agilePHM We are launching a new product called agilePHM In Industrial IoT, I have been working with PHM  (Prognostics and Health Management) for a while and it is a well known discipline Prognostics and Health management(PHM)  is an engineering discipline focused on predicting the time at which a system or a component will no longer perform its intended [...]

The Central American nation of El Salvador currently holds nearly 5,932 Bitcoin (BTC), and sits on over $93 million of… Continue reading El Salvador’s Bitcoin adoption is paying off: $93M unrealized profit

The post El Salvador’s Bitcoin adoption is paying off: $93M unrealized profit appeared first on ReadWrite.

The South African Artificial Intelligence Association wants LinkedIn to be investigated, as it claims the social networking platforms new data use practice violates local personal information protection law.

The PlayStation 5 Pro hits shops on Thursday with a price tag that has raised eyebrows among gamers, but growing sticker shocks in the tech industry have yet to deter consumers.

While the DA may have found that George Deputy Mayor Raybin Figland had no criminal liability for allegedly sexting a teenage pupil – the Public Protector's office could still probe him for misconduct.

International Relations and Cooperation Minister Ronald Lamola threw diplomacy out the window on Tuesday and responded angrily when he was asked whether South Africa and the ANC were "protecting its friend" Frelimo in troubled Mozambique.

Nearly three weeks after they were supposed to be paid, a number of SRD grant beneficiaries who had their applications approved in October are still waiting for their payments.

The Cape South African Jewish Board of Deputies has asked the Equality Court in Cape Town to declare politician Mehmet Vefa Dag's social media posts about about Jewish people hate speech.

The Gauteng education department has postponed the appointment of new office-based staff as well as teachers who applied to be promoted as heads of department, deputy principals and principals until April because of budget constraints.

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

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

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

Announcing the brand new Tom the Dancing Bug book: Volume 8 of The Complete Tom the Dancing Bug book program is "IT'S THE GREAT STORM, TOM THE DANCING BUG!" Now accepting orders right HERE! Get your personalized / signed / sketched / swagged copy today! — Read the rest

The post Tom the Dancing Bug: "Hey, Ladies! Trump will be your protector!" appeared first on Boing Boing.

Jason M. Allen's "Theatre D'Opera Spatial" won an art competition at the 2022 Colorado State Fair, but the work was subsequently denied copyright protection due to his use of AI software to generate it and his unwillingness to disclaim that contribution to the whole. — Read the rest

The post AI artist appeals denial of copyright protection appeared first on Boing Boing.

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

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

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

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

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

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

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

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

The following article, GOP Rep. Luna Says ‘Criminal Prosecutions Necessary’ For Anti-Trump Lawfare Schemers In Government (Video), was first published on Conservative Firing Line.

As President Donald Trump prepares to re-enter the White House after his landslide victory in Tuesday’s election, a U.S. congresswoman says “criminal prosecutions” are “necessary” for the government officials who have been promoting the massive lawfare campaign against the president-elect. On “Sunday Morning Futures” on the Fox News Channel, host Maria Bartiromo asked U.S. Rep. …

Continue reading GOP Rep. Luna Says ‘Criminal Prosecutions Necessary’ For Anti-Trump Lawfare Schemers In Government (Video) ...

The following article, Will These Deranged Celebrities Who Promised To End Their Lives Or Flee The Country If Trump Wins Actually Follow Through?, was first published on Conservative Firing Line.

(Natural News) Similar to what happened in 2016, a host of celebrities and influencers made wild claims that they would leave the country or even end their lives if Donald Trump won another term in the White House. Will any of them actually follow through? Take Rob Reiner, for instance. He promised to “set himself on …

Continue reading Will These Deranged Celebrities Who Promised To End Their Lives Or Flee The Country If Trump Wins Actually Follow Through? ...

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.

On May 16, 2010, at 10:02 AM, "Xx" wrote:

You mentioned you gave a talk at Rutgers about future proofing your passion. Is this available as a podcast? I'd love to listen!

This poor kid emailed me to ask a really simple question. And I went and saddled him with the world's most circuitously long-winded answer. Surprise, surprise.

Hey, Xx,

Thanks for the note, man. No I'm sorry its not up as audio AFAIK.

FWIW, it's a talk I'm asked to do more often lately so I wouldn't be surprised if it turns up sooner or later.

