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Single-molecule level structural dynamics of DNA unwinding by human mitochondrial Twinkle helicase [Molecular Biophysics]

Knowledge of the molecular events in mitochondrial DNA (mtDNA) replication is crucial to understanding the origins of human disorders arising from mitochondrial dysfunction. Twinkle helicase is an essential component of mtDNA replication. Here, we employed atomic force microscopy imaging in air and liquids to visualize ring assembly, DNA binding, and unwinding activity of individual Twinkle hexamers at the single-molecule level. We observed that the Twinkle subunits self-assemble into hexamers and higher-order complexes that can switch between open and closed-ring configurations in the absence of DNA. Our analyses helped visualize Twinkle loading onto and unloading from DNA in an open-ringed configuration. They also revealed that closed-ring conformers bind and unwind several hundred base pairs of duplex DNA at an average rate of ∼240 bp/min. We found that the addition of mitochondrial single-stranded (ss) DNA–binding protein both influences the ways Twinkle loads onto defined DNA substrates and stabilizes the unwound ssDNA product, resulting in a ∼5-fold stimulation of the apparent DNA-unwinding rate. Mitochondrial ssDNA-binding protein also increased the estimated translocation processivity from 1750 to >9000 bp before helicase disassociation, suggesting that more than half of the mitochondrial genome could be unwound by Twinkle during a single DNA-binding event. The strategies used in this work provide a new platform to examine Twinkle disease variants and the core mtDNA replication machinery. They also offer an enhanced framework to investigate molecular mechanisms underlying deletion and depletion of the mitochondrial genome as observed in mitochondrial diseases.




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Prominins control ciliary length throughout the animal kingdom: New lessons from human prominin-1 and zebrafish prominin-3 [Cell Biology]

Prominins (proms) are transmembrane glycoproteins conserved throughout the animal kingdom. They are associated with plasma membrane protrusions, such as primary cilia, as well as extracellular vesicles derived thereof. Primary cilia host numerous signaling pathways affected in diseases known as ciliopathies. Human PROM1 (CD133) is detected in both somatic and cancer stem cells and is also expressed in terminally differentiated epithelial and photoreceptor cells. Genetic mutations in the PROM1 gene result in retinal degeneration by impairing the proper formation of the outer segment of photoreceptors, a modified cilium. Here, we investigated the impact of proms on two distinct examples of ciliogenesis. First, we demonstrate that the overexpression of a dominant-negative mutant variant of human PROM1 (i.e. mutation Y819F/Y828F) significantly decreases ciliary length in Madin–Darby canine kidney cells. These results contrast strongly to the previously observed enhancing effect of WT PROM1 on ciliary length. Mechanistically, the mutation impeded the interaction of PROM1 with ADP-ribosylation factor–like protein 13B, a key regulator of ciliary length. Second, we observed that in vivo knockdown of prom3 in zebrafish alters the number and length of monocilia in the Kupffer's vesicle, resulting in molecular and anatomical defects in the left-right asymmetry. These distinct loss-of-function approaches in two biological systems reveal that prom proteins are critical for the integrity and function of cilia. Our data provide new insights into ciliogenesis and might be of particular interest for investigations of the etiologies of ciliopathies.




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Affinity maturation, humanization, and co-crystallization of a rabbit anti-human ROR2 monoclonal antibody for therapeutic applications [Immunology]

Antibodies are widely used as cancer therapeutics, but their current use is limited by the low number of antigens restricted to cancer cells. A receptor tyrosine kinase, receptor tyrosine kinase-like orphan receptor 2 (ROR2), is normally expressed only during embryogenesis and is tightly down-regulated in postnatal healthy tissues. However, it is up-regulated in a diverse set of hematologic and solid malignancies, thus ROR2 represents a candidate antigen for antibody-based cancer therapy. Here we describe the affinity maturation and humanization of a rabbit mAb that binds human and mouse ROR2 but not human ROR1 or other human cell-surface antigens. Co-crystallization of the parental rabbit mAb in complex with the human ROR2 kringle domain (hROR2-Kr) guided affinity maturation by heavy-chain complementarity-determining region 3 (HCDR3)-focused mutagenesis and selection. The affinity-matured rabbit mAb was then humanized by complementarity-determining region (CDR) grafting and framework fine tuning and again co-crystallized with hROR2-Kr. We show that the affinity-matured and humanized mAb retains strong affinity and specificity to ROR2 and, following conversion to a T cell–engaging bispecific antibody, has potent cytotoxicity toward ROR2-expressing cells. We anticipate that this humanized affinity-matured mAb will find application for antibody-based cancer therapy of ROR2-expressing neoplasms.




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Genetic evidence for reconfiguration of DNA polymerase {theta} active site for error-free translesion synthesis in human cells [DNA and Chromosomes]

The action mechanisms revealed by the biochemical and structural analyses of replicative and translesion synthesis (TLS) DNA polymerases (Pols) are retained in their cellular roles. In this regard, DNA polymerase θ differs from other Pols in that whereas purified Polθ misincorporates an A opposite 1,N6-ethenodeoxyadenosine (ϵdA) using an abasic-like mode, Polθ performs predominantly error-free TLS in human cells. To test the hypothesis that Polθ adopts a different mechanism for replicating through ϵdA in human cells than in the purified Pol, here we analyze the effects of mutations in the two highly conserved tyrosine residues, Tyr-2387 and Tyr-2391, in the Polθ active site. Our findings that these residues are indispensable for TLS by the purified Pol but are not required in human cells, as well as other findings, provide strong evidence that the Polθ active site is reconfigured in human cells to stabilize ϵdA in the syn conformation for Hoogsteen base pairing with the correct nucleotide. The evidence that a DNA polymerase can configure its active site entirely differently in human cells than in the purified Pol establishes a new paradigm for DNA polymerase function.




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Clinical implications of chromatin accessibility in human cancers

(Impact Journals LLC) Volume 11, Issue 18 of @Oncotarget Clinical implications of chromatin accessibility assessed by ATAC-seq profiling in human cancers especially in a large patient cohort is largely unknown.




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Plays exploring human drive and human touch win 2020 Neukom Honors

(Dartmouth College) Expanded Dartmouth awards program gives prizes for 'spec fic' playwriting on what it means to be human in a computerized world.




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Yellow-legged gull adapts its annual lifecycle to human activities to get food

(University of Barcelona) The yellow-legged gull has a high ability to adapt to human activities and benefit from these as a food resource during all year. This is stated in a scientific article published in the journal Ecology and Evolution whose first author is the researcher Francisco Ramírez, from the Faculty of Biology and the Biodiversity Research Institute (IRBio) of the University of Barcelona.




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Simulations forecast nationwide increase in human exposure to extreme climate events

(DOE/Oak Ridge National Laboratory) Using ORNL's now-decommissioned Titan supercomputer, a team of researchers estimated the combined consequences of many different extreme climate events at the county level, a unique approach that provided unprecedented regional and national climate projections that identified the areas most likely to face climate-related challenges.




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Disappearance of animal species takes mental, cultural and material toll on humans

(American Friends of Tel Aviv University) The research reveals that hunter-gatherer societies expressed a deep emotional and psychological connection with the animal species they hunted, especially after their disappearance. The study will help anthropologists and others understand the profound environmental changes taking place in our own lifetimes.




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Evidence of Late Pleistocene human colonization of isolated islands beyond Wallace's Line

(Max Planck Institute for the Science of Human History) What makes our species unique compared to other hominins? High profile genetic, fossil and material culture discoveries present scientists working in the Late Pleistocene with an ever-more complex picture of interactions between early hominin populations. One distinctive characteristic of Homo sapiens, however, appears to be its global distribution. Exploring how Homo sapiens colonized most of the world's continents in a relatively short period could reveal the exceptional capacities of humans relative to other hominins.




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Addressing the ethical considerations of SARS-CoV-2 human challenge trials

(American Association for the Advancement of Science) While an effective vaccine for the SARS-CoV-2 virus is likely many months away, development could be accelerated by conducting controlled human infection (CHI) studies -- which are increasingly being considered by the scientific community due to the urgent need.




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Recommitting to International Criminal Justice and Human Rights in Indonesia

6 April 2018

Agantaranansa Juanda

Academy Associate, International Law Programme

Jason Naselli

Senior Digital Editor
Agantaranansa Juanda speaks to Jason Naselli about the promises the government has made and the steps that still need to be taken for the country to deliver justice for past violations of human rights.

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Indonesian PM Joko Widodo. Photo: Getty Images.

Does the Indonesian government adequately protect human rights?

It does and it does not; it really depends on the context. Indonesia looks good among its neighbours in Southeast Asia in terms of protection of civil and political rights, and to some extent economic, social and cultural rights, although room for improvements exists.

But one of the promises of the current president, Joko Widodo, during his 2014 campaign was about international criminal justice, which involves rights for many victims of past cases of human rights abuses in Indonesia. In that sense, it does not protect these rights, including the rights to justice, truth, reparations or guarantees of non-recurrence.

