Podcasts about nf kb

If you enjoy this episode, we're sure you will enjoy more content like this on The Occult Rejects.  In fact, we have curated playlists on occult topics like grimoires, esoteric concepts and phenomena, occult history, analyzing true crime and cults with an occult lens, Para politics, and occultism in music. 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Lehmann, Mark S. Malhotra, Ralph F. Goldman, Jeffrey Hopkins, and Mark D. Epstein. “Body Temperature Changes During the Practice of g Tum-mo Yoga.” Nature 295 (1982): 234–236.Benson, Herbert, Mark S. Malhotra, Ralph F. Goldman, Gregory D. Jacobs, and Jeffrey Hopkins. “Three Case Reports of the Metabolic and Electroencephalographic Changes During Advanced Buddhist Meditation Techniques.” Behavioral Medicine 16, no. 2 (1990): 90–95.Bremer, Brandon, Lorenzo Wu, Zoran Josipovic, and colleagues. “Mindfulness Meditation Increases Default Mode, Salience, and Central Executive Network Connectivity.” Scientific Reports 12 (2022).Brewer, Judson A., Patrick D. Worhunsky, Jeremy R. Gray, Yi-Yuan Tang, Jochen Weber, and Hedy Kober. “Meditation Experience Is Associated with Differences in Default Mode Network Activity and Connectivity.” Proceedings of the National Academy of Sciences 108, no. 50 (2011): 20254–20259.Britton, Willoughby B. and colleagues. Research associated with the “Varieties of Contemplative Experience” project on meditation-related challenges, adverse effects, and safety considerations in contemplative practice.Crowley, Aleister. Liber E vel Exercitiorum sub figura IX. In the A∴A∴ training corpus. Relevant sections include asana, pranayama, and dharana as foundational magical exercises.Dennison, Paul. “Insights From an EEG Study of Buddhist Jhāna Meditation.” Frontiers in Human Neuroscience 13 (2019).Fialoke, Shantala, Helen Weng, and colleagues. “Functional Connectivity Changes in Meditators and Novices During Yoga Nidra Practice.” Scientific Reports 14 (2024).Fox, Kieran C. R., Savannah Nijeboer, Matthew L. Dixon, James L. Floman, Melissa Ellamil, Samuel P. Rumak, Peter Sedlmeier, and Kalina Christoff. “Is Meditation Associated with Altered Brain Structure? A Systematic Review and Meta-analysis of Morphometric Neuroimaging in Meditation Practitioners.” Neuroscience & Biobehavioral Reviews 43 (2014): 48–73.Hölzel, Britta K., James Carmody, Mark Vangel, Christina Congleton, Sita M. Yerramsetti, Tim Gard, and Sara W. Lazar. “Mindfulness Practice Leads to Increases in Regional Brain Gray Matter Density.” Psychiatry Research: Neuroimaging 191, no. 1 (2011): 36–43.Kozhevnikov, Maria, Olesya Louchakova, Zoran Josipovic, and Michael A. Motes. “The Enhancement of Visuospatial Processing Efficiency Through Buddhist Deity Meditation.” Psychological Science 20, no. 5 (2009): 645–653.Kozhevnikov, Maria, John A. Elliott, Jennifer Shephard, and Klaus Gramann. “Neurocognitive and Somatic Components of Temperature Increases During g-Tummo Meditation: Legend and Reality.” PLOS ONE 8, no. 3 (2013): e58244.Laukkonen, Ruben E., and Heleen A. Slagter. “From Many to (N)one: Meditation and the Plasticity of the Predictive Mind.” Neuroscience & Biobehavioral Reviews 128 (2021): 199–217.Lomas, Tim, Juan Carlos Ivtzan, and Itai K. Fu. “A Systematic Review of the Neurophysiology of Mindfulness on EEG Oscillations.” Neuroscience & Biobehavioral Reviews 57 (2015): 401–410.Lott, James P., Richard J. Davidson, John D. Dunne, Thupten Jinpa, Antoine Lutz, and colleagues. “No Detectable Electroencephalographic Activity After Clinical Declaration of Death Among Tibetan Buddhist Meditators in Apparent Tukdam.” Frontiers in Psychology 11 (2021): 599190.Lutz, Antoine, Lawrence L. Greischar, Nancy B. Rawlings, Matthieu Ricard, and Richard J. Davidson. “Long-term Meditators Self-induce High-amplitude Gamma Synchrony During Mental Practice.” Proceedings of the National Academy of Sciences 101, no. 46 (2004): 16369–16373.Lutz, Antoine, Julie Brefczynski-Lewis, Tom Johnstone, and Richard J. Davidson. “Regulation of the Neural Circuitry of Emotion by Compassion Meditation: Effects of Meditative Expertise.” PLoS ONE 3, no. 3 (2008): e1897.Matko, Karin, Peter Sedlmeier, and colleagues. “Adverse Effects of Meditation and Mindfulness in Clinical Practice.” 2025.Patanjali. Yoga Sutras. Especially Book III, traditionally describing dharana, dhyana, and samadhi.Riegner, Gretchen, Fadel Zeidan, and colleagues. “Disentangling Self from Pain: Mindfulness Meditation-Induced Pain Relief Is Driven by Thalamic-Default Mode Network Decoupling.” Pain 164, no. 2 (2023): 280–291.Tang, Yi-Yuan, Britta K. Hölzel, and Michael I. Posner. “The Neuroscience of Mindfulness Meditation.” Nature Reviews Neuroscience 16 (2015): 213–225.Vago, David R., and David A. Silbersweig. “Self-awareness, Self-regulation, and Self-transcendence: A Framework for Understanding the Neurobiological Mechanisms of Mindfulness.” Frontiers in Human Neuroscience 6 (2012): 296.Zeidan, Fadel, and colleagues. Research on mindfulness meditation, pain modulation, attention, and the neural mechanisms of pain relief.Slagter, Heleen A., Antoine Lutz, Lawrence L. Greischar, Andrew D. Francis, Sander Nieuwenhuis, James M. Davis, and Richard J. Davidson. “Mental Training Affects Distribution of Limited Brain Resources.” PLOS Biology 5, no. 6 (2007): e138. Use for: Attentional blink, limited attention, and meditation changing how the brain allocates resources.Hölzel, Britta K., James Carmody, Mark Vangel, Christina Congleton, Sita M. Yerramsetti, Tim Gard, and Sara W. Lazar. “Mindfulness Practice Leads to Increases in Regional Brain Gray Matter Density.” Psychiatry Research: Neuroimaging 191, no. 1 (2011): 36–43. Use for: Neuroplasticity, repeated practice leaving measurable marks on the brain, and the “practice writes itself into the practitioner” idea.Laukkonen, Ruben E., and Heleen A. Slagter. “From Many to (N)one: Meditation and the Plasticity of the Predictive Mind.” Neuroscience & Biobehavioral Reviews 128 (2021): 199–217. Use for: Predictive processing, the brain as a prediction machine, meditation loosening automatic models, and the “veil” argument.Lutz, Antoine, Julie Brefczynski-Lewis, Tom Johnstone, and Richard J. Davidson. “Regulation of the Neural Circuitry of Emotion by Compassion Meditation: Effects of Meditative Expertise.” PLOS ONE 3, no. 3 (2008): e1897. Use for: Compassion meditation, loving-kindness, emotional circuitry, and training compassion as a repeatable state rather than just a moral idea.Kok, Bethany E., Kimberly A. Coffey, Michael A. Cohn, Lahnna I. Catalino, Tanya Vacharkulksemsuk, Sara B. Algoe, Marc A. Brantley, and Barbara L. Fredrickson. “How Positive Emotions Build Physical Health: Perceived Positive Social Connections Account for the Upward Spiral Between Positive Emotions and Vagal Tone.” Psychological Science 24, no. 7 (2013): 1123–1132. Use for: Loving-kindness, social connection, vagal tone, and the cautious “social nervous system” bridge.Black, David S., and George M. Slavich. “Mindfulness Meditation and the Immune System: A Systematic Review of Randomized Controlled Trials.” Annals of the New York Academy of Sciences 1373, no. 1 (2016): 13–24. Use for: Immune-system caution, inflammation markers, cell-mediated immunity, biological aging, and why this material should be framed as tentative rather than miracle healing.Burić, Ivana, Miguel Farias, Jonathan Jong, Christopher Mee, and Inti A. Brazil. “What Is the Molecular Signature of Mind–Body Interventions? A Systematic Review of Gene Expression Changes Induced by Meditation and Related Practices.” Frontiers in Immunology 8 (2017): 670. Use for: Stress biology, inflammatory gene expression, NF-kB-related language, and the cautious claim that mind-body practices may affect biology below ordinary mood.Also want to remind people about the website, if you're into reading we have tons of information by multiple contributors, and we got t-shirts up on the site if you're interested. Fun fact, the art is all based on the eyeball. A

What if loneliness isn't just an emotion… but one of the most dangerous biological threats to your health? In this deeply personal and scientifically explosive solo episode, Darin opens up about something he recently realized in his own life: despite being surrounded by people, he was lonely. But what began as an emotional realization quickly became a deep dive into some of the most shocking research he's ever uncovered, showing that chronic loneliness may increase the risk of heart disease, dementia, cancer, autoimmune dysfunction, accelerated aging, and early death. From inflammatory gene expression and cortisol dysregulation to oxytocin, vulnerability, and the collapse of real human connection in the digital age, this episode reveals why loneliness may be the most overlooked "fatal convenience" of modern life, and how vulnerability may be the medicine. What You'll Learn Why loneliness is a biological crisis, not just an emotional feeling The shocking link between loneliness and heart disease, dementia, and early death Why the quality of your relationships is the #1 predictor of long-term health How loneliness activates inflammatory genes inside your body The role of cortisol, sleep disruption, and chronic stress in social isolation Why social media and "surface-level connection" are replacing real intimacy The connection between loneliness and Alzheimer's disease How oxytocin and genuine connection reduce inflammation Why vulnerability is the gateway to meaningful relationships Practical ways to create deeper connection starting today Chapters 00:00:33 – Sponsor: the truth about the exploding NAD supplement market 00:01:04 – Why supplement verification and transparency matter 00:02:17 – Opening: Darin admits something deeply personal 00:02:30 – "I realized recently… I'm lonely" 00:02:37 – The difference between being surrounded by people vs being truly known 00:03:06 – Loneliness as a biological experience, not just an emotional one 00:03:27 – The hidden risks: heart disease, dementia, cancer, early death 00:03:45 – Why this is not fringe science 00:04:13 – The most important predictor of long-term health 00:04:34 – Why relationship QUALITY matters more than quantity 00:05:06 – The global loneliness epidemic 00:05:11 – U.S. Surgeon General advisory on loneliness 00:05:39 – Loneliness declared a public health crisis 00:06:02 – 50% of Americans report measurable loneliness 00:06:22 – "A generational collapse of connection" 00:06:30 – 29% of adults have no close friends 00:06:40 – Face-to-face interactions dramatically declining 00:07:01 – The UK, Japan, and Australia loneliness crisis initiatives 00:07:32 – The paradox: hyperconnected but deeply isolated 00:08:04 – Loneliness as a biological alarm signal 00:08:31 – What loneliness actually looks like in modern life 00:08:42 – The lonely CEO, the unseen mother, the isolated social media addict 00:09:31 – "Perceived social isolation" and why the brain can't tell the difference 00:10:21 – Meta-analysis of 3.4 million people 00:10:55 – Loneliness vs obesity and smoking risk comparisons 00:11:18 – The biology of loneliness begins 00:11:50 – NF-kB: inflammatory gene activation explained 00:12:33 – How loneliness changes gene expression 00:13:02 – Chronic inflammation and disease pathways 00:13:21 – Cortisol, sleep disruption, and immune dysfunction 00:14:00 – How loneliness affects brain repair and amyloid plaque clearing 00:14:21 – Sponsor: Fatty15 and cellular health 00:18:02 – The Alzheimer's and dementia connection 00:18:25 – Loneliness as a major modifiable dementia risk factor 00:18:57 – Cortisol, neuroinflammation, and brain degeneration 00:19:16 – The hippocampus physically shrinking in lonely people 00:19:27 – Social media as a "fatal convenience" 00:19:57 – The oxytocin economy: connection as medicine 00:20:15 – Oxytocin as one of the body's strongest anti-inflammatory molecules 00:20:30 – HeartMath research: emotional synchronization between people 00:20:48 – "You regulate each other's biology" 00:21:07 – The real barrier: vulnerability 00:21:32 – Darin's recent experiences with radical vulnerability 00:21:54 – Conversations with family, ex-partners, and loved ones 00:22:35 – Brené Brown's research on connection and worthiness 00:23:14 – The "depth audit" exercise 00:23:42 – Reaching out, expressing appreciation, and owning your emotions 00:24:01 – Sacred hours: spending time without phones 00:24:13 – Questions that create real intimacy 00:24:30 – Darin's emotional conversation with his brother 00:25:03 – Protecting yourself from social media disconnection 00:25:20 – Becoming a source of joy and connection in everyday life 00:25:25 – Darin reflects on seven years of subtle loneliness 00:25:48 – The shift from surface conversations to meaningful connection 00:26:01 – "If you want love, give love" 00:26:19 – Final message: generate the connection you want to receive 00:26:22 – Closing thoughts and outro Thank You to Our Sponsors Truniagen: Go to www.truniagen.com and use code DARIN20 at checkout for 20% off Fatty15: Get an additional 15% off their 90-day subscription Starter Kit by going to fatty15.com/DARIN and using code DARIN at checkout. Join the SuperLife Community Get Darin's deeper wellness breakdowns — beyond social media restrictions: Weekly voice notes Ingredient deep dives Wellness challenges Energy + consciousness tools Community accountability Extended episodes Join for $7.49/month → https://patreon.com/darinolien Connect with Darin Olien: Website: darinolien.com Instagram: @darinolien Book: Fatal Conveniences Platform & Products: superlife.com New Show: Roadmap to Happiness Key Takeaway "Loneliness isn't weakness. It isn't failure. It's a biological signal telling you that something essential is missing. And in a world addicted to surface-level connection, the real medicine may simply be this: vulnerability, presence, eye contact, honesty, and the courage to let yourself truly be seen." Bibliography/Sources The Loneliness Epidemic & Public Health Data Bureau of Labor Statistics. (2023). American time use survey. U.S. Department of Labor. https://www.bls.gov/tus/ Cigna. (2023). Cigna U.S. loneliness index. Evernorth Health Services. https://newsroom.cigna.com/loneliness-epidemic-continues-to-rise-cigna-study Murthy, V. H. (2023). Our epidemic of loneliness and isolation: The U.S. Surgeon General's advisory on the healing effects of social connection and community. U.S. Department of Health and Human Services. https://www.hhs.gov/sites/default/files/surgeon-general-social-connection-advisory.pdf Survey Center on American Life. (2021). The state of American friendship: Change, challenges, and loss. American Enterprise Institute. https://www.americansurveycenter.org/research/the-state-of-american-friendship-change-challenges-and-loss/ Mortality & Systemic Health Risk Cohen, S., Doyle, W. J., Skoner, D. P., Rabin, B. S., & Gwaltney, J. M. (1997). Social ties and susceptibility to the common cold. JAMA, 277(24), 1940–1944. https://pubmed.ncbi.nlm.nih.gov/9200634/ Hawkley, L. C., & Cacioppo, J. T. (2010). Loneliness matters: A theoretical and empirical review of consequences and mechanisms. Annals of Behavioral Medicine, 40(2), 218–227. https://pubmed.ncbi.nlm.nih.gov/20396846/ Holt-Lunstad, J., Smith, T. B., Baker, M., Harris, T., & Stephenson, D. (2015). Loneliness and social isolation as risk factors for mortality: A meta-analytic review. Perspectives on Psychological Science, 10(2), 227–237. https://doi.org/10.1177/1745691614568352 Valtorta, N. K., Kanaan, M., Gilbody, S., Ronzi, S., & Hanratty, B. (2016). Loneliness and social isolation as risk factors for coronary heart disease and stroke. Heart, 102(13), 1009–1016. https://heart.bmj.com/content/102/13/1009 Genetics, Inflammation & The Immune System Cole, S. W. (2013). Social regulation of human gene expression: Mechanisms and implications for public health. American Journal of Public Health, 103(S1), S84–S92. https://pmc.ncbi.nlm.nih.gov/articles/PMC3786756/ Cole, S. W., Hawkley, L. C., Arevalo, J. M. G., Sung, C. Y., Rose, R. M., & Cacioppo, J. T. (2007). Social regulation of gene expression in human leukocytes. Genome Biology, 8(9), Article R189. https://pmc.ncbi.nlm.nih.gov/articles/PMC2375027/ Sleep & Cognitive Decline Cacioppo, J. T., Hawkley, L. C., Berntson, G. G., Ernst, J. M., Gibbs, A. C., Stickgold, R., & Hobson, J. A. (2002). Do lonely days invade the nights? Potential social modulation of sleep efficiency. Psychological Science, 13(4), 384–387. https://pubmed.ncbi.nlm.nih.gov/12137144/ Holwerda, T. J., Deeg, D. J. H., Beekman, A. T. F., et al. (2014). Feelings of loneliness, but not social isolation, predict dementia onset. Journal of Neurology, Neurosurgery & Psychiatry, 85(2), 135–142. https://jnnp.bmj.com/content/85/2/135 Oxytocin & The Biology of Connection Szeto, A., Sun-Suslow, N., Mendez, A. J., Hernandez, R. I., Wagner, K. V., & McCabe, P. M. (2017). Regulation of the macrophage oxytocin receptor in response to inflammation. American Journal of Physiology—Endocrinology and Metabolism, 312(2), E183–E189. https://journals.physiology.org/doi/full/10.1152/ajpendo.00424.2016 Uvnas-Moberg, K. (2003). The oxytocin factor: Tapping the hormone of calm, love, and healing. Da Capo Press. https://books.google.com/books?id=b-aKjQoB_nQC Psychology, Vulnerability & Relationship Science Aron, A., Melinat, E., Aron, E. N., Vallone, R. D., & Bator, R. J. (1997). The experimental generation of interpersonal closeness. Personality and Social Psychology Bulletin, 23(4), 363–377. https://doi.org/10.1177/0146167297234003 Brown, B. (2010). The gifts of imperfection: Let go of who you think you're supposed to be and embrace who you are. Hazelden Publishing. https://brenebrown.com/book/the-gifts-of-imperfection/ Cacioppo, J. T., & Patrick, W. (2008). Loneliness: Human nature and the need for social connection. W. W. Norton & Company. https://wwnorton.com/books/9780393335286 Dunbar, R. I. M. (2012). Bridging evolutionary approaches to the social brain and social bonding. In F. B. M. de Waal & P. F. Ferrari (Eds.), The primate mind. Harvard University Press. https://www.hup.harvard.edu/books/9780674063104 Dunbar, R. I. M. (2021). Friends: Understanding the power of our most important relationships. Little, Brown and Company. https://www.hachettebookgroup.com/titles/robin-dunbar/friends/9781408711736/ Waldinger, R., & Schulz, M. (2023). The good life: Lessons from the world's longest scientific study on happiness. Simon & Schuster. https://www.simonandschuster.com/books/The-Good-Life/Robert-Waldinger/9781982166694

Sleep and weight gain are directly connected. Poor sleep disrupts hormones, raises blood sugar, tanks testosterone and estrogen, causes fatty liver, and wrecks your gut. If you've been doing everything right and the scale won't move, your sleep could be the missing link. FEATURED PRODUCT Chill by MSW Nutrition is a powdered drink mix formulated to support your body's natural calming chemistry — exactly what's needed when chronic stress and cortisol overload are stealing your sleep. Featuring GABA, L-Theanine, myo-Inositol, Taurine, and Magnesium, Chill helps balance neurotransmitters, quiet the nervous system, and promote the deep, restorative sleep your hormones, metabolism, and weight depend on — all five mechanisms discussed in this episode.

