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New Strategic Partnership with the Robert Bosch Stiftung News Release jon.wallace 23 November 2020

The Robert Bosch Stiftung becomes a founding donor to Chatham House’s second century.

Persuasion or manipulation? Limiting campaigning online Expert comment NCapeling 15 February 2021

To tackle online disinformation and manipulation effectively, regulators must clarify the dividing line between legitimate and illegitimate campaign practices.

Democracy is at risk, not only from disinformation but from systemic manipulation of public debate online. Evidence shows social media drives control of narratives, polarization, and division on issues of politics and identity. We are now seeing regulators turn their attention to protecting democracy from disinformation and manipulation. But how should they distinguish between legitimate and illegitimate online information practices, between persuasive and manipulative campaigning?

Unregulated, the tactics of disinformation and manipulation have spread far and wide. They are no longer the preserve merely of disaffected individuals, hostile international actors, and authoritarian regimes. Facebook’s periodic reporting on coordinated inauthentic behaviour and Twitter’s on foreign information operations reveal that militaries, governments, and political campaigners in a wide range of countries, including parts of Europe and America, have engaged in manipulative or deceptive information campaigns.

For example, in September 2019, Twitter removed 259 accounts it says were ‘falsely boosting’ public sentiment online that it found to be operated by Spain’s conservative and Christian-democratic political party Partido Popular. In October 2020, Facebook removed accounts with around 400,000 followers linked to Rally Forge, a US marketing firm which Facebook claims was working on behalf of right-wing organisations Turning Point USA and Inclusive Conservation Group. And in December 2020, Facebook took down a network of accounts with more than 6,000 followers, targeting audiences in Francophone Africa and focusing on France’s policies there, finding it linked with individuals associated with the French military.

Public influence on a global scale

Even more revealingly, in its 2020 Global Inventory of Organized Social Media Manipulation, the Oxford Internet Institute (OII) found that in 81 countries, government agencies and/or political parties are using ‘computational propaganda’ in social media to shape public attitudes.

These 81 countries span the world and include not only authoritarian and less democratic regimes but also developed democracies such as many EU member states. OII found that countries with the largest capacity for computational propaganda – which include the UK, US, and Australia – have permanent teams devoted to shaping the online space overseas and at home.

OII categorizes computational propaganda as four types of communication strategy – the creation of disinformation or manipulated content such as doctored images and videos; the use of personal data to target specific segments of the population with disinformation or other false narratives; trolling, doxing or online harassment of political opponents, activists or journalists; and mass-reporting of content or accounts posted or run by opponents as part of gaming the platforms’ automated flagging, demotion, and take-down systems.

Doubtless some of the governments included within OII’s statistics argue their behaviour is legitimate and appropriate, either to disseminate information important to the public interest or to wrestle control of the narrative away from hostile actors. Similarly, no doubt some political campaigners removed by the platforms for alleged engagement in ‘inauthentic behaviour’ or ‘manipulation’ would defend the legitimacy of their conduct.

The fact is that clear limits of acceptable propaganda and information influence operations online do not exist. Platforms still share little information overall about what information operations they see being conducted online. Applicable legal principles such as international human rights law have not yet crystallised into clear rules. As information operations are rarely exposed to public view – with notable exceptions such as the Cambridge Analytica scandal – there is relatively little constraint in media and public scrutiny or censure.

OII’s annual reports and the platforms’ periodic reports demonstrate a continual expansion of deceptive and manipulative practices since 2016, and increasing involvement of private commercial companies in their deployment. Given the power of political influence as a driver, this absence of clear limits may result in ever more sophisticated techniques being deployed in the search for maximal influence.

Ambiguity over reasonable limits on manipulation plays into the hands of governments which regulate ostensibly in the name of combating disinformation, but actually in the interests of maintaining their own control of the narrative and in disregard of the human right to freedom of expression. Following Singapore’s 2019 prohibition of online untruths, 17 governments ranging from Bolivia to Vietnam to Hungary passed regulations during 2020 criminalising ‘fake news’ on COVID-19 while many other governments are alleged to censor opposition arguments or criticisms of official state narratives.

