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

Synapse loss is associated with motor and cognitive decline in multiple neurodegenerative disorders, and the cellular redistribution of tau is related to synaptic impairment in tauopathies, such as Alzheimer's disease and frontotemporal dementia. Here, we examined the cellular distribution of tau protein species in human tau overexpressing line 66 mice, a transgenic mouse model akin to genetic variants of frontotemporal dementia. Line 66 mice express intracellular tau aggregates in multiple brain regions and exhibit sensorimotor and motor learning deficiencies. Using a series of anti-tau antibodies, we observed, histologically, that nonphosphorylated transgenic human tau is enriched in synapses, whereas phosphorylated tau accumulates predominantly in cell bodies and axons. Subcellular fractionation confirmed that human tau is highly enriched in insoluble cytosolic and synaptosomal fractions, whereas endogenous mouse tau is virtually absent from synapses. Cytosolic tau was resistant to solubilization with urea and Triton X-100, indicating the formation of larger tau aggregates. By contrast, synaptic tau was partially soluble after Triton X-100 treatment and most likely represents aggregates of smaller size. MS corroborated that synaptosomal tau is nonphosphorylated. Tau enriched in the synapse of line 66 mice, therefore, appears to be in an oligomeric and nonphosphorylated state, and one that could have a direct impact on cognitive function.

The UK's new Online Safety Bill 10 February 2021 — 3:00PM TO 3:45PM Anonymous (not verified) 26 January 2021 Online

Discussing the new proposals which include the establishment of a new ‘duty of care’ on companies to ensure they have robust systems in place to keep their users safe.

Governments, regulators and tech companies are currently grappling with the challenge of how to promote an open and vibrant internet at the same time as tackling harmful activity online, including the spread of hateful content, terrorist propaganda, and the conduct of cyberbullying, child sexual exploitation and abuse.

The UK government’s Online Harms proposals include the establishment of a new ‘duty of care’ on companies to ensure they have robust systems in place to keep their users safe. Compliance with this new duty will be overseen by an independent regulator.

On 15 December 2020, DCMS and the Home Office published the full UK government response, setting out the intended policy positions for the regulatory framework, and confirming Ofcom as the regulator.

With the legislation likely to be introduced early this year, the panel will discuss questions including:

• How to strike the balance between freedom of expression and protecting adults from harmful material?

• How to ensure the legislation’s approach to harm is sufficiently future-proofed so new trends and harms are covered as they emerge?

• What additional responsibilities will tech companies have under the new regulation?

• Will the regulator have sufficient powers to tackle the wide range of harms in question?

This event is invite-only for participants, but you can watch the livestream of the discussion on this page at 15.00 GMT on Wednesday 10 February.

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.

The regional and international implications of restrictions to online freedom of expression in Asia 25 March 2021 — 12:30PM TO 1:30PM Anonymous (not verified) 12 March 2021 Online

Panellists discuss the latest developments affecting online freedom of expression in the Asia region.

Please note this is an online event. Please register using the link below to finalize your registration.

In recent years, state-led clampdowns on online freedom of expression have become widespread in several countries across Asia, further intensified by the COVID-19 crisis.

The reasons for this are complex and diverse – drawing upon history, culture and politics, in addition to external influences. Across the region, governments have been accused of silencing online criticism and failing to uphold rights to free speech.

Individuals have been arrested, fined or attacked for the alleged spread of ‘fake news’, raising concern among human rights organizations. In some countries, this has culminated in the imposition of new social media rules, which could require social media companies to censor posts and share decrypted messages.

In China, the government’s restrictive online regime has relied on a combination of legal, technical and manipulation tactics to manage control of the internet, and now includes attempts at censorship beyond its borders.

Panellists will discuss the latest regional developments affecting online freedom of expression in the Asia region, and will consider the broader regional and international implications for technology governance.

This webinar launches the publication Restrictions on online freedom of expression in China: The domestic, regional and international implications of China’s policies and practices.

Battle lines being drawn over online freedoms in Asia Expert comment NCapeling 22 March 2021

Social media giants are increasingly clashing with Asian governments over free expression and censorship as the region lurches towards digital authoritarianism.

Freedom of expression was subject to significant restrictions in Asia even before the pandemic, with several governments having enacted laws that stifle online debate. But since COVID-19, restrictions have increased even further due to a rash of so-called ‘emergency measures’ introduced by governments across the region.

Bangladesh, India, Indonesia, Malaysia, Myanmar, Nepal, Pakistan, the Philippines, Sri Lanka, Thailand, and Vietnam have all put new laws into place, and many restrictions are already being applied in a draconian fashion, such as in the Philippines and Bangladesh.

As outlined in a new Chatham House research paper, one inspiration behind this trend is China, home to the world’s most sophisticated and restrictive system of internet control. The Chinese government’s restrictive online regime, which has tightened further under COVID-19, relies on a combination of legal regulations, technical controls, and proactive manipulation of online debates.

This model was an inspiration for Vietnam’s cybersecurity law, as well as Myanmar’s new draft cybersecurity bill, proposed by the Military-run State Administration Council in the wake of the military coup last month, which would give the military there extensive powers to access individuals’ data, restrict, or suspend access to the internet.

This ‘sovereignty and control’ model of internet governance is also gaining impetus through China’s ‘Digital Silk Road’ initiative, under which the Chinese government is exporting both its technology – such as through the establishment of smart cities, the installation of AI, and surveillance technology – and its vision of how the internet should be governed.

In November 2020, Xi Jinping pledged to further deepen cooperation with ASEAN through the Digital Silk Road, and the pandemic has expanded the appeal of Chinese surveillance technologies and data collection platforms to governments both in Asia and beyond. China’s Health Silk Road, which aims to promote global health cooperation, is centered on the Chinese government’s high-tech model under which civic freedoms are sacrificed in the name of public health.

