Touch down in Vancouver and it was raining. Listening to friends from the Pacific Northwest talk, I always kind of suspected that they were lying when they complained about how grey it was and how much it rains. I’d been to the region four or five times, at across all time of the year and always […]

The article A Perfect Day in Vancouver (Finally!) originated at EverInTransit.com

If anyone could accuse Trump of being on 'defense' during his witch-hunt trials, he's going on full offense now.

The post BOOM: Trump’s Lawyers SAVAGE Letitia James… Threaten PRISON If She Plays More Of Her Games appeared first on Clash Daily.

You know it's bad when you give the Democrats a whoopin and the corprate media clowns have no choice but to concede your point.

The post GLORIOUS: Scott Jennings Gets Van Jones To Cry ‘Uncle’ Live On CNN appeared first on Clash Daily.

Spend enough time talking with entrepreneurs, product people, designers, and anyone charged with proving something, and you’ll bump into questions about validation. “How do you validate if it’s going to work?”“How do you know if people will buy it to not?”“How do you validate product market fit?”“How do you validate if a feature is worth… keep reading

Now that there is a Republican majority in the next Congress, it’s time for the party to bare its internal fault lines. That is likely to take place Wednesday, according […]

The post Another House Speaker Battle? Mike Johnson's Position May Be at Risk as Conservative Anger Heats Up appeared first on The Western Journal.

Carvana is America’s fastest-growing e-tailer   February 23, 2022 (New York, NY) – Americans have taken to buying cars online, so much so that ecommerce car dealer Carvana is now […]

In conversation with Valerii Zaluzhnyi, Ukrainian Ambassador to the UK 17 October 2024 — 10:00AM TO 11:00AM Anonymous (not verified) 16 September 2024 Chatham House and Online

The former Commander-in-Chief of the Armed Forces of Ukraine offers insight into the evolution of Russia’s war against his country, and what to expect next.

More than two and a half years since Russia launched its full-scale invasion, Ukraine has consistently adapted to Moscow’s advances by implementing new strategies.

Ukraine’s recent incursion into Russia’s Kursk region demonstrated operational tactical ingenuity, surprising both Russia and Ukraine’s Western supporters. Success against the Russian Black Sea Fleet has already showcased how Ukraine can skilfully beat back Russian aggression. And increasing numbers of targeted strikes on Russian supply depots and airfields are disrupting Russian operations behind the front lines.

Critical Western supplies continue to resource Ukraine’s military. But questions linger over the quantity and sustainability of these supplies. Kyiv will be watching the US presidential election in November as its biggest backer goes to the polls with the possibility of an outcome that could seriously affect the war. Meanwhile, Russian forces continue to edge forward in Donbas, despite heavy casualties, and strike at Ukrainian towns and cities from the air, demonstrating that President Putin has no intention of relinquishing the fight.

Amid these complexities, Ambassador Zaluzhnyi will discuss how the war is changing both sides, advances on the battlefield, and what dangers lie ahead for Ukraine in the coming months. Other key questions include:

• What kind of enemy is Russia today and how to secure its strategic defeat in Ukraine;
• How have new strategies, such as the recent incursion into the Kursk region, affected the state of play on the battlefield?
• What technologies and armaments does Ukraine need from its Western allies in both the short and long term?

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The human cardiovascular system has adapted to function optimally in Earth's 1G gravity, and microgravity conditions cause myocardial abnormalities, including atrophy and dysfunction. However, the underlying mechanisms linking microgravity and cardiac anomalies are incompletely understood. In this study, we investigated whether and how calpain activation promotes myocardial abnormalities under simulated microgravity conditions. Simulated microgravity was induced by tail suspension in mice with cardiomyocyte-specific deletion of Capns1, which disrupts activity and stability of calpain-1 and calpain-2, and their WT littermates. Tail suspension time-dependently reduced cardiomyocyte size, heart weight, and myocardial function in WT mice, and these changes were accompanied by calpain activation, NADPH oxidase activation, and oxidative stress in heart tissues. The effects of tail suspension were attenuated by deletion of Capns1. Notably, the protective effects of Capns1 deletion were associated with the prevention of phosphorylation of Ser-345 on p47phox and attenuation of ERK1/2 and p38 activation in hearts of tail-suspended mice. Using a rotary cell culture system, we simulated microgravity in cultured neonatal mouse cardiomyocytes and observed decreased total protein/DNA ratio and induced calpain activation, phosphorylation of Ser-345 on p47phox, and activation of ERK1/2 and p38, all of which were prevented by calpain inhibitor-III. Furthermore, inhibition of ERK1/2 or p38 attenuated phosphorylation of Ser-345 on p47phox in cardiomyocytes under simulated microgravity. This study demonstrates for the first time that calpain promotes NADPH oxidase activation and myocardial abnormalities under microgravity by facilitating p47phox phosphorylation via ERK1/2 and p38 pathways. Thus, calpain inhibition may be an effective therapeutic approach to reduce microgravity-induced myocardial abnormalities.