For example, in the case of the conflict over independence for East Timor in 1999, there were many gross violations of human rights. However, there has never been any sort of effective judicial process to address gross violations of human rights, and crimes against humanity in particular.

In 1965–66, during the government’s violent anti-communist operations, 500,000 people or more were killed. Indonesia’s National Commission on Human Rights was tasked with conducting an investigation into this period within its limited mandate, but it led to nothing; there have never been any prosecutions relating to these crimes.

The election promise of the current president was to deal with a number of these past human rights cases, and this promise has not been met at all. His opponent in 2014, Prabowo Subianto, was a former military general involved in alleged past human rights abuses, so it was politically expedient to make such a promise. But it has not been pursued in office.

In 2000, Indonesia established its own Human Rights Court. What is your assessment of its record?

Some human rights activists suggested that the establishment of the Human Rights Court took place under international pressure following the independence of East Timor. To avoid international scrutiny, for example the creation of an ad hoc international tribunal, the government established this court.

Based on the report of the International Commission of Inquiry on East Timor in 2000, it was indeed recommended that an international human rights tribunal be set up. Indonesian government rejected the proposal with strong assurances that it would provide justice for atrocities committed by its nationals. So it is fair for some to see the establishment of Indonesia’s Human Rights Court as a political move by the government at that time, in order to avoid scrutiny by the international community.

When it comes to performance, the Human Rights Court actually investigated and prosecuted cases relating to atrocities in East Timor. There were around 100 suspects identified, and 18 were put on trial. Out of these 18, only one trial, of Eurico Guterres, ended in a conviction for crimes against humanity. However, the Indonesian Supreme Court cleared Guterres of all charges in 2008. So the Human Rights Court did take steps, but the net result amounted to essentially nothing. Impunity remains.

So it has not lived up to its mandate, but there is another factor, which is that the founding law of the Human Rights Court does not accommodate international standards of criminal justice. It only covers two of the four categories of crime as outlined in the Rome Statute – crimes against humanity and genocide. It also does not provide adequate protection for victims and witnesses. So there are issues not only with the performance of the Human Rights Court but also with the legislation establishing it.

Why hasn’t Indonesia become a party to the Rome Statute to join the ICC?

The main opposition came from the military, because they were afraid of being targeted by the ICC. There was also a lot of discussion about Indonesia’s ‘sovereign right to prosecute’.

But what those opposing failed to understand is that the ICC is bound by temporal and territorial boundaries, meaning that it will not intervene if the state in question is able and willing to prosecute. So I think accession to the Rome Statute has not taken place because of this misunderstanding.

I think another factor since this was initially raised is there is a focus on other issues. Indonesia is an emerging country economically; there is a focus on building infrastructure. So many in government feel like they are done with the past. But for the millions of victims of past crimes and their families, the past is not done.

So it’s very important at this point in the country’s history to revisit the commitment to international criminal justice to be able to contribute to sustainable peace and development.

What steps could the Indonesian government take to improve how it handles these issues?

The establishment of the Human Rights Court was an important starting point, but clearly there has to be significant reform, both in terms of the substantive law underpinning it and its procedures.

Clearly the domestic laws need to be reformed, but also, an effort needs to be made to improve the courts capacity in terms of manpower and logistical support. This is why the government needs to restart the discussion about becoming a party to the Rome Statute. Through the outreach programme of the ICC, this would give the Human Rights Court the capacity, in terms of manpower and logistical support, to tackle past human rights violations in Indonesia, which the Human Rights Court is currently lacking.

Only if these two steps are taken – reforming the domestic Human Rights Court and restarting discussion about becoming a party to the Rome Statute – will the Indonesian government be able to say it has made progress on international criminal justice.

The Indonesian government is actually running for a seat on the UN Security Council for the period of 2019–20. So I think it is an urgent discussion that the Indonesian government needs to have before it makes another pledge to contribute to the maintenance of international peace and security. It is difficult to have sustainable peace without justice.




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The Universal Declaration of Human Rights at 70

Research Event

29 November 2018 - 6:00pm to 7:30pm

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

Event participants

Phil Bloomer, Executive Director, Business & Human Rights Resource Centre
Julie Broome, Director, Ariadne Network
Allison Corkery, Director of Rights Claiming and Accountability Program, Centre for Economic and Social Rights; Atlantic Fellow for Social and Economic Equity, London School of Economics
Chair: Sonya Sceats, Associate Fellow, International Law Programme

The Universal Declaration of Human Rights celebrates its 70th anniversary against a backdrop of fractured global politics and the rise of nationalist forces that reject many of the values the Declaration espouses.

What strategies, tools and networks are civil society and other actors developing to adapt to this complex environment for human rights work?

And what role does the Declaration and the human rights treaties it has inspired play in shaping responses to current global challenges such as deepening inequality, new forms of technology and climate change?

Chanu Peiris

Programme Manager, International Law
+44 (0)20 7314 3686




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How Human Rights Law Is Evolving to Address Inequality

10 December 2018

Chanu Peiris

Programme Manager, International Law Programme
On the 70th anniversary of the Universal Declaration of Human Rights, Chanu Peiris examines how its principles apply to one of today’s burning political issues.

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Copies of the Universal Declaration of Human Rights in a variety of languages. Photo: Getty Images.

There is growing attention to human rights in debates on economic inequality. In the UK, concerns about the disproportionate impact of economic policy on vulnerable groups have been raised recently by the UN special rapporteur on extreme poverty and human rights – who issued a statement criticizing the Conservative government’s austerity policies – as well as in a report from the UK government’s independent Equality and Human Rights Commission. These reports echo global concerns about fiscal policies, poverty and extreme economic inequality.

The Universal Declaration of Human Rights – which celebrates its 70th anniversary today – and the human rights treaties it inspired do not expressly address income and wealth gaps. But international human rights law is playing an increasing role in addressing economic polarization. Those concerned about inequality should consider how, especially over the past 25 years, the principles of socioeconomic rights have been clarified by courts and other human rights mechanisms. 

While the focus in the Global North has historically been on civil and political rights, such as the prohibition on torture or the right to fair trial, international human rights law does set out economic and social rights. For example, Article 23(4) of the Declaration – which is replicated in the International Covenant on Economic, Social and Cultural Rights and other treaties – calls for the right to collective bargaining in employment. Weakening protection in this area has been raised as a partial cause of the current escalation in income inequality. 

Human rights law also guarantees rights, including to education, healthcare and social security, that have redistributive potential and so have the potential to mitigate inequality.

Human rights law recognizes that fulfilment of economic and social rights, unlike civil and political rights, can be limited by the resources available to different states, and this conditionality – along with a lack of guidelines to assist with implementation and monitoring – has historically shielded fiscal policies from human rights scrutiny. However, attitudes have shifted.

For example, international human rights law has come to embody a commitment to tackling substantive inequalities which impair human dignity.  This requires the state regulate markets, and redistribute resources, in order to prevent discrimination against disadvantaged groups such as the poor. 

The UN Committee on Economic, Social and Cultural Rights and other human rights bodies assert that states have an immediate obligation, even during times of resource constraint, to ensure the fulfilment, without discrimination, of the minimum essential levels of socioeconomic rights, for example essential subsistence and basic shelter. Thus, austerity measures that scale back the enjoyment of rights may breach human rights standards. In order to justify such measures, governments need to first demonstrate they have considered ‘less restrictive’ avenues, including taxation options.

Although the application of human rights standards to economic policy is an emerging area, human rights campaigners have been successfully leveraging these protections to address the causes and consequences of the inequality crisis. 

For example, in case No. 66/2011 the European Committee of Social Rights overturned austerity measures that would have brought wages under the poverty level, citing breaches of labour rights and protections against discrimination. In Brazil, a coalition of civil society actors successfully used human rights standards to legitimize their critiques of a 2008 tax reform bill that would have given additional tax breaks to the wealthy while withdrawing resources for social services.

Beyond legal enforcement, framing concerns within the architecture of human rights can shift power to rights-bearers and move debates on tackling extreme inequality from the policy sphere into one where the state has a duty for which it is accountable. While the state bears primary responsibility for realizing human rights, non-state actors such as businesses have responsibilities to respect human rights. Thus, human rights can also help communities to recast the scope of the crisis to one of shared responsibility.

While human rights have seen many normative developments and advocacy successes since the adoption of the Universal Declaration of Human Rights, the last 70 years also offer several lessons and strategies to adopt going forward. 

As highlighted at a recent Chatham House event, the continued emphasis on civil and political rights in the discussion about human rights is at odds with the lived experience of individuals and communities worldwide, who may not feel their economic and material concerns are reflected in campaigns for human rights.

There will need to be a greater emphasis on adapting messaging to be more inclusive and to build alliances between disparate groups. Human rights analysis will also need to move beyond documenting the impact of systemic issues towards tackling root causes and creating a positive vision for economic inclusion and governance.




