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Recent Progress in Function Theory and Operator Theory

Alberto A. Condori, Elodie Pozzi, William T. Ross and Alan A. Sola, editors. American Mathematical Society, 2024, CONM, volume 799, approx. 224 pp. ISBN: 978-1-4704-7246-7 (print), 978-1-4704-7612-0 (online).

This volume contains the proceedings of the AMS Special Session on Recent Progress in Function Theory and Operator Theory, held virtually on April 6,...




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Recent Progress in Special Functions

Galina Filipuk, editor. American Mathematical Society, 2024, CONM, volume 807, approx. 242 pp. ISBN: 978-1-4704-7429-4 (print), 978-1-4704-7722-6 (online).

This volume contains a collection of papers that focus on recent research in the broad field of special functions.

The articles cover topics...





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Compressible Euler limit from Boltzmann equation with complete diffusive boundary condition in half-space

Ning Jiang, Yi-Long Luo and Shaojun Tang
Trans. Amer. Math. Soc. 377 (), 5323-5359.
Abstract, references and article information




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Strong laws of large numbers for weighted sums of ????-dimensional arrays of random variables and applications to marked point processes

Ta Cong Son, Tran Manh Cuong, Le Quang Dung and Le Van Dung
Theor. Probability and Math. Statist. 111 (), 153-165.
Abstract, references and article information




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Smoothness and Lévy concentration function inequalities for distributions of random diagonal sums

Bero Roos
Theor. Probability and Math. Statist. 111 (), 137-151.
Abstract, references and article information




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A convolution inequality, yielding a sharper Berry–Esseen theorem for summands Zolotarev-close to normal

Lutz Mattner
Theor. Probability and Math. Statist. 111 (), 45-122.
Abstract, references and article information




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Large deviations for perturbed Gaussian processes and logarithmic asymptotic estimates for some exit probabilities

Claudio Macci and Barbara Pacchiarotti
Theor. Probability and Math. Statist. 111 (), 21-43.
Abstract, references and article information





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Ski resort announces immediate closure as relentless threat brings fewer visitors and increases debts: 'I feel like I'm in mourning'




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Jah Kettle wraps up successful tour

Reggae artiste Jah Kettle says he was pleased with his recently concluded Canada tour and is now excited to release a new single, titled Nothing Gonna Take Your Love Away, done with fellow reggae act Ras Penco. "The fans were riveting and showed...




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Workers at the Secrets and Breathless resorts protest overwork and low wages

Staff at the Secrets and Breathless resorts in Montego Bay, St James, walked off the job this morning complaining of overwork, low wages, lack of overtime pay and disrespect.




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Importance of endothelial Hey1 expression for thoracic great vessel development and its distal enhancer for Notch-dependent endothelial transcription [Gene Regulation]

Thoracic great vessels such as the aorta and subclavian arteries are formed through dynamic remodeling of embryonic pharyngeal arch arteries (PAAs). Previous work has shown that loss of a basic helix-loop-helix transcription factor Hey1 in mice causes abnormal fourth PAA development and lethal great vessel anomalies resembling congenital malformations in humans. However, how Hey1 mediates vascular formation remains unclear. In this study, we revealed that Hey1 in vascular endothelial cells, but not in smooth muscle cells, played essential roles for PAA development and great vessel morphogenesis in mouse embryos. Tek-Cre–mediated Hey1 deletion in endothelial cells affected endothelial tube formation and smooth muscle differentiation in embryonic fourth PAAs and resulted in interruption of the aortic arch and other great vessel malformations. Cell specificity and signal responsiveness of Hey1 expression were controlled through multiple cis-regulatory regions. We found two distal genomic regions that had enhancer activity in endothelial cells and in the pharyngeal epithelium and somites, respectively. The novel endothelial enhancer was conserved across species and was specific to large-caliber arteries. Its transcriptional activity was regulated by Notch signaling in vitro and in vivo, but not by ALK1 signaling and other transcription factors implicated in endothelial cell specificity. The distal endothelial enhancer was not essential for basal Hey1 expression in mouse embryos but may likely serve for Notch-dependent transcriptional control in endothelial cells together with the proximal regulatory region. These findings help in understanding the significance and regulation of endothelial Hey1 as a mediator of multiple signaling pathways in embryonic vascular formation.




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Molecular characterization of the RNA-protein complex directing -2/-1 programmed ribosomal frameshifting during arterivirus replicase expression [Protein Structure and Folding]

Programmed ribosomal frameshifting (PRF) is a mechanism used by arteriviruses like porcine reproductive and respiratory syndrome virus (PRRSV) to generate multiple proteins from overlapping reading frames within its RNA genome. PRRSV employs −1 PRF directed by RNA secondary and tertiary structures within its viral genome (canonical PRF), as well as a noncanonical −1 and −2 PRF that are stimulated by the interactions of PRRSV nonstructural protein 1β (nsp1β) and host protein poly(C)-binding protein (PCBP) 1 or 2 with the viral genome. Together, nsp1β and one of the PCBPs act as transactivators that bind a C-rich motif near the shift site to stimulate −1 and −2 PRF, thereby enabling the ribosome to generate two frameshift products that are implicated in viral immune evasion. How nsp1β and PCBP associate with the viral RNA genome remains unclear. Here, we describe the purification of the nsp1β:PCBP2:viral RNA complex on a scale sufficient for structural analysis using small-angle X-ray scattering and stochiometric analysis by analytical ultracentrifugation. The proteins associate with the RNA C-rich motif as a 1:1:1 complex. The monomeric form of nsp1β within the complex differs from previously reported homodimer identified by X-ray crystallography. Functional analysis of the complex via mutational analysis combined with RNA-binding assays and cell-based frameshifting reporter assays reveal a number of key residues within nsp1β and PCBP2 that are involved in complex formation and function. Our results suggest that nsp1β and PCBP2 both interact directly with viral RNA during formation of the complex to coordinate this unusual PRF mechanism.




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Malawi’s Re-Run Election is Lesson for African Opposition

1 July 2020

Fergus Kell

Projects Assistant, Africa Programme
The overturning of the result in the fresh presidential contest sets a bold precedent for the continent, as a process built upon the resilience of democratic institutions and the collective spirit of opposition.

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Lazarus Chakwera, leader of the Malawi Congress Party (MCP) arriving at the Mtandire suburb of the capital Lilongwe for an election rally. Photo by AMOS GUMULIRA/AFP via Getty Images.

Malawi is only the second African country to annul a presidential election, after Kenya in 2017. It is the first in which the opposition has won the re-run.

The initial May 2019 vote had narrowly returned incumbent Peter Mutharika to the presidency. But in February 2020 a landmark ruling by Malawi’s constitutional court annulled the result citing ‘widespread, systematic and grave’ irregularities, including the now-infamous use of corrective fluid in vote tallying, and the Malawi Electoral Commission’s (MEC) failure to address complaints before announcing results. New elections were ordered within 150 days.

In a decisive contrast with the previous year, the fresh polls on 23 June saw the coming together of Lazarus Chakwera of the Malawi Congress Party (MCP) and running mate Saulos Chilima of the United Transformation Movement (UTM) to head a coalition of nine opposition parties - having fiercely competed as the leading challengers previously.

The constitutional court ruling had also changed Malawi’s electoral system, replacing a first-past-the-post model with one demanding an outright majority, which further encouraged the regional power bases of Malawi’s opposition to cast ego aside and work in alliance with each other.