Since you were kind enough to ask, the talk—which comes out super different each time I do it— consists of a discursive mishmash of advice I wish I'd had the ears to hear in the year or five after graduating from college: primarily, that we never end up anywhere near where we'd expected, and that most of us would have been a lot happier a lot faster if we'd realized that we were often obsessing over the wrong things—starting with how much the world should care about our major. ("Liberal Arts," with a concentration in [ugh] "Cultural Studies," thanks.)

The talk started as a way to encourage students to learn enough about what they care about that any temporary derails and side roads wouldn't scare their horses too badly. But, today, I see it as something a lot bigger that's demonstrably useful to anyone who hopes to survive, evolve, and thrive in this insane world.

A handful of bits I'm (obviously) still synthesizing into something notionally cohesive:

My Kingdom for Some Context!

For myself, I wish I'd known the value of developing early expertise in interesting new skills around emerging technologies (rather than just iteratively pseudo-honing the 202-level skills I thought I "understood"). Alongside that, I wish I'd learned to embrace the non-douchier aspects of building awesome human relationships (as against "networking" in the service of landing some straight job that, as with most hungry young people, locked me into a carpeted prison of monkey work at the worst time possible).

Also how I wish I'd paid more attention to events, contexts, relationships, and change that were happening outside my immediate world —rather than becoming, say, the undisputed master of fretting about status, salary, and whether I was "a success" who had "arrived".

Hint: I was not a "success," and I had not, by any stretch, "arrived."

To my mind, "success" in the real world is much more the equivalent of achieving a new personal best; it's not about whether you won the "Springtime in Springfield SunnyD®/Q105™ 5k FunRun for Entitilitus," and got a little ribbon with a gold crest on it.

Truly, pretty much anyone who feels they've "arrived" anyplace is about to learn a) how much more they could be doing outside the narrowness of an often superficial ambition and b) the surprising number of things they had to give away through the opportunity costs and trade-offs that lead up to every theoretical milestone. It's a real goddamned thistle, and it's more than a little depressing.

Do You Still Really Want to be a Fireman?

[N.B.: I really hope you're taking bathroom breaks here, Xx]

Related, I think this is about how being an adult is not only unbelievably complicated in ways that you can't begin to imagine—that it's frequently defined by impossible decisions and non-stop layers of "hypocrisy"—but that there's an invisible but entirely real risk to doggedly chasing the theoretically laudable notion of "following your dream." Especially if it's a dream you first had while sleeping on Star Wars sheets in a racecar bed.

Not because it's a bad idea to want things or to have ambitions. Quite the opposite. More because, for a lot of us, the "dreams" of youth turn out to be half-finished blueprints for wax wings. And not particularly flattering ones at that.

By starting adult life with an autistically explicit "goal" that's never been tested against any kind of real-world experience or reality-in-context, we can paradoxically miss a thousand more useful, lucrative, or organic opportunities that just…what?…pop up. Often these are one-time chances to do amazing and even unique things—opportunities that many of us continue to reject out of hand because it's "not what we do."

It took me a full decade to learn to embrace the unfamiliar gifts that kismet loves to deliver on our busiest and most stressful days, and which gifts might (maybe/maybe not) even end up bringing the real-life, non-racecar-bed, now me a big step closer to something that's 1000 times more interesting than a hollow, ten-year-old caricature of "what I wanna be when I grow up."

Finding Your "Old Butcher"

Also related, it strikes me that the indisputable wealth of information and options that are provided by the web often comes with a harrowing hidden tradeoff. While we can certainly learn a lot on our own and become (what feels like) an instant expert on any topic in an afternoon, we usually do so in the absence of a mentor and outside the context of applying expertise to solve actual problems. In my opinion, a cadet should have to survive more than a few Kobayashi Maru scenarios before he gets to declare himself, "Captain."

Call it a guru, a wizard, an old butcher, or what have you, the mad echo chamber of a young mind often benefits from the dampening influence of an experienced grownup who can help you understand things that raw data, wikipedia entries, and lists of tips and tricks can't and wont ever do.

We benefit from a hand on the back and a gentle voice, reminding us:

• "Try not to obsess over implementation until you really understand the problem," or
• "Worry more about relationships than org charts or follower counts," or
• "Don't quit looking after you've found that first data point," or—my favorite—
• "Spend less time fantasizing about 'success' and way more time making really cool mistakes."