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Human Rights Impact Assessment of Trade Agreements

Research Event

26 February 2019 - 6:00pm to 7:30pm

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

Event participants

James Harrison, Reader and Associate Professor, University of Warwick School of Law
Richard James, Evaluation Co-ordinator, Directorate-General for Trade European Commission
Jennifer Zerk, Associate Fellow, International Law Programme, Chatham House
Chair: Andrea Shemberg, Chair, Global Business Initiative on Human Rights

The idea that trade agreements should be subject to human rights impact assessment has been gathering momentum in recent years. This idea springs from concern – particularly on the part of trade unions and civil society organizations – that states are not presently doing enough to anticipate and address the human rights-related issues that arise from their trading arrangements with other countries.

This meeting will coincide with the launch of a research paper on human rights impact assessment by Dr Jennifer Zerk. It will bring together experts from law, trade policy, human rights impact assessment practice and civil society to take stock of progress so far and consider the future prospects for human rights impact assessment as a risk-analysis and policymaking tool in the trade context.  

The meeting will explore the key risks and benefits of the human rights impact assessment of trade agreements. What legal, political and practical challenges have been encountered so far? In what ways could communication, stakeholder consultation and follow-up of findings be improved? And what is needed to build political and stakeholder support for these kinds of processes?  

This meeting will be followed by a reception. 

Chanu Peiris

Programme Manager, International Law
+44 (0)20 7314 3686




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'Our Shared Humanity': The Legacy of Kofi Annan

Research Event

3 June 2019 - 10:00am to 4 June 2019 - 5:30pm

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

Event participants

This event is now full and registration has closed.

Participants include

Zeinab Badawi, Presenter, BBC Global Questions and HardTalk
Lakhdar Brahimi, The Elders; Chair, Panel on United Nations Peace Operations (2000)
Alan Doss, President, Kofi Annan Foundation 
Raila Odinga, High Representative for Infrastructure Development, African Union; Prime Minister of Kenya (2008-13)
Patrick Gaspard, President, Open Society Foundations
Michèle Griffin, Senior Policy Advisor to the UN Secretary-General
Ian Martin, Special Representative of the UN Secretary-General in East Timor (1999), Nepal (2007-09) and Libya (2011-12)
Strive Masiyiwa, Chair of the Board, AGRA; CEO, Econet Wireless
Amina Mohammed, Deputy Secretary-General, United Nations
Kumi Naidoo, Secretary-General, Amnesty International
Danny Sriskandarajah, Chief Executive, Oxfam
Mark Suzman, Chief Strategy Officer and President of Global Policy and Advocacy, Bill & Melinda Gates Foundation

In a decade as UN Secretary-General, Kofi Annan championed a vision of global governance anchored in shared responsibility and the rights and dignity of the individual.

Confronted with multiple global crises that raised questions about the UN’s purpose, Annan pressed for human rights and development to be at the centre of international efforts and sought to broaden participation in shaping and delivering solutions to global challenges.

As the UN’s 75th anniversary approaches, this conference will explore Annan’s legacy for the future of global governance.

Questions include the appropriate response to high-profile and ongoing failures to prevent human rights atrocities and protect victims of conflict, the impact of technology on democracy, lessons from the Millennium Development Goals for the Sustainable Development Goals and ways to meaningfully involve civil society, businesses and individuals in addressing global challenges.

The conference will bring together key figures involved in Annan’s initiatives with actors currently engaged in conflict prevention, humanitarian action, human rights and development to identify lessons and generate forward-looking recommendations.

This conference is being held as part of a series, including a public event hosted by UNA-UK at Central Hall in Westminster, exploring Kofi Annan's legacy.

This initiative is generously supported by the Bill & Melinda Gates Foundation and Open Society Foundations and enjoys the cooperation of the Kofi Annan Foundation.

Chanu Peiris

Programme Manager, International Law
+44 (0)20 7314 3686




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Cyber Interference in Elections: Applying a Human Rights Framework

Invitation Only Research Event

7 May 2019 - 10:00am to 4:15pm

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

The use of social media, including algorithms, bots and micro-targeted advertising, has developed rapidly while there has been a policy lag in identifying and addressing the challenges posed to democracy by the manipulation of voters through cyber activity. 
 
What role should international human rights law play in developing a normative framework to address potential harms caused by such cyber activity including the closing down of democratic space, the spread of disinformation and hate speech?
 
This meeting will bring together a small group of academics and practitioners to explore the implications of applying a human rights framework to both the activities of social media companies and the activities of governments and international organizations in seeking to regulate their activity. The purpose of the meeting will be to inform a report that will provide an overview of the applicable law and recommendations for how that law might inform future policy and regulation. 
 
Attendance at this event is by invitation only.

Event attributes

Chatham House Rule




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Democratize Trade Policymaking to Better Protect Human Rights

12 June 2019

Dr Jennifer Ann Zerk

Associate Fellow, International Law Programme
There is growing interest in the use of human rights impact assessment to screen proposed trade agreements for human rights risks, and to ensure appropriate risk mitigation steps are taken.

2019-02-15-HumanRightsTradeAgreements-Smaller.jpg

Tea pickers walk at dawn through the tea plantations of Munnar, Kerala, on 7 May 2017. Copyright: Pardeep Singh Gill/Getty Images

With international trade discourse taking an increasingly transactional and sometimes belligerent tone, it would be easy to overlook the quiet revolution currently under way to bring new voices into trade policy development and monitoring. The traditional division of responsibilities between the executive and legislature – whereby treaties are negotiated and signed by the executive, and the legislature does what is necessary to implement them – may be undergoing some change.

Growing awareness of the implications of trade and investment treaties for many aspects of day-to-day life – food standards, employment opportunities, environmental quality, availability of medicines and data protection, just to name a few – is fuelling demands by people and businesses for more of a say in the way these rules are formulated and developed.

Various options for enhancing public and parliamentary scrutiny of trading proposals have recently been examined by two UK parliamentary select committees.[1] The reason for this interest is obviously Brexit, which has presented UK civil servants and parliamentarians with the unusual (some would say exciting) opportunity to design an approval and scrutiny process for trade agreements from scratch.

Doubtless, EU authorization, liaison and approval procedures (which include a scrutinizing role for the European Parliament) will be influential,[2] as will the European Commission’s experience with stakeholder engagement on trade issues.[3] The recommendations of both UK select committees to include human rights impact assessment processes as part of pre-negotiation preparations[4] echo calls from UN agencies and NGOs for more rigorous and timely analysis of the human rights risks that may be posed by new trading relationships.[5] Again, EU practice with what it terms ‘sustainability impact assessment’ of future trade agreements provides a potential model to draw from.[6] 

However, process is no substitute for action. Human rights impact assessment is never an end in itself; rather, it is a means to a positive end, in this case a trade agreement which is aligned with the trading partners’ respective human rights obligations and aspirations. It bears remembering, though, that the idea of assessing trade proposals for future human rights risks is a relatively recent one. Do we have the tools and resources to make sure that this is a meaningful compliance and risk management exercise?

Thus far there is little evidence that human rights impact assessment and stakeholder engagement exercises are having any real impact on the content of trade agreements.[7] This is the case even in the EU, where practice in these areas is the most advanced and systematic.[8]

There are several possible reasons for this. First, the methodological challenges are enormous. Aside from the crystal-ball gazing needed to forecast the social, economic and environmental effects of a trade intervention well into the future, demonstrating causal links between a trade agreement and a predicted adverse impact is often highly problematic given the number of other economic and political factors that may be in play.[9]

Secondly, there are many challenges around the need to engage with affected people and listen to their views.[10] The sheer number of possible impacts of a trade agreement on different individuals and communities, as well as the range of rights potentially engaged, makes this a difficult (some would say impossible) task. Some prioritization is always necessary.

This makes for difficult decisions about who to engage with and how. Perceived bias or an apparent lack of even-handedness – favouring business compared to civil society, for instance – can sow mistrust about the true aims of such a process, undermining its future effectiveness as participants begin to question whether it is genuine or worthwhile.[11]

The challenges are even more acute where impact assessment practitioners are tasked with investigating potential human rights impacts in other countries. Even if it is possible to get past the inevitable political sensitivities,[12] the sort of in-depth consultations required will be beyond the budget and time constraints of most assignments.[13]

There are good reasons why trade policy should be subject to greater public and parliamentary scrutiny, and why there should be more opportunities for public participation in the formation of new trading regimes. By building more opportunities for stakeholder consultation at these stages, we can acquire perspectives on trade that are not available from other forms of assessment and analysis.

However, policymakers should be wary of overstating the benefits of existing procedural models. Human rights impact assessment processes are still struggling to provide compelling analyses of the relationships between trade agreements and the enjoyment of human rights, let alone a roadmap for policymakers and trade negotiators as to what should be done.[14]

And financial and practical barriers to participation in stakeholder engagement exercises mean that, at best, these will provide only a partial picture of stakeholder impacts and views.

