Human-caused climate change made recent extreme weather events more intense and more likely, new analysis finds.

Over the past year, Aya and Khalid have been filming their lives for a BBC documentary.

England captain Heather Knight and seamers Lauren Bell and Issy Wong are released by their Women's Premier League franchises ahead of the 2025 season.

Latest scorecard from the Women's Big Bash League match between Sydney Thunder and Perth Scorchers at Sydney's Drummoyne Oval.

Lando Norris’ already slim world title hopes were crushed at the Sao Paulo Grand Prix by a performance for the ages from Max Verstappen.

Climate change is wreaking havoc on farmers in Nigeria.

The Prince of Wales is on a trip in South Africa promoting his Earthshot environmental prize.

What is behind the exodus of Economic Freedom Fighters members to ex-President Jacob Zuma's party?

How cheese has become so valuable that it's being stolen to order

Video shows a flooded terminal inside El Prat airport and partially submerged cars on a highway.

Europe’s most powerful economy is left rudderless, when EU leaders are nervous about a new Trump presidency.

John White did the League and Cup Double, but his sudden death left his son searching for the man behind the comic-book persona.

Watch highlights as undefeated Manchester United are held to a 0-0 draw by Aston Villa in the WSL.

Turkish football club Ankaragucu defend their former president Faruk Koca after he was sentenced to jail for assaulting a referee.

1. NASA Alert: Massive 'God of Chaos' Asteroid Apophis Makes Closest Pass by Earth Yet  Bizz Buzz
2. NASA alert! 'God of Chaos' asteroid approaching Earth on November 13 sparks worldwide concern  The Times of India
3. Nasa Alert: Massive 'God of Chaos' asteroid Apophis nears earth in closest pass yet  CNBCTV18
4. Giant Meteorite To Hit Earth On November 13? What We Know  News18
5. 'Astonishingly close': A colossal space rock could wreak havoc on Earth in 2029  Business Today

Ukraine has said that the toll from a Russian strike on the hometown of President Volodymyr Zelensky had risen to four people, identifying the dead as a mother and her three children, including a newborn.

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.

If you have several iPhone’s, as many people do when they buy a new iPhone, upgrade, get a hand-me-down, develop iPhone software, or develop mobile sites or apps where you test things on multiple devices, you might be in a situation where iPhone Mirroring on the Mac is using an iPhone that you do not ... Read More

A new children's book transforms a sad, scared and anxious little boy into a superhero. The book is called "Cape," in honor of the bright-red cape the little boy wears and finds comfort in following the death of his father. "Cape" is Kevin Johnson's debut picture book, and it's vividly illustrated by artist Kitt Thomas.

Billions of dollars were funneled to school districts across the U.S. to help them make up for learning loss from the pandemic. But new research shows that even with that extra money, school districts are still struggling to close the gaps in reading, writing and math. Stephanie Sy discussed the findings with Karyn Lewis of the Center for School and Student Progress and a lead researcher at NWEA.

Are you looking for the perfect way to gamble while flying on a plane? Look no further – here are our picks for the top online casinos! Introduction Flying can be a long and exhausting process. Many travelers seek solace in online gambling, offering the convenience of playing casino games while on-the-go. Thanks to Wi-Fi […]

Police revealed Tuesday they had infiltrated and taken down an encrypted chat app called Ghost used by criminals across the world.

The Internet Archive, an online repository of web pages, was offline Thursday after its founder confirmed a major cyberattack that exposed the data of millions of users and left the site defaced.

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.

[update 2011-01-18 @ 16:07:40: We're up!]

5by5 Live

Before Christ was a corporal, Dan Benjamin was already a bit of a hero to me.

Since the early aughts–long before his insanely great 5by5.tv podcast network–Dan’s Hivelogic Enkoder was saving us millions of spam messages. His thoughtful tutorials on OS X (including unmissable advice on doing sane installs of MySQL and Rails, among others) are among the best on the web. His CSS has been widely stolen and reused without acknowledgment by thieves as diverse as other people and me. And his polymath posts on everything from Buddhism to The Paleo Diet to how to record a “Double-ender” have shown a charming combination of curiosity and empathy that, amongst numerous other reasons, clearly makes Dan a better human than me.