An alternative model

This ‘sovereignty and control’ model is increasingly at odds with the more ‘human-centric’ model of tech governance favoured by many democratic states, Western social media companies, and international institutions, especially the United Nations (UN) and European Union (EU).

Although this emerging model also involves regulation, it is regulation which aims to be inclusive, risk-based, and proportionate – balancing the need for protection against online harms with the need to preserve freedom of expression. It is a multi-stakeholder, rights-based approach which brings together not just governments but also representatives of the private sector, civil society, and academia. The EU’s draft Digital Services Act and the UK’s proposals for an Online Safety Bill are both reflective of this approach.

Western social media giants such as Facebook and Twitter have recently introduced new policies which seek to identify and mitigate online harms, such as hate speech and disinformation. Industry bodies such as the Global Network Initiative, independent oversight bodies such as the Oversight Board established by Facebook, and civil society advocacy and initiatives such as the Santa Clara Principles on Transparency and Accountability in Content Moderation are also an important part of the picture.

Admittedly, these various digital governance initiatives are in some cases embryonic, and are by no means a silver bullet solution to the complex problem of online content moderation, which continues to be hotly debated in democratic societies. But they are at least underpinned by the same philosophy – that international human rights law standards must continue to apply even during emergencies such as COVID-19. With the Biden administration in the US prioritizing tech governance in its policy agenda, there is added momentum to the international leadership behind this model.

A clash of ideology

These conflicting philosophies are playing out in debates on technology governance at the UN, with one group of countries led by China and Russia advocating for greater government control of the internet, and many Western democracies emphasizing the need for an open, global internet that protects human rights.

These differing ideologies are also creating tensions between Western social media companies operating in Asia and the various governments in that region which have increased restrictions on online expression. And the gulf between the two appears to be widening.

In 2017, the Thailand government threatened Facebook with legal action unless it agreed to remove content critical of Thailand’s royal family and, in 2020, Facebook announced it had been ‘forced to block’ such material. Also in 2020, the Vietnam government pressured state-owned telecom companies to throttle internet traffic to Facebook, effectively restricting access to the platform, until Facebook agreed to take down content the government deemed to be anti-state.

Platforms refuse to silence legitimate criticism

However, Silicon Valley’s social media companies have also been pushing back. Facebook restricted the accounts of Myanmar’s military on the basis of ‘spreading misinformation’ in the wake of the military’s imposition of an internet shutdown that blocked access to Facebook, Twitter, and Instagram. And Twitter resisted requests by the Indian government to block accounts involved in protests by farmers.

Twitter stated that while it would block any accounts which it felt incited violence, it would not take action on accounts belonging to news media entities, journalists, activists, and politicians because it believed that would ‘violate the fundamental right to free expression under the Indian law’. The Indian government responded by fast-tracking stringent new social media regulations heavily criticized by rights groups for increasing government power over content on social media platforms, including online news.

So how can social media companies find avenues for operating in Asia and beyond without being co-opted into the lurch towards digital authoritarianism? There are no easy answers here, but collaboration is key. Cooperation between tech companies and local civil society partners can help companies better understand risks to human rights in the country concerned and how they might be mitigated. And tech companies are more effective in alliance with each other than acting on their own, such as the refusal by Facebook, Google, Telegram, and Twitter to hand over data on protestors to the Hong Kong police.

The fact that in many countries in Asia there are no alternatives to Western social media companies – unlike China, where platforms such as WeChat are part of the government’s internet control apparatus – gives the companies concerned some leverage. In February 2020, Facebook, Google, and Twitter together – through the Asia Internet Coalition – threatened to leave Pakistan in response to the government’s draconian proposals to regulate social media. Along with pressure and lawsuits from civil society, this forced the government into retreat, although the tussle over the new rules, introduced in November, continues.

At a time when illiberalism was already on the rise in Asia (including in democracies – Freedom House has just downgraded India’s status from ‘free’ to ‘partly free’), COVID-19 has made tighter state control of online freedom of expression even more attractive to many governments. As it seems increasingly unlikely that restrictions enacted under the guise of pandemic-related emergency measures will be repealed once the COVID-19 crisis ends, it is even more important that tech companies work with civil society on the ground to minimize the censorship of citizen voices.

New UK bill can fight fresh wave of online racist abuse Expert comment NCapeling 21 July 2021

The Euros final and Grand Prix put online abuse once more in the spotlight. The UK’s Online Safety Bill provides a strong framework for tackling the problem.

The ugly online abuse targeted at members of the England football team following the Euros final, and then at Lewis Hamilton after the British Grand Prix, was not only hateful to the individuals concerned, but divisive for the UK more broadly.

More needs to be done to regulate online platforms to avoid the spread of such abuse at scale. Online platforms are making increasing efforts to ‘self-regulate’ in order to tackle online abuse. Over the past year, Facebook and Twitter have strengthened their policies on hateful speech and conduct, such as Facebook’s policy banning Holocaust denial. Both have become more vigilant at deplatforming those who violate their terms of service, such as Donald Trump, and at removing online abuse using a combination of machines and humans.

Twitter announced in the 24 hours following the Euros final that it had removed more than 1,000 tweets, and permanently suspended several accounts, for violating its rules. But inevitably not all abusive posts are picked up given the scale of the issue and, once the post has been seen, arguably the damage is done.

Platforms have also partnered with NGOs on initiatives to counter hate speech and have launched initiatives to tackle the rise in coordinated inauthentic behaviour and information operations that seek to sow distrust and division. But while these efforts are all laudable, they are not enough.

The root of the problem is not the content but a business model in which platforms’ revenue from advertising is directly linked to engagement. This encourages the use of ‘recommender’ algorithms which amplify divisive content by microtargeting users based on previous behaviour, as seen not just with racist abuse but also other toxic content such as anti-vaccination campaigns. Abusers can also remain anonymous, giving them protection from consequences.