Experiences with human rights impact assessment of trade agreements so far demonstrate the need for realism about two things: first, the extent to which one can sensibly anticipate and analyse human rights-related risks and opportunities in the preparation stages for a new trading agreement; and, second, the extent to which problems identified in this way can be headed off with the right form of words in the treaty itself.

Both recent UK select committee reports place considerable faith in the ability of pre-project transparency and scrutiny processes to flush out potential problems and prescribe solutions. Of course, there may be cases where frontloading the analysis in this way could be useful, for instance where the human rights implications are so clear that they can readily be addressed through upfront commitments by the parties concerned, whether by bespoke or standardized approaches.

More often, though, for a trade agreement running many years into the future, human rights impacts and implications will take time to emerge, suggesting the need for robust monitoring and mitigation frameworks designed with longevity in mind. Ideally, pre-signing approval and assessment processes would lay the groundwork for future action by both trading partners, either jointly or separately (though preferably both).

To this end, as well as developing ideas for more robust substantive provisions on human rights, policymakers should consider the institutional arrangements required – whether pursuant to the trade agreement or by complementary processes – to ensure that human rights-related risks identified during the planning stages are properly and proactively followed up, that emerging risks are tackled in a timely fashion, and that there are opportunities for meaningful stakeholder contributions to these processes.

What needs to happen

  • Trade policymakers can use human rights impact assessment to screen proposed trade treaties for human rights-related risks and to identify possible ways of mitigating those risks, whether through the terms of the agreement itself, domestic law reform or flanking measures.
  • Building more opportunities for stakeholder consultations can enable perspectives on trade to be highlighted that are not available from other forms of assessment.
  • Assessment is complicated, however, by methodological challenges and the difficulties of forecasting a trade agreement’s future impacts. Policymakers need to be realistic about the risks that can be anticipated, and the extent to which many of those identified can be addressed upfront in trade agreements’ terms.
  • These inherent limitations may be overcome to some extent by better ongoing monitoring. Future trade agreements should include more robust human rights risk monitoring and mitigation frameworks, designed with longevity in mind.

Notes

[1] UK Joint Committee on Human Rights (2019), ‘Human Rights Protections in International Agreements, Seventeenth Report of Session 2017–19’, HC 1833 HL paper 310, 12 March 2019, https://publications.parliament.uk/pa/jt201719/jtselect/jtrights/1833/1833.pdf; and House of Commons International Trade Committee (2018), ‘UK Trade Policy Transparency and Scrutiny, Sixth Report of Session 2017-2019’, HC 1043, 29 December 2018.

[2] European Parliament and Directorate General for External Policies (2019), Parliamentary scrutiny of trade policies across the western world, study paper, March 2019, http://www.europarl.europa.eu/RegData/etudes/STUD/2019/603477/EXPO_STU(2019)603477_EN.pdf.

[3] European Commission (2019), ‘Trade policy and you’, http://ec.europa.eu/trade/trade-policy-and-you/index_en.htm.

[4] See UK Joint Committee on Human Rights (2019), ‘Human Rights Protections in International Agreements’, para 12; and House of Commons International Trade Committee (2018), ‘UK Trade Policy Transparency and Scrutiny’, paras 124–34.

[5] OHCHR (2003), Report of the High Commissioner for Human Rights on Human Rights, Trade and Investment, 2 July 2003, E/CN.4/Sub.2/2003/9, Annex, at para 63; UN Economic and Social Council (2017), ‘General Comment No 24 (2017) of the Committee on Economic, Social and Cultural Rights on State obligations under the International Covenant on Economic, Social and Cultural Rights in the context of business activities’, UN Doc. E/C.12/GC/24, 10 August 2017, para 13; and UN General Assembly (2011), ‘Guiding principles on human rights impact assessment of trade and investment agreements’, Report of the Special Rapporteur on the Right to Food, Olivier De Schutter, UN Doc. A/HRC/19/59/Add.5, 19 December 2011.

[6] European Commission (2016), Handbook for Sustainability Impact Assessment (2nd ed.), Brussels: European Union, http://trade.ec.europa.eu/doclib/docs/2016/april/tradoc_154464.PDF.

[7] Zerk, J. (2019), Human Rights Impact Assessment of Trade Agreements, Chatham House Research Paper, London: Royal Institute of International Affairs, https://www.chathamhouse.org/publication/human-rights-impact-assessment-trade-agreements.

[8] Ibid., pp. 11–13. For a detailed explanation of the EU’s approach to human rights impact assessment, see European Commission (2016), Handbook for Sustainability Impact Assessment.

[9] Zerk (2019), Human Rights Impact Assessment of Trade Agreements, pp. 14–21.

[10] Ibid., pp. 21–22.

[11] Ergon Associates (2011), Trade and Labour: Making effective use of trade sustainability impact assessments and monitoring mechanisms, Final Report to DG Employment, Social Affairs and Inclusion European Commission, September 2011; and Gammage, C. (2010), ‘A Sustainability Impact Assessment of the Economic Partnership Agreements: Challenging the Participatory Process’, Law and Development Review, 3(1): pp. 107–34. For a civil society view, see Trade Justice Movement (undated), ‘Trade Justice Movement submission to the International Trade Committee inquiry into UK Trade Policy Transparency and Scrutiny’, https://www.tjm.org.uk/resources/briefings/tjm-submission-to-the-international-trade-committee-inquiry-into-uk-trade-policy-transparency-and-scrutiny, esp. paras 23–32.

[12] Zerk (2019), Human Rights Impact Assessment of Trade Agreements, pp. 20–21.

[13] Ibid., pp. 21–22.

[14] Ibid.

This essay was produced for the 2019 edition of Chatham House Expert Perspectives – our annual survey of risks and opportunities in global affairs – in which our researchers identify areas where the current sets of rules, institutions and mechanisms for peaceful international cooperation are falling short, and present ideas for reform and modernization.




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Tackling Cyber Disinformation in Elections: Applying International Human Rights Law

Research Event

6 November 2019 - 5:30pm to 7:00pm

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

Susie Alegre, Barrister and Associate Tenant, Doughty Street Chambers
Evelyn Aswad, Professor of Law and the Herman G. Kaiser Chair in International Law, University of Oklahoma
Barbora Bukovská, Senior Director for Law and Policy, Article 19
Kate Jones, Director, Diplomatic Studies Programme, University of Oxford
Chair: Harriet Moynihan, Associate Fellow, International Law Programme, Chatham House

Cyber operations are increasingly used by political parties, their supporters and foreign states to influence electorates – from algorithms promoting specific messages to micro-targeting based on personal data and the creation of filter bubbles.
 
The risks of digital tools spreading disinformation and polarizing debate, as opposed to deepening democratic engagement, have been highlighted by concerns over cyber interference in the UK’s Brexit referendum, the 2016 US presidential elections and in Ukraine. 
 
While some governments are adopting legislation in an attempt to address some of these issues, for example Germany’s ‘NetzDG’ law and France’s ‘Law against the manipulation of information’, other countries have proposed an independent regulator as in the case of the UK’s Online Harms white paper. Meanwhile, the digital platforms, as the curators of content, are under increasing pressure to take their own measures to address data mining and manipulation in the context of elections. 

How do international human rights standards, for example on freedom of thought, expression and privacy, guide the use of digital technology in the electoral context? What practical steps can governments and technology actors take to ensure policies, laws and practices are in line with these fundamental standards? And with a general election looming in the UK, will these steps come soon enough?
 
This event brings together a wide range of stakeholders including civil society, the tech sector, legal experts and government, coincides with the publication of a Chatham House research paper on disinformation, elections and the human rights framework

Jacqueline Rowe

Programme Assistant, International Law Programme
020 7389 3287




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Cyber, Sovereignty and Human Rights

Our work in this area explores how international law regulates cyber operations by states - such as electoral disinformation campaigns or attacks on critical infrastructure - and asks whether new rules are required. 

Rapid technological change raises urgent questions around equity, transparency, privacy and security. 

We are looking at the human rights dividend from new technologies as well as how international human rights law standards, for example on freedom of thought, expression and privacy, guide the use of digital technology in the electoral context.




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‘Our Shared Humanity’ – The Legacy of Kofi Annan

23 October 2019

The ‘Our Shared Humanity’ conference explored Kofi Annan’s legacy for the future of global governance in the run-up to the UN’s 75th anniversary. This paper summarizes key points raised during the conference, and presents the substantive recommendations that emerged from the discussion.

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Kofi Annan meets with high-school students in Kabul, Afghanistan, in January 2002. Photo: Getty Images.

About the Conference

In the run-up to the UN’s 75th anniversary and almost a year after his death, Chatham House and the United Nations Association – UK (UNA-UK) held a two-day conference to explore Kofi Annan’s legacy in the context of the current period of global uncertainty.