In their comment (1) on our publication (2), the authors make two points: (i) they raise concerns about the possible effect of residual NONOate in our study, and (ii) they promote nitrosylcobalamin (NOCbl) supplied by their own company. Both points lack merit for the following reasons. The authors make the astonishing claim that the spectra of nitric oxide (NO•) and cobalamins overlap. Unlike NO•, cobalamin absorbs in the visible region, permitting unequivocal spectral assignment of NOCbl as reported (3). We demonstrated that whereas NOCbl is highly unstable in solution, it is stabilized by the B12 trafficking protein CblC. So even if present, residual NONOate (which is unstable at neutral pH and is removed during the work-up (3)) could not account for the observed difference.The authors then misrepresent our synthetic method, claiming that anaerobic conditions were used to generate nitrocobalamin (NO2Cbl), which results in the transient formation of NOCbl. We synthesized NO2Cbl aerobically using nitrite as described (4); NOCbl is not an intermediate in this ligand exchange reaction. The aerobic instability of NOCbl has been rigorously described by inorganic chemists (3, 5) and raises obvious questions about its purported biological effects as exemplified by the authors' own 2003 JBC publication, which was later withdrawn.As to promoting NOCbl from their company, the authors refer to a synthetic route from a mixture of NO• gas and aquocobalamin. The authors' method (6) has been described as “dubious” by chemists (5). Whereas DEAE NONOate used in our method is widely known as an NO• donor,...

After a thorough read of this paper (1), we wish to clarify that the authors' anaerobic method of synthesis for the production of nitrocobalamin results in the transient formation of nitrosylcobalamin, an unstable intermediate upon exposure to air. We concur that the authors' method results in the production of nitrocobalamin based on the UV-visible data as shown. The authors' adapted anaerobic method consists of mixing hydroxocobalamin hydrochloride with diethylamine NONOate diethylammonium salt in aqueous solution. Of concern, the UV spectrum of nitric oxide overlaps that of all cobalamin species under anaerobic conditions, making any assignments of the binding of nitric oxide to hydroxocobalamin suspect (2). Additionally, the use of acetone to precipitate the authors' product causes precipitation of diethylamine NONOate, resulting in an impure product. As a result, its utility for drawing experimental conclusions is faulty.The product from the authors' anaerobic synthetic method has not been assessed for purity, and the synthetic method itself has not been validated using a stability-indicating method as required by the International Conference on Harmonization (ICH) (ICH Q2B, Validation of Analytical Procedures) methodology, which is a hallmark for analytical characterization. Our nitrosylcobalamin synthesis involves reacting nitric oxide gas with hydroxocobalamin acetate as a heterogeneous mixture in a non-electron-donating solvent followed by rotary evaporation. Our nitrosylcobalamin product is stable in air, releases nitric oxide gas in situ (3), and meets ICH stability guidelines (4). Additionally, our nitrosylcobalamin product demonstrates biological activity, which has not been observed for nitrocobalamin (3, 5).

G protein–coupled receptors (GPCRs) initiate signaling cascades via G-proteins and beta-arrestins (βarr). βarr-dependent actions begin with recruitment of βarr to the phosphorylated receptor tail and are followed by engagement with the receptor core. βarrs are known to act as adaptor proteins binding receptors and various effectors, but it is unclear whether in addition to the scaffolding role βarrs can allosterically activate their downstream targets. Here we demonstrate the direct allosteric activation of proto-oncogene kinase Src by GPCR–βarr complexes in vitro and establish the conformational basis of the activation. Whereas free βarr1 had no effect on Src activity, βarr1 in complex with M2 muscarinic or β2-adrenergic receptors reconstituted in lipid nanodiscs activate Src by reducing the lag phase in Src autophosphorylation. Interestingly, receptor–βarr1 complexes formed with a βarr1 mutant, in which the finger-loop, required to interact with the receptor core, has been deleted, fully retain the ability to activate Src. Similarly, βarr1 in complex with only a phosphorylated C-terminal tail of the vasopressin 2 receptor activates Src as efficiently as GPCR–βarr complexes. In contrast, βarr1 and chimeric M2 receptor with nonphosphorylated C-terminal tail failed to activate Src. Taken together, these data demonstrate that the phosphorylated GPCR tail interaction with βarr1 is necessary and sufficient to empower it to allosterically activate Src. Our findings may have implications for understanding more broadly the mechanisms of allosteric activation of downstream targets by βarrs.

