to the dual health and economic crises unleashed by the coronavirus, this blame game is not just unhelpful but dangerous.Globally and at the country level, we all desperately need to do everything possible to accelerate the development of a safe and effective vaccine, while in the meantime stepping up collective efforts to deploy the diagnostic and therapeutic tools necessary to keep the health crisis under control.Given there is no other global health organization with the capacity to confront the pandemic, the WHO will remain at the center of the response, whether certain political leaders like it or not.Having dealt with the WHO to a modest degree during my time as chairman of the UK’s independent Review on Antimicrobial Resistance (AMR), I can say that it is similar to most large, bureaucratic international organizations.Like the International Monetary Fund (IMF), the World Bank, and the United Nations, it is not especially dynamic or inclined to think outside the box. But rather than sniping at these organizations from the sidelines, we should be working to improve them.In the current crisis, we all should be doing everything we can to help both the WHO and the IMF to play an effective, leading role in the global response. As I have argued before, the IMF should expand the scope of its annual Article IV assessments to include national public-health systems, given that these are critical determinants in a country’s ability to prevent or at least manage a crisis like the one we are now experiencing.I have even raised this idea with IMF officials themselves, only to be told that such reporting falls outside their remit because they lack the relevant expertise. That answer was not good enough then, and it definitely isn’t good enough now.If the IMF lacks the expertise to assess public health systems, it should acquire it. As the COVID-19 crisis makes abundantly clear, there is no useful distinction to be made between health and finance. The two policy domains are deeply interconnected, and should be treated as such.In thinking about an international response to today’s health and economic emergency, the obvious analogy is the 2008 global financial crisis which started with an unsustainable US housing bubble, fed by foreign savings owing to the lack of domestic savings in the United States.When the bubble finally burst, many other countries sustained more harm than the US did, just as the COVID-19 pandemic has hit some countries much harder than it hit China.And yet not many countries around the world sought to single out the US for presiding over a massively destructive housing bubble, even though the scars from that previous crisis are still visible. On the contrary, many welcomed the US economy’s return to sustained growth in recent years, because a strong US economy benefits the rest of the world.So, rather than applying a double standard and fixating on China’s undoubtedly large errors, we would do better to consider what China can teach us. Specifically, we should be focused on better understanding the technologies and diagnostic techniques that China used to keep its - apparent - death toll so low compared to other countries, and to restart parts of its economy within weeks of the height of the outbreak.And for our own sakes, we also should be considering what policies China could adopt to put itself back on a path toward 6% annual growth, because the Chinese economy inevitably will play a significant role in the global recovery.If China’s post-pandemic growth model makes good on its leaders’ efforts in recent years to boost domestic consumption and imports from the rest of the world, we will all be better off.This article was originally published in Project Syndicate Full Article
ge Webinar: Weekly COVID-19 Pandemic Briefing – The Geopolitics of the Coronavirus By feedproxy.google.com Published On :: Thu, 30 Apr 2020 09:10:01 +0000 Members Event Webinar 6 May 2020 - 10:00am to 10:45am Online Event participants Professor Ilona Kickbusch, Associate Fellow, Global Health Programme, Chatham House; Founding Director and Chair, Global Health Centre, Graduate Institute of International and Development Studies Professor David Heymann CBE, Distinguished Fellow, Global Health Programme, Chatham House; Executive Director, Communicable Diseases Cluster, World Health Organization (1998-03)Chair: Emma Ross, Senior Consulting Fellow, Global Health Programme, Chatham House The coronavirus pandemic continues to claim lives around the world. As countries grapple with how best to tackle the virus and the reverberations the pandemic is sending through their societies and economies, scientific understanding of how the coronavirus is behaving, and what measures might best combat it, continues to advance.Join us for the seventh in a weekly series of interactive webinars on the coronavirus with Professor David Heymann and special guest Professor Ilona Kickbusch helping us to understand the facts and make sense of the latest developments in the global crisis.What will the geopolitics of the pandemic mean for multilateralism? As the US retreats, what dynamics are emerging around other actors and what are the implications for the World Health Organization? Is the EU stepping up to play a bigger role in global health? Will the pandemic galvanize the global cooperation long called for?Professor Heymann is a world-leading authority on infectious disease outbreaks. He led the World Health Organization’s response to SARS and has been advising the organization on its response to the coronavirus. Professor Kickbusch is one of the world’s leading experts in global health diplomacy and governance. She advises international organizations, national governments, NGOs and the private sector on new directions and innovations in global health, governance for health and health promotion. Full Article