A propos of nothing, Dan’s also the guy who conducted one of (mp3) the three best interviews with me in which it’s been my good fortune to participate.1

Today, I’m honored to say that Dan and I are starting a thing together.

If it suits you, drop by 5by5.tv/live in about 35 minutes–at Noon Eastern/9am Pacific–to find out what we’re up to. I think it might be good. I’ll just say I’m as excited about this as I’ve been about any new project I’ve started in the past year or so.

Anyway. You can judge for yourself. Whether you can tolerate me or otherwise, definitely do not miss the work Dan’s doing at 5by5. Because it really is outstanding and very polished stuff.

As for our thing? My own goal, to paraphrase a bit from that interview with Dan, is to help you get excited, get better–and then?–Back to Work.

More soon. Thanks.

And...we're up

Back to Work | Ep.#1: Alligator in the Bathroom

Download MP3 of "'Back to Work,' Ep. 1"

In the inaugural episode of Back to Work, Merlin Mann and Dan Benjamin discuss why they’re doing this show, getting back to work instead of buying berets, the lizard brain, and compare the Shadow of the Mouse to San Francisco, and eventually get to some practical tips for removing friction.

It's a start.

Sexy Audio RSS Feed
Sexy Subscription via iTunes

Episode Links

• Welcome to BrettTerpstra.com, home of Brett Terpstra and his nerdery
• carlhuda/janus – GitHub
• practically efficient — technology, workflows, life
• MacSparky – Blog
• The Brooks Review
• And now it’s all this
• Dan Rodney’s List of Mac OS X Keyboard Shortcuts & Keystrokes
• 43f Podcast: John Gruber & Merlin Mann’s Blogging Panel at SxSW | 43 Folders
• waffle software · ThisService
• One Thing Well
• html2text: THE ASCIINATOR (aka html2txt)
• The Conversation #27: Missionless Statements – 5by5

She likes Kamala's polices enough to put a lawn sign up on her property, but when one toll with a postcard personalizes those policies... she loses it.

The post Harris Supporter Outraged By Postcard Trolling… Did They Go Too Far? appeared first on Clash Daily.

There's a reason Hitler holds a special place of disgrace in public memory. He combined the ambition and destruction of Attila The Hun with the personal malice of a serial killer.

The post The REAL Harm Done By Calling Everyone You Don’t Like ‘Hitler’ Is BIGGER Than Lefties Think appeared first on Clash Daily.

Bob Moesta is a dear friend, mentor, and all around original thinker. He’s helped me see around corners, shine lights on things I didn’t know were there, and approach product development from unusual angles. Every time we talk, I come away inspired and full of optimism. So when he asked me to help him with… keep reading

HEY uses a branch deploy system that I’ve written about here on SvN and talked about frequently on Twitter. Plenty of other companies have implemented their own version of branch deploys (typically under a different name), but this was my own implementation, so I’m proud of it. First, a primer on how it works: Developer… keep reading

There appeared to be a definite frost between first lady Jill Biden and Vice President Kamala Harris during a Veterans Day event at Arlington National Cemetery on Monday. A close-up […]

The post Footage of Jill Biden and Kamala Harris Sitting Side-by-Side at Veterans Day Event Goes Viral appeared first on The Western Journal.

Legendary Christian writer C.S. Lewis gave us an analogy to help explain otherwise inexplicable moments such as this. Tolerance, Lewis once wrote, “parodies love as flippancy parodies merriment.” In a […]

The post Biden Asked If He'll Get a Hostage Deal by the End of His Term, and His Response Is Telling appeared first on The Western Journal.

The race to succeed Bill Beaumont as chairman of World Rugby comes to a conclusion in a vote in Dublin at the governing body's headquarters on Thursday.