In tandem with a slick digital campaign, the new alliance travelled widely to hold rallies across what is one of the world’s youngest countries, while the elderly Mutharika remained largely confined to the capital. It would be a strategy that ultimately delivered Chakwera to the presidency, polling 58 per cent of votes to Mutharika’s 39.

Political opposition elsewhere in Africa should take note from Malawi’s coalition - dialogue, not division, can offer a genuine path to change, especially in those countries with less favourable institutional conditions. Neighbouring Zambia would certainly do well to heed this example ahead of a pivotal election of its own in 2021.

A victory built on institutional precedent

Yet the story here is not only about throwing out an incumbent: Malawians had already done so twice before, rejecting sitting presidents at the polls in 1994 and 2014. It is also not unfamiliar to see public opinion and the judiciary work in parallel to uphold the constitution: former president Bakili Muluzi was twice blocked from abolishing term limits by popular demonstration during his second term, and again prevented from running for a third time in 2009 by the constitutional court.

The new result did not arise as the foregone conclusion of a judicial miracle. Rather, throughout the re-run process Malawi has had to repeatedly draw upon the strength of its broad-based institutional foundations. The image of the constitutional court judges arriving to deliver their annulment verdict in February wearing bulletproof vests under their robes was a stark reminder that this was never the easy route to take.

In contrast to many other African states, Mutharika was unable to call upon military support as the Malawi Defence Forces (MDF) had moved to shield protesting citizens and protect the judiciary since the 2019 election. The MDF also had previous form in this respect, having defended then-vice president Joyce Banda’s constitutional right to assume the presidency after the incumbent’s death in 2012.

And this institutional resilience from the army would facilitate a smooth and mostly peaceful election process during the re-run, despite Mutharika attempts to intervene by replacing the MDF’s commander and his deputy in March 2020.

Just ten days before the fresh vote the Mutharika government switched focus back to the country’s legal system by attempting to enforce the premature retirement of Malawi’s chief justice, only to be blocked by the high court. Even as unofficial tallies trickled in, Mutharika’s Democratic Progressive Party (DPP) demanded the MEC annul the result: claiming their monitors were intimidated in MCP strongholds, and requesting unlawful access to scrutinise null and void votes.

Headed by a new chairperson, this time the MEC displayed enormous patience in the verification process and openly tackled complaints, now mainly from the DPP. On social media, Malawians celebrated the contrast between images of tally sheets from 2019 and the re-run.

Writing a new chapter

There are lessons here too for international partners. UK diplomacy played a subtle role in encouraging Mutharika to accept the legal process - he was invited to appear at the UK-Africa Investment Summit in January - while also helping promoting early dialogue among opposition parties.

At a time of pressure for UK engagement to offer clear strategic value, the impact of less easily quantifiable forms of influence should not be overlooked, especially as international observer missions effectively went missing in the discredited 2019 election. Preliminary statements back then from the Commonwealth, European Union, African Union and Southern African Development Community (SADC) struck a mostly congratulatory tone and were non-committal on the issues that would prove decisive in the court ruling. None went on to release their final reports.

Malawi must now start to move beyond election mode. Though COVID-19 cases remain low by global standards, a budget already heavily dependent on foreign aid and hampered by 18 months of political uncertainty will be slashed further by the pandemic’s impact. The IMF has predicted GDP growth of just 1% in 2020, down from a pre-coronavirus projection of 5%.

As it inherits a major balance of payments crisis, mounting debt and with no tourism revenue to fall back on, the new government will need to use its political capital to push for immediate reform. But it must not forget the core tenet of its campaign. The coalition that defeated Mutharika united the MCP’s rural support base with the middle-class urban following of the UTM. This spirit of unity and inclusion must be expanded and focus on long-term recovery. On this undertaking – unlike the polls – there will be no opportunity for a re-run.




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Clearer Role for Business Regulators Needed in Monitoring Trade Agreements

6 July 2020

Dr Jennifer Ann Zerk

Associate Fellow, International Law Programme
As the economic recovery from coronavirus is worked through, careful steps are needed to ensure actions to enforce human rights commitments in trade agreements do not worsen human rights impacts.

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Garment workers hold stickers bearing US$177 during a demonstration to demand an increase of their minimum salary in Phnom Penh, Cambodia. Photo by Omar Havana/Getty Images.

Trade policy is a blunt instrument for realizing human rights. Although many trade agreements now include commitments on human rights-related issues - particularly labour rights - not everyone agrees that linking trade to compliance with human rights norms is appropriate, let alone effective.

Sceptics point out that such provisions may become an excuse for interference or ‘disguised protectionism’ and admittedly anyone would be hard-pressed to identify many concrete improvements which can be directly attributed to social and human rights clauses in trade agreements.

This lack of discernible impact has a lot to do with weak monitoring and enforcement. A more fundamental problem is the tendency of trading partners to gloss over – both in the way that commitments are framed and in subsequent monitoring efforts – significant implementation gaps between the standards states sign up to, and the reality.

Working from ‘baseline’ international standards and treating each state’s human rights treaty ratification record as an indicator of compliance does offer objective verifiability. But it also means underlying economic, structural, cultural, social, and other problems, often go unidentified and unaddressed in the trading relationship.

Regulatory failings of trading partners

Those with sufficient leverage can use dispute resolution or enforcement proceedings to signal displeasure at the regulatory failings of their trading partners, as recently shown by the European Commission (EC) in relation to labour violations by trading partners – against South Korea under the 2011 EU-South Korea Free Trade Agreement (FTA) and Cambodia under the EU’s Generalised Scheme of Preferences (GSP) scheme.

These actions do show a more proactive and rigorous EU approach to monitoring and enforcement and have been largely welcomed – especially by trade unions – as a necessary political response to persistent failings by the states to address violations of fundamental labour rights. However, claiming any major victories on behalf of the workers who produce the goods being traded seems premature.

The ‘implementation gaps’ - between human rights commitments made in a state-to-state context and the reality of the human rights situation on the ground - mean there may be cases where enforcement action under a trading arrangement, such as the removal of trade preferences, may actually make things worse. Some local unions have expressed concern that the EU action against Cambodia may be detrimental to vulnerable migrant women factory workers, especially in the context of a worsening economic situation due to the pandemic.

Making stakeholder voices heard

There are routes through which people with first-hand knowledge of human rights-related problems arising from trading relationships – such as labour rights abuses in global supply chains – can make their voices heard. Unions have used consultative bodies set up under trade agreements to highlight labour abuses in trading partner countries - this helped to shift the Commission’s strategy towards South Korea.

But the rather vague and open-ended mandates of these consultative bodies, and their reliance on cash-strapped civil society organisations to do much of the heavy lifting, means they are not a solid basis for systematic follow-up of human rights problems.

And yet, every country is likely to have a number of agencies with interests and expertise in these issues. Beyond labour inspectorates, this could include environmental regulators, licensing bodies, ombudsmen, national healthcare bodies, special-purpose commissions, ‘responsible business’ oversight and certification bodies, local government authorities and national human rights institutions.

At present these groups are barely mentioned in trade agreements with monitoring frameworks for human rights. And if they do feature, there tends to be little in the agreement terms to guarantee their participation.