In this episode, Dr. Jockers breaks down the truth about cellular inflammation and chronic disease, explaining how inflammation is a life-saving mechanism that can turn harmful when it persists. You'll learn how stressors like infections, nutrient deficiencies, and emotional turmoil create a cascade of inflammation that can damage your body over time.   Dr. Jockers dives into the science behind the cell danger response, showing how the body reacts to injury or threat, and what happens when it gets stuck in a self-perpetuating cycle. Discover the role of NFKB in amplifying inflammation and how it can be triggered by damage-associated or pathogen-associated molecular patterns.   Learn simple yet powerful strategies to calm inflammation, from proper sleep and movement to reducing toxin exposure and balancing your diet with anti-inflammatory nutrients. Dr. Jockers provides actionable tips on how to regain control and heal from chronic inflammation. In This Episode:  00:13 Show Welcome Overview 00:45 Health Coaching Plug 03:19 Inflammation Basics 03:52 Why Inflammation Saves 05:58 Modern Stress Overload 06:44 DAMPs PAMPs Explained 07:39 NFKB Riot Analogy 09:31 What Drives NFKB 14:49 Oxidative Stress Triggers 16:11 Omega Fats Prostaglandins 17:23 Cell Danger Response 17:44 Turn Off Inflammation 17:53 Lifestyle Sleep Sun Move 19:51 Nature Toxins Nutrients 22:10 Key Supplements List 23:02 Final Summary Outro   Looking for a delicious snack that's good for you? Paleovalley Superfood Bars are packed with organic, whole food ingredients like collagen protein, kale, and blueberries—providing all the nutrients your body needs. With flavors like Lemon Meringue and Red Velvet, you can enjoy a treat that supports gut health, joint function, and even wrinkle-free skin. Visit paleovalley.com/jockers and use the code JOCKERS to save 15% on your order today. Hair loss isn't just about age—it's about hair follicles getting stuck. AnaGain Nu by Purality Health uses a pea sprout extract clinically shown to reactivate follicles and boost regrowth. With their micelle liposomal delivery, your body absorbs it fast and effectively. Try it risk-free with a 180-day money-back guarantee and get a buy-one-get-one-free deal at RenewYourHair.com -  https://renewyourhair.com/drjm/DRJ.   When it comes to cooking, Chef Foundry offers the perfect solution with their P 600 ceramic cookware, which is free from Teflon, PFAS, and plastic coatings. Made with Swiss-engineered ceramic, this cookware makes it easy to prepare healthy meals without the toxins. Take 20% off with code SAFE20 at chefsfoundry.com/jockers and upgrade your kitchen today.     "Your body uses inflammation to prevent infections from spreading and becoming life-threatening." ~ Dr. Jockers     Subscribe to the podcast on: Apple Podcast Stitcher Spotify PodBean TuneIn Radio     Resources: Snack smarter and save 15% on Paleovalley Superfood Bars with code JOCKERS paleovalley.com/jockers Reignite hair growth with AnaGain Nu, risk-free with a 180-day guarantee and a buy-one-get-one-free deal!  RenewYourHair.com/drjm/DRJ Upgrade to P 600 ceramic cookware and save 20% with code SAFE20 today! chefsfoundry.com/jockers Connect with Dr. Jockers: Instagram – https://www.instagram.com/drjockers/ Facebook – https:/www.facebook.com/DrDavidJockers YouTube – https://www.youtube.com/user/djockers Website – https://drjockers.com/   If you are interested in being a guest on the show, we would love to hear from you! Please contact us here! - https://drjockers.com/join-us-dr-jockers-functional-nutrition-podcast/ 

Pain that creeps in, brain fog that lingers, weight that resists every effort—what if the culprit isn't “just getting older,” but inflammaging? We sit down with Dr. Shivani Gupta, author of The Inflammation Code, to connect ancient Ayurvedic wisdom with modern science and map out a practical plan for cooling chronic inflammation. Instead of chasing symptoms, we focus on the terrain: circadian rhythm, gut health, stress load, and daily rituals that nudge the body back into repair mode.Shivani shares a refreshingly doable morning routine—intention setting, hydration, tongue scraping, and early sunlight—that anchors your clock and digestion. She then walks us through soothing evening practices like dry brushing, abhyanga oil massage, and mineral baths to move lymph, calm the nervous system, and deepen sleep. We explore the concept of “mental inflammation,” how chronic stress inflames the body, and why short decompression breaks plus adaptogens such as ashwagandha and shatavari help regulate mood and resilience.We also dive into the science of turmeric: how curcumin modulates NF-kB and TNF-alpha, supports the gut lining, affects AMPK and sirtuins, and promotes neurogenesis and mitochondrial health. You'll hear when food sources are enough, when supplements make sense, how to boost absorption with black pepper and healthy fats, and key safety notes for blood thinners and kidney stone risk. For midlife women, Shivani emphasizes sleep as the non-negotiable lever—assessing progesterone, using calming botanicals, and protecting the 10–2 overnight window where the body clears inflammation.If you're ready to replace quick fixes with smart rhythms, spice up your meals with potent anti-inflammatory allies, and finally feel your energy return, this conversation offers a clear roadmap. Subscribe, share with a friend who needs actionable hope, and leave a review telling us which ritual or spice you'll try first.https://fusionaryformulas.com/            (Use LUFKIN15 for 15% off)Continue this conversation on SubStack: https://robertlufkinmd.substack.com Lies I Taught In Medical School : Free sample chapter- https://www.robertlufkinmd.com/lies/Complete Metabolic Heart Scan (LUFKIN20 for 20% off) https://www.innerscopic.com/Fasting Mimicking Diet (20% off) https://prolonlife.com/Lufkin Web: https://robertlufkinmd.com/X: https://x.com/robertlufkinmdYoutube: https://www.youtube.com/robertLufkinmd Instagram: https://www.instagram.com/robertlufkinmd/LinkedIn: https://www.linkedin.com/in/robertlufkinmd/TikTok: https://www.tiktok.com/@robertlufkinThreads: https://www.threads.net/@robertlufkinmdFacebook: https://www.facebook.com/robertlufkinmd Blu...

Join My Private Group: ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠https://theaxioncollective.manus.space/⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠Email List: ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠https://huntershealthhacks.beehiiv.com/⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠Get My Book On Amazon: ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠https://a.co/d/avbaV48Download⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠The Peptide Cheat Sheet: ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠https://peptidecheatsheet.carrd.co/⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠Download The Bioregulator Cheat Sheet: ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠https://bioregulatorcheatsheet.carrd.co/⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠1 On 1 Coaching Application: ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠https://hunterwilliamscoaching.carrd.co/⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠Book A Call With Me: ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠https://hunterwilliamscall.carrd.co/⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠Supplement Sources: ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠https://hunterwilliamssupplements.carrd.co/⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠Amazon Storefront: ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠https://www.amazon.com/shop/hunterwilliams/list/WE16G2223BXA?ref_=cm_sw_r_cp_ud_aipsflist_R7QWQC0P1RACB2ETY3DY⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠Socials:Instagram: ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠https://www.instagram.com/hunterwilliamscoaching/⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠Video Topic Request: ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠https://hunterwilliamsvideotopic.carrd.co/⁠⁠⁠⁠Today's episode is all about Viagra, but not in the way most people think about it. We're talking sildenafil for longevity, healthspan, and performance. The “little blue pill” has a reputation as an erectile dysfunction drug, but when you actually look at the mechanism and the data, it's doing way more than that.I've been a proponent of low-dose Cialis for a long time, and I still am. But lately I've been experimenting with rotating between Cialis and Viagra because I notice I can build a tolerance to Cialis over time. It still works, but I don't feel the performance benefits as strongly unless I push the dose higher. What I've found is that going four weeks on low-dose Cialis, then four weeks on low-dose Viagra, seems to keep me more responsive overall while still giving me the benefits that matter for longevity.In this episode, I break down the real mechanism. Sildenafil is a PDE5 inhibitor that amplifies nitric oxide signaling and raises cGMP throughout the body. That means systemic vasodilation, improved endothelial function, better blood flow to organs, and anti-thrombotic effects through reduced platelet activation. And the downstream effects get even more interesting. We're talking mitochondrial signaling through PKG, potential ischemic preconditioning effects, PGC-1α and mitochondrial biogenesis, AMPK activation, and dampening inflammatory pathways like NF-kB. This is why I think sildenafil deserves a seat at the longevity table, not just a spot in the performance category.Then we get into the human data and what I think is most compelling. Large datasets show associations with lower rates of cardiovascular events and lower all-cause mortality in PDE5 inhibitor users. We talk heart attacks, strokes, endothelial repair, and why this class may act like an exercise mimetic for certain people by improving hemodynamics and oxygen delivery. We also cover pulmonary benefits, including its FDA-approved use for pulmonary arterial hypertension, and why that matters for aging lungs, sleep apnea-related pulmonary issues, and even high-altitude physiology.The brain section is the one that makes most people stop and rethink everything. There are observational datasets suggesting meaningfully lower Alzheimer's and dementia incidence in sildenafil users, plus plausible mechanisms tied to cerebral blood flow, synaptic plasticity, inflammation reduction, and mitochondrial support inside the brain. I'm not saying it's a magic bullet. I am saying it's one of the more interesting repurposing conversations in longevity right now.

MSM wird gefeiert als Entzündungsbremse, Gelenkretter, Haut-Booster und Regenerationshilfe. Es taucht in immer mehr Supplements auf, oft mit dem Versprechen: weniger Schmerzen, mehr Beweglichkeit, straffere Haut. Doch was steckt wirklich hinter MSM, Methylsulfonylmethan? Ein weiterer Wellness-Hype oder ein biologisch plausibler Wirkstoff mit messbaren Effekten? In dieser Folge HEALTH NERDS Deep Dive ordnen Felix Moese und Matthias Baum MSM wissenschaftlich ein: Was ist MSM überhaupt, was macht diese organische Schwefelverbindung im Körper, und warum ist sie weder Vitamin noch Mineralstoff, geschweige denn ein essenzieller Nährstoff? Im Zentrum stehen die Mechanismen, die in Studien immer wieder genannt werden: anti-entzündliche Effekte über zentrale Signalwege wie NF kB, eine mögliche Unterstützung antioxidativer Systeme und die Frage, ob MSM mehr kann als nur Symptome zu dämpfen. Studien zeigen in welchen Bereichen die Daten am stärksten sind: Arthrose und Gelenkschmerzen. Welche Effekte zeigen randomisierte Studien wirklich und wie groß ist der Nutzen bei Schmerz und Funktion, wenn Dosierungen eher im Grammbereich liegen? Gleichzeitig wird klar abgegrenzt, wo die Evidenz dünner wird: Haut, Anti-Aging, Gewebsaufbau, Longevity. Und auch ein neues, noch junges Forschungsfeld kommt zur Sprache: MSM im Kontext Darm, Fehlbesiedelung und Leaky Gut, spannend, aber noch ohne robuste Langzeitdaten. Zum Schluss der Quick-Check: Für wen kann MSM sinnvoll sein, für wen eher nicht? Warum ist es kein Basissupplement und keine Präventionsroutine, sondern eher ein Baustein für konkrete Situationen wie mechanisch entzündliche Gelenkbeschwerden oder hohe sportliche Belastung mit viel oxidativem Stress? Dazu gibt es den Quick Check zur Anwendung: typische Dosierungen, Einnahmeform, mögliche Nebenwirkungen im Magen-Darm-Trakt, klare Warnhinweise für Schwangerschaft, Stillzeit und Kinder sowie die wichtigsten Qualitätsmerkmale wie Reinheit, Tests auf Schwermetalle und Lösungsmittel. Ist MSM ein Wundermittel? Nein. Kann es in bestimmten Kontexten ein sinnvoller Bestandteil einer Strategie gegen Entzündung, Schmerz und Belastung sein? HEALTH NERDS – Mensch, einfach erklärt. - Spare 15% auf Deine erste Bestellung auf https://artgerecht.com mit dem Code: HEALTHNERDS15 (im Warenkorb eingeben) Ein ALL EARS ON YOU Original Podcast.

ChatGPT said:What if the real fallout from a head knock is not the moment of impact, but the silent systemic storm that unfolds in the weeks, months and even years that follow?In this powerful episode, clinical naturopath Louise Cork reframes concussion as a whole-body injury that is widely underreported, frequently misunderstood, and too often treated as an isolated knock to the head. Drawing on years of clinical experience, Louise explains why symptoms can appear long after the incident, how intestinal permeability and a disrupted microbiome can amplify neuroinflammation, and why a gut-first approach often becomes the missing link in recovery.We explore the systemic cascade that follows impact: increased intestinal permeability, a leaky blood-brain barrier, microglial priming, altered HPA axis signalling and hormone shifts such as low testosterone in men. Louise shows how these shifts can present as headaches, fatigue, anxiety, poor stress tolerance and slow injury recovery. A compelling motocross case study highlights how mapping a patient's clinical timeline across body systems can reveal the turning points many people overlook.We then move into practical strategies. Louise shares evidence-informed tools to repair the terrain and calm an oversensitised brain, including stool-guided treatment plans, endotoxin control with SBI and S. boulardii, targeted probiotics, and nutraceuticals such as saffron for mood and NFkB regulation, PEA for endocannabinoid balance and pain, omega 3s for inflammatory resolution, and thoughtful curcumin use that considers COX LOX balance without overloading the liver. We also explore sleep as a primary therapy, the role of the glymphatic system in clearing neuroinflammation, and how nutrients like L-theanine can deepen rest without immediately reaching for melatonin.Prevention is a major focus. Whether you are working with athletes, military personnel, domestic violence survivors or high-risk workers, Louise outlines how optimising gut health, sleep, recovery rituals and nutritional foundations can reduce the fallout when impacts occur.If you have had a knock, care for someone who has, or support patients navigating persistent symptoms, this episode offers a clear and actionable framework: assess deeply, repair the gut, calm the brain, support sleep and tailor the plan to the individual.If this episode supports you or someone you love, follow the show, share it with a teammate or colleague, and leave a review so more people can access these tools.Connect with Louise:  www.theconcussionnaturopath.comShownotes and references are available on the Designs for Health websiteRegister as a Designs for Health Practitioner and discover quality practitioner- only supplements at www.designsforhealth.com.au Follow us on Socials Instagram: Designsforhealthaus Facebook: Designsforhealthaus DISCLAIMER: The Information provided in the Wellness by Designs podcast is for educational purposes only; the information presented is not intended to be used as medical advice; please seek the advice of a qualified healthcare professional if what you have heard here today raises questions or concerns relating to your health

If you suffer from severe menstrual cramps, this is for you. Find out how to stop menstrual cramps naturally by addressing the root cause with these 13 natural remedies for period pain. Never experience menstrual cramps again! 0:00 Introduction: How to reduce period pain0:23 What is a menstrual cramp? 1:30 What causes severe period cramps? 6:42 Vitamin D3 and painful menstrual cramps 12:38 13 natural remedies for period painToday, I'm going to show you how to relieve period cramps fast, and for good. There are two types of period cramps: the primary type is labeled idiopathic, and secondary cramps that are caused by fibroids, ovarian cysts, or endometriosis.Many women take NSAIDs, birth control pills, and Depo shots for period pain relief. The medical community generally discourages the use of natural remedies for menstrual cramps, but does not discourage the use of medication. Research has shown the effectiveness of vitamin B1 and vitamin E.Upon searching for the root cause, I stumbled upon the following clues:• Painful cramps are caused by pain chemicals called prostaglandins. • Vasopressin, which causes contractions and decreased blood flow, is elevated when you have menstrual cramps.• Painful period cramps are associated with high parathyroid hormone levels. • Women with painful menstrual cramps also have much higher inflammation in the uterus, often related to NF-KB. • Black women have a 33% higher likelihood of getting severe period cramps than white women. • Menstrual cramps are sometimes treated with calcium channel blockers. This led to the conclusion that the root cause of menstrual cramps is a severe vitamin D3 deficiency! Try the following natural remedies for period pain and say goodbye to menstrual cramps for good:1. Take 20,000 IU of vitamin D3 daily2. Take 400-600 mg of magnesium glycinate 3. Follow a low-carb diet4. Intermittent fasting5. Cod liver oil for pain relief6. Vitamin E7. Vitamin B18. Increase iron with red meat9. Zinc for vitamin D3 absorption10. Exercise11. Fenugreek12. Heating pad13. Ginger Dr. Eric Berg DC Bio:Dr. Berg, age 60, is a chiropractor who specializes in Healthy Ketosis & Intermittent Fasting. He is the Director of Dr. Berg Nutritionals and author of the best-selling book The Healthy Keto Plan. He no longer practices, but focuses on health education through social media.Disclaimer: Dr. Eric Berg received his Doctor of Chiropractic degree from Palmer College of Chiropractic in 1988. His use of “doctor” or “Dr.” in relation to himself solely refers to that degree. Dr. Berg is a licensed chiropractor in Virginia, California, and Louisiana, but he no longer practices chiropractic in any state and does not see patients, so he can focus on educating people as a full-time activity, yet he maintains an active license. This video is for general informational purposes only. It should not be used to self-diagnose, and it is not a substitute for a medical exam, cure, treatment, diagnosis, prescription, or recommendation. It does not create a doctor-patient relationship between Dr. Berg and you. You should not make any change in your health regimen or diet before first consulting a physician and obtaining a medical exam, diagnosis, and recommendation. Always seek the advice of a physician or other qualified health provider with any questions you may have regarding a medical condition.