The ‘Our Shared Humanity’ conference brought together a global and diverse group of individualsworking on peace and security, human rights and development issues to:

  • Reflect critically on Annan’s record, and capture lessons learned from his tenure as UN secretary-general, and his later work as a mediator and elder statesperson; and
  • Generate recommendations for current policymakers and influencers.

This paper summarizes key points raised during each session of the conference, and presents the substantive recommendations that emerged from the discussion.

In order to bring the conference themes to a wider audience, UNA-UK held a public event on the eve of the first day of the conference at Central Hall Westminster – where the UN had held its first ever meetings in 1946 – with speakers including Nane Annan, Sherrie Westin (president of global impact and philanthropy, Sesame Workshop), Amina Mohammed (current UN deputy secretary-general) and Mary Robinson (chair of The Elders and former UN High Commissioner for Human Rights).
 




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Human Rights Priorities: An Agenda for Equality and Social Justice

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

Members Events Team




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Online Disinformation and Political Discourse: Applying a Human Rights Framework

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.

Kate Jones

Associate Fellow, International Law Programme

2019-11-05-Disinformation.jpg

A man votes in Manhattan, New York City, during the US elections on 8 November 2016. Photo: Getty Images.

Summary

  • Online 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.




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Investigating Violations of International Humanitarian Law

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.

Jacqueline Rowe

Programme Assistant, International Law Programme
020 7389 3287




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COVID-19 Brings Human Rights into Focus

9 April 2020

Sonya Sceats

Associate Fellow, International Law Programme
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.

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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 measures

Many 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.




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HIGD2A is required for assembly of the COX3 module of human mitochondrial complex IV

Daniella H Hock
Apr 21, 2020; 0:RA120.002076v1-mcp.RA120.002076
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

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

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

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




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

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




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Quantitative Profiling of the Human Substantia Nigra Proteome from Laser-capture Microdissected FFPE Tissue

Eva Griesser
May 1, 2020; 19:839-851
Research




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Human Control Is Essential to the Responsible Use of Military Neurotechnology

8 August 2019

Yasmin Afina

Research Assistant, International Security Programme
The military importance of AI-connected brain–machine interfaces is growing. Steps must be taken to ensure human control at all times over these technologies.

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A model of a human brain is displayed at an exhibition in Lisbon, Portugal. Photo: Getty Images.

Technological progress in neurotechnology and its military use is proceeding apace. As early as the 1970s, brain-machine interfaces have been the subject of study. By 2014, the UK’s Ministry of Defence was arguing that the development of artificial devices, such as artificial limbs, is ‘likely to see refinement of control to provide… new ways to connect the able-bodied to machines and computers.’ Today, brain-machine interface technology is being investigated around the world, including in Russia, China and South Korea.

Recent developments in the private sector are producing exciting new capabilities for people with disabilities and medical conditions. In early July, Elon Musk and Neuralink presented their ‘high-bandwidth’ brain-machine interface system, with small and flexible electrode threads packaged into a small device containing custom chips and to be inserted and implanted into the user’s brain for medical purposes.

In the military realm, in 2018, the United States’ Defense Advanced Research Projects Agency (DARPA) put out a call for proposals to investigate the potential of nonsurgical brain-machine interfaces to allow soldiers to ‘interact regularly and intuitively with artificially intelligent, semi-autonomous and autonomous systems in a manner currently not possible with conventional interfaces’. DARPA further highlighted the need for these interfaces to be bidirectional – where information is sent both from brain to machine (neural recording) and from machine to brain (neural stimulation) – which will eventually allow machines and humans to learn from each other.

This technology may provide soldiers and commanders with a superior level of sensory sensitivity and the ability to process a greater amount of data related to their environment at a faster pace, thus enhancing situational awareness. These capabilities will support military decision-making as well as targeting processes.

Neural recording will also enable the obtention of a tremendous amount of data from operations, including visuals, real-time thought processes and emotions. These sets of data may be used for feedback and training (including for virtual wargaming and for machine learning training), as well as for investigatory purposes. Collected data will also feed into research that may help researchers understand and predict human intent from brain signals – a tremendous advantage from a military standpoint.

Legal and ethical considerations

The flip side of these advancements is the responsibilities they will impose and the risks and vulnerabilities of the technology as well as legal and ethical considerations.

The primary risk would be for users to lose control over the technology, especially in a military context; hence a fail-safe feature is critical for humans to maintain ultimate control over decision-making. Despite the potential benefits of symbiosis between humans and AI, users must have the unconditional possibility to override these technologies should they believe it is appropriate and necessary for them to do so.

This is important given the significance of human control over targeting, as well as strategic and operational decision-making. An integrated fail-safe in brain-machine interfaces may in fact allow for a greater degree of human control over critical, time-sensitive decision-making. In other words, in the event of incoming missiles alert, while the AI may suggest a specific course of action, users must be able to decide in a timely manner whether to execute it or not.

Machines can learn from coded past experiences and decisions, but humans also use gut feelings to make life and death decisions. A gut feeling is a human characteristic that is not completely transferable, as it relies on both rational and emotional traits – and is part of the ‘second-brain’ and the gut-brain axis which is currently poorly understood. It is however risky to take decisions solely on gut feelings or solely on primary brain analysis—therefore, receiving a comprehensive set of data via an AI-connected brain-machine interface may help to verify and evaluate the information in a timely manner, and complement decision-making processes. However, these connections and interactions would have to be much better understood than the current state of knowledge. 

Fail-safe features are necessary to ensure compliance with the law, including international humanitarian law and international human rights law. As a baseline, human control must be used to 1) define areas where technology may or may not be trusted and to what extent, and 2) ensure legal, political and ethical accountability, responsibility and explainability at all times. Legal and ethical considerations must be taken into account from as early as the design and conceptualizing stage of these technologies, and oversight must be ensured across the entirety of the manufacturing supply chain.  

The second point raises the need to further explore and clarify whether existing national, regional and international legal, political and ethical frameworks are sufficient to cover the development and use of these technologies. For instance, there is value in assessing to what extent AI-connected brain-machine interfaces will affect the assessment of the mental element in war crimes and their human rights implications.

In addition, these technologies need to be highly secure and invulnerable to cyber hacks. Neural recording and neural stimulation will be directly affecting brain processes in humans and if an adversary has the ability to connect to a human brain, steps need to be taken to ensure that memory and personality could not be damaged.

Future questions

Military applications of technological progress in neurotechnology is inevitable, and their implications cannot be ignored. There is an urgent need for policymakers to understand the fast-developing neurotechnical capabilities, develop international standards and best practices – and, if necessary, new and dedicated legal instruments – to frame the use of these technologies.

Considering the opportunities that brain-machine interfaces may present in the realms of security and defence, inclusive, multi-stakeholder discussions and negotiations leading to the development of standards must include the following considerations:

  • What degree of human control would be desirable, at what stage and by whom? To what extent could human users be trusted with their own judgment in decision-making processes?
  • How could algorithmic and human biases, the cyber security and vulnerabilities of these technologies and the quality of data be factored into these discussions?
  • How can ethical and legal considerations be incorporated into the design stage of these technologies?
  • How can it be ensured that humans cannot be harmed in the process, either inadvertently or deliberately?
  • Is there a need for a dedicated international forum to discuss the military applications of neurotechnology? How could these discussions be integrated to existing international processes related to emerging military applications of technological progress, such as the Convention on Certain Conventional Weapons (CCW) Group of Governmental Experts on Lethal Autonomous Weapons Systems?




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PARP-1-targeted Auger emitters display high-LET cytotoxic properties in vitro but show limited therapeutic utility in solid tumor models of human neuroblastoma

The currently available therapeutic radiopharmaceutical for high-risk neuroblastoma, 131I-MIBG, is ineffective at targeting micrometastases due to the low linear energy transfer (LET) properties of high-energy beta particles. In contrast, Auger radiation has high-LET properties with nanometer ranges in tissue, efficiently causing DNA damage when emitted in close proximity to DNA. The aim of this study was to evaluate the cytotoxicity of targeted Auger therapy in pre-clinical models of high-risk neuroblastoma. Methods: Using a radiolabeled poly(ADP-ribose) polymerase (PARP) inhibitor, 125I-KX1, we delivered an Auger emitter iodine-125 to PARP-1: a chromatin-binding enzyme overexpressed in neuroblastoma. In vitro cytotoxicity of 125I-KX1 was assessed in nineteen neuroblastoma cell lines, followed by in-depth pharmacological analysis in a sensitive and resistant pair of cell lines. Immunofluorescence microscopy was used to characterize 125I-KX1-induced DNA damage. Finally, in vitro/in vivo microdosimetry was modeled from experimentally derived pharmacological variables. Results: 125I-KX1 was highly cytotoxic in vitro across a panel of neuroblastoma cell lines, directly causing double strand DNA breaks. Based on subcellular dosimetry, 125I-KX1 was approximately twice as effective compared to 131I-KX1, whereas cytoplasmic 125I-MIBG demonstrated low biological effectiveness. Despite the ability to deliver focused radiation dose to the cell nuclei, 125I-KX1 remained less effective than its alpha-emitting analog 211At-MM4, and required significantly higher activity for equivalent in vivo efficacy based on tumor microdosimetry. Conclusion: Chromatin-targeted Auger therapy is lethal to high-risk neuroblastoma cells with potential use in micrometastatic disease. This study provides the first evidence for cellular lethality from a PARP-1 targeted Auger emitter, calling for further investigation into targeted Auger therapy.




