A Chicago-area Democrat hurled an insult at police Sunday after being charged with drunken driving, according to local news reports. Samantha Steele represents the Second District on the Cook County […]

The post Democratic Politician Crashes Her Car While Allegedly Drunk, Hurls Vile Insults at Responding Officer: Police Report appeared first on The Western Journal.

How can young people in MENA thrive despite economic and political insecurity? 24 September 2024 — 2:00PM TO 3:00PM Anonymous (not verified) 30 August 2024 Online

Experts share insights on how young people navigate challenges and find opportunities in a changing domestic and regional landscape.

Across the Middle East and North Africa young people between the ages of 15 and 29 comprise around 24 per cent of the population in the region. As the complex regional geopolitical developments unfold, the majority of these young people are living in a time of economic and political insecurity, with many, such as Iraqis and Libyans, also growing up during conflict and uncertainty.

Enhanced education and employment programs are key opportunities for development and stability in the region. Despite this, limited resources and competing priorities have meant that governments often struggle to deliver competitive educational and employment opportunities and lack the capacity and funding for education reform and active labour market policy development. Key tensions that pit modernity and autonomy against tradition and control continue to frame the education and skills development landscape.

This webinar will address:

• The challenges young people within the MENA region face in different contexts;
• The role education and employment play in developing skills for 21st century challenges;
• Spaces for young people to practice citizenship and participate in political processes;
• Youth’s economic prospects while navigating the tumultuous backdrop of enduring conflict and authoritarianism. 

Hdac3 is a lysine deacetylase that removes acetyl groups from histones and additional proteins. Although Hdac3 functions within mesenchymal lineage skeletal cells are defined, little is known about Hdac3 activities in bone-resorbing osteoclasts. In this study we conditionally deleted Hdac3 within Ctsk-expressing cells and examined the effects on bone modeling and osteoclast differentiation in mice. Hdac3 deficiency reduced femur and tibia periosteal circumference and increased cortical periosteal osteoclast number. Trabecular bone was likewise reduced and was accompanied by increased osteoclast number per trabecular bone surface. We previously showed that Hdac3 deacetylates the p65 subunit of the NF-κB transcriptional complex to decrease DNA-binding and transcriptional activity. Hdac3-deficient osteoclasts demonstrate increased K310 NF-κB acetylation and NF-κB transcriptional activity. Hdac3-deficient osteoclast lineage cells were hyper-responsive to RANKL and showed elevated ex vivo osteoclast number and size and enhanced bone resorption in pit formation assays. Osteoclast-directed Hdac3 deficiency decreased cortical and trabecular bone mass parameters, suggesting that Hdac3 regulates coupling of bone resorption and bone formation. We surveyed a panel of osteoclast-derived coupling factors and found that Hdac3 suppression diminished sphingosine-1-phosphate production. Osteoclast-derived sphingosine-1-phosphate acts in paracrine to promote bone mineralization. Mineralization of WT bone marrow stromal cells cultured with conditioned medium from Hdac3-deficient osteoclasts was markedly reduced. Expression of alkaline phosphatase, type 1a1 collagen, and osteocalcin was also suppressed, but no change in Runx2 expression was observed. Our results demonstrate that Hdac3 controls bone modeling by suppressing osteoclast lineage cell responsiveness to RANKL and coupling to bone formation.

Europe's response to the US Inflation Reduction Act 27 March 2023 — 2:00PM TO 3:15PM Anonymous (not verified) 9 March 2023 Chatham House and Online

This event explores the implications of the US Inflation Reduction Act, how Europe can respond and what options the UK has.

While the US Inflation Reduction Act (IRA) has led to an outcry in the EU, member states have different concerns and preferences for how to respond. The European Commission’s proposed ‘Green Deal Industrial Plan’ includes the relaxation of state aid rules to drive funding. But will this lead to a ‘subsidies race’ between the US and EU and is a ‘green trade war’ brewing?  
 
The UK’s response to the IRA has been much more muted than the EU’s. But caught between US subsidies and EU subsidies, can the UK compete and create an independent response to the IRA? And what steps can be taken to facilitate global cooperation and to make trade work for the green transition?

Dr Martin Porter, Executive Chair at the Cambridge Institute for Sustainability Leadership, will kick off the discussion with short remarks followed by an interactive discussion among all participants

This discussion is part of the Chatham House Global Trade Policy Forum. We would like to take this opportunity to thank our founding partner and supporting partners for their generous support of the forum.  

Sebastian A. Wagner
Oct 1, 2011; 10:M111.013284-M111.013284
Research

Geopolitical corporate responsibility can drive change Expert comment NCapeling 26 July 2022

Russia’s long invasion of Ukraine is testing the commitment of business, but this could see the emergence of a new pillar of support for the rules-based international order.

The massive exit of more than 1,000 international companies from Russia has surpassed – by a factor of nearly ten in merely four months – the number which pulled out of apartheid-led South Africa over an entire decade.

These company exits extend beyond those industries targeted for sanctions – oil and gas, banks and financial services, aerospace, and certain technology sectors – to include hundreds in consumer products ranging from Levi’s and H&M clothing to Coca-Cola and McDonalds. Many of these companies may wish to return to a post-conflict – or post-Putin – Russia, while a few have already sold their Russian operations, as McDonald’s has to an existing Siberian licensee.

Both reputational and operational factors are driving the huge exodus: reputational as companies have chosen to disassociate themselves from Putin’s regime; operational as transportation routes and supply chains have been interrupted.

Few of these companies have made explicit the principles at stake, while many still face ‘tricky legal, operational and ethical considerations’ and some have kept operations in place. But the collective impact of the exit in response to Russia’s affront to international law has sent shockwaves around the world.

Current issues and future implications

Minds now turn to whether this exodus sets a blueprint for the future, and how companies having to make complex and sensitive risk assessments and global business planning decisions can address both current issues as well as similar future challenges.

The new Declaration from the Business for Ukraine Coalition – an international civil society initiative of organizations and individuals – encourages companies to reinforce ‘responsible exit’ from Russia ‘in response to its unprovoked, full-scale war on Ukraine’.