ge Coronavirus: Public Health Emergency or Pandemic – Does Timing Matter? By feedproxy.google.com Published On :: Fri, 01 May 2020 14:48:43 +0000 1 May 2020 Dr Charles Clift Senior Consulting Fellow, Global Health Programme @CliftWorks The World Health Organization (WHO) has been criticized for delaying its announcements of a public health emergency and a pandemic for COVID-19. But could earlier action have influenced the course of events? 2020-05-01-Tedros-WHO-COVID WHO director-general Dr Tedros Adhanom Ghebreyesus at the COVID-19 press briefing on March 11, 2020, the day the coronavirus outbreak was classed as a pandemic. Photo by FABRICE COFFRINI/AFP via Getty Images. The World Health Organization (WHO) declared the spread of COVID-19 to be a Public Health Emergency of International Concern (PHEIC) on January 30 this year and then characterized it as a pandemic on March 11.Declaring a PHEIC is the highest level of alert that WHO is obliged to declare, and is meant to send a powerful signal to countries of the need for urgent action to combat the spread of the disease, mobilize resources to help low- and middle-income countries in this effort and fund research and development on needed treatments, vaccines and diagnostics. It also obligates countries to share information with WHO.Once the PHEIC was declared, the virus continued to spread globally, and WHO began to be asked why it had not yet declared the disease a pandemic. But there is no widely accepted definition of a pandemic, generally it is just considered an epidemic which affects many countries globally.Potentially more deadlyThe term has hitherto been applied almost exclusively to new forms of flu, such as H1N1 in 2009 or Spanish flu in 1918, where the lack of population immunity and absence of a vaccine or effective treatments makes the outbreak potentially much more deadly than seasonal flu (which, although global, is not considered a pandemic).For COVID-19, WHO seemed reluctant to declare a pandemic despite the evidence of global spread. Partly this was because of its influenza origins — WHO’s emergency programme executive director said on March 9 that ‘if this was influenza, we would have called a pandemic ages ago’.He also expressed concern that the word traditionally meant moving — once there was widespread transmission — from trying to contain the disease by testing, isolating the sick and tracing and quarantining their contacts, to a mitigation approach, implying ‘the disease will spread uncontrolled’.WHO’s worry was that the world’s reaction to the word pandemic might be there was now nothing to be done to stop its spread, and so countries would effectively give up trying. WHO wanted to send the message that, unlike flu, it could still be pushed back and the spread slowed down.In announcing the pandemic two days later, WHO’s director-general Dr Tedros Adhanom Ghebreyesus reemphasised this point: ‘We cannot say this loudly enough, or clearly enough, or often enough: all countries can still change the course of this pandemic’ and that WHO was deeply concerned ‘by the alarming levels of inaction’.The evidence suggests that the correct message did in fact get through. On March 13, US president Donald Trump declared a national emergency, referring in passing to WHO’s announcement. On March 12, the UK launched its own strategy to combat the disease. And in the week following WHO’s announcements, at least 16 other countries announced lockdowns of varying rigour including Austria, Belgium, Canada, Czech Republic, Denmark, Finland, France, Germany, Hungary, Netherlands, Norway, Poland, Portugal, Serbia, Spain and Switzerland. Italy and Greece had both already instituted lockdowns prior to the WHO pandemic announcement.It is not possible to say for sure that WHO’s announcement precipitated these measures because, by then, the evidence of the rapid spread was all around for governments to see. It may be that Italy’s dramatic nationwide lockdown on March 9 reverberated around European capitals and elsewhere.But it is difficult to believe the announcement did not have an effect in stimulating government actions, as was intended by Dr Tedros. Considering the speed with which the virus was spreading from late February, might an earlier pandemic announcement by WHO have stimulated earlier aggressive actions by governments?Declaring a global health emergency — when appropriate — is a key part of WHO’s role in administering the International Health Regulations (IHR). Significantly, negotiations on revisions to the IHR, which had been ongoing in a desultory fashion in WHO since 1995, were accelerated by the experience of the first serious