gh MaXLinker: Proteome-wide Cross-link Identifications with High Specificity and Sensitivity [Technological Innovation and Resources] By feedproxy.google.com Published On :: 2020-03-01T00:05:26-08:00 Protein-protein interactions play a vital role in nearly all cellular functions. Hence, understanding their interaction patterns and three-dimensional structural conformations can provide crucial insights about various biological processes and underlying molecular mechanisms for many disease phenotypes. Cross-linking mass spectrometry (XL-MS) has the unique capability to detect protein-protein interactions at a large scale along with spatial constraints between interaction partners. The inception of MS-cleavable cross-linkers enabled the MS2-MS3 XL-MS acquisition strategy that provides cross-link information from both MS2 and MS3 level. However, the current cross-link search algorithm available for MS2-MS3 strategy follows a "MS2-centric" approach and suffers from a high rate of mis-identified cross-links. We demonstrate the problem using two new quality assessment metrics ["fraction of mis-identifications" (FMI) and "fraction of interprotein cross-links from known interactions" (FKI)]. We then address this problem, by designing a novel "MS3-centric" approach for cross-link identification and implementing it as a search engine named MaXLinker. MaXLinker outperforms the currently popular search engine with a lower mis-identification rate, and higher sensitivity and specificity. Moreover, we performed human proteome-wide cross-linking mass spectrometry using K562 cells. Employing MaXLinker, we identified a comprehensive set of 9319 unique cross-links at 1% false discovery rate, comprising 8051 intraprotein and 1268 interprotein cross-links. Finally, we experimentally validated the quality of a large number of novel interactions identified in our study, providing a conclusive evidence for MaXLinker's robust performance. Full Article
gh Guidance Document: Validation of a High-Performance Liquid Chromatography-Tandem Mass Spectrometry Immunopeptidomics Assay for the Identification of HLA Class I Ligands Suitable for Pharmaceutical Therapies [Commentary] By feedproxy.google.com Published On :: 2020-03-01T00:05:26-08:00 For more than two decades naturally presented, human leukocyte antigen (HLA)-restricted peptides (immunopeptidome) have been eluted and sequenced using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Since, identified disease-associated HLA ligands have been characterized and evaluated as potential active substances. Treatments based on HLA-presented peptides have shown promising results in clinical application as personalized T cell-based immunotherapy. Peptide vaccination cocktails are produced as investigational medicinal products under GMP conditions. To support clinical trials based on HLA-presented tumor-associated antigens, in this study the sensitive LC-MS/MS HLA class I antigen identification pipeline was fully validated for our technical equipment according to the current US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines. The immunopeptidomes of JY cells with or without spiked-in, isotope labeled peptides, of peripheral blood mononuclear cells of healthy volunteers as well as a chronic lymphocytic leukemia and a bladder cancer sample were reliably identified using a data-dependent acquisition method. As the LC-MS/MS pipeline is used for identification purposes, the validation parameters include accuracy, precision, specificity, limit of detection and robustness. Full Article
gh Australian Federal Police walk away from $145 million Israeli crime-fighting software deal By www.smh.com.au Published On :: Wed, 19 Aug 2015 06:25:36 GMT Police walk away from deal with contractor, conceding numerous issues have put project beyond rescue. Full Article
gh iiNet CEO David Buckingham leaves company By www.smh.com.au Published On :: Sun, 30 Aug 2015 23:59:15 GMT CEO of Perth-based internet service provider iiNet, David Buckingham, has left the company, according to multiple sources. Full Article
gh St George, Bank of Melbourne and BankSA outage to be fixed on Monday night, St George says By www.smh.com.au Published On :: Mon, 05 Oct 2015 19:22:02 GMT St George, Bank of Melbourne and BankSA customers begin to regain access to their accounts after a system outage. Full Article
gh Apple v FBI: what the fight is about and why you should care By www.smh.com.au Published On :: Fri, 04 Mar 2016 15:27:05 GMT Apple is in the middle of a legal fight with the FBI over creating a 'back door' to unlock a terrorist's iPhone. Full Article
gh Call for a cyber security reserve corps to help fight major attacks By www.smh.com.au Published On :: Mon, 15 Aug 2016 14:15:00 GMT Experienced volunteers would help fight major online threats to governments, private industry and civil institutions. Full Article
gh ACT human rights commission 'concerned' about new app for ACT police By www.smh.com.au Published On :: Sat, 27 Jan 2018 13:00:00 GMT Canberrans' privacy rights could be threatened by the new app. Full Article
gh How to Fight the Economic Fallout From the Coronavirus By feedproxy.google.com Published On :: Wed, 04 Mar 2020 03:56:03 +0000 4 March 2020 Creon Butler Research Director, Trade, Investment & New Governance Models: Director, Global Economy and Finance Programme LinkedIn Finance ministries and central banks have a critical role to play to mitigate the threat Covid-19 poses to the global economy. 2020-03-03-TokyoCV.jpg A pedestrian wearing a face mask walks past stock prices in Tokyo on 25 February. Photo: Getty Images. Epidemics, of the size of Covid-19, have huge economic impacts – not just from the costs of managing the health of people, but stopping them, and keeping the economy working. The 10% fall in global stock markets since it became clear that Covid-19 would not be limited to China has boldly highlighted this.Suppressing the epidemic, but allowing the economy to still function, requires key decisions, in which central banks and finance ministries play a part.The role of fiscal and monetary authorities in managing an epidemic economyThe scope to use monetary policy to manage the economic impact of Covid-19 is limited. The fact that the underlying cause of the shock is an infectious disease outbreak (rather than a banking crisis, as in 2008-09) and nominal interest rates are currently close to zero in most major advanced economies reduces the effectiveness of monetary policy.Since 2010, reductions in fiscal deficits mean there is more scope for supportive fiscal action. But even here, high public debt levels and the desire not to underwrite ‘zombie’ companies that may have been sustained by a decade of ultra-low interest rates remain constraints. However, outside broad based fiscal and monetary policies there are six ways in which finance ministries and central banks will play a critical role in responding to the crisis.A first crucial role for finance ministries and central banks is in helping provide the best possible economic evaluation of strict containment measures (trying to isolate each potential case) versus managing the epidemic (delaying the spread of the virus, protecting the most vulnerable and treating the sick, while enabling the majority of people to get on with daily life). Given the economic consequences, they must play a full part, alongside health experts, in advising political leaders on this key decision.Second, if large numbers of staff are required to work from home to manage the epidemic, they have the lead role in doing whatever is necessary to ensure that financial markets – and thus the wider economy – will continue to function smoothly.Third, they need to ensure adequate funding for the public health response. Steps that can make an enormous difference to the success of containment strategies, such as strengthening surveillance, and guaranteeing the availability of testing kits and protective equipment for front line health workers, must not fail because of a lack of funding. Fourth, they have a lead role in designing targeted economic interventions for the wider economy. Some of these are needed immediately to re-enforce and incentivize strict containment strategies, such as ensuring that employees without full or adequate sick leave cover have the financial support to enable them to report and self-isolate when they get sick. Other interventions may help improve the resilience of the economy in accommodating moderate ‘social distancing’ measures; for example, by providing assistance to small firms to help them gear up for home working.Yet others are needed, as a contingency, to safeguard the most vulnerable sectors (such as tourism, retail and transport) in circumstances where there is a prolonged downturn. The latter may include schemes to allow deferral of tax payments by SMEs, or steps to encourage loan extensions and other forms of liquidity support from the banking system, or by moves to underwrite continued provision of business insurance.Fifth, national economic authorities will need to play their part in combatting ‘fake news’ through providing transparent and high-quality analysis. This includes providing forecasts on the likely economic impact of the virus under different scenarios, but also detailed information on the support and contingency measures they are considering, so they can be improved and refined through feedback. Sixth, they will need to ensure that there is generous international support for poor countries, by ensuring the available multilateral support facilities from the international financial institutions and multilateral development banks are adequately funded and fit for purpose. The World Bank has already announced an initial $12 billion financing package, but much more is likely to be needed.They also need to support coordinated bilateral aid where this is more effective, as well as special measures to support particularly vulnerable groups, for example, in refugee camps and prisons. Given the importance of distributing sophisticated medical equipment and expertise quickly, it is also important that every effort is made to avoid delays due to customs and migration checks.Managing the futureThe response to the immediate crisis will rightly take priority now, but economic authorities must also play their part in ensuring the world finally takes decisive steps to prevent a repeat of Covid-19 in future.The experience with SARS, H1N1 and Ebola shows that, while some progress is made after each outbreak, this is often not sustained. This epidemic shows that managing diseases is absolutely critical to the long-term health of global economy, and doubly so in circumstances where traditional central bank and finance ministry tools for dealing with major global economic shocks are limited.Finance ministries and central banks therefore need to push hard within government to ensure sustained long-term funding of research on prevention and strengthening of public health systems. They also need to ensure that the right lessons are drawn by the private sector on making international supply chains more robust.Critical to the overall success of the economic effort will be effective international coordination. The G20 was established as the premier economic forum for international economic cooperation in 2010, and global health issues have been a substantive part of the G20 agenda since the 2017 Hamburg Summit. At the same time, G7 finance ministers and deputies remain one of the most effective bodies for managing economic crises on a day-to-day basis and should continue this within the framework provided by the G20.However, to be effective, the US, as current president of the G7, will need to put aside its reservations on multilateral economic cooperation and working with China to provide strong leadership. Full Article