To seriously address implementation gaps, there needs to be much greater and more systematic use of these domestic regulatory bodies in human rights monitoring and enforcement activities. These bodies are potentially vital sources of information and analysis about the many different social, economic, environmental and human rights consequences of trade, and can also contribute to designing and delivering ‘flanking measures’ needed to assist with the mitigation of human rights-related risks or adverse impacts which have been detected.

Looking further ahead, monitoring practitioners may find - as those involved in the EU GSP+ scheme have already noticed - that close and visible engagement with domestic regulatory bodies helps strengthen a regulator in getting clearer political support and better resources. It can also help with greater ‘buy-in’ to human rights reform agendas, creating conditions for a positive legacy in the form of more confident, committed, and capable domestic regulatory bodies.

Paying more attention to synergies that exist between the work of domestic regulatory bodies and the principles and objectives which cause states to seek human rights commitments from their trading partners is a vital contribution to the concept of ‘building back better’ from the present crisis.

The goal should be to move from the present system – which veers between largely ineffective consultative arrangements and adversarial, often high stakes, dispute resolution – to more cooperative and collaborative systems which draw more proactively from the knowledge and expertise of domestic regulatory bodies, not only in the identification and monitoring of risks, but also in the delivery of jointly agreed strategies to address them.

This article is part of the Chatham House Global Trade Policy Forum, promoting research and policy recommendations on the future of global trade.




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Tackling Malnutrition: Harnessing the Power of Business

8 July 2020

Simon Pringle

Associate Fellow, Energy, Environment and Resources Programme
Malnutrition negatively impacts individuals, families, societies and economies around the world. Now is the time to align corporate, government and third sector efforts to relegate it to the past.

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A view of a market area in Goma, Democratic Republic of Congo on 10 October 2019. Congo is among the countries with the highest number of acutely malnourished people on a global level. Photo by JC Wenga/Anadolu Agency via Getty Images.

Many people are aware that the scourge of malnutrition affects a vast number of individuals and communities around the world. However, most tend to view it as a problem to be addressed by governments, charities or donors, rather than the corporate sector.

Certainly, when considered at a societal scale, malnutrition makes the complexities of delivering inclusive growth all the harder. It ratchets up the public health burden while restricting the potential for at-risk populations to take part in productive employment.  Economies are hindered, lives are blighted and the potential for people to reach their full potential can be severely limited.

A number of upcoming summits represent a window of opportunity to address nutrition in the context of resilience, particularly in the wake of COVID-19 and the much-referenced ambition for governments to ‘build back better’. The opportunity is there to foster a true partnership between governments, third sector organizations and businesses of all sizes, sectors and geographies to work for the betterment of society and deliver benefits to all participants in such a partnership. 

So what is the role of business in relation to nutrition - where does it sit on their list of priorities and why should it matter to them? A new Chatham House report represents an important contribution to the discussion about the role of business in addressing malnutrition. Through thorough research and direct engagement with businesses, it seeks to find out if malnutrition is on the corporate radar and the extent to which it is considered a material issue.

Surprisingly, whilst many large corporates recognize malnutrition as a matter for concern, this is typically defined only in the context of CSR programmes or related ambitions. These types of commitments have their limitations though; most notably the fact that the communities more severely affected by malnutrition typically sit outside of the sphere of influence of the multi-national companies with the greatest ability to mobilize resources and make an impact. Where populations are marginalized, operating within the informal economy and living in settings that are too fragile for large-scale business investment, corporate CSR programmes are unlikely to have a meaningful impact.

Report Launch: The Business Case for Investment in Nutrition

As COVID-19 pushes UN targets to end global hunger and malnutrition even further off-course, now is the time for businesses to step up and improve nutrition in their workforce and beyond.

The report also asked businesses whether they considered malnutrition to have a material impact on their ability to create value, protect value and manage risk. In the majority of instances the answer was no. This may be surprising, particularly given the evidence provided by new modelling – done for this report using a purpose-built model by Vivid Economics – that illustrates the costs posed to business by malnutrition within a population. On an immediate and direct level, the impacts can be considerable due to lost or reduced productivity from the employee base. However, if even that immediate impact is addressed, the externalities associated with malnutrition can come back and have a negative effect on businesses and investors alike.

When reflecting on externalities and the landscape of risk within which business operates, it is worth considering climate change by way of comparison. Climate change is well embedded in the risk profiling of most progressive and well-managed corporates – although in some instances meaningful action may be well overdue. That said, it is recognized that the direct and indirect impacts have the potential to conspire and permanently reduce shareholder, stakeholder and societal value. 

Similarly, if left unchecked, the externalities associated with malnutrition will undoubtedly contribute to an increased level of risk in terms of both operating and investment environments. This is both an issue of social equity and enlightened self-interest given that good nutrition is key to the success of many of the Sustainable Development Goals (SDGs), and is essential to driving sustainable economic growth. One of the lessons of the COVID-19 pandemic is the manner in which widespread malnutrition can significantly reduce the resilience of populations to external risks, including the outbreaks of infectious disease. We need only to look at the impact of climate stress and related events to understand how closely linked malnutrition is – or may become – to the incidence of social unrest and armed conflict in low-income countries.

Progressive companies and investors have already identified the ability to drive inclusive and sustainable growth as a compelling imperative for investment. In this context, the potential for improved nutrition – both in the workforce and amongst the communities upon which the firms depend – should be a true priority. As fund managers seek increasingly meaningful insight into the way that companies within their portfolio(s) create value, protect value and manage risk, the scope of environmental and social governance is expanding. Many recognize the link between delivering on the SDG agenda and protecting or enhancing shareholder value into the longer term. This is a powerful lever for change, particularly when considering that good nutrition is integral to the success of the ambitions laid out by the various SDGs. Successfully delivering against nutrition-focused targets could unlock growth in developing markets and create an enabling environment for achieving the broader SDG agenda. This may in turn help companies to deliver enduring shareholder value in a way that does not undermine their corporate sustainability commitments.

So, given the insights provided by this report, what can businesses do that have the potential to make a practical and effective impact? There are three main action points around which the private sector can galvanize its efforts and work in partnership to deliver a meaningful impact. 

The first action point is a basic requirement to be proactive and make supportive interventions with existing and future workforces, ensuring that staff are well fed and have appropriate facilities for breastfeeding and childcare. Beyond that foundational commitment, the second action point is to work to build impactful and well-governed partnerships to work within local communities and deliver outcomes at an appropriate scale. The third and final action point sets out the importance of reporting. Businesses should thoroughly assess the impacts of their operations, investments and influence. They should be transparent about those impacts and report both on the current situation and the commitments made to deliver on measurable targets.

Malnutrition is a scourge; it negatively impacts individuals, families, societies and economies. Now is the time to align corporate, government and third sector efforts to consign it to the past. We just need leaders to be bold enough to seize the opportunity.




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Domestic Violence in Ukraine: Lessons from COVID-19

23 July 2020

Kateryna Busol

Robert Bosch Stiftung Academy Fellow, Russia and Eurasia Programme
The pandemic has shed light on domestic violence in Ukraine, mobilizing civil society to demand more nuanced policy on the issue.

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A protester chants slogans on a megaphone during an International Women's Day protest on 8 March 2019 in Kyiv, Ukraine. Photo: Getty Images.

The virus of violence

During quarantine, the greater economic vulnerability of Ukrainian women has locked many of them with abusive partners. The uncertainty of personal finances, health and security in confinement has exacerbated domestic violence against women, in certain cases aggravated by the perpetrator’s war-related post-traumatic stress disorder (PTSD).

