Samsung Electronics issued a rare apology and acknowledged on Tuesday it was facing a "crisis" over its technological competitiveness, reflected in a disappointing profit guidance, despite a global AI boom.

The country is set to experience varied weather conditions, with several impact-based warnings issued across various provinces, according to the South African Weather Service.

KwaZulu-Natal police commissioner Lieutenant General Nhlanhla Mkhwanazi has ordered an "immediate investigation" after a video went viral on social media of a police officer slapping and pulling around a man.

Modern organizations regard data as a strategic asset that drives efficiency, enhances decision making, and creates new value for customers. Across the organization—product management, marketing, operations, finance, and more—teams are overflowing with ideas on how data can elevate the business. To bring these ideas to life, companies are eagerly hiring data scientists for their technical […]

There are laptops sold with NVidia's high-end 4090 graphics chip, but it's a power-constrained mobile version appropriate for portable machines. A Chinese-language blogger modded themselves a beast of a machine with a full desktop-class 4090 card. This thing weighs 15 pounds and its battery life is a Borgesian map of nothing (one must plug it in). — Read the rest

The post "Laptop" with full 4090 GPU weighs 15 pounds appeared first on Boing Boing.

Nintendo is cracking down on emulators of its hardware and media depicting their use. First Yuzu was taken down with a lawsuit, and now departs Ryujinx, a similar project that had sought to avoid the legal landmines Yuzu stepped on. — Read the rest

The post Another emulation project disappears amid Nintendo crackdown appeared first on Boing Boing.

October 1 was officially "International Raccoon Appreciation Day," for those of you who love to love the adorable trash panda. Around here, honestly, every day is raccoon appreciation day, so it's an "International Day" I can genuinely get behind.

National Day Calendar explains the origins of the day:

In 2002, a young girl in California wanted to highlight the good points about the raccoon instead of the bad ones.

— Read the rest

The post Every day should be raccoon appreciation day appeared first on Boing Boing.

Video is beginning to fulfill its promise as a transformational technology. Beyond merely cutting communications costs, video is starting to change the way companies do business, and is rapidly being accepted as a "need to have" rather than a "nice to have."

Cisco CEO John Chambers predicts video traffic on the internet will increase six fold by 2012. Here is a link to Cisco's August 5 earnings call where he makes that prediction.

A classic example of the power of video is that of electronics manufacturer NEC. They have a network of nearly 500 dealers across the United States that sell their products. They saved more than $250,000 annually in training costs by delivering product training with video webcasting rather than sending trainers to the dealers or bringing the dealers to the trainers.

They also dramatically reduced the time it takes to train the entire network on new products. Click here to watch a video case study.

A newer example shows how video can literally transform the way a company does business. A major sneaker company manufacturers its products in China. Each time they re-tooled to manufacture a new sneaker, executives would have to fly to China to ensure the tooling was correct and the sneakers were meeting specifications before they began mass production.

They began to use high definition cameras at the plant in China to webcast video of the sneakers to allow executives to make their inspection virtually. Sure, they save money on travel to China. But more importantly, there was a practical limit to the amount of people who could go to China to see the actual design come off the assembly line. The video process allows them to solicit input from a much broader segment of the company, and even get input from retailers while there is still time to respond to suggestions.

The end result is that they can bring their products to market faster than their competition, which creates a significant competitive advantage. Click here to see the video discussion.

I am particularly pleased to see clear evidence of unmistakable, game-changing ROI.

MediaPlatform WebCaster and Adobe's Flash Media Enterprise Server 4 with Hybrid Flash Multicasting bring a game changing solution to the challenge of delivering video to the enterprise without requiring a seven figure hardware investment for multicasting.

Up to now, solutions for managing streaming video bandwidth issues required networks of expensive hardware, ranging from Enterprise Content Delivery Networks to WAN Acceleration devices. And all of these solutions dictated Windows Media as your video format. Hybrid Flash Multicasting offers a better way; it works seamlessly with traditional IP multicast networks AND it also provides a Peer Assist multicast solution for the parts of your network that are not IP multicast enabled.

Hybrid Flash Multicasting is an outstanding solution because it:

1) allows corporations to continue leveraging the hardware investments they have made and utilize traditional IP Multicasting with Flash instead of Windows Media.

2) allows corporations to reach bandwidth-challenged locations that are not on the multicast WAN or new locations whose networks are not multicast-enabled with a relatively low cost Peer Assist solution (because it does not require new routers and configuration of switches, etc.).

This solution solves the challenge of allowing video to reach 100% of your desktops without requiring a million dollar investment in a new eCDN. And unlike other peering solutions, there is no proprietary agent that has to be propagated to every desktop. All your employees' computers need is the latest Flash player.

