Video: Merlin Mann - "Time & Attention Talk (improvised)"

Audio (mp3): "Merlin Mann - 'Rutgers Time & Attention Talk'"

This is a talk I did at Rutgers earlier this month. I kinda like it, but for a weird reason. Something something, perfect storm of technology Ragnarok, and yadda yadda, I had to start the talk 20 minutes late with no slides. Nothing.

So, I riffed.

And, I ended up talking about a lot of the new stuff you can expect to see in the Inbox Zero book—work culture, managing expectations, the 3 deadly qualities of email, and one surprising reason email's not as much fun as Project Runway.

Some people liked it. I think. I liked it. I hope you do, too.

Here's the slides I would have shown. ;-)

Many thanks, again, to my great pal, Dr. Donald Schaffner, for bringing me in for this visit. I had a great time and met some fantastic, passionate people. Much appreciated.

update 2010-04-27_13-50-00

Apologies—my friends at Rutgers (inexplicably) have placed this video under lock and key. Fortunately, I have a lock-picker called Firefox. Samizdat video available soon...

update 2010-04-27_14-42-24

Yay, fixed! Many thanks to my hero, Jesse Schibilia.

I was excited to finally get the word that an article I wrote sharing my love for my hometown – San Jose, California – is out in Delta Sky Magazine this month! Time Out: San José – (Image / PDF) (Thanks to Deb L. and Ginni R. for sending copies for me!)    

The article EIT Elsewhere | “Time Out: San José” in Delta Sky Magazine originated at EverInTransit.com

A.F Branco Cartoon – The choice in this election is clear: Sleight-of-hand leftist Tricks or the abrasive truth in the..

Chairman Klein and members of the Senate Industry, Business and Labor Committee- My name is David Heinemeier Hansson, and I’m the CTO and co-founder of Basecamp, a small internet company from Chicago that sells project-management software and email services. I first testified on the topic of big tech monopolies at the House Antitrust Subcommittee’s field… keep reading

Member’s question time: Is Russia losing the South Caucasus? 22 October 2024 — 1:00PM TO 1:30PM Anonymous (not verified) 2 September 2024 Online

Join us and ask Chatham House Senior Research Fellow, Natalie Sabanadze anything about the situation in the Caucasus. Submit your questions in advance.

Whilst Russia focuses on its illegal invasion of Ukraine, the situation at its southern border is evolving. Relations between the three states in the South Caucasus and Moscow have never been easy as Russia tried to maintain its dominance by leveraging vulnerabilities, playing one side against another to keep conflicts simmering and even engaging in open military aggression.  Although the violence seen in the 1990s and early 2000s has abated, the war in Ukraine has had an indirect impact on the region, bringing a change to the status quo.

Russia abandoned its long-standing support for Armenia, allowing for the collapse of Nagorny-Karabakh and the restoration of the territorial integrity of Azerbaijan with the backing of Turkey. As a result, Azerbaijan has emerged as a dominant regional player with Baku recently declaring its interest to join BRICS.  Turkey’s influence has grown, while Armenia frustrated by Russia’s change of heart has been turning cautiously towards the EU and the US.

In Georgia, meanwhile, the ruling party has been consolidating its grasp on power, rolling back democratic reforms and pivoting away from the West. Georgia’s long-awaited European integration process has been suspended, following the adoption of the Russian-style foreign agents legislation.

Join us as our Senior Research Fellow in the Russia and Eurasia Programme answers your questions in this quick-fire session assessing the extent to which the Russian influence has changed since the start of the invasion of Ukraine and who is there to fill the vacuum; how geopolitical contestation in the region is going to impact aspirations of Armenia, Azerbaijan and Georgia; and much more.

Submit your questions to Natalie Sabanadze in advance of the event. Your questions will drive the conversation.

Divided US support shows time is not on Ukraine’s side Expert comment LJefferson 17 February 2023

Growing public opinion evidence and uncertainty about the future of the war suggests that continued American support for aiding Ukraine should not be assumed.

One year into Russia’s war on Ukraine, fears that American support for Kyiv would rapidly wane have proven demonstrably wrong. Western financial and military backing has been robust thanks to allied unity and an unexpectedly mild winter. But, as financial analysts constantly remind us, past performance is no guarantee of future results.