The declaration’s objective is to ‘block access to the economic and financial resources enabling Russian aggression’ and it urgently calls on companies that have terminated or suspended their business operations and relationships to ‘stand by those commitments until the territorial sovereignty of Ukraine within internationally recognized borders is restored.’

It also states companies yet to terminate or suspend operations in Russia should do so unless they can demonstrate through due diligence that their provision of ‘essential’ services or products – such as medicines – meet critical humanitarian needs.

The 2022 Edelman Trust Barometer Special Report: The Geopolitical Business suggests Ukraine represents an inflection point posing ‘a new test’ for business. According to an online survey of 14,000 respondents in 14 countries, including employees, NGOs, and other stakeholders, there is a ‘rising call’ for business to be more engaged in geopolitics, with CEOs ‘expected to shape policy’ on societal and geopolitical issues.

Such expectations have been intensifying with the impetus of the combined stakeholder capitalism and corporate purpose agenda, even as a political backlash in the US against the environmental, social, and governance (ESG) movement linking institutional investors and multinational corporations gains momentum.

The emergence of corporate activism is a further development – partly driven by employees and accelerated during the pandemic – on issues of economic inequality, racial injustice, and gender equality, as well as the climate crisis.

When considering what broader purpose should drive this corporate geopolitical engagement, the Business for Ukraine Declaration offers an answer, calling Russia’s aggression ‘an attack on the rules-based international order which must be protected to ‘safeguard the international community and the global economy.’

This points to broader interests and values at stake in the Russian war on Ukraine because supporting the rules-based international order can become the basis of a new geopolitical corporate responsibility. Business, especially multinational corporations and institutional investors, fundamentally depend on and have enormously benefitted from this order.

Economic development needs a stable rules-based international order

Trade and investment, entrepreneurship, and innovation – the sinews of economic development – depend on predictable, rational behaviour by states at home and abroad. Individual companies and entire industries share a stake in upholding this order at a time when its stability and even legitimacy is undergoing a severe challenge.

The rules-based international order has evolved since the adoption of the UN Charter in 1945, the Universal Declaration of Human Rights in 1948, and the establishment of the standards, norms and institutions that reflect and reinforce these lodestars. It defines the international community, the rule of law, accountable governance, civic freedoms, and human rights within nations. It also supports national self-determination, sovereignty, and the disavowal of the use of force to alter borders among nations, and it provides accountability for genocide, crimes against humanity, and war crimes.

Business has a fundamental stake in the international order as the framework for stability, prosperity, open societies, and markets.

A new geopolitical corporate responsibility does not need to become a doctrine but can instead be an agenda to support the international rules-based order under stress. Such an agenda may help multinationals deal with expectations they already face, such as:

Avoiding situations where they cause, contribute, or are directly linked to human rights abuses. This objective is enshrined in the UN Guiding Principles on Business and Human Rights and companies can be further informed by the new UN Guide to Heightened Human Rights Due Diligence for Business in Conflict-Affected Contexts.

Committing to the ‘shared space’ of the rule of law, accountable governance, civic freedoms, and human rights. These are both the enablers of civil society and the underpinning of sustainable and profitable business and investment environments. The Chatham House synthesis paper The role of the private sector in protecting civic space sets forth the rationale for companies to defend these vital elements.

Supporting peace, justice, and strong institutions both within nations and across the international community as set forth by UN Sustainable Development Goal 16. The SDG 16 Business Framework: Inspiring Transformational Governance shows how companies, as well as national governments and international institutions, can contribute to these building blocks of stability and prosperity.

Demonstrating corporate responsibility at the national and geopolitical levels to enhance equity, transparency, and accountability. Multinationals are already challenged to accept minimum corporate taxation within and across jurisdictions, curb excessive executive compensation, endorse mandatory disclosure of environmental and human rights due diligence, and strengthen corporate governance of ESG risks and responsibilities, including with respect to human rights.

Diminishing inequality by tackling poverty and ensuring sustainability by arresting the climate crisis. Alongside governments and international institutions, the business community already faces increasing pressure to improve its efforts in these areas.

The ICC response to Russia’s war gives hope for justice Expert comment NCapeling 19 March 2023

The ICC’s arrest warrants against Putin and Lvova-Belova show the commission of international crimes is not without consequences.

Warrants of arrest for Russian president Vladimir Putin and Maria Alekseyevna Lvova-Belova, commissioner for children’s rights in the president’s office, have been issued because the Pre-Trial Chamber II of the International Criminal Court (ICC) has reasonable grounds to believe they have committed war crimes.

Following an independent investigation and evidence-gathering by the ICC prosecutor Karim Khan in his first new case since taking office, the pair are accused of committing two different war crimes – the unlawful deportation of children from Ukraine to Russia, and the unlawful transfer of children from occupied areas of Ukraine to the Russian Federation.

The focus on those two war crimes is likely due to clear evidence that deportation and forcible transfer of thousands of Ukrainian children have occurred, as the Russian government was overt about its policy of taking Ukrainian children to Russia and placing them in camps or putting them up for adoption by Russian families.

Furthermore, in line with the Office of the Prosecutor’s policy on children, crimes against children are prioritized given their particularly vulnerable status.

Jurisdiction and enforcement

The ICC does not have jurisdiction over crimes committed fully in Russia by Russian nationals, as Russia is not a party to the Rome Statute which created the ICC.

However, it does have jurisdiction over war crimes, crimes against humanity, and genocide committed in Ukraine irrespective of who committed them, pursuant to two declarations lodged by Ukraine in 2014 accepting the Court’s jurisdiction over its territory from November 2013.

Although a prosecution has been initiated, it is ultimately for the judges of the ICC to decide on the accused’s fate. But the chances of Putin getting arrested or tried for these offences are slim.

The ICC lacks enforcement or police powers and depends on state cooperation to execute arrest warrants. Also, because it cannot try individuals in their absence, a trial or conviction cannot occur without Putin and Lvova-Belova being in custody.