Here is how MediaPlatform fits into the equation:

Our WebCaster software is the only streaming video solution that integrates the multicast-enabled Flash player, as well as leveraging Flash's ability to create a cross platform viewing experience, switch between multiple live and pre-recorded video sources, switch bit rates and codecs on the fly, support mobile devices, support H.264 and VP6 to create higher quality video at lower bandwidths, etc. With our software you can take advantage of Flash to upgrade your streaming communications to a more functional format that will work behind the firewall and to the public internet, will work on any browser and operating system, and can deliver content to mobile devices.

An article about Hybrid Flash Multicasting that features MediaPlatform's CTO, Greg Pulier, recently appeared in the Flex Developer's Journal.  Click here to link to the article

Here is the opening paragraph:

Hybrid Flash multicasting is the second and decisive wave of innovation that will enable enterprises to stream video without overtaxing their network infrastructures. It eliminates the usual tradeoffs between video consumption and network investment, regardless of increased video traffic in budget-constrained corporate networks. Hybrid Flash multicasting also solves the cost and complexity challenges of IP multicasting. By combining a new form of multicasting, known as application multicasting, which leverages a peer-assisted model of video sharing with an IP multicast network, a video stream can reach virtually everyone on the network using existing bandwidth and infrastructure. Hybrid multicasting finally unlocks the full potential for video within the enterprise by combining IP and application multicasting to deliver streaming media using the most efficient algorithms within a dynamic self-optimizing topology.

Interactive Media Strategies (IMS) is a market research firm that follows streaming media. They discuss the news of Microsoft’s $8.5 billion acquisition of Skype, and the prospects for Skype to emerge as a viable platform for business video communications. 

Their research compares usage levels for a range of social media and communications applications, including Skype, YouTube and Facebook. Here is a link to the video.

They report that personal use of Facebook and YouTube is relatively high but that has not yet translated into comparable levels of corporate use. They believe this raises the question of whether YouTube and Facebook will be able to outgrow their focus on the consumer side of the business to compete in the enterprise market.

Usage levels for Skype are significantly lower overall, but Skype’s penetration in business communications is higher than they see for other communications apps online among young users most likely to experiment with emerging technologies.

IMS puts forth the opinion that if Microsoft could make it easier for technology laggards to embrace Skype - i.e. integrate Skype with the Microsoft Office suite - then Skype could achieve significant enterprise adoption.

What Is "Demure and Mindful" to Real Estate?

The following article, Major Ruling In CNN Defamation Fight With James O’Keefe (Video), was first published on Conservative Firing Line.

A federal appeals court has ruled against CNN in its attempt to have dismissed a defamation complaint from James O’Keefe and Project Veritas. O’Keefe launched Project Veritas and worked years with the organization, doing undercover interviews to uncover political scandals. He later left and now works with O’Keefe Media Group. But the dispute arose during …

Continue reading Major Ruling In CNN Defamation Fight With James O’Keefe (Video) ...

Have you heard of Locorotondo, Italy? Locorotondo is one of Southern Italy’s most beautiful villages, in my opinion, but it isn’t yet overwhelmed with tourist crowds. A true hidden gem, Locorotondo is just a 12-minute drive from busy Alberobello in the Puglia region, but feels like a world away. Planning your trip to Locorotondo last […]

The post Visiting Locorotondo, Italy – A Guide to the Trulli Town appeared first on Adventurous Kate.

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.

There is a reason Joe Rogan became the world's largest podcaster. He doesn't take his audience -- or his guests -- for granted. He wants MEANINGFUL conversations.

The post Joe Rogan Officially Backs A Candidate… Could Be The Biggest Endorsement Yet appeared first on Clash Daily.

If killjoy leftists can wear their self-parodying and ridiculous 'Handmaid's Tale' outfits, then they can't complain when a MAGA voter plays the same game... only better.

The post MUST-WATCH: MAGA Voter Finds Hilarious Way To Sidestep Election Clothing Rules appeared first on Clash Daily.

It's all over but the crying for a campaign that was supposed to be characterized by 'joy'. There will be no concession speech tonight. At little before 1 am, Kamala is running like a scared rabbit.

The post Cowardly Kamala Pulls A Hillary — Refuses To Concede As Trump Paints The Country Red appeared first on Clash Daily.

There are a few moments in this race that historians will wrangle over as the 'real' reason Kamala lost. There are a couple of key events that are sure to make the list.

The post The RIGHT Rally: On Election Night, MAGA Takes Moment To Honor God Beautifully appeared first on Clash Daily.

Take a good look at the people melting down on social media because their team didn't win an election. That's what it looks likes when your politics becomes your faith.

The post We Dodged A Demonic Political Bullet appeared first on Clash Daily.

We all know that *one* guy who acts like he's doing the world a favor just by showing up.

The post Demonic & Damned to Ridiculously Redeemed! (Eph.2:1-10) appeared first on Clash Daily.