coronavirus outbreak — SARS — in 2002-2003, leading to their final agreement in 2005.Under the IHR, WHO’s director-general decides whether to declare an emergency based on a set of criteria and on the advice of an emergency committee. IHR defines an emergency as an ‘extraordinary event that constitutes a public health risk through the international spread of disease and potentially requires a coordinated international response’.In the case of COVID-19, the committee first met on January 22-23 but were unable to reach consensus on a declaration. Following the director-general’s trip to meet President Xi Jinping in Beijing, the committee reconvened on January 30 and this time advised declaring a PHEIC.But admittedly, public recognition of what a PHEIC means is extremely low. Only six have ever been declared, with the first being the H1N1 flu outbreak which fizzled out quickly, despite possibly causing 280,000 deaths globally. During the H1N1 outbreak, WHO declared a PHEIC in April 2009 and then a pandemic in June, only to rescind both in August as the outbreak was judged to have transitioned to behave like a seasonal flu.WHO was criticized afterwards for prematurely declaring a PHEIC and overreacting. This then may have impacted the delay in declaring the Ebola outbreak in West Africa as a PHEIC in 2014, long after it became a major crisis. WHO’s former legal counsel has suggested the PHEIC — and other aspects of the IHR framework — may not be effective in stimulating appropriate actions by governments and needs to be reconsidered.When the time is right to evaluate lessons about the response, it might be appropriate to consider the relative effectiveness of the PHEIC and pandemic announcements and their optimal timing in stimulating appropriate action by governments. The effectiveness of lockdowns in reducing the overall death toll also needs investigation. Full Article
ge 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
ge 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
ge 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
ge 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
ge 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
ge 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
ge Rigid continuation paths I. Quasilinear average complexity for solving polynomial systems By www.ams.org Published On :: Tue, 10 Mar 2020 10:59 EDT Pierre Lairez J. Amer. Math. Soc. 33 (2019), 487-526. Abstract, references and article information Full Article
ge Weak functoriality of Cohen-Macaulay algebras By www.ams.org Published On :: Tue, 10 Mar 2020 10:59 EDT Yves André J. Amer. Math. Soc. 33 (2020), 363-380. Abstract, references and article information Full Article
ge Mass Spectrometry of Human Leukocyte Antigen Class I Peptidomes Reveals Strong Effects of Protein Abundance and Turnover on Antigen Presentation By feedproxy.google.com Published On :: 2015-03-01 Michal Bassani-SternbergMar 1, 2015; 14:658-673Research Full Article
ge Distinct and Overlapping Sets of SUMO-1 and SUMO-2 Target Proteins Revealed by Quantitative Proteomics By feedproxy.google.com Published On :: 2006-12-01 Alfred C. O. VertegaalDec 1, 2006; 5:2298-2310Research Full Article
ge Parallel Reaction Monitoring for High Resolution and High Mass Accuracy Quantitative, Targeted Proteomics By feedproxy.google.com Published On :: 2012-11-01 Amelia C. PetersonNov 1, 2012; 11:1475-1488Technological Innovation and Resources Full Article
ge High Resolution Clear Native Electrophoresis for In-gel Functional Assays and Fluorescence Studies of Membrane Protein Complexes By feedproxy.google.com Published On :: 2007-07-01 Ilka WittigJul 1, 2007; 6:1215-1225Research Full Article
ge 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
ge 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
ge Quantitative, Multiplexed Assays for Low Abundance Proteins in Plasma by Targeted Mass Spectrometry and Stable Isotope Dilution By feedproxy.google.com Published On :: 2007-12-01 Hasmik KeshishianDec 1, 2007; 6:2212-2229Research Full Article
ge 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
ge Integrated Genomic and Proteomic Analyses of Gene Expression in Mammalian Cells By feedproxy.google.com Published On :: 2004-10-01 Qiang TianOct 1, 2004; 3:960-969Research Full Article
ge Targeted Data Extraction of the MS/MS Spectra Generated by Data-independent Acquisition: A New Concept for Consistent and Accurate Proteome Analysis By feedproxy.google.com Published On :: 2012-06-01 Ludovic C. GilletJun 1, 2012; 11:O111.016717-O111.016717Research Full Article
ge The Paragon Algorithm, a Next Generation Search Engine That Uses Sequence Temperature Values and Feature Probabilities to Identify Peptides from Tandem Mass Spectra By feedproxy.google.com Published On :: 2007-09-01 Ignat V. ShilovSep 1, 2007; 6:1638-1655Technology Full Article
ge 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
ge Multiplexed Protein Quantitation in Saccharomyces cerevisiae Using Amine-reactive Isobaric Tagging Reagents By feedproxy.google.com Published On :: 2004-12-01 Philip L. RossDec 1, 2004; 3:1154-1169Research Full Article