In pre- pandemic times, only one third of domestic violence victims, 78% of whom are women, reported the abuse. During the pandemic, the calls to domestic violence helplines increased by 50% in the Donbas war zone and by 35% in other regions of Ukraine.

However, more precise estimates are hard to make. This is largely because some fractions of Ukrainian society still see domestic violence as a private family matter, which will get little assistance from the police. Also, reporting from a small confinement place permanently shared with a perpetrator during the lockdown can trigger more abuse.

The COVID-19-tested legal framework

The spike in domestic violence during lockdown has intensified the debate about the inadequacy of Ukraine’s approach.

Ukraine adopted the law on domestic violence in 2017 and made such behaviour punishable under administrative and criminal law. Importantly, the law does not limit domestic violence to physical abuse, but recognizes its sexual, psychological and economic variations. Domestic violence is further not limited to a married couple or close family members, but can be perpetrated against a distant relative or a cohabiting partner.

The extended definition of rape now includes rape of a spouse or a family member as an aggravating circumstance. A special police unit has been designated to deal with domestic abuse cases. Police can now issue protection orders in prompt reaction to an offence and immediately distance a perpetrator from a victim.

The victim can also spend time in a shelter - a system which the Ukrainian government has promised to create. A special registry of domestic violence cases has been set up for the exclusive use by the designated law enforcement and social security authorities to help them be more holistically informed in building a response.

However important, the introduced legal and institutional infrastructure was slow in proving its efficiency pre-COVID-19. It is struggling even more to stand the test of the coronavirus.

Changing the established mindset takes time. 38% of Ukraine’s judges and 39% of prosecutors still struggle to see domestic violence not as a household issue. Even though the police are becoming more reactive to home abuse complaints, getting emergency protection orders is still difficult. The court restraining orders are more effective, however they require the unnecessarily protracted and humiliating procedures of proving one’s own victimhood to different state authorities.

In response to the challenges of coronavirus for women, the police spread information posters and created a special chat-bot about the available help. However, while the domestic violence helplines of La Strada and other human rights NGOs are busier than ever, the police statistics suggest that the lockdown has not catalyzed home abuse.

This could indicate a higher trust to non-state institutions and the inability of a considerable group of women to use more sophisticated communication means such as chat-bots when they cannot call the police in the presence of an abuser. This problem is exacerbated by a current  lack of shelters in rural areas, as most are located in urban settings. Overcrowded in ordinary times, the shelters’ capacity to accept survivors during the lockdown is further limited by the social distancing rules.

Istanbul Convention – The bigger picture

Ukraine failed to ratify the Council of Europe Convention on preventing and combating violence against women, better known as the Istanbul Convention, largely due to the opposition of religious organizations. Concerned that the treaty’s terms ‘gender’ and ‘sexual orientation’ would contribute to the promotion of same-sex relationships in Ukraine, they argued that Ukraine’s current legislation provides adequate protection against domestic violence. However, this is not the case.

The Istanbul Convention does not ‘promote’ same-sex relationships, it only mentions sexual orientation among the non-exhaustive list of prohibited discrimination grounds. Remarkably, Ukraine’s domestic violence law itself is against such discrimination.

The Convention defines ‘gender’ as the socially constructed roles a society attributes to women and men. Ukraine’s overcautiousness about the term is ironic at least in two dimensions.

First, the 2017 domestic violence law restates its aim to eliminate discriminating beliefs about the social roles of each ‘sex’. In doing so, the law supports the rationale of what the Istanbul Convention denotes as ‘gender’ without using the term itself.

Second,  it is exactly the constraints of the rigidly defined niches for both sexes in Ukraine that have substantially contributed to the intensified domestic violence, whether it be  war or  coronavirus-related. The lack of sustainable psychological support for traumatized veterans and the stigma of mental health struggles, especially among men, mars their reintegration to peaceful life. This often results in alcohol abuse or even suicide.

As the economic uncertainty of the war and the virus prevents some men from fully living up to their traditional socially - and self-imposed - breadwinner role, this increases the risk of problematic behaviour and domestic violence.

By diverting the focus of the debate  to the term ‘gender’ used in the Istanbul Convention, conservative groups have ignored the fact that it describes the priority already enshrined in Ukraine’s 2017 law - to eliminate discriminatory beliefs about the socially constructed roles of men and women. This has drawn away time and resources needed to protect those vulnerable to domestic abuse.

Ukraine has not addressed the pigeonholing of women and men into gendered stereotypes. This has harmed men while further victimizing women and children, especially during the lockdown. Ironically, this is leading to the undermining of the very traditional family values certain opponents of the Istanbul Convention appealed to.

Fortunately, Ukraine’s ever-vigilant civil society,  dismayed at the wave of the lockdown domestic violence, petitioned President Zelenskyy to ratify the Convention. With a new draft law on ratification, the ball is now in the parliament’s court. It remains to be seen whether Ukraine’s policymakers will be up to the task.            




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Market Rally Contains Hopeful Message for the Economy

21 August 2020

Dame DeAnne Julius DCMG CBE

Senior Adviser, Chatham House; Distinguished Fellow, Global Economy and Finance Programme
There are good reasons for soaring stocks, despite a seeming disconnect from the recession.

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Fearless Girl statue outside the New York Stock Exchange. Photo by Noam Galai/Getty Images.

Among the many unusual features of the pandemic-induced downturn is the disconnect between depressed real economies and buoyant financial markets. This is particularly evident in the US, where output fell 9.5% in the second quarter while the S&P 500 index rose by one-fifth.

This may suggest a huge financial bubble is in the making, or at least a highly optimistic view of a COVID-19 vaccine and treatments. Another possibility is that markets have a better grasp of the economic dynamics of a post-pandemic world than most nervous consumers and governments.

Certainly, markets have been helped by central bank largesse. In March, major central banks reacted forcefully to the possibility of a serious credit crunch with lending guarantees and bond purchases. Such liquidity interventions soothe troubled markets, but they also raise asset prices — potentially into bubble territory. This partly explains the markets’ strength. But it may not be the whole story.

A closer look at market performance suggests they may be on to something more interesting. Compare the US’s broad-based S&P 500 equity index with the tech-focused Nasdaq 100. Since the start of the year, the Nasdaq has risen 24% while the S&P is up just 5%. In the S&P itself, it has been the dramatic rise of the so-called Faang companies — Facebook, Amazon, Apple, Netflix and Google/Alphabet — that offset lesser performances by the other 495 companies. This sharp difference reflects two forces.

First, the COVID-19 crisis has had vastly different effects on different sectors. Lockdown brought a sudden increase in demand for the technology services that enable home learning (with school closures), homeworking (especially by office workers), home entertainment (instead of cinemas and theatres), home shopping (instead of physical shops), and home deliveries of almost everything else, including food. The Faang companies benefited disproportionally from this surge in demand as their production is scalable. Much of it could also be delivered by employees who themselves worked from home. The rise in their share prices reflects this.

Meanwhile, other sectors suffered massively. In the UK, the overall drop in gross domestic product of 20% in the second quarter was led by a fall of 87% in the accommodation and food services sector, which was severely affected by government restrictions. About one-quarter of the UK workforce, according to official figures, was also furloughed or temporarily off work without pay during lockdown. The fall in the share prices of hotels, restaurant franchises and airlines reflects such factors. 