In this episode, we explore the connections between Autism and Parkinson's, focusing particularly on the basal ganglia and its substructures, notably the substantia nigra within the midbrain. We discuss how the substantia nigra, known for its high concentration of neuromelanin, plays a critical role in these disorders. The episode examines how neuromelanin, a dark pigment, not only absorbs all frequencies of light but also has antioxidant properties, binds metals, and acts as a neuroprotector. This discussion leads into the broader implications of environmental signals, particularly light, on human biology, touching on how modern changes in light exposure might affect these conditions.We examine the role of tyrosine in the synthesis of neuromelanin and its derivatives like dopamine, which are crucial for neural function. We look at how deficiencies or imbalances in these pathways could lead to the symptoms observed in Autism and Parkinson's, including motor function issues. The conversation also covers the direct and indirect pathways in the basal ganglia, explaining how these pathways facilitate or inhibit movement, respectively, and how their dysfunction can manifest in the characteristic motor symptoms of both disorders. We also touch on the significance of thyroid function, particularly the roles of T3 and T4 hormones, in brain development and neuron health, tying these elements back to the overarching theme of energy loss and transduction in both Autism and Parkinson's.Autism and Parkinson's are a lack of, or a loss of, energy.Biological Energy: Quantum Mechanisms, Water, DHA, and NF-kB: https://youtu.be/2-IA_gunXbwDaylight Computer Company, use "autism" for $50 off athttps://buy.daylightcomputer.com/autismChroma Light Devices, use "autism" for 10% discount athttps://getchroma.co/?ref=autismCognity AI for Autistic Social Skills, use "autism" for 10% discount athttps://thecognity.com0:00 Autism and Parkinson's; Basal Ganglia; Substantia Nigra; Neuromelanin; Internal Calculators2:15 Tyrosine; Chromophores; Aromatic Amino Acids3:50 Biological Energy; Mitochondria; Environmental Signals; Cytochrome C Oxidase; Autism Research Miss6:20 Deep Brain Stimulation6:48 Neuromelanin9:02 Reverse Engineer ATPase10:48 Tree Examples11:45 Hypoxia and loss of energy & dopamine12:26 Eyes, hair, & skin; RPE; efficiency & power; What is Light?13:58 Light; Information & Energy; electromagnetic; wave-particle duality; sunlight versus artificial light17:08 Thyroid; T3 & T4; Iodine18:31 Roles of T323:00 Loss of energy in the womb & Autism research25:00 Melanin + Water = Electrons26:40 Basal Ganglia; "Motivations" & Movements; Direct Pathway30:55 Indirect Pathway32:52 Go, No-Go; Action selection, learning & habits; fine motor skills34:18 Parkinson's and loss of timing & energy; modulating the two pathways & dopamine37:07 Reviews/Ratings & contact infoX: https://x.com/rps47586YT: https://www.youtube.com/channel/UCGxEzLKXkjppo3nqmpXpzuAemail: info.fromthespectrum@gmail.com

Modern joint pain isn't just wear and tear—it's a systemic, metabolic disease that starts years before symptoms show. In this episode, you'll learn how inflammation, mitochondria dysfunction, and immune imbalance trigger cartilage loss… and how to reverse it using targeted cytokine modulation, cellular regeneration, and smarter supplements for longevity and human performance. Watch this episode on YouTube for the full video experience: https://www.youtube.com/@DaveAspreyBPR Host Dave Asprey sits down with Kiran Krishnan, a research microbiologist and Chief Scientific Officer at Calroy Health Sciences. He's the founder of Microbiome Labs—one of the most trusted microbiome-focused brands in functional medicine—and a formulator behind cutting-edge supplements like Arterosil and Vascanox. With over two decades of experience, Kiran has launched multiple health ventures, authored scientific textbook chapters, published clinical trials, and holds global patents in human health. He's a leading authority on systemic inflammation, mitochondrial dysfunction, and gut-driven disease—and one of the few voices making complex biology accessible for real-world results. He breaks down their new supplement Cartigenix HP, and how cytokines like IL-6 and TNF-alpha flip your cartilage cells from anabolic repair to catabolic destruction, how mitochondrial decline speeds up joint damage, and why most modern painkillers make your joints worse. You'll learn how a specialized blend of boswellia and celery seed reprograms inflammation, why walking beats medication in clinical trials, and how fasting, nitric oxide, and gut health work together to optimize joint regeneration. You'll learn: • How cartilage cells (chondrocytes) rely on mitochondria for tissue repair • Why global cytokines like IL-6 and TNF-alpha drive joint degradation and brain fog • How cartilage begins to break down in your teens—and what to do about it now • The surprising clinical data on walking distance, inflammation markers, and recovery • Why most supplements and NSAIDs fail—and what actually rebuilds joints • How diet and leaky gut create 5-day inflammation spikes from a single fast-food meal • The mitochondrial link between joint pain, cardiovascular risk, and depression • Why perimenopausal women are at 10x higher risk for arthritis—and how to prevent it • How to track your biological joint age using imaging and systemic inflammation labs This is essential listening for anyone serious about biohacking, functional medicine, pain-free aging, and human performance. Whether you're lifting heavy, walking daily, or just trying to stay mobile into old age, this episode gives you the science and tools to reverse joint degeneration and extend your healthspan. Dave Asprey is a four-time New York Times bestselling author, founder of Bulletproof Coffee, and the father of biohacking. With over 1,000 interviews and 1 million monthly listeners, The Human Upgrade brings you the knowledge to take control of your biology, extend your longevity, and optimize every system in your body and mind. Each episode delivers cutting-edge insights in health, performance, neuroscience, supplements, nutrition, biohacking, emotional intelligence, and conscious living. New episodes are released every Tuesday, Thursday, Friday, and Sunday (BONUS). Dave asks the questions no one else will and gives you real tools to become stronger, smarter, and more resilient. Keywords: Joint cartilage regeneration, IL-6 inflammation suppression, TNF-alpha cytokine modulation, Chondrocyte mitochondrial repair, Catabolic to anabolic tissue shift, Osteoarthritis reversal, Rheumatoid arthritis inflammation, Mitochondria and collagen synthesis, Boswellia seratol extract, Celery seed COX inhibition, Matrix metalloproteinase (MMP) inhibition, Synovial fluid inflammation, Leaky gut and joint pain, Six-minute walk test improvement, Global cytokine markers, High sensitivity CRP reduction, ESR sedimentation rate, Uric acid crystal formation, Post-prandial glucose walking, Cartilage MRI biomarkers, Functional medicine joint support, Fasted repair stacking, Vasodilation and nitric oxide, Anti-inflammatory supplement stacking, NF-kB pathway reduction, Joint space biological age, Microvascular circulation and cartilage, Caloric load and cytokine spike, Perimenopause and arthritis risk, Joint tissue anabolic activation **Get an exclusive discount for podcast listeners at calroy.com/dave : https://calroy.com/product/cartigenix-hp/?lp=dave ** Thank you to our sponsors! -BodyGuardz | Visit https://www.bodyguardz.com/ and use code DAVE for 25% off. -BiOptimizers | Go to http://bioptimizers.com/dave and use code DAVE15 to get 15% off your order. -Quantum Upgrade | Go to https://quantumupgrade.io/Dave for a free trial. -Caldera + Lab | Go to https://calderalab.com/DAVE and use code DAVE at checkout for 20% off your first order. Resources: • Danger Coffee: https://dangercoffee.com/discount/dave15 • Dave Asprey's BEYOND Conference: https://beyondconference.com • Dave Asprey's New Book – Heavily Meditated: https://daveasprey.com/heavily-meditated • Upgrade Collective: https://www.ourupgradecollective.com • Upgrade Labs: https://upgradelabs.com • 40 Years of Zen: https://40yearsofzen.com Timestamps: 0:00 — Trailer 1:25 — Introduction 2:01 — Why Modern Medicine Fails at Joint Pain 3:07 — Painkillers That Accelerate Joint Damage 7:35 — Rheumatoid vs. Osteoarthritis Explained 8:54 — Cytokines That Destroy Cartilage 12:10 — Arthritis Begins in Your Teens 15:35 — 75% Pain Reduction in 7 Days 18:35 — The Science Behind Boswellia & Celery Seed 24:10 — Six-Minute Walk Test Results 25:45 — The $200/Month Painkiller Trap 28:53 — Proof Cartilage Can Regrow 31:01 — Mitochondria and Joint Repair 32:29 — Inflammation Links to Heart Disease 35:52 — Why Glucosamine Doesn't Work 37:07 — Silent Arthritis in 90% of Adults 40:44 — Why Women Face Higher Joint Risk After 40 45:52 — Food as the #1 Inflammation Trigger 47:23 — Fasting & Cartogenics Stack for Repair 50:27 — Movement Snacks and Efficient Training 55:54 — Why Joints Heal Slower Than Muscles 57:48 — Dave's Stack and Final Takeaways See Privacy Policy at https://art19.com/privacy and California Privacy Notice at https://art19.com/privacy#do-not-sell-my-info.

Protect your heart and arteries with this one powerful nutrient. In this episode, we dive into fascinating new research showing how omega-3 fatty acids like DHA can stabilize arterial plaque and dampen inflammation - reducing your risk of heart attacks and strokes. Timestamps:- 00:45 - How arterial plaque buildup causes inflammation and instability - 02:30 - Study on DHA's effects on plaque inflammation - 04:15 - How DHA reduces immune cell invasion and inflammation - 06:00 - DHA encourages immune cells to leave plaque- 07:30 - How much DHA we should be taking Key Takeaways:- Unstable arterial plaque prone to rupture causes most heart attacks/strokes- DHA reduces inflammatory immune cell invasion into plaque - DHA dampens inflammation by reducing NF-kB activation- Recommendations on supplements Don't miss this fascinating deep dive into using omega-3s like DHA for heart and artery health. Tune in now to protect yourself against cardiovascular disease!See omnystudio.com/listener for privacy information.

In this episode of The Lindsay Elmore Show, Lindsay sits down with David Roberts, co-founder of Mara Labs and a pioneer in sulforaphane supplementation.Sulforaphane, derived from broccoli sprouts, has been called the "master molecule for health" thanks to its ability to support detoxification, reduce inflammation, enhance brain health, and improve metabolic function. David shares the science behind stabilizing sulforaphane, explains why most supplements fall short, and discusses its synergistic effects with molecules like curcumin. From detoxing microplastics to balancing hormones and boosting mitochondrial energy, sulforaphane has far-reaching benefits for overall resilience.Key TakeawaysSulforaphane Basics: A compound found in broccoli sprouts with over 37 documented pro-health mechanisms.Brain Health: Increases BDNF, supporting neuroprotection, neurogenesis, and even enhanced dreaming.Detoxification: Activates NRF2 pathways, turning on over 200 antioxidant and detox genes for up to 72 hours.Inflammation: Synergizes with curcumin to reduce NF-kB and IL-6, two key pro-inflammatory markers.Practical Use: Each capsule of Mara Labs' stabilized sulforaphane equals the benefit of 2.5 pounds of broccoli.Metabolic Impact: Helps balance estrogen, supports mitochondrial energy, and assists in reducing belly fat and insulin resistance.Environmental Defense: Aids the body in processing toxins like glyphosate and mobilizing microplastics.Chapter Timestamps01:00 – What is sulforaphane and why it's the “master molecule”03:00 – How sulforaphane supports brain health through BDNF05:00 – Stabilizing sulforaphane and the challenges of supplementation06:45 – David's personal story: breast cancer diagnosis and discovery of sulforaphane08:00 – How sulforaphane is delivered and stabilized in capsules10:00 – The NRF2 pathway and turning on antioxidant defense13:00 – Detox done right: why many “detox programs” fail15:00 – Curcumin and sulforaphane synergy for inflammation reduction18:00 – Internal studies on inflammation markers (IL-6, NF-kB)20:00 – The real role of detoxification vs. buzzwords24:00 – Toxins in modern life: microplastics, glyphosate, and more28:00 – Genetic modification, glyphosate, and long-term toxicity29:30 – Sulforaphane for metabolism, mitochondrial energy, and belly fat32:00 – Additional Mara Labs products supporting metabolism (GLP-1 alternatives)33:00 – How to learn more: Mara Labs discount link

Humans have long been exposed to three main types of smoke: from early domestic fires, modern wildfires, and more recently, tobacco and fossil fuel pollution. All release tiny particles from partly burned plants, containing harmful chemicals like nitrogen oxides and carcinogens. These particles raise risks for lung cancer, dementia, and even childhood obesity. Studies show that air pollution can disrupt brain chemistry, increase Alzheimer's-related proteins, and activate stress-related genes (NFkB, Nrf2). A new drug (GSM-15606) shows promise in reducing brain damage from pollution in mice. People with the ApoE4 gene may be more vulnerable, while the ApoE3 gene, possibly evolved 200,000 years ago, may offer some protection. Series: "CARTA - Center for Academic Research and Training in Anthropogeny" [Humanities] [Science] [Show ID: 40700]

Humans have long been exposed to three main types of smoke: from early domestic fires, modern wildfires, and more recently, tobacco and fossil fuel pollution. All release tiny particles from partly burned plants, containing harmful chemicals like nitrogen oxides and carcinogens. These particles raise risks for lung cancer, dementia, and even childhood obesity. Studies show that air pollution can disrupt brain chemistry, increase Alzheimer's-related proteins, and activate stress-related genes (NFkB, Nrf2). A new drug (GSM-15606) shows promise in reducing brain damage from pollution in mice. People with the ApoE4 gene may be more vulnerable, while the ApoE3 gene, possibly evolved 200,000 years ago, may offer some protection. Series: "CARTA - Center for Academic Research and Training in Anthropogeny" [Humanities] [Science] [Show ID: 40700]

Humans have long been exposed to three main types of smoke: from early domestic fires, modern wildfires, and more recently, tobacco and fossil fuel pollution. All release tiny particles from partly burned plants, containing harmful chemicals like nitrogen oxides and carcinogens. These particles raise risks for lung cancer, dementia, and even childhood obesity. Studies show that air pollution can disrupt brain chemistry, increase Alzheimer's-related proteins, and activate stress-related genes (NFkB, Nrf2). A new drug (GSM-15606) shows promise in reducing brain damage from pollution in mice. People with the ApoE4 gene may be more vulnerable, while the ApoE3 gene, possibly evolved 200,000 years ago, may offer some protection. Series: "CARTA - Center for Academic Research and Training in Anthropogeny" [Humanities] [Science] [Show ID: 40700]

Humans have long been exposed to three main types of smoke: from early domestic fires, modern wildfires, and more recently, tobacco and fossil fuel pollution. All release tiny particles from partly burned plants, containing harmful chemicals like nitrogen oxides and carcinogens. These particles raise risks for lung cancer, dementia, and even childhood obesity. Studies show that air pollution can disrupt brain chemistry, increase Alzheimer's-related proteins, and activate stress-related genes (NFkB, Nrf2). A new drug (GSM-15606) shows promise in reducing brain damage from pollution in mice. People with the ApoE4 gene may be more vulnerable, while the ApoE3 gene, possibly evolved 200,000 years ago, may offer some protection. Series: "CARTA - Center for Academic Research and Training in Anthropogeny" [Humanities] [Science] [Show ID: 40700]

Humans have long been exposed to three main types of smoke: from early domestic fires, modern wildfires, and more recently, tobacco and fossil fuel pollution. All release tiny particles from partly burned plants, containing harmful chemicals like nitrogen oxides and carcinogens. These particles raise risks for lung cancer, dementia, and even childhood obesity. Studies show that air pollution can disrupt brain chemistry, increase Alzheimer's-related proteins, and activate stress-related genes (NFkB, Nrf2). A new drug (GSM-15606) shows promise in reducing brain damage from pollution in mice. People with the ApoE4 gene may be more vulnerable, while the ApoE3 gene, possibly evolved 200,000 years ago, may offer some protection. Series: "CARTA - Center for Academic Research and Training in Anthropogeny" [Humanities] [Science] [Show ID: 40700]

Humans have long been exposed to three main types of smoke: from early domestic fires, modern wildfires, and more recently, tobacco and fossil fuel pollution. All release tiny particles from partly burned plants, containing harmful chemicals like nitrogen oxides and carcinogens. These particles raise risks for lung cancer, dementia, and even childhood obesity. Studies show that air pollution can disrupt brain chemistry, increase Alzheimer's-related proteins, and activate stress-related genes (NFkB, Nrf2). A new drug (GSM-15606) shows promise in reducing brain damage from pollution in mice. People with the ApoE4 gene may be more vulnerable, while the ApoE3 gene, possibly evolved 200,000 years ago, may offer some protection. Series: "CARTA - Center for Academic Research and Training in Anthropogeny" [Humanities] [Science] [Show ID: 40700]

TIME STAMPS:02:25 **VIDEO PRESENTATION** - all about GENETICS and EPIGENETICS in natural bodybuilding, and what's within your control to change long term nutritionally.10:10 mRNA & Ribosomes, and amino acids - definitions of key terms for building muscle.17:20 BROCCOLI: superHERO or superVILLAIN?!27:02 A discussion around how quickly plants should be eliminated when going carnivore and which ones might be wise to keep in temporarily depending on your dieting history.29:09 The misunderstood truth about IRON!!! (Spoiler - you can't use the iron that's in spinach) Heme iron & non-heme iron.37:38 IMMUNITY HEALTH & VITAMIN C.56:02 The difference between ANTIOXIDANTS and PRO-OXIDANTS.59:58 CLASTOGENESIS MASTERCLASS! All about the NRF2 pathway and how it's activated by cruciferous vegetables such as BROCCOLI. This often compounds into over-activation, increasing glutathione and the NFKB pathway which poisons the body!01:03:44 How KETOSIS and eating RED MEAT extend the length of chromosome telomeres which is correlated with a longer life span

In this episode, we explore the connections between Autism and Parkinson's, focusing particularly on the basal ganglia and its substructures, notably the substantia nigra within the midbrain. We discuss how the substantia nigra, known for its high concentration of neuromelanin, plays a critical role in these disorders. The episode examines how neuromelanin, a dark pigment, not only absorbs all frequencies of light but also has antioxidant properties, binds metals, and acts as a neuroprotector. This discussion leads into the broader implications of environmental signals, particularly light, on human biology, touching on how modern changes in light exposure might affect these conditions.We examine the role of tyrosine in the synthesis of neuromelanin and its derivatives like dopamine, which are crucial for neural function. We look at how deficiencies or imbalances in these pathways could lead to the symptoms observed in Autism and Parkinson's, including motor function issues. The conversation also covers the direct and indirect pathways in the basal ganglia, explaining how these pathways facilitate or inhibit movement, respectively, and how their dysfunction can manifest in the characteristic motor symptoms of both disorders. We also touch on the significance of thyroid function, particularly the roles of T3 and T4 hormones, in brain development and neuron health, tying these elements back to the overarching theme of energy loss and transduction in both Autism and Parkinson's.Autism and Parkinson's are a lack of, or a loss of, energy.Biological Energy: Quantum Mechanisms, Water, DHA, and NF-kB: https://youtu.be/2-IA_gunXbwTree comparison https://youtube.com/shorts/cLu53oVRRjI0:00 Autism and Parkinson's; Basal Ganglia; Substantia Nigra; Neuromelanin; Internal Calculators2:15 Tyrosine; Chromophores; Aromatic Amino Acids3:50 Biological Energy; Mitochondria; Environmental Signals; Cytochrome C Oxidase; Autism Research Miss6:20 Deep Brain Stimulation6:48 Neuromelanin9:02 Reverse Engineer ATPase10:48 Tree Examples11:45 Hypoxia and loss of energy & dopamine12:26 Eyes, hair, & skin; RPE; efficiency & power; What is Light?13:58 Light; Information & Energy; electromagnetic; wave-particle duality; sunlight versus artificial light17:08 Thyroid; T3 & T4; Iodine18:31 Roles of T323:00 Loss of energy in the womb & Autism research25:00 Melanin + Water = Electrons26:40 Basal Ganglia; "Motivations" & Movements; Direct Pathway30:55 Indirect Pathway32:52 Go, No-Go; Action selection, learning & habits; fine motor skills34:18 Parkinson's and loss of timing & energy; modulating the two pathways & dopamine37:07 Reviews/Ratings & contact infoX: https://x.com/rps47586Hopp: https://www.hopp.bio/fromthespectrumYT: https://www.youtube.com/channel/UCGxEzLKXkjppo3nqmpXpzuATikTok: (I don't love it) https://www.tiktok.com/@fromthespectrumpodcastemail: info.fromthespectrum@gmail.com

