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Human Rights Priorities: An Agenda for Equality and Social Justice

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Published On :: Wed, 23 Oct 2019 13:50:01 +0000

Members Event

19 November 2019 - 6:00pm to 7:00pm

Chatham House | 10 St James's Square | London | SW1Y 4LE

Event participants

Michelle Bachelet, United Nations High Commissioner for Human Rights

Chair: Ruma Mandal, Head, International Law Programme, Chatham House

Following just over one year in office, UN High Commissioner for Human Rights, Michelle Bachelet, outlines her ongoing priorities at a tumultuous time for fundamental rights protections worldwide.

She discusses the rights implications of climate change, gender inequality including the advancement of sexual and reproductive rights, the protection of vulnerable groups and the need to work closely with states, civil society and business to protect and advance human rights.

Department/project

International Law Programme

Members Events Team


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Investigating Violations of International Humanitarian Law

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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 Defence
Larry Lewis, Vice President and Director, Center for Autonomy and Artificial Intelligence, CNA
Jelena Pejic, Senior Legal Adviser, International Committee of the Red Cross
Chair: 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


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Power Politics Could Impede Progress on Responsible Regulation of Cyberspace

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Published On :: Tue, 03 Dec 2019 14:34:13 +0000

3 December 2019

Harriet Moynihan

Senior Research Fellow, International Law Programme
A new Chatham House paper examines the prospects of countries reaching agreement on issues of sovereignty and non-intervention in cyberspace in the face of persistent, low-level, state-to-state cyber attacks.

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.

In discussions to date about how international law applies in cyberspace, commentators have tended to focus their attention on how the rules on the use of force, or the law of armed conflict, apply to cyber activities conducted by states that give rise to physical damage, injury or death.

But in practice, the vast majority of state cyberattacks fall below this threshold. Far more common are persistent, low-level attacks that may leave no physical trace but that are capable of doing significant damage to a state’s ability to control its systems, often at serious economic cost.

Such cyber incursions might include network disruptions in the operation of another government’s websites; tampering with electoral infrastructure to change or undermine the result; or using cyber means to destabilize another state’s financial sector.

For these kinds of cyber operation, the principle of sovereignty, and the principle of non-intervention in another state’s internal affairs, are the starting point.

A UN Group of Government Experts (GGE) agreed in 2013 and 2015 that the principles in the UN Charter, including sovereignty and the prohibition on intervention in another state’s affairs, apply to states’ activities in cyberspace. The 2015 GGE also recommended eleven (non-binding) norms of responsible state behaviour in cyberspace.

However, states have not yet reached agreement on how to apply these principles. Until recently, there has also been very little knowledge of what states actually do in cyberspace, as they usually conduct cyber operations covertly and have been reluctant to put their views on record.

A new Chatham House research paper analyses the application of the principles of sovereignty and non-intervention to state cyberattacks that fall below the principle of use of force. As well as analysing the application of the law in this area, the paper also makes recommendations to governments on how they might best make progress in reaching agreement in this area.

Existing rules or new rules?

As the research paper makes clear, there is currently some debate, principally between countries in the West, about the extent to which sovereignty is a legally binding rule in the context of cyberspace and, if so, how it and the principle of non-intervention might apply in practice.

In the last few years, certain states have put on record how they consider international law to apply to states’ activities in cyberspace, namely the UK, Australia, France and the Netherlands. While there may be some differences in their approaches, which are discussed in the paper, there also remains important common ground: namely, that existing international law already provides a solid framework for regulating states’ cyber activities, as it regulates every other domain of state-to-state activity.

There is also an emerging trend for states to work together when attributing cyberattacks to hostile states, enabling them to call out malign cyber activity when it violates international law. (See, for example, the joint statements made in relation to the NotPetya cyber attack and malicious cyber activity attributed to the Russian government).

However, other countries have questioned whether existing international law as it stands is capable of regulating states’ cyber interactions and have called for ‘new legal instruments’ in this area.

