through NASDAQ Promotes Diversity Through New Listing Requirements By corporatejusticeblog.blogspot.com Published On :: Wed, 09 Dec 2020 20:30:00 +0000 On December 1st, 2020, Nasdaq filed a proposal with the Securities and Exchange Commission to adopt additional listing rules requiring enhanced board diversity and disclosure of firm diversity efforts. The new listing rules require Nasdaq-listed companies to have on their board of directors, at least two diverse directors, including one who self-identifies as female and one who self-identifies as an underrepresented minority or LGBTQ+. If the firm does not meet this listing requirement, it must explain why they do not have at least two diverse directors sitting on their board. Additionally, the new listing rules require Nasdaq-listed companies to publicly disclose consistent, transparent diversity statistics regarding its board of directors. Nasdaq defines underrepresented minorities to include Black or African America, Hispanic or Latinx, Asian, Native American or Alaska Native, Native Hawaiian or Pacific Islander, two or more races or ethnicities. Smaller reporting companies and foreign companies have additional flexibility in satisfying these new listing requirements by seating at least two female directors. These new listing rules require approval from the SEC.NASDAQ's stated goal for requiring diversity among its listed companies board makeups is to provide the investing public with a "better understanding of the company's current board composition and enhance investor confidence that all listed companies are considering diversity in the context of selecting directors, either by including at least two diverse directors on their boards or explaining their rationale for not meeting that objective." To support this new listing requirement, Nasdaq pointed to over 24 studies that found a link between diverse board and more robust financial performance with better corporate governance. Under this proposal, Nasdaq-listed companies are required to publicly disclose board-level diversity statistics within one year of the SEC's approval of the rule.CNN reports that Nasdaq CEO Adena Friedman stated, "Nasdaq's purpose is to champion inclusive growth and prosperity to power stronger economies." Non compliance by Nasdaq-listed companies could lead to delisting. Nasdaq's move is part of a growing momentum to see that corporate board diversity is taken seriously across the United States. California has for two years been requiring gender diversity on corporate boards and has recently begun requiring racial and ethnic diversity on California boards as well. Goldman Sachs has recently announced that it will require any company that it assists in taking public must include at least one diverse board member. The Corporate Justice Blog has long advocated for board diversity as a priority for expanding human capital and realizing greater financial benefits for the firms and its shareholders. We argue that a commitment to diversifying the board, both in gender and racial diversity as well as worldview diversity enhances the performance of the corporations that so commit. See here, here, here and here.hat tip: Deepali Lal, 3L, Arkansas at Little Rock William H. Bowen School of Law photo: courtesy of Wikimedia Commons Full Article
through GitHub - JohannesKaufmann/html-to-markdown: ⚙️ Convert HTML to Markdown. Even works with entire websites and can be extended through rules. By github.com Published On :: 2024-11-13T05:47:01+00:00 Full Article
through Red Rocks’ new holiday show lets you drive through 1 million lights By www.denverpost.com Published On :: Mon, 04 Nov 2024 16:57:58 +0000 Tickets for Christmas in Color, which runs through January, are on sale now. Full Article Amusement Parks Colorado News Entertainment Latest Headlines Music News The Know Things To Do Arapahoe County Christmas events Federal Heights holidays Red Rocks Amphitheatre Water World
through Southbound I-25 through Pueblo opens following pedestrian death By www.denverpost.com Published On :: Sat, 02 Nov 2024 15:21:43 +0000 Southbound Interstate 25 is once again open in Pueblo after a vehicle struck and killed a pedestrian Saturday morning, shutting down the roadway. Full Article Colorado News Crashes and Disasters Crime and Public Safety Latest Headlines News Transportation Interstate 25 police Pueblo