For today's episode, we discussing transferring energy from the environment across our biology. We discuss a few quantum theories, atoms, molecules, water, DHA, and NF-kB. Life on Earth is driven by energy from the environment, and this could be missed with humans, and especially with developmental problems like Autism.Water Podcast 1: Rubin, Kruse, Huberman https://www.youtube.com/watch?v=0lBAcUMGIeI&t=43sWater Podcast 2: Gulhane and Kruse (Light changes the Physics of Water !) https://www.youtube.com/watch?v=l9UbguvfpysWater Podcast 3: Gulhane and Kruse https://www.youtube.com/watch?v=W5w0WainlMMhttps://www.plefa.com/article/S0952-3278(12)00147-0/abstracthttps://pmc.ncbi.nlm.nih.gov/articles/PMC5793004/#:~:text=Electrons%20exist%20in%20all%20matter,role%20in%20oxidation%2Dreduction%20reactions.Quantum-coherent energy transfer: implications for biology and new energy technologies https://pmc.ncbi.nlm.nih.gov/articles/PMC3385675/#:~:text=In%20the%20simplest%20picture%2C%20quantum,transport%20at%20the%20molecular%20scale.Quantum cognition: The possibility of processing with nuclear spins in the brain https://www.sciencedirect.com/science/article/abs/pii/S0003491615003243Role of semiconductivity and ion transport in the electrical conduction of melanin https://www.pnas.org/doi/10.1073/pnas.11199481090:00 Intro0:40 Quantum Biology, Coherence, Thermodynamics, Water, DHA, NF-kB, and transferring energy - Atoms & Molecules2:00 Oxygen and CCO; Mitochondria3:55 Quantum Biology; Environments influence Atoms & Molecules5:50 Coherence & States; Light guides Life on Earth; Light provides Energy after it hits Matter7:16 Modern Human Environments7:41 Quantum Thermodynamics; Melanin, Electrons; Rules9:03 Biophotons, Photons and Lux; Seasonal Impact11:15 Electrons & Mitochondria; Real sources of Energy12:00 Artificial Light versus 280nm-3100nm Light; Big Harma & GLP-1 sidebar14:16 Autism and Loss of Biological Energy; changes in Light15:43 Electrons in Biology; Water; Coherent Domains; Semiconductors17:15 DHA; Electron Efficiency; Cells; Photoreceptors and Converting Energy and Developing Nervous Systems (plural)19:20 Phylogeny of Oxytocin and DHA sidebar; pi-electons; DHA dictates DNA22:40 Jack Kruse Quote23:36 Cells, Tissues, & Synapses; Origins of Autism; DHA roles26:14 Autism and X, Y, Z comorbid conditions (plural); definitions of Autism (modern versus origins), Criteria29:23 DHA takeaways; efficiency31:41 NF-kB; creating the womb and nervous systems; Autism and Orbitofrontal Cortex (OFC)35:06 Reviews/Rating & Contact Info

For today's episode, Dr. Hanna Stevens joins me to discuss early prenatal factors of early brain development. Dr. Stevens received an MD and PhD in Neuroscience from the University of Illinois. Dr. Hanna Stevens leads the Psychiatry and Early Neurobiological Development Lab at the University of Iowa Carver College of Medicine. Dr. Stevens is a distinguished Professor of Psychiatry and holder of the Ida P. Haller Chair.Her work leads groundbreaking research into the molecular and cellular foundations of early brain development, and is pivotal in linking prenatal stress, environmental factors, and genetic influences on childhood behavior and the emergence of disorders. With a focus on the critical periods of pregnancy and early childhood, her research aims to revolutionize the diagnosis and treatment of conditions throughout the lifespan. By the end of this episode, we hope you receive valuable information about the Placenta, Womb, and Development.Dr. Hanna Stevens https://medicine.uiowa.edu/psychiatry/profile/hanna-stevensIowa Healthcare https://uihc.org/childrens/providers/hanna-e-stevensPsychiatry and Early Neurobiological Development Lab (PENDL) https://stevens.lab.uiowa.eduPublications https://stevens.lab.uiowa.edu/publications0:00 Dr. Hanna Stevens2:00 Journey into Neuroscience and Psychiatry8:13 Prenatal Development of Autism14:02 The significance of NF-kB in Brain Development23:10 Serotonin; Leukocytes as a window into our Biology; Cortisol29:02 Steroid Hormones and Stress & Development34:12 Methylation40:00 Cell Proliferation & Migration in Fetal Development; Antioxidants45:56 Oxidative Stress; Mitochondria; Antioxidants48:30 Quantum Biology/Physics** Me shaking my head at minute 48:50 is not intended at Dr. Stevens, but at myself because I tell myself not to keep going to the electrons and light for a Cause of Autism to guests53:19 Future Research & Dorsal Striatum; Volume; Brain Development1:00 Reviews/Rating; Contact InfoX: https://x.com/rps47586Hopp: https://www.hopp.bio/fromthespectrumemail: info.fromthespectrum@gmail.com

Sulforafan er et fantastisk spennende stoff som finnes i blant andre brokkolispirer.I denne episoden møter du gründeren bak Sulfora Plus, et tilskudd som består av tørkede norskproduserte brokkolispirer. Det viktigste stoffet i spirene er sulforafan, som ifølge en rekke studier viser seg å ha mange unike egenskaper. Jeg har latt meg fascinere av de helsefremmende egenskapene til brokkolispirer og har valgt å vie en hel episode til dette spennende stoffet fordi jeg tror det kan ha positiv effekt for svært mange. Her lærer du mye om sulforafan og Sulfora Plus som også er sponsor i Gry Hammer Podcast.Sulforafan aktiverer flere hundre cellebeskyttende gener i kroppen via priteonet Nrf2, samt reduserer inflammasjon ved å blokkere den proinflammatoriske signalveien Nf-kB. Gresk? Du forstår mer etter å ha lyttet til episoden hvor du lærer du mer om dette unike stoffet som du finner i Sulfora Plus- et tilskudd jeg har brukt i flere år, og enda mer aktivt det siste året.Du får et unikt tilbud som lytter av denne episoden: 40% rabatt på abonnement i 6 med ved å bruke rabattkoden Hammer24, hos sulforaplus.noBeste hilsenGry Hosted on Acast. See acast.com/privacy for more information.

In diesem spannenden Interview gibt Dr. Berit Hippe wertvolle Einblicke, wie du deine Langlebigkeit erhöhen kannst. Erfahre, was sich hinter den Begriffen mTOR, AMPK, Sirtuine und NF-kB verbirgt und wie sie deinen Körper beeinflussen. Zusätzlich werden wichtige Themen wie Schlaf, Bewegung, Sport und Ernährung besprochen. Erhalte praktische Empfehlungen, die du mühelos in deinen Alltag integrieren kannst, um gesünder und länger zu leben.Hier erfährst du, wie sich eine sirtuinreiche Ernährung im Alltag umsetzen lässt: Inhaltsverzeichnis: https://www.vegan-athletes.com/mit-sirtfood-diaet-abnehmen/Hier geht es zum grünen Tee Shop (Arigato): https://arigato-tee.de00:00 Intro 00:30 Ausblick auf die Inhalte der Folge & Vorstellung von Dr. Berit Hippe03:00 Wege das biologische Alter zu bestimmen05:40 Die Bedeutung von Sirtuinen für den Körper08:00 Wie kann ich die Sirtuine aktivieren? 11:20 Inwiefern sind Fasten und Kalorienrestriktionen hilfreich, um die eigene Lebenserwartung zu steigern? 13:40 Was verbirgt sich hinter dem Begriff der Autophagie? 15:45 Wie lange muss man fasten, um zu profitieren? 20:00 Wie kommt der Körper in die Ketose?20:55 Welche Lebensmittel sind spermidinreich? 24:20 Wie viel muss man sich bewegen, um seine Langlebigkeit zu steigern?27:15 Empfiehlt sich Nüchterntraining? 30:50 Einflussfaktor Stress36:10 Einflussfaktor Schlaf37:30 Einflussfaktor Ernährung40:50 Kann man auch ohne Ballaststoffe gesund leben? 42:30 OutroHier erfährst du mehr über Dr. Berit Hippe und ihre Arbeit: HomepageDu willst mehr erfahren? Schreibe eine E-Mail an: christian@christian-wenzel.comMehr mr.broccoli: Podcast auf Spotify Apple Podcast Mehr Podcast Skool Community Abonniere meinen YouTube Kanal*Affiliate LinkAchtung betreffend Nahrung, Geräten und Supplements:Vorliegend habe ich meine eigene Erfahrung und die von Interviewpartnern genannt. Das sind die Effekte, die ich bei mir gespürt habe. Diese können bei jedem unterschiedlich ausfallen.Natürlich kann kein Lebensmittel, keine Nahrungsergänzung oder Superfoods sowie Inspirationen aus diesem Podcast alleine für sich eine Heilwirkung erzielen oder versprechen.Die beschriebenen Erfahrungen sind keine wissenschaftlichen Erkenntnisse und keine Tatsachenbehauptungen. Sämtliche Inhalte dieser Podcast Episoden sind keine Heilaussagen und ausschließlich informativ, sie dienen keinesfalls als Ersatz für eine ärztliche Behandlung.Die Aussagen der Interview Gäst:innen stehen für sich. Diese spiegeln nicht zwingend die Meinung des Herausgebers.

I always like learning about topics that can directly or indirectly affect mitochondrial function. At the end of the day, those are other potential strategies for optimizing mitochondrial health and the root cause of health, wellness and longevity. Redox biology fits that to a tee, meaning if you can improve your internal redox signaling you will inherently improve your mitochondrial function. I like that!We will gain a nice overview of exactly what redox is, why it matters and how it impacts all aspects of health. We will turn to Dr. Lee Ostler's book, Redox Matters, to learn the highlights of redox biology and signaling and why it is undoubtedly a foundational aspect of all health and wellness (which should be no surprise given its entanglement with mitochondrial function).For the second part of the episode I will introduce BioLight's fourth version of BioBlue, which certainly lives up to its name: BioBlue Calm. BioBlue Calm is a blend of six herbs and minerals combined with pharmaceutical grade methylene blue (USP >99.5%) to help promote relaxation and a sense of calm. This recipe includes all of the same ingredients as our flagship BioBlue product minus nicotinamide mononucleotide (NMN). We decided to remove NMN because while is not a stimulant, it can be stimulating to our physiology given its properties for improving mitochondrial function and energy production. Between the removal of the NMN and the addition of: AshwagandhaValerianPassionflowerKavaMagnesium glycinateMagnesium L-threonate ...BioBlue Calm functions as a "weighted blanket" for your brain and your nervous system, providing a physiological tranquility in times of stress, anxiety and/or when falling asleep is difficult. All of the above herbs and minerals contribute to reducing cortisol levels and improved GABA activity in the brain. This alone promotes a deep sense of calm. If you found the information in today's episode particularly interesting and/or compelling, please share it with a family member, friend, colleague and/or anyone that you think could benefit and be illuminated by this knowledge. Sharing is caring :)As always, light up your health! - Key points: Introduction (00:00:00 - 00:00:28). Discussion on the summer solstice marking the beginning of summer but also shorter days (00:00:28 - 00:00:48). Episode topics: redox and its connection to health and mitochondrial function (00:00:48 - 00:02:34). Introduction to "Redox Matters" by Dr. Lee Ostler and announcement of BioLight's new BioBlue product (00:02:34 - 00:03:45). Overview of redox, its role in health, and strategies to optimize mitochondrial function (00:03:45 - 00:08:55). Importance of redox signaling in managing oxidative stress and inflammation (00:08:55 - 00:10:43). Decline in mitochondrial efficiency with age and its health impacts (00:10:43 - 00:13:37). Basic principles of redox biology, including key molecules and their roles (00:13:37 - 00:18:59). Discussion on oxidative stress sources and their effects on health (00:18:59 - 00:23:30). Role of glutathione and other antioxidants in reducing oxidative stress (00:23:30 - 00:25:24). Importance of balancing transcription factors Nrf2 and NF-kB for health (00:25:24 - 00:28:54). Introduction to BioBlue products and their benefits for mitochondrial health (00:28:54 - 00:35:38). Challenges with methylene blue affecting sleep; introduction of BioBlue Calm for improved sleep (00:35:38 - 00:39:13). BioBlue Calm's ingredients and their benefits for relaxation and sleep (00:39:13 - 00:52:52). BioBlue Calm promotes calmness and better sleep without grogginess (00:52:52 - 00:55:37). Encouragement to try BioBlue Calm, available for purchase with discounts (00:55:37 - 00:59:35). Closing remarks on maintaining health through good sleep and relaxation techniques (00:59:35 - 00:59:59). - Book referenced:Redox Matters, Dr. Lee Ostler - Introducing the newest BioBlue product: BioBlue Calm — a beautiful blend of six herbs and minerals combined with methylene blue to promote calmness, relaxation and serenity! For the next week, save 15% on BioBlue Calm single bottle orders using coupon code "calm15" - Introducing the Red Light Therapy Treatment Protocols Ecosystem! - To learn more about red light therapy and shop for the highest-quality red light therapy products, visit https://www.biolight.shop - Dr. Mike's #1 recommendations: Grounding products: Earthing.com EMF-mitigating products: Somavedic Blue light-blocking glasses: Ra Optics - Stay up-to-date on social media: Dr. Mike Belkowski: Instagram LinkedIn   BioLight: Website Instagram YouTube Facebook

DrBeen#63 Anti-Inflammatory Effects of Ashwagandha Ashwagandha is an herb that has been used in Indian (Ayurvedic) medicine for nearly 3000 years. It is found in India (native), the Middle East, and Africa. It is reported to have anti-inflammatory, anti-microbial, anti-diabetic, anti-hypertensive, neuroprotective, apoptogenic, and reproductive and hormone-modulating effects. In this episode, we will review the anti-inflammatory aspects of ashwaganda and specifically, will discuss NF-kB pathway modulation. URL list from Thursday, July 20, 2023 Home - FLCCC | Front Line COVID-19 Critical Care Alliance https://covid19criticalcare.com/ Pharmaceutics | Free Full-Text | Ashwagandha (Withania somnifera)—Current Research on the Health-Promoting Activities: A Narrative Review https://www.mdpi.com/1999-4923/15/4/1057 Ashwagandha - Special Subjects - Merck Manuals Consumer Version https://www.merckmanuals.com/home/special-subjects/dietary-supplements-and-vitamins/ashwagandha Ashwagandha root extract exerts anti‑inflammatory effects in HaCaT cells by inhibiting the MAPK/NF‑κB pathways and by regulating cytokines https://www.spandidos-publications.com/ijmm/42/1/425 Targeting NF-κB pathway for the therapy of diseases: mechanism and clinical study | Signal Transduction and Targeted Therapy https://www.nature.com/articles/s41392-020-00312-6 Frontiers | NF-κB Signaling in Macrophages: Dynamics, Crosstalk, and Signal Integration https://www.frontiersin.org/articles/10.3389/fimmu.2019.00705/full fimmu-10-00705-g002.jpg (1084×813) https://www.frontiersin.org/files/Articles/443978/fimmu-10-00705-HTML/image_m/fimmu-10-00705-g002.jpg fimmu-10-00705-g001.jpg (1084×813) https://www.frontiersin.org/files/Articles/443978/fimmu-10-00705-HTML/image_m/fimmu-10-00705-g001.jpg Frontiers | What Is Nuclear Factor Kappa B (NF-κB) Doing in and to the Mitochondrion? https://www.frontiersin.org/articles/10.3389/fcell.2019.00154/full#:~:text=Nuclear%20factor%20kappa%20B%20(NF%2D%CE%BAB)%20is%20an%20ancient,cellular%20resistance%20to%20invading%20pathogens IκBα - Wikipedia https://en.wikipedia.org/wiki/I%CE%BAB%CE%B1 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.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.12.548684v1?rss=1 Authors: Pranty, A. I., Wruck, W., Adjaye, J. Abstract: Bilirubin induced neurological damage (BIND), which is also known as Kernicterus, occurs as a consequence of defects in the bilirubin conjugation machinery, thus resulting in unconjugated bilirubin (UCB) to cross the blood brain barrier (BBB) and accumulation. Severe hyperbilirubinemia can be caused by a mutation within the UGT1A1 encoding gene. This mutation has a direct contribution towards bilirubin conjugation leading to Kernicterus as a symptom of Crigler Najjar Syndromes (CNS1, CNS2) and Gilbert syndrome, which results in permanent neurological sequelae. In this comparative study, we used human induced pluripotent stem cells (hiPSCs) derived 3D-brain organoids to model BIND in vitro and unveil the molecular basis of the detrimental effects of UCB in the developing human brain. hiPSC derived from healthy and CNS patients were differentiated into day 20 brain organoids, these were then stimulated with 200nM UCB. Analyses at 24 and 72 hrs post-treatment point at UCB induced neuro-inflammation in both cell lines. Transcriptome and associated KEGG and Gene Ontology analyses unveiled activation of distinct inflammatory pathways such as cytokine cytokine receptor interaction, MAPK signaling, calcium signaling, NFkB activation. Furthermore, both mRNA expression and secretome analysis confirmed an upregulation of proinflammatory cytokines such as IL6 and IL8 upon UCB stimulation. In summary, this novel study has provided insights into how a human iPSC derived 3D-brain organoid model can serve as a prospective platform for studying the etiology of BIND Kernicterus. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

In this episode we discuss: Why uncoupling is harmful in certain contexts and how PUFA cause constant, low-level uncoupling The involvement of uncoupling, mitochondrial biogenesis, autophagy, heat shock proteins, and hypoxia-inducible factors in the stress response How stress prevents our mitochondria from effectively producing energy How chronic stress causes insulin resistance, high blood pressure, weight gain, depression, and cardiovascular disease How sugar and fat cravings result from stress and why listening to them is beneficial How adaptations to stress get passed on through generations   Sign up for the Free Energy Balance Mini-Course here: https://jayfeldmanwellness.com/energy   Click here to check out the show notes: https://www.jayfeldmanwellness.com/ep-94-how-stress-crashes-your-metabolism-why-hormesis-is-not-the-answer-stress-mitochondria-part-2/   Timestamps: 0:00 – intro  2:59 – the details of how mitochondrial respiration can become disrupted, especially from glucocorticoids 6:05 – the short-term effects of catecholamines 8:34 – why uncoupling is harmful in certain contexts and how PUFA cause constant, low-level uncoupling 14:40 – the protective effects of uncoupling as a part of the stress response 20:08 – the role of cytokines (TNF-alpha, IL-1, IL-6, heat-shock proteins, NF-kB, HIF) in the stress response 37:33 – the effect of acute stress on energy production in mitochondria 45:18– the effect of chronic stress on energy production in mitochondria 48:15 – how stress drives degeneration and the evidence for increased activity of hormetic pathways (including effects like mitochondrial biogenesis and autophagy) in degenerative states 1:05:24 – the relationship between mental health, mood, and metabolic function 1:10:21 – how adaptations to stress get passed on through mitochondrial DNA 1:18:32 – how to best improve mitochondrial function and our health

