Instant Reaction: Mortgage Rates, September 5, 2024

The following article, Amazing: Trump Moved 48 States Toward the Republican Party, was first published on Conservative Firing Line.

When the 2024 election dust settled early on Wednesday morning, it became clear that Donald Trump didn’t just win the election, he trounced Kamala Harris. It was so bad for the Democrats that nearly every state moved to the right. The GOP hasn’t seen so many votes move their way since Ronald Reagan in 1980. …

Continue reading Amazing: Trump Moved 48 States Toward the Republican Party ...

The following article, Lunatic Democrat Murders Wife and Kids, Commits Suicide Over His Hate for Donald Trump, was first published on Conservative Firing Line.

This is how mentally deranged liberals are… a Democrat in Minnesota was so filled with rage that Donald Trump won the election last week that he murdered his own wife and kids and then committed suicide to prevent them all from having to live during the next Trump presidency. Notice how you never heard any …

Continue reading Lunatic Democrat Murders Wife and Kids, Commits Suicide Over His Hate for Donald Trump ...

The following article, ‘Burn The System Down’: Democrats Now Face Charges They Are The Ones Trying To Destroy Democracy, was first published on Conservative Firing Line.

Protecting democracy was a catch phrase that Democrats have used for years to explain their hatred of now President-elect Donald Trump. He was, after all, they said, a “Hitler.” He would be a dictator. He would use the military against his political opponents, jailing them and worse. The only salvation for America’s “democracy” would be …

Continue reading ‘Burn The System Down’: Democrats Now Face Charges They Are The Ones Trying To Destroy Democracy ...

Remember back when turning 40 was about being over the hill? Back when I was a kid, I remember that 40th birthday parties were about those black OVER THE HILL balloons, and joke “you’re old now” gifts like canes with a blowhorn attached to them. That seems to have been phased out with the Boomer […]

The post AK Monthly Recap: August 2024 appeared first on Adventurous Kate.

Ah, September — one of the most beautiful months of the year, and one of the best months to travel. I definitely put this month to good use. This was a busy September for me, beginning with my getaway to South Moravia in the Czech Republic, with a 12-day trip to the Basque Country and […]

The post AK Monthly Recap: September 2024 appeared first on Adventurous Kate.

This was the month of my big, far-flung solo trip of 2024 — my trip to Nepal, Bhutan, and Qatar! It was an incredible trip to three new-to-me countries, and I’m excited to share it with you all. Let’s take a look at the month! Destinations Visited Highlights A fun trip to Bohemian Switzerland and […]

The post AK Monthly Recap: October 2024 appeared first on Adventurous Kate.

I don’t know how old our dog Posey is. She’s a rescue pup that we found at the city shelter back in 2011. We took her home, somewhat unexpectedly, that same day. It was Super Bowl Sunday, so every year at about that time we celebrate (our oh-so-creatively-named) birthday alternative, “Dog Day,” by taking her […]

The article Dog Day & Donuts in Half Moon Bay, CA originated at EverInTransit.com

Finding ways to save money is much easier than you think, because you’re probably spending money you don’t have to spend.

The article 3 Easy Steps to Save Money for Travel originated at EverInTransit.com

This morning we awoke to one story dominating the tech news landscape: OpenAI is “expanding into search,” launching SearchGPT, a prototype that appears to be a direct competitor to Google (and Bing and Perplexity, not that they really matter). But despite the voluminous coverage, my initial take is that once the hype cycle passes – … Continue reading "What’s SearchGPT Really About? Moving Past the Training Data Dilemma."

Shamelessly, Big Media doesn't even try to hide their Democrat preferences anymore. They are happy to lie. But even the lies they tell can point indirectly to the truth.

The post EPIC: When AI Swaps ‘Democracy’ For THIS Word, Journos Start Telling The Truth appeared first on Clash Daily.

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

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

Democrats don't listen.

The post Deaf Democrats appeared first on Clash Daily.

If Democrat politicians want our votes in the future then it would be nice if they said they were sorry for what they have done in the past. We don’t have far to look. Let’s see at why they lost and how they can win.

The post Why Democrats Lost the 2024 Elections appeared first on Clash Daily.

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

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

If anyone could accuse Trump of being on 'defense' during his witch-hunt trials, he's going on full offense now.

