ip Hydrogen/deuterium exchange memory NMR reveals structural epitopes involved in IgE cross-reactivity of allergenic lipid transfer proteins [Protein Structure and Folding] By www.jbc.org Published On :: 2020-12-18T00:06:18-08:00 Identification of antibody-binding epitopes is crucial to understand immunological mechanisms. It is of particular interest for allergenic proteins with high cross-reactivity as observed in the lipid transfer protein (LTP) syndrome, which is characterized by severe allergic reactions. Art v 3, a pollen LTP from mugwort, is frequently involved in this cross-reactivity, but no antibody-binding epitopes have been determined so far. To reveal human IgE-binding regions of Art v 3, we produced three murine high-affinity mAbs, which showed 70–90% coverage of the allergenic epitopes from mugwort pollen–allergic patients. As reliable methods to determine structural epitopes with tightly interacting intact antibodies under native conditions are lacking, we developed a straightforward NMR approach termed hydrogen/deuterium exchange memory (HDXMEM). It relies on the slow exchange between the invisible antigen-mAb complex and the free 15N-labeled antigen whose 1H-15N correlations are detected. Due to a memory effect, changes of NH protection during antibody binding are measured. Differences in H/D exchange rates and analyses of mAb reactivity to homologous LTPs revealed three structural epitopes: two partially cross-reactive regions around α-helices 2 and 4 as well as a novel Art v 3–specific epitope at the C terminus. Protein variants with exchanged epitope residues confirmed the antibody-binding sites and revealed strongly reduced IgE reactivity. Using the novel HDXMEM for NMR epitope mapping allowed identification of the first structural epitopes of an allergenic pollen LTP. This knowledge enables improved cross-reactivity prediction for patients suffering from LTP allergy and facilitates design of therapeutics. Full Article
ip A highly potent CD73 biparatopic antibody blocks organization of the enzyme active site through dual mechanisms [Methods and Resources] By www.jbc.org Published On :: 2020-12-25T00:06:31-08:00 The dimeric ectonucleotidase CD73 catalyzes the hydrolysis of AMP at the cell surface to form adenosine, a potent suppressor of the immune response. Blocking CD73 activity in the tumor microenvironment can have a beneficial effect on tumor eradication and is a promising approach for cancer therapy. Biparatopic antibodies binding different regions of CD73 may be a means to antagonize its enzymatic activity. A panel of biparatopic antibodies representing the pairwise combination of 11 parental monoclonal antibodies against CD73 was generated by Fab-arm exchange. Nine variants vastly exceeded the potency of their parental antibodies with ≥90% inhibition of activity and subnanomolar EC50 values. Pairing the Fabs of parents with nonoverlapping epitopes was both sufficient and necessary whereas monovalent antibodies were poor inhibitors. Some parental antibodies yielded potent biparatopics with multiple partners, one of which (TB19) producing the most potent. The structure of the TB19 Fab with CD73 reveals that it blocks alignment of the N- and C-terminal CD73 domains necessary for catalysis. A separate structure of CD73 with a Fab (TB38) which complements TB19 in a particularly potent biparatopic shows its binding to a nonoverlapping site on the CD73 N-terminal domain. Structural modeling demonstrates a TB19/TB38 biparatopic antibody would be unable to bind the CD73 dimer in a bivalent manner, implicating crosslinking of separate CD73 dimers in its mechanism of action. This ability of a biparatopic antibody to both crosslink CD73 dimers and fix them in an inactive conformation thus represents a highly effective mechanism for the inhibition of CD73 activity. Full Article
ip Role of phospholipid synthesis in the development and differentiation of malaria parasites in the blood [Microbiology] By www.jbc.org Published On :: 2018-11-09T03:40:54-08:00 The life cycle of malaria parasites in both their mammalian host and mosquito vector consists of multiple developmental stages that ensure proper replication and progeny survival. The transition between these stages is fueled by nutrients scavenged from the host and fed into specialized metabolic pathways of the parasite. One such pathway is used by Plasmodium falciparum, which causes the most severe form of human malaria, to synthesize its major phospholipids, phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine. Much is known about the enzymes involved in the synthesis of these phospholipids, and recent advances in genetic engineering, single-cell RNA-Seq analyses, and drug screening have provided new perspectives on the importance of some of these enzymes in parasite development and sexual differentiation and have identified targets for the development of new antimalarial drugs. This Minireview focuses on two phospholipid biosynthesis enzymes of P. falciparum that catalyze phosphoethanolamine transmethylation (PfPMT) and phosphatidylserine decarboxylation (PfPSD) during the blood stages of the parasite. We also discuss our current understanding of the biochemical, structural, and biological functions of these enzymes and highlight efforts to use them as antimalarial drug targets. Full Article
ip Lipid-tuned Zinc Transport Activity of Human ZnT8 Protein Correlates with Risk for Type-2 Diabetes [Molecular Bases of Disease] By www.jbc.org Published On :: 2016-12-30T00:06:37-08:00 Zinc is a critical element for insulin storage in the secretory granules of pancreatic beta cells. The islet-specific zinc transporter ZnT8 mediates granular sequestration of zinc ions. A genetic variant of human ZnT8 arising from a single nonsynonymous nucleotide change contributes to increased susceptibility to type-2 diabetes (T2D), but it remains unclear how the high risk variant (Arg-325), which is also a higher frequency (>50%) allele, is correlated with zinc transport activity. Here, we compared the activity of Arg-325 with that of a low risk ZnT8 variant (Trp-325). The Arg-325 variant was found to be more active than the Trp-325 form following induced expression in HEK293 cells. We further examined the functional consequences of changing lipid conditions to mimic the impact of lipid remodeling on ZnT8 activity during insulin granule biogenesis. Purified ZnT8 variants in proteoliposomes exhibited more than 4-fold functional tunability by the anionic phospholipids, lysophosphatidylcholine and cholesterol. Over a broad range of permissive lipid compositions, the Arg-325 variant consistently exhibited accelerated zinc transport kinetics versus the Trp-form. In agreement with the human genetic finding that rare loss-of-function mutations in ZnT8 are associated with reduced T2D risk, our results suggested that the common high risk Arg-325 variant is hyperactive, and thus may be targeted for inhibition to reduce T2D risk in the general populations. Full Article