Earlier this year, we announced that Basecamp was committing to getting to carbon negative for our cumulative history and moving forward. Today, I want to share an update on that commitment. Note: I edited this post on Nov 5, 2020 to include the prices paid for all carbon offsets and explain a little more about the… keep reading

Left-wing networks had plenty of bad news for their viewers as former President Donald Trump stormed to victory in the Nov. 5 election. Now, they’re getting plenty of bad news […]

The post Insult to Injury: MSNBC and CNN Suffer Staggering Ratings Plunge Following Trump Victory appeared first on The Western Journal.

Melania Trump will not be traveling with her husband to Washington on Wednesday when President-elect Donald Trump and President Joe Biden have a formal transition meeting, according to multiple reports. […]

The post Melania Trump to Give Jill Biden the Cold Shoulder This Week: Report appeared first on The Western Journal.

A Chicago-area Democrat hurled an insult at police Sunday after being charged with drunken driving, according to local news reports. Samantha Steele represents the Second District on the Cook County […]

The post Democratic Politician Crashes Her Car While Allegedly Drunk, Hurls Vile Insults at Responding Officer: Police Report appeared first on The Western Journal.

President-elect Donald Trump is reportedly considering lawyer Alina Habba to be the White House press secretary. Habba often spoke to the media while she was on the legal team representing […]

The post Report Shows New Front-Runner for Trump's Press Secretary Spot: The Media Should Be Terrified appeared first on The Western Journal.

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

Sri Lanka's cricket board named former South African batsman Neil McKenzie as a consultant coach ahead of their Test tour of South Africa.

By SADF – Nov. 30, 2022 Online conversation on The West, a New Haven for the ‘Muslim Brotherhood’s Planetary Nebula’? On November the 29th at 16H.00 (CET), SADF promoted an online conversation in the web platform StreamYard titled ‘The West, a New Haven for the ‘Muslim Brotherhood’s Planetary Nebula’?’ The conversation included the Member of the European Parliament (EPP, […]

TikTok will have more US users than Snapchat and Pinterest in 2022   January 24, 2022 (New York, NY) – YouTube is the “OG” of influencer marketing platforms, and it’s […]

3.6 million will pay with crypto in US; payment value to spike 70% in 2022   April 20, 2022 (New York, NY) – Cryptocurrency usage will continue its meteoric rise, […]

Marcelo Campos, Matthew Jenssen, Marcus Michelen and Julian Sahasrabudhe
J. Amer. Math. Soc. 38 (), 179-224.
Abstract, references and article information

Review: The Cultural Revolution still haunts China The World Today mhiggins.drupal 30 January 2023

Tania Branigan’s searching ‘Red Memory’ reveals the costs to Chinese society of not addressing that upheaval’s lingering injustices, writes Nathan Law.

Red Memory: Living, Remembering and Forgetting China’s Cultural Revolution
Tania Branigan, Faber, £20

The Cultural Revolution, a decade-long socio-political upheaval initiated by Chairman Mao Zedong in 1966, caused as many as two million deaths and reshaped China. Under the influence of Mao’s personality cult, an entire nation was mobilized to purge the ‘reactionary elements’ in society and the Chinese Communist Party through public denunciation and demolition of traditional heritages.

Children turned on their parents; pupils murdered their teachers, and those who survived the summary public trials were often banished – as a young Xi Jinping himself was, living in a cave for seven years, after his father fell from favour.

Impossible moral choices

In her engaging and sensitive narrative account of the revolution’s upheaval and its consequences, Tania Branigan, the Guardian’s China correspondent between 2008 and 2015, speaks to some of those who survived those terrible years, considers their impossible moral choices and explores the far-reaching legacy of the revolution in present-day China.

Mao urged the party to cleanse itself of its ‘class enemies’: ‘capitalists’ such as landowners and shopkeepers, but also artists, farmers and university professors. Often their family members were tainted by association and persecuted. Branigan captures the awful sense of intimate betrayal and tragedy nowhere more than in the testimony of Zhang Hongbing, a lawyer turned zealous Red Guard.

Zhang denounced his mother, a hospital worker, as a ‘counter-revolutionary’ because her father owned land. She was eventually executed but not before her son struck her twice during her arrest to show his party loyalty. ‘What I did to my mother was worse even than to an animal,’ the remorseful Zhang tells Branigan.

Zhang points out that his actions were far from uncommon: ‘The whole country was doing it.’ This unreconciled sense of betrayal and fear still blights China: ‘Our society is ethically hollow. If we trace these problems to their roots, we are likely to find them in the Cultural Revolution,’ one survivor is quoted as writing.

Branigan encapsulates the difficulties around reconciliation and remembering in the story of Song Binbin. As a schoolgirl in 1966, she and two classmates were the first to pin up a poster attacking teachers for urging students to focus on their work instead of the revolution. Song’s classmates then beat the school vice principal Bian Zhongyun to death in the playground. The case was never properly investigated, and the death was dismissed as an accident.

The pain of remembering

In 2014, Song apologized publicly for the poster and expressed a sense of guilt for not intervening on Bian’s behalf. But Bian’s widower rejected the apology. Song did not speak to Branigan herself, instead allowing her friends to speak in her defence. ‘They had spoken of truth and reconciliation, but not once of justice. Every remark brought them towards closure, not accountability,’ Branigan writes.

