sig Endorepellin evokes an angiostatic stress signaling cascade in endothelial cells [Glycobiology and Extracellular Matrices] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Endorepellin, the C-terminal fragment of the heparan sulfate proteoglycan perlecan, influences various signaling pathways in endothelial cells by binding to VEGFR2. In this study, we discovered that soluble endorepellin activates the canonical stress signaling pathway consisting of PERK, eIF2α, ATF4, and GADD45α. Specifically, endorepellin evoked transient activation of VEGFR2, which, in turn, phosphorylated PERK at Thr980. Subsequently, PERK phosphorylated eIF2α at Ser51, upregulating its downstream effector proteins ATF4 and GADD45α. RNAi-mediated knockdown of PERK or eIF2α abrogated the endorepellin-mediated up-regulation of GADD45α, the ultimate effector protein of this stress signaling cascade. To functionally validate these findings, we utilized an ex vivo model of angiogenesis. Exposure of the aortic rings embedded in 3D fibrillar collagen to recombinant endorepellin for 2–4 h activated PERK and induced GADD45α vis à vis vehicle-treated counterparts. Similar effects were obtained with the established cellular stress inducer tunicamycin. Notably, chronic exposure of aortic rings to endorepellin for 7–9 days markedly suppressed vessel sprouting, an angiostatic effect that was rescued by blocking PERK kinase activity. Our findings unravel a mechanism by which an extracellular matrix protein evokes stress signaling in endothelial cells, which leads to angiostasis. Full Article
sig Structural insight into the recognition of pathogen-derived phosphoglycolipids by C-type lectin receptor DCAR [Protein Structure and Folding] By feedproxy.google.com Published On :: 2020-04-24T06:08:45-07:00 The C-type lectin receptors (CLRs) form a family of pattern recognition receptors that recognize numerous pathogens, such as bacteria and fungi, and trigger innate immune responses. The extracellular carbohydrate-recognition domain (CRD) of CLRs forms a globular structure that can coordinate a Ca2+ ion, allowing receptor interactions with sugar-containing ligands. Although well-conserved, the CRD fold can also display differences that directly affect the specificity of the receptors for their ligands. Here, we report crystal structures at 1.8–2.3 Å resolutions of the CRD of murine dendritic cell-immunoactivating receptor (DCAR, or Clec4b1), the CLR that binds phosphoglycolipids such as acylated phosphatidyl-myo-inositol mannosides (AcPIMs) of mycobacteria. Using mutagenesis analysis, we identified critical residues, Ala136 and Gln198, on the surface surrounding the ligand-binding site of DCAR, as well as an atypical Ca2+-binding motif (Glu-Pro-Ser/EPS168–170). By chemically synthesizing a water-soluble ligand analog, inositol-monophosphate dimannose (IPM2), we confirmed the direct interaction of DCAR with the polar moiety of AcPIMs by biolayer interferometry and co-crystallization approaches. We also observed a hydrophobic groove extending from the ligand-binding site that is in a suitable position to interact with the lipid portion of whole AcPIMs. These results suggest that the hydroxyl group-binding ability and hydrophobic groove of DCAR mediate its specific binding to pathogen-derived phosphoglycolipids such as mycobacterial AcPIMs. Full Article
sig Structural basis of cell-surface signaling by a conserved sigma regulator in Gram-negative bacteria [Molecular Biophysics] By feedproxy.google.com Published On :: 2020-04-24T06:08:45-07:00 Cell-surface signaling (CSS) in Gram-negative bacteria involves highly conserved regulatory pathways that optimize gene expression by transducing extracellular environmental signals to the cytoplasm via inner-membrane sigma regulators. The molecular details of ferric siderophore-mediated activation of the iron import machinery through a sigma regulator are unclear. Here, we present the 1.56 Å resolution structure of the periplasmic complex of the C-terminal CSS domain (CCSSD) of PupR, the sigma regulator in the Pseudomonas capeferrum pseudobactin BN7/8 transport system, and the N-terminal signaling domain (NTSD) of PupB, an outer-membrane TonB-dependent transducer. The structure revealed that the CCSSD consists of two subdomains: a juxta-membrane subdomain, which has a novel all-β-fold, followed by a secretin/TonB, short N-terminal subdomain at the C terminus of the CCSSD, a previously unobserved topological arrangement of this domain. Using affinity pulldown assays, isothermal titration calorimetry, and thermal denaturation CD spectroscopy, we show that both subdomains are required for binding the NTSD with micromolar affinity and that NTSD binding improves CCSSD stability. Our findings prompt us to present a revised model of CSS wherein the CCSSD:NTSD complex forms prior to ferric-siderophore binding. Upon siderophore binding, conformational changes in the CCSSD enable regulated intramembrane proteolysis of the sigma regulator, ultimately resulting in transcriptional regulation. Full Article
sig Correction: Rational design, synthesis, and evaluation of uncharged, “smart” bis-oxime antidotes of organophosphate-inhibited human acetylcholinesterase. [Additions and Corrections] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 VOLUME 295 (2020) PAGES 4079–4092There was an error in the abstract. “The pyridinium cation hampers uptake of OPs into the central nervous system (CNS)” should read as “The pyridinium cation hampers uptake into the central nervous system (CNS).” Full Article
sig 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
sig Broadtail Designs hosts ‘Curvy in Quarantine’ Yoga Live on IG By jamaica-gleaner.com Published On :: Fri, 17 Apr 2020 00:11:12 -0500 COVID-19 has completely readjusted how we operate daily. With the proliferation of the ‘work from home’ concept, many persons have become even more stationary as they spend full days on their couches, tapping on their communication devices while... Full Article