Conversely, though, I think this means that everything we think we know, as well as all the fancy advice that gets thrown around—absolutely including the material you're reading now—is the product of what one person knows and what another person has the ears to hear. For us. For now. For who really knows what. But it is a transaction that takes place in a very specific time and within the bounds of a set of "known" "facts." So, fair warning, doing your own due diligence never hurts.

What's Almost Not Impossible?

[N.B.: I swear to God this ends at some point, Xx]

One big pattern for "future-proofing" your passion? Keep your eyes open and your heart even "opener." And, be more than simply tolerant of the notion of change—sure, take it as read that nothing is ever fixed in place for more than a little while.

But, to the extent that your sanity can bear it, always keep an eye on the corners, the edges, and especially learn to watch for those infinitesimally tiny figures starting to shuffle around near the horizon. Because a lot of the things that seem ridiculously small and inconsequential right now will eventually cast a shadow that people will be chasing for decades. It's just that we're never sure which tiny figure that will turn out to be.

So, yeah. It really is true that no one but you cares about your major. But, trust me: everybody is interested in the person who repeatedly notices the things that are about to stop being impossible.

Be the curious one who soaks in all that "irrelevant" stuff. And, even as you stay heads-down on the "now" projects that keep the lights on, remember that the guy who invented those lights made hundreds of "failed" lightbulbs before fundamentally upending the way we think about time, family, industry, and the role of technology in how we live and work. But, yes, first he "failed" a lot a lot at something which more than a few of his contemporaries thought was pointless in the first place.

Ask: What's out there right now that's about to stop being impossible? Where will it happen first? Who will (most loudly and erroneously) declare it's total bullshit? Who will mostly get it right—but possibly too early? Who will figure out what it means to our grandkids? Who will figure out how to put it in everyone's front pocket for a quarter?

Y'know who? I'll tell you who: practically anybody BUT that guy in the racecar bed who wants to talk about his major.

Important: Merlin's Advice is Only Future-Proof to 10 Meters

A few years back, most watch manufacturers decided to come clean and stop categorically declaring that their timepieces were "waterproof." Instead, today, the more credible vendors admit their product is merely "water-resistant"—and, even then, they'll only guarantee the underwater functionality at so many meters, and for so long, and under thus and such conditions.

Truthfully, the same applies here. Nothing can actually "future-proof" anything. Anyone who claims to know the future is either a madman, a charlatan, or, often as not, both.

Thing is, regardless of the passions (or goals or values or priorities or whatever) that we hope to protect or defend, we'd all do well to remember that it is still ultimately OUR passion that's at stake.

That means we're the only one responsible for seeing that its functional components survive and adapt in a world in which each one of us has just north of zero control.

If we embrace the fact that no one can or should ever care about the health of our passions as much as we do, the practical decisions that help ensure Our Good Thing stays alive can become as "simple" as a handful of proven patterns—work hard, stay awake, fail well, hang with smart people, shed bullshit, say "maybe," focus on action, and always always commit yourself to a bracing daily mixture of all the courage, honesty, and information you need to do something awesome—discover whatever it'll take to keep your nose on the side of the ocean where the fresh air lives. This is huge.

Anything else? Yeah. Drink lots of water, play with your kid every chance you get, and quit Facebook today. No, really, do it.

Thanks again for the note, Xx, and sorry for the novella. I'll ping you if the audio ever turns up. Til then, forget your major, and break a leg!

yr internet pal,
/m

For anyone thinking that 'social justice' is less about 'justice' and more about being a delivery system for a poisoned ideology, the story of Dr Hassan Diab, is the proverbial 'Exhibit A'.

The post Convicted Jihadi Terrorist Hired As Social Justice Prof In Western University appeared first on Clash Daily.

Republican primary opponents like Ron DeSantis said that every time they announced another indictment, his poll numbers got better. They should have known better. But they were blinded by hate.

The post BOOM: Trump Prosecutors React To New Post-Election Realities… Here’s Their Plan appeared first on Clash Daily.

Conservative activist Scott Presler, whose organization Early Vote Action helped swing Pennsylvania to the right in the general election, announced Monday he will be working to do the same in […]

The post Democrats Have Another Problem to Worry About as Man Who Helped Trump Win Has Eyes on Blue State appeared first on The Western Journal.

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

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

Bafana Bafana coach Hugo Broos has welcomed the number of young players who are given a chance and backed in the premier division, but has warned that to build on their progress, agents must prioritise players' development over their personal enrichment.