This includes a proposal by the Shanghai Cooperation Organization (led by Russia and China) for an International Code of Conduct on Information Security, a draft of which was submitted to the UN in 2011 and 2015, without success. The UN has also formed a new Open-Ended Working Group (OEWG) under a resolution proposed by Russia to consider how international law applies to states’ activities in cyberspace.

The resolution establishing the OEWG, which began work earlier this year, includes the possibility of the group ‘introducing changes to the rules, norms and principles of responsible behaviour of States’ agreed in the 2013 and 2015 GGE reports. In the OEWG discussions at the UN in September, several countries claimed that a new legal instrument was needed to fill the ‘legal vacuum’ (Cuba) or ‘the gap of ungoverned areas’ (Indonesia).

It would be concerning if the hard-won consensus on the application of international law to cyberspace that has been reached at past GGEs started to unravel. In contrast to 2013 and 2015, the 2017 meeting failed to reach an agreement.

On 9 December, a renewed GGE will meet in New York, but the existence of the OEWG exploring the same issues in a separate process reflects the fact that cyber norms have become an area of geopolitical rivalry.

Aside from the application of international law, states are also adopting divergent approaches to the domestic regulation of cyberspace within their own territory. The emerging trend towards a ‘splinternet’ – i.e. between states that believe the internet should be global and open on the hand, and those that favour a ‘sovereignty and control’ model on the other  – is also likely to make discussions at the GGE more challenging.

Distinct from the international law concept of sovereignty is the notion of ‘cybersovereignty’, a term coined by China to describe the wide-ranging powers it assumes under domestic law to regulate its citizens’ access to the internet and personal data within its territory. This approach is catching on (as reflected in Russia’s recently enacted ‘Sovereign Internet Law’), with other authoritarian states likely to follow suit.

The importance of non-state actors

In parallel with regional and UN discussions on how international law applies, a number of initiatives by non-state actors have also sought to establish voluntary principles about responsible state behaviour in cyberspace.

The Global Commission on the Stability of Cyberspace, a multi-stakeholder body that has proposed principles, norms and recommendations to guide responsible behaviour by all parties in cyberspace, recently published its final report. The Cybersecurity Tech Accord  aims to promote collaboration between tech companies on stability and resilience in cyberspace. President Macron’s ‘Paris Call for Trust and Security in Cyberspace’ has to date received the backing of 67 states, 139 international and civil society organizations, and 358 private-sector organizations.

It remains to be seen in the long term whether the parallel processes at the UN will work constructively together or be competitive. But notwithstanding the challenging geopolitical backdrop, the UN GGE meeting next week at the least offers states the opportunity to consolidate and build on the results of past meetings; to increase knowledge and discussion about how international law might apply; and to encourage more states to put their own views of these issues on the record.


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War Crimes and Their Prosecution

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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 Chambers
Charles Garraway, Visiting Fellow, Human Rights Centre, University of Essex
Chair: 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


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Kate Jones

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Published On :: Mon, 24 Feb 2020 12:00:38 +0000

Associate Fellow, International Law Programme

Biography

Kate focuses on cyber and human rights law issues, and is author of Chatham House’s research paper on Online Disinformation and Political Discourse: Applying a Human Rights Framework.

Kate is based at the University of Oxford, where she is a member of the Law Faculty and directs the Diplomatic Studies Programme, a set of postgraduate courses for diplomats. 

She gained much of her experience in human rights law and public international law as a lawyer at the UK Foreign and Commonwealth Office, both in London and overseas as Legal Adviser at the UK Mission to the United Nations in Geneva and then Deputy Permanent Representative at the UK Delegation to the Council of Europe in Strasbourg. 

She took her undergraduate and postgraduate degrees in law at the University of Oxford, and qualified as a solicitor at Norton Rose.