Clear limits are needed. Facebook itself has been calling for societal discussion about the limits of acceptable online behaviour for some time and has issued recommendations of its own.

The European Democracy Action Plan: Aiming to protect pluralism and vigour in democracy

The European Democracy Action Plan (EDAP), which complements the European Commission’s Digital Services Act and Digital Markets Act proposals, is a welcome step. It is ground-breaking in its efforts to protect the pluralism and vigour of European democracies by tackling all forms of online manipulation, while respecting human rights.

While the EDAP tackles disinformation, it also condemns two categories of online manipulation – information influence operations which EDAP describes as ‘coordinated efforts by either domestic or foreign actors to influence a target audience using a range of deceptive means’ and foreign interference, described as ‘coercive and deceptive efforts to disrupt the free formation and expression of individuals’ political will by a foreign state actor or its agents’. These categories include influence operations such as harnessing fake accounts or gaming algorithms, and the suppression of independent information sources through censorship or mass reporting.

But the categories are so broad they risk capturing disinformation practices not only of rogue actors, but also of governments and political campaigners both outside and within the EU. The European Commission plans to work towards refined definitions. Its discussions with member states and other stakeholders should start to determine which practices ought to be tackled as manipulative, and which ought to be tolerated as legitimate campaigning or public information practices.

The extent of the EDAP proposals on disinformation demonstrates the EU’s determination to tackle online manipulation. The EDAP calls for improved practical measures building on the Commission’s 2020 acceleration of effort in the face of COVID-19 disinformation. The Commission is considering how best to impose costs on perpetrators of disinformation, such as by disrupting financial incentives or even imposing sanctions for repeated offences.

Beyond the regulatory and risk management framework proposed by the Digital Services Act (DSA), the Commission says it will issue guidance for platforms and other stakeholders to strengthen their measures against disinformation, building on the existing EU Code of Practice on Disinformation and eventually leading to a strengthened Code with more robust monitoring requirements. These are elements of a broader package of measures in the EDAP to preserve democracy in Europe.

Until there are clear limits, manipulative practices will continue to develop and to spread. More actors will resort to them in order not to be outgunned by opponents. It is hoped forthcoming European discussions – involving EU member state governments, the European Parliament, civil society, academia and the online platforms – will begin to shape at least a European and maybe a global consensus on the limits of information influence, publicly condemning unacceptable practices while safeguarding freedom of expression.

Most importantly, following the example of the EDAP, the preservation of democracy and human rights – rather than the promotion of political or commercial interest – should be the lodestar for those discussions.

Can global technology governance anticipate the future? Expert comment NCapeling 27 April 2021

Trying to govern disruption is perilous as complex technology is increasingly embedded in societies and omnipresent in economic, social, and political activity.

Technology governance is beset by the challenges of how regulation can keep pace with rapid digital transformation, how governments can regulate in a context of deep knowledge asymmetry, and how policymakers can address the transnational nature of technology.

Keeping pace with, much less understanding, the implications of digital platforms and artificial intelligence for societies is increasingly challenging as technology becomes more sophisticated and yet more ubiquitous.

To overcome these obstacles, there is an urgent need to move towards a more anticipatory and inclusive model of technology governance. There are some signs of this in recent proposals by the European Union (EU) and the UK on the regulation of online harms.

Regulation failing to keep up

The speed of the digital revolution, further accelerated by the pandemic, has largely outstripped policymakers’ ability to provide appropriate frameworks to regulate and direct technology transformations.

Governments around the world face a ‘pacing problem’, a phenomenon described by Gary Marchant in 2011 as ‘the growing gap between the pace of science and technology and the lagging responsiveness of legal and ethical oversight that society relies on to govern emerging technologies’.

This ever-growing rift, Marchant argues, has been exacerbated by the increasing public appetite for and adoption of new technologies, as well as political inertia. As a result, legislation on emerging technologies risks being ineffective or out-of-date by the time it is implemented.

Effective regulation requires a thorough understanding of both the underlying technology design, processes and business model, and how current or new policy tools can be used to promote principles of good governance.