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

Junyi Xie
J. Amer. Math. Soc. 38 (), 1-62.
Abstract, references and article information

Nonphotochemical quenching (NPQ) is a mechanism of regulating light harvesting that protects the photosynthetic apparatus from photodamage by dissipating excess absorbed excitation energy as heat. In higher plants, the major light-harvesting antenna complex (LHCII) of photosystem (PS) II is directly involved in NPQ. The aggregation of LHCII is proposed to be involved in quenching. However, the lack of success in isolating native LHCII aggregates has limited the direct interrogation of this process. The isolation of LHCII in its native state from thylakoid membranes has been problematic because of the use of detergent, which tends to dissociate loosely bound proteins, and the abundance of pigment–protein complexes (e.g. PSI and PSII) embedded in the photosynthetic membrane, which hinders the preparation of aggregated LHCII. Here, we used a novel purification method employing detergent and amphipols to entrap LHCII in its natural states. To enrich the photosynthetic membrane with the major LHCII, we used Arabidopsis thaliana plants lacking the PSII minor antenna complexes (NoM), treated with lincomycin to inhibit the synthesis of PSI and PSII core proteins. Using sucrose density gradients, we succeeded in isolating the trimeric and aggregated forms of LHCII antenna. Violaxanthin- and zeaxanthin-enriched complexes were investigated in dark-adapted, NPQ, and dark recovery states. Zeaxanthin-enriched antenna complexes showed the greatest amount of aggregated LHCII. Notably, the amount of aggregated LHCII decreased upon relaxation of NPQ. Employing this novel preparative method, we obtained a direct evidence for the role of in vivo LHCII aggregation in NPQ.

A feminist and postcolonial approach to nuclear politics Expert comment NCapeling 20 July 2022

The July issue of International Affairs includes eight articles on the global nuclear order and eight more covering Chinese lending, abortion rights, and global security.

Disarmament and arms control has been a consistent area of debate in this journal for the past century, as underscored in our recent archive collection of research on a century of war and conflict.

The July edition moves this debate forward with a collection of papers guest-edited by Shine Choi and Catherine Eschle. The section ‘Feminist interrogations of global nuclear politics’ includes work by nine authors exploring seven global case-studies that help rethink nuclear politics and feminism.

As the guest editors note in their introduction, the section brings together research on nuclear power and nuclear weaponry to ‘begin the process of decentring 1980s white, western experiences of the global nuclear order in feminist IR’.

The articles speak to three core themes: they provide evidence of the ongoing destructive nature of nuclear technologies, extend understanding of the gendered, racialized, and colonial dimensions of nuclear discourses, and unearth the impact of colonialism on the global nuclear order.

Global nuclear politics

Anne Sisson Runyan examines the gendered effects of uranium mining and nuclear waste dumping on North American Indigenous women, showing how the nuclear cycle tends to have a disproportionate effect on certain communities but also that the area of disposal remains problematic.

This is a global problem – for example, the Royal Navy has yet to successfully dispose of a single redundant nuclear-powered submarine and is rapidly running out of space to store further vessels.

Hebatalla Taha goes back to the early years of nuclear development and, using Egypt as a case-study, her article argues the early visualizations of the atomic age were fluid and ambivalent. She concludes – perhaps controversially – that feminizing nuclear politics and nuclear images will not lead to disarmament but rather reinforce the nuclearized world. The piece is a welcome addition to the emerging field of visuality within international relations.

Anand Sreekumar brings together feminist and Gandhian thinking to suggest a way for Narendra Modi’s government to move beyond the possession of nuclear weapons as symbols of power. In doing so, he also critiques the binary labels of ‘West’ and ‘non-West’ that often frame our understanding of the world.

Lorraine Bayard de Volo revisits the Cuban missile crisis – a point in time where nuclear war looked likely. She compares the actions of Khrushchev, Castro, and Kennedy and finds the pursuit of masculinity led to the rejection of approaches considered more feminine, such as diplomacy and negotiation – the crisis was exacerbated by what might be referred to now as toxic masculinity.

Sweden’s and Finland’s recent application to join the nuclear alliance NATO lends a particular urgency to Emma Rosengren’s article on the original Swedish decision to renounce the development of nuclear weapons during the Cold War. Her article concludes much of the emphasis on power in international relations has contributed to a gendered and racialized nuclear order.

Similarly, Laura Rose Brown and Laura Considine’s article on the Non-Proliferation Treaty finds that ‘gender-sensitive’ approaches focus almost exclusively on women’s inclusion as opposed to feminist policy analysis. They end by making recommendations for future policymaking.