The second driver of rising markets is that they are forward-looking while economic statistics reflect the past. For example, that UK GDP shrank during the second quarter is less interesting to a financial investor than the fact that during two months (May and June) GDP expanded by 2.4% and 8.7% respectively. In other words, output troughed in April but recovery began in May and accelerated in June as lockdown restrictions were eased. 

It is likely that rapid adaptations by companies and consumers to the pandemic-supercharged trends are already under way. In Britain, the share of retail sales (excluding fuel) made by ecommerce rose from around 7% in 2010 to 20% at the beginning of 2020 — it has since jumped to more than 30%. 

One-third of those officially working from home meanwhile say that they would like to do that permanently, according to the Centre for Economics and Business Research, and many large companies have offered their staff this choice.

Even in labour-intensive sectors such as healthcare and government services there has been a replacement of face-to-face delivery with digital booking and screen-based consultations.

Still, while this may help some companies in certain sectors, it does not imply a smooth recovery for the whole economy. Rather, it augurs a period of disruption as new companies, new business models and new job openings emerge. If the pandemic has ignited a Schumpeterian process of creative destruction, that is likely to continue whether or not effective vaccines and treatments ever come. 

Governments should ease the pain of this disruption with supportive fiscal and monetary policies, but they should not try to slow it down. The hopeful market message is that one lasting consequence of COVID-19 may be the rejuvenation of productivity growth that eventually spreads far beyond tech. 

This article was originally published in the Financial Times.




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Lessons from COVID-19: A Catalyst for Improving Sanctions?

26 August 2020

Emanuela-Chiara Gillard

Associate Fellow, International Law Programme
As the COVID-19 pandemic continues, efforts by states and humanitarian actors to stop its spread and to treat the sick are being hindered by existing sanctions and counterterrorism measures.

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Syrians walk past a mural painted as part of an awareness campaign by UNICEF and WHO, bearing instructions on protection from COVID-19, in the Kurdish-majority city of Qamishli, Syria, on 16 August 2020. Photo by Delil Souleiman/AFP via Getty Images.

If sanctions imposed by the UN Security Council, the EU, or states unilaterally, are not sufficiently targeted, and do not include adequate safeguards for humanitarian action, they can adversely affect the very populations for whose well-being they were imposed in the first place.  This is not a new concern, but one brought starkly to the fore by their impact on responses to COVID-19.

The detrimental impact of sanctions, which can prevent the supply of medical or personal protective equipment (PPE), or the provision of technical support or training to local health authorities is evident. Sanctions can also affect remote learning if support cannot be provided to local education authorities, export licences cannot be obtained for the necessary equipment and software, or if the companies providing reliable internet coverage are designated under the sanctions.

A comparison of US and EU sanctions on Syria reveals key challenges, but also opportunities for improving current arrangements for the imposition and implementation of sanctions so as to minimize adverse consequences in Syria and more generally.

The US has imposed broad sanctions, such as restrictions on the provision of funds, goods or services – even charitable contributions – to the Syrian government, including the health and education ministries, now playing a central role in the COVID-19 response.

UN agencies are exempted from these restrictions. A general license authorizes NGOs to conduct activities to meet basic needs, but it excludes those involving the government. So NGOs wishing to provide medical devices, PPE, training or other support to ministry of health staff have to apply for a specific licence.

But procedures for applying for licences are complicated, and the approval process notoriously slow.  No accommodation has been made to facilitate the COVID-19 response: no interpretative guidance – that would be valuable for all NGOs – has been issued, and no procedures established for reviewing applications more quickly.  There is no statement of policy indicating the circumstances under which specific licences might be granted.

Transactions with designated entities other than the government, such as internet providers whose services are necessary for remote learning, remain prohibited, and regulations expressly preclude applying for specific licences.

US sanctions frequently have a broad scope, both in direct and indirect application.  NGOs registered in the US, and staff who are US nationals, are directly bound by them, and grant agreements between the US government and non-US NGOs require the latter to comply with US sanctions.

This leaves the non-US NGOs in a Catch-22 situation – as they are not ‘US persons’ they cannot apply for specific licenses, but if they operate without such licences they may be violating grant requirements. This lack of clarity contributes to banks’ unwillingness to provide services, and may lead NGOs to curtail their activities.  This situation is regrettable in Syria, where the US is the first donor to humanitarian action, and also arises in other contexts where the US has imposed similar sanctions.

The EU’s sanctions for Syria are far more targeted. Of relevance to the COVID-19 response, they do not include prohibitions on the provision of support to the government that could impede assistance in the medical field.  There are, however, restrictions on the provision of certain types of PPE or substances used for disinfection, and also on transactions with designated telecommunications providers that affect continuity of education during lockdowns.  Although not prohibited, these activities must be authorized by member states’ competent authorities. Similar concerns arise about the complexity and delays of the processes.

The EU sanctions framework is complex, so the recent European Commission Guidance Note on Syria providing official clarification of how it applies to humanitarian action is welcome.  Although the note only explains the existing rules rather than amending them to facilitate the COVID-19 response, it does include a number of important elements relevant not just to Syria, but to the interplay between sanctions and humanitarian action more broadly.

First, it notes that ‘in accordance with International Humanitarian Law where no other option is available, the provision of humanitarian aid should not be prevented by EU restrictive measures’.  This recognizes that humanitarian assistance takes priority over any inconsistent restrictions in sanctions, and it also applies both to UN sanctions and unilateral measures. It is a starting premise that is frequently overlooked in discussions of whether sanctions should include exceptions for humanitarian action.  Its reaffirmation is timely, and it must guide states in drawing up future sanctions.

Second, the note states that sanctions do not require the screening of final beneficiaries of humanitarian programmes.  This means that once someone has been identified as an individual in need on the basis of humanitarian principles, no further screening is required.  This is extremely important to COVID-19 responses as it reflects a foundational principle of IHL that, to the fullest extent practicable, everyone is entitled to the medical care required by their condition without distinction.

Third, while responsibility for the implementation of sanctions, including the granting of authorizations, lies with member states, the note nudges them to adopt a number of measures to expedite and streamline such processes.  These include the suggestion that states could issue a single authorization for the provision of humanitarian aid in response to the pandemic.

The European Commission is to be commended for this initiative, which should be replicated for other contexts where the COVID-19 response may be undermined by sanctions.  These include Gaza, where it would be important to highlight that the designation of Hamas under EU counterterrorism sanctions must not prevent the provision of assistance to relevant ministries.

Failing to draw a distinction between the designated political party and the structures of civil administration risks turning targeted financial sanctions into measures akin to comprehensive sanctions.

The pandemic should serve as a catalyst for improving the system for the adoption and implementation of sanctions by the UN, the EU and individual states, including the UK as it elaborates its sanctions policy post-Brexit. The principles are clear: without prejudicing the aims for which sanctions have been imposed, humanitarian needs must always be prioritized, and met.




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E3 Cooperation Beyond Brexit: Challenging but Necessary

2 September 2020

Alice Billon-Galland

Research Associate, Europe Programme

Professor Richard G Whitman

Associate Fellow, Europe Programme
In the current uncertain strategic context for Europe, the E3 is establishing itself as a go-to format for diplomatic cooperation for Europe’s ‘big three’.

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British Prime Minister Boris Johnson (R), French President Emmanuel Macron (C) and German Chancellor Angela Merkel (L) speak upon their arrival for a round table meeting as part of an EU summit in Brussels on 17 October 2019. Photo by Olivier Matthys/Pool/AFP via Getty Images.