People like to back winners. If the anticipated Russian spring offensive looks successful or the counterpart Ukrainian offensive is uninspiring, expect louder US voices calling for a negotiated settlement. The warning signs are already here.

American officials privately express growing apprehension that there will be an early resolution of the conflict. As one White House official recently observed to me, by the end of the year the war could well be about where it is today. And a plurality of Americans intuitively grasp this: 46 per cent believe neither Russia nor Ukraine currently has the advantage in the conflict.

Momentum matters  

In public opinion, perception of momentum matters. Americans’ support for the Vietnam War waned as the conflict persisted, falling from six-in-ten Americans in 1965 to four-in-ten in 1973.

Similarly, backing for the Iraq war fell from more than seven-in-ten in 2003 to barely four-in-ten in 2008. And with Afghanistan, as the war dragged on, support for US involvement fell from more than nine-in-ten in 2002 to less than five-in-ten in 2021. Notably, once the American public turned on these wars, support never returned.

Of course, Americans were fighting and dying in those wars, which is not the case in the Ukraine conflict. But initially the Vietnam, Iraq, and Afghanistan war support was buoyed by the belief that continued US engagement was justified, otherwise American sons and daughters had died in vain. With no American lives at stake in Ukraine, only financial and military resources, there is a growing wariness of throwing good money after bad.

In the last year, the share of Americans who say the United States is doing too much for Ukraine has nearly quadrupled, from seven to 26 per cent. And the portion that believe Washington has not done enough has halved, from 49 per cent to 17 per cent.

Sentiment about Ukraine support has become increasingly partisan. In March 2022, nine per cent of Republicans and five per cent of Democrats said the US was doing too much for Ukraine. By January 2023, 40 per cent of Republicans but just 15 per cent of Democrats complained Washington was doing too much.

This erosion of Americans’ support for Ukraine does not bode well for the future. Less than half (48 per cent) of the public in November, compared to 58 per cent in July, believed Washington should support Ukraine for as long as it takes, even if it means American households have to pay higher gas and food prices as a consequence.

A similar share, 47 per cent – up from 38 per cent in July – said the United States should urge Ukraine to settle for peace as soon as possible so the costs aren’t so great for American households, even if that means Ukraine will lose some territory.

A partisan divide

The partisan divide over Ukraine is largely driven by Republican political rhetoric during and after the 2022 midterm elections. Current Republican Speaker of the House Kevin McCarthy observed last October: ‘I think people are going to be sitting in a recession and they’re not going to write a blank cheque to Ukraine.’

More recently, in the wake of Ukrainian president Zelenskyy’s December speech to Congress, Florida Republican Representative Matt Gaetz, whose vote was pivotal in making McCarthy Speaker, tweeted: ‘Hemorrhaging billions in taxpayer dollars for Ukraine while our country is in crisis is the definition of America last.’

In January, newly-elected Ohio Republican Senator J.D. Vance told a Cleveland radio station that it was ‘ultimately not in our national security interest’ to send M1 Abrams tanks to Ukraine, despite the fact that they will be built by his constituents in Ohio.

In addition, ten Republican members of the House of Representatives have introduced legislation asserting ‘that the United States must end its military and financial aid to Ukraine, and urges all combatants to reach a peace agreement.’ 

And this month former President Donald Trump said: ‘That war has to stop, and it has to stop now, and it’s easy to do’ and it ‘can be negotiated within 24 hours’. Why worry about continued support for the war if it’s about to be over?

The road to 2024

With the 2024 US presidential election already revving up, Americans’ appetite for continued backing for Ukraine may hinge on how voters judge the Biden administration’s handling of the conflict.

Democrats are more than twice as likely as Republicans (61 per cent versus 27 per cent) to approve of the Biden administration’s response to the Russia invasion, suggesting Ukraine will be yet another partisan talking point as the campaign heats up. Notably, men are much more likely than women to approve of Biden’s efforts, as are older Americans compared with younger Americans.

