Podcasts about nlrp3

mosaic interaction activation bingen hildegard bacterial mediated biochemical mtdna iii c nlrp3 galectin inflammasome

Play Episode Listen Later Mar 22, 2024 28:50

References Front Immunol. 2020; 11: 591803 Am J Gastroenterol. 2004 Nov;99(11):2147-9. Biochem Biophys Res Commun. 2005 Dec 16;338(2):1031-6 Front Immunol. 2019 Jun 7;10:1309. FASEB J. 2021 May; 35(5): e21439. Hildegard von Bingen 1150.- "Canticles Of Ecstasy --- Send in a voice message: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/message Support this podcast: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/support

Biochemical Mosaic III. C.2 A Non-canonical autophagic inhibition of NLRP3 inflammasome mediated inflammation in UVB-treated human keratinocytes.DJGPhD. 20.3.24.

Pharma Intelligence Podcasts

Play Episode Listen Later Mar 21, 2024 30:00

References Front Immunol. 2019 Jun 7;10:1309. JBC 2024 . March.Article in PressDOI:https://doi.org/10.1016/j.jbc.2024.107173 FASEB J. 2016 Dec;30(12):4202-4213. Nat Rev Gastroenterol Hepatol . 2020 Feb;17(2):93-110 Bach , JS. 1731. Piano Partita No. 2 In C Minor, BWV 826 https://youtu.be/f-OdOuNZciQ?si=AmFtC5CX3x2ndzdV Slade,Mann, and Rogers. 1975 "Time is Right" Manfred Mann https://youtu.be/jzJIej8h5q4?si=3-aCFe0tqur4lfX1 --- Send in a voice message: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/message Support this podcast: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/support

time rogers inflammation mosaic treated js canonical bwv inhibition mediated biochemical jbc iii c nlrp3 inflammasome

NodThera On The Role Of The Brain In Driving Chronic Disease

Play Episode Listen Later Feb 28, 2024 23:54

Alan Watt, CEO of NodThera, a clinical-stage biotech developing brain-penetrant NLRP3 inflammasome inhibitors to treat chronic inflammatory diseases, talks to In Vivo about the company's pipeline and recent data publication in the field of obesity. The company is focused on developing drugs that inhibit the NLRP3 inflammasome, a validated drug target that plays a pivotal role in controlling inflammatory diseases. It has two clinical trials ongoing – both Phase Ib/IIa – in Parkinson's disease and for cardiovascular risk in obese patients.

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PEA (palmitoylethanolamide) and Upper Respiratory Viruses

Functional Medicine Research with Dr. Nikolas Hedberg

Play Episode Listen Later Feb 9, 2024 8:20

A new study entitled, “The Efficacy of Palmitoylethanolamide (Levagen+) on the Incidence and Symptoms of Upper Respiratory Tract Infection-A Double Blind, Randomised, Placebo-Controlled Trial” aimed to evaluate the effectiveness of a signaling lipid called Palmitoylethanolamide (PEA) in reducing the occurrence, duration, and severity of upper respiratory tract infections(URTIs). The results showed that participants who took PEA experienced fewer URTI episodes and had reduced symptoms compared to those who took a placebo, suggesting that PEA may be a safe and effective treatment option for URTIs. Palmitoylethanolamide (PEA) is a lipid compound that belongs to the N-acylethanolamine (NAE) family and has similar properties to endocannabinoids. In the context of cold and flu infections, PEA is suggested to regulate interleukins and inhibit mast cell production, thereby reducing inflammation. PEA activates NF-κB pathways through peroxisome proliferator-activated receptors (PPAR), particularly PPAR-α, and concentration-dependent mechanisms to decrease NLRP3 and inflammasome activation, ultimately leading to a decrease in the expression of cytokines and alleviation of upper respiratory tract infection symptoms. It is worth noting that the natural levels of PEA in the body and the use of PEA supplements have been found to be ineffective in producing significant clinical results due to poor absorption, resulting in low levels of PEA in the bloodstream. However, when PEA is combined with dispersion technology, such as Levagen+, the absorption of PEA is greatly improved, leading to higher concentrations in the bloodstream, which may enable a therapeutic effect. This study was conducted over a period of 12 weeks. It was a double-blind, randomized, placebo-controlled trial, where participants were divided into two groups: an active group receiving 300 mg of Levagen+ PEA twice a day and a placebo group receiving maltodextrin. The purpose of the study was to investigate the efficacy of Levagen+ PEA compared to the placebo in terms of the incidence, severity, and duration of upper respiratory tract infections (URTI). During the study, 87 participants out of the total enrolled experienced at least one URTI, resulting in a total of 103 URTI episodes. The group receiving Levagen+ PEA reported significantly fewer URTI episodes (39) compared to the placebo group (64), and a lower number of participants who fell sick at least once during the study (32 vs. 55) when compared to the placebo group. Participants in the Levagen+ PEA group reported a significantly lower severity score for scratchy throat and cough. Overall, compliance with the study was high for both groups in terms of capsule consumption. The findings of the study indicate that individuals in the Levagen+ PEA group had a significantly lower number of upper respiratory tract infection (URTI) episodes compared to the placebo group. The study suggests that Levagen+ PEA could be a viable treatment for preventing upper respiratory tract infections (URTIs) and alleviating symptoms of cold and flu. The findings indicate that Levagen+ PEA is safe and effective in reducing the frequency of URTI episodes and relieving scratchy throats and coughing in individuals with URTI symptoms. I use PEA Luteolin Select from Moss Nutrition, which contains 300 mg of Levagen+ PEA and 50 mg of the flavonoid luteolin per capsule. PEA and luteolin have been shown to work synergistically in COVID-19-related illnesses such as Long COVID. I have patients take 1 capsule twice a day with meals of PEA Luteolin Select during COVID-19, cold, and flu season for prevention and then increase to 2 capsules three times a day when they feel like they're coming down with something. Hedberg Institute Members can download my latest upper respiratory tract infection protocols by logging in. Click here to learn more about the Hedberg Institute Membership.

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Membrane Raft Redox Signaling Contributes to Visfatin-Induced Inflammation and Kidney Damage

Aging-US

Play Episode Listen Later Dec 5, 2023 4:59

BUFFALO, NY- December 5, 2023 – A new #researchpaper was #published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 15, Issue 22, entitled, “Contribution of membrane raft redox signalling to visfatin-induced inflammasome activation and podocyte injury.” The number of obese patients with end stage renal disease has increased significantly worldwide in the last few decades. Obesity results in an increased risk for chronic kidney diseases like diabetes and hypertension which consequently result in chronic kidney disease or even end-stage renal disease. However, the exact mechanism of how obesity increases the advancement of chronic kidney disease is still uncertain. Recently, researchers Saisudha Koka, Sreenidhi Surineni, Gurinder Bir Singh, and Krishna M. Boini from the University of Houston, Texas A&M University and the University of California Riverside have shown that adipokine visfatin-induced NLRP3 inflammasome activation contributes to podocyte injury. However, the molecular mechanisms of how visfatin induces the Nlrp3 inflammasome activation and podocyte damage is still unknown. The present study tested whether the membrane raft (MR) redox signaling pathway plays a central role in visfatin-induced NLRP3 inflammasomes formation and activation in podocytes. “In this study, it is proposed that visfatin induces the NLRP3 inflammasome activation in podocytes, leading to glomerular inflammatory injury in the kidney and the development of CKD, may be primarily driven by NADPH oxidase-mediated membrane raft redox signalling.” Upon visfatin stimulation, an aggregation of NADPH oxidase subunits, gp91phox and p47phox, was observed in the MR clusters, forming an MR redox signaling platform in podocytes. The formation of this signaling platform was blocked by prior treatment with MR disruptor MCD or NADPH oxidase inhibitor DPI. In addition, visfatin stimulation significantly increased the colocalization of Nlrp3 with Asc or Nlrp3 with caspase-1, IL-β production, cell permeability in podocytes compared to control cells. Pretreatment with MCD, DPI, WEHD significantly abolished the visfatin-induced colocalization of NLRP3 with Asc or NLRP3 with caspase-1, IL-1β production and cell permeability in podocytes. Furthermore, Immunofluorescence analysis demonstrated that visfatin treatment significantly decreased the podocin and nephrin expression (podocyte damage) and prior treatments with DPI, WEHD, MCD attenuated this visfatin-induced podocin and nephrin reduction. In conclusion, their results suggest that visfatin stimulates membrane raft clustering in the membrane of podocytes to form redox signaling platforms by aggregation and activation of NADPH oxidase subunits enhancing O2·− production, leading to NLRP3 inflammasome activation in podocytes and ultimate podocyte injury. “Through experiments conducted on cultured podocytes, we have demonstrated, for the first time that membrane raft-associated redox signalling is essential for the NLRP3 inflammasomes assembly and activation in response to visfatin, subsequently resulting in podocyte dysfunction and injury. These findings shed light on a novel mechanism underlying inflammasome activation and injury of podocytes triggered by visfatin.” DOI - https://doi.org/10.18632/aging.205243 Corresponding author - Krishna M. Boini - kmboini@uh.edu Video short - https://www.youtube.com/watch?v=cIzaHj31GBo Visit our website at https://www.Aging-US.com and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ X - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ MEDIA@IMPACTJOURNALS.COM

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Episode 367: Immune support for virus, cold, cough and beyond

Naturally Nourished

Play Episode Listen Later Oct 23, 2023 79:59

Feel like you or your kids are always getting sick? Not sure how to best support your family during cold, flu and virus season? Want to know our best practices and tricks for keeping the whole household healthy? Tune in to hear us cover how the immune system works, what to do at the first sign of illness or exposure, and how to strategically incorporate food-as-medicine for resilience against disease! In this episode we cover immune support for virus, cold, cough and beyond for all household members. Learn about the first, second and third lines of defense of the immune system and how we can best support our body's natural processes. From why we don't treat a fever, to how conventional cough medicines may be ineffective and even dangerous, to thoughts on flu shots, we cover it all in this jam packed episode. Also in this episode: Episode 114 Boosting your Immune System Naturally Episode 180 The Stress Immune Connection Episode 257 Ask Me Anything Immune Episode 255 Vitamin C and Immune Updates Become a Client Buy 1, Elderberry Plus, & Get 1 Herbal Ginger Syrup for 50% off! Use code EBHGS23 at Checkout Ultimate Medicine Cabinet Bundle How the Immune System WorksThe Role of FeversFever Myths and Bone Broth Popsicles - YouTube Fever - Myths Versus Facts Barrier Defense Support Xlear Nasal Spray NanoSilver - COMING SOON Air Doctor Filter Garlic Mullein for Ear Infections Episode 68 Supporting your Immune System Naturally Herbal Ginger Syrup Elderberry Plus Natural Solutions for Kid's Cough and Cold - YouTube 3 Hot Toddies to Relieve Allergy, Cold, and Flu Symptoms | Easy Hot Toddy GI Immune Builder GI Lining Support Sauna Use for Immune SupportSunlighten Sauna Use ALIMILLERRD to save Episode 244 Infrared Sauna How Probiotics Support Immune HealthTargeted Strength Probiotic Rebuild Spectrum Probiotic Probiotic Challenge Protocol Beat the Bloat Program + Ebook Kids-biotic Essential Nutrients for Immune HealthBio-C Plus Cellular Antiox Vitamin D Balanced Blend Elderberry Gummies Herbal Immune Diet Support for Immune Health3 Day Bone Broth Fast Grassfed Whey Health Benefits of Tea Master Tonic 40 Cloves of Garlic Soup The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease Naturally Nourished Episode 262 The Keto-Immune Connection Immune Webinar use code IMMUNE23 for $5 off This episode is sponsored by: Noble Origins, an animal-based organs focused company serving up Nose-To-Tail Protein With Organs, Collagen, & Colostrum. Our Noble Organs Complex is a powdered blend of high-quality beef organs from New Zealand-sourced grass-fed Beef liver, heart, kidney, pancreas, and spleen. Bring Nose-to-tail nutrition to the masses that need it most: Americans. We do this through a delicious once-a-day shake that the whole family can love. Check it out here and use code ALIMILLERRD to get a free bag of Noble Organs Complex at checkout.

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BioiMedical Portrait III. NLRP3 Inflammasome and senescence-associated heterochromatic foci in macrophages, Kuppfer Cells and Liver sinusoidal endothelial cells contibute to liver/adipose disease

Beyond Biotech - the podcast from Labiotech

Play Episode Listen Later Sep 30, 2023 29:05

References Telemann Georg P. 1765. Overture D Major, TWV 55:D18 | Tafelmusik https://youtu.be/8r-IFLtN9x4?si=T2hp65oGT--dTivY Leukemia 2020 volume 34, pages 75–86 Nat Cell Biol. 2019 Mar; 21(3): 397–407 --- Send in a voice message: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/message Support this podcast: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/support

disease portrait liver cells senescence macrophages endothelial foci adipose nlrp3 twv inflammasome contibute

Inhibiting NLRP3 Signaling in Aging Podocytes Improves Longevity

Aging-US

Play Episode Listen Later Aug 8, 2023 4:39

A new research paper was published in Aging (Aging-US) Volume 15, Issue 14, entitled, “Inhibiting NLRP3 signaling in aging podocytes improves their life- and health-span.” The decrease in the podocyte's lifespan and health-span that typify healthy kidney aging cause a decrease in their normal structure, physiology and function. The ability to halt and even reverse these changes becomes clinically relevant when disease is superimposed on an aged kidney. NLRP3 [nod-like receptor protein 3] expression is increased in podocytes of mice with advanced age and contributes to their damage. “However, the functional consequence of increased levels of NLRP3 in aged podocytes is unknown.” In this new study, researchers Natalya Kaverina, R. Allen Schweickart, Gek Cher Chan, Joseph C. Maggiore, Diana G. Eng, Yuting Zeng, Sierra R. McKinzie, Hannah S. Perry, Adilijiang Ali, Christopher O'Connor, Beatriz Maria Veloso Pereira, Ashleigh B. Theberge, Joshua C. Vaughan, Carol J. Loretz, Anthony Chang, Neil A. Hukriede, Markus Bitzer, Jeffrey W. Pippin, Oliver Wessely, and Stuart J. Shankland from the University of Washington, Cleveland Clinic Foundation, National University Hospital Singapore, University of Pittsburgh, University of Michigan, and the University of Chicago hypothesized that reducing NLRP3 signaling earlier at middle-age improves overall podocyte health and slows down healthy podocyte aging in mice. “To this end, we performed a comprehensive analysis of inflammasome signaling including pharmacological and genetic NLRP3 loss-of-function approaches.” RNA-sequencing of podocytes from middle-aged mice showed an inflammatory phenotype with increases in the NLRP3 inflammasome, signaling for IL2/Stat5, IL6 and TNF, interferon gamma response, allograft rejection and complement, consistent with inflammaging. Furthermore, injury-induced NLRP3 signaling in podocytes was further augmented in aged mice compared to young ones. The NLRP3 inflammasome (NLRP3, Caspase-1, IL1β IL-18) was also increased in podocytes of middle-aged humans. Higher transcript expression for NLRP3 in human glomeruli was accompanied by reduced podocyte density and increased global glomerulosclerosis and glomerular volume. Pharmacological inhibition of NLRP3 with MCC950, or gene deletion, reduced podocyte senescence and the genes typifying aging in middle-aged mice, which was accompanied by an improved podocyte lifespan and health-span. Moreover, modeling the injury-dependent increase in NLRP3 signaling in human kidney organoids confirmed the anti-senescence effect of MC9950. Finally, NLRP3 also impacted liver aging. “In summary, our results demonstrate for the first time that aging podocytes acquire an inflammatory phenotype, which include the NLRP3 inflammasome and which is consistent with inflammaging.” DOI - https://doi.org/10.18632/aging.204897 Corresponding authors - Oliver Wessely - wesselo@ccf.org, and Stuart J. Shankland - stuartjs@uw.edu Keywords - aging, kidney, podocyte, NLRP3 inflammasome, reporter About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Visit our website at https://www.Aging-US.com and connect with us: Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ For media inquiries, please contact: MEDIA@IMPACTJOURNALS.COM

covid-19 university chicago washington michigan pittsburgh longevity thursday night football improves rna doi signaling pharmacological inhibiting cleveland clinic foundation nlrp3 il6 caspase christopher o'connor

Beyond Biotech podcast 55: Inflammasomes

Play Episode Listen Later Jul 20, 2023 33:10

1:54 Labiotech news3:48 NodTheraThis week, we're talking about inflammasome inhibitors with Alan Watt, CEO of NodThera.The company recently announced it is the first to show a reduction in neuroinflammation with an inflammasome inhibitor.NodThera announced positive initial data from four subjects in the elderly volunteer stage of its phase Ib/IIa study evaluating the effects of its lead candidate NT-0796 on inflammatory and disease-specific biomarkers in the blood and cerebrospinal fluid (CSF).NodThera is a clinical-stage biotech developing brain-penetrant NLRP3 inflammasome inhibitors to treat chronic inflammatory diseases.Initial data from the ongoing study confirm earlier findings from the completed first-in-human and preclinical studies with NT-0796 showing excellent pharmacokinetics with a novel capsule formulation.Subjects in the study were cannulated and CSF-sampled on day one (pre-dose) and day seven following daily NT-0796 dosing. CSF drug levels were confirmed as consistent with previous observations and a range of inflammatory CSF biomarkers demonstrated meaningful reductions.Neurofilament light chain (NfL), exclusively synthesized in the central nervous system (CNS), decreased by approximately 25% over seven days in the most inflamed subject and by 13% on average. NfL is now recognised by the U.S. Food and Drug Administration (FDA) as a key biomarker of neuroaxonal damage and neurodegeneration.

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Serum amyloid A-dependent inflammasome activation and acute injury in a mouse model of experimental stroke

Play Episode Listen Later Jun 25, 2023

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.06.22.546125v1?rss=1 Authors: Yu, J. S., Zhu, H., Taheri, S., Lee, J.-Y., Diamond, D. M., Kirstein, C., Kindy, M. S. Abstract: BACKGROUND: Serum amyloid A (SAA) proteins increase dramatically in the blood following inflammation. Recently, SAAs are increased in humans following stroke and in ischemic animal models. However, the impact of SAAs on whether this signal is critical in the ischemic brain remains unknown. Therefore, we investigated the role of SAA and SAA signaling in the ischemic brain. METHODS: Wildtype and SAA deficient mice were exposed to middle cerebral artery occlusion and reperfusion, examined for the impact of infarct volumes, behavioral changes, inflammatory markers, TUNEL staining, and BBB changes. The underlying mechanisms were investigated using SAA deficient mice, transgenic mice and viral vectors. RESULTS: SAA levels were significantly increase following MCAo and mice deficient in SAAs showed reduced infarct volumes and improved behavioral outcomes. SAA deficient mice showed a reduction in TUNEL staining, inflammation and decreased glial activation. Mice lacking acute phase SAAs demonstrated a reduction in expression of the NLRP3 inflammasome and SAA/NLRP3 KO mice showed improvement. Restoration of SAA expression via SAA tg mice or adenoviral expression reestablished the detrimental effects of SAA. A reduction in BBB permeability was seen in the SAA KO mice and anti-SAA antibody treatment reduced the effects on ischemic injury. CONCLUSIONS: SAA signaling plays a critical role in regulating NLRP3-induced inflammation and glial activation in the ischemic brain. Blocking this signal will be a promising approach for treating ischemic stroke. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

P2X7-dependent exchange of extracellular microparticles and mitochondria by mouse microglia

Play Episode Listen Later Apr 19, 2023

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.18.537325v1?rss=1 Authors: Falzoni, S., Chiozzi, P., Vultaggio-Poma, V., Tarantini, M., Adinolfi, E., Boldrini, P., Giuliani, A. L., Gorecki, D. C., Di Virgilio, F. Abstract: Microparticles (MPs) are ubiquitously secreted by all cells and play a fundamental role in numerous biological processes such as cell-to-cell communication, cell differentiation, inflammation, and cell energy transfer. Ligation of the P2X7 receptor (P2X7R) by extracellular ATP (eATP) is the well-known stimulus for MP release, which affects their contents in a cell-specific fashion. We investigated MP release and functional impact in mouse microglial cell lines characterized for high (N13-P2X7RHigh) or low (N13-P2X7RLow) expression of the P2X7R. Stimulation with extracellular ATP triggered a P2X7R-dependent release of a MP population enriched with naked mitochondria. Released mitochondria were taken up and incorporated into the mitochondrial network of the recipient cells in a P2X7R-dependent fashion. Other constituents of the MP cargo, e.g. NLRP3 and the P2X7R itself, were also delivered to the recipient cells. Transfer of mitochondria, NLRP3 and P2X7R increased the energy level of the recipient cells and conferred a pro-inflammatory phenotype. These data show that P2X7R-dependent exchange of MPs and mitochondria modulates energy metabolism and inflammatory responses, pointing to the P2X7R as a master regulator of intercellular organelle and MP trafficking in mouse microglia. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

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The role of microglial LRRK2 in manganese-induced inflammatory neurotoxicity via NLRP3 inflammasome and RAB10-mediated autophagy dysfunction

Play Episode Listen Later Apr 4, 2023

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.03.535418v1?rss=1 Authors: Pajarillo, E., Kim, S., Digman, A., Dutton, M., Son, D.-S., Aschner, M., Lee, E. Abstract: Chronic exposure to manganese (Mn) can lead to manganism, a neurological disorder sharing symptoms with those of Parkinson's disease (PD). Although the mechanisms of Mn toxicity are not fully understood, studies have shown that Mn increased the expression and activity of leucine-rich repeat kinase 2 (LRRK2), leading to inflammation and toxicity in microglia. LRRK2 G2019S mutation is the most common LRRK2 mutant associated with genetic PD and exhibits elevated LRRK2 kinase activity. Thus, we investigated whether Mn-increased microglial LRRK2 kinase function is responsible for Mn-induced toxicity and if it is exacerbated in G2019S using WT and LRRK2 G2019S knock-in mice as well as BV2 microglia cells. Results showed that Mn (MnCl2 30 mg/kg, nostril instillation, daily for 3 weeks) caused motor deficits, cognitive impairments, and dopaminergic dysfunction in WT mice, which were exacerbated in G2019S mice. Mn increased proapoptotic Bax, NLRP3 inflammasome, and inflammatory cytokines IL-1{beta} and TNF- in the striatum and midbrain of WT mice, which were exacerbated in G2019S mice. In addition, BV2 cells were transfected with either human LRRK2 WT or G2019S followed by exposure to Mn (250 uM) to compare Mn toxicity in two genotypes and gain more mechanistic insights. Results showed that Mn increased TNF-, IL-1{beta}, and NLRP3 inflammasome activation in BV2 cells expressing WT LRRK2, which was exacerbated in G2019S-expressing cells, while pharmacological inhibition of LRRK2 mitigated these toxicities in both genotypes. Moreover, the media from Mn-treated BV2 microglia expressing G2019S caused greater toxicity to CAD neuronal cells compared to media from microglia expressing WT. Mn-LRRK2 activated RAB10, an LRRK2 substrate, which was exacerbated in G2019S, and played a critical role in LRRK2-mediated Mn toxicity by dysregulating the autophagy-lysosome pathway, and NLRP3 inflammasome in microglia. Taken together, our findings suggest that microglial LRRK2 via RAB10 plays a critical role in Mn-induced neuroinflammation, and inhibition of LRRK2 kinase activity can be a potential target to mitigate Mn's inflammatory neurotoxicity. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration

