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On this special, year-end episode of Translating Proteomics, hosts Parag Mallick and Andreas Huhmer discuss three of their favorite proteomics publications from 2024. They'll cover one paper in each of the following topic areas:Proteomics in pre-clinical researchProteomics in basic researchTechnology development in proteomicsSynopses of each of the papers can be found below and you can find many more insights in the podcast.Decrypting the molecular basis of cellular drug phenotypes by dose-resolved expression proteomicsIn this work from Professor Bernhard Kuster's Lab at the Technical University of Munich, researchers assess protein abundance changes that result from treating Jurkat acute T cell leukemia cells with 144 drugs over five drug doses. The researchers use their proteomic data to generate millions of dose response curves for the thousands of proteins measured and discover that the drugs impact many more proteins and pathways than those identified as drug targets. In addition, they checked how 7 of the drug treatments impacted the transcriptome and found there was often discordance between impacts at the mRNA level and the protein level. This works highlights the many ways drugs can impact biological systems and suggests that similar studies will help researchers understand the effects of drug treatments and may even aid in the development of more effective or more specific therapies.Find the publication here.Natural proteome diversity links aneuploidy tolerance to protein turnoverAs we discussed on a previous episode of Translating Proteomics, genome alterations often fail to faithfully propagate to the proteome. In this work, researchers from the labs of Professor Judith Berman at Tel Aviv University and Professor Markus Ralser at the Charité - Universitätsmedizin Berlin, investigate the means through which yeast strains adapt chromosome gains or losses (aneuploidy). They assess the concordance between changes in mRNA and protein expression in aneuploid yeast that were either found in nature or generated in the lab. The researchers observed dosage compensation, a tendency to return to expression levels associated with normal chromosome numbers, for both mRNAs and proteins expressed on aneuploid chromosomes. However, dosage compensation was much stronger at the protein level than the mRNA level and even stronger at the protein level in naturally aneuploid strains compared to lab-generated strains. This work suggests that multiomics efforts are necessary to determine the effects of genomic alterations. In addition, the authors find that protein degradation, as observed through increased ubiquitination, increased turnover of proteins encoded in aneuploid chromosomes, and the up regulation of the proteasome complex, is a key means of dosage compensation. Finally, because the naturally aneuploid strains achieved a higher a level of dosage compensation than the lab-generated strains, the authors suggest there has been selection for natural aneuploid strains that down-regulate proteins causing detrimental effects.
While some of us knew a good bit about mRNA prior to 2020, we all got a crash course on mRNA technology and its prophylactic and therapeutic potential as a result of the COVID pandemic and subsequent SARS CoV-2 vaccine development. In fact, most of us have now received at least one mRNA vaccine at this point. Our guest for this episode, Dr. Christian Cobaugh, Co-founder and CEO of Vernal Biosciences, was a passionate believer in mRNA medicines well before the pandemic. Join us to hear his story and his passion for this technology. He walks us through the molecular methods by which high-purity mRNAs are now made and purified, as well as going into the lipid nanoparticle technology by which they're commonly delivered. As a contract development and manufacturing provider, we get to learn about the state of the market and what clients of their care about today. As a seasoned expert in this space, Christian talks about the future potential of mRNA technology for applications such as personalized cancer vaccines. If you enjoy hearing smart people talk about interesting topics with a passion, you won't want to miss this episode! Subscribe to get future episodes as they drop and if you like what you're hearing we hope you'll share a review or recommend the series to a colleague. Download Transcripts: Speaking of Mol Bio Podcast | Thermo Fisher Scientific - US Visit the Invitrogen School of Molecular Biology to access helpful molecular biology resources and educational content, and please share this resource with anyone you know working in molecular biology.
BUFFALO, NY- May 14, 2024 – A new research paper was published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 16, Issue 8, entitled, “Characterization of age-associated gene expression changes in mouse sweat glands.” Evaporation of sweat on the skin surface is the major mechanism for dissipating heat in humans. The secretory capacity of sweat glands (SWGs) declines during aging, leading to heat intolerance in the elderly, but the mechanisms responsible for this decline are poorly understood. In this new study, researchers Alexandra G. Zonnefeld, Chang-Yi Cui, Dimitrios Tsitsipatis, Yulan Piao, Jinshui Fan, Krystyna Mazan-Mamczarz, Yutong Xue, Fred E. Indig, Supriyo De, and Myriam Gorospe from the National Institutes of Health's National Institute on Aging investigated the molecular changes accompanying SWG aging in mice, where sweat tests confirmed a significant reduction of active SWGs in old mice relative to young mice. “We first identified SWG-enriched mRNAs by comparing the skin transcriptome of Eda mutant Tabby male mice, which lack SWGs, with that of wild-type control mice by RNA-sequencing analysis.” This comparison revealed 171 mRNAs enriched in SWGs, including 47 mRNAs encoding ‘core secretory' proteins such as transcription factors, ion channels, ion transporters, and trans-synaptic signaling proteins. Among these, 28 SWG-enriched mRNAs showed significantly altered abundance in the aged male footpad skin, and 11 of them, including Foxa1, Best2, Chrm3, and Foxc1 mRNAs, were found in the ‘core secretory' category. Consistent with the changes in mRNA expression levels, immunohistology revealed that higher numbers of secretory cells from old SWGs express the transcription factor FOXC1, the protein product of Foxc1 mRNA. “In sum, our study identified mRNAs enriched in SWGs, including those that encode core secretory proteins, and altered abundance of these mRNAs and proteins with aging in mouse SWGs.” DOI - https://doi.org/10.18632/aging.205776 Corresponding authors - Chang-Yi Cui - cuic@mail.nih.gov, and Myriam Gorospe - gorospem@grc.nia.nih.gov Author interview - https://www.youtube.com/watch?v=7A_TREuSv54 Video abstract - https://www.youtube.com/watch?v=yJEphCaMhK8 Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.205776 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, FOXA1, BEST2, FOXC1, ectodysplasin/Eda, Tabby About Aging-US Aging publishes research papers in all fields of aging research including but not limited, aging from yeast to mammals, cellular senescence, age-related diseases such as cancer and Alzheimer's diseases and their prevention and treatment, anti-aging strategies and drug development and especially the role of signal transduction pathways such as mTOR in aging and potential approaches to modulate these signaling pathways to extend lifespan. The journal aims to promote treatment of age-related diseases by slowing down aging, validation of anti-aging drugs by treating age-related diseases, prevention of cancer by inhibiting aging. Cancer and COVID-19 are age-related diseases. Please visit our website at https://www.Aging-US.com and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ X - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ MEDIA@IMPACTJOURNALS.COM
Dr. Chang-Yi Cui and Alexandra G. Zonnefeld from the Laboratory of Genetics and Genomics, National Institute on Aging in Baltimore, MD, discuss a research paper they co-authored that was published by Aging (Aging-US) in Volume 16, Issue 8, entitled, “Characterization of age-associated gene expression changes in mouse sweat glands.” DOI - https://doi.org/10.18632/aging.205776 Corresponding authors - Chang-Yi Cui - cuic@mail.nih.gov, and Myriam Gorospe - gorospem@grc.nia.nih.gov Video interview - https://www.youtube.com/watch?v=7A_TREuSv54 Abstract Evaporation of sweat on the skin surface is the major mechanism for dissipating heat in humans. The secretory capacity of sweat glands (SWGs) declines during aging, leading to heat intolerance in the elderly, but the mechanisms responsible for this decline are poorly understood. We investigated the molecular changes accompanying SWG aging in mice, where sweat tests confirmed a significant reduction of active SWGs in old mice relative to young mice. We first identified SWG-enriched mRNAs by comparing the skin transcriptome of Eda mutant Tabby male mice, which lack SWGs, with that of wild-type control mice by RNA-sequencing analysis. This comparison revealed 171 mRNAs enriched in SWGs, including 47 mRNAs encoding ‘core secretory' proteins such as transcription factors, ion channels, ion transporters, and trans-synaptic signaling proteins. Among these, 28 SWG-enriched mRNAs showed significantly altered abundance in the aged male footpad skin, and 11 of them, including Foxa1, Best2, Chrm3, and Foxc1 mRNAs, were found in the ‘core secretory' category. Consistent with the changes in mRNA expression levels, immunohistology revealed that higher numbers of secretory cells from old SWGs express the transcription factor FOXC1, the protein product of Foxc1 mRNA. In sum, our study identified mRNAs enriched in SWGs, including those that encode core secretory proteins, and altered abundance of these mRNAs and proteins with aging in mouse SWGs. Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.205776 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, FOXA1, BEST2, FOXC1, ectodysplasin/Eda, Tabby About Aging-US Aging publishes research papers in all fields of aging research including but not limited, aging from yeast to mammals, cellular senescence, age-related diseases such as cancer and Alzheimer's diseases and their prevention and treatment, anti-aging strategies and drug development and especially the role of signal transduction pathways such as mTOR in aging and potential approaches to modulate these signaling pathways to extend lifespan. The journal aims to promote treatment of age-related diseases by slowing down aging, validation of anti-aging drugs by treating age-related diseases, prevention of cancer by inhibiting aging. Cancer and COVID-19 are age-related diseases. Aging is indexed by PubMed/Medline (abbreviated as “Aging (Albany NY)”), PubMed Central, Web of Science: Science Citation Index Expanded (abbreviated as “Aging‐US” and listed in the Cell Biology and Geriatrics & Gerontology categories), Scopus (abbreviated as “Aging” and listed in the Cell Biology and Aging categories), Biological Abstracts, BIOSIS Previews, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science). Please visit our website at https://www.Aging-US.com and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ X - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ MEDIA@IMPACTJOURNALS.COM
TWiM discusses the identification of natural products from reconstructed ancient bacterial genomes, and how plant mRNAs move into a fungal pathogen via extracellular vesicles to reduce infection. Hosts: Vincent Racaniello, Michael Schmidt, and Petra Levin. Become a patron of TWiM. Links for this episode Natural products from ancient bacterial genomes (Science) Plant mRNAs move into fungal pathogens (Cell Host Microb) Take the TWiM Listener survey! Send your microbiology questions and comments (email or recorded audio) to twim@microbe.tv
RNA, one of the oldest and most versatile biomolecules, has recently entered the therapeutic arena. While for many observers the success of mRNA vaccines seemed to come out of the blue, its build on the fundament of research that has large gone ignored. Now mRNA therapeutics are enjoying the limelight of great economic success for companies like BioNTech / Pfizer and Moderna, and the awarding of the 2023 Nobel Prize to two mRNA researchers. But with the fame also comes a huge public backlash of anti-vaxxers who fear the perceived novelty of mRNAs. In the 19th episode of We're doomed, we're saved Louise von Stechow and Andreas Horchler talk with their guest, mRNA researcher Lucia Lapazio who has known the field before and after the hype.
What are the off-target proteins produced by mRNA vaccines? Can these proteins cause harm? What is the mechanism of their production? Let's review. An article on University of Cambridge contains this statement, "Researchers have discovered that misreading of therapeutic mRNAs by the cell's decoding machinery can cause an unintended immune response in the body. They have identified the sequence within the mRNA that causes this to occur and found a way to prevent ‘off-target' immune responses to enable the safer design of future mRNA therapeutics." DrBeen: Medical Education Online https://www.drbeen.com/ FLCCC | Front Line COVID-19 Critical Care Alliance https://covid19criticalcare.com/ URL list from Friday, Dec. 15, 2023 Long Story Short With Dr. Been - FLCCC | Front Line COVID-19 Critical Care Alliance https://covid19criticalcare.com/courses/long-story-short-with-dr-been/ Researchers redesign future mRNA therapeutics to prevent potentially harmful immune responses | University of Cambridge https://www.cam.ac.uk/research/news/researchers-redesign-future-mrna-therapeutics-to-prevent-potentially-harmful-immune-responses N1-methylpseudouridylation of mRNA causes +1 ribosomal frameshifting | Nature https://www.nature.com/articles/s41586-023-06800-3 Interferon gamma - Wikipedia https://en.wikipedia.org/wiki/Interferon_gamma The Shape and Structure of Proteins - Molecular Biology of the Cell - NCBI Bookshelf https://www.ncbi.nlm.nih.gov/books/NBK26830/#:~:text=A%20protein%20molecule%20is%20made,one%20molecule%20to%20the%20next . Ribosomes, Transcription, Translation | Learn Science at Scitable https://www.nature.com/scitable/topicpage/ribosomes-transcription-and-translation-14120660/#:~:text=Recall%20that%20mRNA%20molecules%20are,protein%20as%20it%20is%20synthesized . Genetic code - Wikipedia https://en.wikipedia.org/wiki/Genetic_code DNA and RNA codon tables - Wikipedia https://en.wikipedia.org/wiki/DNA_and_RNA_codon_tables Pseudouridine - Wikipedia https://en.wikipedia.org/wiki/Pseudouridine Modifications in an Emergency: The Role of N1-Methylpseudouridine in COVID-19 Vaccines | ACS Central Science https://pubs.acs.org/doi/10.1021/acscentsci.1c00197 Ribonucleotide - Wikipedia https://en.wikipedia.org/wiki/Ribonucleotide#:~:text=In%20biochemistry%2C%20a%20ribonucleotide%20is,monomeric%20building%20blocks%20for%20RNA . Translation: DNA to mRNA to Protein | Learn Science at Scitable https://www.nature.com/scitable/topicpage/translation-dna-to-mrna-to-protein-393/#:~:text=The%20process%20of%20translation%20can,transcription%20as%20well%20as%20tRNA.&text=The%20genes%20in%20DNA%20encode,the%20functions%20necessary%20for%20life . Frontiers | On programmed ribosomal frameshifting: the alternative proteomes https://www.frontiersin.org/articles/10.3389/fgene.2012.00242/full#:~:text=Frameshifting%20is%20a%20process%20whereby,downstream%20(%E2%88%921%20frameshift) . Disclaimer: This video is not intended to provide assessment, diagnosis, treatment, or medical advice; it also does not constitute provision of healthcare services. The content provided in this video is for informational and educational purposes only. Please consult with a physician or healthcare professional regarding any medical or mental health related diagnosis or treatment. No information in this video should ever be considered as a substitute for advice from a healthcare professional.
An article from the University of Cambridge contains this statement, "Researchers have discovered that misreading of therapeutic mRNAs by the cell's decoding machinery can cause an unintended immune response in the body. They have identified the sequence within the mRNA that causes this to occur and found a way to prevent ‘off-target' immune responses to enable the safer design of future mRNA therapeutics." Let's review. DrBeen: Medical Education Onlinehttps://www.drbeen.com/ FLCCC | Front Line COVID-19 Critical Care Alliancehttps://covid19criticalcare.com/ Reference list from Dec. 8, 2023Researchers redesign future mRNA therapeutics to prevent potentially harmful immune responses | University of Cambridgehttps://www.cam.ac.uk/research/news/researchers-redesign-future-mrna-therapeutics-to-prevent-potentially-harmful-immune-responses N1-methylpseudouridylation of mRNA causes +1 ribosomal frameshifting | Naturehttps://www.nature.com/articles/s41586-023-06800-3 The Shape and Structure of Proteins - Molecular Biology of the Cell - NCBI Bookshelfhttps://www.ncbi.nlm.nih.gov/books/NBK26830/#:~:text=A%20protein%20molecule%20is%20made,one%20molecule%20to%20the%20next Ribosomes, Transcription, Translation | Learn Science at Scitablehttps://www.nature.com/scitable/topicpage/ribosomes-transcription-and-translation-14120660/#:~:text=Recall%20that%20mRNA%20molecules%20are,protein%20as%20it%20is%20synthesized Genetic code - Wikipediahttps://en.wikipedia.org/wiki/Genetic_code DNA and RNA codon tables - Wikipediahttps://en.wikipedia.org/wiki/DNA_and_RNA_codon_tables Pseudouridine - Wikipediahttps://en.wikipedia.org/wiki/Pseudouridine Modifications in an Emergency: The Role of N1-Methylpseudouridine in COVID-19 Vaccines | ACS Central Sciencehttps://pubs.acs.org/doi/10.1021/acscentsci.1c00197 Ribonucleotide - Wikipediahttps://en.wikipedia.org/wiki/Ribonucleotide#:~:text=In%20biochemistry%2C%20a%20ribonucleotide%20is,monomeric%20building%20blocks%20for%20RNA Translation: DNA to mRNA to Protein | Learn Science at Scitablehttps://www.nature.com/scitable/topicpage/translation-dna-to-mrna-to-protein-393/#:~:text=The%20process%20of%20translation%20can,transcription%20as%20well%20as%20tRNA.&text=The%20genes%20in%20DNA%20encode,the%20functions%20necessary%20for%20life Frontiers | On programmed ribosomal frameshifting: the alternative proteomeshttps://www.frontiersin.org/articles/10.3389/fgene.2012.00242/full#:~:text=Frameshifting%20is%20a%20process%20whereby,downstream%20(%E2%88%921%20frameshift) Disclaimer: This video is not intended to provide assessment, diagnosis, treatment, or medical advice; it also does not constitute provision of healthcare services. The content provided in this video is for informational and educational purposes only. Please consult with a physician or healthcare professional regarding any medical or mental health related diagnosis or treatment. No information in this video should ever be considered as a substitute for advice from a healthcare professional.