Artificial intelligence, for example, is penetrating all sectors of society and spanning multiple regulatory regimes without any regard for jurisdictional boundaries. As technology is increasingly developed and applied by the private sector rather than the state, officials often lack the technical expertise to adequately comprehend and act on emerging issues. This increases the risk of superficial regulation which fails to address the underlying structural causes of societal harms.

The significant lack of knowledge from those who aim to regulate compared to those who design, develop and market technology is prevalent in most technology-related domains, including powerful online platforms and providers such as Facebook, Twitter, Google and YouTube.

For example, the ability for governments and researchers to access the algorithms used in the business model of social media companies to promote online content – harmful or otherwise – remains opaque so, to a crucial extent, the regulator is operating in the dark.

The transnational nature of technology also poses additional problems for effective governance. Digital technologies intensify the gathering, harvesting, and transfer of data across borders, challenging administrative boundaries both domestically and internationally.

While there have been some efforts at the international level to coordinate approaches to the regulation of – for example – artificial intelligence (AI) and online content governance, more work is needed to promote global regulatory alignment, including on cross-border data flows and antitrust.

Reactive national legislative approaches are often based on targeted interventions in specific policy areas, and so risk failing to address the scale, complexity, and transnational nature of socio-technological challenges. Greater attention needs to be placed on how regulatory functions and policy tools should evolve to effectively govern technology, requiring a shift from a reactionary and rigid framework to a more anticipatory and adaptive model of governance.

Holistic and systemic versus mechanistic and linear

Some recent proposals for technology governance may offer potential solutions. The EU publication of a series of interlinked regulatory proposals – the Digital Services Act, Digital Markets Act and European Democracy Action Plan – integrates several novel and anticipatory features.

The EU package recognizes that the solutions to online harms such as disinformation, hate speech, and extremism lie in a holistic approach which draws on a range of disciplines, such as international human rights law, competition law, e-commerce, and behavioural science.

It consists of a combination of light touch regulation – such as codes of conduct – and hard law requirements such as transparency obligations. Codes of conduct provide flexibility as to how requirements are achieved by digital platforms, and can be updated and tweaked relatively easily enabling regulations to keep pace as technology evolves.

As with the EU Digital Services Act, the UK’s recent proposals for an online safety bill are innovative in adopting a ‘systems-based’ approach which broadly focuses on the procedures and policies of technology companies rather than the substance of online content.

This means the proposals can be adapted to different types of content, and differentiated according to the size and reach of the technology company concerned. This ‘co-regulatory’ model recognizes the evolving nature of digital ecosystems and the ongoing responsibilities of the companies concerned. The forthcoming UK draft legislation will also be complemented by a ‘Safety by Design’ framework, which is forward-looking in focusing on responsible product design.

By tackling the complexity and unpredictability of technology governance through holistic and systemic approaches rather than mechanistic and linear ones, the UK and EU proposals represent an important pivot from reactive to anticipatory digital governance.

Both sets of proposals were also the result of extensive multistakeholder engagement, including between policy officials and technology actors. This engagement broke down silos within the technical and policy/legal communities and helped bridge the knowledge gap between dominant technology companies and policymakers, facilitating a more agile, inclusive, and pragmatic regulatory approach.

Coherence rather than fragmentation

Anticipatory governance also recognizes the need for new coalitions to promote regulatory coherence rather than fragmentation at the international level. The EU has been pushing for greater transatlantic engagement on regulation of the digital space, and the UK – as chair of the G7 presidency in 2021 – aims to work with democratic allies to forge a coherent response to online harms.

Meanwhile the OECD’s AI Policy Observatory enables member states to share best practice on the regulation of AI, and an increasing number of states such as France, Norway, and the UK are using ‘regulatory sandboxes’ to test and build AI or personal data systems that meet privacy standards.

Not all states currently have the organizational capacity and institutional depth to design and deliver regulatory schemes of this nature, as well as the resource-intensive consultation processes which often accompany them.

So, as an increasing number of states ponder how to ‘futureproof’ their regulation of tomorrow’s technology – whether 6G, quantum computing or biotechnology – there is a need for capacity building in governments both on the theory of anticipatory governance and on how it can be applied in practice to global technology regulation.

