A quick note to point you toward this piece I wrote for P&G’s Signal publication. Since its inception, I’ve been co-editor of the monthly outlet, which covers innovation in large enterprise. This month I went in search of proof that the hype around generative AI – fueled in large part by both Google and Microsoft … Continue reading "Can GenAI Change Big Companies?"

Mark Fisher was co-founder of the Rhode Island chapter of BLM. He voted for Joe Biden in 2020. Does he have buyers remorse? Yeah, you could say so. His viral video is causing a stir... but there's more to that story.

The post Former BLM Chapter Co-Founder Switches To Trump In ’24 … What Changed His Mind? appeared first on Clash Daily.

There's a reason Hitler holds a special place of disgrace in public memory. He combined the ambition and destruction of Attila The Hun with the personal malice of a serial killer.

The post The REAL Harm Done By Calling Everyone You Don’t Like ‘Hitler’ Is BIGGER Than Lefties Think appeared first on Clash Daily.

While the rest of us were busy cheering (or crying) about the election results, the world kept turning and events continued to unfold at home and around the world.

The post Trump Scores Three Big Wins Less Than One Day After The Election appeared first on Clash Daily.

Republicans have solidified their control of Washington by retaining control of the House of Representatives. President-elect Donald Trump’s overwhelming victory in the presidential race, coupled with GOP control of the […]

The post Breaking: Republicans Retain Control Over House of Representatives, Handing Trump the Keys to His Agenda appeared first on The Western Journal.

Three years ago, Chris Wallace walked away from Fox News over concerns that those at the “Fair and Balanced” network were beginning to, as he put it, “question the truth.” […]

The post CNN Host Reportedly Leaving Network After Short-Lived Stay: His Career Change Is Completely Absurd appeared first on The Western Journal.

Americans will only achieve healthy public discourse when we agree on basic principles and start telling the truth. As it stands, however, too many elected officials engage in hypocrisy by […]

The post Dem Lawmaker Says the Quiet Part Out Loud as She Suddenly Changes Her Tune on the Senate Filibuster appeared first on The Western Journal.

One of the greatest pass rushers in NFL history appears to be taking a pass himself when it comes to directly addressing a raging controversy. Pro Football Hall of Famer […]

The post NFL Analyst Michael Strahan Speaks Out After Becoming Embroiled in National Anthem Controversy appeared first on The Western Journal.

New York Judge Juan Merchan — who is overseeing President-elect Donald Trump’s business records case — agreed to freeze the case until Nov. 19. There was to be a hearing […]

The post Judge Juan Merchan Grants Request from Trump's Legal Team and DA in NY Hush Money Case appeared first on The Western Journal.

Just because you’re paranoid, it doesn’t mean you’re wrong. And for any supporters of President-elect Donald Trump who feel that they’ve been unfairly targeted by the government, but were summarily […]

The post Fired FEMA Worker Reveals Discrimination Against Trump Supporters Was Even Worse Than First Reported appeared first on The Western Journal.

Canan Moodie used his start against Scotland to show that he is about far more than just pace out wide and aerial ability.

As captain, Aiden Markram is allowed a long rope from a wonky form perspective, but how long can that rope be as the run river continues to shrivel, asks Khanyiso Tshwaku.

Former Kaizer Chiefs legend Brian Baloyi says that holding the Kaizer Chiefs No 1 jersey requires a hardened mentality, but he is upbeat over Amakhosi's chances this season.

An important mechanism of resistance to β-lactam antibiotics is via their β-lactamase–catalyzed hydrolysis. Recent work has shown that, in addition to the established hydrolysis products, the reaction of the class D nucleophilic serine β-lactamases (SBLs) with carbapenems also produces β-lactones. We report studies on the factors determining β-lactone formation by class D SBLs. We show that variations in hydrophobic residues at the active site of class D SBLs (i.e. Trp105, Val120, and Leu158, using OXA-48 numbering) impact on the relative levels of β-lactones and hydrolysis products formed. Some variants, i.e. the OXA-48 V120L and OXA-23 V128L variants, catalyze increased β-lactone formation compared with the WT enzymes. The results of kinetic and product studies reveal that variations of residues other than those directly involved in catalysis, including those arising from clinically observed mutations, can alter the reaction outcome of class D SBL catalysis. NMR studies show that some class D SBL variants catalyze formation of β-lactones from all clinically relevant carbapenems regardless of the presence or absence of a 1β-methyl substituent. Analysis of reported crystal structures for carbapenem-derived acyl-enzyme complexes reveals preferred conformations for hydrolysis and β-lactone formation. The observation of increased β-lactone formation by class D SBL variants, including the clinically observed carbapenemase OXA-48 V120L, supports the proposal that class D SBL-catalyzed rearrangement of β-lactams to β-lactones is important as a resistance mechanism.