Areas of expertise

  • Cyber and human rights law (disinformation, elections, social media platforms, etc)
  • Human rights law
  • Public international law
  • Diplomatic skills and training

Past experience

2015 - presentDirector, Diplomatic Studies Programme; Member of University Law Faculty; Fellow of Kellogg College, University of Oxford
2014-15Research and Outreach Specialist, UK Foreign and Commonwealth Office
2011-14Deputy Permanent Representative, UK Delegation to Council of Europe
2008-11Legal Adviser, UK Mission to the United Nations
2002-07Assistant Legal Adviser, UK Foreign and Commonwealth Office
1997-2001Trainee, then Assistant Solicitor, Norton Rose
1999Judicial Assistant, Court of Appeal (secondment)


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12-LOX catalyzes the oxidation of 2-arachidonoyl-lysolipids in platelets generating eicosanoid-lysolipids that are attenuated by iPLA2{gamma} knockout [Signal Transduction]

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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.


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Glucocerebrosidases catalyze a transgalactosylation reaction that yields a newly-identified brain sterol metabolite, galactosylated cholesterol [Glycobiology and Extracellular Matrices]

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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.


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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]

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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.


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MtrP, a putative methyltransferase in Corynebacteria, is required for optimal membrane transport of trehalose mycolates [Lipids]

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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.


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COQ11 deletion mitigates respiratory deficiency caused by mutations in the gene encoding the coenzyme Q chaperone protein Coq10 [Lipids]

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Published On :: 2020-05-01T00:06:09-07:00

Coenzyme Q (Qn) is a vital lipid component of the electron transport chain that functions in cellular energy metabolism and as a membrane antioxidant. In the yeast Saccharomyces cerevisiae, coq1–coq9 deletion mutants are respiratory-incompetent, sensitive to lipid peroxidation stress, and unable to synthesize Q6. The yeast coq10 deletion mutant is also respiratory-deficient and sensitive to lipid peroxidation, yet it continues to produce Q6 at an impaired rate. Thus, Coq10 is required for the function of Q6 in respiration and as an antioxidant and is believed to chaperone Q6 from its site of synthesis to the respiratory complexes. In several fungi, Coq10 is encoded as a fusion polypeptide with Coq11, a recently identified protein of unknown function required for efficient Q6 biosynthesis. Because “fused” proteins are often involved in similar biochemical pathways, here we examined the putative functional relationship between Coq10 and Coq11 in yeast. We used plate growth and Seahorse assays and LC-MS/MS analysis to show that COQ11 deletion rescues respiratory deficiency, sensitivity to lipid peroxidation, and decreased Q6 biosynthesis of the coq10Δ mutant. Additionally, immunoblotting indicated that yeast coq11Δ mutants accumulate increased amounts of certain Coq polypeptides and display a stabilized CoQ synthome. These effects suggest that Coq11 modulates Q6 biosynthesis and that its absence increases mitochondrial Q6 content in the coq10Δcoq11Δ double mutant. This augmented mitochondrial Q6 content counteracts the respiratory deficiency and lipid peroxidation sensitivity phenotypes of the coq10Δ mutant. This study further clarifies the intricate connection between Q6 biosynthesis, trafficking, and function in mitochondrial metabolism.


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AIG1 and ADTRP are endogenous hydrolases of fatty acid esters of hydroxy fatty acids (FAHFAs) in mice [Metabolism]

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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.


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The transcriptional regulator MEIS2 sets up the ground state for palatal osteogenesis in mice [Gene Regulation]

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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.


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Certain ortho-hydroxylated brominated ethers are promiscuous kinase inhibitors that impair neuronal signaling and neurodevelopmental processes [Cell Biology]

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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.


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The testis-specific LINC component SUN3 is essential for sperm head shaping during mouse spermiogenesis [Cell Biology]

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Published On :: 2020-05-08T03:41:14-07:00