Arguments Over Innovation Capacity Miss How Much the US and China Are Intertwined Expert comment sysadmin 30 May 2018

Most discussions of current US–China trade tensions fundamentally misrepresent the globalized nature of innovation.

Among the many issues at play in the ongoing economic and trade tensions between the US and China are questions of technological capability and innovation.

Two of the main complaints in the US Section 301 report were that American companies have been forced to transfer technology to China and been the subject of cyber espionage. The presentation of the issues in this report has been disputed, but behind it lies concern in the US that Chinese innovative and technological capability is catching up with that in the US, thanks partly to the support of state policies set out in the Made in China 2025 initiative.

One important feature of the package of measures announced by the US last month is that it was designed to contain China’s technological development as much as to reduce the trade deficit, even though the latter has been the focus of President Donald Trump’s rhetoric.

(Some have cast doubt on this picture of Chinese innovation, suggesting that China is more of a ‘fat tech dragon’ whose massive inputs into research and development do not translate into real innovative capacity.)

The problem with the debate comparing Chinese and American technological capability is that it misunderstands or misrepresents the globalized nature of innovation in today’s world.

Contrary to the economic nationalist rhetoric emanating mainly from Washington, and to a lesser extent from Beijing, the US and China are not two separate economies competing for economic hegemony. As part of the globalization of manufacturing and production over the last 40 years and the more recent globalization of consumption, the shape and structure of innovation has also changed.

As we argue in a new paper, the key to understanding this is to think of innovation as being carried out through global or transnational networks linking economic actors, not within separated economies. What the recent phase of globalization has demonstrated is that innovation is achieved most effectively and efficiently when those engaged in innovation are connected not just within national borders but across them.

China has become integrated into these global innovation networks in ways which reflect its relative strengths and weaknesses in research and development. China’s extensive manufacturing ecosystem has enabled its companies to perform well in production-related and efficiency-driven innovation. Moreover the rapid growth in its large and dynamic consumer market provides fertile ground for consumer-related innovation by Chinese and foreign-invested enterprises alike. The rapidly increasing talent pool in China also provides additional human capital for innovation and technology.

Apart from the increased emphasis by Chinese enterprises on innovation, multinationals have also been stepping up their research and development (R&D) efforts in China. These now consitute a significant part of China’s R&D landscape, and are an increasingly important part of the global innovation by multinationals.

Things are of course changing. China’s overall innovation capacity is improving, and there are concerns in both in the US and Europe that Chinese policy is moving backwards towards the promotion of ‘indigenous innovation’ – or self-reliant innovation – and away from openness. In other words, we may be seeing a more ‘techno-nationalist’ China as well as a protectionist US.

China has also been criticized for inadequate protection of intellectual property rights, though the establishment of special courts for such disputes marks a commitment to improve – and the rights of Chinese companies increasingly need protection too.

As the benefits of globalization increasingly come under question, and with some degree of nationalist political pressure in both the West and China, it is not going to be possible – or politically desirable – to do away with national borders when it comes to innovation. But at the same time, the extent to which businesses and consumers have globalized means that fully ‘indigenous’ innovation is not possible, even if it were politically desirable.

EU-China innovation relations, as well as those between Washington and Beijing, therefore need careful management. But both Americans and Europeans should have more confidence in their innovation capability, given the relative strengths and weaknesses of Chinese innovation.

Americans and Europeans should acknowledge and promote the opportunities that come from globally networked innovation processes. Taking advantage of the comparative advantage of all the players in these networks means working with China as an innovation partner.

Mobile Ecosystems as a Driver of Innovation and Growth in the Asia-Pacific 19 September 2018 — 12:30PM TO 3:00PM Anonymous (not verified) 18 September 2018 Chatham House, London

Boris Macek
Feb 1, 2008; 7:299-307
Research

Tamar Geiger
Mar 1, 2012; 11:M111.014050-M111.014050
Special Issue: Prospects in Space and Time