sig Tacrolimus-Induced BMP/SMAD Signaling Associates With Metabolic Stress-Activated FOXO1 to Trigger {beta}-Cell Failure By diabetes.diabetesjournals.org Published On :: 2020-01-20T12:00:26-08:00 Active maintenance of β-cell identity through fine-tuned regulation of key transcription factors ensures β-cell function. Tacrolimus, a widely used immunosuppressant, accelerates onset of diabetes after organ transplantation, but underlying molecular mechanisms are unclear. Here we show that tacrolimus induces loss of human β-cell maturity and β-cell failure through activation of the BMP/SMAD signaling pathway when administered under mild metabolic stress conditions. Tacrolimus-induced phosphorylated SMAD1/5 acts in synergy with metabolic stress–activated FOXO1 through formation of a complex. This interaction is associated with reduced expression of the key β-cell transcription factor MAFA and abolished insulin secretion, both in vitro in primary human islets and in vivo in human islets transplanted into high-fat diet–fed mice. Pharmacological inhibition of BMP signaling protects human β-cells from tacrolimus-induced β-cell dysfunction in vitro. Furthermore, we confirm that BMP/SMAD signaling is activated in protocol pancreas allograft biopsies from recipients on tacrolimus. To conclude, we propose a novel mechanism underlying the diabetogenicity of tacrolimus in primary human β-cells. This insight could lead to new treatment strategies for new-onset diabetes and may have implications for other forms of diabetes. Full Article
sig HB-EGF Signaling Is Required for Glucose-Induced Pancreatic {beta}-Cell Proliferation in Rats By diabetes.diabetesjournals.org Published On :: 2020-02-20T11:55:30-08:00 The molecular mechanisms of β-cell compensation to metabolic stress are poorly understood. We previously observed that nutrient-induced β-cell proliferation in rats is dependent on epidermal growth factor receptor (EGFR) signaling. The aim of this study was to determine the role of the EGFR ligand heparin-binding EGF-like growth factor (HB-EGF) in the β-cell proliferative response to glucose, a β-cell mitogen and key regulator of β-cell mass in response to increased insulin demand. We show that exposure of isolated rat and human islets to HB-EGF stimulates β-cell proliferation. In rat islets, inhibition of EGFR or HB-EGF blocks the proliferative response not only to HB-EGF but also to glucose. Furthermore, knockdown of HB-EGF in rat islets blocks β-cell proliferation in response to glucose ex vivo and in vivo in transplanted glucose-infused rats. Mechanistically, we demonstrate that HB-EGF mRNA levels are increased in β-cells in response to glucose in a carbohydrate-response element–binding protein (ChREBP)–dependent manner. In addition, chromatin immunoprecipitation studies identified ChREBP binding sites in proximity to the HB-EGF gene. Finally, inhibition of Src family kinases, known to be involved in HB-EGF processing, abrogated glucose-induced β-cell proliferation. Our findings identify a novel glucose/HB-EGF/EGFR axis implicated in β-cell compensation to increased metabolic demand. Full Article
sig Ramdin among new Patriots signings By jamaica-gleaner.com Published On :: Wed, 06 May 2020 23:06:19 -0500 BASSETERRE, St Kitts (CMC): ST KITTS AND Nevis Patriots have made some significant changes to their line-up for the upcoming Caribbean Premier League (CPL) season. Captain Carlos Brathwaite has gone to the Jamaica Tallawahs, while the Patriots have... Full Article
sig Signals from the NIHR By feeds.bmj.com Published On :: Thu, 07 Mar 2019 18:02:07 +0000 If you've been keeping up to day with The BMJ - online on in print, you might have noticed that we've got a new type of article - NIHR Signals - and they are here to give busy clinicians a quick overview of practice changing research that has come out of the UK's National Institute for Health Research. Tara Lamont, director of the NIHR... Full Article
sig Are the {beta}-Cell Signaling Molecules Malonyl-CoA and Cystolic Long-Chain Acyl-CoA Implicated in Multiple Tissue Defects of Obesity and NIDDM? By diabetes.diabetesjournals.org Published On :: 1996-03-01 Marc PrentkiMar 1, 1996; 45:273-283Original Article Full Article
sig Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade By diabetes.diabetesjournals.org Published On :: 1999-06-01 ME GriffinJun 1, 1999; 48:1270-1274Articles Full Article
sig De Novo Mutations in EIF2B1 Affecting eIF2 Signaling Cause Neonatal/Early-Onset Diabetes and Transient Hepatic Dysfunction By diabetes.diabetesjournals.org Published On :: 2020-02-20T11:55:30-08:00 Permanent neonatal diabetes mellitus (PNDM) is caused by reduced β-cell number or impaired β-cell function. Understanding of the genetic basis of this disorder highlights fundamental β-cell mechanisms. We performed trio genome sequencing for 44 patients with PNDM and their unaffected parents to identify causative de novo variants. Replication studies were performed in 188 patients diagnosed with diabetes before 2 years of age without a genetic diagnosis. EIF2B1 (encoding the eIF2B complex α subunit) was the only gene with novel de novo variants (all missense) in at least three patients. Replication studies identified two further patients with de novo EIF2B1 variants. In addition to having diabetes, four of five patients had hepatitis-like episodes in childhood. The EIF2B1 de novo mutations were found to map to the same protein surface. We propose that these variants render the eIF2B complex insensitive to eIF2 phosphorylation, which occurs under stress conditions and triggers expression of stress response genes. Failure of eIF2B to sense eIF2 phosphorylation likely leads to unregulated unfolded protein response and cell death. Our results establish de novo EIF2B1 mutations as a novel cause of permanent diabetes and liver dysfunction. These findings confirm the importance of cell stress regulation for β-cells and highlight EIF2B1’s fundamental role within this pathway. Full Article
