red News24.com | UPDATED: CORONAVIRUS FAQs | All your questions answered By www.news24.com Published On :: Wed, 06 May 2020 06:36:15 +0200 News24 answers some of the most frequently asked questions on coronavirus and level 4 of the lockdown in South Africa. Full Article
red News24.com | Covid-19: Five new cases among prisoners, 3 officials recovered By www.news24.com Published On :: Sat, 09 May 2020 11:26:03 +0200 Five new Covid-19 cases have been recorded among prison inmates and three Department of Correctional Services officials have recovered. Full Article
red Op-Ed: The Case Against Red Flag Laws By www.westernjournal.com Published On :: Fri, 08 May 2020 21:50:24 +0000 If you’ve been holding on to the presumption that gun confiscation will never take place in the United States, it’s time for you to wake up. Gun confiscation is already here, and it’s not slowing down anytime soon. As a result of the passage of red flag laws, 412 guns have been confiscated in Broward… The post Op-Ed: The Case Against Red Flag Laws appeared first on The Western Journal. Full Article Op-Ed American Left Bill of Rights Constitution gun control guns Second Amendment
red Predictions Review: Trump, Zuck Crush My Optimism In 2019 By feedproxy.google.com Published On :: Fri, 27 Dec 2019 18:08:18 +0000 This past year, I predicted the fall of both Zuck and Trump, not to mention the triumph of cannabis and rationale markets. But in 2019, the sociopaths won – bigly. Damn, was I wrong. One year ago this week, I sat down to write my annual list of ten or so predictions for the coming … Continue reading "Predictions Review: Trump, Zuck Crush My Optimism In 2019" Full Article Uncategorized 2019 Election 2020 facebook politics predictions tech technology Trump
red Predictions 2020: Facebook Caves, Google Zags, Netflix Sells Out, and Data Policy Gets Sexy By feedproxy.google.com Published On :: Mon, 06 Jan 2020 02:52:58 +0000 A new year brings another run at my annual predictions: For 17 years now, I’ve taken a few hours to imagine what might happen over the course of the coming twelve months. And my goodness did I swing for the fences last year — and I pretty much whiffed. Batting .300 is great in the majors, but it … Continue reading "Predictions 2020: Facebook Caves, Google Zags, Netflix Sells Out, and Data Policy Gets Sexy" Full Article Joints After Midnight & Rants Media/Tech Business Models Policy Top Posts Uncategorized advertising data facebook Google marketing netflix policy politics technology
red "Leopards ate my face" subreddit bans posts about coronavirus scoffers who later die of it By feedproxy.google.com Published On :: Fri, 08 May 2020 07:19:06 PDT The Leopards Ate My Face subreddit is dedicated to mocking people who thought the Republican party would hurt their enemies only to be surprised to find that it hurts them, too. Inspired by a tweet by Adrian Bott—'I never thought leopards would eat MY face,' sobs woman who voted for the Leopards Eating People's Faces Party—it has now banned posts about people who claimed Covid-19 was bullshit only to die of Covid-19. There are simply too many, and it's getting depressing. "We've seen a billion of them in the past two weeks and the vast majority of them don't fit the subreddit," writes moderator u/ROBOT_OF_WORLD. "People dying from their decisions isn't justice, karmic, or funny." Read the rest Full Article Post depressing rona
red Jupiter looks pretty angry in "lucky" infrared shot By feedproxy.google.com Published On :: Fri, 08 May 2020 07:47:42 PDT It took hundreds of exposures and a complex method of removing occlusions, but this "lucky" shot is the result: a depiction of the hot regions lurking under Jupiter's uppermost clouds. The picture was captured in infared by the Gemini North Telescope in Hawaii, and is one of the sharpest observations of the planet ever made from the ground. To achieve the resolution, scientists used a technique called "lucky imaging" which scrubs out the blurring effect of looking through Earth's turbulent atmosphere. This method involves acquiring multiple exposures of the target and only keeping those segments of an image where that turbulence is at a minimum. Read the rest Full Article Post Space
red Scared Shitless By feedproxy.google.com Published On :: Mon, 28 Mar 2011 14:51:05 +0000 Merlin Mann - "Scared Shitless: How I (Mostly) Learned to Love Being Afraid of Pretty Much Everything" Download MP4 Video of "Scared Shitless" This is the video of a talk I did last month at Webstock in Wellington, New Zealand. It's pretty different from a lot of stuff I've done. It's about being scared. As I mentioned on Back to Work, Webstock is—what? Well. Webstock is unique. Truly. If you get the chance, you should go. Really. I could not and would not have done this talk in this way had I had not been so inspired (and, frankly, so terrified) by the awesomeness of the other speakers, by the quality of their talks, and by the astounding graciousness and empathy of the audience that this particular event attracts. Tash and Mike and their crackerjack team have made something really special here. I'm honored that they even invited me, and I'm insanely grateful for the care and hospitality that they showed to the speakers and to the attendees at every step of the way. Seriously. Thank you. So, yeah. I did something really weird at Webstock. Weird for me and, honestly, just plain weird for "a talk." I'm not sure if it succeeded. But, I did the best I could to make myself (along with some really heroic friends and fellow speakers) into a legitimate guinea pig for a concept that means the world to me: You can be scared and still do it anyway. Regardless of whatever it is. And, you can. No. Really. You. You can do this. You can run toward the shitstorm, let it cover you with shit, but, still never let it stop you from running. Because, like Crazy Bob says: "They can't eat you." And, they can't. And, they won't. Okay? Well, okay, then. ”Scared Shitless” was written by Merlin Mann for 43Folders.com and was originally posted on March 28, 2011. Except as noted, it's ©2010 Merlin Mann and licensed for reuse under CC BY-NC-ND 3.0. "Why a footer?" Full Article Elsewhere Fear Merlin Speaks Webstock
red Local health unit credits public with slowing COVID spread, encourages cottagers to stay home By barrie.ctvnews.ca Published On :: Fri, 8 May 2020 16:50:00 -0400 While infection rates remain steady across the region, the Simcoe Muskoka District Health Unit is reporting more than half of all 360 cases have now recovered. Full Article
red Univ of Pittsburg Researcher, China Native, Dr. Bing Liu, “On the verge” of COVID19 Breakthrough Is Murdered…Alleged Gunman, Hao Gu, Kills Himself By 100percentfedup.com Published On :: Wed, 06 May 2020 03:23:08 +0000 The following article, Univ of Pittsburg Researcher, China Native, Dr. Bing Liu, “On the verge” of COVID19 Breakthrough Is Murdered…Alleged Gunman, Hao Gu, Kills Himself, was first published on 100PercentFedUp.com. A 37-year-old China native and "outstanding researcher" at the University of Pittsburgh... Continue reading: Univ of Pittsburg Researcher, China Native, Dr. Bing Liu, “On the verge” of COVID19 Breakthrough Is Murdered…Alleged Gunman, Hao Gu, Kills Himself ... Full Article Featured Politics
red Rush Limbaugh Predicts Joe Biden Won’t Be The Dem Nominee: “Something’s Gonna Happen” By 100percentfedup.com Published On :: Sat, 09 May 2020 02:15:43 +0000 The following article, Rush Limbaugh Predicts Joe Biden Won’t Be The Dem Nominee: “Something’s Gonna Happen”, was first published on 100PercentFedUp.com. Is Joe Biden going to become the Democrat nominee and run against Trump in the fall? Continue reading: Rush Limbaugh Predicts Joe Biden Won’t Be The Dem Nominee: “Something’s Gonna Happen” ... Full Article Featured Left News Politics