Ignat V. Shilov
Sep 1, 2007; 6:1638-1655
Technology

Staphylococcus aureus adhesion to the host's skin and mucosae enables asymptomatic colonization and the establishment of infection. This process is facilitated by cell wall-anchored adhesins that bind to host ligands. Therapeutics targeting this process could provide significant clinical benefits; however, the development of anti-adhesives requires an in-depth knowledge of adhesion-associated factors and an assay amenable to high-throughput applications. Here, we describe the development of a sensitive and robust whole cell assay to enable the large-scale profiling of S. aureus adhesion to host ligands. To validate the assay, and to gain insight into cellular factors contributing to adhesion, we profiled a sequence-defined S. aureus transposon mutant library, identifying mutants with attenuated adhesion to human-derived fibronectin, keratin, and fibrinogen. Our screening approach was validated by the identification of known adhesion-related proteins, such as the housekeeping sortase responsible for covalently linking adhesins to the cell wall. In addition, we also identified genetic loci that could represent undescribed anti-adhesive targets. To compare and contrast the genetic requirements of adhesion to each host ligand, we generated a S. aureus Genetic Adhesion Network, which identified a core gene set involved in adhesion to all three host ligands, and unique genetic signatures. In summary, this assay will enable high-throughput chemical screens to identify anti-adhesives and our findings provide insight into the target space of such an approach.

HIV Type 1 (HIV-1) and simian immunodeficiency virus (SIV) display differential replication kinetics in macrophages. This is because high expression levels of the active host deoxynucleotide triphosphohydrolase sterile α motif domain and histidine-aspartate domain–containing protein 1 (SAMHD1) deplete intracellular dNTPs, which restrict HIV-1 reverse transcription, and result in a restrictive infection in this myeloid cell type. Some SIVs overcome SAMHD1 restriction using viral protein X (Vpx), a viral accessory protein that induces proteasomal degradation of SAMHD1, increasing cellular dNTP concentrations and enabling efficient proviral DNA synthesis. We previously reported that SAMHD1-noncounteracting lentiviruses may have evolved to harbor RT proteins that efficiently polymerize DNA, even at low dNTP concentrations, to circumvent SAMHD1 restriction. Here we investigated whether RTs from SIVmac239 virus lacking a Vpx protein evolve during in vivo infection to more efficiently synthesize DNA at the low dNTP concentrations found in macrophages. Sequence analysis of RTs cloned from Vpx (+) and Vpx (−) SIVmac239–infected animals revealed that Vpx (−) RTs contained more extensive mutations than Vpx (+) RTs. Although the amino acid substitutions were dispersed indiscriminately across the protein, steady-state and pre-steady-state analysis demonstrated that selected SIVmac239 Vpx (−) RTs are characterized by higher catalytic efficiency and incorporation efficiency values than RTs cloned from SIVmac239 Vpx (+) infections. Overall, this study supports the possibility that the loss of Vpx may generate in vivo SIVmac239 RT variants that can counteract the limited availability of dNTP substrate in macrophages.

Candida albicans and Aspergillus fumigatus are dangerous fungal pathogens with high morbidity and mortality, particularly in immunocompromised patients. Innate immune-mediated programmed cell death (pyroptosis, apoptosis, necroptosis) is an integral part of host defense against pathogens. Inflammasomes, which are canonically formed upstream of pyroptosis, have been characterized as key mediators of fungal sensing and drivers of proinflammatory responses. However, the specific cell death pathways and key upstream sensors activated in the context of Candida and Aspergillus infections are unknown. Here, we report that C. albicans and A. fumigatus infection induced inflammatory programmed cell death in the form of pyroptosis, apoptosis, and necroptosis (PANoptosis). Further, we identified the innate immune sensor Z-DNA binding protein 1 (ZBP1) as the apical sensor of fungal infection responsible for activating the inflammasome/pyroptosis, apoptosis, and necroptosis. The Zα2 domain of ZBP1 was required to promote this inflammasome activation and PANoptosis. Overall, our results demonstrate that C. albicans and A. fumigatus induce PANoptosis and that ZBP1 plays a vital role in inflammasome activation and PANoptosis in response to fungal pathogens.

Lys234 is one of the residues present in class A β-lactamases that is under selective pressure due to antibiotic use. Located adjacent to proton shuttle residue Ser130, it is suggested to play a role in proton transfer during catalysis of the antibiotics. The mechanism underpinning how substitutions in this position modulate inhibitor efficiency and substrate specificity leading to drug resistance is unclear. The K234R substitution identified in several inhibitor-resistant β-lactamase variants is associated with decreased potency of the inhibitor clavulanic acid, which is used in combination with amoxicillin to overcome β-lactamase–mediated antibiotic resistance. Here we show that for CTX-M-14 β-lactamase, whereas Lys234 is required for hydrolysis of cephalosporins such as cefotaxime, either lysine or arginine is sufficient for hydrolysis of ampicillin. Further, by determining the acylation and deacylation rates for cefotaxime hydrolysis, we show that both rates are fast, and neither is rate-limiting. The K234R substitution causes a 1500-fold decrease in the cefotaxime acylation rate but a 5-fold increase in kcat for ampicillin, suggesting that the K234R enzyme is a good penicillinase but a poor cephalosporinase due to slow acylation. Structural results suggest that the slow acylation by the K234R enzyme is due to a conformational change in Ser130, and this change also leads to decreased inhibition potency of clavulanic acid. Because other inhibitor resistance mutations also act through changes at Ser130 and such changes drastically reduce cephalosporin but not penicillin hydrolysis, we suggest that clavulanic acid paired with an oxyimino-cephalosporin rather than penicillin would impede the evolution of resistance.