The post BOOM: Trump’s Lawyers SAVAGE Letitia James… Threaten PRISON If She Plays More Of Her Games appeared first on Clash Daily.

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

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

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

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

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.

New York Judge Juan Merchan — who is overseeing President-elect Donald Trump’s business records case — agreed to freeze the case until Nov. 19. There was to be a hearing […]

The post Judge Juan Merchan Grants Request from Trump's Legal Team and DA in NY Hush Money Case appeared first on The Western Journal.

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

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

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

In his latest Rucking with Rob newsletter, Rob Houwing argues that for England to have any hopes of beating the Springboks, they'll have to be on the ball in the final stages.

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.

Originally posted on Oct 28, 2022 It was an honor to be interviewed by the beautiful and patriotic Sandy Rios about my book and my journey writing it on her show, “Sandy Rios In the Morning.” https://afr.net/podcasts/sandy-rios-in-the-morning/2022/october/cynthia-farahat-discusses-her-new-book-the-secret-apparatus-the-muslim-brotherhood-s-industry-of-death/

January 12, 2022 (New York, NY) – The total value of residential mortgage debt in the US will continue to experience solid growth into 2022 and 2023. In our inaugural […]

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

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 […]

Toni Annala, Marc Hoyois and Ryomei Iwasa
J. Amer. Math. Soc. 38 (), 243-289.
Abstract, references and article information

Alexander Kupers and Oscar Randal-Williams
J. Amer. Math. Soc. 38 (), 63-178.
Abstract, references and article information

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

Why a more inward-looking China is bad news for the world economy Expert comment LToremark 16 October 2022

The increased role of geopolitics and ideology in Beijing’s economic decision-making is bad news not just for China but for the world.

This quote by President Xi clearly outlines the inward tilt of Chinese economic policymaking that is now becoming increasingly obvious to the rest of the world. But it actually has deep roots. Ever since the 2008 global financial crisis, when the West’s reliability as a trading partner was thrown into question, self-reliance has become a more decisive organizing principle for Chinese officials.

As a result, the export-dependent growth model on which China built its economic rise in recent decades has been fraying. Exports as a share of China’s GDP peaked at 35 per cent in 2007 but had fallen to around 20 per cent by last year, a level not seen since before China’s accession to the WTO in 2001. This shows that net exports no longer make any meaningful contribution to Chinese GDP growth.

Although China’s inward tilt may have started out as a response to purely economic phenomena – the post-crisis global recession, belt-tightening in the West, the eurozone crisis, and a general softening of global trade growth in the post-crisis years – geopolitical considerations are now dominant in shaping this shift toward self-reliance.

The role of geopolitics in pushing China towards a more inward-looking development path became clear in China’s response to the aggressive tariffs and export controls introduced by the Trump administration in the US. Because of these new constraints on China’s access to international markets and technology, Beijing sought to limit its dependence on the rest of the world.   

The most obvious result of this was the introduction of the ‘dual circulation’ strategy in May 2020, which sets out a rebalancing of China’s economy away from a reliance on external demand as a stimulus to growth (‘international circulation’) towards increased self-dependence (‘domestic circulation’). 

Russia’s invasion of Ukraine has provided another geopolitical impetus to China’s pursuit of self-reliance. Since it is not far-fetched to think that China, like Russia, might one day also face coordinated sanctions, Chinese authorities must be thinking hard about how to respond to such a risk. 

The only credible strategy that China can adopt is to reduce its economic dependence on the West by creating, in effect, a kind of economic fortress, as its dependence on imported technology, food, and fossil fuels in particular, has created a substantial strategic vulnerability.

Over the next few years, Chinese policymakers will likely attempt to build up the country’s ability to supply its own semi-conductors, food, and green energy sources.

This new approach to economic policymaking isn’t just about China’s relationship with the rest of the world. Within China itself, a new emphasis on the role of the state is increasingly apparent – and seemingly rooted in ideology. 

The previous National Congress of the Chinese Communist Party (CCP), in October 2017, made a push for ‘stronger, better, and bigger’ state-owned enterprises (SOEs) and the past five years have indeed seen a measurable rise in the role that SOEs play in the Chinese economy. These firms now account for more fixed investment in the economy than private firms, for the first time since 2005.

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.

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.