Mitochondria are specialized compartments that produce requisite ATP to fuel cellular functions and serve as centers of metabolite processing, cellular signaling, and apoptosis. To accomplish these roles, mitochondria rely on the genetic information in their small genome (mitochondrial DNA) and the nucleus. A growing appreciation for mitochondria's role in a myriad of human diseases, including inherited genetic disorders, degenerative diseases, inflammation, and cancer, has fueled the study of biochemical mechanisms that control mitochondrial function. The mitochondrial transcriptional machinery is different from nuclear machinery. The in vitro re-constituted transcriptional complexes of Saccharomyces cerevisiae (yeast) and humans, aided with high-resolution structures and biochemical characterizations, have provided a deeper understanding of the mechanism and regulation of mitochondrial DNA transcription. In this review, we will discuss recent advances in the structure and mechanism of mitochondrial transcription initiation. We will follow up with recent discoveries and formative findings regarding the regulatory events that control mitochondrial DNA transcription, focusing on those involved in cross-talk between the mitochondria and nucleus.

The QT interval is a recording of cardiac electrical activity. Previous genome-wide association studies identified genetic variants that modify the QT interval upstream of LITAF (lipopolysaccharide-induced tumor necrosis factor-α factor), a protein encoding a regulator of endosomal trafficking. However, it was not clear how LITAF might impact cardiac excitation. We investigated the effect of LITAF on the voltage-gated sodium channel Nav1.5, which is critical for cardiac depolarization. We show that overexpressed LITAF resulted in a significant increase in the density of Nav1.5-generated voltage-gated sodium current INa and Nav1.5 surface protein levels in rabbit cardiomyocytes and in HEK cells stably expressing Nav1.5. Proximity ligation assays showed co-localization of endogenous LITAF and Nav1.5 in cardiomyocytes, whereas co-immunoprecipitations confirmed they are in the same complex when overexpressed in HEK cells. In vitro data suggest that LITAF interacts with the ubiquitin ligase NEDD4-2, a regulator of Nav1.5. LITAF overexpression down-regulated NEDD4-2 in cardiomyocytes and HEK cells. In HEK cells, LITAF increased ubiquitination and proteasomal degradation of co-expressed NEDD4-2 and significantly blunted the negative effect of NEDD4-2 on INa. We conclude that LITAF controls cardiac excitability by promoting degradation of NEDD4-2, which is essential for removal of surface Nav1.5. LITAF-knockout zebrafish showed increased variation in and a nonsignificant 15% prolongation of action potential duration. Computer simulations using a rabbit-cardiomyocyte model demonstrated that changes in Ca2+ and Na+ homeostasis are responsible for the surprisingly modest action potential duration shortening. These computational data thus corroborate findings from several genome-wide association studies that associated LITAF with QT interval variation.

The cystic fibrosis transmembrane conductance regulator (CFTR) is a plasma membrane anion channel that plays a key role in controlling transepithelial fluid movement. Excessive activation results in intestinal fluid loss during secretory diarrheas, whereas CFTR mutations underlie cystic fibrosis (CF). Anion permeability depends both on how well CFTR channels work (permeation/gating) and on how many are present at the membrane. Recently, treatments with two drug classes targeting CFTR—one boosting ion-channel function (potentiators) and the other increasing plasma membrane density (correctors)—have provided significant health benefits to CF patients. Here, we present an image-based fluorescence assay that can rapidly and simultaneously estimate both CFTR ion-channel function and the protein's proximity to the membrane. We monitor F508del-CFTR, the most common CF-causing variant, and confirm rescue by low temperature, CFTR-targeting drugs and second-site revertant mutation R1070W. In addition, we characterize a panel of 62 CF-causing mutations. Our measurements correlate well with published data (electrophysiology and biochemistry), further confirming validity of the assay. Finally, we profile effects of acute treatment with approved potentiator drug VX-770 on the rare-mutation panel. Mapping the potentiation profile on CFTR structures raises mechanistic hypotheses on drug action, suggesting that VX-770 might allow an open-channel conformation with an alternative arrangement of domain interfaces. The assay is a valuable tool for investigation of CFTR molecular mechanisms, allowing accurate inferences on gating/permeation. In addition, by providing a two-dimensional characterization of the CFTR protein, it could better inform development of single-drug and precision therapies addressing the root cause of CF disease.

The novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) has emerged to a pandemic and caused global public health crisis. Human angiotensin-converting enzyme 2(ACE2) was identified as the entry receptor for SARS-CoV-2. As a carboxypeptidase, ACE2 cleaves many biological substrates besides angiotensin II to control vasodilatation and vascular permeability. Given the nanomolar high affinity between ACE2 and SARS-CoV-2 spike protein, we investigated how this interaction would affect the enzymatic activity of ACE2. Surprisingly, SARS-CoV-2 trimeric spike protein increased ACE2 proteolytic activity ∼3-10 fold against model peptide substrates, such as caspase-1 substrate and Bradykinin-analog. The enhancement in ACE2 enzymatic function was mediated by the binding of SARS-CoV-2 spike RBD domain. These results highlighted the potential for SARS-CoV-2 infection to enhance ACE2 activity, which may be relevant to the cardiovascular symptoms associated with COVID-19.

The inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs), which form tetrameric channels, play pivotal roles in regulating the spatiotemporal patterns of intracellular calcium signals. Mutations in IP3Rs have been increasingly associated with many debilitating human diseases such as ataxia, Gillespie syndrome, and generalized anhidrosis. However, how these mutations affect IP3R function, and how the perturbation of as-sociated calcium signals contribute to the pathogenesis and severity of these diseases remains largely uncharacterized. Moreover, many of these diseases occur as the result of autosomal dominant inheritance, suggesting that WT and mutant subunits associate in heterotetrameric channels. How the in-corporation of different numbers of mutant subunits within the tetrameric channels affects its activities and results in different disease phenotypes is also unclear. In this report, we investigated representative disease-associated missense mutations to determine their effects on IP3R channel activity. Additionally, we designed concatenated IP3R constructs to create tetrameric channels with a predefined subunit composition to explore the functionality of heteromeric channels. Using calcium imaging techniques to assess IP3R channel function, we observed that all the mutations studied resulted in severely attenuated Ca2+ release when expressed as homotetramers. However, some heterotetramers retained varied degrees of function dependent on the composition of the tetramer. Our findings suggest that the effect of mutations depends on the location of the mutation in the IP3R structure, as well as on the stoichiometry of mutant subunits assembled within the tetrameric channel. These studies provide insight into the pathogenesis and penetrance of these devastating human diseases.

Digital politics threatens democracy and must change Expert comment NCapeling 13 January 2023

Violence in Brazil has again brought into focus the need for technology platforms to prioritize social responsibility to help prevent anti-democratic action.

Immediately following the violent storming of Brazil’s congressional building, supreme court, and presidential palace, comparisons to the infamous events of 6 January 2021 in the US came quickly and easily – and with good reason.

Both Donald Trump and Jair Bolsonaro built a fervent – albeit inchoate – political base of grievance which included Christian evangelicals, gun enthusiasts, and the disenfranchised. Both cynically spread doubts about the election victories of their successors without evidence. And it has been claimed both incited their supporters to overturn these results.

But this list of similarities extend beyond mere politics. The attack on democracy in Brazil was recorded, amplified, coordinated, and funded by exactly the same technologies used by the protesters in the US on 6 January.

In Brazil, the main engines of misinformation and insurrection planning were Telegram, Facebook, and WhatsApp, although some election-denying diehards also shifted to Twitter.

Tactical use of social media to mobilize and fundraise

When Bolsonaro was originally elected in 2018, these platforms were already a medium for promoting disinformation, conspiracy, and fear. But in the lead-up to the violence of 8 January, they became a means by which ‘Bolsonaristas’ raised funding for an attack and mobilized supporters to come to Brasilia – advertising the availability of buses and even free food for marchers – using the Festa da Selma hashtag.

To avoid detection by authorities, organizers used a simple switch of the letter ‘v’ to ‘m’ so that Selva, meaning ‘jungle’, became Selma – which means ‘party in the jungle’ to those in the know. But the authorities in the Brasilia state of Distrito Federal appeared to care little about preventing the attack anyway.

Civil society organizations have warned for decades that policies made in a Silicon Valley boardroom fit poorly to the realities of countries such as Brazil, Somalia, or Myanmar. Content moderation is a near-impossible task at the scale demanded by platforms as vast as those operated by big tech, and automated solutions are far from being a silver bullet as they create as many problems as they solve.

Extremism has found an unfettered enabler on mainstream platforms, and an increasingly sprawling network of alternative tech has made such voices resilient to challenge. Platforms such as Gettr, Gab, and Telegram have become go-to platforms for extremist networks when fringe voices find themselves blocked by mainstream platforms.

Telegram has come under significant scrutiny for the role it played in the storming of Congress in Brasilia but any number of tools and platforms – each with millions of users – could have achieved similar results.

The sordid events in Brasilia are just the latest chapter in digital extremism and conspiracy- mongering which often erupts into anti-democratic violence, and should serve as a reminder of the urgent risks of disinformation and the role digital technology plays in inciting, coordinating, fundraising, and amplifying such events.

But the checks on the power of private social media companies are still few and splintered. In Brazil, Supreme Court Justice Alexandre de Moraes, head of the elections tribunal, attempted to crack down on social media, banning users for spreading misinformation in a move which sparked complaints of censorship from Bolsonaro supporters.