Independent Thinking: Iran protests, Iraq's invasion legacy Audio NCapeling 17 November 2022

Episode five of our new weekly podcast has a Middle East focus with insights into what is driving the ongoing protests in Iran, and the progress of Iraq in the years since the fall of Saddam Hussein.

Since September, Iran has been swept by thousands of women-led protests, demanding an end to the morality police and the even calling for the fall of the Islamic Republic.

Meanwhile at Chatham House this week saw our Iraq Initiative conference 2022, which delved heavily into the multiple challenges facing Iraq two decades on from the invasion which toppled Saddam Hussein.

Joining Bronwen Maddox on the podcast this week are the Chatham House Middle East and North Africa programme deputy director Dr Sanam Vakil and senior research fellow Dr Renad Mansour, who is also project director of the Iraq Initiative. They are joined by Sanya Burgess, digital investigations journalist with Sky News.

Independent Thinking: Russia’s invasion one year on Audio NCapeling 23 February 2023

Episode 16 of our weekly podcast examines the global impact of Russia’s war on Ukraine one year on from when Vladimir Putin launched his all-out assault.

Following a decision which unleashed the largest war seen in Europe since 1945, with hundreds of thousands of casualties on all sides, the panel examines the impact of the invasion for Ukraine and its people, but also the world.

Also under discussion are key insights from the recent Munich Security Conference, and the announcement this week by Russian president Vladimir Putin to susend his country’s participation in the vital New START nuclear weapons treaty.

Joining Bronwen on the show this week from the Russia and Eurasia programme at Chatham House is programme director James Nixey and associate fellow Samantha de Bendern, alongside Patricia Lewis, director of our International Security programme. They are joined on the panel by Mariya Ionova, a Ukrainian opposition MP.

About Independent Thinking

A weekly podcast hosted by Chatham House director Bronwen Maddox, in conversation with leading policymakers, journalists, and Chatham House experts providing insight on the latest international issues.

UK is too tight on the money and too vague on China Expert comment NCapeling 13 March 2023

The new UK Integrated Review fills gaps left by the last one but is dominated by defence. It needs more clarity on Europe, trade, and development – and more money.

Following a long two years, the UK’s Integrated Review from March 2021 now looks prescient in calling Russia the main threat to UK interests. And Russia’s invasion of Ukraine is the main – but not the only – reason forcing an update of the review only 24 months later.

The UK’s commitment to Ukraine is now centre stage and so therefore is its cost, which immediately exposes a prime weakness of this review. An extra £5 billion on defence is more than nothing, as was originally rumoured, but far less than £11 billion which UK defence secretary Ben Wallace argues is needed.

UK military support for Ukraine cost £2.3 billion in the past year and a continuation will use up £2 billion of the new money. The report also notes £3 billion will go on infrastructure for building nuclear submarines at Barrow and nuclear training. That does not leave much for anything else.

There is a pledge to end the reduction of the armed forces which is essential if the UK contribution to Ukraine and European defence is to be credible. But an ambition to spend 2.5 per cent of GDP on defence by an unspecified date is all but meaningless – albeit prudent phrasing given fiscal uncertainties.

China challenge is one of balance

Ministers have been wrestling for months over their choice of language on China, and ‘epoch defining challenge’ is what has emerged, while also expressing concern over China’s links with Russia. But the review is careful to stop short of calling China a threat as Liz Truss intended.

The choice of vocabulary reflects a long desire to balance forging commercial ties with an increasing wariness of data and security threats under President Xi’s leadership of China. The UK wants to support the US in its concerns but not to presume conflict is inescapable.

The review does acknowledge the threat to Taiwan for the first time. Two years ago, it was fiercely criticized for not including any mention of that despite the potential disruption supposedly being ‘far more damaging than the renewed illegal invasion of Ukraine’ as MPs on the Foreign Affairs Select Committee put it.

But again the question of resources is inescapable. The ‘Indo-Pacific tilt’ which the UK declared two years ago is offered not just as a recognition of the region’s political and economic heft in any vision of the future, but as a favour to the US.

The UK lacks the resources to make that tilt credible in terms of substantial support to the US – nor, arguably, would it do the US any favours by neglecting the defence of Europe or the Middle East, which gets scant mention.