Sperm head shaping is a key event in spermiogenesis and is tightly controlled via the acrosome–manchette network. Linker of nucleoskeleton and cytoskeleton (LINC) complexes consist of Sad1 and UNC84 domain–containing (SUN) and Klarsicht/ANC-1/Syne-1 homology (KASH) domain proteins and form conserved nuclear envelope bridges implicated in transducing mechanical forces from the manchette to sculpt sperm nuclei into a hook-like shape. However, the role of LINC complexes in sperm head shaping is still poorly understood. Here we assessed the role of SUN3, a testis-specific LINC component harboring a conserved SUN domain, in spermiogenesis. We show that CRISPR/Cas9-generated Sun3 knockout male mice are infertile, displaying drastically reduced sperm counts and a globozoospermia-like phenotype, including a missing, mislocalized, or fragmented acrosome, as well as multiple defects in sperm flagella. Further examination revealed that the sperm head abnormalities are apparent at step 9 and that the sperm nuclei fail to elongate because of the absence of manchette microtubules and perinuclear rings. These observations indicate that Sun3 deletion likely impairs the ability of the LINC complex to transduce the cytoskeletal force to the nuclear envelope, required for sperm head elongation. We also found that SUN3 interacts with SUN4 in mouse testes and that the level of SUN4 proteins is drastically reduced in Sun3-null mice. Altogether, our results indicate that SUN3 is essential for sperm head shaping and male fertility, providing molecular clues regarding the underlying pathology of the globozoospermia-like phenotype.


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A Quantitative Tri-fluorescent Yeast Two-hybrid System: From Flow Cytometry to In cellula Affinities

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Published On :: 2020-04-01

David Cluet
Apr 1, 2020; 19:701-715
Technological Innovation and Resources


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Phenotypic Adaption of Pseudomonas aeruginosa by Hacking Siderophores Produced by Other Microorganisms

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Published On :: 2020-04-01

Quentin Perraud
Apr 1, 2020; 19:589-607
Research


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Chemical Genetics of AGC-kinases Reveals Shared Targets of Ypk1, Protein Kinase A and Sch9

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Published On :: 2020-04-01

Michael Plank
Apr 1, 2020; 19:655-671
Research


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Characterization of Prenylated C-terminal Peptides Using a Thiopropyl-based Capture Technique and LC-MS/MS

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Published On :: 2020-04-13

James A. Wilkins
Apr 13, 2020; 0:RA120.001944v1-mcp.RA120.001944
Research


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Investigation of inter- and intra-tumoral heterogeneity of glioblastoma using TOF-SIMS

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Published On :: 2020-04-06

Samvel K Gularyan
Apr 6, 2020; 0:RA120.001986v1-mcp.RA120.001986
Research


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Dysregulation of Exosome Cargo by Mutant Tau Expressed in Human-Induced Pluripotent Stem Cell (iPSC) Neurons Revealed by Proteomics Analyses

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Published On :: 2020-04-15

Sonia Podvin
Apr 15, 2020; 0:RA120.002079v1-mcp.RA120.002079
Research


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Human Hepatocyte Nuclear Factor 4-{alpha} Encodes Isoforms with Distinct Transcriptional Functions

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Published On :: 2020-05-01

Élie Lambert
May 1, 2020; 19:808-827
Research


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Quantitative proteomics of human heart samples collected in vivo reveal the remodeled protein landscape of dilated left atrium without atrial fibrillation

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Published On :: 2020-04-14

Nora Linscheid
Apr 14, 2020; 0:RA119.001878v1-mcp.RA119.001878
Research


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Arginine in C9ORF72 Dipolypeptides Mediates Promiscuous Proteome Binding and Multiple Modes of Toxicity

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Published On :: 2020-04-01

Mona Radwan
Apr 1, 2020; 19:640-654
Research


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Immediate adaptation analysis implicates BCL6 as an EGFR-TKI combination therapy target in NSCLC

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Published On :: 2020-03-31

Yan Zhou Tran
Mar 31, 2020; 0:RA120.002036v1-mcp.RA120.002036
Research


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A cross-linking mass spectrometry approach defines protein interactions in yeast mitochondria

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Published On :: 2020-04-24

Andreas Linden
Apr 24, 2020; 0:RA120.002028v1-mcp.RA120.002028
Research


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Characterization of signaling pathways associated with pancreatic {beta}-cell adaptive flexibility in compensation of obesity-linked diabetes in db/db mice

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Published On :: 2020-04-07

Taewook Kang
Apr 7, 2020; 0:RA119.001882v1-mcp.RA119.001882
Research


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The Data Must Be Accessible to All