Jacek R. Wiśniewski
Dec 1, 2014; 13:3497-3506
Research

Yi Zhang
Sep 1, 2005; 4:1240-1250
Research

Yasushi Ishihama
Sep 1, 2005; 4:1265-1272
Research

Time to accelerate the sustainability pivot Expert comment NCapeling 26 May 2021

Higher stakes make it more important than ever to safeguard the integrity of sustainability commitments, and ensure high quality in delivery and implementation.

Regular headlines reaffirm the rise of sustainability on the global stage. Political momentum behind climate action has not been derailed by COVID-19, sustainability is increasingly central to national political debates, and what once might have been confined to scientific pursuits and UN conferences has now percolated through to international financial affairs and the wider political summits.

Much is made of the scale of the challenge, from climate change, water stresses, and biodiversity loss to the looming spectre of environment-induced societal breakdown triggering unprecedented civilizational challenges on the back of decades of systemic neglect over the true cost of social and environmental imbalances and unencumbered consumption.

But the good news is that talk of sustainability solutions is picking up pace and growing in its reach into the mainstream. The Wall Street Journal recently charted the shift of sustainable finance from being a niche interest of socially conscious investors into a sustainable ‘gold rush’, further bolstering its financial credentials with trillions of dollars designated for the global energy transition.

Assets in investment funds with links to the environment came to almost $2 trillion globally in the first quarter of 2021, more than tripling in just three years, and investors are putting some $3 billion a day into these funds while bonds and loans worth $5 billion looking to bankroll green initiatives are issued every day.

Climate ambitions and power diplomacy

Should the number of zeros fail to persuade, other signs of a sustainability pivot abound. Climate ambition was the driving force in major power diplomacy as France, Germany, China, and the US jostled for leadership positions in a high octane theatre of ‘climate one upmanship’ in the run-up to the Climate Summit hosted by US president Joe Biden. The G7 has agreed to stop international financing of coal projects, and an International Energy Agency report says delivering net zero emissions by 2050 means no new coal, oil, or gas development from now on.

Governments are sending unmistakable policy signals which are redrawing multiple frontiers of the real economy, such as the banning of single use plastic in multiple jurisdictions from Europe, China, and more than 30 African states as well as New York and California. The sale of internal combustion engine vehicles is also set to end by 2035 or sooner in the EU, the UK, and California, and China is expected to follow suit with similar plans. France has proposed a ban on domestic flights when there are less carbon intensive alternatives on the ground.

But these signals did not spring out of a political vacuum. A global climate poll conducted by the United Nations (UN) in 50 countries showed two-thirds of the 1.2 million people polled thought there is a global climate emergency, and most indicated their support for stronger climate action even in countries with strong fossil energy interest.

Real economy responses to noticeable changes in risk calculus and political appetite will likely underpin further rapid shifts in market sentiment as investors begin to fully factor in the scale of the challenge and escalate their interrogation of company-level climate action plans.

Rapid pace of change still needed

But despite this ever-clearer direction of travel and growing availability of new technology and policy options, the need for speed remains. The rationale for moving fast in the next decade and a half to avoid the clear and present threats of environmental and breakdown is increasingly clear.

Getting up to scale is an ongoing and daunting challenge not least because exponential growth has brought growing pains. The recent spat over the definition and the usefulness of net zero targets for corporations and investors as seen in the shareholder votes over the climate plans put forward by Shell and other companies are all testimony to the challenge of mainstreaming.

While some have characterized these debates as political infighting, the reality is higher stakes simply mean it is more important than ever to safeguard the integrity of sustainability commitments as well as the quality of their delivery and implementation.

The move from ‘what’ to ‘how’ points to a clear demand for new, innovative collaborative efforts to help mitigate myriad political economy challenges associated with the upcoming great transition and ensure this sustainability pivot will deliver the promised outcomes. Launching the Chatham House Sustainability Accelerator in support of these once-in-a-generation efforts is a proud moment for the institute, and a clear sign that this pivot to sustainability is here to stay.

China’s economic policy pendulum has swung towards stimulus – but keep expectations low Expert comment jon.wallace 14 October 2024

Beijing historically swings between stimulus and frugality. But Xi Jinping’s ambition for self-reliance will constrain any new efforts to boost the economy.