gh Webinar: Coordinating the Fight Against Financial Crime By feedproxy.google.com Published On :: Fri, 17 Apr 2020 16:10:01 +0000 Corporate Members Event Webinar 1 July 2020 - 5:00pm to 6:00pmAdd to CalendariCalendar Outlook Google Yahoo Che Sidanius, Global Head of Regulation & Industry Affairs, RefinitivPatricia Sullivan, Global Co-Head, Financial Crime Compliance, Standard CharteredDame Sara Thornton, Independent Anti-Slavery Commissioner, UKChair: Tom Keatinge, Director, Centre for Financial Crime and Security Studies, RUSI Illicit finance not only threatens financial stability and inclusion but also provides support for terrorism and is a primary incentive for human trafficking, the illegal wildlife trade and narcotics smuggling. Frequently, actors capitalize on loopholes and inefficiencies resulting from the lack of a coordinated response to financial crime and an underpowered global system for tracking illicit financial flows. Enhanced public-private partnerships, in addition to investment in tackling financial crime from governments, international bodies and private industries, are necessary to develop regulatory frameworks, effective responses and valuable coordination between law enforcement, policymakers, regulators and financial institutions. But how should businesses structure their efforts so that their business interests are protected and the work they do is of use to others fighting financial crime?This webinar will explore solutions to enable public-private partnerships to work together to combat financial crime. What do successful partnerships need from each side to ensure that the work being done is efficient and effective? How can the industry’s internal effectiveness impact the ‘real-world’ victims? And what barriers impede public-private partnerships operating as a force for good? This event is part of a fortnightly series of 'Business in Focus' webinars reflecting on the impact of COVID-19 on areas of particular professional interest for our corporate members and giving circles.Not a corporate member? Find out more. Full Article
gh An LC/MS/MS method for analyzing the steroid metabolome with high accuracy and from small serum samples By feedproxy.google.com Published On :: 2020-04-01 Teng-Fei YuanApr 1, 2020; 61:580-586Methods Full Article
gh Episode Eight: The Internet of Genocidal Chatbots (IoGC) Tay, Microsoft Build and Apple vs FBI By play.acast.com Published On :: Fri, 01 Apr 2016 14:40:24 GMT In this week's UK Tech Weekly Podcast host Matt Egan is joined by online editor at Techworld.com Scott Carey to discuss all of the news coming out of Microsoft's Build 2016 developer conference, before being joined by producer Chris to talk about the company's genocidal AI chatbot Tay's public meltdown (13:00). Then, acting editor at Macworld.co.uk David Price jumps in to discuss the apparent resolution to the Apple vs FBI fight (29:00). See acast.com/privacy for privacy and opt-out information. Full Article
gh Episode 68 - The Internet of Motherzuckers (IoM) Snopes and AI fighting By play.acast.com Published On :: Fri, 28 Jul 2017 15:07:55 GMT Join Henry Burrell as he asks Davids Price why Snopes, the fact checking website, has run into trouble and how crowdfunding could save the day. Is it still important in this age of fake news? Then Scott Carey commentates on the bout between Mark Zuckerberg and Elon Musk. Who knows the most about AI? When will the killer robots descend upon us? Does Mark do all his online Q & A’s in front of a cooking brisket? All this answered and more. See acast.com/privacy for privacy and opt-out information. Full Article technology ai pod podcast tech
gh Episode 97 - The Internet of Big Companies (IoBC) Apple results, Amazon worker rights and Google Cloud Next By play.acast.com Published On :: Thu, 02 Aug 2018 14:59:41 GMT This week our host Scott Carey is joined by Macworld UK editor Karen Khan to chat about Apple's latest blockbuster results.Then group production editor Tamlin Magee jumps in to discuss Amazon's working practices following the collective action around Prime Day.Finally, Scott chats through his experience at the Google Cloud Next conference in San Francisco last week to see how it is trying to compete with the big boys at Amazon and Microsoft. See acast.com/privacy for privacy and opt-out information. Full Article
gh Bisretinoid phospholipid and vitamin A aldehyde: Shining a light [Thematic Reviews] By feedproxy.google.com Published On :: 2020-05-05T13:30:26-07:00 Vitamin A aldehyde covalently bound to opsin protein is embedded in a phospholipid-rich membrane that supports photon absorption and phototransduction in photoreceptor cell outer segments. Following absorption of a photon, the 11-cis-retinal chromophore of visual pigment in photoreceptor cells isomerizes to all-trans-retinal. To maintain photosensitivity 11-cis-retinal must be replaced. At the same time, however, all-trans-retinal has to be handled so as to prevent nonspecific aldehyde activity. Some molecules of retinaldehyde upon release from opsin are efficiently reduced to retinol. Other molecules are released into the lipid phase of the disc membrane where they form a conjugate (N-retinylidene-PE, NRPE) through a Schiff base linkage with phosphatidylethanolamine (PE). The reversible formation of NRPE serves as a transient sink for retinaldehyde that is intended to return retinaldehyde to the visual cycle. However, if instead of hydrolyzing to PE and retinaldehyde, NRPE reacts with a second molecule of retinaldehyde a synthetic pathway is initiated that leads to the formation of multiple species of unwanted bisretinoid fluorophores. We report on recently identified members of the bisretinoid family some of which differ with respect to the acyl chains associated with the glycerol backbone. We discuss processing of the lipid moieties of these fluorophores in lysosomes of retinal pigment epithelial (RPE) cells, their fluorescence characters and new findings related to light and iron-associated oxidation of bisretinoids. Full Article
gh COVID-19 Brings Human Rights into Focus By feedproxy.google.com Published On :: Thu, 09 Apr 2020 10:59:58 +0000 9 April 2020 Sonya Sceats Associate Fellow, International Law Programme @SonyaSceats With a reawakened sense of our shared humanity and vulnerability, and the benefits of collective action, this crisis may translate into a comeback for human rights as a popular idea. 2020-04-09-US-COVID-homeless A previously homeless family in the backyard of their newly reclaimed home in Los Angeles, where officials are trying to find homes to protect the state's huge homeless population from COVID-19. Photo by FREDERIC J. BROWN/AFP via Getty Images. During this extraordinary global public health emergency, governments must strike the right balance between assertive measures to slow the spread of the virus and protect lives on the one hand, and respect for human autonomy, dignity and equality on the other.International law already recognises the grave impact of pandemics and other catastrophic events on social order and provides criteria to guide states in their emergency action. The International Covenant on Civil and Political Rights permits curbs on the right to ‘liberty of movement’ so long as restrictions are provided by law, deemed necessary to protect public health, and consistent with other rights in that treaty.Freedom of expression and association, and the rights to privacy and family life are also qualified in these terms under international and regional human rights treaties. But, as emphasised in the Siracusa Principles, any limitations must not be applied in an arbitrary or discriminatory way, and must be of limited duration and subject to review.International law also guarantees the right to the highest attainable standard of health, while states are specifically required to take steps to prevent, treat and control epidemics under the International Covenant on Economic, Social and Cultural Rights. Even in health emergencies, access to health services must be ensured on a non-discriminatory basis, especially for vulnerable or marginalised groups.Abuse of coronavirus emergency measuresMany governments have taken pains to craft emergency laws that respect human rights, such as permitting reasonable exceptions to lockdowns for essential shopping and exercise, and making them subject to ongoing parliamentary review and sunset clauses. But even laws that appear to be human rights compliant can still easily be misapplied, as the recent debates about over-zealous policing of people walking and travelling in the UK illustrate.And disturbing stories are emerging from states where police brutality is entrenched. In Kenya, a 13-year-old boy was reportedly shot on the balcony of his home by police enforcing a coronavirus curfew. Authorities in the Philippines' are allegedly locking those caught defying the curfew in dog cages.As the recent history of counterterrorism demonstrates, emergency laws tend to be sticky, remaining on the statute books far longer than desirable.The virus is also proving a powerful accelerant for the current global authoritarian drift which is so detrimental to progress on human rights. Many authoritarian leaders have seized the opportunity to further reduce constraints on their power.Hungary's prime minister Viktor Orbán has used the pandemic as a pretext for new laws enabling him to rule by decree, completing the country's transition to an elected dictatorship. In Brazil, president Jair Bolsonaro has suspended deadlines for public bodies to reply to freedom of information requests. Iran is the latest of many repressive states in the Middle East to ban the printing and distribution of all newspapers. In China, the government brushed off criticism over ‘disappearances’ of whistleblowers and citizen journalists who questioned its response to the crisis.Others have exploited the turmoil to undermine justice for human rights abuses - Sri Lanka's president Gotabaya Rajapaksa pardoned one of the only soldiers held accountable for crimes during the country's brutal civil war.Coronavirus also places liberal values under further strain. Fear is a major driver in the appeal of populist authoritarians and the virus is stoking it. One poll showed 73% of British citizens agreed coronavirus is just the latest sign that the world we live in is increasingly dangerous. Extremists are exploiting these fears to spread hate by blaming the outbreak on ethnic or religious groups, and encouraging those infected to spread it to these groups.The closure of borders helps reinforce xenophobic tendencies, and high public tolerance of emergency measures could easily spill into normalisation of intrusive digital surveillance and restrictions on liberty for other reasons well into the future.Disadvantaged groups face a higher level of risk from the crisis. The health of aboriginal Australians is so poor that those aged 50 and above are being urged to stay home, advice otherwise given to those over 70 in the general population. The Moria refugee camp on Lesbos is reporting no soap and just one water tap for 1,300 refugees. In the UK, asylum seekers struggle to self-isolate in shared accommodation and have a daily allowance of just £5.40 for food, medicine and toiletries. Women's rights groups are reporting a spike in domestic violence.For countries racked by war and extreme poverty, the impact is catastrophic. The virus is set to run rampant in slums, refugee camps and informal settlements where public health systems - if they exist at all - will struggle to cope. And detainees are among the most at risk, with the UN calling for release of political prisoners and anyone detained without sufficient legal basis.But the crisis has galvanised debate around the right to health and universal health coverage. Many governments have quickly bankrolled generous relief packages which will actually safeguard the socio-economic rights of many, even if they are not being justified in those terms. Portugal and Ireland have rolled back barriers to accessing healthcare for asylum seekers and other marginalised migrants.The pandemic strikes as many powerful governments have become increasingly nationalistic, undermining or retreating from international rules and institutions on human rights. But as the crisis spreads, the role of well-established international human rights standards in shaping and implementing effective - but also legitimate - measures is becoming ever clearer.The virus has reminded us of our interconnectedness as human beings and the need for global cooperation to protect our lives and health. This may help to revive popular support for human rights, creating momentum for the efforts to tackle inequality and repression - factors which have made the global impact of coronavirus so much worse than it might have been. Full Article
