West Indies fast bowler Alzarri Joseph is suspended for two matches after storming off against England following an argument with captain Shai Hope.

They will be performing one final time at this year's Remembrance Sunday commemorations in Dagenham.

I haven’t written for Powdered Wig since October 2020. This once profitable site has now been destroyed by Big Tech, especially Fascistbook, Twitter, and Google. So, at 66 years old, I find myself making a living in the construction field […]

The post Is populism dead? Are We the People now forever under the thumb of unbridled global tyranny? Madame Defarge chimes in appeared first on Powdered Wig Society.

1. Coldplay announces fourth show in Ahmedabad on 25 January. Tickets available from… | Today News  Mint
2. Coldplay announces new show in Ahmedabad: Check date, how to book tickets and more  India Today
3. Coldplay Announces Fourth Concert In India. Check Out Date, Venue And Ticket Prices  NDTV Movies
4. Coldplay announces new show in Ahmedabad, check details here  CNBCTV18
5. entertainment News Live Today November 13, 2024: Coldplay announced 4th India show in Ahmedabad: Check out ticket sale details  Hindustan Times

The leader of the world's Anglican communion, Archbishop of Canterbury Justin Welby, announced Tuesday he was resigning following a damning report that concluded the Church of England covered up a serial abuse case.

Financial planner Anthony Carlton says his richest clients are teachers and other unassuming professionals who have good money habits.

The 2Checkout team kicked off Feb 2019 by joining over 12,000 participants in San Jose for SaaStr Annual 2019, the largest conference in the world for B2B software. The general consensus of 2Checkout team members at the end of the conference was simple and to the point: “It. Was. Amazing.”

Nowadays many shoppers don’t even remember how they learned about an eCommerce brand in the first place. If you ask them, the most popular answer is “I found it somewhere on the Internet”. Commercial information is all over the place, so nobody cares about the “channel” they use to find it anymore.

Soldiers and police were patrolling Mozambique's capital Maputo early on Thursday ahead of a planned protest against election results seen by the opposition as fraudulent.

Many fans of Huawei on Friday were disappointed that its much-anticipated phone, Mate XT - more than twice the price of the iPhone 16 Pro Max - was not available for walk-in customers.

Tech accelerator Startupbootcamp, British-East African business tycoon Ashish Thakkar’s Mara Group and Blend Financial Services are planning a $250 million (R4.4 billion) fund to invest in new African technology companies.

A Boring Day's DIY head speaker is a one-of-a-kind speaker straight out of the uncanny valley. It's fantastic. 

The speaker is built inside of a plastic mannequin head, with exposed wires that look like the mannequin's hairdo. The sound comes out of the mannequins eye holes which look like bug eyes.To — Read the rest

The post Bluetooth speaker inside a mannequin head appeared first on Boing Boing.

The following article, Steve Bannon Issues 90-Second WARNING To Deep State At Trump Victory Party (Video), was first published on Conservative Firing Line.

(Natural News) Steve Bannon, one of Donald Trump’s most fired-up supporters and allies all throughout the former president’s tumultuous political career, delivered a powerful speech after Trump’s victory warning the deep state that justice is coming. Fresh out of federal prison for his involvement in the events of Jan. 6, 2021, Bannon took the stage to deliver …

Continue reading Steve Bannon Issues 90-Second WARNING To Deep State At Trump Victory Party (Video) ...

The following article, Left Already Losing It As Trump Announces Starting Lineup (Video), was first published on Conservative Firing Line.

Trump learned some hard lessons from his first kick at the can. This time, he’s not making the same mistakes. Personnel IS policy. Last time around DJT was hamstrung right out of the gate when the Alabama Senator he tapped to be his AG was stuck in purgatory under bogus Russia allegations. The Deep State …

Continue reading Left Already Losing It As Trump Announces Starting Lineup (Video) ...

He learned some hard lessons from his first kick at the can. This time, he's not making the same mistakes. Personnel IS policy.

The post Left Already Losing It As Trump Announces His Starting Lineup (VIDEO) appeared first on Clash Daily.