Following the elections, Moraes has advocated for greater judicial authority to regulate social media – but the justice is only one person and his impartiality is already being challenged given his aggressive pursuit of Bolsonaro supporters posting inflammatory messages.

And one justice doing it alone only inflames an already volatile situation. Effective regulation of social media requires an independent body vested with multiparty support and operating under clearly-defined rules and authority.

A global movement to find solutions

Brazil is not alone in an increasingly frantic search for checks on digital power as dozens of regulatory regimes are springing up around the world. All are premised on platforms being responsible for their own fiefdoms, but few tackle the threat posed to democracy by unchecked corporate power over digital commons.

Well-intentioned regulation will fall short so long as it is narrowly focused on a never-ending game of ‘content whack-a-mole’ and is hamstrung by powerful voices who see any rules as an attack on freedoms of expression or corporate decision-making.

Democracies are traditionally cautious in managing speech, in separating good information from bad information, or in defining acceptable politics. The steady watering down of the UK’s Online Safety Bill, now so thin on disinformation as to be essentially homeopathic, shows that democratic regulation is willing to go only so far in tackling challenges posed by digital politics.

Despite its major importance in human health, the metabolic potential of the human gut microbiota is still poorly understood. We have recently shown that biosynthesis of Ruminococcin C (RumC), a novel ribosomally synthesized and posttranslationally modified peptide (RiPP) produced by the commensal bacterium Ruminococcus gnavus, requires two radical SAM enzymes (RumMC1 and RumMC2) catalyzing the formation of four Cα-thioether bridges. These bridges, which are essential for RumC's antibiotic properties against human pathogens such as Clostridium perfringens, define two hairpin domains giving this sactipeptide (sulfur-to-α-carbon thioether–containing peptide) an unusual architecture among natural products. We report here the biochemical and spectroscopic characterizations of RumMC2. EPR spectroscopy and mutagenesis data support that RumMC2 is a member of the large family of SPASM domain radical SAM enzymes characterized by the presence of three [4Fe-4S] clusters. We also demonstrate that this enzyme initiates its reaction by Cα H-atom abstraction and is able to catalyze the formation of nonnatural thioether bonds in engineered peptide substrates. Unexpectedly, our data support the formation of a ketoimine rather than an α,β-dehydro-amino acid intermediate during Cα-thioether bridge LC–MS/MS fragmentation. Finally, we explored the roles of the leader peptide and of the RiPP precursor peptide recognition element, present in myriad RiPP-modifying enzymes. Collectively, our data support a more complex role for the peptide recognition element and the core peptide for the installation of posttranslational modifications in RiPPs than previously anticipated and suggest a possible reaction intermediate for thioether bond formation.

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.

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.

The aftermath: Navigating a Taliban-led Afghanistan Expert comment NCapeling 20 August 2021

In the coming weeks, governments and international organizations must work through an approach to the Taliban takeover of Afghanistan. It will not be simple.

A failure to acknowledge that the legitimate, elected representatives of Afghanistan are no longer in control of territory or institutions, and to refuse to deal with those that are, will only make for further misery for a population which has already endured decades of violence and poverty.

But to recognize the Taliban risks condemning tens of thousands of Afghan women, children, and men to brutal repression and, for some, potential death, as well as mocking the human rights and rule of law which the US and its allies sought to promote in Afghanistan, and globally, as cornerstones of values-based foreign policies.

The dilemma western governments find themselves in is one they have studiously sought to avoid despite mounting evidence that, without a negotiated deal, a Taliban takeover was only a matter of time. As late as 6 August, the UN Security Council refused to countenance appeals by the UN mission and Afghan civil society activists to press the Taliban and the government to negotiate a ceasefire.

The US reiterated its refrain that it ‘will not accept a military takeover of Afghanistan’ and the UK stressed the Taliban’s only route to power was through meaningful engagement in a peace process. Meanwhile, not until 11 August did Germany and the Netherlands stop deporting Afghan migrants despite the pleas of Afghan authorities and refugee organizations that the country was on the brink of crisis.

Delaying the inevitable

Belief that a military takeover was still some months away may have led diplomats to view dealing with the Taliban as a distant task. The unilateral nature of the US deal with the Taliban and the resistance of the Ghani government to any suggestion of power-sharing arrangements compounded a lack of international coordination and planning on what the conditions for engagement might be.

It cannot be delayed further. The scale of the humanitarian crisis in Afghanistan is daunting, with more than half a million displaced by fighting in 2021 alone, almost 17 million facing crisis levels of food insecurity, and nearly half of all children under five malnourished as a consequence of drought and the COVID-19 pandemic.