The AUKUS announcement on the same day appears to fill that gap. UK prime minister Rishi Sunak was in San Diego, California to greet the declaration that Australia will draw on British designs for its new nuclear submarines – a decision which brings more British jobs and underpins an alliance of both symbolic and practical weight in the region. But for the UK to play its part fully, it may need to divert resources from elsewhere, and this review sidesteps that hard choice.

More broadly, the UK would benefit from considering how to respond to the reality of China’s rise – analysing what happens to supply chains if tension disrupted them and how it might use membership of the Asia-Pacific CPTPP trading bloc, which appears likely to happen soon.

One of the biggest omissions in the 2021 review was relations with Europe and that is somewhat remedied but more is needed. The UK has been a leader for Europe in its clear response to Russia’s invasion of Ukraine – almost the only common thread of passionate agreement between the three UK prime ministers since the invasion – but it should now consider if it wants to take part in joint development of military assets. And a clear statement of cooperation with European Union (EU) governments would be a boost to NATO.

There is also now a Europe-shaped hole in the review’s discussion of trade. The 2021 version mentioned trade 79 times with the focus on new trade agreements outside Europe. It is now clear, if it was not before, these make little difference to GDP. The recent repairing of relations with the EU – and France in particular – may yield more practical results two years from now.

UK power in the world is changing

The review is also largely silent on another difficulty in the UK’s foreign policy which are the aims and size of its development aid – much changed from its original goal of poverty reduction to a focus on national interest with a reduced budget. This is sensitive political territory but must be better spelled out to count as a plan.

The FCDO intends to appoint a second permanent under-secretary to deliver the government’s development priorities and the minister for international development will join the National Security Council. This acknowledges the disruption caused by the merger of the FCO with DFID and the need for development staff to have clear leadership as well as, hopefully soon, a clear policy.

The pledge of a one-off payment of £20 million for the BBC World Service 42 foreign language channels for two years is welcome too as an acknowledgement of their ‘soft power’ value, especially in parts of the world where democracy is absent or in retreat.

Moldova and Georgia face crucial elections – and diverging paths Expert comment LToremark 16 October 2024

The two countries face unusually consequential elections where their populations must choose between moving unambiguously towards the West – or towards closer ties with Russia.

Moldova and Georgia both go to the polls at the end of October; Moldova for presidential elections on the 20^th and Georgia for parliamentary elections on the 26^th. The two countries share a number of similarities – beyond their justified reputation as world-class wine producers. They are both small, low- to middle-income countries that have struggled to consolidate their democracies and have experienced oligarchic political influence. Both are candidate countries for EU membership, with Moldova a step ahead having been invited to start negotiations. 

For both countries these elections represent a fork in the road: either move unambiguously into the Western world, or step back from it and become more closely tied to Russia again and its way of governance. However, the second option has caused yet-to-be-resolved territorial conflicts in both countries – Transnistria for Moldova, and Abkhazia and South Ossetia for Georgia.

Some would say it should not be such a ‘zero sum’ choice. Why must a nation choose between Russia and the West? While that may be a fair statement for countries like India or South Africa, it does not work for Russia’s former colonies, which Moscow wishes to control. 

Moldova and Georgia’s final similarity is that they face Russian interference and attempts to manipulate votes in their elections. In Moldova this has been especially brazen with the uncovering in September of a $15 million vote-buying scheme, including instructions on who to vote for distributed to over 130,000 citizens. Russian interference in Georgia’s election is less overt but at the same time more endemic considering its government has in effect been captured by pro-Russia forces.

Diverging paths

But this is where the similarities end and the contrasts become clear.

Moldova has a young, pro-Western and equality-conscious government, and 44 of the 100 MPs in its parliament are women. In this election, Maia Sandu is seeking her second and final term as president. The election is combined with a referendum asking the people if they wish to embed Moldova’s EU aspirations into the country’s constitution. The results of both the presidential election and the EU referendum will be close, reflecting a genuine split in attitudes (and debate) in the country. 

Georgia’s EU aspirations, meanwhile, are already embedded in its constitution – but that has not prevented Tbilisi from pivoting away from the West. Polls show   that around 80 per cent of Georgia’s population desires EU (and NATO) membership – rising to 90 per cent among the under 30s – but its government seems determined to deny them that future. 

Its new ‘foreign agents’ law is seemingly copy-pasted from Russia – and incompatible with EU membership. The election can be seen as a de facto referendum on the EU too. Georgia’s accession is suspended until its political crisis is resolved. 