sig Longitudinal Metabolome-Wide Signals Prior to the Appearance of a First Islet Autoantibody in Children Participating in the TEDDY Study By diabetes.diabetesjournals.org Published On :: 2020-02-20T11:55:30-08:00 Children at increased genetic risk for type 1 diabetes (T1D) after environmental exposures may develop pancreatic islet autoantibodies (IA) at a very young age. Metabolic profile changes over time may imply responses to exposures and signal development of the first IA. Our present research in The Environmental Determinants of Diabetes in the Young (TEDDY) study aimed to identify metabolome-wide signals preceding the first IA against GAD (GADA-first) or against insulin (IAA-first). We profiled metabolomes by mass spectrometry from children’s plasma at 3-month intervals after birth until appearance of the first IA. A trajectory analysis discovered each first IA preceded by reduced amino acid proline and branched-chain amino acids (BCAAs), respectively. With independent time point analysis following birth, we discovered dehydroascorbic acid (DHAA) contributing to the risk of each first IA, and -aminobutyric acid (GABAs) associated with the first autoantibody against insulin (IAA-first). Methionine and alanine, compounds produced in BCAA metabolism and fatty acids, also preceded IA at different time points. Unsaturated triglycerides and phosphatidylethanolamines decreased in abundance before appearance of either autoantibody. Our findings suggest that IAA-first and GADA-first are heralded by different patterns of DHAA, GABA, multiple amino acids, and fatty acids, which may be important to primary prevention of T1D. Full Article
sig L-Cell Differentiation Is Induced by Bile Acids Through GPBAR1 and Paracrine GLP-1 and Serotonin Signaling By diabetes.diabetesjournals.org Published On :: 2020-03-20T11:50:28-07:00 Glucagon-like peptide 1 (GLP-1) mimetics are effective drugs for treatment of type 2 diabetes, and there is consequently extensive interest in increasing endogenous GLP-1 secretion and L-cell abundance. Here we identify G-protein–coupled bile acid receptor 1 (GPBAR1) as a selective regulator of intestinal L-cell differentiation. Lithocholic acid and the synthetic GPBAR1 agonist, L3740, selectively increased L-cell density in mouse and human intestinal organoids and elevated GLP-1 secretory capacity. L3740 induced expression of Gcg and transcription factors Ngn3 and NeuroD1. L3740 also increased the L-cell number and GLP-1 levels and improved glucose tolerance in vivo. Further mechanistic examination revealed that the effect of L3740 on L cells required intact GLP-1 receptor and serotonin 5-hydroxytryptamine receptor 4 (5-HT4) signaling. Importantly, serotonin signaling through 5-HT4 mimicked the effects of L3740, acting downstream of GLP-1. Thus, GPBAR1 agonists and other powerful GLP-1 secretagogues facilitate L-cell differentiation through a paracrine GLP-1–dependent and serotonin-mediated mechanism. Full Article
sig Inhibition of NFAT Signaling Restores Microvascular Endothelial Function in Diabetic Mice By diabetes.diabetesjournals.org Published On :: 2020-02-20T11:55:30-08:00 Central to the development of diabetic macro- and microvascular disease is endothelial dysfunction, which appears well before any clinical sign but, importantly, is potentially reversible. We previously demonstrated that hyperglycemia activates nuclear factor of activated T cells (NFAT) in conduit and medium-sized resistance arteries and that NFAT blockade abolishes diabetes-driven aggravation of atherosclerosis. In this study, we test whether NFAT plays a role in the development of endothelial dysfunction in diabetes. NFAT-dependent transcriptional activity was elevated in skin microvessels of diabetic Akita (Ins2+/–) mice when compared with nondiabetic littermates. Treatment of diabetic mice with the NFAT blocker A-285222 reduced NFATc3 nuclear accumulation and NFAT-luciferase transcriptional activity in skin microvessels, resulting in improved microvascular function, as assessed by laser Doppler imaging and iontophoresis of acetylcholine and localized heating. This improvement was abolished by pretreatment with the nitric oxide (NO) synthase inhibitor l-NG-nitro-l-arginine methyl ester, while iontophoresis of the NO donor sodium nitroprusside eliminated the observed differences. A-285222 treatment enhanced dermis endothelial NO synthase expression and plasma NO levels of diabetic mice. It also prevented induction of inflammatory cytokines interleukin-6 and osteopontin, lowered plasma endothelin-1 and blood pressure, and improved mouse survival without affecting blood glucose. In vivo inhibition of NFAT may represent a novel therapeutic modality to preserve endothelial function in diabetes. Full Article
sig {beta}-Cell Stress Shapes CTL Immune Recognition of Preproinsulin Signal Peptide by Posttranscriptional Regulation of Endoplasmic Reticulum Aminopeptidase 1 By diabetes.diabetesjournals.org Published On :: 2020-03-20T11:50:28-07:00 The signal peptide of preproinsulin is a major source for HLA class I autoantigen epitopes implicated in CD8 T cell (CTL)–mediated β-cell destruction in type 1 diabetes (T1D). Among them, the 10-mer epitope located at the C-terminal end of the signal peptide was found to be the most prevalent in patients with recent-onset T1D. While the combined action of signal peptide peptidase and endoplasmic reticulum (ER) aminopeptidase 1 (ERAP1) is required for processing of the signal peptide, the mechanisms controlling signal peptide trimming and the contribution of the T1D inflammatory milieu on these mechanisms are unknown. Here, we show in human β-cells that ER stress regulates ERAP1 gene expression at posttranscriptional level via the IRE1α/miR-17-5p axis and demonstrate that inhibition of the IRE1α activity impairs processing of preproinsulin signal peptide antigen and its recognition by specific autoreactive CTLs during inflammation. These results underscore the impact of ER stress in the increased visibility of β-cells to the immune system and position the IRE1α/miR-17 pathway as a central component in β-cell destruction processes and as a potential target for the treatment of autoimmune T1D. Full Article
sig Artificial intelligence versus clinicians: systematic review of design, reporting standards, and claims of deep learning studies By feeds.bmj.com Published On :: Wednesday, March 25, 2020 - 22:30 Full Article
