an Sovereignty and Non-Intervention: The Application of International Law to State Cyberattacks By feedproxy.google.com Published On :: Fri, 01 Nov 2019 10:55:01 +0000 Research Event 4 December 2019 - 5:30pm to 7:00pm Chatham House | 10 St James's Square | London | SW1Y 4LE Event participants Douglas, Legal Director, GCHQZhixiong Huang, Luojia Chair of International Law, Wuhan UniversityNemanja Malisevic, Director of Digital Diplomacy, MicrosoftHarriet Moynihan, Associate Fellow, International Law Programme, Chatham HouseChair: Elizabeth Wilmshurst, Distinguished Fellow, International Law Programme, Chatham House International law applies to cyber operations – but views differ on exactly how. Does state-sponsored interference in another state's affairs using cyber means – for example, disinformation campaigns in elections, disabling government websites, or disrupting transport systems – breach international law? If so, on what basis and how are the principles of sovereignty and non-intervention relevant? States are increasingly attributing cyber operations to other states and engaging in the debate on how international law applies, including circumstances that would justify countermeasures.As states meet to debate these issues at the UN, the panel will explore how international law regulates cyberoperations by states, consider the prospects of progress at the UN, and assess the value of other initiatives.This event coincides with the launch of a Chatham House research paper which analyses how the principles of sovereignty and intervention apply in the context of cyberoperations, and considers a way forward for agreeing a common understanding of cyber norms.This event will bring together a broad group of actors, including policymakers, the private sector, legal experts and civil society, and will be followed by a drinks reception. Department/project International Law Programme, Cyber, Sovereignty and Human Rights Jacqueline Rowe Programme Assistant, International Law Programme 020 7389 3287 Email Full Article
an Security and Prosperity in Asia: The Role of International Law By feedproxy.google.com Published On :: Fri, 01 Nov 2019 11:38:35 +0000 1 November 2019 The 'Security and Prosperity in Asia' conference looked at the impact of international law in the Asia-Pacific with a focus on regional economic and security issues such as the South China Sea disputes. Read online Download PDF Security and Prosperity in Asia Cover Image.jpg Singapore skyline at sunset, 2016. Photo: Getty Images. About the ConferenceAt a time of geopolitical uncertainty and with multilateralism under pressure, this conference brought together diverse actors to explore the evolving role of international law on critical security and economic issues in the Asia-Pacific. From trade agreements to deep-sea mining, cyberwarfare to territorial disputes, the breadth of the discussion illustrated the growing reach of international law in the region.Hosted by the International Law Programme and the Asia-Pacific Programme at Chatham House on 27 March 2019, the conference focused on three themes: trade and investment, maritime security and governance, and emerging security challenges. What trends are emerging in terms of engagement with international law in the region, and how can international standards play a greater role in encouraging collaboration and reducing tensions? And, with the eastward shift in geopolitical power, how will Asia-Pacific states shape the future of international law? Department/project International Law Programme, Global Governance and the Rule of Law, Asia-Pacific Programme, Geopolitics and Governance, Trade, Investment and Economics Full Article
an Online Disinformation and Political Discourse: Applying a Human Rights Framework By feedproxy.google.com Published On :: Tue, 05 Nov 2019 11:03:02 +0000 6 November 2019 Although some digital platforms now have an impact on more people’s lives than does any one state authority, the international community has been slow to hold to account these platforms’ activities by reference to human rights law. This paper examines how human rights frameworks should guide digital technology. Download PDF Kate Jones Associate Fellow, International Law Programme @katejones77 LinkedIn 2019-11-05-Disinformation.jpg A man votes in Manhattan, New York City, during the US elections on 8 November 2016. Photo: Getty Images. SummaryOnline political campaigning techniques are distorting our democratic political processes. These techniques include the creation of disinformation and divisive content; exploiting digital platforms’ algorithms, and using bots, cyborgs and fake accounts to distribute this content; maximizing influence through harnessing emotional responses such as anger and disgust; and micro-targeting on the basis of collated personal data and sophisticated psychological profiling techniques. Some state authorities distort political debate by restricting, filtering, shutting down or censoring online networks.Such techniques have outpaced regulatory initiatives and, save in egregious cases such as shutdown of networks, there is no international consensus on how they should be tackled. Digital platforms, driven by their commercial impetus to encourage users to spend as long as possible on them and to attract advertisers, may provide an environment conducive to manipulative techniques.International human rights law, with its careful calibrations designed to protect individuals from abuse of power by authority, provides a normative framework that should underpin responses to online disinformation and distortion of political debate. Contrary to popular view, it does not entail that there should be no control of the online environment; rather, controls should balance the interests at stake appropriately.The rights to freedom of thought and opinion are critical to delimiting the appropriate boundary between legitimate influence and illegitimate manipulation. When digital platforms exploit decision-making biases in prioritizing bad news and divisive, emotion-arousing information, they may be breaching these rights. States and digital platforms should consider structural changes to digital platforms to ensure