ration EU–US Cooperation on Tackling Disinformation By feedproxy.google.com Published On :: Tue, 17 Sep 2019 15:23:58 +0000 3 October 2019 Disinformation, as the latest iteration of propaganda suitable for a digitally interconnected world, shows no signs of abating. This paper provides a holistic overview of the current state of play and outlines how EU and US cooperation can mitigate disinformation in the future. Read online Download PDF Sophia Ignatidou Academy Associate, International Security Programme @SophiaIgnatidou LinkedIn 2019-09-19-FakeNews.jpg A congressional staff member displays print outs of social media posts during a hearing before the House Select Intelligence Committee 1 November 2017 in Washington, DC. Photo: Getty Images. EU and US cooperation on tackling disinformation needs to be grounded in an international human rights framework in order to bridge the differences of both parties and include other countries facing this challenge.The disinformation debate needs to be reformulated to cover systemic issues rather than merely technical or security concerns. A lag in regulatory development has led to systemic vulnerabilities. In this context, policymakers need to push for more evidence-based analysis, which is only attainable if technology companies engage in honest debate and allow meaningful access to data – as determined by government appointed researchers rather than the companies themselves – taking into account and respecting users’ privacy.Data governance needs to be the focus of attempts to tackle disinformation. Data’s implications for information, market and power asymmetries, feed into and exacerbate the problem.Policymakers should focus on regulating the distribution of online content rather than the subject matter itself, which may have implications for freedom of speech.Disinformation is mainly the result of inefficient gatekeeping of highly extractive digital companies. The old gatekeepers, journalists and their respective regulators, need to be actively engaged in devising the new regulatory framework.Legacy media need to urgently consider the issue of ‘strategic silence’ and avoid being co-opted by political actors aiming to manipulate the accelerated, reactive news cycle by engaging in divisive ‘clickbait’ rhetoric verging on disinformation and propaganda. When strategic silence is not an option, contextual analysis is fundamental. The EU delegation should assist the coordination of EU–US efforts to tackle disinformation by drawing on the work and expertise at the G7 Rapid Response Mechanism (RRM), the Transatlantic Commission on Election Integrity (TCEI), the European Centre of Excellence for Countering Hybrid Threats (Hybrid CoE), the High-level Panel on Digital Cooperation, and work with the International Telecommunication Union (ITU) to foster a long-term interdisciplinary forum to harness technological innovation to protect and support democracy from threats such as disinformation.The EU and US must avoid rushed regulation that may condone enhanced surveillance or vilify journalism that scrutinizes those in power in the name of security. Department/project International Security Programme, Internet Governance Full Article
ration The Commonwealth Cyber Declaration: Achievements and Way Forward By feedproxy.google.com Published On :: Thu, 23 Jan 2020 11:20:01 +0000 Invitation Only Research Event 4 February 2020 - 9:15am to 5:30pm Chatham House, London Agendapdf | 149.42 KB In April 2018, the Commonwealth Heads of Government Meeting (CHOGM), held in London, saw the creation and the adoption of the Commonwealth Cyber Declaration. The declaration outlines the framework for a concerted effort to advance cybersecurity practices to promote a safe and prosperous cyberspace for Commonwealth citizens, businesses and societies. The conference will aim to provide an overview on the progress made on cybersecurity in the Commonwealth since the declaration was announced in 2018. In addition, it will examine future challenges and potential solutions going forward.This conference is part of the International Security Programme's project on Implementing the Commonwealth Cybersecurity Agenda and will convene a range of senior Commonwealth representatives as well as a selection of civil society and industry stakeholders. This project aims to develop a pan-Commonwealth platform to take the Commonwealth Cyber Declaration forward by means of a holistic, inclusive and representative approach.Please see below meeting summaries from previous events on Cybersecurity in the Commonwealth: A cyberspace that supports economic and social rights online (London)Build the foundations of an effective national cybersecurity response (Barbados)Promote stability in cyberspace through international cooperation (Addis Ababa)Attendance at this event is by invitation only. Department/project International Security Programme Esther Naylor Research Assistant, International Security Programme +44 (0)20 7314 3628 Email Full Article
ration Synergy in North Africa: Furthering Cooperation By feedproxy.google.com Published On :: Mon, 20 Jan 2020 15:57:54 +0000 21 January 2020 Discussions of North African integration have evoked ideas of a shared identity and a common destiny in the region. However, recent attempts to build regional blocs in North Africa have been unsuccessful. This paper examines the benefits of a ‘synergistic’ approach to North African cooperation. Read online Download PDF in English Download PDF in Arabic Dr Mohammed Masbah Associate Fellow, Middle East and North Africa Programme @MasbahMohammed LinkedIn Google Scholar Mohamed El Dahshan Associate Fellow, Middle East and North Africa Programme @eldahshan LinkedIn Google Scholar 2020-01-21-Market.jpg A Tunisian vendor poses as he sells white truffles at a market in the town of Ben Guerdane, 40km west of the Libyan border, in February 2016. Photo: Getty Images. SummaryNorth African integration is not a new idea. However, countries in the region have so far struggled to form a cohesive bloc with deep political, economic and social ties. Political instability has effectively deprioritized North African integration. A focus on thematic (political, economic and security) ‘synergies’ may provide a better framework for cooperation than seeking opportunities for all-encompassing ‘deep’ and ‘comprehensive’ integration.Governments of North Africa dedicate considerable resources to domestic security. Much of their efforts are conducted at the national-level and directed towards threats from terrorists, insurgents and militias. Improved security cooperation would achieve better outcomes and economies of scale, including efforts to tackle human trafficking.A new generation of jihadis has emerged in North Africa since 2011. Nearly 27 per cent of the 30,000 fighters who travelled to Syria are from the Maghreb. While government counterterrorism operations have been effective, countries have failed to address the root causes of radicalization.Border economies have suffered as a consequence of a security focus on terrorism and smuggling, which has rendered many previously accepted cross-border trade activities illegal. States have struggled to provide alternative livelihoods for those who have lost this source of income. Border forces tend to lack the right combination of capacity, training and equipment to secure borders and often resort to heavy-handed tactics.New thinking is required to develop a more human-centric and proactive approach to migration issues in the region, which continues to witness huge flows of migrants. The migration policy of Morocco, introduced through legislation in 2014, could be a model for North Africa.The countries of North Africa have varying economic profiles, ranging from economically diverse Morocco to oil-and-gas-dependant Libya. However, they all face similar challenges including unemployment (particularly among the young), poor public-service delivery, low FDI levels, an oversized public sector, ineffective tax collection, and high informality.Fostering entrepreneurship and the development of small and medium-sized enterprises (SMEs) are priorities for North African countries, particularly regarding job creation. Regulatory cooperation – such as harmonizing SME definitions, legislation and support institutions – across North Africa is an obvious area where further integration would encourage the development of start-ups and small businesses.With the advent of the fourth industrial revolution, North African governments must address their technological gaps and work to improve public–private cooperation. In some sectors, such as the fintech industry, North African countries can build upon nascent synergies that have developed organically, such as those of start-up incubators and angel investors that work across the region.Renewables, particularly solar energy production, are a promising development for North Africa. While regional initiatives, such as Desertec, have stalled due to political differences between countries, the sector has witnessed exponential growth in Tunisia, Egypt and Morocco, where the involvement of the private sector has proved successful. Department/project Middle East and North Africa Programme, North Africa Dialogues Full Article
ration Evidence Against an Important Role of Plasma Insulin and Glucagon Concentrations in the Increase in EGP Caused by SGLT2 Inhibitors By diabetes.diabetesjournals.org Published On :: 2020-03-20T11:50:28-07:00 Sodium–glucose cotransport 2 inhibitors (SGLT2i) lower plasma glucose but stimulate endogenous glucose production (EGP). The current study examined the effect of dapagliflozin on EGP while clamping plasma glucose, insulin, and glucagon concentrations at their fasting level. Thirty-eight patients with type 2 diabetes received an 8-h measurement of EGP ([3-3H]-glucose) on three occasions. After a 3-h tracer equilibration, subjects received 1) dapagliflozin 10 mg (n = 26) or placebo (n = 12); 2) repeat EGP measurement with the plasma glucose concentration clamped at the fasting level; and 3) repeat EGP measurement with inhibition of insulin and glucagon secretion with somatostatin infusion and replacement of basal plasma insulin and glucagon concentrations. In study 1, the change in EGP (baseline to last hour of EGP measurement) in subjects receiving dapagliflozin was 22% greater (+0.66 ± 0.11 mg/kg/min, P < 0.05) than in subjects receiving placebo, and it was associated with a significant increase in plasma glucagon and a decrease in the plasma insulin concentration compared with placebo. Under glucose clamp conditions (study 2), the change in plasma insulin and glucagon concentrations was comparable in subjects receiving dapagliflozin and placebo, yet the difference in EGP between dapagliflozin and placebo persisted (+0.71 ± 0.13 mg/kg/min, P < 0.01). Under pancreatic clamp conditions (study 3), dapagliflozin produced an initial large decrease in EGP (8% below placebo), followed by a progressive increase in EGP that was 10.6% greater than placebo during the last hour. Collectively, these results indicate that 1) the changes in plasma insulin and glucagon concentration after SGLT2i administration are secondary to the decrease in plasma glucose concentration, and 2) the dapagliflozin-induced increase in EGP cannot be explained by the increase in plasma glucagon or decrease in plasma insulin or glucose concentrations. Full Article
ration Will SPECT/CT Cameras soon be able to display Absorbed Doses? Dosimetry from Single Activity Concentration Measurements. By jnm.snmjournals.org Published On :: 2020-01-10T04:59:09-08:00 Full Article
ration Digital Solid-State SPECT/CT Quantitation of Absolute 177Lu-Radiotracer Concentration: In Vivo/In Vitro Validation By jnm.snmjournals.org Published On :: 2020-02-28T13:52:17-08:00 The accuracy of lutetium-177 (177Lu) radiotracer concentration measurements using quantitative clinical software was determined by comparing in vivo results for a digital solid-state cadmium-zinc-telluride SPECT/CT (single photon emission computed tomography / x-ray computed tomography) system to in vitro sampling. First, image acquisition parameters were assessed for an International Electrotechnical Commission (IEC) body phantom emulating clinical count rates loaded with a "lung" insert and 6 hot spheres with a 12:1 target-to-background ratio of 177Lu solution. Then, the data of 28 whole-body SPECT/CT scans of 7 patients who underwent 177Lu prostate membrane antigen (177Lu-PSMA) radioligand therapy was retrospectively analyzed. Three users analyzed SPECT/CT images for in vivo urinary bladder radiotracer uptake using quantitative software (Q.Metrix, GE Healthcare). In vitro radiopharmaceutical concentrations were calculated using urine sampling obtained immediately after each scan, scaled to standardized uptake values (SUVs). Any in vivo/in vitro identity relations were determined by linear regression (ideally slope=1, intercept=0), within a 95 % confidence interval (CI). Phantom results demonstrated lower quantitative error for acquisitions using the 113 keV 177Lu energy peak rather than including the 208 keV peak, given that only low-energy collimation was available in this camera configuration. In the clinical study, 24 in vivo/in vitro pairs were eligible for further analysis, having rejected 4 as outliers (via Cook’s distance calculations). All linear regressions (R2 ≥ 0.92, P<0.0001) provided identity in vivo/in vitro relations (95 % CI), with SUV averages from all users giving a slope of 1.03±0.09, an intercept of –0.25±0.64 g/mL, and an average residual difference of 20.4 %. Acquiring with the lower energy 177Lu energy peak, solid-state SPECT/CT imaging provides an accuracy to within ~20 % for in vivo urinary bladder radiotracer concentrations. This non-invasive in vivo quantitation method can potentially improve diagnosis, improve patient management and treatment response assessment, and provide data essential to 177Lu dosimetry. Full Article