Creating a legal duty of care

The UK government’s Online Safety Bill, published in May 2021, aims to tackle harmful content online by placing a duty of care on online platforms to keep users safe and imposing obligations tailored to the size, functionality, and features of the service.

Social media companies will be expected to comply with their duties by carrying out risk assessments for specified categories of harm, guided by codes of practice published by the independent regulator, OFCOM. The bill gives OFCOM the power to fine platforms up to £18 million or ten per cent of global turnover, whichever is higher, for failure to comply.

Following the Euros final, the UK government spoke of referring some racist messages and conduct online to the police. But only a small proportion of it can be prosecuted given the scale of the abuse and the fact only a minority constitutes criminal activity. The majority is ‘lawful but harmful’ content – toxic and dangerous but not technically falling foul of any law.

When addressing ‘lawful but harmful’ material, it is crucial that regulation negotiates the tension between tackling the abuse and preserving freedom of expression. The scale at which such expression can spread online is key here – freedom of speech should not automatically mean freedom of reach. But it is equally important that regulation does not have a chilling effect on free speech, as with the creeping digital authoritarianism in much of the world.

The Online Safety Bill’s co-regulatory approach aims to address these tensions by requiring platforms within the scope of the bill to specify in their terms and conditions how they deal with content on their services that is legal but harmful to adults, and by giving the regulator powers to police how platforms enforce them. Platforms such as Facebook and Twitter may already have strong policies on hate speech – now there will be a regulator to hold them to account.

Devil is in the detail

How successful OFCOM is in doing so will depend on the precise powers bestowed on it in the bill, and how OFCOM chooses to use them. It’s still early days - the bill will be scrutinized this autumn by a committee of MPs before being introduced to parliament. This committee stage will provide an opportunity for consideration of how the bill may need to evolve to get to grips with online abuse.

These latest two divisive and toxic episodes in UK sport are only likely to increase pressure from the public, parliament, and politicians for the bill to reserve robust powers for OFCOM in this area. If companies do not improve at dealing with online abuse, then OFCOM should have the power to force platforms to take more robust action, including by conducting an audit of platforms’ algorithms, enabling it to establish the extent to which their ‘recommender’ settings play a part in spreading hateful content.

Currently, the bill’s definition of harm is confined to harm to individuals, and the government has stated it does not intend this bill to tackle harm to society more broadly. But if racist abuse of individuals provokes racist attacks more widely, as has happened, the regulator should be able to take that wider context into account in its investigation and response.

Responses to the draft bill so far indicate challenges ahead. Some argue the bill does not go far enough to tackle online abuse, especially on the issue of users’ anonymity, while others fear the bill goes too far in stifling freedom of expression, labelling it a recipe for censorship.

Parliamentary scrutiny will need to take into account issues of identity, trust, and authenticity in social networks. While some call for a ban on the cloak of anonymity behind which racist abusers can hide online, anonymity does have benefits for those in vulnerable groups trying to expose hate.

An alternative approach gaining attention is each citizen being designated a secure digital identity, which would both provide users with greater control over what they can see online and enable social media platforms to verify specific accounts. Instituted with appropriate privacy and security safeguards, a secure digital ID would have benefits beyond social media, particularly in an online COVID-19 era.

The online public square is global so countries other than the UK and international organizations must also take measures. It is encouraging to see synergies between the UK’s Online Safety Bill and the EU’s Digital Services Act, published in draft form in December 2020, which also adopts a risk-based, co-regulatory approach to tackling harmful online content. And the UK is using its G7 presidency to work with allies to forge a more coherent response to internet regulation at the international level, at least among democratic states.

Addressing the scourge of online hate speech is challenging so the UK’s Online Safety Bill will not satisfy everyone. But it can give the public, parliament, and politicians a structure to debate these crucial issues and, ultimately, achieve more effective ways of tackling them.

Webinar: On the Front Line: The Impact of COVID-19 on Asia's Migrant Workers 21 May 2020 — 2:00PM TO 2:45PM Anonymous (not verified) 15 May 2020

Asia’s army of migrant workers are on the frontline in confronting the health and economic effects of COVID-19. Lacking formal safety nets, health care access, and facing social dislocation, hundreds of millions across the region are bearing the brunt of the coronavirus lockdown. Asian governments have scrambled to come up with an effective health and humanitarian response, exposing public apathy and significant shortcomings in public policy.

Is better regional coordination necessary to mitigate the impact of the COVID-19 on migrant labourers? Is the private sector in Asia part of the problem or part of the solution?

In this webinar, the speakers will discuss the likely implications of lasting economic damage on the livelihoods of Asia’s migrant workers, as well as responses and measures to effectively mitigate the impact.

Constantin Carle and Marlis Hochbruck
Math. Comp. 93 (), 2611-2641.
Abstract, references and article information

Shoham Letzter
Trans. Amer. Math. Soc. 377 (), 5583-5615.
Abstract, references and article information

Anh Tuan Nguyen, Tómas Caraballo and Nguyen Huy Tuan
Proc. Amer. Math. Soc. 152 (), 5175-5189.
Abstract, references and article information

Yong Suk Moon
Proc. Amer. Math. Soc. 152 (), 5095-5103.
Abstract, references and article information

Alin Bostan, Xavier Caruso and Julien Roques
Bull. Amer. Math. Soc. 61 (), 609-658.
Abstract, references and article information