Empowered Patient Podcast

Play Episode Listen Later Apr 3, 2023

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.03.534570v1?rss=1 Authors: Hartmann, J., Bajaj, T., Otten, J., Klengel, C., Gellner, A.-K., Junglas, E., Hafner, K., Anderzhanova, E. A., Tang, F., Missig, G., Rexrode, L., Li, K., Poehlmann, M. L., Heinz, D. E., Lardenoije, R., Dedic, N., McCullough, K. M., Prochnicki, T., Rhomberg, T., Martinelli, S., Payton, A., Robinson, A. C., Stein, V., Latz, E., Carlezon, W. A., Schmidt, M. V., Murgatroyd, C., Berretta, S., Klengel, T., Pantazopoulos, H., Ressler, K. J., Gassen, N. C. Abstract: High levels of proinflammatory cytokines induce neurotoxicity and catalyze inflammation-driven neurodegeneration, but the specific release mechanisms from microglia remain elusive. We demonstrate that secretory autophagy (SA), a non-lytic modality of autophagy for secretion of vesicular cargo, regulates neuroinflammation-mediated neurodegeneration via SKA2 and FKBP5 signaling. SKA2 inhibits SA-dependent IL-1b release by counteracting FKBP5 function. Hippocampal Ska2 knockdown in mice hyperactivates SA resulting in neuroinflammation, subsequent neurodegeneration and complete hippocampal atrophy within six weeks. The hyperactivation of SA increases IL-1b release, initiating an inflammatory feed-forward vicious cycle including NLRP3-inflammasome activation and Gasdermin D (GSDMD)-mediated neurotoxicity, which ultimately drives neurodegeneration. Results from protein expression and co-immunoprecipitation analyses of postmortem brains demonstrate that SA is hyperactivated in Alzheimer's disease. Overall, our findings suggest that SKA2-regulated, hyperactive SA facilitates neuroinflammation and is linked to Alzheimer's disease, providing new mechanistic insight into the biology of neuroinflammation. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Blocking the Root Cause of Chronic Inflammation with David Bearss Halia Therapeutics

Play Episode Listen Later Mar 21, 2023 20:09

David Bearss the Co-Founder, CEO and President of Halia Therapeutics, points out that despite traditional thinking, chronic inflammation is not just an unresolved acute inflammatory response. It has been discovered that a different pathway leads to the activation of this inflammatory response in diseases with components of chronic inflammation, such as Alzheimer's disease, heart disease, COPD, psoriasis, IBD, and cancer. Their potential drug target is the NLRP3 inflammasome which has been identified as being associated with the activation of inflammation. David explains, "We've gotten better and better at trying to narrow down on how we can block these inflammatory responses. But there's just been, in the past few years, a real explosion in our knowledge of what the root drivers of chronic inflammation are. At Halia, we're focused on trying to take out the root cause, not some of the downstream effects or the signaling molecules, but take out the responsible thing, the machine inside the cell that's activated, that's propagating these signals. If we can turn that off, we think we can get to the root cause of what's driving these problems and all these different diseases." "It's just in the past few years that we've discovered that there are these cellular machines that get formed under the right conditions that help propagate or signal this inflammatory response. We call those machines inflammasomes, and there are five that we know of. There are probably a few more that are what we call non-canonical inflammasomes. But the inflammasomes have been a really hot area of research in lots of different diseases to try to understand how these protein complexes get formed inside cells and how they stay stuck on in chronic inflammation." @Halia_Tx #ChronicInflammation #Immunity #Neuroscience #AlzheimersDisease #InflammatoryDisease #DrugDevelopment #Biotech haliatherapeutics.com Download the transcript here

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Blocking the Root Cause of Chronic Inflammation with David Bearss Halia Therapeutics TRANSCRIPT

Empowered Patient Podcast

Play Episode Listen Later Mar 21, 2023

David Bearss the Co-Founder, CEO and President of Halia Therapeutics, points out that despite traditional thinking, chronic inflammation is not just an unresolved acute inflammatory response. It has been discovered that a different pathway leads to the activation of this inflammatory response in diseases with components of chronic inflammation, such as Alzheimer's disease, heart disease, COPD, psoriasis, IBD, and cancer. Their potential drug target is the NLRP3 inflammasome which has been identified as being associated with the activation of inflammation. David explains, "We've gotten better and better at trying to narrow down on how we can block these inflammatory responses. But there's just been, in the past few years, a real explosion in our knowledge of what the root drivers of chronic inflammation are. At Halia, we're focused on trying to take out the root cause, not some of the downstream effects or the signaling molecules, but take out the responsible thing, the machine inside the cell that's activated, that's propagating these signals. If we can turn that off, we think we can get to the root cause of what's driving these problems and all these different diseases." "It's just in the past few years that we've discovered that there are these cellular machines that get formed under the right conditions that help propagate or signal this inflammatory response. We call those machines inflammasomes, and there are five that we know of. There are probably a few more that are what we call non-canonical inflammasomes. But the inflammasomes have been a really hot area of research in lots of different diseases to try to understand how these protein complexes get formed inside cells and how they stay stuck on in chronic inflammation." @Halia_Tx #ChronicInflammation #Immunity #Neuroscience #AlzheimersDisease #InflammatoryDisease #DrugDevelopment #Biotech haliatherapeutics.com Listen to the podcast here

ceo president co founders alzheimer's disease blocking root cause copd therapeutics ibd chronic inflammation nlrp3

INPP5D/SHIP1 regulates inflammasome activation in human microglia

Play Episode Listen Later Feb 26, 2023

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.25.530025v1?rss=1 Authors: Chou, V., Pearse, R. V., Aylward, A. J., Fancher, S. B., Ashour, N., Lee, H., Lam, M., Benoit, C. R., Seyfried, N. T., Bennett, D. A., De Jager, P. L., Menon, V., Young-Pearse, T. L. Abstract: Microglia and neuroinflammation are implicated in the development and progression of Alzheimer's disease (AD). To better understand microglia-mediated processes in AD, we studied the function of INPP5D/SHIP1, a gene linked to AD through GWAS. Immunostaining and single nucleus RNA sequencing confirmed that INPP5D expression in the adult human brain is largely restricted to microglia. Examination of prefrontal cortex across a large cohort revealed reduced full length INPP5D protein levels in AD patient brains compared to cognitively normal controls. The functional consequences of reduced INPP5D activity were evaluated in human induced pluripotent stem cell derived microglia (iMGLs), using both pharmacological inhibition of the phosphatase activity of INPP5D and genetic reduction in copy number. Unbiased transcriptional and proteomic profiling of iMGLs suggested an upregulation of innate immune signaling pathways, lower levels of scavenger receptors, and altered inflammasome signaling with INPP5D reduction. INPP5D inhibition induced the secretion of IL-1{beta} and IL-18, further implicating inflammasome activation. Inflammasome activation was confirmed through visualization of inflammasome formation through ASC immunostaining in INPP5D-inhibited iMGLs, increased cleaved caspase-1 and through rescue of elevated IL-1{beta} and IL-18 with caspase-1 and NLRP3 inhibitors. This work implicates INPP5D as a regulator of inflammasome signaling in human microglia. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

llc alzheimer's disease copy activation lam examination benoit rna asc unbiased menon pearse regulates seyfried gwas fancher biorxiv microglia nlrp3 inflammasome

A role for fibroblast-derived SASP factors in the activation of pyroptotic cell death in mammary epithelial cells

BetterHealthGuy Blogcasts

Play Episode Listen Later Feb 22, 2023

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.21.529458v1?rss=1 Authors: Hom, L. M., Sun, S., Campbell, J., Liu, P., Culbert, S., Murphy, I. M., Schafer, Z. T. Abstract: In normal tissue homeostasis, bidirectional communication between different cell types can shape numerous biological outcomes. Many studies have documented instances of reciprocal communication between fibroblasts and cancer cells that functionally change cancer cell behavior. However, less is known about how these heterotypic interactions shape epithelial cell function in the absence of oncogenic transformation. Furthermore, fibroblasts are prone to undergo senescence, which is typified by an irreversible cell cycle arrest. Senescent fibroblasts are also known to secrete various cytokines into the extracellular space; a phenomenon that is termed the senescence-associated secretory phenotype (SASP). While the role of fibroblast derived SASP factors on cancer cells has been well studied, the impact of these factors on normal epithelial cells remains poorly understood. We discovered that treatment of normal mammary epithelial cells with conditioned media (CM) from senescent fibroblasts (SASP CM) results in a caspase-dependent cell death. This capacity of SASP CM to cause cell death is maintained across multiple senescence-inducing stimuli. However, the activation of oncogenic signaling in mammary epithelial cells mitigates the ability of SASP CM to induce cell death. Despite the reliance of this cell death on caspase activation, we discovered that SASP CM does not cause cell death by the extrinsic or intrinsic apoptotic pathway. Instead, these cells die by an NLRP3, caspase-1, and gasdermin D (GSDMD)-dependent induction of pyroptosis. Taken together, our findings reveal that senescent fibroblasts can cause pyroptosis in neighboring mammary epithelial cells, which has implications for therapeutic strategies that perturb the behavior of senescent cells. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

sun llc campbell factors copy cells activation cm liu schafer derived epithelial biorxiv mammary senescent culbert cell death fibroblast nlrp3 sasp

February 2023 Discover CircRes

Discover CircRes

Play Episode Listen Later Feb 16, 2023 30:30

This month on Episode 45 of Discover CircRes, host Cynthia St. Hilaire highlights four original research articles featured in the February 3rd and February 17th issues of Circulation Research. This episode also features an interview with Dr Hind Lal and Dr Tousif Sultan from the University of Alabama at Birmingham about their study Ponatinib Drives Cardiotoxicity by S100A8/A9-NLRP3-IL-1β Mediated Inflammation. Article highlights: Pi, et al. Metabolomic Signatures in PAH Carnevale, et al. Thrombosis TLR4-Mediated in SARS-CoV-2 Infection Cai, et al. Macrophage ADAR1 in AAA Koide, et al. sEVs Accelerate Vascular Calcification in CKD Cindy St. Hilaire: Hi, and welcome to Discover CircRes, the podcast of the American Heart Association's journal, Circulation Research. I'm your host, Dr Cynthia St. Hilaire from the Vascular Medicine Institute at the University of Pittsburgh, and today I'm going to be highlighting the articles from our February 3rd and 17th issues of Circulation Research. I'm also going to have a chat with Dr Hind Lal and Dr Tousif Sultan from the University of Alabama at Birmingham about their study, Ponatinib Drives Cardiotoxicity by S100A8/A9-NLRP3-IL-1β Mediated Inflammation. But before I get to the interviews, here are a few article highlights. Cindy St. Hilaire: The first article I want to highlight comes from the laboratory of Dr Peter Leary at the University of Washington, and the title is Metabolomic Signatures Associated With Pulmonary Arterial Hypertension Outcomes. Pulmonary Arterial Hypertension or PAH is a rare but life-threatening disease in which progressive thickening of the walls of the lung's blood vessels causes increased blood pressure and that increased blood pressure ultimately damages the heart's right ventricle. Interestingly, progression to heart failure varies considerably among patients, but the reasons why there is variability are not well understood. To find out, this group turned their attention to patient metabolomes, which differ significantly from those of healthy people and thus may also change with severity. Blood samples from 117 PAH patients were analyzed for more than a thousand metabolites by mass spectrometry and the patient's progress was followed for the next three years. 22 patients died within a three-year period and 27 developed significant right ventricle dilation. Other measures of severity included pulmonary vascular resistance, exercise capacity and levels of BNP, which is a metric of heart health. Two metabolic pathways, those relating to polyamine and histidine metabolism, were found to be linked with all measures of severity suggesting a key role for them in disease pathology. While determining how these pathways influence disease as a subject for further study, the current findings may nevertheless lead to new prognostic indicators to inform patient care. Cindy St. Hilaire: The next article I want to discuss is coming from our February 3rd issue of Circulation Research and this is coming from the laboratory of Dr Francisco Violi at the University of Rome and the title is Toll-Like Receptor 4-Dependent Platelet-Related Thrombosis in SARS-CoV-2 Infection. Thrombosis can be a complication of COVID-19 and it is associated with poor outcomes, including death. However, the exact mechanism by which the virus activates platelets, which are the cells that drive thrombosis, is not clear. For one thing, platelets do not appear to express the receptor for SARS-CoV-2. They do however, express the TLR4 receptor and that's a receptor that mediates entry of other viruses as part of the immune response. And TLR4 is ramped up in COVID-19 patient platelets. This group now confirms that, indeed, SARS-CoV-2 interacts with TLR4, which in turn triggers thrombosis. The team analyzed platelets from 25 patients and 10 healthy controls and they found that the platelet activation and thrombic activity were both boosted in the patient samples and could not be blocked using a TLR4 inhibitor. Additionally, immunoprecipitation and immunofluorescent experiments further revealed colocalization between the virus protein and the TLR4 receptor on patient platelets. The team went on to show that the signaling pathway involved reactive oxygen species producing factors p47phox and Nox2, and that inhibition of phox 47, like that of the TLR4 receptor itsel,f could prevent platelet activation. As such, this study suggests that inhibiting either of these proteins may form the basis of an antithrombotic treatment for COVID-19. Cindy St. Hilaire: The third article I want to highlight is coming from the lab of Shi-You Chen at University of Missouri and the title of this article is ADAR1 Non-Editing Function in Macrophage Activation and Abdominal Aortic Aneurysm. Macrophage activation plays a critical role in abdominal aortic aneurysm development, or AAA development. Inflammation is a component of this pathology; however, the mechanisms controlling macrophage activation and vascular inflammation in AAA are largely unknown. The ADAR1 enzyme catalyzes the conversion of adenosine to inosine in RNA molecules and thus this conversion can serve as a rheostat to regulate RNA structure or the gene coding sequence of proteins. Several studies have explored the role of ADAR1 in inflammation, but its precise contribution is not fully understood, so the objective of this group was to study the role of ADAR1 in macrophage activation and AAA formation. Aortic transplantation was conducted to determine the importance of nonvascular ADAR1 in AAA development and dissection and angiotensin II infusion of ApoE knockout mice combined with a macrophage specific knockout of ADAR1 was used to study the role of ADAR1 macrophage specific contributions to AAA formation and dissection. Allograft transplantation of wild type abdominal aortas to ADAR1 haploinsufficient recipient mice significantly attenuated AAA formation. ADAR1 deficiency in hematopoietic stem cells also decreased the prevalence and the severity of AAA and it also inhibited macrophage infiltration into the aortic wall. ADAR1 deletion blocked the classic macrophage activation pathway. It diminished NF-κB signaling and it enhanced the expression of a number of anti-inflammatory microRNAs. Reconstitution of ADAR1 deficient but not wild type human monocytes to immunodeficient mice blocked the aneurysm formation in transplanted human arteries. Together these results suggest that macrophage ADAR1 promotes aneurysm formation in both mouse and human arteries through a novel mechanism of editing the microRNAs that target NF-κB signaling, which ultimately promotes vascular inflammation in AAA. Cindy St. Hilaire: The last article I want to highlight is also from our February 17th issue of Circulation Research and it is coming from the lab of Shintaro Mandai at Tokyo Medical and Dental University and the title of the article is Circulating Extracellular Vesicle Propagated MicroRNA signatures as a Vascular Calcification Factor in Chronic Kidney Disease. Chronic Kidney Disease or CKD accelerates vascular calcification in part by promoting the phenotypic switching of vascular smooth muscle cells to osteoblast like cells. This study investigated the role of circulating small extracellular vesicles or SUVs from the kidneys in promoting this osteogenic switch. CKD was induced in rats and in mice by an adenine induced tubular interstitial fibrosis and serum from these animals induced calcification in in vitro cultures of A-10 embryonic rat smooth muscle cells. Intraperitoneal administration of a compound that prevents SEV biosynthesis and release inhibited thoracic aortic calcification in CKD mice under a high phosphorus diet. In Chronic Kidney Disease, the microRNA transcriptome of SUVs revealed a depletion of four microRNAs and the expression of the microRNAs inversely correlated with kidney function in CKD patients. In vitro studies found that transected microRNA mimics prevented smooth muscle cell calcification in vitro. In silico analyses revealed that VEGF-A was a convergent target of all four microRNAs and leveraging this, the group used in vitro and in vivo models of calcification to show the inhibition of the VEGF-A, VEGFR-2 signaling pathway mitigated calcification. So in addition to identifying a new potential therapeutic target, these SUV propagated microRNAs are a potential biomarker that can be used for screening patients to determine the severity of CKD and possibly even vascular calcification. Cindy St. Hilaire: Today I have with me Dr Hind Lal who's an associate professor of medicine at the University of Alabama Birmingham and his post-doctoral fellow and the lead author of the study Dr Tousif Sultan. And their manuscript is titled Ponatinib Drives Cardiotoxicity by S100A8/A9-NLRP3-IL-1β Mediated Inflammation. And this article is in our February 3rd issue of Circulation Research. So thank you both so much for joining me today. Tousif Sultan: Thank you. Hind Lal: Thank you for taking time. Cindy St. Hilaire: So ponatinib, it's a tyrosine kinase inhibitor and from my understanding it's the only treatment option for a specific group of patients who have chronic myelogenous leukemia and they have to harbor a specific mutation. And while this drug helps to keep these patients alive essentially, it's extremely cardiotoxic. So cardiotoxicity is somewhat of a new field. So Dr Lal, I was wondering how did you get into this line of research? Hind Lal: So I was fortunate enough to be in the lab of Dr Tom Force and he was kind of father of this new area, now is very developed, it's called cardio-oncology. On those days there were basically everything started in cardio-oncology. So I just recall the first tyrosine kinase approved by FDA was in 2000 and that was... Imagine and our paper came in Nature Medicine 2005 and discovering there is... so to elaborate it a little bit, the cancer therapy broadly divided in two parts. One is called non-targeted therapy like chemotherapy, radiations, et cetera, and then there are cytotoxic drugs. So those cytotoxic drugs because they do not have any targeted name on it so they are, cardiotoxic are toxic to any organ was very obvious and understanding. When these targeted therapy came, which is mainly kinase inhibitor are monoclonal antibodies. So these are targeted to a specific pathway that is activated only in the cancer cells but not in any other cells in the body so they were proposed as like magic bullets that can take off the cancer without any cardiotoxity or minimal side effects. But even in the early phase like 2005 to 2010, these came out, these so-called targeted, they are not very targeted and they are not also the magic bullets and they have serious cardiotoxicity. Cindy St. Hilaire: And so what's the mechanism of action of ponatinib in the leukemia and how does that intersect with the cardiovascular system? Hind Lal: Yeah, so this is very good question I must say. So what we believe at this point because, so leukemia if you know is driven by the famous Philadelphia chromosome, which is a translicational gene, one part of human chromosome nine and one part of human chromosome 22 and they translocate make a new gene which is BCR-ABL gene. And because it was discovered in Philadelphia UPENN, is named that Philadelphia chromosome, which is very established mechanism, that's how CML is driven. But what we have discovered that the cardiotoxicity driven by totally, totally different from the ponatinib is one of the inflammatory So it's kind of goodening. So this question is so good. One kind of toxicity is called on-target, when toxicity is mediated by the same mechanism, what is the mechanism of the drug to cure the cancer? So in that case your absolute is minimal because if you manipulate that, the drug's ability to cure the cancer will be affected but if the toxicity and the efficacy is driven by two different mechanism, then as in case of ponatinib seems like it's NLRP3 and inflammasome related mechanism. So this can be managed by manipulating this pathway without hampering the drug efficacy on the cancer. Cindy St. Hilaire: So what exactly is cardiotoxicity and how does it present itself in these patients? Hind Lal: So these drugs like ponatinib, they call broader CVD effects. So it's not just cardiac, so they also in hypertensives and atherosclerosis and thrombosis, those kind of thing. But our lab is primarily focused on the heart. So that's why in this paper we have given impresses on the heart. So what we believe at this point that ponatinib lead to this proinflammatory pathway described in this paper, which is just 108A9-NLRP3-IL-1β and this inflammatory pathway lead to a cytokine storm very much like in the COVID-19 and these cytokine storms lead to excessive myocarditis and then finally cardiac dysfunction. Cindy St. Hilaire: Is the cytokine storm just local in the cardiac tissue or is it also systemic in the patients? Is cardiotoxicity localized only or is it a more systemic problem? Tousif Sultan: I would like to add in this paper we have included that we look this cytokine things and explain blood circulation, bone marrow. So the effect is everywhere, it's not local. So we didn't check other organs, maybe other organs also being affected with the ponatinib treatment. Cindy St. Hilaire: And what's the initial phenotype of a patient has when they start to get cardiotoxicity, what's kind of like a telltale symptom? Hind Lal: So good thing that in recent years cardio-oncology developed. So initially the patient that were going for cancer treatment, they were not monitored very closely. So they only end up in cardiology clinic when they are having some cardiac events already. So thanks to the lot of development and growth in the cardio-oncology field, now most patients who going for a long-term cancer treatment, they are closely monitored by cardiology clinics. Cindy St. Hilaire: Got it. So they can often catch it before a symptom or an event. That's wonderful. Hind Lal: Yeah, so there's a lot of development in monitoring. Cindy St. Hilaire: Wonderful. So you were really interested in figuring out why ponatinib induces cardiotoxicity and you mentioned that really up until now it's been very difficult to study and that's because of the limitation of available murine models. If you just inject a wild type mouse with ponatinib, nothing happens really. So what was your approach to finding relatively good murine models? How did you go about that? Hind Lal: So this is the top scientific question you can ask. So like science, the field is try and try again. So initially this is the first paper with the ponatinib toxicity using the real in vivo models. Any paper before this including ours studies published, they were done on the cellular model in hiPSC, that isolated cardiomyocytes. So you directly putting the ponatinib directly the isolated cells. So this is first case when we were trying to do in vivo, maybe other attempt in vivo but at least not published. So first we also treated the animals with ponatinib and that failed, we don't see any cardiotoxic effect. And then when we going back to the literature, the clinical data is very, very clear from pharmacovigilance that ponatinib is cardiotoxic in humans. So when we're not able to see any phenotype in mouse, we realize that we are not mimicking what's happening in the humans. So we certainly missing something. Now once again I quote this COVID-19, so many people get infected with COVID-19 but people are having preexisting conditions are on high risk to developing CVD. So there was some literature on that line. So we use this very, very same concept that if there is preexisting conditions, so likely who'd have developing future cardiac event will be more. So we use two model in this paper one atherosclerosis model which is APoE null mice mice, another is tag branding which is pressure overload model for the heart and as soon as we start using what we call comorbidity model like patient is having some preexisting conditions and we very clearly see the robust defect of ponatinib on cardiac dysfunction. Cindy St. Hilaire: Yeah, it's really, really well done and I really like that you use kind of two different models of this. Do you think it's also going to be operative in maybe like the diabetic mirroring models? Do you think if we expand to other comorbidities, you might also recapitulate the cardiotoxicity? Hind Lal: So you got all the best questions. Cindy St. Hilaire: Thank you. I try. Hind Lal: So because this is CML drug and lot of the risk factor for cardiovascular and cancer are common and even metabolic disease. So most of the time these patients are elderly patients and they're having metabolic conditions and most of the time they have blood pressure or something CVD risk factors. So I agree with you, it'll be very relevant to expand this to the diabetes or metabolic models, but these were the first study, we put all our focus to get this one out so news is there then we can expand the field adding additional models et cetera. But I agree with you that will be very logical next step to do. Cindy St. Hilaire: Yeah. And so I guess going back to what you know from the human study or the clinical trials or the human observations, are different populations of patients with CML more predisposed to cardio toxicity than others or is that not known yet? Hind Lal: So one other area called pharmacovigilance. So what pharmacovigilance does patient all over the world taking these drugs. So WHO have their own vigilance system and FDA have their own, so it's called BG-Base for the WHO and it's called the FAERS for the FDA. So one can go back in those data sets and see if X patient taking this Y drug and what kind of symptoms or adverse effect they are seeing and if these symptoms are associated with something else. So there is data that if patients having CVD risk factor, they are more prone to develop ponatinib induced cardiac events. But it needs more polish like you asked the just previous question, diabetes versus maybe blood pressure means hypertension, atherosclerosis, or thrombosis. So it has not been delineated further but in a one big bucket if patients are having CVD risk factor before they are more prone and more likely to develop the cardiac events. Cindy St. Hilaire: So after you established that these two murine models could pretty robustly recapitulate the human phenotype, what did you do next? How did you come upon the S100A8/A9-NLRP3-IL-1β signaling circuit? How did you get to that? Hind Lal: So in basic science work, whenever we do mouse is called until we get there is cardiac dysfunction, it's called phenotype, right? So mouse had a cardiac phenotype. So next step is, "Why? What is leading to that phenotype?" That's what we call mechanism. So there the best idea to fit the mechanism is using one of the unbiased approaches like you do unbiased proteomics, unbiased RNC analysis, something like this that will analyze the entire transcript like RNC and say, "Okay, these pathway are," then you can do further analysis that will indicate these pathway are different, are altered. So in this case we used RNC analysis and it came out that this yes A8 and yes A9, 100A8 and nine, they were the most upregulated in this whole set. And thereafter we were very lucky. So we started this study at Vanderbilt, where my lab was and thereafter we very lucky to move here and found Sultan who had a lot of experience with this inflammation and immune system and then Sultan may add something on this so he'll be the better person to say something on this. Tousif Sultan: So after our RNC analysis, so we got this S100A8 and nine as top hit with the ponatinib treatment. So then we validated this finding with our flow cytometric, qRT PCR aand then we started which pathway is going to release cytokine and all that. So we found that is NLRP3 inflammasome. Cindy St. Hilaire: Yeah and well and I guess maybe step back, what is S100A8/A9? What are those? Tousif Sultan: Yeah, S10A8/A9 is a calcium binding protein. So that's also called alarmin and they basically binds with the pathogen associated pattern and other TLR2 like receptors and then start inflammatory pathway to release cytokine and all that and it's stable in heterodimer form. So S100A8 heterodimer with A9 and then bind with TLR and a start in this inflammatory pathway. Cindy St. Hilaire: And what type of cell is that happening in? Is that happening in the immune cells only or is it also in the cardiomyocyte, or...? Tousif Sultan: Yeah, we have included all this data. So from where this alarmin is coming with ponatinib treatment, so literature also suggested that neutrophils and monocytes, those cells are the potential to release the alarmin. So here we also found these two type of cells, neutrophils and monocytes. They release huge alarmin with the treatment of ponatinib. Cindy St. Hilaire: And so really taking this really neat mechanism to the next level, you then tried attenuating it by using broad anti-inflammatory steroid dexamethasone but also by targeting these specific components, the NLRP and the S100A specific inhibitors and they worked well. It worked really nicely. Does your data show that any of these therapies work better than the other and then are these viable options to use in humans? Hind Lal: Yeah, we have some data in the paper. Are very broad which help a lot in COVID patients, far very acute infections. So in this case, situation is very different cause most of CML patients will going to take ponatinib for lifelong, there is no remission, right? So in those case, its certainly not a very attractive option. We have shown data in the paper that dexamethasone help with the heart but lead to some metabolic changes. So we have compared those with the NLRP3 inhibitors, those metabolic alterations, dexa versus the NLRP3 inhibitors, CY-09. And we demonstrated that targeting is specifically with paquinimod, our NLRP3 inhibitor CY-09, feel better. It can still rescue the cardiac phenotype without having those adverse effect on metabolic parameters. Cindy St. Hilaire: That's wonderful. Do you think though that because you have to take ponatinib for life, that long-term NLRP inhibition would also cause problems or...? Hind Lal: So because not every patient who taking ponatinib would develop the cardiac phenotype, right? Which is like a 10%, 12%, patient developing cardiac dysfunction. So I think someone like I strongly believe paquinimod, which is inhibitor of S100A9, will be really good option or at least we have enough data that make us nail for at least a small clinical trial. And we quickly moving on that. At UAB we have our clinical cardio-oncology program and we are already in touch with the director for the clinical cardio-oncology program. So what we trying to do in that small trial is if one of the standard therapy for heart like beta blocker or ARBs inhibitor, is there any preference like one work better than the other in the standard care? So first we doing that project, then we obviously looking forward if one small clinical trial can be done with paquinimod. I strongly believe it should be helpful. Cindy St. Hilaire: That is wonderful. And so do you think... There's other chemotherapeutic agents or probably even other non-cancer drugs that cause cardiotoxicity, do you think this mechanism, this pathway, this S100A-NLRP-IL-1β axis is operative in all cardiotoxicities or do you think it's going to be very specific to the ponatinib? Hind Lal: So it's certainly not all, but it'll be certainly more than ponatinib. So in our lab we are using another kinase inhibitor, which is osimertinib and it's not published yet, but now we know that it's also cardiotoxic because it's taking metabolic root or energetics disruption but not this pro-inflammatory part, but we're doing another project which is strep pneumonia induced cardiac dysfunction, which is called pneumonia. So strep pneumoniae, which leads to the pneumonia ,and lot patient die because of the failing heart we see here in the hospitals and we see these pathways operational over there and we gearing up to do clinical trial on that aspect as well, but it's not generalized like all kind of heart will have the same mechanism. Cindy St. Hilaire: It's wonderful to see you're already taking those next steps towards really kind of bringing this to a translational/clinical study. So what was the most challenging aspect of this study? Tousif Sultan: The challenging aspect, ponatinib is a kinase inhibitor and that was surprising for us how it's activating immune cells. Generally kinase inhibitors, inhibits all the cells like that. So that was challenging. So we repeated it many times did in vitro experiment to confirm that. So we just added, just treated in vitro immune cells with the ponatinib and confirmed it. So that was little challenging. Cindy St. Hilaire: So what's next? You mentioned you're going to try some clinical trials, early stage clinical trials. What's next mechanistically, what do you want to go after? Hind Lal: So what we are doing next and we are very, very eagerly trying to do that. So what it was done, we used the cardiac comorbidity models, but as you know, anybody who will take ponatinib will have cancer, right? So we strongly believe that we miss one factor. There was no cancer on these. So that is very logical next step. What that will allow us to do, what rescue experiment we'll have done in this paper. So we saw, "Okay, this rescue the cardiac phenotype, which is taken care of now," but very same time, we not able to demonstrate that this is happening without hurting the cancer efficacy. So if we have the dual comorbid mouse, which have CML a real thing and we have cardiac thing, then that will allow us to demonstrate, "Okay, we got something that can take care of the cardiac problem without hurting the efficacy on the cancer." And it will be best if you also help little bit to more potentiate the cancer efficacy. Cindy St. Hilaire: Yes. Excellent. Well, congratulations on a beautiful study, really exciting findings. Dr Lal and Dr Sultan, thank you so much for taking the time to talk with me today. Tousif Sultan: Thank you so much. Hind Lal: Well thank you, Cynthia. We really appreciate your time. Thank you for having us. Cindy St. Hilaire: Yeah, it was great. Cindy St. Hilaire: That's it for our highlights from the February 3rd and February 17th issues of Circulation Research. Thank you so much for listening. Please check out the Circulation Research Facebook page and follow us on Twitter and Instagram with the handle @CircRes and #DiscoverCircRes. Thank you to our guests, Dr Hind Lal and Dr Tousif Sultan. This podcast is produced by Ishara Ratnayake, edited by Melissa Stoner and supported by the editorial team at Circulation Research. Some of the copy text for the highlighted articles was provided by Ruth Williams. I'm your host, Dr Cynthia St. Hilaire, and this is Discover CircRes, you're on-the-go source for most exciting discoveries in basic cardiovascular research. This program is copyright of the American Heart Association 2023. And the opinions expressed by the speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more information, please visit ahajournals.org.