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

30 Years of Non-Maghreb: What next for Algeria-Morocco relations? 10 September 2024 — 2:00PM TO 3:15PM Anonymous (not verified) 13 August 2024 Online

Experts discuss Algeria-Morocco relations and implications for regional actors.

In 1989, the establishment of the Arab Maghreb Union (UMA) brought a promise of economic integration and strengthening of ties between Algeria, Libya, Mauritania, Morocco and Tunisia for the benefit and prosperity of their societies.

Decades on, very little has been accomplished in developing the Maghreb project, and the region remains one of the least integrated in the world, despite significant social and cultural similarities between member countries. The last time the full UMA leadership met was back in 1994, with August 2024 marking 30 years of closed borders between Algeria and Morocco.

Relations between the two largest Maghreb countries have deteriorated further since 2020 due to disagreements over issues of Western Sahara, and, most recently, the Abraham Accords, with Algeria cutting diplomatic ties with Morocco in 2021.

In this webinar, experts will discuss:

• Which primary obstacles are hindering Maghreb integration and Algeria-Morocco relations?
• What are the costs and implications for regional countries?
• What are the positions of Libya, Tunisia, and Mauritania?
• What is required for a rapprochement and how can external partners support this? 

Celebrating Black History Month at Chatham House 24 October 2024 — 6:00PM TO 8:00PM Anonymous (not verified) 2 October 2024 Chatham House

Join us for the ‘Beyond expectations: The impact and legacy of migration exhibition 2024’ exhibition and drinks reception.

About the Photographer  

Neil Kenlock, a photographer and media professional, has lived in London since arriving from Jamaica in 1963 to join his parents. He spent the early years of his career as a professional photographer, specialising in fashion, beauty, celebrities, and the cultural lifestyles of Black people in the UK. In the late 1960s and 1970s, he captured images of the UK Black Panther movement and documented demonstrations and anti-racism protests across the country.

“Neil Kenlock helps us to better understand the story of London’s Black communities and to appreciate the huge artistic and cultural impact they have had on all our lives. He is a significant photographer whose work documents a key chapter in London’s post-war history.” — Mike Seaborne, former curator of photographs at the Museum of London.

About the exhibition

This exhibition unveils a collection of photographs by Neil Kenlock, capturing Black British individuals who migrated from their homelands and settled in the UK. Curated by his daughter Emelia Kenlock, the series explores the theme of ‘expectations’ and its enduring legacy, featuring African and Caribbean subjects who brought their skills, passions, and dreams—contributions that have profoundly shaped British culture today.

Reflecting on the work, Kenlock stated: “Over 50 years since the concept of ‘black excellence’ first manifested, and more than 70 years since the Windrush, I truly hope this exhibition will add to the national cultural narrative and resonate with new audiences.” 

Shaping modern Britain: the role of African and Caribbean communities 24 October 2024 — 5:00PM TO 6:00PM Anonymous (not verified) 3 October 2024 Chatham House and Online

As part of Black History Month, this event celebrates the enduring contributions of African and Caribbean communities to the UK.

When British colonial rule ended, newly independent countries in Africa and the Caribbean retained influences such as the English language and governance systems modelled on that of the UK. Initially, these post-independence relations were largely marked by the UK’s soft power, shaping the nation-building processes in these regions.

Over time, however, this influence has become a two-way exchange. African and Caribbean cultures have profoundly shaped modern Britain – from music and food to sports, arts, literature and beyond. These evolving dynamics have not only enriched the UK’s cultural landscape but also provided significant benefits for diaspora communities, fostering a sense of belonging and promoting cultural exchange. Diaspora groups and civil society organizations have adeptly utilised these connections to advocate for their communities and advance their interests.

At this event, speakers will explore how African and Caribbean influences rose to prominence in the UK and how this cultural momentum can be harnessed to build stronger, forward-looking partnerships. By highlighting the shared histories and more vibrant present-day exchanges, this event will explore how these ties can be used to break down stereotypes, promote social cohesion, and contribute to a more inclusive future.

This event forms part of our series of events celebrating Black History Month, including a photo exhibition and drinks reception.

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

The 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.

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

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

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

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.

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.