that methods of online political discourse respect personal agency and prevent the use of sophisticated manipulative techniques.The right to privacy includes a right to choose not to divulge your personal information, and a right to opt out of trading in and profiling on the basis of your personal data. Current practices in collecting, trading and using extensive personal data to ‘micro-target’ voters without their knowledge are not consistent with this right. Significant changes are needed.Data protection laws should be implemented robustly, and should not legitimate extensive harvesting of personal data on the basis of either notional ‘consent’ or the data handler’s commercial interests. The right to privacy should be embedded in technological design (such as by allowing the user to access all information held on them at the click of a button); and political parties should be transparent in their collection and use of personal data, and in their targeting of messages. Arguably, the value of personal data should be shared with the individuals from whom it derives.The rules on the boundaries of permissible content online should be set by states, and should be consistent with the right to freedom of expression. Digital platforms have had to rapidly develop policies on retention or removal of content, but those policies do not necessarily reflect the right to freedom of expression, and platforms are currently not well placed to take account of the public interest. Platforms should be far more transparent in their content regulation policies and decision-making, and should develop frameworks enabling efficient, fair, consistent internal complaints and content monitoring processes. Expertise on international human rights law should be integral to their systems.The right to participate in public affairs and to vote includes the right to engage in public debate. States and digital platforms should ensure an environment in which all can participate in debate online and are not discouraged from standing for election, from participating or from voting by online threats or abuse. Department/project International Law Programme, Cyber, Sovereignty and Human Rights, Rights, Accountability and Justice Full Article
an Investigating Violations of International Humanitarian Law By feedproxy.google.com Published On :: Wed, 13 Nov 2019 13:25:01 +0000 Research Event 21 January 2020 - 5:30pm to 7:00pm Chatham House | 10 St James's Square | London | SW1Y 4LE Event participants Andrew Cayley, Director, Service Prosecuting Authority, UK Ministry of DefenceLarry Lewis, Vice President and Director, Center for Autonomy and Artificial Intelligence, CNAJelena Pejic, Senior Legal Adviser, International Committee of the Red CrossChair: Elizabeth Wilmshurst, Distinguished Fellow, International Law Programme, Chatham House Countries should have adequate systems in place for investigating violations of international humanitarian law, for launching criminal prosecutions for war crimes and for inquiring into responsibility for unlawful actions of national armed forces. There also needs to be proper counting and recording of the civilian casualties of military operations. This event, which will be introduced by the director of the UK Service Prosecuting Authority, Andrew Cayley, will discuss the new report by the International Committee of the Red Cross and the Geneva Academy of International Humanitarian Law, Guidelines on Investigating Violations of International Humanitarian Law: Law, Policy and Good Practice, as well as the problems and challenges associated with recording civilian casualties of armed conflict. This meeting is the third in a series of three commemorating the 70th anniversary of the 1949 Geneva Conventions supported by the British Red Cross. It will be followed by a drinks reception. Department/project International Law Programme, The Limits on War and Preserving the Peace Jacqueline Rowe Programme Assistant, International Law Programme 020 7389 3287 Email Full Article
an The Application of International Law to State Cyberattacks: Sovereignty and Non-Intervention By feedproxy.google.com Published On :: Fri, 29 Nov 2019 16:56:12 +0000 2 December 2019 Hostile cyber operations by one state against another state are increasingly common. This paper analyzes the application of the sovereignty and non-intervention principles in relation to states’ cyber operations in another state below the threshold of the use of force. Read online Download PDF Harriet Moynihan Senior Research Fellow, International Law Programme @HarrietMoyniha9 2019-11-29-Intl-Law-Cyberattacks.jpg A computer hacked by a virus known as Petya. The Petya ransomware cyberattack hit computers of Russian and Ukrainian companies on 27 June 2017. Photo: Getty Images. SummaryThe vast majority of state-to-state cyberattacks consist of persistent, low-level intrusions that take place below the threshold of use of force. International law, including the principle of non-intervention in another state’s internal affairs and the principle of sovereignty, applies to these cyber operations.It is not clear whether any unauthorized cyber intrusion would violate the target state’s sovereignty, or whether there is a threshold in operation. While some would like to set limits by reference to effects of the cyber activity, at this time such limits are not reflected in customary international law. The assessment of whether sovereignty has been violated therefore has to be made on a case by case basis, if no other more specific rules of international law apply.In due course, further state practice and opinio iuris may give rise to an emerging cyber-specific understanding of sovereignty, just as specific rules deriving from the sovereignty principle have crystallized in other areas of international law.Before a principle of due diligence can be invoked in the cyber context, further work is needed by states to agree upon rules as to what might be expected of a state in this context.The principle of non-intervention applies to a state’s cyber operations as it does to other state activities. It consists of coercive behaviour by one state that deprives the target state of its free will in relation