Policymakers in Beijing have spent the past three weeks trying to convince the world that they are determined to deliver meaningful support to China’s sagging economy. 

Since late September statements have come from the central bank, which promised to cut interest rates, release liquidity, and provide funding to securities firms; from the politburo, which said it wanted to stabilize the real estate market, boost the capital market and shift towards looser fiscal and monetary policy; from the government’s main planning body, which promised a package of policies to support domestic demand; and from the finance minister himself, who at the weekend committed to issue more debt to recapitalize banks, support local governments and aid unhappy consumers.

Though details have been scant, the Chinese stock market has responded enthusiastically to this flurry of rhetoric. But the bigger question for the global economy is whether a boost in Chinese demand can return the country to its former status as a reliable destination for global exports and capital.

With that measure of success in mind, it is worth keeping expectations low. For the past 15 years, Chinese authorities have been wrestling with two conflicting objectives: to grow the economy, and to minimize the risk of financial instability. Those goals sit uneasily with each other because the effort to boost growth has relied on borrowing; and yet a rise in debt can increase the risk of a debt crisis.  

Chinese policymaking has responded to this dilemma by taking on a pendulum-like quality. Sometimes the authorities boost the economy by funding more investment spending. At other times that stimulus gets reined back as policymakers worry about the economy’s indebtedness.

In the aftermath of the great financial crisis of 2008, for example, Beijing’s over-riding priority was to protect the Chinese economy from the risk of recession by implementing a huge credit-financed stimulus to spur investment in infrastructure and real estate. 

By 2012, though, concerns about over-indebtedness began to dominate, and a withdrawal of stimulus saw the Chinese economy sag. In late 2015,a new round of stimulus measures emerged, only to be withdrawn again around 2018.

With that pendulum in mind, the optimistic take on what policymakers have said in recent weeks is that we are now back in stimulus mode. That’s true in part, but three factors suggest that this time is a little different.

Different times

First, China’s rising debt burden increases authorities’ worries about financial stability. Data from the BIS show that China’s private sector debt almost doubled in the past 15 years to 200 per cent of GDP at the end of 2023. The comparable debt stock for the US and the Eurozone was much lower, at 150 per cent each.

Second, ideology is playing a growing role in shaping Chinese economic policy. The most visible effect has been to prioritize Chinese state-owned enterprises, at the expense of the private sector. This became especially visible in 2021 with a campaign against the ‘unrestrained expansion of capital’ – Beijing’s way of expressing its anxiety that China’s corporate sector was behaving in a manner inconsistent with Chinese Communist Party goals. 

Although that phrase is no longer current, entrepreneurs’ animal spirits remain in the doldrums. They are likely to stay there as long as President Xi Jinping’s preference is for ‘bigger, better, stronger’ state-owned enterprises, which use capital much less efficiently than private firms.

Third, today Chinese policy is shaped by Beijing’s perception of geopolitical risks that it faces. Those risks became starkly apparent in February 2022 after Russia’s invasion of Ukraine, when essentially every country that prints a reserve currency joined to freeze Russia’s access to its foreign exchange reserves. That enveloped the Russian economy in a network of sanctions that sharply constrained its access to a whole range of imports.

It is not difficult to consider a similar scenario confronting China. Beijing’s approach to economic policy is therefore heavily influenced by the need to insulate itself from that kind of risk (though Chinese policy had in any case been tilting in this direction for years).

‘Asymmetric decoupling’

This policy can be described as ‘asymmetric decoupling’: a simultaneous effort on the one hand to reduce China’s reliance on the rest of the world by substituting imports with domestic production; and, on the other hand, to increase the rest of the world’s reliance on China by establishing itself as a ‘zhizao qiangguo’, or manufacturing powerhouse.

This is the right context in which to understand a central economic goal of the authorities, which is to reduce the economy’s dependence on real estate investment. 

The intention is to allow capital and credit resources to migrate to new sectors of the economy that will help to build that manufacturing powerhouse: high-tech and green energy, in particular. What that means in practice is that any forthcoming support for the real estate sector will be rather limited.