God knows everything whispered in secret, and one day those things will be shouted from the rooftops. The people who run Biden, Tony Fauci being one of them, were whispering in the dark about the deaths and injuries from the mRNA injections. They knew. It's obvious how these injections were designed, that they would kill people. God knows their motives and 17 million people are most likely dead and will keep dying from these injections. We examine the state of things as we look at Britain, where a politician presents his concerns on the increased deaths following the pandemic to a 98% empty House of Commons. And in New Zealand, Liz Gunn spoke with a whistleblower about the deaths they are seeing as a consequence of the injections and how those in charge also knew about the adverse effects. What does God's Word say? Exodus 20:13“You shall not murder.”Galatians 6:7 Do not be deceived: God is not mocked, for whatever one sows, that will he also reap.Luke 12:3 3 What you have said in the dark will be heard in the daylight, and what you have whispered in the ear in the inner rooms will be proclaimed from the roofs.Which ones describes Fauci? The War Within; Flesh Versus SpiritEpisode 1,179 Links:Step Right Up And Spend $10,000 To Get Your Picture Taken With Prolific Liar Anthony FauciMichigan judge denies drug manufacturer's immunity in case of contaminated COVID-19 medicationA mass iatrogenic event that killed 17 million (0.213%) of world population so far. That's the conclusion of a September 2023 study of 17 countries that covered 10% of world population. The average global death rate is about 0.8% per annum (about 67 million), so the iatrogenic event corresponds to about 25% of of the annual global death rate. Andrew Bridgen, @ABridgen MP of North West Leicestershire, is so far the only western hemisphere politician to debate this topic in a public setting, today (!) in the UK House of Commons, with an empty row of seats. The good news: global birth rate still hovers around 1.2% per annum, so we're still producing about 30 million net lives per year. Not so good news: the fertility rate is dropping perpendicularly, due to the same iatrogenic factor.Andrew Bridgen's opening statement to an empty House of CommonsNew @FDA pre-print study: Active surveillance system finds elevated risk of seizures in toddlers and myocarditis in teenagers associated with covid mRNA vaccination.More proof the mRNAs rewire the immune system with unknown long-term effects; The biggest study yet on post-jab IgG4 "class switching" just came out. You will be shocked - SHOCKED - to hear American researchers had nothing to do with it.EXCLUSIVE: American Academy of Pediatrics Named In Bombshell Detransitioner LawsuitYoung girl was "unfortunate victim of a collection of actors who prioritized politics and ideology over children's safety," lawsuit states45 Predators caught in sting operation targeting children including one who was a cannibal. These Predators knowingly have Sexually Transmitted Disease. Parents please keep a close eye on your children4Patriots https://4patriots.com Protect your family with Food kits, solar generators and more at 4Patriots. Use code TODD for 10% off your first purchase. Alan's Soaps https://alanssoaps.com/TODD Use coupon code ‘TODD' to save an additional 10% off the bundle price. American Financing https://americanfinancing.net Visit to see what American Financing can do for you or call 866-887-2275 BiOptimizers https://bioptimizers.com/todd Use promo code TODD for 10% off your order. Bonefrog https://bonefrog.us Enter promo code TODD at checkout to receive 10% off your subscription. Bulwark Capital http://KnowYourRiskRadio.com Find out how Bulwark Capital Actively Manages risk. Call 866-779-RISK or visit KnowYourRiskRadio.com Patriot Mobile https://patriotmobile.com/herman Get free activation today with offer code HERMAN. Visit or call 878-PATRIOT. SOTA Weight Loss https://sotaweightloss.com SOTA Weight Loss is, say it with me now, STATE OF THE ART! Sound of Freedom https://angel.com/freedom Join the two million and see Sound of Freedom in theaters July 4th. GreenHaven Interactive https://greenhaveninteractive.com Digital Marketing including search engine optimization and website design.
On today's show, Dr. Julie Sladden delves into the allegations surrounding the potential contamination of mRNAs with DNA and endotoxin. Following that, Simeon and Lembit will analyze the day's most significant stories in Australia. Additionally, Elliot will provide an in-depth examination of the Sexual Harassment Act within the British Parliament. GUEST 1 OVERVIEW: Dr Julie Sladden is a medical doctor and freelance writer with a passion for transparency in healthcare. Her op-eds have been published in both The Spectator Australia and The Daily Declaration. In 2022, she was elected as a Local Government Councillor for West Tamar in Tasmania. GUEST 2 OVERVIEW: Australian-born Aussie Cossack rose to prominence during the NSW lockdowns as an outspoken media personality notorious for his hilarious interactions with the NSW police and numerous large-scale campaigns against corrupt politicians. Boikov left Australia at the age of 18 to study at the Moscow Sretensky Seminary. It was here that he had his first posting as a journalist Whilst in Russia Boikov became heavily involved in the Russian Cossack movement. Upon returning to Australia Boikov was elected the Ataman of the Australian Cossack chapter and founded a pro-Russian political newspaper called Russian Frontier. In May of 2022 the Aussie Cossack was jailed for 10 months for breaching a suppression and non-publication order for content posted to his YouTube channel. After successfully winning an appeal against the severity of the sentence Aussie Cossack left prison. In December 2022 the Aussie Cossack defected to the Russian Consulate in Sydney where he was granted diplomatic asylum. From his studio within the Consulate building, he now broadcasts daily on TNT Radio. GUEST 3 OVERVIEW: Elliot is a Partner of the firms and leads the Employment Department at Branch Austin. Elliot is a seasoned litigator in the employment field, able to represent high-profile clients in the Employment Tribunal, the Employment Appeal Tribunal, the High Court and the Court of Appeal.
By Allison Krug, Dr. Ram Duriseti, Xiaoxu Sean Lin and Yuhong Dong
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.08.01.551382v1?rss=1 Authors: Choi, H., Liao, Y.-C., Yoon, Y. J., Grimm, J. B., Lavis, L., Singer, R. H., Lippincott-Schwartz, J. Abstract: One-third of the mammalian proteome is comprised of transmembrane and secretory proteins that are synthesized on endoplasmic reticulum (ER). Here, we investigate the spatial distribution and regulation of mRNAs encoding these membrane and secretory proteins (termed 'secretome' mRNAs) through live cell, single molecule tracking to directly monitor the position and translation states of secretome mRNAs on ER and their relationship to other organelles. Notably, translation of secretome mRNAs occurred preferentially near lysosomes on ER marked by the ER junction-associated protein, Lunapark. Knockdown of Lunapark reduced the extent of secretome mRNA translation without affecting translation of other mRNAs. Less secretome mRNA translation also occurred when lysosome function was perturbed by raising lysosomal pH or inhibiting lysosomal proteases. Secretome mRNA translation near lysosomes was enhanced during amino acid deprivation. Addition of the integrated stress response inhibitor, ISRIB, reversed the translation inhibition seen in Lunapark knockdown cells, implying an eIF2 dependency. Altogether, these findings uncover a novel coordination between ER and lysosomes, in which local release of amino acids and other factors from ER-associated lysosomes patterns and regulates translation of mRNAs encoding secretory and membrane proteins. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.31.551329v1?rss=1 Authors: Imaz-Iruretagoyena, J., Blanco-Urrejola, M., de la Cruz-Gambra, A., Marquez, M., Sierra, A., Baleriola, J. Abstract: Polarized cells in the brain, such as neurons and glia, rely on the asymmetric distribution of their proteins compartmentalizing the function of dendrites, axons, glial projections and endfeet. Subcellular proteomes can be assembled either by the transport of proteins synthesized in the cell soma or by the delivery of mRNAs to target compartments where they are locally translated into protein. This latter mechanism is known as local protein synthesis or local translation, and it has been best studied in neurons. Increasing evidence suggest it is also required to maintain local protein homeostasis in glial cells, however, in microglia, local translation remains largely unexplored. Given the scant evidence, we aimed at exploring the existence of local translation in microglial peripheral processes (MPPs) and unravel its functional significance. We report that local translation indeed happens in MPPs and it is enhanced by triggering a microglial inflammatory response with bacterial lipopolysaccharides (LPS) suggesting a functional relevance of this molecular mechanism in response to inflammation. We found that Actb and Par3 mRNAs polarize to MMPs and are locally translated upon LPS exposure. Interestingly, downregulation of the Actb binding protein IMP1/ZBP1 impaired Actb mRNA polarization and its localized translation, leading to defects in filopodia distribution, lamellar directed migration and phagocytosis in microglia. Thus, our work contributes to recent findings that localized translation occurs in microglia and gives a mechanistic insight into the relevance of this molecular mechanism in fundamental microglial functions in response to LPS-induced inflammation. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.25.550497v1?rss=1 Authors: Avila-Gutierrez, K., Slaoui, L., Alvear, R., Kozlowski, E., Oudart, M. F., Augustin, E., Mailly, P., Monnet, H., Mignon, V., Saubamea, B., Boulay, A.-C., Cohen-Salmon, M. Abstract: Astrocytes (the main glial cells in the brain) are highly ramified and send out perivascular processes (PvAPs) that entirely sheathe the brain s blood vessels. PvAPs are equipped with an enriched molecular repertoire that sustains astrocytic regulatory functions at the vascular interface. In the mouse, PvAP development starts after birth and is essentially complete by postnatal day (P) 15. Progressive molecular maturation also occurs over this period, with the acquisition of proteins enriched in PvAPs. The mechanisms controlling the development and molecular maturation of PvAPs have not been extensively characterized. We reported previously that mRNAs are distributed unequally in mature PvAPs and are locally translated. Since dynamic mRNA distribution and local translation influence the cell s polarity, we hypothesized that they might sustain the postnatal maturation of PvAPs. Here, we used a combination of molecular biology and imaging approaches to demonstrate that the development of PvAPs is accompanied by the transport of mRNA and polysomal mRNA into PvAPs, the development of a rough endoplasmic reticulum (RER) network and Golgi cisternae, and local translation. By focusing on genes and proteins that are selectively or specifically expressed in astrocytes, we characterized the developmental profile of mRNAs, polysomal mRNAs and proteins in PvAPs from P5 to P60. Furthermore, we found that distribution of mRNAs in PvAPs is perturbed in a mouse model of megalencephalic leukoencephalopathy with subcortical cysts. Lastly, we found that some polysomal mRNAs polarized progressively towards the PvAPs. Our results indicate that dynamic mRNA distribution and local translation influence the postnatal maturation of PvAPs. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.10.548401v1?rss=1 Authors: Chen, X., Sokirniy, I., Wang, X., Jiang, M., Mseis-Jackson, N., Williams, C., Mayes, K., Jiang, N., Puls, B., Du, Q., Shi, Y., Li, H. Abstract: While astrocyte-to-neuron (AtN) reprogramming holds great promise in regenerative medicine, the molecular mechanisms that govern this unique biological process remain elusive. MicroRNAs (miRNAs), as post-transcriptional regulators of gene expression, play crucial roles during development and under various pathological conditions. To understand the function of miRNAs during AtN reprogramming process, we performed RNA-seq of both mRNAs and miRNAs on human astrocyte (HA) cultures upon NeuroD1 overexpression. Bioinformatics analyses showed that NeuroD1 not only activates essential neuronal genes to initiate reprogramming process but also induces miRNA changes in HA. Among the upregulated miRNAs, we identified miR-375 and its targets, neuronal ELAVL genes (nELAVLs), which encode a family of RNA-binding proteins and are also upregulated by NeuroD1. We further showed that manipulating miR-375 level regulates nELAVLs expression during NeuroD1-mediated reprogramming. Interestingly, miR-375/nELAVLs are also induced by reprogramming factors Neurog2 and ASCL1 in HA suggesting a conserved function to neuronal reprogramming, and by NeuroD1 in the mouse astrocyte culture and spinal cord. Functionally, we showed that miR-375 overexpression improves NeuroD1-mediated reprogramming efficiency by promoting cell survival at early stages in HA even in cultures treated with the chemotherapy drug Cisplatin. Moreover, miR-375 overexpression does not appear to compromise maturation of the reprogrammed neurons in long term HA cultures. Lastly, overexpression of miR-375-refractory ELAVL4 induces apoptosis and reverses the cell survival-promoting effect of miR-375 during AtN reprogramming. Together, we demonstrate a neuro-protective role of miR-375 during NeuroD1-mediated AtN reprogramming and suggest a strategy of combinatory overexpression of NeuroD1 and miR-375 for improving neuronal reprogramming efficiency. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.06.27.546770v1?rss=1 Authors: Freibaum, B. D., Messing, J., Nakamura, H., Yurtsever, U., Wu, J., Kim, H. J., Hixon, J., Lemieux, R., Duffner, J., Huynh, W., Wong, K., White, M., Lee, C., Meyers, R., Parker, R. D., Taylor, J. P. Abstract: Stress granule formation is triggered by the release of mRNAs from polysomes and is promoted by the action of the paralogs G3BP1 and G3BP2. G3BP1/2 proteins bind mRNAs and thereby promote the condensation of mRNPs into stress granules. Stress granules have been implicated in several disease states, including cancer and neurodegeneration. Consequently, compounds that limit stress granule formation or promote their dissolution have potential as both experimental tools and novel therapeutics. Herein, we describe two small molecules, referred to as G3BP inhibitor a and b (G3Ia and G3Ib), designed to bind to a specific pocket in G3BP1/2 that is known to be targeted by viral inhibitors of G3BP1/2 function. In addition to disrupting co-condensation of RNA, G3BP1, and caprin 1 in vitro, these compounds inhibit stress granule formation in cells treated prior to or concurrent with stress, and dissolve pre-existing stress granules when added to cells after stress granule formation. These effects are consistent across multiple cell types and a variety of initiating stressors. Thus, these compounds represent ideal tools to probe the biology of stress granules and hold promise for therapeutic interventions designed to modulate stress granule formation. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.06.23.546336v1?rss=1 Authors: Badal, K. K., Sadhu, A., McCracken, C., Raveendra, B. L., Lozano-Villada, S., Shetty, A. C., Gillette, P., Zhao, Y., Stommes, D., Fieber, L. A., Schmale, M. C., Mahurkar, A., Hawkins, R. D., Puthanveettil, S. V. Abstract: Molecular mechanisms underlying aging associated impairments in learning and long-term memory storage are poorly understood. Here we leveraged the single identified motor neuron L7 in Aplysia, which mediates a form of non-associative learning, sensitization of the siphon-withdraw reflex, to assess the transcriptomic correlates of aging associated changes in learning. RNAseq analysis of the single L7 motor neuron isolated following short-term or long-term sensitization training of 8,10 and 12 months old Aplysia, corresponding to mature, late mature and senescent stages, has revealed progressive impairments in transcriptional plasticity during aging. Specifically, we observed modulation of the expression of multiple lncRNAs and mRNAs encoding transcription factors, regulators of translation, RNA methylation, and cytoskeletal rearrangements during learning and their deficits during aging. Our comparative gene expression analysis also revealed the recruitment of specific transcriptional changes in two other neurons, the motor neuron L11 and the giant cholinergic neuron R2 whose roles in long-term sensitization were previously not known. Taken together, our analyses establish cell type specific progressive impairments in the expression of learning- and memory-related components of the transcriptome during aging. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
A new research paper was published in Aging (Aging-US) Volume 15, Issue 8, entitled, “Single-cell transcriptomic analysis uncovers diverse and dynamic senescent cell populations.” Senescence is a state of enduring growth arrest triggered by sublethal cell damage. Given that senescent cells actively secrete proinflammatory and matrix-remodeling proteins, their accumulation in tissues of older persons has been linked to many diseases of aging. Despite intense interest in identifying robust markers of senescence, the highly heterogeneous and dynamic nature of the senescent phenotype has made this task difficult. In this new study, researchers Noah Wechter, Martina Rossi, Carlos Anerillas, Dimitrios Tsitsipatis, Yulan Piao, Jinshui Fan, Jennifer L. Martindale, Supriyo De, Krystyna Mazan-Mamczarz, and Myriam Gorospe from the National Institute on Aging set out to comprehensively analyze the senescent transcriptome of human diploid fibroblasts at the individual-cell scale by performing single-cell RNA-sequencing analysis through two approaches. “Here, we used single-cell RNA sequencing (scRNA-seq) analysis to document both the diverse transcriptomes of human senescent fibroblasts at an individual-cell scale, and the changes in the transcriptome over time during etoposide-triggered senescence.” First, the researchers characterized the different cell states in cultures undergoing senescence triggered by different stresses, and found distinct cell subpopulations that expressed mRNAs encoding proteins with roles in growth arrest, survival and the secretory phenotype. Second, they characterized the dynamic changes in the transcriptomes of cells as they developed etoposide-induced senescence; by tracking cell transitions across this process, the researchers found two different senescence programs that developed divergently, one in which cells expressed traditional senescence markers such as p16 (CDKN2A) mRNA, and another in which cells expressed long noncoding RNAs and splicing was dysregulated. Finally, they obtained evidence that the proliferation status at the time of senescence initiation affected the path of senescence, as determined based on the expressed RNAs. “We propose that a deeper understanding of the transcriptomes during the progression of different senescent cell phenotypes will help develop more effective interventions directed at this detrimental cell population.” DOI - https://doi.org/10.18632/aging.204666 Corresponding authors - Krystyna Mazan-Mamczarz - krystyna.mazan-mamczarz@nih.gov, and Myriam Gorospe - myriam-gorospe@nih.gov Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204666 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, senescence, single-cell analysis, transcriptome About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at https://www.Aging-US.com and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM
Welcome to The Nonlinear Library, where we use Text-to-Speech software to convert the best writing from the Rationalist and EA communities into audio. This is: Biological DOOM: a brief overview of biological computation, published by Metacelsus on April 29, 2023 on LessWrong. (no, not that kind of biological doom) DOOM is a classic first-person shooter game released in 1993 by id Software. Because it's from 1993, it doesn't require much computing power compared to modern games. Additionally, the code (written in C) is easy to compile to run on a variety of processors. Over the years, hackers have made DOOM run on things such as an ATM, a touchbar of a MacBook, a Porsche 911, and even a TI-84 calculator powered by potato batteries. But what about cells? Requirements for DOOM The inputs to DOOM are based on button presses, traditionally on a keyboard. 9 keys in total are required (assuming “switch weapon” is implemented as one key that cycles through weapons). For computation, the original 1993 release required: 4 MB of RAM and 12 MB of hard-drive storage Intel 386 (bare minimum) or 486 processor. There is some flexibility regarding the processor, but slower processors will have worse frame-rates. The Intel 386 had 275,000 transistors in its most basic configuration. DOOM also requires a graphical output. The smallest resolution I've seen is 128x32 pixels, and that was cutting it a bit close. We'll assume we need 4096 black-and-white pixels for the display. Finally, DOOM has audio. For the purposes of this thought experiment, we can ignore this output. Although the soundtrack is great, it's not strictly required to play the game. Approaches to biological computation So, how could we potentially run DOOM? Biological systems can perform computations in several ways: Nucleic acid hybridization These logic gates are based on strand displacement between complementary DNA sequences. A recent paper demonstrated a set of DNA-based logic gates that could add two 6-bit binary numbers. Pros and cons: Memory capacity is good (encoded in DNA or RNA) Switching speed is OK (rate constants vary by design but are typically around 106M−1s−1) Visual output could be provided by fluorophore/quencher conjugated oligonucleotides, but . . . Coupling to a macroscopic output display would be far too slow, because it would have to rely on diffusion (taking a few minutes to cover a millimeter-scale distance). So, the game would have to be played using a microscope. It's hard to “reset” gates after using them, this requires coupling to some energy source It's also hard to integrate DNA-based logic gates into other biological systems, since not many organisms use short pieces of ssDNA. RNA might be used instead. Transcription and translation These logic gates use the same tools that cells use to regulate gene expression. For example, the classic lac operon in bacteria implements: Biologists have exploited similar systems to build logic gates, as well as systems involving the regulation of translation (the production of proteins using mRNAs as templates). A recent paper used Cas9 binding to a sgRNA-like sequence inserted in an mRNA to control its translation. To form a NAND gate, they split Cas9 into two fragments; if both were present, the output protein was not produced. Pros and cons: Memory capacity is acceptable (encoded in DNA or RNA) There will be challenges with implementing the number of logic gates required while avoiding cross-talk The dealbreaker: far too slow to run DOOM. RNA and protein half-lives are on the order of minutes to hours. Protein phosphorylation (kinases/phosphatases) Many cell signaling pathways use protein phosphorylation as a signal. This is much faster than transcription and translation, since no new RNAs or proteins need to be produced. A paper in 2021 built a toggle switch in yeast out of several kinases and phosphatases. Pros and cons: Response speed is adequate, similar to nucleic acid hybridization gates (i.e., largely l...