through WATCH: Kangaroo spotted hopping through Durango streets By www.denverpost.com Published On :: Thu, 24 Oct 2024 12:00:53 +0000 A kangaroo gave three Durango police officers a late-night workout after taking an evening hop through the southern Colorado city's streets, according to a video shared by police Wednesday. Full Article Colorado News Latest Headlines News animals durango Durango Police Department Facebook
through After guiding industry through big changes, head of Colorado oil-gas group to step down By www.denverpost.com Published On :: Thu, 03 Oct 2024 12:10:42 +0000 Dan Haley is stepping down as CEO and president of the trade association after nine years. Full Article Business Energy Latest Headlines News air quality automobiles climate change CoBank Colorado General Assembly Colorado Oil and Gas Association Colorado Oil and Gas Conservation Commission Denver-Julesburg Basin drilling economy emissions energy environment Jared Polis jobs oil and gas ozone renewable energy Senate Bill 181 technology
through Gloria Govan and Matt Barnes Through the Years By www.bet.com Published On :: Fri, 18 Jul 2014 12:46:00 EDT Gloria Govan and Matt Barnes through the years. Full Article Just Keke
through Antron Brown, first Black drag racing champion, insists he’s still got plenty left in the tank: “I’m halfway through” By www.denverpost.com Published On :: Sat, 15 Jul 2023 02:13:38 +0000 As a child, Antron Brown’s trips to Old Bridge Township Raceway Park in Englishtown, New Jersey, were a source of inspiration. Full Article Latest Headlines Motorsports Sports Bandimere Speedway NHRA
through Kiszla: Fearless prediction for 2024? Nikola Jokic and Nathan MacKinnon will lead dueling victory parades through streets of Denver By www.denverpost.com Published On :: Sun, 14 Jan 2024 01:40:28 +0000 On any given night, Nuggets center Nikola Jokic or Avalanche center Nathan MacKinnon can be a whole flight of stairs above any competitor on the court or in the rink. Full Article Colorado Avalanche Denver Nuggets Latest Headlines NBA NHL Sports Sports Columnists Ball Arena Bruce Brown Gabriel Landeskog Jared Bednar Mark Kiszla Michael Malone More Avalanche News More Nuggets News Nathan MacKinnon Nikola Jokic Peyton Watson Stanley Cup
through James Earl Jones’ Darth Vader voice lives on through AI. Voice actors see promise and peril in that By www.denverpost.com Published On :: Sat, 21 Sep 2024 12:00:15 +0000 Voice actors say they fear AI could reduce or eliminate job opportunities because the technology could be used to replicate one performance into a number of other movements without their consent. Full Article Business Latest Headlines Technology artificial intelligence Field of Dreams media More Business News Star Wars technology television video games
through Apollo Theater Through the Years By www.bet.com Published On :: Wed, 14 Nov 2012 13:20:00 EST Check out the evolution of the historic Apollo. Full Article Apollo Live
through Justin Continues to Drag Kara's Name Through the Mud By www.bet.com Published On :: Tue, 25 Jul 2017 23:00:00 EDT #FireableOffense Full Article Being Mary Jane Lisa Vidal Kara Lynch Michael Ealy Highlights
through Welch’s Rise Through Ranks At The MarketPlace By bernews.com Published On :: Thu, 07 Nov 2024 00:06:34 +0000 Tahjae Welch has risen from an entry-level position all the way to Store Manager at the MarketPlace, with the company noting how “determination, hard work, and a positive support system can lead to impressive career advancement in Bermuda’s retail grocery industry.” A spokesperson said, “Starting his journey with The MarketPlace in 2016 straight out of […] Full Article All Business News #BermudaBusiness #GoodNews
through ‘Walk Through History’ Event On May 1 By bernews.com Published On :: Tue, 30 Apr 2024 16:22:22 +0000 A lunchtime ‘Walk Through History’ will take place on May 1 at Victoria Park, retracing the pivotal events of May 1, 1981, during the General Strike. A spokesperson said, “Wednesday, May 1st, there will be a lunchtime ‘Walk Through History’ starting at Victoria Park at noon. This 45 minute procession, will follow footsteps made more […] Full Article All History News #BermudaHistory
