Trying to find the balance between pure engineering and entertainment has been a very difficult balancing act over the years in Formula 1, but many in the sport think we seeing the signs of change as the cost cap takes effect on track.

Tyrell Malacia returns to action after 17 months out with injury in Manchester United Under-21 side’s EFL Trophy defeat at Huddersfield.

The following article, ‘Blatant Weaponization’: FEMA Facing Investigations For Targeting Suffering Trump Supporters, was first published on Conservative Firing Line.

Republicans are calling for investigations, or are already launching their own, into charges that the federal government deliberately and willfully discriminated against supporters of President-elect Donald Trump following a hurricane disaster in Florida. It was the Daily Wire that initially documented how Marn’I Washington, a Federal Emergency Management Agency supervisor, instructed employees under her authority …

Continue reading ‘Blatant Weaponization’: FEMA Facing Investigations For Targeting Suffering Trump Supporters ...

For years, the Dems and their media enablers have complained about the 'divisive' nature of politics, and invariably laid blame on the 'other' party.

The post Campaign Door-Knocker Caught Going Full Racist On Camera — Guess Which Party? appeared first on Clash Daily.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The Indo-Pacific: Geostrategic Perspectives 2019-24 – Workshop 2 24 September 2019 — 9:00AM TO 2:00PM Anonymous (not verified) 4 September 2019 Chatham House | 10 St James's Square | London | SW1Y 4LE

The roundtable brought together stakeholders within the UK strategic and policymaking communities to explore British perceptions of evolving strategic shifts in the Indo-Pacific until 2024.

The roundtable took place at Chatham House in London. The report below contains a summary of the discussions.

Read a summary

The Indo-Pacific: Geostrategic Perspectives 2019-20 – Workshop 1 11 September 2019 — 10:00AM TO 2:30PM Anonymous (not verified) 4 September 2019 East-West Center, 1819 L St., NW, Suite 600, Washington, DC 20036, USA

The roundtable brought together stakeholders within the US strategic and policymaking communities to explore American perceptions of evolving strategic shifts in the Indo-Pacific until 2024. The roundtable was organized in cooperation with, and was held at, the East-West Center in Washington D.C.

The report below contains a summary of the discussions and an essay by Satu Limaye, Vice President and Director of the East-West Center in Washington, DC.

Read a summary report and essay

Development Prospects in the Asia-Pacific: The Role of the Asian Development Bank 25 September 2019 — 12:30PM TO 1:30PM Anonymous (not verified) 4 September 2019 Chatham House | 10 St James's Square | London | SW1Y 4LE

The speaker will discuss development prospects in the Asia-Pacific and their implications for Europe and the UK. He will outline prospects for the region’s growth, the impact of the current US-China trade conflict as well as other challenges faced by the region. He will also discuss the future role of the Asian Development Bank and how it plans to support the further development of the region.

The Indo-Pacific: Geostrategic Perspectives to 2024 - Workshop 3 17 October 2019 — 9:30AM TO 2:00PM Anonymous (not verified) 14 October 2019 Institut Francais des Relations Internationales, 27 rue de la Procession, 75740 Paris Cedex 15, France

The roundtable brought together stakeholders within the French strategic and policymaking community to explore French perceptions of evolving strategic shifts in the Indo-Pacific until 2024. The roundtable was organized in cooperation with, and was held at, the Institut français des relations internationals in Paris.

The report below contains a summary of the discussions and an essay by Céline Pajon, Research Fellow, Center for Asian Studies, Institut français des relations internationals.

Read a summary and essay

The Indo-Pacific: Geostrategic Outlook to 2024 - Workshop 4 26 November 2019 — 9:30AM TO 12:00PM Anonymous (not verified) 9 January 2020 Gateway House, Stevens Street, Colaba

The roundtable brought together stakeholders within India’s strategic and policymaking communities to explore Indian perceptions of evolving strategic shifts in the Indo-Pacific until 2024. The roundtable was organized in cooperation with, and was held at, Gateway House in Mumbai.