The inability to come to terms with the past pervades the book, most of whose interviewees express feelings of resentment, fear and shame about the Cultural Revolution. I sensed the same emotions when, as a boy, I talked to a neighbour in Hong Kong who was then in his 70s. He escaped from China in the late 1960s due to political and economic strains. He simply nodded and fell silent when I asked him to elaborate.

As Branigan writes: ‘Most Cultural Revolution survivors had learnt to bend with the will of the time; not only to do as they were told but to imply that doing so was their own idea. It was better – safer – to stay silent or lie.’

This collective trauma is exacerbated by official unwillingness to address the past. The Cultural Revolution warrants no more than a few paragraphs in official textbooks with no mention of the suffering it unleashed. Documents of the period that might tarnish the CCP remain unavailable; any attempts to interrogate the Cultural Revolution are condemned as ‘historical nihilism’ by the party.

Chinese supply chains could tip the balance in Ukraine Expert comment NCapeling 29 March 2023

Disrupting supply chains of critical minerals to those supporting Ukraine could give China a key advantage in its wider international trade competition.

Direct military intervention from China into the war on Ukraine, with Chinese troops and airmen appearing at the front line, would be highly escalatory and highly unlikely.

Equipping Russia with weapons and equipment is much more likely – if indeed it hasn’t already happened – and considering the West is supplying armaments to Ukraine, a joust with western technologies would be an interesting development to follow.

But if Chinese weapons underperform in the heat of battle, this may have implications for the current situation with Taiwan and the US, as a poor outcome on the Ukraine front could give the West more confidence over the tensions in the South China Sea. And the use of Chinese weapons in Ukraine would also be a feast for Western technical intelligence to capture.

Creating economic disruption

A much more likely development for China is to put in place export controls on critical minerals for Western powers supplying arms to Ukraine. This is a significant lever which China has used before during its fishing dispute with Japan in 2010 when hi-tech industrial production in Japan was affected by shortages of China-sourced critical minerals. Once normal supplies were resumed, Japan started to stockpile critical mineral reserves.

In October 2020, the Chinese Communist Party (CCP) passed a new statute enabling – when necessary – restriction of critical mineral supplies to third party nations intending to use them for defence and security applications, adding a ‘versatile weapon to Beijing’s arsenal’ in its trade competition with the US.

That legal control has been applied to Lockheed Martin production of Taiwan-bound F-35s and it applies not only to critical minerals mined on the Chinese mainland, but also to Chinese-controlled enterprises within international supply chains, of which there are many.

Responding to any such restrictions by opening up new mines and setting up new supply chains can take more than a decade, so the countries involved may need to start stockpiling critical materials as Japan has been doing since 2010.

Commodity markets also need to be ready for some interesting price wobbles – a persistent problem in critical minerals extractives investment as is overcoming environmental, social, and governance (ESG) challenges in this new game of global supplies.

In addition, those markets include the London Metal Exchange, now owned by Hong Kong Exchanges & Clearing whose biggest shareholder is the Hong Kong government which is struggling to operate with complete independence from Beijing.

Splitting the West’s consensus

By extending the thinking on China’s potential to throttle global critical mineral supply chains and the ensuing latency of extraction from new mining resources, progress to the Paris Agreement 2050 goals on climate change will inevitably be affected.

Given there are no supply chain assurance mechanisms, such as distributed ledger technologies, in place within global mining supply chains, a key issue to overcome would be how the West assures China that critical mineral supplies are not destined for military applications.

But if China’s default position becomes a total refusal to supply client nations unless end-to-end assurances can be achieved to prove non-military use, the West’s aspirations regarding the Paris 2050 goals will certainly be put in jeopardy, or even made unachievable.

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

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

Business Briefing: Assessing the geopolitical implications of EU AI regulation 17 September 2024 — 4:00PM TO 5:00PM Anonymous (not verified) 8 August 2024 Chatham House

Join us for this critical discussion of how the EU AI Act will shape the world’s approach to the technology.

Join us for this critical discussion of how the EU AI Act will shape the world’s approach to the technology

Governments, technology companies and civil society groups across the world are now advocating firmer AI regulation. Machine learning algorithms have changed the way we interact with technology and powered much of our online lives for decades: why has this pendulum swung back so far toward greater control, and why now?

In 2023 the UK government seized the initiative with its Bletchley AI Safety Summit. The event attempted to address the so called ‘frontier risks’ associated with AI development. Global competition on AI is reflected in AI governance efforts in China, US, the Gulf and beyond. But to date, it is the EU that has led the West in passing AI legislation. The EU AI Act, has separated AI systems into graded risk categories carrying different regulatory requirements, and it remains to be seen whether global AI will feel the Brussels effect.