through Community Gathers For ‘Walk Through History’ By bernews.com Published On :: Mon, 06 May 2024 09:31:14 +0000 A group of approximately 40 people, including members of the Bermuda Trade Union Congress [BTUC], Somersfield Academy students, and event coordinator Glenn Fubler gathered at Victoria Park on Wednesday, May 1 for the Walk Through History event. A spokesperson said, “The Walk Through History, held on Wednesday, May 1st, began at noon at Victoria Park, […] Full Article All History News #BermudaHistory
through #57 Enlightenment – Ending Our Suffering through Witnessing Our Suffering By www.enlightenmentpodcast.com Published On :: Sun, 07 Oct 2012 06:41:13 +0000 #57 Enlightenment - Ending Our Suffering through Witnessing Our SufferingThe post #57 Enlightenment – Ending Our Suffering through Witnessing Our Suffering appeared first on Enlightenment Podcast. Full Article Advaita Vedanta Awareness Bliss emptiness Enlighten Enlightened Meditate Meditation meditation enlightenment Mindfulness no-self non-duality nonduality Peace Peak-Experiences Self-Actualization spiritual enlightenment Dr. Puff Dr. Robert Puff Enlightenment Podcast Mental Health Music by Kevin MacLeod Musings on "I Am That" Peak-Experience Podcast Self-Help
through SLC-2L-13: Shoot Through Your Sunset By strobist.blogspot.com Published On :: Sat, 22 Aug 2020 20:35:00 +0000 Whenever you have control over the time of day in which you'll be shooting a location portrait, always remember that the hour that wraps around sunset will offer you at least five different lighting environments in which to work. And for today's portrait of birders Jo (left) and Bob Solem, we're going to use three of them. Read more » Full Article
through C.J. Stroud tops the list of best-selling NFL jerseys midway through 2024 season By www.foxsports.com Published On :: Tue, 12 Nov 2024 19:29:22 -0500 Three quarterbacks lead the way in top NFL jerseys sales so far this season. Full Article nfl
through YouTube is now letting creators remix songs through AI prompting By biztoc.com Published On :: Wed, 13 Nov 2024 05:24:47 GMT YouTube added a capability for select creators in the U.S. to create AI-generated songs via prompts using the vocals of artists like Charlie Puth, Charli XCX, Demi Lovato, John Legend, Sia, T-Pain, and Troye Sivan last year. Now, the company is adding a feature for select creators to remix a track… Full Article
through YouTube is testing a new feature that will let a small group of creators use AI to “restyle” licensed songs for their Shorts through prompts By biztoc.com Published On :: Wed, 13 Nov 2024 07:02:16 GMT YouTube is testing a new feature that will let creators use AI to “restyle” licensed songs for their shorts. The small group of creators with access can enter a prompt to change up different elements in a song, such as its mood or genre, and the expansion of YouTube’s Dream Track AI feature will… Full Article
through Make Way, Pirate Ship Coming Through! By cheezburger.com Published On :: Mon, 13 May 2013 12:00:00 -0700 Full Article pirate ship design cars
through Pivotal Transfers Throughout Chelsea’s History By www.chelseafcblog.com Published On :: Mon, 08 Jul 2024 10:08:18 +0000 Now one of the most influential teams in the world, Chelsea have always pushed the boundaries both on the field.. The post Pivotal Transfers Throughout Chelsea’s History appeared first on Chelsea FC Blog. Full Article Legends Transfer News
through Building Lasting Relationships Through Words of Affirmation By www.lifehack.org Published On :: Mon, 21 Oct 2024 16:58:32 +0000 Words have the power to lift us up or tear us down, and nowhere is this more true than in our closest relationships. Understanding how language shapes our emotional connections can make all the difference between feeling deeply loved or feeling disconnected. One of the most potent tools for enhancing intimacy and trust in a ... Read more The post Building Lasting Relationships Through Words of Affirmation appeared first on LifeHack. Full Article Mental Wellness Relationships
through How to Develop Resilience: Key Steps for Thriving Through Adversity By www.lifehack.org Published On :: Mon, 21 Oct 2024 19:20:29 +0000 Resilience is the key to transforming challenges into opportunities for personal growth. It’s not just about bouncing back from setbacks—it’s about thriving despite them. Resilience is not something you either have or you don’t. Instead, it is a skill you can cultivate and strengthen over time. In this article, we’ll explore the multifaceted nature of ... Read more The post How to Develop Resilience: Key Steps for Thriving Through Adversity appeared first on LifeHack. Full Article Mental Wellness