Finally, Rebecca Hogue and Anais Maurer look at the anti-nuclear poetry of Pacific women. This article raises fundamental questions about what is currently considered to constitute evidence. They point to the role of oral history in many communities and the tendency of policymakers and social scientists to ignore this source of understanding.

National politics with international implications

This edition’s ‘Editor’s Choice’ is Jeffrey A. Friedman’s article which questions whether US grand strategy is dead in a post-Trump world. Running counter to much of the existing literature, he suggests there is a strong bilateral commitment to existing partnerships and alliances within the US political establishment.

Following the US Supreme Court decision over Roe vs Wade, it is important to note the issue of abortion rights can have an international dimension. Megan Daigle, Deirdre N. Duffy, and Diana López Castañeda reveal that, although Colombia now has the most progressive legal framework for abortion in Latin America, intense backlash persists as legacies of the civil war overshadow the issue and lead to barriers to safe abortion care.

China

Ric Neo and Chen Xiang look at Chinese public opinion and finds that citizens can be upset by foreign policies of other states even when they have no impact on their daily lives. It reminds us of the potency of nationalism and the importance of who controls the prevailing narrative.

Deborah Brautigam examines China’s role in creating Zambia’s debt crisis, arguing this has not been brought about by a centralized master plan which would give China control over Zambia. Instead, the crisis has been caused by the failure of Chinese bureaucracy with too many state organs offering funding in an uncoordinated fashion.

Security and defence

Using Iran as a case-study, Henrik Stålhane Hiim argues the development of nuclear-capable ballistic missiles is a key indicator when looking for potential nuclear proliferators.

Eray Alim demonstrates the impact of an external great power interacting with local states. Russia’s involvement in the Syrian civil war has allowed it – sometimes through restrictive and punitive measures – to ensure Turkey and Israel do not harm its interests in the region.

Nina Wilén draws on fieldwork in Niger to study how Security Force Assistance (SFA) impacts on Niger’s security sector and compares this to global trends in security. She finds these developments contribute to blurred borders and confusion regarding labour division in the security sector and points to wider questions for intervenors in developing local units.

Epoxide hydrolases (EHs) have been characterized and engineered as biocatalysts that convert epoxides to valuable chiral vicinal diol precursors of drugs and bioactive compounds. Nonetheless, the regioselectivity control of the epoxide ring opening by EHs remains challenging. Alp1U is an α/β-fold EH that exhibits poor regioselectivity in the epoxide hydrolysis of fluostatin C (compound 1) and produces a pair of stereoisomers. Herein, we established the absolute configuration of the two stereoisomeric products and determined the crystal structure of Alp1U. A Trp-186/Trp-187/Tyr-247 oxirane oxygen hole was identified in Alp1U that replaced the canonical Tyr/Tyr pair in α/β-EHs. Mutation of residues in the atypical oxirane oxygen hole of Alp1U improved the regioselectivity for epoxide hydrolysis on 1. The single site Y247F mutation led to highly regioselective (98%) attack at C-3 of 1, whereas the double mutation W187F/Y247F resulted in regioselective (94%) nucleophilic attack at C-2. Furthermore, single-crystal X-ray structures of the two regioselective Alp1U variants in complex with 1 were determined. These findings allowed insights into the reaction details of Alp1U and provided a new approach for engineering regioselective epoxide hydrolases.

In conversation with David Miliband: Finding a new approach to tackle conflict, climate and extreme poverty 11 September 2024 — 5:00PM TO 5:45PM Anonymous (not verified) 15 August 2024 Chatham House and Online

David Miliband discusses how the climate crisis, extreme poverty and conflict are becoming inextricably linked and how the global community must respond.

Combatting the climate crisis, ending protracted conflicts, and alleviating poverty are three of the greatest priorities for international action. However, these three challenges become increasingly concentrated in a handful of countries. The subsequent feedback loop makes addressing these challenges even more complex.

The International Rescue Committee’s (IRC’s) work in crisis-affected communities highlights this new geography of crisis. Just 16 countries, which are both climate-vulnerable and conflict-affected. This represents 43% of all people living in extreme poverty, 44% of all people affected by natural disasters and 79% of all people in humanitarian need. This trend towards the concentration of crisis is only deepening. In three decades, the number of conflict-affected, climate-vulnerable states has increased from 44% to more than two-thirds.

