do Fluctuation in O-GlcNAcylation inactivates STIM1 to reduce store-operated calcium ion entry via down-regulation of Ser621 phosphorylation [Molecular Bases of Disease] By www.jbc.org Published On :: 2020-12-11T00:06:20-08:00 Stromal interaction molecule 1 (STIM1) plays a pivotal role in store-operated Ca2+ entry (SOCE), an essential mechanism in cellular calcium signaling and in maintaining cellular calcium balance. Because O-GlcNAcylation plays pivotal roles in various cellular function, we examined the effect of fluctuation in STIM1 O-GlcNAcylation on SOCE activity. We found that both increase and decrease in STIM1 O-GlcNAcylation impaired SOCE activity. To determine the molecular basis, we established STIM1-knockout HEK293 (STIM1-KO-HEK) cells using the CRISPR/Cas9 system and transfected STIM1 WT (STIM1-KO-WT-HEK), S621A (STIM1-KO-S621A-HEK), or T626A (STIM1-KO-T626A-HEK) cells. Using these cells, we examined the possible O-GlcNAcylation sites of STIM1 to determine whether the sites were O-GlcNAcylated. Co-immunoprecipitation analysis revealed that Ser621 and Thr626 were O-GlcNAcylated and that Thr626 was O-GlcNAcylated in the steady state but Ser621 was not. The SOCE activity in STIM1-KO-S621A-HEK and STIM1-KO-T626A-HEK cells was lower than that in STIM1-KO-WT-HEK cells because of reduced phosphorylation at Ser621. Treatment with the O-GlcNAcase inhibitor Thiamet G or O-GlcNAc transferase (OGT) transfection, which increases O-GlcNAcylation, reduced SOCE activity, whereas treatment with the OGT inhibitor ST045849 or siOGT transfection, which decreases O-GlcNAcylation, also reduced SOCE activity. Decrease in SOCE activity due to increase and decrease in O-GlcNAcylation was attributable to reduced phosphorylation at Ser621. These data suggest that both decrease in O-GlcNAcylation at Thr626 and increase in O-GlcNAcylation at Ser621 in STIM1 lead to impairment of SOCE activity through decrease in Ser621 phosphorylation. Targeting STIM1 O-GlcNAcylation could provide a promising treatment option for the related diseases, such as neurodegenerative diseases. Full Article
do Ischemic stroke disrupts the endothelial glycocalyx through activation of proHPSE via acrolein exposure [Molecular Bases of Disease] By www.jbc.org Published On :: 2020-12-25T00:06:31-08:00 Infiltration of peripheral immune cells after blood-brain barrier dysfunction causes severe inflammation after a stroke. Although the endothelial glycocalyx, a network of membrane-bound glycoproteins and proteoglycans that covers the lumen of endothelial cells, functions as a barrier to circulating cells, the relationship between stroke severity and glycocalyx dysfunction remains unclear. In this study, glycosaminoglycans, a component of the endothelial glycocalyx, were studied in the context of ischemic stroke using a photochemically induced thrombosis mouse model. Decreased levels of heparan sulfate and chondroitin sulfate and increased activity of hyaluronidase 1 and heparanase (HPSE) were observed in ischemic brain tissues. HPSE expression in cerebral vessels increased after stroke onset and infarct volume greatly decreased after co-administration of N-acetylcysteine + glycosaminoglycan oligosaccharides as compared with N-acetylcysteine administration alone. These results suggest that the endothelial glycocalyx was injured after the onset of stroke. Interestingly, scission activity of proHPSE produced by immortalized endothelial cells and HEK293 cells transfected with hHPSE1 cDNA were activated by acrolein (ACR) exposure. We identified the ACR-modified amino acid residues of proHPSE using nano LC–MS/MS, suggesting that ACR modification of Lys139 (6-kDa linker), Lys107, and Lys161, located in the immediate vicinity of the 6-kDa linker, at least in part is attributed to the activation of proHPSE. Because proHPSE, but not HPSE, localizes outside cells by binding with heparan sulfate proteoglycans, ACR-modified proHPSE represents a promising target to protect the endothelial glycocalyx. Full Article
do Molecular architecture and domain arrangement of the placental malaria protein VAR2CSA suggests a model for carbohydrate binding [Glycobiology and Extracellular Matrices] By www.jbc.org Published On :: 2020-12-25T00:06:31-08:00 VAR2CSA is the placental-malaria–specific member of the antigenically variant Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family. It is expressed on the surface of Plasmodium falciparum-infected host red blood cells and binds to specific chondroitin-4-sulfate chains of the placental proteoglycan receptor. The functional ∼310 kDa ectodomain of VAR2CSA is a multidomain protein that requires a minimum 12-mer chondroitin-4-sulfate molecule for specific, high affinity receptor binding. However, it is not known how the individual domains are organized and interact to create the receptor-binding surface, limiting efforts to exploit its potential as an effective vaccine or drug target. Using small angle X-ray scattering and single particle reconstruction from negative-stained electron micrographs of the ectodomain and multidomain constructs, we have determined the structural architecture of VAR2CSA. The relative locations of the domains creates two distinct pores that can each accommodate the 12-mer of chondroitin-4-sulfate, suggesting a model for receptor binding. This model has important implications for understanding cytoadherence of infected red blood cells and potentially provides a starting point for developing novel strategies to prevent and/or treat placental malaria. Full Article
do The cation diffusion facilitator protein MamM's cytoplasmic domain exhibits metal-type dependent binding modes and discriminates against Mn2+ [Molecular Biophysics] By www.jbc.org Published On :: 2020-12-04T00:06:05-08:00 Cation diffusion facilitator (CDF) proteins are a conserved family of divalent transition metal cation transporters. CDF proteins are usually composed of two domains: the transmembrane domain, in which the metal cations are transported through, and a regulatory cytoplasmic C-terminal domain (CTD). Each CDF protein transports either one specific metal or multiple metals from the cytoplasm, and it is not known whether the CTD takes an active regulatory role in metal recognition and discrimination during cation transport. Here, the model CDF protein MamM, an iron transporter from magnetotactic bacteria, was used to probe the role of the CTD in metal recognition and selectivity. Using a combination of biophysical and structural approaches, the binding of different metals to MamM CTD was characterized. Results reveal that different metals bind distinctively to MamM CTD in terms of their binding sites, thermodynamics, and binding-dependent conformations, both in crystal form and in solution, which suggests a varying level of functional discrimination between CDF domains. Furthermore, these results provide the first direct evidence that CDF CTDs play a role in metal selectivity. We demonstrate that MamM's CTD can discriminate against Mn2+, supporting its postulated role in preventing magnetite formation poisoning in magnetotactic bacteria via Mn2+ incorporation. Full Article
do A structural and kinetic survey of GH5_4 endoglucanases reveals determinants of broad substrate specificity and opportunities for biomass hydrolysis [Protein Structure and Folding] By www.jbc.org Published On :: 2020-12-18T00:06:18-08:00 Broad-specificity glycoside hydrolases (GHs) contribute to plant biomass hydrolysis by degrading a diverse range of polysaccharides, making them useful catalysts for renewable energy and biocommodity production. Discovery of new GHs with improved kinetic parameters or more tolerant substrate-binding sites could increase the efficiency of renewable bioenergy production even further. GH5 has over 50 subfamilies exhibiting selectivities for reaction with β-(1,4)–linked oligo- and polysaccharides. Among these, subfamily 4 (GH5_4) contains numerous broad-selectivity endoglucanases that hydrolyze cellulose, xyloglucan, and mixed-linkage glucans. We previously surveyed the whole subfamily and found over 100 new broad-specificity endoglucanases, although the structural origins of broad specificity remained unclear. A mechanistic understanding of GH5_4 substrate specificity would help inform the best protein design strategies and the most appropriate industrial application of broad-specificity endoglucanases. Here we report structures of 10 new GH5_4 enzymes from cellulolytic microbes and characterize their substrate selectivity using normalized reducing sugar assays and MS. We found that GH5_4 enzymes have the highest catalytic efficiency for hydrolysis of xyloglucan, glucomannan, and soluble β-glucans, with opportunistic secondary reactions on cellulose, mannan, and xylan. The positions of key aromatic residues determine the overall reaction rate and breadth of substrate tolerance, and they contribute to differences in oligosaccharide cleavage patterns. Our new composite model identifies several critical structural features that confer broad specificity and may be readily engineered into existing industrial enzymes. We demonstrate that GH5_4 endoglucanases can have broad specificity without sacrificing high activity, making them a valuable addition to the biomass deconstruction toolset. Full Article
do Structural transitions in Orb2 prion-like domain relevant for functional aggregation in memory consolidation [Molecular Biophysics] By www.jbc.org Published On :: 2020-12-25T00:06:30-08:00 The recent structural elucidation of ex vivo Drosophila Orb2 fibrils revealed a novel amyloid formed by interdigitated Gln and His residue side chains belonging to the prion-like domain. However, atomic-level details on the conformational transitions associated with memory consolidation remain unknown. Here, we have characterized the nascent conformation and dynamics of the prion-like domain (PLD) of Orb2A using a nonconventional liquid-state NMR spectroscopy strategy based on 13C detection to afford an essentially complete set of 13Cα, 13Cβ, 1Hα, and backbone 13CO and 15N assignments. At pH 4, where His residues are protonated, the PLD is disordered and flexible, except for a partially populated α-helix spanning residues 55–60, and binds RNA oligos, but not divalent cations. At pH 7, in contrast, His residues are predominantly neutral, and the Q/H segments adopt minor populations of helical structure, show decreased mobility and start to self-associate. At pH 7, the His residues do not bind RNA or Ca2+, but do bind Zn2+, which promotes further association. These findings represent a remarkable case of structural plasticity, based on which an updated model for Orb2A functional amyloidogenesis is suggested. Full Article