Link to original articleWelcome to The Nonlinear Library, where we use Text-to-Speech software to convert the best writing from the Rationalist and EA communities into audio. This is: Biological DOOM: a brief overview of biological computation, published by Metacelsus on April 29, 2023 on LessWrong. (no, not that kind of biological doom) DOOM is a classic first-person shooter game released in 1993 by id Software. Because it's from 1993, it doesn't require much computing power compared to modern games. Additionally, the code (written in C) is easy to compile to run on a variety of processors. Over the years, hackers have made DOOM run on things such as an ATM, a touchbar of a MacBook, a Porsche 911, and even a TI-84 calculator powered by potato batteries. But what about cells? Requirements for DOOM The inputs to DOOM are based on button presses, traditionally on a keyboard. 9 keys in total are required (assuming “switch weapon” is implemented as one key that cycles through weapons). For computation, the original 1993 release required: 4 MB of RAM and 12 MB of hard-drive storage Intel 386 (bare minimum) or 486 processor. There is some flexibility regarding the processor, but slower processors will have worse frame-rates. The Intel 386 had 275,000 transistors in its most basic configuration. DOOM also requires a graphical output. The smallest resolution I've seen is 128x32 pixels, and that was cutting it a bit close. We'll assume we need 4096 black-and-white pixels for the display. Finally, DOOM has audio. For the purposes of this thought experiment, we can ignore this output. Although the soundtrack is great, it's not strictly required to play the game. Approaches to biological computation So, how could we potentially run DOOM? Biological systems can perform computations in several ways: Nucleic acid hybridization These logic gates are based on strand displacement between complementary DNA sequences. A recent paper demonstrated a set of DNA-based logic gates that could add two 6-bit binary numbers. Pros and cons: Memory capacity is good (encoded in DNA or RNA) Switching speed is OK (rate constants vary by design but are typically around 106M−1s−1) Visual output could be provided by fluorophore/quencher conjugated oligonucleotides, but . . . Coupling to a macroscopic output display would be far too slow, because it would have to rely on diffusion (taking a few minutes to cover a millimeter-scale distance). So, the game would have to be played using a microscope. It's hard to “reset” gates after using them, this requires coupling to some energy source It's also hard to integrate DNA-based logic gates into other biological systems, since not many organisms use short pieces of ssDNA. RNA might be used instead. Transcription and translation These logic gates use the same tools that cells use to regulate gene expression. For example, the classic lac operon in bacteria implements: Biologists have exploited similar systems to build logic gates, as well as systems involving the regulation of translation (the production of proteins using mRNAs as templates). A recent paper used Cas9 binding to a sgRNA-like sequence inserted in an mRNA to control its translation. To form a NAND gate, they split Cas9 into two fragments; if both were present, the output protein was not produced. Pros and cons: Memory capacity is acceptable (encoded in DNA or RNA) There will be challenges with implementing the number of logic gates required while avoiding cross-talk The dealbreaker: far too slow to run DOOM. RNA and protein half-lives are on the order of minutes to hours. Protein phosphorylation (kinases/phosphatases) Many cell signaling pathways use protein phosphorylation as a signal. This is much faster than transcription and translation, since no new RNAs or proteins need to be produced. A paper in 2021 built a toggle switch in yeast out of several kinases and phosphatases. Pros and cons: Response speed is adequate, similar to nucleic acid hybridization gates (i.e., largely l...
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.26.538466v1?rss=1 Authors: Siddiq, M. M., Toro, C. A., Johnson, N. P., Hansen, J., Xiong, Y., Mellado, W., Tolentino, R. E., Johnson, K., Jayaraman, G., Suhail, Z., Harlow, L., Beaumont, K. G., Sebra, R. G., Willis, D. E., Cardozo, C. P., Iyengar, R. Abstract: Introduction- Neurons transport mRNA and translational machinery to axons for local translation. After spinal cord injury (SCI), de novo translation is assumed to enable neurorepair. Knowledge of the identity of axonal mRNAs that participate in neurorepair after SCI is limited. We sought to identify and understand how axonal RNAs play a role in axonal regeneration. Methods- We obtained preparations enriched in axonal mRNAs from control and SCI rats by digesting spinal cord tissue with cold-active protease (CAP). The digested samples were then centrifuged to obtain a supernatant that were then sequenced. We used bioinformatics analyses to identify DEGS and map them to various biological processes. We validated the DEGs by RT-qPCR and RNA-scope. Results- The supernatant fraction was highly enriched for axonal mRNA. Using Gene Ontology, the second most significant pathway for all differentially expressed genes (DEGs) was axonogenesis. Among the DEGs was Rims2, which is predominately a circular RNA (circRNA) in the CNS. We show that Rims2 RNA within spinal cord axons is circular. We found an additional 200 putative circRNAs in the axonal-enriched fraction. Knockdown in primary rat cortical neurons of the RNA editing enzyme ADAR1, which inhibits formation of circRNAs, significantly increased axonal outgrowth. Focusing on Rims2 we used Circular RNA Interactome to predict that several of the miRNAs that bind to circRims2 also bind to the 3 prime UTR of GAP-43, PTEN or CREB1, all known regulators of axonal outgrowth. Axonally-translated GAP-43 supports axonal elongation and we detect GAP-43 mRNA in the rat axons by RNAscope. Discussion- By using our method for enrichment of axonal RNA, we detect SCI induced DEGs, including circRNA such as Rims2. Ablation of ADAR1, the enzyme that regulates circRNA formation, promotes axonal outgrowth of cortical neurons. We developed a pathway model using Circular RNA Interactome that indicates that Rims2 through miRNAs can regulate the axonal translation GAP-43 a known regulator of axonal regeneration indicating that axonal mRNA contribute to regeneration. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.06.535851v1?rss=1 Authors: Stankovic, D., Tain, L., Uhlirova, M. Abstract: Co-transcriptional processing of nascent pre-mRNAs by the spliceosome is vital to regulating gene expression and maintaining genome integrity. Here, we show that the deficiency of functional U5 snRNPs in Drosophila imaginal cells causes extensive transcriptome remodeling and accumulation of highly mutagenic R-loops, triggering a robust stress response and cell cycle arrest. Despite compromised proliferative capacity, the U5 snRNP deficient cells increased protein translation and cell size, causing intra-organ growth disbalance before being gradually eliminated via apoptosis. We identify the Xrp1-Irbp18 heterodimer as the primary driver of transcriptional and cellular stress program downstream of U5 snRNP malfunction. Knockdown of Xrp1 or Irbp18 in U5 snRNP deficient cells attenuated JNK and p53 activity, restored normal cell cycle progression and growth, and inhibited cell death. Reducing Xrp1-Irbp18, however, did not rescue the splicing defects and the organismal lethality, highlighting the requirement of accurate splicing for cellular and tissue homeostasis. Our work provides novel insights into the crosstalk between splicing and the DNA damage response and defines the Xrp1-Irbp18 heterodimer as a critical sensor of spliceosome malfunction. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.01.535193v1?rss=1 Authors: Huang, Y., Abdelgawad, A. G. A., Turchinovich, A., Queen, S., Abreu, C. M., Zhu, X., Batish, M., Zheng, L., Witwer, K. W. Abstract: Introduction: Antiretroviral treatment regimens can effectively control HIV replication and some aspects of disease progression. However, molecular events in end-organ diseases such as central nervous system (CNS) disease are not yet fully understood, and routine eradication of latent reservoirs is not yet in reach. Extracellular vesicle (EV) RNAs have emerged as important participants in HIV disease pathogenesis. Brain tissue-derived EVs (bdEVs) act locally in the source tissue and may indicate molecular mechanisms in HIV CNS pathology. Using brain tissue and bdEVs from the simian immunodeficiency virus (SIV) model of HIV disease, we profiled messenger RNAs (mRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), seeking to identify possible networks of RNA interaction in SIV infection and neuroinflammation. Methods: Postmortem occipital cortex tissues were obtained from pigtailed macaques either not infected or dual-inoculated with SIV swarm B670 and clone SIV/17E-Fr. SIV-inoculated groups included samples collected at different time points during acute infection or chronic infection without or with CNS pathology (CP- or CP+). bdEVs were separated and characterized in accordance with international consensus standards. RNAs from bdEVs and source tissue were used for sequencing and qPCR to detect mRNA, miRNA, and circRNA levels. Results: Multiple dysregulated bdEV RNAs, including mRNAs, miRNAs, and circRNAs, were identified in acute and CP+. Most dysregulated mRNAs in bdEVs reflected dysregulation in their source tissues. These mRNAs are disproportionately involved in inflammation and immune responses, especially interferon pathways. For miRNAs, qPCR assays confirmed the differential abundance of miR-19a-3p, let-7a-5p, and miR-29a-3p (acute phase), and miR-146a-5p and miR-449a-5p (CP+) in bdEVs. In addition, target prediction suggested that several circRNAs that were differentially abundant in source tissue might be responsible for specific differences in small RNA levels in bdEVs during SIV infection. Conclusions: RNA profiling of bdEVs and source tissues reveals potential regulatory networks in SIV infection and SIV-related CNS pathology. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
HR 1 Dr. Kelly Victory: mRNAs, Serious New Worldwide Health Problems, Rise in Stillbirths 3-2-23 by John Rush
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.31.526464v1?rss=1 Authors: Liu, J., Nagy, N., Aguilar-Alonso, F., Esteves, F., Ayala-Torres, C., Xu, S., Masucci, M. G. Abstract: The strategies adopted by viruses to reprogram the protein translation and quality control machineries to promote infection are poorly understood. Here, we discovered that the viral ubiquitin deconjugase (vDUB) encoded in the large tegument protein of Epstein-Barr virus (EBV) regulates ribosomal stress responses. The vDUB participates in protein complexes that include the ubiquitin ligases ZNF598 and LTN1 and the UFM1 ligase UFL1. Upon ribosomal stalling, the vDUB counteracts the ubiquitination of 40S ribosome subunits, inhibits the degradation of translation-stalled polypeptides by the proteasome, and prevents UFMylation of the 60S particle, which impairs the ER-phagy-dependent clearance of stalled products. Inhibition of the ribosome quality control activates a GCN2-dependent integrated stress response that decreases global protein translation while promoting the readthrough of stall-inducing mRNAs. The vDUB enhances viral mRNAs translation and virus release during productive infection, pointing to a pivotal role in cell reprogramming that enables virus production and underlies the pathogenesis of EBV-associated cancers and autoimmune diseases. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.25.525483v1?rss=1 Authors: Zhang, C., Yi, X., Hou, M., Li, Q., Li, X., Lu, L., Qi, E., Wu, M., Qi, L., Huan, J., Qi, Z., Lv, Y., Kong, X., Bi, M., Feng, S., Zhou, H. Abstract: Cerebral ischaemia-reperfusion injury, during which neurons undergo oxygen-glucose deprivation/reoxygenation (OGD/R), is a notable pathological process in many neurological diseases. N1-methyladenosine (m1A) is an RNA modification that can affect gene expression and RNA stability. The m1A landscape and potential functions of m1A modification in neurons remain poorly understood. We explored RNA (mRNA, lncRNA, and circRNA) m1A modification in normal and OGD/R-treated neurons and the effect of m1A on diverse RNAs. We investigated the m1A landscape in primary neurons, identified m1A-modified RNAs, and found that OGD/R increased the number of m1A RNAs. m1A modification might also affect the regulatory mechanisms of noncoding RNAs, e.g., lncRNA-RBP interactions and circRNA translation. We showed that m1A modification mediates the circRNA/lncRNA-miRNA-mRNA ceRNA mechanism and that 3'UTR methylation of mRNAs can hinder miRNA-mRNA binding. Three methylation patterns were identified, and genes with different patterns had intrinsic mechanisms with potential m1A-regulatory specificity. Systematic analysis of the m1A landscape in normal and OGD/R neurons lays a critical foundation for understanding RNA methylation and provides new perspectives and a theoretical basis for treating and developing drugs for OGD/R pathology related diseases. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.09.523364v1?rss=1 Authors: Albright, A. R., Angeles-Albores, D., Marshall, W. F. Abstract: Cells have complex and beautiful structures that are important for their function, but understanding the molecular mechanisms that produce these structures is a challenging problem due to the gap in size scales between molecular interactions and cellular structures. The giant ciliate Stentor coeruleus is a unicellular model organism whose large size, reproducible structure, and ability to heal wounds and regenerate has historically allowed the formation of structure in a single cell to be addressed using methods of experimental embryology. Such studies have shown that specific cellular structures, such as the oral apparatus, always form in specific regions of the cell, which raises the question of what is the source of positional information within this organism? By analogy with embryonic development, in which localized mRNA is often used to mark position, we asked whether position along the anterior-posterior axis of Stentor might be marked by specific regionalized mRNAs. By physically bisecting cells and using single-cell RNAseq analysis on each half, we were able to identify sets of messages enriched in either the anterior or posterior half. We repeated this analysis in cells in which a set of longitudinal microtubule bundles running down the whole length of the cell, known as KM-fibers, were disrupted by RNAi of beta tubulin. We found that many messages either lost their regionalized distribution , or else switched to an opposite distribution, such that anterior-enriched messages in control became posterior-enriched in the RNAi cells, or vice versa. This study indicates that mRNA can be regionalized within a single giant cell, and that microtubules may play a role, possibly by serving as tracks for movement of the messages. This study also illustrates a strategy for subcellular spatial genomics based on physical dissection, allowing the high throughput and sensitivity of sequencing technology to be brought to bear as a rapid, low cost alternative to current fluorescence imaging based methods. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.03.522592v1?rss=1 Authors: Singh, B. N., Tran, H., Kramer, J., Kirishenko, E., Changela, N., Wang, F., Feng, Y., Kumar, D., Tu, M., Liang, S., Lan, J., Bizet, M., Fuks, F., Steward, R. Abstract: Modifications of mRNA, especially methylation of adenosine, have recently drawn much attention. The much rarer modification, 5-hydroxymethylation of cytosine (5hmC), is not well understood and is the subject of this study. Vertebrate Tet proteins are 5-methylcytosine (5mC) hydroxylases enzymes catalyzing the transition of 5mC to 5hmC in DNA and have recently been shown to have the same function in messenger RNAs in both vertebrates and in Drosophila. The Tet gene is essential in Drosophila because Tet knock-out animals do not reach adulthood. We describe the identification of Tet-target genes in the embryo and larval brain by determining Tet DNA-binding sites throughout the genome and by mapping the Tet-dependent 5hmrC modifications transcriptome-wide. 5hmrC-modified sites can be found along the entire transcript and are preferentially located at the promoter where they overlap with histone H3K4me3 peaks. The identified mRNAs are frequently involved in neuron and axon development and Tet knock-out led to a reduction of 5hmrC marks on specific mRNAs. Among the Tet-target genes were the robo2 receptor and its slit ligand that function in axon guidance in Drosophila and in vertebrates. Tet knock-out embryos show overlapping phenotypes with robo2 and are sensitized to reduced levels of slit. Both Robo2 and Slit protein levels were markedly reduced in Tet KO larval brains. Our results establish a role for Tet-dependent 5hmrC in facilitating the translation of modified mRNAs, primarily in developing nerve cells. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.05.522855v1?rss=1 Authors: Niu, F., Long, G., Zhang, J., She, Y., Yu, J., Ji, S.-J. Abstract: Aging-related retinal degeneration and vision loss have been severely affecting the elder worldwide. Previously we showed that the m6A reader YTHDF2 is a negative regulator for dendrite development and maintenance of retinal ganglion cells (RGC) in mice (Niu et al. 2022). Here, we show that conditional ablation of Ythdf2 protects retina from RGC dendrite shrinking and vision loss in the aged mice. Further, we identify Hspa12a and Islr2 as the YTHDF2 target mRNAs mediating these effects. Together our results indicate that m6A modification regulates retinal degeneration caused by aging, which might provide therapeutical potentials for developing new treatment approaches against aging-related vision loss. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.04.522773v1?rss=1 Authors: Shiers, S., Sahn, J. J., Price, T. J. Abstract: Mitogen activated protein kinase interacting kinases (MNK) 1 and 2 are serine-threonine protein kinases that play an important role in translation of mRNAs through their phosphorylation of the RNA 5 prime-cap binding protein, eukaryotic translation initiation factor (eIF) 4E. These kinases are downstream targets for mitogen activated protein kinases (MAPKs), extracellular activity regulated protein kinase (ERK) and p38. MNKs have been implicated in the sensitization of peripheral nociceptors of the dorsal root and trigeminal ganglion (DRG and TG) using transgenic mouse lines and through the use of specific inhibitors of MNK1 and MNK2. While specific knockout of the Mknk1 gene suggests that it is the key isoform for regulation of nociceptor excitability and nociceptive behaviors in mice, both MKNK1 and MKNK2 genes are expressed in the DRG and TG of mice and humans based on RNA sequencing experiments. Single cell sequencing in mice suggests that Mknk1 and Mknk2 may be expressed in different populations of nociceptors. We sought to characterize mRNA expression in human DRG and TG for both MNK1 and MNK2. Our results show that both genes are expressed by nearly all neurons in both human ganglia with expression in other cell types as well. Our findings provide evidence that MNK1 and MNK2 are expressed by human nociceptors and suggest that efforts to pharmacologically target MNKs for pain would likely be translatable due its conserved expression in both species. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
I admit it, non-fungible Trump and the Premonitions Bureau + this day in history w/the Boston Tea Party and our song of the day by Perry Carditis and the mRNAs on your #MorningMonarchy for December 16, 2022.