Ep. 47: “Structural and Mechanistic Immunology” Featuring Dr. Hao Wu

The Immunology Podcast

Play Episode Listen Later Feb 14, 2023 76:10

Dr. Hao Wu is the Asa and Patricia Springer Professor of Structural Biology at Harvard Medical School. Her lab focuses on the molecular and cellular mechanisms that govern the assembly, regulation, and therapeutic intervention of supramolecular complexes in innate immunity. She talks about cryo-electron microscopy and how her team used it to study the structures of the NLRP3 inflammasome disc, the B cell antigen receptor, and the Gasdermin D pore. She also discusses the role of AlphaFold in structural biology research.

harvard medical school structural immunology alphafold mechanistic structural biology nlrp3 hao wu

Circulation January 24, 2023 Issue

Circulation on the Run

Play Episode Listen Later Jan 23, 2023 29:55

Please join author Subodh Verma and Guest Editor Christopher Granger as they discuss the article "Empagliflozin and Left Ventricular Remodeling in People Without Diabetes: Primary Results of the EMPA-HEART 2 CardioLink-7 Randomized Clinical Trial." 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-host. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Peder Myhre: And I'm Dr. Peder Myhre, social media editor and doctor at Akershus University Hospital at University of Oslo in Norway. Dr. Carolyn Lam: Peder, I am so excited to be discussing this issue. So many great articles and a feature discussion coming up on the SGLT2 inhibitor, empagliflozin. And do you think it's got effects on left ventricular remodeling in people without diabetes? Very interesting question. Dr. Peder Myhre: That is so interesting, Carolyn. I can't wait to hear this discussion. Dr. Carolyn Lam: Yep, I agree, but we got to wait till we discuss the other papers in today's issue. I want to go first. So we know that non-vitamin K oral anticoagulants, or NOACs, they've become the standard therapy for preventing stroke and ischemic thromboembolism in most patients with atrial fibrillation. But, what is the effectiveness and safety of NOACs in patients on dialysis? That is hemodialysis. The AXADIA-AFNET 8 study sought to test the hypothesis that apixaban would be non-inferior to vitamin K antagonists in these very patients undergoing hemodialysis. Dr. Peder Myhre: Oh wow. This is really a gap of knowledge that we've been waiting to hear more about. NOACs in patients with hemodialysis. Tell us about this trial, Carolyn. Dr. Carolyn Lam: Sure. So this is from corresponding author, Dr. Reinecke, and colleagues, from University of Munster in Germany. And it's an investigator initiated prospective randomized open-blinded outcome assessment of 97 patients with atrial fibrillation on chronic hemodialysis randomized to either apixaban 2.5 mg BID, or a vitamin K antagonist, aiming for an INR between 2 and 3. Over a median follow-up time of 429 days for apixaban, and 506 days for the vitamin K antagonist, the composite primary safety outcome of first, major bleeding, clinically relevant, non-major bleeding, or all cause death, occurred in 46% of patients on apixaban, and 51% of patients on the vitamin K antagonist. That would be a hazard ratio of 0.91, with a p for non-inferiority being 0.157. How about the primary efficacy outcome? While this was a composite of ischemic stroke, all cause death, myocardial infarction, or deep vein thrombosis, and/or pulmonary embolism, and that occurred in 21% of patients on apixaban and 31% of patients on the vitamin K antagonists. Again, no difference when there was testing. So, in summary, Peder, there were no differences in the safety or efficacy observed between apixaban and vitamin K antagonists in patients with atrial fibrillation on chronic hemodialysis. Of note, however, even receiving oral anticoagulations, these patients remain at very high risk of cardiovascular events. So these data really support the consideration of apixaban for prevention of cardiovascular complications in patients with atrial fibrillation on chronic hemodialysis, but larger studies are definitely needed. Dr. Peder Myhre: Oh wow, Carolyn, that is so clinically relevant. And the next paper is also a clinically relevant paper. And it comes to us from the SPRINT authors. And to remind you, the SPRINT study was a study of intensive systolic blood pressure lowering compared to standard blood pressure lowering. And the results demonstrated that there was a robust reduction in both heart failure endpoints and all cause mortality. And in this sub-study that comes to us from corresponding author Jarett Berry from University of Texas Tyler School of Medicine, these authors look at the mechanisms through which intensive blood pressure lowering reduces the risk of these endpoints. And given the important role of cardiac injury and neurohormonal activation in the pathways leading from hypertension to heart failure, and strong association that has been observed between hypertension and levels of cardiac troponin and NT-proBNP, the authors hypothesized that intensive systolic blood pressure lowering would decrease levels of high sensitivity cardiac troponin T and NT-proBNP. Dr. Carolyn Lam: Cool. That's interesting. So how did they do this, and what did they find? Dr. Peder Myhre: So, as expected, Carolyn, the authors found that increases in troponin and NT-proBNP from baseline to 1 year were associated with a higher risk of heart failure and death. And there were really no significant interaction by treatment assignment. But let's look at the changes in troponin. And these results showed that randomization to intensive blood pressure lowering versus standard blood pressure lowering resulted in a significant 3% increase in cardiac troponin T level over 1 year follow up, and a higher proportion of participants with more than 50% increase, and that's with an odds ratio of 1.47. And Carolyn, in contrast, NT-proBNP decreased by 10% in intensive blood pressure arm. And these patients had substantially lower probability of increasing more than 50% in NT-proBNP, with an odds ratio of 0.57 compared to the standard arm. And now, to the most interesting part of this analysis, Carolyn, the association of randomized treatment assignment on changes in troponin was completely attenuated after accounting for changes in eGFR during the follow up, whereas the association of treatment with NT-proBNP changes were completely attenuated after adjusting for changes in systolic blood pressure. So Carolyn, the authors highlight in their discussion the importance of non-cardiac factors influencing variation in cardiac biomarkers, and raise questions about the potential role of cardiac troponin T as a surrogate marker for heart failure or death in blood pressure lowering studies. Dr. Carolyn Lam: Wow, very interesting. Thanks, Peder. Can I tell you now about a preclinical study? Very interesting, because it shows that cardiac inflammation and hypertrophy are regulated by a heart-brain interaction. Dr. Peder Myhre: Wow, Carolyn, a heart-brain interaction. I'm excited to hear more about this. Please explain. Dr. Carolyn Lam: I'd love to, but first some background. Interleukin-1 beta, now that is a pro-inflammatory cytokine that causes cardiac hypertrophy and heart failure. I need to familiarize you with this, the nucleotide-binding domain leucine-rich containing family, pyrin domain-containing-3, NLRP3 for short, which is an inflammasome, which is a cytosolic multiprotein complex that mediates active interleukin-1 beta production. Okay? So you know these terms, and now I want to tell you about the study. This is an elegant series of experiments performed by co-corresponding authors, Dr. Higashikuni, from University of Tokyo, and Dr. Sata, from Tokushima University Graduate School of Medicine, and their colleagues. They first showed that genetic disruption of the NLRP3 inflammasome resulted in significant loss of interleukin-1 beta production, cardiac hypertrophy, and contractile function during pressure overload. Next, a bone marrow transplantation experiment revealed an essential role of NLRP3 inflammasome in cardiac non-immune cells in myocardial interleukin-1 beta production and the cardiac phenotype. It was extracellular ATP released from sympathetic nerve terminals that induced the hypertrophic changes of cardiac cells in an NLRP3 and interleukin-1 beta dependent manner in vitro. And finally, depletion of ATP release from sympathetic efferent nerves, or ablation of cardiac afferent nerves, or a lipophilic beta-blocker, all reduced cardiac extracellular ATP, and inhibited the NLRP3 inflammasome activation, the interleukin-1 beta production, and the adaptive cardiac hypertrophy during pressure overload. So all of this suggests that controlling the neuronal brain signals might have therapeutic potential for the treatment of hypertensive heart disease. Neat, huh? Dr. Peder Myhre: Oh, that is so interesting. The heart and brain interaction. And, Carolyn, we're going to stay in the field of preclinical science. And now we're going to talk about another field that is really interesting, and that is regeneration of cardiomyocytes. Because, Carolyn, developmental cardiac tissue holds remarkable capacity to regenerate after injury, and consists of regenerative mononuclear and deployed cardiomyocytes. Whether reprogramming metabolism promotes persistence of these regenerative mononuclear and deployed cardiomyocytes that enhance cardiac function in repair after injury is unknown. Therefore, these researcher, led by corresponding author, Mohsin Khan, from Temple University School of Medicine, investigated whether the RNA binding protein, LIN28a, which is a master regulator of cellular metabolism, plays a role in cardiac repair following injury. Dr. Carolyn Lam: Wow. That is always, always interesting, regeneration and repair following injury. So what did the authors find? Dr. Peder Myhre: Well, Carolyn, through a number of elegant experiments, the authors made the following key findings. For the first time, they documented a role for RNA binding protein LIN28A in regulating cardiomyocyte turnover in the postnatal and adult heart. And LIN28a overexpression promotes cardiomyocyte cell cycle activity during postnatal development and extends cardiac regenerative ability of the mammalian heart to postnatal day 7. And in the adult heart, the authors could demonstrate that LIN28a drives new myocyte formation, augmenting cardiac structure and function after myocardial injury. And Carolyn, I'm sure you're going to ask the clinical implications of this study. Dr. Carolyn Lam: Indeed. Dr. Peder Myhre: And that is that these results may suggest a novel translational role for LIN28a based strategy to replenish cardiomyocytes in the adult heart after injury. Dr. Carolyn Lam: Very nice, Peder. Thank you. Also in the issue is a Research Letter by Dr. Bick on interleukin-6 receptor polymorphism attenuates clonal hematopoiesis mediated coronary artery disease risk among many individuals in the UK Biobank. There's also Cardiology News by Tracy Hampton, where she highlights few really interesting things, like aging cardiomyocytes accumulate new genetic mutations that was published in Nature Aging, cytokines promote tissue repair after a heart attack in mice, and that was published in Science, and scientists identifying molecular alterations in a failing heart at a single cell resolution, which was published in Nature. Dr. Peder Myhre: And there are a couple of other papers also in this issue, Carolyn. And there's first, an exchange of letters by Drs. Halushka, Lu, and Mayr, regarding the article "Circulating MicroRNA-122-5p is Associated with a Lack of Improvement in Left Ventricular Function after TAVR and Regulates Viability of Cardiomyocytes Through Extracellular Vesicles." And finally, we have an "On My Mind" piece by doctors Monda and Limongelli entitled "An Integrated Sudden Cardiac Risk Prediction Model for Patients with Hypertrophic Cardiomyopathy." Dr. Carolyn Lam: Oh, nice. Nice full issue. Thank you, Peder. Let's go to our feature discussion now. Shall we? Dr. Peder Myhre: Let's go. Dr. Greg Hundley: Welcome listeners to this feature discussion on January 24th. And we have with us Dr. Subodh Verma, from St. Michael's University in Toronto, Canada. And a guest editor, Dr. Christopher Granger, from Duke University in Durham, North Carolina. Welcome gentlemen. Well, Subodh, we will start with you. Can you describe for us some of the background information that went into the preparation of your study, and what was the hypothesis that you wanted to address? Dr. Subodh Verma: First, my great pleasure to be here, and thank you very much for the opportunity to discuss this paper with your viewers. As you know, SGLT2 inhibitors have been truly transformative therapies. From a heart failure perspective, we know that they prevent incident heart failure in people with diabetes who have vascular disease or risk factors. They also have been shown to treat prevalent heart failure in people with heart failure and either a reduced, mildly reduced, or preserved ejection fraction independent of glycemic status. And really, these have been the basis of very strong recommendations to use these agents in the prevention of heart failure in people with diabetes, and also in the treatment of prevalent heart failure in people with and without diabetes. Now, the fact that these drugs have such broad effects in people with heart failure has led to a theory that maybe these drugs could be introduced earlier on in the natural history of heart failure in people who neither have diabetes nor have significant heart failure, the so-called sort of stage A or stage B patient. But there really have been no clinical trials evaluating this question. There've been a lot of translational randomized trials that have provided some mechanistic insights about LV remodeling in people with diabetes or in people with prevalent heart failure. And we hypothesized that maybe the first step to evaluate whether SGLT2 inhibitors may have favorable effects on cardiac remodeling in people without diabetes or without heart failure would be to conduct a randomized double-blind control trial looking at indices of left ventricular remodeling in a population that I've just described. Dr. Greg Hundley: Very nice, Subodh. So you've started us into your study design. Maybe describe that a little more fully, and then who was included in your study population? Dr. Subodh Verma: So EMPA-HEART 2 CardioLink was a multi-center double-blind placebo control randomized trial in which we studied the effects of empagliflozin, an SGLT2 inhibitor, at a dose of 10 mg per day versus placebo in people who did not have type 2 diabetes or significant heart failure. We included people who were adults between the age of 40 and 80 who met 1 of 2 entry criteria. Either they had to have one major criteria, which was an increase in left ventricular mass index by specific echo criteria or MRI criteria, or they could have increased LVH as identified by ECG or by intraventricular septal or posterior wall thickness. They could also get in if they had resistant hypertension, hypertension despite being on 3 antihypertensive agents, or the second strata was entry through 2 minor criteria, which included a history of myocardial infarction, a GFR between 30 or 60, or evidence of overweight or obesity. Dr. Greg Hundley: And how many subjects did you randomize? Dr. Subodh Verma: So we randomized, of the 318 that we screened, 169 were randomized to receive empagliflozin 10 mg or a placebo. Patients had a baseline cardiac MRI done, and then the exposure was 6 months. They had a follow-up MRI at the end of 6 months. And the primary outcome measure was a 6-month change in left ventricular mass index from baseline to 6 months between the two groups. Dr. Greg Hundley: Very nice. And so , Subodh, can you describe for us now, what did you find? What were your study results? Dr. Subodh Verma: So, first and foremost, what we found in terms of baseline characteristics was that we enrolled a population of people with a mean age of around 60 with a BMI of around 30 kg/m2, predominantly men, about 80% or so were men. These were patients who did not have significant heart failure. The NT-proBNP at baseline was around 50 pg/mL. The eGFR was around 80 mL/minute, and the vast majority of these patients actually had a history of hypertension. Of course, none of them had diabetes by definition. The hemoglobin A1C was around 5.8%. Now what we found was, despite the fact that we went after patients who we thought would be enriched for a baseline increase in LV mass indices, the baseline LV mass index was mildly elevated, was around 63 g/m2. And over the course of 6 months, we did not find any significant difference in terms of LV mass regression between the placebo and empagliflozin groups. In fact, the adjusted treatment effect was minus 0.30 g/m2, which was not statistically significant. No other differences were found in terms of other indices of a remodeling, including left ventricular and diastolic or end systolic volume indices or in terms of left ventricular ejection fraction. There was a 2% increase in ejection fraction, and the p-value for that was 0.07, but really was not statistically significant. Dr. Greg Hundley: And very nice. And realizing that women may have smaller LV masses, any stratified analysis that evaluated effects on men versus women? And then what about, perhaps in the higher quartile versus lower quartile, of age? Dr. Subodh Verma: Right. So, Greg, we actually did look at various subgroups and covariates, including gender, including age. And age or gender did not really influence the overall result that we obtained. There was really a neutral result in empagliflozin, irrespective of these 2 covariates. We also looked at baseline blood pressure, baseline NT-proBNP, LV mass indices, the presence or absence of heart failure, chronic kidney disease. So for the covariates that we have evaluated over a short term of 6 months in this relatively low risk population, we did not find any heterogeneity the result, per se. Dr. Greg Hundley: Very good. Well, Subodh, thank you so much for that beautiful presentation. And listeners, now we're going to turn to our guest editor, Dr. Chris Granger. And Chris is an expert in the field of heart failure. Also, a lot of familiarity with HFpEF, which sounds a little bit, we're looking at precursors. We don't have HFpEF yet, but maybe trying to inhibit this from happening using empagliflozin. How do you put these results in the context with other studies that have emphasized utilizing SGLT2 inhibitors in patients with sort of a preserved ejection fraction and absence of diabetes? Dr. Christopher Granger: Yeah. Well thanks, Greg. And again, congratulations, Subodh, to your study. And I think you framed some of the context here as these drugs, the SGLT2 inhibitors, as being transformative, which I think is exactly right. And it's such a fascinating story. Right? These drugs, which we thought originally, with their cause of glucose spilling in the urine, and a modest decrease in blood glucose, might have a role for modestly improving glucose control in diabetes. And low and behold, they've turned out to be one of the great stories I think in recent, across all of medicine, in terms of their consistent and substantial improving clinical outcomes for patients with heart failure, with diabetes and cardiovascular disease, and now even kidney protection, and much broader implications. And their well tolerated, and they don't have dose titration. So there's some practical appeal to this class of drugs in terms of their benefits, in terms of clinical outcomes. But we're left with having this amazing evidence-based generated without really understanding why are these drugs so effective? And what are they doing? And you've provided, I think, an important piece to the puzzle. We did have the data from patients with diabetes and heart failure, with diabetes and left ventricular hypertrophy, that there is a modest reduce in LV mass with SGLT2 inhibitors. And what you've shown is that for patients that with mild LVH, with risk for LVH, that we simply don't see a substantial reduction in LV mass with the use of these drugs. So I think that provides this evidence that that's not a major cause of benefit, at least in this earlier phase of development of heart failure. And I think it really underscores the fact that there's a lot of work to do still to understand. We know that the renal effects are obvious place that these drugs have such an important benefit. And then the linkage of renal disease and cardiac performance is one of the areas, I think, that's a very exciting aspect of a probable contribution of the mechanism of these drugs. But I think in the end, we're left with still not really understanding why these drugs are so beneficial. But understanding that, I think, will be important, both for opening new avenues of targeting pathways, as well as being able to tell the clinical community, okay, you have these important benefits, but people do want to also know why are we seeing these benefits. Dr. Greg Hundley: Very nice. Well, listeners, we're going to turn back to Dr. Verma here. Subodh, what do you see is the next study to be performed in this sphere of research? Dr. Subodh Verma: Well, first, my thanks to Professor Granger, Chris, for handling this paper and for his very thoughtful comments. And he's absolutely right. We have such wonderful clinical data, and these results, of course, should not in any way take away from the importance of using empagliflozin or other SGLT2 inhibitors in the prevention of heart failure in people with diabetes, or in the treatment of HFpEF or HFrEF. But we're struggling with trying to understand what is the dominant mechanism of action here. And, in the previous precursor to EMPA-HEART 2, we did EMPA-HEART 1 in people with diabetes, and we saw a modest effect that was statistically significant of reduction in LV mass index. And we did not see this, of course, in a lower risk population without diabetes. And that tells me that remodeling may be occurring to a modest effect, it may require a longer time to actually show its benefits, but that this is unlikely a dominant sort of mechanism through which these drugs are working. And I do share Chris's thoughts that one of the key mechanisms of benefit that needs to be further explored is looking at the renal cardiac axes. We know that these drugs are profoundly renal protective, and that the benefits may actually be secondary to improvements in renal hemodynamics, improvements in renal function. And I think that is a population that needs to be, that's a mechanism that needs to be studied further. So I think the next generation of translational mechanistic studies need to really tease out the renal cardiac axes, maybe tease out populations that are at risk but have more significant left ventricular hypertrophy, maybe evaluate patients for a longer duration of treatment, or select people who truly have significant hypertension at baseline. I think those are groups and questions that need further exploration. And, of course, the translational science needs to be also studied in the context of larger completed clinical trials, where biomarkers are currently available and they can be linked, of course, to the outcomes in those trials. So those are some of my thoughts as to where the field could move towards. Dr. Greg Hundley: Very nice. And Chris, do you have anything to add? Dr. Christopher Granger: Subodh, I think that was a great summary. And I might just make a comment on the other end of the spectrum. That is, we have these drugs and the evidence of their benefit, and yet they're grossly underused in the populations that have proven to have benefit. Now it takes some time to educate, to get people familiar with, and get them to integrate these treatments into practice, but there's an enormous opportunity, and I think there is a linkage here. I think when people understand the mechanism, and when they're thoughtful about how these drugs may be working, that that really helps to make the case that the drug should be used, and that people are on board with using them. So I think there's this linkage here, there's the need to both better understand mechanism, and there's the need to have systems of care where these treatments are integrated to provide the benefit that's been so clearly shown in the randomized trials. Dr. Greg Hundley: Very nice. Well, listeners, we want to thank Dr. Subodh Verma, from St. Michael's University in Toronto, and our guest editor, Dr. Chris Granger, from Duke University in Durham, North Carolina, for bringing this paper highlighting that among people with neither diabetes nor significant heart failure but with risk factors for adverse cardiac remodeling, that SGLT2 inhibition with empagliflozin did not, did not, result in a meaningful reduction in LV mass index after 6 months. Well, on behalf of Carolyn, Peder, and myself, we want to wish you a great week, and we will catch you next week on the run. This program is copyright of the American Heart Association 2023. 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.