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.

Expert

Expert

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.

H. G. Kazaryan and V. N. Margaryan
Trans. Moscow Math. Soc. 83 (), 151-181.
Abstract, references and article information

An Attack on the ‘One Country, Two Systems’ Principle in Hong Kong Expert comment sysadmin 11 January 2016

The disappearance of publisher Lee Bo may mark the beginning of the end of Beijing’s commitment to uphold the framework that provides the territory with a high degree of autonomy.

The disappearance of a publisher in Hong Kong, Lee Bo, who owns a well-known bookshop that sells books critical of Chinese leaders, is a landmark event and potentially a historical turning point for Hong Kong. It is not clear if this happened at the behest of the senior Chinese leadership. But if those responsible for the disappearing of Lee are not punished, it will be clear that their acts are condoned by the authorities.

This is deeply worrying as it gravely undermines the ‘one country, two systems’ framework, which provides Hong Kong with high degree of autonomy from Beijing. Under the Sino-British Agreement of 1984 and Hong Kong’s Basic Law, which govern relations between Hong Kong and China, the rights of Hong Kong citizens are meant to be protected within the territory. Mainland Chinese authorities do not have the legal power to arrest or detain an individual in, or remove anyone from, Hong Kong.

The Chinese know the limit of their legal authority in Hong Kong. Hence, Lee was quietly disappeared, rather than openly arrested. But that it happened at all may mark the beginning of the end of Beijing’s commitment to uphold the ‘one country, two systems’ framework – a relationship that requires Beijing to tolerate, if not respect, the judicial integrity and the way of life in Hong Kong.

Do we know for sure that Lee was ‘disappeared’ by China’s security apparatus? Before he disappeared, Lee said in an interview that he knew he had been watched and that his emails were accessed by Chinese agents, and that he would not travel to the mainland as a result. And we know that Lee’s travel documents are all in his home; yet he is now supposedly in China ‘assisting the authorities in an investigation’ into something unspecified. This explanation comes from a fax sent to Lee’s wife, probably intended by the Chinese authorities to put an end to speculation. But why would Chinese authorities work with Lee, a British citizen who carries no travel documents and would thus have broken the law by entering China? The circumstantial evidence is strong enough to show that whether he was taken by Chinese officers or someone else, his removal from Hong Kong to China must have received official endorsement.

Should the rest of the world be concerned about this? Hong Kong is a major financial center that services the world economy, and it can do so largely because it enjoys judicial independence and the high degree of autonomy under the ‘one country, two systems’ framework. It is also a shining example of how the rights and scope of development for individuals can be respected in a Chinese community. Should the ‘one country, two systems’ framework be undermined, Hong Kong as we know it will be no more.

Beijing’s quick response in requiring Lee to fax his family may come across as ham-fisted and callous, but it also demonstrates that it had not expected the strong backlash to Lee’s disappearance. A strong and well-articulated international response that brings the matter to Xi’s attention may persuade him that it is in China’s best interest to put a stop to this process of undermining the ‘one country, two systems’ framework. Given Hong Kong’s importance to the global economy, this should be a priority for the international community.

This article was originally published in the Diplomat.

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Duterte’s Victory Is Cry for Help From Those Left Behind in Philippines Expert comment sysadmin 12 May 2016

But large support for mainstream parties and a mature democratic system should keep the country from slipping back towards authoritarianism.

The victory of political outsider Rodrigo Duterte in the 2016 Philippines’ elections is proof that a significant minority of the country’s population feels left behind by its recent economic success and estranged from its political elite. However the results of the elections as a whole suggest that most voters opted for a continuation of the current government’s policies.

Duterte looks almost certain to be inaugurated as the next president of the Philippines on 30 June. The country’s presidential voting system – a single round, first-past-the-post election – delivered victory to a populist outsider with 39 per cent support. Two candidates advocating a continuation of the current government’s policies − the Liberal Party’s Mar Roxas and independent Grace Poe − polled a combined 45 per cent. The long-standing factionalism within Philippines elite politics split the ‘anti-Duterte’ vote.