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.06.26.546513v1?rss=1 Authors: Spits, C., Lei, Y., Al Delbany, D., Krivec, N., Regin, M., Couvreu de Deckersberg, E., Janssens, C., Ghosh, M., Sermon, K. D. Abstract: Human pluripotent stem cell (hPSC) cultures are prone to genetic drift, as cells that have acquired specific genetic abnormalities experience a selective advantage in vitro. These abnormalities are highly recurrent in hPSC lines worldwide, but currently their functional consequences in differentiating cells are scarcely described. An accurate assessment of the risk associated with these genetic variants in both research and clinical settings is therefore lacking. In this work, we established that one of these recurrent abnormalities, the loss of chromosome 18q, impairs neuroectoderm commitment and affects the cardiac progenitor differentiation of hESCs. We show that downregulation of SALL3, a gene located in the common 18q loss region, is responsible for failed neuroectodermal differentiation. Knockdown of SALL3 in control lines impaired differentiation in a manner similar to the loss of 18q, while transgenic overexpression of SALL3 in hESCs with 18q loss rescued the differentiation capacity of the cells. Finally, we show by gene expression analysis that loss of 18q and downregulation of SALL3 leads to changes in the expression of genes involved in pathways regulating pluripotency and differentiation, including the WNT, NOTCH, JAK-STAT, TGF-beta and NF-kB pathways, suggesting that these cells are in an altered state of pluripotency. 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/2023.06.24.546372v1?rss=1 Authors: Dasgupta, N., Lei, X., Arnold, R., Teneche, M. G., Miller, K. N., Rajesh, A., Davis, A., Anschau, V., Campos, A. R., Gilson, R., Havas, A., Yin, S., Chua, Z. M., Proulx, J., Alcaraz, M., Rather, M. I., Baeza, J., Schultz, D. C., Berger, S. L., Adams, P. D. Abstract: Cellular senescence, a stable proliferation arrest caused by a range of cellular stresses, is a bona fide cause of cell and tissue aging. As well as proliferation arrest, cell senescence is associated with a potent pro-inflammatory phenotype, the senescence-associated secretory phenotype (SASP). Recent studies have shown the importance of cytoplasmic DNA and chromatin, either reverse transcribed expressed retrotransposons or cytoplasmic chromatin fragments (CCF) expelled from the nucleus, in activation of nuclear SASP gene expression via the cGAS/STING cytoplasmic DNA-sensing pathway. As a source of chronic inflammation, over the long term SASP promotes tissue aging and disease. Thus, it is important to better define the mechanism of SASP activation in senescence. We show here that both the Promyelocytic Leukemia (PML) protein and HIRA histone chaperone are required for SASP expression in senescent cells. PML protein is the key organizer of PML nuclear bodies, nuclear features up to 1 micron in diameter, containing many proteins and previously implicated in diverse cellular processes, including control of cell senescence and cellular intrinsic anti-viral immunity. HIRA is a histone chaperone best known for its ability to incorporate histone variant H3.3 into nuclear chromatin in a DNA replication-independent manner, including in non-proliferating senescent cells. HIRA localizes to PML nuclear bodies in senescent cells. We show that both HIRA and PML are required for activation of NF-kB and SASP. We found that HIRA regulates cytoplasmic NF-kB signaling in senescent cells through the CCF-cGAS-STING-TBK1 pathway. HIRA physically interacts with the autophagy cargo receptor p62 Sequestosome-1 (p62), and HIRA and p62 antagonistically regulate SASP. PML is required to maintain integrity of colocalized HIRA and p62 foci in the cell nucleus. Overall, our findings point to functions for HIRA and PML in coordination of cytoplasmic signalling and nuclear gene expression to regulate inflammation during cell senescence and aging. 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/2023.03.29.534819v1?rss=1 Authors: Kim, T. W., Koo, S. Y., Riessland, M., Cho, H., Chaudhry, F., Kolisnyk, B., Russo, M. V., Saurat, N., Mehta, S., Garippa, R., Betel, D., Studer, L. Abstract: Ongoing, first-in-human clinical trials illustrate the feasibility and translational potential of human pluripotent stem cell (hPSC)-based cell therapies in Parkinson's disease (PD). However, a major unresolved challenge in the field is the extensive cell death following transplantation with less than 10% of grafted dopamine neurons surviving. Here, we performed a pooled CRISPR/Cas9 screen to enhance the survival of postmitotic dopamine neurons in vivo. We identified p53-mediated apoptotic cell death as a major contributor to dopamine neuron loss and uncovered a causal link of TNFa-NFkB signaling in limiting cell survival. As a translationally applicable strategy to purify postmitotic dopamine neurons, we performed a cell surface marker screen that enabled purification without the need for genetic reporters. Combining cell sorting with adalimumab pretreatment, a clinically approved and widely used TNFa inhibitor, enabled efficient engraftment of postmitotic dopamine neurons leading to extensive re-innervation and functional recovery in a preclinical PD mouse model. Thus, transient TNFa inhibition presents a clinically relevant strategy to enhance survival and enable the engraftment of postmitotic human PSC-derived dopamine neurons in PD. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Welcome to another episode of the Biohacking Beauty podcast brought to you by Young Goose Skincare! In this episode, host Amitay Eshel, the CEO of Young Goose, is joined and interviewed by Jodi Duval–which originally aired on the the Revital Health Podcast. The two discuss how you can optimize how your skin behaves by providing it with the right building blocks for your skin to function well and not only appear younger but behave younger.Jodi Duval is the Head Naturopath and owner of Revital Health. She is also the CEO of HomeHope Australia, host of the Revital Health Podcast, and lecturer at Endeavour College.What we discuss:01:10: How did Young Goose start?09:40: What's the science and difference behind quality skincare products?21:26: Which key ingredients do Young Goose products contain?30:50: What are indications of the skincare working?33:17: What is Amitay's perspective of peptides?45:10: What is skin trauma?58:03: What are the possible harms of skincare?1:08:14: What can you do to optimize your skin?1:23:34: How can you support your skin's health from an internal perspective?Key Takeaways:Resveratrol is a naturally-occurring compound present in grapes, some berries, and other fruits and nuts. This plant compound acts as an antioxidant. But what people don't know is that when applied to the skin, we don't benefit from the resveratrol itself, but from the defense mechanism of the plant compound. It acts as an antioxidant and thus can protect cells against oxidative damage of free radicals and UV radiation on the skin by reducing the expression of AP-1 and NF-kB factors. It also slows down the process of photoaging the skin. Glycation is a process that is caused by the presence of excess glucose in skin fibers. This excess triggers an internal reaction in which sugar molecules adhere to the collagen and elastin proteins, which normally help keep skin firm and supple. As a direct result of glycation, our skin becomes more rigid which may increase the appearance of concerns such as puffiness, loss of elasticity, wrinkles, and fine lines.Both mineral and chemical sunscreen technically do the job, they aren't made equally! Mineral sunscreens allow your skin to detoxify itself in a way that chemical sunscreen does NOT. With this process being crucial for your body's detoxification process, you can't afford to go the chemical sunscreen route.Skin trauma is the process in which the skin shows the appearance of past emotional traumas. Whether they are from repressed emotions or the expression of many negative emotions over time, these tend to manifest in the skin through different types of fine lines and wrinkles on one's skin. To learn more about Jodi:Instagram: @ketoconWebsite: https://www.revitalhealth.com.au/ Podcast: To learn more about Young Goose:Website: https://www.younggoose.com/Instagram: @young_goose_skincareGet 20% off your first purchase by using code PODCAST20 at www.younggoose.com

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.06.522894v1?rss=1 Authors: Cao, F., Deliz-Aguirre, R., Gerpott, F. H. U., Ziska, E., Taylor, M. J. Abstract: Signaling pathways can produce digital outputs that are invariant and analogue outputs that scale with the amount of stimulation. In IL-1 receptor (IL-1R) signaling both types of outputs require the Myddosome, a multi-protein complex. The Myddosome is required for polyubiquitin chain formation and NF-kB signaling. However, the ways in which these signals are spatially and temporally regulated to drive switch-like and proportional outcomes is not understood. We find that during IL-1R signaling, Myddosomes dynamically re-organize into large, multi-Myddosome clusters at the cell membrane. Blockade of Myddosome clustering using nanoscale extracellular barriers reduces NF-kB activation. We find that Myddosomes function as a scaffold that assembles an NF-kB signalosome consisting of E3-ubiquitin ligases TRAF6 and LUBAC, K63/M1-linked polyubiquitin chains, phospho-IKK, and phospho-p65. This signalosome preferentially assembles at regions of high Myddosome density, which enhances the recruitment of TRAF6 and LUBAC. Extracellular barriers that restrict Myddosome clustering perturbed the recruitment of both ligases. We found that LUBAC was especially sensitive to clustering, with a sevenfold lower recruitment to single Myddosomes than clustered Myddosomes. This data reveals that the clustering behavior of Myddosome provides the basis for digital and analogue IL-1R signaling. 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/2022.12.11.519940v1?rss=1 Authors: Theret, M., Messing, M., White, Z., Henry, L. W., Rempel, L., Hamer, M., Hashimoto, J., Li, F. F., Brassard, J., Li, Y., Sauge, E., Shin, S., Day, K., Uppal, M., Low, M., Eisner, C., Sato, S., Akira, S., Bernatchez, P., McNagny, K., Rossi, F. M. V. Abstract: The ability of mesenchymal stromal cells to modulate inflammation is at the basis of the ongoing interest in their therapeutic potential. Yet, reliable success in clinical trials is limited, possibly due to a limited understanding of their impact on the inflammatory milieu in physiological conditions. Here we show that, at steady state, mesenchymal progenitors regulate the balance between type 1 and type 2 inflammatory milieus by acting on innate immune cells through the TAK1-NFkB pathway. Suppressing the constitutive activity of this pathway in MPs leads to skewing of the immune system toward systemic Type 2 inflammation (Th2). These changes have significant effects on diseases with an important inflammatory component, leading to a worsening of disease in a preclinical model of Th2-dependent Asthma, and a reduction of symptoms associated with Th1/Th17-dependent experimental autoimmune encephalitis. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Videos : Niall Ferguson – Woke Totalitarianism (0:19 to 18:14) Heather Mac Donald On How The Delusion of Diversity Destroys Our Common Humanity (11:14) Elon Musk: “Klaus Schwab Is LYING!!!” (9:45) Lycopene, lutein supplements show skin protection from within against UV radiation Leibniz Research Institute for Environmental Medicine (Germany), November 10, 2022 The study's findings, published in the British Journal of Dermatology , indicated that oral supplementation with the carotenoids changed the expression of genes that are indicators of oxidative stress, photo-dermatoses and photo-aging. “To the best of our knowledge we show here for the 1st time that (i) tomato nutrient complex as well as lutein do not only protect healthy human skin against UVB/A, but also against long wave UVA1 radiation, and (ii) that oral photo-protection of healthy human skin can be demonstrated at the level of HO-1, ICAM-1 and MMP-1 gene expression,” wrote researchers from IUF – Leibniz Research Institute for Environmental Medicine in Dusseldorf. Heme oxygenase-1 (HO-1), intercellular adhesion molecule-1 (ICAM-1) and matrix metalloproteinase-1 (MMP-1) are reported to be UVA1/UVB radiation-inducible genes. “On top of that, as part of the photo-aging process we have evidence of the effect of our ingredients on the levels of expression of genes involved in collagen degradation, suggesting a link not only to skin health but also to skin appearance. This study suggests an effect of natural antioxidants on overall skin wellness, which is relevant for men and women in all age groups.” The new study included 65 healthy volunteers aged between 18 and 60. The participants were randomly assigned to randomly consume 20 mg per day of the tomato nutrient complex or placebo for 12 weeks, or 20 mg per day of lutein or placebo for 12 weeks. A two-week washout period separated the placebo and active intervention periods. At the beginning and at the end of each phase the skin was irradiated.Results of the placebo-controlled, double blinded, randomized cross-over study indicated that the tomato nutrient complex (TNC) totally inhibited the upregulation of HO-1, ICAM-1 and MMP1 mRNA by both UVA1 and UVA/B. On the other hand, lutein only completely inhibited gene expression if taken during the first 12 weeks (ie. prior to placebo), while a significantly smaller effect was observed if it was taken during the second 12 week phase (ie. after placebo), compared to TNC. (NEXT) Diallyl trisulfide in garlic induces apoptosis in primary effusion lymphoma Kyoto Pharmaceutical University (Japan), November 7, 2022 Reports from Kyoto Pharmaceutical University stated, “The allyl sulfides, including diallyl sulfide (DAS), diallyl disulfide (DAD), and diallyl trisulfide (DAT), contained in garlic and members of the Allium family, have a variety of pharmacological activities. Therefore, allyl sulfides have been evaluated as potential novel chemotherapeutic agents.” Our news editors obtained a quote from the research, “Here, we found that DAT inhibited nuclear factor-kB (NF-kB) signaling and induced apoptosis in primary effusion lymphoma (PEL), a subtype of non-Hodgkin's B-cell lymphoma caused by Kaposi's sarcoma-associated herpesvirus (KSHV). We examined the cytotoxic effects of DAS, DAD and DAT on PEL cells. DAT significantly reduced the viability of PEL cells compared with uninfected B-lymphoma cells, and induced the apoptosis of PEL cells by activating caspase-9. DAT induced stabilization of IkBa, and suppressed NF-kB transcriptional activity in PEL cells. We examined the mechanism underlying DAT-mediated IkBa stabilization. The results indicated that DAT stabilized IkBa by inhibiting the phosphorylation of IkBa by the IkB kinase (IKK) complex. Furthermore, DAT induced proteasomal degradation of TRAF6, and DAT suppressed IKKb-phosphorylation through downregulation of TRAF6. It is known that activation of NF-kB is essential for survival of PEL cells. In fact, the NF-kB inhibitor BAY11-7082 induced apoptosis in PEL cells. In addition, DAT suppressed the production of progeny virus from PEL cells. The administration of DAT suppressed the development of PEL cells and ascites in SCID mice xenografted with PEL cells.” According to the news editors, the research concluded: “These findings provide evidence that DAT has antitumor activity against PEL cells in-vitro and in-vivo, suggesting it to be a novel therapeutic agent for the treatment of PEL.” (NEXT) PTSD May Speed Up Cellular Aging Boston University, November 13, 2022 From birth to death, a lot may change, but our DNA—the long, double-helix molecule that contains all of a person's genetic code—stays the same. The instructions for reading that code can shift, however, as the chemical tags on and around a DNA sequence change throughout our lives, depending on our age, environment, and behavior. This outside influence on how our genes are read and expressed by cells is called epigenetics—and researchers studying it have discovered clues that may show why some veterans live longer than others. In a new study of military veterans published in Translational Psychiatry, researchers report findings that suggest former service personnel with PTSD are at greater risk of early death. “Our study found that PTSD and comorbid conditions, like substance misuse, are associated with a cellular marker of early death found in DNA methylation patterns,” says Erika Wolf, a professor of psychiatry at the Boston University School of Medicine and senior author of the study. The study included two samples of veterans that had representative levels of trauma and other psychiatric conditions, like substance use and personality disorders. One group included 434 veterans in their early 30s, who had served in post-9/11 conflicts; the other group included 647 middle-age veterans and their trauma-exposed spouses. Both groups were assessed for a range of psychological conditions, and had blood drawn to obtain genetic information and to test for levels of a variety of inflammatory molecules. The results indicate PTSD symptoms were a factor in faster cellular aging—.36 of a year faster. So, for every year that the cells of someone without PTSD age, the cells of someone with more severe PTSD symptoms age a year and a third. (NEXT) Higher sense of purpose in life may be linked to lower mortality risk Boston University, November 14, 2022 Growing research indicates that one's purpose—i.e., the extent to which someone perceives a sense of direction and goals in their life—may be linked to health-protective benefits such as better physical functioning and lower risks of cardiovascular disease or cognitive decline. Now, a new study led by a Boston University School of Public Health (BUSPH) researcher found that people with higher levels of purpose may have a lower risk of death from any cause, and that this association is applicable across race/ethnicity and gender. Published in the journal Preventive Medicine, the study results did suggest that this association is slightly stronger among women than it is among men, but there was no significant difference by race/ethnicity. “In another study I led, we found that the effect of purpose on lowering all-cause mortality may differ by socioeconomic status. In this study, we extended the prior evidence and found that the beneficial effect of purpose persisted regardless of gender and race/ethnicity.” For the study, the team assessed self-reported sense of purpose among more than 13,000 people, based on the “purpose in life” of the Ryff Psychological Well-being Scales, a widely used tool that measures different aspects of well-being and happiness. The researchers also examined mortality risk over an eight-year period beginning between 2006-2008. The results showed that people with the highest sense of purpose indicated the lowest risk of death (15.2 percent mortality risk), compared to people with the lowest sense of purpose (36.5 percent mortality risk). The team also gathered data on additional factors that can influence health, such socioeconomic status, other demographic characteristics, baseline physical health, and depression, and found that an increase in these factors was also associated with increases in a higher sense of purpose. (NEXT) Hibiscus compound shows anti-Alzheimer disease activity Pohang University of Science and Technology, November 16 2022. A report published in Alzheimer's Research & Therapy revealed that gossypetin, a flavonoid occurring in the calyx of the hibiscus flower, activates a process that reduces brain accumulation of amyloid beta, a protein that clumps to form toxic brain plaques in people with Alzheimer disease. Gossypetin has been reported to have antioxidant, antiatherosclerotic and anticancer effects. Earlier research had suggested a benefit for gossypetin, which is structurally similar to quercetin, against the aggregation of amyloid beta and tau proteins that occurs in Alzheimer disease. However, gossypetin's action in animal models of the disease had not been evaluated. Researchers at Pohang University of Science and Technology administered gossypetin or a control substance to mice that were bred to develop a condition similar to that of Alzheimer disease in humans. After 13 weeks of daily treatment, mice that received the flavonoid had less amyloid beta in the brain's hippocampus (an area involved in memory and learning) and cortex in comparison with the control mice. Gossypetin-treated animals also demonstrated better spatial learning and memory than untreated mice. Rather than affecting the production of amyloid beta, the research team found that gossypetin helped clear it by enhancing the scavenging ability of the brain's immune cells, which are known as microglia. Microglia normally consume amyloid beta but can become exhausted by continual exposure, which leads to a chronic damaging inflammatory reaction. (NEXT) Over a billion young people are potentially at risk of hearing loss from headphones, earbuds, loud music venues Mayo Clinic, November 15, 2022 More than 1 billion teens and young people are potentially at risk of hearing loss because of their use of headphones and earbuds and attendance at loud music venues, concludes a pooled data analysis of the available evidence, published in the open access journal BMJ Global Health. The World Health Organization (WHO) estimates that over 430 million people worldwide currently have disabling hearing loss. Young people are particularly vulnerable because of their use of personal listening devices (PLDs), such as smartphones, headphones and earbuds, and attendance at loud music venues, amid poor regulatory enforcement. Previously published research suggests that PLD users often choose volumes as high as 105 dB while average sound levels at entertainment venues range from 104 to 112 dB, exceeding permissible levels (80 dB for adults; 75 dB for children) even if for very short periods of time. A group of 33 studies, corresponding to data from 35 records and 19,046 participants, was included; 17 records focused on PLD use and 18 focused on loud entertainment venues. The pooled data analysis indicates that the prevalence of unsafe listening practices from PLD use and attendance at loud entertainment venues is common worldwide—24% and 48%, respectively, among teens and young people. Based on these figures, the researchers estimate that the global number of teens and young adults who could potentially be at risk of hearing loss as a result ranges from 0.67 to 1.35 billion.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.11.17.516971v1?rss=1 Authors: Thambyrajah, R., Fadlullah, Z., Proffitt, M., Neo, W. H., Guillen, Y., Casado-Pelaez, M., Herrero-Molinero, P., Brujas, C., Castelluccio, N., Gonzalez, J., Iglesias, A., Marruecos, L., Ruiz-Herguido, C., Esteller, M., Mereu, E., Lacaud, G., Espinosa, L., Bigas, A. Abstract: Recent findings are challenging the classical hematopoietic model in which long-term hematopoietic stem cells (LT-HSC) are the base of the hematopoietic system. Clonal dynamics analysis of the hematopoietic system indicate that LT-HSC are not the main contributors of normal hemapoiesis in physiological conditions and the hematopoietic system is mainly maintained by multipotent progenitors (MPPs, hereafter HPC) and LT-HSCs are mostly in a non-active state. The first HSCs emerge from the aorta-gonad and mesonephros (AGM) region along with hematopoietic progenitors (HPC) within hematopoietic clusters. Molecular pathways that determine the HSC fate instead of HPC are still unknown, although inflammatory signaling, including NF-KB has been implicated in the development of HSCs. Here, we identify a chromatin binding function for IKB (also known as the inhibitor of NF-KB) that is Polycomb repression complex 2 (PRC2)- dependent and specifically determines dormant vs proliferating HSCs from the onset of their emergence in the AGM. We find a specific reduction of LT-HSCs in the IKB knockout new-born pups. This defect is manifested at the FL stage already, and traceable to the first emerging HSCs in the E11.5 AGM, without affecting the general HPC population. IKB-deficient LT-HSCs express dormancy signature genes, are less proliferative and can robustly respond to activation stimuli such as in vitro culture and serial transplantation. At the molecular level, we find decreased PRC2-dependent H3K27me3 at the promoters of several retinoic acid signaling elements in the IKB- deficient aortic endothelium and E14.5 FL LT-HSCs. Additionally, IKB binding itself is found in the promoters of retinoic acid receptors rar in the AGM, and rar{gamma} in the LT-HSC of FL. Overall, we demonstrate that the retinoic acid pathway is over-activated in the hematopoietic clusters of IKB-deficient AGMs leading to premature dormancy of LT- HSCs that persists in the FL LT-HSCs. 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/2022.10.17.512513v1?rss=1 Authors: Jiang, Y., He, Y., Liu, S., Li, G., Chen, D., Deng, W., Li, P., Zhang, Y., Wu, J., Li, J., Wang, L., Lin, J., Wang, H., Kong, S., Shi, G. Abstract: Decidualization, denoting the transformation of endometrial stromal cells into specialized decidual cells, is a prerequisite for normal embryo implantation and a successful pregnancy in human. Here we demonstrated that knockout of Gaq lead to an aberrantly enhanced inflammatory state during decidualization. Furthermore, we showed that deficiency of Gaq resulted in over-activation of nuclear factor (NF)-{kappa}B signaling, due to the decreased expression of NF{kappa}BIA, which encode the I{kappa}B protein and is the negative regulator for NF{kappa}B. Mechanistically, Gaq deficiency decreased the PKD/PKC phosphorylation levels, so leading to attenuated HDAC5 phosphorylation and thus its nuclear export. Aberrantly high level of nuclear HADC5 retarded histone acetylation to inhibit NF{kappa}BIA transcription during decidualization. Consistently, pharmacological activation of the PKD/PKC or inhibition of the HDAC5 signaling restored the inflammatory state and proper decidual response. Finally, we disclosed that over-active inflammatory state in Gaq deficient decidua deferred the blastocyst hatching and adhesion in vitro, and the decidual expression of Gq was significantly lower in women with recurrent pregnancy loss compared with normal pregnancy. In brief, we showed here that Gq as a key regulator of the inflammatory cytokine's expression and decidual homeostasis in response to differentiation cues, which is required for successful implantation and early pregnancy. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