Episode #174: Demystifying PANS/PANDAS with Dr. Nancy O'Hara, MD, MPH, FAAP

Play Episode Listen Later Nov 2, 2022 96:04

Why You Should Listen: In this episode, you will learn how to demystify PANS and PANDAS. About My Guest: My guest for this episode is Dr. Nancy O'Hara. Nancy O'Hara, MD, MPH, FAAP is a board-certified pediatrician. Prior to her medical career, Dr. O'Hara taught children with autism. She graduated with highest honors from Bryn Ma gdwr College and as a member of the Alpha Omega Alpha Honor Society from the University of Pennsylvania School of Medicine. She earned a Master's degree in Public Health from the University of Pittsburgh. After residency, chief residency, and general pediatric fellowship at the University of Pittsburgh, Dr. O' Hara entered general private practice in 1993, and in 1999, began her consultative, integrative practice solely for children with special needs. Since 1999, she has dedicated her functional medicine practice to the integrative and holistic care of children with chronic illness and neurodevelopmental disorders such as ADHD, PANDAS/PANS, OCD, Lyme, and ASD. She is a leader in the training of clinicians, both in the United States and abroad. Dr. O'Hara has written a comprehensive guidebook, “Demystifying PANS/PANDAS: A Functional Medicine Desktop Reference on Basal Ganglia Encephalitis”, which is available on Amazon. Key Takeaways: How is PANS and PANDAS different from Autoimmune Encephalitis and Basal Ganglia Encephalitis? Does the onset have to be acute, or can there be a more smoldering presentation? How much of the condition is the microbe vs. the host response? Can PANS occur in adults? What is the role of mitochondrial dysfunction? What role do the tonsils play in these conditions? Which microbes may be triggers for PANS and PANDAS? Are antibiotics required for successful treatment? How often do Lyme and coinfections play a role? What are some natural interventions for addressing microbial overgrowths? Does mold illness contribute to PANS and PANDAS? How important is immune modulation reducing inflammation? How might helminth therapy be used to modulate the immune response? What are some tools for modulating the NLRP3 inflammasome? When might antioxidants be necessary? How much of the inflammatory burden overlaps with MCAS? Might FMT or stem cells play a role in recovery? Connect With My Guest: http://DrOHara.com Interview Date: October 10, 2022 Transcript: To review a transcript of this show, visit https://BetterHealthGuy.com/Episode174. Additional Information: To learn more, visit https://BetterHealthGuy.com. Disclaimer: The content of this show is for informational purposes only and is not intended to diagnose, treat, or cure any illness or medical condition. Nothing in today's discussion is meant to serve as medical advice or as information to facilitate self-treatment. As always, please discuss any potential health-related decisions with your own personal medical authority.

Genetics and Epigenetics of Digestion With Steph Jackson

ReInvent Healthcare

Play Episode Listen Later Oct 26, 2022 42:16

In this week's episode of ReInvent Healthcare, we're discussing digestion, and the genetic factors that influence the microbiome. Our guest Steph Jackson is a graduate of our nutritional endocrinology program and is our resident microbiome expert. Steph is an ex yogurt maker, currently called the ‘Gut Whisperer' by her clients. She advocates using probiotic bacteria functionally in consideration of each and every person's unique biochemistry, in order to achieve optimal health. Tune in to learn how intricately our digestive bacteria is connected to food and overall health and the role our genes play with all of these factors. IN THIS EPISODE: [03:00] Is there a higher likelihood of having Celiac or Crohn's, if testing positive to certain genes? [5:15] FUT2 SNP gene that is responsible for our secretion of H antigen into our mucosa. [10:00] The Bifido bacteria are like the grandmother of all the short chain fatty acid producing bacteria in the large intestine. [12:50] RS 110402, and RS 242924 are the RS numbers to search for when testing for gut stress and IBS. If you test positive for these numbers, the stress you feel is more likely to affect your gut, than someone else without these results. [16:00] Stress isn't good in any context, unless it's a healthy stress like going for a run. [18:30] AOC1 gene RS 10156191, RS 2052129, RS 1049742. These are RS numbers to search in regards to histamine. [22:00] Many people have mast cell activation and histamine intolerance, and they're struggling and limiting their diet. There may be another reason why the body is sending out these signals. [30:20] The NLRP3 gene that's been associated with Crohn's, colitis, and even celiac disease. RS 10754558 and RS 10733113. [32:00] With the RS 4353135 T variation, there is an increased prevalence of Crohn's. RS 3806265 C variation, it encodes the making of cryopyrin. KEY TAKEAWAYS: Single nucleotide polymorphisms, and the genetic variations can affect the way certain biochemical pathways work for digestion. Due to genetics, stress may affect some people's gut health more than others. Stress isn't good in any sense, unless it's the healthy kind associated with exercise. GUEST BIO: Steph Jackson, ex-yogurt maker now called the Gut Whisperer by her clients, advocates using probiotic bacteria functionally in consideration of your own biochemistry in order to achieve optimal health. After doing the research to build her non-dairy yogurt company she could not keep quiet about some of the things she discovered and is now using her experience in education and curriculum design to create the Friendly Flora Collective. If you are fascinated by how intricately our digestive bacteria are connected to our food and our overall health you will enjoy our time together today. RESOURCES: reinventhealthcare.com/genes/ www.plantpoweredprobiotics.com https://www.friendlyfloracollective.com/

stress single gut health key takeaways ibs crohn rs microbiome digestion epigenetics celiac genetic testing nlrp3 reinvent healthcare bifido

Membrane Biochemistry 67. VDAC oligimerization inhibition can block mitochondria-mediated apoptosis and NLRP3 inflammasome activation. DJGPhD.22.10.22.Authentic Biochemistry.

authentic activation biochemistry mitochondria membrane inhibition mediated apoptosis nlrp3 inflammasome

Play Episode Listen Later Oct 22, 2022 29:59

References Immunity 2022 551370-1385.e8DOI: (10.1016/j.immuni.2022.06.007 J Biol Chem. 2016 Nov 25; 291(48): 24986–25003. J of Visualized Experiments. 2013; (81): 50966 --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

Membrane Biochemistry 66. Staph aureus infection, autoimmune disease, biliary cholangitis, and neurodegeneration involve NLRP3 Inflammasome activation with core bioenergetic involvement. DJGPhD.

Play Episode Listen Later Oct 21, 2022 29:57

References Dr Guerra's immunology lecture notes J Vis Exp. 2013; (81): 50966 Front Immunol. 2019; 10: 1309. Infect Immun. 2013 Dec; 81(12): 4478–4489. Immunity 2022. Volume 55 Issue 8 Pages 1370-1385.e8 --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

pages immunity infection involvement activation biochemistry autoimmune disease membrane bioenergetics neurodegeneration biliary cholangitis nlrp3 inflammasome staph aureus

IRE-1α is a key switch of pyroptosis and necroptosis in mice by dominating Gasdermin D

Play Episode Listen Later Oct 14, 2022

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.12.511926v1?rss=1 Authors: Xin, Z., Qing, Z., Yong, L. D., Meng, L. Y., Qing, X., Hong, L. X., Wen, L., Min, Z., Li, L., Lu, Y., Cheng, J., Chen, Y. Abstract: Necroptosis and pyroptosis are lytic and inflammatory types of programmed cell death that require the membrane destruction predominantly driven by the mixed lineage kinase domain-like (MLKL) and gasdermin D (GSDMD) proteins. However, the crosstalk between them remains largely unknown. Here, our research discloses that endoplasmic reticulumn transmembrane protein inositol-requiring enzyme-1 (IRE-1) is a potential modulator of both necroptosis and pyroptosis, paricularly in liver pathology. Interestingly, enhanced expression of IRE-1 triggers hepatic pyroptosis, while defective IRE-1 level activates hepatic necroptosis, and both processes are closed related to the activity of GSDMD. To elucidate unknown crosstalk, by using pharmacological and genetic methods, we first demonstrated that IRE-1 suppresses necroptosis by promoting the expression of GSDMD and cleaves caspase-8 and by inhibiting the expression of receptor-interacting serine/threonine-protein kinase 1 (RIPK1), RIPK3 and MLKL. Unexpectedly, excess IRE-1 initiates pyroptosis by increasing GSDMD and NLRP3 levels. Our work clearly provides insight into the modulation of IRE-1 to dominate necroptosis and pyroptosis and suggests that IRE-1 may be a promising therapeutic target for drug discovery in both types of tissue injuries. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

llc switch copy li chen mice dominating hong wen cheng unexpectedly meng yong qing ire biorxiv nlrp3

Endosomal Trafficking of Two Pore K+ Efflux Channel TWIK2 to Plasmalemma Mediates NLRP3 Inflammasome Activation and Inflammatory Injury

depression alzheimer's disease dementia thursday night football antioxidants powerful tools vitamin k nlrp3

Play Episode Listen Later Oct 12, 2022

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.12.511914v1?rss=1 Authors: Di, A., Huang, L. S., Zhou, B., Toth, P. T., Krishnan, Y., Malik, A. B. Abstract: Potassium efflux via the two pore K+ channel TWIK2 is a requisite step for the activation of the NLRP3 inflammasome, however it is unclear how the efflux is activated in response to cues. Here we report that during homeostasis, TWIK2 resides in endosomal compartments. TWIK2 is transported by endosomal fusion to the plasmalemma in response to increased extracellular ATP resulting in extrusion of K+ ATP-induced endosomal TWIK2 plasmalemma translocation is regulated by Rab11a. Deleting Rab11a or ATP ligated purinergic receptor P2X7 prevented endosomal fusion with the plasmalemma and K+ efflux and NLRP3 inflammasome activation in macrophages. Adoptive transfer of Rab11a-deleted macrophages into mouse lungs prevented NLRP3 inflammasome activation and inflammatory lung injury. Rab11a-mediated endosomal trafficking in macrophages thus regulates TWIK2 abundance and activity on the cell surface and downstream activation of the NLRP3 inflammasome. Endosomal trafficking of TWIK2 to the plasmalemma is therefore a potential therapy target in acute or chronic inflammatory states. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

llc injury copy activation trafficking atp huang zhou inflammatory toth krishnan adoptive pore biorxiv nlrp3 inflammasome efflux