do Economy Must Not Get Stuck Between Lockdown and Recovery By www.chathamhouse.org Published On :: Thu, 02 Jul 2020 17:29:32 +0000 2 July 2020 Creon Butler Research Director, Trade, Investment & New Governance Models: Director, Global Economy and Finance Programme LinkedIn Despite recent outbreaks in several countries which had appeared to be close to excluding the virus, focusing on suppression and elimination is the best economic as well as health strategy. 2020-07-02-Plane-Virus-Business An almost empty British Airways passenger plane flies from Milan to London. Photo by Laurel Chor/Getty Images. Lockdowns are being eased in many countries, but from different starting points in terms of prevalence of the virus, and with different near-term trade-offs between protecting life and easing constraints on economic activity.The pressure to ease is understandable. The IMF estimates $10tn has been spent so far on official support measures worldwide, and forecasts global GDP will contract by an unprecedented 4.9% in 2020.However, the WHO director general, Dr Tedros Adhanom Ghebreyesus, recently insisted that there is an ‘urgent responsibility to do everything we can with the tools we have now to suppress transmission and save lives’, even as research into vaccines and therapeutics continues.Focusing on suppressing and eliminating the virus as quickly as possible is not just the best strategy for saving life, it also makes most sense in terms of minimising the long-term economic damage from the pandemic.The alternatives remain uncertainNeither a vaccine nor improved treatment are currently sufficiently certain to be the focal point for an economic recovery strategy. Despite optimism about vaccine development, there is no certainty of a decisive outcome by a given date. And, even if a vaccine proved effective, manufacturing and distributing it to 8bn people will present an unprecedented set of logistical and economic challenges and take many months, if not years.In the meantime, although substantial progress has been made in reducing loss of life among those made seriously ill by the virus - and who have access to advanced medical facilities - it remains highly dangerous for a significant proportion of the population - around 20% in advanced economies.An alternative containment strategy based on gradually reducing the prevalence of the virus in the population by maintaining an “R” number (replication coefficient) just below one will be both economically costly and highly risky when compared with a decisive push to eliminate the virus quickly.With an R number just below one it is true the virus may eventually disappear, but only over a lengthy period, during which economically damaging social distancing measures will have to stay in place, dragging out the impact on both demand and supply.Wage support measures to limit ‘economic scarring’ will have to be maintained, and kickstarting the economy with a conventional fiscal stimulus will be difficult, if not impossible, especially when the ability - or willingness - of consumers to spend is still heavily constrained either by social distancing measures or a lack of confidence.There is also a major risk when the R number is close to one that the virus could suddenly take off again, leading to a complete failure of the strategy.Benefits of suppress and eliminateA successful policy focused on suppressing and eliminating the virus offers much better prospects. First, the government can then protect the vast bulk of the economy within its territory, even if it means continuing travel restrictions for some time vis-a-vis countries that are less committed to or less successful in eliminating the virus.Some sectors - particularly long-haul air transport - will be hard hit, but other critical high value or employment intensive sectors - such as domestic hospitality, leisure and the arts - will be able to make a substantial recovery. To put it bluntly, the authorities may have to hold back some sectors to save others. Such a strategy would also ensure an economy can participate sustainably in free travel zones with other countries.Second, a drive to suppress and eliminate the virus in the shortest possible timeframe, and then maintain that status, will help authorities communicate clearly to the public the overarching framework guiding the application of social distancing measures, and the nature of the ‘new normal’ economy that can be expected to emerge over the medium to long-term.Achieving such clarity will enhance the public’s trust in the government’s strategy and hence responsiveness to government instructions. It will also minimise unnecessary and costly adaptations by business and increase its ability to target new opportunities arising from the genuine long-term changes brought about by the crisis.In addition, a suppress and eliminate strategy is the only sure way to address the disproportionate impact of the virus on ethnic minorities and the poor, and to put an end to the isolation of the millions who currently have to shield themselves.We know that suppressing the virus almost completely within a given territory is possible because some countries have already done it - notably New Zealand, South Korea, and Taiwan. Some which started with a serious epidemic, such as China, Spain and Italy, have also managed to reach a point where almost complete elimination within their territory can be envisaged.Renewed outbreaks are likely to happen, particularly while the virus remains in active circulation globally. But this does not invalidate the underlying suppress and eliminate strategy.Key policies to suppress and eliminate the virus include: a rapid and decisive national lockdown to reduce the disease to levels low enough for test, trace and quarantine systems to identify and suppress local outbreaks; social distancing measures for a limited period or in a specific locality to limit spread while, as far as possible, minimising economic impact; and effective quarantine and track systems applied at borders to prevent the disease from being re-introduced by non-essential travellers and returning nationals.The precise form of these policies is evolving rapidly as we learn more about the virus. For example, if there is a need today to stop a rapidly escalating epidemic in a given territory, it won’t necessarily mean adopting exactly the same package of lock down measures across the board as were applied three months ago. Several activities had to cease then simply because the virus was spreading so fast there was no time to put in place effective mitigation measures. This does not have to be repeated.In addition, the benefits of the widespread use of face masks are now much better understood. As is the value of deploying a battery of measures, each one only partially effective on its own but, in combination, with a decisive impact. Financial support measures may need to be adjusted or extended to underpin local lockdowns and, at any given point, the authorities will need to work within an overall budget for relaxation measures and prioritise - getting pupils back in school may mean holding back easing of restrictions elsewhere.Choosing an effective strategy inevitably means making tough choices. Delaying short-term recovery measures, even by a matter of weeks in whole economies or specific localities, can make a decisive difference to delivering a long-term sustainable economic outcome. The authorities may also be forced to hold back some economic sectors, possibly even leading to permanent damage, as the price of a general recovery. But if we are not ready to make these choices, the economy may become permanently stuck in a halfway house between lockdown and recovery. Full Article
do Flaring in MENA: The Multibillion Dollar Decarbonization Lever By www.chathamhouse.org Published On :: Wed, 15 Jul 2020 12:05:58 +0000 15 July 2020 Adel Hamaizia Associate Fellow, Middle East and North Africa Programme Dr Mark Davis CEO, Capterio The climate crisis and ‘energy transition’ is driving a response from the oil and gas industry to decarbonize, with flaring – the deliberate combustion of gas associated with oil production – as a critical lever, especially in the Middle East and North Africa, write Adel Hamaizia and Mark Davis. 2020-07-15-Flare-Oil-Iraq Iraqi Southern Oil Company engineers look towards the flares in the Zubair oil field in southern Iraq. Photo by ESSAM -AL-SUDANI/AFP via Getty Images. Flaring is a significant source of economic and environmental waste. Except when safety-related, flared gas can often be captured and monetised using low-cost proven solutions.In doing so, governments can improve health and safety, reduce emissions (of carbon dioxide, methane, and particulates) and add value by driving up revenue, increasing reserves and production, creating jobs and improving the industry’s ‘social license to operate’.Flare capture also helps countries to deliver on the Paris Agreement and the UN’s Sustainable Development Goal #13 while, for example, providing affordable alternatives for heating and cooking.The Middle East and North Africa (MENA) region accounts for 40% of the world’s flaring. In the region, flaring has increased year-on-year - apart from 2018 - to almost six billion cubic feet of gas per day, generating up to 300-500 million tonnes of CO2-equivalent emissions per year.These emissions result not only from the combustion of gas, but also from the venting, from inefficient flares, of un-combusted methane, a more potent greenhouse gas. Yet much of this is avoidable.There are many commercially attractive options to reduce flaring in MENA. The key is to use the right proven technology and to be agile in commercial structuring. And the prize could be a boost to MENA’s annual revenues by up to $200 per second (up to $6.4 billion per year) by delivering wasted gas to market by pipeline, as power or in liquid form.The chart highlights the abundance of flaring across the MENA region, and in many cases, their proximity to population centres. While Iran, Iraq, and Algeria generate 75% of MENA’s flaring, Saudi Arabia, Kuwait, UAE and Qatar are notable for their relatively low ‘flaring intensity’ i.e. flaring normalized to oil production.In today’s world of lower energy prices, it makes sense to monetise every molecule. Even more so for national oil companies, which are responsible for most of the flaring, since they are not only the custodians of their countries’ natural resources, but they also generate a dominant source of government revenue.Most oil producers in MENA have already made commitments to the World Bank’s flaring-reduction initiatives (e.g. ‘Zero Routine Flaring by 2030’), but to date, delivery is mostly lacking. Three main issues have hindered progress.Firstly, operators, regulators, and governments highlight that flaring is often not ‘sufficiently on the radar’. Flaring is often underreported if not ignored or denied - although satellite detection gives unavoidable transparency. In MENA alone, more than 1,700 flare clusters are visible every day from space.Secondly, flare capture is sometimes not perceived to be economically viable due to costs, taxes, or inappropriate technology. Thirdly, there are often issues around resources, especially concerning management bandwidth, delivery capabilities or financing.Yet these issues can be solved if the right proven technologies are combined with the right commercial structures. To accelerate flare capture projects, stakeholders in the MENA hydrocarbons sector must consider several complementary, action-oriented initiatives.In particular, they should:Promote transparency and disclosure to drive greater awareness of flaring. Governments, regulators and operators must understand the real scale of their gas flaring opportunity and be capable of acting, as a recent report for the EBRD on Egypt highlighted. Compliance with clear standards for measuring, monitoring and verification is critical.Advance policies and incentives which encourage action. Better commercial terms will incentivise and accelerate flare investments. Stronger penalties will help, but independent and capable regulators must actually enforce these penalties. Through the use of such clear anti-flaring policies, Norway’s flaring intensity is almost 20 times lower than the MENA region.Improve the investment climate, beyond economics and open access to a broader range of players. Local market failures can be avoided by reducing the complexity and cost of in-country operations and by removing excessive, rigid, or redundant regulations. By enabling greater ‘third-party’ access to gas and power projects and infrastructure, new players can accelerate change by deploying new technologies and new operating models. Better third-party access will also unlock ideas, capital, skills and project-specific financing options. Algeria is making steps towards such liberalisation through its new 2019 Hydrocarbon Law.Reduce subsidies and improve energy efficiency and reduce demand, increase gas exports and boost national revenues. Countries with large subsidies on transport fuels and power, such as Algeria and Iraq, stand to gain the most.Encourage collaboration between stakeholders in industry and government by creating working groups to radiate best practices, build capacity, deploy technology and local content, such as the flare minimization programme in Saudi Arabia or Iraq’s major flare-to-power project operated by the Basrah Gas Company.The industry needs to prepare for a greener world after COVID-19 and investors and consumers are demanding cleaner fuels. Since gas is widely viewed as a transition fuel, MENA governments and stakeholders must work to eliminate its wastage and seize the revenue, production and environmental opportunities that flare capture projects offer.There is much new leadership in the region in government and critical institutions with new mandates for change. The time to act is now. Full Article