This conversation will cover the following questions:

• Critics have painted regulation including the AI Act as anti-innovation. Is this a fair assessment?
• What lessons can we learn from the successes and shortcomings of GDPR?
• How do we tackle the challenge of low public trust in AI and low public trust in government technology projects, particularly in Western democracies?
• Does the proliferation of safety institutes, and the AI office, point to the emergence of a new type of technical governance institution? What is its future?

Making the circular economy work for global development: how the UN Summit of the Future can deliver 23 September 2024 — 6:15PM TO 9:00PM Anonymous (not verified) 5 September 2024 Online

This policy roundtable focusses on how to advance implementation of a global approach and collaboration to an inclusive circular economy for an updated post-2030 SDG framework.

As the world looks beyond the Sustainable Development Goals (SDGs) towards the post-2030 era, integrating the principles of the circular economy into the future global development agenda becomes imperative.  

A new Chatham House research paper about the role of the circular economy for the SDGs and their possible extension into the post-2030 development agenda will be launched in September 2024 during the UN Summit of the Future and the New York Climate Week. The paper outlines the rationale for the integration of circular economy goals into for the next crucial phase of international development and how to meet net-zero 2050 targets. It provides actionable recommendations on international cooperation mechanisms for policymakers and stakeholders at the UN Summit for the Future in 2024 and beyond.

The aim of the roundtable is to bring together stakeholders and leaders from intergovernmental organisations, business, governments and civil society. The focus of the roundtable meeting is: 

• Reflections on the Summit of the Future and the role of circularity for an updated post-2030 SDG framework.
• Discussion on key aspects of the institutional arrangements and international coordination that are needed for a globally coordinated approach to achieve an inclusive circular economy that supports SDG implementation. 
• Development of joint strategies on how to advance implementation of a global approach and collaboration to an inclusive circular economy as a follow-up from the Summit of the Future.

The objective is to emerge from the roundtable with a clearer roadmap for translating the recommendations for international coordination into concrete actions, with a shared commitment to driving meaningful change on the international level.

The event is co-hosted by Chatham House and partners from the Global Circular Economy Roadmap initiative including the African Circular Economy Network, the African Development Bank, Circular Change, Circular Innovation Lab, Circle Economy, EU CE Stakeholder Platform, Hanns Seidel Foundation, Institute of Global Environmental Strategies, Sitra, UNIDO, World Business Council on Sustainable Development, World Economic Forum and the Wyss Academy for Nature.

Further background information is available on the initiative website.

More speakers to be announced.

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

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

Dilated cardiomyopathy (DCM) is associated with mutations in cardiomyocyte sarcomeric proteins, including α-tropomyosin. In conjunction with troponin, tropomyosin shifts to regulate actomyosin interactions. Tropomyosin molecules overlap via tropomyosin–tropomyosin head-to-tail associations, forming a continuous strand along the thin filament. These associations are critical for propagation of tropomyosin's reconfiguration along the thin filament and key for the cooperative switching between heart muscle contraction and relaxation. Here, we tested perturbations in tropomyosin structure, biochemistry, and function caused by the DCM-linked mutation, M8R, which is located at the overlap junction. Localized and nonlocalized structural effects of the mutation were found in tropomyosin that ultimately perturb its thin filament regulatory function. Comparison of mutant and WT α-tropomyosin was carried out using in vitro motility assays, CD, actin co-sedimentation, and molecular dynamics simulations. Regulated thin filament velocity measurements showed that the presence of M8R tropomyosin decreased calcium sensitivity and thin filament cooperativity. The co-sedimentation of actin and tropomyosin showed weakening of actin-mutant tropomyosin binding. The binding of troponin T's N terminus to the actin-mutant tropomyosin complex was also weakened. CD and molecular dynamics indicate that the M8R mutation disrupts the four-helix bundle at the head-to-tail junction, leading to weaker tropomyosin–tropomyosin binding and weaker tropomyosin–actin binding. Molecular dynamics revealed that altered end-to-end bond formation has effects extending toward the central region of the tropomyosin molecule, which alter the azimuthal position of tropomyosin, likely disrupting the mutant thin filament response to calcium. These results demonstrate that mutation-induced alterations in tropomyosin–thin filament interactions underlie the altered regulatory phenotype and ultimately the pathogenesis of DCM.