But by issuing and unsealing these arrest warrants, the ICC is relying on the symbolic function of international criminal law – it is publicly naming and shaming Putin and Lvova-Belova for the commission of serious atrocities, and it is sending a message to other leaders and the international community that such actions are not without consequence.

The arrest warrants also give victims some form of vindication or recognition for their suffering and hope for justice in the future. And making the warrants public enables the ICC to reclaim itself as a key avenue for ensuring accountability for international crimes, following a wave of criticism and disenchantment about its work in Africa and delays in advancing its investigation on Afghanistan.

International courts gearing into action

This ICC case is the latest in a series of ongoing cases related to Russia’s war in Ukraine before different international courts and tribunals. Others include at least four cases before the European Court of Human Rights for events that occurred before Russia was excluded from the Council of Europe, such as the MH17 flight case and the annexation of Crimea.

Two cases have also been brought by Ukraine against Russia before the International Court of Justice – in 2017 and 2022 – with hearings scheduled for June. An unprecedented number of states parties have sought to intervene in one or more of these cases.

Each case must be considered on its own merits and the decisions cannot be prejudged. But they showcase an important feature of the global legal system and its judicial architecture that cannot be underestimated – the ability to quickly swing into action in response to violations of international law. In this case, the response was prompted by Russia’s aggression against Ukraine in breach of the United Nations Charter and fundamental principles of international law.

A starting point for a bigger case

The ICC prosecutor already has a broader investigation into other international crimes committed in Ukraine since 21 November 2013. So this is likely to be just the starting point of a much bigger case against Putin and other senior Russian officials for international crimes committed in the context of the war in Ukraine and within the ICC’s jurisdiction.

These potentially include other war crimes such as the indiscriminate or disproportionate targeting of civilians, crimes against humanity, and genocide.

Mammalian circadian clocks are driven by transcription/translation feedback loops composed of positive transcriptional activators (BMAL1 and CLOCK) and negative repressors (CRYPTOCHROMEs (CRYs) and PERIODs (PERs)). CRYs, in complex with PERs, bind to the BMAL1/CLOCK complex and repress E-box–driven transcription of clock-associated genes. There are two individual CRYs, with CRY1 exhibiting higher affinity to the BMAL1/CLOCK complex than CRY2. It is known that this differential binding is regulated by a dynamic serine-rich loop adjacent to the secondary pocket of both CRYs, but the underlying features controlling loop dynamics are not known. Here we report that allosteric regulation of the serine-rich loop is mediated by Arg-293 of CRY1, identified as a rare CRY1 SNP in the Ensembl and 1000 Genomes databases. The p.Arg293His CRY1 variant caused a shortened circadian period in a Cry1−/−Cry2−/− double knockout mouse embryonic fibroblast cell line. Moreover, the variant displayed reduced repressor activity on BMAL1/CLOCK driven transcription, which is explained by reduced affinity to BMAL1/CLOCK in the absence of PER2 compared with CRY1. Molecular dynamics simulations revealed that the p.Arg293His CRY1 variant altered a communication pathway between Arg-293 and the serine loop by reducing its dynamicity. Collectively, this study provides direct evidence that allosterism in CRY1 is critical for the regulation of circadian rhythm.

Expert

Expert

Expert

Expert

India's Response to COVID-19: Political and Social Implications 12 May 2020 — 12:00PM TO 12:45PM Anonymous (not verified) 14 May 2020

On March 23rd, India’s Prime Minister Narendra Modi ordered the world’s largest lockdown on its population of 1.3 billion. The strict measures were praised by some for their success in slowing the spread of coronavirus but faced criticism for the lack of warning which led millions of migrant workers to return home without assistance. Recently the government has begun to lift restrictions in an attempt to revive the economy.

The Indian government has sought technological solutions to contain the pandemic and these have raised concerns around privacy, surveillance, equity and mass use. Furthermore, some low wage workers are forced to accept these solutions if they are to return to work, leaving them with little choice.

In this webinar, the speakers discuss the economic, political and healthcare implications of the coronavirus pandemic on India. Will India seek to rethink its strategy for leadership in the post-COVID-19 global order? Is it possible to develop technologies that can effectively limit the spread of the coronavirus and ensure privacy?

The speakers argue that careful consideration of the second and third-order effects of the pandemic, and the tools being used to contain it, are necessary to preserve rights, liberties, and even democracy.

Clostridium difficile is an anaerobic and spore-forming bacterium responsible for 15–25% of postantibiotic diarrhea and 95% of pseudomembranous colitis. Peptidoglycan is a crucial element of the bacterial cell wall that is exposed to the host, making it an important target for the innate immune system. The C. difficile peptidoglycan is largely N-deacetylated on its glucosamine (93% of muropeptides) through the activity of enzymes known as N-deacetylases, and this N-deacetylation modulates host–pathogen interactions, such as resistance to the bacteriolytic activity of lysozyme, virulence, and host innate immune responses. C. difficile genome analysis showed that 12 genes potentially encode N-deacetylases; however, which of these N-deacetylases are involved in peptidoglycan N-deacetylation remains unknown. Here, we report the enzymes responsible for peptidoglycan N-deacetylation and their respective regulation. Through peptidoglycan analysis of several mutants, we found that the N-deacetylases PdaV and PgdA act in synergy. Together they are responsible for the high level of peptidoglycan N-deacetylation in C. difficile and the consequent resistance to lysozyme. We also characterized a third enzyme, PgdB, as a glucosamine N-deacetylase. However, its impact on N-deacetylation and lysozyme resistance is limited, and its physiological role remains to be dissected. Finally, given the influence of peptidoglycan N-deacetylation on host defense against pathogens, we investigated the virulence and colonization ability of the mutants. Unlike what has been shown in other pathogenic bacteria, a lack of N-deacetylation in C. difficile is not linked to a decrease in virulence.

11 July 2020

Visual Abstract

Visual Abstract

Kyle Swovick
Dec 28, 2020; 0:RA120.002301v1-mcp.RA120.002301
Research

David Durán
Nov 19, 2020; 0:RA120.002276v1-mcp.RA120.002276
Research

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.