do The Folly and Risk of Lopez Obrador’s Washington Trip By www.chathamhouse.org Published On :: Wed, 15 Jul 2020 16:34:54 +0000 15 July 2020 Arturo Sarukhan Associate Fellow, US and the Americas Programme (based in the US) @Arturo_Sarukhan LinkedIn President Andres Manuel Lopez Obrador’s decision to travel to the US was met with concern and incredulity in Mexico and bafflement among many Democrats in the US. Being seen as a close ally to Donald Trump could be detrimental to the future of bilateral relations. 2020-07-15-Mexico-Protest-US-Migration Demo against Donald Trump's migration policies at the San Ysidro port of entry in Tijuana, Baja California state, Mexico. Photo by GUILLERMO ARIAS/AFP via Getty Images. For a leader who had not travelled abroad since his inauguration – skipping G20 and APEC summits and the UN General Assembly – and who is probably one of the most intellectually incurious and disinterested Mexican presidents of the modern era when it comes to global issues, President Andres Manuel Lopez Obrador could have certainly waited until after the US elections in November to travel to Washington and personally engage with President Donald Trump .Instead, Lopez Obrador – who has sought at all cost to avoid conflict with his US counterpart, having decided that bending the knee was a better option than standing his ground with Trump – waded straight into electoral politics in the US, despite his repeated assurances to the contrary.The decision to travel now to Washington was fraught with political and diplomatic challenges, not least the fact that President Trump will use President Lopez Obrador as an electoral prop.To American audiences, at a time when the US is riven by social and political convulsion unseen in 50 years since the Vietnam War and the civil rights movement, meeting with Trump in Washington just before the general campaign starts was seen by many as a pat on the back for a polarizing and unpopular president.In Mexico, most discussion has been about the merits and timing of the visit, with one El Financiero newspaper poll conducted a week before showing public support (59%) for the trip, while a post-visit Reforma newspaper survey showed that a substantial majority of those polled (69%) believe a Biden victory in November is a better outcome for Mexico.While it’s true that Lopez Obrador returned to Mexico unscathed, his visit – and his baffling Rose Garden remarks stating that Trump (the most anti-Mexican US president in modern history) has shown respect to Mexico and Mexicans – is certainly a slap in the face to migrants in the US, 11 million of whom are Mexicans, to American NGOs and activists that defend the rights of migrants and enlightened immigration and asylum policies, and a boon to Trump’s dog-whistle xenophobia and chauvinism.Lopez Obrador’s words added insult to injury by asserting the US president has never imposed anything on Mexico, blithely ignoring Trump’s March 2019 threat to impose punitive tariffs on Mexico unless the country deterred and stopped Central American transmigration flows through Mexico on their way to the US.Certainly if the purpose of the visit was to celebrate the July 1 entry into force of the USMCA – a spin made even more hollow by the fact that Canadian Prime minister Justin Trudeau decided to skip the event – then Lopez Obrador should have been reaching out to the Speaker Nancy Pelosi and the Democratic leadership to meet and thank them too, given the important role they played in supporting the revamping of NAFTA and the ratification of the USMCA.The best-case scenario is that the meeting between the presidents will be leveraged by both governments to address looming hurdles with the entry into force of the USMCA.But Trump still seems intent on wielding punitive tariffs and mercantilist measures to extract concessions from either Canada or Mexico. And across the border, the Lopez Obrador government – and his party in Congress – continue enacting abrupt policy shifts and changes to the rules across different sectors of the economy that bode ill for the level playing field required under the USMCA.What could have easily been achieved via a virtual event has now morphed into a second successive Mexican government jumping on the Trump electoral bandwagon, after Enrique Peña Nieto’s ill-advised invitation to then-candidate Trump to travel to Mexico, and a new opportunity for the US president to ‘pimp’ Mexico for his campaign purposes. Perceptions have certainly deepened among Democrats that Lopez Obrador prefers to see Trump re-elected.Although Lopez Obrador’s aim was to buy Mexico time between now and January of next year by hoping this visit will contain Trump’s anti-Mexican tirades on the campaign trail, whether or not Trump stops using Mexico as a political-electoral piñata is yet to be seen. I would not hold my breath.Moreover, for a leader whose default position is ‘the best foreign policy is domestic policy’, the trip lays bare a paradox in Lopez Obrador’s mantra. It is precisely Mexico’s domestic weaknesses and failings that create foreign policy vulnerabilities, particularly vis-à-vis the Trump administration. And it is likely these will be used in the coming weeks and months to once again to pressure Mexico in what has become Trump’s ‘Sinatra Policy’ towards his southern neighbour: 'My Way'.Perception is indeed reality, and Lopez Obrador – and more importantly Mexico – can ill-afford to be perceived as Trump’s patsies at this juncture of American history. As many expected, it only took four hours after President Lopez Obrador’s White House remarks for Trump-supporting Hispanic-outreach social media accounts to start piggybacking on them. Campaign officials have also specifically said they will likely use his quotes in TV ads aimed at Hispanic voters later this year.In addition, there is a potentially bumpy road ahead for Mexico’s relationship with the Democratic Party. The statements and tweets issued by former vice-president Joe Biden, Biden campaign surrogates and officials, prominent Hispanic Democrats in Congress, and the Democratic National Chair signal as such, as does a letter sent the same day of the visit by Democratic representatives regarding outstanding labour issues in Mexico related to USMCA compliance and enforcement.This trip could have a long-standing impact for Mexico’s relationship with the US – and US society – and the voters that will determine the future of this country in the decades to come. Lopez Obrador’s meeting with Trump could well become a ‘travel now, pay later’ moment in Mexico-US relations. Full Article
do Domestic Violence in Russia: The Impact of the COVID-19 Pandemic By www.chathamhouse.org Published On :: Fri, 17 Jul 2020 12:00:04 +0000 20 July 2020 Ekaterina Aleynikova Research Assistant, Russia and Eurasia Programme @AleynikovaKatya LinkedIn The COVID-19 pandemic has made Russia’s domestic violence problem more visible, with shifting public opinion potentially incentivizing the government to change its approach, argues Ekaterina Aleynikova. GettyImages-1159506648 (1).jpg Campaigners during a rally held in 2019 in support of a Russian law on domestic violence. Photo: Getty Images Russia is one of the few countries in the region to have no legal definition of domestic violence and, as a result, there are no protective measures specific to domestic violence such as restraining orders or compulsory anger management training for abusers. In fact, the government has taken steps in recent years to remove any legal distinction between assault happening in one’s home, and elsewhere, with battery among family or household members for first-time offences decriminalized in 2017.The Russian Ministry of Justice explicitly defended this position in its response to an enquiry into Russian domestic violence cases by the European Court of Human Rights (ECtHR) in November 2019. The ministry claimed existing legislation adequately protects citizens from domestic violence, ‘even though it has never been considered a separate offence’, reiterating that there is ‘no need’ for adopting specific legislation.However, the four cases that led to the ECtHR’s enquiry demonstrate that current legislation is not sufficient. The most prominent case is that of Margarita Gracheva whose ex-husband severed her hands in 2017 despite her having made multiple complaints to the police ahead of the act being committed. If Russian legislation had mechanisms in place to isolate victims from their abusers, then Gracheva could have been protected by the law.Instead, systemic impunity for abusers is supported by statements from people in power excusing domestic violence. The most recent of such statements came from the head of the Chechen Republic, Ramzan Kadyrov, in June 2020. When meeting with the family of a young woman allegedly murdered by her husband, Chechnya’s leader said, husbands beating their wives ‘happens’ and that the young woman should have tried harder to hold on to her marriage. These statements send clear signals to abusers that their actions are justified, and to the victims, that they won’t be protected if they were to come forward.Similarly, to other parts of the world, civil society organizations in Russia have reported an increase in the number of cases of domestic violence during the COVID-19 pandemic. On a personal level, the pandemic has often exacerbated many of the factors that can lead to domestic violence such as stress, economic anxiety or social isolation.On a systemic level, many of the provisions intended to protect victims of violence, which were already ineffective in Russia, have been worsened during the lockdown. Where police may not have rapidly responded to reports of domestic violence previously, under lockdown, they have become focused on other priorities and, where shelters and support networks for the victims may have been scarce in the past, they have been further constrained.Unsurprisingly, the strategy of the Russian state so far has been to deny that there is a problem of domestic violence, with the Ministry of Interior reporting that, according to their statistics, the number of domestic violence cases have gone down during the lockdown. Indeed, Chairwoman of the Federation Council, Valentina Matvienko, has said she does not believe lockdown has increased domestic violence because, on the contrary, families have been ‘brought together’, reflecting wishful thinking at best and negligence at worst.The pandemic has also been used as an excuse to postpone discussion of a federal law on domestic violence, drafted by civil society, that was submitted for review by the Duma last year. This bill would have introduced different types of domestic violence such as psychological and economic violence and transferred domestic violence offences from private to public prosecutions to make it easier for victims to seek justice.The government’s disregard for domestic violence reflects, in part, the patriarchal mindsets of those in power but perhaps, more significantly, the Kremlin’s belief that conservative social groups constitute its main support base. This has been made evident by the politicization of Russia’s ‘traditional’ values in recent years which was vigorously deployed throughout the constitutional amendments campaign. While it is clear that the true purpose of amending the constitution has always been to allow Vladimir Putin to stay in power beyond 2024, amendments relating to this were absent from the government’s campaign. Instead, Russians were encouraged to vote by populist socially-conservative messages, hence why respect for traditional values has been added to the constitution.Despite this, attitudes in Russian society are changing. A February 2020 survey by the Levada Centre showed that 61 per cent of Russians – and 74 per cent of Russian women – think domestic violence is a serious problem.Moreover, the survey shows that women are much more aware of domestic violence than men – with every third woman in Russia admits being aware of domestic violence in their social circles while only every fifth man admits the same. This could be a sign that Russian men and women, on average, have a different understanding of what constitutes domestic violence. If so, adopting a law that defines domestic violence and holding a public awareness campaign is of paramount importance to eliminate any misunderstanding.The difference could also be a sign that victims of domestic violence are more likely to confide in women hence making domestic violence less visible to men. This awareness gap perhaps explains the difference between men’s and women’s assessments of how serious the issue in Russia is.The pandemic has provoked a new wave of discussions of domestic violence among Russia’s population with stories and statistics widely shared in the media and on the internet. As domestic violence becomes more visible, public perceptions are likely to shift further towards recognizing, and hopefully condemning, it. But, while legislation is crucial, the experience of other countries in the region, such as Armenia or Kazakhstan, shows that adopting laws on domestic violence is not enough. Measures are needed to ensure implementation of the law including training police officers and state officials and instituting disciplinary action for negligence of victims’ complaints.Nevertheless, admitting there is a problem with domestic violence in Russia, and introducing laws, are an essential first step. The Russian government seems to have placed its bet on the support of conservative social groups but changing public opinion may prove this strategy unsustainable. Full Article