ip 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
ip Nile Basin States Must Persist with Water Diplomacy By www.chathamhouse.org Published On :: Tue, 11 Aug 2020 14:03:31 +0000 11 August 2020 Owen Grafham Assistant Director, Energy, Environment and Resources Programme LinkedIn Google Scholar Ahmed Soliman Research Fellow, Horn of Africa, Africa Programme @AhmedSolHoA Dr Nouar Shamout Water Resources and Sustainability (Independent Researcher) After multiple failed negotiations, any serious breakdown in current talks mediated by the African Union would be dangerous for regional stability. The international community must ramp up its support for this crucial diplomacy to ensure that an agreement is reached. 2020-08-12-Dam-Nile-Ethiopia The Blue Nile river passes through the Grand Ethiopian Renaissance Dam (GERD) near Guba in Ethiopia. Photo by EDUARDO SOTERAS/AFP via Getty Images. Ongoing talks between Egypt, Ethiopia and Sudan attempting to find a diplomatic and peaceful solution to the dispute over the Blue Nile Basin offer a unique opportunity for trans-boundary cooperation and have huge significance for a region dealing with multiple complex issues.With trust clearly at a premium, the continuation of talks demonstrates good faith, but there is an urgent need to strengthen negotiations through all available diplomatic channels. The African Union (AU) is well-placed to continue mediating, but sustained high-level engagement is also needed from regional and international partners such as the EU and US, as well as multilateral support in terms of both financial and technical resources.A tense history to overcomeAt the heart of this dispute is the new Grand Ethiopian Renaissance Dam (GERD) – set to become Africa's biggest hydroelectric dam when complete. Egypt and Sudan, who lie downstream, fear that Ethiopia, as the dam builders, will effectively gain control of the flow of the Nile, a turn of events that radically changes the way that water resources have been shared in the region.Egypt - widely described as a ‘gift of the Nile’ - is almost entirely dependent on the Nile to meet its various water needs, and is the major beneficiary of the 1929 and 1959 agreements on using the shared river’s water. The 1959 agreement gives Egypt a share of 55.5 billion cubic meters (BCM) annually out of 74 billion available, and a veto right over projects being developed upstream, while Sudan is allocated 18.5 BCM.Crucially neither of these old agreements recognises the interests of other upstream countries on the Nile, some of which have asserted their own development ambitions on the river over the last two decades and pushed for a new agreement to enshrine equitable rights and harmonious use of the water.One such country is Ethiopia where the Blue Nile River originates. The GERD is a central part of Ethiopia’s ambitions for economic prosperity. The dam, which is largely self-financed, will have a capacity of 74 BCM when completed, enough to provide abundant cheap energy to power both national and regional developments. Currently, more than half Ethiopia’s 110 million people do not have access to electricity, but demand is increasing by 30 per cent annually.Unclear impactsThe unclear impact of the GERD – and lower volumes of water – on food security and agriculture complicate the negotiations. Egypt, Ethiopia and Sudan’s populations are set to increase significantly in the coming decades and each are already dealing with significant challenges around food insecurity and nutrition, which in Egypt and Sudan, are partly exacerbated by the colonial-era agricultural structures set up to exploit cash crops.Any change in water quality would have a huge impact on the 67% of Egyptian farm holdings considered as ‘small’ – the majority of which are on the banks of the Nile. And changes in water volumes might increase desertification and loss of livelihoods, potentially causing civil unrest if not addressed properly.The environmental impact of the GERD on the complex Nile River system also raises concerns about the river’s ecosystem, the surrounding environment, and the river’s downstream course. Despite talks in 2015 leading to an agreement on declaration of principles, thorough technical studies have not been implemented.Although there is little evidence that overall water levels in the Nile Basin have reduced in recent years, climate change is causing more variation in the Nile’s flow which increases the risk of flooding and extended droughts. Downstream states are also concerned about impacts from any breaches, damage or failure of the dam, including possible seismic activity.Of course, the GERD also offers some added value to the downstream states. The dam can help manage floods in Sudan, reduce the significant water loss to evaporation - as in the case of Lake Nasser - and lessen the effect of sediment on downstream dams. In Sudan, where less than one-quarter of the estimated 70 million hectares of arable land is currently cultivated, any reduction in seasonal flooding would boost agricultural output and aid economic recovery. The dam will offer Ethiopia significant opportunities for the trade of cheap renewable energy to Sudan and neighbouring states earning it a possible $1bn a year in revenues. And adopting a more ‘basin-integrated’ management approach can be a springboard for enhanced regional cooperation between the three states.But geopolitical tensions between the three have escalated since satellite imagery revealed apparent significant filling of the dam prior to reaching any agreement. Ethiopia has long said it would begin filling the dam during its rainy season, but insists the filling occurred