As the UK’s post-Brexit foreign policy takes shape, it is increasingly clear that joint cooperation with France and Germany will be of key importance. The current dispute with the US over imposing further sanctions on Iran shows that the UK values continuing strong cooperation with its European partners on key international issues, even at the cost of a major transatlantic dispute. Moreover, the recent first meeting of the German, French and British defence ministers in an E3 (European/EU 3) format signalled political commitment by all three partners to double down on joint diplomatic cooperation despite troubled UK-EU Brexit negotiations.

The UK working with France and Germany as part of the E3 has evolved in recent years from a shared approach to diplomacy on Iran’s nuclear programme to include a broader range of international security issues, such as the conflict in Syria and freedom of navigation in the South China Sea. E3 cooperation has so far been largely low-key, marked by close relationships and daily contacts between officials rather than high-profile summits between the leaders of the three countries. In the absence of any EU-UK negotiations on a future foreign, security and defence policy relationship, the E3 represents a key arrangement for aligning and mobilizing Europe’s ‘big three’ states. In a recent Chatham House research paper, we argue that Germany, France and the UK could and should maintain the E3 as a platform for flexible diplomatic coordination and crisis response, and expand its focus to address a new set of thematic, regional or multilateral topics. These could range from further cooperation on arms control to a reform agenda for multilateral institutions or a joint approach to the broader European neighbourhood.

The E3 countries have complementary reasons for wanting to make the format work. France and Germany recognize that the high degree of shared foreign and security policy interests with the UK require a pragmatic format for close cooperation, to provide insurance against an underdeveloped EU-UK relationship, help efficiently combine European forces and bring added value to the EU and NATO – but also to see the UK aligned with Europe on major international issues. Close foreign and security policy relationships with France and Germany will remain of interest to the UK as well, in order for it to keep playing an effective role in European security and to work with like-minded partners on key international issues.

Brexit presents both a major challenge for the E3 relationship and a major rationale for developing the format further. Neither France nor Germany see E3 cooperation as a substitute for a deal on a future EU-UK relationship or for the development of the EU’s own foreign, security and defence policy. Failure to reach a Brexit deal and a collapse of the EU-UK relationship into hostility and antagonism could make E3 cooperation politically difficult in the short term. In the longer term, were the UK and the EU to adopt very different foreign and security policies, E3 cooperation would also make less sense.

Even if an agreement is reached on the future EU-UK relationship by the end of this year, for France and Germany the challenge will be to reconcile their work with the UK through the E3 with their commitment to the EU. France and Germany have different rationales for favouring E3 cooperation. While France is more relaxed about its intergovernmental approach and prioritizes deliverables, Germany is worried about the perceived competition between the E3 and the EU. However, they both share the view that E3 cooperation should complement rather than undermine EU foreign, security and defence policy cooperation, while acting to bridge or smooth cooperation between the EU and the UK. If E3 cooperation were to conflict with broader EU policy by generating hostility from excluded member states (such as Poland or Italy) and therefore distract from building consensus for broader EU initiatives, such as post-COVID economic recovery, E3 cooperation may falter.

Another key factor for the E3 will be the evolution of transatlantic relations, and whether the next US administration presents Europe with the dilemma of choosing between broad alignment with the US or open confrontation, as in the case of the Iran nuclear deal’s ‘snapback’ mechanism. As a non-EU state, the UK may have more autonomy to set its own policies but it will not be able to escape a choice between either a broad alliance with European states or a more ambivalent and ad-hoc relationship with the continent, while also creating new formats for cooperation with other democracies such as the Five Eyes states. This type of diplomatic ‘venue shopping’ could create tensions with European partners, especially Germany and France who hope to anchor London into a broad European approach. The UK’s ongoing Integrated Security, Defence and Foreign Policy Review should provide clarity as to the UK’s future European ambitions and what that means for the E3.

Given the growing instability surrounding Europe, reinforced by an eventful summer 2020– with the Iran nuclear deal in limbo, renewed tensions between Turkey and Greece in the Mediterranean, protests in Belarus, increasing US-China rivalry and further instability in the Sahel – the E3 has recently been developing a more visible profile. By convening the first meeting of E3 defence ministers in August, Germany showed leadership and a commitment to the format despite its fears of hostility from other EU member states towards increased E3 cooperation. Officially widening E3 cooperation to include defence, while mostly symbolic for now, satisfies Berlin by marking a step towards institutionalization, appeases Paris by putting on the joint agenda issues such as the recent coup in Mali and the crisis in the Eastern Mediterranean, and shows some political commitment by London at a time of tense UK-EU Brexit negotiations.

France, the UK and Germany all agree that the E3 is a necessary cooperation format that needs to be developed further. Recent events seem to show willingness on the part of the three countries to make it work, both in spite of and because of upcoming Brexit tensions. Longer-term challenges – relating to intra-EU tensions over the role of the E3, the future EU-UK relationship and transatlantic divergences – are still to be addressed and managed for the format to reach its full potential. Nevertheless, in today’s uncertain strategic context for Europe, the E3 is establishing itself as a go-to format for cooperation for Europe’s ‘big three’.




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CDKN2A/p16INK4a suppresses hepatic fatty acid oxidation through the AMPK{alpha}2-SIRT1-PPAR{alpha} signaling pathway [Metabolism]

In addition to their well-known role in the control of cellular proliferation and cancer, cell cycle regulators are increasingly identified as important metabolic modulators. Several GWAS have identified SNPs near CDKN2A, the locus encoding for p16INK4a (p16), associated with elevated risk for cardiovascular diseases and type-2 diabetes development, two pathologies associated with impaired hepatic lipid metabolism. Although p16 was recently shown to control hepatic glucose homeostasis, it is unknown whether p16 also controls hepatic lipid metabolism. Using a combination of in vivo and in vitro approaches, we found that p16 modulates fasting-induced hepatic fatty acid oxidation (FAO) and lipid droplet accumulation. In primary hepatocytes, p16-deficiency was associated with elevated expression of genes involved in fatty acid catabolism. These transcriptional changes led to increased FAO and were associated with enhanced activation of PPARα through a mechanism requiring the catalytic AMPKα2 subunit and SIRT1, two known activators of PPARα. By contrast, p16 overexpression was associated with triglyceride accumulation and increased lipid droplet numbers in vitro, and decreased ketogenesis and hepatic mitochondrial activity in vivo. Finally, gene expression analysis of liver samples from obese patients revealed a negative correlation between CDKN2A expression and PPARA and its target genes. Our findings demonstrate that p16 represses hepatic lipid catabolism during fasting and may thus participate in the preservation of metabolic flexibility.