Georgia faces other challenges to its democracy. Due to the country’s limited presidential powers, Georgia is in effect run by the unelected Bidzina Ivanishvili – founder of the ruling Georgian Dream (GD) party – whose relationship with Russia is murky at best. Judging by his recent speeches, Ivanishvili now blames the Western world not just for igniting the war in Ukraine, but also for the war in Georgia 16 years ago which resulted in the loss of 20 per cent of its territory at the hands of Russia. This extraordinary position is both factually incorrect and out of step with the Georgian people.

Both countries are now at a critical point. Whatever the outcome in Moldova, the election will pass off peacefully and competently. Its problems (Russia aside) are demographic and economic, and the country’s pro-Russian opposition is relatively weak.

Georgia’s election looks like it is going to be messy. Ivanishvili’s party will likely manipulate the election to a win. There is still a chance that Georgia’s pro-Western but also weak opposition will regain power and return the country to its European path. But if the manipulation by the incumbency is heavy, people will likely take to the streets in protest, as in April this year – and in the 2003 Rose Revolution.

Regime change via popular revolution shows political immaturity but the Georgian people may feel it is the only way they can have their views represented and their ambitions realised. 

MS Brown
Jul 1, 1980; 21:505-517
Reviews

Jorge H. Capdevila
Feb 1, 2000; 41:163-181
Reviews

M el-Saadani
Apr 1, 1989; 30:627-630
Articles

JF Oram
Dec 1, 1996; 37:2473-2491
Reviews

George H. Rothblat
May 1, 1999; 40:781-796
Reviews

K Schoonjans
May 1, 1996; 37:907-925
Reviews

JE Hixson
Mar 1, 1990; 31:545-548
Articles

Supporting Civic Space: The Role and Impact of the Private Sector 23 September 2020 — 2:00PM TO 4:15PM Anonymous (not verified) 23 December 2020 Online

The meeting provides an opportunity to explore the drivers of – and barriers to – corporate activism.

A healthy civic space is vital for an enabling business environment. In recognition of this, a growing number of private sector actors are challenging, publicly or otherwise, the deteriorating environment for civic freedoms.

However, this corporate activism is often limited and largely ad hoc. It remains confined to a small cluster of multinationals leaving potential routes for effective coordination and collaboration with other actors underexplored.

This roundtable brings together a diverse and international group of business actors, civil society actors and foreign policy experts to exchange perspectives and experiences on how the private sector can be involved in issues around civic space.

The meeting provides an opportunity to explore the drivers of – and barriers to – corporate activism, develop a better understanding of existing initiatives, identify good practice and discuss practical strategies for the business community.

This meeting is the first of a series of roundtables at Chatham House in support of initiatives to build broad alliances for the protection of civic space. 

Innovating Governance: Examples from the Digital Arena 25 February 2020 TO 26 February 2020 — 10:00AM TO 11:30AM Anonymous (not verified) 9 February 2021 Chatham House

The Inclusive Governance Initiative is launched with this roundtable on digital governance.

The Inclusive Governance Initiative, a centenary project which is examining how to build more inclusive models and mechanisms of global governance fit for purpose in today’s world, is launched with this roundtable on digital governance.

The event brings together a diverse and multidisciplinary group of leading experts to consider where and how early initiatives around governance of the digital sphere have succeeded – or not – and how they are evolving today.

The conversation will include the debate between multilateral and multi-stakeholder approaches, the opportunities and challenges of collective non-binding commitments, and converting civil society collaboration into policy contribution.

How can the investor community address the ‘S’ in ESG? – the role of social purpose values 16 November 2021 — 1:30PM TO 2:30PM Anonymous (not verified) 18 October 2021 Online

This webinar highlights the crucial relationship between an open civic space and a profitable business environment.

2020 was a tipping point for investors to think and act more responsibly, galvanized by catalysts like the killing of George Floyd and the pandemic. There is increasing investor support for social and environmental causes. Younger investors are placing increasing emphasis on values and social issues in their investment decisions.

The ‘S’ in the Environment Social and Governance (ESG) agenda is clearly gaining traction, but how far does it extend to civil and political liberties i.e. the right of citizens, NGOs and journalists to speak freely, assemble and associate which are increasingly shrinking around the world?

While there is increasing focus on human rights issues such as modern slavery and supply chains, civil society space issues often fall between the cracks when investors consider ESG.

This webinar also explores opportunities and challenges that arise for the investor community in terms of factoring civic space issues into their political risk and ESG analysis.

• To what extent are civic space issues being factored into ESG social purpose values, especially by younger investors?
• What is the best methodology for assessing these issues in order to ensure a common and coherent set of global standards in this area?
• And how can investors mitigate the risks of their activities to civic space in practice?