Akt3 regulates mitochondrial content in endothelial cells through the inhibition of PGC-1α nuclear localization and is also required for angiogenesis. However, whether there is a direct link between mitochondrial function and angiogenesis is unknown. Here we show that Akt3 depletion in primary endothelial cells results in decreased uncoupled oxygen consumption, increased fission, decreased membrane potential, and increased expression of the mitochondria-specific protein chaperones, HSP60 and HSP10, suggesting that Akt3 is required for mitochondrial homeostasis. Direct inhibition of mitochondrial homeostasis by the model oxidant paraquat results in decreased angiogenesis, showing a direct link between angiogenesis and mitochondrial function. Next, in exploring functional links to PGC-1α, the master regulator of mitochondrial biogenesis, we searched for compounds that induce this process. We found that, sildenafil, a phosphodiesterase 5 inhibitor, induced mitochondrial biogenesis as measured by increased uncoupled oxygen consumption, mitochondrial DNA content, and voltage-dependent anion channel protein expression. Sildenafil rescued the effects on mitochondria by Akt3 depletion or pharmacological inhibition and promoted angiogenesis, further supporting that mitochondrial homeostasis is required for angiogenesis. Sildenafil also induces the expression of PGC-1 family member PRC and can compensate for PGC-1α activity during mitochondrial stress by an Akt3-independent mechanism. The induction of PRC by sildenafil depends upon cAMP and the transcription factor CREB. Thus, PRC can functionally substitute during Akt3 depletion for absent PGC-1α activity to restore mitochondrial homeostasis and promote angiogenesis. These findings show that mitochondrial homeostasis as controlled by the PGC family of transcriptional activators is required for angiogenic responses.

In SAS Customer Intelligence Studio, you might notice that the user interface becomes unresponsive, as shown below: imgalt="SAS Customer Intelligence Studio UI becomes unresponsive" src="{fusion_66537

Since the publication of the Age-Related Eye Disease Study (AREDS2) in 2013, the macular pigment carotenoids lutein and zeaxanthin have become well known to both the eye care community and the public. It is a fascinating aspect of evolution that primates have repurposed photoprotective pigments and binding proteins from plants and insects to protect and enhance visual acuity. Moreover, utilization of these plant-derived nutrients has been widely embraced for preventing vision loss from age-related macular degeneration (AMD). More recently, there has been growing awareness that these nutrients can also play a role in improving visual performance in adults. On the other hand, the potential benefits of lutein and zeaxanthin supplementation at very young ages have been underappreciated. In this review, we examine the biochemical mechanisms and supportive data for lutein and zeaxanthin supplementation throughout the lifespan, with particular emphasis on prenatal supplementation. We propose that prenatal nutritional recommendations may aim at improving maternal and infant carotenoid status. Prenatal supplementation with lutein and zeaxanthin might enhance infant visual development and performance and may even prevent retinopathy of prematurity, possibilities that should be examined in future clinical studies.

Ventilator-associated pneumonia (VAP) is a common hospital-acquired infection, leading to high morbidity and mortality. Currently, bronchoalveolar lavage (BAL) is used in hospitals for VAP diagnosis and guiding treatment options. Although BAL collection procedures are invasive, alternatives such as endotracheal aspirates (ETA) may be of diagnostic value, however, their use has not been thoroughly explored. Longitudinal ETA and BAL were collected from 16 intubated patients up to 15 days, of which 11 developed VAP. We conducted a comprehensive LC–MS/MS based proteome and metabolome characterization of longitudinal ETA and BAL to detect host and pathogen responses to VAP infection. We discovered a diverse ETA proteome of the upper airways reflective of a rich and dynamic host-microbe interface. Prior to VAP diagnosis by microbial cultures from BAL, patient ETA presented characteristic signatures of reactive oxygen species and neutrophil degranulation, indicative of neutrophil mediated pathogen processing as a key host response to the VAP infection. Along with an increase in amino acids, this is suggestive of extracellular membrane degradation resulting from proteolytic activity of neutrophil proteases. The metaproteome approach successfully allowed simultaneous detection of pathogen peptides in patients' ETA, which may have potential use in diagnosis. Our findings suggest that ETA may facilitate early mechanistic insights into host-pathogen interactions associated with VAP infection and therefore provide its diagnosis and treatment.

The histidine kinase Hik33 plays important roles in mediating cyanobacterial response to divergent types of abiotic stresses including cold, salt, high light (HL), and osmotic stresses. However, how these functions are regulated by Hik33 remains to be addressed. Using a hik33-deficient strain (hik33) of Synechocystis sp. PCC 6803 (Synechocystis) and quantitative proteomics, we found that Hik33 depletion induces differential protein expression highly similar to that induced by divergent types of stresses. This typically includes downregulation of proteins in photosynthesis and carbon assimilation that are necessary for cell propagation, and upregulation of heat shock proteins, chaperons, and proteases that are important for cell survival. This observation indicates that depletion of Hik33 alone mimics divergent types of abiotic stresses, and that Hik33 could be important for preventing abnormal stress response in the normal condition. Moreover, we found the majority of proteins of plasmid origin were significantly upregulated in hik33, though their biological significance remains to be addressed. Together, the systematically characterized Hik33-regulated cyanobacterial proteome, which is largely involved in stress responses, builds the molecular basis for Hik33 as a general regulator of stress responses.