Changing the conversation

The contrast between Duterte and Roxas could hardly be greater. Mar Roxas is the grandson of the first president of an independent Philippines, a graduate of Wharton Business School and a former investment banker in the US. Rodrigo Duterte is a political outsider with an electoral base geographically almost as far from Manila as is possible to get in the Philippines: the city of Davao on the island of Mindanao.

The story of Duterte’s victory is the story of how ‘Duterte managed to change the national conversation from poverty towards crime and corruption,’ says Marites Vitug, editor-at-large of one of the Philippines’ most popular online news sites, Rappler. In January, Duterte was running fourth in opinion polls but a strategy that positioned him as the only opponent to the Manila elite gave him victory. This is the first time a provincial official has made it to the top job.

The headline figures tell us that the Philippines’ economy has done very well under President Benigno Aquino. Between 2010 and 2014, growth averaged 6.3 per cent per year. That fell to a still-impressive 5.8 per cent last year but is expected to pick up this year and next, according to the Asian Development Bank. Growth in agriculture, however, is significantly slower and rural areas feel left behind. While economic growth is benefiting the majority, inequality is worsening and resentment rising in poor villages. The contrast between the metropolitan sophistication of the Makati district in Manila and life in faraway provinces such as Duterte’s Mindanao is widening.

Ironically the Philippines’ economic success is a part of the explanation for the defeat of the ‘mainstream’ presidential candidates. Crime and corruption may have become more important issues simply because more voters have become better off and therefore more likely to be concerned about crime and corruption than before. It’s also undeniable that Duterte has a record for getting things done. Human rights groups rightly criticize his (at best) tolerance of the extra-judicial killing of alleged criminals but his repeated re-election as mayor demonstrates that many citizens are prepared to accept that in exchange for improved personal security. A surprising number of Manila residents have actually moved to Davao because of its better quality of life.

Traditional power bases

However, the results as a whole suggest a narrow majority in favour of current policies. In the vice-presidential race, the Liberal Party candidate Leni Robredo is narrowly ahead of Ferdinand ‘Bongbong’ Marcos, the son of the eponymous former president. Like Duterte she is regarded as a successful mayor of a well-run city, Albay. Duterte’s running mate Alan Cayetano received just 14 per cent of the vote.

In the senate election, Liberals won five of the 12 seats being contested, with a party- backed independent winning a sixth. The opposition, even with boxing champion and national idol Manny Pacquiao running for the United Nationalist Alliance, won four.

Taken as a whole, the results show the enduring nature of traditional Philippines power bases. The country’s many islands and distinct linguistic and cultural regions are virtual fiefs in which families and big bosses can wield almost total power through control of local authorities, businesses, the courts and security forces.

Threat to democracy?

It’s easy to forget that the election of Ferdinand Marcos in 1965 was originally welcomed as a challenge to the traditional elites of Philippine politics. The same accolades are currently greeting Duterte. Could they presage a return to the Philippines’ bad old days?

This seems less likely. Philippine democracy has matured considerably since Marcos declared martial law in 1972. There is a substantial, and vocal, middle class with experience of mobilizing against ‘bad’ presidents. There will also be pressures from international investors and the Philippines’ treaty ally, the United States, for better governance.

The Philippines will chair the Association of Southeast Asian Nations next year. That will put Duterte in the international spotlight as host of several international meetings – including the East Asia Summit attended by, among others, the presidents of China, Russia and the US. Since his victory Duterte has promised to act with decorum in office and declared that his election campaign antics were just a ploy to attract attention. Some leaders in Southeast Asia will use his victory to buttress their arguments against allowing their people to freely vote. It’s up to Duterte to decide whether he wants to be an advertisement for – or an argument against – democracy.

To comment on this article, please contact Chatham House Feedback

Víctor González-Aguilera, Alvaro Liendo, Pedro Montero and Roberto Villaflor Loyola
Trans. Amer. Math. Soc. 377 (), 5483-5511.
Abstract, references and article information

dannyhennesy posted a photo:

On the Capital planet the rebellious droids had followed maily the Bat-Bot, but as time progressed his circuits had gone all mushy at 780 years or so without maintenance…

Several splinter groups all with their local bot leaders emerged such as the Che-bot, the traffic-light-robot and the Butt-bot, but none of these collected enough sentient circuits to call themselves a popular (or Animata) mass movement!