ration Early prostate-specific antigen changes and clinical outcome following 177Lu-PSMA radionuclide treatment in patients with metastatic castration-resistant prostate cancer By jnm.snmjournals.org Published On :: 2020-02-28T13:52:17-08:00 Background: Prostate-specific antigen (PSA) is widely used to monitor treatment response in patients with metastatic castration-resistant prostate cancer (mCRPC). However, PSA measurements are considered only after 12 wk of treatment. We aimed to evaluate the prognostic value of early PSA changes following 177Lu-labelled prostate specific membrane antigen (LuPSMA) radionuclide treatment in mCRPC patients. Methods: Men who were treated under a compassionate access program with LuPSMA at our institution and had available PSA values at baseline, at 6 wk after treatment initiation were included in this retrospective analysis. Patients were assigned to three groups based on PSA changes: 1) response: ≥30% decline, 2) progression: ≥25% increase and 3) stable: <30% decline and <25% increase. The co-primary endpoints were overall survival and imaging-based progression-free survival. The secondary end points were PSA changes at 12 wk and PSA flare-up. Results: We identified 124 eligible patients with PSA values at 6 wk. A ≥30% decline in PSA at 6 wk was associated with longer overall survival (median 16.7 mo; 95%CI 14.4–19.0) compared with patients with stable PSA (median: 11.8 mo; 95%CI 8.6–15.1; P = 0.007) and progression (median: 6.5 mo; 95%CI 5.2–7.8; p<0.001). Patients with ≥30% decline in PSA at 6 wk also had a reduced risk of imaging-based progression compared with patients with stable PSA (HR: 0.60; 95%CI 0.38–0.94; P = 0.02), while patients with PSA progression had a higher risk of imaging-based progression compared with those showing stable PSA (HR: 3.18; 95%CI 1.95–5.21; p<0.001). The percentage changes of PSA at 6 wk and 12 wk were highly associated (r=0.90; p<0.001). 29 of 31 (94%) patients who experienced early PSA progression at 6 wk achieved biochemical progression at 12 wk. Overall, only 1 of 36 (3%) patients with PSA progression at 6 wk achieved any PSA decline at 12 wk (1% of the entire cohort). Limitations of the study included its retrospective nature and the single center experience. Conclusion: PSA changes at 6 wk after LuPSMA initiation are an early indicator of long-term clinical outcome. Patients progressing by PSA after 6 wk of treatment could benefit from a very early treatment switch decision. PSA flare-up during LuPSMA treatment is very uncommon. Prospective studies are now warranted to validate our findings and potentially inform clinicians earlier on the effectiveness of LuPSMA. Full Article
ration Neuroendocrine Differentiation and Response toPSMA-Targeted Radioligand Therapy in Advanced Metastatic Castration-Resistant Prostate Cancer: a Single-Center Retrospective Study By jnm.snmjournals.org Published On :: 2020-03-13T14:12:30-07:00 Introduction: Neuroendocrine differentiation is associated with treatment failure and poor outcome in metastatic castration-resistant prostate cancer (mCRPC). We investigated the effect of circulating neuroendocrine biomarkers on the efficacy of PSMA-targeted radioligand therapy (RLT). Methods: Neuroendocrine biomarker profiles (progastrin-releasing peptide, neuron-specific enolase, and chromogranin-A) were analyzed in 50 patients commencing 177Lu-PSMA-617 RLT. The primary endpoint was PSA response in relation to baseline neuroendocrine marker profiles. Additional endpoints included progression-free survival. Tumor uptake on post-therapeutic scans, a known predictive marker for response, was used as control-variable. Results: Neuroendocrine biomarker profiles were abnormal in the majority of patients. Neuroendocrine biomarker levels did not predict treatment failure or early progression (P ≥ 0.13). By contrast, intense PSMA-ligand uptake in metastases predicted both treatment response (P = 0.0030) and reduced risk of early progression (P = 0.0111). Conclusion: Neuroendocrine marker profiles do not predict adverse outcome of RLT. By contrast, high ligand uptake was confirmed to be crucial for achieving tumor-response. Full Article
ration 177Lu-EB-PSMA radioligand therapy with escalating doses in patients with metastatic castration-resistant prostate cancer By jnm.snmjournals.org Published On :: 2020-05-01T11:16:57-07:00 Purpose: This study is designed to assess the safety and therapeutic response to 177Lu-EB-PSMA treatment with escalating doses in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: With institutional review board approval and informed consent, patients were randomly divided into three groups: Group A (n = 10) were treated with 1.18 ± 0.09 GBq/dose of 177Lu-EB-PSMA. Group B (n = 10) were treated with 2.12 ± 0.19 GBq/dose of 177Lu-EB-PSMA. Group C (n = 8) were treated with 3.52 ± 0.58 GBq/dose of 177Lu-EB-PSMA. Eligible patients received up to three cycles of 177Lu-EB-PSMA therapy, at eight-week intervals. Results: Due to disease progression or bone marrow suppression, 4 out of 10, 5 out of 10, and 5 out of 10 patients completed three cycles therapy as planned in Groups A, B, and C, respectively. The prostate-specific antigen (PSA) response was correlated with treatment dose, with PSA disease control rates in Group B (70%) and C (75%) being higher than that in Group A (10%) (P = 0.007), but no correlation between Group B and Group C was found. 68Ga-PSMA PET/CT showed response in all the treatment groups, however, there was no significant difference between the three groups. Hematologic toxicity study found that platelets in Group B and Group C decreased more than those in Group A, and that Grade 4 thrombocytopenia occurred in 2 (25.0%) patients in Group C. No serious nephritic or hepatic side effects were observed. Conclusion: This study demonstrates that 2.12 GBq/dose of 177Lu-EB-PSMA seems to be safe and adequate in tumor treatment. Further investigations with increased number of patients are warranted. Full Article
ration Time for a Next-Generation Nuclear Medicine Gamma Camera? [NEWSLINE] By jnm.snmjournals.org Published On :: 2020-05-08T13:18:58-07:00 Full Article
ration Mobilizing Multinational Military Operations in Africa: Quick Fixes or Sustainable Solutions? By feedproxy.google.com Published On :: Wed, 16 Oct 2019 09:55:01 +0000 Research Event 25 October 2019 - 9:30am to 11:15am Chatham House | 10 St James's Square | London | SW1Y 4LE Event participants Professor Tony Chafer, University of PortsmouthProfessor Gordon Cumming, Cardiff UniversityDr Roel van der Velde, Cardiff UniversityAhmed Soliman, Research Fellow, Horn of Africa, Chatham HouseDr Elisa Lopez Lucia, Université Libre de Bruxelles; University of PortsmouthChair: Janet Adama Mohammed, West Africa Programme Director, Conciliation Resources Peacekeeping missions which have sought to address evolving forms of conflict and instability on the African continent – led by the United Nations, African Union and European Union – have frequently been overstretched.Across regions including the Sahel, the Horn and West Africa, the issues of violent extremism and criminality – often set against a backdrop of collapsing or severely weakened central states – have led to the mobilisation of a diverse set of new collective responses.These include notable African-led efforts such as AMISOM in Somalia or more recently the G5 Sahel, where France have played a pivotal role in initiating new and more ad hoc approaches to coalition-building.As existing multinational missions in Africa continue to evolve on the ground and while new collective opportunities increasingly present themselves, it is critical for policymakers to understand how far such efforts reflect meaningful long-term solutions to the challenges of conflict and insecurity.At this roundtable event, participants will reflect on how such missions become mobilised and legitimised, the extent to which they can be defined as ‘new’, and whether they represent a truly sustainable means to tackle the issue of conflict in Africa.This roundtable is held in partnership with Cardiff University and the University of Portsmouth and is supported by the Leverhulme Trust. Department/project Africa Programme, West Africa, African Peace and Security, Horn of Africa Fergus Kell Projects Assistant, Africa Programme + 44 (0) 20 7314 3671 Email Full Article
ration Can Liberation Movements Really Rid Southern Africa of Corruption? By feedproxy.google.com Published On :: Mon, 16 Dec 2019 16:20:43 +0000 17 December 2019 Christopher Vandome Research Fellow, Africa Programme LinkedIn Southern Africa’s national liberation movements have survived ‘end of decade’ elections across the region. Combating corruption has been at the heart of many of the campaigns, but the question is can they succeed? 2019-12-16-Namibia-Election.jpg Supporters of the Namibian incumbent president and ruling party South West Africa People's Organisation (SWAPO) presidential candidate Hage Geingob cheer and dance. Photo by GIANLUIGI GUERCIA/AFP via Getty Images. Swapo’s victory in Namibia two weeks ago was the last in a series of recent ‘end of decade’ elections that have returned dominant parties to power across Southern Africa. However, the “enduring appeal of liberation” is wearing thin.Experiences across the region show that if governments are to deliver on their electoral promises, they must empower institutions, actively promote a culture of accountability and transparency within their party ranks and pursue economic reforms that untangle the web of party-state-business alliances. Such actions are critical for the survival of national liberation movements as the dominant force in the politics of Southern Africa – but will be difficult to implement.Avoid political factionalismSouth Africa, Botswana, Angola and Zimbabwe all saw new presidents take over just before elections. All used the rhetoric of anti-corruption to distance themselves from the tainted image of their predecessors. But acting on this requires a shift in mind-set in parties that have always preferred to deal with their problems behind closed doors. High profile adversaries from past regimes make tempting targets but could also drive party divisions.In Angola, the transition of power was safeguarded by an agreement that former president José Eduardo dos Santos would be immune from prosecution. But this week his son faced corruption charges before the country’s supreme court, a high-profile example of a wave of anti-corruption cases across Southern Africa, driven by dominant parties wary of their future.The allegations against José Filemino De Sousa Dos Santos, nickname ‘Zenu’, include a $500-million fraud involving the country’s central bank. Pressure is also mounting on Zenu’s sister Isabel — once prominent in Angola, she is now absent from public life.Other leaders have had to tread more carefully. Immunity was a luxury Cyril Ramaphosa was neither willing nor politically able to grant Jacob Zuma in South Africa. Reliant on a few close allies at the top of the party, Ramaphosa lacks foot soldiers at the grassroots level, and his campaign against corruption within the ANC has faced persistent opposition.Rebuilding institutions and empowering authorities takes time, and with few high-profile cases to point to, people are getting restless. This is also the case in Zimbabwe, where a worsening economic situation has left policy reformers politically isolated.Party, state, and businessLong term incumbency has blurred the distinction between the party and the state. Liberation movements have created vast party-linked business empires. Political allegiance grants access to economic resources through appointments to lucrative positions in state-owned enterprises, preferential bids for tenders and licenses, and direct access to decision makers.In Angola, this was fuelled by oil revenues. In South Africa, state capture flourished in an environment where the ANC and its constituent elements had significant power on the panels that chose leaders for state-owned enterprises (SOEs). In Namibia, an Icelandic fishing company paid backhanders to officials for fishing rights in what has become known as the ‘Fishrot’ scandal. Zanu-PF officials’ access to preferential foreign exchange rates present them with lucrative opportunities in Zimbabwe.Ending this bureaucratic rent seeking goes beyond appointing ‘clean’ officials, which has been central to the anti-corruption campaigns in Angola and South Africa. Governments must also allow scrutiny of the state and empower those institutions designed for that role, such as the National Prosecuting Authority and the Public Protector in South Africa. Zimbabwe’s auditor general has published an in-depth report of the state of corruption in the country’s SOEs.Companies must also be held to account for their role in aiding, and at worst directly benefitting, from state graft. International businesses have actively sought to benefit from corruption. They are now starting to face the consequences. A former Credit Suisse banker has pleaded guilty in the US over handling alleged kickbacks in Mozambique’s $2-billion “tuna bond” scandal. Global banks and consultancies continue to feel the squeeze for their complicity in state capture in South Africa.Competition and pluralismNational liberation movements may only have a limited window within which to act. Across the region civil society campaigns and investigative journalists have shed light on some of the worst abuses of power. Anti-corruption campaigns are starting to bite. The state will continue to play a central role in Southern African economies, an important arbiter of economic transformation able to balance the region’s highly unequal and resource-dependent economies.But opposition, civil society and the media are also critical for the progression towards democratic competition and pluralism in Southern Africa. Parliaments remain vital for holding rulers to account. Long used to unchallenged dominance, liberation movements have significant adjustments to make to rise to the challenge of a new era.This article was originally published in the Mail and Guardian. Full Article