Without a consequence-free hook-up culture, Planned Parenthood's business model collapses. The left's response to Trump's election is an existential threat... to itself!

The post OOPS: Planned Parenthood Sounds Alarm As Lefties Weaponize Abstinence appeared first on Clash Daily.

China’s zero-COVID cannot continue, reopening is needed Expert comment NCapeling 1 December 2022

Unsure of how to loosen rules, local officials have doubled down on severe restrictions behind so much economic damage. Reopening will quell public anger.

When President Xi Jinping was seen unmasked at the G20 summit in Indonesia, he maintained a largely positive tone with President Joe Biden and other world leaders. This left an impression that China was on the verge of withdrawing its zero-COVID strategy.

A set of loosening policy measures introduced by Beijing seemed to further suggest that China was on track to reopen. As outlined in the 20th party congress, Xi wants to forge a pathway towards economic modernization and this means building economic resilience and a further increase in household incomes.

However, a series of displays of public defiance against the government’s zero-COVID policy has left the rest of the world perplexed. Some loosening of restrictions announced on 11 November by the central government, with the number of new cases still rising rapidly, left the provincial governments in confusion as to which direction to turn.

Absolute political loyalty

The persistent slogan of ‘zero-COVID’ was in stark contrast to the slackening of restrictions. Local officials decided to double down on stringent COVID measures as a way of displaying absolute political loyalty to the top, which inevitably caused daily agonies among large parts of the Chinese population.

This decision-making process sheds some light on the way the Chinese bureaucracy approaches crises at a time when the party leadership is tightening political control. Lower-level officials avoided making important decisions and instead decided to wait for instructions from the top. As the rules were unclear, they implemented policies according to past precedents, in this case zero-COVID, which had worked relatively well for China in 2020 and 2021.

For decades, local governments have been major political actors in China and have known what works best under local conditions. But with tighter regulation being exercised by lower-level bureaucrats and civil servants, there is less opportunity for the input of local knowledge, increasing the risk of ineffective policies being implemented.

Away from Beijing, those not employed by the state have been hit particularly hard by zero-COVID measures. The strategy has intensified economic pressures, exacerbated rising levels of youth unemployment, and tested the patience of the entire country.

Billions of Chinese people want to have their life return to normal without the fear of having the wrong colour – yellow or red – on their COVID health QR code or endless mandatory testing. Only a green code shows that a person is healthy and able to move around freely.

Economy is suffering

China is still balancing its twin aims of containing the spread of COVID and re-engineering its economy along similar lines to the rest of the world. It is difficult to see how China’s economy can crank up again until the country reduces its internal restrictions and reconnects with the world.

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.

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.

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.

The Chatham House Centenary Award winners announced News release jon.wallace 29 July 2021

Black Lives Matter, Greta Thunberg and Sir David Attenborough have been recognized for their achievements tackling racial inequality, climate change and biodiversity loss.

As Chatham House wraps up its centenary activities, the institute has made three Centenary Awards recognizing outstanding contributions to confronting the critical challenges facing the world today.

The awards are unique as they were voted on by the institute’s staff and pay tribute to the individual or organization they believe has played a significant role in progressing the Chatham House mission: to help governments and societies build a sustainably secure, prosperous and just world.

Greta Thunberg has been awarded the Chatham House Centenary Changemakers Award in recognition of her vanguard role in mobilizing young people to take up climate activism.

Greta’s message has cut through where politicians and scientists have failed time and time again. She has commanded the attention of world leaders, addressed intergovernmental organizations and inspired millions of people to join the global climate strike. She has demonstrated the electrifying power of young voices speaking truth to power and focused the world’s attention on environmental injustices.

Sir David Attenborough has been named as the Chatham House Centenary Lifetime Award winner for his tireless commitment to conservation and raising public and political awareness of the growing climate crisis.

Together with the BBC, he has pioneered the way in which we experience and understand life on this planet, bringing the wonders of the natural world into our homes. Over the last 60 years, from black-and-white to 4K TV, his pioneering documentaries have been broadcast around the world and have sounded the alarm on the devastating impact humanity has had on the environment.