red COVID-19 outbreak at Health Sciences Centre declared over By winnipeg.ctvnews.ca Published On :: Fri, 8 May 2020 13:34:00 -0600 Health officials with the Manitoba government announced on Friday that a COVID-19 outbreak at the Health Sciences Centre has officially been declared over. Full Article
red Inhibition of the erythropoietin-producing receptor EPHB4 antagonizes androgen receptor overexpression and reduces enzalutamide resistance [Molecular Bases of Disease] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 Prostate cancer (PCa) cells heavily rely on an active androgen receptor (AR) pathway for their survival. Enzalutamide (MDV3100) is a second-generation antiandrogenic drug that was approved by the Food and Drug Administration in 2012 to treat patients with castration-resistant prostate cancer (CRPC). However, emergence of resistance against this drug is inevitable, and it has been a major challenge to develop interventions that help manage enzalutamide-resistant CRPC. Erythropoietin-producing human hepatocellular (Eph) receptors are targeted by ephrin protein ligands and have a broad range of functions. Increasing evidence indicates that this signaling pathway plays an important role in tumorigenesis. Overexpression of EPH receptor B4 (EPHB4) has been observed in multiple types of cancer, being closely associated with proliferation, invasion, and metastasis of tumors. Here, using RNA-Seq analyses of clinical and preclinical samples, along with several biochemical and molecular methods, we report that enzalutamide-resistant PCa requires an active EPHB4 pathway that supports drug resistance of this tumor type. Using a small kinase inhibitor and RNAi-based gene silencing to disrupt EPHB4 activity, we found that these disruptions re-sensitize enzalutamide-resistant PCa to the drug both in vitro and in vivo. Mechanistically, we found that EPHB4 stimulates the AR by inducing proto-oncogene c-Myc (c-Myc) expression. Taken together, these results provide critical insight into the mechanism of enzalutamide resistance in PCa, potentially offering a therapeutic avenue for enhancing the efficacy of enzalutamide to better manage this common malignancy. Full Article
red A peroxisome deficiency-induced reductive cytosol state up-regulates the brain-derived neurotrophic factor pathway [Metabolism] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 The peroxisome is a subcellular organelle that functions in essential metabolic pathways, including biosynthesis of plasmalogens, fatty acid β-oxidation of very-long-chain fatty acids, and degradation of hydrogen peroxide. Peroxisome biogenesis disorders (PBDs) manifest as severe dysfunction in multiple organs, including the central nervous system (CNS), but the pathogenic mechanisms in PBDs are largely unknown. Because CNS integrity is coordinately established and maintained by neural cell interactions, we here investigated whether cell-cell communication is impaired and responsible for the neurological defects associated with PBDs. Results from a noncontact co-culture system consisting of primary hippocampal neurons with glial cells revealed that a peroxisome-deficient astrocytic cell line secretes increased levels of brain-derived neurotrophic factor (BDNF), resulting in axonal branching of the neurons. Of note, the BDNF expression in astrocytes was not affected by defects in plasmalogen biosynthesis and peroxisomal fatty acid β-oxidation in the astrocytes. Instead, we found that cytosolic reductive states caused by a mislocalized catalase in the peroxisome-deficient cells induce the elevation in BDNF secretion. Our results suggest that peroxisome deficiency dysregulates neuronal axogenesis by causing a cytosolic reductive state in astrocytes. We conclude that astrocytic peroxisomes regulate BDNF expression and thereby support neuronal integrity and function. Full Article
red N{alpha}-Acetylation of the virulence factor EsxA is required for mycobacterial cytosolic translocation and virulence [Molecular Bases of Disease] By feedproxy.google.com Published On :: 2020-04-24T06:08:45-07:00 The Mycobacterium tuberculosis virulence factor EsxA and its chaperone EsxB are secreted as a heterodimer (EsxA:B) and are crucial for mycobacterial escape from phagosomes and cytosolic translocation. Current findings support the idea that for EsxA to interact with host membranes, EsxA must dissociate from EsxB at low pH. However, the molecular mechanism by which the EsxA:B heterodimer separates is not clear. In the present study, using liposome-leakage and cytotoxicity assays, LC-MS/MS–based proteomics, and CCF-4 FRET analysis, we obtained evidence that the Nα-acetylation of the Thr-2 residue on EsxA, a post-translational modification that is present in mycobacteria but absent in Escherichia coli, is required for the EsxA:B separation. Substitutions at Thr-2 that precluded Nα-acetylation inhibited the heterodimer separation and hence prevented EsxA from interacting with the host membrane, resulting in attenuated mycobacterial cytosolic translocation and virulence. Molecular dynamics simulations revealed that at low pH, the Nα-acetylated Thr-2 makes direct and frequent “bind-and-release” contacts with EsxB, which generates a force that pulls EsxB away from EsxA. In summary, our findings provide evidence that the Nα-acetylation at Thr-2 of EsxA facilitates dissociation of the EsxA:B heterodimer required for EsxA membrane permeabilization and mycobacterial cytosolic translocation and virulence. Full Article
red Reducing meat consumption critical to achieving global climate goal By feedproxy.google.com Published On :: Tue, 24 Nov 2015 16:35:54 +0000 18 November 2015 20151124DietClimateChange.jpg Grand Central Market in Los Angeles, California, October 2015. Photo: Getty Images. In the week before governments assemble in Paris to agree a global climate deal, a new report from Chatham House shows that a worldwide shift to healthier diets could help close the gap between current emissions reduction plans and what is needed to prevent dangerous climate change.Pledges from countries attending the 21st UNFCCC Conference of the Parties put the world on track for around 3 degrees of warming by 2100, leaving governments with much more still to do. Changing diets to healthy levels of meat consumption could generate a quarter of the remaining emission reductions needed to keep warming below the ‘danger level’ of 2 degrees Celsius – the main goal of the climate negotiations.Changing Climate, Changing Diets: Pathways to Lower Meat Consumption by Laura Wellesley, Catherine Happer and Antony Froggatt argues that, ultimately, dietary change is fundamental to achieving the 2 degrees goal. The livestock sector is already responsible for 15 per cent of global greenhouse gas emissions. Unless strong demand growth for meat is curtailed, livestock sector emissions will increase to the point where dangerous climate change is unavoidable.Dietary change would also have major health benefits. Global per capita meat consumption is already above healthy levels, and double the recommended amount in industrialized countries. Too much red and processed meat is associated with an increased risk of non-communicable diseases, in particular cancer, as found most recently by the World Health Organization.'Reducing meat consumption is a real win-win for health and for the climate,' says report author Laura Wellesley. 