do Domestic Violence in Ukraine: Lessons from COVID-19 By www.chathamhouse.org Published On :: Thu, 23 Jul 2020 13:45:42 +0000 23 July 2020 Kateryna Busol Robert Bosch Stiftung Academy Fellow, Russia and Eurasia Programme @KaterynaBusol LinkedIn The pandemic has shed light on domestic violence in Ukraine, mobilizing civil society to demand more nuanced policy on the issue. 2020-07-23-UkraineIWD.jpg A protester chants slogans on a megaphone during an International Women's Day protest on 8 March 2019 in Kyiv, Ukraine. Photo: Getty Images. The virus of violenceDuring quarantine, the greater economic vulnerability of Ukrainian women has locked many of them with abusive partners. The uncertainty of personal finances, health and security in confinement has exacerbated domestic violence against women, in certain cases aggravated by the perpetrator’s war-related post-traumatic stress disorder (PTSD).In pre- pandemic times, only one third of domestic violence victims, 78% of whom are women, reported the abuse. During the pandemic, the calls to domestic violence helplines increased by 50% in the Donbas war zone and by 35% in other regions of Ukraine.However, more precise estimates are hard to make. This is largely because some fractions of Ukrainian society still see domestic violence as a private family matter, which will get little assistance from the police. Also, reporting from a small confinement place permanently shared with a perpetrator during the lockdown can trigger more abuse.The COVID-19-tested legal frameworkThe spike in domestic violence during lockdown has intensified the debate about the inadequacy of Ukraine’s approach.Ukraine adopted the law on domestic violence in 2017 and made such behaviour punishable under administrative and criminal law. Importantly, the law does not limit domestic violence to physical abuse, but recognizes its sexual, psychological and economic variations. Domestic violence is further not limited to a married couple or close family members, but can be perpetrated against a distant relative or a cohabiting partner.The extended definition of rape now includes rape of a spouse or a family member as an aggravating circumstance. A special police unit has been designated to deal with domestic abuse cases. Police can now issue protection orders in prompt reaction to an offence and immediately distance a perpetrator from a victim.The victim can also spend time in a shelter - a system which the Ukrainian government has promised to create. A special registry of domestic violence cases has been set up for the exclusive use by the designated law enforcement and social security authorities to help them be more holistically informed in building a response.However important, the introduced legal and institutional infrastructure was slow in proving its efficiency pre-COVID-19. It is struggling even more to stand the test of the coronavirus.Changing the established mindset takes time. 38% of Ukraine’s judges and 39% of prosecutors still struggle to see domestic violence not as a household issue. Even though the police are becoming more reactive to home abuse complaints, getting emergency protection orders is still difficult. The court restraining orders are more effective, however they require the unnecessarily protracted and humiliating procedures of proving one’s own victimhood to different state authorities.In response to the challenges of coronavirus for women, the police spread information posters and created a special chat-bot about the available help. However, while the domestic violence helplines of La Strada and other human rights NGOs are busier than ever, the police statistics suggest that the lockdown has not catalyzed home abuse.This could indicate a higher trust to non-state institutions and the inability of a considerable group of women to use more sophisticated communication means such as chat-bots when they cannot call the police in the presence of an abuser. This problem is exacerbated by a current lack of shelters in rural areas, as most are located in urban settings. Overcrowded in ordinary times, the shelters’ capacity to accept survivors during the lockdown is further limited by the social distancing rules.Istanbul Convention – The bigger pictureUkraine failed to ratify the Council of Europe Convention on preventing and combating violence against women, better known as the Istanbul Convention, largely due to the opposition of religious organizations. Concerned that the treaty’s terms ‘gender’ and ‘sexual orientation’ would contribute to the promotion of same-sex relationships in Ukraine, they argued that Ukraine’s current legislation provides adequate protection against domestic violence. However, this is not the case.The Istanbul Convention does not ‘promote’ same-sex relationships, it only mentions sexual orientation among the non-exhaustive list of prohibited discrimination grounds. Remarkably, Ukraine’s domestic violence law itself is against such discrimination.The Convention defines ‘gender’ as the socially constructed roles a society attributes to women and men. Ukraine’s overcautiousness about the term is ironic at least in two dimensions.First, the 2017 domestic violence law restates its aim to eliminate discriminating beliefs about the social roles of each ‘sex’. In doing so, the law supports the rationale of what the Istanbul Convention denotes as ‘gender’ without using the term itself.Second, it is exactly the constraints of the rigidly defined niches for both sexes in Ukraine that have substantially contributed to the intensified domestic violence, whether it be war or coronavirus-related. The lack of sustainable psychological support for traumatized veterans and the stigma of mental health struggles, especially among men, mars their reintegration to peaceful life. This often results in alcohol abuse or even suicide.As the economic uncertainty of the war and the virus prevents some men from fully living up to their traditional socially - and self-imposed - breadwinner role, this increases the risk of problematic behaviour and domestic violence.By diverting the focus of the debate to the term ‘gender’ used in the Istanbul Convention, conservative groups have ignored the fact that it describes the priority already enshrined in Ukraine’s 2017 law - to eliminate discriminatory beliefs about the socially constructed roles of men and women. This has drawn away time and resources needed to protect those vulnerable to domestic abuse.Ukraine has not addressed the pigeonholing of women and men into gendered stereotypes. This has harmed men while further victimizing women and children, especially during the lockdown. Ironically, this is leading to the undermining of the very traditional family values certain opponents of the Istanbul Convention appealed to.Fortunately, Ukraine’s ever-vigilant civil society, dismayed at the wave of the lockdown domestic violence, petitioned President Zelenskyy to ratify the Convention. With a new draft law on ratification, the ball is now in the parliament’s court. It remains to be seen whether Ukraine’s policymakers will be up to the task. Full Article
do COVID-19 Teaches Resilience and the ‘Vulnerability Paradox’ By www.chathamhouse.org Published On :: Fri, 07 Aug 2020 17:37:37 +0000 7 August 2020 Dr Gareth Price Senior Research Fellow, Asia-Pacific Programme @DrGarethPrice Google Scholar Christopher Vandome Research Fellow, Africa Programme LinkedIn Humility from decision-makers, building trust in leaders and institutions, and learning from international experience are critical if countries are to better prepare for the next global crisis. 2020-08-07-Vietnam-Health-Virus-Art An information poster on preventing the spread of COVID-19 in Hanoi, Vietnam. Photo by MANAN VATSYAYANA/AFP via Getty Images. While we must wait for the final reckoning of most successful national coronavirus responses, it does still appear those countries with memories of MERS and SARS - such as Singapore, Taiwan, Hong-Kong, and South Korea – led the way in being best prepared for COVID-19, with strong contract tracing and isolation measures.Experience of previous outbreaks informed the containment strategies adopted by countries in East Asia in response to COVID-19. Vietnam reported its first case of COVID-19 in January but, over the following four months with rapid targeted testing, contact tracing and successful containment, only around 300 additional cases with no deaths were confirmed.These countries learned to be flexible fast when new transmissions occurred, establishing quick lockdown measures targeted at key groups such as Singapore’s schools or South Korea’s night clubs and religious centres. In stark contrast, most European countries were overwhelmed by the pandemic despite enjoying world-class health systems, predictive models, scientific expertise, wealth, and resources.Asia may have suffered first from coronavirus, but there is no ‘first mover advantage’ in dealing with a pandemic. The more resilient a society, the better placed it is to cope with a variety of risks and challenges. But to become resilient, a society needs to have faced setbacks and learned from them. And to remain resilient, it needs to stay aware of its own vulnerabilities and avoid complacency.Prior experience of crises and disturbances, coupled with a ‘trial and error’ process of learning to deal with them, makes a society more resilient, whereas high levels of economic welfare and relative lack of recent crises leave some societies less prepared to face shocks. This is known as the ‘vulnerability paradox’.Within Europe, it has actually been the Greek handling of COVID-19 that so far appears more successful than others. Greece is a country which has suffered a decade of austerity leading to a weakened healthcare system. And with one of Europe’s oldest populations, the Greek government was keenly aware of its own vulnerabilities. This prompted an early lockdown and a rapid increase in intensive care beds.Although better state capacity and health system capability are clearly positives for mitigating disasters, citizens do tend to be less familiar with risk preparedness. This lack of experience can then breed complacency which threatens societies where risks are often complex, numerous, transboundary and inter-related.Conversely, the absence of systemic resilience at a national level often puts the onus on family units or local communities – creating resilience as a necessary response to weak government capacity. There is little choice but to learn to look after yourself and your community.However, although the vulnerability paradox helps explain why prior experience makes a system more resilient, societies need to stay aware of their own vulnerabilities and avoid complacency if they are to continually remain resilient.Complacency coupled with a belief in the virtues of the free market has left some countries hit harder than others by the pandemic. In normal times, ‘just in time’ business models can be highly efficient compared to holding vast stocks. But it does not require hindsight to know that a global health crisis will see demand for protective equipment soar and these business models severely challenged.Several societies have also witnessed a decline in trust towards institutions, especially politicians or the media. The deployment of science as justification for political decisions around coronavirus was presumably intended to help garner trust in those decisions. But when the science itself is inexact because of inadequate or emerging knowledge, this strategy is hardly fail-safe.COVID-19 does provide an opportunity to rebuild trust by rethinking the relationship between the state and its citizens, to engage people more directly in a discussion about societal resilience with empowered citizens, and to rebuild a social contract between state and society in the context of recent significant changes and further potential threats.It should also provide a salutary wake-up call to a range of ‘strongmen’ leaders prone to portraying issues rather simplistically. Although COVID-19 may be one of the few complex problems to which simplistic measures do apply - such as wearing a mask and using social distancing – these do not provide the whole solution.Generally, declining trust in politicians reflects the ongoing inability of current politics to deal with a range of societal challenges. COVID-19 is certainly the most sudden and presents the biggest immediate economic shock of recent times, but it is just the latest in a long line of examples of political failure, such as conflict in the Middle East, climate change, terrorism, and cyber-attacks.Along with the growth of automation and digitization which provide opportunities at the macro-level but threats at a more micro-level, what most of these issues have in common is that national responses are likely to fail. Restoring trust requires re-energized global governance, and this means compromise and humility – qualities which appear in short supply to many current politicians.But, regardless of political will, building resilience to tackle ongoing or rapidly forthcoming challenges also rubs up against free market beliefs, because building resilience is a long-term investment and comes at a price. But by acknowledging vulnerabilities, avoiding complacency, implementing lessons from past experiences, and learning from others, policymakers will be better prepared for the next crisis.Reconstructing societies through the prism of resilience creates fundamentally different outcomes to global challenges, and can build trust between elected representatives and the wider population. Accepting the vulnerability paradox and acknowledging that those generally less prone to disasters are actually less able to cope when change happens creates a powerful argument for this new approach. Full Article