The report below contains a summary of the discussions and an essay by the International Security Studies Programme at Gateway House.

Read a summary and essay

Network Power in the Asia-Pacific: Making Sense of the New Regionalism and Opportunities for Cooperation 7 February 2020 — 9:45AM TO 5:30PM Anonymous (not verified) 17 January 2020 Chatham House | 10 St James's Square | London | SW1Y 4LE

The Asia-Pacific region continues to increase in geopolitical and geoeconomic importance. The rise of China and tensions with the US are affecting bilateral relationships and traditional alliances in the region. Whether seen from the perspective of the Quad – Australia, India, Japan and the US – or the Indo-Pacific concept embraced by a wide range of countries but with no shared consensus on scope and objectives or with ASEAN who insists on the importance of its own centrality, the region is redefining and reconceptualising itself.

With a diverse range of initiatives – including the Regional Comprehensive Economic Partnership (RCEP) and Comprehensive and Progressive Agreement for Trans-Pacific Partnership (CPTPP) – there are a plethora of regional agreements and institutional groupings that add further complexity.

As the Bretton Woods architecture continues to be dominated by Western powers, China is also spearheading parallel governance initiatives such as the Asian Infrastructure Investment Bank (AIIB), the Belt and Road Initiative and the Shanghai Cooperation Organization (SCO) as a means of enhancing its geopolitical and geoeconomic influence.

This one-day conference will focus on how such networks and alliances have been built, and sustained, in the Asia-Pacific region. In order to understand how new regional initiatives might open up opportunities for new forms of international cooperation, the conference will focus on the themes of cyber-technology and innovation, sustainable development and mitigating the impacts of climate change and new infrastructure initiatives. It will assess whether there is a zero-sum conflict between competing networks and agendas or whether a common approach can be developed.

The Indo-Pacific: Geostrategic Outlook From Now to 2024 - Workshop 5 18 February 2020 — 12:00PM TO 4:30PM Anonymous (not verified) 17 February 2020 Langafonua Centre

The roundtable brought together stakeholders within Tonga’s strategic and policymaking communities to explore Tongan perceptions of evolving strategic shifts in the Indo-Pacific until 2024. The roundtable took place in Nuku’alofa and was co-hosted by the Royal Oceania Institute in Tonga.

The report below contains a summary of the discussions and an essay by Lady Fane Fakafanua, Director of Operations at the Royal Oceania Institute.

Read a summary and essay

The Indo-Pacific: Geostrategic Perspectives until 2024 – Japanese perceptions 24 February 2020 — 9:00AM TO 1:00PM Anonymous (not verified) 22 March 2021 Chatham House

The roundtable brought together stakeholders within Japan’s strategic and policymaking communities to explore Japanese perceptions of evolving strategic shifts in the Indo-Pacific until 2024. The roundtable took place in Tokyo and was organized in partnership with the Indo-Pacific Studies Group.

The report below contains a summary of the discussions and an essay by Hiroki Sekine, Visiting Fellow, Asia-Pacific Programme, Chatham House.

Read a summary and essay

Transatlantic Cooperation in the Indo-Pacific

This project aims to recommend ways for the US, UK and EU member-states to work together more effectively to achieve shared aims in the Indo-Pacific.

This project is Phase II of a wider research collaboration with the Royal United Services Institute: “An Evolving Transatlantic Agenda to Meet the Challenge of China in the Indo-Pacific”. The work is funded by the Carnegie Corporation of New York.

Through interviews with policymakers and workshops, the project will:

• Identify specific areas of policy convergence and divergence;
• Establish practical recommendations for how the US, UK and EU member-states can better align and coordinate their activities in the Indo-Pacific.

The project is led at Chatham House by the Asia-Pacific Programme, working with the Global Economy and Finance Programme and the Europe Programme.