to the exercise of its sovereign functions in order to compel an outcome in, or conduct with respect to, a matter reserved to the target state.In practice, activities that contravene the non-intervention principle and activities that violates sovereignty will often overlap.In order to reach agreement on how international law applies to states’ cyber operations below the level of use of force, states should put their views on record, where possible giving examples of when they consider that an obligation may be breached, as states such as the UK, Australia, France and the Netherlands have done.Further discussion between states should focus on how the rules apply to practical examples of state-sponsored cyber operations. There is likely to be more commonality about specific applications of the law than there is about abstract principles.The prospects of a general treaty in this area are still far off. In due course, there may be benefit in considering limited rules, for example on due diligence and a prohibition on attacking critical infrastructure, before tackling broad principles. Department/project International Law Programme, Cyber, Sovereignty and Human Rights Full Article
an POSTPONED: Supporting Civic Space: The Role and Impact of the Private Sector By feedproxy.google.com Published On :: Wed, 22 Jan 2020 17:05:01 +0000 Invitation Only Research Event 16 March 2020 - 11:00am to 5:00pm Chatham House | 10 St James's Square | London | SW1Y 4LE A healthy civic space is vital for an enabling business environment. In recognition of this, a growing number of private sector actors are challenging, publicly or otherwise, the deteriorating environment for civic freedoms.However, this corporate activism is often limited and largely ad hoc. It remains confined to a small cluster of multinationals leaving potential routes for effective coordination and collaboration with other actors underexplored.This roundtable will bring together a diverse and international group of business actors, civil society actors and foreign policy experts to exchange perspectives and experiences on how the private sector can be involved in issues around civic space. The meeting will provide an opportunity to explore the drivers of – and barriers to – corporate activism, develop a better understanding of existing initiatives, identify good practice and discuss practical strategies for the business community.This meeting will be the first of a series of roundtables at Chatham House in support of initiatives to build broad alliances for the protection of civic space. Attendance at this event is by invitation only. PLEASE NOTE THIS EVENT IS POSTPONED UNTIL FURTHER NOTICE. Department/project International Law Programme, Global Governance and the Rule of Law, Rights, Accountability and Justice Jacqueline Rowe Programme Assistant, International Law Programme 020 7389 3287 Email Full Article
an The Use of Sanctions to Protect Journalists By feedproxy.google.com Published On :: Wed, 29 Jan 2020 15:00:02 +0000 Members Event 13 February 2020 - 12:30pm to 1:45pm Chatham House | 10 St James's Square | London | SW1Y 4LE Event participants Professor Sarah Cleveland, Louis Henkin Professor of Human and Constitutional Rights; Faculty Co-Director, Human Rights Institute, Columbia Law SchoolAmal Clooney, Barrister, Doughty Street ChambersThe Honourable Irwin Cotler, Chair, Raoul Wallenberg Centre for Human Rights; Minister of Justice and Attorney-General of Canada (2003-06)Baroness Helena Kennedy QC, Director, International Bar Association’s Human Rights InstituteLord Neuberger, President, Supreme Court of the United Kingdom (2012-17)Maria Ressa, CEO, Rappler Online News NetworkChair: Elizabeth Wilmshurst CMG, Distinguished Fellow, International Law Programme, Chatham House Attacks against journalists and challenges to media freedom are urgent and global. The sharp decline globally of democratic values which are underpinned in international values highlights the need for a free press and the necessity for states to take concerted action to protect media freedom.The High-Level Panel of Legal Experts on Media Freedom is an independent body convened at the request of the UK and Canadian governments in July 2019.The remit of the panel is to provide recommendations to governments on how to better protect journalists and address abuses of media freedom in line with international human rights law.Drawing on the panel’s new report, the speakers will discuss the use of targeted sanctions to protect journalists and a free press. Can the threat of targeted sanctions help curb the trend of increasing abuses against journalists?And what legal frameworks and mechanisms will be necessary to ensure targeted sanctions achieve their goal of identifying, preventing and punishing abuses against journalists? This event is organized in collaboration with the International Bar Association’s Human Rights Institute which acts as the secretariat to the High-Level Panel of Legal Experts on Media Freedom. Department/project International Law Programme, Rights, Accountability and Justice Members Events Team Email Full Article
an War Crimes and Their Prosecution By feedproxy.google.com Published On :: Wed, 19 Feb 2020 12:40:01 +0000 Invitation Only Research Event 5 March 2020 - 9:00am to 10:30am Chatham House | 10 St James's Square | London | SW1Y 4LE Event participants Michelle Butler, Barrister, Matrix ChambersCharles Garraway, Visiting Fellow, Human Rights Centre, University of EssexChair: Elizabeth Wilmshurst, Distinguished Fellow, International Law Programme, Chatham House The International Criminal Court cannot act when crimes are being genuinely prosecuted in a state. The meeting will discuss whether the ICC complementarity rules apply when a state puts restrictions on the prosecution of war crimes committed in particular circumstances or within a particular time period. In this context, the discussion will also cover the extent to which such restrictions are precluded by international obligations such as those in the Geneva Conventions with regard to the investigation and prosecution of war crimes. Event attributes Chatham House Rule Department/project International Law Programme, Global Governance and the Rule of Law, Rights, Accountability and Justice, The Limits on War and Preserving the Peace Jacqueline Rowe Programme Assistant, International Law Programme 020 7389 3287 Email Full Article