This month on Episode 42 of Discover CircRes, host Cynthia St. Hilaire highlights four original research articles featured in the October 28 and November 11th issues of Circulation Research. This episode also features an interview with Dr Miguel Lopez-Ramirez and undergraduate student Bliss Nelson from University of California San Diego about their study, Neuroinflammation Plays a Critical Role in Cerebral Cavernous Malformations. Article highlights: Jia, et al. Prohibitin2 Maintains VSMC Contractile Phenotype Rammah, et al. PPARg and Non-Canonical NOTCH Signaling in the OFT Wang, et al. Histone Lactylation in Myocardial Infarction Katsuki, et al. PCSK9 Promotes Vein Graft Lesion Development Cindy St. Hilaire: Hi, and welcome to Discover CircRes, the podcast of the American Heart Association's Journal, Circulation Research. I'm your host, Dr Cindy St. Hilaire from the Vascular Medicine Institute at the University of Pittsburgh, and today, I'm going to be highlighting articles from our October 28th and our November 11th issues of Circ Res. I'm also going to have a chat with Dr Miguel Lopez-Ramirez and undergraduate student Bliss Nelson, about their study, Neuroinflammation Plays a Critical Role in Cerebral Cavernous Malformations. But, before I get into the interviews, here are a few article highlights. Cindy St. Hilaire: The first article is from our October 28th issue, and the title is, PHB2 Maintains the Contractile Phenotype of Smooth Muscle Cells by Counteracting PKM Splicing. The corresponding author is Wei Kong, and the first authors are Yiting Jia and Chengfeng Mao, and they are all from Peking University. Insults to blood vessels, whether in the form of atherosclerosis, physical injury, or inflammation, can trigger vascular smooth muscle cells to transition from a contractile state to a proliferative and migratory one. Accompanying this conversion is a switch in the cells' metabolism from the mitochondria to glycolysis. But what controls this switch? To investigate, this group compared the transcriptomes of contractile and proliferative smooth muscle cells. Among the differentially expressed genes, more than 1800 were reciprocally up and down regulated. Of those, six were associated with glucose metabolism, including one called Prohibitin-2, or PHB2, which the team showed localized to the artery wall. In cultured smooth muscle cells, suppression of PHB2 reduced expression of several contractile genes. While in rat arteries, injury caused a decrease in production of PHB2 itself, and of contractile markers. Furthermore, expression of PHB2 in proliferative smooth muscle cells could revert these cells to a contractile phenotype. Further experiments revealed PHB2 controlled the splicing of the metabolic enzyme to up-regulate the phenotypic switch. Regardless of mechanism, the results suggest that boosting PHB2 might be a way to reduce adverse smooth muscle cell overgrowth and conditions such as atherosclerosis and restenosis. Cindy St. Hilaire: The second article I'm going to highlight is also from our October 28th issue, and the first authors are Mayassa Rammah and Magali Theveniau-Ruissy. And the corresponding authors are Francesca Rochais and Robert Kelly. And they are all from Marseille University. Abnormal development of the heart's outflow track, which ultimately forms the bases of the aorta and the pulmonary artery, accounts for more than 30% of all human congenital heart defects. To gain a better understanding of outflow tract development, and thus the origins of such defects, this group investigated the role of transcription factors thought to be involved in specifying the superior outflow tract, or SOFT, which gives rise to the subaortic myocardium, and the inferior outflow tract, which gives rise to the subpulmonary myocardium. Transcription factor S1 is over-expressed in superior outflow tract cells and the transcription factors, TBX1 and PPAR gamma, are expressed in inferior outflow tract cells. And now this group has shown that TBX1 drives PPAR gamma expression in the inferior outflow tract, while Hess-1 surpasses PPAR gamma expression in the superior outflow tract. Indeed, in mouse embryos lacking TBX1, PPAR gamma expression was absent in the outflow tract. While in mouse embryos lacking Hess-1, PPAR gamma expression was increased and PPAR gamma positive cells were more widespread in the outflow tract. The team also identified that signaling kinase DLK is an upstream activator of Hess-1 and a suppressor of PPAR gamma. In further detailing the molecular interplay regulating outflow tract patterning, the work will shed light on congenital heart disease etiologies, and inform potential interventions for future therapies. Cindy St. Hilaire: The third article I want to highlight is from our November 11th issue of Circulation Research, and the title is Histone Lactylation Boosts Reparative Gene Activation Post Myocardial Infarction. The first author is Jinjin Wang and the corresponding author is Maomao Zhang, and they're from Harbin Medical University. Lactylation of histones is a recently discovered epigenetic modification that regulates gene expression in a variety of biological processes. In inflammation, for example, a significant increase in histone lactylation is responsible for switching on reparative genes and macrophages when pro-inflammatory processes give way to pro-resolvin ones. The role of histone lactylation in inflammation resolution has been shown in a variety of pathologies, but has not been examined in myocardial infarction. Wang and colleagues have now done just that. They isolated monocytes from the bone marrow and the circulation of mice at various time points after induced myocardial infarctions, and examined the cells' gene expression patterns. Within a day of myocardial infarction, monocytes from both bone marrow and the blood had begun upregulating genes involved in inflammation resolution. And, concordant with this, histone lactylation was dramatically increased in the cells, specifically at genes involved in repair processes. The team went on to show that injection of sodium lactate into mice boosted monocyte histone lactylation and improved heart function after myocardial infarction, findings that suggest further studies of lactylation's pro-resolving benefits are warranted. Cindy St. Hilaire: The last article I want to highlight is titled, PCSK9 Promotes Macrophage Activation via LDL Receptor Independent Mechanisms. The first authors are Shunsuke Katsuki and Prabhash Kumar Jha, and the corresponding author is Masanori Aikawa, and they are from Brigham and Women's Hospital in Harvard. Statins are the go-to drug for lowering cholesterol in atherosclerosis patients. But the more recently approved PCSK9 inhibitors also lower cholesterol and can be used to augment or replace statins in patients where these drugs are insufficient. PCSK9 is an enzyme that circulates in the blood and destroys the LDL receptor, thereby impeding the removal of bad cholesterol. The enzyme also appears to promote inflammation, thus potentially contributing to atherosclerosis in two ways. This group now confirms that PCSK9 does indeed promote pro-inflammatory macrophage activation and lesion development, and does so independent of its actions on the LDL receptor. The team assessed PCSK9-induced lesions in animals with saphenous vein grafts, which are commonly used in bypass surgery but are prone to lesion regrowth. They found that LDL receptor lacking graft containing mice had greater graft macrophage accumulation and lesion development when PCSK9 activity was boosted than when it was not. The animal's macrophages also had higher levels of the pro-inflammatory factor expression. Together, this work shows that PCSK9 inhibitors provide a double punch against atherosclerosis and might be effective drugs for preventing the all too common failure of saphenous vein grafts. Cindy St. Hilaire: So, today with me I have Dr Miguel Lopez-Ramirez and undergraduate student Bliss Nelson from the University of California in San Diego, and we're going to talk about their study, Neuroinflammation Plays a Critical Role in Cerebral Cavernous Malformation Disease, and this article is in our November 11th issue of Circulation Research. Thank you both so much for joining me today. Before we talk about the science, want to just maybe tell me a little bit about yourselves? Bliss Nelson: My name is Bliss Nelson. I'm a member of Miguel Lopez-Ramirez's lab here at UC San Diego at the School of Medicine. I'm an undergraduate student here at UC San Diego. I'm actually a transfer student. I went to a community college here in California and I got involved in research after I transferred. Cindy St. Hilaire: What's your major? Bliss Nelson: I'm a cognitive science major. Cindy St. Hilaire: Excellent. You might be the first undergrad on the podcast, which is exciting. Bliss Nelson: Wow. What an honor. Thank so much. Cindy St. Hilaire: And Miguel, how about you? Miguel Lopez-Ramirez: Yes, thank you. Well, first thank you very much for the opportunity to present our work through this media. It's very exciting for us. My name is Miguel Alejandro Lopez-Ramirez, and I'm an assistant professor in the Department of Medicine and Pharmacology here at UCSD. Cindy St. Hilaire: Wonderful. I loved your paper, because, well, first, I don't think I've talked about cerebral cavernous malformations. So what are CCMs, and why are they so bad? Bliss Nelson: Cerebral cavernous malformations, or CCMs for short, are common neurovascular lesions caused by a loss of function mutation in one of three genes. These genes are KRIT1, or CCM1, CCM2 and PDCD10, or CCM3, and generally regarded as an endothelial cell autonomous disease found in the central nervous system, so the brain and the spinal cord. The relevance of CCMs is that it affects about one in every 200 children and adults, and this causes a lifelong risk of chronic and acute hemorrhaging. CCMs can be quiescent or dynamic lesions. If they are dynamic, they can enlarge, regress, or behave progressively, producing repetitive hemorrhaging and exacerbations of the disease. Other side effects of the disease could be chronic bleedings, focal neurological deficits, headaches, epileptic seizures and, in some cases, death. There's no pharmacological treatment for CCMs. There's only one type of option some patients may have, which would be to have surgery to cut out the lesions. But of course this depends on where the lesion or lesions are in the central nervous system, if that's even an option. So sometimes there's no option these patients have, there's no treatment, which is what propels our lab to towards finding a pharmacological treatment or uncovering some of the mechanisms behind that. Cindy St. Hilaire: Do people who have CCM know that they have them or sometimes it not detected? And when it is detected, what are the symptoms? Bliss Nelson: Sometimes patients who have them may not show any symptoms either ever in their lifetime or until a certain point, so really the only way to find out if you were to have them is if you went to go get a brain scan, if you went to go see a doctor, or if you started having symptoms. But also, one of the issues with CCMs is that they're very hard to diagnose, and in the medical community there's a lack of knowledge for CCMs, so sometimes you may not get directed to the right specialist in time, or even ever, and be diagnosed. Miguel Lopez-Ramirez: I will just add a little bit. It is fabulous, what you're doing. I think this is very, very good. But yes, that's why they're considered rare disease, because it's not obvious disease, so sometimes most of the patient, they go asymptomatic even when they have one lesions, but there's still no answers of why patients that are asymptomatics can become symptomatics. And there is a lot in neuro study, this study that we will start mentioning a little bit more in detail. We try to explain these transitions from silent or, quiescent, lesion, into a more active lesion that gives the disability to the patient. Some of the symptoms, it can start even with headaches, or, in some cases, they have more neurological deficits that could be like weakness in the arms or loss of vision. In many cases also problems with the speech or balance. So it depends where the lesion is present, in the brain or in the spinal cord, the symptoms that the patient will experience. And some of the most, I will say, severe symptoms is the hemorrhagic stroke and the vascular thrombosis and seizure that the patients can present. Those would be the most significant symptoms that the patient will experience. Cindy St. Hilaire: What have been some limitations in the study of CCMs? What have been limitations in trying to figure out what's going on here? Bliss Nelson: The limitations to the disease is that, well, one, the propensity for lesions, or the disease, to come about, isn't known, so a lot of the labs that work on it, just going down to the basic building blocks of what's even happening in the disease is a major problem, because until that's well established, it's really hard to go over to the pharmacological side of treating the disease or helping patients with the disease, without knowing what's going on at the molecular level. Cindy St. Hilaire: You just mentioned molecular level. Maybe let's take a step back. What's actually going on at the cellular level in CCMs? What are the major cell types that are not happy, that shift and become unhappy cells? Which are the key players? Bliss Nelson: That's a great question and a great part of this paper. So when we're talking about the neuroinflammation in the disease, our paper, we're reporting the interactions between the endothelium, the astrocytes, leukocytes, microglia and neutrophils, and we've actually coined this term as the CaLM interaction. Cindy St. Hilaire: Great name, by the way. Bliss Nelson: Thank you. All props to Miguel. And if you look at our paper, in figure seven we actually have a great graphic that's showing this interaction in play, showing the different components happening and the different cell types involved in the CaLM interaction that's happening within or around the CCM lesions. Cindy St. Hilaire: What does a astrocyte normally do? I think our podcast listening base is definitely well versed in probably endothelial and smooth muscle cell and pericyte, but not many of us, not going to lie, including me, really know what a astrocyte does. So what does that cell do and why do we care about its interaction with the endothelium? Miguel Lopez-Ramirez: Well, the astrocytes play a very important role. Actually, there are more astrocytes than any other cells in the central nervous system, so that can tell you how important they are. Obviously play a very important role maintaining the neurological synapses, maintaining also the hemostasis of the central nervous system by supporting not only the neurons during the neural communication, but also by supporting the blood vessels of the brain. All this is telling us that also another important role is the inflammation, or the response to damage. So in this case, what also this study proposed, is that new signature for these reactive astrocytes during cerebral malformation disease. So understanding better how the vasculature with malformations can activate the astrocytes, and how the astrocytes can contribute back to these developing of malformations. It will teach us a lot of how new therapeutic targets can be implemented for the disease. This is part of this work, and now we extend it to see how it can also contribute to the communication with immune cells as Bliss already mentioned. Cindy St. Hilaire: Is it a fair analogy to say that a astrocyte is more similar to a pericyte in the periphery? Is that accurate? Miguel Lopez-Ramirez: No, actually there are pericytes in the central nervous system as well. They have different roles. The pericyte is still a neuron cell that give the shape, plays a role in the contractility and maintains the integrity of the vessels, while the astrocyte is more like part of the immune system, but also part of the supporting of growth factors or maintaining if something leaks out of the vasculature to be able to capture that. Cindy St. Hilaire: You used a handful of really interesting mouse models to conduct this study. Can you tell us a little bit about, I guess, the base model for CCM and then some of the unique tools that you used to study the cells specifically? Bliss Nelson: Yeah, of course. I do a lot of the animal work in the lab. I'd love to tell you about the mouse model. So to this study we use the animal model with CCM3 mutation. We use this one because it is the most aggressive form of CCM and it really gives us a wide range of options to study the disease super intricately. We use tamoxifen-regulated Cre recombinase under the control of brain endothelial specific promoter, driving the silencing of the gene CCM3, which we call the PDCD10 betco animal, as you can see in our manuscript. To this, the animal without the Cre system, that does not develop any lesions, that we use as a control, we call the PDCD10 plox. And these animals are injected with the tamoxifen postnatally day one, and then for brain collection to investigate, wcollected at different stages. So we do P15, which we call the acute stage, P50, which we term the progressive stage, and then P80, which is the chronocytes stage. And after enough brain collections, we use them for histology, gene expression, RNA analysis, flow cytometry, and different imaging to help us further look into CCMs. Cindy St. Hilaire: How similar is a murine CCM to a human CCM? Is there really good overlap or are there some differences? Miguel Lopez-Ramirez: Yes. So, actually, that's a very good question, and that's part of the work that we are doing. This model definitely has advantages in which the lesions of the vascular formations are in an adult and juvenile animals, which represent an advantage for the field in which now we will be able to test pharmacological therapies in a more meaningful, way where we can test different doses, different, again, approaches. But definitely, I mean, I think I cannot say that it's only one perfect model for to mimic the human disease. It's the complementary of multiple models that give us certain advantages in another, so the integration of this knowledge is what will help us to understand better the disease. Cindy St. Hilaire: That's great. I now want to hear a little bit about your findings, because they're really cool. So you took two approaches to study this, and the first was looking at the astrocytes and how they become these, what you're calling reactive astrocytes, and then you look specifically at the brain endothelium. So could you maybe just summarize those two big findings for us? Miguel Lopez-Ramirez: Yeah, so, basically by doing these studies we use trangenic animal in this case that they give us the visibility to obtain the transcripts in the astrocytes. And basically this is very important because we don't need to isolate the cells, we don't need to manipulate anything, we just took all the ribosomes that were basically capturing the mRNAs and we profile those RNAs that are specifically expressed in the astrocytes. By doing this, we actually went into looking at in depth the transcripts that were altered in the animals that developed the disease, in this case the cerebral cavernous malformation disease, and what we look at is multiple genes that were changing. Many of them were already described in our previous work, which were associated with hypoxia and angiogenesis. But what we found in this work is that now there were a lot of genes associated with inflammation and coagulation actually, which were not identified before. What we notice is that now these astrocytes, during the initial phase of the vascular malformation, may play a more important role in angiogenesis or the degradation of the vessels. Later during the stage of the malformation, they play a more important role in the thrombosis, in the inflammation, and recruitment of leukocyte That was a great advantage in this work by using this approach and looking in detail, these astrocytes. Also, we identified there were very important signature in these astrocytes that we refer as a reactive astrocytes with neuroinflammatory properties. In the same animals, basically, not in the same animal, but in the same basically the experimental approach, we isolated brain vasculature. And by doing the same, we actually identified not only the astrocyte but also the endothelium was quite a different pattern that we were not seeing before. And this pattern was also associated with inflammation, hypoxia and coagulation pathways. That lead us to go into more detail of what was relevant in this vascular malformations. And one additional part that in the paper this is novel and very impactful, is that we identify inflammasome as a one important component, and particularly in those lesions that are multi-cavernous. Now we have two different approaches. One, we see this temporality in which the lesions forms different patterns in which the initial phase maybe is more aneugenic, but as they become more progressive in chronocytes, inflammation and hypoxy pathways are more relevant for the recruitment of the inflammatory cells and also the precipitation of immunothrombosis. But also what we notice is that inflammasome in endothelial and in the leukocytes may play an important role in the multi-cavernous formation, and that's something that we are looking in more detail, if therapeutics or also interventions in these pathways could ameliorate the transition of phases between single lesions into a more aggressive lesions. Cindy St. Hilaire: That's kind of one of the follow up questions I was thinking about too is, from looking at the data that you have, obviously to get a CCM, there's a physical issue in the vessel, right? It's not formed properly. Does that form influence the activation of the astrocyte, and then the astrocytes, I guess, secrete inflammatory factors, target more inflammation in the vessel? Or is there something coming from the CCM initially that's then activating the astrocyte? It's kind of a chicken and the egg question, but do you have a sense of secondary to the malformation, what is the initial trigger? Miguel Lopez-Ramirez: The malformations in our model, and this is important in our model, definitely start by producing changes in the brain endothelial. And as you mention it, these endothelium start secreting molecules that actually directly affect the neighboring cells. One of the first neighboring cells that at least we have identified to be affected is the astrocytes, but clearly could be also pericytes or other cells that are in the neurovascular unit or form part of the neurovascular unit. But what we have seen now is that this interaction gets extended into more robust interactions that what you were referring as the CaLM interactions. Definitely I think during the vascular malformations maybe is the discommunication that we identify already few of those very strong iteration that is part of the follow up manuscript that we have. But also it could be the blood brain barrier breakdown and other changes in the endothelium could also trigger the activation of the astrocytes and brain cells. Cindy St. Hilaire: What does your data suggest about potential future therapies of CCM? I know you have a really intriguing statement or data that showed targeting NF-kappa B isn't likely going to be a good therapeutic strategy. So maybe tell us just a little bit about that, but also, what does that imply, perhaps, of what a therapeutic strategy could be? Bliss Nelson: Originally we did think that the inhibition of NF-kappa B would cause an improvement potentially downstream of the CCMs. And unexpectedly, to our surprise, the partial or total loss of the brain endothelial NF-kappa B activity in the chronic model of the mice, it didn't prevent or cause any improvement in the lesion genesis or neuroinflammation, but instead it resulted in a trend to increase the number of lesions and immunothrombosis, suggesting that the inhibition of it is actually worsening the disease and shouldn't be used as a target for therapeutical approaches. Miguel Lopez-Ramirez: Yes, particularly that's also part of the work that we have ongoing in which NF-kappa B may also play a role in preventing the further increase of inflammation. So that is something that it can also be very important. And this is very particular for certain cell types. It's very little known what the NF-kappa B actually is doing in the brain endothelial during malformations or inflammation per se. So now it's telling us that this is something that we have to consider for the future. Also, our future therapeutics of what we propose are two main therapeutic targets. One is the harmful hypoxia pathway, which involves activation, again, of the population pathway inflammation, but also the inflammasomes. So these two venues are part of our ongoing work in trying to see if we have a way to target with a more safe and basically efficient way this inflammation. However, knowing the mechanisms of how these neuroinflammation take place is what is the key for understanding the disease. And maybe even that inflammatory and inflammatory compounds may not be the direct therapeutic approach, but by understanding these mechanisms, we may come with new approaches that will help for safe and effective therapies. Cindy St. Hilaire: What was the most challenging part of this study? I'm going to guess it has something to do with the mice, but in terms of collecting the data or figure out what's going on, what was the most challenging? Bliss Nelson: To this, I'd like to say that I think our team is very strong. We work very well together, so I think even the most challenging part of completing this paper wasn't so challenging because we have a really strong support system among ourselves, with Miguel as a great mentor. And then there's also two postdocs in the lab who are also first authors that contributed a lot to it. Cindy St. Hilaire: Great. Well, I just want to commend both of you on an amazing, beautiful story. I loved a lot of the imaging in it, really well done, very technically challenging, I think, pulling out these specific sets of cells and investigating what's happening in them. Really well done study. And Bliss, as an undergraduate student, quite an impressive amount of work. And I congratulate both you and your team on such a wonderful story. Bliss Nelson: Thank you very much. Miguel Lopez-Ramirez: Thank you for Bliss and also Elios and Edo and Katrine, who all contributed enormously to the completion of this project. Cindy St. Hilaire: It always takes a team. Miguel Lopez-Ramirez: Yes. Cindy St. Hilaire: Great. Well, thank you so much, and I can't wait to see what's next for this story. Cindy St. Hilaire: That's it for the highlights from October 28th and November 11th issues of Circulation Research. Thank you so much for listening. Please check out the Circ Res Facebook page and follow us on Twitter and Instagram with the handle @circres and #discovercircres. Thank you to our guests, Dr Miguel Lopez-Ramirez and Bliss Nelson. This podcast is produced by Ashara Retniyaka, edited by Melissa Stoner, and supported by the editorial team of Circulation Research. Some of the copy text for our highlighted articles is provided by Ruth Williams. I'm your host, Dr Cindy St. Hilaire, and this is Discover CircRes, you're on the go source for the most exciting discoveries in basic cardiovascular research. This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more information, please visit ahagenerals.org.