gh Legal Provision for Crisis Preparedness: Foresight not Hindsight By feedproxy.google.com Published On :: Tue, 21 Apr 2020 17:03:31 +0000 21 April 2020 Dr Patricia Lewis Research Director, Conflict, Science & Transformation; Director, International Security Programme @PatriciaMary COVID-19 is proving to be a grave threat to humanity. But this is not a one-off, there will be future crises, and we can be better prepared to mitigate them. 2020-04-21-Nurse-COVID-Test Examining a patient while testing for COVID-19 at the Velocity Urgent Care in Woodbridge, Virginia. Photo by Chip Somodevilla/Getty Images. A controversial debate during COVID-19 is the state of readiness within governments and health systems for a pandemic, with lines of the debate drawn on the issues of testing provision, personal protective equipment (PPE), and the speed of decision-making.President Macron in a speech to the nation admitted French medical workers did not have enough PPE and that mistakes had been made: ‘Were we prepared for this crisis? We have to say that no, we weren’t, but we have to admit our errors … and we will learn from this’.In reality few governments were fully prepared. In years to come, all will ask: ‘how could we have been better prepared, what did we do wrong, and what can we learn?’. But after every crisis, governments ask these same questions.Most countries have put in place national risk assessments and established processes and systems to monitor and stress-test crisis-preparedness. So why have some countries been seemingly better prepared?Comparing different approachesSome have had more time and been able to watch the spread of the disease and learn from those countries that had it first. Others have taken their own routes, and there will be much to learn from comparing these different approaches in the longer run.Governments in Asia have been strongly influenced by the experience of the SARS epidemic in 2002-3 and - South Korea in particular - the MERS-CoV outbreak in 2015 which was the largest outside the Middle East. Several carried out preparatory work in terms of risk assessment, preparedness measures and resilience planning for a wide range of threats.Case Study of Preparedness: South KoreaBy 2007, South Korea had established the Division of Public Health Crisis Response in Korea Centers for Disease Control and Prevention (KCDC) and, in 2016, the KCDC Center for Public Health Emergency Preparedness and Response had established a round-the-clock Emergency Operations Center with rapid response teams.KCDC is responsible for the distribution of antiviral stockpiles to 16 cities and provinces that are required by law to hold and manage antiviral stockpiles.And, at the international level, there are frameworks for preparedness for pandemics. The International Health Regulations (IHR) - adopted at the 2005 World Health Assembly and binding on member states - require countries to report certain disease outbreaks and public health events to the World Health Organization (WHO) and ‘prevent, protect against, control and provide a public health response to the international spread of disease in ways that are commensurate with and restricted to public health risks, and which avoid unnecessary interference with international traffic and trade’.Under IHR, governments committed to a programme of building core capacities including coordination, surveillance, response and preparedness. The UN Sendai Framework for Disaster Risk highlights disaster preparedness for effective response as one of its main purposes and has already incorporated these measures into the Sustainable Development Goals (SDGs) and other Agenda 2030 initiatives. UN Secretary-General António Guterres has said COVID-19 ‘poses a significant threat to the maintenance of international peace and security’ and that ‘a signal of unity and resolve from the Council would count for a lot at this anxious time’.Case Study of Preparedness: United StatesThe National Institutes of Health (NIH) and the Center for Disease Control (CDC) established PERRC – the Preparedness for Emergency Response Research Centers - as a requirement of the 2006 Pandemic and All-Hazards Preparedness Act, which required research to ‘improve federal, state, local, and tribal public health preparedness and response systems’.The 2006 Act has since been supplanted by the 2019 Pandemic and All-Hazards Preparedness and Advancing Innovation Act. This created the post of Assistant Secretary for Preparedness and Response (ASPR) in the Department for Health and Human Services (HHS) and authorised the development and acquisitions of medical countermeasures and a quadrennial National Health Security Strategy.The 2019 Act also set in place a number of measures including the requirement for the US government to re-evaluate several important metrics of the Public Health Emergency Preparedness cooperative agreement and the Hospital Preparedness Program, and a requirement for a report on the states of preparedness and response in US healthcare facilities.This pandemic looks set to continue to be a grave threat to humanity. But there will also be future pandemics – whether another type of coronavirus or a new influenza virus – and our species will be threatened again, we just don’t know when.Other disasters too will befall us – we already see the impacts of climate change arriving on our doorsteps characterised by increased numbers and intensity of floods, hurricanes, fires, crop failure and other manifestations of a warming, increasingly turbulent atmosphere and we will continue to suffer major volcanic eruptions, earthquakes and tsunamis. All high impact, unknown probability events.Preparedness for an unknown future is expensive and requires a great deal of effort for events that may not happen within the preparers’ lifetimes. It is hard to imagine now, but people will forget this crisis, and revert to their imagined projections of the future where crises don’t occur, and progress follows progress. But history shows us otherwise.Preparations for future crises always fall prey to financial cuts and austerity measures in lean times unless there is a mechanism to prevent that. Cost-benefit analyses will understandably tend to prioritise the urgent over the long-term. So governments should put in place legislation – or strengthen existing legislation – now to ensure their countries are as prepared as possible for whatever crisis is coming.Such a legal requirement would require governments to report back to parliament every year on the state of their national preparations detailing such measures as:The exact levels of stocks of essential materials (including medical equipment)The ability of hospitals to cope with large influx of patientsHow many drills, exercises and simulations had been organised – and their findingsWhat was being done to implement lessons learned & improve preparednessIn addition, further actions should be taken:Parliamentary committees such as the UK Joint Committee on the National Security Strategy should scrutinise the government’s readiness for the potential threats outlined in the National Risk register for Civil Emergencies in-depth on an annual basis.Parliamentarians, including ministers, with responsibility for national security and resilience should participate in drills, table-top exercises and simulations to see for themselves the problems inherent with dealing with crises.All governments should have a minister (or equivalent) with the sole responsibility for national crisis preparedness and resilience. The Minister would be empowered to liaise internationally and coordinate local responses such as local resilience groups.There should be ring-fenced budget lines in annual budgets specifically for preparedness and resilience measures, annually reported on and assessed by parliaments as part of the due diligence process.And at the international level:The UN Security Council should establish a Crisis Preparedness Committee to bolster the ability of United Nations Member States to respond to international crisis such as pandemics, within their borders and across regions. The Committee would function in a similar fashion as the Counter Terrorism Committee that was established following the 9/11 terrorist attacks in the United States.States should present reports on their level of preparedness to the UN Security Council. The Crisis Preparedness Committee could establish a group of experts who would conduct expert assessments of each member state’s risks and preparedness and facilitate technical assistance as required.Regional bodies such as the OSCE, ASEAN and ARF, the AU, the OAS, the PIF etc could also request national reports on crisis preparedness for discussion and cooperation at the regional level.COVID-19 has been referred to as the 9/11 of crisis preparedness and response. Just as that shocking terrorist attack shifted the world and created a series of measures to address terrorism, we now recognise our security frameworks need far more emphasis on being prepared and being resilient. Whatever has been done in the past, it is clear that was nowhere near enough and that has to change.Case Study of Preparedness: The UKThe National Risk Register was first published in 2008 as part of the undertakings laid out in the National Security Strategy (the UK also published the Biological Security Strategy in July 2018). Now entitled the National Risk Register for Civil Emergencies it has been updated regularly to analyse the risks of major emergencies that could affect the UK in the next five years and provide resilience advice and guidance.The latest edition - produced in 2017 when the UK had a Minister for Government Resilience and Efficiency - placed the risk of a pandemic influenza in the ‘highly likely and most severe’ category. It stood out from all the other identified risks, whereas an emerging disease (such as COVID-19) was identified as ‘highly likely but with moderate impact’.However, much preparatory work for an influenza pandemic is the same as for COVID-19, particularly in prepositioning large stocks of PPE, readiness within large hospitals, and the creation of new hospitals and facilities.One key issue is that the 2017 NHS Operating Framework for Managing the Response to Pandemic Influenza was dependent on pre-positioned ’just in case’ stockpiles of PPE. But as it became clear the PPE stocks were not adequate for the pandemic, it was reported that recommendations about the stockpile by NERVTAG (the New and Emerging Respiratory Virus Threats Advisory Group which advises the government on the threat posed by new and emerging respiratory viruses) had been subjected to an ‘economic assessment’ and decisions reversed on, for example, eye protection.The UK chief medical officer Dame Sally Davies, when speaking at the World Health Organization about Operation Cygnus – a 2016 three-day exercise on a flu pandemic in the UK – reportedly said the UK was not ready for a severe flu attack and ‘a lot of things need improving’.Aware of the significance of the situation, the UK Parliamentary Joint Committee on the National Security Strategy launched an inquiry in 2019 on ‘Biosecurity and human health: preparing for emerging infectious diseases and bioweapons’ which intended to coordinate a cross-government approach to biosecurity threats. But the inquiry had to postpone its oral hearings scheduled for late October 2019 and, because of the general election in December 2019, the committee was obliged to close the inquiry. Full Article