Systemic antibody light chains (AL) amyloidosis is characterized by deposition of amyloid fibrils derived from a particular antibody light chain. Cardiac involvement is a major risk factor for mortality. Using MAS solid-state NMR, we studied the fibril structure of a recombinant light chain fragment corresponding to the fibril protein from patient FOR005, together with fibrils formed by protein sequence variants that are derived from the closest germline (GL) sequence. Both analyzed fibril structures were seeded with ex-vivo amyloid fibrils purified from the explanted heart of this patient. We find that residues 11-42 and 69-102 adopt β-sheet conformation in patient protein fibrils. We identify arginine-49 as a key residue that forms a salt bridge to aspartate-25 in the patient protein fibril structure. In the germline sequence, this residue is replaced by a glycine. Fibrils from the GL protein and from the patient protein harboring the single point mutation R49G can be both heterologously seeded using patient ex-vivo fibrils. Seeded R49G fibrils show an increased heterogeneity in the C-terminal residues 80-102, which is reflected by the disappearance of all resonances of these residues. By contrast, residues 11-42 and 69-77, which are visible in the MAS solid-state NMR spectra, show 13Cα chemical shifts that are highly like patient fibrils. The mutation R49G thus induces a conformational heterogeneity at the C terminus in the fibril state, whereas the overall fibril topology is retained. These findings imply that patient mutations in FOR005 can stabilize the fibril structure.

28 August 2020

Cellular energy demands are met by uptake and metabolism of nutrients like glucose. The principal transcriptional regulator for adapting glycolytic flux and downstream pathways like de novo lipogenesis to glucose availability in many cell types is carbohydrate response element–binding protein (ChREBP). ChREBP is activated by glucose metabolites and post-translational modifications, inducing nuclear accumulation and regulation of target genes. Here we report that ChREBP is modified by proline hydroxylation at several residues. Proline hydroxylation targets both ectopically expressed ChREBP in cells and endogenous ChREBP in mouse liver. Functionally, we found that specific hydroxylated prolines were dispensable for protein stability but required for the adequate activation of ChREBP upon exposure to high glucose. Accordingly, ChREBP target gene expression was rescued by re-expressing WT but not ChREBP that lacks hydroxylated prolines in ChREBP-deleted hepatocytes. Thus, proline hydroxylation of ChREBP is a novel post-translational modification that may allow for therapeutic interference in metabolic diseases.

Pyrroline-5-carboxylate reductase 1 (PYCR1) catalyzes the biosynthetic half-reaction of the proline cycle by reducing Δ1-pyrroline-5-carboxylate (P5C) to proline through the oxidation of NAD(P)H. Many cancers alter their proline metabolism by up-regulating the proline cycle and proline biosynthesis, and knockdowns of PYCR1 lead to decreased cell proliferation. Thus, evidence is growing for PYCR1 as a potential cancer therapy target. Inhibitors of cancer targets are useful as chemical probes for studying cancer mechanisms and starting compounds for drug discovery; however, there is a notable lack of validated inhibitors for PYCR1. To fill this gap, we performed a small-scale focused screen of proline analogs using X-ray crystallography. Five inhibitors of human PYCR1 were discovered: l-tetrahydro-2-furoic acid, cyclopentanecarboxylate, l-thiazolidine-4-carboxylate, l-thiazolidine-2-carboxylate, and N-formyl l-proline (NFLP). The most potent inhibitor was NFLP, which had a competitive (with P5C) inhibition constant of 100 μm. The structure of PYCR1 complexed with NFLP shows that inhibitor binding is accompanied by conformational changes in the active site, including the translation of an α-helix by 1 Å. These changes are unique to NFLP and enable additional hydrogen bonds with the enzyme. NFLP was also shown to phenocopy the PYCR1 knockdown in MCF10A H-RASV12 breast cancer cells by inhibiting de novo proline biosynthesis and impairing spheroidal growth. In summary, we generated the first validated chemical probe of PYCR1 and demonstrated proof-of-concept for screening proline analogs to discover inhibitors of the proline cycle.

The online media changing African news The World Today mhiggins.drupal 2 August 2022

Africa’s news sites are gripping audiences with digital innovation and bold directions. Helen Fitzwilliam talks to editors at three platforms.

Lydia Namubiru
News editor of ‘The Continent’ (South Africa)

At the start of the pandemic, we realized a lot of fake news was being shared on WhatsApp. So, The Continent chose to launch on that platform to insert some real journalism in a way that could easily be shared. We now have about 100,000 readers across Africa and the rest of the world, but we had to dramatically change the way we write and edit stories: to compete with the likes of Twitter and Instagram, we try to keep stories tight at 300 words. 

There’s a real variety. We can run an investigation into corruption in the Democratic Republic of the Congo a week after a front page on the fashion designer who dresses Africa’s ‘big men’ [powerful leaders]. We cover feminist issues, the backlash against LGBT people in Ghana; we’ve had the Namibian first lady talking to us about misogyny. These are not the sort of topics a typical African newspaper is going to lead with.

With a story such as Ukraine, the war’s impact on the cost of living has been the most obvious angle for us. It has driven countries such as Malawi into crisis, forcing a devaluation of the currency.
 
As for the future, we see two issues looming. Workers’ economic rights and their treatment by multinationals will be a big story. There are refugees in camps in Kenya working in data operations and being paid a pittance to help create huge, potentially multimillion-dollar systems for US companies. 

Second, Africa has the world’s youngest population and the oldest leaders, so this will likely lead to activism and protests. The young are exposed to the global village, so they want different things and have different values. They speak a completely different language their leaders do not understand. It will be an interesting conflict, but could lead to real violence. 

John Githongo
Editor of ‘The Elephant’ (Kenya)

We set up this platform four years ago. Due to political and commercial pressures, mainstream media wasn’t doing much critical reporting. We have between 30,000 and 80,000 readers a week, the majority of them in Africa. 

The digital space reaches a completely different demographic. When The Elephant started, it was 80 per cent male and over 40, but we have gained more younger people and more women. Now it is 60 per cent men, 40 per cent women and that is something we have been working at. 