Members' question time: What has COP29 achieved? 25 November 2024 — 1:00PM TO 1:45PM Anonymous (not verified) 8 November 2024 Online

Join us and ask our senior research fellow, Ruth Townend anything about the outcome from COP29. Submit your questions in advance.

As COP29 prepares to conclude in Baku, Azerbaijan, this year’s conference has taken place against a backdrop of ever worsening climate impacts and escalating financial needs for developing countries. Being hosted by Azerbaijan has been significant, a country whose economy is heavily reliant on fossil fuels. As delegates and officials prepare to leave, the urgency for global climate action intensifies.

Join us as Ruth Townend, our Senior Research Fellow for the Environment and Society Centre to provide the latest insight and analysis from COP. She will give an overview of the key developments from Baku, new global commitments that have been agreed and how this sets up COP 30 in Brazil in 2025.

Submit your questions to Ruth Townend in advance of the event. Your questions will drive the conversation.

Chatham House appoints Tim Benton as Research Director for Energy, Environment and Resources News Release sysadmin 30 May 2019

Chatham House is pleased to announce that Professor Tim Benton has been appointed as research director of the Energy, Environment and Resources Department.

Is Myanmar Running Out of Time? 17 February 2020 — 1:00PM TO 2:00PM Anonymous (not verified) 10 January 2020 Chatham House | 10 St James's Square | London | SW1Y 4LE

Just a few years ago the West was celebrating what appeared to be the conclusion of a quarter-century long contest between Myanmar’s democrats and a military dictatorship. Today, the country stands charged with genocide at the International Court of Justice, with Aung San Suu Kyi leading the defence. Is Myanmar a democratic transition gone awry? Or something else entirely?

The speaker will argue that Myanmar is not the simple morality tale often portrayed. It has instead become the stage for some of the world’s most pressing challenges such as climate change, explosive inequality and rising populism, the impact of social media; and the rise of China as the next global superpower.

In this context, are 20th century democratic institutions and free-market reforms the correct remedy for a country plagued by the legacies of colonialism, decades of civil war, tyranny and a predatory economic system? The speaker will offer a prognosis for Myanmar’s future, assessing the question of whether it will become Asia’s next failed state.

This event will be held off the record.

Katherine Baker, Lehel Banjai and Mariya Ptashnyk
Math. Comp. 93 (), 2711-2743.
Abstract, references and article information

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

Simone Cecchini and Rudolf Zeidler
Trans. Amer. Math. Soc. 377 (), 5271-5288.
Abstract, references and article information

Olha Prykhodko and Kostiantyn Ralchenko
Theor. Probability and Math. Statist. 111 (), 123-135.
Abstract, references and article information

Claudio Macci and Barbara Pacchiarotti
Theor. Probability and Math. Statist. 111 (), 21-43.
Abstract, references and article information

Giovanni Catino and Alberto Roncoroni
Proc. Amer. Math. Soc. 152 (), 5339-5354.
Abstract, references and article information

Xiaoshang Jin
Proc. Amer. Math. Soc. 152 (), 5327-5337.
Abstract, references and article information