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Published On :: 2020-04-01

Lila M. Gierasch
Apr 1, 2020; 19:569-570
Editorial


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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 Entwisle
Apr 6, 2020; 0:RA120.001946v2-mcp.RA120.001946
Research


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Large-scale Identification of N-linked Intact Glycopeptides in Human Serum using HILIC Enrichment and Spectral Library Search

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Published On :: 2020-04-01

Qingbo Shu
Apr 1, 2020; 19:672-689
Research


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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 Tsai
Mar 31, 2020; 0:RA119.001792v1-mcp.RA119.001792
Research


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Profiling Cell Signaling Networks at Single-cell Resolution

By feedproxy.google.com
Published On :: 2020-05-01

Xiao-Kang Lun
May 1, 2020; 19:744-756
Review


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DEqMS: a method for accurate variance estimation in differential protein expression analysis

By feedproxy.google.com
Published On :: 2020-03-23

Yafeng Zhu
Mar 23, 2020; 0:TIR119.001646v1-mcp.TIR119.001646
Technological Innovation and Resources


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Acquiring and Analyzing Data Independent Acquisition Proteomics Experiments without Spectrum Libraries

By feedproxy.google.com
Published On :: 2020-04-20

Lindsay K Pino
Apr 20, 2020; 0:P119.001913v1-mcp.P119.001913
Perspective


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A Compact Quadrupole-Orbitrap Mass Spectrometer with FAIMS Interface Improves Proteome Coverage in Short LC Gradients

By feedproxy.google.com
Published On :: 2020-04-01

Dorte B. Bekker-Jensen
Apr 1, 2020; 19:716-729
Technological Innovation and Resources


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Proximity Dependent Biotinylation: Key Enzymes and Adaptation to Proteomics Approaches

By feedproxy.google.com
Published On :: 2020-05-01

Payman Samavarchi-Tehrani
May 1, 2020; 19:757-773
Review


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Microsoft delivers fixes for 110 bugs in April, 2020 Patch Tuesday

By feedproxy.google.com
Published On :: Tue, 14 Apr 2020 17:43:55 +0000

For the April edition of Patch Tuesday, Microsoft repaired a total of 110 security vulnerabilities across their product line. Included in this count are 37 remote code execution bugs, and 33 elevation of privilege bugs. The company rated eighteen of the vulnerabilities “Critical.” This release’s most notable item is the follow-up to last month’s announcement, […]


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Rising to the challenge in the worst circumstances

By feedproxy.google.com
Published On :: Thu, 16 Apr 2020 14:28:47 +0000

In this era when we need to do everything possible to keep essential businesses operational, the people of the information security community have banded together in an inspirational effort to protect us all.


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How to remove unused devices from Sophos Central

By feedproxy.google.com
Published On :: Tue, 28 Apr 2020 18:17:03 +0000

We take you through the steps to clear your old devices from Sophos Central, so you've got more time to focus on the devices that matter.


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Protecting the Cloud: Securing access to public cloud accounts

By feedproxy.google.com
Published On :: Tue, 05 May 2020 12:44:15 +0000

How Sophos Cloud Optix helps you secure access to your AWS, Azure and Google Cloud Platform accounts.


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Protecting the Cloud: Securing user remote access to AWS

By feedproxy.google.com
Published On :: Thu, 07 May 2020 13:19:27 +0000

How to create secure access to services hosted in AWS with Sophos XG Firewall.


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Mathematical light shines blindly on us

By blogs.ams.org
Published On :: Mon, 09 Dec 2019 18:57:58 +0000

By William Yslas Vélez Professor Emeritus University of Arizona “When I go to a Mexican restaurant I would gladly pay the musicians to stop playing.” John (not his real name) did not like the noise level. This statement came up … Continue reading →


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Bank of REU/Grad Fair Questions

By blogs.ams.org
Published On :: Fri, 24 Jan 2020 19:14:06 +0000

By Lucy Martinez and Eduardo Torres Davila We attended the Joint Math Meetings (JMM) conference in Denver to present our research from our work at the Mathematical Sciences Research Institute Undergraduate Program. At JMM, there was a fair of graduate … Continue reading →


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Learning During the Pandemic: What we wish our professors and mentors knew