ration Decentralization and Cross-border Integration in the Horn of Africa By feedproxy.google.com Published On :: Mon, 27 Jan 2020 15:10:01 +0000 Research Event 4 February 2020 - 5:00pm to 6:15pm Chatham House | 10 St James's Square | London | SW1Y 4LE Event participants Mohamed Guleid, Chief Executive Officer, Frontier Counties Development CouncilNuradin Dirie, Chair, Puntland Presidential Advisory CouncilAden Abdi, Horn of Africa Programme Director, Conciliation ResourcesChair: Dr Zahbia Yousuf, Senior Research Advisor, Saferworld The interdependence of communities across the Horn of Africa results from social, familial, linguistic and cultural ties that cross territorial borders. Such linkages are reinforced by established patterns of movement and trade, often leading to stronger political and social connections between communities on either side of borders, than with their respective national capitals. States in the region are increasingly being challenged by demands for decentralization and more effective local governance. Improved understanding of the complexity of sub-national and cross-border political and economic contexts will be required to meet these demands and support enhanced governance so that challenges such as marginalization, intercommunal conflict and more equitable sharing of resources can be effectively addressed.At this event, speakers will examine some of the key subnational and cross-border relations in the Horn of Africa. They will also discuss initiatives and stakeholders needed to support common solutions to building peace, furthering development and bolstering inclusive growth and integration. THIS EVENT IS NOW FULL AND REGISTRATION HAS CLOSED. Department/project Africa Programme, African Peace and Security, Foreign Relations and Africa’s Agency in the International System, Horn of Africa Sahar Eljack Programme Administrator, Africa Programme + 44 (0) 20 7314 3660 Email Full Article
ration Concentration Determination of >200 Proteins in Dried Blood Spots for Biomarker Discovery and Validation [Technological Innovation and Resources] By feedproxy.google.com Published On :: 2020-03-01T00:05:26-08:00 The use of protein biomarkers as surrogates for clinical endpoints requires extensive multilevel validation including development of robust and sensitive assays for precise measurement of protein concentration. Multiple reaction monitoring (MRM) is a well-established mass-spectrometric method that can be used for reproducible protein-concentration measurements in biological specimens collected via microsampling. The dried blood spot (DBS) microsampling technique can be performed non-invasively without the expertise of a phlebotomist, and can enhance analyte stability which facilitate the application of this technique in retrospective studies while providing lower storage and shipping costs, because cold-chain logistics can be eliminated. Thus, precise, sensitive, and multiplexed methods for measuring protein concentrations in DBSs can be used for de novo biomarker discovery and for biomarker quantification or verification experiments. To achieve this goal, MRM assays were developed for multiplexed concentration measurement of proteins in DBSs. The lower limit of quantification (LLOQ) was found to have a median total coefficient of variation (CV) of 18% for 245 proteins, whereas the median LLOQ was 5 fmol of peptide injected on column, and the median inter-day CV over 4 days for measuring endogenous protein concentration was 8%. The majority (88%) of the assays displayed parallelism, whereas the peptide standards remained stable throughout the assay workflow and after exposure to multiple freeze-thaw cycles. For 190 proteins, the measured protein concentrations remained stable in DBS stored at ambient laboratory temperature for up to 2 months. Finally, the developed assays were used to measure the concentration ranges for 200 proteins in twenty same sex, same race and age matched individuals. Full Article
ration Integration of IgA and IgG Autoantigens Improves Performance of Biomarker Panels for Early Diagnosis of Lung Cancer [Research] By feedproxy.google.com Published On :: 2020-03-01T00:05:26-08:00 Lung cancer (LC) remains the leading cause of mortality from malignant tumors worldwide. In our previous study, we surveyed both IgG and IgM-bound serological biomarkers and validated a panel of IgG-bound autoantigens for early LC diagnosis with 50% sensitivity at 90% specificity. To further improve the performance of these serological biomarkers, we surveyed HuProt arrays, comprised of 20,240 human proteins, for IgA-bound autoantigens because IgAs are a major immunoglobulin isotype in the lung. Integrating with IgG-bound autoantigens, we discovered and validated a combined biomarker panel using ELISA-format tests. Specifically, in Phase I, we obtained IgA-based autoimmune profiles of 69 early stage LC patients, 30 healthy subjects and 25 patients with lung benign lesions (LBL) on HuProt arrays and identified 28 proteins as candidate autoantigens that were significantly associated with early stage LC. In Phase II, we re-purified the autoantigens and converted them into an ELISA-format testing to profile an additional large cohort, comprised of 136 early stage LC patients, 58 healthy individuals, and 29 LBL patients. Integration of IgG autoimmune profiles allowed us to identify and validate a biomarker panel of three IgA autoantigens (i.e. BCL7A, and TRIM33 and MTERF4) and three IgG autoantigens (i.e. CTAG1A, DDX4 and MAGEC2) for diagnosis of early stage LC with 73.5% sensitivity at >85% specificity. In Phase III, the performance of this biomarker panel was confirmed with an independent cohort, comprised of 88 early stage LC patients, 18 LBL patients, and 36 healthy subjects. Finally, a blind test on 178 serum samples was conducted to confirm the performance of the biomarker panel. In summary, this study demonstrates for the first time that an integrated panel of IgA/IgG autoantigens can serve as valuable biomarkers to further improve the performance of early diagnosis of LC. Full Article
ration The Syrian Pound Signals Economic Deterioration By feedproxy.google.com Published On :: Thu, 26 Sep 2019 11:30:45 +0000 26 September 2019 Zaki Mehchy Senior Consulting Fellow, Middle East and North Africa Programme @mehchy LinkedIn The Syrian pound’s volatile exchange rate over the past month is not a short-term monetary crisis. It reflects the destruction of the economic foundations in Syria. 2019-09-26-SyriaBank.jpg The Syrian Central Bank building in 2008. Photo: Getty Images. The Syrian currency depreciated by 11% between mid-August and the first week of September, to reach an unprecedented level of SYP692 to the US dollar. According to the government, the main reasons behind this collapse are the international sanctions imposed on Syria and currency speculation.Accordingly, the government has forced speculators and local foreign exchange companies to sell the US dollar instead of holding it. Moreover, Syrian security agencies have pressured profiteers with close links to the regime to effectively participate in campaigns that support the local currency. Indeed, the Syrian pound appreciated in value in only a few days to reach an average of SYP615 for $1 in the second week of September.This high volatility in currency prices results in monetary uncertainty among traders, and thus, increases the possibility of other depreciations in the near future.Currency speculation could be the reason behind the high fluctuations. However, the fall in the exchange rate has been a continuous and steady trend ever since the beginning of the conflict. The Syrian currency is about 13 times less valuable than before conflict, and fell by 20% between January and September 2019. It is therefore more likely that the devaluation reflects a structural deterioration of the Syrian economy.There are a number of interlinked reasons behind this trend: Economic collapseThe conflict in Syria has led to a drastic decline in economic activity. By 2018, the total accumulated economic loss was estimated at about $428 billion, which equaled 6 times Syria’s GDP in 2010. The country’s GDP lost about 65% of its value compared to its level before the war. The conflict has also caused a reallocation of resources to destructive and war-related activities. This drop in economic productivity weighs on the Syrian pound’s stability. Dramatic export declineThe total value of Syrian exports contracted from $12.2 billion in 2010 to less than $700 million in 2018, whereas imports declined from $19.7 billion to $4.4 billion during the same period. Thus, the coverage ratio of exports to imports dropped from 62% to 16% in this period, indicating that the government has become very dependent on external trade partners. Almost all import payments are made in foreign currencies, which increases the devaluation pressure on the Syrian pound.Iran has provided the Syrian regime with credit lines estimated at about $6 billion to import oil and consumer goods from the Islamic Republic. These credit lines do not include all the Iranian financial support to the regime. Iranian oil exports to Syria are estimated at about 2 million barrels a month (a total of around $16 billion during the eight years of conflict). The increasing external debt to Iran, also due to military support, may contribute in stabilizing the Syrian pound for short period, yet it is bound to sustain the devaluation pressure in the long run. Damaging monetary policiesSince the beginning of the conflict, the Central Bank of Syria has issued a series of decisions that have contributed to the weakening of the Syrian pound. For instance, until 2015, the bank adopted a policy of selling hard currencies to local foreign exchange companies. This policy depleted their foreign currency reserves by about $1.2 billion, without halting the deterioration of the pound. The bank has also increased the money supply; there is three times the amount of currency in the local market as today compared to before the conflict, causing a surge in inflation and currency devaluation.The absence of foreign direct investmentBetween 2005 and 2010, Syria received an annual average of $1.5 billion as foreign direct investment (FDI); this amount has dropped almost to zero during the years of conflict. Russia and Iran have continued to invest in Syria, mainly in the mining sector, but the conditions of these investments have limited the inflows of foreign currency to Syria. FDI inflows were a major source of hard currency; their absence is an additional driver of currency depreciation.International sanctionsMany countries have imposed sanctions on various sectors in Syria, including energy and financial transactions. During the last two years, the US has tightened its sanctions by introducing the Caesar law, which aims to isolate the Syrian regime. These sanctions have increased the cost of the Syrian imports and therefore raised demand for foreign currencies. Remittances, estimated at $4.5 million per day as well as foreign investments and exports were also negatively affected, and this has reduced the supply side of hard currencies inside Syria.Currency speculationThe Syrian regime usually intervenes to manage currency speculation through government agencies and friendly business entities. But such speculations are very difficult to control in Syria given the poor economic conditions, the high level of business uncertainty and the lack of trust in institutions. This has driven the Syrian households, those who did not already lose their savings, to buy gold or hard currencies as safe investments.The Syrian pound’s depreciation and its high fluctuations reflect the fragile political and economic situation in the country. The government’s improvised decisions have failed to stabilize it, causing a rise in the prices of basic goods. This has left more than 90% of Syria’s population under the poverty line. Long-term stability in exchange rates requires an inclusive and sustainable development strategy, one that would need to be based on an accountable and transparent political landscape. That seems a long way off. Full Article
ration Episode 43 - The Internet of Procedural Generation (IoPG) By play.acast.com Published On :: Fri, 02 Dec 2016 11:25:02 GMT Join host David Price for a dive into all things tech: Round 43. Things go mobile as Senior Staff Writer at PC Advisor and Macworld UK Henry Burrell tells us why Sky getting into the market is a big deal. Quad-play ahoy. Then fellow Senior Staff Writer Lewis Painter (14 mins) tells us why No Man's Sky is still making the headlines, this time for making stuff up. How far have companies taken false advertising in recent years? Third up is Techworld editor Charlotte Jee (25 mins) to talk about how the government has perhaps avoided taking responsibility when it comes to sex-ed and instead suggested it ban sexting - is that even possible? Listen on to find out. See acast.com/privacy for privacy and opt-out information. Full Article tech technology podcast