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Ascertaining the biochemical function of an essential pectin methylesterase in the gut microbe Bacteroides thetaiotaomicron [Metabolism]

Pectins are a major dietary nutrient source for the human gut microbiota. The prominent gut microbe Bacteroides thetaiotaomicron was recently shown to encode the founding member (BT1017) of a new family of pectin methylesterases essential for the metabolism of the complex pectin rhamnogalacturonan-II (RG-II). However, biochemical and structural knowledge of this family is lacking. Here, we showed that BT1017 is critical for the metabolism of an RG-II–derived oligosaccharide ΔBT1017oligoB generated by a BT1017 deletion mutant (ΔBT1017) during growth on carbohydrate extract from apple juice. Structural analyses of ΔBT1017oligoB using a combination of enzymatic, mass spectrometric, and NMR approaches revealed that it is a bimethylated nonaoligosaccharide (GlcA-β1,4-(2-O-Me-Xyl-α1,3)-Fuc-α1,4-(GalA-β1,3)-Rha-α1,3-Api-β1,2-(Araf-α1,3)-(GalA-α1,4)-GalA) containing components of the RG-II backbone and its side chains. We showed that the catalytic module of BT1017 adopts an α/β-hydrolase fold, consisting of a central twisted 10-stranded β-sheet sandwiched by several α-helices. This constitutes a new fold for pectin methylesterases, which are predominantly right-handed β-helical proteins. Bioinformatic analyses revealed that the family is dominated by sequences from prominent genera of the human gut microbiota, including Bacteroides and Prevotella. Our re-sults not only highlight the critical role played by this family of enzymes in pectin metabolism but also provide new insights into the molecular basis of the adaptation of B. thetaiotaomicron to the human gut.




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Coronavirus infection and PARP expression dysregulate the NAD metabolome: An actionable component of innate immunity [Molecular Bases of Disease]

Poly(ADP-ribose) polymerase (PARP) superfamily members covalently link either a single ADP-ribose (ADPR) or a chain of ADPR units to proteins using NAD as the source of ADPR. Although the well-known poly(ADP-ribosylating) (PARylating) PARPs primarily function in the DNA damage response, many noncanonical mono(ADP-ribosylating) (MARylating) PARPs are associated with cellular antiviral responses. We recently demonstrated robust up-regulation of several PARPs following infection with murine hepatitis virus (MHV), a model coronavirus. Here we show that SARS-CoV-2 infection strikingly up-regulates MARylating PARPs and induces the expression of genes encoding enzymes for salvage NAD synthesis from nicotinamide (NAM) and nicotinamide riboside (NR), while down-regulating other NAD biosynthetic pathways. We show that overexpression of PARP10 is sufficient to depress cellular NAD and that the activities of the transcriptionally induced enzymes PARP7, PARP10, PARP12 and PARP14 are limited by cellular NAD and can be enhanced by pharmacological activation of NAD synthesis. We further demonstrate that infection with MHV induces a severe attack on host cell NAD+ and NADP+. Finally, we show that NAMPT activation, NAM, and NR dramatically decrease the replication of an MHV that is sensitive to PARP activity. These data suggest that the antiviral activities of noncanonical PARP isozyme activities are limited by the availability of NAD and that nutritional and pharmacological interventions to enhance NAD levels may boost innate immunity to coronaviruses.




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Silencing the Guns in Africa by 2030: Lessons from Mozambique

Silencing the Guns in Africa by 2030: Lessons from Mozambique 17 February 2023 — 7:00AM TO 9:00AM Anonymous (not verified) 7 February 2023 Addis Ababa and online

A hybrid event in Addis Ababa reflecting on Mozambique’s 2019 peace agreement and the lessons it offers for the African Union’s ‘Silencing the Guns’ agenda by 2030.

This event will explore opportunities for furthering the AU’s Silencing the Guns agenda by 2030 to assist Africa’s transformative development, highlighting lessons learnt from Mozambique’s experience.

The ‘Silencing the Guns in Africa’ agenda, a flagship initiative of the African Union’s (AU) Agenda 2063, aspires to end all wars and conflict, prevent genocide, and stop gender-based violence.

The 2019 peace agreement in Mozambique and the subsequent disarmament, demobilization and reintegration process supported by the United Nations (UN) but implemented by Mozambique’s government and institutions, provides experience and learning for other continental conflicts that have recently ended or resumed.

Mozambique is seeking to break from the cyclical ‘conflict trap’ where once a country experiences one civil war, it is significantly more likely to experience additional episodes of violence.

Since the end of Mozambique’s civil war in 1992, targeted armed conflict by RENAMO resumed in 2013 and ended through the new agreement in August 2019. The final reintegration into civilian life of former Mozambican combatants of opposition RENAMO will be completed in 2023.

Mozambique and Switzerland – a key supporter of successive Mozambican peace processes – have become non-permanent members of the UN Security Council for the first time in their respective histories.

At a moment when old vulnerabilities and new threats are apparent on the African continent, this seminar, held by Chatham House in partnership with the United Nations Development Programme (UNDP), explores opportunities to furthering the AU’s Silencing the Guns agenda by 2030 to assist Africa’s transformative development, as outlined by the UNDP in a report published in February 2022.

This hybrid event is held in partnership with the African Union Commission and the United Nations Development Programme (UNDP).

This event will also be broadcast live via the Africa Programme Facebook page.




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Impact of the ISCHEMIA Trial on Stress Nuclear Myocardial Perfusion Imaging




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Comparison of Posttherapy 4- and 24-Hour [177Lu]Lu-PSMA SPECT/CT and Pretherapy PSMA PET/CT in Assessment of Disease in Men with Metastatic Castration-Resistant Prostate Cancer

Visual Abstract




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FAP and PSMA Expression by Immunohistochemistry and PET Imaging in Castration-Resistant Prostate Cancer: A Translational Pilot Study

Visual Abstract




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Oncologist, Business Leader, and Investor Arie S. Belldegrun Discusses a Career in Innovative Medical Entrepreneurship: A Conversation with Ken Herrmann and Johannes Czernin




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Feasibility, Tolerability, and Preliminary Clinical Response of Fractionated Radiopharmaceutical Therapy with 213Bi-FAPI-46: Pilot Experience in Patients with End-Stage, Progressive Metastatic Tumors

Visual Abstract




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SPECT/CT in Early Response Assessment of Patients with Metastatic Castration-Resistant Prostate Cancer Receiving 177Lu-PSMA-617

Visual Abstract




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Re: Voluntary assisted death: how to ensure access and safety




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Overdose crisis: more common sense and less ideology




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Addressing Climate Catastrophe Concerns in Asthma Medication Delivery: Rethinking Inhaler Use for Environmental and Clinical Efficacy




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Re: Decompression alone or with fusion for degenerative lumbar spondylolisthesis (Nordsten-DS): five year follow-up of a randomised, multicentre, non-inferiority trial




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Citrus Vascular Proteomics Highlights the Role of Peroxidases and Serine Proteases during Huanglongbing Disease Progression

Jessica Y. Franco
Dec 1, 2020; 19:1936-1951
Research




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Systematic identification of P. falciparum sporozoite membrane protein interactions reveals an essential role for the p24 complex in host infection

Julia Knöckel
Dec 22, 2020; 0:RA120.002432v1-mcp.RA120.002432
Research




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On the robustness of graph-based clustering to random network alterations

R. Greg Stacey
Nov 4, 2020; 0:RA120.002275v1-mcp.RA120.002275
Research




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A proteomics-based assessment of inflammation signatures in endotoxemia

Sean A Burnap
Dec 7, 2020; 0:RA120.002305v1-mcp.RA120.002305
Research




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Proteomic analyses identify differentially expressed proteins and pathways between low-risk and high-risk subtypes of early-stage lung adenocarcinoma and their prognostic impacts

Juntuo Zhou
Nov 30, 2020; 0:RA120.002384v1-mcp.RA120.002384
Research




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A proteomic approach to understand the clinical significance of acute myeloid leukemia-derived extracellular vesicles reflecting essential characteristics of leukemia