The researchers are Ben Bland (project lead), Dr Yu Jie, Dr Gareth Price, Marianne Schneider-Petsinger, and Alice Billon-Galland.

The project builds on research from Phase I, a Transatlantic Dialogue on China, which explored how transatlantic partners are responding to China’s rise and its effects in the Indo-Pacific.

Shao-En Ong
May 1, 2002; 1:376-386
Research

Independent Thinking: The UK tilts to the Indo-Pacific Audio NCapeling 14 December 2022

Episode nine discusses the UK’s foreign policy ‘tilt’ to the Indo-Pacific and whether its desire to be a strategic player in the region is sustainable.

The past 18 months has seen the deployment of a Royal Navy carrier strike group to the Indo-Pacific, the emergence of the AUKUS partnership, talk of closer diplomatic ties with India and ASEAN and, in the context of Brexit, the UK potentially joining the CPTPP pan-Pacific trade deal.

But just how sustainable is a UK presence in the Indo-Pacific? And what are the UK’s strategic objectives in the region?

Joining Bronwen Maddox to discuss the UK’s high ambitions in the Indo-Pacific are Shashank Joshi, defence editor at The Economist, and Veerle Nouwens, senior research fellow at RUSI and the co-author of a recent Chatham House report on transatlantic cooperation in the Indo-Pacific.

James M. Ntambi
Sep 1, 1999; 40:1549-1558
Reviews

Margrit Schwarz
Sep 1, 1998; 39:1833-1843
Articles

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

James E. Balmer
Nov 1, 2002; 43:1773-1808
Reviews

Gijs den Besten
Sep 1, 2013; 54:2325-2340
Reviews

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

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

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.

Expert

Expert

Climate Change and the Pacific: Impacts and Adaptation 27 November 2018 — 8:30AM TO 10:00AM Anonymous (not verified) 14 November 2018 Royal Academy of Arts

Asia-Pacific

Research explores geopolitics, population and migration, technology and its impact, conflict, and promoting sustainable development.

Covering the region from Afghanistan to Australia, the region is a major centre of geostrategic interest, with factories in the Far East and South East Asia exporting manufactured products, while importing energy and raw materials, and half of the world’s maritime trade passing through the Indonesian Straits of Sunda, Lombok and Malacca.

The competition to establish control and supremacy over these trade routes has seen major regional powers such as China, Japan and India try to expand their presence in the south China Sea and the Indian Ocean - in the face of a massive US military presence in the area to contain Chinese expansion.

Territorial disputes also loom large on land. In addition to the dispute between North and South Korea, the Senkaku islands in Japan and the Diaoyu islands in the East China Sea cause regional tension, as does a growing Australia-Japan defence relationship. 

Key issues covered include China’s influence in the region and globally, the UK and Japan’s relationship in a changing world, and the economic relationship between the EU and China over the coming decade.

Gabriele Benedetti, Johanna Bimmermann and Kai Zehmisch
Proc. Amer. Math. Soc. 152 (), 5367-5372.
Abstract, references and article information

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.

Cation diffusion facilitator (CDF) proteins are a conserved family of divalent transition metal cation transporters. CDF proteins are usually composed of two domains: the transmembrane domain, in which the metal cations are transported through, and a regulatory cytoplasmic C-terminal domain (CTD). Each CDF protein transports either one specific metal or multiple metals from the cytoplasm, and it is not known whether the CTD takes an active regulatory role in metal recognition and discrimination during cation transport. Here, the model CDF protein MamM, an iron transporter from magnetotactic bacteria, was used to probe the role of the CTD in metal recognition and selectivity. Using a combination of biophysical and structural approaches, the binding of different metals to MamM CTD was characterized. Results reveal that different metals bind distinctively to MamM CTD in terms of their binding sites, thermodynamics, and binding-dependent conformations, both in crystal form and in solution, which suggests a varying level of functional discrimination between CDF domains. Furthermore, these results provide the first direct evidence that CDF CTDs play a role in metal selectivity. We demonstrate that MamM's CTD can discriminate against Mn2+, supporting its postulated role in preventing magnetite formation poisoning in magnetotactic bacteria via Mn2+ incorporation.