This week, please join author Jonathan Sterne and Associate Editor Shinya Goto as they discuss the article "Association of COVID-19 With Major Arterial and Venous Thrombotic Diseases: A Population-Wide Cohort Study of 48 Million Adults in England and Wales." 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: Oh, Greg, we've got a special treat for everyone today. We have a third co-host and he is none other than Peder Myhre from Norway! Really adding to the diversity of our podcast: me from Asia, you from the US, and Peder from Europe. Welcome, Peder. Dr. Peder Myhre: Thank you so much, Carolyn. It's truly an honor to be here and I'm looking forward to being part of this podcast today. Dr. Carolyn Lam: Awesome. Well, here we go. Looks like we have a feature paper, Greg? Dr. Greg Hundley: Absolutely, Carolyn. Peder, welcome. So, listeners, our feature today will involve COVID-19 and its association with arterial and venous thrombotic diseases. But before we get to that, we're going to all grab a cup of coffee from all over the world and get into some of the other articles in the issue. Peder, Carolyn, how about I go first? My first study involves a prospective cohort of 94,000 individuals from the UK Biobank, who had device-measured physical activity from 2013 to 2015 and were free from myocardial infarction and heart failure. Now, Peder and Carolyn, the study was performed because although objectively measured physical activity has been found associated with acute cardiovascular outcomes, it has not been found associated with heart failure and, of course, a syndrome that's been expanding worldwide. As such this study led by Carlos Celis-Morales from the University of Glasgow aimed to investigate the dose response relationship between device-measured physical activity and heart failure by intensity of the physical activity. Now physical activity was measured with a wrist-worn accelerometer and time spent on light, moderate, and vigorous intensity physical activity was extracted. Incidental heart failure was ascertained from linked hospital and death records. Dr. Peder Myhre: Wow, Greg. That sounds amazing. Tell us, what did they find? Dr. Greg Hundley: You bet, Peder! These investigators found that, compared with participants who undertook no moderate to vigorous intensity physical activity, those who performed 150 to 300 minutes per week of moderate intensity physical activity or 75 to 150 minutes per week of vigorous intensity physical activity were at lower risk of heart failure. Now, interestingly, the association between vigorous intensity physical activity and heart failure was a reverse J-shaped curve with a potentially lower risk reduction above 150 minutes per week. And so, the take-home message for this first paper is that device-measured physical activity, especially moderate intensity physical activity, was associated with a lower risk of heart failure. Probably current vigorous intensity physical activity recommendations should be encouraged, but not necessarily increased. In contrast, increasing moderate intensity physical activity may be beneficial, even among those meeting current recommendations. Dr. Peder Myhre: Wow, Greg. That was a great summary. And the second original research article today is about high density lipoproteins. As you know, raising HDL cholesterol levels to prevent cardiovascular disease remains a hot topic. HDL plays a key role in reverse cholesterol transport and may be cardioprotective and reduce infarct size in the setting of myocardial injury. Lecithin cholesterol acyl transferase, LCAT, is the rate limiting enzyme in the reverse cholesterol transport and a recombinant human LCAT called MEDI6012 has previously been shown to increase HDL cholesterol. So in this study from the corresponding author, Marc Bonaca from University of Colorado School of Medicine, the investigators in the real team is 63B multicenter placebo control trial investigated whether randomized patients to, MEDI6012 or placebo would reduce the infarct size as measured by cardiac MRI, 10 to 12 weeks after the STEMI. Dr. Greg Hundley: Very interesting, Peder. So, MRI assessments of LV mass after PCI. So, what did they find? Dr. Peder Myhre: So, Greg, the authors successfully enrolled 593 patients with a median age of 62 years and 78% males. And the median time from symptom onset to randomization was 146 minutes and only 13 minutes from hospitalization to randomization. And the index MI was anterior in 70% and 65% had TIMI Flow grade 0-1. And then to the main results at 12 weeks, the infarct size did not defer between the treatment group. So that was a 9.7% infarct size for MEDI6012 versus 10.5% for placebo with a P value of 0.79. And there was also no difference in noncalcified black volume. So the authors conclude that enhanced reverse cholesterol transport with recombinant human LCAT did not reduce infarct size or late regression of noncalcified coronary REPL at 12 weeks. Okay, Greg. So tell me about the 3rd paper you have today? Dr. Greg Hundley: Peder, what a great description on that previous paper, beautiful job there. So Peder, this next article pertains to cardio toxicity related to the administration of anthracycline-based chemotherapy. And an example would be Doxorubicin. And this occurs in patients often with certain types of cancer. As you know, Doxorubicin is still utilized for the treatment of leukemia, lymphoma, soft tissue sarcoma and in the setting of adjuvant breast cancer treatment. And so to this end, the authors, led by Lorrie Kirshenbaum from St. Boniface Hospital abstract research, wanted to assess cytokine mediated inflammation in myocellular injury, as a result of some of the inflammation that's induced by the administration of Doxorubicin. So as a little bit of background, cytokines, such as TNF alpha, have been implicated in cardiac dysfunction and toxicity associated with Doxorubicin. Now, while TNF alpha can elicit different cellular responses, including survival or death, the mechanisms underlying these divergent outcomes in the heart really somewhat remain cryptic. The E3 ubiquitin ligase, TRAF2, provides a critical signaling platform for K63 length poly ubiquitin nation of rip K1, crucial for NF-kB activation by TNF alpha and survival. Whether alterations in TNF alpha, TRAF2, NF-kB activation signaling underlie the cardiotoxic effects of Doxorubicin, remains poorly understood. So herein, these authors investigated TRAF2 signaling in the pathogenesis of Doxorubicin cardio toxicity. Dr. Peder Myhre: Oh wow, Greg. So we're talking mitochondrial dysfunction in Doxorubicin cardiomyopathy. So please tell me, what did they find and what were the clinical implications? Dr. Greg Hundley: Very nice. Peder, you remind me of Carolyn, asking me the clinical implications. Okay, so first, in mouse models and in vitro measures in rats, mouse and human pluripotent stem cell derived cardiomyocytes, these investigators monitored TNF alpha levels, LDH, cardiac ultra structure and function, mitochondrial biogenics, as you just suggested, and cardiac cell viability. They found that a novel signaling axis exists that functionally connects the cardiotoxic effects of Doxorubicin to proteasomal degradation of TRAF2. Disruption of the critical TRAF2 survival pathway by Doxorubicin, sensitizes cardiomyocytes to TNF alpha and BNIP3 mediated necrotic cell death. Perhaps, interventions that stabilize TRAF2, so here's the clinical implication, may prove beneficial in mitigating the cardiotoxic effects in cancer patients undergoing anthracycline-based chemotherapy. Dr. Carolyn Lam: So Greg, he may sound like me, but this is me going what an amazing summary and especially in something that is your specialty cardio-oncology, that's amazing. Thank you. Peder, I assume you've got one more paper? Dr. Peder Myhre: So Greg, now I'm going to sound like you and say that we are going to stay within the world of preclinical science. So genome-wide association studies have identified many genetic loci that are robustly associated with coronary artery disease. However, the underlying biological mechanisms are still unknown for most of these loci, hindering the progress to medical translation. And there is evidence to suggest that the genetic influence of coronary artery disease sociability may partly act through vascular smooth muscle cells. So corresponding author, Shu Ye from University of Leicester, performed genotyping, RNA sequencing and cell behavior assays on the large bank of vascular smooth muscle cells with an N of almost 1500. And through these extensive analysis, they saw to identify genes whose expression was influenced by coronary artery disease associated variants. Dr. Greg Hundley: Very nice, Peder. So, more about cardiac gene expression. So, what did they find? Dr. Peder Myhre: Approximately 60% of the known coronary artery disease associated variants show statistically significant effects in vascular smooth muscle cells and the study identified 84 candidate causal genes whose expression quantitative trait, loci signals in vascular smooth muscle cells, significantly co-localized with reported coronary artery disease association signals, of which 38 of them are potentially druggable, so, that was the clinical implications. The authors conclude that a large percentage of coronary artery disease loci can modulate genes, gene expression in vascular smooth muscle cells and influence these cell behavior. Several candidate causal genes identified are likely to be druggable and thus represent potential therapeutic targets. And Greg, accompanying this paper is a beautiful editorial by doctors O'Donnell and Bradner entitled "Bridging the Gap to Translating Genome-Wide Discoveries into Therapies to Prevent and Treat Atherosclerotic Cardiovascular Disease." Dr. Greg Hundley: Very nicely done Peder, very nicely done. Well, as usual, we have some other items, we call it in the mail bag because we receive these wonderful research letters and also research correspondence. So I'll go first. First, Dr. Al-Khatib has a research letter entitled, "Duration of Anticoagulation Interruption before Invasive Procedures and Outcomes in Patients with Atrial Fibrillation Insights from the Aristotle Trial." And also there's a nice ECG analysis by Dr. Tsai entitled, "A Peculiar Wide-Complex Tachycardia During Flecainide Treatment." Dr. Peder Myhre: Nice, Greg, and there's also an exchange on letters to the editors and the response from Professors Zhao and Ding, and again, a response from Professor Zhang regarding the prior letter by Jin et al. pertaining to the previously published article "Micro RNA, 210 Controls, Mitochondrial Metabolism and Protects Heart Function in Myocardial Infarction." Dr. Greg Hundley: Beautifully done, Peder. Oh, wow. Welcome to this team. We're so excited to have you. And now Carolyn, I think we're going to jump over to that feature discussion and learn a little bit more about COVID-19 and arterial and venous thrombotic disease. Dr. Carolyn Lam: You bet! Let's go, Greg and Peder. Now we all know that infection with COVID 19 induces a pro-thrombotic state, but the long term effects of COVID-19 on the incidence of vascular disease, both arterial and venous, remain unclear. That is until today's feature paper. We're so grateful to have corresponding author Dr. Jonathan Stern, from the University of Bristol, as well as our associate editor, Dr. Shinya Goto from Tokai University School of Medicine to join us and discuss this very important paper today. Jonathan, could you start us off on telling us why it's so important to look at this? Haven't we always known that infections, COVID or not, are associated with pro-thrombotic state? So what's so different about what you did and what you found this time? Dr. Jonathan Stern: So, yes, I think we already knew that serious infections, in particular infections leading to hospitalization, can result in thrombotic events, either arterial or venous. And it was also clear from January, February, March 2020, that COVID led to very serious infection and therefore was likely to lead to vascular events. The questions that we set out to address, beyond simply establishing that COVID does indeed do this, was to quantify by how much COVID multiplies the rate at which these thrombotic events occurred, to do that separately for different events, such as myocardial infarction, stroke, venous thromboembolism, pulmonary embolism. And then to importantly, because we analyzed a very large dataset, which we might want to talk about, to try to separate out the amount by which the rating events was multiplied over time and in important subgroups, for example, in hospital people who were hospitalized for their COVID, compared with people who weren't hospitalized for their COVID, by age and sex, and by other demographic characteristics. Dr. Carolyn Lam: I love that, you see, that really set out the novel information this added with, may I add, very important clinical implications, which we'll get to them. You've already teed me up to talk about this 48 million adults that you managed to look at. Oh my goodness! Tell us, how in the world did you do that? Dr. Jonathan Stern: Well, I think the first thing to say is that it's my absolute privilege to talk about this paper on behalf of a really incredible team that put the work together. And a lot of that work, or that work started with really unlocking the power of NHS data because of the COVID pandemic. So in the UK, we have a national health service, free at the point of delivery to everybody. The NHS assembled electronic health records, and there's been a long and proud history of research based on electronic health records in the UK. But for the first time, because of the pandemic, a combined data resource for the whole of England, so that's a population of about 58 million people, was established and that linked primary care data - data from family doctors, data on secondary care hospital admissions, data on COVID testing and subsequently, although it's not the subject of this paper, data on vaccination. So those data were all linked and put into one place within what's called a trusted research environment with very strict controls on what can be output from the environment in order to protect patient privacy. And that was really done during 2020. And then the analyses for this paper took place during 2021, and it was an enormous amount of work by a large and absolutely fantastic team of people across multiple UK universities and national health service institutions. Dr. Carolyn Lam: Wow. Bravo! We talk about big data, we talk about using it. I trained in the NHS system. Who knew that this could come out to reveal such important results? So thank you for that as a background, but now, tell us what you found please? Dr. Jonathan Stern: So we found that rates of these conditions, they were primarily acute lymph infarction and ischemic stroke, which we grouped together with other conditions as arterial thrombotic events, and then deep vein thrombosis and pulmonary embolism, which we grouped together with other conditions as venous events. And we found that rates were substantially multiplied immediately after a diagnosis of COVID by up to 748 times, that the amount by which rates were multiplied diminished with time since COVID, but importantly that even six months to a year after that first diagnosis of COVID, rates of venous events were still about double in people who'd had COVID, compared to people who had COVID. And we found, it seemed quite clear that the persistence of the elevated risk was longer for venous events than for arterial events. Dr. Carolyn Lam: Just really fascinating results and Shinya, could I ask, what are your thoughts on this? And as you were managing this paper, the implications? Dr. Shinya Goto: First of all, thank you very much, Jonathan, for choosing saturation for your great paper. I'm handling quite a lot of papers, but your paper was very attractive. As Carolyn mentioned, it's huge data! 48 million, it's surprising, and also you also pick up booster rate of arterial embolism event for years, and you have also shown adjusted rate is initially increased quite a lot and then decreased gradually. And even after two months, three months still, there is a persisted higher risk. And as you mentioned, for the venous thrombo embolism, it's persisted for more than year to year. It's surprising. COVID-19's a different disease. Perhaps COVID-19 infection cuts to the vascular endarterial cell, perhaps, your research raised a lot of research questions, like endarterial damage induced by COVID-19 in the past 6 months; I would say more than half a year to one year. So that mechanistical insight is very important. And you raise a lot of any clinical questions. Dr. Jonathan Stern: Well, thank you very much for your kind words and you are right, I think we are left with questions about maybe in three areas. Firstly, for how long is there an elevation in risk? I should probably say, for those who haven't read the paper, that these results relate to events that occurred in England and Wales during 2020. And so that is in an era before vaccination and when we were dealing with the original variant, and to some extent, the alpha variant. So we are still waiting to see what the implications were over longer periods, and we will be doing that, we will be extending follow up. In fact, we are at the moment extending those results. I think, secondly, we are left with questions about the mechanisms, which you articulated, and thirdly, there's the question about, well, what are the implications for clinical management of patients with COVID-19? And in particular, for patients who've had severe COVID-19, for example, severe enough to be hospitalized for it? Dr. Shinya Goto: Yeah, you have also showed a very important point that even known hospitalization for COVID-19, the risk of thrombosis becomes high. So it's very surprising. And even non-hospitalized patients have a higher risk of thrombosis. That is probably the huge difference between other virus infections and COVID-19. Dr. Jonathan Stern: Yes. The good news, if you weren't hospitalized for your COVID, is that the elevation in risk declines more rapidly for people with less severe COVID who weren't hospitalized than for people with more severe COVID who were hospitalized. But nonetheless, as you say, particularly in the first week, two weeks, three weeks after COVID, there is a clear elevation in the risk of both arterial and venous events, even if you were not hospitalized for your COVID. We should probably also bear in mind that these results for 2020, when there were severe constraints for some of the time on health service resources. So you probably had to be pretty sick to get hospitalized at that time. Dr. Carolyn Lam: That was a very important caveat that you just highlighted. So thank you for contextualizing those findings for us, Jonathan, but then I kind of wish all podcast guests were like you, and you already asked a question, I was going to ask you. Which is, okay, so what's the clinical implication? Should we all be taking some low dose NOAC or aspirin? Whether you're hospitalized or not? Or if you were in 2020? Because, jokes aside, I know that you found some very important risk factors? Or these events which had clinical implications? Could you expand on it? Dr. Jonathan Stern: So maybe I'd start by saying that we didn't find that these patterns varied dramatically either by sex or by age. And in fact, when we were planning the analyses, I was convinced that we would see dramatic differences in these hazard ratios by age. And, broadly speaking, the facts on a multiplicative scale, the amount by which your rate is multiplied, looked similar across age groups and by sex. On the other hand, we did see the amount by rates of arterial and venous events were multiplied, appeared greater in people of Asian ethnicity or Black ethnicity than in people of White ethnicity. A counterintuitive finding was that the amount by which your rate was multiplied is lower, if you've had a prior event than if you hadn't. Those are the sorts of extents to which we can say something about how your own characteristics predict the consequences once you've had COVID. In terms of management, obviously the pandemic has been tumultuous for medicine and for medical research and things have moved on greatly since the pre-vaccination era, 2020 and early 2021, to which these analyses relate. So the first thing to say is, don't get hospitalized with COVID, and the best way to not be hospitalized with COVID, is to be fully vaccinated for COVID. And that's a message that I think the whole of the medical profession has communicated loudly and clearly for a long time now. So the second thing is, well, okay, what about if, nonetheless, you got COVID, particularly severe COVID, and we discussed this in the team extensively, and I particularly want to mention the senior clinical author, Dr. Will Whiteley from the University of Edinburgh in this regard, and I think the main message here is that risk factor management, cardiovascular risk factor management is always important, but it's probably particularly important in people who've had severe COVID to review risk factor management and make sure that existing guidelines in terms of cholesterol lowering, blood pressure lowering and so on, are being adhered to. We don't... So the most important thing is adherence to existing cardiovascular risk management guidelines. I think we don't have evidence that specific additional interventions are indicated in people who've had COVID, and COVID now in the era of Omicron and widespread vaccination is not the same as COVID during 2020. Dr. Shinya Goto: Jonathan, you have raised a very important issue. I strongly recommend all audiences to read this paper. We have to know persistent or higher risk of myocardial infarction, ischemic stroke, may be controlled more regularly controlled. Don't fear the COVID-19 infection to visiting the healthcare professional. In my country, some of the population stopped coming to the healthcare professional because they fear so much about infection from the hospital or clinic. But it's very important to keep that regular control like static and blood pressure control. Maybe we don't have that data about aspiring or not, but strong message your paper gave is that risk factor control after COVID-19 is very important. Dr. Jonathan Stern: I completely agree. Dr. Carolyn Lam: And I would add to that, remember the days when people were stopping their ACE inhibitors and so on for those fear? So what a great message and thank you for giving us a little bit of a peek into the future of what you're planning next with more follow up, in a population that is vaccinated from a different strain perhaps. And I think this still encourages hopefully more trials and research into this whole area of how we should be managing these patients. Well, thank you so much both of you for discussing this very, very current relevant, important paper. Thank you for publishing it in circulation with us. And to the audience, thank you for joining us today. From Greg and I, you've been listening to Circulation on the Run, and don't forget to tune in again next week. Speaker 6: 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.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.05.506638v1?rss=1 Authors: Uzay, B., Hokelekli, F. O., Yilmaz, M., Esen, E. C., Basar, K., Bahadir-Varol, A., Ayhan, Y., Dalkara, T., Eren-Kocak, E. Abstract: Fibroblast growth factor-2 (FGF2) is involved in the regulation of affective behavior and shows antidepressant effects through Akt and ERK1/2 pathways. NUDT6 is a protein encoded from the antisense strand of the FGF2 gene and its role in the regulation of affective behavior is unclear. Here, we show that increasing NUDT6 expression in the hippocampus results in depression-like behavior in rats without changing FGF2 levels or activating its downstream effectors, Akt and ERK1/2. Instead, NUDT6 acts by inducing inflammatory signaling, specifically by increasing S100A9 levels, activating NF-kB, and rising microglia number along with a reduction in neurogenesis. Conversely, inhibition of hippocampal NUDT6 expression by shRNA results in antidepressant effects and increases neurogenesis without altering FGF2 levels. Together these findings suggest that NUDT6 may play a role in major depression by inducing a proinflammatory state and serve as a novel therapeutic target for antidepressant development. The opposite effects of NUDT6 and FGF2 on depression-like behavior may serve as a mechanism to fine-tune affective behavior. Our findings open up new venues for studying the differential regulation and functional interactions of sense and antisense proteins in neural function and behavior as well as in neuropsychiatric disorders. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