sig To address AML oversight, BOJ creates sandbox for fintech applicants By jamaica-gleaner.com Published On :: Thu, 07 May 2020 15:55:34 -0500 FOUR MORE applicants are vying to provide mobile payment services in various formats, including one applicant seeking to use phone credit as a cash equivalent, but successful applicants will fall under a new framework the regulator calls its “... Full Article
sig Energy and Displacement in Eight Objects: Insights from Sub-Saharan Africa By feedproxy.google.com Published On :: Mon, 04 Nov 2019 15:27:35 +0000 5 November 2019 This ethnographic study is the first of its kind to analyse energy access and resilience strategies deployed in two refugee camps in Kenya and Burkina Faso. It highlights the need for new methodological approaches to expand the evidence base for humanitarian energy interventions and policies. Read online Download PDF Owen Grafham Manager, Energy, Environment and Resources Programme Glada Lahn Senior Research Fellow, Energy, Environment and Resources Programme @Glada_Lahn Jamie Cross Senior Lecturer in Social Anthropology, University of Edinburgh Megan Douglas PhD Candidate in International Development, University of Edinburgh Craig Martin Reader in Design, University of Edinburgh. Charlotte Ray Research Associate, University of Loughborough Arno Verhoeven Lecturer in Design, University of Edinburgh L1050878-Modifica.jpg Portable battery connected to a solar PV and used to recharge mobile phones and power a radio in Goudoubo Refugee camp (Burkina Faso). Photo: Edoardo Santangelo In recent years, clean energy access for refugees and internally displaced people has emerged as a potential method of improving humanitarian outcomes and enabling self-reliance. While recent research emphasizes the need for more quantitative data to inform energy access interventions, better qualitative understanding would also improve innovation in this area.This ethnographic study is the first of its kind to analyse energy access and resilience strategies deployed in two refugee camps, Kakuma in Kenya and Goudoubo in Burkina Faso. The stories of residents in these camps demonstrate the importance of considering everyday experiences of displaced people in developing sustainable humanitarian energy interventions.This paper highlights the need for new methodological approaches to expand the evidence base for humanitarian energy interventions and policies. Future research could usefully inform humanitarian energy projects by examining the technical knowledge and existing practices of refugees in the design of energy technologies, systems and business models. Uptake and sustained use of new systems may be more likely where interventions build on or work in harmony with these factors. Department/project Energy, Environment and Resources Programme, Moving Energy Initiative Full Article
sig Doctor alleged to have performed “designer vagina” surgery won’t be prosecuted By feeds.bmj.com Published On :: Monday, November 28, 2016 - 10:46 Full Article
sig African Countries Relax Short-Term Visa Policies for Chinese in Sign of Increased Openness to China By www.migrationpolicy.org Published On :: Wed, 31 Jul 2019 18:14:34 -0400 China has been Africa’s largest trading partner since 2009, and as commerce and investment have increased, so have flows of people in both directions. With an estimated 1 million to 2 million Chinese migrants across Africa, some countries have relaxed their short-term visa requirements in hopes of facilitating cultural and business exchanges. High levels of Chinese investment do not, however, correlate with more liberal visa policies, as this article explores. Full Article
sig Signs Your COVID-19 Anxiety Has Become Unhealthy, and What to Do By feeds.socialpsychology.org Published On :: 2020-05-05T02:40:13-04:00 Source: CNN - HealthAs the coronavirus pandemic drags on, experts fear that some of us may begin to lose our ability to cope with the anxiety and stress. Here are five signs that coronavirus anxiety is becoming unhealthy, and tips on how to reduce it. Full Article
sig Dallas Cowboys sign former first-round pick Cameron Erving By www.upi.com Published On :: Wed, 06 May 2020 19:14:49 -0400 The Dallas Cowboys agreed to terms with free-agent offensive lineman Cameron Erving, the team announced Wednesday. Full Article
sig Redesigning Primary Care to Improve Diabetes Outcomes (the UNITED Study) By care.diabetesjournals.org Published On :: 2020-02-20T11:55:29-08:00 OBJECTIVE The effective redesign of primary care delivery systems to improve diabetes care requires an understanding of which particular components of delivery consistently lead to better clinical outcomes. We identified associations between common systems of care management (SysCMs) and the frequency of meeting standardized performance targets for Optimal Diabetes Care (NQF#0729) in primary care practices. RESEARCH DESIGN AND METHODS A validated survey of 585 eligible family or general internal medicine practices seeing ≥30 adult patients with diabetes in or near Minnesota during 2017 evaluated the presence of 62 SysCMs. From 419 (72%) practices completing the survey, NQF#0729 was determined in 396 (95%) from electronic health records, including 215,842 patients with type 1 or type 2 diabetes. RESULTS Three SysCMs were associated with higher rates of meeting performance targets across all practices: 1) a systematic process for shared decision making with patients (P = 0.001), 2) checklists of tests or interventions needed for prevention or monitoring of diabetes (P = 0.002), and 3) physician reminders of guideline-based age-appropriate risk assessments due at the patient visit (P = 0.002). When all three were in place, an additional 10.8% of the population achieved recommended performance measures. In subgroup analysis, 15 additional SysCMs were associated with better care in particular types of practices. CONCLUSIONS Diabetes care outcomes are better in primary care settings that use a patient-centered approach to systematically engage patients in decision making, remind physicians of age-appropriate risk assessments, and provide checklists for recommended diabetes interventions. Practice size and location are important considerations when redesigning delivery systems to improve performance. Full Article