The Rhizobium-legume symbiosis is a beneficial interaction in which the bacterium converts atmospheric nitrogen into ammonia and delivers it to the plant in exchange for carbon compounds. This symbiosis implies the adaptation of bacteria to live inside host plant cells. In this work we apply RP-LC-MS/MS and  iTRAQ techniques to study the proteomic profile of endosymbiotic cells (bacteroids) induced by Rhizobium leguminosarum bv viciae strain UPM791 in legume nodules. Nitrogenase subunits, tricarboxylic acid cycle enzymes, and stress response proteins are amongst the most abundant from over one thousand rhizobial proteins identified in pea (Pisum sativum) bacteroids. Comparative analysis of bacteroids induced in pea and in lentil (Lens culinaris)nodules revealed the existence of a significant host-specific differential response affecting dozens of bacterial proteins, including stress-related proteins, transcriptional regulators, and proteins involved in the carbon and nitrogen metabolisms. A mutant affected in one of these proteins, homologous to a GntR-like transcriptional regulator, showed a symbiotic performance significantly  impaired in symbiosis with pea, but not with lentil plants. Analysis of the proteomes of bacteroids isolated from both hosts also revealed the presence of different sets of plant-derived nodule-specific cysteine rich (NCR) peptides, indicating that the endosymbiotic bacteria find a host-specific cocktail of chemical stressors inside the nodule. By studying variations of the bacterial response to different plant cell environments we will be able to identify specific limitations imposed by the host that might give us clues for the improvement of rhizobial performance.

Cells continually degrade and replace damaged proteins. However, the high energetic demand of protein turnover generates reactive oxygen species (ROS) that compromise the long-term health of the proteome. Thus, the relationship between aging, protein turnover and energetic demand remains unclear. Here, we used a proteomic approach to measure rates of protein turnover within primary fibroblasts isolated from a number of species with diverse lifespans including the longest-lived mammal, the bowhead whale. We show that organismal lifespan is negatively correlated with turnover rates of highly abundant proteins. In comparison to mice, cells from long-lived naked mole rats have slower rates of protein turnover, lower levels of ATP production and reduced ROS levels. Despite having slower rates of protein turnover, naked mole rat cells tolerate protein misfolding stress more effectively than mouse cells. We suggest that in lieu of rapid constitutive turnover, long-lived species may have evolved more energetically efficient mechanisms for selective detection and clearance of damaged proteins.

Exploring Transatlantic Responses to Far-right Populism in Europe: Simulation Exercise Research paper sysadmin 1 May 2018

A new paper summarizes the findings of a recent simulation exercise exploring how governments on both sides of the Atlantic might respond to a descent towards populist authoritarianism in an EU member state.

Summary

• To better understand how governments on both sides of the Atlantic might respond to a descent towards populist authoritarianism in an EU member state, Chatham House organized a simulation event involving a group of experts drawn from the public sector, academia and NGOs.
• Simulation exercises enable the testing and modelling of the responses of different actors when presented with specific situations; participants’ interactions in a given set of circumstances are explored, and patterns of negotiation are captured and analysed.
• In this simulation, European, US and multilateral representatives were given the task of managing relations with Baltia, a fictional Eastern European state on the verge of electing a far-right nationalist, Eurosceptic government. They were then challenged to manage their relationship with Baltia after it had elected such a government, which was pushing for a ‘leave’ vote in a planned referendum on the country’s continued EU membership.
• The simulation highlighted a number of issues:
  • Limited instruments are available to liberal democratic governments where there is cause for concern regarding the outcome of an election in an allied country. There are relatively few tools at the disposal of governments to support political allies, or to prevent outcomes that are perceived as threatening democratic norms. The simulation reinforced the view that interventionist moves, either from the European Commission or from individual national governments, would be more likely to come in response to an unfavourable development rather than pre-emptively.
  • The EU, and caucuses of European states, are the main international interlocutors in this type of political crisis involving an EU member state. The US opted to play a limited role in the negotiations; the same was largely true for NATO, aside from its action in sharing intelligence about a potential coup in Baltia. France and Germany formed a natural working partnership, taking meetings together and coordinating policies first before discussing them with a wider European circle, although their positions did not always align.
  • The UK’s capacity to shape the outcome of collective EU discussions appeared more restricted, while Brexit also seemed to shape the response of other EU states to the developing situation in Baltia. Although member states were undoubtedly reluctant to see another country go down this route, they were also resolute in demonstrating a unity of approach and limited flexibility in the face of the new populist government’s attempt to divide them.

New Frontiers in Gender-responsive Governance: Five Years of the W20 Research paper sysadmin 2 November 2018

After five years of the W20, women and gender equality remain at the margin of the G20. There is a real risk of the W20 representing a one-off territorial gain at a frontier that could easily be pushed back again.

Summary

• 2018 marks the fifth anniversary of the first grouping of the W20, the engagement group of the G20 that focuses on gender-inclusive economic growth and advocates for gender equality across the G20 agenda. Formally launched under the Turkish G20 presidency in 2015, the W20 is made up of women from business, international organizations, civil society, think-tanks and academia across the G20 member states.
• This paper takes stock of the critical steps in the development of the W20 over the last five years, examining its background, rationale and foundations, and identifying the areas of economic governance where it has so far contributed the most – and those where more action is needed. The W20 has filled a gap, it but needs to carefully assess its coherence with the UN agencies, the private sector, the G7 and other G20 engagement groups.
• The establishment of the W20 has contributed to defining new frontiers for economic governance and shifting the traditional approach from gender-neutral to gender-responsive. Whereas in 2013 gender in the G20 was considered a marginal issue better dealt with by ministers for equal opportunities, now gender equality and women’s economic empowerment are part of the mainstream economic dialogue. The next step is to ensure more structural and monitored policy reforms at the G20 level.
• Already, the W20 can count among its achievements the ‘25 by 25’ female labour force participation commitment adopted at the G20’s Brisbane summit in 2014, and the Women Entrepreneurs Finance Initiative (We-Fi) and Business Women Leaders’ Taskforce, both agreed at the Hamburg summit in 2017.
• The W20 is constrained in its policy impact by limited engagement with the finance track and a lack of consistent resourcing levels. Addressing these issues would strengthen its role as a credible player in shifting global economic governance while contributing to good gender-responsive domestic policies.
• Progress on gender equality has been too slow and too peripheral to drive change in the relatively short term – over one generation, for example. G20 governments must therefore embrace active, credible policies to bring more women into the labour market, improve access to education and finance, close the pay gap, invest in social infrastructure – especially childcare and assistance for the elderly – and support female entrepreneurs. These domestic policies need to be internationally coordinated so that action and benefits can be widespread.
• A feminist, inclusive agenda at the G20 level should highlight the current empirical evidence of women’s exclusion from the benefit of their economic activity, both in G20 members and beyond. The W20 should also focus on efforts to remedy the lack of women’s representation in G20 processes and in economic governance as a whole.