I am the Rachford and Carlota A. Harris Professor in the Department of Pathology at Stanford University School of Medicine. I trained with Leonard Herzenberg (for my Ph.D.) and Nobelist Dr. David Baltimore (for postdoctoral work for the first cloning/characterization of NF-kB p65/RelA and the development of 293T rapid retroviral production systems). I have published 307 peer-reviewed research papers, hold 40 US patents, and have been honored as one of the top 25 inventors at Stanford University.I am well known for my ability to bring novel technologies to commercial fruition. My contributions to the implementation of mass cytometry (CyTOF) and its use for immuno-oncology research are a case in point, winning Nature's “Outstanding Research Achievement” for 2011. My current research is focused on the development of multiparameter, single-cell tissue imaging technologies and computational approaches for systems immuno-oncology. Two recent innovations from my lab include multiplexed ion beam imaging (MIBI) and CO-Detection by indEXing (CODEX), which allow for simultaneous spatial quantification of 50+ parameters in a single tissue section. Another focus of my lab is the development and utilization of machine learning algorithms to interpret the large, high-dimensional datasets produced by CyTOF, multiplexed ion beam imaging (MIBI), and CODEX. Collectively, our efforts are to provide a deeper understanding of normal and impaired immune function - including detailed substructures of the immune system as it relates to various cancerous states - to enable wholly new understandings that lead to improved clinical outcomes. Additionally, I am dedicated to teaching and mentoring. I am currently mentoring 9 postdoctoral fellows and 5 graduate students, and I have taught multiple courses at Stanford and through NIH-sponsored programs. I have assisted students and colleagues in commercializing technologies via eight companies with a sum estimated present market capitalization of $800 million.

The 5th and final pillar of hormone balance and control is your inflammatory load. But is taking antiinflammatory supplements like Turmeric the right thing to do? Turns out it's better to find and fix the mechanisms causing inflammation, which is messing up your hormones. Hit the subscribe or follow button to be notified when new episodes drop. Rate and review your favorite episodes to let me know the things you like so I can keep delivering great content that brings value to your life and health. Check out my online DIY programs for thyroid, gut health and detox.  https://www.drnoseworthy.com/store

Videos: 1.Covid has torn apart our social fabric (Feat. Dr. Matt Strauss) 2.  A Christian Response to Wokeness (FULL VIDEO) | Noelle Mering | Leadership Institute (21:51) 3.  NBC News just SMEARED real journalists in shameful hit piece | Redacted with Clayton Morris (22:00) 4. COME HELL OR HIGH WATER! Four minutes of WOW! (talking about the shootings and blame)   Vitamin D deficiency directly linked to dementia University of South Australia, June 14, 2022 Dementia is one of the major causes of disability and dependency among older people worldwide, affecting thinking and behaviors as you age. But what if you could stop this degenerative disease in its tracks? A world-first study from the University of South Australia could make this a reality as new genetic research shows a direct link between dementia and a lack of vitamin D. Investigating the association between vitamin D, neuroimaging features, and the risk of dementia and stroke, the study found: low levels of vitamin D were associated with lower brain volumes and an increased risk of dementia and stroke genetic analyses supported a causal effect of vitamin D deficiency and dementia. in some populations as much as 17% of dementia cases might be prevented by increasing everyone to normal levels of vitamin D (50 nmol/L). Flaxseed supplements linked to improved blood pressure: Meta-analysis University of Medicine and Pharmacy (Romania), June 9, 2022 Supplements of flaxseed may effectively management blood pressure, says a new meta-analysis of 15 clinical trials. Data from 1,302 participants indicated that flaxseed supplements are associated with significant reductions in both systolic and diastolic blood pressure of about 2.85 mmHg and 2.39 mmHg, respectively. “The results obtained in the present meta-analysis – a decrease of 2.85/2.39 mmHg after flaxseed supplementation – might be valuable for the hypertension management using nutraceuticals, since Heart Outcome Evaluation study demonstrated that a 3.3/1.4 mmHg reduction was associated with a 22% decline of relative risk of cardiovascular mortality,” wrote scientists from Romania, Iran, Australia and Poland in Clinical Nutrition . The scientists also report that supplementation for longer than 12 weeks resulted in even greater reductions in systolic and diastolic blood pressure of 3.10 mmHg and 2.62 mmHg, respectively, compared to trials of shorter duration. The potential biological mechanism are not completely understood, said the researchers, but could be linked to the lignan content of flaxseed. Specifically, a lignan named SDG is known to be an angiotensin-converting enzyme (ACE) inhibitor. ACE inhibitors work by inhibiting the conversion of angiotensin I to the potent vasoconstrictor, angiotensin II, thereby improving blood flow and blood pressure. Finally, an arginine-rich protein fraction (KCl-F1) from flaxseed may also impact blood pressure. Flaxseed powder supplements were found to affect systolic blood pressure (SBP) and diastolic blood pressure (DBP), whereas flaxseed oil preparations only affected DBP. On the other hand, lignan extracts was not associated with any changes in SBP and DBP, they said. Keep calm and carry on — for the sake of your long-term health Penn State University, June 9, 2022 Reacting positively to stressful situations may play a key role in long-term health, according to researchers. In a study measuring adults' reactions to stress and how it affects their bodies, researchers found that adults who fail to maintain positive moods such as cheerfulness or calm when faced with the minor stressors of everyday life appear to have elevated levels of inflammation. Furthermore, women can be at heightened risk. Nancy Sin, in the Center for Healthy Aging, Penn State and her colleagues showed that the frequency of daily stressors, in and of itself, was less consequential for inflammation than how an individual reacted to those stressors. “A person's frequency of stress may be less related to inflammation than responses to stress,” said Sin. “It is how a person reacts to stress that is important.” In the short-term, with illness or exercise, the body experiences a high immune response to help repair itself. However, in the long term, heightened inflammatory immune responses may not be healthy. Individuals who have trouble regulating their responses may be at risk for certain age-related conditions, such as cardiovascular disease, frailty and cognitive decline, Sin said. “To our knowledge, this paper is the first to link biomarkers of inflammation with positive mood responses to stressors in everyday life,” said Jennifer E. Graham-Engeland, associate professor of biobehavioral health, Penn State. For breast cancer prevention, diet quality matters Healthy, plant-based diet linked with lower cancer risk for postmenopausal women  Paris-Saclay University (France), June 14, 2022 Research shows that what we eat can influence our cancer risk, but it's not always clear which foods or dietary patterns are best for cancer prevention. Results from a new study suggest that the quality or overall healthiness of a person's diet may be key. The study, based on data from over 65,000 postmenopausal women who were tracked for more than two decades, found that a healthy plant-based diet was linked with a 14% lower risk of breast cancer while an unhealthy plant-based diet was linked with a 20% higher risk of breast cancer. The findings were consistent across all breast cancer subtypes. “These findings highlight that increasing the consumption of healthy plant foods and decreasing the consumption of less healthy plant foods and animal foods might help prevent all types of breast cancer,” said Sanam Shah, at Paris-Saclay University, Gustave Roussy, France, the study's lead author.  Previous studies have examined cancer risks associated with various dietary patterns such as the Western diet, the Mediterranean diet and vegetarian diets. Although some studies suggest diets with less or no meat consumption offer health benefits, results have been somewhat mixed. For the new study, researchers focused on differentiating between healthy plant-based foods — such as whole grains, fruit, vegetables, nuts, legumes, vegetable oils and tea or coffee — and plant-based foods the study categorized as less healthy including fruit juices, refined grains, potatoes, sugar-sweetened beverages and desserts. Regular exercise beneficial in suppressing inflammation in rheumatic disease Exercise results in physiological changes that decrease inflammation on a local and systemic level Ohio State University, June 12, 202 Research findings suggest that exercise transiently suppresses local and systemic inflammation, reinforcing the beneficial effects of exercise and the need for this to be regular in order to achieve clinical efficacy in rheumatic disease. These new research findings focused on the physiological changes created by exercise and their impact on inflammation. The researchers have found that exercise generates a true biological response and induces changes on a molecular level that stimulate anti-inflammatory effects. This in-vivo study measured the regulation and activation of NF-kB* in mice. NF-kB, a protein complex that controls many genes involved in inflammation, is found to be chronically active in many inflammatory diseases, such as inflammatory bowel disease and arthritis. The effect of exercise on the inhibition of NF-kB activation was identified as a transient effect, lasting only 24 hours after exercise.The role of exercise in inhibiting NF-kB activation was linked to the suppression of multiple pro-inflammatory cytokines.  Keeping the faith – or your willingness to push yourself – as you grow older Norwegian University of Science and Technology, June 14, 2022 So you could have become a pro footballer when you were younger, you say? Or really good at chess? Perhaps a world-renowned chef? Well, maybe not anymore, we think as we get older. And maybe that's actually okay. A research group has investigated how important the motivational factors for becoming really proficient at a skill change over the years. “We wanted to see how the passion, grit and belief that you'll succeed at getting better – your growth mindset – change with age and in relation to gender,” says Hermundur Sigmundsson, a professor at the Norwegian University of Science and Technology's (NTNU) Department of Psychology. “The passion for what you used to burn for declines. And so does the belief that you can succeed at becoming really good at it,” says Professor Sigmundsson. But this is where it is important to take hold of yourself and not give up. You might not become a world champion in anything, but you could still get really proficient if you go for it. Or at least better. “That's when it's important to maintain a growth mindset. You can't stop believing in growth even though you're getting older,” says Sigmundsson. “Passion and a growth mindset decrease with age, but the willingness to persevere increases if we look at the elderly population as a whole,” says Sigmundsson.

What Is Nuclear Factor Kappa B (NF-κB) Doing in and to the Mitochondrion? Evidence for the Involvement of TNF and NF-kB in Hippocampal Synaptic Plasticity, NF-κB p50 subunit knockout impairs late LTP and alters long term memory in the mouse hippocampus, Early Growth Response 2 (Egr-2) Expression is Triggered by NF-κB Activation, and Chronic dietary creatine enhances hippocampaldependent spatial memory, bioenergetics, and levels of plasticity-related proteins associated with NF-κB Scientific Sense ® by Gill Eapen: Prof. Benedict C. Albensi is a Professor and Chair of the Department of Pharmaceutical Sciences and the co-director of the BRAIN Center at Nova SouthEastern University. His research interests include factors involved in ageing, cognition, and Alzheimer's disease (AD), such as nuclear factor kappa B (NF-kB), a mediator of inflammation but also a required molecule for memory. Please subscribe to this channel: https://www.youtube.com/c/ScientificSense?sub_confirmation=1 --- Send in a voice message: https://anchor.fm/scientificsense/message Support this podcast: https://anchor.fm/scientificsense/support