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Tau PET imaging with 18F-PI-2620 in patients with Alzheimer's disease and healthy controls: a first-in-human study

18F-PI-2620 is a positron emission tomography (PET) tracer with high binding affinity for aggregated tau, a key pathologic feature of Alzheimer’s disease (AD) and other neurodegenerative disorders. Preclinically, 18F-PI-2620 binds to both, 3R and 4R tau isoforms. The purpose of this first-in-human study was to evaluate the ability of 18F-PI-2620 to detect tau pathology in AD patients using PET imaging, as well as to assess its safety and tolerability of this new tau PET tracer. Methods: Participants with clinical diagnosis of probable AD and healthy controls (HC) underwent dynamic 18F-PI-2620 PET imaging for 180 min. 18F-PI-2620 binding was assessed visually and quantitatively using Distribution Volume Ratios (DVR) estimated from non-invasive tracer kinetics and standardized uptake value ratios (SUVR) measured at different time points post-injection (p.i.) with the cerebellar cortex as the reference region. Time-activity curves and SUVR were assessed in AD and HC, as well as DVR and SUVR correlations and effect size (Cohen’s d) over time. Results: 18F-PI-2620 showed peak brain uptake around 5 min p.i. and fast wash-out in non-target regions. In AD subjects, focal asymmetric uptake was evident in temporal and parietal lobes, precuneus, and posterior cingulate cortex. DVR and SUVR in these regions were significantly higher in AD compared to HC. Very low background signal was observed in HC. 18F-PI-2620 administration was safe and well tolerated. SUVR time activity curves in most regions and subjects achieved a secular equilibrium after 40 min p.i.. A strong correlation (R2 > 0.93) was found between non-invasive DVR and SUVR for all imaging windows starting >30 min p.i.. Similar effect sizes between AD and HC groups were obtained across the different imaging windows. 18F-PI-2620 uptake in neocortical regions was significantly correlated with the degree of cognitive impairment. Conclusion: Initial clinical data obtained in AD and HC demonstrate the high image quality with excellent signal-to-noise of 18F-PI-2620 PET for imaging tau deposition in AD subjects. Non-invasive quantification using DVR and SUVR for 30 min imaging windows between 30-90 min p.i., e.g. 45-75 min, provides robust and significant discrimination between AD and HC subjects. 18F-PI-2620 uptake in expected regions is highly correlated to neurocognitive performance.




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Evaluation of dosimetry, quantitative methods and test-retest variability of 18F-PI-2620 PET for the assessment of tau deposits in the human brain

18F-PI-2620 is a next generation tau positron emission tomography (PET)-tracer that has demonstrated ability to image the spatial distribution of suspected tau pathology. The objective of this study was to assess the tracer biodistribution, dosimetry and quantitative methods of 18F-PI-2620 in the human brain. Full kinetic modelling approaches to quantify tau load were investigated. Non-invasive kinetic modeling approaches and semi-quantitative methods were evaluated against the full tracer kinetics. Finally, the reproducibility of PET measurements from test and retest scans was assessed. Methods: Three healthy controls (HC) and 4 Alzheimer disease (AD) subjects underwent two dynamic PET scans including arterial sampling. Distribution volume ratio (DVR) was estimated using full tracer kinetics (2 Tissue Compartment (2TC) models, Logan Graphical Analysis (LGA)) and non-invasive kinetic models (Non-Invasive Logan Graphical Analysis (NI-LGA) and the multilinear reference tissue model (MRTM2)). Standardized uptake value ratio (SUVR) was determined at different imaging windows after injection. Correlation between DVR and SUVR, effect size (Cohen’s d) and test-retest variability (TRV) were evaluated. Additionally, 6 HC subjects received one tracer administration and underwent whole-body PET for dosimetry calculation. Organ doses and the whole-body effective dose were calculated using OLINDA 2.0. Results: Strong correlation was found across different kinetic models (R2 >0.97) and between DVR(2TC) and SUVRs between 30 to 90 min with R2>0.95. Secular equilibrium was reached around 40 min post injection (p.i.) in most regions and subjects. The TRV and effect size for the SUVR across different regions was similar at 30-60 min (TRV=3.8%, d=3.80), 45-75 min (TRV=4.3%, d=3.77) and 60-90 min (TRV=4.9%, d=3.73) and increased at later time points. Elimination was via the hepatobiliary and urinary system. The whole-body effective dose was determined to be 33.3±2.1 μSv/MBq for an adult female and 33.1±1.4 μSv/MBq for an adult male with a 1.5 hour urinary bladder voiding interval. Conclusion: 18F-PI-2620 exhibits fast kinetics, suitable dosimetry and low TRV. DVR measured using the 2TC model with arterial sampling correlated strongly with DVR measured by NI-LGA, MRTM2 and SUVR. SUVR can be used for 18F-PI-2620 PET quantification of tau deposits avoiding arterial blood sampling. Static 18F-PI-2620 PET scans between 45-75min p.i. provide excellent quantification accuracy, large effect size and low TRV.




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Comparison between 18F-FDG-PET- and CT-based criteria in non-small cell lung cancer (NSCLC) patients treated with Nivolumab

Due to their peculiar mechanism of action, the evaluation of radiological response to immune checkpoint inhibitors (ICI) presents many challenges in solid tumors. We aimed to compare the evaluation of first response to Nivolumab by means of CT-based criteria with respect to fluorodeoxyglucose positron emission tomography (FDG-PET) response criteria in non-small-cell lung cancer (NSCLC) patients. Methods: 72 patients with advanced NSCLC were recruited in a mono-institutional ancillary trial within the expanded access program (EAP; NCT02475382) for Nivolumab. Patients underwent CT scan and FDG-PET at baseline and after 4 cycles (first evaluation). In case of progressive disease (PD), an additional evaluation was performed after two further cycles in order to confirm progression. We evaluated the response to treatment with CT scan by means of response evaluation criteria in solid tumors (RECIST) 1.1 and Immuno-related Response Criteria (IrRC) and with FDG-PET by means of PERCIST and immunotherapy-modified-PERCIST (imPERCIST) criteria. The concordance between CT- and PET-based criteria and the capability of each method to predict overall survival (OS) were evaluated. Results: 48/72 patients were evaluable for first response assessment with both PET- and CT-based criteria. We observed low concordance between CT- and PET-based criteria (Kappa value of 0.346 and 0.355 and Kappa value of 0.128 and 0.198 between PERCIST and imPERCIST versus RECIST and irRC respectively). Looking at OS, IrRC were more reliable to distinguish responders from non-responders. However thanks to the prognostic value of partial metabolic response assessed by both PERCIST and Immuno-PERCIST, PET-based response maintained prognostic significant in patients classified as progressive disease on the basis of irRC. Conclusion: Even though the present study did not support the routine use of FDG-PET in the general population of NSCLC patients treated with ICI, it suggests the added prognostic value of the metabolic response assessment, potentially improving the therapeutic decision-making.




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Light-induced radiosynthesis of 89ZrDFO-azepin-onartuzumab for imaging the hepatocyte growth factor receptor