naturally through June-July from rainfall and runoff and its first-year target of 4.9 BCM was reached without needing to close the dam gates. Egypt and Sudan have restated their calls for a binding legal agreement on the rules for filling and management of disputes.Security response not the answerInternal pressures are particularly acute, with all three countries experiencing public uprisings and regime change in the last decade, and current leaders are under pressure not to appear weak from influential sections of society pushing a hard nationalist line.Hawkish elements in Egypt have long supported a more securitized response to any potential threats from the GERD, and the recent request from President Sisi that Egyptian air forces be ready to handle targets inside and outside of the country was interpreted as a threat to Turkey in Libya, and Ethiopia.Egypt has also asked for the GERD to be discussed at the UN Security Council but Ethiopia’s Nobel peace prize-winning prime minister Abiy Ahmed, facing significant internal unrest himself, has made it clear that a costly confrontation is not in anyone’s interests. Meanwhile, Sudan’s transitional government - being jointly run by civilians and the military - is keen to assert its own interests on the Nile but has also played a conciliatory role with its neighbours. Increased engagement of Gulf states in the Horn of Africa and the impacts of conflicts in Libya, Yemen and Syria add more complexity to the overall regional picture.Certainly none of the major parties sharing the river would benefit from a hard security response to the dam. For Egypt, such a move would torpedo its re-engagement in Sub-Saharan Africa under President Sisi and likely lead to its expulsion from the AU. For Ethiopia, overt conflict would be a huge setback for its development and regional integration ambitions. And Sudan’s nascent transition can ill-afford to be part of another regional conflict.Thankfully, such an outcome is both highly unlikely and historically rare, and behind the scenes there has been significant progress. Some reports suggest a provisional agreement has been reached on the volume of filling required and the timeframe for the filling to happen. If so, most dispute now revolves around what to do in the event of a drought, provisions for information exchange, and how to translate all this into a binding agreement.A two-phase approach, consisting of a short-term deal on filling and operating the GERD followed by discussions on future developments and allocation, could be the best way to reach a lasting settlement and replace the extremely outdated existing water-sharing agreements.Reaching a successful deal between the three countries is not easy as it requires brave leadership and political goodwill, a de-escalation of long-standing rhetoric and brinkmanship, and a willingness to compromise on all sides to ensure the gaps between the countries' positions are significantly narrowed.What is required is a determined effort to keep the countries talking and provide the solutions which can bridge the parties’ differences, build confidence, and secure the vital diplomatic success so badly needed for wider stability and progress in the region. Full Article
ip Saudi Leadership Must Focus on Innovation for the Future By www.chathamhouse.org Published On :: Wed, 16 Sep 2020 11:43:35 +0000 16 September 2020 Dr Neil Quilliam Associate Fellow, Middle East and North Africa Programme @NeilQuilliam1 A glorious year beckoned for Saudi Arabia, in leading the G20 and hosting the G20 Leaders' Summit in Riyadh in November. Instead, empowering its people and capitalizing on its youth should become the focus for an embattled leadership. 2020-09-16-Saudi-G20 Meeting of finance ministers and central bank governors of the G20 nations in the Saudi capital Riyadh on February 23, 2020. Photo by FAYEZ NURELDINE/AFP via Getty Images. The G20 summit in November was to be a moment when the world focused its attention on Saudi Arabia. As the leaders of the world's 20 largest economies came together for the first time in an Arab capital and presided over the world’s greatest challenges and opportunities, King Salman would have taken centre stage with his son and crown prince Mohammed bin Salman not far behind in the spotlight.However this will now be a virtual summit, and that is probably a blessing in disguise for the kingdom and its leadership which has not enjoyed a good year. It shares responsibility for crashing the price of oil, which, in conjunction with COVID-19, has brought the global economy to its knees. And it continues to be mired in the Yemen conflict, whereas its ally the United Arab Emirates (UAE) has, by and large, managed to extract itself while also seeking to rescue its reputation by signing a ‘peace deal’ with Israel.More recently, it has been forced to push back plans to host the next instalment of ‘Davos in Desert’ until 2021 and the crown prince’s flagship charity Misk is currently under review. The Public Investment Fund (PIF) made a wholly unsuccessful bid to secure a major stake in Newcastle United Football Club which brought an unfavourable ruling at the World Trade Organization (WTO) and a heap of damaging media attention.Squandered opportunityNothing washes away the stain of Jamal Khashoggi’s murder or the continuing imprisonment of women and men charged with being traitors. But in many ways, leading the G20 offered the Saudi leadership, especially Mohammed bin Salman, a chance to press reset and atone for some of the excesses of his more controversial policies, such as the war in Yemen and blockade of Qatar. But he appears to have squandered the opportunity so far and there are no signs that is about to change.Hosting the summit in Riyadh would have given Mohammed bin Salman an opportunity to try and recapture the heady days of 2018, when many of the world's leaders and even the media still viewed him as a force for good. He would have had a captive audience and, instead of staying away from Western capitals which he has chosen to do recently, he could have been feted by world leaders on his home turf. Moreover, the presidency agenda — empowering people, safeguarding the planet, and shaping new frontiers — would have lent itself to meaningful engagement on key policy issues.Although many analysts and commentators