gh Fighting COVID-19 the Ukrainian Way By feedproxy.google.com Published On :: Tue, 28 Apr 2020 08:29:19 +0000 28 April 2020 Orysia Lutsevych Research Fellow and Manager, Ukraine Forum, Russia and Eurasia Programme @Orysiaua LinkedIn Google Scholar Coronavirus has exposed vulnerabilities in Ukraine but also activated private sector and citizen engagement in delivering help. This could accelerate social change if a smart response is adopted and political reforms follow. 2020-04-28-Ukraine-COVID-Chernobyl Girls wearing face masks at the monument to Chernobyl victims in Slavutich during a memorial ceremony amid the COVID-19 pandemic. Photo by SERGEI SUPINSKY/AFP via Getty Images. Ukrainians are accustomed to crisis. As COVID-19 spread, forest fires were raging in the Chernobyl exclusion zone, turning Kyiv into the most polluted city in the world. The fighting in Donbas continued, claiming the lives of more Ukrainian soldiers, bringing the total to more than 4,000 — and, on top of that, President Zelenskyy overhauled his government. So Ukraine is fighting three battles at the same time — war with Russia, the struggle against its own ineffective system, and now COVID-19.Every crisis is a reality check — the coronavirus provoked and exposed the strategic vulnerabilities and deep-rooted features of Ukraine’s system of governance. Three trends have come to the fore. First, the inefficiency and paralysis of many state agencies, particularly the lack of coordination between them and the prevalence of vested interests. Second, the reliance of the country’s leaders on large financial-industrial groups (FIGs) to compensate for weak institutional capacity. Third, a strong societal and private sector mobilization to fill the gaps in the dilapidated public health system.State agencies are rigid and ineffective. Despite the modern Prozorro digital public procurement system, and the government’s allocation of $2.5 million from the early days of the epidemic, the Ministry of Health blocked COVID-related purchases for over a month. This was a tactic by — now ex-minister — Yemets to pressure the state medical procurement agency into appointing a protégé of his as one of its deputy heads.Lowest testing rate in EuropeSimilarly, in some regions, notably Odesa, procurement stalled and orders went to politically connected businesses at higher-than-market prices. Lack of tests and laboratory equipment means Ukraine has administered only 72,000 tests within a population of 42 million to date — the lowest rate in Europe.Doctors were given orders to ensure they only test patients in hospitals with COVID-19 symptoms and only those arriving from Asia, while ignoring the fact that millions of Ukrainian labour migrants were in Europe. Indeed, the first confirmed case was imported from Italy.Ukrainian government and public health officials lack information to take informed decisions. There is no accurate electronic database of registered deaths and reporting is lagging behind events. Information on testing availability in the regions is missing.Thirteen days after the first case of the virus was recorded, Zelenskyy exhorted business tycoons to come to the rescue. Taking a populist tone, Zelenskyy said ‘Ukraine has been feeding you for a long time and it is time that you helped the country’. The tycoons divided the regions among themselves to deliver relief efforts according to the location of their enterprises.It is believed FIGs have donated around $25 million to procure testing kits, ventilators, personal protective equipment (PPE) and disinfectants. This may sound impressive, but many of those same tycoons actually owe millions to the state, some even billions, and cause serious problems by perpetuating the current rent-seeking system, where public resources benefit those groups resulting in serious social losses.Reliance on these groups makes Zelenskyy a hostage to their favour in any potential reform efforts. It is a dangerous solution, as these tycoons often obstruct Ukraine’s economic development.An alternative — and more transformative — trend of public-private partnerships is emerging in some regions. Across Ukraine, hundreds of small- and medium-sized enterprises (SMEs) have led efforts to deliver PPE, support the vulnerable with food supplies, and to procure ventilators for key hospitals.They have mobilised hundreds of volunteers to deliver assistance and partnered with local non-profits. Fundraising initiatives have begun in Lviv, Odesa, Kyiv and Poltava with donations and expenditure has been posted online for transparency. Companies have repurposed to produce PPE kits and medical equipment. The efforts unfolded quickly and, in some cases, in smooth collaboration with municipal and regional authorities.Ukraine cannot afford to ‘waste’ this crisis, which could help accelerate healthcare reform, decentralization, modernize governance, and boost citizen empowerment. But for this to happen, the country has to deploy a ‘smart response’.Such ‘smart response’ means applying a resilience framework that nurtures the agility of the system of governance, ensures a diversity of actors in decision-making, supporting both self-regulation and better coordination. Rather than reaching out to tycoons, Zelenskyy should enter a coalition with true agents of change — SME leaders, volunteers, and mayors who have mobilized effective grassroots action. These actors demand a level playing field with accountable governance and effective state institutions.Civic COVID-19 response hubs and local authorities should be joined in a network that spans the regions, and connected with the national agencies designing pandemic responses. For a national strategy to be effective, central headquarters should draw information from local communities and manage a ‘team of teams’ in a decentralised fashion.Ensuring effective public service delivery without compromising integrity and keeping the risk of corruption low should also be a priority of political reform, with volunteers and the private sector ensuring civic oversight of both regional and national funding.Civic engagement such as this can be transformative as it defies the Soviet legacy of paternalism and expands the belief among citizens that society can work for them. By assisting the relief effort, citizens are gaining valuable insights into quality of public services and participate in holding them to account.Citizens are also developing a better understanding of the purpose of having effective armed forces, police, border guards and modern hospitals. They are coming to understand the value of taxpayer money and witnessing how corruption erodes institutions.This survival mobilization — if properly harnessed by the state — could drive transformative change and make Ukraine more resilient, not just against present crises, but future ones too. Full Article
gh Translating Divergent Environmental Stresses into a Common Proteome Response through Hik33 in a Model Cyanobacterium [Research] By feedproxy.google.com Published On :: 2017-05-12T06:53:48-07:00 The histidine kinase Hik33 plays important roles in mediating cyanobacterial response to divergent types of abiotic stresses including cold, salt, high light (HL), and osmotic stresses. However, how these functions are regulated by Hik33 remains to be addressed. Using a hik33-deficient strain (hik33) of Synechocystis sp. PCC 6803 (Synechocystis) and quantitative proteomics, we found that Hik33 depletion induces differential protein expression highly similar to that induced by divergent types of stresses. This typically includes downregulation of proteins in photosynthesis and carbon assimilation that are necessary for cell propagation, and upregulation of heat shock proteins, chaperons, and proteases that are important for cell survival. This observation indicates that depletion of Hik33 alone mimics divergent types of abiotic stresses, and that Hik33 could be important for preventing abnormal stress response in the normal condition. Moreover, we found the majority of proteins of plasmid origin were significantly upregulated in hik33, though their biological significance remains to be addressed. Together, the systematically characterized Hik33-regulated cyanobacterial proteome, which is largely involved in stress responses, builds the molecular basis for Hik33 as a general regulator of stress responses. Full Article
gh Organellar maps through proteomic profiling - a conceptual guide [Review] By feedproxy.google.com Published On :: 2020-04-28T08:36:25-07:00 Protein subcellular localization is an essential and highly regulated determinant of protein function. Major advances in mass spectrometry and imaging have allowed the development of powerful spatial proteomics approaches for determining protein localization at the whole cell scale. Here, a brief overview of current methods is presented, followed by a detailed discussion of organellar mapping through proteomic profiling. This relatively simple yet flexible approach is rapidly gaining popularity, due to its ability to capture the localizations of thousands of proteins in a single experiment. It can be used to generate high-resolution cell maps, and as a tool for monitoring protein localization dynamics. This review highlights the strengths and limitations of the approach, and provides guidance to designing and interpreting profiling experiments. Full Article
gh Ghana: Following the Gentle Giant By feedproxy.google.com Published On :: Mon, 20 Apr 2020 13:40:24 +0000 1 November 2008 , Number 8 Ghana’s President John Kufuor has successfully promoted his country as a haven of political and economic stability, but as he comes to the end of his two terms in office, the cracks are beginning to appear. Can Ghana escape the election traumas that have been so destructive in Kenya and Zimbabwe? Sola Tayo Associate Fellow, Africa Programme @tayos02 flickrGhana.jpg Full Article
gh Human Rights: Right for You, Right for Us? By feedproxy.google.com Published On :: Mon, 04 May 2020 08:54:20 +0000 1 October 2007 , Number 5 Internationally, Britain has traded for decades on its human rights laurels. Its key role in building the successful European human rights system has long been celebrated, and human rights promotion remains a cornerstone of foreign and development policy. Domestically, the contrast could not be stronger. Newspapers are actively campaigning to ‘axe’ the Human Rights Act, and mainstream political leaders are joining in, hoping for electoral gains. Does this mean the British people have turned their backs on human rights? Sonya Sceats Associate Fellow, International Law Programme @SonyaSceats GettyImages-71296579.jpg The leader of Britain's Conservative Party, David Cameron Full Article