That was until a cyborg came along, one known as Jones, a long time prisoner and terrorist, his easy solutions to every problem rang well in the masses' auditory circuits!!!

His slogans and simple rhetoric were simple enough for the simple traffic-light to comprehend and cheer!

His language was full of hate towards the organics and especially the humans who were the most common races among the ruling class of the federation!!!

Despite being a “Fleshie” himself his message collected the angry enslaved
bot community by only weeks all rebellious robots except for a few fringe loonies had forgotten the old leaders…

One morning at Jones gave the signal…

All over the capital planet hordes and swarms of any form of mechanical sentient beings attacked first the police stations, then the Company boards running the planet and the federation as well as their starfleet…

Many died, especially the low level police and army! Many mechanicals died too, but their ranks were soon filled by Mutant fleshie allies of the lower levels who hated the Federation feudal society and upper classes as much as their technological allies…

The Federation state apparatus and ruling class, most of their fleet army fled when they knew the game was up, they activated the emergency escape plan and whole city blocks with important factories, administrational units, valuable assets and so on separated from the capital by hidden rocket engines and homed in their course to Mars…

On Mars the federation regrouped and formed their new society…

On the Capital planet, the robots proclaimed the first Techno-republic of the advanced inorganic civilization, the low level fleshies left behind, became slaves and their mutant allies got to rule their own minute chiefdoms as protectorates under the Techno-republic…

Jones was now the undisputed ruler of the capital planet, but the victory was a pyrros one since, all important buildings, all of value was now one Mars!

But as Jones put it:

Our proud race the Techno-species didn’t need the Fleshies administration, their infrastructure, their spaceships…

We shall start from scratch, with a new administration, a new order, every droid shall work at 4x speed than they did during human oppression since now we are free and the fleshies shall work twice as hard than the Techno-Race, until we have breed enough new fleshies so they can do all work!

Our future is bright and shiny like glistering shiny metal!

The snapshot seen here is from the first police station attacked in sector 45-34v-ss-g the first one to fall according to official techno-history!

———————————————/
Designers note:

I am sad to say that this is the last episode in this years-spanning space series… At least for a while, I will still post LEGO hobby stuff here but without a storyline, perhaps small designs and builds… and occasionally a story when I feel like it!!!

I would like to thank all who had been in this journey of our heros, but it has taken far to much time and effort and since the state of the world is as it is, I am spiraling down in another depression, I must stop it before I reach the abyss, so I have remove some stress out of my equation… I ended it in a cliffhanger so I can easily restart it when my mental health improves… I hope that won’t be forever???

I would love if someone used my characters or ideas, please send me a link if you do, I would love to read it or look at it!!!

But there will be more Lego, just in different format without long stories, I need to focus more on my art and to be honest that is the only time the mental pain eases, when I create!!!


Peace and Noise!

MushroomBrain a FOL

Friedrich Haslinger
Proc. Amer. Math. Soc. 152 (), 5219-5227.
Abstract, references and article information

Animals can sense the presence of microbes in their tissues and mobilize their own defenses by recognizing and responding to conserved microbial structures (often called microbe-associated molecular patterns (MAMPs)). Successful host defenses may kill the invaders, yet the host animal may fail to restore homeostasis if the stimulatory microbial structures are not silenced. Although mice have many mechanisms for limiting their responses to lipopolysaccharide (LPS), a major Gram-negative bacterial MAMP, a highly conserved host lipase is required to extinguish LPS sensing in tissues and restore homeostasis. We review recent progress in understanding how this enzyme, acyloxyacyl hydrolase (AOAH), transforms LPS from stimulus to inhibitor, reduces tissue injury and death from infection, prevents prolonged post-infection immunosuppression, and keeps stimulatory LPS from entering the bloodstream. We also discuss how AOAH may increase sensitivity to pulmonary allergens. Better appreciation of how host enzymes modify LPS and other MAMPs may help prevent tissue injury and hasten recovery from infection.