With one of the highest global refugee populations and an estimated up 20-30,000 Afghans fleeing the country weekly – even before the government collapsed – Afghanistan evokes still raw memories of the 2015 Syria migrant crisis for Europe. Pakistan and Turkey, home to some of the largest Afghan refugee communities, have already closed their borders to more.

The ongoing chaos at Kabul airport highlights the challenges ahead. But there is a small window – before the UN Security Council is scheduled to review the mandate of the UN mission in Afghanistan by 17 September – for the US and its allies to craft an approach to dealing with the Taliban.

Formal recognition of a Taliban-led government is simply not an option, even for those maintaining a diplomatic presence in Kabul such as China, Iran, Pakistan, and Russia. Technically the Afghan republic has not yet dissolved with vice-president Amrullah Saleh, reportedly in hiding in the Panjshir valley, claiming he is the country’s ‘caretaker’ president.

Conditions for international acceptance

Afghanistan’s ‘enduring partners’ must now focus on building a consensus around five conditions for international acceptance of a Taliban-administered Afghanistan and prevent the Taliban again reaping the benefits of international divisions. The G7 began to articulate some of these conditions but they need to be set out and negotiated with Afghanistan’s neighbours before being formally articulated by the UN Security Council.

1. Adherence to Afghanistan’s human rights obligations. This must specify the rights of women and girls to education and work, the protection of ethnic and religious minorities, and safe passage for all Afghans and internationals leaving the country.
2. Amnesty for all individuals who worked for the Afghan government or international embassies, forces, or aid organizations since 2001.
3. No harbouring of terrorist groups. This has been the central condition for the US deal with the Taliban, and the overriding concern for both China and Russia.
4. Non-lethal public order. The provision of public order to enable supply routes to open, evacuations to continue, and aid to be delivered, is essential and one that Russia has made as a condition for its future relations.
5. Negotiation of inclusive political arrangements with Afghanistan’s political and ethnic factions.

The UN mission in Afghanistan, including its human rights component, and the Al-Qaida Sanctions Committee’s Analytical Support and Sanctions Monitoring Team should be mandated with reporting monthly on the progress toward these five conditions. Their assessments should form the basis for any reconsideration of the Taliban’s status as a terrorist organization. And a negotiated political settlement must be a precondition to the release of the government’s foreign reserves, estimated to be $9.5 billion.

Before this, the humanitarian and development aid on which Afghanistan is almost completely reliant must be recalibrated to flow through international agencies. Models such as Hamas-run Gaza, Assad’s Syria, or Aristide’s Haiti, show that while far from effective, it is possible to provide urgent assistance outside government channels.

This is one of the reasons why the Taliban has sought to retain a strong UN presence across Afghanistan and why the UN must be given a more significant political mandate and resources. The World Bank-administered Afghan Reconstruction Trust Fund should remain the principal channel for international funds.

It is difficult in the short-term to see the US leading this collective effort, given its defensive and domestic-focused position. It could be a moment for the UK and EU to demonstrate their multilateral commitments and forge a coordinated conditions-based approach to a Taliban-administered Afghanistan at the UN.

Going beyond handwringing or gesture politics will be difficult and messy and, ultimately, Afghanistan’s future must be decided by Afghans. Until that day, however, this will save lives.

How the world has changed on my watch The World Today mhiggins.drupal 25 May 2022

As Robin Niblett steps down from his role as Director of Chatham House he reflects on the past 15 years of international affairs

International relations had resumed a steadier rhythm in January 2007 when I became Director of Chatham House. The aftershock of the 2001 terrorist attacks on the United States and the Bush administration’s contentious responses in Iraq and its ‘global war on terror’ had settled down somewhat.

That year President George W Bush’s second administration was mending fences with its European allies. China’s GDP growth hit a three-decade peak of 14 per cent, and the idea that this could drive a ‘win-win’ economic cycle did not yet grate. Financial regulators had not woken up to the credit crisis that they had enabled. And the European Union was still obsessed with ‘widening versus deepening’, while Britain tried to have its cake and eat it on the sidelines.

With hindsight, 2007 acted as the fulcrum between a cautiously optimistic post-Cold War world and the contested environment we live in today. Russian President Vladimir Putin chose that year’s Munich Security Conference to deliver a tirade against the injustices of a US-led world, with arguments that presaged this year’s invasion of Ukraine.

By the start of 2008, Alan Greenspan’s belief in the rationality of financial markets turned out to be a fallacy as US and European banks imploded. The subsequent economic turmoil, followed by monetary easing and fiscal austerity, sowed the seeds for the populist politics that emerged on both sides of the Atlantic.

Nevertheless, world leaders did not give up on the promise of international cooperation. The global financial crisis led to the elevation of the G20 as the premier forum for coordinating global economic policy between the world’s major economies.