gh Political Will Was Not Enough for Justice Reform in Moldova By feedproxy.google.com Published On :: Tue, 26 Nov 2019 15:51:37 +0000 27 November 2019 Cristina Gherasimov Former Academy Associate, Russia and Eurasia Programme @cgherasimov The pro-reform Sandu government had the will to dismantle oligarchic power structures, but was taken down by limited political experience. 2019-11-26-Sandu.jpg Maia Sandu in Germany in July. Photo: Getty Images. The lack of political will to carry out rule of law reforms is frequently the reason why reforms are not fully implemented. The case of Moldova proves that in societies where strong vested interests still persist, political savviness is equally as important as political will.Old and new political power brokers in Moldova struck a fragile pact in June to oust Vladimir Plahotniuc. Plahotniuc had built a network of corruption and patronage with the help of the Democratic Party, which he treated as a personal vehicle and which allowed him and a small economic elite circle to enrich themselves off of government institutions and state-owned enterprises, to the detriment of Moldovan citizens and the health of their political process.Maia Sandu, co-leader of the pro-reform ACUM electoral bloc, then formed a technocratic government with a remit to implement Moldova’s lagging reform agenda. Though made up of ministers with the integrity and political will to implement difficult transformational reforms, its biggest weakness was its coalition partner – the pro-Russian Socialists’ Party and its informal leader, Igor Dodon, the president of Moldova.Now the Socialists – threatened by how key reforms to the justice system would impact their interests – have joined forces with Plahotniuc’s former allies, the Democratic Party, to oust ACUM, exploiting the party’s lack of political savviness. Reform interruptedIt was always clear the coalition would be short-lived. President Dodon and the co-ruling Socialists joined to buy themselves time, with the hope that they could restrict the most far-reaching reforms and tie the hands of ACUM ministers. In less than five months, however, the Sandu government initiated key reforms in the judicial system, aimed at dismantling Plahotniuc’s networks of patronage but also impacting the Socialists, who to a large degree also profited from the previous status quo.The red line came over a last-minute change in the selection process of the prosecutor general proposed by Sandu on 6 November, which the Socialists claimed was unconstitutional and gave them the justification to put forward a motion of no confidence in the Sandu government. This was conveniently supported by the Democratic Party, who appeared threatened by an independent prosecutor’s office and saw an opportunity to return to power.Thus, the political will to reform proved insufficient in the absence of a clear strategy on how to address the concerns of the old regime that they would be prosecuted and their vested interests threatened. Here, ACUM’s lack of political experience let them down. With their hands tied from the beginning in a fragile coalition with the Socialists, ACUM were unable to prevent sabotage from within state institutions and their own coalition, and could not find consensus to proceed with more radical methods to tackle corruption.Less than two days after the Sandu government was out, a new government was sworn in on 14 November. Prime Minister Ion Chicu was an adviser to President Dodon before taking office and former minister of finance under the Plahotniuc-backed government of Pavel Filip, as part of a cabinet of ministers consisting largely of other presidential advisers and former high-level bureaucrats and ministers from the Plahotniuc era. The new governmentA top priority for the Chicu government is to convince the international community that it is independent from President Dodon, and that its ‘technocrats’ will keep the course of reforms of the Sandu government. This is critical to preserving the financial assistance of Western partners, which the Moldovan government heavily relies on, particularly with a presidential election campaign next year, when they will likely want to create fiscal space for various giveaways to voters.But within its first week in office, Chicu appears incapable of walking this line. Reverting to the initially proposed pre-selection process of prosecutor general signals that the post could be filled by a loyal appointee of President Dodon. Moreover, Chicu’s first visit abroad was to Russia, allegedly a major financial contributor of the Socialists’ Party. With the Socialists now holding the presidency, government, Chisinau mayoralty, and the parliament speaker’s seat, the danger of an increased Russian influence on key political decisions is very real.A government steered by President Dodon risks bringing Moldova back to where it was before June, with a political elite mimicking reforms while misusing power for private gains. The biggest danger is that instead of continuing the reform process to bring Moldova back on its European integration path, the new government may focus on strengthening the old patronage system, this time with President Dodon at the top of the pyramid.LessonsThis new minority government, supported by the Democrats, is a more natural one for President Dodon and therefore has more chances to survive, at least until presidential elections in autumn of 2020. Both the Socialists and the Democrats will likely seek to use this time to rebuild their own methods of capturing state resources. But with the Socialists relying on the Democrats’ votes in parliament, this is a recipe for further political instability.Similar to Moldova, several other states across the post-Soviet space such as Ukraine and Armenia have had new political forces come to power with the political will and mandate to carry out difficult reforms to strengthen rule of law and fight systemic corruption in their countries. What they all have in common is the lack of political experience of how to create change, while old elites, used to thinking on their feet to defend their vested interests, retain their connections and economic and political influence.Moldova is a good example of why political will needs to be backed up by clear strategy on how to deal with threatened vested interests in order for new political forces to be able to maintain themselves in power and reforms to be sustainable. When the chance comes again for fresh leaders to come to power, it is importantthey are politically prepared to use it swiftly and wisely. Full Article
gh Kazakhstan: Reaching Out to Central Asian Neighbours By feedproxy.google.com Published On :: Wed, 04 Dec 2019 10:21:03 +0000 4 December 2019 Annette Bohr Associate Fellow, Russia and Eurasia Programme Despite its regional outreach, Kazakhstan’s diplomatic priority will remain Russia, China, and Europe. 2019-12-04-Kaz.jpg Kazakhstan's President Kassym-Jomart Tokayev, Kazakh Majilis Chairman Nurlan Nigmatulin and ex-president Nursultan Nazarbayev at an inauguration ceremony in parliament. Photo: Pavel AleksandrovTASS via Getty Images. Leaders of the resource-rich Central Asian region have the propensity to remain in power until mortality dictates otherwise. Much like the UK and Brexit, however, few wanted to see Central Asia’s longest reigning ruler, Kazakhstan’s septuagenarian president Nursultan Nazarbayev, crash out without a deal.The sudden departure of the country’s official leader of the nation with no clear succession plan could have led to investment chaos, intra-elite fighting and the unravelling in a matter of months of a system he had built over decades, à la Uzbekistan following the death of long-serving autocrat Islam Karimov in 2016.In order to avoid just such a ‘no-deal’ scenario and ensure the continuity of his policies, in March Nazarbayev carefully choreographed his own resignation and the election of a hand-picked successor, President Kassym-Jomart Tokayev, while retaining plum positions and powers for himself.Tokayev’s assumption of the presidency was accompanied by protesters in the streets, increasing wealth inequality, rising Sinophobia among rank-and-file Kazakhstanis, a hard-to-kick economic dependence on oil revenues and a lack of clarity as to which leader—the old or the new president—would actually be calling the shots. But, amidst this plethora of concerns, as argued in a recent Chatham House report, Kazakhstan: Tested by Transition, one bright spot has been the tangible growth of intra-Central Asian cooperation, with the Nazarbayev-Tokayev ruling duo appearing eager to improve the regional dialogue.Kazakhstan has long shaped its identity as a Eurasian state that has acted as more of an intermediary between Russia and Central Asia than as an integral part of the Central Asian region. But since 2017, in particular, Kazakhstan has been increasingly looking for opportunities to boost hitherto weak cooperation with its Central Asian neighbours. While this is first and foremost owing to the liberalization of Uzbekistan’s large market, there are other factors at work that get less airplay.One such factor is a perceptible disentangling from the Kremlin’s policy directions as Kazakhstan has come to view Russia’s foreign policy as increasingly neo-colonial. The example of the Russia-led Eurasian Economic Union is in many respects more off-putting than inspiring, and Nur-Sultan does not want to be locked tightly into the union’s economic orbit. And in distancing itself slightly from Moscow in order to limit Russian leverage in its affairs, Nur-Sultan has shown itself to be more open to Central Asian regional initiatives.As part of the leadership’s plan to offset oil dependence, Kazakhstan aspires to become the transport, telecommunications and investment hub for Eurasian integration. The intense focus on connectivity and the development of logistical arteries and infrastructure could have the knock-on effect of boosting trade within the Central Asian region and reducing transit times, which are currently greater than in most other parts of the globe.In addition, demographic trends and educational shifts that favour ethnic Kazakhs, together with a growing ethno-nationalist narrative, have allowed the state’s leadership to identify more closely with Kazakhstan’s common Central Asian heritage and, by extension, a common Central Asian region—although Kazakhstan’s leadership still remains eager to demonstrate that the country is not just another ‘stan’. The coming to power of President Mirziyoyev in Uzbekistan appears to have made Kazakhstan more aware of the interconnectedness of the two countries in terms of geographical location and potential economic complementarities, as well as culture and history.Not least, there is a growing recognition among the Central Asian states themselves—including isolationist Turkmenistan to a degree—that deepening regional trade is mutually beneficial, especially given the constraints associated with Russia’s economic problems. The strengthening of Kazakhstan’s ties with Uzbekistan has slowly kick-started regional cooperation as a whole: trade turnover between the Central Asian states in 2018 grew by 35 per cent on the previous year.But both Kazakhstan and Uzbekistan are keen to stress that there is no discussion of integration or institutionalization, not least because previous attempts at integration have