Why the private sector should protect civic society Explainer Video NCapeling 10 December 2021

A short animation explaining the crucial role that the private sector can play in protecting and defending civic space.

This video explainer introduces a synthesis paper which analyses how the private sector can support the protection of civic society space.

The private sector is in a unique position to work with civil society organizations to uphold and defend civic freedoms and support sustainable and profitable business environments. Companies have the capacity, resources and expertise to enhance the protection of civic space.

By doing so, this helps create a society in which fundamental rights and the rule of law are respected and exercised by governments, private citizens, and all organizations which, in turn, is critical to a sustainable and profitable business environment.  

For more information, download the report.

Reactive oxygen species (ROS) are an unavoidable host environmental cue for intracellular pathogens such as Mycobacterium tuberculosis and Mycobacterium bovis; however, the signaling pathway in mycobacteria for sensing and responding to environmental stress remains largely unclear. Here, we characterize a novel CmtR-Zur-ESX3-Zn2+ regulatory pathway in M. bovis that aids mycobacterial survival under oxidative stress. We demonstrate that CmtR functions as a novel redox sensor and that its expression can be significantly induced under H2O2 stress. CmtR can physically interact with the negative regulator Zur and de-represses the expression of the esx-3 operon, which leads to Zn2+ accumulation and promotion of reactive oxygen species detoxication in mycobacterial cells. Zn2+ can also act as an effector molecule of the CmtR regulator, using which the latter can de-repress its own expression for further inducing bacterial antioxidant adaptation. Consistently, CmtR can induce the expression of EsxH, a component of esx-3 operon involved in Zn2+ transportation that has been reported earlier, and inhibit phagosome maturation in macrophages. Lastly, CmtR significantly contributes to bacterial survival in macrophages and in the lungs of infected mice. Our findings reveal the existence of an antioxidant regulatory pathway in mycobacteria and provide novel information on stress-triggered gene regulation and its association with host–pathogen interaction.

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Phospholipase Cε (PLCε) is activated downstream of G protein–coupled receptors and receptor tyrosine kinases through direct interactions with small GTPases, including Rap1A and Ras. Although Ras has been reported to allosterically activate the lipase, it is not known whether Rap1A has the same ability or what its molecular mechanism might be. Rap1A activates PLCε in response to the stimulation of β-adrenergic receptors, translocating the complex to the perinuclear membrane. Because the C-terminal Ras association (RA2) domain of PLCε was proposed to the primary binding site for Rap1A, we first confirmed using purified proteins that the RA2 domain is indeed essential for activation by Rap1A. However, we also showed that the PLCε pleckstrin homology (PH) domain and first two EF hands (EF1/2) are required for Rap1A activation and identified hydrophobic residues on the surface of the RA2 domain that are also necessary. Small-angle X-ray scattering showed that Rap1A binding induces and stabilizes discrete conformational states in PLCε variants that can be activated by the GTPase. These data, together with the recent structure of a catalytically active fragment of PLCε, provide the first evidence that Rap1A, and by extension Ras, allosterically activate the lipase by promoting and stabilizing interactions between the RA2 domain and the PLCε core.

Pyruvate kinase muscle isoform 2 (PKM2) is a key glycolytic enzyme and transcriptional coactivator and is critical for tumor metabolism. In cancer cells, native tetrameric PKM2 is phosphorylated or acetylated, which initiates a switch to a dimeric/monomeric form that translocates into the nucleus, causing oncogene transcription. However, it is not known how these post-translational modifications (PTMs) disrupt the oligomeric state of PKM2. We explored this question via crystallographic and biophysical analyses of PKM2 mutants containing residues that mimic phosphorylation and acetylation. We find that the PTMs elicit major structural reorganization of the fructose 1,6-bisphosphate (FBP), an allosteric activator, binding site, impacting the interaction with FBP and causing a disruption in oligomerization. To gain insight into how these modifications might cause unique outcomes in cancer cells, we examined the impact of increasing the intracellular pH (pHi) from ∼7.1 (in normal cells) to ∼7.5 (in cancer cells). Biochemical studies of WT PKM2 (wtPKM2) and the two mimetic variants demonstrated that the activity decreases as the pH is increased from 7.0 to 8.0, and wtPKM2 is optimally active and amenable to FBP-mediated allosteric regulation at pHi 7.5. However, the PTM mimetics exist as a mixture of tetramer and dimer, indicating that physiologically dimeric fraction is important and might be necessary for the modified PKM2 to translocate into the nucleus. Thus, our findings provide insight into how PTMs and pH regulate PKM2 and offer a broader understanding of its intricate allosteric regulation mechanism by phosphorylation or acetylation.