quite rightly argue that Riyadh’s focus on empowerment and safeguarding the planet is widely hypocritical given the kingdom has lurched further towards quashing any signs of opposition and remains highly dependent upon hydrocarbons, at least the ambitious goals of Vision 2030 ought to align with the G20 agenda. The goals of Vision 2030 remain aspirational and are far from ever being met, but there is synchronicity between the two agendas. In fact, the overview of Saudi Arabia’s G20 Presidency documentation states ‘the G20 agenda has a strong echo in the daily lives of the people in the Kingdom’.Saudi Arabia really needs to empower its people and capitalize upon its youth dividend but that requires, as so many have argued persuasively, long-term investment in education, training, and skills acquisition, and will not be achieved overnight. It needs strategic thinking, capacity-building, commitment, scope for course correction, and patience. There are no quick wins, no shortcuts.Safeguarding the planet is common to one and all but breaking a dependency upon hydrocarbons, diversifying its economy, and mitigating against the growing impact of climate change are all pressing issues Saudi Arabia needs to address. A failure to achieve these goals in a time-sensitive fashion poses a threat to the well-being of the kingdom and, in order to do so, it must empower its people and use technology wisely to advance the process. Saudi Arabia should be at the front of the pack, but is being surpassed by its neighbours and is in danger of being left way behind.With its wealth and youthful population, the kingdom can be at the cutting edge of shaping new frontiers. It can deploy its substantive funds to support its own innovators and — to borrow the jargon — create an ecosystem that not only offers Saudis an environment fostering creativity, but also one that draws talent into the kingdom.This does not mean investing in ‘white elephant’ projects that fail to spark the imagination of Saudis, or following the crowd to buy football clubs without rhyme or reason. It means gearing up to address everyday issues that preoccupy minds of Saudis, such as employment, housing, healthcare, and the well-being of family members. It is notable how the excitement of ‘bread and circus’ issues has abated and the focus moved once again towards family, faith and finance.The Saudi presidency of the G20 is in danger of passing by with a whimper and the November summit may now be unremarkable. This does not mean the hard work of the continuously active engagement groups will go unnoticed or to waste, but it does mean the photo-opportunity will be passed up and the joint statement garner less interest than usual.While it may feel like a lost opportunity for the kingdom and, in particular, Mohammed bin Salman, they should both breathe a sigh of relief. In many ways, they will be let off the hook by avoiding the direct scrutiny of the world’s media and human rights organizations. However, the crown prince could still seize the initiative given the spotlight will be on him, albeit from afar, and take bold steps towards resolving the thorny issues that have come to mar his pathway to power. Full Article
ip Economic Diplomacy in the Era of Great Powers By www.chathamhouse.org Published On :: Thu, 17 Sep 2020 10:04:54 +0000 17 September 2020 Dr Linda Yueh Associate Fellow, Global Economy and Finance Programme and US and the Americas Programme @lindayueh The 21st-century global economy has different drivers from those in the previous century. Amid ever more politicized trade relations, economic diplomacy needs a more transparent framework. 2020-09-17-Trump-Economy-WEF-World-Economic-Forum-Davos US president Donald Trump at the World Economic Forum in Davos, Switzerland, on January 22, 2020. Photo by JIM WATSON/AFP via Getty Images. The emergence of a multipolar global economy in which the US is no longer the main engine of growth has boosted the role of economic diplomacy, the setting of foreign economic policy. While the EU remains the world’s biggest economic bloc and the US is still an economic powerhouse, it is Asia – China in particular – which has created hundreds of millions of new middle-class consumers, helping to drive global economic growth.This shift has ignited an era of competition between the US and China and, by implication, a debate about the merits of different political and legal systems. The difficulty for the rest of the world is how best to navigate this highly polarized climate – in recent history, only the Cold War comes close to having matched the adversarial dynamics of such a divided international community.In conducting economic diplomacy, governments should consider their economic strengths, the importance of transparency, and how best to operate in a fragmented international system.First, the setting of trade and investment policy should take into account developments in the global economy. One trend worth noting is the rising importance of services – in particular digital services – in international trade. The expanding cross-border trade in intangibles such as business services and data means the negotiation, definition and enforcement of standards to regulate these are of growing importance for the global economy, and for policymakers in many countries.In contrast, negotiations around merchandise trade are likely to take a somewhat lower profile. Under the World Trade Organization (WTO), tariffs on manufactured goods have dropped significantly in any case – though there is still scope to lower them. Contemporary diplomacy, as well as disputes, around the lowering or raising of barriers to international trade will increasingly concern non-tariff measures applicable to services rather than those, such as tariffs, that traditionally apply to goods.For service-based economies, it is vital free-trade agreements (FTAs) encompass regulations and standards for intangibles. But this is difficult in a multipolar global economy where the US, China and the EU all have different legal and regulatory systems, and raises the prospect of a fragmented global trading system divided into blocs of countries adhering to different standards.A pluralistic or mini-multilateral approach to trade such as the stalled Trade in Services Agreement (TiSA) could help resolve elements of this