through Nature will help you get through this By engrish.com Published On :: Thu, 07 Nov 2024 11:00:44 +0000 Photo courtesy of Cheryl Smith. Bag found in Japan. Full Article Bags/Packaging
through Oregon green building design embraces timber throughout By inhabitat.com Published On :: Fri, 23 Jun 2023 15:30:00 +0000 Have you heard about Mississippi? It's a construction project brought to life by Waechter Architecture after more than 10 years of planning and investigation. This building isn't just your ordinary structure; it's a game-changer in terms of sustainability and creativity.[...] Full Article Architecture Green Building Portland Oregon timber architecture post-format-gallery
through Leave no trace rafting through the Grand Canyon this year By inhabitat.com Published On :: Fri, 28 Jul 2023 15:30:00 +0000 It’s a hot and beautiful summer day at the bottom of the Grand Canyon as I stand in line for a sandwich. Our rafting guides have set up an amazing spread of fixings. There’s even vegan cheese for me. All that’s missing are plates and napkins. After washing our hands with river water and soap in a foot-pumped bucket sink, we put our bread on one hand and try to layer on all the sandwich ingredients with the other. Scooping out avocado is especially difficult one-handed. It's clumsy, but admirable when you realize we are generating no paper or plastic[...] Full Article Travel grand canyon leave no trace lifestyle rafting Water Travel
through Noncomformity Through The Ages By cheezburger.com Published On :: Sat, 27 Nov 2010 05:49:47 -0800 Beggin' your pardon sir, but if we're all dressed differently, exactly why is it called a uniform? Full Article art color funny illustration military
through Winos 4.0 Malware Infects Gamers Through Malicious Game Optimization Apps By thehackernews.com Published On :: Wed, 06 Nov 2024 19:29:00 +0530 Cybersecurity researchers are warning that a command-and-control (C&C) framework called Winos is being distributed within gaming-related applications like installation tools, speed boosters, and optimization utilities. "Winos 4.0 is an advanced malicious framework that offers comprehensive functionality, a stable architecture, and efficient control over numerous online endpoints to execute Full Article
through Writing through cringe By www.cygnoir.net Published On :: Fri, 01 Nov 2024 17:22:23 -0800 For the first day of NaBloPoMo (National Blog Posting Month), I want to start with something difficult, and the reason why I’m participating in this monthly challenge. I’ve lost all affection for my writing voice, and I don’t entirely know why. These days, it’s challenging for me to get excited about writing anything personal. Everything I post, aside from ink swatches, makes me cringe, even simple replies to others' posts. When I started writing online, it was so easy to share any little moss-bulb of detail, despite lacking confidence in my voice or purpose. It was enough to noodle in public; I had a stage (my website) and tap-tap-tapping its microphone didn’t make me feel immediately self-conscious. A few years ago, I pushed — harder than I’ve pushed for many things in my life — for the “community” aspect of Micro.blog to be more than a shared timeline. I wanted it to be something I could lean back softly into, both an audience and support group, comprised of people who shared the same penchant for collecting and amplifying small treasures of moments. The people exist (and they are wonderful, I read what they share with delight) but the community? I know now that what I was asking for doesn’t exist online in the same way it did, but I didn’t know that yet. I kept pushing and pushing, until one day I just … stopped. Everything I said seemed to repulse people instead of drawing them closer. It was easier to find what I needed and wanted in the friendships I was slowly and intentionally building offline than it was for me to do that online. And that was a first for me. Much of my life, up to that point, had been spent focusing on connecting online. Because much of my life, up to that point, had been lived online. I don’t really want to go back to living so much online. But sometimes I’m nostalgic for the feeling of being understood through my writing, shades of myself that I don’t know how to represent except through words. It’s supremely cringey even to post this, but I’m going to push through in the hopes there’s some self-acceptance on the other side of it. I’m not ready to stop writing altogether. In some ways, I feel like I’ve barely begun. Full Article