sig Panthers' Derrick Brown to become first 2020 Round 1 pick to sign rookie deal By www.upi.com Published On :: Fri, 08 May 2020 20:02:40 -0400 Former Auburn defensive tackle Derrick Brown agreed to his rookie contract with the Carolina Panthers on Friday. Full Article
sig Early Signs of Cardiovascular Disease in Youth With Obesity and Type 2 Diabetes By care.diabetesjournals.org Published On :: 2005-05-01 Neslihan GungorMay 1, 2005; 28:1219-1221BR Pathophysiology/Complications Full Article
sig Liraglutide, a Long-Acting Human Glucagon-Like Peptide-1 Analog, Given as Monotherapy Significantly Improves Glycemic Control and Lowers Body Weight Without Risk of Hypoglycemia in Patients With Type 2 Diabetes By care.diabetesjournals.org Published On :: 2007-06-01 Tina VilsbøllJun 1, 2007; 30:1608-1610BR Emerging Treatments and Technologies Full Article
sig Effects of Metformin, Metformin Plus Rosiglitazone, and Metformin Plus Lifestyle on Insulin Sensitivity and {beta}-Cell Function in TODAY By care.diabetesjournals.org Published On :: 2013-06-01 TODAY Study GroupJun 1, 2013; 36:1749-1757TODAY Study Full Article
sig HbA1c Levels Are Significantly Lower in Early and Late Pregnancy By care.diabetesjournals.org Published On :: 2004-05-01 Lene R. NielsenMay 1, 2004; 27:1200-1201Brief Reports Full Article
sig HbA1c Levels Are Significantly Lower in Early and Late Pregnancy By care.diabetesjournals.org Published On :: 2004-05-01 Lene R. NielsenMay 1, 2004; 27:1200-1201Brief Reports Full Article
sig Steroid Metabolomic Signature of Insulin Resistance in Childhood Obesity By care.diabetesjournals.org Published On :: 2020-01-20T12:00:30-08:00 OBJECTIVE On the basis of urinary steroidal gas chromatography-mass spectrometry (GC-MS), we previously defined a novel concept of a disease-specific "steroid metabolomic signature" and reclassified childhood obesity into five groups with distinctive signatures. The objective of the current study was to delineate the steroidal signature of insulin resistance (IR) in obese children. RESEARCH DESIGN AND METHODS Urinary samples of 87 children (44 girls) aged 8.5–17.9 years with obesity (BMI >97th percentile) were quantified for 31 steroid metabolites by GC-MS. Defined as HOMA-IR >95th percentile and fasting glucose-to-insulin ratio >0.3, IR was diagnosed in 20 (of 87 [23%]) of the examined patients. The steroidal fingerprints of subjects with IR were compared with those of obese children without IR (non-IR). The steroidal signature of IR was created from the product of IR – non-IR for each of the 31 steroids. RESULTS IR and non-IR groups of children had comparable mean age (13.7 ± 1.9 and 14.6 ± 2.4 years, respectively) and z score BMI (2.7 ± 0.5 and 2.7 ± 0.5, respectively). The steroidal signature of IR was characterized by high adrenal androgens, glucocorticoids, and mineralocorticoid metabolites; higher 5α-reductase (An/Et) (P = 0.007) and 21-hydroxylase [(THE + THF + αTHF)/PT] activity (P = 0.006); and lower 11βHSD1 [(THF + αTHF)/THE] activity (P = 0.012). CONCLUSIONS The steroidal metabolomic signature of IR in obese children is characterized by enhanced secretion of steroids from all three adrenal pathways. As only the fasciculata and reticularis are stimulated by ACTH, these findings suggest that IR directly affects the adrenals. We suggest a vicious cycle model, whereby glucocorticoids induce IR, which could further stimulate steroidogenesis, even directly. We do not know whether obese children with IR and the new signature may benefit from amelioration of their hyperadrenalism. Full Article
sig ADA Practice Transitions offering promotional trial for dentists who sign up through March 1 By www.ada.org Published On :: Thu, 27 Feb 2020 16:18:00 -0600 ADA Practice Transitions, a service offered by the ADA focused on helping dentists make the process of joining or leaving a practice successful, is offering a free three-month trial. Full Article
sig Prognostic Significance of Long-term HbA1c Variability for All-Cause Mortality in the ACCORD Trial By care.diabetesjournals.org Published On :: 2020-03-30T13:26:58-07:00 OBJECTIVEThe association between high glycemic variability and all-cause mortality has been widely investigated in epidemiological studies but rarely validated in glucose-lowering clinical trials. We aimed to identify the prognostic significance of visit-to-visit HbA1c variability in treated patients in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial population.RESEARCH DESIGN AND METHODSWe studied the risk of all-cause mortality in relation to long-term visit-to-visit HbA1c variability, expressed as coefficient of variation (CV), variability independent of the mean (VIM), and average real variability (ARV), from the 8th month to the transition. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratio (HR) and 95% CI.RESULTSCompared with the standard therapy group (n = 4,728), the intensive therapy group (n = 4,755) had significantly lower mean HbA1c (6.6% [49 mmol/mol] vs. 7.7% [61 mmol/mol], P < 0.0001) and lower CV, VIM, and ARV (P < 0.0001). In multivariate adjusted analysis, all three HbA1c variability indices were significantly associated with total mortality in all patients as well as in the standard- and intensive-therapy groups analyzed separately. The hazard ratios for a 1-SD increase in HbA1c variability indices for the all-cause mortality were 1.19 and 1.23 in intensive and standard therapy, respectively. Cross-tabulation analysis showed the third tertile of HbA1c mean and VIM had significantly higher all-cause mortality (HR 2.05; 95% CI, 1.17–3.61; P < 0.01) only in the intensive-therapy group.CONCLUSIONSLong-term visit-to-visit HbA1c variability was a strong predictor of all-cause mortality. HbA1c VIM combined with HbA1c mean conferred an increased risk for all-cause mortality in the intensive-therapy group. Full Article