By 2015, with Barack Obama in the White House, two landmark deals were reached: the Paris Agreement and the Joint Comprehensive Plan of Action, an example of truly global cooperation between all five permanent members of the UN Security Council. The next year, China’s first female chair of the Foreign Affairs Committee of the National People’s Congress, Fu Ying, pointed to a ‘decentralization of world power’ that might lead to a more inclusive world order.

But this sense of relative optimism about the future masked two fundamental changes. The first was the erosion of the cohesion of democratic societies under the pressures of globalization and the aftershocks of the financial crisis.

Instant access to unintermediated and often manipulated information ended up stimulating and polarizing societies in equal measure, deepening the divide between those searching for the certainties of the past and those open to the uncertainties of a more globalized future.

The second change is the end of the global hierarchy that followed the Second World War, in which the US and the West remained at the top, even with the advent of a more polycentric world. This change is driven by several factors, above all the growing economic and technological parity between China and the US, and by America’s schizophrenic response.

The Obama administration sought to restore a more inclusive form of global leadership, but it unwittingly revealed the limits of US power by breaking its red lines over Bashir al-Assad’s use of chemical weapons in Syria and by turning a blind eye to China’s takeover of disputed islands in the South China Sea. Donald Trump’s America First policies then flipped the US into an overbearing version of other self-interested powers. After this zigzagging by the US, leaders in the Middle East have developed their own assertive foreign policies, while two nascent democracies in Southeast Asia, Thailand and Myanmar, are again ruled by military juntas.

EU leaders became obsessed with the idea of strategic autonomy. And, although Joe Biden’s election was welcomed across most of Europe, it could not assuage concerns about the potentially transitory nature of his claim that ‘America is back’.

Putin has seized on this moment of transatlantic uncertainty and post-Covid navel-gazing to try to create a personal legacy as the leader who reunited a greater Russia out of the rubble of the Soviet Union. Instead, he has united Ukrainians and reunited the world’s liberal democracies in opposition to his brutal invasion and blatant rupture of international law. His actions have also drawn the contours of a new, trilateral international system.

Some 40 democracies across North America, Europe and the Indo-Pacific now see Putin and Xi Jinping – given China’s rhetorical support for Putin’s invasion – as interconnected threats to their long-term security. They are organizing to resist, using a re-energized Nato, new structures for Indo-Pacific cooperation and cross-linkages between these two spheres. For their part, Putin and Xi, though not formal allies, are tied together by each one’s need that the other survives and prospers while they are in confrontation with the liberal democracies.

The third, largest and most diverse group of countries are the newly non-aligned. India stands proudly in the foreground, but other major democracies such as Brazil, Indonesia and South Africa, and non-democracies such as Egypt and Vietnam, are triangulating strategically between the world’s dominant democratic and authoritarian poles. Multilateral institutions will be weaker as a result.

Does this more divided world presage major conflict between the great powers? Hopefully not; after all, nuclear weapons remain a potent deterrent. Does global division herald the end of economic globalization and of the international cooperation needed to manage shared global challenges? Not necessarily.

While Russia will be excluded from liberal democratic markets for as long as Putin is in the Kremlin, China’s reliance on global markets and the importance of its market to the world make it unlikely that we will return to a new Cold War. Global supply chains and foreign investment will be more tightly circumscribed than today, but they will persist. And international cooperation to combat climate change and manage the environment will continue.

Meanwhile, technological innovation will accelerate, opening new prospects for sustainable development and employment, even as it sharpens the facets of geopolitical competition. And we may soon cross the tipping point at which women hold a critical mass of positions of political and community leadership in many parts of the world. Given that male leaders are, once again, the instigators of the latest spasms of violence, a more gender-balanced approach to leadership holds the prospect of greater political stability and more inclusive and sustainable development.

As I step down as Chatham House Director, I find myself torn between fury at the senseless human tragedy of a drawn-out war in Ukraine and the way its spillover effects are devastating the welfare of hundreds of millions across the globe, and hope that human courage, resilience and ingenuity will nevertheless sustain us on the path to a better future.

I am reassured in this by the knowledge that Chatham House’s researchers, professional staff and increasingly diverse membership mean that it is well placed to help decision-makers and societies navigate this complex world.

SNF Dialogues: Social media, social movements and political change 6 July 2022 — 2:30PM TO 3:45PM Anonymous (not verified) 15 June 2022 Online

Experts and activists explore how the digital world has changed the nature of social movements and the impact this has on policymaking.

From Extinction Rebellion to Black Lives Matter, social movements are increasingly harnessing social media to project their calls for action. This event, convened in partnership with the SNF Dialogues series, will reflect on the value of social media to social movements and the effects of such digital movements on policymakers. Experts and activists from around the world will explore whether social media is an effective tool for social movements or a distraction, the extent to which digital forms of protest incite social change, and finally if this change has an impact on policy decisions.