through Viking Ring Styles Through Different Historical Periods By www.star2.org Published On :: Fri, 22 Sep 2023 20:12:09 +0000 Viking rings, with their intricate designs and cultural significance, offer a captivating glimpse into the history of the Viking Age. These rings, often crafted from precious metals and adorned with intricate motifs, are not only exquisite pieces of jewelry but also artifacts that provide insights into the evolving tastes, craftsmanship, and societal changes of the ... Read more The post Viking Ring Styles Through Different Historical Periods appeared first on Star Two. Full Article Style Jewelers Viking jewelry Viking Ring Styles Viking symbols
through TV Week: Hanoch, Hopkins, and Billy muddle through By www.jpost.com Published On :: Fri, 08 Nov 2024 20:51:59 GMT Hot’s Bad Boy debuts Nov. 21, joined by Daum's Life is a Difficult Age, Crystal’s Before, and Armageddon Time on Netflix. Full Article culture film TV Show Reviews
through India Abraham: Healing physical and psychological scars through medical tattooing By www.jpost.com Published On :: Sun, 10 Nov 2024 08:41:01 GMT Jerusalemite of the week: India Abraham is a practitioner of medical tattooing who had already helped scores of people before Oct. 7, but her work has taken on even greater significance since then. Full Article health cancer Tattoos Beauty Jerusalemite of the Week
through Williams through to Champion of Champions semis By www.bbc.com Published On :: Tue, 12 Nov 2024 23:49:19 GMT Mark Williams progresses to the semi-finals of the Champion of Champions tournament by defeating Kyren Wilson 6-5 in Bolton. Full Article
through 10,000 miles across US as seen through train window By www.bbc.com Published On :: Thu, 26 Sep 2024 00:44:56 GMT Photographer Katie Edwards captures America from the window of a train. Full Article
through Keeper's penalty heroics send Wigan through in EFL Trophy By www.bbc.com Published On :: Tue, 12 Nov 2024 22:38:48 GMT Wigan Athletic goalkeeper Tom Watson saves all three penalties in a shootout victory over Nottingham Forest U21s to send them through to the EFL Trophy knockout phase. Full Article
through “If the Democrats could fight wars as well as they execute Election Fraud, we would have obliterated all of our many enemies throughout the World, and would have nothing to worry about!” ~ Donald J. Trump By powderedwigsociety.com Published On :: Sun, 29 Aug 2021 14:34:49 +0000 Touché! .@POTUS45: "If the Democrats could fight wars as well as they execute Election Fraud, we would have obliterated all of our many enemies throughout the World, and would have nothing to worry about!" pic.twitter.com/GpMO46zrNQ — Natalie Harp (@NatalieJHarp) August […] The post “If the Democrats could fight wars as well as they execute Election Fraud, we would have obliterated all of our many enemies throughout the World, and would have nothing to worry about!” ~ Donald J. Trump appeared first on Powdered Wig Society. Full Article 2020 presidential election 2020 election fraud afghanistan donald trump
through Understanding through history By www.readingrockets.org Published On :: Tue, 22 Mar 2022 17:30 EDT War is back in daily headlines. It’s devastating to think about the impact on children here and where the actual fighting is taking place. Full Article
through AI labs – Learning unsupervised learning through Robotics By www.opengardensblog.futuretext.com Published On :: Sun, 06 May 2018 17:24:21 +0000 We are launching an AI lab. The goal is to learn unsupervised learning through Robotics (Cobots) Long seen as a poor cousin to supervised learning - with Variational autoencoders, Reinforcement learning and Generative-Adversarial networks , unsupervised learning techniques have moved beyond the limitations of autoencoders. From Oct 2018 to March 2019 , we are running a [...] Full Article BIG DATA FEATURED POSTS LATEST POSTS
through Will These Deranged Celebrities Who Promised To End Their Lives Or Flee The Country If Trump Wins Actually Follow Through? By conservativefiringline.com Published On :: Mon, 11 Nov 2024 00:15:19 +0000 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? ... Full Article Politics Bono celebrities Drano kill leave meltdown Midler suicide