'As governments look for strategies to close the Paris emissions gap quickly and cheaply, dietary change should be high on the list.'However, the report finds that governments are ignoring the opportunity. Reducing meat consumption does not feature in a single national emissions reduction plan submitted in advance of the Paris meeting. Governments are afraid to interfere in lifestyle choices for fear of public backlash.But new research undertaken for the report, including an innovative public survey in 12 countries and focus groups in Brazil, China, the United Kingdom, and the United States shows that government fears are exaggerated. Once aware of the link between meat and climate change, consumers accept the need for government action. Even unpopular interventions to make meat more expensive, for example through a carbon tax, would face diminishing resistance as publics come to understand the rationale behind intervention.To build support for government action, the report recommends initiatives to raise public awareness of the climate and health impacts of excessive meat consumption. Governments should pursue comprehensive strategies to shift diets, including policies on labelling, public procurement, regulation and pricing.'Raising awareness about the health and environmental impacts of meat is an important first step, but on its own it will not lead to significant behaviour change. Governments must do more to influence diets,' added Wellesley. Editor's notes Read Changing Climate, Changing Diets: Pathways to Lower Meat Consumption by Laura Wellesley, Catherine Happer and Antony Froggatt.This report is embargoed until 00:01 GMT on Tuesday 24 November. To arrange an interview with the authors please contact the press office.This research project was carried out in conjunction with Glasgow University Media Group. Further research findings:Meat consumption has already reached excessive levels in many Western countries: in industrialized countries, it is around twice the amount deemed healthy by experts. And with the rise of new meat-eating middle classes in developing countries, global meat consumption is set to increase by 76 per cent by 2050.Action on diets could also lower the costs of climate action across the rest of the economy by 50 per cent, while presenting a win-win strategy for policy-makers in terms of public health benefits.In the UK and US, men are more likely to want to eat more meat than women.In China, the desire to eat meat increases in line with income, while in the US and UK, wealthier people are less likely to say they want to eat more meat.In the UK and US, climate change is a more politicized and divisive issue, and people are more sceptical about the science.The US respondents remained most sceptical about the data presented to them.In the UK and US, people were reluctant to take personal responsibility for climate change, seeing it as something those in public roles were responsible for.The highest levels of concern around food safety and animal welfare associated with meat production were found among US respondents. People in the UK were most likely to eat less meat for health reasons.In the UK and US, meat was associated positively with nutrition and fulfilment, but negatively with health and food safety.The executive summary of the report is available in Mandarin and Portuguese. Read the International Agency for Research on Cancer/World Health Organization monographs evaluation on consumption of red meat and processed meat, 26 October 2015. Contacts Press Office +44 (0)20 7957 5739 Email Full Article
red Dame Margaret Anstee remembered By feedproxy.google.com Published On :: Fri, 20 Jan 2017 10:13:00 +0000 20 January 2017 Dame Margaret Anstee, the first female UN under-secretary general, who died last year after a long and distinguished career as a diplomat, was remembered this week at Chatham House. bc-4619793545001.jpg Dame Margaret Anstee was a diplomat whose postings as UN representative included in Colombia, Uruguay and Argentina, Bolivia, Ethiopia, Morocco and Chile. She was also special representative of the secretary-general to Angola (1992-93) and, when Chatham House launched its British Angola Forum in 1998 Dame Margaret served on its board until 2009.Her involvement with the institute’s work on Angola included most recently a Chatham House conference on Angola in 2015 where she sent a video message to delegates. In a separate interview, recorded at the same time, she reflected on the UN on its 70th anniversary and discussed its successes and failures and her optimism for its future.On 17 January 2017 a memorial service was held at St James’s Church and a message from José Eduardo dos Santos, Angola’s president, acknowledged Dame Margaret’s courage and the remarkable role she played in Angola’s transition to democracy. A eulogy address was delivered by Sir Jeremy Greenstock, member of Chatham House’s council, and the service was followed by a reception at Chatham House. In an obituary published last year Alex Vines, head of Chatham House’s Africa programme, wrote about the vital role she played in Angola’s recent history. Full Article
red The Future of NATO: A Strong Alliance in an Unpredictable World By feedproxy.google.com Published On :: Tue, 10 Jun 2014 11:00:03 +0000 Members Event 19 June 2014 - 11:00am to 12:00pm Chatham House, London Transcriptpdf | 51.86 KB Transcript Q&Apdf | 75.72 KB Event participants Anders Fogh Rasmussen, Secretary-General, North Atlantic Treaty Organization (NATO)Chair: Robin Niblett, Director, Chatham House In September, the UK will host a summit on the future of NATO. The Wales Summit will chart the course of the alliance as it deals with the long-term implications of Russia’s policy towards Ukraine and prepares to complete its longest combat mission in Afghanistan. The secretary-general will outline the decisions that need to be taken to ensure that the alliance remains fit to face the future. He will set out NATO’s readiness action plan, address the debate on declining defence budgets, and explain how NATO intends to turn a new page in Afghanistan. Members Events Team Email Full Article
red 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
red Long noncoding RNA pncRNA-D reduces cyclin D1 gene expression and arrests cell cycle through RNA m6A modification [RNA] By feedproxy.google.com Published On :: 2020-04-24T06:08:45-07:00 pncRNA-D is an irradiation-induced 602-nt long noncoding RNA transcribed from the promoter region of the cyclin D1 (CCND1) gene. CCND1 expression is predicted to be inhibited through an interplay between pncRNA-D and RNA-binding protein TLS/FUS. Because the pncRNA-D–TLS interaction is essential for pncRNA-D–stimulated CCND1 inhibition, here we studied the possible role of RNA modification in this interaction in HeLa cells. We found that osmotic stress induces pncRNA-D by recruiting RNA polymerase II to its promoter. pncRNA-D was highly m6A-methylated in control cells, but osmotic stress reduced the methylation and also arginine methylation of TLS in the nucleus. Knockdown of the m6A modification enzyme methyltransferase-like 3 (METTL3) prolonged the half-life of pncRNA-D, and among the known m6A recognition proteins, YTH domain-containing 1 (YTHDC1) was responsible for binding m6A of pncRNA-D. Knockdown of METTL3 or YTHDC1 also enhanced the interaction of pncRNA-D with TLS, and results from RNA pulldown assays implicated YTHDC1 in the inhibitory effect on the TLS–pncRNA-D interaction. CRISPR/Cas9-mediated deletion of candidate m6A site decreased the m6A level in pncRNA-D and altered its interaction with the RNA-binding proteins. Of note, a reduction in the m6A modification arrested the cell cycle at the G0/G1 phase, and pncRNA-D knockdown partially reversed this arrest. Moreover, pncRNA-D induction in HeLa cells significantly suppressed cell growth. Collectively, these findings suggest that m6A modification of the long noncoding RNA pncRNA-D plays a role in the regulation of CCND1 gene expression and cell cycle progression. Full Article