sig microRNA-21/PDCD4 Proapoptotic Signaling From Circulating CD34+ Cells to Vascular Endothelial Cells: A Potential Contributor to Adverse Cardiovascular Outcomes in Patients With Critical Limb Ischemia By care.diabetesjournals.org Published On :: 2020-05-01T07:23:01-07:00 OBJECTIVEIn patients with type 2 diabetes (T2D) and critical limb ischemia (CLI), migration of circulating CD34+ cells predicted cardiovascular mortality at 18 months after revascularization. This study aimed to provide long-term validation and mechanistic understanding of the biomarker.RESEARCH DESIGN AND METHODSThe association between CD34+ cell migration and cardiovascular mortality was reassessed at 6 years after revascularization. In a new series of T2D-CLI and control subjects, immuno-sorted bone marrow CD34+ cells were profiled for miRNA expression and assessed for apoptosis and angiogenesis activity. The differentially regulated miRNA-21 and its proapoptotic target, PDCD4, were titrated to verify their contribution in transferring damaging signals from CD34+ cells to endothelial cells.RESULTSMultivariable regression analysis confirmed that CD34+ cell migration forecasts long-term cardiovascular mortality. CD34+ cells from T2D-CLI patients were more apoptotic and less proangiogenic than control subjects and featured miRNA-21 downregulation, modulation of several long noncoding RNAs acting as miRNA-21 sponges, and upregulation of the miRNA-21 proapoptotic target PDCD4. Silencing miR-21 in control subject CD34+ cells phenocopied the T2D-CLI cell behavior. In coculture, T2D-CLI CD34+ cells imprinted naïve endothelial cells, increasing apoptosis, reducing network formation, and modulating the TUG1 sponge/miRNA-21/PDCD4 axis. Silencing PDCD4 or scavenging reactive oxygen species protected endothelial cells from the negative influence of T2D-CLI CD34+ cells.CONCLUSIONSMigration of CD34+ cells predicts long-term cardiovascular mortality in T2D-CLI patients. An altered paracrine signaling conveys antiangiogenic and proapoptotic features from CD34+ cells to the endothelium. This damaging interaction may increase the risk for life-threatening complications. Full Article
sig Do I Have to Sign? By schoolpsychologistfiles.blogspot.com Published On :: Mon, 03 Jan 2011 18:00:00 +0000 Parents are asked to sign paperwork when services begin, when changes are made, and if services end. Let's not stop there. Parents must sign before any assessments begin. Parents must sign that they attended meetings. Parents sign that they received a copy of special education rights. The reasoning is to protect everyone involved. It gives documentation to show who attended the meetings, shows parental consent for what is outlined in the plan, and documents what has occurred at the meeting. Should I sign if I don't agree? You do not have to sign what you do not agree with. That being said- if you attended the meeting, please sign where it says to sign that you attended the meeting. If you received paperwork, please sign that you received it. If you do not agree with the findings or do not agree with the services offered, then do not sign where it asks if you are in agreement. There may also be an area to sign that you do not agree with the findings and you may have an opportunity to write a dissenting opinion.What will happen if I don't sign?In general, the answer is nothing. Literally nothing will happen if you don't sign. Services can not begin until the parent signs. Changes can not take place until the parents sign. Services can not end (in most states) until the parent signs. In most cases if the parent refuses to sign, everything will remain basically the same. Laws vary between states on this issue, so make sure to check your own state laws.Is it okay to think about it overnight before signing?Absolutely. If you aren't sure, take some time to think things over or check in with an advocate. However, please do so in a timely manner, for the sake of everyone involved. What if we do not come to an agreement?There are times when parents and the school system do not agree. Usually, when all parties stop and listen to each other, an agreement can be made that is in the best interest of the child. Remember that schools have very strict guidelines that must be followed and there are restrictions to what a school can do. Think about exactly what it is you disagree with. If you do not agree with the guidelines the school is following, then there is not much that can be done unless you are willing to go through an expensive and drawn out process in court that will still likely amount to no changes. In this case, it would be my best advice to work with the school to determine what can be done for your child within the guidelines. If you disagree because you feel the school is not following state or federal guidelines, there are steps you can take. Start by discussing the area you feel is not being followed with the school or the special education administrator. Usually a resolution can be made by providing a second opinion at the cost of the school system or through the use of a mediator.What is Erin's advice?Try to reach an agreement, where you can feel comfortable signing as quickly as possible. You don't want to leave this open. If you need time to take it in to discuss it and then suggest some changes, that is within your right. However, I do not suggest refusing to sign for long periods of time. Those battles rarely end well for parents, the school, or the child. Full Article IEP Special Education Law
sig "Merit-Based" Immigration: Designing Successful Selection Systems By www.migrationpolicy.org Published On :: Fri, 17 May 2019 16:51:28 -0400 With the U.S. administration calling for the United States to adopt a more “merit-based” immigrant selection system, this conversation focused on what policymakers should consider in designing—and managing—immigrant selection systems in a time of intense labor-market and demographic change. Full Article
sig "Merit-Based" Immigration: Designing Successful Selection Systems By www.migrationpolicy.org Published On :: Thu, 09 May 2019 15:57:37 -0400 MPI and OECD experts discuss what policymakers should consider in designing and managing immigrant selection systems in a time of intense labor-market and demographic change. Full Article
sig Signs of Modern Human Cognition Were Found in an Indonesian Cave By rss.sciam.com Published On :: Fri, 17 Apr 2020 10:45:00 GMT Painted images of intriguing human-animal hybrids are signs of modern thought -- Read more on ScientificAmerican.com Full Article Mind Cognition The Sciences Arts & Culture Evolution