through Basecamp has offset our cumulative emissions through 2019 By signalvnoise.com Published On :: Fri, 30 Oct 2020 19:07:02 +0000 Earlier this year, we announced that Basecamp was committing to getting to carbon negative for our cumulative history and moving forward. Today, I want to share an update on that commitment. Note: I edited this post on Nov 5, 2020 to include the prices paid for all carbon offsets and explain a little more about the… keep reading Full Article Uncategorized
through Development and validation of a high-throughput whole cell assay to investigate Staphylococcus aureus adhesion to host ligands [Microbiology] By www.jbc.org Published On :: 2020-12-04T00:06:05-08:00 Staphylococcus aureus adhesion to the host's skin and mucosae enables asymptomatic colonization and the establishment of infection. This process is facilitated by cell wall-anchored adhesins that bind to host ligands. Therapeutics targeting this process could provide significant clinical benefits; however, the development of anti-adhesives requires an in-depth knowledge of adhesion-associated factors and an assay amenable to high-throughput applications. Here, we describe the development of a sensitive and robust whole cell assay to enable the large-scale profiling of S. aureus adhesion to host ligands. To validate the assay, and to gain insight into cellular factors contributing to adhesion, we profiled a sequence-defined S. aureus transposon mutant library, identifying mutants with attenuated adhesion to human-derived fibronectin, keratin, and fibrinogen. Our screening approach was validated by the identification of known adhesion-related proteins, such as the housekeeping sortase responsible for covalently linking adhesins to the cell wall. In addition, we also identified genetic loci that could represent undescribed anti-adhesive targets. To compare and contrast the genetic requirements of adhesion to each host ligand, we generated a S. aureus Genetic Adhesion Network, which identified a core gene set involved in adhesion to all three host ligands, and unique genetic signatures. In summary, this assay will enable high-throughput chemical screens to identify anti-adhesives and our findings provide insight into the target space of such an approach. Full Article
through China and the US: Through Each Other’s Eyes By f1.media.brightcove.com Published On :: Wed, 13 Feb 2019 00:00:00 +0000 Full Article
through Lipid extraction by methyl-tert-butyl ether for high-throughput lipidomics By www.jlr.org Published On :: 2008-05-01 Vitali MatyashMay 1, 2008; 49:1137-1146Methods Full Article
through Stop codon read-through of mammalian MTCH2 leading to an unstable isoform regulates mitochondrial membrane potential [Gene Regulation] By www.jbc.org Published On :: 2020-12-11T00:06:20-08:00 Stop codon read-through (SCR) is a process of continuation of translation beyond a stop codon. This phenomenon, which occurs only in certain mRNAs under specific conditions, leads to a longer isoform with properties different from that of the canonical isoform. MTCH2, which encodes a mitochondrial protein that regulates mitochondrial metabolism, was selected as a potential read-through candidate based on evolutionary conservation observed in the proximal region of its 3' UTR. Here, we demonstrate translational read-through across two evolutionarily conserved, in-frame stop codons of MTCH2 using luminescence- and fluorescence-based assays, and by analyzing ribosome-profiling and mass spectrometry (MS) data. This phenomenon generates two isoforms, MTCH2x and MTCH2xx (single- and double-SCR products, respectively), in addition to the canonical isoform MTCH2, from the same mRNA. Our experiments revealed that a cis-acting 12-nucleotide sequence in the proximal 3' UTR of MTCH2 is the necessary signal for SCR. Functional characterization showed that MTCH2 and MTCH2x were localized to mitochondria with a long t1/2 (>36 h). However, MTCH2xx was found predominantly in the cytoplasm. This mislocalization and its unique C terminus led to increased degradation, as shown by greatly reduced t1/2 (<1 h). MTCH2 read-through–deficient cells, generated using CRISPR-Cas9, showed increased MTCH2 expression and, consistent with this, decreased mitochondrial membrane potential. Thus, double-SCR of MTCH2 regulates its own expression levels contributing toward the maintenance of normal mitochondrial membrane potential. Full Article