Highly engineered phytases, which sequentially hydrolyze the hexakisphosphate ester of inositol known as phytic acid, are routinely added to the feeds of monogastric animals to improve phosphate bioavailability. New phytases are sought as starting points to further optimize the rate and extent of dephosphorylation of phytate in the animal digestive tract. Multiple inositol polyphosphate phosphatases (MINPPs) are clade 2 histidine phosphatases (HP2P) able to carry out the stepwise hydrolysis of phytate. MINPPs are not restricted by a strong positional specificity making them attractive targets for development as feed enzymes. Here, we describe the characterization of a MINPP from the Gram-positive bacterium Bifidobacterium longum (BlMINPP). BlMINPP has a typical HP2P-fold but, unusually, possesses a large α-domain polypeptide insertion relative to other MINPPs. This insertion, termed the U-loop, spans the active site and contributes to substrate specificity pockets underpopulated in other HP2Ps. Mutagenesis of U-loop residues reveals its contribution to enzyme kinetics and thermostability. Moreover, four crystal structures of the protein along the catalytic cycle capture, for the first time in an HP2P, a large ligand-driven α-domain motion essential to allow substrate access to the active site. This motion recruits residues both downstream of a molecular hinge and on the U-loop to participate in specificity subsites, and mutagenesis identified a mobile lysine residue as a key determinant of positional specificity of the enzyme. Taken together, these data provide important new insights to the factors determining stability, substrate recognition, and the structural mechanism of hydrolysis in this industrially important group of enzymes.

Sirtuin 6, SIRT6, is critical for both glucose and lipid homeostasis and is involved in maintaining genomic stability under conditions of oxidative DNA damage such as those observed in age-related diseases. There is an intense search for modulators of SIRT6 activity, however, not many specific activators have been reported. Long acyl-chain fatty acids have been shown to increase the weak in vitro deacetylase activity of SIRT6 but this effect is modest at best. Herein we report that electrophilic nitro-fatty acids (nitro-oleic acid and nitro-conjugated linoleic acid) potently activate SIRT6. Binding of the nitro-fatty acid to the hydrophobic crevice of the SIRT6 active site exerted a moderate activation (2-fold at 20 μm), similar to that previously reported for non-nitrated fatty acids. However, covalent Michael adduct formation with Cys-18, a residue present at the N terminus of SIRT6 but absent from other isoforms, induced a conformational change that resulted in a much stronger activation (40-fold at 20 μm). Molecular modeling of the resulting Michael adduct suggested stabilization of the co-substrate and acyl-binding loops as a possible additional mechanism of SIRT6 activation by the nitro-fatty acid. Importantly, treatment of cells with nitro-oleic acid promoted H3K9 deacetylation, whereas oleic acid had no effect. Altogether, our results show that nitrated fatty acids can be considered a valuable tool for specific SIRT6 activation, and that SIRT6 should be considered as a molecular target for in vivo actions of these anti-inflammatory nitro-lipids.

In addition to their well-known role in the control of cellular proliferation and cancer, cell cycle regulators are increasingly identified as important metabolic modulators. Several GWAS have identified SNPs near CDKN2A, the locus encoding for p16INK4a (p16), associated with elevated risk for cardiovascular diseases and type-2 diabetes development, two pathologies associated with impaired hepatic lipid metabolism. Although p16 was recently shown to control hepatic glucose homeostasis, it is unknown whether p16 also controls hepatic lipid metabolism. Using a combination of in vivo and in vitro approaches, we found that p16 modulates fasting-induced hepatic fatty acid oxidation (FAO) and lipid droplet accumulation. In primary hepatocytes, p16-deficiency was associated with elevated expression of genes involved in fatty acid catabolism. These transcriptional changes led to increased FAO and were associated with enhanced activation of PPARα through a mechanism requiring the catalytic AMPKα2 subunit and SIRT1, two known activators of PPARα. By contrast, p16 overexpression was associated with triglyceride accumulation and increased lipid droplet numbers in vitro, and decreased ketogenesis and hepatic mitochondrial activity in vivo. Finally, gene expression analysis of liver samples from obese patients revealed a negative correlation between CDKN2A expression and PPARA and its target genes. Our findings demonstrate that p16 represses hepatic lipid catabolism during fasting and may thus participate in the preservation of metabolic flexibility.