sig Iraq War Naysayers May Have Hindsight Bias By www.washingtonpost.com Published On :: Mon, 02 Oct 2006 00:00:00 EDT Antiwar liberals last week got to savor the four most satisfying words in the English language: "I told you so." Full Article Opinions Iraq War Naysayers May Have Hindsight Bias
sig Deciding Which Road to Take: Insights into How Migrants and Refugees in Greece Plan Onward Movement By www.migrationpolicy.org Published On :: Tue, 21 Aug 2018 16:27:27 -0400 EU policy debates about moving asylum seekers from overburdened frontline countries, such as Greece and Italy, to other Member States rarely consider how migrants form and act on preferences for certain destinations—and how difficult it may be to change these views. This issue brief explores decision-making among migrants in Greece, including how living conditions, jobs, and legal status factor in. Full Article
sig Preparing for the Unknown: Designing Effective Predeparture Orientation for Resettling Refugees By www.migrationpolicy.org Published On :: Tue, 30 Apr 2019 09:28:31 -0400 Refugees encounter a range of challenges after resettlement—from adjusting to a new culture and language, to finding a job. Many resettlement countries invest in predeparture orientation to help refugees develop the knowledge, skills, and attitudes to face these challenges. This report explores the many forms these programs take, highlighting important design questions and key elements that effective programs share. Full Article
sig Microvascular and Cardiovascular Outcomes According to Renal Function in Patients Treated With Once-Weekly Exenatide: Insights From the EXSCEL Trial By care.diabetesjournals.org Published On :: 2020-01-20T12:00:30-08:00 OBJECTIVE To evaluate the impact of once-weekly exenatide (EQW) on microvascular and cardiovascular (CV) outcomes by baseline renal function in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL). RESEARCH DESIGN AND METHODS Least squares mean difference (LSMD) in estimated glomerular filtration rate (eGFR) from baseline between the EQW and placebo groups was calculated for 13,844 participants. Cox regression models were used to estimate effects by group on incident macroalbuminuria, retinopathy, and major adverse CV events (MACE). Interval-censored time-to-event models estimated effects on renal composite 1 (40% eGFR decline, renal replacement, or renal death) and renal composite 2 (composite 1 variables plus macroalbuminuria). RESULTS EQW did not change eGFR significantly (LSMD 0.21 mL/min/1.73 m2 [95% CI –0.27 to 0.70]). Macroalbuminuria occurred in 2.2% of patients in the EQW group and in 2.5% of those in the placebo group (hazard ratio [HR] 0.87 [95% CI 0.70–1.07]). Neither renal composite was reduced with EQW in unadjusted analyses, but renal composite 2 was reduced after adjustment (HR 0.85 [95% CI 0.74–0.98]). Retinopathy rates did not differ by treatment group or in the HbA1c-lowering or prior retinopathy subgroups. CV outcomes in those with eGFR <60 mL/min/1.73 m2 did not differ by group. Those with eGFR ≥60 mL/min/1.73 m2 had nominal risk reductions for MACE, all-cause mortality, and CV death, but interactions by renal function group were significant for only stroke (HR 0.74 [95% CI 0.58–0.93]; P for interaction = 0.035) and CV death (HR 1.08 [95% CI 0.85–1.38]; P for interaction = 0.031). CONCLUSIONS EQW had no impact on unadjusted retinopathy or renal outcomes. CV risk was modestly reduced only in those with eGFR ≥60 mL/min/1.73 m2 in analyses unadjusted for multiplicity. Full Article
sig Confirming the Bidirectional Nature of the Association Between Severe Hypoglycemic and Cardiovascular Events in Type 2 Diabetes: Insights From EXSCEL By care.diabetesjournals.org Published On :: 2020-02-20T11:55:30-08:00 OBJECTIVE We sought to confirm a bidirectional association between severe hypoglycemic events (SHEs) and cardiovascular (CV) event risk and to characterize individuals at dual risk. RESEARCH DESIGN AND METHODS In a post hoc analysis of 14,752 Exenatide Study of Cardiovascular Event Lowering (EXSCEL) participants, we examined time-dependent associations between SHEs and subsequent major adverse cardiac events (CV death, nonfatal myocardial infarction [MI] or stroke), fatal/nonfatal MI, fatal/nonfatal stroke, hospitalization for acute coronary syndrome (hACS), hospitalization for heart failure (hHF), and all-cause mortality (ACM), as well as time-dependent associations between nonfatal CV events and subsequent SHEs. RESULTS SHEs were uncommon and not associated with once-weekly exenatide therapy (hazard ratio 1.13 [95% CI 0.94–1.36], P = 0.179). In fully adjusted models, SHEs were associated with an increased risk of subsequent ACM (1.83 [1.38–2.42], P < 0.001), CV death (1.60 [1.11–2.30], P = 0.012), and hHF (2.09 [1.37–3.17], P = 0.001), while nonfatal MI (2.02 [1.35–3.01], P = 0.001), nonfatal stroke (2.30 [1.25–4.23], P = 0.007), hACS (2.00 [1.39–2.90], P < 0.001), and hHF (3.24 [1.98–5.30], P < 0.001) were all associated with a subsequent increased risk of SHEs. The elevated bidirectional time-dependent hazards linking SHEs and a composite of all CV events were approximately constant over time, with those individuals at dual risk showing higher comorbidity scores compared with those without. CONCLUSIONS These findings, showing greater risk of SHEs after CV events as well as greater risk of CV events after SHEs, validate a bidirectional relationship between CV events and SHEs in patients with high comorbidity scores. Full Article
sig Thinking with AND: Insights from KIND’s story By brandleadership.wordpress.com Published On :: Fri, 24 Jun 2016 16:29:46 +0000 “I’m a confused Mexican Jew.” So says Daniel Lubetzky, Founder and CEO of KIND Snack, in his very personal interview with Columbia faculty member David Rogers at BRITE ’16. Their discussion touched on the many ideas behind KIND Snacks, from the beginnings of the company, to the strategic thinking that forces Lubetzky to stay away […] Full Article *Gabriela Torres Patiño Brand Strategy Brand Value Business Values Consumer Insights Event Leadership Marketing Video