Did you know the cells in your body have a housekeeping function called autophagy? Research by Sarven Sabunciyan and colleagues at Johns Hopkins has shown that aberrant messenger RNAs, or mRNAs, in pregnancy may alter this pathway and lead to … How are messenger RNAs involved with disorders like depression? Elizabeth Tracey reports Read More »
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A new review paper was published in Aging (listed as "Aging (Albany NY)" by MEDLINE/PubMed and "Aging-US" by Web of Science) Volume 14, Issue 19, entitled, “RNA modifications in aging-associated cardiovascular diseases.” Cardiovascular disease (CVD) is a leading cause of morbidity and mortality worldwide that bears an enormous healthcare burden. Aging is a major contributing factor to CVDs. Functional gene expression network during aging is regulated by mRNAs transcriptionally and by non-coding RNAs epi-transcriptionally. RNA modifications alter the stability and function of both mRNAs and non-coding RNAs and are involved in differentiation, development and diseases. In this new review paper, researchers Xinyu Yang, Priyanka Gokulnath, H. Immo Lehmann, Zhitao Hou, Sun Yang, Liangzhen You, Guoxia Zhang, Yanwei Xing, Ji Lei, Guoping Li, Shuwen Guo, and Hongcai Shang from Fangshan Hospital and Dongzhimen Hospital (affiliated with Beijing University of Chinese Medicine), Massachusetts General Hospital, Harvard Medical School, Heilongjiang University of Chinese Medicine, and Chinese Academy of Chinese Medical Sciences reviewed major chemical RNA modifications on mRNAs and non-coding RNAs, including N6-adenosine methylation, N1-adenosine methylation, 5-methylcytidine, pseudouridylation, 2′ -O-ribose-methylation, and N7-methylguanosine, in the aging process with an emphasis on cardiovascular aging. They also summarize the currently available methods to detect RNA modifications and the bioinformatic tools to study RNA modifications. “More importantly, we discussed the specific implication of the RNA modifications on mRNAs and non-coding RNAs in the pathogenesis of aging-associated CVDs, including atherosclerosis, hypertension, coronary heart diseases, congestive heart failure, atrial fibrillation, peripheral artery disease, venous insufficiency, and stroke.” DOI: https://doi.org/10.18632/aging.204311 Corresponding Authors: Guoping Li; Shuwen Guo; Hongcai Shang - Corresponding Emails: gli21@mgh.harvard.edu; guo1163@163.com; shanghongcai@bucm.edu.cn Keywords: RNA modifications, aging, aging-related cardiovascular diseases, epitranscriptome Sign up for free Altmetric alerts about this article: https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204311 About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at https://www.Aging-US.com and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/agingus LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM
This week, please join author Sunil Rao and Guest Editor and Editorialist Gregory Lip as they discuss the article "A Multicenter, Phase 2, Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Dose-Finding Trial of the Oral Factor XIa Inhibitor Asundexian to Prevent Adverse Cardiovascular Outcomes After Acute Myocardial Infarction" and the editorial "Factor XIa Inhibition: Is It a Novel Alternative Antithrombotic Strategy for High-Risk ACS Patients?" Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, Associate Editor Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Greg, today's feature paper is about the factor XI inhibitor asundexian. It's the trial that we've been waiting for the PACIFIC-AMI trial. You really have to listen to it because these factor XI inhibitors are super interesting. What? We're going to tell you about the other papers in today's issue first. Aren't we, Greg? Do you want to go first? Dr. Greg Hundley: You bet, Carolyn. Thank you so much. Carolyn, did you ever consider the genetic underpinnings of venous thromboembolism? Well, as you know, venous thromboembolism is a complex disease with environmental and genetic determinants. And in this study, this large investigative team represented by Dr. Nicholas Smith from the University of Washington in Seattle, and their colleagues present new cross-ancestry meta-analyzed genome-wide association study results from 30 studies with replication of novel loci and their characterization through in silicone genomic interrogations. Dr. Carolyn Lam: Wow. Sounds like a really large effort, Greg. What did they find? Dr. Greg Hundley: Right, Carolyn. In the author's initial genetic discovery effort that included 55,330 participants with venous thromboembolism: 47,000 were European, 6,000 African, and a little over 1000 Hispanic ancestry. They identified 48 novel associations of which 34 are replicated after correction for multiple testing. In their combined discovery replication analysis, so that's 81,669 venous thromboembolism participants and ancestry stratified meta-analyses from the European, African and Hispanic ethnic groups. They identified another 44 novel associations, which are new candidate venous thromboembolism associated loci requiring replication. And many of the replicated loci were outside of known or currently hypothesized pathways to thrombosis. Carolyn, in summary, these findings from this very large GWAS analysis highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of anti-thrombosis treatments with reducing the risk of bleed. Dr. Carolyn Lam: Wow. Super interesting and very related to that feature paper that we just discuss. But nonetheless, this next paper I love as well, if I may say so myself. It deals with frailty and as we know, frailty is increasing in prevalence. And because frail patients are often perceived to have a less favorable benefit risk profile, they may be less likely to receive new pharmacological treatments. And so, we and led by Professor John McMurray from the University of Glasgow, decided to investigate the efficacy and tolerability of dapagliflozin according to frailty status in the DELIVER trial. Dr. Greg Hundley: The DELIVER trial. Carolyn, tell us about the DELIVER trial? Dr. Carolyn Lam: Sure. In deliver dapagliflozin compared to placebo, reduced the risk of worsening heart failure events or cardiovascular death and improved symptoms in more than 6,000 patients with heart failure and mildly reduced and preserved ejection fraction, so ejection fraction above 40%. Now in this pre-specified analysis, we examine the efficacy and safety of dapagliflozin according to frailty status. That was determined using the Rockwood cumulative deficit approach. And so, what we found was that greater frailty was associated with more impairment of health status and worse clinical outcomes in patients with heart failure and ejection fraction of 40%. The beneficial effects of dapagliflozin compared to placebo on clinical outcomes were consistent regardless of frailty class. But interestingly, the improvement in symptoms, physical function and quality of life were larger in the frailest patients. Adverse events were not more common in individuals randomized to receive dapagliflozin compared to placebo irrespective of frailty class. And so, the take home message is the benefit risk balance related to frailty in patients with heart failure with mildly reduced and preserved ejection fraction is favorable for dapagliflozin. And so, these findings should challenge any clinical reluctance to introduce dapagliflozin in patients perceived to be frail. Dr. Greg Hundley: Wow. Carolyn, really interesting. You could see with the diuretic effect in someone that's frail, the potential hesitancy, but very interesting study results in this world of frailty and the use of dapagliflozin. Well, Carolyn, this next study is very interesting and it comes to us from the world of preclinical science that takes a very interesting approach to a scientific question. Now, as you may know, RNA-binding proteins or RBPs are master orchestrators of genetic expression regulation. They regulate hundreds of transcripts at once by recognizing specific motifs, thus characterizing RBPs targets is critical to harvest their full therapeutic potential. However, such investigation has often been restricted to a few RBP targets, thereby limiting our understanding of their function. Carolyn, these investigators led by Dr. Grégoire Ruffenach from UCLA were interested in assessing pulmonary arterial hypertension and they turned to the world of cancer research. Carolyn, in cancer, the RNA-binding protein hnRNPA2B1, and we're going to abbreviate that as A2B1, promotes a pro proliferative anti-apoptotic phenotype. The same phenotype is present in pulmonary arterial smooth muscle cells and is responsible for the development of pulmonary arterial hypertension. However, the A2B1 function that's never really been investigated in pulmonary arterial hypertension. Dr. Carolyn Lam: Oh, Greg, that's not only fascinating, but so beautifully described. Thank you. What did they find? Dr. Greg Hundley: Right, Carolyn. These authors found that A2B1 expression and it's nuclear localization are increased in human pulmonary arterial hypertension, pulmonary arterial smooth muscle cells. Using bioinformatics, they identified three known motifs of A2B1 and all mRNAs carrying them and demonstrated the complimentary non-redundant function of A2B1 motifs as all motifs are implicated in different aspects of the cell cycle. In addition, they showed that pulmonary arterial smooth muscle cells and A2B1 promote the expression of its targets. Additionally, in vivo A2B1 inhibition in the lungs rescued pulmonary hypertension in rats. And so, Carolyn, through the integration of computational and experimental biology, this team study revealed the role of A2B1 as a master orchestrator of pulmonary arterial smooth muscle cells in pulmonary hypertension and that phenotype and its relevance as a therapeutic target in pulmonary arterial hypertension. Dr. Carolyn Lam: Wow, that's super, Greg. Thanks. Shall we go through what else is in today's issue? Dr. Greg Hundley: You bet, Carolyn. There's a Research Letter from Professor Mustroph entitled, “Empagliflozin Inhibits Cardiac Late Sodium Current versus Calcium Calmodulin‐dependent Kinase II.” Dr. Carolyn Lam: There's also an exchange of letters between Doctors Omarjee and Diederichsen regarding vitamin K2 and D in patients with aortic valve calcification: [an] absence of evidence might not be evidence of absence? And finally, there's an On My Mind paper by me and Scott Solomon and it's entitled, “Delivering Therapeutic Efficacy Across the Ejection Fraction Spectrum of Heart Failure.” But let's go on now to talk about the Factor XI inhibitor, shall we, Greg? Dr. Greg Hundley: You bet. Well, listeners, welcome to this feature discussion on October 18th at a very special article today. And we have with us the lead author, Dr. Sunil Rao from NYU in New York City and also our associate guest editor as well as editorialist, Dr. Gregory Lip from Liverpool. Welcome, gentlemen. Sunil, we'll start with you. Can you describe for us some of the background information that went into the preparation of your study and what was the hypothesis that you wanted to address? Dr. Sunil Rao: Yeah, great. Thanks so much, Greg. It's a real pleasure to be here with you. The background of the PACIFIC-AMI study is really rooted in the fact that patients who have acute myocardial infarction are really at risk for recurrent thrombotic events, even after their event. And this risk continues despite the fact that we have evidence based therapies that are really around targeting the platelet as well as aspects of the coagulation cascade. There have been studies that have looked at the use of dual antiplatelet therapy plus an anticoagulant or single antiplatelet therapy plus an anticoagulant. And those studies have shown a benefit. However, their clinical use is limited because of the bleeding risk. Factor XI is an interesting target, because factor XI is likely involved in the amplification of thrombin generation after plaque rupture. But it really doesn't play much of a role in hemostasis. And so, as a target in reducing events after acute coronary syndrome, activated factor XI is a very attractive one. And so, the hypothesis of this study was that a highly bioavailable oral, direct, selective activated factor XI inhibitor called asundexian would be safe and effective in the treatment of patients who experience acute coronary syndrome at reducing adverse events. Now, this is a phase two study, so it really wasn't powered for clinical events. It was really a dose-finding study, so it was really looking at adverse events and sort of bleeding complications. Dr. Greg Hundley: Very nice. Asundexian, a new factor XI inhibitor. And Sunil, can you describe for us your study design and then maybe a little bit more about the study population, how many subjects? Dr. Sunil Rao: Sure. Again, this is a phase two study. It was a randomized, double-blind, parallel-group design where patients, who were admitted with acute coronary syndrome were randomized to three different doses of asundexian and or placebo in a one-to-one to one-to-one fashion. Patients who met criteria for enrollment were: patients who were admitted with a diagnosis of acute MI; if they were older than or equal to 45 years of age; they were hospitalized in acute coronary syndrome that did not occur in the context of revascularization, so it was not a type 4 event; and they were planned to be treated with dual antiplatelet therapy after hospital discharge. Dr. Greg Hundley: Sunil, thank you for describing this very interesting study design. Now, how many subjects did you include and could you just describe for us the study population? Dr. Sunil Rao: We had a total of 1,601 patients that were randomized at 157 centers in 14 countries between June 2020 and July 2021. And in order to be eligible for enrollment into the study: patients had to be admitted with a diagnosis of acute MI, they had to be greater than or equal to 45 years of age, and be hospitalized with that acute MI that did not occur in the context of revascularization, so type 4 MIs were excluded. The other inclusion criteria was that they had to be planned to be treated with dual antiplatelet therapy after hospital discharge. Now, we allowed randomization up to five days after hospital admission and randomization occurred after patients were clinically stabilized and any planned PCI was performed. We included both patients with STEMI as well as non-ST segmental elevation ACS, but we capped the number of patients with STEMI that were included to no more than 50%. Now, the main exclusion criteria were things that you would expect for a phase two trial. Obviously, hemodynamic instability at the time of randomization, active bleeding or bleeding dialysis, severe renal dysfunction, planned use of full-dose anticoagulation. Dr. Greg Hundley: Very nice. And so, we have several doses of this new factor XI inhibitor. Describe for us your study results? Dr. Sunil Rao: Again, this was a phase two trial that was really looking at safety and adverse events as you would expect. The study groups were pretty balanced across all of the dosing arms. When we looked at the pharmacokinetic and pharmacodynamic data, we found something really interesting, which was that there was a dose relationship between the dose of asundexian and the factor XIa activity. Factor XIa is activated factor XI. The higher the dose, the more suppression of factor XI activity. In fact, the highest dose nearly eliminated factor XI activity. The drug clearly works in the way that it was intended. Now again, the clinical data, it wasn't powered for clinical data. But when we look at the bleeding results, we found that there was in fact an increase in bleeding as the dose of asundexian increased. The overall rate of bleeding in the highest dose of asundexian was in 50 milligrams was 10.5% with type 2 or 3 or 5 BARC bleeding, a placebo is about 9.02%. Again, the efficacy outcomes, very, very low rates of overall events. Again, not powered to show a difference. Essentially, very similar across all the arms. Dr. Greg Hundley: And did you find the same results for the men and the women? And what about older individuals and younger individuals? Dr. Sunil Rao: Yeah. We did look at some subgroups. And you had to be a little bit cautious because again, the trial itself is relatively small. I mean, we didn't notice any significant patterns across these subgroups. And the overall interaction p-values were really non-significant. But I think what this does show is like a phase two trial that the drug works as in the way that it's intended. Overall, safety was as expected. And I think it really sets up data for a larger study. Dr. Greg Hundley: Well, listeners, what a fantastic presentation. And now, we're going to turn to our guest editor and editorialist, Dr. Gregory Lip from Liverpool. Greg, I know working for circulation, you have many papers come across your desk. What attracted you to this particular paper? And then maybe secondly, can you help us put the results of this study in the context of other studies that have been evaluating these factor XI therapies? Dr. Gregory Lip: Thanks, Greg. Well, I think this is an important paper, because it is a phase two trial with a novel, orally bioavailable inhibitor factor XI. And this is intriguing because factor XI efficiency in humans and experimentally in animals is associated with a reduced risk of thrombotic events like stroke or venous thromboembolism. But spontaneous bleeding is rare and also bleeding in response to trauma or surgery is much milder. Really it's the holy grail of trying to get an anticoagulant that reduces thrombosis but doesn't cause an excess of bleeding. Now, this was the quest with different anticoagulants. And I think it was very exciting to see this particular paper in the patients who've had an acute coronary syndrome, because there was a lot of interest in the use of anticoagulants, particularly in combination with antiplatelet therapy from trials such as ATLAS and COMPASS, where there was certainly a reduction in adverse cardiovascular events. But a downside with those drugs and when using combination, was an excess of bleeding by the combination of the available anticoagulants now plus antiplatelets. The factor XIs agents offered the possibilities we might have combination therapy to reduce cardiovascular events but not causing an excess of bleeding. Dr. Greg Hundley: Well, listeners, what a wonderful discussion that we've had here. Let's circle back with both individuals. Sunil, we'll start with you. What do you see as the next study to really be performed in this sphere of research? Dr. Sunil Rao: I think that factor XI is a very attractive target in patients with acute coronary syndrome. Again, the rationale for why we did this phase two trial was to show that inhibition of activated factor XI should result in a low rate of ischemic events without a significant increase in bleeding. This phase two trial was really to try and decide which doses result in potent inhibition of factor XIa and potentially which doses should be carried forward into a larger study. What we found in the PACIFIC-AMI trial was that the doses of asundexian and the factor XIa inhibitor were very, very well tolerated with a low rate of adverse events. It resulted in a dose-dependent near complete inhibition of factor XIa activity without a significant increase in bleeding and a low rate of ischemic events. I think, again, it's a very attractive target in patients with ACS and this really provides support for a larger adequately powered clinical trial in patients with acute coronary syndrome that is really looking at clinical events such as MACE as well as bleeding. Dr. Greg Hundley: And Greg as an editorialist, what did you see with this paper? Maybe some unanswered questions that we'd like to pursue further? Dr. Gregory Lip: Well, I think this does raise a lot of questions in the sense that it'll be interesting because as a phase two trial, it's a relatively moderate sized trial. It's not like a phase three large outcome trial and phase two trials also testing different doses of the novel agent. We need to see the definitive phase three trial and to look at the magnitude of benefit versus potential for bleeding if in the large phase three trial and obviously, the net clinical benefit and importantly are some of the subgroups: ST elevation, myocardial infarction, undergoing primary PCI, for example, those with renal impairment. And I think particularly intriguing would be looking at the patients in this scenario who get the new antiplatelet drugs such as ticagrelor and prasugrel. And the reason I say that is what we have with warfarin or Coumadin and from the current DOACs or NOACs, depending on the risk side upon. We refer to them, that's the direct oral anticoagulants or non-vitamin K antagonist or anticoagulants. Well, if you give a more potent antiplatelet like prasugrel or ticagrelor, the risk of bleeding not surprisingly is higher. Hence, the guidelines recommend that if you use an anticoagulant or a DOAC, you use it with a P2Y 12 inhibitor clopidogrel as opposed to the more potent ones. If this new class of drugs, the factor XI inhibitors can work well in combination with one of the more potent antiplatelets without causing an excessive bleeding, again, this is going to be a substantial advance. Well, with these new class of anticoagulants, will be really interesting to see the phase three trials when applied to other chronic conditions. For example, stroke prevention and atrial fibrillation. And the other category of patients would be those who've had an embolic stroke of uncertain source or ESUS or in old terminology cryptogenic stroke. With the ESUS group of patients, they're currently treated with aspirin because the trials which tried a NOAC or DOAC, they were not showing a positive result. They'll be interesting again with the factor XI inhibitors, whether we are going to see this benefit with the reduction in recurrence stroke with no excessive bleeding. Dr. Greg Hundley: Very nice. Well, listeners, we want to thank Dr. Sunil Rao from NYU in New York City and Dr. Gregory Lip from the University of Liverpool for bringing us this study highlighting that in patients with recent acute myocardial infarction, three doses of asundexian when added to aspirin plus a P2Y 12 inhibitor resulted in dose-dependent near complete inhibition of factor XIa activity without a significant increase in bleeding and a low rate of ischemic events. And certainly, the data from this study support the investigation of asundexian at a dose of 50 milligrams daily in an adequately powered clinical trial of patients following acute myocardial infection. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week On the Run. This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
On today's show we discuss that the latest news has confirmed that the COVID-19 vaccination has an effect on women's menstrual cycle and that trace amounts of Covid vaccine MRNAs are detected in breast milk. GUEST OVERVIEW: Justin Hart, founder of Rational Ground which helps companies and communities gauge the impact of COVID-19, responds to these recent findings with swift evidence showing how the CDC convinced millions of women that the vaccine was perfectly safe to take, especially while pregnant. In Hart's upcoming book, Gone Viral: How COVID Drove the World Insane, he addresses all that we have been told about Covid-19 and peels back the lies through his heavily researched data to reveal clarity and truth to its reader. This book is a guide that gives a point-by-point breakdown to disassemble every bit of misinformation we've been told.