through Hepatocyte nuclear factor 1{beta} suppresses canonical Wnt signaling through transcriptional repression of lymphoid enhancer-binding factor 1 [Molecular Bases of Disease] By www.jbc.org Published On :: 2020-12-18T00:06:18-08:00 Hepatocyte nuclear factor-1β (HNF-1β) is a tissue-specific transcription factor that is required for normal kidney development and renal epithelial differentiation. Mutations of HNF-1β produce congenital kidney abnormalities and inherited renal tubulopathies. Here, we show that ablation of HNF-1β in mIMCD3 renal epithelial cells results in activation of β-catenin and increased expression of lymphoid enhancer–binding factor 1 (LEF1), a downstream effector in the canonical Wnt signaling pathway. Increased expression and nuclear localization of LEF1 are also observed in cystic kidneys from Hnf1b mutant mice. Expression of dominant-negative mutant HNF-1β in mIMCD3 cells produces hyperresponsiveness to exogenous Wnt ligands, which is inhibited by siRNA-mediated knockdown of Lef1. WT HNF-1β binds to two evolutionarily conserved sites located 94 and 30 kb from the mouse Lef1 promoter. Ablation of HNF-1β decreases H3K27 trimethylation repressive marks and increases β-catenin occupancy at a site 4 kb upstream to Lef1. Mechanistically, WT HNF-1β recruits the polycomb-repressive complex 2 that catalyzes H3K27 trimethylation. Deletion of the β-catenin–binding domain of LEF1 in HNF-1β–deficient cells abolishes the increase in Lef1 transcription and decreases the expression of downstream Wnt target genes. The canonical Wnt target gene, Axin2, is also a direct transcriptional target of HNF-1β through binding to negative regulatory elements in the gene promoter. These findings demonstrate that HNF-1β regulates canonical Wnt target genes through long-range effects on histone methylation at Wnt enhancers and reveal a new mode of active transcriptional repression by HNF-1β. Full Article
through Explaining Wildfires Through Curvature By www.ams.org Published On :: Tue, 17 Oct 2023 10:33:14 -0400 Dr. Valentina Wheeler of University of Wollongong, Australia, shares how her work influences efforts to understand wildfires and red blood cells. In Australia, where bushfires are a concern year-round, researchers have long tried to model these wildfires, hoping to learn information that can help with firefighting policy. Mathematician Valentina Wheeler and colleagues began studying a particularly dangerous phenomenon: When two wildfires meet, they create a new, V-shaped fire whose pointed tip races along to catch up with the two branches of the V, moving faster than either of the fires alone. This is exactly what happens in a mathematical process known as mean curvature flow. Mean curvature flow is a process in which a shape smooths out its boundaries over time. Just as with wildfires, pointed corners and sharp bumps will change the fastest. Full Article
through Ischemic stroke disrupts the endothelial glycocalyx through activation of proHPSE via acrolein exposure [Molecular Bases of Disease] By www.jbc.org Published On :: 2020-12-25T00:06:31-08:00 Infiltration of peripheral immune cells after blood-brain barrier dysfunction causes severe inflammation after a stroke. Although the endothelial glycocalyx, a network of membrane-bound glycoproteins and proteoglycans that covers the lumen of endothelial cells, functions as a barrier to circulating cells, the relationship between stroke severity and glycocalyx dysfunction remains unclear. In this study, glycosaminoglycans, a component of the endothelial glycocalyx, were studied in the context of ischemic stroke using a photochemically induced thrombosis mouse model. Decreased levels of heparan sulfate and chondroitin sulfate and increased activity of hyaluronidase 1 and heparanase (HPSE) were observed in ischemic brain tissues. HPSE expression in cerebral vessels increased after stroke onset and infarct volume greatly decreased after co-administration of N-acetylcysteine + glycosaminoglycan oligosaccharides as compared with N-acetylcysteine administration alone. These results suggest that the endothelial glycocalyx was injured after the onset of stroke. Interestingly, scission activity of proHPSE produced by immortalized endothelial cells and HEK293 cells transfected with hHPSE1 cDNA were activated by acrolein (ACR) exposure. We identified the ACR-modified amino acid residues of proHPSE using nano LC–MS/MS, suggesting that ACR modification of Lys139 (6-kDa linker), Lys107, and Lys161, located in the immediate vicinity of the 6-kDa linker, at least in part is attributed to the activation of proHPSE. Because proHPSE, but not HPSE, localizes outside cells by binding with heparan sulfate proteoglycans, ACR-modified proHPSE represents a promising target to protect the endothelial glycocalyx. Full Article