sig No-Failure Design and Disaster Recovery: Lessons from Fukushima By decisions-and-info-gaps.blogspot.com Published On :: Tue, 09 Aug 2011 10:21:00 +0000 One of the striking aspects of the early stages of the nuclear accident at Fukushima-Daiichi last March was the nearly total absence of disaster recovery capability. For instance, while Japan is a super-power of robotic technology, the nuclear authorities had to import robots from France for probing the damaged nuclear plants. Fukushima can teach us an important lesson about technology.The failure of critical technologies can be disastrous. The crash of a civilian airliner can cause hundreds of deaths. The meltdown of a nuclear reactor can release highly toxic isotopes. Failure of flood protection systems can result in vast death and damage. Society therefore insists that critical technologies be designed, operated and maintained to extremely high levels of reliability. We benefit from technology, but we also insist that the designers and operators "do their best" to protect us from their dangers.Industries and government agencies who provide critical technologies almost invariably act in good faith for a range of reasons. Morality dictates responsible behavior, liability legislation establishes sanctions for irresponsible behavior, and economic or political self-interest makes continuous safe operation desirable.The language of performance-optimization − not only doing our best, but also achieving the best − may tend to undermine the successful management of technological danger. A probability of severe failure of one in a million per device per year is exceedingly − and very reassuringly − small. When we honestly believe that we have designed and implemented a technology to have vanishingly small probability of catastrophe, we can honestly ignore the need for disaster recovery.Or can we?Let's contrast this with an ethos that is consistent with a thorough awareness of the potential for adverse surprise. We now acknowledge that our predictions are uncertain, perhaps highly uncertain on some specific points. We attempt to achieve very demanding outcomes − for instance vanishingly small probabilities of catastrophe − but we recognize that our ability to reliably calculate such small probabilities is compromised by the deficiency of our knowledge and understanding. We robustify ourselves against those deficiencies by choosing a design which would be acceptable over a wide range of deviations from our current best understanding. (This is called "robust-satisficing".) Not only does "vanishingly small probability of failure" still entail the possibility of failure, but our predictions of that probability may err.Acknowledging the need for disaster recovery capability (DRC) is awkward and uncomfortable for designers and advocates of a technology. We would much rather believe that DRC is not needed, that we have in fact made catastrophe negligible. But let's not conflate good-faith attempts to deal with complex uncertainties, with guaranteed outcomes based on full knowledge. Our best models are in part wrong, so we robustify against the designer's bounded rationality. But robustness cannot guarantee success. The design and implementation of DRC is a necessary part of the design of any critical technology, and is consistent with the strategy of robust satisficing.One final point: moral hazard and its dilemma. The design of any critical technology entails two distinct and essential elements: failure prevention and disaster recovery. What economists call a `moral hazard' exists since the failure prevention team might rely on the disaster-recovery team, and vice versa. Each team might, at least implicitly, depend on the capabilities of the other team, and thereby relinquish some of its own responsibility. Institutional provisions are needed to manage this conflict.The alleviation of this moral hazard entails a dilemma. Considerations of failure prevention and disaster recovery must be combined in the design process. The design teams must be aware of each other, and even collaborate, because a single coherent system must emerge. But we don't want either team to relinquish any responsibility. On the one hand we want the failure prevention team to work as though there is no disaster recovery, and the disaster recovery team should presume that failures will occur. On the other hand, we want these teams to collaborate on the design.This moral hazard and its dilemma do not obviate the need for both elements of the design. Fukushima has taught us an important lesson by highlighting the special challenge of high-risk critical technologies: design so failure cannot occur, and prepare to respond to the unanticipated. Full Article
sig Six Simple Signs Of A Narcissist (M) By www.spring.org.uk Published On :: Tue, 05 May 2020 15:30:33 +0000 One of the most commonly believed signs of a narcissist is a myth. → Support PsyBlog for just $5 per month. Enables access to articles marked (M) and removes ads. → Explore PsyBlog's ebooks, all written by Dr Jeremy Dean: Accept Yourself: How to feel a profound sense of warmth and self-compassion The Anxiety Plan: 42 Strategies For Worry, Phobias, OCD and Panic Spark: 17 Steps That Will Boost Your Motivation For Anything Activate: How To Find Joy Again By Changing What You Do Full Article Narcissism subscribers-only
sig Feds Plan Fresh Oversight of Texas Special Education Plan By feedproxy.google.com Published On :: Tue, 30 Oct 2018 00:00:00 +0000 The state has developed an extensive plan for fixing a violation of federal special education law, but federal officials want to see additional corrective actions and plan a visit to follow up. Full Article Texas
sig How Teachers' Insights Inform State Policy in Tennessee By feedproxy.google.com Published On :: Thu, 20 Sep 2018 00:00:00 +0000 Teachers in Tennessee have an important voice in shaping state initiatives and policies. Full Article Tennessee
sig New Jersey Education Commissioner Resigns By feedproxy.google.com Published On :: Fri, 02 Sep 2016 00:00:00 +0000 With David Hespe's resignation, announced Friday, New Jersey has had five education commissioners in the last seven years. Full Article New_Jersey