Paul Offit returns to TWiV for a discussion of SARS-CoV-2 bivalent boosters containing ancestral and Omicron spike mRNAs, including their composition, why they are being recommended by CDC, and who would benefit the most from them. Hosts: Vincent Racaniello, Dickson Despommier, Rich Condit, Kathy Spindler, and Brianne Barker Guest: Paul Offit Subscribe (free): Apple Podcasts, Google Podcasts, RSS, email Become a patron of TWiV! Links for this episode Research assistant position at FDA (pdf) Support MicrobeTV with a Spike t-shirt (Vaccinated.us) CDC oversells bivalent booster (Wall St Journal) FDA authorizes bivalent COVID-19 booster Timestamps by Jolene. Thanks! Weekly Picks Dickson – Jazz favorites: Small group #4: Gerry Mulligan Quartet with Chet Baker: Gerry Mulligan, Baritone saxophone; Carson Smith, Bass; Larry Bunker, Drums, Chet Baker, Trumpet. Signature album: The Best Of The Gerry Mulligan Quartet With Chet Baker: Signature song: My Funny Valentine. Second pick: Wonder: Childhood and the Lifelong love of Science. Frank C. Keil. Brianne – A Devious Cellular Trick Cancers Can Use to Escape Your Immune System Kathy – Durable antimicrobial coating Rich – One Health Vincent – The works of Dashiell Hammett Intro music is by Ronald Jenkees Send your virology questions and comments to twiv@microbe.tv
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A new study from the Journal of the American Medical Association revealed trace amounts of COVID vaccine mRNAs were found in the breast milk of some lactating women. Plus, Karine Jean-Pierre can't answer whether or not Joe Biden believes American cities are safe. And why did Netflix label the Jeffrey Dahmer series "LGBTQ"? Today's Sponsors: Moink delivers grass-fed and grass-finished beef and lamb, pastured pork and chicken, and sustainable wild-caught Alaskan salmon straight to your door. Go to https://MoinkBox.com/NEWS and get FREE filet mignon in every order for a year Learn more about your ad choices. Visit megaphone.fm/adchoices
This week, please join authors Hanna-Kaisa Nordenswan and Jukka Lehtonen, as well as Associate Editor Mark Link as they discuss the article "Incidence of Sudden Cardiac Death and Life-Threatening Arrhythmias in Clinically Manifest Cardiac Sarcoidosis With and Without Current Indications for an Implantable Cardioverter Defibrillator." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center, VCU Health in Richmond, Virginia. Dr. Peder Myhre: And I'm Dr. Peder Myhre, Social Media Editor in Circulation from Akershus University Hospital, and University of Oslo, Norway. Dr. Carolyn Lam: Oh, I am so excited about our feature paper today. It is about a condition that may not be as commonly encountered, but this paper can change clinical practice. It's about cardiac sarcoidosis and the indications for an ICD. Listen up. Very important stuff and discussion coming right up. But first, let's grab coffees and discuss the other papers in today's issues. Shall we? Dr. Greg Hundley: Right. So Carolyn, Peder, how about I go first? And so, both of you... we start with a really interesting, very practical study. It's somewhat unclear whether replacing an oral glucose tolerance test with just a hemoglobin A1C measurement for diagnosing diabetes is justified. And so these authors led by Adam Tabák, from University College of London in the United Kingdom, aimed to assess proportion of oral glucose tolerance tests, diagnosed diabetes cases that can be confirmed with hemoglobin A1C measures. And to examine whether individuals with oral glucose tolerance test diagnoses, but non-diagnostic hemoglobin and A1C are at higher risk of macro and microvascular disease. So the study included 5,773 men and women from the population based Whitehall II prospective of cohort study in the United Kingdom. New oral glucose tolerance tests, diabetes cases diagnosed in clinical examinations between the years of 2002 and 2004. And again, in 2007 and 2009 were assessed for hemoglobin A1C confirmation of a value greater than 6.5% in these. And then again, so in those years, and then again, in subsequent clinical examinations in the periods of 2012 to 2013 and 2015 to 2016, now all participants were followed for major cardiovascular events via linkage to electronic health records until the year of 2017. And for incident chronic kidney disease by an estimated glomerular filtration blade of less than 60 mLs per minute per meter squared, until the last clinical examination. Dr. Peder Myhre: Thank you, Greg. That is such an important study with direct clinical implications. And I'm so curious to know what did they find? Dr. Greg Hundley: Right, Peder. Right, Carolyn. Carolyn's in the background, it's like a mind meld with Peder. She's going to keep pounding me with these same questions. Okay. So in this population based cohort study, with five yearly repeated oral glucose tolerance tests and hemoglobin A1C measurements, only 59.3% of the oral glucose tolerance tests diagnosed diabetes cases were confirmed by hemoglobin A1C at the same or a subsequent examination during 4.1 years of follow up. Incident oral glucose tolerance test diagnosed diabetes cases with hemoglobin A1C confirmation, and preexisting diabetes cases had similarly increased risks of cardiovascular disease and chronic kidney disease. While notably unconfirmed oral glucose tolerance test cases had a similar risk as the diabetes free population. Dr. Peder Myhre: Wow. That is really remarkable, Greg. Thank you for that summary. But can you please just give us, from this complicated paper, can you just give us some take-home points for the listeners. Dr. Greg Hundley: Right, Peder. So first, in this study, people with oral glucose tolerance tests diagnosed diabetes without diagnostic hemoglobin A1C have a risk of cardiovascular disease and chronic kidney disease, similar to the diabetes free population. And therefore, replacement of oral glucose tolerance tests with hemoglobin A1C based diagnoses appears justified. Second, there seems to be no need to consider oral glucose tolerance testing when hemoglobin A1C and fasting glucose levels are apparently inconclusive. Fasting glucose tests are needed only in exceptional circumstances where hemoglobin A1C results are felt to be unreliable. And then, finally, these findings lend confidence to widespread use of hemoglobin A1C for diagnosing diabetes in the vast majority of clinical settings. Dr. Peder Myhre: Wow. Greg, thank you so much. This was so helpful. Well, I'm going to move on to the second original research article. And that is from the DAPA-HF trial, that I know Carolyn has been quizzing you throughout the years about. So I'm not going to quiz you, but I'm just going to ask you. Did you know that SGLT-2 inhibitors increase hematocrit and that it has been identified as one of the key mediators of the clinical benefits on this class of drugs. Dr. Greg Hundley: So Peder, they're really interesting. And the second week of this you're popping out with these quizzes. I didn't do this to Carolyn. It was like a couple months. So anyway, but- Dr. Carolyn Lam: Way to go, Peder. Way to go. Dr. Greg Hundley: Yeah. Well, the good news is, I can just say yes. I did know that. Dr. Peder Myhre: That's nice. And in this paper, we're going to learn even more. Because the authors are taking this further by looking into the iron metabolism and assessing iron deficiency in the DAPA-HF trial. So just to remind you, although, you are familiar with it at this point, Greg, and of course, Carolyn, the DAPA-HF trial was large RCT testing efficacy and safety of the SGLT-2 inhibitor compared to placebo in patients with heart failure and a reduced ejection fraction. And in this post talk analysis, the authors examine the prevalence and consequences of iron deficiency and the effect of dapagliflozin on markers of iron metabolism. They also analyze the effect dapagliflozin on outcomes according to iron status at baseline. Dr. Greg Hundley: Oh, wow, Peder. So what did they find? Dr. Peder Myhre: So in total, 44% of patients in DAPA-HF were defined as iron deficient. And that was defined as having less than 100 nanogram per milliliter of ferritin or a key set of less than 20% and a ferritin level between 100 and 299 nanogram per milliliter. So the rate of the primary outcome was higher in patients with iron deficiency compared to those without. That was 16 versus 10 per 100% years. And the effect of dapagliflozin on the primary outcome was consistent in iron deficient compared to iron replace patients with a fever interaction of 4.59. And similar findings were observed for cardiovascular death, heart failure hospitalizations and all-cause mortality. And finally, and very importantly, ferritin, T cell, and hepcidin were reduced with dapagliflozin versus placebo. So the authors conclude that iron deficiency was common in DAPA-HF. And associated with worse outcomes. Dapagliflozin, appeared to increase iron utilization, but improved outcomes, irrespective of iron status at baseline. Dr. Greg Hundley: Very nice, Peder. Wow. Just another important piece of information that we're learning about SGLT-2 inhibition. Well, Peder, my next paper comes from the world of preclinical science and it's from a group of authors led by Dr. Osamu Takeuchi from Kyoto University. Primary pulmonary arterial hypertension, Peder, is often characterized by obliterative pulmonary vascular remodeling, resulting in right heart failure. And although, the pathogenesis of pulmonary arterial hypertension is not fully understood. Inflammatory responses and cytokines have been shown to be associated with pulmonary arterial hypertension, particularly with connective tissue disease. So in this sense, Regnase-1 and RNAs, which regulates mRNAs in coding genes related to immune reactions was investigated in relationship to the pathogenesis of pulmonary hypertension. Dr. Peder Myhre: Wow, Greg. Pulmonary arterial, a hypertension and mRNA degradation of IL-6. So what did they find, Greg? Dr. Greg Hundley: Right, Peder. So these investigators examined the expression levels of Z3H12A in coding Regnase-1, in peripheral blood mononuclear cells from pulmonary hypertension patients classified under various types of pulmonary hypertension, searching for an association between the ZC3H12A expression and the clinical features associated with pulmonary hypertension. They then generated mice lacking Regnase-1 and myeloid cells, including alveolar macrophages and examined right ventricular systolic pressures, and histologic changes in the lung. They found that Regnase-1 maintains lung innate immune homeostasis via the control of IL-6 and PDGF in alveolar macrophages, thereby, suppressing the development of pulmonary arterial hypertension in mice. And furthermore, the decreased expression of Regnase-1 in various types of pulmonary hypertension implied its involvement in pulmonary hypertension pathogenesis. And then, therefore, may serve as a disease biomarker as well as a therapeutic target for pulmonary hypertension. Very, very interesting work from the world of preclinical science. So how about we jump and see what else is in the mail bag? Dr. Peder Myhre: So we have From the Literature by Dr. Tracy Hampton, and this time we get three summaries from preclinical science papers published on their journals. First, there is a summary of a paper suggesting that circadian and pluripotency networks control longevity related genes, and that was published in cell metabolism. There is also a summary from a paper on the varied responses to a high fat diet using mouse models published in high science. And finally, there is a summary related to Brugada syndrome and how gene therapy is a potential future therapy. And that was published in scientific translational medicine. So Greg, what did you have in the mail bag? Dr. Greg Hundley: Sure. Well, Peder, I've got a research letter from Professor Fang entitled “Mitochondrial Stress Induces HRIEIF2A Pathway that's Protective for Cardiomyopathy.” Dr. Peder Myhre: And finally, we have clinical implications of basic research from Dr. Garry and colleagues entitled “Cardiac Xenotransplantation, the Clinical Impact of Science and Discovery.” So let's move on the future discussion, Carolyn. Dr. Carolyn Lam: Absolutely. Thank you for excellent summary, Greg and Peder. Now, let's go the feature discussion on cardiac sarcoidosis. Dr. Greg Hundley: You bet. Dr. Carolyn Lam: Wow. Today's feature discussion is on a rare, but very important topic. And it's that of cardiac sarcoidosis. And you have to listen up because today's paper could actually change practice. So I'm very pleased and grateful to have the authors of this paper. The corresponding author, Dr. Hanna-Kaisa Nordenswan and coauthor, Dr. Jukka Lehtonen both from Helsinki University Hospital. As well as our associate editor, Dr. Mark Link, from UT Southwestern to discuss this very important paper. Hannah-Kaisa if you don't mind, could you start by just telling us about your paper and what you found? Dr. Hanna-Kaisa Nordenswan: Thank you so much for inviting us to the podcast. So cardiac sarcoidosis predisposes to sudden cardiac death. But how well the current guidelines for implantable cardioverter-defibrillators in CS issued by the Heart Rhythm Society in 2014 and the American College of Cardiology, American Heart Association and Heart Rhythm Society, consortium guidelines from 2017, discriminate high from low risk of sudden cardiac death is unknown. And this is what we wanted to examine. So our study is a nationwide study, including 398 patients with cardiac sarcoidosis. All patients had clinical cardiac manifestations and a histological diagnosis of sarcoidosis. The histological diagnosis was myocardial in nearly one half of the population. So patients with and without class 1 to 2A indications for an implantable cardioverting-defibrillator at presentation were identified from this population. The occurrence of fatal or aborted sudden cardiac death and sustained ventricular tachycardias in follow-up were recorded. We also noted ICD indications emerging first on, follow up. Dr. Carolyn Lam: Great. What did you find? Dr. Hanna-Kaisa Nordenswan: So, first of all, we found that by the current ICD guidelines, 85 to 100% of our patients had at least one strong to modest class 1 to 2a indication for an early ICD implementation. And we also found a 10%, five-year cumulative incidence of sudden cardiac death in our population of cardiac sarcoidosis patients. Further, we found that patients without an early indication for an ICD by the Heart Rhythm Society guidelines had nearly 5% cumulative risk of sudden cardiac death at five years. These patients further had a 53% cumulative risk of either developing an indication or suffering from a life-threatening ventricular arrhythmia at five years follow up. Finally, we also found that a diagnosis of cardiac sarcoidosis based on myocardial histology, IE definite CS. So definite cardiac sarcoidosis predicted twice higher combined five-year risk of sudden cardiac death and life-threatening ventricular arrhythmia than diagnosis based on extra cardiac histology, IE probable cardiac sarcoidosis. Dr. Carolyn Lam: Wow. Thank you so much, Hannah-Kaisa and congratulations on such impactful findings. 398 patients and if I read correctly, a cohort spanning 30 years. Jukka, could you tell us a little bit more on how these patients were identified? And I think this is important too, because it speaks to the generalizability of your findings. Dr. Jukka Lehtonen: Exactly. Yeah. So we have a very proactive approach to cardiac sarcoidosis. So basically, if I give you an example, so we screen all patients less than 60 years of age with MRI. And if the MRI shows that there's any signs of myocardial damage, we do endomyocardial biopsy. And then, if we do biopsy, once take 10 samples from the right ventricular septum. If that comes out negative, as it very often comes, then we do a PET study. And if there's an extra cardiac signal, then we do biopsy that side. So usually, it's lymph nodes very often. And that gives us a probable cardiac sarcoidosis. So probable cardiac sarcoidosis is the terminology that's used in Heart Rhythm Society, 2014 guidelines. It has the same prognosis, basically, the definite cardiac sarcoidosis that's based on endomyocardial biopsy. So if the PET shows no signal outside the heart, we usually repeat the biopsy either right or left side, depending where there's most signal. And we can do that up to three times. So we have a very proactive approach. And that explains why we have so many patients. So because you may end up taking 30 biopsy samples and you have one sample that's positive. So that explains why 5.3 million people can have such a huge number of sarcoid patients. We don't think that we are special. We just think that we are very active in biopsy area. And I know that this is something that differs in different places, and the different centers in the US have very different policies, and in Europe as well. So why I think this explains why we have such a large population and why they're all biopsy verified cases. Dr. Carolyn Lam: Thank you so much, Mark. I know that as editors we spotted immediately what a precious, valuable cohort in data we were looking at. Could you frame that for us? Take us behind the scenes a little bit on what you thought when this paper first crossed your desk. Dr. Mark Link: Yeah. This was a paper that caught our interest right away for a number of reasons. One, is the large number of sarcoid patients, nearly 400, that's one of the largest series that's ever been published. And two, is the systematic way in which sarcoid was approached. And what we found fascinating is that once you had a diagnosis of cardiac sarcoid, be it either probable or actual, there was a high risk of having ventricular arrhythmias. And this is something that in the guidelines, it's not so clear, because it's clear if the EF's less than 35%, you should get an ICD. But if your EF's greater than 35% by current guidelines, that's not a class 1 indication. So we thought this paper had the possibility to move guidelines and that perhaps we should think about an ICD and any patient that has diagnosis of cardiac sarcoid. Dr. Carolyn Lam: Wow. That's a brave postulation though. Exactly, as I said at the beginning, I think it may be practice changing. What do you think about that? Jukka and Hannah? Dr. Jukka Lehtonen: I think that's exactly what we have noticed that we have, most of the cardiac sarcoid patients are less than 50 years of age. So I think, the average age is 49 or something. And they're mostly females, so 70% are females. So it's pretty unique cardiac disease, that's more common in females than in males. And I think this population is benefiting tremendously from the ICD therapy, so that's something that we can see. It's not based on randomized data, it's follow up data, but these patients have lots of ICD events, events treated by an ICD. So we think that this is a major problem. Our previous papers have shown that the mortality in sarcoidosis is 90% is ventricle arrhythmia. So this conclusion fits with that previous findings as well. Dr. Carolyn Lam: Wow. Hannah has this impacted your personal clinical practice? I mean, do you now therefore think any patient, especially, if they've got confirmed cardiac sarcoidosis biopsy proven. Are you going to just, no matter what, regardless, anything else be more likely to put an ICD? Dr. Hanna-Kaisa Nordenswan: Yeah. Based on this study, we think that all cardiac sarcoidosis patients presenting with clinical cardiac manifestations and with histologically proven cardiac sarcoidosis should be considered for an ICD implantation. But with patients, with having non-definite cardiac sarcoidosis and without class 1 to 2A indications for an ICD in these patients, probably, the pros and cons of an ICD should be carefully discussed. Well, if an ICD is not implanted, at least repeated risk appraisal is needed regularly during follow up. Dr. Carolyn Lam: That's great comments. Mark, what do you think is going to be needed as future steps to get it to change practice? Or do you think this is it? Because, I mean, this is... the issue is, it's not easy to say let's just do a trial in cardiac sarcoidosis, right? Where are we going to find those patients and so on. What do you think, Mark? Dr. Mark Link: Yeah. That's a very good question. Because this isn't randomized trial data, and the strength of evidence is best with randomized trial data. And will we get a randomized trial in sarcoid? I doubt it. I really doubt it. So we're going to be left with registry data. And so where I would see this going is other registries coming out, showing their data. I think we do need confirmatory data from another large registry or two, and that's going to change practice, but are we there yet? I don't know. I don't know. Based on the lack of randomized trial data. Dr. Carolyn Lam: Thanks. If I could then for the last questions, if I could give it to the authors, what are your plans for next steps, if any. Maybe, Jukka, do you want to start first? Dr. Jukka Lehtonen: Well, I think cardiac sarcoidosis has lots of open questions. It has only open questions. I think the direction we are going is to go to the drug trial. So whether treatment of the inflammation by different agents would provide benefit in terms of arrhythmias and heart failure. So there's an idea that take patients with, for example, that's something that we haven't finalized yet, but take patients with normal ejection fraction, randomized them to cortisone and no cortisone and see how they do. Because we don't really know whether even corticosteroids actually make a huge difference. I think we have more than 200 cardiac sarcoid patients under follow up in our hospital. And I can see that there are patients that have very good prognosis and no events whatsoever over many years or even decade. And then we have other patients that have lots of events, arrhythmias and develop heart failure. So I think we need trials that help us to distinguish those patients and also trials that help us select right medications for each group. Dr. Carolyn Lam: Thank you, Hannah? Dr. Hanna-Kaisa Nordenswan: Based on this particular study, we think that also the next study should preferably be a larger multicenter study that would focus on the prognostic factors in cardiac sarcoidosis. Perhaps, a risk score could be developed by using more detailed information of the presenting manifestations and ventricular function and imaging findings, cardiac magnetic resonance and positron emission tomography. Dr. Mark Link: Yeah. And we at the editorial staff thought this was important enough paper to have an editorial, to comment on its usefulness and way forward in dealing with cardiac sarcoid patients. And this editorial is written by Rick Patton and will accompany the printed issue. Dr. Carolyn Lam: Thanks. And so, you heard it, everyone pick up that editorial, pick up that paper. This is an important topic, and so grateful that it was published with us. Thank you once again to the authors. Thank you once again, Mark, for managing this paper. So lovely. And thank you, audience for joining us today from Greg and I, you've been listening to Circulation on the Run. Don't forget to tune in again next week. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.