Our editorial approach is that as long as a piece has a strong argument and fits into our pan-African brief, we will publish it – even if we don’t agree with it.

The conflicts in Ethiopia and parts of the Sahel make the war in Ukraine pale in comparison. So many people have died in Ethiopia or been displaced and now we have the onset of a famine after four years of failed rain. During the 1960s and 1970s, when the Cold War found its way on to African soil, millions of people died – so there is caution about getting involved in a European fight.

There is always a lot of fake news around during elections. But people are beginning to be more sceptical. We go after those who attempt to change the level of debate with reputation-laundering and try to expose their actions. 
 
The future of democracy is going to be a big issue. When Africans were watching the attack on the US Capitol last year, they were hoping it was not a Black Lives Matter protest, which could have resulted in a ‘blackbath’. As soon as they saw the white guys wearing horns, people laughed with relief. 

There is an ongoing recalibration of Africa’s geopolitical relations with the rest of the world. A poll released in June showed China has overtaken the United States as the foreign power having the biggest positive influence in Africa in the eyes of young people across the continent. The younger generation is writing its own narrative. 

Wale Lawal
Editor of ‘The Republic’ (Nigeria)

Nigerian audiences are increasingly online and tend to read both local and international publications. They also know that the issues they care about are either under-reported or reported at lower quality levels. 

At The Republic, we provide political journalism that tends to require high levels of expertise. Yet online audiences also prioritize engagement: it is not enough for an issue to be important, it also needs to be interesting.

Some topics we have covered that Western media tend not to include how people experience blackness in different parts of the world; the waves of mostly female-led and youth-led movements rising up against autocratic governments across Africa; and relationships between countries within Africa itself. In the early days of the pandemic, we launched a Covid-19 and Africa series, having noticed a glaring lack of African expert voices in global media.
 
We also cover Africa’s evolving relations with Russia. Whenever we encounter a story like Russia’s invasion of Ukraine, the first thing we always ask ourselves is what missing voice can we add to the current discussion? All we were reading about after the invasion was how neighbouring countries were opening their borders and their homes to Ukrainians. Most people saw only that. 

But we knew that around 15,000 Africans were studying in Ukraine, that Africans routinely face harsh treatment at international borders, and that clearly their voices were missing from the discussion.

With fake news and information gaps on social media, our usual approach is to develop expert-led columns and circulate these as widely as possible.

Our next mission is to think about the role that independent media can play in supporting democracies, such as by increasing voter turnout. During the last election in Nigeria, less than 35 per cent of those who registered to vote eventually did so.

PREAMBLE

The Society of Nuclear Medicine and Molecular Imaging (SNMMI) is an international scientific and professional organization founded in 1954 to promote the science, technology, and practical application of nuclear medicine. The European Association of Nuclear Medicine (EANM) is a professional nonprofit medical association that facilitates communication worldwide between individuals pursuing clinical and research excellence in nuclear medicine. The EANM was founded in 1985. The EANM was founded in 1985. SNMMI and EANM members are physicians, technologists, and scientists specializing in the research and practice of nuclear medicine.

The SNMMI and EANM will periodically define new guidelines for nuclear medicine practice to help advance the science of nuclear medicine and to improve the quality of service to patients throughout the world. Existing practice guidelines will be reviewed for revision or renewal, as appropriate, on their fifth anniversary or sooner, if indicated.

Each practice guideline, representing a policy statement by the SNMMI/EANM, has undergone a thorough consensus process in which it has been subjected to extensive review. The SNMMI and EANM recognize that the safe and effective use of diagnostic nuclear medicine imaging requires specific training, skills, and techniques, as described in each document. Reproduction or modification of the published practice guideline by those entities not providing these services is not authorized.

These guidelines are an educational tool designed to assist practitioners in providing appropriate care for patients. They are not inflexible rules or requirements of practice and are not intended, nor should they be used, to establish a legal standard of care. For these reasons and those set forth below, both the SNMMI and the EANM caution against the use of these guidelines in litigation in which the clinical decisions of a practitioner are called into question.

The ultimate judgment regarding the propriety of any specific procedure or course of action must be made by the physician or medical physicist in light of all the circumstances presented. Thus, there is no implication that an approach differing from the guidelines, standing alone, is below the standard of care. To the contrary, a conscientious practitioner may responsibly adopt a course of action different from that set forth in the guidelines when, in the reasonable judgment of the practitioner, such course of action is indicated by the condition of the patient, limitations of available resources, or advances in knowledge or technology subsequent to publication of the guidelines.

The practice of medicine includes both the art and the science of the prevention, diagnosis, alleviation, and treatment of disease. The variety and complexity of human conditions make it impossible to always reach the most appropriate diagnosis or to predict with certainty a particular response to treatment.

Therefore, it should be recognized that adherence to these guidelines will not ensure an accurate diagnosis or a successful outcome. All that should be expected is that the practitioner will follow a reasonable course of action based on current knowledge, available resources, and the needs of the patient to deliver effective and safe medical care. The sole purpose of these guidelines is to assist practitioners in achieving this objective.