He has become one of the most compelling voices on important issues such as biodiversity loss, climate change and the destruction of natural habitats. Sir David was previously awarded the Chatham House Prize in 2019 for his work on Blue Planet II and tackling ocean plastic pollution.

Melina Abdullah, one of the co-founders of the Los Angeles chapter of the Black Lives Matter movement and co-director of Black Lives Matter Grassroots, has accepted the Chatham House Centenary Diversity Champion Award on behalf of the movement.

This award is in recognition of the momentous work Black Lives Matter has done towards empowering black people and promoting a more inclusive approach to race in policy-making. The movement has brought global attention to systemic injustice against black lives and is helping to build a better world that draws on more diverse voices and inclusive approaches.

Dr Robin Niblett, Director of Chatham House said:

‘We are delighted to recognise three special centenary awards today in recognition of the individuals who our staff believe are redefining the ways in which each of us can drive positive global change.

‘The vision and achievements of each of the winners echo Chatham House’s own goals for its second century and demonstrate a shared commitment to building a more sustainable and inclusive world.

‘We are inspired by the ways the award winners are leading global efforts to combat climate change, protect biodiversity and bring about more equal and inclusive societies.’

For more information, please contact: pressoffice@chathamhouse.org

In conversation with the Rt Hon Anneliese Dodds 17 October 2024 — 1:00PM TO 2:00PM Anonymous (not verified) 10 October 2024 Chatham House and Online

The Minister of State for Development discusses the new government’s international development priorities.

Following its election victory in July 2024, the new government has set out an ambition to reset its relationships with countries in the Global South. Its stated mission is to modernise the UK’s approach to international development, helping to create ‘a world free from poverty on a liveable planet’.

Where can the UK make a meaningful difference in a more volatile and insecure world? The government is looking to address priorities including unsustainable debt, empowering women and girls, conflict prevention, and unlocking climate finance. But it does this with a much-reduced Official Development Assistance budget, in a world where progress to meet the UN’s Sustainable Development Goals is off track. And while the UK has been debating its own approach to development, the landscape has been changing, with non-allied states vying for influence in the Global South, and developing countries themselves becoming more vocal on climate, debt, and global institutional reform. What kind of role can the government set out for the UK in this context?

In this discussion, the Rt Hon Anneliese Dodds, Minister of State for Development in the Foreign, Commonwealth and Development Office, will lay out her priorities for meeting international development goals over the coming parliament.

Individual membership provides you with the complete Chatham House experience, connecting you with a unique global policy community. Find out more about membership.

Announcing Design Resonance in an Age of Crisis News Release sysadmin 1 June 2020

London Design Biennale and Chatham House announce Design Resonance in an Age of Crisis, which calls for action by designers around the world to create radical design solutions to critical problems across four key areas: Health, Environment, Society and Work.

N. R. Ikonomov and S. P. Suetin
Trans. Moscow Math. Soc. 83 (), 33-54.
Abstract, references and article information

‘Hong Kong is now in the hands of its people – they cannot rely on others to stick up for them now.’ Expert comment sysadmin 29 June 2017

Kerry Brown on ‘one country, two systems’, the UK’s diminishing influence and the territory’s future, 20 years after the handover.

1 July marks the 20th anniversary of the transfer of Hong Kong’s sovereignty from Britain to China. Kerry Brown speaks with Jason Naselli about what the future holds for the territory.

How sustainable is the ‘one country, two systems’ framework? Will the arrangement last the full 50 years (until 2047) as originally envisioned?

It is questionable whether the arrangement that exists today was the one envisioned in 1997 when the handover happened. It was always a very abstract, flexible system, granting Hong Kong a high degree of autonomy, meaning it could maintain its capitalist system. Of course, in the lead up to 1997 all these things were broadly seen as being in Beijing’s interests to preserve.

But these days, the one thing that few said in 1997 has come to pass – the People’s Republic has maintained one-party rule as a political system, but become one of the world’s great economies. It has been so far a huge success.

Hong Kong therefore has diminished in importance over the years to the point that maintaining at least some semblance of one country, two systems is almost like an act of charity. It has been nibbled at, compromised and seems to grow weaker by the day. Most in Hong Kong would say there is a system: one country, one system. That’s the deal.