PROMOTED RACING, CHAPELTON MAROONS RENEW RIVALRY IN JPL - A16 FUNCAANDUN SET FOR FIFTH STRAIGHT WIN - A21

Stromal interaction molecule 1 (STIM1) plays a pivotal role in store-operated Ca2+ entry (SOCE), an essential mechanism in cellular calcium signaling and in maintaining cellular calcium balance. Because O-GlcNAcylation plays pivotal roles in various cellular function, we examined the effect of fluctuation in STIM1 O-GlcNAcylation on SOCE activity. We found that both increase and decrease in STIM1 O-GlcNAcylation impaired SOCE activity. To determine the molecular basis, we established STIM1-knockout HEK293 (STIM1-KO-HEK) cells using the CRISPR/Cas9 system and transfected STIM1 WT (STIM1-KO-WT-HEK), S621A (STIM1-KO-S621A-HEK), or T626A (STIM1-KO-T626A-HEK) cells. Using these cells, we examined the possible O-GlcNAcylation sites of STIM1 to determine whether the sites were O-GlcNAcylated. Co-immunoprecipitation analysis revealed that Ser621 and Thr626 were O-GlcNAcylated and that Thr626 was O-GlcNAcylated in the steady state but Ser621 was not. The SOCE activity in STIM1-KO-S621A-HEK and STIM1-KO-T626A-HEK cells was lower than that in STIM1-KO-WT-HEK cells because of reduced phosphorylation at Ser621. Treatment with the O-GlcNAcase inhibitor Thiamet G or O-GlcNAc transferase (OGT) transfection, which increases O-GlcNAcylation, reduced SOCE activity, whereas treatment with the OGT inhibitor ST045849 or siOGT transfection, which decreases O-GlcNAcylation, also reduced SOCE activity. Decrease in SOCE activity due to increase and decrease in O-GlcNAcylation was attributable to reduced phosphorylation at Ser621. These data suggest that both decrease in O-GlcNAcylation at Thr626 and increase in O-GlcNAcylation at Ser621 in STIM1 lead to impairment of SOCE activity through decrease in Ser621 phosphorylation. Targeting STIM1 O-GlcNAcylation could provide a promising treatment option for the related diseases, such as neurodegenerative diseases.

12 August 2020

27 August 2020

Africa’s maritime agency cannot be overlooked Expert comment LJefferson 3 November 2022

Increasing maritime awareness has already delivered impact, but consistency and continental leadership are needed to realize the sector’s full potential.

Africa’s 48,000 kilometres of coastline, shared among 38 coastal states, are resource rich and hold some of the world’s most strategic sea lanes, including the approaches to the Suez Canal, which carries 12 per cent of worldwide trade, and the Gulf of Guinea, a critical route for global energy. But despite the vast potential this represents, piracy and maritime insecurity have dominated the narrative of Africa’s coasts, and further propagated the image of African states as beholden to external intervention.

Yet African agency is established and evolving in the sector, with African littoral states enhancing their capacity to face collective security threats and exercising increasing autonomy in responding to the recent rush of external actors looking for port facilities and military bases. Enhanced continental coordination, consistency and leadership can help Africa’s maritime endowment become a resource that can bring sustainable benefit across the continent.  

Agency beyond piracy: the Gulf of Aden and Western Indian Ocean

Piracy became the dominant frame of reference for the East African maritime space as a result of the crisis off the coast of Somalia, which peaked between 2008 and 2012. In 2008, the UN Security Council (UNSC) took the unprecedented step of authorizing international naval operations in Somali territorial waters, contributing to a gradual reduction in attacks. There have been no successful hijackings reported since 2017.

But progress has not just been down to international assistance. Somalia is prioritizing increased domestic enforcement capacity – as demonstrated in the establishment of  a new specialized maritime unit and the wider region enhanced collaboration and information sharing through the Djibouti Code of Conduct of 2009, amended in 2017.

South Africa’s recent admission as a new signatory demonstrates its continued relevance. In March 2022, the UNSC authorization lapsed, following pressure from the Somali government. Although it is not yet clear whether Somali efforts will be sufficient to repress piracy in the long term, this reverse was a clear statement of Somalia’s agency at a level unthinkable during the outset of the crisis.

As the immediate threat of piracy has quietened, broader geopolitical dynamics have come to the fore, notably in a surge by external actors to establish strategic ports and military bases. Here too, African states have demonstrated enhanced agency, for better or worse. Consider Djibouti’s unilateral seizure of a container terminal from an Emirati firm, Sudan’s review of Russian and Turkish deals for maritime facilities, Tanzania’s rejection of a Chinese-led port investment, or the Seychelles withdrawing agreement for an Indian naval base.

Such examples point to a growing awareness of the value of maritime resources within African states, alongside a willingness and ability to push back against external imposition – and indeed to innovate in finding solutions beyond infrastructure and ‘hard’ security. In 2018, the Seychelles launched the world’s first sovereign blue bond to fund sustainable marine projects. That other countries are seeking to replicate this model points to the potentially global impact of African leadership on maritime issues.

Regional cooperation or competition in the Gulf of Guinea?