red The Human Plasma Proteome: A Nonredundant List Developed by Combination of Four Separate Sources By feedproxy.google.com Published On :: 2004-04-01 N. Leigh AndersonApr 1, 2004; 3:311-326Research Full Article
red GPS 2.0, a Tool to Predict Kinase-specific Phosphorylation Sites in Hierarchy By feedproxy.google.com Published On :: 2008-09-01 Yu XueSep 1, 2008; 7:1598-1608Research Full Article
red Reduction of protein phosphatase 2A (PP2A) complexity reveals cellular functions and dephosphorylation motifs of the PP2A/B'{delta} holoenzyme [Enzymology] By feedproxy.google.com Published On :: 2020-04-24T06:08:45-07:00 Protein phosphatase 2A (PP2A) is a large enzyme family responsible for most cellular Ser/Thr dephosphorylation events. PP2A substrate specificity, localization, and regulation by second messengers rely on more than a dozen regulatory subunits (including B/R2, B'/R5, and B″/R3), which form the PP2A heterotrimeric holoenzyme by associating with a dimer comprising scaffolding (A) and catalytic (C) subunits. Because of partial redundancy and high endogenous expression of PP2A holoenzymes, traditional approaches of overexpressing, knocking down, or knocking out PP2A regulatory subunits have yielded only limited insights into their biological roles and substrates. To this end, here we sought to reduce the complexity of cellular PP2A holoenzymes. We used tetracycline-inducible expression of pairs of scaffolding and regulatory subunits with complementary charge-reversal substitutions in their interaction interfaces. For each of the three regulatory subunit families, we engineered A/B charge–swap variants that could bind to one another, but not to endogenous A and B subunits. Because endogenous Aα was targeted by a co-induced shRNA, endogenous B subunits were rapidly degraded, resulting in expression of predominantly a single PP2A heterotrimer composed of the A/B charge–swap pair and the endogenous catalytic subunit. Using B'δ/PPP2R5D, we show that PP2A complexity reduction, but not PP2A overexpression, reveals a role of this holoenzyme in suppression of extracellular signal–regulated kinase signaling and protein kinase A substrate dephosphorylation. When combined with global phosphoproteomics, the PP2A/B'δ reduction approach identified consensus dephosphorylation motifs in its substrates and suggested that residues surrounding the phosphorylation site play roles in PP2A substrate specificity. Full Article
red Polarization of protease-activated receptor 2 (PAR-2) signaling is altered during airway epithelial remodeling and deciliation [Immunology] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Protease-activated receptor 2 (PAR-2) is activated by secreted proteases from immune cells or fungi. PAR-2 is normally expressed basolaterally in differentiated nasal ciliated cells. We hypothesized that epithelial remodeling during diseases characterized by cilial loss and squamous metaplasia may alter PAR-2 polarization. Here, using a fluorescent arrestin assay, we confirmed that the common fungal airway pathogen Aspergillus fumigatus activates heterologously-expressed PAR-2. Endogenous PAR-2 activation in submerged airway RPMI 2650 or NCI–H520 squamous cells increased intracellular calcium levels and granulocyte macrophage–colony-stimulating factor, tumor necrosis factor α, and interleukin (IL)-6 secretion. RPMI 2650 cells cultured at an air–liquid interface (ALI) responded to apically or basolaterally applied PAR-2 agonists. However, well-differentiated primary nasal epithelial ALIs responded only to basolateral PAR-2 stimulation, indicated by calcium elevation, increased cilia beat frequency, and increased fluid and cytokine secretion. We exposed primary cells to disease-related modifiers that alter epithelial morphology, including IL-13, cigarette smoke condensate, and retinoic acid deficiency, at concentrations and times that altered epithelial morphology without causing breakdown of the epithelial barrier to model early disease states. These altered primary cultures responded to both apical and basolateral PAR-2 stimulation. Imaging nasal polyps and control middle turbinate explants, we found that nasal polyps, but not turbinates, exhibit apical calcium responses to PAR-2 stimulation. However, isolated ciliated cells from both polyps and turbinates maintained basolateral PAR-2 polarization, suggesting that the calcium responses originated from nonciliated cells. Altered PAR-2 polarization in disease-remodeled epithelia may enhance apical responses and increase sensitivity to inhaled proteases. Full Article
red Why Britain’s 2019 Election Is Its Most Unpredictable in Recent History By feedproxy.google.com Published On :: Thu, 07 Nov 2019 15:33:23 +0000 7 November 2019 Professor Matthew Goodwin Visiting Senior Fellow, Europe Programme @GoodwinMJ LinkedIn Google Scholar Leadership concerns and a collapse of traditional party loyalties make the December vote uncommonly volatile. Explainer: UK General Election - Five Things to Watch On 12 December, Britain will hold the most consequential election in its postwar history. The outcome of the election will influence not only the fate of Brexit but also the likelihood of a second referendum on EU membership, a second independence referendum in Scotland, the most economically radical Labour Party for a generation, Britain’s foreign and security policy and, ultimately, its position in the wider international order.If you look only at the latest polls, then the outcome looks fairly certain. Ever since a majority of MPs voted to hold the election, the incumbent Conservative Party has averaged 38%, the opposition Labour Party 27%, the Liberal Democrats 16%, Brexit Party 10%, Greens 4% and Scottish National Party 3%. Prime Minister Boris Johnson and his party continue to average an 11-point lead which, if this holds until the election, would likely deliver a comfortable majority.Johnson can also point to other favourable metrics. When voters are asked who would make the ‘best prime minister’, a clear plurality (43%) say Johnson while only a small minority (20%) choose the Labour Party leader, Jeremy Corbyn. Polls also suggest that, on the whole, Johnson is more trusted by voters than Corbyn to deal with Brexit, the economy and crime, while Jeremy Corbyn only tends to enjoy leads on health. All of this lends credence to the claim that Britain could be set for a Conservative majority and, in turn, the passing of a withdrawal agreement bill in early 2020.But these polls also hide a lot of other shifts that are taking place and which, combined, make the 2019 general election unpredictable. One concerns leadership. While Boris Johnson enjoys stronger leadership ratings than Jeremy Corbyn, it should be remembered that what unites Britain’s current generation of party leaders is that they are all unpopular. Data compiled by Ipsos-MORI reveals that while Johnson has the lowest ratings of any new prime minister, Labour’s Jeremy Corbyn has the lowest ratings of any opposition leader since records began.Another deeper shift is fragmentation. One irony of Britain’s Brexit moment is that ever since the country voted to leave the European Union its politics have looked more ‘European’. Over the past year, one of the world’s most stable two-party systems has imploded into a four-party race, with the anti-Brexit Liberal Democrats and Nigel Farage’s strongly Eurosceptic Brexit Party both presenting a serious challenge to the two mainstream parties.In the latest polls, for example, Labour and the Conservatives are attracting only 61 per cent of the overall vote, well down on the 80 per cent they polled in 2017. Labour is weakened by the fact that it is only currently attracting 53 per cent of people who voted Labour at the last election, in 2017. A large number of these 2017 Labour voters, nearly one in four, have