August 2022 Discover CircRes

Discover CircRes

Play Episode Listen Later Aug 18, 2022 32:38

This month on Episode 39 of Discover CircRes, host Cynthia St. Hilaire highlights four original research articles featured in the August 5th and 19th issues of the journal. This episode also features an interview with Dr Annet Kirabo and Dr Ashley Pitzer from Vanderbilt University on their article, Dendritic Cell ENaC-Dependent Inflammasome Activation Contributes to Salt-Sensitive Hypertension. Article highlights: Jain, et al. Role of UPR in Platelets Orlich et al: SRF Function in Mural Cells of the CNS Xue et al: Gut Microbial IPA Inhibits Atherosclerosis Wang et al: Endothelial ETS1 on Heart Development Cindy St. Hilaire: Hi, welcome to Discover CircRes, the podcast of the American Heart Association's journal Circulation Research. I'm your host, Dr Cindy St. Hilaire from the Vascular Medicine Institute at the University of Pittsburgh, and today I'm going to be highlighting articles from our August 5th and August 19th issues of Circulation Research. I'm also going to have a chat with Dr Annet Kirabo and Dr Ashley Pitzer from Vanderbilt University about their study, Dendritic Cell ENaC-Dependent Inflammasome Activation Contributes to Salt-Sensitive Hypertension. But before I get to the interview, I first want to share an article from our August 5th issue, and that article is titled, Unfolded Protein Response Differentially Modulates the Platelet Phenotype. The first author of this study is Kanika Jain and the corresponding author is John Hwa from Yale University. Self-stress can lead to protein misfolding, and the accumulation of misfolded proteins can lead to a reduction in protein translation and may alter gene transcription, a process collectively known as the unfolded protein response, or UPR. UPR is well documented in nucleated cells; however, it has not been studied in platelets, which are anuclear, but do have a rapid response to cellular stress. In this study, they investigated the UPR in anucleate platelets and explore its role, if any, in platelet physiology and function. They found that treating human and mouse platelets with various stressors caused aggregations of misfolded proteins and induction of UPR-specific factors. Oxidative stress, for example, induced the UPR kinase PERK, while an endoplasmic reticulum stressor induced the transcription of the UPR factor XBP1. The team went on to study the UPR in platelets from people with type II diabetes, which is a population in which platelet mediated thrombosis is a major complication. They showed that protein aggregation and upregulation of the XBP1 pathway in diabetic patient platelets correlated with disease severity. Furthermore, treating the diabetic patient platelets with a chemical chaperone that helps to correct protein misfolding reduced protein aggregations and prevented the cells prothrombotic activation. This work confirms that even without transcription, platelets display stress-induced UPR, and that targeting this response may be a way to reduce thrombotic risk in diabetic patients. Cindy St. Hilaire: The second article I want to share with you is from our August 5th issue and is titled, Mural Cell SRF Controls Pericyte Migration, Vessel Patterning and Blood Flow, and it was led by Michael Orlich from Uppsala University in Sweden. Blood vessels are lined with endothelial cells and surrounded by mural cells. Vascular smooth muscle cells are the mural cells in the case of veins and arteries, and pericytes are the mural cells in the case of capillaries. In the capillaries, pericytes maintain blood-brain and blood-retina barrier function and can mediate vascular tone, similar to smooth muscle cells. While these pericytes and smooth muscle cells are related, they have distinct roles and characteristics. To learn more about the similarities and the differences between pericytes and smooth muscle cells, this group examined how each would be affected by the absence of SRF in the other. SRF is a transcription factor, essential for nonvascular or visceral smooth muscle cell function. In visceral smooth muscle cells, SRF drives expression of smooth muscle actin and other smooth muscle genes. Using mice engineered to lack SRF in mural cells, they show that SRF drives smooth muscle gene expression in these pericytes and smooth muscle cells, and its loss from smooth muscle cells causes atrial venous malformations and diminishes vascular tone. In pericytes, loss of SRF impaired cell migration in angiogenic sprouting. In a mouse model of retinopathy, activation of SRF drove pathological growth of pericytes. This work not only highlights the various functions of SRF in mural cell biology, but it also suggests that it has a role in pathological capillary patterning. Cindy St. Hilaire: The third article I want to share is from our August 19th issue of Circulation Research and is titled, Gut Microbially Produced Indole-3-Propionic Acid Inhibits Atherosclerosis by Promoting Reverse Cholesterol Transport and its Deficiency Is Causally Related to Atherosclerotic Cardiovascular Disease. The first authors are Hongliang Xue and Xu Chen, and the corresponding author is Wenhua Ling from Sun Yat-Sen University in Guangzhou, China. Recent studies provide evidence that disorders in the gut microbiota and gut microbiome derived metabolites affect the development of atherosclerosis. However, which and how specific gut microbial metabolites contribute to the progression of atherosclerosis and the clinical relevance of these alterations remain unclear. Gut microbiome derived metabolites, such as short-chain fatty acids and trimethylamine N-oxide, or TMAO, have been found to correlate with atherosclerotic disease severity. This study has now found that serum levels of indole-3-propionic acid, or IPA, are lower in atherosclerosis patients than controls. The team performed unbiased metagenomic and metabolomic analyses on fecal and serum samples from 30 coronary artery disease patients and found that, compared with controls, patients with atherosclerosis had lower gut bacterial diversity, depletion of species that commonly produce IPA and lower levels of IPA in their blood. Examination of a second larger cohort of atherosclerosis patients confirmed this IPA disease correlation. The team also showed serum IPA was reduced in a mouse model of atherosclerosis, and that supplementing such mice with dietary IPA could slow disease progression. Analysis of the macrophages from these mice showed that IPA increased cholesterol efflux, and the team went on to elucidate the molecular steps involved. The results of this study not only unraveled the details of IPA's influence on atherosclerosis, but suggest boosting levels of this metabolite could slow atherosclerotic disease progression. Cindy St. Hilaire: The last article I want to share is also from our August 19th issue, and it's titled, Endothelial Loss of ETS1 Impairs Coronary Vascular Development and Leads to Ventricular Non-Compaction. The first author is Lu Wang and the corresponding author is Paul Grossfeld, and they are at UCSD. Congenital heart defects, or CHDs, are present in nearly 1% of the human population. In some cases, the heart defects result from a genetic error, which can give researchers clues to its etiology. Jacobson syndrome is a complex condition caused by deletions from one end of chromosome 11, and the occurrence of a congenital heart defect in this syndrome has been associated with the loss of the gene ETS1. ETS1 is an angiogenesis promoting transcription factor, but how ETS1 functions in heart development was not known. Wang and colleagues now show that both global or endothelial-specific loss of ETS1 in mice caused differences in embryonic heart development that ultimately led to a muscular wall defect known as ventricular non-compaction. The mice also had defective coronary vasculogenesis associated with decreased abundance of endothelial cells in the ventricular myocardium. RNA sequencing of ventricular tissue revealed that, compared with controls, mice lacking ETS1 had reduced expression of several important angiogenesis genes and upregulation of extracellular matrix factors, which together contributed to the muscular and vascular defects. Cindy St. Hilaire: Today I have with me, Dr Annet Kirabo and Dr Ashley Pitzer, both from Vanderbilt University, and we're going to talk about their paper, Dendritic Cell ENaC-Dependent Inflammasome Activation Contributes to Salt-Sensitive Hypertension. This article is in our August 5th issue of Circulation Research. Thank you both so much for joining me today. Annet Kirabo: Yeah, thank you so much for having us. Ashley Pitzer: Yeah, thank you for having us. Cindy St. Hilaire: Yeah, it's a great paper. I think we're all familiar with hypertension and this idea that too much salt is bad for our cardiovascular system. When I was a kid, my grandparents had those salt replacements on their kitchen table, Mrs. Dash and whatever. But, like you said in the start of your paper, the exact mechanism by which salt intake increases blood pressure and also increases cardiovascular risk, it's not really well understood, and you guys are focusing on the contribution of immune responses in this process or in this pathogenesis. Before we dig into the details of your paper, I was wondering if you could give us a little bit of background about what's known regarding the role of inflammation in this salt-sensitive hypertension pathogenesis. Annet Kirabo: Yeah. It's difficult to know where begin to from, but the role of inflammation in cardiovascular disease have been known for many, many decades. Right now, Dr David Harrison showed more than 10 years ago that T cells contribute to hypertension, but the mechanisms were not known. Back when I was a post doc in David Harrison's lab, we discovered a new mechanism, how immune cells are activated in inflammation and hypertension, whereby we found that there is increased oxidative stress in antigen-presenting cells. This leads to formation of oxidative products known as arachidonic acid or lipid products known as isolevuglandin, or IsoLGs. These IsoLGs are highly, highly reactive and they adapt to lysines on proteins. This is a covalent binding, which leads to permanent alteration of proteins, and so these proteins act as neoantigens that are presented as self-antigens to T cells, leading to an autoimmune-like state in hypertension. Annet Kirabo: We found that these antigen-presenting cells are activated and they start producing a lot of cytokines that paralyze T cells to IL-17 producing T cells that contribute to hypertension. And so, when I started my lab back in 2016, we discovered that excess dietary salt profoundly activates this pathway, and we found for the first time that these antigen-presenting cells, they express ENaC, the epithelial sodium channel, and sodium goes into these antigen-presenting cells and activates the NADPH oxidase, which is an enzyme which produces this reactive oxygen species, leading to this IsoLG formation, which I've talked about, and leading to inflammation. So, three years ago when Ashley joined my lab, she had extensively studied the inflammasome in her PhD program, and she suggested why don't we look at the role of the inflammasome in this pathway and how IsoLG may contribute to this. In her paper that we are discussing right now, she found that in a dependent manner, sodium enters the cell and activates this pathway, and the NLRP3 inflammasome is involved in this process. Cindy St. Hilaire: That's such a wonderful story that fits together so many pieces. One of the things you talk about, which I guess I didn't even appreciate myself is, there are certain individuals out there who are more salt-sensitive than others. Annet Kirabo: Yeah. Cindy St. Hilaire: What is that difference? Do we know the root cause of that? And then also, how many individuals are we talking about are salt-sensitive? Annet Kirabo: Salt-sensitive blood pressure, it is a variable trait and it's normally distributed in the population, but it happens more in some individuals than others. It happens even in 25% of people without any hypertension. These people go to that doctor, that doctor thinks they're normal, they don't have any hypertension, but these people can be at a risk of sudden heart attack or cardiovascular risk or even a stroke, simply because when they eat a salty meal, their blood pressure will go up. Cindy St. Hilaire: Yeah, that's one of my questions. How much salt are we talking about here? And not only how much in a meal, but a sustained amount? How bad is a miso soup a day? Annet Kirabo: Yes. The American Heart Association and the World Health Organization have recommendations. American Heart Association recommends one spoon per day. We have refused to adapt to this recommendation, but that is the recommendation that they have recommended per day to eat. But this is difficult because most of the salt, as you know, is already in our food through processing in our processed foods and we don't have any control over how much salt we have, and there's also a lot of adding of salt at a table. Cindy St. Hilaire: Ashley, your background was more the inflammasome. What were your thoughts entering into this project? Did you have much of a hypertension background? Ashley Pitzer: No. My graduate thesis focused mainly on endothelial dysfunction and cardiovascular disease, and so it was a pretty easy segue. But it was just with Annet, so excited about the project and showing me all the data and this robust IL-1 beta production that she was seeing after these immune cells being exposed to high salt, I, with my inflammasome background, was immediately like, this could be playing a role. And so it was, like I said, a pretty easy transition and, as is in the paper, we're doing human studies. All of my research back in grad school was very basic research, so it was very exciting to see how our research was being translated with people having this condition and potentially finding mechanisms where we can target this to help actual people. Cindy St. Hilaire: I think a lot of us who are not in the hypertension field, and maybe this was you before you joined Annet's lab, we really only kind of think of the kidneys and the blood vessels when we think about hypertension, but studies like this are changing that. And I think a lot of Annet's earlier work, as well as the work of others, have shown a role for this epithelial sodium channel as an important player in this salt-induced hypertension. New to me, it's not just found in the kidney, which I totally did not appreciate that. And it's this channel sensing the salt that can trigger this IL-1 beta production that does a whole bunch of other things. Cindy St. Hilaire: What are those other things? What are those cells that are affected and where is this happening? Obviously it's not just kidney cells, but is it only in the kidney or are these systemic cells? What do we think is happening? Ashley Pitzer: That's the question, is, where is this happening? There's been studies at Vanderbilt by Jens Titze and his lab showing, where are these immune cells sensing the salt? And so they've shown that sodium accumulates in the skin, a huge argument is for they're sensing the sodium in the kidney because that's where a lot of it is being processed. But these immune cells travel through the whole body, so they're seeing it where there are the highest amounts of sodium concentration, and so I would argue it's in the kidney. Annet Kirabo: Indeed, because we're now collaborating with Tina Kon, and we have recently published with her a paper in the International Journal of Science, where we have done sodium MRI and we find this accumulation of sodium in the kidney even much more than in the skin. And we know that the kidney is where sodium is highly concentrated. So the working hypothesis in the lab is that these immune cells can be activated wherever they are, in the lymph nodes or not, in other tissues, but they can travel to the kidney. We find that in high salt, if you feed high salt to the mouse, the endothelium in the kidney becomes dysfunctional and it expresses molecules, chemoattractants, that attract these immune cells in the kidney. We think that the high salt accumulation in the kidney can activate these, and then these immune cells are activated and they produce cytokines. Dr Steve Crowley showed that they can produce IL-1 beta, which induces activation of sodium channels that can be induced. We have also actually found that even IL-17 can be produced by these immune cells in the kidney and they can activate sodium channels in the kidney, leading retention of sodium and water and hypertension. Cindy St. Hilaire: Very cool. You used a lot of mice in this paper. Can you tell us, I just want to know a little bit about the models you chose to use, but also how similar is hypertension in mouse and humans? Obviously for atherosclerosis, we have to do lots of things to get them to form a plaque. Is hypertension similar in a mouse and do mice also show this salt-sensitive phenotype? Annet Kirabo: That is an extremely important point. If you read our paper, we use a slightly different approach. Most people do benchside to bed approach. We did the opposite. We did a bed to benchside approach. Cindy St. Hilaire: Always smart. Annet Kirabo: Yeah. We first started humans, and then with some references, we went to the mice, because I think when it comes to salt-sensitive blood pressure, mice are different from humans. In fact, if we look in the lab, we find that female mice are protected from salt-sensitive blood pressure, but we find that in the humans, it's the opposite. Females are more prone to salt-sensitive hypertension. Those are studies that we are doing right now. We haven't published. But we know that it can be different. The model we use most of the time in the lab, the C57 mice, are resistant to salt-sensitive hypertension. These C57 mice would rather die before they raise their blood pressure in response to salt. We can induce salt-sensitivity in these mice like in the paper that we are discussing. When we induce the endothelial dysfunction using L-NAME and we wash it out, then these mice, when you give them, subsequently, salt, suggests that they become salt-sensitive. But we also have a salt-sensitive mouse model that we use, the 129/SV mouse. So we use several models to kind of prove the same thing over and over again with the findings that we found in humans. Cindy St. Hilaire: And you used a technique, which I'm a little bit familiar with, but I'd like to hear, A, about it from you, but also your experience in using it, and that is CITE-seq. So, how does that work? Ashley Pitzer: That was with our human study where we actually had patients come in, who were hypertensive, took them off medication for 2 weeks. They come in, we get baseline samples, we give them a salt load on one day, and then the next day we completely salt deplete them. Cindy St. Hilaire: How much is a salt load? Like a Big Mac? What's a salt load? Ashley Pitzer: Yeah, it's pretty much just like eating Lays chips all day. It's a lot of salt. It's a very salty meal. Annet Kirabo: And then in addition, we also infuse saline too. Cindy St. Hilaire: Oh, wow. Annet Kirabo: Because these people, when they come into the hospital, some them have already eating high salt. This approach is to just maximize the whole system so that then when we sort deplete everybody, it's at the same level and it's just to unify the whole process. But sorry, Ashley, you go ahead. Ashley Pitzer: With the CITE-seq, we're able to take different patients on different days. So we take samples each day, and we can give each sample a barcode, basically. Give them a barcode, we can pool them all together, process them, and we can sequence their RNA, we can probe for a certain amount of protein expression as well. So then when we analyze, we can look at protein expression, so you get the translation and the transcription for each person on each day, and then you're able to compare. And so you get this huge picture and it's a lot of data. Cindy St. Hilaire: How long did it take you to sort through? Ashley Pitzer: Well, we have a statistician who does all of that, because my wheelhouse is here and it is on a different planet. So we have somebody who helps us with that who does an unbiased approach. And then once he does an analysis, gives us back what are the things that are changing the most, and one of those was IL-1 beta. Annet Kirabo: As you can see, our list is huge, this is a massive input of so many collaborators. We have computational people on there that help us with this. I can't even begin to learn these techniques, but with all this collaboration and the resources at Vanderbilt, these things are possible. And so, this is a really powerful approach where you can combine protein expression and you get the specific cells that express the genes and you couple the channel type to the gene expression. Annet Kirabo: We actually found that not all monocytes are the same. There's a specific class that of monocytes, A small class of monocytes that is so angry, and the inflammasome is activated and producing this IL-1 beta, and that is enough to contribute to this phenotype of salt-sensitive hypertension, which dynamically changed according to blood pressure, suggesting that this is a targetable salt-sensitive blood pressure, even in normotensive people, is a targetable trait. And because these monocytes are in blood, can we get a blood sample and routinely diagnose salt-sensitive blood pressure so that doctors are aware and they can appropriately advise patients. Cindy St. Hilaire: This was samples obviously taken from a blood draw, right? So they're circulating. Annet Kirabo: It was a blood draw, yes. Cindy St. Hilaire: What do you think about these immune cells, perhaps, native in the kidney? Do you think the small population of angry cells, like you said, is escaping from the kidney environment? What do you think? Annet Kirabo: When I was a post-doc in David Harrison's lab, we found that the most angry dendritic cells that contribute to this inflammation and hypertension are monocyte-derived. So that's why in the human study we focused on monocytes, because there are so many subtypes of dendritic cells, plasmacytoid dendritic, classical dendritic cells. We have studied all of these subtypes, and we have focused on monocyte-derived dendritic cells because they're the ones that seem to be contributing to this phenotype the most. Cindy St. Hilaire: You guys focused in on the NLRP3 inflammasome, which, obviously it's a really critical component broadly for the innate immune system. Do you think that this is going to be a targetable approach that can be leveraged for hypertension? Or do you think it's too broad? What do you think about that as a therapeutic potential? Ashley Pitzer: Even when you look in our paper, and we use a knockout model, where we use a completely global knockout model, put them on high salt, and we give them back only dendritic cells that are from wild-type mice, so they have that NLRP3, that have been exposed to high salt. We were able to increase blood pressure, but I also did, in mice, where I gave them an IL-1 beta neutralizing antibody, similar to canakinumab, which is the CANTOS trial, and there's not much of a difference. There is, but it's minor. It's very minor. Ashley Pitzer: So, to be able to target in specific cell types in humans one thing, it's very difficult, and maybe one day we can get there. But I think it at least gives us a better idea of what is the full picture, what's the big mechanism going on with immune cells? In part of our human study, we are looking at something to try and be able to identify who is salt sensitive. So if anything, we're able to sit here and potentially have a way of identifying salt-sensitive patients, where, right now, all we can do is have them come in like we do and do a 3-day study, and not everybody can do that. Annet Kirabo: To add onto that, perhaps you know, we are talking about precision medicine. This is an era of precision medicine where you need to really tailor treatments if we can get there, and I think this is one way. CANTOS trial. They had no way of knowing who is salt-sensitive and who is not, it was a global approach, and the lack of differences in blood pressure might be explained that this IL-1 beta pathway is targetable in a specific population whose blood pressure is probably driven by inflammation. There are so many, many mechanisms that drive hypertension, and so perhaps we need to focus this on salt-sensitive people, and maybe we can really use this approach to target. Plus, this is ENaC-dependent. As you know, amiloride has lost favor in the clinic as a treatment of hypertension, because in the majority, it's not effective. But studies have shown that in Black men, for example, who had been categorized salt-resistant, when they give them amiloride, their blood pressure went down, and yet it's not effective in the majority of the people. So, can we bring back, can we take another look at amiloride. As our studies indicate that blockade of ENaC is anti-inflammatory and it's also antioxidant agent, can we at least bring back amiloride and look at it again and we focus it for specific populations of people that may be more prone to salt-sensitive hypertension? Here we have so many targets for potential precision treatment of salt-sensitive potential in this paper. You can target SGK1, which we know is possible, we listed a number of clinical trials that they have used NLRP3 inflammasome inhibitors, you can use amiloride for these people, and you can also potentially scavenge IsoLGs. Cindy St. Hilaire: What was the most challenging aspect of this study? There's a lot of moving parts, so what was the biggest challenge? And then, also, what was the most surprising part or the most pleasantly surprising part? Ashley Pitzer: You have to think, most of this was going on right when the pandemic hit. And right before that, we had started our human recruitment for the human study. And so that put a little bit of a time damper on it. Ashley Pitzer: Other than that, it was just, we were finding one thing, developing a new experiment, doing it again, doing it again. And honestly, what was the most surprising and rewarding was just seeing the same thing in, because we took just PBMCs from normotensive patients, treated them with high salt, and saw the changes that we did with the inflammasome. And to see that exactly again in an in vivo model of giving patients high salt and seeing the same thing, it was very rewarding and confirmed that, okay, we're on the right path. Seeing the same thing over and over and over again, it kind of reaffirms that you had a good idea. Annet Kirabo: I might add, one of the most challenging was, initially, the computational. Oh, part of the pandemic I was, the pandemic hit, I had a baby during the pandemic, and it was my time to leave my home, and then all these things were going on. We had a clinical trial where patients had to come in. Vanderbilt was so super supportive ,even checking for COVID-19. Our patients could not have COVID-19. We needed to check them. Cindy St. Hilaire: Yeah. Annet Kirabo: They also had to check for COVID-19. And so during that time, I realized, wait, I need learn computation analysis. I realized I cannot learn, and then reached out to collaborators that helped. That was extremely challenging. And then the other challenging thing that we faced later during the pandemic is vaccinations. In our criteria, these people cannot be vaccinated for reasons. We've studied inflammation, hypertension, and so vaccination was confounding. And even COVID-19 is even more for confounding. So we had this exclusion criteria where we could not recruit anyone. Annet Kirabo: Everybody was having COVID, everybody was being vaccinated, and everybody was in that exclusion criteria, so it was difficult to get people. We have had some slow down, but right now it's beginning to build up. Cindy St. Hilaire: So, what's next? What's the next question? Annet Kirabo: We have so many. Cindy St. Hilaire: That means it was a great study. If you have more, that means it was a great study. Annet Kirabo: Yeah. This study and us, it kind of warms. The inside seat just opened up, we have primary data in the genetic regulation of ENaC, we have primary data where we found. We are trying to figure out the specific ENaC channel in these antigen-presenting cells. We don't know. We found that ENaC delta, for example, it's not found in a kidney or you talked about a kidney contribution versus immune cells. ENaC delta is not found in the kidney, but we have primary data that show that ENaC delta is the most correlated with cardiovascular risk, is the most correlated with kidney disease and all forms of hypertension. So now we're like, ENaC delta expressed in the immune cells, not in the kidney, it is the one that is most involved in cardiovascular disease, so how are we going to tell the world that. Cindy St. Hilaire: Yeah, very cool. Annet Kirabo: Those cells, not necessarily the kidney. The kidney plays a part because the cells are going there, but it's very, very exciting. Plus a number of other lines that we are investigating. Cindy St. Hilaire: It's great. Well, congratulations, again, on this publication, on just getting all this done with what sounds like extremely difficult patient recruitment. So, Dr Kirabo and Dr Pitzer, thank you so much for joining me today and I'm looking forward to these next studies on maybe ENaC delta. Annet Kirabo: Thank you. Thank you so much. Ashley Pitzer: Thank you for having us. Cindy St. Hilaire: That's it for the highlights from the August 5th and August 19th issues of Circulation Research. Thank you for listening. Please check out the CircRes Facebook page and follow us on Twitter and Instagram with the handle @CircRes and hashtag Discover CircRes. Thank you to our guests, Dr Annet Kirabo and Dr Ashley Pitzer. This podcast is produced by Ashara Ratnayaka, edited by Melissa Stoner, and supported by the editorial team of Circulation Research. Some of the copy text for the highlighted articles is provided by Ruth Williams. I'm your host, Dr Cindy St. Hilaire, and this is Discover CircRes, your on the go source for the most exciting discoveries in basic cardiovascular research. This program is copyright of the American Heart Association 2022. Opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more information, visit ahajournals.org.