an COVID-19 Brings Human Rights into Focus By feedproxy.google.com Published On :: Thu, 09 Apr 2020 10:59:58 +0000 9 April 2020 Sonya Sceats Associate Fellow, International Law Programme @SonyaSceats With a reawakened sense of our shared humanity and vulnerability, and the benefits of collective action, this crisis may translate into a comeback for human rights as a popular idea. 2020-04-09-US-COVID-homeless A previously homeless family in the backyard of their newly reclaimed home in Los Angeles, where officials are trying to find homes to protect the state's huge homeless population from COVID-19. Photo by FREDERIC J. BROWN/AFP via Getty Images. During this extraordinary global public health emergency, governments must strike the right balance between assertive measures to slow the spread of the virus and protect lives on the one hand, and respect for human autonomy, dignity and equality on the other.International law already recognises the grave impact of pandemics and other catastrophic events on social order and provides criteria to guide states in their emergency action. The International Covenant on Civil and Political Rights permits curbs on the right to ‘liberty of movement’ so long as restrictions are provided by law, deemed necessary to protect public health, and consistent with other rights in that treaty.Freedom of expression and association, and the rights to privacy and family life are also qualified in these terms under international and regional human rights treaties. But, as emphasised in the Siracusa Principles, any limitations must not be applied in an arbitrary or discriminatory way, and must be of limited duration and subject to review.International law also guarantees the right to the highest attainable standard of health, while states are specifically required to take steps to prevent, treat and control epidemics under the International Covenant on Economic, Social and Cultural Rights. Even in health emergencies, access to health services must be ensured on a non-discriminatory basis, especially for vulnerable or marginalised groups.Abuse of coronavirus emergency measuresMany governments have taken pains to craft emergency laws that respect human rights, such as permitting reasonable exceptions to lockdowns for essential shopping and exercise, and making them subject to ongoing parliamentary review and sunset clauses. But even laws that appear to be human rights compliant can still easily be misapplied, as the recent debates about over-zealous policing of people walking and travelling in the UK illustrate.And disturbing stories are emerging from states where police brutality is entrenched. In Kenya, a 13-year-old boy was reportedly shot on the balcony of his home by police enforcing a coronavirus curfew. Authorities in the Philippines' are allegedly locking those caught defying the curfew in dog cages.As the recent history of counterterrorism demonstrates, emergency laws tend to be sticky, remaining on the statute books far longer than desirable.The virus is also proving a powerful accelerant for the current global authoritarian drift which is so detrimental to progress on human rights. Many authoritarian leaders have seized the opportunity to further reduce constraints on their power.Hungary's prime minister Viktor Orbán has used the pandemic as a pretext for new laws enabling him to rule by decree, completing the country's transition to an elected dictatorship. In Brazil, president Jair Bolsonaro has suspended deadlines for public bodies to reply to freedom of information requests. Iran is the latest of many repressive states in the Middle East to ban the printing and distribution of all newspapers. In China, the government brushed off criticism over ‘disappearances’ of whistleblowers and citizen journalists who questioned its response to the crisis.Others have exploited the turmoil to undermine justice for human rights abuses - Sri Lanka's president Gotabaya Rajapaksa pardoned one of the only soldiers held accountable for crimes during the country's brutal civil war.Coronavirus also places liberal values under further strain. Fear is a major driver in the appeal of populist authoritarians and the virus is stoking it. One poll showed 73% of British citizens agreed coronavirus is just the latest sign that the world we live in is increasingly dangerous. Extremists are exploiting these fears to spread hate by blaming the outbreak on ethnic or religious groups, and encouraging those infected to spread it to these groups.The closure of borders helps reinforce xenophobic tendencies, and high public tolerance of emergency measures could easily spill into normalisation of intrusive digital surveillance and restrictions on liberty for other reasons well into the future.Disadvantaged groups face a higher level of risk from the crisis. The health of aboriginal Australians is so poor that those aged 50 and above are being urged to stay home, advice otherwise given to those over 70 in the general population. The Moria refugee camp on Lesbos is reporting no soap and just one water tap for 1,300 refugees. In the UK, asylum seekers struggle to self-isolate in shared accommodation and have a daily allowance of just £5.40 for food, medicine and toiletries. Women's rights groups are reporting a spike in domestic violence.For countries racked by war and extreme poverty, the impact is catastrophic. The virus is set to run rampant in slums, refugee camps and informal settlements where public health systems - if they exist at all - will struggle to cope. And detainees are among the most at risk, with the UN calling for release of political prisoners and anyone detained without sufficient legal basis.But the crisis has galvanised debate around the right to health and universal health coverage. Many governments have quickly bankrolled generous relief packages which will actually safeguard the socio-economic rights of many, even if they are not being justified in those terms. Portugal and Ireland have rolled back barriers to accessing healthcare for asylum seekers and other marginalised migrants.The pandemic strikes as many powerful governments have become increasingly nationalistic, undermining or retreating from international rules and institutions on human rights. But as the crisis spreads, the role of well-established international human rights standards in shaping and implementing effective - but also legitimate - measures is becoming ever clearer.The virus has reminded us of our interconnectedness as human beings and the need for global cooperation to protect our lives and health. This may help to revive popular support for human rights, creating momentum for the efforts to tackle inequality and repression - factors which have made the global impact of coronavirus so much worse than it might have been. Full Article