The SNF Dialogues, an initiative of the Stavros Niarchos Foundation (SNF), are a series of monthly discussions whose goal is to foster the exchange of ideas, inspire a new way of thinking and acting, and encourage and elevate public discourse across geographic boundaries. The Dialogues discussions are free and open to the public, aiming to bring to light timely questions and developments, share informed reflections and concerns, highlight new data and angles, and present fascinating people, projects and ideas.

The Dialogues are curated and moderated by Anna-Kynthia Bousdoukou and are facilitated by the non-profit journalism organization iMEdD (incubator for Media Education and Development).

The discussion will be conducted in English with simultaneous interpretation into Greek. If you wish to watch the discussion in Greek, tune in here.

Grassroots to global: Young changemakers against violence 24 October 2024 — 3:00PM TO 4:00PM Anonymous (not verified) 11 October 2024 Chatham House

As part of Black History Month, this event will look at how youth activism against violence can influence change.

To address the alarming increase knife crime, a 10% rise in knife-related homicides between April 2022 and March 2023, the UK government launched a coalition of community leaders, campaigners and policy makers to tackle this tragic loss of life.

With people under 25 disproportionately affected, the ‘knife crime epidemic’ represents an example of how youth activist groups are central to tackling the problem. Organisations for and operated by young people form a key part of the strategy to ensure people are better protected from violent crime.

Around the world, a network of youth groups are similarly striving to make a difference and build a better life for future generations. Operating in different political and economic conditions, there are learnings to be found in groups working across the world.

This session will discuss how grassroot activism and youth organisations can influence governments to prevent young people falling into crime, the role of race and religion, and whether organisations are improving in their effectiveness around the world.

This event is a collaboration with Integrate UK.

The killing of Yahya Sinwar won’t change the course of the Gaza war Expert comment jon.wallace 18 October 2024

Israel has larger ambitions for Gaza beyond the Hamas leader’s death and the armed group is still asserting its influence despite its degradation.

After a year of being hunted as one of the most wanted men in the Middle East, Hamas leader Yahya Sinwar was killed by Israeli forces on 17 October, in the city of Rafah in the Gaza Strip.

Hailing from Khan Younis refugee camp, Sinwar was imprisoned in Israel in 1989 for the abduction and killing of two Israeli soldiers. He was freed alongside 1,000 other prisoners during a major 2011 exchange, gradually building a notorious reputation as an intelligent and ruthless political figure.

As Hamas’ Gaza chief since 2017, Sinwar oversaw the consolidation of the movement’s authoritarian rule in the Strip and co-directed its military confrontations with Israel. He is regarded as a chief architect of Hamas’ deadly assault of 7 October, which killed 1,200 Israelis, mostly civilians, in southern communities.

Many world leaders and pundits were quick to embrace Sinwar’s death as an opportunity to press for a ceasefire in Gaza and secure the release of roughly 100 Israeli hostages still held by Hamas and other groups. It is too early to know the full repercussions of this development, but these hopes are largely misplaced – and reflect a reluctance to confront the larger obstacles and motivations that are preventing an end to the war.

Morale amid aimlessness

For Israelis, Sinwar’s death is undoubtedly a morale booster. It is a symbolic victory over a man deemed responsible for the 7 October massacres, and a tactical success that rids Israel of a formidable foe – one who was also an invested ally of Iran and the Axis of Resistance. Israeli politicians and generals will relish the news as another step towards restoring their reputations after their failure to prevent the 7 October attack.

Yet contrary to some wishful thinking, Sinwar’s death is unlikely to change Israel’s calculus in Gaza. Prime Minister Benjamin Netanyahu, whose popularity has been slowly recovering in recent months, described the news as ‘the beginning of the end’ but warned that ‘the task before us is not yet complete’.

The intensification of Israel’s war with Hezbollah – including a ground invasion of Lebanon, airstrikes across the country, and the displacement of over 1 million people – has shifted Israelis’ focus away from Gaza over the past month, especially as Hezbollah rockets disrupt life in Israel’s central cities as well as the north.

During that time, the Israeli army has begun a major offensive in the northern part of the Strip, implementing what appears to be the first part of the so-called ‘General’s Plan’ – an operation to besiege and force out roughly 300,000 Palestinian civilians who remain in the area. It could also pave the way for Israel’s absorption of part of the territory. (Israel’s military has denied pursuing the plan).

As such, the Israeli government has relegated the importance of the hostages. Netanyahu is eager to divert the public’s frustration with his months-long sabotage of a deal, while the military – despite its clashes with the prime minister – is seizing the chance to redraw Israel’s geopolitical environment. Even if a deal is struck in the wake of Sinwar’s death, Israel’s bombing and carving-up of Gaza and south Lebanon will likely continue.