K2 (MK-7) From Depression To Dementia May be a Powerful Tool

ClinicalNews.Org

Play Episode Listen Later Apr 13, 2022 12:16

Vitamin K supplementation was associated with reduced evidence of cognitive impairment, depression and anxiety, along with improved spatial memory and learning ability. Elkattawy HA, Ghoneim FM, Eladl MA, Said E, Ebrahim HA, El-Shafey M, Asseri SM, El-Sherbiny M, Alsalamah RH, Elsherbiny NM, Hadhod S. Vitamin K2 (Menaquinone-7) Reverses Age-Related Structural and Cognitive Deterioration in Naturally Aging Rats. Antioxidants. 2022; 11(3):514. https://doi.org/10.3390/antiox11030514 #k2 #depression #dementia Vitamin k2, menaquinone-7, Dementia, Alzheimer's, neuro inflammation, cognitive impairment, depression, anxiety, spatial memory, learning ability, NLRP3, caspase-1, Il-1β, TNFα, IL-6, CD68, k2, mk-7, frontal cortex, hippocampal --- Support this podcast: https://anchor.fm/ralph-turchiano/support

Circulation January 4, 2022 Issue

Circulation on the Run

Play Episode Listen Later Jan 3, 2022 26:39

Please join author George Dangas and Associate Editor Brendan Everett as they discuss the article “Colchicine in Cardiovascular Disease.” 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: Welcome, everyone, to 2022. I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Carolyn, oh, we're starting off the year with a twist on the feature article. It's a review article on colchicine and cardiovascular disease. But before we get to that, how about we grab a cup of coffee and jump into some of the other articles in the issue? Dr. Carolyn Lam: Absolutely. The new year is starting off with a bonanza issue. This first topic is so important. We know that various non-invasive, intermittent rhythm monitoring strategies have been used to assess arrhythmia recurrences in atrial fibrillation ablation trials. But the question is, what is the frequency and duration of non-invasive rhythm monitoring that accurately detects arrhythmia recurrences and approximates the atrial fibrillation burden derived from continuous monitoring using the gold standard, implantable cardiac monitor? Now to answer this question, investigators Jason Andrade and colleagues from the Montreal Heart Institute, who looked at the rhythm history in 346 patients enrolled in the CIRCA-DOSE trial. They reconstructed the rhythm history using computer simulations and evaluated event-free survivals, sensitivity, negative predictive value, and AF burden in a range of non-invasive monitoring strategies including those used in contemporary AF ablation trials. Dr. Greg Hundley: Ah, very interesting, Carolyn. So what did they find? Dr. Carolyn Lam: Detection of arrhythmia recurrence following ablation was highly sensitive to the monitoring strategy employed between trial discrepancies and outcomes, in fact, may reflect these different monitoring protocols. Binary efficacy outcomes, such as time to AF recurrence, appeared to underestimate the true impact of catheter ablation on the burden of atrial arrhythmia. The most commonly performed intermittent rhythm monitoring techniques, like short duration 24- or 48-hour ambulatory Holter, they do miss a substantial proportion of arrhythmia recurrences and significantly overestimate the true AF burden in patients with recurrences. So based on measures of agreement, serial long-term, that is four seven-day or two 14-day intermittent monitors accumulating at least 28 days of annual monitoring provide estimates of AF burden that are comparable with the implantable cardiac monitor. However, implantable cardiac monitors outperform intermittent monitoring for arrhythmias and should be considered the gold standard for clinical trials. Dr. Greg Hundley: Very nice, Carolyn. It sounds like a lot of clarification on monitoring of AF burden. Well, my first paper comes to us from Dr. Prabhakara Nagareddy from The Ohio State University, The Wexner Medical Center. Carolyn, acute myocardial infarction results in an overzealous production and infiltration of neutrophils in the ischemic heart, and this is mediated in part by granulopoiesis induced by the S100A8/A9 NLRP3, IL-1 beta signaling axis in injury-exposed neutrophils. In this study, Carolyn, the investigators evaluated a hypothesis as to whether IL-1 beta is released locally within the bone marrow by inflammasome prime and reverse migrating neutrophils. Dr. Carolyn Lam: Ah, okay. So what did they find, Greg? Dr. Greg Hundley: Okay, Carolyn. In response to myocardial infarction, the NLRP3 inflammasome prime neutrophils upregulated CXCR4 and reverse migrated to the bone marrow, where they adhered to adhesion molecules like P-selectin on the bone marrow endothelial cells. Second, Carolyn, in the bone marrow, the inflammasome prime neutrophils released IL-1 beta through gasdermin-dependent conduit pores without undergoing the mandatory pyroptosis. Third, genetic and/or pharmacological strategies aimed at limiting reverse migration of inflammasome prime neutrophils to the bone marrow or release of IL-1 beta, both suppressed granulopoiesis and improved cardiac function in mouse models of myocardial infarction. So Carolyn, therefore, strategies aimed at targeting specific signaling pathways within the neutrophils or reducing retention of the inflammasome prime neutrophils in the bone marrow may provide novel avenues to regulate inflammation and improve cardiac outcomes. Dr. Carolyn Lam: Wow, neat, Greg. Thanks for explaining that so nicely. Well, the next paper deals with my favorite topic, heart failure with preserved ejection fraction of HFpEF, and this time looks at mechanisms of sinoatrial node dysfunction. The investigators, led by Dr. Cingolani from Smidt Heart Institute at Cedars-Sinai Medical Center, sought to investigate the role of the intrinsic pacemaker on chronotropic incompetence in HFpEF. They performed extensive sinoatrial node phenotyping, both at baseline and after stress in the well-characterized Dahl salt-sensitive rat model of HFpEF. These rats exhibited limited chronotropic response associated with intrinsic sinoatrial node dysfunction, including impaired beta-adrenergic responsiveness and an alternating leading pacemaker within the sinoatrial node. Prolonged sinoatrial node recovery time and reduced sinoatrial node sensitivity to isoproterenol were confirmed in the two hit mouse model. Adenosine challenge unmasked conduction blocks within the sinoatrial node, which were associated with structural remodeling. Finally, single-cell studies and transcriptomic profiling revealed HFpEF-related alterations in both the membrane clock or iron channels and the calcium clock of the spontaneous calcium release events. Dr. Greg Hundley: Wow, Carolyn, lot of really interesting data here. So what were the clinical implications? Dr. Carolyn Lam: Yeah, it's a really great study. Two models of HFpEF-consistent result in an important topic. Basically, here at the take-home messages. Provocative testing can be valuable to elicit functional abnormalities to facilitate HFpEF diagnosis and considering the exceptionally high clinical and epidemiologic convergence between AFib and HFpEF, sinoatrial node dysfunction may underlie the development of abnormal atrial rhythms in HFpEF. Dr. Greg Hundley: Very nice, Carolyn. More information on HFpEF, again, one of your favorite subjects. Next, we're going to turn to a paper from Dr. Jian Li from the Peking Union Medical College Hospital. Carolyn, doxycycline has previously been demonstrated in a retrospective study to be associated with greater survival in patients with light chain AL amyloidosis. Therefore, Carolyn, this group prospectively compared the efficacy of bortezomib, cyclophosphamide, dexamethasone, or cyclophosphamide B or D, and cyclophosphamide B or D combined with doxycycline for cardiac amyloidosis. Dr. Carolyn Lam: Cool. So what did they find, Greg? Dr. Greg Hundley: Carolyn, this was a multi-center, open-label, randomized controlled trial, and 140 patients underwent randomization. The primary outcome was two-year progression-free survival. Progression-free survival was defined as the time from randomization to death, hematologic progression or organ progression, and that's the heart, the kidney, or the liver. And so Carolyn, these investigators in this trial demonstrated that doxycycline combined with cyclophosphamide B or D failed to prolong progression-free survival or cardiac progression-free survival compared with cyclophosphamide B or D alone in patients with cardiac AL amyloidosis. So Carolyn, a negative study that's quite informative and a very nice editorial that accompanies this article pertaining to future directions for management of AL cardiac amyloid. Dr. Carolyn Lam: Indeed important. Thank you. And there are other important papers in today's issue. There's a Research Letter by Dr. Pfeffer on the impact of sacubitril/valsartan versus ramipril on total heart failure events in the PARADISE-MI trial. Dr. Greg Hundley: Great, Carolyn. In the nail bag, boy, I've got a big list today. First, Dr. Churchwell has an AHA update on the need for policy change to improve maternal cardiovascular health. Next, Dr. Piazza has a Perspective piece on expanding the role of coronary CT angiography in interventional cardiology. There's an ECG challenge from Dr. Yarmohammadi entitled “Dancing Bundles with Stable Sinus Rhythm.” And next, we have our own Darren McGuire who, in this issue for all of 2021, is really recognizing our outstanding reviewers. And we want to thank all the listeners and everyone that reviews for us in this journal. Such an important feature and aspect to the publication of the wonderful articles that we receive. And then finally, there are some highlights from the circulation family of journals. Well, Carolyn, how about we get on to that feature discussion and learn more about colchicine and its use in cardiovascular disease. Dr. Carolyn Lam: Let's go and a Happy New Year, again, everyone. Dr. Greg Hundley: Welcome listeners to this January 4th feature discussion. This week, we're deviating a little bit because we are going to have an author discuss one of our in-depth reviews. As you know, we select those occasionally where they're is a topic that's very relevant in cardiovascular medicine and an investigator or team of investigators or authors will put together a very nice review of a topic. This week, we're going to talk about colchicine, and we have with us Dr. George Dangas from the Icahn School of Medicine at Mount Sinai and our associate editor, Dr. Brendan Everett, who manages this paper and he is from Brigham and Women's Hospital. Welcome, gentlemen. George, we'll start with you. George, why colchicine? Can you tell us a little bit about mechanism of action? Tolerability? Why would we want to use this particular agent in patients with cardiovascular disease? Dr. George Dangas: Thank you very much for the opportunity to join this interesting podcast. Colchicine is indeed an interesting drug. It's been around for centuries, in all honesty. In general, I would say it's a mild anti-inflammatory and in general, it's rather well tolerated. We'll go into those perhaps a little bit later. The precise mechanism is actually interestingly not quite defined. It may have a few ways to act by blocking perhaps the chemotaxis of the leukocytes or the adhesion of the leukocytes or the ability to release their granules, et cetera, but there isn't a specific major one that is targeting. Perhaps, it's targeting more than one mechanism in a mild way, and I think that goes into each utility, as well as the absence of the major side effect that might limit it. Dr. Greg Hundley: Very nice. So you started to mention the word utility, so maybe let's go through some clinical indications, or clinical uses perhaps rather than indications, can you tell us a little bit about its use in individuals with pericarditis? Dr. George Dangas: I think this is where it started to enter the cardiovascular field because we all recognize that pericarditis is an inflammatory disease and inflammation of the pericardium of different reasons perhaps. And anti-inflammatory drug is rather fitted to treat an inflammatory disease and besides, it's not like we had any other drug, in all honesty. Clearly, recurrent pericarditis might be treated with steroids for example, but steroids is not something any cardiologist would jump as a first line and give high doses and all that. Colchicine made its way to pericarditis like acute or recurrent pericarditis, post-cardiac cardiology syndrome, restless syndrome or the specific post-cardiac surgery, major inflammation. And indeed has a daily dosage perhaps with some loading dose or double the daily dosage or something initially and then we give it for a prolonged period of time in order to suppress. I would say this is a reasonable choice rather than jumping to the steroid. And of course, you reserve the steroid for the, I would say, more severe or more recurrent cases. I think everybody understands this type of activity. There've been quite a few clinical studies in this aspect. Again, in the absence of a competitor, I think it's a winner in this area. Dr. Greg Hundley: Very nice. And then, how about atrial fibrillation? Are there uses of this colchicine in patients with atrial fibrillation? Dr. George Dangas: Well, again, it's very interesting that a lot of atrial fibrillation, it may be in some ways inflammatory in origin. And quite frankly, we had an interesting [inaudible 00:14:50] clinical trial in American Heart Association in 2021. I'd like to point out here, the study that postoperative atrial fibrillation was mitigated when, during cardiac surgery, there was a slicing of the posterior pericardial. This allowing the inflammation in some ways that's related there. To me, that was a very interesting observation, though I related to colchicine because it validates the fact that there is something inflammatory in pericardial that related with the postoperative atrial fibrillation. So along these lines, let's go back to colchicine, Afib, and postop Afib, and post-ablation I would say patients. Again, there are risks of some inflammation and that's where the theory of a mild, rather well-tolerated, anti-inflammatory might come in. And there's been few studies, not a large definitive study, but several studies that are the, I would say, component with interesting results with colchicine in these patients. Dr. Greg Hundley: Very good. Another area of cardiovascular disease that's emerging literally with some demonstrable results using colchicine is the realm of ischemic heart disease. Can you walk us through some of the utility myocardial infarction or maybe even post-percutaneous coronary artery intervention? Dr. George Dangas: Again, the hallmark in this type of diseases, cardiovascular disease or coronary heart disease, is the hallmark of role of inflammation in this disease. And we know very well from the studies of the C-reactive protein, importance is a marker of inflammation. Very, very important in the CAD as well as in even the treatment with the antibody canakinumab a little bit earlier in the CANTOS trial a few years earlier at the very high level inhibited inflammation had a benefit and colchicine comes in maybe a milder anti-inflammatory about this agent, but at the same time with significantly less cause and significantly better recognition among the clinicians and a lot less, I would say, tolerability problems or issues are less unknowns. And I think that's where it comes in. The difficulty has been that whenever you go to cardiovascular, the cardiovascular, I would say coronary artery disease specifically, ACS and all that, the level evidence required for the doctors to believe in a therapy is very different than the areas we discussed before where there's little bit of a pericardial disease, for example, not that many drugs, all of a sudden, coronary artery disease, the bar is so high, and that's where the difficulty has been. There've been several studies. They've been interesting results with some benefits, particularly due to the decrease in inflammation and the secondary prevention, one can say. That is really the hallmark of where it aims to benefit in the secondary prevention, but there hasn't been one massive study with clearly superb results. I would say adequately powered single study that is missing in some ways. But several studies have been, again, very, very encouraging, but we learned that there's no much point if loading a lot of doses of high doses of colchicine, and it's a little bit better, again, when you aim with a daily dose towards reduced recurrences, particularly if you started early after an acute event. Dr. Greg Hundley: Very nice. Well, listeners, we're going to now turn to our associate editor, Dr. Brendan Everett, from Brigham and Women's Hospital. Brendan, you have a lot of papers come across your desk. First and foremost, what attracted you to this particular article? Dr. Brendan Everett: Well, thanks, Greg. And kudos to George and his team for putting together a really nice paper. It's great to have this kind of paper come into my inbox. That's specifically because colchicine, I think, has exploded as a really important novel therapy even though the therapy itself is perhaps hundreds of years old, as you heard George say a moment ago, but its role in treating cardiovascular diseases has really begun to emerge rapidly. I think there's a tremendous amount of enthusiasm for other ways to treat our patients who have really a recalcitrant cardiovascular disease, whether that's pericarditis, atrial fibrillation or I think, importantly, ischemic heart disease, because that's such a common disease and something where we're always looking for new ways to help patients live longer with fewer recurrent events. And so this paper I thought did a really good job of capturing the existing evidence for these conditions and some others and giving us a sense of where the strengths of that evidence lay and where the weaknesses were. I thought particular strength was in the tables where the authors laid out each of the trials and the results of the trial, their endpoints, where the benefit was potentially. And also importantly, where risks were seen because I think that's one of the really important questions that remains open with respect to colchicine therapy when we begin to talk about using it in a vast population of people with stable ischemic heart disease or post-myocardial infarction ischemic heart disease. Dr. Greg Hundley: Brendan, tell us a little bit about those risks. Dr. Brendan Everett: I'd be happy to do that. I want to emphasize before I dive in that I think the benefits that George has laid out are important, and I don't want to overshadow what the major trials have seen. But I think the thing that it is at least a little bit of the fly in the ointment, if you will, for colchicine in ischemic heart disease is that a couple of the large trials have shown an increased risk of non cardiovascular mortality or bad non-cardiovascular outcomes. And that's of concern, I think, as we saw in the CANTOS trial, which was the monoclonal antibody trial for canakinumab that George mentioned earlier, there was an increase in infection-related mortality. And so whenever you use an anti-inflammatory drug, you're worried about whether or not you're blunting other compensatory mechanisms that the body has to protect against infection and other diseases. I think it's likely that these findings are the play of chance, but we don't know for sure. For example, in the COLCOT trial, which I think is probably the largest and most interesting trial, which was designed and run in Canada, there was a slightly higher level of pneumonia in patients who got active therapy as compared to placebo. And then, two of the trials that were published more recently including LoDoCo2, which was a trial of about 5,000 patients run in the Netherlands and Australia. There was actually a marginally increased risk of non-cardiovascular mortality. That didn't reach statistical significance, but it was awfully close, and I think it gave people some concern. And then, there was also the COPS trial. Again, all these are really outlined in wonderful detail in the manuscript where there was a slight increase of total death and non-cardiovascular death. These events are few, but they're in a direction in two trials, and so they make people a little bit worried. I think the other thing that I noticed was the high prevalence of myalgia as a side effect. I think, Greg, you're always interested in the clinical implications and yesterday I was in clinic and saw a young patient who had had pericarditis. He had been prescribed colchicine by his primary care physician, and he literally couldn't stand and walk up straight because of the amount of abdominal pain he had, which was unusual. To be honest, I've given colchicine to a hundred patients at least, and none of them have had that profound of a side effect, but it's at least worth considering that some patients will not tolerate the therapy because of adverse effects. Dr. Greg Hundley: Very good. Well, in just 30 seconds or so, for each of you, first George and then Brendan. George, balancing some of the efficacy and then some of the concerns, what do you see is the next studies to be performed really in this sphere of research? Dr. George Dangas: This is a great question. And indeed, the concerns one can say or the issues, I would say, regarding this drug, are indeed real because any drug that suppresses inflammation has this risk. There are two ways one can address those. One is with term administration. You don't prescribe it as an annuity forever, but you prescribe it in a three- to six-month or one-month or try to control the time. I think this is done in clinical practice, in all honesty. I don't think that people are prescribing colchicine for life. Same way when we prescribe statins, for example. On the other hand or from investigational point of view, I think the two sets of information we need and, in all honesty, when you investigate issues regarding mortality or these are rare events, there's only one. You need a very large trial or a very large register. A very large trial preferably and colchicine being an often genetic drug, funding sources are rather limited, but we have NIH chipping in with some funding periodically and that might really be needed. So I want to outline that in the last table of our very large, I would say large table of our manuscript but were very happily outlined many ongoing trials. There are, in atrial fibrillation, three coronary artery disease. One in PCI and two in stroke. Something we didn't touch up again. But again, there's the question of inflammation in stroke. I think there's a lot of work ongoing. Perhaps you can see some meta-analysis, again, in order to get a handle of those risks, but at a rather low rate. It's just a difficult thing to come around. Dr. Greg Hundley: Very good. Brendan, anything to add? Dr. Brendan Everett: I would just add I agree a hundred percent with George just said. I think the only missing piece there is heart failure, which I think is and many have shown that there's an inflammatory component to heart failure, whether it's heart failure with reduced ejection fraction or preserved ejection fraction. And the timing of when that intervention might be, whether it might be before the development of symptoms or because there's a lot of trials out there that have struggled with this question and have unfortunately failed to show any benefit, I would just encourage the listeners of the podcast to look at this paper because it's a really marvelous compilation of the evidence for what is a really hot topic in cardiovascular medicine, a really important topic for a lot of the reasons that George mentioned. It's just very well done and comprehensive. Again, kudos to the authors for making such a great effort at putting something together that has a lot of clinical relevance, I think, and also points the way forward for research as you ask, Greg. Dr. Greg Hundley: Very nice. Well, listeners, we want to thank Dr. George Dangas from Icahn School of Medicine in Mount Sinai and our own associate editor, Dr. Brendan Everett from Brigham and Women's Hospital for bringing us this data pertaining to colchicine benefits, as we know in acute and recurrent pericarditis, but also emerging indications related to post-procedural atrial fibrillation or coronary artery disease. And really, colchicine's targeting of cardiovascular inflammation is being helpful in those alleviating those processes. Well, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week on the run. Dr. Greg Hundley: This program, this 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.