ration The Hurdles to Developing a COVID-19 Vaccine: Why International Cooperation is Needed By feedproxy.google.com Published On :: Thu, 23 Apr 2020 09:26:36 +0000 23 April 2020 Professor David Salisbury CB Associate Fellow, Global Health Programme LinkedIn Dr Champa Patel Director, Asia-Pacific Programme @patel_champa While the world pins its hopes on vaccines to prevent COVID-19, there are scientific, regulatory and market hurdles to overcome. Furthermore, with geopolitical tensions and nationalistic approaches, there is a high risk that the most vulnerable will not get the life-saving interventions they need. 2020-04-23-Covid-Vaccine.jpg A biologist works on the virus inactivation process in Belo Horizonte, Brazil on 24 March 2020. The Brazilian Ministry of Health convened The Technological Vaccine Center to conduct research on COVID-19 in order to diagnose, test and develop a vaccine. Photo: Getty Images. On 10 January 2020, Chinese scientists released the sequence of the COVID-19 genome on the internet. This provided the starting gun for scientists around the world to start developing vaccines or therapies. With at least 80 different vaccines in development, many governments are pinning their hopes on a quick solution. However, there are many hurdles to overcome. Vaccine developmentFirstly, vaccine development is normally a very long process to ensure vaccines are safe and effective before they are used. Safety is not a given: a recent dengue vaccine caused heightened disease in vaccinated children when they later were exposed to dengue, while Respiratory Syncytial Virus vaccine caused the same problem. Nor is effectiveness a given. Candidate vaccines that use novel techniques where minute fragments of the viruses’ genetic code are either injected directly into humans or incorporated into a vaccine (as is being pursued, or could be pursued for COVID-19) have higher risks of failure simply because they haven’t worked before. For some vaccines, we know what levels of immunity post-vaccination are likely to be protective. This is not the case for coronavirus. Clinical trials will have to be done for efficacy. This is not optional – regulators will need to know extensive testing has taken place before licencing any vaccine. Even if animal tests are done in parallel with early human tests, the remainder of the process is still lengthy. There is also great interest in the use of passive immunization, whereby antibodies to SARS-CoV-2 (collected from people who have recovered from infection or laboratory-created) are given to people who are currently ill. Antivirals may prove to be a quicker route than vaccine development, as the testing requirements would be shorter, manufacturing may be easier and only ill people would need to be treated, as opposed to all at-risk individuals being vaccinated.Vaccine manufacturingDevelopers, especially small biotechs, will have to make partnerships with large vaccine manufacturers in order to bring products to market. One notorious bottleneck in vaccine development is getting from proof-of-principle to commercial development: about 95 per cent of vaccines fail at this step. Another bottleneck is at the end of production. The final stages of vaccine production involve detailed testing to ensure that the vaccine meets the necessary criteria and there are always constraints on access to the technologies necessary to finalize the product. Only large vaccine manufacturers have these capacities. There is a graveyard of failed vaccine candidates that have not managed to pass through this development and manufacturing process.Another consideration is adverse or unintended consequences. Highly specialized scientists may have to defer their work on other new vaccines to work on COVID-19 products and production of existing products may have to be set aside, raising the possibility of shortages of other essential vaccines. Cost is another challenge. Vaccines for industrialized markets can be very lucrative for pharmaceutical companies, but many countries have price caps on vaccines. Important lessons have been learned from the 2009 H1N1 flu pandemic when industrialized countries took all the vaccines first. Supplies were made available to lower-income countries at a lower price but this was much later in the evolution of the pandemic. For the recent Ebola outbreaks, vaccines were made available at low or no cost. Geopolitics may also play a role. Should countries that manufacture a vaccine share it widely with other countries or prioritize their own populations first? It has been reported that President Trump attempted to purchase CureVac, a German company with a candidate vaccine. There are certainly precedents for countries prioritizing their own populations. With H1N1 flu in 2009, the Australian Government required a vaccine company to meet the needs of the Australian population first. Vaccine distributionGlobal leadership and a coordinated and coherent response will be needed to ensure that any vaccine is distributed equitably. There have been recent calls for a G20 on health, but existing global bodies such as the Coalition for Epidemic Preparedness Innovations (CEPI) and GAVI are working on vaccines and worldwide access to them. Any new bodies should seek to boost funding for these entities so they can ensure products reach the most disadvantaged. While countries that cannot afford vaccines may be priced out of markets, access for poor, vulnerable or marginalized peoples, whether in developed or developing countries, is of concern. Developing countries are at particular risk from the impacts of COVID-19. People living in conflict-affected and fragile states – whether they are refugees or asylum seekers, internally displaced or stateless, or in detention facilities – are at especially high risk of devastating impacts. Mature economies will also face challenges. Equitable access to COVID-19 vaccine will be challenging where inequalities and unequal access to essential services have been compromised within some political systems. The need for global leadership There is an urgent need for international coordination on COVID-19 vaccines. While the WHO provides technical support and UNICEF acts as a procurement agency, responding to coronavirus needs clarity of global leadership that arches over national interests and is capable of mobilizing resources at a time when economies are facing painful recessions. We see vaccines as a salvation but remain ill-equipped to accelerate their development.While everyone hopes for rapid availability of safe, effective and affordable vaccines that will be produced in sufficient quantities to meet everyone’s needs, realistically, we face huge hurdles. Full Article
ration Integration on Hold for Russia and Belarus By feedproxy.google.com Published On :: Tue, 14 Jan 2020 09:42:49 +0000 14 January 2020 John Lough Associate Fellow, Russia and Eurasia Programme @JohnLough Katia Glod Academy Robert Bosch Fellow (2012) Despite intense efforts by the two governments to finalize plans for deeper integration between the countries, agreement remains elusive. 2020-01-14-BelRus.jpg Vladimir Putin and Alexander Lukashenka at a Collective Security Treaty Organization meeting in Kyrgyzstan in November 2019. Photo: Getty Images. Two December meetings between Presidents Vladimir Putin and Alexander Lukashenka failed to deliver Moscow’s hopes of securing Minsk’s acceptance of closer alignment between Russia and Belarus.Over the past year, relations between Belarus and Russia have been under unprecedented strain as Moscow has tried to encourage Minsk to sign up to a different format of relations designed to keep Belarus firmly in a Russian orbit. Details of the negotiations have remained secret, yet issues on the table appear to include unification of tax and customs systems, a common energy regulator and joint governing bodies.The Kremlin believes that Belarus needs to deliver more in return for Russia’s continued economic support, worth around $10 billion per year. In December 2018, it issued an ultimatum: Belarus would only continue to receive a discounted price for oil and gas and enjoy preferential access to the Russian market if it agreed to reanimate the largely dormant 1999 Union Treaty that called for the unification of Belarus with Russia.During 2019, frantic work took place on both sides to prepare a detailed framework for achieving deeper integration between the two countries. This did not succeed in overcoming a set of long-standing issues related to economic relations.To step up pressure, the Russian prime minister, Dmitri Medvedev, signalled in early December that Russia would withhold economic privileges for Belarus pending full implementation of 30 integration road maps that he claimed had already been agreed. To the alarm of Minsk, he also suggested that discussion of a 31st roadmap would follow to include the creation of a single currency and supranational institutions. The Belarusian authorities view this level of integration as a threat to national sovereignty.On the surface, Belarus’ negotiating position is weak. By resisting market reforms that could have diversified imports and exports, Lukashenka has instead kept the economy tied to Russia; 40% of Belarusian exports go to Russia. In addition, Russia has decreased its reliance on imports from Belarus as part of a broad policy of import substitution.Raising the gas price will deprive Belarusian companies of their comparative advantage. Approximately 90% of Belarus’s electricity and heat is generated by natural gas imported from Russia at below market prices. Petroleum products refined from Russian crude oil that is supplied duty-free to Belarus account for the largest source of the country’s export earnings.Minsk fears that the current oil taxation reform in Russia could cause Belarus losses of up to $9 billion by 2024 as a result of higher prices for Russian oil and the loss of export duties. Economic growth slowed from 3% in 2018 to just over 1% in 2019 and could fall further if Russia does not grant concessions on the oil price.The country’s high level of public debt denominated in foreign currency makes the need to find cash more urgent and exacerbates the Russian pressure. Russia is Belarus’ biggest creditor, accounting for 38% of state debt.However, Lukashenka is a master of negotiation with the Kremlin, with a talent for turning weakness into strength.First, by eliminating political competition in Belarus, he has given Putin no option but to deal with him personally. Second, he understands that Moscow needs to present integration between the two countries as voluntary and does not want to use economic sanctions or other tools of persuasion that could destabilize Belarus. Third, he knows that there is no consensus in Moscow on creating a single currency. Unification of the tax systems would also be problematic because of their different structures. If these measures were implemented, Moscow could end up paying much larger subsidies to keep Belarus stable.Minsk is therefore likely to pursue three options: dragging out the negotiations with Moscow, while continuing to declare its commitment to closer union with Russia; seeking alternative sources of energy and credits; and reforming the economy to lower its dependency on Russia.Although Lukashenka is mindful of potential risks and threats to his power from economic liberalization, he is open to changes in some areas, such as further developing the successful IT sector, privatising non-strategic state-owned enterprises and increasing trade with EU countries.These reforms will most likely continue, although this year’s presidential election may distract attention, as Lukashenka seeks a sixth term in the knowledge that his popularity is falling. He may also need to divert some economic resources to maintain the support of his core electorate.For the moment, Moscow does not appear to be in a hurry, believing that Lukashenka and Belarus are going nowhere and that concessions by Minsk are only a matter of time. Full Article
ration Virtual Roundtable: Re-integration or Dis-integration: What Does the Future Hold for Occupied Donbas? By feedproxy.google.com Published On :: Tue, 21 Apr 2020 22:55:01 +0000 Invitation Only Research Event 28 April 2020 - 4:00pm to 5:30pm Event participants Paul D’anieri, Professor of Public Policy and Political Science, University of California, RiversideVlad Mykhnenko, Associate Professor of Sustainable Urban Development, St Peter’s College, University of OxfordChair: Orysia Lutsevych, Research Fellow and Manager, Ukraine Forum, Chatham House The armed conflict in Donbas has now entered its seventh year. President Zelenskyy, who came to power in May 2019, promised to end the war with Russia and bring peace to Ukraine.Since assuming office, Zelenskyy has managed to revive the Normandy Format talks, complete military disengagement at three points along the line of contact and negotiate the release of over a hundred Ukrainians held as prisoners of war in Russia. However, ceasefire violations continue to occur frequently.Looking at the origins of the armed conflict in Donbas and the region’s economic role in Ukraine’s economy, this event discusses the prospects for conflict resolution. Do the recent events signify an opportunity for peace? Does Zelenskyy have a viable plan for re-integrating Donbas or will the region be cut off from mainland Ukraine for the foreseeable future?The speakers assess the strategy and track record of the Ukrainian government and its Western allies in bringing parts of the occupied Donbas under Kyiv’s control. They also review possible policy implications of the COVID-19 pandemic for the conflict. Department/project Russia and Eurasia Programme, Ukraine Forum Anna Morgan Administrator, Ukraine Forum +44 (0)20 7389 3274 Email Full Article