Methods that provide rapid access to radiolabeled antibodies are vital in the development of diagnostic and radiotherapeutic agents for positron emission tomography (PET) or radioimmunotherapy. The human hepatocyte growth factor receptor (c-MET) signaling pathway is dysregulated in a number of malignancies including gastric cancer, and is an important biomarker in drug discovery. Here, we used a photoradiochemical approach to produce 89Zr-radiolabeled onartuzumab (a monovalent, anti-human c-MET antibody), starting directly from the fully formulated drug (MetMAb). Methods: Simultaneous 89Zr-radiolabeling and protein conjugation was performed in one-pot reactions containing 89Zr-oxalate, the photoactive chelate DFO-aryl azide (DFO-ArN3) and MetMAb to give 89ZrDFO-azepin-onartuzumab. As a control, 89ZrDFO-Bn-NCS-onartuzumab was prepared via a conventional two-step process using pre-purified onartuzumab and DFO-Bn-NCS. Radiotracers were purified by using size-exclusion methods and evaluated by radiochromatography. Radiochemical stability was studied in human serum and immunoreactivity was determined by cellular binding assays using MKN-45 gastric carcinoma cells. PET imaging at multiple time points (0–72 h) was performed in female athymic nude mice bearing subcutaneous MKN-45 xenografts. Biodistribution experiments were performed after the final image. Tumor specificity of 89ZrDFO-azepin-onartuzumab was assessed by competitive inhibition (blocking) studies. Results: Initial photoradiosynthesis experiments produced 89ZrDFO-azepin-onartuzumab in <15 min. with an isolated decay-corrected radiochemical yield (RCY) of 24.8%, a radiochemical purity (RCP) ~90% and a molar activity (Am) of ~1.5 MBq nmol-1. Reaction optimization improved the radiochemical conversion (RCC) of 89ZrDFO-azepin-onartuzumab to 56.9±4.1% (n = 3), with isolated RCYs of 41.2±10.6% (n = 3), and RCPs >90%. Conventional methods produced 89ZrDFO-Bn-NCS-onartuzumab with isolated RCY >97%, RCP >97% and Am ~14.0 MBq nmol-1. Both radiotracers were immunoreactive and stable in human serum. PET imaging and biodistribution studies showed high tumor uptake for both radiotracers. By 72 h, tumor and liver uptake reached 15.37±5.21 %ID g-1, 6.56±4.03 %ID g-1, respectively for 89ZrDFO-azepin-onartuzumab (n = 4), and 21.38±11.57 %ID g-1 and 18.84±6.03 %ID g-1 for 89ZrDFO-Bn-NCS-onartuzumab (n = 4). Blocking experiments gave a statistically significant reduction in tumor uptake (6.34±0.47 %ID g-1) of 89ZrDFO-azepin-onartuzumab (n = 4). Conclusion: Experiments demonstrate that photoradiosynthesis is a viable alternative approach for producing 89Zr-radiolabeled antibodies direct in protein formulation buffer which reduces protein aggregation and liver uptake.




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Kinetic modeling and test-retest reproducibility of 11C-EKAP and 11C-FEKAP, novel agonist radiotracers for PET imaging of the kappa opioid receptor in humans

The kappa opioid receptor (KOR) is implicated in various neuropsychiatric disorders. We previously evaluated an agonist tracer, 11C-GR103545, for PET imaging of KOR in humans. Although 11C-GR103545 showed high brain uptake, good binding specificity, and selectivity to KOR, it displayed slow kinetics and relatively large test-retest variability (TRV) of distribution volume (VT) estimates (15%). Therefore we set out to develop two novel KOR agonist radiotracers, 11C-EKAP and 11C-FEKAP, and in nonhuman primates, both tracers exhibited faster kinetics and comparable binding parameters to 11C-GR103545. The aim of this study was to assess their kinetic and binding properties in humans. Methods: Six healthy subjects underwent 120-min test-retest PET scans with both 11C-EKAP and 11C-FEKAP. Metabolite-corrected arterial input functions were measured. Regional time-activity curves (TACs) were generated for 14 regions of interest. One- and two-tissue compartment models (1TC, 2TC) and the multilinear analysis-1 (MA1) method were applied to the regional TACs to calculate VT. Time-stability of VT values and test-retest reproducibility were evaluated. Levels of specific binding, as measured by the non-displaceable binding potential (BPND) for the three tracers (11C-EKAP, 11C-FEKAP and 11C-GR103545), were compared using a graphical method. Results: For both tracers, regional TACs were fitted well with the 2TC model and MA1 method (t*=20min), but not with the 1TC model. Given unreliably estimated parameters in several fits with the 2TC model and a good match between VT values from MA1 and 2TC, MA1 was chosen as the appropriate model for both tracers. Mean MA1 VT values were highest for 11C-GR103545, followed by 11C-EKAP, then 11C-FEKAP. Minimum scan time for stable VT measurement was 90 and 110min for 11C-EKAP and 11C-FEKAP, respectively, compared with 140min for 11C-GR103545. The mean absolute TRV in MA1 VT estimates was 7% and 18% for 11C-EKAP and 11C-FEKAP, respectively. BPND levels were similar for 11C-FEKAP and 11C-GR103545, but ~25% lower for 11C-EKAP. Conclusion: The two novel KOR agonist tracers showed faster tissue kinetics than 11C-GR103545. Even with slightly lower BPND, 11C-EKAP is judged to be a better tracer for imaging and quantification of KOR in humans, based on the shorter minimum scan time and excellent test-retest.




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First-in-Human Trial of Dasatinib-Derivative Tracer for Tumor Kinase-Targeted Positron Emission Tomography

We developed a first-of-kind dasatinib-derivative imaging agent, 18F-SKI-249380 (18F-SKI), and validated its use for noninvasive in vivo tyrosine kinase-targeted tumor detection in preclinical models. In this study, we assess the feasibility of using 18F-SKI for PET imaging in patients with malignancies. Methods: Five patients with a prior diagnosis of breast cancer, renal cell cancer, or leukemia underwent whole-body PET/CT imaging 90 min post-injection of 18F-SKI (mean: 241.24 ± 116.36 MBq) as part of a prospective study. In addition, patients underwent either a 30-min dynamic scan of the upper abdomen including, at least partly, cardiac left ventricle, liver, spleen, and kidney (n = 2) or three 10-min whole-body PET/CT scans (n = 3) immediately post-injection and blood-based radioactivity measurements to determine the time course of tracer distribution and facilitate radiation dose estimates. A subset of three patients had a delayed whole-body PET/CT scan at 180 min. Biodistribution, dosimetry, and tumor uptake were quantified. Absorbed doses were calculated using OLINDA/EXM 1.0. Results: No adverse events occurred after injection of 18F-SKI. A total of 27 tumor lesions were analyzed with median SUVpeak 1.4 (range, 0.7–2.3) and tumor-to-blood ratios of 1.6 (range, 0.8–2.5) at 90 min post-injection. Intratumoral drug concentrations calculated for four reference lesions ranged from 0.03–0.07 nM. In all reference lesions, constant tracer accumulation was observed between 30–90 min post-injection. Blood radio-assay indicated that radiotracer clearance from blood and plasma was initially rapid (blood half-time 1.31 ± 0.81 min, plasma 1.07 ± 0.66 min; n = 4), followed variably by either a prolonged terminal phase (blood half-time 285 ± 148.49 min, plasma 240 ± 84.85 min; n = 2) or a small rise to plateau (n = 2). Like dasatinib, 18F-SKI underwent extensive metabolism post-administration, as evidenced by metabolite analysis. Radioactivity was predominantly cleared via the hepatobiliary route. The highest absorbed dose estimates (mGy/MBq) in normal tissues were to the right colon (0.167 ± 0.04) and small intestine (0.153 ± 0.03). The effective dose was 0.0258 (SD 0.0034) mSv/MBq. Conclusion: 18F-SKI demonstrated significant tumor uptake, distinct image contrast despite low injected doses, and rapid clearance from blood.




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11C-PABA as a Novel PET Radiotracer for Functional Renal Imaging: Preclinical and First-in-Human Studies

para-Aminobenzoic acid (PABA) has been previously used as an exogenous marker to verify completion of 24-hour urine sampling. Therefore, we hypothesized that radiolabeled PABA with 11C could allow high-quality dynamic PET of the kidneys while reducing the radiation exposure due to its short biological and physical half-lives. We evaluated if 11C-PABA could visualize renal anatomy and quantify function in healthy rats, rabbits, and first-in-human studies in healthy volunteers. Methods: Healthy rats and rabbits were injected with 11C-PABA intravenously. Subsequently, a dynamic PET was performed, followed by post-mortem tissue biodistribution studies. 11C-PABA PET was directly compared with the current standard, 99mTc-MAG3 in rats. Three healthy human subjects also underwent dynamic PET after intravenous injection of 11C-PABA. Results: In healthy rats and rabbits, dynamic PET demonstrated a rapid accumulation of 11C-PABA in the renal cortex, followed by rapid excretion through the pelvicalyceal system. In humans, 11C-PABA PET was safe and well tolerated. There were no adverse or clinically detectable pharmacologic effects in any subject. The cortex was delineated on PET, and the activity gradually transited to the medulla and then renal pelvis with high spatiotemporal resolution. Conclusion: 11C-PABA demonstrated fast renal excretion with very low background signal in animals and humans. These results suggest that 11C-PABA could be used as a novel radiotracer for functional renal imaging, providing high-quality spatiotemporal images with low radiation exposure.




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Innovative Funding for Humanitarian Impact in Africa

Research Event

3 February 2020 - 5:00pm to 6:15pm

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

Event participants

Helen Alderson, Head of Regional Delegation to UK and Ireland, International Committee of the Red Cross
Paul van Zyl, Co-Founder and Chief Creative Officer, The Conduit
Maya Marissa Malek, Chief Executive Officer, Amanie Advisors Global Office
Chair: Maram Ahmed, Senior Teaching Fellow, SOAS, University of London

The cost of humanitarian assistance is forecast to rise to $50 billion per year by 2030 as a result of long-running, complex conflicts as well as natural disasters. Requirements are particularly acute in fragile contexts in sub-Saharan Africa that have lacked the fiscal and technical capacity for crisis prevention and response. As a result, traditional humanitarian actors are increasingly collaborating with the private sector and utilizing tools such as impact bonds, faith-based finance and other innovative financial products and services to mobilize greater funding to address humanitarian needs.