Carvana is America’s fastest-growing e-tailer   February 23, 2022 (New York, NY) – Americans have taken to buying cars online, so much so that ecommerce car dealer Carvana is now […]

June 22, 2022 (New York, NY) – Will Apple’s entry into the buy now, pay later (BNPL) space upend the already competitive industry? That’s the question many are trying to […]

An important mechanism of resistance to β-lactam antibiotics is via their β-lactamase–catalyzed hydrolysis. Recent work has shown that, in addition to the established hydrolysis products, the reaction of the class D nucleophilic serine β-lactamases (SBLs) with carbapenems also produces β-lactones. We report studies on the factors determining β-lactone formation by class D SBLs. We show that variations in hydrophobic residues at the active site of class D SBLs (i.e. Trp105, Val120, and Leu158, using OXA-48 numbering) impact on the relative levels of β-lactones and hydrolysis products formed. Some variants, i.e. the OXA-48 V120L and OXA-23 V128L variants, catalyze increased β-lactone formation compared with the WT enzymes. The results of kinetic and product studies reveal that variations of residues other than those directly involved in catalysis, including those arising from clinically observed mutations, can alter the reaction outcome of class D SBL catalysis. NMR studies show that some class D SBL variants catalyze formation of β-lactones from all clinically relevant carbapenems regardless of the presence or absence of a 1β-methyl substituent. Analysis of reported crystal structures for carbapenem-derived acyl-enzyme complexes reveals preferred conformations for hydrolysis and β-lactone formation. The observation of increased β-lactone formation by class D SBL variants, including the clinically observed carbapenemase OXA-48 V120L, supports the proposal that class D SBL-catalyzed rearrangement of β-lactams to β-lactones is important as a resistance mechanism.

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 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.

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.

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

Nuclear stability for all put at risk by Putin's speech Explainer NCapeling 22 February 2023

Explaining the risks of Russia’s decision to suspend the New START nuclear treaty with the US, and the wider implications for international relations.

Why is New START important?

Following the collapse of the Intermediate-range Nuclear Forces treaty (INF), New START is the only remaining nuclear arms control treaty between the US and Russia.

This means that without it there would be no limits on numbers or the type of Russian and US deployed nuclear warheads. The limits set under New START are lower than those set under its predecessor, the Strategic Arms Reduction Treaty (START).

It is also important for maintaining some form of strategic arms control between Russia and the US. The treaty provides the US and Russia with mechanisms for transparency and confidence-building, for instance through regular biannual data exchanges, as well as measures for verification.

What is Russia able to do next after suspending participation?

President Vladimir Putin’s decision to suspend its participation could pave the way for Russia to increase the number of deployed warheads, delivery vehicles and launchers, potentially exceeding the limits placed on numbers under the new START.

Putin stated he would resume testing of nuclear weapons if the US resumed – Russia is a full state party to the nuclear Comprehensive Test Ban Treaty (CTBT) negotiated in 1996, as is the UK and France. The US has signed, as has China, but neither state has yet ratified the treaty.

Other countries required to ratify the treaty for it to enter into force include Egypt, India, Iran, Israel, North Korea, and Pakistan.

Although the US is modernizing its nuclear weapons forces, there is no need – or plan – for the US to test nuclear warheads, and it is the same for the UK and France.

Concerns are now rising that Russia could point to no-fissionable yield experiments – which are allowed under the treaty and which the US and other nuclear weapons possessors conduct primarily for safety purposes – and then falsely declare those to be nuclear weapons tests, thus paving the way for a narrative to justify the resumption of nuclear testing by Russia.

Conducting a nuclear weapons test would be seen clearly as a further step on the escalation scale towards nuclear use for Russia.

While inspections of nuclear weapons sites had not resumed since COVID-19, Russia’s suspension of its participation could result in the further halting of other transparency and verification measures under New START, including the regular mutual data exchanges between the US and Russia – for example on warhead numbers, locations, and technical information on weapons systems and their sites – which are conducted through the Bilateral Consultative Commission (BCC).