ration Functional recombinant apolipoprotein A5 that is stable at high concentrations at physiological pH [Methods] By feedproxy.google.com Published On :: 2020-02-01T00:05:23-08:00 APOA5 is a low-abundance exchangeable apolipoprotein that plays critical roles in human triglyceride (TG) metabolism. Indeed, aberrations in the plasma concentration or structure of APOA5 are linked to hypertriglyceridemia, hyperchylomicronemia, myocardial infarction risk, obesity, and coronary artery disease. While it has been successfully produced at low yield in bacteria, the resulting protein had limitations for structure-function studies due to its low solubility under physiological buffer conditions. We hypothesized that the yield and solubility of recombinant APOA5 could be increased by: i) engineering a fusion protein construct in a codon optimized expression vector, ii) optimizing an efficient refolding protocol, and iii) screening buffer systems at physiological pH. The result was a high-yield (25 mg/l) bacterial expression system that produces lipid-free APOA5 soluble at concentrations of up to 10 mg/ml at a pH of 7.8 in bicarbonate buffers. Physical characterization of lipid-free APOA5 indicated that it exists as an array of multimers in solution, and far UV circular dichroism analyses show differences in total α-helicity between acidic and neutral pH buffering conditions. The protein was functional in that it bound and emulsified multilamellar dimyristoyl-phosphatidylcholine vesicles and could inhibit postprandial plasma TG accumulation when injected into C57BL/6J mice orally gavaged with Intralipid. Full Article
ration Effects of omega-O-acylceramide structures and concentrations in healthy and diseased skin barrier lipid membrane models [Research Articles] By feedproxy.google.com Published On :: 2020-02-01T00:05:23-08:00 Ceramides (Cers) with ultralong (~32-carbon) chains and -esterified linoleic acid, composing a subclass called omega-O-acylceramides (acylCers), are indispensable components of the skin barrier. Normal barriers typically contain acylCer concentrations of ~10 mol%; diminished concentrations, along with altered or missing long periodicity lamellar phase (LPP), and increased permeability accompany an array of skin disorders, including atopic dermatitis, psoriasis, and ichthyoses. We developed model membranes to investigate the effects of the acylCer structure and concentration on skin lipid organization and permeability. The model membrane systems contained six to nine Cer subclasses as well as fatty acids, cholesterol, and cholesterol sulfate; acylCer content—namely, acylCers containing sphingosine (Cer EOS), dihydrosphingosine (Cer EOdS), and phytosphingosine (Cer EOP) ranged from zero to 30 mol%. Systems with normal physiologic concentrations of acylCer mixture mimicked the permeability and nanostructure of human skin lipids (with regard to LPP, chain order, and lateral packing). The models also showed that the sphingoid base in acylCer significantly affects the membrane architecture and permeability and that Cer EOP, notably, is a weaker barrier component than Cer EOS and Cer EOdS. Membranes with diminished or missing acylCers displayed some of the hallmarks of diseased skin lipid barriers (i.e., lack of LPP, less ordered lipids, less orthorhombic chain packing, and increased permeability). These results could inform the rational design of new and improved strategies for the barrier-targeted treatment of skin diseases. Full Article
ration Separation of postprandial lipoproteins: improved purification of chylomicrons using an ApoB100 immunoaffinity method [Methods] By feedproxy.google.com Published On :: 2020-03-01T00:06:33-08:00 Elevated levels of triglyceride-rich lipoproteins (TRLs), both fasting and postprandial, are associated with increased risk for atherosclerosis. However, guidelines for treatment are defined solely by fasting lipid levels, even though postprandial lipids may be more informative. In the postprandial state, circulating lipids consist of dietary fat transported from the intestine in chylomicrons (CMs; containing ApoB48) and fat transported from the liver in VLDL (containing ApoB100). Research into the roles of endogenous versus dietary fat has been hindered because of the difficulty in separating these particles by ultracentrifugation. CM fractions have considerable contamination from VLDL (purity, 10%). To separate CMs from VLDL, we produced polyclonal antibodies against ApoB100 and generated immunoaffinity columns. TRLs isolated by ultracentrifugation of plasma were applied to these columns, and highly purified CMs were collected (purity, 90–94%). Overall eight healthy unmedicated adult volunteers (BMI, 27.2 ± 1.4 kg/m2; fasting triacylglycerol, 102.6 ± 19.5 mg/dl) participated in a feeding study, which contained an oral stable-isotope tracer (1-13C acetate). We then used this technique on plasma samples freshly collected during an 8 h human feeding study from a subset of four subjects. We analyzed fractionated lipoproteins by Western blot, isolated and derivatized triacylglycerols, and calculated fractional de novo lipogenesis. The results demonstrated effective separation of postprandial lipoproteins and substantially improved purity compared with ultracentrifugation protocols, using the immunoaffinity method. This method can be used to better delineate the role of dietary sugar and fat on postprandial lipids in cardiovascular risk and explore the potential role of CM remnants in atherosclerosis. Full Article
ration Lipid rafts and neurodegeneration: structural and functional roles in physiologic aging and neurodegenerative diseases [Thematic Reviews] By feedproxy.google.com Published On :: 2020-05-01T00:05:27-07:00 Lipid rafts are small, dynamic membrane areas characterized by the clustering of selected membrane lipids as the result of the spontaneous separation of glycolipids, sphingolipids, and cholesterol in a liquid-ordered phase. The exact dynamics underlying phase separation of membrane lipids in the complex biological membranes are still not fully understood. Nevertheless, alterations in the membrane lipid composition affect the lateral organization of molecules belonging to lipid rafts. Neural lipid rafts are found in brain cells, including neurons, astrocytes, and microglia, and are characterized by a high enrichment of specific lipids depending on the cell type. These lipid rafts seem to organize and determine the function of multiprotein complexes involved in several aspects of signal transduction, thus regulating the homeostasis of the brain. The progressive decline of brain performance along with physiological aging is at least in part associated with alterations in the composition and structure of neural lipid rafts. In addition, neurodegenerative conditions, such as lysosomal storage disorders, multiple sclerosis, and Parkinson’s, Huntington’s, and Alzheimer’s diseases, are frequently characterized by dysregulated lipid metabolism, which in turn affects the structure of lipid rafts. Several events underlying the pathogenesis of these diseases appear to depend on the altered composition of lipid rafts. Thus, the structure and function of lipid rafts play a central role in the pathogenesis of many common neurodegenerative diseases. Full Article
ration Problem Notes for SAS®9 - 64285: The SCD Type 2 Loader transformation in SAS Data Integration Studio generates "ERROR 22-322: Syntax error, expecting one of the following:..." By feedproxy.google.com Published On :: Wed, 6 May 2020 12:38:17 EST If your business key column is a name literal, like " business key "n, a syntax error occurs when that variable name does not follow standard SAS naming conventions. Full Article DATABUILDER+SAS+Data+Integration+Studio
ration Problem Notes for SAS®9 - 64459: A SAS Data Integration Studio job receives an error that states "The name '; index_name '; has the wrong number of qualifiers" By feedproxy.google.com Published On :: Wed, 6 May 2020 12:37:37 EST An error occurs because of an incorrectly generated CREATE INDEX clause in an SQL query that is sent to DB2 when the DB2 schema value is SESSION . The error message says "The name '; index_name '; has the wrong number of qualifie Full Article DATABUILDER+SAS+Data+Integration+Studio
ration Problem Notes for SAS®9 - 65904: SAS Federation Server stops responding when you run queries against X_OBJECT_PRIVILEGES in SYSCAT and the queries run for hours By feedproxy.google.com Published On :: Fri, 1 May 2020 14:48:24 EST The select * from "SYSCAT"."SYSCAT"."X_EFFECTIVE_OBJECT_PRIVILEGES" query runs for hours. In this scenario, SAS Federation Server stops responding, making it unavailable for use. Restarting SAS Federation Server solves t Full Article DFFEDSVR+SAS+Federation+Server
ration Obesity Reduces Maternal Blood Triglyceride Concentrations by Reducing Angiopoietin-like Protein 4 Expression in Mice By diabetes.diabetesjournals.org Published On :: 2020-02-12T14:26:05-08:00 To ensure fetal lipid supply, maternal blood triglyceride (TG) concentrations are robustly elevated during pregnancy. Interestingly, a lower increase in maternal blood TG concentrations has been observed in some obese mothers. We have shown that high-fat (HF) feeding during pregnancy significantly reduces maternal blood TG levels. Therefore, we performed this study to investigate if and how obesity alters maternal blood TG levels. Maternal obesity was established by prepregnant HF feeding (ppHF), which avoided the dietary effect during pregnancy. We found that maternal blood TG concentrations in ppHF dams were not only remarkably lower than control dams, but the TG peak occurred earlier during gestation. Hepatic TG production and intestinal TG absorption were unchanged in ppHF dams, but systemic lipoprotein lipase (LPL) activity was increased, suggesting that increased blood TG clearance contributes to the decreased blood TG concentrations in ppHF dams. Although significantly higher levels of UCP1 protein were observed in iBAT of ppHF dams, Ucp1 gene deletion did not restore blood TG concentrations in ppHF dams. Expression of the angiopoietin-like protein 4 (ANGPTL4), a potent endogenous LPL inhibitor, was significantly increased during pregnancy. However, the pregnancy-induced elevation of blood TG was almost abolished in Angptl4-/- dams. Compared with control dams, Angptl4 mRNA levels were significantly lower in iBAT, gWAT and livers of ppHF dams. Importantly, ectopic overexpression of ANGPTL4 restored maternal blood TG concentrations in ppHF dams. Together, these results indicate that ANGPTL4 plays a vital role in increasing maternal blood TG concentrations during pregnancy. Obesity impairs the rise of maternal blood TG concentrations by reducing ANGPTL4 expression in mice. Full Article
ration Pathogenic Role of PPAR{alpha} Down-Regulation in Corneal Nerve Degeneration and Impaired Corneal Sensitivity in Diabetes By diabetes.diabetesjournals.org Published On :: 2020-04-24T13:05:31-07:00 The purpose of this study was to investigate the protective role of Peroxisome Proliferator-Activated Receptor-alpha (PPARα) against diabetic keratopathy and corneal neuropathy. Corneal samples were obtained from diabetic and non-diabetic human donors. Streptozotocin-induced diabetic rats and mice were orally treated with PPARα agonist fenofibrate. As shown by immunohistochemistry and Western blotting, PPARα was down-regulated in the corneas of diabetic humans and rats. Immunostaining of β-III tubulin demonstrated that corneal nerve fiber metrics were decreased significantly in diabetic rats and mice, which was partially prevented by fenofibrate treatment. As evaluated using a Cochet-Bonnet aesthesiometer, corneal sensitivity was significantly decreased in diabetic mice, which was prevented by fenofibrate. PPARα-/- mice displayed progressive decreases in the corneal nerve fiber density. Consistently, corneal sensitivity was decreased in PPARα-/- mice relative to wild-type mice by nine months of age. Diabetic mice showed increased incidence of spontaneous corneal epithelial lesion, which was prevented by fenofibrate while exacerbated by PPARα knockout. Western blot analysis revealed significantly altered neurotrophic factor levels in diabetic rat corneas, which were partially restored by fenofibrate treatment. These results indicate that PPARα protects corneal nerve from degeneration induced by diabetes, and PPARα agonists have therapeutic potential in the treatment of diabetic keratopathy. Full Article
ration Acute Hyperglycemia Increases Brain Pregenual Anterior Cingulate Cortex Glutamate Concentrations in Type 1 Diabetes Mellitus By diabetes.diabetesjournals.org Published On :: 2020-04-24T14:58:49-07:00 The brain mechanisms underlying the association of hyperglycemia with depressive symptoms are unknown. We hypothesized that disrupted glutamate metabolism in pregenual anterior cingulate cortex (ACC) in type 1 diabetes (T1D) without depression affects emotional processing. Using proton magnetic resonance spectroscopy (MRS), we measured glutamate concentrations in ACC and occipital cortex (OCC) in 13 T1D without major depression (HbA1c=7.1±0.7% [54±7mmol/mol]) and 11 healthy non-diabetic controls (HbA1c=5.5±0.2% [37±3mmol/mol]) during fasting euglycemia (EU) followed by a 60-minute +5.5mmol/l hyperglycemic clamp (HG). Intrinsic neuronal activity was assessed using resting-state blood oxygen level dependent functional MRI to measure the fractional amplitude of low frequency fluctuations in slow-band 4 (fALFF4). Emotional processing and depressive symptoms were assessed using emotional tasks (Emotional-Stroop, Self-Referent-Encoding-Task SRET) and clinical ratings (HAM-D, SCL-90-R), respectively. During HG, ACC glutamate increased (1.2mmol/kg, +10%, p=0.014) while ACC fALFF4 was unchanged (-0.007, -2%, p=0.449) in T1D; in contrast, glutamate was unchanged (-0.2mmol/kg, -2%, p=0.578) while fALFF4 decreased (-0.05, -13%, p=0.002) in controls. OCC glutamate and fALFF4 were unchanged in both groups. T1D had longer SRET negative-word response-times (p=0.017) and higher depression-rating scores (HAM-D p=0.020; SCL-90-R-depression p=0.008). Higher glutamate change tended to associate with longer Emotional-Stroop response-times in T1D only. Brain glutamate must be tightly controlled during hyperglycemia due to the risk for neurotoxicity with excessive levels. Results suggest that ACC glutamate control mechanisms are disrupted in T1D, which affects glutamatergic neurotransmission related to emotional or cognitive processing. Increased prefrontal glutamate during acute hyperglycemic episodes could explain our previous findings of associations between chronic hyperglycemia, cortical thinning and depressive symptoms in T1D. Full Article