The central government’s deepening involvement in the territory’s politics is a subject of growing controversy in Hong Kong. Does the Chinese government need to alter its approach?

Not particularly. It doesn’t want to see Hong Kong fail as an economy. That doesn’t suit its interests at all. But nor does it want a truculent, disobedient polity that is meant to be part of its sovereign territory.

So it has increasingly set political parameters. Hong Kong can have its unique system – as long as it is obedient. And on the whole, that is the deal that all of the city’s chief executives until now have internally understood perfectly.

As part of the 1997 handover, the UK has ‘a continuing moral and political obligation’ to Hong Kong. How will this relationship play out as Brexit shifts Britain’s place in the world?

The Foreign Office offers a six-monthly report to Parliament, updating on how the handover deal is going. As the years go on, however, it becomes increasingly illusive how the UK has any real locus to say much about the situation on Hong Kong. It did say, rightly, that the detainment of one of the booksellers taken in in 2015 was a violation of the treaty because he was British. This was the strongest wording that has ever appeared from an official British source. But with dependence on creating a new kind of relationship with China now foremost in people’s minds because of Brexit and other economic pressures, it is not surprising that the priority increasingly lies elsewhere.

With direct management of Hong Kong gone, the UK was always going to be more and more irrelevant. That has happened. And in any case, relations with China have had to become more complex and multifaceted. Hong Kong was always the tail wagging the dog for the UK relations with China. Now there has been a rebalancing, the calculation always has to be how much unilaterally supporting Hong Kong will damage relations with Beijing. This has become an increasingly asymmetrical question: in a playoff, preserving links with Beijing will always prevail. That’s just the reality of the new world we are seeing come into being.

Hong Kong has played an important financial role for China over the past 20 years, but where will it fit as markets and financial institutions on the mainland mature?

It maintains is role as a major RMB hub, and as a finance centre. But it is surrounded by competition. Singapore, and Sydney, and other places in the region have RMB deals. Shanghai and Tianjin aspire to be portals for entry to the domestic Chinese market. Hong Kong every day has to think of new ways to maintain its relevance and beat back competition. So far, it has done well. But this is an issue it can never be complacent about.

What has been the most significant change in Hong Kong society since 1997?

The rising cultural and linguistic influence of the mainland on Hong Kong. Hong Kong has maintained its difference – but it has had to change. It is clear that Hong Kong is now in the hands of Hong Kongese – they cannot rely on others to stick up for them now. The culture, identity and future of the territory are in their hands. In that sense, they have autonomy.

Ahmed Elshafei, Ana Cristina Ferreira, Miguel Sánchez and Abdelghani Zeghib
Trans. Amer. Math. Soc. 377 (), 5837-5862.
Abstract, references and article information

Ning Jiang, Yi-Long Luo and Shaojun Tang
Trans. Amer. Math. Soc. 377 (), 5323-5359.
Abstract, references and article information

Robert McCann, University of Toronto, will receive the 2025 American Mathematical Society (AMS) - Society for Industrial and Applied Mathematics (SIAM) Norbert Wiener Prize in Applied Mathematics “in recognition of his groundbreaking contributions to optimal transport theory, and for pioneering deep applications to economics and physics,” according to the citation. McCann holds a Canada Research Chair in Mathematics, Economics, and Physics.

From the citation

Robert McCann has made fundamental contributions to optimal transport theory, reflecting remarkable technical abilities and amazing conceptual creativity. His discovery of displacement convexity and his solution to Monge’s (1746-1818) problem for different transportation costs were early, foundational advances that preceded by nearly 30 years the current enormous attention bestowed on optimal transport theory and its applications. Beyond these, McCann produced many important, unexpected results, linking optimal transport to new areas of application within and outside mathematics: different notions of curvature, new and hidden convexities in the economics of information, and a non-smooth theory of gravity based on the interaction of entropy with the Einstein field equation.