700 Seiten umfassen die Unterlagen, die Moderna zur Zulassung seines mRNA-Corona-Impfstoffs eingereicht hat. 400 Seiten und zwei Drittel der Studien beschäftigten sich jedoch nicht mit „Spikevax“, sondern mit „irrelevanten“ und nicht zugelassenen mRNAs. Lediglich zwei bezogen sich auf die Sicherheit des eigentlichen Impfbausteins – hielten sich aber nicht an die gute Laborpraxis. Web: https://www.epochtimes.de Probeabo der Epoch Times Wochenzeitung: https://bit.ly/EpochProbeabo Twitter: https://twitter.com/EpochTimesDE YouTube: https://www.youtube.com/channel/UC81ACRSbWNgmnVSK6M1p_Ug Telegram: https://t.me/epochtimesde Gettr: https://gettr.com/user/epochtimesde Facebook: https://www.facebook.com/EpochTimesWelt/ Unseren Podcast finden Sie unter anderem auch hier: iTunes: https://podcasts.apple.com/at/podcast/etdpodcast/id1496589910 Spotify: https://open.spotify.com/show/277zmVduHgYooQyFIxPH97 Unterstützen Sie unabhängigen Journalismus: Per Paypal: http://bit.ly/SpendenEpochTimesDeutsch Per Banküberweisung (Epoch Times Europe GmbH, IBAN: DE 2110 0700 2405 2550 5400, BIC/SWIFT: DEUTDEDBBER, Verwendungszweck: Spenden) Vielen Dank! (c) 2022 Epoch Times
Vidcast: https://youtu.be/VkvPO5zGP18 Several days ago I reported that the Moderna Omicron Booster slated to be approved by the FDA and then the CDC for distributed was their bivalent mRNA 1273.214 vaccine. This vaccine contains mRNA that would encode for the original CoVid strain and the Omicron B.1 subvariant. This vaccine had been tested in a human clinical trail. It turns out that just before the FDA panel was considering their application, Moderna submitted another EUA application for a bivalent vaccine that contained mRNA to encode for spike proteins from the Omicron BA.4./BA.5 subvariants. This was the one that was approved. So it turns out that both the Moderna and the Pfizer Omicron Boosters approved by the FDA and CDC both contain mRNAs that encode for both the original CoVid and the Omicron subvariants BA.4/BA.5. If it is time for your booster, which is the case for most of us, take your choice! https://investors.modernatx.com/news/news-details/2022/Moderna-Receives-FDA-Authorization-for-Emergency-Use-of-Omicron-Targeting-Bivalent-COVID-19-Booster-Vaccine-for-Adults-18-Years-and-Older/default.aspx #moderna #omicron #booster #ba5 #pfizer
Vidcast: https://youtu.be/874VfupQy_I Pfizer has developed two Omicron-targeting boosters: one is their Omicron BA.1 adapted vaccine and the other is their Omicron BA.4/BA.5 adapted vaccine. The former has been tested in humans while the latter has only been tested in mice and human studies are expected to begin soon. Pfizer has applied to the FDA and the European Medicines Agency for EUAs for both versions. The BA.1 version contains mRNAs that encode for the antigens associated with both the original CoVid version and the Omicron BA.1 subvariant. The BA.4/BA.5 version contains the same mRNAs that encode for the antigens associated with both the original CoVid version but also mRNAs the encode for Omicron BA.4 and BA.5 subvariant antigens. Pfizer has human data only for the BA.1 version and that shows a 9.1 fold rise in protective antibodies against BA.1. There is no human data regarding this booster's protective antibodies against BA.4/BA.5. The mouse data shows shows a good protective antibody boost. The FDA has today approved the BA.4/BA.5 adapted version without human test data. Scientists there have accepted Pfizer's argument that this booster is fundamentally similar to their original vaccine and BA.1 booster in efficacy and safety. We'll see tomorrow what the CDC decides before release to the general public. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-announce-omicron-adapted-covid-19 #pfizer #CoVid #vaccine #booster #omicron #ba1 #ba5
On this episode, Alex Amram and Joe Daccache interview special guest, Jacob Becraft the CEO and co-founder of Strand Therapeutics— a company leveraging synthetic biology to create the next-generation of messenger RNA (mRNA) therapeutics using a platform of programmable, precise, and multi-functional mRNAs through the implementation of genetic logic circuits and other genomic features.
We get to rebuild the world that we want to live in and we will. We'll start by doing that in our own communities. As scary and uncomfortable as that feels, we were born for this day and we get to actually create the world that you and I have been talking about and envisioning for so many years. - Leslie Manookian Are You Stressed Out Lately? Take a deep breath with the M21™ wellness guide: a simple yet powerful 21 minute morning system that melts stress and gives you more energy through 6 science-backed practices and breathwork. Click HERE to download for free. Is Your Energy Low? Get more superfoods to improve your energy, digestion, gut health plus also reduce inflammation and blood sugar. Click HERE to try Paleovalley's Apple Cider Vinegar Complex + Save 15% with the code 'JOSH' *Review The WF Podcast & WIN $150 in wellness prizes! *Join The Facebook Group Wellness + Wisdom Episode 443 President and Founder of the Health Freedom Defense Fund as well as Award-winning Filmmaker of The Greater Good, Leslie Manookian, shares how companies make statistics favor their financial goals, unpacks the spiritual and informational war that is happening right now, explains the misuse of medical interventions, and provides information for what you can do right now for the right to bodily autonomy. How much do you know about health freedom laws? Do you know what medical providers and government officials are allowed and not allowed to do when it comes to bodily autonomy? Leslie Manookian returns this week to share how the Health Freedom Defense Fund is helping people all across the nation. Shop the BEST Organic Snacks at PaleoValley Save 15% with the code 'JOSH' PaleoValley's 100% Grass-Fed Beef Sticks Paleovalley 100% Grass Fed Beef Sticks are the only beef sticks in the USA made from 100% grass fed/grass finished beef and organic spices that are naturally fermented. Their 100% Grass Fed Beef Sticks are unlike anything else on the market. In fact, they were recently voted in Paleo Magazine as one of the top snacks of the year. The reason is that they are committed to making the highest quality, clean products that are free from problematic ingredients. Their beef comes from 100% grass fed cows raised entirely on natural grass pastures by family farmers right here in the USA. As a result they are healthy and happy. PaleoValley's Pasture-Raised Turkey Sticks Paleovalley Pasture-Raised Turkey Sticks were created to make healthy snacking easier. Their turkey sticks are made from turkeys who are allowed to live as nature intended... on organic grass pastures with plenty of sunshine, fresh air and room to exercise. The result of raising turkeys in such a natural way is a much healthier, clean protein with higher levels of vitamins, minerals, and omega-3s. Unfortunately, virtually all turkey in the USA is conventionally raised with a small portion being "free range" – a virtually meaningless term that simply means the turkeys were allowed access to the outdoors. However, most "free range" turkeys only have access to an outdoor dirt field with no pasture in sight. Their truly pasture-raised turkeys are given full access to outdoor, pesticide-free pasture with plenty of grass and insects for them to nibble on. Listen To Episode 443 As Leslie Manookian Uncovers: [1:30] The Health Freedom Defense Fund Leslie Manookian CV 19 Truth Series: Protecting Your Health Freedom The Greater Good 344 Leslie Manookian: CV 19 - The Truth About Flattening The Curve Health Freedom Defense Fund Leslie's background of doing 10-15 very intense years of research on health and medical intervention. Her past career working for Goldman Sachs and her involvement in the early years of telecom and running research teams. What she witnessed while working on Wall Street that she found very disquieting about pharmaceutical companies. Her own health issues and why neither she nor her doctor could understand what was wrong and western medicine couldn't cure her so they sent her to visit a homeopathic practitioner. Vaccines Are They Really Safe and Effective? by Neil Z. Miller The moment she first heard about the medical intervention debate and began looking into it. Why she decided to start the Health Freedom Defense Fund. What lawsuits they have filed and the current status on some of them including mask and medical intervention mandates. [18:00] Bodily Autonomy Unpacking what bodily autonomy is and how it plays a part in protecting our sovereign selves. Josh and Carrie's own experience taking Novah to the NICU and how they were treated for taking their son home before the hospital wanted them to. Her research on bodily autonomy and the 3 major things that people should be taking into account. Vaccine Adverse Event Reporting System (VAERS) Indiana life insurance CEO says deaths are up 40% among people ages 18-64 Deaths associated with newly launched SARS-CoV-2 vaccination (Comirnaty®) VERIFY: CDC & FDA data doesn't support false claims thousands have died from COVID-19 vaccines Arizona police officers forcibly removed 2-year-old boy with fever from home, video shows [34:45] How to Make Statistics Lie How to Lie with Statistics by Darrell Huff What the data about CV 19 and medical intervention are telling us today. How you can make statistics about CV 19 lie and where we're seeing this in the media. Why there is such a small chance of getting CV 19 without the medical intervention compared to getting it. The dramatic decrease we saw in numbers from the CDC at the same moment Russa invaded Ukraine. Why not all adverse reactions to vaccines have been reported to VEARS. The number of people who experience reactions according to the research data. [41:35] The HFDF's Mission Fighting Mandates The Health Freedom Defense Fund's mission and how they operate. Some of the team members of HFDF and how they've contributed to the mission with their expertise. The incredible demand for assistance they have received and so much so that they haven't been able to help with every case yet. How they're guiding the people that they're unable to help right now to form their own groups and find support amongst themselves. Their current law fight with Los Angeles as well as with other organizations throughout the country and what positive results Leslie hopes will come from it. Where is Fauci? Questioning why he has been out of the spotlight for a while now and why. Rising health concerns for people who do receive the medical intervention compared to those who do not. [57:00] The Spiritual & Informational War Joe Rogan Experience #1757 – Dr. Robert Malone, MD Full Transcript Yuval Harari on Transhumanism and The Singularity The misuse of mRNAs as spoken about by the patent owner himself, Robert Malone. Breaking down the spiritual and informational war that we are in the middle of right now. Why she believes that globalism is the problem and localism is the solution and what that means for our modern world. The power we have to do everything that we can to develop a local food system, a local currency, and a true healthcare system. What the government's plan to regulate cryptocurrency could mean for the USA and our monetization system. 442 Robert Breedlove What collectivism is and how it's present in the USA and its connection to our current cancel culture and the need for dialogue dilemma. Why we're no longer on the same page as a culture educationally or morally. [1:04:30] Our Moral Fight for Freedom The duty we have to defend our country and why it's not okay that we have become so relaxed with it. Who Martin Armstrong is and the economical models he's created that Leslie believes we should pay attention to. Armstrong Economics Why it's predicted that the USA will divorce into those who do care to fight for our freedom and those who don't by 2032. The dark nights of the soul that Leslie has gone through since the start of 2020 and lockdowns began to happen. How we can begin rebuilding the world that we want to live in by starting with our own local communities with a positive vision. What wellness means to her now compared to when Josh interviewed her in 2020. Why the mass resignation is a sign that people are waking up and they don't want to be mindless robots, they want to do something that empowers them and serves their inner purpose. Power Quotes From The Show The Ongoing Spiritual War "We are in a spiritual and informational war; it's just that most people don't realize it because no shots have been fired in this country. The spiritual war is between those who believe that you're nothing more than a bag of bones and those who believe, like you and I do, that we're much greater, more powerful, and more important beings than that. I personally believe that we are individual points of consciousness; spiritual beings having a physical experience here on this planet." - Leslie Manookian Globalism is the Problem, Localism is the Solution "We have to lead with love. My new mantra is, 'Globalism is the problem, localism is the solution.' When I say that, what I mean is that we need to come together and build, strengthen, fortify, and reclaim our communities. We must reclaim them from the powers that are trying to centralize them under a one world's government. That means doing everything you can to develop a local food system, a true healthcare - not sickcare - system, and even create a local currency." - Leslie Manookian How to Live Life Well in 2022 "Part of our modern-day crisis is that people are waking up and realizing that maybe they're not happy with what they're doing with their lives. They don't want to be mindless robots; they want to be something else and I think that is really critical. You have to do something that actually fulfills and inspires you; I don't think you can be well unless you are doing that. Second, I think you have to keep working on yourself; whether it's your anxiety or your anger to the point that you recognize your behavior patterns and take action to change. Lastly; you have to have community. You need that support system when you face events like the ones since 2020." - Leslie Manookian Links From Today's Show CV 19 Truth Series: Protecting Your Health Freedom Health Freedom Defense Fund Grand Jury Day Five with Leslie Manookian Health Freedom Defense Fund Interviews 344 Leslie Manookian: CV 19 - The Truth About Flattening The Curve Vaccines Are They Really Safe and Effective? by Neil Z. Miller Arizona police officers forcibly removed 2-year-old boy with fever from home, video shows Vaccine Adverse Event Reporting System (VAERS) How to Lie with Statistics by Darrell Huff Joe Rogan Experience #1757 – Dr. Robert Malone, MD Full Transcript Yuval Harari on Transhumanism and The Singularity 442 Robert Breedlove Armstrong Economics Supporting Research And Fact Check For The Greater Good Indiana life insurance CEO says deaths are up 40% among people ages 18-64 Deaths associated with newly launched SARS-CoV-2 vaccination (Comirnaty®) VERIFY: CDC & FDA data doesn't support false claims thousands have died from COVID-19 vaccines Lawsuit: Leslie sued Biden (3), Los Angeles, San Francisco CDC's new approach to covid means most Americans can go without masks Shop the Wellness Force Store breathwork.io Paleovalley – Save 15% on your ACV Complex with the code ‘JOSH' Seeking Health - Save 10% with the code 'JOSH' Organifi – Special 20% off to our listeners with the code ‘WELLNESSFORCE' Drink LMNT – Zero Sugar Hydration: Get your free LMNT Sample Pack, you only cover the cost of shipping Botanic Tonics – Save 40% when you use the code ‘WELLNESS40' Essential Oil Wizardry: Save 10% with the code 'WELLNESSFORCE' Cured Nutrition – Get 15% off of your order when you visit wellnessforce.com/cured + use the code ‘WELLNESSFORCE' M21 Wellness Guide Wellness Force Community Leave Wellness Force a review on iTunes Leslie Manookian Facebook YouTube Twitter The Greater Good Facebook Twitter YouTube About Leslie Manookian Leslie Manookian is an award-winning documentary film producer and writer and former successful Wall Street business executive. She chose to leave Wall Street at the height of her career in order to pursue a more meaningful path. She is also a qualified homeopath, nutrition and wellbeing junky, and a health freedom advocate. Originally from Idaho, Manookian's career in finance took her from New York to London with Goldman Sachs. She later became Director of Alliance Capital in London running their European Growth Portfolio Management and Research business. She has been featured in a cover article in Barron's, in numerous other financial publications, in dozens of TV, radio, print and Internet interviews, and a presenter at numerous conferences. Research on Medical Interventions She learned of the medical intervention debate while living and working in London and determined that one day she would make a documentary exploring the issue. The Greater Good movie is the result. She is Chapter leader for the Weston A. Price Foundation and advocates for nutrient dense traditional foods and sustainable farming. She has served on the board, managed or consulted for many organizations in her community. Leslei has been active legislatively, playing a leading role in defeating the extension of a medical intervention-tracking registry in Idaho and helping to secure legislation protecting consumer access to raw milk. She holds an MBA from the University of Chicago and a BA from Middlebury College. The Greater Good The award-winning documentary The Greater Good is the result of 11 years of work. She has also been featured in dozens of TV, radio, print and internet interviews as well as appearing at numerous conferences discussing medical intervention issues. Furthermore, Leslie has been featured in a cover article in Barron's as well as in other financial publications. In addition, Leslie has served on the board, managed or consulted for many organizations in her community and successfully led the charge to defeat a proposed coal plant in her state and helped secure legislation providing consumer access to raw milk. She holds an MBA from the University of Chicago and a BA from Middlebury College.