CWRW #197 Dr David Martin Presents

Play Episode Listen Later Nov 16, 2021 78:58

This is the Morning Show that Makes you Hate All Morning Shows. Don't forget to follow https://twitter.com/https://linktr.ee/Theralphwilliam If you want a place to voice your opinions to all platforms sign up to podbean with this affiliate link https://www.podbean.com/GetCoffee Link for business hosting https://www.podbean.com/pro/GetCoffee Get some Merchandise TearzESC Shop | Redbubble Join us on Twitch! theralphwilliampodcast - Get 10% off when you use promo code RW at checkout Fromthedoctors.com Download our internet radio station in your App Store W-ESN Epic Strategies Network Epicstrategiesnetwork.com Rumble https://rumble.com/vh7g39-doggy-handling-competition.html If you are interested being apart of the discord server shoot us a DM on the social media's and joint the crew! Please Read the Rules: By calling in the show you are aware that the show will be published and that you are responsible for your own words and comments. Your opinions and commments does not reflect the views of the show. Say hello and acknowledge those in the chat when entering. Mute yourself when not talking or I will Mute You. Allow others to speak before speaking. Not a requirement but would appreciate it if you would SHARE the show Hello, My name is Spartacus, and I've had enough. We have been forced to watch America and the Free World spin into inexorable decline due to a biowarfare attack. We, along with countless others, have been victimized and gaslit by propaganda and psychological warfare operations being conducted by an unelected, unaccountable Elite against the American people and our allies. Our mental and physical health have suffered immensely over the course of the past year and a half. We have felt the sting of isolation, lockdown, masking, quarantines, and other completely nonsensical acts of healthcare theater that have done absolutely nothing to protect the health or wellbeing of the public from the ongoing COVID-19 pandemic. Now, we are watching the medical establishment inject literal poison into millions of our fellow Americans without so much as a fight. We have been told that we will be fired and denied our livelihoods if we refuse to vaccinate. This was the last straw. We have spent thousands of hours analyzing leaked footage from Wuhan, scientific papers from primary sources, as well as the paper trails left by the medical establishment. What we have discovered would shock anyone to their core. First, we will summarize our findings, and then, we will explain them in detail. References will be placed at the end. Summary: COVID-19 is a blood and blood vessel disease. SARS-CoV-2 infects the lining of human blood vessels, causing them to leak into the lungs. Current treatment protocols (e.g. invasive ventilation) are actively harmful to patients, accelerating oxidative stress and causing severe VILI (ventilator-induced lung injuries). The continued use of ventilators in the absence of any proven medical benefit constitutes mass murder. Existing countermeasures are inadequate to slow the spread of what is an aerosolized and potentially wastewater-borne virus, and constitute a form of medical theater. Various non-vaccine interventions have been suppressed by both the media and the medical establishment in favor of vaccines and expensive patented drugs. The authorities have denied the usefulness of natural immunity against COVID-19, despite the fact that natural immunity confers protection against all of the virus's proteins, and not just one. Vaccines will do more harm than good. The antigen that these vaccines are based on, SARS-CoV- 2 Spike, is a toxic protein. SARS-CoV-2 may have ADE, or antibody-dependent enhancement; current antibodies may not neutralize future strains, but instead help them infect immune cells. Also, vaccinating during a pandemic with a leaky vaccine removes the evolutionary pressure for a virus to become less lethal. There is a vast and appalling criminal conspiracy that directly links both Anthony Fauci and Moderna to the Wuhan Institute of Virology. COVID-19 vaccine researchers are directly linked to scientists involved in brain-computer interface (“neural lace”) tech, one of whom was indicted for taking grant money from China. Independent researchers have discovered mysterious nanoparticles inside the vaccines that are not supposed to be present. The entire pandemic is being used as an excuse for a vast political and economic transformation of Western society that will enrich the already rich and turn the rest of us into serfs and untouchables. COVID-19 Pathophysiology and Treatments: COVID-19 is not a viral pneumonia. It is a viral vascular endotheliitis and attacks the lining of blood vessels, particularly the small pulmonary alveolar capillaries, leading to endothelial cell activation and sloughing, coagulopathy, sepsis, pulmonary edema, and ARDS-like symptoms. This is a disease of the blood and blood vessels. The circulatory system. Any pneumonia that it causes is secondary to that. In severe cases, this leads to sepsis, blood clots, and multiple organ failure, including hypoxic and inflammatory damage to various vital organs, such as the brain, heart, liver, pancreas, kidneys, and intestines. Some of the most common laboratory findings in COVID-19 are elevated D-dimer, elevated prothrombin time, elevated C-reactive protein, neutrophilia, lymphopenia, hypocalcemia, and hyperferritinemia, essentially matching a profile of coagulopathy and immune system hyperactivation/immune cell exhaustion. COVID-19 can present as almost anything, due to the wide tropism of SARS-CoV-2 for various tissues in the body's vital organs. While its most common initial presentation is respiratory illness and flu-like symptoms, it can present as brain inflammation, gastrointestinal disease, or even heart attack or pulmonary embolism. COVID-19 is more severe in those with specific comorbidities, such as obesity, diabetes, and hypertension. This is because these conditions involve endothelial dysfunction, which renders the circulatory system more susceptible to infection and injury by this particular virus. The vast majority of COVID-19 cases are mild and do not cause significant disease. In known cases, there is something known as the 80/20 rule, where 80% of cases are mild and 20% are severe or critical. However, this ratio is only correct for known cases, not all infections. The number of actual infections is much, much higher. Consequently, the mortality and morbidity rate is lower. However, COVID-19 spreads very quickly, meaning that there are a significant number of severely-ill and critically-ill patients appearing in a short time frame. In those who have critical COVID-19-induced sepsis, hypoxia, coagulopathy, and ARDS, the most common treatments are intubation, injected corticosteroids, and blood thinners. This is not the correct treatment for COVID-19. In severe hypoxia, cellular metabolic shifts cause ATP to break down into hypoxanthine, which, upon the reintroduction of oxygen, causes xanthine oxidase to produce tons of highly damaging radicals that attack tissue. This is called ischemia-reperfusion injury, and it's why the majority of people who go on a ventilator are dying. In the mitochondria, succinate buildup due to sepsis does the same exact thing; when oxygen is reintroduced, it makes superoxide radicals. Make no mistake, intubation will kill people who have COVID-19. The end-stage of COVID-19 is severe lipid peroxidation, where fats in the body start to “rust” due to damage by oxidative stress. This drives autoimmunity. Oxidized lipids appear as foreign objects to the immune system, which recognizes and forms antibodies against OSEs, or oxidation-specific epitopes. Also, oxidized lipids feed directly into pattern recognition receptors, triggering even more inflammation and summoning even more cells of the innate immune system that release even more destructive enzymes. This is similar to the pathophysiology of Lupus. COVID-19's pathology is dominated by extreme oxidative stress and neutrophil respiratory burst, to the point where hemoglobin becomes incapable of carrying oxygen due to heme iron being stripped out of heme by hypochlorous acid. No amount of supplemental oxygen can oxygenate blood that chemically refuses to bind O2. The breakdown of the pathology is as follows: SARS-CoV-2 Spike binds to ACE2. Angiotensin Converting Enzyme 2 is an enzyme that is part of the renin-angiotensin-aldosterone system, or RAAS. The RAAS is a hormone control system that moderates fluid volume in the body and in the bloodstream (i.e. osmolarity) by controlling salt retention and excretion. This protein, ACE2, is ubiquitous in every part of the body that interfaces with the circulatory system, particularly in vascular endothelial cells and pericytes, brain astrocytes, renal tubules and podocytes, pancreatic islet cells, bile duct and intestinal epithelial cells, and the seminiferous ducts of the testis, all of which SARS-CoV-2 can infect, not just the lungs. SARS-CoV-2 infects a cell as follows: SARS-CoV-2 Spike undergoes a conformational change where the S1 trimers flip up and extend, locking onto ACE2 bound to the surface of a cell. TMPRSS2, or transmembrane protease serine 2, comes along and cuts off the heads of the Spike, exposing the S2 stalk-shaped subunit inside. The remainder of the Spike undergoes a conformational change that causes it to unfold like an extension ladder, embedding itself in the cell membrane. Then, it folds back upon itself, pulling the viral membrane and the cell membrane together. The two membranes fuse, with the virus's proteins migrating out onto the surface of the cell. The SARS-CoV-2 nucleocapsid enters the cell, disgorging its genetic material and beginning the viral replication process, hijacking the cell's own structures to produce more virus. SARS-CoV-2 Spike proteins embedded in a cell can actually cause human cells to fuse together, forming syncytia/MGCs (multinuclear giant cells). They also have other pathogenic, harmful effects. SARS-CoV- 2's viroporins, such as its Envelope protein, act as calcium ion channels, introducing calcium into infected cells. The virus suppresses the natural interferon response, resulting in delayed inflammation. SARS-CoV-2 N protein can also directly activate the NLRP3 inflammasome. Also, it suppresses the Nrf2 antioxidant pathway. The suppression of ACE2 by binding with Spike causes a buildup of bradykinin that would otherwise be broken down by ACE2. This constant calcium influx into the cells results in (or is accompanied by) noticeable hypocalcemia, or low blood calcium, especially in people with Vitamin D deficiencies and pre-existing endothelial dysfunction. Bradykinin upregulates cAMP, cGMP, COX, and Phospholipase C activity. This results in prostaglandin release and vastly increased intracellular calcium signaling, which promotes highly aggressive ROS release and ATP depletion. NADPH oxidase releases superoxide into the extracellular space. Superoxide radicals react with nitric oxide to form peroxynitrite. Peroxynitrite reacts with the tetrahydrobiopterin cofactor needed by endothelial nitric oxide synthase, destroying it and “uncoupling” the enzymes, causing nitric oxide synthase to synthesize more superoxide instead. This proceeds in a positive feedback loop until nitric oxide bioavailability in the circulatory system is depleted. Dissolved nitric oxide gas produced constantly by eNOS serves many important functions, but it is also antiviral against SARS-like coronaviruses, preventing the palmitoylation of the viral Spike protein and making it harder for it to bind to host receptors. The loss of NO allows the virus to begin replicating with impunity in the body. Those with endothelial dysfunction (i.e. hypertension, diabetes, obesity, old age, African-American race) have redox equilibrium issues to begin with, giving the virus an advantage. Due to the extreme cytokine release triggered by these processes, the body summons a great deal of neutrophils and monocyte-derived alveolar macrophages to the lungs. Cells of the innate immune system are the first-line defenders against pathogens. They work by engulfing invaders and trying to attack them with enzymes that produce powerful oxidants, like SOD and MPO. Superoxide dismutase takes superoxide and makes hydrogen peroxide, and myeloperoxidase takes hydrogen peroxide and chlorine ions and makes hypochlorous acid, which is many, many times more reactive than sodium hypochlorite bleach. Cytokine Storm Compilation: Covid-19 Vaccine Side Effects Neutrophils have a nasty trick. They can also eject these enzymes into the extracellular space, where they will continuously spit out peroxide and bleach into the bloodstream. This is called neutrophil extracellular trap formation, or, when it becomes pathogenic and counterproductive, NETosis. In severe and critical COVID-19, there is actually rather severe NETosis. Hypochlorous acid building up in the bloodstream begins to bleach the iron out of heme and compete for O2 binding sites. Red blood cells lose the ability to transport oxygen, causing the sufferer to turn blue in the face. Unliganded iron, hydrogen peroxide, and superoxide in the bloodstream undergo the Haber- Weiss and Fenton reactions, producing extremely reactive hydroxyl radicals that violently strip electrons from surrounding fats and DNA, oxidizing them severely. This condition is not unknown to medical science. The actual name for all of this is acute sepsis. We know this is happening in COVID-19 because people who have died of the disease have noticeable ferroptosis signatures in their tissues, as well as various other oxidative stress markers such as nitrotyrosine, 4-HNE, and malondialdehyde. When you intubate someone with this condition, you are setting off a free radical bomb by supplying the cells with O2. It's a catch-22, because we need oxygen to make Adenosine Triphosphate (that is, to live), but O2 is also the precursor of all these damaging radicals that lead to lipid peroxidation. The correct treatment for severe COVID-19 related sepsis is non-invasive ventilation, steroids, and antioxidant infusions. Most of the drugs repurposed for COVID-19 that show any benefit whatsoever in rescuing critically-ill COVID-19 patients are antioxidants. N-acetylcysteine, melatonin, fluvoxamine, budesonide, famotidine, cimetidine, and ranitidine are all antioxidants. Indomethacin prevents iron- driven oxidation of arachidonic acid to isoprostanes. There are powerful antioxidants such as apocynin that have not even been tested on COVID-19 patients yet which could defang neutrophils, prevent lipid peroxidation, restore endothelial health, and restore oxygenation to the tissues. Scientists who know anything about pulmonary neutrophilia, ARDS, and redox biology have known or surmised much of this since March 2020. In April 2020, Swiss scientists confirmed that COVID-19 was a vascular endotheliitis. By late 2020, experts had already concluded that COVID-19 causes a form of viral sepsis. They also know that sepsis can be effectively treated with antioxidants. None of this information is particularly new, and yet, for the most part, it has not been acted upon. Doctors continue to use damaging intubation techniques with high PEEP settings despite high lung compliance and poor oxygenation, killing an untold number of critically ill patients with medical malpractice. Because of the way they are constructed, Randomized Control Trials will never show any benefit for any antiviral against COVID-19. Not Remdesivir, not Kaletra, not HCQ, and not Ivermectin. The reason for this is simple; for the patients that they have recruited for these studies, such as Oxford's ludicrous RECOVERY study, the intervention is too late to have any positive effect. The clinical course of COVID-19 is such that by the time most people seek medical attention for hypoxia, their viral load has already tapered off to almost nothing. If someone is about 10 days post-exposure and has already been symptomatic for five days, there is hardly any virus left in their bodies, only cellular damage and derangement that has initiated a hyperinflammatory response. It is from this group that the clinical trials for antivirals have recruited, pretty much exclusively. In these trials, they give antivirals to severely ill patients who have no virus in their bodies, only a delayed hyperinflammatory response, and then absurdly claim that antivirals have no utility in treating or preventing COVID-19. These clinical trials do not recruit people who are pre-symptomatic. They do not test pre-exposure or post-exposure prophylaxis. This is like using a defibrillator to shock only flatline, and then absurdly claiming that defibrillators have no medical utility whatsoever when the patients refuse to rise from the dead. The intervention is too late. These trials for antivirals show systematic, egregious selection bias. They are providing a treatment that is futile to the specific cohort they are enrolling. India went against the instructions of the WHO and mandated the prophylactic usage of Ivermectin. They have almost completely eradicated COVID-19. The Indian Bar Association of Mumbai has brought criminal charges against WHO Chief Scientist Dr. Soumya Swaminathan for recommending against the use of Ivermectin. Ivermectin is not “horse dewormer”. Yes, it is sold in veterinary paste form as a dewormer for animals. It has also been available in pill form for humans for decades, as an antiparasitic drug. The media have disingenuously claimed that because Ivermectin is an antiparasitic drug, it has no utility as an antivirus. This is incorrect. Ivermectin has utility as an antiviral. It blocks importin, preventing nuclear import, effectively inhibiting viral access to cell nuclei. Many drugs currently on the market have multiple modes of action. Ivermectin is one such drug. It is both antiparasitic and antiviral. In Bangladesh, Ivermectin costs $1.80 for an entire 5-day course. Remdesivir, which is toxic to the liver, costs $3,120 for a 5-day course of the drug. Billions of dollars of utterly useless Remdesivir were sold to our governments on the taxpayer's dime, and it ended up being totally useless for treating hyperinflammatory COVID-19. The media has hardly even covered this at all. The opposition to the use of generic Ivermectin is not based in science. It is purely financially and politically-motivated. An effective non-vaccine intervention would jeopardize the rushed FDA approval of patented vaccines and medicines for which the pharmaceutical industry stands to rake in billions upon billions of dollars in sales on an ongoing basis. The majority of the public are scientifically illiterate and cannot grasp what any of this even means, thanks to a pathetic educational system that has miseducated them. You would be lucky to find 1 in 100 people who have even the faintest clue what any of this actually means. COVID-19 Transmission: COVID-19 is airborne. The WHO carried water for China by claiming that the virus was only droplet- borne. Our own CDC absurdly claimed that it was mostly transmitted by fomite-to-face contact, which, given its rapid spread from Wuhan to the rest of the world, would have been physically impossible. The ridiculous belief in fomite-to-face being a primary mode of transmission led to the use of surface disinfection protocols that wasted time, energy, productivity, and disinfectant. The 6-foot guidelines are absolutely useless. The minimum safe distance to protect oneself from an aerosolized virus is to be 15+ feet away from an infected person, no closer. Realistically, no public transit is safe. Surgical masks do not protect you from aerosols. The virus is too small and the filter media has too large of gaps to filter it out. They may catch respiratory droplets and keep the virus from being expelled by someone who is sick, but they do not filter a cloud of infectious aerosols if someone were to walk into said cloud. The minimum level of protection against this virus is quite literally a P100 respirator, a PAPR/CAPR, or a 40mm NATO CBRN respirator, ideally paired with a full-body tyvek or tychem suit, gloves, and booties, with all the holes and gaps taped. Live SARS-CoV-2 may potentially be detected in sewage outflows, and there may be oral-fecal transmission. During the SARS outbreak in 2003, in the Amoy Gardens incident, hundreds of people were infected by aerosolized fecal matter rising from floor drains in their apartments. COVID-19 Vaccine Dangers: The vaccines for COVID-19 are not sterilizing and do not prevent infection or transmission. They are “leaky” vaccines. This means they remove the evolutionary pressure on the virus to become less lethal. It also means that the vaccinated are perfect carriers. In other words, those who are vaccinated are a threat to the unvaccinated, not the other way around. All of the COVID-19 vaccines currently in use have undergone minimal testing, with highly accelerated clinical trials. Though they appear to limit severe illness, the long-term safety profile of these vaccines remains unknown. Some of these so-called “vaccines” utilize an untested new technology that has never been used in vaccines before. Traditional vaccines use weakened or killed virus to stimulate an immune response. The Moderna and Pfizer-BioNTech vaccines do not. They are purported to consist of an intramuscular shot containing a suspension of lipid nanoparticles filled with messenger RNA. The way they generate an immune response is by fusing with cells in a vaccine recipient's shoulder, undergoing endocytosis, releasing their mRNA cargo into those cells, and then utilizing the ribosomes in those cells to synthesize modified SARS-CoV-2 Spike proteins in-situ. These modified Spike proteins then migrate to the surface of the cell, where they are anchored in place by a transmembrane domain. The adaptive immune system detects the non-human viral protein being expressed by these cells, and then forms antibodies against that protein. This is purported to confer protection against the virus, by training the adaptive immune system to recognize and produce antibodies against the Spike on the actual virus. The J&J and AstraZeneca vaccines do something similar, but use an adenovirus vector for genetic material delivery instead of a lipid nanoparticle. These vaccines were produced or validated with the aid of fetal cell lines HEK-293 and PER.C6, which people with certain religious convictions may object strongly to. SARS-CoV-2 Spike is a highly pathogenic protein on its own. It is impossible to overstate the danger presented by introducing this protein into the human body. It is claimed by vaccine manufacturers that the vaccine remains in cells in the shoulder, and that SARS- CoV-2 Spike produced and expressed by these cells from the vaccine's genetic material is harmless and inert, thanks to the insertion of prolines in the Spike sequence to stabilize it in the prefusion conformation, preventing the Spike from becoming active and fusing with other cells. However, a pharmacokinetic study from Japan showed that the lipid nanoparticles and mRNA from the Pfizer vaccine did not stay in the shoulder, and in fact bioaccumulated in many different organs, including the reproductive organs and adrenal glands, meaning that modified Spike is being expressed quite literally all over the place. These lipid nanoparticles may trigger anaphylaxis in an unlucky few, but far more concerning is the unregulated expression of Spike in various somatic cell lines far from the injection site and the unknown consequences of that. Messenger RNA is normally consumed right after it is produced in the body, being translated into a protein by a ribosome. COVID-19 vaccine mRNA is produced outside the body, long before a ribosome translates it. In the meantime, it could accumulate damage if inadequately preserved. When a ribosome attempts to translate a damaged strand of mRNA, it can become stalled. When this happens, the ribosome becomes useless for translating proteins because it now has a piece of mRNA stuck in it, like a lace card in an old punch card reader. The whole thing has to be cleaned up and new ribosomes synthesized to replace it. In cells with low ribosome turnover, like nerve cells, this can lead to reduced protein synthesis, cytopathic effects, and neuropathies. Certain proteins, including SARS-CoV-2 Spike, have proteolytic cleavage sites that are basically like little dotted lines that say “cut here”, which attract a living organism's own proteases (essentially, molecular scissors) to cut them. There is a possibility that S1 may be proteolytically cleaved from S2, causing active S1 to float away into the bloodstream while leaving the S2 “stalk” embedded in the membrane of the cell that expressed the protein. SARS-CoV-2 Spike has a Superantigenic region (SAg), which may promote extreme inflammation. Anti-Spike antibodies were found in one study to function as autoantibodies and attack the body's own cells. Those who have been immunized with COVID-19 vaccines have developed blood clots, myocarditis, Guillain-Barre Syndrome, Bell's Palsy, and multiple sclerosis flares, indicating that the vaccine promotes autoimmune reactions against healthy tissue. SARS-CoV-2 Spike does not only bind to ACE2. It was suspected to have regions that bind to basigin, integrins, neuropilin-1, and bacterial lipopolysaccharides as well. SARS-CoV-2 Spike, on its own, can potentially bind any of these things and act as a ligand for them, triggering unspecified and likely highly inflammatory cellular activity. SARS-CoV-2 Spike contains an unusual PRRA insert that forms a furin cleavage site. Furin is a ubiquitous human protease, making this an ideal property for the Spike to have, giving it a high degree of cell tropism. No wild-type SARS-like coronaviruses related to SARS-CoV-2 possess this feature, making it highly suspicious, and perhaps a sign of human tampering. SARS-CoV-2 Spike has a prion-like domain that enhances its infectiousness. The Spike S1 RBD may bind to heparin-binding proteins and promote amyloid aggregation. In humans, this could lead to Parkinson's, Lewy Body Dementia, premature Alzheimer's, or various other neurodegenerative diseases. This is very concerning because SARS-CoV-2 S1 is capable of injuring and penetrating the blood-brain barrier and entering the brain. It is also capable of increasing the permeability of the blood-brain barrier to other molecules. SARS-CoV-2, like other betacoronaviruses, may have Dengue-like ADE, or antibody-dependent enhancement of disease. For those who aren't aware, some viruses, including betacoronaviruses, have a feature called ADE. There is also something called Original Antigenic Sin, which is the observation that the body prefers to produce antibodies based on previously-encountered strains of a virus over newly- encountered ones. In ADE, antibodies from a previous infection become non-neutralizing due to mutations in the virus's proteins. These non-neutralizing antibodies then act as trojan horses, allowing live, active virus to be pulled into macrophages through their Fc receptor pathways, allowing the virus to infect immune cells that it would not have been able to infect before. This has been known to happen with Dengue Fever; when someone gets sick with Dengue, recovers, and then contracts a different strain, they can get very, very ill. If someone is vaccinated with mRNA based on the Spike from the initial Wuhan strain of SARS-CoV-2, and then they become infected with a future, mutated strain of the virus, they may become severely ill. In other words, it is possible for vaccines to sensitize someone to disease. There is a precedent for this in recent history. Sanofi's Dengvaxia vaccine for Dengue failed because it caused immune sensitization in people whose immune systems were Dengue-naive. In mice immunized against SARS-CoV and challenged with the virus, a close relative of SARS-CoV-2, they developed immune sensitization, Th2 immunopathology, and eosinophil infiltration in their lungs. We have been told that SARS-CoV-2 mRNA vaccines cannot be integrated into the human genome, because messenger RNA cannot be turned back into DNA. This is false. There are elements in human cells called LINE-1 retrotransposons, which can indeed integrate mRNA into a human genome by endogenous reverse transcription. Because the mRNA used in the vaccines is stabilized, it hangs around in cells longer, increasing the chances for this to happen. If the gene for SARS-CoV-2 Spike is integrated into a portion of the genome that is not silent and actually expresses a protein, it is possible that people who take this vaccine may continuously express SARS-CoV-2 Spike from their somatic cells for the rest of their lives. By inoculating people with a vaccine that causes their bodies to produce Spike in-situ, they are being inoculated with a pathogenic protein. A toxin that may cause long-term inflammation, heart problems, and a raised risk of cancers. In the long-term, it may also potentially lead to premature neurodegenerative disease. Absolutely nobody should be compelled to take this vaccine under any circumstances, and in actual fact, the vaccination campaign must be stopped immediately. COVID-19 Criminal Conspiracy: The vaccine and the virus were made by the same people. In 2014, there was a moratorium on SARS gain-of-function research that lasted until 2017. This research was not halted. Instead, it was outsourced, with the federal grants being laundered through NGOs. Ralph Baric is a virologist and SARS expert at UNC Chapel Hill in North Carolina. This is who Anthony Fauci was referring to when he insisted, before Congress, that if any gain-of-function research was being conducted, it was being conducted in North Carolina. This was a lie. Anthony Fauci lied before Congress. A felony. Ralph Baric and Shi Zhengli are colleagues and have co-written papers together. Ralph Baric mentored Shi Zhengli in his gain-of-function manipulation techniques, particularly serial passage, which results in a virus that appears as if it originated naturally. In other words, deniable bioweapons. Serial passage in humanized hACE2 mice may have produced something like SARS-CoV-2. The funding for the gain-of-function research being conducted at the Wuhan Institute of Virology came from Peter Daszak. Peter Daszak runs an NGO called EcoHealth Alliance. EcoHealth Alliance received millions of dollars in grant money from the National Institutes of Health/National Institute of Allergy and Infectious Diseases (that is, Anthony Fauci), the Defense Threat Reduction Agency (part of the US Department of Defense), and the United States Agency for International Development. NIH/NIAID contributed a few million dollars, and DTRA and USAID each contributed tens of millions of dollars towards this research. Altogether, it was over a hundred million dollars. EcoHealth Alliance subcontracted these grants to the Wuhan Institute of Virology, a lab in China with a very questionable safety record and poorly trained staff, so that they could conduct gain-of-function research, not in their fancy P4 lab, but in a level-2 lab where technicians wore nothing more sophisticated than perhaps a hairnet, latex gloves, and a surgical mask, instead of the bubble suits used when working with dangerous viruses. Chinese scientists in Wuhan reported being routinely bitten and urinated on by laboratory animals. Why anyone would outsource this dangerous and delicate work to the People's Republic of China, a country infamous for industrial accidents and massive explosions that have claimed hundreds of lives, is completely beyond me, unless the aim was to start a pandemic on purpose. In November of 2019, three technicians at the Wuhan Institute of Virology developed symptoms consistent with a flu-like illness. Anthony Fauci, Peter Daszak, and Ralph Baric knew at once what had happened, because back channels exist between this laboratory and our scientists and officials. December 12th, 2019, Ralph Baric signed a Material Transfer Agreement (essentially, an NDA) to receive Coronavirus mRNA vaccine-related materials co-owned by Moderna and NIH. It wasn't until a whole month later, on January 11th, 2020, that China allegedly sent us the sequence to what would become known as SARS-CoV-2. Moderna claims, rather absurdly, that they developed a working vaccine from this sequence in under 48 hours. Stephane Bancel, the current CEO of Moderna, was formerly the CEO of bioMerieux, a French multinational corporation specializing in medical diagnostic tech, founded by one Alain Merieux. Alain Merieux was one of the individuals who was instrumental in the construction of the Wuhan Institute of Virology's P4 lab. The sequence given as the closest relative to SARS-CoV-2, RaTG13, is not a real virus. It is a forgery. It was made by entering a gene sequence by hand into a database, to create a cover story for the existence of SARS-CoV-2, which is very likely a gain-of-function chimera produced at the Wuhan Institute of Virology and was either leaked by accident or intentionally released. The animal reservoir of SARS-CoV-2 has never been found. This is not a conspiracy “theory”. It is an actual criminal conspiracy, in which people connected to the development of Moderna's mRNA-1273 are directly connected to the Wuhan Institute of Virology and their gain-of-function research by very few degrees of separation, if any. The paper trail is well- established. The lab-leak theory has been suppressed because pulling that thread leads one to inevitably conclude that there is enough circumstantial evidence to link Moderna, the NIH, the WIV, and both the vaccine and the virus's creation together. In a sane country, this would have immediately led to the world's biggest RICO and mass murder case. Anthony Fauci, Peter Daszak, Ralph Baric, Shi Zhengli, and Stephane Bancel, and their accomplices, would have been indicted and prosecuted to the fullest extent of the law. Instead, billions of our tax dollars were awarded to the perpetrators. The FBI raided Allure Medical in Shelby Township north of Detroit for billing insurance for “fraudulent COVID-19 cures”. The treatment they were using? Intravenous Vitamin C. An antioxidant. Which, as described above, is an entirely valid treatment for COVID-19-induced sepsis, and indeed, is now part of the MATH+ protocol advanced by Dr. Paul E. Marik. The FDA banned ranitidine (Zantac) due to supposed NDMA (N-nitrosodimethylamine) contamination. Ranitidine is not only an H2 blocker used as antacid, but also has a powerful antioxidant effect, scavenging hydroxyl radicals. This gives it utility in treating COVID-19. The FDA also attempted to take N-acetylcysteine, a harmless amino acid supplement and antioxidant, off the shelves, compelling Amazon to remove it from their online storefront. This leaves us with a chilling question: did the FDA knowingly suppress antioxidants useful for treating COVID-19 sepsis as part of a criminal conspiracy against the American public? The establishment is cooperating with, and facilitating, the worst criminals in human history, and are actively suppressing non-vaccine treatments and therapies in order to compel us to inject these criminals' products into our bodies. This is absolutely unacceptable. COVID-19 Vaccine Development and Links to Transhumanism: This section deals with some more speculative aspects of the pandemic and the medical and scientific establishment's reaction to it, as well as the disturbing links between scientists involved in vaccine research and scientists whose work involved merging nanotechnology with living cells. On June 9th, 2020, Charles Lieber, a Harvard nanotechnology researcher with decades of experience, was indicted by the DOJ for fraud. Charles Lieber received millions of dollars in grant money from the US Department of Defense, specifically the military think tanks DARPA, AFOSR, and ONR, as well as NIH and MITRE. His specialty is the use of silicon nanowires in lieu of patch clamp electrodes to monitor and modulate intracellular activity, something he has been working on at Harvard for the past twenty years. He was claimed to have been working on silicon nanowire batteries in China, but none of his colleagues can recall him ever having worked on battery technology in his life; all of his research deals with bionanotechnology, or the blending of nanotech with living cells. The indictment was over his collaboration with the Wuhan University of Technology. He had double- dipped, against the terms of his DOD grants, and taken money from the PRC's Thousand Talents plan, a program which the Chinese government uses to bribe Western scientists into sharing proprietary R&D information that can be exploited by the PLA for strategic advantage. Charles Lieber's own papers describe the use of silicon nanowires for brain-computer interfaces, or “neural lace” technology. His papers describe how neurons can endocytose whole silicon nanowires or parts of them, monitoring and even modulating neuronal activity. Charles Lieber was a colleague of Robert Langer. Together, along with Daniel S. Kohane, they worked on a paper describing artificial tissue scaffolds that could be implanted in a human heart to monitor its activity remotely. Robert Langer, an MIT alumnus and expert in nanotech drug delivery, is one of the co-founders of Moderna. His net worth is now $5.1 billion USD thanks to Moderna's mRNA-1273 vaccine sales. Both Charles Lieber and Robert Langer's bibliographies describe, essentially, techniques for human enhancement, i.e. transhumanism. Klaus Schwab, the founder of the World Economic Forum and the architect behind the so-called “Great Reset”, has long spoken of the “blending of biology and machinery” in his books. Since these revelations, it has come to the attention of independent researchers that the COVID-19 vaccines may contain reduced graphene oxide nanoparticles. Japanese researchers have also found unexplained contaminants in COVID-19 vaccines. Graphene oxide is an anxiolytic. It has been shown to reduce the anxiety of laboratory mice when injected into their brains. Indeed, given SARS-CoV-2 Spike's propensity to compromise the blood-brain barrier and increase its permeability, it is the perfect protein for preparing brain tissue for extravasation of nanoparticles from the bloodstream and into the brain. Graphene is also highly conductive and, in some circumstances, paramagnetic. In 2013, under the Obama administration, DARPA launched the BRAIN Initiative; BRAIN is an acronym for Brain Research Through Advancing Innovative Neurotechnologies®. This program involves the development of brain-computer interface technologies for the military, particularly non-invasive, injectable systems that cause minimal damage to brain tissue when removed. Supposedly, this technology would be used for healing wounded soldiers with traumatic brain injuries, the direct brain control of prosthetic limbs, and even new abilities such as controlling drones with one's mind. Various methods have been proposed for achieving this, including optogenetics, magnetogenetics, ultrasound, implanted electrodes, and transcranial electromagnetic stimulation. In all instances, the goal is to obtain read or read-write capability over neurons, either by stimulating and probing them, or by rendering them especially sensitive to stimulation and probing. However, the notion of the widespread use of BCI technology, such as Elon Musk's Neuralink device, raises many concerns over privacy and personal autonomy. Reading from neurons is problematic enough on its own. Wireless brain-computer interfaces may interact with current or future wireless GSM infrastructure, creating neurological data security concerns. A hacker or other malicious actor may compromise such networks to obtain people's brain data, and then exploit it for nefarious purposes. However, a device capable of writing to human neurons, not just reading from them, presents another, even more serious set of ethical concerns. A BCI that is capable of altering the contents of one's mind for innocuous purposes, such as projecting a heads-up display onto their brain's visual center or sending audio into one's auditory cortex, would also theoretically be capable of altering mood and personality, or perhaps even subjugating someone's very will, rendering them utterly obedient to authority. This technology would be a tyrant's wet dream. Imagine soldiers who would shoot their own countrymen without hesitation, or helpless serfs who are satisfied to live in literal dog kennels. BCIs could be used to unscrupulously alter perceptions of basic things such as emotions and values, changing people's thresholds of satiety, happiness, anger, disgust, and so forth. This is not inconsequential. Someone's entire regime of behaviors could be altered by a BCI, including such things as suppressing their appetite or desire for virtually anything on Maslow's Hierarchy of Needs. Anything is possible when you have direct access to someone's brain and its contents. Someone who is obese could be made to feel disgust at the sight of food. Someone who is involuntarily celibate could have their libido disabled so they don't even desire sex to begin with. Someone who is racist could be forced to feel delight over cohabiting with people of other races. Someone who is violent could be forced to be meek and submissive. These things might sound good to you if you are a tyrant, but to normal people, the idea of personal autonomy being overridden to such a degree is appalling. For the wealthy, neural laces would be an unequaled boon, giving them the opportunity to enhance their intelligence with neuroprosthetics (i.e. an “exocortex”), and to deliver irresistible commands directly into the minds of their BCI-augmented servants, even physically or sexually abusive commands that they would normally refuse. If the vaccine is a method to surreptitiously introduce an injectable BCI into millions of people without their knowledge or consent, then what we are witnessing is the rise of a tyrannical regime unlike anything ever seen before on the face of this planet, one that fully intends to strip every man, woman, and child of our free will. Our flaws are what make us human. A utopia arrived at by removing people's free will is not a utopia at all. It is a monomaniacal nightmare. Furthermore, the people who rule over us are Dark Triad types who cannot be trusted with such power. Imagine being beaten and sexually assaulted by a wealthy and powerful psychopath and being forced to smile and laugh over it because your neural lace gives you no choice but to obey your master. The Elites are forging ahead with this technology without giving people any room to question the social or ethical ramifications, or to establish regulatory frameworks that ensure that our personal agency and autonomy will not be overridden by these devices. They do this because they secretly dream of a future where they can treat you worse than an animal and you cannot even fight back. If this evil plan is allowed to continue, it will spell the end of humanity as we know it. Conclusions: The current pandemic was produced and perpetuated by the establishment, through the use of a virus engineered in a PLA-connected Chinese biowarfare laboratory, with the aid of American taxpayer dollars and French expertise. This research was conducted under the absolutely ridiculous euphemism of “gain-of-function” research, which is supposedly carried out in order to determine which viruses have the highest potential for zoonotic spillover and preemptively vaccinate or guard against them. Gain-of-function/gain-of-threat research, a.k.a. “Dual-Use Research of Concern”, or DURC, is bioweapon research by another, friendlier-sounding name, simply to avoid the taboo of calling it what it actually is. It has always been bioweapon research. The people who are conducting this research fully understand that they are taking wild pathogens that are not infectious in humans and making them more infectious, often taking grants from military think tanks encouraging them to do so. These virologists conducting this type of research are enemies of their fellow man, like pyromaniac firefighters. GOF research has never protected anyone from any pandemic. In fact, it has now started one, meaning its utility for preventing pandemics is actually negative. It should have been banned globally, and the lunatics performing it should have been put in straitjackets long ago. Either through a leak or an intentional release from the Wuhan Institute of Virology, a deadly SARS strain is now endemic across the globe, after the WHO and CDC and public officials first downplayed the risks, and then intentionally incited a panic and lockdowns that jeopardized people's health and their livelihoods. This was then used by the utterly depraved and psychopathic aristocratic class who rule over us as an excuse to coerce people into accepting an injected poison which may be a depopulation agent, a mind control/pacification agent in the form of injectable “smart dust”, or both in one. They believe they can get away with this by weaponizing the social stigma of vaccine refusal. They are incorrect. Their motives are clear and obvious to anyone who has been paying attention. These megalomaniacs have raided the pension funds of the free world. Wall Street is insolvent and has had an ongoing liquidity crisis since the end of 2019. The aim now is to exert total, full-spectrum physical, mental, and financial control over humanity before we realize just how badly we've been extorted by these maniacs. The pandemic and its response served multiple purposes for the Elite: Concealing a depression brought on by the usurious plunder of our economies conducted by rentier-capitalists and absentee owners who produce absolutely nothing of any value to society whatsoever. Instead of us having a very predictable Occupy Wall Street Part II, the Elites and their stooges got to stand up on television and paint themselves as wise and all-powerful saviors instead of the marauding cabal of despicable land pirates that they are. Destroying small businesses and eroding the middle class. Transferring trillions of dollars of wealth from the American public and into the pockets of billionaires and special interests. Engaging in insider trading, buying stock in biotech companies and shorting brick-and-mortar businesses and travel companies, with the aim of collapsing face-to-face commerce and tourism and replacing it with e-commerce and servitization. Creating a casus belli for war with China, encouraging us to attack them, wasting American lives and treasure and driving us to the brink of nuclear armageddon. Establishing technological and biosecurity frameworks for population control and technocratic- socialist “smart cities” where everyone's movements are despotically tracked, all in anticipation of widespread automation, joblessness, and food shortages, by using the false guise of a vaccine to compel cooperation. Any one of these things would constitute a vicious rape of Western society. Taken together, they beggar belief; they are a complete inversion of our most treasured values. What is the purpose of all of this? One can only speculate as to the perpetrators' motives, however, we have some theories. The Elites are trying to pull up the ladder, erase upward mobility for large segments of the population, cull political opponents and other “undesirables”, and put the remainder of humanity on a tight leash, rationing our access to certain goods and services that they have deemed “high-impact”, such as automobile use, tourism, meat consumption, and so on. Naturally, they will continue to have their own luxuries, as part of a strict caste system akin to feudalism. Why are they doing this? Simple. The Elites are Neo-Malthusians and believe that we are overpopulated and that resource depletion will collapse civilization in a matter of a few short decades. They are not necessarily incorrect in this belief. We are overpopulated, and we are consuming too many resources. However, orchestrating such a gruesome and murderous power grab in response to a looming crisis demonstrates that they have nothing but the utmost contempt for their fellow man. To those who are participating in this disgusting farce without any understanding of what they are doing, we have one word for you. Stop. You are causing irreparable harm to your country and to your fellow citizens. To those who may be reading this warning and have full knowledge and understanding of what they are doing and how it will unjustly harm millions of innocent people, we have a few more words. Damn you to hell. You will not destroy America and the Free World, and you will not have your New World Order. We will make certain of