ration TWIST1-Reprogrammed Endothelial Cell Transplantation Potentiates Neovascularization-Mediated Diabetic Wound Tissue Regeneration By diabetes.diabetesjournals.org Published On :: 2020-04-24T20:01:59-07:00 Hypo-vascularised diabetic non-healing wounds are due to reduced number and impaired physiology of endogenous endothelial progenitor cell (EPC) population that, limits their recruitment and mobilization at the wound site. To enrich the EPC repertoire from non-endothelial precursors, abundantly available mesenchymal stromal cells (MSCs) were reprogrammed into induced-endothelial cells (iECs). We identified cell signaling molecular targets by meta-analysis of microarray datasets. BMP-2 induction leads to the expression of inhibitory Smad 6/7-dependent negative transcriptional regulation of ID1, rendering the latter's reduced binding to TWIST1 during transdifferentiation of WJ-MSC into iEC. TWIST1, in turn, regulates endothelial genes transcription, positively of pro-angiogenic-KDR and negatively, in part, of anti-angiogenic-SFRP4. Twist1 reprogramming enhanced the endothelial lineage commitment of WJ-MSC, increased the vasculogenic potential of reprogrammed EC (rEC). Transplantation of stable TWIST1-rECs into full-thickness type 1 and 2 diabetic-splinted wound healing murine model enhanced the microcirculatory blood flow and accelerated the wound tissue regeneration. An increased or decreased co-localization of GFP with KDR/SFRP4 and CD31 in the regenerated diabetic wound bed with TWIST1 overexpression or silencing (piLenti-TWIST1-shRNA-GFP), respectively further confirmed improved neovascularization. This study depicted the reprogramming of WJ-MSCs into rECs using unique transcription factors, TWIST1 for an efficacious cell transplantation therapy to induce neovascularization–mediated diabetic wound tissue regeneration. Full Article
ration The Metabolic Responses to 24-h Fasting and Mild Cold Exposure in Overweight Individuals are Correlated and Accompanied by Changes in FGF21 Concentration By diabetes.diabetesjournals.org Published On :: 2020-04-27T16:35:54-07:00 A greater decrease in 24-h energy expenditure (24EE) during 24h fasting defines a thriftier metabolic phenotype prone to weight gain during overfeeding and resistant to weight loss during caloric restriction. As the thermogenic response to mild cold exposure (COLD) may similarly characterize this human phenotype identified by acute fasting conditions, we analyzed changes in 24EE and sleeping metabolic rate (SLEEP) in a whole-room indirect calorimeter during 24h fasting at thermoneutrality (24°C) and during energy balance both at thermoneutrality (24°C) and mild cold (19°C) in 20 healthy volunteers (80% male, age: 36.6±11.4y, percentage body fat: 34.8±10.5%). Greater decrease in 24EE during fasting (thriftier phenotype) was associated with less increase in 24EE during COLD, i.e. less cold-induced thermogenesis. Greater decreases in plasma fibroblast growth factor 21 (FGF21) after 24h fasting and after COLD were highly correlated and associated with greater decreases in SLEEP in both conditions. We conclude that the metabolic responses to short-term fasting and COLD are associated and mediated by the liver-derived hormone FGF21. Thus, the 24EE response to COLD further identifies the thrifty versus spendthrift phenotype, providing an additional setting to investigate the physiological mechanisms underlying the human metabolic phenotype and characterizing the individual susceptibility to weight change. Full Article
ration Role of VIP and Sonic Hedgehog Signaling Pathways in Mediating Epithelial Wound Healing, Sensory Nerve Regeneration and their Defects in Diabetic Corneas By diabetes.diabetesjournals.org Published On :: 2020-04-28T07:09:24-07:00 Diabetic Keratopathy, a sight-threatening corneal disease, comprises several symptomatic conditions including delayed epithelial wound healing, recurrent erosions, and sensory nerve (SN) neuropathy. We investigated the role of neuropeptides in mediating corneal wound healing, including epithelial wound closure and SN regeneration. Denervation by Resiniferatoxin severely impaired corneal wound healing and markedly up-regulated pro-inflammatory gene expression. Exogenous neuropeptides CGRP, SP, and VIP partially reversed Resiniferatoxin’s effects, with VIP specifically inducing IL-10 expression. Hence, we focused on VIP and observed that wounding induced VIP and VIPR1 expression in normal (NL), but not diabetic (DM) mouse corneas. Targeting VIPR1 in NL corneas attenuated corneal wound healing, dampened wound-induced expression of neurotrophic factors, and exacerbated inflammatory responses while exogenous VIP had the opposite effects in DM corneas. Remarkably, wounding and diabetes also affected the expression of Sonic Hedgehog (SHH) in a VIP-dependent manner. Downregulating SHH expression in NL corneas decreased, while exogenous SHH in DM corneas increased the rates of corneal wound healing. Furthermore, inhibition of SHH signaling dampened VIP-promoted corneal wound healing. We conclude that VIP regulates epithelial wound healing, inflammatory response, and nerve regeneration in the corneas in a SHH-dependent manner, suggesting a therapeutic potential for these molecules in treating diabetic keratopathy. Full Article
ration Necrostatin-1 Mitigates Cognitive Dysfunction in Prediabetic Rats With no Alteration in Insulin Sensitivity By diabetes.diabetesjournals.org Published On :: 2020-04-28T14:32:29-07:00 Previous studies show that 12-week of high-fat diet (HFD) consumption caused not only prediabetes, but also cognitive decline and brain pathologies. Recently, necrostatin-1 (nec-1), a necroptosis inhibitor, showed beneficial effects in brain against stroke. However, the comparative effects of nec-1 and metformin on cognition and brain pathologies in prediabetes have not been investigated. We hypothesized that nec-1 and metformin equally attenuated cognitive decline and brain pathologies in prediabetic rats. Rats (n=32) were fed with either normal diet (ND) or high-fat diet (HFD) for 20 weeks. At week 13, ND-fed rats were given a vehicle (n=8) and HFD-fed rats were randomly assigned into 3 subgroups (n=8/subgroup) with vehicle, nec-1 or metformin for 8 weeks. Metabolic parameters, cognitive function, brain insulin receptor function, synaptic plasticity, dendritic spine density, microglial morphology, brain mitochondrial function, Alzheimer’s protein, and cell death were determined. HFD-fed rats exhibited prediabetes, cognitive decline, and brain pathologies. Nec-1 and metformin equally improved cognitive function, synaptic plasticity, dendritic spine density, microglial morphology, brain mitochondrial function, reduced hyperphosphorylated-tau and necroptosis in HFD-fed rats. Interestingly metformin, but not nec-1, improved brain insulin sensitivity in those rats. In conclusion, necroptosis inhibition directly improved cognition in prediabetic rats without alteration in insulin sensitivity. Full Article
ration Erratum. Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control. Diabetes 2019;68:441--456 By diabetes.diabetesjournals.org Published On :: 2020-05-06T12:11:43-07:00 Full Article
ration MANF Promotes Diabetic Corneal Epithelial Wound Healing and Nerve Regeneration by Attenuating Hyperglycemia-Induced Endoplasmic Reticulum Stress By diabetes.diabetesjournals.org Published On :: 2020-05-07T08:35:09-07:00 Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a neurotrophic factor widely expressed in mammalian tissues, and it exerts critical protective effects on neurons and other cell types in various disease models, such as those for diabetes. However, to date, the expression and roles of MANF in the cornea, with or without diabetic keratopathy (DK), remain unclear. Here, we demonstrate that MANF is abundantly expressed in normal corneal epithelial cells; however, MANF expression was significantly reduced in both unwounded and wounded corneal epithelium in streptozotocin-induced type 1 diabetic C57BL/6 mice. Recombinant human MANF significantly promoted normal and diabetic corneal epithelial wound healing and nerve regeneration. Furthermore, MANF inhibited hyperglycemia-induced endoplasmic reticulum (ER) stress and ER stress–mediated apoptosis. Attenuation of ER stress with 4-phenylbutyric acid (4-PBA) also ameliorated corneal epithelial closure and nerve regeneration. However, the beneficial effects of MANF and 4-PBA were abolished by an Akt inhibitor and Akt-specific small interfering RNA (siRNA). Finally, we reveal that the subconjunctival injection of MANF-specific siRNA prevents corneal epithelial wound healing and nerve regeneration. Our results provide important evidence that hyperglycemia-suppressed MANF expression may contribute to delayed corneal epithelial wound healing and impaired nerve regeneration by increasing ER stress, and MANF may be a useful therapeutic modality for treating DK. Full Article
ration The cytochrome P450 enzyme CYP24A1 increases proliferation of mutant KRAS-dependent lung adenocarcinoma independent of its catalytic activity [Cell Biology] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 We previously reported that overexpression of cytochrome P450 family 24 subfamily A member 1 (CYP24A1) increases lung cancer cell proliferation by activating RAS signaling and that CYP24A1 knockdown inhibits tumor growth. However, the mechanism of CYP24A1-mediated cancer cell proliferation remains unclear. Here, we conducted cell synchronization and biochemical experiments in lung adenocarcinoma cells, revealing a link between CYP24A1 and anaphase-promoting complex (APC), a key cell cycle regulator. We demonstrate that CYP24A1 expression is cell cycle–dependent; it was higher in the G2-M phase and diminished upon G1 entry. CYP24A1 has a functional destruction box (D-box) motif that allows binding with two APC adaptors, CDC20-homologue 1 (CDH1) and cell division cycle 20 (CDC20). Unlike other APC substrates, however, CYP24A1 acted as a pseudo-substrate, inhibiting CDH1 activity and promoting mitotic progression. Conversely, overexpression of a CYP24A1 D-box mutant compromised CDH1 binding, allowing CDH1 hyperactivation, thereby hastening degradation of its substrates cyclin B1 and CDC20, and accumulation of the CDC20 substrate p21, prolonging mitotic exit. These activities also occurred with a CYP24A1 isoform 2 lacking the catalytic cysteine (Cys-462), suggesting that CYP24A1's oncogenic potential is independent of its catalytic activity. CYP24A1 degradation reduced clonogenic survival of mutant KRAS-driven lung cancer cells, and calcitriol treatment increased CYP24A1 levels and tumor burden in Lsl-KRASG12D mice. These results disclose a catalytic activity-independent growth-promoting role of CYP24A1 in mutant KRAS-driven lung cancer. This suggests that CYP24A1 could be therapeutically targeted in lung cancers in which its expression is high. Full Article
ration SUMOylation of the transcription factor ZFHX3 at Lys-2806 requires SAE1, UBC9, and PIAS2 and enhances its stability and function in cell proliferation [Protein Synthesis and Degradation] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 SUMOylation is a posttranslational modification (PTM) at a lysine residue and is crucial for the proper functions of many proteins, particularly of transcription factors, in various biological processes. Zinc finger homeobox 3 (ZFHX3), also known as AT motif-binding factor 1 (ATBF1), is a large transcription factor that is active in multiple pathological processes, including atrial fibrillation and carcinogenesis, and in circadian regulation and development. We have previously demonstrated that ZFHX3 is SUMOylated at three or more lysine residues. Here, we investigated which enzymes regulate ZFHX3 SUMOylation and whether SUMOylation modulates ZFHX3 stability and function. We found that SUMO1, SUMO2, and SUMO3 each are conjugated to ZFHX3. Multiple lysine residues in ZFHX3 were SUMOylated, but Lys-2806 was the major SUMOylation site, and we also found that it is highly conserved among ZFHX3 orthologs from different animal species. Using molecular analyses, we identified the enzymes that mediate ZFHX3 SUMOylation; these included SUMO1-activating enzyme subunit 1 (SAE1), an E1-activating enzyme; SUMO-conjugating enzyme UBC9 (UBC9), an E2-conjugating enzyme; and protein inhibitor of activated STAT2 (PIAS2), an E3 ligase. Multiple analyses established that both SUMO-specific peptidase 1 (SENP1) and SENP2 deSUMOylate ZFHX3. SUMOylation at Lys-2806 enhanced ZFHX3 stability by interfering with its ubiquitination and proteasomal degradation. Functionally, Lys-2806 SUMOylation enabled ZFHX3-mediated cell proliferation and xenograft tumor growth of the MDA-MB-231 breast cancer cell line. These findings reveal the enzymes involved in, and the functional consequences of, ZFHX3 SUMOylation, insights that may help shed light on ZFHX3's roles in various cellular and pathophysiological processes. Full Article