Sophos X-Ops unveils five-year investigation tracking China-based groups targeting perimeter devices

On beyond “Detect and Respond” and “Secure by Design”

Weixian Deng
Dec 22, 2020; 0:RA120.002411v1-mcp.RA120.002411
Research

AMP-activated protein kinase (AMPK) is a key regulator of energy metabolism that phosphorylates a wide range of proteins to maintain cellular homeostasis. AMPK consists of three subunits: α, β, and γ. AMPKα and β are encoded by two genes, the γ subunit by three genes, all of which are expressed in a tissue-specific manner. It is not fully understood, whether individual isoforms have different functions. Using RNA-Seq technology, we provide evidence that the loss of AMPKβ1 and AMPKβ2 lead to different gene expression profiles in human induced pluripotent stem cells (hiPSCs), indicating isoform-specific function. The knockout of AMPKβ2 was associated with a higher number of differentially regulated genes than the deletion of AMPKβ1, suggesting that AMPKβ2 has a more comprehensive impact on the transcriptome. Bioinformatics analysis identified cell differentiation as one biological function being specifically associated with AMPKβ2. Correspondingly, the two isoforms differentially affected lineage decision toward a cardiac cell fate. Although the lack of PRKAB1 impacted differentiation into cardiomyocytes only at late stages of cardiac maturation, the availability of PRKAB2 was indispensable for mesoderm specification as shown by gene expression analysis and histochemical staining for cardiac lineage markers such as cTnT, GATA4, and NKX2.5. Ultimately, the lack of AMPKβ1 impairs, whereas deficiency of AMPKβ2 abrogates differentiation into cardiomyocytes. Finally, we demonstrate that AMPK affects cellular physiology by engaging in the regulation of hiPSC transcription in an isoform-specific manner, providing the basis for further investigations elucidating the role of dedicated AMPK subunits in the modulation of gene expression.

Martin Prescher
Dec 1, 2020; 61:1605-1616
Research Articles

Thibaut Bourgeois
Dec 11, 2020; 0:jlr.RA120000737v1-jlr.RA120000737
Research Articles

Recent studies have highlighted an important role for lysophosphatidylcholine acyltransferase 3 (LPCAT3) in controlling the PUFA composition of cell membranes in the liver and intestine. In these organs, LPCAT3 critically supports cell membrane-associated processes such as lipid absorption or lipoprotein secretion. However, the role of LPCAT3 in macrophages remains controversial. Here, we investigated LPCAT3’s role in macrophages both in vitro and in vivo in mice with atherosclerosis and obesity. To accomplish this, we used the LysMCre strategy to develop a mouse model with conditional Lpcat3 deficiency in myeloid cells (Lpcat3KOMac). We observed that partial Lpcat3 deficiency (approx. 75% reduction) in macrophages alters the PUFA composition of all phospholipid (PL) subclasses, including phosphatidylinositols and phosphatidylserines. A reduced incorporation of C20 PUFAs (mainly arachidonic acid [AA]) into PLs was associated with a redistribution of these FAs toward other cellular lipids such as cholesteryl esters. Lpcat3 deficiency had no obvious impact on macrophage inflammatory response or endoplasmic reticulum (ER) stress; however, Lpcat3KOMac macrophages exhibited a reduction in cholesterol efflux in vitro. In vivo, myeloid Lpcat3 deficiency did not affect atherosclerosis development in LDL receptor deficient mouse (Ldlr-/-) mice. Lpcat3KOMac mice on a high-fat diet displayed a mild increase in hepatic steatosis associated with alterations in several liver metabolic pathways and in liver eicosanoid composition. We conclude that alterations in AA metabolism along with myeloid Lpcat3 deficiency may secondarily affect AA homeostasis in the whole liver, leading to metabolic disorders and triglyceride accumulation.

Cognitive decline with age is a harmful process that can reduce quality of life. Multiple factors have been established to contribute to cognitive decline, but the overall etiology remains unknown. Here, we hypothesized that cognitive dysfunction is mediated, in part, by increased levels of inflammatory cytokines that alter allopregnanolone (AlloP) levels, an important neurosteroid in the brain. We assessed the levels and regulation of AlloP and the effects of AlloP supplementation on cognitive function in 4-month-old and 24-month-old male C57BL/6 mice. With age, the expression of enzymes involved in the AlloP synthetic pathway was decreased and corticosterone (CORT) synthesis increased. Supplementation of AlloP improved cognitive function. Interestingly, interleukin 6 (IL-6) infusion in young animals significantly reduced the production of AlloP compared with controls. It is notable that inhibition of IL-6 with its natural inhibitor, soluble membrane glycoprotein 130, significantly improved spatial memory in aged mice. These findings were supported by in vitro experiments in primary murine astrocyte cultures, indicating that IL-6 decreases production of AlloP and increases CORT levels. Our results indicate that age-related increases in IL-6 levels reduce progesterone substrate availability, resulting in a decline in AlloP levels and an increase in CORT. Furthermore, our results indicate that AlloP is a critical link between inflammatory cytokines and the age-related decline in cognitive function.

ABCB4/MDR3 is located in the canalicular membrane of hepatocytes and translocates PC-lipids from the cytoplasmic to the extracellular leaflet. ABCB4 is an ATP-dependent transporter that reduces the harsh detergent effect of the bile salts by counteracting self-digestion. To do so, ABCB4 provides PC lipids for extraction into bile. PC lipids account for 40% of the entire pool of lipids in the canalicular membrane with an unknown distribution over both leaflets. Extracted PC lipids end up in so-called mixed micelles. Mixed micelles are composed of phospholipids, bile salts, and cholesterol. Ninety to ninety-five percent of the phospholipids are members of the PC family, but only a subset of mainly 16.0-18:1 PC and 16:0-18:2 PC variants are present. To elucidate whether ABCB4 is the key discriminator in this enrichment of specific PC lipids, we used in vitro studies to identify crucial determinants in substrate selection. We demonstrate that PC-lipid moieties alone are insufficient for stimulating ABCB4 ATPase activity, and that at least two acyl chains and the backbone itself are required for a productive interaction. The nature of the fatty acids, like length or saturation has a quantitative impact on the ATPase activity. Our data demonstrate a two-step enrichment and protective function of ABCB4 to mitigate the harsh detergent effect of the bile salts, because ABCB4 can translocate more than just the PC-lipid variants found in bile.