Timely repair of DNA double-strand breaks (DSBs) is essential to maintaining genomic integrity and preventing illnesses induced by genetic abnormalities. We previously demonstrated that the E3 ubiquitin ligase SMURF2 plays a critical tumor suppressing role via its interaction with RNF20 (ring finger protein 20) in shaping chromatin landscape and preserving genomic stability. However, the mechanism that mobilizes SMURF2 in response to DNA damage remains unclear. Using biochemical approaches and MS analysis, we show that upon the onset of the DNA-damage response, SMURF2 becomes phosphorylated at Ser384 by ataxia telangiectasia mutated (ATM) serine/threonine kinase, and this phosphorylation is required for its interaction with RNF20. We demonstrate that a SMURF2 mutant with an S384A substitution has reduced capacity to ubiquitinate RNF20 while promoting Smad3 ubiquitination unabatedly. More importantly, mouse embryonic fibroblasts expressing the SMURF2 S384A mutant show a weakened ability to sustain the DSB response compared with those expressing WT SMURF2 following etoposide treatment. These data indicate that SMURF2-mediated RNF20 ubiquitination and degradation controlled by ataxia telangiectasia mutated–induced phosphorylation at Ser384 constitutes a negative feedback loop that regulates DSB repair.

War on Ukraine: The state of the global response 17 October 2022 — 6:30PM TO 7:30PM Anonymous (not verified) 3 October 2022 Chatham House and Online

Implications of the war for the future of multilateralism.

Russia’s war on Ukraine has tested the capacity for a unified global response to grave violations of the UN Charter. The world is in unchartered territory as a nuclear member of the United Nations Security Council attacks a non-nuclear country. 

Multilateral institutions that were born out of an effort to prevent war are struggling to prove their relevance in the face of growing existential threats to humanity. The war is exacerbating divisions within the global community, disrupting food and energy supplies worldwide and contributing to a profound crisis of multilateralism.

The longer these divisions last, the longer the war in the middle of Europe and the harder it will be to respond to the interconnected global crises that threaten everyone.

This discussion offers a unique insight into the macro-geopolitical questions in relation to the war in Ukraine with members of the Elders and other experts:

The panel considers:

• How can a more united global response to Russian aggression be built?

• What stands in the way of an effective multilateral response based on international norms?

• In what ways are divisions between UN member states influencing the trajectory of the war or prospects for peace?

• How is the conflict changing geopolitics and the ability of the multilateral system to address global challenges?

As with all members events, questions from the audience drive the conversation. This event is organised in partnership between Chatham House and The Elders, the group of independent global leaders founded by Nelson Mandela who work for peace, justice and human rights.

Read the transcript.

Disruptive technologies by nation states and malign cyber actors – the US response 16 February 2023 — 1:00PM TO 2:00PM Anonymous (not verified) 2 February 2023 Chatham House and Online

Lisa Monaco, the US deputy attorney general, discusses how autocratic governments and malign cyber actors use disruptive technologies to project power and engage in illicit activity.

Weaponizing data, ransomware attacks and other illicit cyber activity represent significant threats to national security. 

Governments and malicious cyber actors around the world exploit disruptive technology to engage in criminal activity, track citizens and coerce other countries thereby weakening the rules-based order and fundamental principles of democracy. 

Lisa Monaco discusses how the world is at an inflection point when it comes to meeting this challenge and describes how the US and partner nations are responding to protect their citizens and the broader international community.

Key questions to discuss include:

• What steps does the US government need to take to properly address this threat?
• How are countries coordinating policies to confront the problem?
• To what extent does this challenge go beyond US-China competition?

As with all member events, questions from the audience drive the conversation.

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Ukraine response reveals Europe’s security is changing Expert comment NCapeling 8 February 2022

Recent events regarding Ukraine show an active UK responding quickly while EU powers deliberate. But pulling ahead of the pack is not the same as leadership.

Britain’s relationship with Ukraine appears to be thriving, with Ukrainian defence journalist Illia Ponomarenko recently tweeting the ‘British are just unstoppable these days’ and that the UK finds itself ‘on the right side of history’ while one Ukrainian wine bar has started offering free drinks to British nationals.

Ponomarenko’s remarks and the wine bar offer – certainly one post-Brexit benefit of having a British passport – are down to the UK decision to send anti-tank weapons to support Ukraine’s forces against a potential Russian attack.

The UK’s quick response was praised by Ponomarenko as being ‘wise enough not to be lured into going the easiest way, which is always the fastest lane straight to hell’ and strikes a clear contrast with that of Germany, whose typically moderated approach to geopolitical tensions went down badly in Kyiv.

The chief of Germany’s navy was forced to resign after saying Russian president Vladimir Putin ‘deserved respect’ and that Ukraine will never win back annexed Crimea. The German government also sought an energy exception to proposed US sanctions, so that gas can continue to flow into Europe.

France’s response was somewhat stronger but rather confusing as Emmanuel Macron initially called for European Union (EU) member states to ‘conduct their own dialogue’ with Russia, seemingly as an alternative to supporting the US-led NATO response.

Risks of a ‘bullying’ Russia

Although positioning himself as the convener of a transatlantic response to the Ukraine crisis brings welcome respite for UK prime minister Boris Johnson from his domestic ‘partygate’ fiasco, he is also reported as saying some world leaders ‘may not appreciate the deteriorating picture on the Ukrainian border, or fully comprehend the risks posed by a bullying Russia’.

One particular image sums up the difference in approach between the UK and the EU, as a flight path shows a British RAF plane flying around Germany before taking a detour over Denmark on route to Ukraine.

Given that Germany later blocked the export of NATO ally Estonia’s weapons to Ukraine, this image gives ‘Global Britain’ advocates a strong symbol of apparent British reliability and resourcefulness in the face of supposed European deliberation and disunity.