division. TiSA was launched in 2013 by a group of advanced economies, not the entirety of the WTO, to further opening up global services trade. However, talks have been on hold since 2016 and, in the current climate, it is near impossible to conclude negotiations when the major economies do not come to the table and instead promote their own standards with their closest trading partners.Second, policymakers should consider that, in an era of heightened trade tensions, any framework for economic diplomacy needs to be transparent if it is to be trusted and credible. Such a framework could centre on commercial openness and consistency with a country’s foreign and intelligence policy aims. For example, clearly spelling out how a country reviews prospective foreign investment and applying this consistently would demonstrate that all projects are treated equally without singling out any individual country. This would be an improvement over an ad hoc and less transparent approach .A major challenge in creating a ‘principle-based’ economic diplomacy framework of this kind is reconciling competing policy aims. To this end, several key questions need answering. Should trade agreements encompass non-economic elements, such as foreign policy aims? Do concerns over national security mean that trade and investment agreements should favour allies? Could such a framework assess a trading or investment partner in terms of national security as well as potential economic benefit?A country should also re-think how to undertake a wider international role when embarking on economic diplomacy. The inability of the major powers to set new global rules has had a detrimental impact on an international system under significant strain. The stalling of multilateral trade talks and urgency of international coordinated action on global public goods, such as health and the environment, shows there is a pressing need for a new approach to international relations.Economic diplomacy could, and should, bolster the rules-based multilateral system. The challenge is engaging the major powers without whom widespread adoption of global policies and standards is less likely. Yet the chances of wider adoption might actually be better if a proposal does not come from either the US or China. This opens up the opportunity for other countries to be ‘honest brokers’ and potentially improve their own international standing.In an era of increasing tension between great powers, economic diplomacy requires re-tooling. It should consider not just economic considerations, but also broader foreign policy aims, greater transparency, and a pluralistic approach to global rules to strengthen the multilateral system. Full Article
ip The glucose-sensing transcription factor ChREBP is targeted by proline hydroxylation [Metabolism] By www.jbc.org Published On :: 2020-12-11T00:06:20-08:00 Cellular energy demands are met by uptake and metabolism of nutrients like glucose. The principal transcriptional regulator for adapting glycolytic flux and downstream pathways like de novo lipogenesis to glucose availability in many cell types is carbohydrate response element–binding protein (ChREBP). ChREBP is activated by glucose metabolites and post-translational modifications, inducing nuclear accumulation and regulation of target genes. Here we report that ChREBP is modified by proline hydroxylation at several residues. Proline hydroxylation targets both ectopically expressed ChREBP in cells and endogenous ChREBP in mouse liver. Functionally, we found that specific hydroxylated prolines were dispensable for protein stability but required for the adequate activation of ChREBP upon exposure to high glucose. Accordingly, ChREBP target gene expression was rescued by re-expressing WT but not ChREBP that lacks hydroxylated prolines in ChREBP-deleted hepatocytes. Thus, proline hydroxylation of ChREBP is a novel post-translational modification that may allow for therapeutic interference in metabolic diseases. Full Article
ip Post-translational control of the long and winding road to cholesterol [Lipids] By www.jbc.org Published On :: 2020-12-18T00:06:18-08:00 The synthesis of cholesterol requires more than 20 enzymes, many of which are intricately regulated. Post-translational control of these enzymes provides a rapid means for modifying flux through the pathway. So far, several enzymes have been shown to be rapidly degraded through the ubiquitin–proteasome pathway in response to cholesterol and other sterol intermediates. Additionally, several enzymes have their activity altered through phosphorylation mechanisms. Most work has focused on the two rate-limiting enzymes: 3-hydroxy-3-methylglutaryl CoA reductase and squalene monooxygenase. Here, we review current literature in the area to define some common themes in the regulation of the entire cholesterol synthesis pathway. We highlight the rich variety of inputs controlling each enzyme, discuss the interplay that exists between regulatory mechanisms, and summarize findings that reveal an intricately coordinated network of regulation along the cholesterol synthesis pathway. We provide a roadmap for future research into the post-translational control of cholesterol synthesis, and no doubt the road ahead will reveal further twists and turns for this fascinating pathway crucial for human health and disease. Full Article
ip The role of uncoupling protein 2 in macrophages and its impact on obesity-induced adipose tissue inflammation and insulin resistance [Immunology] By www.jbc.org Published On :: 2020-12-18T00:06:18-08:00 The development of a chronic, low-grade inflammation originating from adipose tissue in obese subjects is widely recognized to induce insulin resistance, leading to the development of type 2 diabetes. The adipose tissue microenvironment drives specific metabolic reprogramming of adipose tissue macrophages, contributing to the induction of tissue inflammation. Uncoupling protein 2 (UCP2), a mitochondrial anion carrier, is thought to separately modulate inflammatory and metabolic processes in macrophages and is up-regulated in macrophages in the context of obesity and diabetes. Here, we investigate the role of UCP2 in macrophage activation in the context of obesity-induced adipose tissue inflammation and insulin resistance. Using a myeloid-specific knockout of UCP2 (Ucp2ΔLysM), we found that UCP2 deficiency significantly increases glycolysis and oxidative respiration, both unstimulated and after inflammatory conditions. Strikingly, fatty acid loading abolished the metabolic differences between Ucp2ΔLysM macrophages and their floxed controls. Furthermore, Ucp2ΔLysM macrophages show attenuated pro-inflammatory responses toward Toll-like receptor-2 and -4 stimulation. To test the relevance of macrophage-specific Ucp2 deletion in vivo, Ucp2ΔLysM and Ucp2fl/fl mice were rendered obese and insulin resistant through high-fat feeding. Although no differences in adipose tissue inflammation or insulin resistance was found between the two genotypes, adipose tissue macrophages isolated from diet-induced obese Ucp2ΔLysM mice showed decreased TNFα secretion after ex vivo lipopolysaccharide stimulation compared with their Ucp2fl/fl littermates. Together, these results demonstrate that although UCP2 regulates both metabolism and the inflammatory response of macrophages, its activity is not crucial in shaping macrophage activation in the adipose tissue during obesity-induced insulin resistance. Full Article
ip Serum lipoprotein-derived fatty acids regulate hypoxia-inducible factor [Metabolism] By www.jbc.org Published On :: 2020-12-25T00:06:31-08:00 Oxygen regulates hypoxia-inducible factor (HIF) transcription factors to control cell metabolism, erythrogenesis, and angiogenesis. Whereas much has been elucidated about how oxygen regulates HIF, whether lipids affect HIF activity is un-known. Here, using cultured cells and two animal models, we demonstrate that lipoprotein-derived fatty acids are an independent regulator of HIF. Decreasing extracellular lipid supply inhibited HIF prolyl hydroxylation, leading to accumulation of the HIFα subunit of these heterodimeric transcription factors comparable with hypoxia with activation of downstream target genes. The addition of fatty acids to culture medium suppressed this signal, which required an intact mitochondrial respiratory chain. Mechanistically, fatty acids and oxygen are distinct signals integrated to control HIF activity. Finally, we observed lipid signaling to HIF and changes in target gene expression in developing zebrafish and adult mice, and this pathway operates in cancer cells from a range of tissues. This study identifies fatty acids as a physiological modulator of HIF, defining a mechanism for lipoprotein regulation that functions in parallel to oxygen. Full Article
ip Comparison Between Brain and Cerebellar Autoradiography Using [18F]Flortaucipir, [18F]MK6240, and [18F]PI2620 in Postmortem Human Brain Tissue By jnm.snmjournals.org Published On :: 2024-10-30T08:04:16-07:00 Visual Abstract Full Article
ip Clinical, Pathologic, and Imaging Variables Associated with Prostate Cancer Detection by PSMA PET/CT and Multiparametric MRI By jnm.snmjournals.org Published On :: 2024-10-30T08:04:14-07:00 Visual Abstract Full Article
ip Oncologist, Business Leader, and Investor Arie S. Belldegrun Discusses a Career in Innovative Medical Entrepreneurship: A Conversation with Ken Herrmann and Johannes Czernin By jnm.snmjournals.org Published On :: 2024-10-30T08:04:15-07:00 Full Article
ip Kinetic Analysis and Metabolism of Poly(Adenosine Diphosphate-Ribose) Polymerase-1-Targeted 18F-Fluorthanatrace PET in Breast Cancer By jnm.snmjournals.org Published On :: 2024-10-30T08:04:15-07:00 Visual Abstract Full Article
ip 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
ip Systematic identification of P. falciparum sporozoite membrane protein interactions reveals an essential role for the p24 complex in host infection By www.mcponline.org Published On :: 2020-12-22 Julia KnöckelDec 22, 2020; 0:RA120.002432v1-mcp.RA120.002432Research Full Article
ip A potential role for the Gsdf-eEF1{alpha} complex in inhibiting germ cell proliferation: A protein-interaction analysis in medaka (Oryzias latipes) from a proteomics perspective By www.mcponline.org Published On :: 2020-12-08 Xinting ZhangDec 8, 2020; 0:RA120.002306v1-mcp.RA120.002306Research Full Article
ip Spatially Resolved Activity-based Proteomic Profiles of the Murine Small Intestinal Lipases By www.mcponline.org Published On :: 2020-12-01 Matthias SchittmayerDec 1, 2020; 19:2104-2114Research Full Article
ip Protein modification characteristics of the malaria parasite Plasmodium falciparum and the infected erythrocytes By www.mcponline.org Published On :: 2020-11-04 Jianhua WangNov 4, 2020; 0:RA120.002375v1-mcp.RA120.002375Research Full Article
ip 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
ip VBP1 modulates Wnt/{beta}-catenin signaling by mediating the stability of the transcription factors TCF/LEFs [Signal Transduction] By www.jbc.org Published On :: 2020-12-04T00:06:06-08:00 The Wnt/β-catenin pathway is one of the major pathways that regulates embryonic development, adult homeostasis, and stem cell self-renewal. In this pathway, transcription factors T-cell factor and lymphoid enhancer factor (TCF/LEF) serve as a key switch to repress or activate Wnt target gene transcription by recruiting repressor molecules or interacting with the β-catenin effector, respectively. It has become evident that the protein stability of the TCF/LEF family members may play a critical role in controlling the activity of the Wnt/β-catenin signaling pathway. However, factors that regulate the stability of TCF/LEFs remain largely unknown. Here, we report that pVHL binding protein 1 (VBP1) regulates the Wnt/β-catenin signaling pathway by controlling the stability of TCF/LEFs. Surprisingly, we found that either overexpression or knockdown of VBP1 decreased Wnt/β-catenin signaling activity in both cultured cells and zebrafish embryos. Mechanistically, VBP1 directly binds to all four TCF/LEF family members and von Hippel-Lindau tumor-suppressor protein (pVHL). Either overexpression or knockdown of VBP1 increases the association between TCF/LEFs and pVHL and then decreases the protein levels of TCF/LEFs via proteasomal degradation. Together, our results provide mechanistic insights into the roles of VBP1 in controlling TCF/LEFs protein stability and regulating Wnt/β-catenin signaling pathway activity. Full Article