Affected countries - like Sudan, Myanmar, and Syria - are also among the least supported financially. Debt burdens are siphoning away critical resources needed for adaptation and resilience. Humanitarian aid budgets are being slashed by donor governments. The private sector refuses to invest in these communities they view as too risky. And the international financial institutions meant to alleviate poverty and spur climate action are not well-designed to work with crisis-affected states or local communities. With the upcoming COP29 Summit in Azerbaijan focused on the New Collective Quantified Goal for climate finance, vulnerable communities will be watching closely whether they will get support in their fight against the worst impacts of the climate crisis.

Conflict, the climate crisis, and extreme poverty are taking their toll. But how can the world best respond?

Key questions to be discussed during the session include:

• At a time of political disruption, how does the West engage with vulnerable countries? What actions should be prioritised in providing support to such countries?
• Can global institutions evolve to better protect vulnerable and displaced people from conflict and climate-risk, particularly as geopolitical rivalries reduce space for cooperation?
• What is the UK’s role in supporting climate action in fragile states and how does this align with its agenda on the Sustainable Development Goals and extreme poverty?

Numerous iron-sulfur (Fe-S) proteins with diverse functions are present in the matrix and respiratory chain complexes of mitochondria. Although [4Fe-4S] clusters are the most common type of Fe-S cluster in mitochondria, the molecular mechanism of [4Fe-4S] cluster assembly and insertion into target proteins by the mitochondrial iron-sulfur cluster (ISC) maturation system is not well-understood. Here we report a detailed characterization of two late-acting Fe-S cluster-carrier proteins from Arabidopsis thaliana, NFU4 and NFU5. Yeast two-hybrid and bimolecular fluorescence complementation studies demonstrated interaction of both the NFU4 and NFU5 proteins with the ISCA class of Fe-S carrier proteins. Recombinant NFU4 and NFU5 were purified as apo-proteins after expression in Escherichia coli. In vitro Fe-S cluster reconstitution led to the insertion of one [4Fe-4S]2+ cluster per homodimer as determined by UV-visible absorption/CD, resonance Raman and EPR spectroscopy, and analytical studies. Cluster transfer reactions, monitored by UV-visible absorption and CD spectroscopy, showed that a [4Fe-4S]2+ cluster-bound ISCA1a/2 heterodimer is effective in transferring [4Fe-4S]2+ clusters to both NFU4 and NFU5 with negligible back reaction. In addition, [4Fe-4S]2+ cluster-bound ISCA1a/2, NFU4, and NFU5 were all found to be effective [4Fe-4S]2+ cluster donors for maturation of the mitochondrial apo-aconitase 2 as assessed by enzyme activity measurements. The results demonstrate rapid, unidirectional, and quantitative [4Fe-4S]2+ cluster transfer from ISCA1a/2 to NFU4 or NFU5 that further delineates their respective positions in the plant ISC machinery and their contributions to the maturation of client [4Fe-4S] cluster-containing proteins.

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 main protease (3CL Mpro) from SARS–CoV-2, the etiological agent of COVID-19, is an essential enzyme for viral replication. 3CL Mpro possesses an unusual catalytic dyad composed of Cys145 and His41 residues. A critical question in the field has been what the protonation states of the ionizable residues in the substrate-binding active-site cavity are; resolving this point would help understand the catalytic details of the enzyme and inform rational drug development against this pernicious virus. Here, we present the room-temperature neutron structure of 3CL Mpro, which allowed direct determination of hydrogen atom positions and, hence, protonation states in the protease. We observe that the catalytic site natively adopts a zwitterionic reactive form in which Cys145 is in the negatively charged thiolate state and His41 is doubly protonated and positively charged, instead of the neutral unreactive state usually envisaged. The neutron structure also identified the protonation states, and thus electrical charges, of all other amino acid residues and revealed intricate hydrogen-bonding networks in the active-site cavity and at the dimer interface. The fine atomic details present in this structure were made possible by the unique scattering properties of the neutron, which is an ideal probe for locating hydrogen positions and experimentally determining protonation states at near-physiological temperature. Our observations provide critical information for structure-assisted and computational drug design, allowing precise tailoring of inhibitors to the enzyme's electrostatic environment.