Response of Robert McCann

I am honored and humbled to have my work on optimal transportation and its applications to economics and physics recognized by the AMS-SIAM 2025 Norbert Wiener Prize (endowed by MIT). I think the whole optimal transport community can join me in taking pride in this acknowledgement of the impact and success of our efforts and can view this award as an incentive to further achievements. After singling out my PhD advisor, Elliott Lieb, who first taught me about the mines and the factories, I'd like to thank the many other mentors, collaborators, colleagues, and students – too numerous to name – who shared in my mathematical, physical, and economic adventures (and those who wrote letters to document!). Our interactions inspire and sustain me on my scientific journey; I could not have achieved these results without you, and my life is enriched by your presence. I try to pass it forward by giving as good as I got, and I encourage you to do the same. I also thank my family for their love and support, and their willingness to share me by putting up with my long hours of distraction and frequent travels. I hope this recognition helps to reassure them that their sacrifices are not for nought.

Biographical sketch of Robert McCann

Robert McCann studied engineering and physics before graduating with a degree in mathematics from Queen's University at Kingston, Ontario, and a doctorate from Princeton University. Following a Tamarkin appointment at Brown University and a postdoctoral fellowship at Institut des Hautes Études Scientifiques (IHES), he became a professor of mathematics at the University of Toronto, where he now holds a Canada Research Chair in Mathematics, Economics, and Physics. He is an authority on optimal transportation and has played a pioneering role in its rapid development since the 1990s. In particular, the notion of displacement convexity introduced in his 1994 PhD thesis lies behind many of the area's myriad applications. He serves on the editorial board of various journals, and as editor-in-chief of the Canadian Journal of Mathematics since 2007 (with a hiatus from 2017-21). His research has been recognized by awards such as an invitation to lecture at the 2014 International Congress of Mathematicians in Seoul; election to the Royal Society of Canada in 2014; the 2017 Jeffery-Williams Prize of the Canadian Mathematical Society; and the 2023 W.T. and Idalia Reid Prize of the Society for Industrial and Applied Mathematics (SIAM).

About the prize

The AMS-SIAM Norbert Wiener Prize in Applied Mathematics is awarded every three years for an outstanding contribution to applied mathematics in the highest and broadest sense.The American Mathematical Society (AMS) and the Society for Industrial and Applied Mathematics (SIAM) award the prize jointly. Recipients must be a member of one of these societies. 

This prize was established in 1967 in honor of Professor Norbert Wiener and was endowed by a fund from the Department of Mathematics of the Massachusetts Institute of Technology. The endowment was supplemented further by a generous donor. The current award is $5,000.

The 2025 prize will be presented at the 2025 Joint Mathematics Meetings in Seattle.

Learn more about the prize and previous recipients.

Contact: AMS Communications

*****

The American Mathematical Society is dedicated to advancing research and connecting the diverse global mathematical community through our publications, meetings and conferences, MathSciNet, professional services, advocacy, and awareness programs.

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

Connexin (Cx) protein forms hemichannels and gap junctional channels, which play diverse and profound roles in human physiology and diseases. Gap junctions are arrays of intercellular channels formed by the docking of two hemichannels from adjacent cells. Each hexameric hemichannel contains the same or different Cx isoform. Although homomeric Cxs forms have been largely described functionally and structurally, the stoichiometry and arrangement of heteromeric Cx channels remain unknown. The latter, however, are widely expressed in human tissues and variation might have important implications on channel function. Investigating properties of heteromeric Cx channels is challenging considering the high number of potential subunit arrangements and stoichiometries, even when only combining two Cx isoforms. To tackle this problem, we engineered an HA tag onto Cx26 or Cx30 subunits and imaged hemichannels that were liganded by Fab-epitope antibody fragments via atomic force microscopy. For Cx26-HA/Cx30 or Cx30-HA/Cx26 heteromeric channels, the Fab-HA binding distribution was binomial with a maximum of three Fab-HA bound. Furthermore, imaged Cx26/Cx30-HA triple liganded by Fab-HA showed multiple arrangements that can be derived from the law of total probabilities. Atomic force microscopy imaging of ringlike structures of Cx26/Cx30-HA hemichannels confirmed these findings and also detected a polydisperse distribution of stoichiometries. Our results indicate a dominant subunit stoichiometry of 3Cx26:3Cx30 with the most abundant subunit arrangement of Cx26-Cx26-Cx30-Cx26-Cx30-Cx30. To our knowledge, this is the first time that the molecular architecture of heteromeric Cx channels has been revealed, thus providing the basis to explore the functional effect of these channels in biology.