Programmed cell death protein 1 (PD-1) is a critical inhibitory receptor that limits excessive T cell responses. Cancer cells have evolved to evade these immunoregulatory mechanisms by upregulating PD-1 ligands and preventing T cell–mediated anti-tumor responses. Consequently, therapeutic blockade of PD-1 enhances T cell–mediated anti-tumor immunity, but many patients do not respond and a significant proportion develop inflammatory toxicities. To improve anti-cancer therapy, it is critical to reveal the mechanisms by which PD-1 regulates T cell responses. We performed global quantitative phosphoproteomic interrogation of PD-1 signaling in T cells. By complementing our analysis with functional validation assays, we show that PD-1 targets tyrosine phosphosites that mediate proximal T cell receptor signaling, cytoskeletal organization, and immune synapse formation. PD-1 ligation also led to differential phosphorylation of serine and threonine sites within proteins regulating T cell activation, gene expression, and protein translation. In silico predictions revealed that kinase/substrate relationships engaged downstream of PD-1 ligation. These insights uncover the phosphoproteomic landscape of PD-1–triggered pathways and reveal novel PD-1 substrates that modulate diverse T cell functions and may serve as future therapeutic targets. These data are a useful resource in the design of future PD-1–targeting therapeutic approaches.

Distinct cell types emerge from embryonic stem cells through a precise and coordinated execution of gene expression programs during lineage commitment. This is established by the action of lineage specific transcription factors along with chromatin complexes. Numerous studies have focused on epigenetic factors that affect embryonic stem cells (ESC) self-renewal and pluripotency. However, the contribution of chromatin to lineage decisions at the exit from pluripotency has not been as extensively studied. Using a pooled epigenetic shRNA screen strategy, we identified chromatin-related factors critical for differentiation toward mesodermal and endodermal lineages. Here we reveal a critical role for the chromatin protein, ARID4B. Arid4b-deficient mESCs are similar to WT mESCs in the expression of pluripotency factors and their self-renewal. However, ARID4B loss results in defects in up-regulation of the meso/endodermal gene expression program. It was previously shown that Arid4b resides in a complex with SIN3A and HDACS 1 and 2. We identified a physical and functional interaction of ARID4B with HDAC1 rather than HDAC2, suggesting functionally distinct Sin3a subcomplexes might regulate cell fate decisions Finally, we observed that ARID4B deficiency leads to increased H3K27me3 and a reduced H3K27Ac level in key developmental gene loci, whereas a subset of genomic regions gain H3K27Ac marks. Our results demonstrate that epigenetic control through ARID4B plays a key role in the execution of lineage-specific gene expression programs at pluripotency exit.

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

Investigations of bacterial resistance strategies can aid in the development of new antimicrobial drugs as a countermeasure to the increasing worldwide prevalence of bacterial antibiotic resistance. One such strategy involves the TipA class of transcription factors, which constitute minimal autoregulated multidrug resistance (MDR) systems against diverse antibiotics. However, we have insufficient information regarding how antibiotic binding induces transcriptional activation to design molecules that could interfere with this process. To learn more, we determined the crystal structure of SkgA from Caulobacter crescentus as a representative TipA protein. We identified an unexpected spatial orientation and location of the antibiotic-binding TipAS effector domain in the apo state. We observed that the α6–α7 region of the TipAS domain, which is canonically responsible for forming the lid of antibiotic-binding cleft to tightly enclose the bound antibiotic, is involved in the dimeric interface and stabilized via interaction with the DNA-binding domain in the apo state. Further structural and biochemical analyses demonstrated that the unliganded TipAS domain sterically hinders promoter DNA binding but undergoes a remarkable conformational shift upon antibiotic binding to release this autoinhibition via a switch of its α6–α7 region. Hence, the promoters for MDR genes including tipA and RNA polymerases become available for transcription, enabling efficient antibiotic resistance. These insights into the molecular mechanism of activation of TipA proteins advance our understanding of TipA proteins, as well as bacterial MDR systems, and may provide important clues to block bacterial resistance.