Dynamic but degraded

For Hamas, the killing of its fiery politburo chief – just over two months after the assassination of his predecessor Ismail Haniyeh in Tehran – is certainly a blow to its leadership and internal stability. But the Islamist movement’s dynamism has not changed. Hamas’s decision-making processes are not pegged to specific individuals, and other figures, whether in Gaza or in exile, will be rotated into senior positions.

It is unclear whether Hamas will promote a leader who shares Sinwar’s hardline orientation, or drift back to a more moderate figure similar to Haniyeh. Regardless, Hamas’s core demands in any ceasefire and hostage negotiations are unlikely to shift significantly. The movement is still seeking a permanent end to the war, and Israel is still refusing to grant it.

Hamas’s military capacity has been severely degraded by the Israeli offensive, not least by the fact that much of Gaza has been made unliveable and ungovernable. But the movement is far from destroyed. Its militants continue to fight a guerrilla war to undermine Israel’s foothold in Gaza, while trying to reassert Hamas control over public order, the war economy, and the distribution of aid.

Moreover, as the history of movements like Hamas and Hezbollah shows, the devastating nature of Israel’s campaigns and occupations are planting the seeds for further militancy among Palestinians, whether organized under Hamas or smaller, decentralized groups. The war has brutally decimated Gaza’s society, and the notion that killing figures like Sinwar will dissuade future recruits to fight Israel is fanciful.

On the Palestinian political level, Hamas and Fatah are still in talks about forming a unity agreement, though negotiations have so far remained fruitless. Even if a pact is made, Israel’s relentless targeting of Hamas personnel, the perception of the Fatah-led Palestinian Authority (PA) as feckless collaborators, and Palestinians’ feeling of total abandonment raise doubts about the parties’ ability to regain popular support or legitimacy – whether to lead an interim government or the wider national movement.

The gravest threat

The killing of Sinwar is a significant marker in the Gaza war, with important ramifications for the movement he led and the conflict he seismically shaped. Israel will portray his death as validation of its aggressive military approach, and a further step in the erosion of Iran’s regional influence – an agenda the US has actively supported.

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

Weerapan Khovidhunkit
Jul 1, 2004; 45:1169-1196
Thematic Reviews

William R. Morrison
Oct 1, 1964; 5:600-608
Articles

JP Segrest
Feb 1, 1992; 33:141-166
Reviews

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.

Seven ways Russia’s war on Ukraine has changed the world Feature jon.wallace 17 February 2023

Chatham House experts examine the shifts in geopolitical alliances, security, energy, and supply chains and whether these changes are likely to be long-lasting.

President Vladimir Putin’s decision to launch a full-scale re-invasion of Ukraine one year ago was a global shock which ‘marked an abrupt end to 30 years of globalization and all the international co-operation that made that possible’ with serious implications for countries around the world, outlined Chatham House director Bronwen Maddox in her inaugural lecture.

Not only has the war threatened the stability of Europe but it has also impacted food and energy security globally including in the Middle East and Africa, creating shock waves in a world barely recovering from the COVID-19 pandemic.

Hepatocyte nuclear factor-1β (HNF-1β) is a tissue-specific transcription factor that is required for normal kidney development and renal epithelial differentiation. Mutations of HNF-1β produce congenital kidney abnormalities and inherited renal tubulopathies. Here, we show that ablation of HNF-1β in mIMCD3 renal epithelial cells results in activation of β-catenin and increased expression of lymphoid enhancer–binding factor 1 (LEF1), a downstream effector in the canonical Wnt signaling pathway. Increased expression and nuclear localization of LEF1 are also observed in cystic kidneys from Hnf1b mutant mice. Expression of dominant-negative mutant HNF-1β in mIMCD3 cells produces hyperresponsiveness to exogenous Wnt ligands, which is inhibited by siRNA-mediated knockdown of Lef1. WT HNF-1β binds to two evolutionarily conserved sites located 94 and 30 kb from the mouse Lef1 promoter. Ablation of HNF-1β decreases H3K27 trimethylation repressive marks and increases β-catenin occupancy at a site 4 kb upstream to Lef1. Mechanistically, WT HNF-1β recruits the polycomb-repressive complex 2 that catalyzes H3K27 trimethylation. Deletion of the β-catenin–binding domain of LEF1 in HNF-1β–deficient cells abolishes the increase in Lef1 transcription and decreases the expression of downstream Wnt target genes. The canonical Wnt target gene, Axin2, is also a direct transcriptional target of HNF-1β through binding to negative regulatory elements in the gene promoter. These findings demonstrate that HNF-1β regulates canonical Wnt target genes through long-range effects on histone methylation at Wnt enhancers and reveal a new mode of active transcriptional repression by HNF-1β.

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