been overtaken by Russia, leaving Central Asia without its own coordinating body.The official consensus in Kazakhstan is that Uzbekistan’s economic reforms after years of isolation will spur ‘a healthy rivalry’ and ultimately boost Kazakhstan’s own economy, in so far as the competition for foreign investment will require both countries to work harder to improve their respective business and regulatory environments.At the unofficial level, however, some Kazakhstani analysts view Uzbekistan’s rise as potentially unprofitable, given the possible diversion of some investments and market activity from Kazakhstan to Uzbekistan. Moreover, Uzbekistan has the advantage of having undergone a clear change of executive, while it remains unclear which developments await Kazakhstan once First President Nazarbayev leaves the scene for good.It can certainly be argued that Uzbekistan does pose a potential threat in the long-term to Kazakhstan’s entrenched position as Central Asia’s economic powerhouse: Uzbekistan’s population is one-and-a-half times bigger, even if its nominal GDP is three times smaller. Uzbekistan has a bigger market and a well-developed industrial sector, and is already the regional leader in terms of security. But it is not as though the world’s interest is moving from Kazakhstan to Uzbekistan; rather, Uzbekistan is in the process of trying to catch up.Despite this relatively upbeat picture, Kazakhstan’s combined trade with the other Central Asian states accounts for less than 5 per cent of its total volume of foreign trade—a figure that cannot begin to equal its trade with Russia, China, and Europe. As a result, Kazakhstan will continue to give greater importance to positioning itself as a global player than as a regional leader.This article was originally published in The Diplomat. Full Article
gh POSTPONED: Transitional Justice in Ukraine: What Might it Look Like? By feedproxy.google.com Published On :: Tue, 03 Mar 2020 10:10:01 +0000 Invitation Only Research Event 17 March 2020 - 9:30am to 1:00pm Chatham House | 10 St James's Square | London | SW1Y 4LE Agendapdf | 107.46 KB Event participants Kirsty Brimelow QC, Barrister, Doughty Street ChambersMiles Jackson, Associate Professor of Law, University of OxfordAnton Korynevych, Representative of the President of Ukraine for CrimeaOleksandra Matviychuk, Head of the Board, Centre for Civil LibertiesTaras Tsymbrivksyy, Head, USAID Human Rights in Action Program; Ukrainian Helsinki Human Rights Union Still grappling with the war in the east and the occupation of Crimea, Ukraine’s new leadership has announced its intention to develop its transitional justice infrastructure to respond to the human rights violations arising from Russia’s aggression. Numerous reports (not least ones by the UN Human Rights Monitoring Mission in Ukraine) list persecutions, illegal detentions, enforced disappearances, torture and killings among the crimes perpetrated in Crimea and parts of occupied Donbas. As Ukraine has only just started developing its transitional justice roadmap, this event will seek to discuss viable initial approaches, such as a ‘truth-telling commission’ or amnesties. The panellists will also discuss the role for civil society and those directly affected by hostilities in the transitional justice process. PLEASE NOTE THIS EVENT IS POSTPONED UNTIL FURTHER NOTICE. Event attributes Chatham House Rule Department/project Russia and Eurasia Programme, Ukraine Forum Anna Morgan Administrator, Ukraine Forum +44 (0)20 7389 3274 Email Full Article
gh Virtual Roundtable: Russia in Light of the COVID-19 Pandemic By feedproxy.google.com Published On :: Sun, 29 Mar 2020 21:25:01 +0000 Invitation Only Research Event 1 April 2020 - 1:00pm to 2:30pm Event participants Mathieu Boulegue, Research Fellow, Russia and Eurasia Programme, Chatham HouseNikolai Petrov, Senior Research Fellow, Russia and Eurasia Programme, Chatham HouseEkaterina Schulmann, Associate Fellow, Russia and Eurasia Programme, Chatham HouseChair: James Nixey, Programme Director, Russia and Eurasia, Chatham House Politically speaking, Russia has been isolating itself from the West for some years now, feeding its citizens a ‘besieged fortress’ mentality. Its uniqueness, however, means its approach to - and outcome from - the COVID-19 pandemic will also be distinctive. This webinar will explore how Russia is adapting its internal politics and its international relations to the ‘new normal’ of today. Department/project Russia and Eurasia Programme Anna Morgan Administrator, Ukraine Forum +44 (0)20 7389 3274 Email Full Article
gh Fighting COVID-19 the Ukrainian Way By feedproxy.google.com Published On :: Tue, 28 Apr 2020 08:29:19 +0000 28 April 2020 Orysia Lutsevych Research Fellow and Manager, Ukraine Forum, Russia and Eurasia Programme @Orysiaua LinkedIn Google Scholar Coronavirus has exposed vulnerabilities in Ukraine but also activated private sector and citizen engagement in delivering help. This could accelerate social change if a smart response is adopted and political reforms follow. 2020-04-28-Ukraine-COVID-Chernobyl Girls wearing face masks at the monument to Chernobyl victims in Slavutich during a memorial ceremony amid the COVID-19 pandemic. Photo by SERGEI SUPINSKY/AFP via Getty Images. Ukrainians are accustomed to crisis. As COVID-19 spread, forest fires were raging in the Chernobyl exclusion zone, turning Kyiv into the most polluted city in the world. The fighting in Donbas continued, claiming the lives of more Ukrainian soldiers, bringing the total to more than 4,000 — and, on top of that, President Zelenskyy overhauled his government. So Ukraine is fighting three battles at the same time — war with Russia, the struggle against its own ineffective system, and now COVID-19.Every crisis is a reality check — the coronavirus provoked and exposed the strategic vulnerabilities and deep-rooted features of Ukraine’s system of governance. Three trends have come to the fore. First, the inefficiency and paralysis of many state agencies, particularly the lack of coordination between them and the prevalence of vested interests. Second, the reliance of the country’s leaders on large financial-industrial groups (FIGs) to compensate for weak institutional capacity. Third, a strong societal and private sector mobilization to fill the gaps in the dilapidated public health system.State agencies are rigid and ineffective. Despite the modern Prozorro digital public procurement system, and the government’s allocation of $2.5 million from the early days of the epidemic, the Ministry of Health blocked COVID-related purchases for over a month. This was a tactic by — now ex-minister — Yemets to pressure the state medical procurement agency into appointing a protégé of his as one of its deputy heads.Lowest testing rate in EuropeSimilarly, in some regions, notably Odesa, procurement stalled and orders went to politically connected businesses at higher-than-market prices. Lack of tests and laboratory equipment means Ukraine has administered only 72,000 tests within a population of 42 million to date — the lowest rate in Europe.Doctors were given orders to ensure they only test patients in hospitals with COVID-19 symptoms and only those arriving from Asia, while ignoring the fact that millions of Ukrainian labour migrants were in Europe. Indeed, the first confirmed case was imported from Italy.Ukrainian government and public health officials lack information to take informed decisions. There is no accurate electronic database of registered deaths and reporting is lagging behind events. Information on testing availability in the regions is missing.Thirteen days after the first case of the virus was recorded, Zelenskyy exhorted business tycoons to come to the rescue. Taking a populist tone, Zelenskyy said ‘Ukraine has been feeding you for a long time and it is time that you helped the country’. The tycoons divided the regions among themselves to deliver relief efforts according to the location of their enterprises.It is believed FIGs have donated around $25 million to procure testing kits, ventilators, personal protective equipment (PPE) and disinfectants. This may sound impressive, but many of those same tycoons actually owe millions to the state, some even billions, and cause serious problems by perpetuating the current rent-seeking system, where public resources benefit those groups resulting in serious social losses.Reliance on these groups makes Zelenskyy a hostage to their favour in any potential reform efforts. It is a dangerous solution, as these tycoons often obstruct Ukraine’s economic development.An alternative — and more transformative — trend of public-private partnerships is emerging in some regions. Across Ukraine, hundreds of small- and medium-sized enterprises (SMEs) have led efforts to deliver PPE, support the vulnerable with food supplies, and to procure ventilators for key hospitals.They have mobilised hundreds of volunteers to deliver assistance and partnered with local non-profits. Fundraising initiatives have begun in Lviv, Odesa, Kyiv and Poltava with donations and expenditure has been posted online for transparency. Companies have repurposed to produce PPE kits and medical equipment. The efforts unfolded quickly and, in some cases, in smooth collaboration with municipal and regional authorities.Ukraine cannot afford to ‘waste’ this crisis, which could help accelerate healthcare reform, decentralization, modernize governance, and boost citizen empowerment. But for this to happen, the country has to deploy a ‘smart response’.Such ‘smart response’ means applying a resilience framework that nurtures the agility of the system of governance, ensures a diversity of actors in decision-making, supporting both self-regulation and better coordination. Rather than reaching out to tycoons, Zelenskyy should enter a coalition with true agents of change — SME leaders, volunteers, and mayors who have mobilized effective grassroots action. These actors demand a level playing field with accountable governance and effective state institutions.Civic COVID-19 response hubs and local authorities should be joined in a network that spans the regions, and connected with the national agencies designing pandemic responses. For a national strategy to be effective, central headquarters should draw information from local communities and manage a ‘team of teams’ in a decentralised fashion.Ensuring effective public service delivery without compromising integrity and keeping the risk of corruption low should also be a priority of political reform, with volunteers and the private sector ensuring civic oversight of both regional and national funding.Civic engagement such as this can be transformative as it defies the Soviet legacy of paternalism and expands the belief among citizens that society can work for them. By assisting the relief effort, citizens are gaining valuable insights into quality of public services and participate in holding them to account.Citizens are also developing a better understanding of the purpose of having effective armed forces, police, border guards and modern hospitals. They are coming to understand the value of taxpayer money and witnessing how corruption erodes institutions.This survival mobilization — if properly harnessed by the state — could drive transformative change and make Ukraine more resilient, not just against present crises, but future ones too. Full Article