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

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

G protein–coupled receptors (GPCRs) initiate signaling cascades via G-proteins and beta-arrestins (βarr). βarr-dependent actions begin with recruitment of βarr to the phosphorylated receptor tail and are followed by engagement with the receptor core. βarrs are known to act as adaptor proteins binding receptors and various effectors, but it is unclear whether in addition to the scaffolding role βarrs can allosterically activate their downstream targets. Here we demonstrate the direct allosteric activation of proto-oncogene kinase Src by GPCR–βarr complexes in vitro and establish the conformational basis of the activation. Whereas free βarr1 had no effect on Src activity, βarr1 in complex with M2 muscarinic or β2-adrenergic receptors reconstituted in lipid nanodiscs activate Src by reducing the lag phase in Src autophosphorylation. Interestingly, receptor–βarr1 complexes formed with a βarr1 mutant, in which the finger-loop, required to interact with the receptor core, has been deleted, fully retain the ability to activate Src. Similarly, βarr1 in complex with only a phosphorylated C-terminal tail of the vasopressin 2 receptor activates Src as efficiently as GPCR–βarr complexes. In contrast, βarr1 and chimeric M2 receptor with nonphosphorylated C-terminal tail failed to activate Src. Taken together, these data demonstrate that the phosphorylated GPCR tail interaction with βarr1 is necessary and sufficient to empower it to allosterically activate Src. Our findings may have implications for understanding more broadly the mechanisms of allosteric activation of downstream targets by βarrs.

IQGAP1 is a key scaffold protein that regulates numerous cellular processes and signaling pathways. Analogous to many other cellular proteins, IQGAP1 undergoes post-translational modifications, including phosphorylation. Nevertheless, very little is known about the specific sites of phosphorylation or the effects on IQGAP1 function. Here, using several approaches, including MS, site-directed mutagenesis, siRNA-mediated gene silencing, and chemical inhibitors, we identified the specific tyrosine residues that are phosphorylated on IQGAP1 and evaluated the effect on function. Tyr-172, Tyr-654, Tyr-855, and Tyr-1510 were phosphorylated on IQGAP1 when phosphotyrosine phosphatase activity was inhibited in cells. IQGAP1 was phosphorylated exclusively on Tyr-1510 under conditions with enhanced MET or c-Src signaling, including in human lung cancer cell lines. This phosphorylation was significantly reduced by chemical inhibitors of MET or c-Src or by siRNA-mediated knockdown of MET. To investigate the biological sequelae of phosphorylation, we generated a nonphosphorylatable IQGAP1 construct by replacing Tyr-1510 with alanine. The ability of hepatocyte growth factor, the ligand for MET, to promote AKT activation and cell migration was significantly greater when IQGAP1-null cells were reconstituted with IQGAP1 Y1510A than when cells were reconstituted with WT IQGAP1. Collectively, our data suggest that phosphorylation of Tyr-1510 of IQGAP1 alters cell function. Because increased MET signaling is implicated in the development and progression of several types of carcinoma, IQGAP1 may be a potential therapeutic target in selected malignancies.

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

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

Nuclear proliferation in a fragmenting world 13 September 2022 — 1:00PM TO 2:00PM Anonymous (not verified) 5 September 2022 Online

Where does the Treaty on the Non-Proliferation of Nuclear Weapons (NPT) stand in 2022?

With the war in Ukraine and China–US tensions rising, the threat of a nuclear arms race has never been as high since the Cold War.

Global efforts to control the appropriation and use of nuclear weapons are strained with the war in Ukraine, US–Russia and US–China tension, Iran on the nuclear threshold, instability in Pakistan and the ongoing threat from North Korea.

The Review Conference of the NPT that took place in New York this August sought to deal with the multiple nuclear threats, but new missile technology such as hypersonic glide vehicles and torpedoes are not covered by a treaty.

Russia and the US are in a development phase for a host of new technologies and delivery systems, especially after both withdrew from various arms-control treaties in the 2000s and 2010s. Now the nuclear stockpile is growing again and major superpowers are adopting confrontational geostrategic positions.

As the world’s established orders and system fragment, there is a possibility the nine countries with confirmed nuclear weapons could grow. Events in Ukraine highlight the need for a new, modern agreement on nuclear weapons control, needed today more than ever.

The panel of experts discuss key questions including:

• What did ‘RevCon’ in New York tell us about the adoption or update to the NPT?

• Will the war in Ukraine deter or prevent any agreement between nations or does nuclear weapons control represent an area of potential multilateral harmony?

• Are we likely to see a new arms race akin to the Cold War? Where does China fit into this race?