through {alpha}2-Macroglobulin-like protein 1 can conȷugate and inhibit proteases through their hydroxyl groups, because of an enhanced reactivity of its thiol ester [Protein Structure and Folding] By www.jbc.org Published On :: 2020-12-04T00:06:05-08:00 Proteins in the α-macroglobulin (αM) superfamily use thiol esters to form covalent conjugation products upon their proteolytic activation. αM protease inhibitors use theirs to conjugate proteases and preferentially react with primary amines (e.g. on lysine side chains), whereas those of αM complement components C3 and C4B have an increased hydroxyl reactivity that is conveyed by a conserved histidine residue and allows conjugation to cell surface glycans. Human α2-macroglobulin–like protein 1 (A2ML1) is a monomeric protease inhibitor but has the hydroxyl reactivity–conveying histidine residue. Here, we have investigated the role of hydroxyl reactivity in a protease inhibitor by comparing recombinant WT A2ML1 and the A2ML1 H1084N mutant in which this histidine is removed. Both of A2ML1s' thiol esters were reactive toward the amine substrate glycine, but only WT A2ML1 reacted with the hydroxyl substrate glycerol, demonstrating that His-1084 increases the hydroxyl reactivity of A2ML1's thiol ester. Although both A2ML1s conjugated and inhibited thermolysin, His-1084 was required for the conjugation and inhibition of acetylated thermolysin, which lacks primary amines. Using MS, we identified an ester bond formed between a thermolysin serine residue and the A2ML1 thiol ester. These results demonstrate that a histidine-enhanced hydroxyl reactivity can contribute to protease inhibition by an αM protein. His-1084 did not improve A2ML1's protease inhibition at pH 5, indicating that A2ML1's hydroxyl reactivity is not an adaption to its acidic epidermal environment. Full Article
through A highly potent CD73 biparatopic antibody blocks organization of the enzyme active site through dual mechanisms [Methods and Resources] By www.jbc.org Published On :: 2020-12-25T00:06:31-08:00 The dimeric ectonucleotidase CD73 catalyzes the hydrolysis of AMP at the cell surface to form adenosine, a potent suppressor of the immune response. Blocking CD73 activity in the tumor microenvironment can have a beneficial effect on tumor eradication and is a promising approach for cancer therapy. Biparatopic antibodies binding different regions of CD73 may be a means to antagonize its enzymatic activity. A panel of biparatopic antibodies representing the pairwise combination of 11 parental monoclonal antibodies against CD73 was generated by Fab-arm exchange. Nine variants vastly exceeded the potency of their parental antibodies with ≥90% inhibition of activity and subnanomolar EC50 values. Pairing the Fabs of parents with nonoverlapping epitopes was both sufficient and necessary whereas monovalent antibodies were poor inhibitors. Some parental antibodies yielded potent biparatopics with multiple partners, one of which (TB19) producing the most potent. The structure of the TB19 Fab with CD73 reveals that it blocks alignment of the N- and C-terminal CD73 domains necessary for catalysis. A separate structure of CD73 with a Fab (TB38) which complements TB19 in a particularly potent biparatopic shows its binding to a nonoverlapping site on the CD73 N-terminal domain. Structural modeling demonstrates a TB19/TB38 biparatopic antibody would be unable to bind the CD73 dimer in a bivalent manner, implicating crosslinking of separate CD73 dimers in its mechanism of action. This ability of a biparatopic antibody to both crosslink CD73 dimers and fix them in an inactive conformation thus represents a highly effective mechanism for the inhibition of CD73 activity. Full Article