do International Donors Can End Lebanon's Corruption By www.chathamhouse.org Published On :: Mon, 10 Aug 2020 19:46:51 +0000 10 August 2020 Dr Lina Khatib Director, Middle East and North Africa Programme @LinaKhatibUK Change must come from within Lebanon, but Emmanuel Macron and others can help by ending their patronage of a disastrous regime. 2020-08-10-Lebanon-Beirut-Corruption-Protest An anti-government protester in Beirut puts up a poster accusing corruption in Lebanon's state judiciary. Photo by Sam Tarling/Getty Images. In the aftermath of the devastating Beirut port explosion last week, it is not just the role of the Lebanese political class that has come under scrutiny, but that of their international peers too.Sunday’s international donor conference led by the French president, Emmanuel Macron, raised €253m (£228m) in relief funds, but it also signalled an important change in rhetoric. For the first time, donors affirmed that relief funds would directly go to the Lebanese people, and that longer-term economic assistance would be dependent on Lebanon implementing structural reforms.This affirmation came hot on the heels of growing international attention on rampant corruption among Lebanon’s ruling political class, which is widely blamed for the port explosion. It sends the message to Lebanon’s rulers that, while their country desperately needs foreign assistance to stand on its feet, no one can help Lebanon if it does not also help itself.But the communique issued following the conference glossed over the international community’s own role in sustaining Lebanon’s corrupt political class over a period of decades. At the aid conference, Macron said that Lebanon’s future is at stake. What donors need to recognise is that this future is a shared responsibility for them and Lebanon’s leaders alike.With Lebanon’s debt greater than 170% of its GDP, and with the port explosion costing an estimated $15bn of damage, Lebanon needs foreign assistance to prevent it becoming a failed state. But what it needs even more desperately are reforms that would counter the corruption and lack of accountability that led it to this sorry state of affairs in the first place.It is Lebanon’s existing political system – a power-sharing pact between different sects rather than a system of governance on the basis of competence – that facilitates its leaders’ reckless behaviour.The international community is partly responsible for sustaining this system through cascading patronage. For decades, Lebanese leaders grew accustomed to neglecting the national interest and eventually being bailed out by international assistance. Dollar deposits would land in the central bank from Gulf donors, loans would be offered by European countries and foreign aid packages would flow to Lebanese state institutions – only for the majority of this money to end up lining the pockets of the country’s rulers, who frequently overcame their political differences to share state resources between them. The Lebanese state came to exist as a shell in the eyes of its citizens.Lebanon’s rulers benefited from citizens’ low expectations from the state and the lack of measures ensuring transparency and accountability in the country. They brokered a social contract that cast the leaders as patrons and the people as clients rather than citizens. Foreign powers were well aware of this dynamic but they often turned a blind eye to it, and even nurtured it, because they believed the Lebanese political system brought stability and predictability following the tumultuous civil war.With time the leaders’ greed grew, and with that the economic situation worsened. Leaders who behaved as de facto local authorities, granting constituents civil service jobs or minor privileges, provided them less and less. There was some international recognition that this dynamic was becoming unsustainable – international donors pledged $11bn during the CEDRE conference of 2018 on condition that Lebanon implemented structural reforms.And in the wake of Lebanon’s recent economic deterioration, the International Monetary Fund said in April that any discussion of a loan to Lebanon would be subject to more reforms. On both occasions, Lebanon’s rulers ignored the calls for reform, counting on foreign support eventually coming in unconditionally as it used to in the past. International donor follow-up was sluggish.The port explosion needs to be a wake-up call for any international entity seeking a stable Lebanon. The blast is ultimately the result of the decades during which political classes in Lebanon and outside it fostered the country’s dysfunctional political system. No long-term assistance should flow into Lebanon without strong conditions on transparency and accountability in how this assistance would be employed.Foreign support is not the problem per se, but rather when it is handed on a plate unconditionally, maintaining the patronage cascade, exacerbating the weakness of state institutions, and further impoverishing Lebanese citizens.With Lebanon’s economy almost crumbling in the aftermath of the explosion, there is an opportunity for the international community to exert leverage over Lebanese leaders – whose personal wealth grew partially from legal and illegal transactions through the devastated port – so that necessary reforms are implemented. Such leverage would not remove Lebanon’s defective political system, but would pressure its leaders to accept at least some basic reforms.But for Lebanon to really turn a new page, it needs a new social contract and a new political system based on fairness, transparency and accountability. This is a change that can only start from within Lebanon, but it also depends on the international community abandoning their tacit support of a disastrous political status quo.This article was originally published in The Guardian. Full Article
do Has the Dollar Started Its Long Decline? By www.chathamhouse.org Published On :: Fri, 28 Aug 2020 11:54:24 +0000 28 August 2020 Jim O'Neill Chair, Chatham House Ultimately, the dollar’s dominance cannot persistently outweigh the relative decline of the US economy in the world. At some point, it will start to be replaced by something else. But don’t confuse that with where the dollar’s price is heading against other currencies. 2020-08-28-us-dollar-oneill.jpg A statue of George Washington is pictured in front of the New York Stock Exchange (NYSE) on 16 March 2020, at Wall Street in New York City. Photo by JOHANNES EISELE/AFP via Getty Images. One of the features of financial markets since early summer has been a decline in the value of the dollar against many currencies, and with it, an especially interesting acceleration in the price of gold. In addition to the usual professional market analysis about the dollar’s movement, this has led to speculation that it might be the beginning of the end of the dollar’s pre-eminence.Having spent far too much of my professional life as a supposed currency expert, I reiterate something I learnt early on: the foreign exchange business sometimes grants an analyst their 15 minutes of fame, but no expert is a match for the millions who participate in this huge global market all day long. But I spent over 30 years in the financial markets, the vast majority in the hubbub of the forex market. And along the journey, I think I learnt a few tricks of the trade.At the core of trying to answer questions about the dollar, I learnt a long time ago that there are two entirely separate questions, one of which has two subsections, about the dollar. Firstly, there is the question about the use of the dollar. Will it continue to dominate the world’s financial system as the most widely accepted medium of exchange?This is not at all the same issue as the dollar’s day-to-day performance against other currencies. This is the second question, which is almost definitely the most pertinent one to what has happened during the summer. How the dollar’s value moves against other currencies is driven by a structural, or a valuation component, and a cyclical component. Each can be analysed separately, and if you were daft enough to devote the years I did to the process, you can combine the two, to have a dynamically adjusted fair value, persuading yourself at least that such an approach combines all available information at any point in time.In terms of valuation, the most common approach is so-called purchasing power parity, which holds that a currency, in equilibrium, will ultimately reflect the difference in prices between two countries. If inflation is persistently higher in the US than in the eurozone, then the equilibrium value of the dollar will decline over time. I developed my own version of equilibrium currency rates, as it seemed to me in the real world, that the real inflation adjusted value of a currency was not stable, and that it moved over time. This was a reflection of productivity differentials between two countries. I christened it GSDEER: 'the Goldman Sachs Dynamic Equilibrium Real Exchange Rate' when I joined the firm in 1995.What I learned is that when a currency is more than two standard deviations away from its fair value, it makes a huge amount of sense to watch closely, and when the momentum changes, it is worth going with this trend reversal. The momentum can change based on a change in the forces that have driven the currency away from its fair value, although it can be often easier to detect simply by watching the change in price.One of the things that has frustrated currency participants over the past decade, with the exception of the Swiss franc and the pound, is that other major currencies have not been that far away from their fair value against the dollar or each other. Even during the dollar’s rise in recent years, including the period up to the summer, while it had clearly become overvalued, with the possible exception of the pound, it hadn’t become more than two standard deviations above its own fair value. In this regard, I have believed that one might be on the lookout for a chance to buy the pound against the dollar, and perhaps against the yen.The cyclical component of a currency’s movement around its conceptual equilibrium can perhaps best be captured in the nominal interest rate adjusted for inflation expectations. I persuaded myself that the actual spot exchange rate of the dollar on any one day should be close to the adjusted GSDEER, and if it was not, then it would be useful for traders.The dollar had become more interesting pre-COVID, as it appeared to have risen notably against many currencies, including the euro. And in this regard, the dollar was highly susceptible, and has turned out to be actually vulnerable, to a change in the state of the US and euro area economies. Now that the Federal Reserve has returned to extremely expansive