• How has technology changed the arms control landscape?

 As with all Chatham House member events, questions from members drive the conversation.

World in brief: Ukraine and nuclear proliferation to dominate G7 The World Today mhiggins.drupal 28 March 2023

Following Russia’s ongoing intimidation, Japan will use its presidency of the G7 – and its history – to prioritize the dangers of nuclear threats, writes James Orr.

Two issues are expected to dominate the agenda as Japan hosts the G7 summit in Hiroshima from May 19-21. Central to talks will be the conflict in Ukraine, with member states eager to highlight a message of unity and resolve in the face of Russia’s continuing aggression.

Fumio Kishida, Japan’s prime minister, made an unannounced visit to Kyiv on March 21, meeting the Ukrainian president Volodymyr Zelenskyy.  This coincided with a visit to Moscow by China’s leader Xi Jinping, who described Russian president Vladimir Putin as a friend and partner.

‘Absolutely unacceptable’

Hosting the G7 summit in Hiroshima is significant, too, with Kishida expected to emphasize the ‘absolutely unacceptable’ threat of nuclear proliferation. Ongoing tensions between China and Taiwan, together with recent North Korean ballistic missile tests, have heightened fears of a breakdown in security in the region.

Meanwhile, President Vladimir Putin’s menacing references to the use of nuclear weapons in Ukraine has raised the prospect of a potentially devastating conflict with NATO. ‘Kishida’s principal goal for the presidency of the G7 is to try to draw the world away from the path of destruction that is another nuclear conflict,’ said Duncan Bartlett, a research associate at SOAS, the School of Oriental and African Studies, in London.

‘Early last year, Putin warned of terrible consequences if NATO and the West interfered in the Ukraine conflict, and that was widely seen as being a nuclear threat. North Korea is also pursuing its nuclear weapons programme, and in February an intercontinental ballistic missile went into the sea just near the northern Japanese island of Hokkaido,’ said Bartlett.

After Russia invaded Ukraine in February 2022, Kishida has taken a firm position on Putin, in line with his G7 peers. President Zelenskyy has addressed the Japanese parliament via video link and Dmytro Kuleba, Ukraine’s minister of foreign affairs, was invited by his Japanese counterpart to a G7 meeting held during the Munich Security Conference earlier this year.

Kishida committed $600 million in financial support to Ukraine and his government may well announce the provision of further non-lethal assistance to Zelenskyy at the summit. The country’s constitution effectively outlaws the export of deadly weapons to foreign forces. On his visit to Kyiv, Kishida promised a further $30 million to Ukraine.

‘Kishida has revised key defence documents and is pursuing a radical and controversial expansion of Japan’s defence budget and capabilities,’ said Hugo Dobson, Professor of Japan’s International Relations at the University of Sheffield.

‘He and his G7 partners have signed historic defence agreements, pledged to strengthen ties or declared the inseparability of their security in light of actual conflict in Ukraine and potential conflict in East Asia. Kishida has linked the two by emphasizing that Ukraine today may be East Asia tomorrow,’ said Dobson.

Aside from security matters, Kishida will at the summit address issues on clean energy, climate change, global health and boosting multilateral cooperation to drive post-pandemic economic recovery.

Invitation to Nagasaki

He is understood to have invited President Joe Biden to visit Nagasaki, where the second of America’s two atomic bombs is estimated to have killed 60,000 people in August 1945. No sitting US president has ever visited the city, and Kishida, who grew up in Hiroshima, may see the visit as an opportunity to boost his flagging domestic approval ratings. It may also serve as a timely reminder to Russia and others that the G7 opposes any future nuclear weapon use.

Alexander S. Hebert
Jan 1, 2014; 13:339-347
Technological Innovation and Resources

Alfred C. O. Vertegaal
Dec 1, 2006; 5:2298-2310
Research

Boris Macek
Feb 1, 2008; 7:299-307
Research

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

Dongmei Cheng
Jun 1, 2006; 5:1158-1170
Datasets

Yue Chen
May 1, 2007; 6:812-819
Research

Steven A. Carr
Mar 1, 2014; 13:907-917
Technological Innovation and Resources

Michal Bassani-Sternberg
Mar 1, 2015; 14:658-673
Research

Ileana M. Cristea
Dec 1, 2005; 4:1933-1941
Research

Ilka Wittig
Jul 1, 2007; 6:1215-1225
Research