14 July 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.

Mouse embryonic stem cells (mESCs) display unique mechanical properties, including low cellular stiffness in contrast to differentiated cells, which are stiffer. We have previously shown that mESCs lacking the clathrin heavy chain (Cltc), an essential component for clathrin-mediated endocytosis (CME), display a loss of pluripotency and an enhanced expression of differentiation markers. However, it is not known whether physical properties such as cellular stiffness also change upon loss of Cltc, similar to what is seen in differentiated cells, and if so, how these altered properties specifically impact pluripotency. Using atomic force microscopy (AFM), we demonstrate that mESCs lacking Cltc display higher Young's modulus, indicative of greater cellular stiffness, compared with WT mESCs. The increase in stiffness was accompanied by the presence of actin stress fibers and accumulation of the inactive, phosphorylated, actin-binding protein cofilin. Treatment of Cltc knockdown mESCs with actin polymerization inhibitors resulted in a decrease in the Young's modulus to values similar to those obtained with WT mESCs. However, a rescue in the expression profile of pluripotency factors was not obtained. Additionally, whereas WT mouse embryonic fibroblasts could be reprogrammed to a state of pluripotency, this was inhibited in the absence of Cltc. This indicates that the presence of active CME is essential for the pluripotency of embryonic stem cells. Additionally, whereas physical properties may serve as a simple readout of the cellular state, they may not always faithfully recapitulate the underlying molecular fate.

Transient receptor potential vanilloid 1 (TRPV1) channel is a multimodal receptor that is responsible for nociceptive, thermal, and mechanical sensations. However, which biomolecular partners specifically interact with TRPV1 remains to be elucidated. Here, we used cDNA library screening of genes from mouse dorsal root ganglia combined with patch-clamp electrophysiology to identify the voltage-gated potassium channel auxiliary subunit Kvβ1 physically interacting with TRPV1 channel and regulating its function. The interaction was validated in situ using endogenous dorsal root ganglia neurons, as well as a recombinant expression model in HEK 293T cells. The presence of Kvβ1 enhanced the expression stability of TRPV1 channels on the plasma membrane and the nociceptive current density. Surprisingly, Kvβ1 interaction also shifted the temperature threshold for TRPV1 thermal activation. Using site-specific mapping, we further revealed that Kvβ1 interacted with the membrane-distal domain and membrane-proximal domain of TRPV1 to regulate its membrane expression and temperature-activation threshold, respectively. Our data therefore suggest that Kvβ1 is a key element in the TRPV1 signaling complex and exerts dual regulatory effects in a site-specific manner.

Protein quality control is maintained by a number of integrated cellular pathways that monitor the folding and functionality of the cellular proteome. Defects in these pathways lead to the accumulation of misfolded or faulty proteins that may become insoluble and aggregate over time. Protein aggregates significantly contribute to the development of a number of human diseases such as amyotrophic lateral sclerosis, Huntington's disease, and Alzheimer's disease. In vitro, imaging-based, cellular studies have defined key biomolecular components that recognize and clear aggregates; however, no unifying method is available to quantify cellular aggregates, limiting our ability to reproducibly and accurately quantify these structures. Here we describe an ImageJ macro called AggreCount to identify and measure protein aggregates in cells. AggreCount is designed to be intuitive, easy to use, and customizable for different types of aggregates observed in cells. Minimal experience in coding is required to utilize the script. Based on a user-defined image, AggreCount will report a number of metrics: (i) total number of cellular aggregates, (ii) percentage of cells with aggregates, (iii) aggregates per cell, (iv) area of aggregates, and (v) localization of aggregates (cytosol, perinuclear, or nuclear). A data table of aggregate information on a per cell basis, as well as a summary table, is provided for further data analysis. We demonstrate the versatility of AggreCount by analyzing a number of different cellular aggregates including aggresomes, stress granules, and inclusion bodies caused by huntingtin polyglutamine expansion.