an 12-LOX catalyzes the oxidation of 2-arachidonoyl-lysolipids in platelets generating eicosanoid-lysolipids that are attenuated by iPLA2{gamma} knockout [Signal Transduction] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 The canonical pathway of eicosanoid production in most mammalian cells is initiated by phospholipase A2-mediated release of arachidonic acid, followed by its enzymatic oxidation resulting in a vast array of eicosanoid products. However, recent work has demonstrated that the major phospholipase in mitochondria, iPLA2γ (patatin-like phospholipase domain containing 8 (PNPLA8)), possesses sn-1 specificity, with polyunsaturated fatty acids at the sn-2 position generating polyunsaturated sn-2-acyl lysophospholipids. Through strategic chemical derivatization, chiral chromatographic separation, and multistage tandem MS, here we first demonstrate that human platelet-type 12-lipoxygenase (12-LOX) can directly catalyze the regioselective and stereospecific oxidation of 2-arachidonoyl-lysophosphatidylcholine (2-AA-LPC) and 2-arachidonoyl-lysophosphatidylethanolamine (2-AA-LPE). Next, we identified these two eicosanoid-lysophospholipids in murine myocardium and in isolated platelets. Moreover, we observed robust increases in 2-AA-LPC, 2-AA-LPE, and their downstream 12-LOX oxidation products, 12(S)-HETE-LPC and 12(S)-HETE-LPE, in calcium ionophore (A23187)-stimulated murine platelets. Mechanistically, genetic ablation of iPLA2γ markedly decreased the calcium-stimulated production of 2-AA-LPC, 2-AA-LPE, and 12-HETE-lysophospholipids in mouse platelets. Importantly, a potent and selective 12-LOX inhibitor, ML355, significantly inhibited the production of 12-HETE-LPC and 12-HETE-LPE in activated platelets. Furthermore, we found that aging is accompanied by significant changes in 12-HETE-LPC in murine serum that were also markedly attenuated by iPLA2γ genetic ablation. Collectively, these results identify previously unknown iPLA2γ-initiated signaling pathways mediated by direct 12-LOX oxidation of 2-AA-LPC and 2-AA-LPE. This oxidation generates previously unrecognized eicosanoid-lysophospholipids that may serve as biomarkers for age-related diseases and could potentially be used as targets in therapeutic interventions. Full Article
an Glucocerebrosidases catalyze a transgalactosylation reaction that yields a newly-identified brain sterol metabolite, galactosylated cholesterol [Glycobiology and Extracellular Matrices] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 β-Glucocerebrosidase (GBA) hydrolyzes glucosylceramide (GlcCer) to generate ceramide. Previously, we demonstrated that lysosomal GBA1 and nonlysosomal GBA2 possess not only GlcCer hydrolase activity, but also transglucosylation activity to transfer the glucose residue from GlcCer to cholesterol to form β-cholesterylglucoside (β-GlcChol) in vitro. β-GlcChol is a member of sterylglycosides present in diverse species. How GBA1 and GBA2 mediate β-GlcChol metabolism in the brain is unknown. Here, we purified and characterized sterylglycosides from rodent and fish brains. Although glucose is thought to be the sole carbohydrate component of sterylglycosides in vertebrates, structural analysis of rat brain sterylglycosides revealed the presence of galactosylated cholesterol (β-GalChol), in addition to β-GlcChol. Analyses of brain tissues from GBA2-deficient mice and GBA1- and/or GBA2-deficient Japanese rice fish (Oryzias latipes) revealed that GBA1 and GBA2 are responsible for β-GlcChol degradation and formation, respectively, and that both GBA1 and GBA2 are responsible for β-GalChol formation. Liquid chromatography–tandem MS revealed that β-GlcChol and β-GalChol are present throughout development from embryo to adult in the mouse brain. We found that β-GalChol expression depends on galactosylceramide (GalCer), and developmental onset of β-GalChol biosynthesis appeared to be during myelination. We also found that β-GlcChol and β-GalChol are secreted from neurons and glial cells in association with exosomes. In vitro enzyme assays confirmed that GBA1 and GBA2 have transgalactosylation activity to transfer the galactose residue from GalCer to cholesterol to form β-GalChol. This is the first report of the existence of β-GalChol in vertebrates and how β-GlcChol and β-GalChol are formed in the brain. Full Article
an Deletion of fatty acid transport protein 2 (FATP2) in the mouse liver changes the metabolic landscape by increasing the expression of PPAR{alpha}-regulated genes [Lipids] By feedproxy.google.com Published On :: 2020-04-24T06:08:45-07:00 Fatty acid transport protein 2 (FATP2) is highly expressed in the liver, small intestine, and kidney, where it functions in both the transport of exogenous long-chain fatty acids and the activation of very-long-chain fatty acids. Here, using a murine model, we investigated the phenotypic impacts of deleting FATP2, followed by a transcriptomic analysis using unbiased RNA-Seq to identify concomitant changes in the liver transcriptome. WT and FATP2-null (Fatp2−/−) mice (5 weeks) were maintained on a standard chow diet for 6 weeks. The Fatp2−/− mice had reduced weight gain, lowered serum triglyceride, and increased serum cholesterol levels and attenuated dietary fatty acid absorption. Transcriptomic analysis of the liver revealed 258 differentially expressed genes in male Fatp2−/− mice and a total of 