The Gulf of Guinea is likewise resource rich and geographically strategic, and has faced diverse maritime security threats including piracy, smuggling, illegal fishing, oil theft and pollution. Gulf of Guinea states put in place several initiatives to promote security, including the Yaoundé Code of Conduct (YCoC), signed by 25 states in 2013, that led to information-sharing and cooperation on interdiction, investigation and prosecution. But crime in the Gulf of Guinea nonetheless reached an all-time high in 2020, suffering 130 of the 135 maritime kidnappings recorded worldwide, due to the non-binding nature of the YCoC and gaps in capacity and finance.

Though external actors have become increasingly engaged, including the EU, US, France, Denmark, and the G7++ Group of Friends of the Gulf of Guinea (FOGG), states within the region, especially those most affected by piracy and armed robbery, have nonetheless demonstrated leadership. Nigeria, Ghana, and Cote D’Ivoire have all developed maritime security strategies; Nigeria launched its Deep Blue Project to secure Nigerian waters; Ghana has strengthened its navy; and Togo has changed its laws and judicial system to allow the arrest and prosecution of ships and persons. Maritime security incidents have consequently reduced in 2022.

Visual Abstract

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

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

Amyloid fibrils are polymeric structures originating from aggregation of misfolded proteins. In vivo, proteolysis may modulate amyloidogenesis and fibril stability. In light chain (AL) amyloidosis, fragmented light chains (LCs) are abundant components of amyloid deposits; however, site and timing of proteolysis are debated. Identification of the N and C termini of LC fragments is instrumental to understanding involved processes and enzymes. We investigated the N and C terminome of the LC proteoforms in fibrils extracted from the hearts of two AL cardiomyopathy patients, using a proteomic approach based on derivatization of N- and C-terminal residues, followed by mapping of fragmentation sites on the structures of native and fibrillar relevant LCs. We provide the first high-specificity map of proteolytic cleavages in natural AL amyloid. Proteolysis occurs both on the LC variable and constant domains, generating a complex fragmentation pattern. The structural analysis indicates extensive remodeling by multiple proteases, largely taking place on poorly folded regions of the fibril surfaces. This study adds novel important knowledge on amyloid LC processing: although our data do not exclude that proteolysis of native LC dimers may destabilize their structure and favor fibril formation, the data show that LC deposition largely precedes the proteolytic events documentable in mature AL fibrils.

In SAS Merchandise Financial Planning, custom time frame-based data versions do not aggregate correctly when referenced in worksheets with standard hierarchy levels. The data does not aggregate correctly from l

In SAS Customer Intelligence, a decision campaign can become corrupted and impossible to open. When you try to open the campaign, an error message is displayed that asks you to check the SAS Customer Intel

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

Ion mobility brings an additional dimension of separation to LC–MS, improving identification of peptides and proteins in complex mixtures. A recently introduced timsTOF mass spectrometer (Bruker) couples trapped ion mobility separation to TOF mass analysis. With the parallel accumulation serial fragmentation (PASEF) method, the timsTOF platform achieves promising results, yet analysis of the data generated on this platform represents a major bottleneck. Currently, MaxQuant and PEAKS are most used to analyze these data. However, because of the high complexity of timsTOF PASEF data, both require substantial time to perform even standard tryptic searches. Advanced searches (e.g. with many variable modifications, semi- or non-enzymatic searches, or open searches for post-translational modification discovery) are practically impossible. We have extended our fast peptide identification tool MSFragger to support timsTOF PASEF data, and developed a label-free quantification tool, IonQuant, for fast and accurate 4-D feature extraction and quantification. Using a HeLa data set published by Meier et al. (2018), we demonstrate that MSFragger identifies significantly (~30%) more unique peptides than MaxQuant (1.6.10.43), and performs comparably or better than PEAKS X+ (~10% more peptides). IonQuant outperforms both in terms of number of quantified proteins while maintaining good quantification precision and accuracy. Runtime tests show that MSFragger and IonQuant can fully process a typical two-hour PASEF run in under 70 min on a typical desktop (6 CPU cores, 32 GB RAM), significantly faster than other tools. Finally, through semi-enzymatic searching, we significantly increase the number of identified peptides. Within these semi-tryptic identifications, we report evidence of gas-phase fragmentation before MS/MS analysis.