left for the Liberal Democrats, who are promising to revoke Article 50 and ‘cancel Brexit’. This divide in the Remain vote will produce unpredictable outcomes at the constituency level.Embed this image <img src="https://www.chathamhouse.org/sites/default/files/images/2019-11-07-Parliament.jpg" alt="The Houses of Parliament in autumn. Photo: Getty Images." title="The Houses of Parliament in autumn. Photo: Getty Images." />At the other end of the spectrum, the Conservatives are grappling with a similar but less severe threat. Nigel Farage and the Brexit Party are attracting around one in ten people who voted Conservative in 2017, which will make Boris Johnson’s task of capturing the crucial ‘Labour Leave’ seats harder. There is clear evidence that Johnson has been curbing Farage’s appeal, but it remains unclear how this rivalry on the right will play out from one seat to the next.One clue as to what happens next can be found in those leadership ratings. While 80 per cent of Brexit Party voters back Johnson over Corbyn, only 25 per cent of Liberal Democrat voters back Corbyn over Johnson. Johnson may find it easier to consolidate the Leave vote than Corbyn will find the task of consolidating the Remain vote.All of this reflects another reason why the election is unpredictable: volatility. This election is already Britain’s fifth nationwide election in only four years. After the 2015 general election, 2016 EU referendum, 2017 general election and 2019 European parliament elections, Britain’s political system and electorate have been in a state of almost continual flux. Along the way, a large number of voters have reassessed their loyalties.As the British Election Study makes clear, the current rate of ‘vote-switching’ in British politics, where people switch their vote from one election to the next, is largely unprecedented in the post-war era. Across the three elections held in 2010, 2015 and 2017, a striking 49 per cent of people switched their vote.This is not all about Brexit. Attachment to the main parties has been weakening since the 1960s. But Brexit is now accelerating this process as tribal identities as ‘Remainers’ or ‘Leavers’ cut across traditional party loyalties. All this volatility not only gives good reason to expect further shifts in support during the campaign but to also meet any confident predictions about the election result with a healthy dose of scepticism. Full Article
red A Credit-fuelled Economic Recovery Stores Up Trouble for Turkey By feedproxy.google.com Published On :: Mon, 17 Feb 2020 13:47:40 +0000 17 February 2020 Fadi Hakura Consulting Fellow, Europe Programme LinkedIn Turkey is repeating the mistakes that led to the 2018 lira crisis and another freefall for the currency may not be far off. 2020-02-17-TurCB.jpg Headquarters of the Central Bank of the Republic of Turkey. Photo: Getty Images. Since the 2018 economic crisis, when the value of the lira plummeted and borrowing costs soared, Turkey’s economy has achieved a miraculous ‘V-shaped’ economic recovery from a recession lasting three quarters to a return back to quarterly growth above 1 per cent in the first three months of 2019.But this quick turnaround has been built on vast amounts of cheap credit used to re-stimulate a consumption and construction boom. This so-called ‘triple C’ economy generated a rapid growth spurt akin to a modestly able professional sprinter injected with steroids.This has made the currency vulnerable. The lira has steadily depreciated by 11 per cent against the US dollar since the beginning of 2019 and crossed the rate of 6 lira versus the US dollar on 7 February. And there are further warning signs on the horizon.Credit bonanzaStatistics reveal that Turkish domestic credit grew by around 13 per cent on average throughout 2019. The credit bonanza is still ongoing. Mortgage-backed home sales jumped by a record high of 600 per cent last December alone and the 2019 budget deficit catapulted by 70 per cent due to higher government spending.Turkey’s central bank fuelled this credit expansion by cutting interest rates aggressively to below inflation and, since the start of this year, purchasing lira-denominated bonds equivalent to around one-third of total acquisitions last year to push yields lower.Equally, it has linked bank lending to reserve requirements – the money that banks have to keep at the central bank – to boost borrowings via state and private banks. Banks with a ‘real’ loan growth (including inflation) of between 5 and 15 per cent enjoy a 2 per cent reserve ratio on most lira deposits, which authorities adjusted from an earlier band of 10-20 per cent that did not consider double-digit inflation.Cumulatively, bond purchases (effectively quantitative easing) and reserve management policies have also contributed to eased credit conditions.Commercial banks have also reduced deposit rates on lira accounts to less than inflation to encourage consumption over saving. Together with low lending rates, the boost to the economy has flowed via mortgages, credit card loans, vehicle leasing transactions and general business borrowings.Accordingly, stimulus is at the forefront of the government’s economic approach, as it was in 2017 and 2018. It does not seem to be implementing structural change to re-orient growth away from consumption towards productivity. In addition, governance is, again, a central issue. President Recep Tayyip Erdogan’s near total monopolization of policymaking means he guides all domestic and external policies. He forced out the previous central bank governor, Murat Cetinkaya, in July 2019 because he did not share the president’s desire for an accelerated pace of interest rate reductions.New challengesDespite the similarities, the expected future financial turbulence will be materially different from its 2018 predecessor in four crucial respects. Firstly, foreign investors will only be marginally involved. Turkey has shut out foreign investors since 2018 from lira-denominated assets by restricting lira swap arrangements. Unsurprisingly, the non-resident holdings of lira bonds has plummeted from 20 per cent in 2018 to less than 10 per cent today.Secondly, the Turkish government has recently introduced indirect domestic capital controls by constraining most commercial transactions to the lira rather than to the US dollar or euro to reduce foreign currency demand in light of short-term external debt obligations of $191 billion.Thirdly, the Turkish state banks are intervening quite regularly to soften Lira volatility, thereby transitioning from a ‘free float’ to a ‘managed float’. So far, they have spent over $37 billion over the last two years in a futile effort to buttress the lira. This level of involvement in currency markets cannot be maintained.Fourthly, the Turkish state is being far more interventionist in the Turkish stock exchange and bond markets to keep asset prices elevated. Government-controlled local funds have participated in the Borsa Istanbul and state banks in sovereign debt to sustain rallies or reverse a bear market. All these measures have one running idea: exclude foreign investors and no crisis will recur. Yet, when the credit boom heads to a downturn sooner or later, Turks will probably escalate lira conversions to US dollars; 51 per cent of all Turkish bank deposits are already dollar-denominated and the figure is still rising.If Turkey’s limited foreign reserves cannot satisfy the domestic dollar demand, the government may have to impose comprehensive capital controls and allow for a double digit depreciation in the value of the lira to from its current level, with significant repercussions on Turkey’s political stability and economic climate.To avoid this scenario, it needs to restore fiscal and monetary prudence, deal the with the foreign debt overhang in the private sector and focus on productivity-improving economic and institutional reforms to gain the confidence of global financial markets and Turks alike. Full Article