This podcast is about two scientists, Dr. Patrik Ståhl and Dr. Fredrik Salmén, who are joint first authors of a paper that kickstarted a field. It's about finding work they did with colleagues to enable finding out where in tissue gene expressions is happening. It's called spatially resolved transcriptomics. It is a Nature Methods Method of the Year and I did a story about it here: https://www.nature.com/articles/s41592-020-01033-y . This is a podcast series that shares more of what I found out in my reporting. The piece is about patience, stamina, friendship, surfing the Baltic Sea, genomics and imaging. [00:00:05.560] - Vivien MarxHi and welcome to Conversations with Scientists, I'm Vivien Marx. This podcast is with and about two scientists and about space space in biology. Actually, you'll meet Patrik Ståhl. He's on the faculty of KTH Royal Institute of Technology in Stockholm, Sweden, and Fredrik Salmén, who is currently a postdoctoral fellow at Hubrecht Institute in the Netherlands. They will talk about a field.[00:00:33.280] - Patrik StåhlThe whole field. It's really it's it's an awesome field.[00:00:36.940] - Vivien That's Patrik Ståhl. Their work led to a major publication in the journal Science, and they are both joint first authors of this paper,[00:00:47.710] - Patrik StåhlWe share the honor[00:00:47.710] - Fredrik Salménand the pain.[00:00:47.710] - Vivien The honor and the pain. That's research for you. Just briefly, before we get to that about this podcast series, in my reporting, I speak with scientists around the world, and this podcast is a way to share more of what I find out. This podcast takes you into the science, and it's about the people doing the science. You can find some of my work, for example, in Nature journals that are part of the nature portfolio. That's where you find studies by working scientists.[00:01:19.960] - Vivien And those are about the latest aspect of their research in a number of these journals offer science journalism. These are pieces by science journalists like me. This podcast episode is one of several I'm producing about space in biology. Months ago, I interviewed researchers who work on Spatially resolved transcriptomics for a story and in my slowpokey DIY podcast production. This is part one in a series about this field of study. So Patrik Stahl and Fredrik Salmen here they are introducing themselves to help me learn how to pronounce their names.[00:02:02.890] - Patrik Ståhl Fredrik you go first.[00:02:03.560] - Fredrik SalménFredrik Salmén. [00:02:12.290] - Vivien All right. I have to practice. OK, so in[00:02:16.750] - Patrik StåhlEnglish it's Patrick. It's Patrik Stahl.[00:02:21.650] - Vivien Patrick Sahl? So no t, Stahl[00:02:29.210] all right, you have to brace yourselves.[00:02:33.980] - Patrik StåhlStahl means steel in English,[00:02:36.393] - Patrik StåhlPatrik Ståhl[00:02:36.780] - Vivien Wow I apologize . Despite their lessons, I am doing the Swedish pronunciation of their names badly. I hope they and Sweden will forgive me. So I interviewed these two Swedish scientists together and when we started to chat, I noticed a poster on the wall behind Fredrik Salmen. It showed a surfer riding a big wave. So I asked about that.[00:03:03.530] - Patrik StåhlFredrik actually quite advanced surfer, like wave surfer at the time when we started this project.[00:03:14.540] - Fredrik SalménYah, it's true. Oh, it's actually me. It's a little bit self-centered, I guess, to have their own picture on the wall. But it's fun, though. It's[00:03:27.620] - Vivien where was this taken?[00:03:30.290] - Fredrik SalménThis is actually Sweden. So it's the Baltic Sea.[00:03:35.900] - VivienThe Baltic Sea is cold. You need to wear a special suit if you want to surf there.[00:03:41.240] - Fredrik SalménYeah. It's like a frog suit with hood and gloves and boots.[00:03:45.920] - VivienSo do you still do this or.[00:03:48.320] - Fredrik SalménYeah, I still do. I'm a little bit, I would say much less nowadays and I'm also a little bit heavier these days, so not as agile anymore. But still when I get the opportunity I try to surf, it's nice. [00:04:06.020] - Vivien The two researchers worked together along with many others, but their connection was quite intense and you will hear more about that in this podcast.[00:04:13.260] - VivienIt was work that took around six years and led to a publication in the journal Science. And that publication kick-started a field. And there was a company spin out to the field of study is called spatially resolved transcriptomics, and it was crowned a Nature Methods method of the year. In this area of spatially resolved transcriptomics, scientists want to know where something takes place. It's part of understanding larger issues, such as why does the head grow where it does?[00:04:44.750] - Vivien Why does a part of the brain develop where it does? Why does a tumor grow where it does? It's genes that tune such events, genes are turned on or off, they are expressed at high levels or low levels or silenced, their expression can shift. With gene expression, it's like tissues are playing a kind of music, just one you need to find ways to hear. Patrik Stahl and Fredrik Salmen and their colleagues found one way to do just that.[00:05:15.370] - Vivien The work took place in Sweden. It involved surfing the cold waves of the Baltic, as you just heard. It's about friendship. It's about patience, about science, careers. If you're interested in any of that, as well as biology, genomics and imaging, please stick around. So this work in particular took six years and Fredrik Salmen and Patrik Stahl worked intensely together. They are the first authors of this paper in Science published in 2016, and it led to a company called Spatial Transcriptomics.[00:05:45.790] - Vivien What these scientists and their colleagues developed was a way to see where, for example, in a tissue genes are expressed. It's not the first way to do this, but it was a way to analyze a lot of mRNAs, a lot of gene transcripts at the same time. To understand why this matters, we can step back for a moment and consider a practical example that they told me about. A pathologist gets a tissue sample. It might be from a person who was just on the operating table.[00:06:13.300] - VivienThe tissue is prepared with chemical stains and then studied. The pathologist interprets what is going on in this tissue. Sometimes pathologists look at many tissue slides from many patients and want to compare them. In other cases, it is information that has to travel quickly to determine how a patient might need to be treated. Or the analysis is for a basic research lab that is studying a particular disease or development. As Patrik Stahl explains, scientists can look at a tissue slide and use stains and dyes to see what is happening there.[00:06:46.630] - VivienWell, sort of. This immunohistochemistry doesn't always answer all the questions of pathologist or other scientists might have[00:06:55.990] - Patrik StåhlSo I think this was like late 2009 and it was Jonas Frisen, who is a who is, s stem cell professor working at Karolinska Institute who is subjected to this kind of immunohistorchemistry a lot during his daily work. And I think that he was the one who first grew tired of a lack of spatial information that they could get out of a stain. And so late 2009, he contacted Joakim Lundeberg and they together in early 2010, initiated this project , trying and then...
Welcome back! Jason and Jeffrey sit down and discuss the week world and weirdness all from their neutral perspectives. Sunday podcasts are always part one to our bi weekly episodes which are generated from our live stream conversations on Youtube. Monday - The Guardian.Thousands march in Cuba amid economic crisishttps://www.theguardian.com/global-development/2021/jul/12/thousands-march-in-cuba-in-rare-mass-protests-amid-economic-crisisI'm here because of hunger, because there's no medicine, because of power cuts – because there's a lack of everything,” said a man in his 40s who didn't want to give his name for fear of reprisals.Tuesday - BloombergModerna's Next Act Is Using mRNA vs. Flu, Zika, HIV, and Cancerhttps://www.bloomberg.com/news/features/2021-07-14/moderna-mrna-targets-hiv-cancer-flu-zika-after-covid-vaccine?utm_source=twitter&utm_campaign=socialflow-organic&utm_content=businessweek&utm_medium=social&cmpid=socialflow-twitter-businessweekThe company has vaccines for 10 viruses that are in, or about to be in, human trials. These include three types of Covid-19 boosters that are in mid-stage trials, a seasonal flu shot that began its first human study in July, and HIV shots that are slated to begin studies later this year. Shots to combats cytomegalovirus, a ubiquitous bug that spreads through bodily fluids and is a common cause of birth defects; it's set to begin a Phase III trial this year in women of childbearing age. In the long term, Moderna is aiming to develop an annual super-shot that could suppress numerous respiratory ailments, including Covid, the flu, and others. “Our goal is to give you several mRNAs in a single shot at your local CVS or GP every August or September,” Bancel says.Wednesday - Public access AmericaVice President Harris Meets with Disabilities Advocates to Discuss Voting Rightshttps://www.whitehouse.gov/briefing-room/speeches-remarks/2021/07/14/remarks-by-vice-president-harris-before-meeting-with-disabilities-advocates-to-discuss-voting-rights/Something has happened. The damn is breaking and the mainstream media is getting the message. “Yes. The active measures by republicans to disenfranchise Americans across the country disproportionately affects black and brown voters, But it also drastically disproportionately affects the 38 million voting age disabled folks living in America right now”. What Republicans are taking away may be options to most, but to the disabled, these things are accommodations, agreed to by the government, and once granted can not be just taken away. We count on a variety of accommodations because we are a diverse demographic. If you make this an African American thing, people will brush it off as an African American problem. If you can imagine the intersectionality voter suppression affects, you'll begin to build a coalition, There are 49 million disabled. 45 million Black Americans. Almost one third of the country. Hi Al Sharpton. My name is Jason. I'd like to be friends. Twitter @PublicAccessPodhttps://twitter.com/PublicAccessPodinstagram @PublicAccessAmericahttps://www.instagram.com/publicaccessamericaYouTube Live stream Sunday Noon est 9 am psthttps://www.youtube.com/c/PublicAccessAmericaPodcast/featuredfacebookhttps://www.facebook.com/PublicAccessAmericaSupport this podcast at — https://redcircle.com/public-access-america/exclusive-contentAdvertising Inquiries: https://redcircle.com/brandsPrivacy & Opt-Out: https://redcircle.com/privacy
My AP Biology Thoughts Unit 6 Gene Expression and RegulationWelcome to My AP Biology Thoughts podcast, my name is Saarim Rizavi and I am your host for episode #108 called Unit 6 Gene Expression and Regulation: Translation. Today we will be discussing everything there is to know about translation. I will first be giving a brief overview of what translation is, it's overall function, the 3 steps involved in translation, and some of the different components and organelles involved in translation. I'll then go into greater detail on the individual steps of translation which will involve the organelles and different components mentioned before. Finally, I will relate the process of translation to the broader topic of gene expression and regulation. Before I begin, I would like to give credit to Khan Academy, biologydictionary.com, and nature.com for the information they provided me with in order for this podcast to be possible. So thanks to them. Alright, so here we go: Segment 1: Introduction to TranslationTranslation is the process of creating proteins from an mRNA template A cell reads information from mRNA molecules and uses this information to build a protein - involves decoding an mRNA and using its information to build a polypeptide, and multiple polypeptide chains form a protein Three basic steps of translation - initiation, elongation, and termination Initiation - the ribosomes get together with the mRNA and the first tRNA so translation can begin Elongation - the amino acids are brought to the ribosome by tRNAs and linked together to form a chain of amino acids Termination - the finished polypeptide is released to go and do its job in the cell In mRNA, the instructions for building a polypeptide come in groups of 3 nucleotides called codons - there are 61 codons for amino acids and each of them is read to specify a certain amino acid out of the 20 possible amino acids Stop codons tell the cell when polypeptide is complete and the AUG codon is the start codon which signals the start of protein construction In translation, the codons of an mRNA are read in order, from the 5' end to the 3' end, by tRNAs. tRNA's = molecular bridges that connect mRNA codons to the amino acid they encode One end of the tRNA has a sequence of 3 nucleotides called an anticodon, which binds to a matching mRNA codon through base pairing; the other end of the tRNA carries the amino acid specified by the codons tRNAs bind to mRNAs inside the ribosomes - ribosomes are made up of protein and ribosomal RNA The ribosomes provide a set of slots where tRNAs can find their matching codons on the mRNA template and deliver their amino acids. As these tRNAs enter slots in the ribosome and bind to codons, their amino acids are linked to the growing polypeptide chain in a chemical reaction. Segment 2: More About Translation Initiation Ribosome, an mRNA with instructions for the protein to be built, and an initiator tRNA carrying the first amino acid in the protein - these components come together to form the initiation complex which is the molecular setup needed to make a new protein The tRNA carrying the methionine attaches to the small ribosomal subunit - they bind to the 5' end of the mRNA by recognizing the 5' GTP cap which was added during processing in the nucleus They go along the mRNA in the 3' direction, stopping when they reach the start codon (eukaryotic cells) In bacteria, the small ribosomal subunit attaches directly to certain sequences in the mRNA - these Shine-Dalgarno sequences mark the start of each coding sequence, letting the ribosome find the right start codon for each gene. Elongation The amino acid chain gets longer and the mRNA is read one codon at a time, and the amino acid matching each codon is added to a growing protein chain Detailed: The first methionine- carrying tRNA (methionine is an amino acid specified by the start codon, AUG) starts out in the middle slot of the ribosome,...
In their latest episode, Amanda & Mel tackle the vastly important topic of COVID-19 & Vaccines. Understanding the sensitivity around this hot topic, the duo aim to present facts, research and details to equip their audience with easy-to-digest information without any bias. Amanda & Mel rely on personal experience, research studies and info from The Whole View, a podcast by Dr. Sarah Ballantyne, PhD & Stacy Toth to bring you this very special episode. Intro: Decisions, Disclaimers & Details (1:27) Topic: COVID-19, mRNA Vaccines & Chronic Illness Mel's Covid Journey (6:00) Is it Covid or Chronic Illness? (15:00) Things that Helped Deal with Covid-19 (17:35) What you need to make the big V decision (24:00) Vaccine Injury & Chronic Disease (28:41) mNRA Vaccines: How, What, Why (33:15) Vaccine & Chronic Illness Flares (40:00) Allergic Reactions to the V & Should I get the Second Dose (47:00) Myth Busting! (52:00) Menstruation, Hormones & Shedding (53:33) Do the mRNAs override our DNA? (1:01:00) Pregnancy & Pre-pregnancy (1:07:00) Can you get Covid-19 after getting Vaccinated? (1:19:00) Long Haul Symptoms and Moving Forward (1:29:00) Disclaimer: The content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. The scientific research and information provided in this episode were provided by Dr. Sarah Ballantyne, PhD of the Paleo Mom and The Whole View Podcast. If interested in references to the studies presented, please visit their website or listen to their vaccine series: episodes 440, 441, 443, 444, 454, and 455.
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