Natural compounds that can stimulate salivary secretion are of interest in developing treatments for xerostomia, the perception of a dry mouth, that affects between 10 and 30% of the adult and elderly population. Chemesthetic transient receptor potential (TRP) channels are expressed in the surface of the oral mucosa. The TRPV1 agonists capsaicin and piperine have been shown to increase salivary flow when introduced into the oral cavity but the sialogogic properties of other TRP channel agonists have not been investigated. In this study we have determined the influence of different TRP channel agonists on the flow and protein composition of saliva. Mouth rinsing with the TRPV1 agonist nonivamide or menthol, a TRPM8 agonist, increased whole mouth saliva (WMS) flow and total protein secretion compared with unstimulated saliva, the vehicle control mouth rinse or cinnamaldehyde, a TRPA1 agonist. Nonivamide also increased the flow of labial minor gland saliva but parotid saliva flow rate was not increased. The influence of TRP channel agonists on the composition and function of the salivary proteome was investigated using a multi-batch quantitative MS method novel to salivary proteomics. Inter-personal and inter-mouth rinse variation was observed in the secreted proteomes and, using a novel bioinformatics method, inter-day variation was identified with some of the mouth rinses. Significant changes in specific salivary proteins were identified after all mouth rinses. In the case of nonivamide, these changes were attributed to functional shifts in the WMS secreted, primarily the over representation of salivary and nonsalivary cystatins which was confirmed by immunoassay. This study provides new evidence of the impact of TRP channel agonists on the salivary proteome and the stimulation of salivary secretion by a TRPM8 channel agonist, which suggests that TRP channel agonists are potential candidates for developing treatments for sufferers of xerostomia.

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

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

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

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

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

This book is part of the Insights series.

Watch the event

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

Praise for War Time

About the editors

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

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

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

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• Students (via Browns Books)

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Single-domain antibodies (sdAbs) demonstrate favorable pharmacokinetic profiles for molecular imaging applications. However, their renal excretion and retention are obstacles for applications in targeted radionuclide therapy (TRT). Methods: Using a click-chemistry–based pretargeting approach, we aimed to reduce kidney retention of a fibroblast activation protein α (FAP)–targeted sdAb, 4AH29, for ¹⁷⁷Lu-TRT. Key pretargeting parameters (sdAb-injected mass and lag time) were optimized in healthy mice and U87MG (FAP⁺) xenografts. A TRT study in a pancreatic ductal adenocarcinoma (PDAC) patient-derived xenograft (PDX) model was performed as a pilot study for sdAb-based pretargeting applications. Results: Modification of 4AH29 with trans-cyclooctene (TCO) moieties did not modify the sdAb pharmacokinetic profile. A 200-µg injected mass of 4AH29-TCO and an 8-h lag time for the injection of [¹⁷⁷Lu]Lu-DOTA-PEG₇-tetrazine resulted in the highest kidney therapeutic index (2.0 ± 0.4), which was 5-fold higher than that of [¹⁷⁷Lu]Lu-DOTA-4AH29 (0.4 ± 0.1). FAP expression in the tumor microenvironment was validated in a PDAC PDX model with both immunohistochemistry and PET/CT imaging. Mice treated with the pretargeting high-activity approach (4AH29-TCO + [¹⁷⁷Lu]Lu-DOTA-PEG₇-tetrazine; 3 x 88 MBq, 1 injection per week for 3 wk) demonstrated prolonged survival compared with the vehicle control and conventionally treated ([¹⁷⁷Lu]Lu-DOTA-4AH29; 3 x 37 MBq, 1 injection per week for 3 wk) mice. Mesangial expansion was reported in 7 of 10 mice in the conventional cohort, suggesting treatment-related kidney morphologic changes, but was not observed in the pretargeting cohort. Conclusion: This study validates pretargeting to mitigate sdAbs’ kidney retention with no observation of morphologic changes on therapy regimen at early time points. Clinical translation of click-chemistry–based pre-TRT is warranted on the basis of its ability to alleviate toxicities related to biovectors’ intrinsic pharmacokinetic profiles. The absence of representative animal models with extensive stroma and high FAP expression on cancer-associated fibroblasts led to a low mean tumor-absorbed dose even with high injected activity and consequently to modest survival benefit in this PDAC PDX.