red Reduction of protein phosphatase 2A (PP2A) complexity reveals cellular functions and dephosphorylation motifs of the PP2A/B'{delta} holoenzyme [Enzymology] By feedproxy.google.com Published On :: 2020-04-24T06:08:45-07:00 Protein phosphatase 2A (PP2A) is a large enzyme family responsible for most cellular Ser/Thr dephosphorylation events. PP2A substrate specificity, localization, and regulation by second messengers rely on more than a dozen regulatory subunits (including B/R2, B'/R5, and B″/R3), which form the PP2A heterotrimeric holoenzyme by associating with a dimer comprising scaffolding (A) and catalytic (C) subunits. Because of partial redundancy and high endogenous expression of PP2A holoenzymes, traditional approaches of overexpressing, knocking down, or knocking out PP2A regulatory subunits have yielded only limited insights into their biological roles and substrates. To this end, here we sought to reduce the complexity of cellular PP2A holoenzymes. We used tetracycline-inducible expression of pairs of scaffolding and regulatory subunits with complementary charge-reversal substitutions in their interaction interfaces. For each of the three regulatory subunit families, we engineered A/B charge–swap variants that could bind to one another, but not to endogenous A and B subunits. Because endogenous Aα was targeted by a co-induced shRNA, endogenous B subunits were rapidly degraded, resulting in expression of predominantly a single PP2A heterotrimer composed of the A/B charge–swap pair and the endogenous catalytic subunit. Using B'δ/PPP2R5D, we show that PP2A complexity reduction, but not PP2A overexpression, reveals a role of this holoenzyme in suppression of extracellular signal–regulated kinase signaling and protein kinase A substrate dephosphorylation. When combined with global phosphoproteomics, the PP2A/B'δ reduction approach identified consensus dephosphorylation motifs in its substrates and suggested that residues surrounding the phosphorylation site play roles in PP2A substrate specificity. Full Article
red Thioredoxin regulates human mercaptopyruvate sulfurtransferase at physiologically-relevant concentrations [Enzymology] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 3-Mercaptopyruvate sulfur transferase (MPST) catalyzes the desulfuration of 3-mercaptopyruvate (3-MP) and transfers sulfane sulfur from an enzyme-bound persulfide intermediate to thiophilic acceptors such as thioredoxin and cysteine. Hydrogen sulfide (H2S), a signaling molecule implicated in many physiological processes, can be released from the persulfide product of the MPST reaction. Two splice variants of MPST, differing by 20 amino acids at the N terminus, give rise to the cytosolic MPST1 and mitochondrial MPST2 isoforms. Here, we characterized the poorly-studied MPST1 variant and demonstrated that substitutions in its Ser–His–Asp triad, proposed to serve a general acid–base role, minimally affect catalytic activity. We estimated the 3-MP concentration in murine liver, kidney, and brain tissues, finding that it ranges from 0.4 μmol·kg−1 in brain to 1.4 μmol·kg−1 in kidney. We also show that N-acetylcysteine, a widely-used antioxidant, is a poor substrate for MPST and is unlikely to function as a thiophilic acceptor. Thioredoxin exhibits substrate inhibition, increasing the KM for 3-MP ∼15-fold compared with other sulfur acceptors. Kinetic simulations at physiologically-relevant substrate concentrations predicted that the proportion of sulfur transfer to thioredoxin increases ∼3.5-fold as its concentration decreases from 10 to 1 μm, whereas the total MPST reaction rate increases ∼7-fold. The simulations also predicted that cysteine is a quantitatively-significant sulfane sulfur acceptor, revealing MPST's potential to generate low-molecular-weight persulfides. We conclude that the MPST1 and MPST2 isoforms are kinetically indistinguishable and that thioredoxin modulates the MPST-catalyzed reaction in a physiologically-relevant concentration range. Full Article
red Predictions and Policymaking: Complex Modelling Beyond COVID-19 By feedproxy.google.com Published On :: Wed, 01 Apr 2020 09:11:23 +0000 1 April 2020 Yasmin Afina Research Assistant, International Security Programme @afinayasmin LinkedIn Calum Inverarity Research Analyst and Coordinator, International Security Programme LinkedIn The COVID-19 pandemic has highlighted the potential of complex systems modelling for policymaking but it is crucial to also understand its limitations. GettyImages-1208425931.jpg A member of the media wearing a protective face mask works in Downing Street where Britain's Prime Minister Boris Johnson is self-isolating in central London, 27 March 2020. Photo by TOLGA AKMEN/AFP via Getty Images. Complex systems models have played a significant role in informing and shaping the public health measures adopted by governments in the context of the COVID-19 pandemic. For instance, modelling carried out by a team at Imperial College London is widely reported to have driven the approach in the UK from a strategy of mitigation to one of suppression.Complex systems modelling will increasingly feed into policymaking by predicting a range of potential correlations, results and outcomes based on a set of parameters, assumptions, data and pre-defined interactions. It is already instrumental in developing risk mitigation and resilience measures to address and prepare for existential crises such as pandemics, prospects of a nuclear war, as well as climate change.The human factorIn the end, model-driven approaches must stand up to the test of real-life data. Modelling for policymaking must take into account a number of caveats and limitations. Models are developed to help answer specific questions, and their predictions will depend on the hypotheses and definitions set by the modellers, which are subject to their individual and collective biases and assumptions. For instance, the models developed by Imperial College came with the caveated assumption that a policy of social distancing for people over 70 will have a 75 per cent compliance rate. This assumption is based on the modellers’ own perceptions of demographics and society, and may not reflect all societal factors that could impact this compliance rate in real life, such as gender, age, ethnicity, genetic diversity, economic stability, as well as access to food, supplies and healthcare. This is why modelling benefits from a cognitively diverse team who bring a wide range of knowledge and understanding to the early creation of a model.The potential of artificial intelligenceMachine learning, or artificial intelligence (AI), has the potential to advance the capacity and accuracy of modelling techniques by identifying new patterns and interactions, and overcoming some of the limitations resulting from human assumptions and bias. Yet, increasing reliance on these techniques raises the issue of explainability. Policymakers need to be fully aware and understand the model, assumptions and input data behind any predictions and must be able to communicate this aspect of modelling in order to uphold democratic accountability and transparency in public decision-making.In addition, models using machine learning techniques require extensive amounts of data, which must also be of high quality and as free from bias as possible to ensure accuracy and address the issues at stake. Although technology may be used in the process (i.e. automated extraction and processing of information with big data), data is ultimately created, collected, aggregated and analysed by and for human users. Datasets