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

Heterotrimeric G-proteins are signaling switches broadly divided into four families based on the sequence and functional similarity of their Gα subunits: Gs, Gi/o, Gq/11, and G12/13. Artificial mutations that activate Gα subunits of each of these families have long been known to induce oncogenic transformation in experimental systems. With the advent of next-generation sequencing, activating hotspot mutations in Gs, Gi/o, or Gq/11 proteins have also been identified in patient tumor samples. In contrast, patient tumor-associated G12/13 mutations characterized to date lead to inactivation rather than activation. By using bioinformatic pathway analysis and signaling assays, here we identified cancer-associated hotspot mutations in Arg-200 of Gα13 (encoded by GNA13) as potent activators of oncogenic signaling. First, we found that components of a G12/13-dependent signaling cascade that culminates in activation of the Hippo pathway effectors YAP and TAZ is frequently altered in bladder cancer. Up-regulation of this signaling cascade correlates with increased YAP/TAZ activation transcriptional signatures in this cancer type. Among the G12/13 pathway alterations were mutations in Arg-200 of Gα13, which we validated to promote YAP/TAZ-dependent (TEAD) and MRTF-A/B-dependent (SRE.L) transcriptional activity. We further showed that this mechanism relies on the same RhoGEF-RhoGTPase cascade components that are up-regulated in bladder cancers. Moreover, Gα13 Arg-200 mutants induced oncogenic transformation in vitro as determined by focus formation assays. In summary, our findings on Gα13 mutants establish that naturally occurring hotspot mutations in Gα subunits of any of the four families of heterotrimeric G-proteins are putative cancer drivers.

Hdac3 is a lysine deacetylase that removes acetyl groups from histones and additional proteins. Although Hdac3 functions within mesenchymal lineage skeletal cells are defined, little is known about Hdac3 activities in bone-resorbing osteoclasts. In this study we conditionally deleted Hdac3 within Ctsk-expressing cells and examined the effects on bone modeling and osteoclast differentiation in mice. Hdac3 deficiency reduced femur and tibia periosteal circumference and increased cortical periosteal osteoclast number. Trabecular bone was likewise reduced and was accompanied by increased osteoclast number per trabecular bone surface. We previously showed that Hdac3 deacetylates the p65 subunit of the NF-κB transcriptional complex to decrease DNA-binding and transcriptional activity. Hdac3-deficient osteoclasts demonstrate increased K310 NF-κB acetylation and NF-κB transcriptional activity. Hdac3-deficient osteoclast lineage cells were hyper-responsive to RANKL and showed elevated ex vivo osteoclast number and size and enhanced bone resorption in pit formation assays. Osteoclast-directed Hdac3 deficiency decreased cortical and trabecular bone mass parameters, suggesting that Hdac3 regulates coupling of bone resorption and bone formation. We surveyed a panel of osteoclast-derived coupling factors and found that Hdac3 suppression diminished sphingosine-1-phosphate production. Osteoclast-derived sphingosine-1-phosphate acts in paracrine to promote bone mineralization. Mineralization of WT bone marrow stromal cells cultured with conditioned medium from Hdac3-deficient osteoclasts was markedly reduced. Expression of alkaline phosphatase, type 1a1 collagen, and osteocalcin was also suppressed, but no change in Runx2 expression was observed. Our results demonstrate that Hdac3 controls bone modeling by suppressing osteoclast lineage cell responsiveness to RANKL and coupling to bone formation.

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

A Digital India Must Embrace the Circular Economy Expert comment sysadmin 15 January 2018

A growing amount of e-waste should draw attention to the broader sustainability of a digital society.

The latest Global E-Waste Monitor places India as one of the highest contributors to global e-waste, generating over 2 million metric tonnes in 2016. Posing serious health and environmental risks, growing e-waste represents the hidden cost of increasingly digital lives in an information society.

With just 33 per cent of the population owning a smart phone, India already has the second largest number of smart phone users in the world, nearly 4 times that of the United States. The amount of e-waste generated will exponentially increase in the coming decade as the cost of consumer electronics decline, middle-class incomes rise, and the frequency at which devices are discarded increases.

As governance instruments are increasingly digitized and industry re-repositions itself to leverage Industry 4.0 solutions, the generation of e-waste will become a byproduct of institutional choices rather than consumer consumption and behaviour alone.

India is already a leader in the management and recycling of e-waste. But over 90 per cent is managed in the unorganized sector by small businesses and individual entrepreneurs, typically from low-income marginalized communities, and often women. E-waste contains various toxic substances such as mercury and lead, prolonged exposure to which can lead to major health problems.

Almost 80 per cent of e-waste workers in India suffer from respiratory ailments due to improper standards and nearly 500,000 children are engaged in e-waste collection without adequate protection and safeguards. The bulk of the dirty and dangerous work supporting India’s march towards an increasingly digital society is done by those who have the least access to technology gains. Government regulations for the management of e-waste, on the other hand, are becoming more relaxed, presumably as a result of industry pressure. To streamline e-waste management, the government notified Electronic Waste Rules in 2011, based on the concept of extended producer responsibility (EPR).

EPR makes manufacturers of electronic products responsible for the end-of-life management of their products, including setting up collection centres. By shifting the burden to manufacturers, the EPR framework, in theory, creates incentives for more environmentally friendly design. But the impact of EPR rules on manufacturers has been minimal, at best. The recently released Draft Notification (2017) by the Ministry of Environment, Forest and Climate Change further relaxes the EPR rule by reducing the e-waste collection targets for industries.