91 in female Fatp2−/− mice. These genes mapped to the following gene ontology categories: fatty acid degradation, peroxisome biogenesis, fatty acid synthesis, and retinol and arachidonic acid metabolism. Targeted RT-quantitative PCR verified the altered expression of selected genes. Of note, most of the genes with increased expression were known to be regulated by peroxisome proliferator–activated receptor α (PPARα), suggesting that FATP2 activity is linked to a PPARα-specific proximal ligand. Targeted metabolomic experiments in the Fatp2−/− liver revealed increases of total C16:0, C16:1, and C18:1 fatty acids; increases in lipoxin A4 and prostaglandin J2; and a decrease in 20-hydroxyeicosatetraenoic acid. We conclude that the expression of FATP2 in the liver broadly affects the metabolic landscape through PPARα, indicating that FATP2 provides an important role in liver lipid metabolism through its transport or activation activities. Full Article
an Determination of globotriaosylceramide analogs in the organs of a mouse model of Fabry disease [Lipids] By feedproxy.google.com Published On :: 2020-04-24T06:08:45-07:00 Fabry disease is a heritable lipid disorder caused by the low activity of α-galactosidase A and characterized by the systemic accumulation of globotriaosylceramide (Gb3). Recent studies have reported a structural heterogeneity of Gb3 in Fabry disease, including Gb3 isoforms with different fatty acids and Gb3 analogs with modifications on the sphingosine moiety. However, Gb3 assays are often performed only on the selected Gb3 isoforms. To precisely determine the total Gb3 concentration, here we established two methods for determining both Gb3 isoforms and analogs. One was the deacylation method, involving Gb3 treatment with sphingolipid ceramide N-deacylase, followed by an assay of the deacylated products, globotriaosylsphingosine (lyso-Gb3) and its analogs, by ultra-performance LC coupled to tandem MS (UPLC-MS/MS). The other method was a direct assay established in the present study for 37 Gb3 isoforms and analogs/isoforms by UPLC-MS/MS. Gb3s from the organs of symptomatic animals of a Fabry disease mouse model were mainly Gb3 isoforms and two Gb3 analogs, such as Gb3(+18) containing the lyso-Gb3(+18) moiety and Gb3(−2) containing the lyso-Gb3(−2) moiety. The total concentrations and Gb3 analog distributions determined by the two methods were comparable. Gb3(+18) levels were high in the kidneys (24% of total Gb3) and the liver (13%), and we observed Gb3(−2) in the heart (10%) and the kidneys (5%). These results indicate organ-specific expression of Gb3 analogs, insights that may lead to a deeper understanding of the pathophysiology of Fabry disease. Full Article
an MtrP, a putative methyltransferase in Corynebacteria, is required for optimal membrane transport of trehalose mycolates [Lipids] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 Pathogenic bacteria of the genera Mycobacterium and Corynebacterium cause severe human diseases such as tuberculosis (Mycobacterium tuberculosis) and diphtheria (Corynebacterium diphtheriae). The cells of these species are surrounded by protective cell walls rich in long-chain mycolic acids. These fatty acids are conjugated to the disaccharide trehalose on the cytoplasmic side of the bacterial cell membrane. They are then transported across the membrane to the periplasm where they act as donors for other reactions. We have previously shown that transient acetylation of the glycolipid trehalose monohydroxycorynomycolate (hTMCM) enables its efficient transport to the periplasm in Corynebacterium glutamicum and that acetylation is mediated by the membrane protein TmaT. Here, we show that a putative methyltransferase, encoded at the same genetic locus as TmaT, is also required for optimal hTMCM transport. Deletion of the C. glutamicum gene NCgl2764 (Rv0224c in M. tuberculosis) abolished acetyltrehalose monocorynomycolate (AcTMCM) synthesis, leading to accumulation of hTMCM in the inner membrane and delaying its conversion to trehalose dihydroxycorynomycolate (h2TDCM). Complementation with NCgl2764 normalized turnover of hTMCM to h2TDCM. In contrast, complementation with NCgl2764 derivatives mutated at residues essential for methyltransferase activity failed to rectify the defect, suggesting that NCgl2764/Rv0224c encodes a methyltransferase, designated here as MtrP. Comprehensive analyses of the individual mtrP and tmaT mutants and of a double mutant revealed strikingly similar changes across several lipid classes compared with WT bacteria. These findings indicate that both MtrP and TmaT have nonredundant roles in regulating AcTMCM synthesis, revealing additional complexity in the regulation of trehalose mycolate transport in the Corynebacterineae. Full Article
an AIG1 and ADTRP are endogenous hydrolases of fatty acid esters of hydroxy fatty acids (FAHFAs) in mice [Metabolism] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 Fatty acid esters of hydroxy fatty acids (FAHFAs) are a newly discovered class of signaling lipids with anti-inflammatory and anti-diabetic properties. However, the endogenous regulation of FAHFAs remains a pressing but unanswered question. Here, using MS-based FAHFA hydrolysis assays, LC-MS–based lipidomics analyses, and activity-based protein profiling, we found that androgen-induced gene 1 (AIG1) and androgen-dependent TFPI-regulating protein (ADTRP), two threonine hydrolases, control FAHFA levels in vivo in both genetic and pharmacologic mouse models. Tissues from mice lacking ADTRP (Adtrp-KO), or both AIG1 and ADTRP (DKO) had higher concentrations of FAHFAs particularly isomers with the ester bond at the 9th carbon due to decreased FAHFA hydrolysis activity. The levels of other lipid classes were unaltered indicating that AIG1 and ADTRP specifically hydrolyze FAHFAs. Complementing these genetic studies, we also identified a dual AIG1/ADTRP inhibitor, ABD-110207, which is active in vivo. Acute treatment of WT mice with ABD-110207 resulted in elevated FAHFA levels, further supporting the notion that AIG1 and ADTRP activity control endogenous FAHFA levels. However, loss of AIG1/ADTRP did not mimic the changes associated with pharmacologically administered FAHFAs on extent of upregulation of FAHFA levels, glucose tolerance, or insulin sensitivity in mice, indicating that therapeutic strategies should weigh more on FAHFA administration. Together, these findings identify AIG1 and ADTRP as the first endogenous FAHFA hydrolases identified and provide critical genetic and chemical tools for further characterization of these enzymes and endogenous FAHFAs to unravel their physiological functions and roles in health and disease. Full Article