ge The hibernating 100S complex is a target of ribosome-recycling factor and elongation factor G in Staphylococcus aureus [Protein Synthesis and Degradation] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 The formation of translationally inactive 70S dimers (called 100S ribosomes) by hibernation-promoting factor is a widespread survival strategy among bacteria. Ribosome dimerization is thought to be reversible, with the dissociation of the 100S complexes enabling ribosome recycling for participation in new rounds of translation. The precise pathway of 100S ribosome recycling has been unclear. We previously found that the heat-shock GTPase HflX in the human pathogen Staphylococcus aureus is a minor disassembly factor. Cells lacking hflX do not accumulate 100S ribosomes unless they are subjected to heat exposure, suggesting the existence of an alternative pathway during nonstressed conditions. Here, we provide biochemical and genetic evidence that two essential translation factors, ribosome-recycling factor (RRF) and GTPase elongation factor G (EF-G), synergistically split 100S ribosomes in a GTP-dependent but tRNA translocation-independent manner. We found that although HflX and the RRF/EF-G pair are functionally interchangeable, HflX is expressed at low levels and is dispensable under normal growth conditions. The bacterial RRF/EF-G pair was previously known to target only the post-termination 70S complexes; our results reveal a new role in the reversal of ribosome hibernation that is intimately linked to bacterial pathogenesis, persister formation, stress responses, and ribosome integrity. Full Article
ge 12-LOX catalyzes the oxidation of 2-arachidonoyl-lysolipids in platelets generating eicosanoid-lysolipids that are attenuated by iPLA2{gamma} knockout [Signal Transduction] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 The canonical pathway of eicosanoid production in most mammalian cells is initiated by phospholipase A2-mediated release of arachidonic acid, followed by its enzymatic oxidation resulting in a vast array of eicosanoid products. However, recent work has demonstrated that the major phospholipase in mitochondria, iPLA2γ (patatin-like phospholipase domain containing 8 (PNPLA8)), possesses sn-1 specificity, with polyunsaturated fatty acids at the sn-2 position generating polyunsaturated sn-2-acyl lysophospholipids. Through strategic chemical derivatization, chiral chromatographic separation, and multistage tandem MS, here we first demonstrate that human platelet-type 12-lipoxygenase (12-LOX) can directly catalyze the regioselective and stereospecific oxidation of 2-arachidonoyl-lysophosphatidylcholine (2-AA-LPC) and 2-arachidonoyl-lysophosphatidylethanolamine (2-AA-LPE). Next, we identified these two eicosanoid-lysophospholipids in murine myocardium and in isolated platelets. Moreover, we observed robust increases in 2-AA-LPC, 2-AA-LPE, and their downstream 12-LOX oxidation products, 12(S)-HETE-LPC and 12(S)-HETE-LPE, in calcium ionophore (A23187)-stimulated murine platelets. Mechanistically, genetic ablation of iPLA2γ markedly decreased the calcium-stimulated production of 2-AA-LPC, 2-AA-LPE, and 12-HETE-lysophospholipids in mouse platelets. Importantly, a potent and selective 12-LOX inhibitor, ML355, significantly inhibited the production of 12-HETE-LPC and 12-HETE-LPE in activated platelets. Furthermore, we found that aging is accompanied by significant changes in 12-HETE-LPC in murine serum that were also markedly attenuated by iPLA2γ genetic ablation. Collectively, these results identify previously unknown iPLA2γ-initiated signaling pathways mediated by direct 12-LOX oxidation of 2-AA-LPC and 2-AA-LPE. This oxidation generates previously unrecognized eicosanoid-lysophospholipids that may serve as biomarkers for age-related diseases and could potentially be used as targets in therapeutic interventions. Full Article
ge Heterotrimeric Gq proteins as therapeutic targets? [Molecular Bases of Disease] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 Heterotrimeric G proteins are the core upstream elements that transduce and amplify the cellular signals from G protein–coupled receptors (GPCRs) to intracellular effectors. GPCRs are the largest family of membrane proteins encoded in the human genome and are the targets of about one-third of prescription medicines. However, to date, no single therapeutic agent exerts its effects via perturbing heterotrimeric G protein function, despite a plethora of evidence linking G protein malfunction to human disease. Several recent studies have brought to light that the Gq family–specific inhibitor FR900359 (FR) is unexpectedly efficacious in silencing the signaling of Gq oncoproteins, mutant Gq variants that mostly exist in the active state. These data not only raise the hope that researchers working in drug discovery may be able to potentially strike Gq oncoproteins from the list of undruggable targets, but also raise questions as to how FR achieves its therapeutic effect. Here, we place emphasis on these recent studies and explain why they expand our pharmacological armamentarium for targeting Gq protein oncogenes as well as broaden our mechanistic understanding of Gq protein oncogene function. We also highlight how this novel insight impacts the significance and utility of using G(q) proteins as targets in drug discovery efforts. Full Article