What is the difference between withdrawing from New START and ‘suspending’ participation?

In his speech, Putin announced the suspension of Russian participation in New START. While this does not mean Russia has formally withdrawn from the treaty, the suspension could enable Russia to continue preventing the US from inspecting its nuclear weapons sites and halt Russia’s participation in other obligations, such as the routine reporting and data exchanges on nuclear weapons as well as meetings of the BCC.

The decision to suspend participation rather than withdraw from the treaty means Russia retains the option to return to compliance at a later point. However, it is not yet clear under what conditions Russia would opt to return to compliance with the treaty, or whether this means the US will, in turn, suspend their own obligations.

The treaty text itself does not provide for a suspension of participation by parties to the treaty. However, the Vienna Convention on the Law of Treaties does address the mechanisms for suspension of participation in a treaty. Russia is a full state party to the Vienna Convention, but the US has remained a signatory without ratification since 1970.

There is a precedent of Russia suspending its membership in arms control treaties rather than withdrawing, which is when Russia suspended its participation in the original Treaty on Conventional Armed Forces in Europe (CFE) in 2007.

The US does not recognize Russia’s suspension of its participation in the CFE treaty, but this does not make a material difference to Russian actions.

What does the suspension mean for the wider international treaty regime?

Russia’s suspension of the New START could signal the end of strategic arms control between the two countries. There is now virtually no regular scheduled arms control communication between the two countries bilaterally – this is a dangerous position to be in, especially in times of crisis.

The suspension of New START further erodes limited recourse for communication between the two countries, by suspending information exchange and meetings of the BCC under the treaty.

This is likely to have wider implications for progress on nuclear non-proliferation under the Treaty on the Non-Proliferation of Nuclear Weapons (NPT), as well as the wider international security treaty regime.

Will this increase the nuclear threat or the likelihood of nuclear use?

New START provides both the US and Russia with a degree of transparency surrounding nuclear weapons systems. Without an avenue for regular data exchange and notification, and mechanisms for verification through mutual nuclear weapons site inspections, the risk of misperception or misunderstanding could increase and fuel uncertainty which could increases the perception of threat between Russia and the US.

What are Putin’s reasons for suspending Russia’s participation?

Putin and various members of his government have been linking the future of New START to the war in Ukraine rhetorically for several months now, threatening that Russia may not be willing to negotiate a follow-on treaty for when New START expires in Feb 2026 because of US support for Ukraine.

By announcing Russia’s suspension of the treaty in his main address on the anniversary of the invasion of Ukraine, Putin is sending a signal about Russia’s intent for the future.

Russia’s new hypersonic glide vehicle Avangard was already counted under New START and it is likely follow-on negotiations would have focused on some of Russia’s other hypersonic capabilities or other new nuclear systems.

Without the treaty, Russia might be less inhibited in its development of new nuclear systems.

Have both the US and Russia been compliant with the treaty until now?

Both the US and Russia have remained within the central limits of the treaty since its entry into force in 2011. Following the outbreak of COVID-19, both sides agreed to suspend in-person inspections due to restrictions on travel, and attempts to recommence in-person inspections in 2022 were unsuccessful.

In August 2022, Russia prevented US on-site inspections under New START and a November 2022 meeting of the BCC was called off by Russian officials. Russia has blamed both the ongoing COVID-19 pandemic and the sanctions burden on Russia as reasons for not wanting to resume inspections.

Alfred C. O. Vertegaal
Dec 1, 2006; 5:2298-2310
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Ivan Matic
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Hasmik Keshishian
Dec 1, 2007; 6:2212-2229
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William M. Old
Oct 1, 2005; 4:1487-1502
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Ludovic C. Gillet
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Jeffrey C. Silva
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Yasushi Ishihama
Sep 1, 2005; 4:1265-1272
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Linn Fagerberg
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Jürgen Cox
Sep 1, 2014; 13:2513-2526
Technological Innovation and Resources

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