an The transcriptional regulator MEIS2 sets up the ground state for palatal osteogenesis in mice [Gene Regulation] By feedproxy.google.com Published On :: 2020-04-17T00:06:05-07:00 Haploinsufficiency of Meis homeobox 2 (MEIS2), encoding a transcriptional regulator, is associated with human cleft palate, and Meis2 inactivation leads to abnormal palate development in mice, implicating MEIS2 functions in palate development. However, its functional mechanisms remain unknown. Here we observed widespread MEIS2 expression in the developing palate in mice. Wnt1Cre-mediated Meis2 inactivation in cranial neural crest cells led to a secondary palate cleft. Importantly, about half of the Wnt1Cre;Meis2f/f mice exhibited a submucous cleft, providing a model for studying palatal bone formation and patterning. Consistent with complete absence of palatal bones, the results from integrative analyses of MEIS2 by ChIP sequencing, RNA-Seq, and an assay for transposase-accessible chromatin sequencing identified key osteogenic genes regulated directly by MEIS2, indicating that it plays a fundamental role in palatal osteogenesis. De novo motif analysis uncovered that the MEIS2-bound regions are highly enriched in binding motifs for several key osteogenic transcription factors, particularly short stature homeobox 2 (SHOX2). Comparative ChIP sequencing analyses revealed genome-wide co-occupancy of MEIS2 and SHOX2 in addition to their colocalization in the developing palate and physical interaction, suggesting that SHOX2 and MEIS2 functionally interact. However, although SHOX2 was required for proper palatal bone formation and was a direct downstream target of MEIS2, Shox2 overexpression failed to rescue the palatal bone defects in a Meis2-mutant background. These results, together with the fact that Meis2 expression is associated with high osteogenic potential and required for chromatin accessibility of osteogenic genes, support a vital function of MEIS2 in setting up a ground state for palatal osteogenesis. Full Article
an Certain ortho-hydroxylated brominated ethers are promiscuous kinase inhibitors that impair neuronal signaling and neurodevelopmental processes [Cell Biology] By feedproxy.google.com Published On :: 2020-05-01T00:06:09-07:00 The developing nervous system is remarkably sensitive to environmental signals, including disruptive toxins, such as polybrominated diphenyl ethers (PBDEs). PBDEs are an environmentally pervasive class of brominated flame retardants whose neurodevelopmental toxicity mechanisms remain largely unclear. Using dissociated cortical neurons from embryonic Rattus norvegicus, we found here that chronic exposure to 6-OH–BDE-47, one of the most prevalent hydroxylated PBDE metabolites, suppresses both spontaneous and evoked neuronal electrical activity. On the basis of our previous work on mitogen-activated protein kinase (MAPK)/extracellular signal-related kinase (ERK) (MEK) biology and our observation that 6-OH–BDE-47 is structurally similar to kinase inhibitors, we hypothesized that certain hydroxylated PBDEs mediate neurotoxicity, at least in part, by impairing the MEK–ERK axis of MAPK signal transduction. We tested this hypothesis on three experimental platforms: 1) in silico, where modeling ligand–protein docking suggested that 6-OH–BDE-47 is a promiscuous ATP-competitive kinase inhibitor; 2) in vitro in dissociated neurons, where 6-OH–BDE-47 and another specific hydroxylated BDE metabolite similarly impaired phosphorylation of MEK/ERK1/2 and activity-induced transcription of a neuronal immediate early gene; and 3) in vivo in Drosophila melanogaster, where developmental exposures to 6-OH–BDE-47 and a MAPK inhibitor resulted in offspring displaying similarly increased frequency of mushroom-body β–lobe midline crossing, a metric of axonal guidance. Taken together, our results support that certain ortho-hydroxylated PBDE metabolites are promiscuous kinase inhibitors and can cause disruptions of critical neurodevelopmental processes, including neuronal electrical activity, pre-synaptic functions, MEK–ERK signaling, and axonal guidance. Full Article
an Genetic Profile and Functional Proteomics of Anal Squamous Cell Carcinoma: Proposal for a Molecular Classification By feedproxy.google.com Published On :: 2020-04-01 Lucía Trilla-FuertesApr 1, 2020; 19:690-700Research Full Article
an A Quantitative Tri-fluorescent Yeast Two-hybrid System: From Flow Cytometry to In cellula Affinities By feedproxy.google.com Published On :: 2020-04-01 David CluetApr 1, 2020; 19:701-715Technological Innovation and Resources Full Article
an Phenotypic Adaption of Pseudomonas aeruginosa by Hacking Siderophores Produced by Other Microorganisms By feedproxy.google.com Published On :: 2020-04-01 Quentin PerraudApr 1, 2020; 19:589-607Research Full Article
an Tandem Mass Tag Approach Utilizing Pervanadate BOOST Channels Delivers Deeper Quantitative Characterization of the Tyrosine Phosphoproteome By feedproxy.google.com Published On :: 2020-04-01 Xien Yu ChuaApr 1, 2020; 19:730-743Technological Innovation and Resources Full Article
an Integrative Metabolic Pathway Analysis Reveals Novel Therapeutic Targets in Osteoarthritis By feedproxy.google.com Published On :: 2020-04-01 Beatriz RochaApr 1, 2020; 19:574-588Research Full Article
an Organellar maps through proteomic profiling - a conceptual guide By feedproxy.google.com Published On :: 2020-04-28 Georg H H BornerApr 28, 2020; 0:R120.001971v1-mcp.R120.001971Review Full Article
an The DNA sensor cGAS is decorated by acetylation and phosphorylation modifications in the context of immune signaling By feedproxy.google.com Published On :: 2020-04-28 Bokai SongApr 28, 2020; 0:RA120.001981v1-mcp.RA120.001981Research Full Article