ration A flexible network of vimentin intermediate filaments promotes migration of amoeboid cancer cells through confined environments [Cell Biology] By feedproxy.google.com Published On :: 2020-05-08T03:41:14-07:00 Tumor cells can spread to distant sites through their ability to switch between mesenchymal and amoeboid (bleb-based) migration. Because of this difference, inhibitors of metastasis must account for each migration mode. However, the role of vimentin in amoeboid migration has not been determined. Because amoeboid leader bleb–based migration (LBBM) occurs in confined spaces and vimentin is known to strongly influence cell-mechanical properties, we hypothesized that a flexible vimentin network is required for fast amoeboid migration. To this end, here we determined the precise role of the vimentin intermediate filament system in regulating the migration of amoeboid human cancer cells. Vimentin is a classic marker of epithelial-to-mesenchymal transition and is therefore an ideal target for a metastasis inhibitor. Using a previously developed polydimethylsiloxane slab–based approach to confine cells, RNAi-based vimentin silencing, vimentin overexpression, pharmacological treatments, and measurements of cell stiffness, we found that RNAi-mediated depletion of vimentin increases LBBM by ∼50% compared with control cells and that vimentin overexpression and simvastatin-induced vimentin bundling inhibit fast amoeboid migration and proliferation. Importantly, these effects were independent of changes in actomyosin contractility. Our results indicate that a flexible vimentin intermediate filament network promotes LBBM of amoeboid cancer cells in confined environments and that vimentin bundling perturbs cell-mechanical properties and inhibits the invasive properties of cancer cells. Full Article
ration Affinity maturation, humanization, and co-crystallization of a rabbit anti-human ROR2 monoclonal antibody for therapeutic applications [Immunology] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 Antibodies are widely used as cancer therapeutics, but their current use is limited by the low number of antigens restricted to cancer cells. A receptor tyrosine kinase, receptor tyrosine kinase-like orphan receptor 2 (ROR2), is normally expressed only during embryogenesis and is tightly down-regulated in postnatal healthy tissues. However, it is up-regulated in a diverse set of hematologic and solid malignancies, thus ROR2 represents a candidate antigen for antibody-based cancer therapy. Here we describe the affinity maturation and humanization of a rabbit mAb that binds human and mouse ROR2 but not human ROR1 or other human cell-surface antigens. Co-crystallization of the parental rabbit mAb in complex with the human ROR2 kringle domain (hROR2-Kr) guided affinity maturation by heavy-chain complementarity-determining region 3 (HCDR3)-focused mutagenesis and selection. The affinity-matured rabbit mAb was then humanized by complementarity-determining region (CDR) grafting and framework fine tuning and again co-crystallized with hROR2-Kr. We show that the affinity-matured and humanized mAb retains strong affinity and specificity to ROR2 and, following conversion to a T cell–engaging bispecific antibody, has potent cytotoxicity toward ROR2-expressing cells. We anticipate that this humanized affinity-matured mAb will find application for antibody-based cancer therapy of ROR2-expressing neoplasms. Full Article
ration Zinc promotes liquid-liquid phase separation of tau protein [Protein Structure and Folding] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 Tau is a microtubule-associated protein that plays a major role in Alzheimer's disease (AD) and other tauopathies. Recent reports indicate that, in the presence of crowding agents, tau can undergo liquid–liquid phase separation (LLPS), forming highly dynamic liquid droplets. Here, using recombinantly expressed proteins, turbidimetry, fluorescence microscopy imaging, and fluorescence recovery after photobleaching (FRAP) assays, we show that the divalent transition metal zinc strongly promotes this process, shifting the equilibrium phase boundary to lower protein or crowding agent concentrations. We observed no tau LLPS-promoting effect for any other divalent transition metal ions tested, including Mn2+, Fe2+, Co2+, Ni2+, and Cu2+. We also demonstrate that multiple zinc-binding sites on tau are involved in the LLPS-promoting effect and provide insights into the mechanism of this process. Zinc concentration is highly elevated in AD brains, and this metal ion is believed to be an important player in the pathogenesis of this disease. Thus, the present findings bring a new dimension to understanding the relationship between zinc homeostasis and the pathogenic process in AD and related neurodegenerative disorders. Full Article
ration Effect of a Sustained Reduction in Plasma Free Fatty Acid Concentration on Intramuscular Long-Chain Fatty Acyl-CoAs and Insulin Action in Type 2 Diabetic Patients By diabetes.diabetesjournals.org Published On :: 2005-11-01 Mandeep BajajNov 1, 2005; 54:3148-3153Metabolism Full Article
ration Evidence Against an Important Role of Plasma Insulin and Glucagon Concentrations in the Increase in EGP Caused by SGLT2 Inhibitors By diabetes.diabetesjournals.org Published On :: 2020-04-01 Mariam AlatrachApr 1, 2020; 69:681-688Pathophysiology Full Article
ration 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
ration Don’t Overstretch on Regional Integration By feedproxy.google.com Published On :: Thu, 23 May 2019 11:39:22 +0000 12 June 2019 Hans Kundnani Senior Research Fellow, Europe Programme @hanskundnani How the European Union took the idea of a ‘rules-based order’ too far – and how it can regain legitimacy. Young woman at the March for Europe in May 2018 Young woman at the March for Europe in May 2018. Photo by Emanuele Cremaschi/Getty Images The European Union is the ultimate ‘rules-based order’. Since the end of the Cold War, the world has become increasingly integrated, in a process that Dani Rodrik has called ‘hyper-globalization’ to distinguish this from the more moderate form of globalization that occurred during the Cold War period.But Europe, which was already more integrated than the rest of the world, has gone even further in removing barriers to the internal movement of capital, goods and people. The consequence of this has been the need for a more developed system of rules to govern this deep integration.For much of this period, many Europeans – and also many outside Europe who had a liberal view of international politics – believed that the EU was a kind of blueprint for global governance.They believed that the rest of the world would simply catch up with the enlightened and apparently successful approach that Europeans had taken. In short, Europeans were showing the way forward for the world.However, after a decade of crisis, it now seems as if Europe may have overreached. In particular with the creation of the single currency, European rules increasingly extended into areas of life in which member states had previously had relative autonomy.Since the beginning of the euro crisis in 2010, there has been a backlash against EU rules, which has raised the difficult question of whether international rule-making can go too far.What makes international rules problematic is that they depoliticize – that is, they take the policy areas they cover out of the realm of democratic contestation. This can be a good thing when applied to policy areas that we think should be non-negotiable, like human rights.But since the 1980s, and especially since the end of the Cold War, international rules have increasingly applied to areas of policy that not only should be contested but that should be at the centre of contestation – in particular, economic policy areas that have distributional consequences (that is, they create winners and losers).The EU’s rules constrain its member states even more than global rules – for example, those of the World Trade Organization (WTO) – or rules associated with other regional integration projects constrain nation states elsewhere in the world. In particular, the EU’s fiscal rules – created along with the euro – set strict limits on the ability of member states to run budget deficits and accumulate debt.Since the beginning of the euro crisis, these fiscal rules have been further tightened, which in turn has magnified the political backlash against the EU system and fuelled tensions between member states.In democratic nation states, rules are made through a process that gives them what is sometimes called ‘input legitimacy’. International rule-making, by contrast, is essentially the product of power relations between states and therefore lacks this specific kind of legitimacy.Supporters of European integration as currently constituted – whom one might term ‘pro-Europeans’ – would argue that EU rules are more like domestic rules than international rules: after all, they are agreed through a process involving democratic institutions such as the European Parliament. But even within the EU, power matters – as notably illustrated by Germany’s prominent (and controversial) role in driving the development of fiscal rules since the beginning of the euro crisis.In addition, because European integration is meant to be an irreversible process, it is extremely difficult to change or abolish rules that have already been agreed. To do so would be ‘disintegration’ in the sense that powers would be returned to member states.For example, there are good economic and political arguments for abolishing the ‘debt brake’, based on a German model, that EU member states agreed to incorporate into their national constitutions as part of the Fiscal Compact in 2011. But anyone making those arguments is labelled as Eurosceptic or ‘anti-European’.There is also insufficient differentiation between EU rules. Any decision taken at a European level – even those decisions, such as on the Fiscal Compact, that are outside the EU treaties – becomes part of the EU’s system of rules. To challenge such a decision is therefore to violate the rule of law and therefore the EU’s ‘values’.As Dieter Grimm has shown, legislation that would normally have the status of secondary law in a nation state has constitutional status in EU law and is therefore ‘immunized against political correction’.[1]Though European leaders still often speak of the EU as a model for the rest of the world, the reality is that it now illustrates what other regional integration projects should avoid as much as what they should emulate. Even before the euro crisis, few other regions were thinking of creating a common currency.But they will now think even more carefully about how far to follow Europe down the route of economic integration it has taken – and in particular will be unlikely to introduce EU-style fiscal rules.The difficult question is where exactly the limits of international rule-making should be set. The European experience in the past decade suggests that rules on economic policy are particularly problematic because of the distributional consequences they have.But European integration focused on economic policy from its beginnings with the European Coal and Steel Community in the 1950s. Moreover, because globalization is to a large extent an economic phenomenon, economic policy is precisely where international rules are needed.A good place to start in thinking about where to set the limits of international rule-making may be in terms of the objectives of rules. During the early phase of European integration and the more moderate phase of globalization in the 30 years after the end of the Second World War, integration strengthened nation states – indeed, Alan Milward argued that integration ‘rescued’ the nation state in Europe.[2]But since the end of the Cold War, rules at both the global level and a European level have been driven by the maximization of economic efficiency. This has undermined the nation state. As Rodrik has argued, a reprioritization is now needed – rules should be made above all with their impact on democracy in mind.[3]In order to regain legitimacy, Europe should apply this idea of democracy-enhancing rules to its own approach to integration. It should begin by differentiating more clearly between rules that are fundamental to the European project and those about which Europeans can – and should – disagree.The consequence of thinking of rules above all in terms of legitimacy may be that in some policy areas, particularly those with distributive consequences, rules should be abolished and power returned to member states.‘Pro-Europeans’ should be open to this kind of ‘disintegration’ as a way to help the EU regain legitimacy and thus be sustainable in the medium term. It is also only by successfully recalibrating the balance between rules and democracy that the EU will once again be seen as a model for regional integration projects in the rest of the world, and for global governance more generally.What needs to happenThe EU offers a cautionary tale on the limits of regional integration, with its status as a model for international governance eroded by a decade of crisis.In certain areas, notably fiscal policy, democratically contested decision-making has been subordinated to ‘depoliticized’ supranational rules. The crisis over the single currency exemplifies the tensions between autonomy and integration.To restore its legitimacy, the EU needs to recalibrate the balance between rules and democracy. Policymakers should ensure that laws are made with their impact on democracy in mind.Politicians and policymakers should differentiate more clearly between rules that are fundamental to the European project and those about which Europeans can – and should – disagree.In some policy areas, this could include returning powers to member states. Though politically challenging, this will require ‘pro-Europeans’ to tolerate some ‘disintegration’ as the price of ensuring the future stability of the EU.Notes[1] Grimm, D. (2015), ‘The Democratic Costs of Constitutionalisation: The European Case’, European Law Journal, Volume 21, Issue 4, July 2015, https://onlinelibrary.wiley.com/doi/abs/10.1111/eulj.12139.[2] Milward, A. (1999), The European Rescue of the Nation State, London: Routledge.[3] Rodrik, D. (2006), ‘Put Globalization to Work for Democracies’, New York Times, 17 September 2006, https://www.nytimes.com/2016/09/18/opinion/sunday/put-globalization-to-work-for-democracies.html.This essay was produced for the 2019 edition of Chatham House Expert Perspectives – our annual survey of risks and opportunities in global affairs – in which our researchers identify areas where the current sets of rules, institutions and mechanisms for peaceful international cooperation are falling short, and present ideas for reform and modernization. Full Article