Getting to the Heart of Cannabis Health Risks Cell Press Cannabis has deleterious effects on cardiovascular physiology. Wei et al. (Cell 185, May 12, 2022) confirm that important inflammatory markers increase transiently after a single marijuana joint and prove a mechanistic link between THC induced vascular inflammation, endothelial dysfunction, cellular oxidative stress, and atherosclerosis using cell-based and mouse models of atherosclerosis. They provide a pharmacological model in which THC-mediated activation of CB1 receptor signaling pathways converge on MAP kinase, TNFa, and NF-kB outputs to create a proinflammatory and atherogenic environment in endothelial cells.   That genistein can antagonize the negative effects of THC with minimal central effects is exciting because genistein is a common component of soy and is already a widely consumed dietary product.   Electronic Cigarettes Versus Nicotine Patches for Smoking Cessation in Pregnancy: A Randomized Controlled Trial Nature Medicine Pregnant smokers were randomized to use either nicotine replacement therapy with patches (NRT, n=571) or e-cigarettes (n=569) for smoking cessation. For the primary outcome, validated prolonged quit rates at the end of pregnancy, the results were 4.4% for NRT and 6.8% for e-cigarettes (P=0.08). However, 25 participants in the NRT arm who reported abstinence also used e-cigarettes. When these participants were excluded from data analysis the quit rates were 3.6% for NRT and 6.8% for e-cigarettes (P=0.02). Low birthweight was less common in the e-cigarette arm, 9.6% versus 14.8% for NRT (P=0.01). The authors conclude that “e-cigarettes were markedly more effective than patches” and do not pose more risk.   Daily Cannabis Use, Cannabis Use Disorder, and Any Medical Cannabis Use Among US Adults: Associations Within Racial, Ethnic, and Sexual Minoritized Identities in a Changing Policy Context Preventive Medicine Reports Cannabis use has steadily increased in the United States, with daily and medical use associated with cannabis use disorder (CUD) and the negative consequences more frequent among marginalized groups. In this study, the authors use the National Survey on Drug Use and Health (NSDUH) to examine medical and daily use and CUD across the intersections of racial, ethnic, and sexual minorities. They found that sexual minorities were more likely to have medical and daily use and CUD than their heterosexual counterparts within each racial and ethnic group. However, when examining the intersection of race, ethnicity and sexual identity, there was more heterogeneity across these groups. In addition, they found that in states with medical cannabis laws (MCL) daily cannabis use was higher across all intersectional groups.     Effect of AXS-05 (Dextromethorphan-Bupropion) in Major Depressive Disorder: A Randomized Double-Blind Controlled Trial AJP Psychiatry Altered glutamatergic neurotransmission is implicated in the pathogenesis of major depressive disorder. AXS-05 (dextromethorphan-bupropion) is an oral NMDA receptor antagonist and sigma-1 receptor agonist, which utilizes inhibition of CYP2D6 to increase its bioavailability. This phase 2 trial assessed the efficacy and safety of dextromethorphan-bupropion in the treatment of major depressive disorder. In patients with major depression, dextromethorphan-bupropion (AXS-05) significantly improved depressive symptoms compared with bupropion and was generally well tolerated.  The most common adverse events were dizziness, nausea, dry mouth, decreased appetite, and anxiety. Dextromethorphan-bupropion was not associated with psychotomimetic effects, weight gain, or sexual dysfunction.   Mental Health and Substance Use Among Homeless Adolescents in the US JAMA Network This study evaluated mental health and substance use outcomes among homeless and non-homeless adolescents in 2019. Alcohol, cigarette, marijuana, and binge drinking during the prior 30 days was assessed, along with lifetime use of cocaine, methamphetamine, heroin, ecstasy, and injection drugs or prescription opioid misuse. Results found current substance use ranging from cigarettes to alcohol were higher among homeless adolescents. Lifetime cocaine use was significantly higher among homeless adolescents, as were methamphetamine, heroin, ecstasy, and injection drug use. Homeless adolescents experience worse mental health outcomes, including depression and suicidality, and struggle with more SUDs than their counterparts.   The Importance of Federal Action Supporting Overdose-Prevention Centers NEJM In this prospective piece, the authors discuss the need for new approaches to harm reduction and substance use disorder treatment in the face of substantially increasing overdose deaths, particularly since the start of the COVID-19 pandemic. One such strategy they discuss is overdose-prevention centers, which operate in other countries and are associated with significant reductions in opioid-overdose morbidity and mortality. However, under Section 856 of the Controlled Substances Act, such facilities may be subject to federal legal sanctions. The authors recommend that the Biden administration declare they will not interfere with such public health interventions or declare that section 856 does not apply to legally sanctioned centers. Further, Congress should modify the Controlled Substance Act to exempt overdose-prevention centers.    Complex Persistent Benzodiazepine Dependence—When Benzodiazepine Deprescribing Goes Awry JAMA Psychiatry Benzodiazepines remain popular medications among patients due to rapid symptom relief and reinforcing effects. As clinicians and patients become more aware of potential risks, and clinical guidelines increasingly urge caution in prescribing, guidance for benzodiazepine deprescribing is needed. The authors propose a new clinical concept for patients experiencing significant psychological or functional decline during or after a benzodiazepine taper—complex persistent benzodiazepine dependence (CPBD). CPBD can be described as symptomatic or functional decompensation with or without the development of aberrant medication behaviors in the setting of benzodiazepine deprescribing–in the absence of a benzodiazepine use disorder. Further research is needed to validate this concept.    What is Success in Treatment for Opioid Use Disorder? Perspectives of Physicians and Patients in Primary Care Settings JSAT Opioid abstinence and treatment retention are typically used as measures of success of MOUD treatment. This study sought to identify other important treatment outcomes and patient-centered measures of success. Qualitative, structured interviews were conducted with physicians (n=14)  and patients (n=18) in 2 family medicine residency programs. The physicians (7 faculty and 7 residents) were experienced buprenorphine prescribers. Both patients and physicians identified 5 themes: staying sober, and improvement in physical health, mental health, relationships, and role functioning. Patients, but not physicians, identified 2 additional themes: tapering off buprenorphine, and decreased stigma and shame. The authors conclude that “clinicians and researchers need to consider a broader scope of success indicators.”  

We continue our discussion with Dr. Adewunmi Adelaja (M.D., Ph.D.), from the University of California Los Angeles, about NFkB signaling and how signals to different stimuli are relayed inside macrophages.

We sit down with Dr. Adewunmi Adelaja (M.D., Ph.D.) from the University of California Los Angeles to discuss NFkB signaling and how signals to different stimuli are relayed inside macrophages.

Anti-aging science is big business, with billions of dollars being poured into pharmaceutical and technological approaches. However, there are natural and nutritional means protect health, increase longevity, slow aging processes and even reverse the damage. Spices are real superstars on this stage. From helping prevent plaque in your arteries, cooling chronic inflammation, supporting digestion, easing aching joints, protecting DNA, supporting insulin sensitivity, protecting tissues from cross-linking, preventing tumor growth, stabilizing cellular membranes, clearing extracellular junk, aiding cellular renewal through apoptosis, to thinning

Anti-aging science is big business, with billions of dollars being poured into pharmaceutical and technological approaches. However, there are natural and nutritional means protect health, increase longevity, slow aging processes and even reverse the damage. Spices are real superstars on this stage. From helping prevent plaque in your arteries, cooling chronic inflammation, supporting digestion, easing aching joints, protecting DNA, supporting insulin sensitivity, protecting tissues from cross-linking, preventing tumor growth, stabilizing cellular membranes, clearing extracellular junk, aiding cellular renewal through apoptosis, to thinning

Dr Carolyn Lam:     Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. And Dr. Carolyn Lam, Associate Editor from the National Heart Center, and Duke National University at Singapore.                                 What is the effect of obesity and underweight status on perioperative outcomes of congenital heart operations?                                 Our feature paper this week sheds light from the Society of Thoracic Surgeons Database. More soon, right after these summaries.                                 The first original paper highlights the role of micro RNAs in metabolic remodeling and heart failure. As a reminder, micro RNAs are small, noncoding RNAs important in post transcriptional modification and influencing many cellular processes simultaneously.                                 First author, Dr. Heggermont, corresponding author, Dr. Heymans, and colleagues from Maastricht University in the Netherlands use mice subjected to pressure overload by means of endotension to infusion or transverse aortic constriction. They show that micro RNA 146A was up regulated in whole-heart tissues in these murine pressure overload models, as well in left ventricular biopsies of aortic stenosis patients. Over expression of micro RNA 146A in cardio cardiomyocytes provoked cardiac hypertrophy and left ventricular dysfunction in vivo, whereas genetic knockdown or pharmacological blockade of micro RNA 146A blunted the hypertrophic response and attenuated cardiac dysfunction in Vivo.                                 Mechanistically, micro RNA 146A reduced its target dihydrolipoyl succinyltransferase or DLST, a mitochondrial protein that functions as a TCA cycle transferase. DLST protein levels were reduced in pressure overload mice, while they were partially maintained in micro RNA 146A knockout mice. Furthermore, overexpression of DLST in wild type mice, protected against cardiac hypertrophy and dysfunction in Vivo. Thus, micro RNA 146A and its target DLST are important metabolic players in LV dysfunction. These results also opened the door to novel therapies to treat metabolic disturbances and improve energy efficiency of a failing heart.                                 Program cell death is critically involved in ischemic cardiac injury, pathologic cardiac remodeling, and heart failure progression. Our next paper sheds light on the regulatory mechanisms of necroptosis and its significance in the pathogenesis of heart failure. Using genetic mouse models, first authors Dr. Guo and Yin, corresponding author Dr. Liu, and colleagues from University of Washington in Seattle, identified a critical role for a tumor necrosis factor receptor associated factor 2 or TRAF2 in myocardial survival and homeostasis by suppressing necroptosis.                                 The authors delineated an important TRAF2 mediated NF-KB independent pro-survival pathway in the heart by suppressing necroptotic signaling. They identified novel molecular mechanisms whereby TRAF2 suppressed TNF receptor 1 mediated, receptor interacting protein 3 dependent necroptosis, which is critical for myocardial survival and homeostasis. Thus, this finding suggests that the necroptosis suppressing TRAF2 signaling pathway and its effectors may serve as novel therapeutic targets for pathologic cardiac remodeling and heart failure.                                 Our next paper tells us that cerebral hyperperfusion may be associated with accelerated cognitive decline and an increased risk of dementia in the general population. First author Dr. Walters, corresponding authors Dr. Ikram, and colleagues from Erasmus University Medical Center in Rotterdam, The Netherlands, measured cerebral blood flow by 2D phase contrast MRI in non-demented participants of the population based Rotterdam study. A 4,759 participants with a median age of 61 years, and a median follow up of 6.9 years, 123 participants developed dementia.                                 Lower cerebral perfusion was associated with higher risk of dementia and this risk was even higher with increasing severity of white matter hyperintensities on MRI. At cognitive reexamination after an average of 5.7 years, lower baseline perfusion was associated with accelerated decline in cognition, which was similar after excluding those with incident dementia, and again, most pronounced in individuals with higher volumes of white matter hyperintensities.                                 Thus, lower cerebral perfusion was associated with accelerated cognitive decline and increased risk of dementia in the general population. This association was modified by hypertension and cerebral small vessel disease, possibly reflecting impaired arteriola and capillary function. This paper calls for further long term study and evaluation of optimizing cerebral perfusion as a means to prevent cognitive deterioration, for example, in patients with heart failure or carotid artery stenosis.                                 Well, that wraps it up for our summaries. Now for our feature discussion. For today's feature discussion, we will be looking at data from the Society of Thoracic Surgeons Database. This time looking at the effect of body mass index on perioperative outcomes of congenital heart operations in children, adolescents, and young adults. To discuss this, we have none other than the first and corresponding author, Dr. Michael O'Byrne from Children's National Medical Center in Washington D.C., as well as Dr. Naveed Sattar, Associate Editor from University of Oxford. Welcome gentlemen. Dr Michael O'Byrne:       Good morning. Dr Naveed Sattar:            Good morning. Dr Carolyn Lam:                Michael, we know that extreme body mass indices, very high or very low, has been associated with increased risk of at first, perioperative outcomes in mainly older adults undergoing cardiac surgery. We also know about the obesity paradox in conditions like heart failure, so why was it important to look at this specific group of patients? Congenital heart patients and children, adolescents, and young adults? Dr Michael O'Byrne:       Yeah, I think that as a pediatric cardiologist, a lot of the data that we use to guide our management is extrapolated from adult studies. However, in this particular case, it wasn't clear necessarily that adult data would necessarily be applicable to children and adolescents and young adults. We are aware that there are epidemiologic trends that congenital heart disease population ages and there are also in increasing problems of obesity among children in the United States.                                 The convention wisdom among surgeons in the United States is that obesity would increase perioperative risk and the thought is that some combination of exposure to hypertension and diabetes and peripheral vascular disease might impede wound healing and that body habit as itself might be a risk for the technical approach in wound healing. Acknowledging that there's a lot of evidence both for extreme BMI being a risk in surgical patients and adults, but also the idea that obesity paradox might be important in children because the biological mechanisms might be different.                                 Children themselves are exposed, their sort of dose response or dose exposure is less, they're younger, and so haven't been obese for a prolonged period of time, so that the integrated effect of having diabetes, hypertension, and obesity might be less. At the same time, we also acknowledge that in children with heart disease, we have congenital cardiac disease, the same issues with cachexia and frailty are present. i.e. that children with very low body mass index might be assigned to their own medical frailty, or a part of a heart failure cachexia syndrome.                                 One of the challenges in dealing with children with congenital heart disease, however, as you know is that its rarer than cardiac disease of the aging and additionally, that the population is very heterogenous in terms of the actual defects that are present and the surgeries that are performed. It was relevant to look and see over a wide range of sort of technical complexity surgeries with a wide range of sort of intrinsic preoperative risk of perioperative outcome, whether or not BMI would be associated with an adverse outcome. Either operative mortality in this case, or a composite outcome of mortality, major adverse events, and wound infection. Dr Carolyn Lam:                Wow, that makes a lot of sense and congratulations. This is not just the first, it's huge and really comprehensive. Could you just tell us a little bit more about what you did and what you found? Dr Michael O'Byrne:       I think as this point, I'd have to acknowledge that the challenges that we described in terms of both a sample size and in terms of getting a representative sample, is a constant challenge in our field and we have to give credit to my co-authors Marshall and Jeff Jacobs for their work in developing the collaboration that allowed for the STS Congenital Heart Surgery Database to exist. Also, on top of shepherding the database, their research, along with the people at Duke Clinical Research Institute, they've developed a robust risk stratification model for mortality that we utilize as part of this study. Without that, this would be really be very challenging.                                 What we did is performed an observational cohort study using the STS Congenital Heart Surgery Database to look at the risk of perioperative mortality and composite outcome in patients undergoing surgery in the United States between 2010 and 2015. We looked at both the actual events, the sort of observed events, in terms of mortality and adverse events, and then created multivariate models to adjust for the known covariance.                                 We hypothesized that extreme BMI, either very high or very low, would be associated with increased risk of mortality and increased risk of that composite outcome. What we found that operative mortality and that perioperative adverse events occurred more frequently in obese and severely underweight subjects. However, because they have an unequal distribution of potentially important covariance, we used multivariate modeling to adjust for those covariance.                                 Our multivariate models for death, however, the severely underweight subjects had an odds ratio of 1.4 and obese subjects had an odds ratio of 1.3, but neither was specifically significant in that context. We sort of anticipated that with a possibility given the very low event rate. That's the reason we've used a composite outcome, a higher event rate.                                 For that composite outcome, in both different versions of the multivariate model that we used, the severely underweight subjects had an odds ratio of 1.5, underweight subjects had an odds ratio of 1.3, and obese subjects had an odds ratio of 1.2. An increased risk in all three of those populations of interest relative to normal weight or just overweight subjects. Dr Carolyn Lam:                We're always saying that at circulation we do want to publish papers that have direct and important clinical implications, so Naveed, could you share some thoughts on what this means clinically? Dr Naveed Sattar:            Yeah, I think they went through the review process and I think the paper was very well written. I think Michael and his colleagues clearly understood the strength and the limitations of the data so that you can only ever itself prove associations here and therefore, clinically when we push them on trying to make clinical inferences, I think clearly they recognize that once they find associations between obesity and adverse outcomes and underweight.                                 What they need to do next, now this is a paper that then leads you to think, "Well actually, I need to do some clinical trials to prove that module ..." You're preventing these outcomes or in very under knowledge where they're actually increasing the BMI but improving their nutrition, cannot also improve outcomes following surgery. Now those are tough things to do. Michael, what do you think from some of the clinical inference? My inferences were the associations were there, particularly for the normal [inaudible 00:12:35] outcomes, but actually to prove that, to make a difference, you probably might need to do some intervention trials or is that how you take it as well? Dr Michael O'Byrne:       I agree with you 100%. I think that as an epidemiologist, I think that what we see in an observational study like this is an association. The two next levels of research that are necessary at this point are to see whether or not in this population BMI is a modifiable factor in the short run before surgery, or even in the long run. And the second question to answer is whether those adjustments in BMI, if they are achievable, affect outcome with surgery. Absolutely.                                 It's a tremendous challenge, both logistically in organizing a study, and honestly, in terms of capturing a cohort that would be large enough, given that this is almost 100% of the surgeries that occurred over a six year period in the United States. Dr Naveed Sattar:            I looked at it and thought, "Well, the mortality association once you adjusted were not quite significant but are there any individuals you would not do surgery on based on their BMI based on these results? Dr Michael O'Byrne:       The motivation for the study is exactly to try to begin to shed light on that kind of question. I think that it might be what I would call a tiebreaker potentially, if you have a situation where a patient is near meeting criteria but isn't quite at a place where you need to do surgery at that point. It might dissuade you from proceeding immediately potentially pursuing a course that might adjust their BMI in the correct direction.                                 At the same time also, in a patient who's underweight particularly to evaluate whether their medical regimen has been optimized and if there are other residual lesions that can be addressed in a non-surgical or medical fashion. Dr Naveed Sattar:            I suppose the other trick with this type of research research is always trying to make sure that people understand these are the associations and not trying to attribute causality because it's always physical, isn't it? But I think you and your team did that very well and I'm sure we had a back and forth with review but I think your discussion section, your limitation section, is beautifully written and covers those kinds of caveats, which I think is important as well. Dr Michael O'Byrne:       I thank you for that. That's very complimentary and we certainly strived for that, but I think that you as an editor, and also in terms of the reviewers also, were very helpful in that sort of collaborative process to try to make sure that we're communicating it. It's not always clear in a project that takes months and years to finish when you're writing it necessarily, you may be constantly aware of trying to be clear in your communication but it's also helpful to have a reviewer from the outside carefully read the study. Dr Carolyn Lam:                That's wonderful and Michael, may I just join Naveed in congratulating you on beautiful paper? And maybe just one other little question, did you have any insights into the mechanisms of increased risk for composite events in the extremes of BMI? Dr Michael O'Byrne:       I think it's an important question. There's been a tremendous amount of research in adult cardiac disease about whether it is the BMI as a steady state or BMI changes immediately before and after surgery that are relevant in this case. From this kind of observational study, it's very hard and very challenging to try to make any sort of inferences about the causes. It would be an important part of any study moving forward to include ways to investigate that, and honestly, as an interventional cardiologist and epidemiologist, I probably would defer to Naveed, he might have more cogent and logical ideas about that than I do. Dr Naveed Sattar:            We've had lots of research from a whole variety of researchers. We all understand it's finally serious but recognize it's difficult, so one of the ways moving forward and I think Michael and his colleagues have this is if you have serial BMI data prior to surgery, that could try and inform on reverse causality because of the low BMI, but in terms of the mechanisms, remember these are associations, but I think mechanisms are well covered if you are obese and clearly you have risk factors for death, across the vasculature, across the cardiac functions, across the whole variety of things.                                 We know those mechanisms, question is, to what extent are they actually operating and causing increased risk in the surgical arena and that's a really tough ask. I think people can come up with a multitude of mechanisms. I think the key things, like this particular paper, is that there are potential mechanisms but these are associations ... Look, this is what we found, and clinically now we need to try and address this within the following types of interventions or at least provide some guidance to colleagues and clinicians.                                 Exactly as Michael says, if there is somebody who is approaching surgery whose quite obese, perhaps they should try and intervene to try and lessen their weight for a short period of time prior to [inaudible 00:17:07], you know what happens. It would be nice to do some big trials but I think doing trials in this area is going to be really tough, but with imagination, with good collaboration across centers, trials are not impossible. I think they can be done. Dr Michael O'Byrne:       Naveed, I think, actually articulated what I think is both the difficulty of doing that trial but also the importance of it. I think that looking at ... In these databases, we don't have a serial BMI and I think that's an important missing piece of information that we tried to address in our discussion and I think it's something that would be really valuable moving forward. And certainly testing interventions, whether they're medical, interventional, or surgical, to help these patients who are obese either lose or maintain an appropriate weight is the next step.                                 On the converse side, this research highlighted to me the prevalence of chachectic or underweight patients in our population and it's something that outside of the infant period, we don't necessarily think about tremendously and we don't think about it as a modifiable factor. I think that's another group of patients who also deserve some attention. Dr Carolyn Lam:                Listeners, you've been listening to Circulation on the Run. I'm sure you learned a lot as I did. Don't forget to tune in again next week.