Co-fractionation MS (CF-MS) is a technique with potential to characterize endogenous and unmanipulated protein complexes on an unprecedented scale. However this potential has been offset by a lack of guidelines for best-practice CF-MS data collection and analysis. To obtain such guidelines, this study thoroughly evaluates novel and published Saccharomyces cerevisiae CF-MS data sets using very high proteome coverage libraries of yeast gold standard complexes. A new method for identifying gold standard complexes in CF-MS data, Reference Complex Profiling, and the Extending 'Guilt-by-Association' by Degree (EGAD) R package are used for these evaluations, which are verified with concurrent analyses of published human data. By evaluating data collection designs, which involve fractionation of cell lysates, it is found that near-maximum recall of complexes can be achieved with fewer samples than published studies. Distributing sample collection across orthogonal fractionation methods, rather than a single high resolution data set, leads to particularly efficient recall. By evaluating 17 different similarity scoring metrics, which are central to CF-MS data analysis, it is found that two metrics rarely used in past CF-MS studies – Spearman and Kendall correlations – and the recently introduced Co-apex metric frequently maximize recall, whereas a popular metric—Euclidean distance—delivers poor recall. The common practice of integrating external genomic data into CF-MS data analysis is also evaluated, revealing that this practice may improve the precision and recall of known complexes but is generally unsuitable for predicting novel complexes in model organisms. If studying nonmodel organisms using orthologous genomic data, it is found that particular subsets of fractionation profiles (e.g. the lowest abundance quartile) should be excluded to minimize false discovery. These assessments are summarized in a series of universally applicable guidelines for precise, sensitive and efficient CF-MS studies of known complexes, and effective predictions of novel complexes for orthogonal experimental validation.

Protein tyrosine kinases (PTKs) play key roles in cellular signal transduction, cell cycle regulation, cell division, and cell differentiation. Dysregulation of PTK-activated pathways, often by receptor overexpression, gene amplification, or genetic mutation, is a causal factor underlying numerous cancers. In this study, we have developed a parallel reaction monitoring (PRM)-based assay for quantitative profiling of 83 PTKs. The assay detects 308 proteotypic peptides from 54 receptor tyrosine kinases and 29 nonreceptor tyrosine kinases in a single run. Quantitative comparisons were based on the labeled reference peptide method. We implemented the assay in four cell models: 1) a comparison of proliferating versus epidermal growth factor (EGF)-stimulated A431 cells, 2) a comparison of SW480Null (mutant APC) and SW480APC (APC restored) colon tumor cell lines, and 3) a comparison of 10 colorectal cancer cell lines with different genomic abnormalities, and 4) lung cancer cell lines with either susceptibility (11-18) or acquired resistance (11-18R) to the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib. We observed distinct PTK expression changes that were induced by stimuli, genomic features or drug resistance, which were consistent with previous reports. However, most of the measured expression differences were novel observations. For example, acquired resistance to erlotinib in the 11-18 cell model was associated not only with previously reported upregulation of MET, but also with upregulation of FLK2 and downregulation of LYN and PTK7. Immunoblot analyses and shotgun proteomics data were highly consistent with PRM data. Multiplexed PRM assays provide a targeted, systems-level profiling approach to evaluate cancer-related proteotypes and adaptations. Data are available through Proteome eXchange Accession PXD002706.

Deep proteome coverage in bottom-up proteomics requires peptide-level fractionation to simplify the complex peptide mixture before analysis by tandem mass spectrometry. By decreasing the number of co-eluting precursor peptide ions, fractionation effectively reduces the complexity of the sample leading to higher sample coverage and reduced bias towards high abundance precursors that are preferentially identified in data-dependent acquisition strategies. To achieve this goal, we report a bead-based off-line peptide fractionation method termed CIF or Carboxylate modified magnetic bead-based isopropanol gradient peptide fractionation. CIF is an extension of the SP3 (single-pot solid-phase-enhanced sample preparation) strategy and provides an effective but complementary approach to other commonly used fractionation methods including strong cation exchange (SCX) and reversed phase (RP)-based chromatography. We demonstrate that CIF is an effective offline separation strategy capable of increasing the depth of peptide analyte coverage both when used alone or as a second dimension of peptide fractionation in conjunction with high pH RP. These features make it ideally suited for a wide range of proteomic applications including the affinity purification of low abundance bait proteins.

Online Disinformation and Political Discourse: Applying a Human Rights Framework Research paper sysadmin 5 November 2019

Although some digital platforms now have an impact on more people’s lives than does any one state authority, the international community has been slow to hold to account these platforms’ activities by reference to human rights law.

This paper examines how human rights frameworks should guide digital technology.