ip ERAD deficiency promotes mitochondrial dysfunction and transcriptional rewiring in human hepatic cells [Cell Biology] By www.jbc.org Published On :: 2020-12-04T00:06:05-08:00 Mitochondrial dysfunction is associated with a variety of human diseases including neurodegeneration, diabetes, nonalcohol fatty liver disease (NAFLD), and cancer, but its underlying causes are incompletely understood. Using the human hepatic cell line HepG2 as a model, we show here that endoplasmic reticulum-associated degradation (ERAD), an ER protein quality control process, is critically required for mitochondrial function in mammalian cells. Pharmacological inhibition or genetic ablation of key proteins involved in ERAD increased cell death under both basal conditions and in response to proinflammatory cytokines, a situation frequently found in NAFLD. Decreased viability of ERAD-deficient HepG2 cells was traced to impaired mitochondrial functions including reduced ATP production, enhanced reactive oxygen species (ROS) accumulation, and increased mitochondrial outer membrane permeability. Transcriptome profiling revealed widespread down-regulation of genes underpinning mitochondrial functions, and up-regulation of genes associated with tumor growth and aggression. These results highlight a critical role for ERAD in maintaining mitochondrial functional and structural integrity and raise the possibility of improving cellular and organismal mitochondrial function via enhancing cellular ERAD capacity. Full Article
ip The amphipathic helices of Arfrp1 and Arl14 are sufficient to determine subcellular localizations [Cell Biology] By www.jbc.org Published On :: 2020-12-04T00:06:05-08:00 The subcellular localization of Arf family proteins is generally thought to be determined by their corresponding guanine nucleotide exchange factors. By promoting GTP binding, guanine nucleotide exchange factors induce conformational changes of Arf proteins exposing their N-terminal amphipathic helices, which then insert into the membranes to stabilize the membrane association process. Here, we found that the N-terminal amphipathic motifs of the Golgi-localized Arf family protein, Arfrp1, and the endosome- and plasma membrane–localized Arf family protein, Arl14, play critical roles in spatial determination. Exchanging the amphipathic helix motifs between these two Arf proteins causes the switch of their localizations. Moreover, the amphipathic helices of Arfrp1 and Arl14 are sufficient for cytosolic proteins to be localized into a specific cellular compartment. The spatial determination mediated by the Arfrp1 helix requires its binding partner Sys1. In addition, the residues that are required for the acetylation of the Arfrp1 helix and the myristoylation of the Arl14 helix are important for the specific subcellular localization. Interestingly, Arfrp1 and Arl14 are recruited to their specific cellular compartments independent of GTP binding. Our results demonstrate that the amphipathic motifs of Arfrp1 and Arl14 are sufficient for determining specific subcellular localizations in a GTP-independent manner, suggesting that the membrane association and activation of some Arf proteins are uncoupled. Full Article
ip AMPK{beta}1 and AMPK{beta}2 define an isoform-specific gene signature in human pluripotent stem cells, differentially mediating cardiac lineage specification [Cell Biology] By www.jbc.org Published On :: 2020-12-18T00:06:18-08:00 AMP-activated protein kinase (AMPK) is a key regulator of energy metabolism that phosphorylates a wide range of proteins to maintain cellular homeostasis. AMPK consists of three subunits: α, β, and γ. AMPKα and β are encoded by two genes, the γ subunit by three genes, all of which are expressed in a tissue-specific manner. It is not fully understood, whether individual isoforms have different functions. Using RNA-Seq technology, we provide evidence that the loss of AMPKβ1 and AMPKβ2 lead to different gene expression profiles in human induced pluripotent stem cells (hiPSCs), indicating isoform-specific function. The knockout of AMPKβ2 was associated with a higher number of differentially regulated genes than the deletion of AMPKβ1, suggesting that AMPKβ2 has a more comprehensive impact on the transcriptome. Bioinformatics analysis identified cell differentiation as one biological function being specifically associated with AMPKβ2. Correspondingly, the two isoforms differentially affected lineage decision toward a cardiac cell fate. Although the lack of PRKAB1 impacted differentiation into cardiomyocytes only at late stages of cardiac maturation, the availability of PRKAB2 was indispensable for mesoderm specification as shown by gene expression analysis and histochemical staining for cardiac lineage markers such as cTnT, GATA4, and NKX2.5. Ultimately, the lack of AMPKβ1 impairs, whereas deficiency of AMPKβ2 abrogates differentiation into cardiomyocytes. Finally, we demonstrate that AMPK affects cellular physiology by engaging in the regulation of hiPSC transcription in an isoform-specific manner, providing the basis for further investigations elucidating the role of dedicated AMPK subunits in the modulation of gene expression. Full Article
ip Visualizing, quantifying, and manipulating mitochondrial DNA in vivo [Methods and Resources] By www.jbc.org Published On :: 2020-12-18T00:06:18-08:00 Mitochondrial DNA (mtDNA) encodes proteins and RNAs that support the functions of mitochondria and thereby numerous physiological processes. Mutations of mtDNA can cause mitochondrial diseases and are implicated in aging. The mtDNA within cells is organized into nucleoids within the mitochondrial matrix, but how mtDNA nucleoids are formed and regulated within cells remains incompletely resolved. Visualization of mtDNA within cells is a powerful means by which mechanistic insight can be gained. Manipulation of the amount and sequence of mtDNA within cells is important experimentally and for developing therapeutic interventions to treat mitochondrial disease. This review details recent developments and opportunities for improvements in the experimental tools and techniques that can be used to visualize, quantify, and manipulate the properties of mtDNA within cells. Full Article
ip 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
ip High resolution structure of human apolipoprotein (a) kringle IV type 2: beyond the lysine binding site By www.jlr.org Published On :: 2020-12-01 Alice SantonastasoDec 1, 2020; 61:1687-1696Research Articles Full Article