monetary policy, and with it, lower real interest rates, a dollar decline seemed pretty inevitable.At current prices, on 26 August, the dollar still seems modestly expensive compared to dynamically adjusted fair value. The dollar decline could persist. In the late 1980s and mid 1990s, the dollar fell to very low levels and became very undervalued — this tended to coincide with widespread talk about the dollar’s preeminence, which turned out to be, at least for that era, wrong. And I do share the views of some people who believe, as a result of US policies, conditions are more conducive to a sustained period of dollar weakness. This requires strong ongoing evidence that Europe, China and much of the rest of Asia continue to manage COVID-19 better than the US, and that their cyclical recoveries from the pandemic continue to surprise relative to the US.Now as for the first question, about the demise of the dollar’s dominance, let me repeat that this is largely a separate issue, but I encourage any reader to be careful about getting sucked into this belief in making an investment or hedging decision.It is quite possible that the use of the dollar can decline, and start off a systematic decline even when its value is strong. Indeed, in the past couple of years when its value was largely rising, decisions made by US policymakers to use the dollar’s dominance as a way of penalising other countries has resulted in those countries reducing their share of dollar currency reserves. Russia is a particular example, and there is some modest evidence that China is doing likewise.And the opposite can also be true.Ultimately, the dollar’s dominance cannot persistently outweigh the relative decline of the US economy in the world, which has been occurring now for 20 years. At some point, it will start to be replaced by something else. Whether that is, the renminbi, the euro, Bitcoin, the return of gold — all are conceivable, and may happen. It might be starting now. But don’t confuse that with where the dollar’s price is heading against other currencies in coming days, weeks, or in 2021.This article was originally published in The Article. Full Article
do Kuwait: Brighter Future Beckons for Domestic Violence Sufferers By www.chathamhouse.org Published On :: Wed, 16 Sep 2020 10:10:59 +0000 16 September 2020 Dr Alanoud Alsharekh Associate Fellow, Middle East and North Africa Programme @aalsharekh LinkedIn The passing of a new family protection law is a major step forward for a country which has long suffered from high levels of hidden domestic abuse. But much work remains to be done in ensuring the principles it enshrines are translated to practical action and support for victims. 2020-09-16-Kuwait-Parliament-Women Safa Al Hashem MP holds a red rose to mark Valentine's Day at the National Assembly in Kuwait City on February 14, 2017, the year a domestic violence bill was first introduced. Photo by YASSER AL-ZAYYAT/AFP via Getty Images. Domestic violence has always been a complex issue in Kuwaiti culture, often tied to norms and beliefs relating to family structures and concepts of guardianship, honour and discipline. As with other forms of abuse within the family, it is also considered a private matter and therefore not addressed publicly.Despite a lack of up to date figures, the problem is widespread, affecting 53.1% of women in Kuwait according to a 2018 study. But Kuwait’s last submission to the Committee on the Elimination of Discrimination against Women (CEDAW) showed only 447 domestic violence cases had been through the court system in 2016, and only 76 of those resulted in a conviction. Given the known difficulties of reporting abuse and getting a case to court, it is not a stretch to conclude the actual figures of abused women is much higher than this figure given by the Ministry of Justice.In one recently reported case, a pregnant woman was shot in the head and killed by one of her brothers while she was recovering in the in the intensive care unit of Mubarak Hospital from being shot by her other brother the day before. The reason for such a horrific double attack was she had married without her sibling's consent, even though her father had accepted the match.Worryingly, activists and experts claim domestic violence has been rising in Kuwait during COVID-19, in keeping with global trends during lockdowns, and aggravated by the lack of legal resources and shelters for survivors. Highlighting this unfortunate situation, along with worldwide interest in the issue of domestic violence within the current epidemic, did lead to renewed media interest in the issue in Kuwait, and brought the lack of resources available to abuse survivors into the public eye.And it is this renewed attention – alongside the fact Kuwait is about to enter an election cycle in November – that may well have driven recent governmental and parliamentary moves on the long-awaited family protection law, which recently passed in Kuwait’s national assembly with 38 votes for, one MP abstaining, and another voting against.But 17 MPs were conspicuously absent from the room, including the Women and Family Committee rapporteur Alhumaidi Alsubaei, known for his human rights activism. This signals how complex the social and political issues associated with domestic violence as, although the official version of the law is yet to be made public, the submitted bill contained 26 articles.The articles call for the formation of a National Family Protection Committee to draw up plans countering the spread of domestic violence in Kuwait, as well as the review and amendment of existing national laws which may be perpetuating the violence. Other provisions cover mandatory training programs for all government sectors involved in family protection, awareness programmes on detection, reporting and survivor advocacy, and issuing an annual report about domestic violence statistics.Article 5 specifically calls for activating a domestic violence shelter and offering rehabilitation and advisory services, while Article 13 tackles the punishment of those who try and coerce survivors not to report abuse. These two articles are especially important because, although the Fanar Advisory Service and Domestic Abuse Shelter was formally opened in 2017, it has never actually been functional due to the delay of legislation needed to make it operational. Described as a ’stillborn dream’, the unused building is surrounded by sewage water.The new family protection law also gives important provision for cooperation with civil society organizations, such as Eithar, Abolish 153, and Soroptomists Kuwait working on this issue. Although Kuwait already has several official bodies meant to be dealing with ending violence against women, in reality it has been these groups effectively dealing with the plight of abuse survivors. With no functional shelters, dedicated hotlines or specialized resources to assist victims, Eithar and Soroptimists Kuwait provide resources and support, while Abolish 153 focuses on filling the hitherto legal vacuum.The path to getting this law put to a vote has been a long and winding one. Back in 2017, Saleh Ashoor MP submitted the first version of the domestic violence bill when he was heading up the Women and Family Affairs Committee. At that time, the bill was signed by just four other MPs - Safa Al Hashem, Ahmad Al Fadhel, Khalil Al Saleh and Faisal Al Kanderi. But it was the starting point and, several iterations later, it is essentially a version of that proposal which has been voted into law.Much of the delay over the past three years, both with the legislation and activation of the shelter, has been due to the fact there were many bodies involved, such as the Ministry of Interior, the Ministry of Social and Labor Affairs, and civil society representatives, all of whom at times had different agendas. But alongside the amendment to the press and publication law which also passed that same historic day in parliament, the family protection law is undoubtedly a major win for all those liberal civil society activists who have lobbied long and hard to change these dangerous and restrictive legislations in Kuwait. Full Article
do The bacterial cell division protein fragment EFtsN binds to and activates the major peptidoglycan synthase PBP1b [Metabolism] By www.jbc.org Published On :: 2020-12-25T00:06:31-08:00 Peptidoglycan (PG) is an essential constituent of the bacterial cell wall. During cell division, the machinery responsible for PG synthesis localizes mid-cell, at the septum, under the control of a multiprotein complex called the divisome. In Escherichia coli, septal PG synthesis and cell constriction rely on the accumulation of FtsN at the division site. Interestingly, a short sequence of FtsN (Leu75–Gln93, known as EFtsN) was shown to be essential and sufficient for its functioning in vivo, but what exactly this sequence is doing remained unknown. Here, we show that EFtsN binds specifically to the major PG synthase PBP1b and is sufficient to stimulate its biosynthetic glycosyltransferase (GTase) activity. We also report the crystal structure of PBP1b in complex with EFtsN, which demonstrates that EFtsN binds at the junction between the GTase and UB2H domains of PBP1b. Interestingly, mutations to two residues (R141A/R397A) within the EFtsN-binding pocket reduced the activation of PBP1b by FtsN but not by the lipoprotein LpoB. This mutant was unable to rescue the ΔponB-ponAts strain, which lacks PBP1b and has a thermosensitive PBP1a, at nonpermissive temperature and induced a mild cell-chaining phenotype and cell lysis. Altogether, the results show that EFtsN interacts with PBP1b and that this interaction plays a role in the activation of its GTase activity by FtsN, which may contribute to the overall septal PG synthesis and regulation during cell division. Full Article
do What challenges does the new president of Somalia face? By www.chathamhouse.org Published On :: Tue, 28 Jun 2022 12:56:43 +0000 What challenges does the new president of Somalia face? Explainer Video aboudiaf.drupal 28 June 2022 Ahmed Soliman examines the challenges the new president Hassan Sheikh Mohamud faces in his first 100 days as president. Key issues for the new administration are a deteriorating situation with regards to drought as close to half the population are facing food insecurity due to a fourth failed rainy season. Combined with an inflation rate above ten per cent, many Somalis are at risk of famine and starvation. Many areas of the country are affected from the pastoralist regions to those which house IDP camps around the capital city and other towns, all being exacerbated by the war in Ukraine as Somalia was importing much of its wheat imports from Ukraine and Russia. Full Article
do The Translation of Dosimetry into Clinical Practice: What It Takes to Make Dosimetry a Mandatory Part of Clinical Practice By jnm.snmjournals.org Published On :: 2024-09-05T07:37:49-07:00 Full Article
do Impact of 18F-FDG PET/MRI on Therapeutic Management of Women with Newly Diagnosed Breast Cancer: Results from a Prospective Double-Center Trial By jnm.snmjournals.org Published On :: 2024-10-10T08:33:38-07:00 Visual Abstract Full Article
do [18F]FDG and [68Ga]Ga-FAPI-04-Directed Imaging for Outcome Prediction in Patients with High-Grade Neuroendocrine Neoplasms By jnm.snmjournals.org Published On :: 2024-10-30T08:04:15-07:00 Visual Abstract Full Article
do Overdose crisis: more common sense and less ideology By www.bmj.com Published On :: Tuesday, November 12, 2024 - 10:55 Full Article
do Re: Decompression alone or with fusion for degenerative lumbar spondylolisthesis (Nordsten-DS): five year follow-up of a randomised, multicentre, non-inferiority trial By www.bmj.com Published On :: Tuesday, November 12, 2024 - 16:16 Full Article
do Novel Proteomic Profiling of Epididymal Extracellular Vesicles in the Domestic Cat Reveals Proteins Related to Sequential Sperm Maturation with Differences Observed between Normospermic and Teratospermic Individuals By www.mcponline.org Published On :: 2020-12-01 Tricia RowlisonDec 1, 2020; 19:2090-2103Research Full Article
do Kinome Profiling of Primary Endometrial Tumors Using Multiplexed Inhibitor Beads and Mass Spectrometry Identifies SRPK1 as Candidate Therapeutic Target By www.mcponline.org Published On :: 2020-12-01 Alison M. KurimchakDec 1, 2020; 19:2068-2089Research Full Article
do Unraveling the MAX2 Protein Network in Arabidopsis thaliana: Identification of the Protein Phosphatase PAPP5 as a Novel MAX2 Interactor By www.mcponline.org Published On :: 2020-12-28 Sylwia StrukDec 28, 2020; 0:RA119.001766v1-mcp.RA119.001766Research Full Article