By blogs.ams.org
Published On :: Tue, 05 May 2020 12:45:41 +0000

Student Authors: Mayleen Cortez, Brooke Keene-Gomez, Lucy Martinez, Amaury V. Miniño, Jenna Race, Kelemua Tesfaye, and Stephanie. Blog post compiled by Melissa Gutiérrez González, Pamela E. Harris, and Alicia Prieto Langarica. In this blog we center the voices of mathematics students as … Continue reading →


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Strengthening Urban Preparedness and Resilience Against Biological Threats in Accra

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Published On :: Wed, 23 Jan 2019 17:40:01 +0000

Invitation Only Research Event

1 March 2019 - 10:30am to 2 March 2019 - 3:00pm

Chatham House, London

Capacity to contain and respond to biological threats varies considerably across the world. Yet such preparedness is vital for prevention, impact-reduction and resilience in the face of biological events, whether they be natural or deliberate outbreaks.

Chatham House is conducting a series of meetings to strengthen urban preparedness for, and resilience against, biological threats in African countries. This meeting will examine the preparedness and prevention mechanisms in Accra, reviewing the comprehensiveness of city-level preparedness.  

This meeting will focus on the formation and implementation of city-level action plans in the context of preparedness for managing biological threats. It will also explore how local authorities are contributing to this effort with their knowledge and expertise.

Attendance at this event is by invitation only.

Department/project

International Security Programme, Strengthening Urban Preparedness and Resilience against Biological Threats

Nilza Amaral

Project Manager, International Security Programme


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Cybersecurity in the Commonwealth: Building the Foundations of Effective National Responses in the Caribbean

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Published On :: Thu, 07 Feb 2019 14:20:01 +0000

Invitation Only Research Event

8 March 2019 - 9:00am to 5:30pm

Bridgetown, Barbados

Event participants

Joyce Hakmeh, Cyber Research Fellow, International Security Department, Chatham House

This workshop is the second in a series in the 'Implementing the Commonwealth Cybersecurity Agenda' project. The workshop aims to provide a multi-stakeholder pan-Commonwealth platform to discuss how to take the implementation of the 'Commonwealth Cyber Declaration' forward with a focus on the second pillar of the declaration – building the foundations of an effective national cybersecurity response with eight action points. 

As such, the workshop gathers different project implementers under the UK Foreign and Commonwealth Office’s Cyber Programme, in addition to other key relevant stakeholders from the global level, to explore ongoing initiatives which aim to deliver one or more of pillar two’s action points.

The workshop addresses issues from a global perspective and a Commonwealth perspective and will include presentations from selected partners from different Commonwealth countries.

Department/project

International Security Programme

Calum Inverarity

Research Analyst and Coordinator, International Security Department
+44 (0) 207 957 5751


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Transparency and Accountability for Drone Use: European Approaches

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Published On :: Thu, 07 Mar 2019 17:35:01 +0000

Invitation Only Research Event

11 March 2019 - 9:30am to 12 March 2019 - 12:30pm

Chatham House

With increased use of military drones in recent years there have also been many calls for greater transparency and accountability with regards to drone operations.

This would allow for greater public understanding, particularly as the complex nature of military operations today intensifies difficulties in sustaining perceptions of the legitimate use of force.

For example, in Europe, leading states rely on the US for drone platforms and for the infrastructure - such as military communication networks - that enable those operations, while the US also relies on airbases in European states to operate its drone programme.

In addition, with reports that the US is loosening the rules on the use of drones, it is important to understand how European approaches to transparency and accountability may be affected by these developments.

This workshop focuses on how European states can facilitate transparency to ensure accountability for drone use, as well as what the limits might be, considering both the complexity of military operations today and the need for achieving operational goals.

With the US easing restrictions on export controls, the discussion also considers the role of regulation in ensuring accountability and prospects for developing common standards.

Attendance at this event is by invitation only.