an Modulation of natural HLA-B*27:05 ligandome by ankylosing spondylitis-associated endoplasmic reticulum aminopeptidase 2 (ERAP2) By feedproxy.google.com Published On :: 2020-04-07 Elena LorenteApr 7, 2020; 0:RA120.002014v1-mcp.RA120.002014Research Full Article
an HIGD2A is required for assembly of the COX3 module of human mitochondrial complex IV By feedproxy.google.com Published On :: 2020-04-21 Daniella H HockApr 21, 2020; 0:RA120.002076v1-mcp.RA120.002076Research Full Article
an Chemical Genetics of AGC-kinases Reveals Shared Targets of Ypk1, Protein Kinase A and Sch9 By feedproxy.google.com Published On :: 2020-04-01 Michael PlankApr 1, 2020; 19:655-671Research Full Article
an Characterization of Prenylated C-terminal Peptides Using a Thiopropyl-based Capture Technique and LC-MS/MS By feedproxy.google.com Published On :: 2020-04-13 James A. WilkinsApr 13, 2020; 0:RA120.001944v1-mcp.RA120.001944Research Full Article
an Flow-induced reorganization of laminin-integrin networks within the endothelial basement membrane uncovered by proteomics By feedproxy.google.com Published On :: 2020-04-24 Eelke P. BéguinApr 24, 2020; 0:RA120.001964v1-mcp.RA120.001964Research Full Article
an Seminal Plasma Proteome as an Indicator of Sperm Dysfunction and Low Sperm Motility By feedproxy.google.com Published On :: 2020-04-20 Yunlei LiApr 20, 2020; 0:RA120.002017v1-mcp.RA120.002017Research Full Article
an Cell Cycle Profiling Reveals Protein Oscillation, Phosphorylation, and Localization Dynamics By feedproxy.google.com Published On :: 2020-04-01 Patrick HerrApr 1, 2020; 19:608-623Research Full Article
an Proteaphagy in mammalian cells can function independent of ATG5/ATG7 By feedproxy.google.com Published On :: 2020-04-16 Tatjana GoebelApr 16, 2020; 0:RA120.001983v1-mcp.RA120.001983Research Full Article
an Robust summarization and inference in proteome-wide label-free quantification By feedproxy.google.com Published On :: 2020-04-22 Adriaan StickerApr 22, 2020; 0:RA119.001624v1-mcp.RA119.001624Research Full Article
an Investigation of inter- and intra-tumoral heterogeneity of glioblastoma using TOF-SIMS By feedproxy.google.com Published On :: 2020-04-06 Samvel K GularyanApr 6, 2020; 0:RA120.001986v1-mcp.RA120.001986Research Full Article
an Dysregulation of Exosome Cargo by Mutant Tau Expressed in Human-Induced Pluripotent Stem Cell (iPSC) Neurons Revealed by Proteomics Analyses By feedproxy.google.com Published On :: 2020-04-15 Sonia PodvinApr 15, 2020; 0:RA120.002079v1-mcp.RA120.002079Research Full Article
an Developments and Applications of Functional Protein Microarrays By feedproxy.google.com Published On :: 2020-04-17 Guan-Da SyuApr 17, 2020; 0:R120.001936v1-mcp.R120.001936Review Full Article
an Identification of an Unconventional Subpeptidome Bound to the Behcet's Disease-associated HLA-B*51:01 that is Regulated by Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) By feedproxy.google.com Published On :: 2020-05-01 Liye ChenMay 1, 2020; 19:871-883Research Full Article
an Human Hepatocyte Nuclear Factor 4-{alpha} Encodes Isoforms with Distinct Transcriptional Functions By feedproxy.google.com Published On :: 2020-05-01 Élie LambertMay 1, 2020; 19:808-827Research Full Article
an Quantitative proteomics of human heart samples collected in vivo reveal the remodeled protein landscape of dilated left atrium without atrial fibrillation By feedproxy.google.com Published On :: 2020-04-14 Nora LinscheidApr 14, 2020; 0:RA119.001878v1-mcp.RA119.001878Research Full Article
an Arginine in C9ORF72 Dipolypeptides Mediates Promiscuous Proteome Binding and Multiple Modes of Toxicity By feedproxy.google.com Published On :: 2020-04-01 Mona RadwanApr 1, 2020; 19:640-654Research Full Article
an Immediate adaptation analysis implicates BCL6 as an EGFR-TKI combination therapy target in NSCLC By feedproxy.google.com Published On :: 2020-03-31 Yan Zhou TranMar 31, 2020; 0:RA120.002036v1-mcp.RA120.002036Research Full Article
an Characterization of signaling pathways associated with pancreatic {beta}-cell adaptive flexibility in compensation of obesity-linked diabetes in db/db mice By feedproxy.google.com Published On :: 2020-04-07 Taewook KangApr 7, 2020; 0:RA119.001882v1-mcp.RA119.001882Research Full Article
an Proteome and phosphoproteome analysis of brown adipocytes reveals that RICTOR loss dampens global insulin/AKT signaling By feedproxy.google.com Published On :: 2020-04-06 Samuel W EntwisleApr 6, 2020; 0:RA120.001946v2-mcp.RA120.001946Research Full Article
an Large-scale Identification of N-linked Intact Glycopeptides in Human Serum using HILIC Enrichment and Spectral Library Search By feedproxy.google.com Published On :: 2020-04-01 Qingbo ShuApr 1, 2020; 19:672-689Research Full Article
an Selection of features with consistent profiles improves relative protein quantification in mass spectrometry experiments By feedproxy.google.com Published On :: 2020-03-31 Tsung-Heng TsaiMar 31, 2020; 0:RA119.001792v1-mcp.RA119.001792Research Full Article
an Quantitative Profiling of the Human Substantia Nigra Proteome from Laser-capture Microdissected FFPE Tissue By feedproxy.google.com Published On :: 2020-05-01 Eva GriesserMay 1, 2020; 19:839-851Research Full Article
an DEqMS: a method for accurate variance estimation in differential protein expression analysis By feedproxy.google.com Published On :: 2020-03-23 Yafeng ZhuMar 23, 2020; 0:TIR119.001646v1-mcp.TIR119.001646Technological Innovation and Resources Full Article
an Compliance Checklists No Longer Required at Initial Manuscript Submission By feedproxy.google.com Published On :: 2020-04-01 Alma L. BurlingameApr 1, 2020; 19:571-571Editorial Full Article
an Improving Identification of In-organello Protein-Protein Interactions Using an Affinity-enrichable, Isotopically Coded, and Mass Spectrometry-cleavable Chemical Crosslinker By feedproxy.google.com Published On :: 2020-04-01 Karl A. T. MakepeaceApr 1, 2020; 19:624-639Research Full Article
an MaxQuant software for ion mobility enhanced shotgun proteomics By feedproxy.google.com Published On :: 2020-03-10 Nikita PrianichnikovMar 10, 2020; 0:TIR119.001720v1-mcp.TIR119.001720Technological Innovation and Resources Full Article