do On the robustness of graph-based clustering to random network alterations By www.mcponline.org Published On :: 2020-11-04 R. Greg StaceyNov 4, 2020; 0:RA120.002275v1-mcp.RA120.002275Research Full Article
do Proteome analysis reveals a significant host-specific response in Rhizobium leguminosarum bv viciae endosymbiotic cells By www.mcponline.org Published On :: 2020-11-19 David DuránNov 19, 2020; 0:RA120.002276v1-mcp.RA120.002276Research Full Article
do A proteomics-based assessment of inflammation signatures in endotoxemia By www.mcponline.org Published On :: 2020-12-07 Sean A BurnapDec 7, 2020; 0:RA120.002305v1-mcp.RA120.002305Research Full Article
do Peptidomics-driven strategy reveals peptides and predicted proteases associated with oral cancer prognosis By www.mcponline.org Published On :: 2020-11-11 Leandro Xavier NevesNov 11, 2020; 0:RA120.002227v1-mcp.RA120.002227Research Full Article
do Pluripotency of embryonic stem cells lacking clathrin-mediated endocytosis cannot be rescued by restoring cellular stiffness [Molecular Biophysics] By www.jbc.org Published On :: 2020-12-04T00:06:06-08:00 Mouse embryonic stem cells (mESCs) display unique mechanical properties, including low cellular stiffness in contrast to differentiated cells, which are stiffer. We have previously shown that mESCs lacking the clathrin heavy chain (Cltc), an essential component for clathrin-mediated endocytosis (CME), display a loss of pluripotency and an enhanced expression of differentiation markers. However, it is not known whether physical properties such as cellular stiffness also change upon loss of Cltc, similar to what is seen in differentiated cells, and if so, how these altered properties specifically impact pluripotency. Using atomic force microscopy (AFM), we demonstrate that mESCs lacking Cltc display higher Young's modulus, indicative of greater cellular stiffness, compared with WT mESCs. The increase in stiffness was accompanied by the presence of actin stress fibers and accumulation of the inactive, phosphorylated, actin-binding protein cofilin. Treatment of Cltc knockdown mESCs with actin polymerization inhibitors resulted in a decrease in the Young's modulus to values similar to those obtained with WT mESCs. However, a rescue in the expression profile of pluripotency factors was not obtained. Additionally, whereas WT mouse embryonic fibroblasts could be reprogrammed to a state of pluripotency, this was inhibited in the absence of Cltc. This indicates that the presence of active CME is essential for the pluripotency of embryonic stem cells. Additionally, whereas physical properties may serve as a simple readout of the cellular state, they may not always faithfully recapitulate the underlying molecular fate. Full Article
do Angiostatic cues from the matrix: Endothelial cell autophagy meets hyaluronan biology [Glycobiology and Extracellular Matrices] By www.jbc.org Published On :: 2020-12-04T00:06:06-08:00 The extracellular matrix encompasses a reservoir of bioactive macromolecules that modulates a cornucopia of biological functions. A prominent body of work posits matrix constituents as master regulators of autophagy and angiogenesis and provides molecular insight into how these two processes are coordinated. Here, we review current understanding of the molecular mechanisms underlying hyaluronan and HAS2 regulation and the role of soluble proteoglycan in affecting autophagy and angiogenesis. Specifically, we assess the role of proteoglycan-evoked autophagy in regulating angiogenesis via the HAS2-hyaluronan axis and ATG9A, a novel HAS2 binding partner. We discuss extracellular hyaluronan biology and the post-transcriptional and post-translational modifications that regulate its main synthesizer, HAS2. We highlight the emerging group of proteoglycans that utilize outside-in signaling to modulate autophagy and angiogenesis in cancer microenvironments and thoroughly review the most up-to-date understanding of endorepellin signaling in vascular endothelia, providing insight into the temporal complexities involved. Full Article
do Human pancreatic cancer cells under nutrient deprivation are vulnerable to redox system inhibition [Cell Biology] By www.jbc.org Published On :: 2020-12-04T00:06:05-08:00 Large regions in tumor tissues, particularly pancreatic cancer, are hypoxic and nutrient-deprived because of unregulated cell growth and insufficient vascular supply. Certain cancer cells, such as those inside a tumor, can tolerate these severe conditions and survive for prolonged periods. We hypothesized that small molecular agents, which can preferentially reduce cancer cell survival under nutrient-deprived conditions, could function as anticancer drugs. In this study, we constructed a high-throughput screening system to identify such small molecules and screened chemical libraries and microbial culture extracts. We were able to determine that some small molecular compounds, such as penicillic acid, papyracillic acid, and auranofin, exhibit preferential cytotoxicity to human pancreatic cancer cells under nutrient-deprived compared with nutrient-sufficient conditions. Further analysis revealed that these compounds target to redox systems such as GSH and thioredoxin and induce accumulation of reactive oxygen species in nutrient-deprived cancer cells, potentially contributing to apoptosis under nutrient-deprived conditions. Nutrient-deficient cancer cells are often deficient in GSH; thus, they are susceptible to redox system inhibitors. Targeting redox systems might be an attractive therapeutic strategy under nutrient-deprived conditions of the tumor microenvironment. Full Article
do Agonist-activated glucagon receptors are deubiquitinated at early endosomes by two distinct deubiquitinases to facilitate Rab4a-dependent recycling [Signal Transduction] By www.jbc.org Published On :: 2020-12-04T00:06:05-08:00 The glucagon receptor (GCGR) activated by the peptide hormone glucagon is a seven-transmembrane G protein–coupled receptor (GPCR) that regulates blood glucose levels. Ubiquitination influences trafficking and signaling of many GPCRs, but its characterization for the GCGR is lacking. Using endocytic colocalization and ubiquitination assays, we have identified a correlation between the ubiquitination profile and recycling of the GCGR. Our experiments revealed that GCGRs are constitutively ubiquitinated at the cell surface. Glucagon stimulation not only promoted GCGR endocytic trafficking through Rab5a early endosomes and Rab4a recycling endosomes, but also induced rapid deubiquitination of GCGRs. Inhibiting GCGR internalization or disrupting endocytic trafficking prevented agonist-induced deubiquitination of the GCGR. Furthermore, a Rab4a dominant negative (DN) that blocks trafficking at recycling endosomes enabled GCGR deubiquitination, whereas a Rab5a DN that blocks trafficking at early endosomes eliminated agonist-induced GCGR deubiquitination. By down-regulating candidate deubiquitinases that are either linked with GPCR trafficking or localized on endosomes, we identified signal-transducing adaptor molecule–binding protein (STAMBP) and ubiquitin-specific protease 33 (USP33) as cognate deubiquitinases for the GCGR. Our data suggest that USP33 constitutively deubiquitinates the GCGR, whereas both STAMBP and USP33 deubiquitinate agonist-activated GCGRs at early endosomes. A mutant GCGR with all five intracellular lysines altered to arginines remains deubiquitinated and shows augmented trafficking to Rab4a recycling endosomes compared with the WT, thus affirming the role of deubiquitination in GCGR recycling. We conclude that the GCGRs are rapidly deubiquitinated after agonist-activation to facilitate Rab4a-dependent recycling and that USP33 and STAMBP activities are critical for the endocytic recycling of the GCGR. Full Article
do Transcription factor NF-{kappa}B promotes acute lung inȷury via microRNA-99b-mediated PRDM1 down-regulation [Developmental Biology] By www.jbc.org Published On :: 2020-12-25T00:06:31-08:00 Acute lung injury (ALI), is a rapidly progressing heterogenous pulmonary disorder that possesses a high risk of mortality. Accumulating evidence has implicated the activation of the p65 subunit of NF-κB [NF-κB(p65)] activation in the pathological process of ALI. microRNAs (miRNAs), a group of small RNA molecules, have emerged as major governors due to their post-transcriptional regulation of gene expression in a wide array of pathological processes, including ALI. The dysregulation of miRNAs and NF-κB activation has been implicated in human diseases. In the current study, we set out to decipher the convergence of miR-99b and p65 NF-κB activation in ALI pathology. We measured the release of pro-inflammatory cytokines (IL-1β, IL-6, and TNFα) in bronchoalveolar lavage fluid using ELISA. MH-S cells were cultured and their viability were detected with cell counting kit 8 (CCK8) assays. The results showed that miR-99b was up-regulated, while PRDM1 was down-regulated in a lipopolysaccharide (LPS)-induced murine model of ALI. Mechanistic investigations showed that NF-κB(p65) was enriched at the miR-99b promoter region, and further promoted its transcriptional activity. Furthermore, miR-99b targeted PRDM1 by binding to its 3'UTR, causing its down-regulation. This in-creased lung injury, as evidenced by increased wet/dry ratio of mouse lung, myeloperoxidase activity and pro-inflammatory cytokine secretion, and enhanced infiltration of inflammatory cells in lung tissues. Together, our findings indicate that NF-κB(p65) promotion of miR-99b can aggravate ALI in mice by down-regulating the expression of PRDM1. Full Article
do GUCY2D mutations in retinal guanylyl cyclase 1 provide biochemical reasons for dominant cone-rod dystrophy but not for stationary night blindness [Cell Biology] By www.jbc.org Published On :: 2020-12-25T00:06:31-08:00 Mutations in the GUCY2D gene coding for the dimeric human retinal membrane guanylyl cyclase (RetGC) isozyme RetGC1 cause various forms of blindness, ranging from rod dysfunction to rod and cone degeneration. We tested how the mutations causing recessive congenital stationary night blindness (CSNB), recessive Leber's congenital amaurosis (LCA1), and dominant cone–rod dystrophy-6 (CORD6) affected RetGC1 activity and regulation by RetGC-activating proteins (GCAPs) and retinal degeneration-3 protein (RD3). CSNB mutations R666W, R761W, and L911F, as well as LCA1 mutations R768W and G982VfsX39, disabled RetGC1 activation by human GCAP1, -2, and -3. The R666W and R761W substitutions compromised binding of GCAP1 with RetGC1 in HEK293 cells. In contrast, G982VfsX39 and L911F RetGC1 retained the ability to bind GCAP1 in cyto but failed to effectively bind RD3. R768W RetGC1 did not bind either GCAP1 or RD3. The co-expression of GUCY2D allelic combinations linked to CSNB did not restore RetGC1 activity in vitro. The CORD6 mutation R838S in the RetGC1 dimerization domain strongly dominated the Ca2+ sensitivity of cyclase regulation by GCAP1 in RetGC1 heterodimer produced by co-expression of WT and the R838S subunits. It required higher Ca2+ concentrations to decelerate GCAP-activated RetGC1 heterodimer—6-fold higher than WT and 2-fold higher than the Ser838-harboring homodimer. The heterodimer was also more resistant than homodimers to inhibition by RD3. The observed biochemical changes can explain the dominant CORD6 blindness and recessive LCA1 blindness, both of which affect rods and cones, but they cannot explain the selective loss of rod function in recessive CSNB. Full Article
do BMP-9 and LDL crosstalk regulates ALK-1 endocytosis and LDL transcytosis in endothelial cells [Signal Transduction] By www.jbc.org Published On :: 2020-12-25T00:06:30-08:00 Bone morphogenetic protein-9 (BMP-9) is a circulating cytokine that is known to play an essential role in the endothelial homeostasis and the binding of BMP-9 to the receptor activin-like kinase 1 (ALK-1) promotes endothelial cell quiescence. Previously, using an unbiased screen, we identified ALK-1 as a high-capacity receptor for low-density lipoprotein (LDL) in endothelial cells that mediates its transcytosis in a nondegradative manner. Here we examine the crosstalk between BMP-9 and LDL and how it influences their interactions with ALK-1. Treatment of endothelial cells with BMP-9 triggers the extensive endocytosis of ALK-1, and it is mediated by caveolin-1 (CAV-1) and dynamin-2 (DNM2) but not clathrin heavy chain. Knockdown of CAV-1 reduces BMP-9–mediated internalization of ALK-1, BMP-9–dependent signaling and gene expression. Similarly, treatment of endothelial cells with LDL reduces BMP-9–induced SMAD1/5 phosphorylation and gene expression and silencing of CAV-1 and DNM2 diminishes LDL-mediated ALK-1 internalization. Interestingly, BMP-9–mediated ALK-1 internalization strongly re-duces LDL transcytosis to levels seen with ALK-1 deficiency. Thus, BMP-9 levels can control cell surface levels of ALK-1, via CAV-1, to regulate both BMP-9 signaling and LDL transcytosis. Full Article