But although the UK’s response to the Ukraine crisis has rightly been credited as swift and substantial, it also reveals deeper developments in the current European security landscape as EU countries had worried Britain might choose to become absent post-Brexit.

Losing one of its two main military powers would certainly have been a blow to Europe, particularly as Russia’s threat has grown in recent years, so there will be relief that the Ukraine crisis shows Britain is undoubtedly committed to the region. Now the question for leaders in Paris, Berlin, and Brussels is how to deal with an active Britain committed to Europe but under no obligation to work within EU processes.

The UK already has an interesting network of bilateral and mini-lateral relationships with European allies. Its Joint Expeditionary Force brings together ten European countries – including Scandinavian and Baltic states – and is well-placed to support NATO activities while also remaining flexible and independent. In the past year, the UK worked with Norway in the Arctic region, provided military engineers support to Poland, and worked directly with France and Germany through the E3 grouping – once again bypassing EU institutions.

The UK also brings a unique diplomatic, technology, and intelligence-sharing relationship with the US which is unavoidably important in dealing with the threat from Russia. As the US sees European security through a NATO lens – rather than an EU one – this makes Britain a leading player as one of the few countries meeting its NATO spending commitments.

UK must do more to win trust

But despite such creative partnerships transcending the constraints of Brexit, the UK must do more to win the trust of the EU’s biggest players France and Germany to be a permanent power in the region. And relations with France have deteriorated following disputes over fishing, a lack of cooperation on migrants, and the AUKUS defence technology agreement between the UK, US, and Australia.

When it comes to Germany, the UK must not use the Ukraine crisis as an opportunity for geopolitical point-scoring. There are good historical reasons for Germany’s cautious approach to military engagement, even if these do constrain the country’s response to this challenge.

In dealing with Russia, some members of Germany’s ruling SPD sincerely believe their party’s less confrontational posture was central to de-escalating conflict during the Cold War. And although some historians may dispute that belief, it is still a distinct and more noble motivation for ‘dovishness’ than pure economic self-interest.

Cooperation always requires some compromise on all sides. Germany must accept some level of economic risk if sanctions against Russia are to be meaningful and France has to accept the necessity of the UK and US’s involvement and that the most effective dialogue is unlikely to be achieved through EU institutions.

Meanwhile, the UK must accept some role for the two biggest EU players, particularly as the Normandy Format which includes Russia, Ukraine, France, and Germany has proved productive in the past. And the UK needs to clamp down on its own economic ties with Russia.

War on Ukraine: Exploring the humanitarian response to the conflict 12 April 2022 — 12:00PM TO 1:00PM Anonymous (not verified) 6 April 2022 Online

This event explores the implications of the humanitarian realities from Russia’s invasion of Ukraine, the largest ground campaign in Europe since World War Two.

Reports from humanitarian organizations working in Ukraine are dire and reveal that a humanitarian disaster on an epic scale is unfolding.

The United Nations (UN) and other organizations estimate 12 million of Ukraine’s population are in need of assistance, 4.1 million have been displaced to neighbouring countries, and 6.4 million have become internally displaced.

Gillian Triggs, the assistant secretary-general and assistant high commissioner for protection at the UNHCR, joins other experts to discuss the humanitarian situation in Ukraine.

The panel considers:

• What are the greatest needs in Ukraine now?
• How can aid agencies meet those needs?
• What are the short and long-term implications of the crisis for Ukraine and Europe?
• How do international organizations work with local NGOs to provide food, medical aid and shelter?

This event is part of a regular series of events offering insight and analysis from experts and policymakers on how the war is affecting Ukraine, the region and the world.

This event is part of Chatham House’s ongoing work on the future of conflict.

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Preclinical data have shown that ¹⁶¹Tb-labeled peptides targeting the somatostatin receptor are therapeutically more effective for peptide receptor radionuclide therapy than are their ¹⁷⁷Lu-labeled counterparts. To further substantiate this enhanced therapeutic effect, we performed cellular dosimetry to quantify the absorbed dose to the cell nucleus and compared dose–response curves to evaluate differences in relative biological effectiveness in vitro. Methods: CA20948 cell survival was assessed after treatment with [¹⁶¹Tb]Tb- and [¹⁷⁷Lu]Lu-DOTATATE (agonist) and with [¹⁶¹Tb]Tb- and [¹⁷⁷Lu]Lu-DOTA-LM3 (antagonist) via a clonogenic assay. Cell binding, internalization, and dissociation assays were performed up to 7 d to acquire time-integrated activity coefficients. Separate S values for each type of particle emission (Auger/internal conversion [IC] electrons and β^– particles) were computed via Monte Carlo simulations, while considering spheric cells. Once the absorbed dose to the cell nucleus was calculated, survival curves were fitted to the appropriate linear or linear-quadratic model and corresponding relative biological effectiveness was evaluated. Results: Although the radiopeptide uptake was independent of the radionuclide, [¹⁶¹Tb]Tb-DOTATATE and [¹⁶¹Tb]Tb-DOTA-LM3 delivered a 3.6 and 3.8 times higher dose to the nucleus, respectively, than their ¹⁷⁷Lu-labeled counterparts on saturated receptor binding. This increased nucleus-absorbed dose was mainly due to the additional emission of IC and not Auger electrons by ¹⁶¹Tb. When activity concentrations were considered, both [¹⁶¹Tb]Tb-DOTATATE and [¹⁶¹Tb]Tb-DOTA-LM3 showed a lower survival fraction than did labeling with ¹⁷⁷Lu. When the absorbed dose to the nucleus was considered, no significant difference could be observed between the dose–response curves for [¹⁶¹Tb]Tb- and [¹⁷⁷Lu]Lu-DOTATATE. [¹⁶¹Tb]Tb-DOTA-LM3 showed a linear-quadratic dose response, whereas [¹⁶¹Tb]Tb-DOTATATE showed only a linear dose response within the observed dose range, suggesting additional cell membrane damage by Auger electrons. Conclusion: The IC, rather than Auger, electrons emitted by ¹⁶¹Tb resulted in a higher absorbed dose to the cell nucleus and lower clonogenic survival for [¹⁶¹Tb]Tb-DOTATATE and [¹⁶¹Tb]Tb-DOTA-LM3 than for the ¹⁷⁷Lu-labeled analogs. In contrast, [¹⁶¹Tb]Tb-DOTATATE showed no higher dose response than [¹⁷⁷Lu]Lu-DOTATATE, whereas for [¹⁶¹Tb]Tb-DOTA-LM3 an additional quadratic response was observed. Because of this quadratic response, potentially caused by cell membrane damage, [¹⁶¹Tb]Tb-DOTA-LM3 is a more effective radiopeptide than [¹⁶¹Tb]Tb-DOTATATE for labeling with ¹⁶¹Tb.