While the efficiency and productivity gains of Digital India are to be welcomed, growing e-waste should draw attention to the broader sustainability of a digital society. Data centres, for example, are one the largest contributors to global warming, contributing a similar amount to global greenhouse emissions as the aviation industry.

This amount is expected to triple in the next decade. In many ways, the sustainability challenge is a ‘wicked problem’ – where possible solutions create a new set of additional challenges and the choice between available alternatives is largely about competing values.

For example, data centres powered by renewable sources of energy such as solar provide a greener alternative, but will also create new forms of e-waste in the form of photovoltaic cells and panels. An unverified estimate suggests that India’s projected solar capacity of 100 gigawatts by 2022 will create 7.76 million tonnes of e-waste. Without adequate and preemptive consideration of how this waste should be disposed and recycled, renewable energy solutions can create new negative externalities.

For Digital India to be sustainable, we need to develop anticipatory knowledge for preemptive solutions. It is an opportune moment to think of the broader architecture of a digital society, one that avoids getting locked into unsustainable models of production and consumption, as is the case with many industrialized economies.

The argument that such considerations are premature for India, given high levels of poverty and unemployment, are misplaced. Enquiries into the sustainability of Digital India are no less urgent than the need for sustained job-creating economic growth. These issues should not be addressed in a sequential or linear manner, but in parallel, or else we will be only partially aware of available choices and their consequences, creating new forms of technological and economic lock-ins.

The value-based choice demanded by the ‘wicked problem’ at hand is one that embraces the idea of a circular economy — one that departs from the linear economic growth model predicated on ‘take, make, dispose’ to embrace a growth model based on creating closed loops of production, consumption and re-use. A circular economy model is built on the idea of designing out waste and pollution; keeping products and materials in use; and regenerating natural systems. In many ways, India is already a leader in the circular economy.

Alongside, the management of e-waste and other forms of recycling, high levels of repair and reuse are distinctly observable. A number of reports note that the informal waste management sector in India works better than systems in many industrialized economies.

A circular economy vision for Digital India would include organizing informal waste management systems, including safety and social protection initiatives for workers; revising and tightening existent e-waste rules for increased accountability by manufacturers both in terms of durable design and responsible disposal; green data centres; and building future smart cities with a view towards energy and water efficiency, among others.

A recent report by the Ellen McArthur Foundation and the World Economic Forum also estimates that a circular economy path to development could bring India annual benefits of $624 billion by 2050. Greenhouse gas emissions could also be 44 per cent lower in 2050, compared with current development path.

Unsurprisingly, Nordic countries are leading the way in promoting the idea of a circular economy. Sweden recently announced tax breaks for repair related activities and Finland hosted the first global conference on the circular economy earlier this year. The circular economy provides an opportunity for India to capitalize and leverage an already existing culture of circular activities, and promote it as a policy agenda that will create new forms of employment while facilitating sustainable environmental management.

This article was originally published in the Indian Express.

In conversation with Ursula Burns 27 September 2022 — 1:00PM TO 2:00PM Anonymous (not verified) 15 September 2022 Chatham House and Online

Ursula Burns and Fred P. Hochberg share insights on American business and corporate life.

In the next of our conversations with CEOs, Ursula Burns, former CEO of the Xerox corporation, joins Fred P. Hochberg, former chairman of the Export-Import Bank of the United States, to share her insights on American business and corporate life.

Drawing from her recent book, Where You Are is not Who You Are, Burns will offer her reflections on the challenges leadership faces in a corporate world with rapidly changing technology and creating a diverse work environment. Hochberg and Burns will also discuss her views on racial and economic justice, as well as prospects for future business and economic growth.

China’s renewed influence in the Gulf Interview LJefferson 14 April 2023

By disseminating narratives of its own supremacy, China deepened relations with the Gulf during the COVID-19 pandemic.

China has used the COVID-19 pandemic as an opportunity to rebrand its international role as a ‘responsible’ and ‘great’ power by voicing narratives of its own supremacy to regions like the Gulf.

In this interview, Julia Gurol-Haller draws on her International Affairs article to trace how the UAE, Saudi Arabia, Qatar and Iran have responded to China’s narratives, with key implications for Sino-US competition and regional autonomy for the Gulf. This illustrates how words and narratives help bolster authoritarian power.

What have the China-Gulf relations looked like in context of the COVID-19 pandemic?

Bilateral relations between China and the Gulf countries have grown in importance over the past decade, particularly since 2013 with the Belt and Road Initiative. The Gulf plays a crucial role in China’s Belt and Road Initiative and its westward expansion, owing to its favourable geographic position and proximity to the Red Sea. 

In the beginning, transregional relations were mainly economic partnerships since China has a growing appetite for oil and gas and the Gulf monarchies fulfil these needs. China is one of the most important markets for Saudi Arabia, the UAE, and Qatar to export these goods.

Over time, we’ve seen the Sino-Gulf relations expand beyond just economic ties and towards policy fields like security and cultural relations. While these processes were already in place, they were boosted during the COVID-19 pandemic, not only in material terms but also in respect of Chinese attempts to advance its soft power, leverage, and influence in the Gulf region.