do A kinetic dissection of the fast and superprocessive kinesin-3 KIF1A reveals a predominant one-head-bound state during its chemomechanical cycle [Molecular Biophysics] By www.jbc.org Published On :: 2020-12-25T00:06:30-08:00 The kinesin-3 family contains the fastest and most processive motors of the three neuronal transport kinesin families, yet the sequence of states and rates of kinetic transitions that comprise the chemomechanical cycle and give rise to their unique properties are poorly understood. We used stopped-flow fluorescence spectroscopy and single-molecule motility assays to delineate the chemomechanical cycle of the kinesin-3, KIF1A. Our bacterially expressed KIF1A construct, dimerized via a kinesin-1 coiled-coil, exhibits fast velocity and superprocessivity behavior similar to WT KIF1A. We established that the KIF1A forward step is triggered by hydrolysis of ATP and not by ATP binding, meaning that KIF1A follows the same chemomechanical cycle as established for kinesin-1 and -2. The ATP-triggered half-site release rate of KIF1A was similar to the stepping rate, indicating that during stepping, rear-head detachment is an order of magnitude faster than in kinesin-1 and kinesin-2. Thus, KIF1A spends the majority of its hydrolysis cycle in a one-head-bound state. Both the ADP off-rate and the ATP on-rate at physiological ATP concentration were fast, eliminating these steps as possible rate-limiting transitions. Based on the measured run length and the relatively slow off-rate in ADP, we conclude that attachment of the tethered head is the rate-limiting transition in the KIF1A stepping cycle. Thus, KIF1A's activity can be explained by a fast rear-head detachment rate, a rate-limiting step of tethered-head attachment that follows ATP hydrolysis, and a relatively strong electrostatic interaction with the microtubule in the weakly bound post-hydrolysis state. Full Article
do Myeloid deletion and therapeutic activation of AMPK do not alter atherosclerosis in male or female mice By www.jlr.org Published On :: 2020-12-01 Nicholas D. LeBlondDec 1, 2020; 61:1697-1706Research Articles Full Article
do Structure dynamics of ApoA-I amyloidogenic variants in small HDL increase their ability to mediate cholesterol efflux By www.jlr.org Published On :: 2020-11-17 Oktawia NilssonNov 17, 2020; 0:jlr.RA120000920v1-jlr.RA120000920Research Articles Full Article
do Adiponectin forms a complex with atherogenic LDL and inhibits its downstream effects By www.jlr.org Published On :: 2020-11-03 Akemi KakinoNov 3, 2020; 0:jlr.RA120000767v1-jlr.RA120000767Research Articles Full Article
do Mass spectrometry characterization of light chain fragmentation sites in cardiac AL amyloidosis: insights into the timing of proteolysis [Genomics and Proteomics] By www.jbc.org Published On :: 2020-12-04T00:06:05-08:00 Amyloid fibrils are polymeric structures originating from aggregation of misfolded proteins. In vivo, proteolysis may modulate amyloidogenesis and fibril stability. In light chain (AL) amyloidosis, fragmented light chains (LCs) are abundant components of amyloid deposits; however, site and timing of proteolysis are debated. Identification of the N and C termini of LC fragments is instrumental to understanding involved processes and enzymes. We investigated the N and C terminome of the LC proteoforms in fibrils extracted from the hearts of two AL cardiomyopathy patients, using a proteomic approach based on derivatization of N- and C-terminal residues, followed by mapping of fragmentation sites on the structures of native and fibrillar relevant LCs. We provide the first high-specificity map of proteolytic cleavages in natural AL amyloid. Proteolysis occurs both on the LC variable and constant domains, generating a complex fragmentation pattern. The structural analysis indicates extensive remodeling by multiple proteases, largely taking place on poorly folded regions of the fibril surfaces. This study adds novel important knowledge on amyloid LC processing: although our data do not exclude that proteolysis of native LC dimers may destabilize their structure and favor fibril formation, the data show that LC deposition largely precedes the proteolytic events documentable in mature AL fibrils. Full Article
do Problem Notes for SAS®9 - 66487: Authentication to the CAS server fails with the error "Access denied..." when initiated on a SAS/CONNECT server in a Microsoft Windows environment By Published On :: Mon, 31 Aug 2020 10:33:55 EST You might see the following error messages: "ERROR: Connection failed. Server returned: SAS Logon Manager authentication failed: Access denied." and "ERROR: Unable to connect to Cloud Analytic Services host-name on port 5570. Veri Full Article CONNECT+SAS/CONNECT
do Problem Notes for SAS®9 - 55516: Opening the Edit Action Columns dialog box requires that you wait up to a minute to display a window By Published On :: Fri, 28 Aug 2020 11:23:00 EST Editing and/or saving an action column can take up to a minute to display a window. There are no workarounds identified at this time. Full Article SCDOFR+SAS+Visual+Scenario+Designer
do Problem Notes for SAS®9 - 48028: Custom Time Frame-based data versions do not aggregate correctly when referenced in worksheets with standard hierarchy levels By Published On :: Wed, 26 Aug 2020 16:17:42 EST In SAS Merchandise Financial Planning, custom time frame-based data versions do not aggregate correctly when referenced in worksheets with standard hierarchy levels. The data does not aggregate correctly from l Full Article MMFINANCPLN+SAS+Merchandise+Financial+Pl
do Problem Notes for SAS®9 - 66505: The OBS= option does not generate a limit clause when you use SAS/ACCESS Interface to PostgreSQL to access a Yellowbrick database By Published On :: Wed, 26 Aug 2020 11:35:41 EST When you use SAS/ACCESS Interface to PostgreSQL to query a Yellowbrick database, the SAS OBS= option is not generating a limit clause on the query that is passed to the database. Click the Full Article POSTGRESOFR+SAS/ACCESS+Interface+to+Post
do Problem Notes for SAS®9 - 66496: Titles and footnotes do not span the full width of a page when you use the COLUMNS= option with the TAGSETS.RTF_SAMPLE tagset By Published On :: Thu, 20 Aug 2020 10:19:10 EST Titles and footnotes do not span the entire width of the page when you use the COLUMNS= option with a value that is greater than 1 with the TAGSETS.RTF_SAMPLE tagset. When a value that is greater than 1 is specified for th Full Article BASE+Base+SAS
do Problem Notes for SAS®9 - 66500: A content release on the SAS Risk Governance Framework fails to load when you use SAS 9.4M7 (TS1M7) on the Microsoft Windows operating system By Published On :: Wed, 19 Aug 2020 17:45:15 EST When you log on to the SAS Risk Governance Framework and choose a solution, the web application might fail to load the solution content. When the problem occurs, you continue to see "Loading..." on the screen, an Full Article RGPBNDL+SAS+Risk+Governance+Framework
do Docosanoid signaling modulates corneal nerve regeneration: effect on tear secretion, wound healing, and neuropathic pain [Thematic Reviews] By www.jlr.org Published On :: 2020-08-11T12:36:10-07:00 The cornea is densely innervated, mainly by sensory nerves of the ophthalmic branch of the trigeminal ganglia (TG). These nerves are important to maintain corneal homeostasis, and nerve damage can lead to a decrease in wound healing, an increase in corneal ulceration and dry eye disease (DED), and neuropathic pain. Pathologies, such as diabetes, aging, viral and bacterial infection, as well as prolonged use of contact lenses and surgeries to correct vision can produce nerve damage. There are no effective therapies to alleviate DED (a multifunctional disease) and several clinical trials using -3 supplementation show unclear and sometimes negative results. Using animal models of corneal nerve damage, we show that treating corneas with pigment epithelium-derived factor (PEDF) plus docosahexaenoic acid (DHA) increases nerve regeneration, wound healing, and tear secretion. The mechanism involves the activation of a calcium-independent phospholipase A2 (iPLA2) that releases the incorporated DHA from phospholipids and enhances the synthesis of docosanoids neuroprotectin D1 (NPD1) and a new resolvin stereoisomer RvD6i. NPD1 stimulates the synthesis of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and of semaphorin 7A (Sema7A). RvD6i treatment of injured corneas modulates gene expression in the TG resulting in enhanced neurogenesis; decreased neuropathic pain and increased sensitivity. Taken together, these results represent a promising therapeutic option to re-establish the homeostasis of the cornea. Full Article
do Lipid and Metabolic Syndrome Traits in Coronary Artery Disease: A Mendelian Randomization Study [Patient-Oriented and Epidemiological Research] By www.jlr.org Published On :: 2020-09-09T12:33:17-07:00 Mendelian randomization (MR) of lipid traits in coronary artery disease (CAD) has provided evidence for causal associations of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) in CAD, but many lipid trait genetic variants have pleiotropic effects on other cardiovascular risk factors that may bias MR associations. The goal of this study was to evaluate pleiotropic effects of lipid trait genetic variants and to account for these effects in MR of lipid traits in CAD. We performed multivariable MR using inverse variance-weighted (IVW) and MR-Egger methods in large (n ≥ 300,000) GWAS datasets. We found that 30% of lipid trait genetic variants have effects on metabolic syndrome traits, including body mass index (BMI), type 2 diabetes (T2D), and systolic blood pressure (SBP). Nonetheless, in multivariable MR analysis, LDL-C, high-density lipoprotein cholesterol (HDL-C), TG, BMI, T2D, and SBP are independently associated with CAD, and each of these associations is robust to adjustment for directional pleiotropy. MR at loci linked to direct effects on HDL-C and TG suggests locus- and mechanism-specific causal effects of these factors on CAD. Full Article
do Adiponectin forms a complex with atherogenic LDL and inhibits its downstream effects [Research Articles] By www.jlr.org Published On :: 2020-11-03T06:36:28-08:00 Adiponectin, an adipocyte-derived protein, has anti-atherogenic and anti-diabetic effects, but how it confers the anti-atherogenic effects is not well understood. To study the anti-atherogenic mechanisms of adiponectin, we examined whether it interacts with atherogenic low-density lipoprotein (LDL) to attenuate LDL’s atherogenicity. L5, the most electronegative subfraction of LDL, induces atherogenic responses similarly to copper-oxidized LDL (oxLDL). Unlike native LDL endocytosed via the LDL receptor, L5 and oxLDL are internalized by cells via the lectin-like oxidized LDL receptor-1 (LOX-1). Using enzyme-linked immunosorbent assays (ELISAs), we showed that adiponectin preferentially bound oxLDL but not native LDL. In Chinese hamster ovary (CHO) cells transfected with LOX-1 or LDL receptor, adiponectin selectively inhibited the uptake of oxLDL but not of native LDL, respectively. Furthermore, adiponectin suppressed the internalization of oxLDL in human coronary artery endothelial cells (HCAECs) and THP-1–derived macrophages. Western blot analysis of human plasma showed that adiponectin was abundant in L5 but not in L1, the least electronegative subfraction of LDL. Sandwich ELISAs with anti-adiponectin and anti–apolipoprotein B antibodies confirmed the binding of adiponectin to L5 and oxLDL. In LOX-1–expressing CHO cells, adiponectin inhibited cellular responses to oxLDL and L5, including nuclear factor-B activation and ERK phosphorylation. In HCAECs, adiponectin inhibited oxLDL-induced endothelin-1 secretion and ERK phosphorylation. Conversely, oxLDL suppressed the adiponectin-induced activation of adenosine monophosphate–activated protein kinase in COS-7 cells expressing adiponectin receptor AdipoR1. Our findings suggest that adiponectin binds and inactivates atherogenic LDL, providing novel insight into the anti-atherogenic mechanisms of adiponectin. Full Article