gh Virtual Roundtable: Land Reform in Ukraine: Is Zelenskyy's Government Getting it Right? By feedproxy.google.com Published On :: Thu, 07 May 2020 00:05:01 +0000 Invitation Only Research Event 14 May 2020 - 12:00pm to 1:30pmAdd to CalendariCalendar Outlook Google Yahoo Ihor Petrashko, Minister of Economic Development and Trade, UkraineAndriy Dykun, Chair, Ukrainian Agricultural CouncilVadim Tolpeco, Ukrlandfarming PlcChair: Orysia Lutsevych, Research Fellow and Manager, Ukraine Forum, Chatham House Ukraine is known as the ‘breadbasket of Europe’ thanks to its grain exports. On 31 March 2020, the Ukrainian parliament passed a landmark law ending a 19-year ban on the sale of privately owned agricultural land. Due to come into force in July 2021, the law applies to 41.5 million hectares of farmland and economists predict substantial economic gains from this liberalization. This event will discuss the impact of the law on Ukraine’s agricultural sector and food security. How can the government best implement this reform and ensure that small and medium-sized agricultural companies increase their productivity? What does this change mean for Ukraine’s capacity to export grain? Can the country’s food supply withstand crises such as the COVID-19 pandemic? What role could foreign direct investors play in boosting production? This event will be held on the record. Anna Morgan Administrator, Ukraine Forum +44 (0)20 7389 3274 Email Department/project Russia and Eurasia Programme, Ukraine Forum Full Article
gh Functional recombinant apolipoprotein A5 that is stable at high concentrations at physiological pH [Methods] By feedproxy.google.com Published On :: 2020-02-01T00:05:23-08:00 APOA5 is a low-abundance exchangeable apolipoprotein that plays critical roles in human triglyceride (TG) metabolism. Indeed, aberrations in the plasma concentration or structure of APOA5 are linked to hypertriglyceridemia, hyperchylomicronemia, myocardial infarction risk, obesity, and coronary artery disease. While it has been successfully produced at low yield in bacteria, the resulting protein had limitations for structure-function studies due to its low solubility under physiological buffer conditions. We hypothesized that the yield and solubility of recombinant APOA5 could be increased by: i) engineering a fusion protein construct in a codon optimized expression vector, ii) optimizing an efficient refolding protocol, and iii) screening buffer systems at physiological pH. The result was a high-yield (25 mg/l) bacterial expression system that produces lipid-free APOA5 soluble at concentrations of up to 10 mg/ml at a pH of 7.8 in bicarbonate buffers. Physical characterization of lipid-free APOA5 indicated that it exists as an array of multimers in solution, and far UV circular dichroism analyses show differences in total α-helicity between acidic and neutral pH buffering conditions. The protein was functional in that it bound and emulsified multilamellar dimyristoyl-phosphatidylcholine vesicles and could inhibit postprandial plasma TG accumulation when injected into C57BL/6J mice orally gavaged with Intralipid. Full Article
gh High density lipoprotein and its apolipoprotein-defined subspecies and risk of dementia [Patient-Oriented and Epidemiological Research] By feedproxy.google.com Published On :: 2020-03-01T00:06:33-08:00 Whether HDL is associated with dementia risk is unclear. In addition to apoA1, other apolipoproteins are found in HDL, creating subspecies of HDL that may have distinct metabolic properties. We measured apoA1, apoC3, and apoJ levels in plasma and apoA1 levels in HDL that contains or lacks apoE, apoJ, or apoC3 using a modified sandwich ELISA in a case-cohort study nested within the Ginkgo Evaluation of Memory Study. We included 995 randomly selected participants and 521 participants who developed dementia during a mean of 5.1 years of follow-up. The level of total apoA1 was not significantly related to dementia risk, regardless of the coexistence of apoC3, apoJ, or apoE. Higher levels of total plasma apoC3 were associated with better cognitive function at baseline (difference in Modified Mini-Mental State Examination scores tertile 3 vs. tertile 1: 0.60; 95% CI: 0.23, 0.98) and a lower dementia risk (adjusted hazard ratio tertile 3 vs. tertile 1: 0.73; 95% CI: 0.55, 0.96). Plasma concentrations of apoA1 in HDL and its apolipoprotein-defined subspecies were not associated with cognitive function at baseline or with the risk of dementia during follow-up. Similar studies in other populations are required to better understand the association between apoC3 and Alzheimer’s disease pathology. Full Article
gh The citrus flavonoid nobiletin confers protection from metabolic dysregulation in high-fat-fed mice independent of AMPK [Research Articles] By feedproxy.google.com Published On :: 2020-03-01T00:06:33-08:00 Obesity, dyslipidemia, and insulin resistance, the increasingly common metabolic syndrome, are risk factors for CVD and type 2 diabetes that warrant novel therapeutic interventions. The flavonoid nobiletin displays potent lipid-lowering and insulin-sensitizing properties in mice with metabolic dysfunction. However, the mechanisms by which nobiletin mediates metabolic protection are not clearly established. The central role of AMP-activated protein kinase (AMPK) as an energy sensor suggests that AMPK is a target of nobiletin. We tested the hypothesis that metabolic protection by nobiletin required phosphorylation of AMPK and acetyl-CoA carboxylase (ACC) in mouse hepatocytes, in mice deficient in hepatic AMPK (Ampkβ1–/–), in mice incapable of inhibitory phosphorylation of ACC (AccDKI), and in mice with adipocyte-specific AMPK deficiency (iβ1β2AKO). We fed mice a high-fat/high-cholesterol diet with or without nobiletin. Nobiletin increased phosphorylation of AMPK and ACC in primary mouse hepatocytes, which was associated with increased FA oxidation and attenuated FA synthesis. Despite loss of ACC phosphorylation in Ampkβ1–/– hepatocytes, nobiletin suppressed FA synthesis and enhanced FA oxidation. Acute injection of nobiletin into mice did not increase phosphorylation of either AMPK or ACC in liver. In mice fed a high-fat diet, nobiletin robustly prevented obesity, hepatic steatosis, dyslipidemia, and insulin resistance, and it improved energy expenditure in Ampkβ1–/–, AccDKI, and iβ1β2AKO mice to the same extent as in WT controls. Thus, the beneficial metabolic effects of nobiletin in vivo are conferred independently of hepatic or adipocyte AMPK activation. These studies further underscore the therapeutic potential of nobiletin and begin to clarify possible mechanisms. Full Article
gh An LC/MS/MS method for analyzing the steroid metabolome with high accuracy and from small serum samples [Methods] By feedproxy.google.com Published On :: 2020-04-01T00:05:29-07:00 Analyzing global steroid metabolism in humans can shed light on the etiologies of steroid-related diseases. However, existing methods require large amounts of serum and lack the evaluation of accuracy. Here, we developed an LC/MS/MS method for the simultaneous quantification of 12 steroid hormones: testosterone, pregnenolone, progesterone, androstenedione, corticosterone, 11-deoxycortisol, cortisol, 17-hydroxypregnenolone, 17-hydroxyprogesterone, dehydroepiandrosterone, estriol, and estradiol. Steroids and spiked internal standards in 100 μl serum were extracted by protein precipitation and liquid-liquid extraction. The organic phase was dried by evaporation, and isonicotinoyl chloride was added for steroid derivatization, followed by evaporation under nitrogen and redissolution in 50% methanol. Chromatographic separation was performed on a reverse-phase PFP column, and analytes were detected on a triple quadrupole mass spectrometer with ESI. The lower limits of quantification ranged from 0.005 ng/ml for estradiol to 1 ng/ml for cortisol. Apparent recoveries of steroids at high, medium, and low concentrations in quality control samples were between 86.4% and 115.0%. There were limited biases (–10.7% to 10.5%) between the measured values and the authentic values, indicating that the method has excellent reliability. An analysis of the steroid metabolome in pregnant women highlighted the applicability of the method in clinical serum samples. We conclude that the LC/MS/MS method reported here enables steroid metabolome analysis with high accuracy and reduced serum consumption, indicating that it may be a useful tool in both clinical and scientific laboratory research. Full Article
gh Problem Notes for SAS®9 - 65940: You might receive "ERROR: PI Point not found" when you query a PI tag name that contains a special character such as an ampersand (&) By feedproxy.google.com Published On :: Fri, 8 May 2020 11:20:36 EST When you query a PI tag name or element that contains a special character, such as an ampersand (&), you might receive the following error: Full Article OSISOFT+SAS/ACCESS+Interface+to+the+PI+S
gh Problem Notes for SAS®9 - 65938: Incorrect values might be written to Hadoop for columns defined with the BIGINT data type By feedproxy.google.com Published On :: Fri, 8 May 2020 10:20:46 EST Large numeric values consisting of 16 digits in SAS might be incorrect when written to Hadoop for columns defined with the BIGINT data type. This problem was introduced in SAS 9 Full Article HADOOP+SAS/ACCESS+Interface+to+Hadoop
gh Problem Notes for SAS®9 - 65900: Registering an Oracle table to the metadata might fail and generate an error By feedproxy.google.com Published On :: Fri, 8 May 2020 09:38:11 EST When you register an Oracle table to the metadata, it might fail and generate an error similar to the following: "ERROR: An exception has been encountered...ERROR: Read Access Violation METALIB..." Full Article METADATASRV+SAS+Metadata+Server
gh Problem Notes for SAS®9 - 65922: Trying to read a Google BigQuery table that contains a variable defined as an array might result in a panic error and SAS shutting down By feedproxy.google.com Published On :: Wed, 6 May 2020 10:30:19 EST Trying to read a Google BigQuery table that contains a variable that is defined as an array of records might result in an error and cause SAS to shut down. This issue occurs when one of the variables contained in Full Article BIGQUERY+SAS/ACCESS+Interface+to+Google+
gh Problem Notes for SAS®9 - 65916: Accessing a Google BigQuery table without including the SCHEMA= option in the LIBNAME statement might result in an error By feedproxy.google.com Published On :: Wed, 6 May 2020 09:41:22 EST When you issue a LIBNAME statement for a Google BigQuery database without including the SCHEMA= option, all tables in the project are shown when the libref is expanded. However, if you try to acces Full Article BIGQUERY+SAS/ACCESS+Interface+to+Google+
gh Problem Notes for SAS®9 - 34294: A missing discrete dependent variable in the selection model together with a OUTPUT statement might cause an Access Violation error By feedproxy.google.com Published On :: Tue, 5 May 2020 13:04:13 EST If the following conditions are met in PROC QLIM: the SELECT option and DISCRETE option are specified in the same MODEL statement or ENDOGENOUS statement the same dependent variable with S Full Article ETS+SAS/ETS
gh Problem Notes for SAS®9 - 65886: Trying to bulk load data into a Google BigQuery database might result in an error By feedproxy.google.com Published On :: Fri, 1 May 2020 10:00:17 EST When you bulk load data into a Google BigQuery database, you might encounter this error: "Error while reading data, error message: CSV table encountered too many errors, giving up...Error detected while parsing row starting at position: 0...Data Full Article BIGQUERY+SAS/ACCESS+Interface+to+Google+