When COVID-19 began to ravage the globe, China took that window of opportunity to rebrand its international role. Through efforts such as mask diplomacy, vaccine diplomacy and the strategic diffusion of narratives, China tried to project its image as a ‘global saviour’ and a responsible and great power.

The Gulf monarchies and Iran were among the main target audiences for this public diplomacy campaign. So, the COVID-19 pandemic has been a catalysing factor for deepening relations between China and the Gulf region.

What exactly are narratives and why are they important in China’s approach to the Gulf states during the COVID-19 pandemic?

Through diplomatic statements, news outlets and social media, China has engaged in, what I call, a ‘narrative power-play’. To understand what that is, we need to understand the political importance of narratives.

Narratives are deliberately constructed by (political) actors to influence a certain target audience. In authoritarian contexts, narratives are a useful resource for political actors to bind audiences to their rule and to appeal to people’s emotions by strategically projecting certain images. 

Ultimately, this creates linkages via attraction or persuasion that enhance the actors’ legitimacy and consolidate their power. So, in the narrative power-play, authoritarian leaders function as ‘storytellers-in-chief’, shaping reality in their favour.

What kinds of narratives has China disseminated to the Gulf region in backdrop of the COVID-19 pandemic?

There are two sets of narratives that China disseminated to the Gulf: narratives of supremacy and narratives of a new world order.

China disseminates narratives of systemic supremacy which include praising the overall efficiency of its governance structures. For instance, the Chinese political system is presented as highly efficient and centralized. It has high amounts of ‘state capacity’ for mobilization and the ability to ‘quickly adapt’ to changing situations.

Narratives of performative supremacy refer to the tangible performance of the Chinese Communist Party or China as a whole, such as economic performance, performance in governance, provision of public goods or pandemic response. The performance narratives also highlight the ‘incredible logistical efficacy’, the highly professionalized medical sector and the innovative scientific sector. 

Narratives of normative supremacy are often informed by nationalist notions such as the reclaiming of China’s rightful position in the world and negative feelings towards Western imperial powers who are depicted as having inflicted great pains on China during the ‘century of humiliation’. Overall, these narratives serve to depict China as a responsible, caring and loyal world power that helps other states. The whole idea of mask diplomacy was also carved into that notion of China’s normative supremacy.

Together, China has used these narratives to construct the idea of a new world order in which China is believed to play a much bigger role. The world order narratives are closely linked to stories about the failure of the Western system and show the intertwinement of practices of othering and self-glorification that can also be observed in Chinese official media narratives in other contexts such as diplomatic stand-offs with the United States.

What do these narratives tell us about how China understands the world order?

The narratives China disseminated to the Gulf region show that in the Chinese understanding of politics, the world order is in flux and undergoing major power reconfigurations. For China, this implies a window of opportunity to position itself as a responsible and great power and move from the side-lines to the centre stage of international politics.

This is a trend that has been long in the making in Chinese foreign policy. For instance, the launch of the Chinese Global Security Initiative or the recent brokering of the Iran-Saudi rapprochement agreement show clearly that China is becoming much more than an economic powerhouse and is adopting a more proactive foreign policy.

During the recent state visit of Xi Jinping to Moscow, he said at one point that China stands ready to ‘safeguard (…) the international order underpinned by international law ’. These examples are quite telling regarding the role China ascribes itself on the international stage.

How have the Gulf countries responded to China’s power narratives during the COVID-19 pandemic?

Saudi Arabia, the UAE, Qatar and Iran all picked up the narrative of China’s superior performance during the global crisis. That was a unified response, but they did that to different degrees and by highlighting different aspects.

The strongest reproduction of Chinese narratives can be found in the Emirati media. They buy into the story of the COVID-19 pandemic as evoking a global power shift, which includes a decline of US hegemony and a corresponding rise of China. The explicit wording of Chinese narratives such as ‘community of shared future of humankind’ has been picked up word-for-word by some Emirati media outlets.

Iranian newspapers have also reproduced Chinese narratives. However, the difference is that they also praise China’s unconditional solidarity during the COVID-19 pandemic, which is believed to be superior and more ‘responsible’ than the ostensible individualism of the West. This tells us a lot about Iran’s relationship with the West and how China is believed to be a lifeline or anchor for stability.

Saudi Arabia has been more cautious in reproducing the Chinese narratives. While it does not contest China’s role in containing the COVID-19 pandemic, Saudi Arabia has adopted a more inward-looking perspective, stressing its own role as a responsible regional player during the pandemic.

This might be explained by the kingdom’s own regional leadership claims and the attempt to use the crisis as an opportunity to strengthen this role. The most pressing questions seem to be whether the post-COVID world will be a multipolar order, and what Saudi Arabia’s own position within it might be. 

Lars Jønson
May 1, 2007; 6:798-811
Research