Ka-Won Kang
Nov 30, 2020; 0:RA120.002169v1-mcp.RA120.002169
Research




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Prediction and validation of mouse meiosis-essential genes based on spermatogenesis proteome dynamics

Kailun Fang
Nov 30, 2020; 0:RA120.002081v1-mcp.RA120.002081
Research




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Mutation-independent Proteomic Signatures of Pathological Progression in Murine Models of Duchenne Muscular Dystrophy

Tirsa L. E. van Westering
Dec 1, 2020; 19:2047-2067
Research




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Pluripotency of embryonic stem cells lacking clathrin-mediated endocytosis cannot be rescued by restoring cellular stiffness [Molecular Biophysics]

Mouse embryonic stem cells (mESCs) display unique mechanical properties, including low cellular stiffness in contrast to differentiated cells, which are stiffer. We have previously shown that mESCs lacking the clathrin heavy chain (Cltc), an essential component for clathrin-mediated endocytosis (CME), display a loss of pluripotency and an enhanced expression of differentiation markers. However, it is not known whether physical properties such as cellular stiffness also change upon loss of Cltc, similar to what is seen in differentiated cells, and if so, how these altered properties specifically impact pluripotency. Using atomic force microscopy (AFM), we demonstrate that mESCs lacking Cltc display higher Young's modulus, indicative of greater cellular stiffness, compared with WT mESCs. The increase in stiffness was accompanied by the presence of actin stress fibers and accumulation of the inactive, phosphorylated, actin-binding protein cofilin. Treatment of Cltc knockdown mESCs with actin polymerization inhibitors resulted in a decrease in the Young's modulus to values similar to those obtained with WT mESCs. However, a rescue in the expression profile of pluripotency factors was not obtained. Additionally, whereas WT mouse embryonic fibroblasts could be reprogrammed to a state of pluripotency, this was inhibited in the absence of Cltc. This indicates that the presence of active CME is essential for the pluripotency of embryonic stem cells. Additionally, whereas physical properties may serve as a simple readout of the cellular state, they may not always faithfully recapitulate the underlying molecular fate.




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Secretory galectin-3 induced by glucocorticoid stress triggers stemness exhaustion of hepatic progenitor cells [Signal Transduction]

Adult progenitor cell populations typically exist in a quiescent state within a controlled niche environment. However, various stresses or forms of damage can disrupt this state, which often leads to dysfunction and aging. We built a glucocorticoid (GC)-induced liver damage model of mice, found that GC stress induced liver damage, leading to consequences for progenitor cells expansion. However, the mechanisms by which niche factors cause progenitor cells proliferation are largely unknown. We demonstrate that, within the liver progenitor cells niche, Galectin-3 (Gal-3) is responsible for driving a subset of progenitor cells to break quiescence. We show that GC stress causes aging of the niche, which induces the up-regulation of Gal-3. The increased Gal-3 population increasingly interacts with the progenitor cell marker CD133, which triggers focal adhesion kinase (FAK)/AMP-activated kinase (AMPK) signaling. This results in the loss of quiescence and leads to the eventual stemness exhaustion of progenitor cells. Conversely, blocking Gal-3 with the inhibitor TD139 prevents the loss of stemness and improves liver function. These experiments identify a stress-dependent change in progenitor cell niche that directly influence liver progenitor cell quiescence and function.




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Iron-mediated degradation of ribosomes under oxidative stress is attenuated by manganese [Cell Biology]

Protein biosynthesis is fundamental to cellular life and requires the efficient functioning of the translational machinery. At the center of this machinery is the ribosome, a ribonucleoprotein complex that depends heavily on Mg2+ for structure. Recent work has indicated that other metal cations can substitute for Mg2+, raising questions about the role different metals may play in the maintenance of the ribosome under oxidative stress conditions. Here, we assess ribosomal integrity following oxidative stress both in vitro and in cells to elucidate details of the interactions between Fe2+ and the ribosome and identify Mn2+ as a factor capable of attenuating oxidant-induced Fe2+-mediated degradation of rRNA. We report that Fe2+ promotes degradation of all rRNA species of the yeast ribosome and that it is bound directly to RNA molecules. Furthermore, we demonstrate that Mn2+ competes with Fe2+ for rRNA-binding sites and that protection of ribosomes from Fe2+-mediated rRNA hydrolysis correlates with the restoration of cell viability. Our data, therefore, suggest a relationship between these two transition metals in controlling ribosome stability under oxidative stress.




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Dysregulation of hsa-miR-34a and hsa-miR-449a leads to overexpression of PACS-1 and loss of DNA damage response (DDR) in cervical cancer [Cell Biology]

We have observed overexpression of PACS-1, a cytosolic sorting protein in primary cervical tumors. Absence of exonic mutations and overexpression at the RNA level suggested a transcriptional and/or posttranscriptional regulation. University of California Santa Cruz genome browser analysis of PACS-1 micro RNAs (miR), revealed two 8-base target sequences at the 3' terminus for hsa-miR-34a and hsa-miR-449a. Quantitative RT-PCR and Northern blotting studies showed reduced or loss of expression of the two microRNAs in cervical cancer cell lines and primary tumors, indicating dysregulation of these two microRNAs in cervical cancer. Loss of PACS-1 with siRNA or exogenous expression of hsa-miR-34a or hsa-miR-449a in HeLa and SiHa cervical cancer cell lines resulted in DNA damage response, S-phase cell cycle arrest, and reduction in cell growth. Furthermore, the siRNA studies showed that loss of PACS-1 expression was accompanied by increased nuclear γH2AX expression, Lys382-p53 acetylation, and genomic instability. PACS-1 re-expression through LNA-hsa-anti-miR-34a or -449a or through PACS-1 cDNA transfection led to the reversal of DNA damage response and restoration of cell growth. Release of cells post 24-h serum starvation showed PACS-1 nuclear localization at G1-S phase of the cell cycle. Our results therefore indicate that the loss of hsa-miR-34a and hsa-miR-449a expression in cervical cancer leads to overexpression of PACS-1 and suppression of DNA damage response, resulting in the development of chemo-resistant tumors.




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Mycobacterium tuberculosis infection up-regulates MFN2 expression to promote NLRP3 inflammasome formation [Cell Biology]

Tuberculosis (TB), caused by the infection of Mycobacterium tuberculosis (MTB), is one of the leading causes of death worldwide, especially in children. However, the mechanisms by which MTB infects its cellular host, activates an immune response, and triggers inflammation remain unknown. Mitochondria play important roles in the initiation and activation of the nucleotide-binding oligomerization domain-like receptor with a pyrin domain 3 (NLRP3) inflammasome, where mitochondria-associated endoplasmic reticulum membranes (MAMs) may serve as the platform for inflammasome assembly and activation. Additionally, mitofusin 2 (MFN2) is implicated in the formation of MAMs, but, the roles of mitochondria and MFN2 in MTB infection have not been elucidated. Using mircroarry profiling of TB patients and in vitro MTB stimulation of macrophages, we observed an up-regulation of MFN2 in the peripheral blood mononuclear cells of active TB patients. Furthermore, we found that MTB stimulation by MTB-specific antigen ESAT-6 or lysate of MTB promoted MFN2 interaction with NLRP3 inflammasomes, resulting in the assembly and activation of the inflammasome and, subsequently, IL-1β secretion. These findings suggest that MFN2 and mitochondria play important role in the pathogen-host interaction during MTB infection.