gh Problem Notes for SAS®9 - 65835: A series of PROC SQL queries might not generate a distinct set of rows By feedproxy.google.com Published On :: Tue, 28 Apr 2020 12:39:06 EST A set of PROC SQL queries that create a view, contain a constant column, contain a computed column, and a create a table do not generate a unique set of rows in the table that is created. Full Article BASE+Base+SAS
gh Problem Notes for SAS®9 - 65597: An SQL procedure query with a WHERE clause that contains multiple subselects might return incorrect results By feedproxy.google.com Published On :: Tue, 28 Apr 2020 12:37:41 EST An issue occurs when code contains a complex SQL procedure query with a WHERE clause that contains multiple subselects. Incorrect results might be returned. Click the Hot Fix tab in this note to Full Article BASE+Base+SAS
gh Problem Notes for SAS®9 - 65572: The length of a string variable might be longer than specified with the MAX_CHAR_LEN= option By feedproxy.google.com Published On :: Tue, 28 Apr 2020 08:30:03 EST When you read in a BigQuery table, the length of string variables might be longer than the length specified with the MAX_CHAR_LEN= option when running your SAS software with UTF-8. By Full Article BIGQUERY+SAS/ACCESS+Interface+to+Google+
gh Faria enters camp fighting for bullpen spot By mlb.mlb.com Published On :: Fri, 15 Feb 2019 13:24:43 EDT After a disappointing 2018 season, Jake Faria is looking to show that last season isn't reflective of the type of pitcher he is. Full Article
gh Dopamine and Early Retinal Dysfunction in Diabetes: Insights From a Phase 1 Study By diabetes.diabetesjournals.org Published On :: 2020-04-20T15:26:16-07:00 Full Article
gh Empagliflozin Ameliorates Obesity-Related Cardiac Dysfunction by Regulating Sestrin2-Mediated AMPK-mTOR Signaling and Redox Homeostasis in High-Fat Induced Obese Mice By diabetes.diabetesjournals.org Published On :: 2020-04-24T18:07:35-07:00 Sodium glucose co-transporter-2 inhibitors (SGLT2i) have favorable cardiovascular outcomes in diabetic patients. However, whether SGLT2i can improve obesity-related cardiac dysfunction is unknown. Sestrin2 is a novel stress-inducible protein that regulates AMPK-mTOR and suppresses oxidative damage. The aim of this study was to determine whether empagliflozin (EMPA) improves obesity-related cardiac dysfunction via regulating Sestrin2-mediated pathways in diet-induced obesity. C57BL/6J mice and Sestrin2 knockout mice were fed a high-fat diet (HFD) for 12 weeks and then treated with or without EMPA (10 mg/kg) for 8 weeks. Treating HFD-fed C57BL/6J mice with EMPA reduced body weight, whole-body fat, and improved metabolic disorders. Furthermore, EMPA improved myocardial hypertrophy/fibrosis and cardiac function, and reduced cardiac fat accumulation and mitochondria injury. Additionally, EMPA significantly augmented Sestrin2 levels, increased AMPK and eNOS phosphorylation, but inhibited Akt and mTOR phosphorylation. These beneficial effects were partially attenuated in HFD-fed Sestrin2 knockout mice. Intriguingly, EMPA treatment enhanced the Nrf2/HO-1-mediated oxidative stress response, suggesting antioxidant and anti-inflammatory activity. Thus, EMPA improved obesity-related cardiac dysfunction via regulating Sestrin2-mediated AMPK-mTOR signaling and maintaining redox homeostasis. These findings provide a novel mechanism for the cardiovascular protection of SGLT2i in obesity. Full Article
gh Potential Protection Against Type 2 Diabetes in Obesity Through Lower CD36 Expression and Improved Exocytosis in {beta}-Cells By diabetes.diabetesjournals.org Published On :: 2020-04-27T15:42:34-07:00 Obesity is a risk factor for type 2 diabetes (T2D), however not all obese individuals develop the disease. In this study, we aimed to investigate the cause of differential insulin secretion capacity of pancreatic islets from T2D and non-T2D (ND) especially obese donors (BMI ≥30 kg/m2). Islets from obese T2D donors had reduced insulin secretion, decreased β-cell exocytosis and higher expression of fatty acid translocase CD36. We tested the hypothesis that CD36 is a key molecule in the reduced insulin secretion capacity. Indeed, CD36 overexpression led to decreased insulin secretion, impaired exocytosis and reduced granule docking. This was accompanied with reduced expression of the exocytotic proteins, SNAP25, STXBP1 and VAMP2, likely because CD36 induced down-regulation of the IRS proteins, suppressed insulin signaling PI3K-AKT pathway and increased nuclear localization of the transcription factor FoxO1. CD36 antibody treatment of the human β-cell line, EndoC-βH1, increased IRS1 and exocytotic protein levels, improved granule docking and enhanced insulin secretion. Our results demonstrate that β-cells from obese T2D donors have dysfunctional exocytosis likely due to an abnormal lipid handling represented by differential CD36 expression. Hence, CD36 could be a key molecule to limit β-cell function in T2D associated with obesity. Full Article
gh The Metabolic Responses to 24-h Fasting and Mild Cold Exposure in Overweight Individuals are Correlated and Accompanied by Changes in FGF21 Concentration By diabetes.diabetesjournals.org Published On :: 2020-04-27T16:35:54-07:00 A greater decrease in 24-h energy expenditure (24EE) during 24h fasting defines a thriftier metabolic phenotype prone to weight gain during overfeeding and resistant to weight loss during caloric restriction. As the thermogenic response to mild cold exposure (COLD) may similarly characterize this human phenotype identified by acute fasting conditions, we analyzed changes in 24EE and sleeping metabolic rate (SLEEP) in a whole-room indirect calorimeter during 24h fasting at thermoneutrality (24°C) and during energy balance both at thermoneutrality (24°C) and mild cold (19°C) in 20 healthy volunteers (80% male, age: 36.6±11.4y, percentage body fat: 34.8±10.5%). Greater decrease in 24EE during fasting (thriftier phenotype) was associated with less increase in 24EE during COLD, i.e. less cold-induced thermogenesis. Greater decreases in plasma fibroblast growth factor 21 (FGF21) after 24h fasting and after COLD were highly correlated and associated with greater decreases in SLEEP in both conditions. We conclude that the metabolic responses to short-term fasting and COLD are associated and mediated by the liver-derived hormone FGF21. Thus, the 24EE response to COLD further identifies the thrifty versus spendthrift phenotype, providing an additional setting to investigate the physiological mechanisms underlying the human metabolic phenotype and characterizing the individual susceptibility to weight change. Full Article
gh Genetic Causes of Severe Childhood Obesity: A Remarkably High Prevalence (>=49%) in an Inbred Population of Pakistan By diabetes.diabetesjournals.org Published On :: 2020-04-29T13:57:29-07:00 Monogenic forms of obesity have been identified in ≤10% of severely obese European patients. However, the overall spectrum of deleterious variants (point mutations and structural variants) responsible for childhood severe obesity remains elusive. In this study, we genetically screened 225 severely obese children from consanguineous Pakistani families through a combination of techniques including an in-house developed augmented whole-exome sequencing (CoDE-seq) enabling simultaneous detection of whole exome copy number variations (CNVs) and of point mutations in coding regions. We identified 110 probands (49%) carrying 55 different pathogenic point mutations and CNVs in 13 genes/loci responsible for non-syndromic and syndromic monofactorial obesity. CoDE-seq also identified 28 rare or novel CNVs associated with intellectual disability in 22 additional obese subjects (10%). Additionally, we highlight variants in candidate genes for obesity warranting further investigation. Altogether, 59% of the studied cohort are likely to have a discrete genetic cause with 13% of these due to CNVs demonstrating a remarkably higher prevalence of monofactorial obesity than hitherto reported and a plausible over lapping of obesity and intellectual disabilities in several cases. Finally, inbred populations with high prevalence of obesity, provide a unique genetically enriched material in quest of new genes/variants influencing energy balance. Full Article
gh Two- and three-color STORM analysis reveals higher-order assembly of leukotriene synthetic complexes on the nuclear envelope of murine neutrophils [Computational Biology] By feedproxy.google.com Published On :: 2020-04-24T06:08:45-07:00 Over the last several years it has become clear that higher order assemblies on membranes, exemplified by signalosomes, are a paradigm for the regulation of many membrane signaling processes. We have recently combined two-color direct stochastic optical reconstruction microscopy (dSTORM) with the (Clus-DoC) algorithm that combines cluster detection and colocalization analysis to observe the organization of 5-lipoxygenase (5-LO) and 5-lipoxygenase–activating protein (FLAP) into higher order assemblies on the nuclear envelope of mast cells; these assemblies were linked to leukotriene (LT) C4 production. In this study we investigated whether higher order assemblies of 5-LO and FLAP included cytosolic phospholipase A2 (cPLA2) and were linked to LTB4 production in murine neutrophils. Using two- and three-color dSTORM supported by fluorescence lifetime imaging microscopy we identified higher order assemblies containing 40 molecules (median) (IQR: 23, 87) of 5-LO, and 53 molecules (62, 156) of FLAP monomer. 98 (18, 154) molecules of cPLA2 were clustered with 5-LO, and 77 (33, 114) molecules of cPLA2 were associated with FLAP. These assemblies were tightly linked to LTB4 formation. The activation-dependent close associations of cPLA2, FLAP, and 5-LO in higher order assemblies on the nuclear envelope support a model in which arachidonic acid is generated by cPLA2 in apposition to FLAP, facilitating its transfer to 5-LO to initiate LT synthesis. Full Article
gh Prominins control ciliary length throughout the animal kingdom: New lessons from human prominin-1 and zebrafish prominin-3 [Cell Biology] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 Prominins (proms) are transmembrane glycoproteins conserved throughout the animal kingdom. They are associated with plasma membrane protrusions, such as primary cilia, as well as extracellular vesicles derived thereof. Primary cilia host numerous signaling pathways affected in diseases known as ciliopathies. Human PROM1 (CD133) is detected in both somatic and cancer stem cells and is also expressed in terminally differentiated epithelial and photoreceptor cells. Genetic mutations in the PROM1 gene result in retinal degeneration by impairing the proper formation of the outer segment of photoreceptors, a modified cilium. Here, we investigated the impact of proms on two distinct examples of ciliogenesis. First, we demonstrate that the overexpression of a dominant-negative mutant variant of human PROM1 (i.e. mutation Y819F/Y828F) significantly decreases ciliary length in Madin–Darby canine kidney cells. These results contrast strongly to the previously observed enhancing effect of WT PROM1 on ciliary length. Mechanistically, the mutation impeded the interaction of PROM1 with ADP-ribosylation factor–like protein 13B, a key regulator of ciliary length. Second, we observed that in vivo knockdown of prom3 in zebrafish alters the number and length of monocilia in the Kupffer's vesicle, resulting in molecular and anatomical defects in the left-right asymmetry. These distinct loss-of-function approaches in two biological systems reveal that prom proteins are critical for the integrity and function of cilia. Our data provide new insights into ciliogenesis and might be of particular interest for investigations of the etiologies of ciliopathies. Full Article