Post-transcriptional modifications of pre-mRNAs expand the diversity of proteomes in higher eukaryotes. In the brain, these modifications diversify the functional output of many critical neuronal signal molecules. In this study, we identified a brain-specific A-to-I RNA editing that changed glutamine to arginine (Q/R) at exon 20 and an alternative splicing of exon 4 in Tmem63b, which encodes a ubiquitously expressed osmosensitive cation channel. The channel isoforms lacking exon 4 occurred in ∼80% of Tmem63b mRNAs in the brain but were not detected in other tissues, suggesting a brain-specific splicing. We found that the Q/R editing was catalyzed by Adar2 (Adarb1) and required an editing site complementary sequence located in the proximal 5' end of intron 20. Moreover, the Q/R editing was almost exclusively identified in the splicing isoform lacking exon 4, indicating a coupling between the editing and the splicing. Elimination of the Q/R editing in brain-specific Adar2 knockout mice did not affect the splicing efficiency of exon 4. Furthermore, transfection with the splicing isoform containing exon 4 suppressed the Q/R editing in primary cultured cerebellar granule neurons. Thus, our study revealed a coupling between an RNA editing and a distant alternative splicing in the Tmem63b pre-mRNA, in which the splicing plays a dominant role. Finally, physiological analysis showed that the splicing and the editing coordinately regulate Ca2+ permeability and osmosensitivity of channel proteins, which may contribute to their functions in the brain.

In SAS Customer Intelligence Studio, you might notice that you cannot clear warnings for decision campaign nodes by selecting either the Clear Warnings  option or the Clear All Warnin

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

S-Acylation, a reversible post-translational lipid modification of proteins, controls the properties and function of various proteins, including ion channels. Large conductance Ca2+-activated potassium (BK) channels are S-acylated at two sites that impart distinct functional effects. Whereas the enzymes that attach lipid groups are known, the enzymes mediating lipid removal (i.e. deacylation) are largely unknown. Here, McClafferty et al. identify two enzymes, ABHD17a and ABHD17c, that excise BK channel lipid groups with remarkable precision. These findings lend insights into mechanisms that orchestrate the (de)acylation that fine-tunes ion channel function in physiology and disease.

S-Acylation, the reversible post-translational lipid modification of proteins, is an important mechanism to control the properties and function of ion channels and other polytopic transmembrane proteins. However, although increasing evidence reveals the role of diverse acyl protein transferases (zDHHC) in controlling ion channel S-acylation, the acyl protein thioesterases that control ion channel deacylation are very poorly defined. Here we show that ABHD17a (α/β-hydrolase domain-containing protein 17a) deacylates the stress-regulated exon domain of large conductance voltage- and calcium-activated potassium (BK) channels inhibiting channel activity independently of effects on channel surface expression. Importantly, ABHD17a deacylates BK channels in a site-specific manner because it has no effect on the S-acylated S0–S1 domain conserved in all BK channels that controls membrane trafficking and is deacylated by the acyl protein thioesterase Lypla1. Thus, distinct S-acylated domains in the same polytopic transmembrane protein can be regulated by different acyl protein thioesterases revealing mechanisms for generating both specificity and diversity for these important enzymes to control the properties and functions of ion channels.