will reflect the individual and collective biases and assumptions of those creating, collecting, processing and analysing this data. Algorithmic bias is inevitable, and it is essential that policy- and decision-makers are fully aware of how reliable the systems are, as well as their potential social implications.The age of distrustIncreasing use of emerging technologies for data- and evidence-based policymaking is taking place, paradoxically, in an era of growing mistrust towards expertise and experts, as infamously surmised by Michael Gove. Policymakers and subject-matter experts have faced increased public scrutiny of their findings and the resultant policies that they have been used to justify.This distrust and scepticism within public discourse has only been fuelled by an ever-increasing availability of diffuse sources of information, not all of which are verifiable and robust. This has caused tension between experts, policymakers and public, which has led to conflicts and uncertainty over what data and predictions can be trusted, and to what degree. This dynamic is exacerbated when considering that certain individuals may purposefully misappropriate, or simply misinterpret, data to support their argument or policies. Politicians are presently considered the least trusted professionals by the UK public, highlighting the importance of better and more effective communication between the scientific community, policymakers and the populations affected by policy decisions.Acknowledging limitationsWhile measures can and should be built in to improve the transparency and robustness of scientific models in order to counteract these common criticisms, it is important to acknowledge that there are limitations to the steps that can be taken. This is particularly the case when dealing with predictions of future events, which inherently involve degrees of uncertainty that cannot be fully accounted for by human or machine. As a result, if not carefully considered and communicated, the increased use of complex modelling in policymaking holds the potential to undermine and obfuscate the policymaking process, which may contribute towards significant mistakes being made, increased uncertainty, lack of trust in the models and in the political process and further disaffection of citizens.The potential contribution of complexity modelling to the work of policymakers is undeniable. However, it is imperative to appreciate the inner workings and limitations of these models, such as the biases that underpin their functioning and the uncertainties that they will not be fully capable of accounting for, in spite of their immense power. They must be tested against the data, again and again, as new information becomes available or there is a risk of scientific models becoming embroiled in partisan politicization and potentially weaponized for political purposes. It is therefore important not to consider these models as oracles, but instead as one of many contributions to the process of policymaking. Full Article
red 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
red The Power of Sacred Geography in Iraq By feedproxy.google.com Published On :: Wed, 18 Jun 2014 14:08:09 +0000 18 June 2014 Sasan Aghlani Former Consultant, International Security Too much of a focus on body counts, resource scarcity and national borders as the main indicators of why people fight can obscure the significant impact that religious space can have on a conflict. 20140618Ladyzaynabmosque.jpg Lady Zaynab mosque, Sayyidah Zaynab, in the southern suburbs of Damascus, Syria, 2007. Photo: Wikimedia. Loss of territory to the Islamic State of Iraq and al-Sham (ISIS) and the mass executions of Shia have undoubtedly had an impact on the mobilization of fighters inside Iraq opposing the group. But after the capture of Mosul and Tikrit by ISIS, a message from the group’s spokesman, Abu Muhammad al-Adnani, highlighted the power of religion as a mobilizing force in armed conflict. In the audio message Adnani addressed Prime Minister Nouri al Maliki as ‘Rafidi’, a derogatory term for Shia meaning rejectionist. He pledged that ‘the settling of debts will not be in Samarra and Baghdad, rather in Karbala al-munajjasah [Karbala the defiled] and Najaf al-ashrak [Najaf the most polytheistic]’.His use of the words ‘munajjasah’ and ‘ashrak’ was a sectarian play on words referring to the two cities viewed by the Shia as being the most important cities in Islam after Mecca and Medina. Karbala is also known as Karbala al-Muqaddasa (Karbala the Holy), and contains the mausoleum of the third Shia Imam, Hussein ibn Ali. Najaf is commonly referred to as Najaf al-Ashraf (Najaf the Most Honourable), and contains the mausoleum of the first Shia Imam and fourth ‘rightly guided’ caliph, Ali ibn Abi Talib.Threats against Karbala and Najaf have prompted an immediate reaction from Shia both inside Iraq and beyond its borders. When a representative of Grand Ayatollah Ali Sistani, the most influential living Shia religious authority, called on all able-bodied Iraqis to ’confront and fight the terrorists’, Sistani was compelled to reiterate that the subject of his call were Iraqis, and not just Shia. Ayatollah Fadhil al-Milani, Sistani’s representative in London, also released a video message clarifying that there was no need for Shia outside of Iraq to confront ISIS.Fighters are already mobilized in Syria on the basis that Shia shrines in Damascus such as the Sayyidah Zainab Mosque are under threat from extremist ‘Takfiri’ militant groups intent on destroying these holy sites. The narrative of protecting Zainab’s shrine is a potent one: militias in the country bear names such as the Brigade of Zainab’s Protector and the Abu al-Fadhl Abbas Brigades. In 2013, Hezbollah Secretary General Hassan Nasrallah warned that the destruction of Zainab’s shrine would ‘carry with it grave consequences’, and that ‘countries supporting these groups [would] be held responsible for this crime if it takes place.’ Iran’s President Hassan Rouhani has also stated unequivocally on live television that ‘regarding the holy Shia shines in Karbala, Najaf, Khadhimiya and Samarra, we announce to the killers and terrorists that the big Iranian nation will not hesitate to protect holy shrines’.Understanding sacred geography in conflictThe explicit threat against the sacred geography of Najaf and Karbala has the potential to escalate the crisis in Iraq from a domestic to transnational conflict, drawing in fighters from around the world. For this reason, there should be a greater attempt to understand how sacred geography can transform the stakes of armed conflict.In 2001, UN General Assembly Resolution 55/254 called upon states to ‘exert their utmost efforts to ensure that religious sites are fully respected and protected’ and ‘adopt adequate measures aimed at preventing […] acts or threats of violence’. Just what these ‘adequate measures’ should be remains unclear. Armed forces across the world often need to operate in religious sites but at the risk of undermining long-term relations with the local population; and those making the calculations are often unaware of the repercussions.This is not to assert that sacred geography is the only factor to look at when assessing militant mobilization in Iraq and elsewhere. Nevertheless, incorporating a less secular lens for analysing international security would be useful and working through the practical implications of the UN resolution – and setting firmer guidelines − should therefore become a priority.To comment on this article, please contact Chatham House Feedback Full Article
red Multivalent feedback regulation of HMG CoA reductase, a control mechanism coordinating isoprenoid synthesis and cell growth By feedproxy.google.com Published On :: 1980-07-01 MS BrownJul 1, 1980; 21:505-517Reviews Full Article