At this event, a panel of speakers will assess the challenges for sustainable financing in the humanitarian sector and prospects for multi-stakeholder collaboration and innovative funding tools to fill the widening deficit in assistance needs.

THIS EVENT IS NOW FULL AND REGISTRATION HAS CLOSED.

Sahar Eljack

Programme Administrator, Africa Programme
+ 44 (0) 20 7314 3660




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The Central African Republic: Security, Development and Responding to the Humanitarian Situation

Invitation Only Research Event

3 February 2020 - 2:00pm to 3:00pm

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

Event participants

Denise Brown, United Nations Deputy Special Representative of the Secretary-General, Resident and Humanitarian Coordinator in the Central African Republic
Chair: Ben Shepherd, Consulting Fellow, Africa Programme, Chatham House

With two-thirds of the country’s population estimated to be in need of humanitarian aid and one-quarter either internally displaced or living as refugees in neighbouring countries, the Central African Republic (CAR) continues to face serious and complex humanitarian challenges. The country’s forthcoming presidential elections scheduled for December 2020 risk inflaming CAR’s volatile security situation particularly with the return of former leader, François Bozizé, ousted by the Séléka rebel coalition leader, Michel Djotodia, who has also returned from exile.

At this event, Denise Brown will discuss CAR’s current security, humanitarian and development situations and the role of actors such as the United Nations Multidimensional Integrated Stabilization Mission in the Central African Republic (MINUSCA). She will also discuss prospects for much-needed governance reform and reconciliation.

Attendance at this event is by invitation only. 

Event attributes

Chatham House Rule

Hanna Desta

Programme Assistant, Africa Programme




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Site-specific N-glycan Analysis of Antibody-binding Fc {gamma} Receptors from Primary Human Monocytes [Research]

FcRIIIa (CD16a) and FcRIIa (CD32a) on monocytes are essential for proper effector functions including antibody dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). Indeed, therapeutic monoclonal antibodies (mAbs) that bind FcRs with greater affinity exhibit greater efficacy. Furthermore, post-translational modification impacts antibody binding affinity, most notably the composition of the asparagine(N)-linked glycan at N162 of CD16a. CD16a is widely recognized as the key receptor for the monocyte response, however the post-translational modifications of CD16a from endogenous monocytes are not described. Here we isolated monocytes from individual donors and characterized the composition of CD16a and CD32a N-glycans from all modified sites. The composition of CD16a N-glycans varied by glycosylation site and donor. CD16a displayed primarily complex-type biantennary N-glycans at N162, however some individuals expressed CD16a V158 with ~20% hybrid and oligomannose types which increased affinity for IgG1 Fc according to surface plasmon resonance binding analyses. The CD16a N45-glycans contain markedly less processing than other sites with >75% hybrid and oligomannose forms. N38 and N74 of CD16a both contain highly processed complex-type N-glycans with N-acetyllactosamine repeats and complex-type biantennary N-glycans dominate at N169. The composition of CD16a N-glycans isolated from monocytes included a higher proportion of oligomannose-type N-glycans at N45 and less sialylation plus greater branch fucosylation than we observed in a recent analysis of NK cell CD16a. The additional analysis of CD32a from monocytes revealed different features than observed for CD16a including the presence of a predominantly biantennary complex-type N-glycans with two sialic acids at both sites (N64 and N145).




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Deep Characterization of the Human Antibody Response to Natural Infection Using Longitudinal Immune Repertoire Sequencing [Research]

Human antibody response studies are largely restricted to periods of high immune activity (e.g. vaccination). To comprehensively understand the healthy B cell immune repertoire and how this changes over time and through natural infection, we conducted immune repertoire RNA sequencing on flow cytometry-sorted B cell subsets to profile a single individual's antibodies over 11 months through two periods of natural viral infection. We found that 1) a baseline of healthy variable (V) gene usage in antibodies exists and is stable over time, but antibodies in memory cells consistently have a different usage profile relative to earlier B cell stages; 2) a single complementarity-determining region 3 (CDR3) is potentially generated from more than one VJ gene combination; and 3) IgG and IgA antibody transcripts are found at low levels in early human B cell development, suggesting that class switching may occur earlier than previously realized. These findings provide insight into immune repertoire stability, response to natural infections, and human B cell development.




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

Large-scale identification of N-linked intact glycopeptides by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) in human serum is challenging because of the wide dynamic range of serum protein abundances, the lack of a complete serum N-glycan database and the existence of proteoforms. In this regard, a spectral library search method was presented for the identification of N-linked intact glycopeptides from N-linked glycoproteins in human serum with target-decoy and motif-specific false discovery rate (FDR) control. Serum proteins were firstly separated into low-abundance and high-abundance proteins by acetonitrile (ACN) precipitation. After digestion, the N-linked intact glycopeptides were enriched by hydrophilic interaction liquid chromatography (HILIC) and a portion of the enriched N-linked intact glycopeptides were processed by Peptide-N-Glycosidase F (PNGase F) to generate N-linked deglycopeptides. Both N-linked intact glycopeptides and deglycopeptides were analyzed by LC-MS/MS. From N-linked deglycopeptides data sets, 764 N-linked glycoproteins, 1699 N-linked glycosites and 3328 unique N-linked deglycopeptides were identified. Four types of N-linked glycosylation motifs (NXS/T/C/V, X=P) were used to recognize the N-linked deglycopeptides. The spectra of these N-linked deglycopeptides were utilized for N-linked deglycopeptides library construction and identification of N-linked intact glycopeptides. A database containing 739 N-glycan masses was constructed and utilized during spectral library search for the identification of N-linked intact glycopeptides. In total, 526 N-linked glycoproteins, 1036 N-linked glycosites, 22,677 N-linked intact glycopeptides and 738 N-glycan masses were identified under 1% FDR, representing the most in-depth serum N-glycoproteome identified by LC-MS/MS at N-linked intact glycopeptide level.




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Quantitative Profiling of the Human Substantia Nigra Proteome from Laser-capture Microdissected FFPE Tissue [Research]

Laser-capture microdissection (LCM) allows the visualization and isolation of morphologically distinct subpopulations of cells from heterogeneous tissue specimens. In combination with formalin-fixed and paraffin-embedded (FFPE) tissue it provides a powerful tool for retrospective and clinically relevant studies of tissue proteins in a healthy and diseased context. We first optimized the protocol for efficient LCM analysis of FFPE tissue specimens. The use of SDS containing extraction buffer in combination with the single-pot solid-phase-enhanced sample preparation (SP3) digest method gave the best results regarding protein yield and protein/peptide identifications. Microdissected FFPE human substantia nigra tissue samples (~3,000 cells) were then analyzed, using tandem mass tag (TMT) labeling and LC-MS/MS, resulting in the quantification of >5,600 protein groups. Nigral proteins were classified and analyzed by abundance, showing an enrichment of extracellular exosome and neuron-specific gene ontology (GO) terms among the higher abundance proteins. Comparison of microdissected samples with intact tissue sections, using a label-free shotgun approach, revealed an enrichment of neuronal cell type markers, such as tyrosine hydroxylase and alpha-synuclein, as well as proteins annotated with neuron-specific GO terms. Overall, this study provides a detailed protocol for laser-capture proteomics using FFPE tissue and demonstrates the efficiency of LCM analysis of distinct cell subpopulations for proteomic analysis using low sample amounts.




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

HNF4α is a nuclear receptor produced as 12 isoforms from two promoters by alternative splicing. To characterize the transcriptional capacities of all 12 HNF4α isoforms, stable lines expressing each isoform were generated. The entire transcriptome associated with each isoform was analyzed as well as their respective interacting proteome. Major differences were noted in the transcriptional function of these isoforms. The α1 and α2 isoforms were the strongest regulators of gene expression whereas the α3 isoform exhibited significantly reduced activity. The α4, α5, and α6 isoforms, which use an alternative first exon, were characterized for the first time, and showed a greatly reduced transcriptional potential with an inability to recognize the consensus response element of HNF4α. Several transcription factors and coregulators were identified as potential specific partners for certain HNF4α isoforms. An analysis integrating the vast amount of omics data enabled the identification of transcriptional regulatory mechanisms specific to certain HNF4α isoforms, hence demonstrating the importance of considering all isoforms given their seemingly diverse functions.




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Human Services' computers keep disabled out of work

Disabled workers are caught in bureaucratic limbo by problematic computer systems.




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Troubled myGov website to be taken from Human Services and given to Digital Transformation Office for streamlining

Malcolm Turnbull's DTO has been critical of myGov, now it has the chance to show it can do better.




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ACT human rights commission 'concerned' about new app for ACT police

Canberrans' privacy rights could be threatened by the new app.