ration Taking Inspiration From Kofi Annan By feedproxy.google.com Published On :: Fri, 31 May 2019 07:27:15 +0000 31 May 2019 Robin Niblett Director and Chief Executive, Chatham House @RobinNiblett Robin Niblett reflects on the legacy of the former UN secretary-general and what current leaders can learn from his example. 2019-05-31-Annan.jpg Kofi Annan in 2017. Photo: Getty Images. On 3 and 4 June, Chatham House will host a major conference in partnership with the UN Association (UK), supported by the Bill and Melinda Gates and Open Society Foundations, to reflect on the lessons learned from the remarkable life of Kofi Annan, who served as UN secretary-general from 1997 to 2006 and passed away almost a year ago, on 18 August 2018.The conference will fall on the same days as Donald Trump’s state visit to the United Kingdom, which, though unplanned, brings into stark relief the ways in which current changes in international relations are affecting Kofi Annan’s legacy of UN-led multilateralism that Ban Ki-moon and now Antonio Guterres have carried forward.A vision of multilateral governanceKofi Annan advocated a vision of multilateral governance anchored in shared responsibility for global challenges and in promoting the rights and dignity of the individual. He placed the importance of individual freedom and justice alongside the global challenges of poverty and health. The launch of the Millennium Development Goals (MDGs) and the UN Global Fund on HIV/Aids, which brought together both strands of his approach to global governance, stand among his landmark contributions to international affairs.Kofi Annan’s time as secretary-general also saw him involved in managing numerous crises. The 2003 US-led military intervention in Iraq raised acute questions about the purpose and future of the UN Security Council. The aftermath of the conflict also exposed serious failings in the broader UN system under his leadership.It was to his credit that he leveraged the investigation into the corruption surrounding the UN’s 1995–2003 ‘oil-for-food’ programme in order to introduce procedures for greater scrutiny over UN financial programmes and personnel appointments. In 2000, he set up and then took on board the criticisms of the Brahimi Report into the failed UN peacekeeping operations in Rwanda and Srebrenica during his tenure as undersecretary-general for peacekeeping.Global governance on the defensiveOne can look back at Kofi Annan’s term as UN secretary-general as a period when ideas for how to improve global governance were in the ascendant, despite the persistence of civil wars and interstate disputes. Today, the persistence of long-standing conflicts and growing competition between the world’s major powers appear to be overwhelming the global agenda, putting ideas for global governance on the defensive.America’s purposeful disengagement from and disruption of the multilateral institutions that it helped establish during the 20th century is a major factor in this shift. The principal difference with the Cold War is that China’s rise might divide America from its allies rather than unite them. China has become embedded in the global economy that America championed, creating new webs of interdependence. On the other hand, China is promoting a system of domestic and international governance that gives primacy to the state over the rights of the individual. In recent years, China has not only supported the world’s most repressive regimes, like North Korea, Venezuela and Zimbabwe, but also corrupt and opaque practices in countries in southeast Asia and Africa. And it is offering new digital surveillance tools that leaders in these countries can use to suppress popular dissent.Despite concerns over its direction, most states around the world continue to engage China, even US allies in Europe and Asia. America, however, has decided to challenge it. With the world’s two most powerful states in confrontation, and Russia happy to play a disruptive role in between, there is little scope for state-led multilateralism to regain its momentum.This rise of a more competitive international system has had a negative effect on Kofi Annan’s legacy, eroding some of its highlights, such as expectations for Responsibility to Protect, and weakening multilateralism and respect for human rights in general.The question for the future is whether Annan’s successors can build on the more radical, transformative aspects of his tenure and bypass this state-led confrontation. The shift from the MDGs to the Sustainable Development Goals (SDGs) could prove critical in this respect.A more inclusive approach to complex problem-solvingIn order to have a chance of achieving the SDGs, the world needs to deploy a more inclusive approach to complex problem-solving of the sort that Kofi Annan promoted with his Global Compact. Bringing the private sector and civil society proactively into multilateral responses offers the only prospect to end poverty and reduce inequality, build sustainable cities, and shift to responsible production and consumption, along with the other SDGs.A more inclusive approach also means giving a greater sense of agency to individuals, who can now mobilize digitally and engage in responding to global challenges, such as creating more energy-efficient and climate-friendly lifestyles, with minimal government support. Annan was a pioneer of this more bottom-up approach to development and rights issues after leaving the UN, through his work on youth leadership against violent extremism and on transforming agriculture in Africa.Thinking of systemic change as a more societal rather than government-led process demands leaders capable of mobilizing mass individual action towards public policy goals, as reflected, for example, in Secretary-General Guterres’ High Level Panel on Digital Cooperation.The fact that Kofi Annan was dubbed by some ‘the secular pope’ points to people’s search for leadership towards shared global challenges that goes beyond what can be achieved by national action alone. If an important part of his legacy is the idea of more inclusive forms of global governance, then Kofi Annan has provided an essential starting point for the debates that will accompany the UN’s upcoming 75th anniversary. Full Article
ration The Morass of Central American Migration: Dynamics, Dilemmas and Policy Alternatives By feedproxy.google.com Published On :: Mon, 11 Nov 2019 16:10:01 +0000 Invitation Only Research Event 22 November 2019 - 8:15am to 9:30am Chatham House | 10 St James's Square | London | SW1Y 4LE Event participants Anita Isaacs, Professor of Political Science, Haverford College; Co-Director, Migration Encounters ProjectJuan Ricardo Ortega, Principal Advisor for Central America, Inter-American Development BankChair: Amy Pope, Associate Fellow, Chatham House; US Deputy Homeland Security Adviser for the Obama Administration (2015-17) 2019 has seen a record number of people migrating from Central America’s Northern Triangle – an area that covers El Salvador, Guatemala and Honduras. Estimates from June 2019 have placed the number of migrants at nearly double of what they were in 2018 with the increase in numbers stemming from a lack of economic opportunity combined with a rise in crime and insecurity in the region. The impacts of migration can already be felt within the affected states as the exodus has played a significant role in weakening labour markets and contributing to a ‘brain drain’ in the region. It has also played an increasingly active role in the upcoming US presidential election with some calling for more security on the border to curb immigration while others argue that a more effective strategy is needed to address the sources of migration. What are the core causes of Central American migration and how have the US, Central American and now also Mexican governments facilitated and deterred migration from the region? Can institutions be strengthened to alleviate the causes of migration? And what possible policy alternatives and solutions are there that could alleviate the pressures individuals and communities feel to migrate? Anita Isaacs, professor of Political Science at Haverford College and co-director of the Migration Encounters Project, and Juan Ricard Ortega, principal advisor for Central America at the Inter-American Development Bank, will join us for a discussion on the core drivers of migration within and across Central America.Attendance at this event is by invitation only. Event attributes Chatham House Rule Department/project US and the Americas Programme US and Americas Programme Email Full Article
ration Coronavirus in Latin America and Mexico: Infection Rates, Immigration and Policy Responses By feedproxy.google.com Published On :: Mon, 23 Mar 2020 17:20:01 +0000 Invitation Only Research Event 25 March 2020 - 4:00pm to 5:00pm Event participants Jude Webber, Mexico and Central America Correspondent, Financial TimesMichael Stott, Latin America Editor, Financial TimesChair: Dr Christopher Sabatini, Senior Research Fellow for Latin America, US and the Americas Programme, Chatham House This event is part of the Inaugural Virtual Roundtable Series on the US, Americas and the State of the World and will take place virtually only. Participants should not come to Chatham House for these events Department/project US and the Americas Programme, Latin America Initiative US and Americas Programme Email Full Article
ration Webinar: COVID-19 and the Impact on Latin American Migration By feedproxy.google.com Published On :: Fri, 01 May 2020 15:45:01 +0000 Research Event 14 May 2020 - 3:00pm to 4:00pmAdd to CalendariCalendar Outlook Google Yahoo Ambassador Arturo Sarukhan, Associate Fellow, US and the Americas Programme, Chatham House; Mexican Ambassador to the US, 2007 - 13Professor Anita Isaacs, Benjamin R. Collins Professor of Social Sciences, Haverford CollegeChair: Dr Christopher Sabatini, Senior Research Fellow for Latin America, US and the Americas Programme, Chatham House The US government recently announced restrictions on immigration, stating the new measures were necessary due to COVID-19 and the effect the pandemic has had on the US economy. But what is the role of immigrants in the essential official and unofficial services in the COVID-19 stay-at-home era? How is COVID-19 affecting immigration from Central America and Mexico? Separately, there have also been instances of outbreaks among detainees in US Immigration and Customs Enforcement centers and claims that immigrants who are returning to Guatemala are spreading the virus. How have US immigration policies affected infection rates in Central America and Mexico and among its citizens?Arturo Sarukhan, Mexican Ambassador to the US from 2007 - 13, and Anita Isaacs, Benjamin R. Collins Professor of Social Sciences, Haverford College, will join us to discuss the impact COVID-19 is having on migrants.Chatham House would like to thank BTG Pactual, Cairn Energy plc, Diageo plc, Equinor, Fresnillo Management Services, HSBC Holdings plc and Wintershall Dea for their generous support of the Latin America Initiative.This event is scheduled to take place from 15:00 – 16:00 BST. US and Americas Programme Email Department/project US and the Americas Programme, Latin America Initiative Full Article
ration Diabetes Core Update: Covid-19 and Diabetes – Considerations for Health Care Professionals - April 2019 By diabetescoreupdate.libsyn.com Published On :: Thu, 23 Apr 2020 18:00:00 +0000 Diabetes Core Update: Covid-19 and Diabetes – Considerations for Health Care Professionals - April 2019 This special issue is an audio version of the American Diabetes Associations Covid-19 leadership team discussing a range of issues on Covid-19 and Diabetes. Recorded March 31, 2020. Topics include: Access to medications Effect on Diabetes Self-management Can Patients take their own Supplies if they are an inpatient in the hospital – particularly insulin pumps and CGM Considerations for Specific Hypoglycemic Medications during Inpatient Hospitalization Differences in Management for Persons with Type 1 and Type 2 Diabetes SGLT-2 inhibitors and GLP-1 Receptor Agonists use During Covid-19 Infection Diabetes and Cardiovascular Disease during Covid-19 ACEs and ARBs Stress among Healthcare Professionals Intended for practicing physicians and health care professionals, Diabetes Core Update discusses how the latest research and information published in journals of the American Diabetes Association are relevant to clinical practice and can be applied in a treatment setting. Presented by: Robert Eckel, MD ADA President, Medicine & Science University of Colorado Mary de Groot, PhD ADA President, Health Care & Education Indiana University Irl Hirsch, MD University of Washington Anne Peters, MD University of Southern California Louis Philipson, MD, PhD ADA Past President, Medicine & Science University of Chicago Neil Skolnik, MD Abington Jefferson Health Full Article