red Marked reduction in bile acid synthesis in cholesterol 7{alpha}-hydroxylase-deficient mice does not lead to diminished tissue cholesterol turnover or to hypercholesterolemia By feedproxy.google.com Published On :: 1998-09-01 Margrit SchwarzSep 1, 1998; 39:1833-1843Articles Full Article
red Procedure for determination of free and total cholesterol in micro- or nanogram amounts suitable for studies with cultured cells By feedproxy.google.com Published On :: 1978-11-01 W GambleNov 1, 1978; 19:1068-1070Articles Full Article
red Regulation of hepatic secretion of apolipoprotein B-containing lipoproteins: information obtained from cultured liver cells By feedproxy.google.com Published On :: 1993-02-01 JL DixonFeb 1, 1993; 34:167-179Reviews Full Article
red Chatham House Forum: Are Humans Psychologically Wired to Fight? By feedproxy.google.com Published On :: Tue, 05 Jun 2018 00:00:00 +0100 Full Article
red Red Flags: The Outlook for Xi Jinping's China By feedproxy.google.com Published On :: Wed, 12 Sep 2018 00:00:00 +0100 Full Article
red Restraining Great Powers: Soft Balancing Strategies Reconsidered By feedproxy.google.com Published On :: Tue, 15 Jan 2019 00:00:00 +0000 Full Article
red Ukraine's Unpredictable Presidential Elections By feedproxy.google.com Published On :: Tue, 30 Apr 2019 00:00:00 +0100 Full Article
red Our Shared Humanity: In Larger Freedom By feedproxy.google.com Published On :: Mon, 03 Jun 2019 00:00:00 +0100 Full Article
red Our Shared Humanity: Welcome and Panel One - The Arc of Intervention By feedproxy.google.com Published On :: Mon, 03 Jun 2019 00:00:00 +0100 Full Article
red Our Shared Humanity: Cool and Reasoned Judgement By feedproxy.google.com Published On :: Mon, 03 Jun 2019 00:00:00 +0100 Full Article
red Our Shared Humanity: Looking Forward By feedproxy.google.com Published On :: Tue, 04 Jun 2019 00:00:00 +0100 Full Article
red Our Shared Humanity: We the Peoples By feedproxy.google.com Published On :: Tue, 04 Jun 2019 00:00:00 +0100 Full Article
red Our Shared Humanity: The Fork in the Road By feedproxy.google.com Published On :: Tue, 04 Jun 2019 00:00:00 +0100 Full Article
red Our Shared Humanity: Governance, Youth and Leadership By feedproxy.google.com Published On :: Tue, 04 Jun 2019 00:00:00 +0100 Full Article
red Our Shared Humanity: Global Market, Global Values By feedproxy.google.com Published On :: Tue, 04 Jun 2019 00:00:00 +0100 Full Article
red Phosphotyrosine-based Phosphoproteomics for Target Identification and Drug Response Prediction in AML Cell Lines [Research] By feedproxy.google.com Published On :: 2020-05-01T00:05:26-07:00 Acute myeloid leukemia (AML) is a clonal disorder arising from hematopoietic myeloid progenitors. Aberrantly activated tyrosine kinases (TK) are involved in leukemogenesis and are associated with poor treatment outcome. Kinase inhibitor (KI) treatment has shown promise in improving patient outcome in AML. However, inhibitor selection for patients is suboptimal. In a preclinical effort to address KI selection, we analyzed a panel of 16 AML cell lines using phosphotyrosine (pY) enrichment-based, label-free phosphoproteomics. The Integrative Inferred Kinase Activity (INKA) algorithm was used to identify hyperphosphorylated, active kinases as candidates for KI treatment, and efficacy of selected KIs was tested. Heterogeneous signaling was observed with between 241 and 2764 phosphopeptides detected per cell line. Of 4853 identified phosphopeptides with 4229 phosphosites, 4459 phosphopeptides (4430 pY) were linked to 3605 class I sites (3525 pY). INKA analysis in single cell lines successfully pinpointed driver kinases (PDGFRA, JAK2, KIT and FLT3) corresponding with activating mutations present in these cell lines. Furthermore, potential receptor tyrosine kinase (RTK) drivers, undetected by standard molecular analyses, were identified in four cell lines (FGFR1 in KG-1 and KG-1a, PDGFRA in Kasumi-3, and FLT3 in MM6). These cell lines proved highly sensitive to specific KIs. Six AML cell lines without a clear RTK driver showed evidence of MAPK1/3 activation, indicative of the presence of activating upstream RAS mutations. Importantly, FLT3 phosphorylation was demonstrated in two clinical AML samples with a FLT3 internal tandem duplication (ITD) mutation. Our data show the potential of pY-phosphoproteomics and INKA analysis to provide insight in AML TK signaling and identify hyperactive kinases as potential targets for treatment in AML cell lines. These results warrant future investigation of clinical samples to further our understanding of TK phosphorylation in relation to clinical response in the individual patient. Full Article
red Discovery of a Redox Thiol Switch: Implications for Cellular Energy Metabolism [Research] By feedproxy.google.com Published On :: 2020-05-01T00:05:26-07:00 The redox-based modifications of cysteine residues in proteins regulate their function in many biological processes. The gas molecule H2S has been shown to persulfidate redox sensitive cysteine residues resulting in an H2S-modified proteome known as the sulfhydrome. Tandem Mass Tags (TMT) multiplexing strategies for large-scale proteomic analyses have become increasingly prevalent in detecting cysteine modifications. Here we developed a TMT-based proteomics approach for selectively trapping and tagging cysteine persulfides in the cellular proteomes. We revealed the natural protein sulfhydrome of two human cell lines, and identified insulin as a novel substrate in pancreatic beta cells. Moreover, we showed that under oxidative stress conditions, increased H2S can target enzymes involved in energy metabolism by switching specific cysteine modifications to persulfides. Specifically, we discovered a Redox Thiol Switch, from protein S-glutathioinylation to S-persulfidation (RTSGS). We propose that the RTSGS from S-glutathioinylation to S-persulfidation is a potential mechanism to fine tune cellular energy metabolism in response to different levels of oxidative stress. Full Article
red Delineating an extracellular redox-sensitive module in T-type Ca2+ channels [Membrane Biology] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 T-type (Cav3) Ca2+ channels are important regulators of excitability and rhythmic activity of excitable cells. Among other voltage-gated Ca2+ channels, Cav3 channels are uniquely sensitive to oxidation and zinc. Using recombinant protein expression in HEK293 cells, patch clamp electrophysiology, site-directed mutagenesis, and homology modeling, we report here that modulation of Cav3.2 by redox agents and zinc is mediated by a unique extracellular module containing a high-affinity metal-binding site formed by the extracellular IS1–IS2 and IS3–IS4 loops of domain I and a cluster of extracellular cysteines in the IS1–IS2 loop. Patch clamp recording of recombinant Cav3.2 currents revealed that two cysteine-modifying agents, sodium (2-sulfonatoethyl) methanethiosulfonate (MTSES) and N-ethylmaleimide, as well as a reactive oxygen species–producing neuropeptide, substance P (SP), inhibit Cav3.2 current to similar degrees and that this inhibition is reversed by a reducing agent and a zinc chelator. Pre-application of MTSES prevented further SP-mediated current inhibition. Substitution of the zinc-binding residue His191 in Cav3.2 reduced the channel's sensitivity to MTSES, and introduction of the corresponding histidine into Cav3.1 sensitized it to MTSES. Removal of extracellular cysteines from the IS1–IS2 loop of Cav3.2 reduced its sensitivity to MTSES and SP. We hypothesize that oxidative modification of IS1–IS2 loop cysteines induces allosteric changes in the zinc-binding site of Cav3.2 so that it becomes sensitive to ambient zinc. Full Article