ip Nuclear translocation ability of Lipin differentially affects gene expression and survival in fed and fasting Drosophila By www.jlr.org Published On :: 2020-12-01 Stephanie E. HoodDec 1, 2020; 61:1720-1732Research Articles Full Article
ip Stimulation of ABCB4/MDR3 ATPase activity requires an intact phosphatidylcholine lipid By www.jlr.org Published On :: 2020-12-01 Martin PrescherDec 1, 2020; 61:1605-1616Research Articles Full Article
ip A novel phosphoglycerol serine-glycine lipodipeptide of Porphyromonas gingivalis is a TLR2 ligand By www.jlr.org Published On :: 2020-12-01 Frank C. NicholsDec 1, 2020; 61:1645-1657Research Articles Full Article
ip PLRP2 selectively localizes synaptic membrane proteins via acyl-chain remodeling of phospholipids By www.jlr.org Published On :: 2020-12-01 Hideaki KugeDec 1, 2020; 61:1747-1763Research Articles Full Article
ip Gene Networks and Pathways for Plasma Lipid Traits via Multi-tissue Multi-omics Systems Analysis By www.jlr.org Published On :: 2020-12-23 Montgomery BlencoweDec 23, 2020; 0:jlr.RA120000713v1-jlr.RA120000713Research Articles Full Article
ip LDL apheresis as an alternate method for plasma LPS purification in healthy volunteers and dyslipidemic and septic patients By www.jlr.org Published On :: 2020-12-01 Auguste DargentDec 1, 2020; 61:1776-1783Research Articles Full Article
ip Lipid signature of advanced human carotid atherosclerosis assessed by mass spectrometry imaging By www.jlr.org Published On :: 2020-12-23 Astrid M. MoermanDec 23, 2020; 0:jlr.RA120000974v1-jlr.RA120000974Research Articles Full Article
ip Cholesterol transport between red blood cells and lipoproteins contributes to cholesterol metabolism in blood By www.jlr.org Published On :: 2020-12-01 Ryunosuke OhkawaDec 1, 2020; 61:1577-1588Research Articles Full Article
ip Identification of unusual phospholipids from bovine heart mitochondria by HPLC-MS/MS By www.jlr.org Published On :: 2020-12-01 Junhwan KimDec 1, 2020; 61:1707-1719Research Articles Full Article
ip Lipid metabolism dysregulation in diabetic retinopathy By www.jlr.org Published On :: 2020-12-23 Julia V BusikDec 23, 2020; 0:jlr.TR120000981v1-jlr.TR120000981Thematic Reviews Full Article
ip Human CETP lacks lipopolysaccharide transfer activity, but worsens inflammation and sepsis outcomes in mice By www.jlr.org Published On :: 2020-12-09 Aloïs DusuelDec 9, 2020; 0:jlr.RA120000704v1-jlr.RA120000704Research Articles Full Article
ip Mutation in the distal NPxY motif of LRP1 alleviates dietary cholesterol-induced dyslipidemia and tissue inflammation By www.jlr.org Published On :: 2020-12-09 Anja JaeschkeDec 9, 2020; 0:jlr.RA120001141v1-jlr.RA120001141Research Articles Full Article
ip SCD1 promotes lipid mobilization in subcutaneous white adipose tissue By www.jlr.org Published On :: 2020-12-01 Ying ZouDec 1, 2020; 61:1589-1604Research Articles Full Article
ip Apolipoprotein C3 and apolipoprotein B colocalize in proximity to macrophages in atherosclerotic lesions in diabetes By www.jlr.org Published On :: 2020-12-08 Jenny E. KanterDec 8, 2020; 0:jlr.ILR120001217v1-jlr.ILR120001217Images in Lipid Research Full Article
ip Distinct patterns of apolipoprotein C-I, C-II and C-III isoforms are associated with markers of Alzheimers disease By www.jlr.org Published On :: 2020-12-11 Yueming HuDec 11, 2020; 0:jlr.RA120000919v1-jlr.RA120000919Research Articles Full Article
ip Perilipin 5 S155 phosphorylation by PKA is required for the control of hepatic lipid metabolism and glycemic control By www.jlr.org Published On :: 2020-12-17 Stacey N KeenanDec 17, 2020; 0:jlr.RA120001126v1-jlr.RA120001126Research Articles Full Article
ip 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
ip Update on LIPID MAPS classification, nomenclature, and shorthand notation for MS-derived lipid structures By www.jlr.org Published On :: 2020-12-01 Gerhard LiebischDec 1, 2020; 61:1539-1555Special Report Full Article
ip Multi-modal Functional Imaging of Brown Adipose Tissue By www.jlr.org Published On :: 2020-11-18 Amanda D.V. MacCannellNov 18, 2020; 0:jlr.ILR120001204v1-jlr.ILR120001204Images in Lipid Research Full Article
ip Problem Notes for SAS®9 - 58465: SAS Life Science Analytics Framework 4.6 - Group membership removal fails with an exception for Process Flows that exist in the Recycle Bin By Published On :: Wed, 26 Aug 2020 16:27:10 EST In SAS Life Science Analytics Framework 4.6, group membership removal fails with an exception if a user is set as assignee, a candidate, or a notification recipient in a user task for a Process Flow . The Process Full Article LSAFOFR+SAS+Life+Science+Analytics+Frame
ip Bisretinoid phospholipid and vitamin A aldehyde: Shining a light [Thematic Reviews] By www.jlr.org Published On :: 2020-05-05T13:30:26-07:00 Vitamin A aldehyde covalently bound to opsin protein is embedded in a phospholipid-rich membrane that supports photon absorption and phototransduction in photoreceptor cell outer segments. Following absorption of a photon, the 11-cis-retinal chromophore of visual pigment in photoreceptor cells isomerizes to all-trans-retinal. To maintain photosensitivity 11-cis-retinal must be replaced. At the same time, however, all-trans-retinal has to be handled so as to prevent nonspecific aldehyde activity. Some molecules of retinaldehyde upon release from opsin are efficiently reduced to retinol. Other molecules are released into the lipid phase of the disc membrane where they form a conjugate (N-retinylidene-PE, NRPE) through a Schiff base linkage with phosphatidylethanolamine (PE). The reversible formation of NRPE serves as a transient sink for retinaldehyde that is intended to return retinaldehyde to the visual cycle. However, if instead of hydrolyzing to PE and retinaldehyde, NRPE reacts with a second molecule of retinaldehyde a synthetic pathway is initiated that leads to the formation of multiple species of unwanted bisretinoid fluorophores. We report on recently identified members of the bisretinoid family some of which differ with respect to the acyl chains associated with the glycerol backbone. We discuss processing of the lipid moieties of these fluorophores in lysosomes of retinal pigment epithelial (RPE) cells, their fluorescence characters and new findings related to light and iron-associated oxidation of bisretinoids. Full Article