Mobile Ecosystems as a Driver of Innovation and Growth in the Asia-Pacific 19 September 2018 — 12:30PM TO 3:00PM Anonymous (not verified) 18 September 2018 Chatham House, London

China Needs to Make the Belt and Road Initiative More Transparent and Predictable Expert comment sysadmin 29 April 2019

The global infrastructure project must move beyond mish-mash of opaque bilateral deals

As China welcomes dozens of world leaders to Beijing for its second Belt and Road forum, it has one simple aim: relaunching President Xi Jinping’s controversial global infrastructure drive.

Since it began five years ago, the Belt and Road Initiative (BRI) has sunk hundreds of billions into port, railway and power projects stretching from south-east Asia to central Europe. But its path has been bumpy, drawing sharp criticism over the ruinous debts that some countries have racked up amid Chinese largesse.

Xi will stress sustainable financing and transparency this week, amid the usual talk of ‘win win’ cooperation. Yet BRI’s problems are structural, not presentational. For any pledges to be meaningful, China must move beyond its present mish-mash of opaque, bilateral deals.

After bad headlines last year, BRI has in fact enjoyed a good run in recent weeks. Malaysia announced it would resume a previously cancelled high-speed rail project, while Italy’s decision to join up last month marked a further European incursion. Indeed, if attendance is any guide to success, BRI looks in fine fettle. The first forum in 2017 attracted 29 world leaders. China says 37 will turn up this week. Phillip Hammond, UK chancellor, arrives hunting deals too, just a day after news that Chinese technology group Huawei will be allowed to help build 5G networks in Britain.

Even so, three interlinked problems remain at the heart of President Xi’s pet project, all of which must be addressed if BRI is to move beyond the pitfalls that have damaged its reputation.

The first and most obvious is debt. Critics allege that China ‘traps’ its BRI partners financially, often pointing to a debt-for-equity deal that handed China control of a port in Sri Lanka. These claims are exaggerated — few other projects have ended up this way. Yet poorer nations from Laos to Tajikistan are still signing up to vastly expensive Chinese schemes that offer poor value for money while straining their public finances.

The second problem is transparency. Despite its grand scale there is still no reliable list of BRI projects, no disclosure of the lending standards China follows, nor even the amount China has invested. Beijing claims more than $1 trillion; independent estimates suggest perhaps a few hundred billion. Either way, it will be hard for China to convince doubters on debts until it is open about the criteria it uses in deciding who to lend to and why.

BRI’s third and most important challenge is its muddled organization. Despite BRI’s image as a centrally run mega-project, China has allowed many deals to be struck locally, via a mix of state-backed companies, public sector banks and freewheeling regional governments. And it is here that the problems began.

Infrastructure deals are notoriously complex, especially for transnational projects like high-speed rail. Renegotiations are common, even for experienced bodies like the World Bank. Yet BRI has repeatedly seen terms negotiated behind closed doors, in countries such as Malaysia and Pakistan, come unstuck in the face of public outcry.

Rather than seeking to trap others with debt, China’s central government more often has to step in to fix dubious projects agreed by underlings lower down the chain.

These negotiations go one of two ways. Either China’s partners complain and win terms, as was true in Malaysia and in Myanmar over a multibillion-dollar deep-sea port. Or, as in the case of Sri Lanka, the renegotiations go in China’s favour, but at the cost of accusations of debt trickery. In both cases China looks bad.

Speaking last year, Xi responded to criticism of BRI by describing it as ‘an open platform for cooperation’. Yet, so far, he has proved resistant to the step that would deliver on that vision — namely turning BRI into an institution with open standards and international partners.

The reasons for his reluctance are obvious. Ending BRI’s reliance on loose bilateral deals would limit Beijing’s room for geopolitical manoeuvre. Yet what might be lost in political flexibility could easily be gained in economic credibility, while avoiding some of the painful renegotiations that have dogged many BRI projects.

At a time when China’s economy is slowing and its current account surplus is shrinking, formalising and institutionalising, BRI could also help avoid wasting scarce public resources on white elephant projects. China even has an easy template in the form of the Asian Infrastructure Investment Bank, the Beijing-based institution that has won plaudits for its project quality and openness since it started in 2016.

Whichever model is chosen, a dose of Chinese-style central planning is called for, along with more openness. Without it, the oddly chaotic and decentralised model pioneered in BRI’s first five years is unlikely to help the project thrive over the next five.

This article was originally published in the Financial Times.