Voltage-gated Cav1 and Cav2 Ca2+ channels are comprised of a pore-forming α1 subunit (Cav1.1-1.4, Cav2.1-2.3) and auxiliary β (β1-4) and α2δ (α2δ−1−4) subunits. The properties of these channels vary with distinct combinations of Cav subunits and alternative splicing of the encoding transcripts. Therefore, the impact of disease-causing mutations affecting these channels may depend on the identities of Cav subunits and splice variants. Here, we analyzed the effects of a congenital stationary night blindness type 2 (CSNB2)-causing mutation, I745T (IT), in Cav1.4 channels typical of those in human retina: Cav1.4 splice variants with or without exon 47 (Cav1.4+ex47 and Cav1.4Δex47, respectively), and the auxiliary subunits, β2X13 and α2δ-4. We find that IT caused both Cav1.4 splice variants to activate at significantly more negative voltages and with slower deactivation kinetics than the corresponding WT channels. These effects of the IT mutation, along with unexpected alterations in ion selectivity, were generally larger in channels lacking exon 47. The weaker ion selectivity caused by IT led to hyperpolarizing shifts in the reversal potential and large outward currents that were evident in channels containing the auxiliary subunits β2X13 and α2δ-4 but not in those with β2A and α2δ-1. We conclude that the IT mutation stabilizes channel opening and alters ion selectivity of Cav1.4 in a manner that is strengthened by exclusion of exon 47 and inclusion of β2X13 and α2δ-4. Our results reveal complex actions of IT in modifying the properties of Cav1.4 channels, which may influence the pathological consequences of this mutation in retinal photoreceptors.

The dominant role of CaV2 voltage-gated calcium channels for driving neurotransmitter release is broadly conserved. Given the overlapping functional properties of CaV2 and CaV1 channels, and less so CaV3 channels, it is unclear why there have not been major shifts toward dependence on other CaV channels for synaptic transmission. Here, we provide a structural and functional profile of the CaV2 channel cloned from the early-diverging animal Trichoplax adhaerens, which lacks a nervous system but possesses single gene homologues for CaV1–CaV3 channels. Remarkably, the highly divergent channel possesses similar features as human CaV2.1 and other CaV2 channels, including high voltage–activated currents that are larger in external Ba2+ than in Ca2+; voltage-dependent kinetics of activation, inactivation, and deactivation; and bimodal recovery from inactivation. Altogether, the functional profile of Trichoplax CaV2 suggests that the core features of presynaptic CaV2 channels were established early during animal evolution, after CaV1 and CaV2 channels emerged via proposed gene duplication from an ancestral CaV1/2 type channel. The Trichoplax channel was relatively insensitive to mammalian CaV2 channel blockers ω-agatoxin-IVA and ω-conotoxin-GVIA and to metal cation blockers Cd2+ and Ni2+. Also absent was the capacity for voltage-dependent G-protein inhibition by co-expressed Trichoplax Gβγ subunits, which nevertheless inhibited the human CaV2.1 channel, suggesting that this modulatory capacity evolved via changes in channel sequence/structure, and not G proteins. Last, the Trichoplax channel was immunolocalized in cells that express an endomorphin-like peptide implicated in cell signaling and locomotive behavior and other likely secretory cells, suggesting contributions to regulated exocytosis.

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.

Glycopeptides in peptide or digested protein samples pose a number of analytical and bioinformatics challenges beyond those posed by unmodified peptides or peptides with smaller posttranslational modifications. Exact structural elucidation of glycans is generally beyond the capability of a single mass spectrometry experiment, so a reasonable level of identification for tandem mass spectrometry, taken by several glycopeptide software tools, is that of peptide sequence and glycan composition, meaning the number of monosaccharides of each distinct mass, for example HexNAc(2)Hex(5) rather than man5. Even at this level, however, glycopeptide analysis poses challenges:  finding glycopeptide spectra when they are a tiny fraction of the total spectra; assigning spectra with unanticipated glycans, not in the initial glycan database; and finding, scoring, and labeling diagnostic peaks in tandem mass spectra.  Here we discuss recent improvements to Byonic, a glycoproteomics search program, that address these three issues. Byonic now supports filtering spectra by m/z peaks, so that the user can limit attention to spectra with diagnostic peaks, for example, at least two out of three of 204.087 for HexNAc, 274.092 for NeuAc (with water loss), and 366.139 for HexNAc-Hex, all within a set mass tolerance, for example, ± 0.01 Daltons. Also new is glycan "wildcard" search, which allows an unspecified mass within a user-set mass range to be applied to N- or O-linked glycans and enables assignment of spectra with unanticipated glycans. Finally the next release of Byonic supports user-specified peak annotations from user-defined posttranslational modifications. We demonstrate the utility of these new software features by finding previously unrecognized glycopeptides in publicly available data, including glycosylated neuropeptides from rat brain.