Our objective is to explore quantitative imaging markers for early prediction of treatment response in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) undergoing [¹⁷⁷Lu]Lu-DOTATATE therapy. By doing so, we aim to enable timely switching to more effective therapies in order to prevent time-resource waste and minimize toxicities. Methods: Patients diagnosed with unresectable or metastatic, progressive, well-differentiated, receptor-positive GEP-NETs who received 4 sessions of [¹⁷⁷Lu]Lu-DOTATATE were retrospectively selected. Using SPECT/CT images taken at the end of treatment sessions, we counted all visible tumors and measured their largest diameters to calculate the tumor burden score (TBS). Up to 4 target lesions were selected and semiautomatically segmented. Target lesion peak counts and spleen peak counts were measured, and normalized peak counts were calculated. Changes in TBS (TBS) and changes in normalized peak count (nPC) throughout treatment sessions in relation to the first treatment session were calculated. Treatment responses were evaluated using third-month CT and were binarized as progressive disease (PD) or non-PD. Results: Twenty-seven patients were included (7 PD, 20 non-PD). Significant differences were observed in TBS_second-first, TBS_third-first, and TBS_fourth-first (where second-first, third-first, and fourth-first denote scan number between the second and first, third and first, and fourth and first [¹⁷⁷Lu]Lu-DOTATATE treatment cycles), respectively) between the PD and non-PD groups (median, 0.043 vs. –0.049, 0.08 vs. –0.116, and 0.109 vs. –0.123 [P = 0.023, P = 0.002, and P < 0.001], respectively). nPC_second-first showed significant group differences (mean, –0.107 vs. –0.282; P = 0.033); nPC_third-first and nPC_fourth-first did not reach statistical significance (mean, –0.122 vs. –0.312 and –0.183 vs. –0.405 [P = 0.117 and 0.067], respectively). At the optimal threshold, TBS_fourth-first exhibited an area under the curve (AUC) of 0.957, achieving 100% sensitivity and 80% specificity. TBS_second-first and TBS_third-first reached AUCs of 0.793 and 0.893, sensitivities of 71.4%, and specificities of 85% and 95%, respectively. nPC_second-first, nPC_third-first, and nPC_fourth-first showed AUCs of 0.764, 0.693, and 0.679; sensitivities of 71.4%, 71.4%, and 100%; and specificities of 75%, 70%, and 35%, respectively. Conclusion: TBS and nPC can predict [¹⁷⁷Lu]Lu-DOTATATE response by the second treatment session.

Neoadjuvant therapy in patients with locally advanced rectal cancer (LARC) has achieved good pathologic complete response (pCR) rates, potentially eliminating the need for surgical intervention. This study investigated preoperative methods for predicting pCR after neoadjuvant short-course radiotherapy (SCRT) combined with immunochemotherapy. Methods: Treatment-naïve patients with histologically confirmed LARC were enrolled from February 2023 to July 2023. Before surgery, the patients received neoadjuvant SCRT followed by 2 cycles of capecitabine and oxaliplatin plus camrelizumab. ⁶⁸Ga-labeled fibroblast activation protein inhibitor ([⁶⁸Ga]Ga-FAPI-04) PET/MRI, [¹⁸F]FDG PET/CT, and contrast-enhanced MRI were performed before treatment initiation and before surgery in each patient. PET and MRI features and the size and number of lesions were also collected from each scan. Each parameter’s sensitivity, specificity, and diagnostic cutoff were derived via receiver-operating-characteristic curve analysis. Results: Twenty eligible patients (13 men, 7 women; mean age, 60.2 y) were enrolled and completed the entire trial, and all patients had proficient mismatch repair or microsatellite-stable LARC. A postoperative pCR was achieved in 9 patients (45.0%). In the visual evaluation, both [⁶⁸Ga]Ga-FAPI-04 PET/MRI and [¹⁸F]FDG PET/CT were limited to forecasting pCR. Contrast-enhanced MRI had a low sensitivity of 55.56% to predict pCR. In the quantitative evaluation, [⁶⁸Ga]Ga-FAPI-04 change in SUL_peak percentage, where SUL_peak is SUV_peak standardized by lean body mass, had the largest area under the curve (0.929) with high specificity (sensitivity, 77.78%; specificity, 100.0%; cutoff, 63.92%). Conclusion: [⁶⁸Ga]Ga-FAPI-04 PET/MRI is a promising imaging modality for predicting pCR after SCRT combined with immunochemotherapy. The SUL_peak decrease exceeding 63.92% may provide valuable guidance in selecting patients who can forgo surgery after neoadjuvant therapy.

Billy Napier will remain in place as head football coach at Florida, despite the Gators producing another lackluster campaign during his third season, athletic director Scott Stricklin announced Thursday.

As U.S. and Slovenian troops wrapped up a joint exercise, military officials from both countries met to discuss their response to potential threats, the Air Force said Wednesday.

The allergy and asthma drug montelukast, also known as Singulair, can cause psychiatric side effects—and researchers aren’t sure why

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TED Fellow and equity bioengineer Erika Moore investigates how cells controlling inflammation behave differently depending on a patient's background. By focusing on the "who" behind the disease, Moore is uncovering why certain diseases disproportionately affect certain ethnicities, paving the way for more inclusive and effective health care.