Summary

• Online political campaigning techniques are distorting our democratic political processes. These techniques include the creation of disinformation and divisive content; exploiting digital platforms’ algorithms, and using bots, cyborgs and fake accounts to distribute this content; maximizing influence through harnessing emotional responses such as anger and disgust; and micro-targeting on the basis of collated personal data and sophisticated psychological profiling techniques. Some state authorities distort political debate by restricting, filtering, shutting down or censoring online networks.
• Such techniques have outpaced regulatory initiatives and, save in egregious cases such as shutdown of networks, there is no international consensus on how they should be tackled. Digital platforms, driven by their commercial impetus to encourage users to spend as long as possible on them and to attract advertisers, may provide an environment conducive to manipulative techniques.
• International human rights law, with its careful calibrations designed to protect individuals from abuse of power by authority, provides a normative framework that should underpin responses to online disinformation and distortion of political debate. Contrary to popular view, it does not entail that there should be no control of the online environment; rather, controls should balance the interests at stake appropriately.
• The rights to freedom of thought and opinion are critical to delimiting the appropriate boundary between legitimate influence and illegitimate manipulation. When digital platforms exploit decision-making biases in prioritizing bad news and divisive, emotion-arousing information, they may be breaching these rights. States and digital platforms should consider structural changes to digital platforms to ensure that methods of online political discourse respect personal agency and prevent the use of sophisticated manipulative techniques.
• The right to privacy includes a right to choose not to divulge your personal information, and a right to opt out of trading in and profiling on the basis of your personal data. Current practices in collecting, trading and using extensive personal data to ‘micro-target’ voters without their knowledge are not consistent with this right. Significant changes are needed.
• Data protection laws should be implemented robustly, and should not legitimate extensive harvesting of personal data on the basis of either notional ‘consent’ or the data handler’s commercial interests. The right to privacy should be embedded in technological design (such as by allowing the user to access all information held on them at the click of a button); and political parties should be transparent in their collection and use of personal data, and in their targeting of messages. Arguably, the value of personal data should be shared with the individuals from whom it derives.
• The rules on the boundaries of permissible content online should be set by states, and should be consistent with the right to freedom of expression. Digital platforms have had to rapidly develop policies on retention or removal of content, but those policies do not necessarily reflect the right to freedom of expression, and platforms are currently not well placed to take account of the public interest. Platforms should be far more transparent in their content regulation policies and decision-making, and should develop frameworks enabling efficient, fair, consistent internal complaints and content monitoring processes. Expertise on international human rights law should be integral to their systems.
• The right to participate in public affairs and to vote includes the right to engage in public debate. States and digital platforms should ensure an environment in which all can participate in debate online and are not discouraged from standing for election, from participating or from voting by online threats or abuse.

War Time: Temporality and the Decline of Western Military Power Book dora.popova 22 February 2021

In War Time the Western way of war, its pace and timing, are discussed and analysed by experts who question the West’s ability to maintain its military superiority given the political and strategic failures of interventions in Iraq and Afghanistan.

In War Time, war studies experts examine the trajectory of Western military power. They discuss conflicting perceptions of time anchored within Western political and military institutions, and the Western attachment to fast-paced warfare at the expense of longer-term political solutions.

Divided into three sections, the book covers ‘civic militarism’ and the trajectory of Western power, Western perceptions of time and the international normative order, and military operations and temporality. War Time explains why the West has been overwhelmingly powerful on the battlefield and yet strategically and politically weak as exemplified by the return of the Taliban and the hasty evacuation of troops and personnel from Afghanistan.

The book identifies policies that decision-makers must adopt to stave off the decline of Western military dominance.

This book is part of the Insights series.

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A special event was held in March 2021 to mark the launch of the book. View the event here.

Praise for War Time

About the editors

Sten Rynning is professor of war studies at the University of Southern Denmark.

Olivier Schmitt is professor with special responsibilities at the Center for War Studies, University of Southern Denmark, and currently director of research and studies at the French Institute for Higher National Defence Studies.

Amelie Theussen is assistant professor at the Center for War Studies, University of 
Southern Denmark.

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The origin recognition complex (ORC), composed of six subunits, ORC1–6, binds to origins of replication as a ring-shaped heterohexameric ATPase that is believed to be essential to recruit and load MCM2–7, the minichromosome maintenance protein complex, around DNA and initiate DNA replication. We previously reported the creation of viable cancer cell lines that lacked detectable ORC1 or ORC2 protein without a reduction in the number of origins firing. Here, using CRISPR-Cas9–mediated mutations, we report that human HCT116 colon cancer cells also survive when ORC5 protein expression is abolished via a mutation in the initiator ATG of the ORC5 gene. Even if an internal methionine is used to produce an undetectable, N terminally deleted ORC5, the protein would lack 80% of the AAA+ ATPase domain, including the Walker A motif. The ORC5-depleted cells show normal chromatin binding of MCM2–7 and initiate replication from a similar number of origins as WT cells. In addition, we introduced a second mutation in ORC2 in the ORC5 mutant cells, rendering both ORC5 and ORC2 proteins undetectable in the same cells and destabilizing the ORC1, ORC3, and ORC4 proteins. Yet the double mutant cells grow, recruit MCM2–7 normally to chromatin, and initiate DNA replication with normal number of origins. Thus, in these selected cancer cells, either a crippled ORC lacking ORC2 and ORC5 and present at minimal levels on the chromatin can recruit and load enough MCM2–7 to initiate DNA replication, or human cell lines can sometimes recruit MCM2–7 to origins independent of ORC.

Cesar Hernandez scored 91 runs last season, the Phillies' highest mark since Rollins scored 102 in 2012. Now the luster is no longer there for players who score 100 runs or post 100 RBIs, but Hernandez should score at least 100 runs this season, if he stays healthy and if the Phillies' offense improves as expected.

A flight of Florida-based Spirit Airlines was hit by gunfire while attempting to land in Haiti with a crew member that sustained "minor injuries."

Being a "weekend warrior" -- engaging in exercise once or twice per week -- may be as beneficial as regular sessions in decreasing the risk of cognitive decline that often leads to dementia, a new study concludes.

The U.S. Department of Veterans Affairs announced plans Monday to eliminate copayments for all VA telehealth services, while expanding online emergency care access for rural veterans.

Discover why more content isn’t solving your boredom but making it worse.

Your brain could stay sharp for years just by doing these simple activities.

What if you could take something as tiny as a grain of sand — and as common as a glass bottle — and use it to tackle the climate crisis? Waste alchemist Franziska Trautmann shares how the spark of an idea turned into a large-scale operation helping restore the eroded shores of Louisiana and beyond. (Created in collaboration with Ignite Talks)

Call for papers: SJDM, San Francisco, Nov 17-20, 2023. Submission deadline June 22, 2023

Ohio auditor Dave Yost, a Republican, says that virtual schools should be compensated based on what their students learn.