Nilza Amaral

Project Manager, International Security Programme

Department/project

International Security Programme, Policy Implications of Armed Drone Use


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European Approaches to Remote Warfare

By feedproxy.google.com
Published On :: Fri, 26 Apr 2019 14:50:01 +0000

Research Event

15 May 2019 - 9:00am to 6:00pm

Brussels, Belgium

With continuing instability at Europe's borders, along with uncertainty on future US support for NATO, many European countries are increasing their allocations to defence budgets and to collective European strategic defence. In addition, with non-state armed groups creating instability and threatening civilian lives and livelihoods in proximity to the EU’s borders, various operations have been carried out in conflict theatres in the Middle East, North Africa and the Sahel under the auspices of NATO, the UN, the EU or by single EU member states.

Although European military personnel have been deployed in many regions, with countries becoming more reluctant to deploy ‘boots on the ground’, warfare has been increasingly conducted through remote means. This has led to criticism on the limited transparency and accountability mechanisms at work in these operations, while some have questioned the military effectiveness of such tactics or the capacity and willingness of states to ensure that targets are struck accurately and without impact on civilian populations.

Against this background, the EU has started allocating resources to military research and development projects with a focus on unmanned systems and related technologies. Under the auspices of the European Defence Fund such funding is set to increase, while potential bilateral programmes between some states have also been explored. Despite concerns raised by the European Parliament, the development of these policies and technologies has taken place without significant consideration of what the legal, ethical and military-strategic impact of these instruments might be.    

This event will bring together a range of experts, policymakers and civil society organizations to discuss the technology horizon of European defence investments and policy developments around remote warfare. Participants will discuss the implications of the new EU defence fund, legal, ethical, and transparency issues in military research and development and the position of the EU as a global actor. 

This event is being organized in partnership with PAX Netherlands.

THIS EVENT IS NOW FULL AND REGISTRATION HAS CLOSED.

Department/project

International Security Programme

Nilza Amaral

Project Manager, International Security Programme


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Cyber Insurance for Civil Nuclear Facilities: Risks and Opportunities

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Published On :: Wed, 08 May 2019 15:21:25 +0000

8 May 2019

This paper sets out a roadmap for how organizations in the civil nuclear sector can explore their options and review their cyber risk exposure.

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Éireann Leverett

Senior Risk Researcher, University of Cambridge

GettyImages-667179424.jpg

The control room inside the Paks nuclear power plant in Hungary, 10 April 2017. Photo: Getty Images
  • Civil nuclear facilities and organizations hold sensitive information on security clearances, national security, health and safety, nuclear regulatory issues and international inspection obligations. The sensitivity and variety of such data mean that products tailored for insuring the civil nuclear industry have evolved independently and are likely to continue to do so.
  • ‘Air-gaps’ – measures designed to isolate computer systems from the internet – need to be continually maintained for industrial systems. Yet years of evidence indicate that proper maintenance of such protections is often lacking (mainly because very real economic drivers exist that push users towards keeping infrastructure connected). Indeed, even when air-gaps are maintained, security breaches can still occur.
  • Even if a particular organization has staff that are highly trained, ready and capable of handling a technological accident, hacking attack or incidence of insider sabotage, it still has to do business and/or communicate with other organizations that may not have the essentials of cybersecurity in place.
  • Regardless of whether the choice is made to buy external insurance or put aside revenues in preparation for costly incidents, the approach to cyber risk calculation should be the same. Prevention is one part of the equation, but an organization will also need to consider the resources and contingency measures available to it should prevention strategies fail. Can it balance the likelihood of a hacker’s success against the maximum cost to the organization, and put aside enough capital and manpower to get it through a crisis?
  • All civil nuclear facilities should consider the establishment of computer security incident response (CSIR) teams as a relevant concern, if such arrangements are not already in place. The existence of a CSIR team will be a prerequisite for any facility seeking to obtain civil nuclear cyber insurance.
  • Preventing attacks such as those involving phishing and ransomware requires good cyber hygiene practices throughout the workforce. Reducing an organization’s ‘time to recovery’ takes training and dedication. Practising the necessary tasks in crisis simulations greatly reduces the likelihood of friction and the potential for error in a crisis.

Department/project

International Security Programme, Cyber and Nuclear Security


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