Oxygen regulates hypoxia-inducible factor (HIF) transcription factors to control cell metabolism, erythrogenesis, and angiogenesis. Whereas much has been elucidated about how oxygen regulates HIF, whether lipids affect HIF activity is un-known. Here, using cultured cells and two animal models, we demonstrate that lipoprotein-derived fatty acids are an independent regulator of HIF. Decreasing extracellular lipid supply inhibited HIF prolyl hydroxylation, leading to accumulation of the HIFα subunit of these heterodimeric transcription factors comparable with hypoxia with activation of downstream target genes. The addition of fatty acids to culture medium suppressed this signal, which required an intact mitochondrial respiratory chain. Mechanistically, fatty acids and oxygen are distinct signals integrated to control HIF activity. Finally, we observed lipid signaling to HIF and changes in target gene expression in developing zebrafish and adult mice, and this pathway operates in cancer cells from a range of tissues. This study identifies fatty acids as a physiological modulator of HIF, defining a mechanism for lipoprotein regulation that functions in parallel to oxygen.

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

Decades of obsolete and unpatched hardware and software endanger us all

What our incident responders know from five years of fighting an octopus

Thirty-five years after the first great cat-and-mouse infosecurity story, here we are again

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

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

Toma Keser
Dec 29, 2020; 0:RA120.002433v1-mcp.RA120.002433
Research

The glucagon receptor (GCGR) activated by the peptide hormone glucagon is a seven-transmembrane G protein–coupled receptor (GPCR) that regulates blood glucose levels. Ubiquitination influences trafficking and signaling of many GPCRs, but its characterization for the GCGR is lacking. Using endocytic colocalization and ubiquitination assays, we have identified a correlation between the ubiquitination profile and recycling of the GCGR. Our experiments revealed that GCGRs are constitutively ubiquitinated at the cell surface. Glucagon stimulation not only promoted GCGR endocytic trafficking through Rab5a early endosomes and Rab4a recycling endosomes, but also induced rapid deubiquitination of GCGRs. Inhibiting GCGR internalization or disrupting endocytic trafficking prevented agonist-induced deubiquitination of the GCGR. Furthermore, a Rab4a dominant negative (DN) that blocks trafficking at recycling endosomes enabled GCGR deubiquitination, whereas a Rab5a DN that blocks trafficking at early endosomes eliminated agonist-induced GCGR deubiquitination. By down-regulating candidate deubiquitinases that are either linked with GPCR trafficking or localized on endosomes, we identified signal-transducing adaptor molecule–binding protein (STAMBP) and ubiquitin-specific protease 33 (USP33) as cognate deubiquitinases for the GCGR. Our data suggest that USP33 constitutively deubiquitinates the GCGR, whereas both STAMBP and USP33 deubiquitinate agonist-activated GCGRs at early endosomes. A mutant GCGR with all five intracellular lysines altered to arginines remains deubiquitinated and shows augmented trafficking to Rab4a recycling endosomes compared with the WT, thus affirming the role of deubiquitination in GCGR recycling. We conclude that the GCGRs are rapidly deubiquitinated after agonist-activation to facilitate Rab4a-dependent recycling and that USP33 and STAMBP activities are critical for the endocytic recycling of the GCGR.