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CWRW #196 Crypto Craziness

Play Episode Listen Later Nov 11, 2021 117:42

his is the Morning Show that Makes you Hate All Morning Shows. Don't forget to follow https://twitter.com/https://linktr.ee/Theralphwilliam If you want a place to voice your opinions to all platforms sign up to podbean with this affiliate link https://www.podbean.com/GetCoffee Link for business hosting https://www.podbean.com/pro/GetCoffee Get some Merchandise TearzESC Shop | Redbubble Join us on Twitch! theralphwilliampodcast - Get 10% off when you use promo code RW at checkout Fromthedoctors.com Download our internet radio station in your App Store W-ESN Epic Strategies Network Epicstrategiesnetwork.com Rumble https://rumble.com/vh7g39-doggy-handling-competition.html If you are interested being apart of the discord server shoot us a DM on the social media's and joint the crew! Please Read the Rules: By calling in the show you are aware that the show will be published and that you are responsible for your own words and comments. Your opinions and commments does not reflect the views of the show. Say hello and acknowledge those in the chat when entering. Mute yourself when not talking or I will Mute You. Allow others to speak before speaking. Not a requirement but would appreciate it if you would SHARE the show Hello, My name is Spartacus, and I've had enough. We have been forced to watch America and the Free World spin into inexorable decline due to a biowarfare attack. We, along with countless others, have been victimized and gaslit by propaganda and psychological warfare operations being conducted by an unelected, unaccountable Elite against the American people and our allies. Our mental and physical health have suffered immensely over the course of the past year and a half. We have felt the sting of isolation, lockdown, masking, quarantines, and other completely nonsensical acts of healthcare theater that have done absolutely nothing to protect the health or wellbeing of the public from the ongoing COVID-19 pandemic. Now, we are watching the medical establishment inject literal poison into millions of our fellow Americans without so much as a fight. We have been told that we will be fired and denied our livelihoods if we refuse to vaccinate. This was the last straw. We have spent thousands of hours analyzing leaked footage from Wuhan, scientific papers from primary sources, as well as the paper trails left by the medical establishment. What we have discovered would shock anyone to their core. First, we will summarize our findings, and then, we will explain them in detail. References will be placed at the end. Summary: COVID-19 is a blood and blood vessel disease. SARS-CoV-2 infects the lining of human blood vessels, causing them to leak into the lungs. Current treatment protocols (e.g. invasive ventilation) are actively harmful to patients, accelerating oxidative stress and causing severe VILI (ventilator-induced lung injuries). The continued use of ventilators in the absence of any proven medical benefit constitutes mass murder. Existing countermeasures are inadequate to slow the spread of what is an aerosolized and potentially wastewater-borne virus, and constitute a form of medical theater. Various non-vaccine interventions have been suppressed by both the media and the medical establishment in favor of vaccines and expensive patented drugs. The authorities have denied the usefulness of natural immunity against COVID-19, despite the fact that natural immunity confers protection against all of the virus's proteins, and not just one. Vaccines will do more harm than good. The antigen that these vaccines are based on, SARS-CoV- 2 Spike, is a toxic protein. SARS-CoV-2 may have ADE, or antibody-dependent enhancement; current antibodies may not neutralize future strains, but instead help them infect immune cells. Also, vaccinating during a pandemic with a leaky vaccine removes the evolutionary pressure for a virus to become less lethal. There is a vast and appalling criminal conspiracy that directly links both Anthony Fauci and Moderna to the Wuhan Institute of Virology. COVID-19 vaccine researchers are directly linked to scientists involved in brain-computer interface (“neural lace”) tech, one of whom was indicted for taking grant money from China. Independent researchers have discovered mysterious nanoparticles inside the vaccines that are not supposed to be present. The entire pandemic is being used as an excuse for a vast political and economic transformation of Western society that will enrich the already rich and turn the rest of us into serfs and untouchables. COVID-19 Pathophysiology and Treatments: COVID-19 is not a viral pneumonia. It is a viral vascular endotheliitis and attacks the lining of blood vessels, particularly the small pulmonary alveolar capillaries, leading to endothelial cell activation and sloughing, coagulopathy, sepsis, pulmonary edema, and ARDS-like symptoms. This is a disease of the blood and blood vessels. The circulatory system. Any pneumonia that it causes is secondary to that. In severe cases, this leads to sepsis, blood clots, and multiple organ failure, including hypoxic and inflammatory damage to various vital organs, such as the brain, heart, liver, pancreas, kidneys, and intestines. Some of the most common laboratory findings in COVID-19 are elevated D-dimer, elevated prothrombin time, elevated C-reactive protein, neutrophilia, lymphopenia, hypocalcemia, and hyperferritinemia, essentially matching a profile of coagulopathy and immune system hyperactivation/immune cell exhaustion. COVID-19 can present as almost anything, due to the wide tropism of SARS-CoV-2 for various tissues in the body's vital organs. While its most common initial presentation is respiratory illness and flu-like symptoms, it can present as brain inflammation, gastrointestinal disease, or even heart attack or pulmonary embolism. COVID-19 is more severe in those with specific comorbidities, such as obesity, diabetes, and hypertension. This is because these conditions involve endothelial dysfunction, which renders the circulatory system more susceptible to infection and injury by this particular virus. The vast majority of COVID-19 cases are mild and do not cause significant disease. In known cases, there is something known as the 80/20 rule, where 80% of cases are mild and 20% are severe or critical. However, this ratio is only correct for known cases, not all infections. The number of actual infections is much, much higher. Consequently, the mortality and morbidity rate is lower. However, COVID-19 spreads very quickly, meaning that there are a significant number of severely-ill and critically-ill patients appearing in a short time frame. In those who have critical COVID-19-induced sepsis, hypoxia, coagulopathy, and ARDS, the most common treatments are intubation, injected corticosteroids, and blood thinners. This is not the correct treatment for COVID-19. In severe hypoxia, cellular metabolic shifts cause ATP to break down into hypoxanthine, which, upon the reintroduction of oxygen, causes xanthine oxidase to produce tons of highly damaging radicals that attack tissue. This is called ischemia-reperfusion injury, and it's why the majority of people who go on a ventilator are dying. In the mitochondria, succinate buildup due to sepsis does the same exact thing; when oxygen is reintroduced, it makes superoxide radicals. Make no mistake, intubation will kill people who have COVID-19. The end-stage of COVID-19 is severe lipid peroxidation, where fats in the body start to “rust” due to damage by oxidative stress. This drives autoimmunity. Oxidized lipids appear as foreign objects to the immune system, which recognizes and forms antibodies against OSEs, or oxidation-specific epitopes. Also, oxidized lipids feed directly into pattern recognition receptors, triggering even more inflammation and summoning even more cells of the innate immune system that release even more destructive enzymes. This is similar to the pathophysiology of Lupus. COVID-19's pathology is dominated by extreme oxidative stress and neutrophil respiratory burst, to the point where hemoglobin becomes incapable of carrying oxygen due to heme iron being stripped out of heme by hypochlorous acid. No amount of supplemental oxygen can oxygenate blood that chemically refuses to bind O2. The breakdown of the pathology is as follows: SARS-CoV-2 Spike binds to ACE2. Angiotensin Converting Enzyme 2 is an enzyme that is part of the renin-angiotensin-aldosterone system, or RAAS. The RAAS is a hormone control system that moderates fluid volume in the body and in the bloodstream (i.e. osmolarity) by controlling salt retention and excretion. This protein, ACE2, is ubiquitous in every part of the body that interfaces with the circulatory system, particularly in vascular endothelial cells and pericytes, brain astrocytes, renal tubules and podocytes, pancreatic islet cells, bile duct and intestinal epithelial cells, and the seminiferous ducts of the testis, all of which SARS-CoV-2 can infect, not just the lungs. SARS-CoV-2 infects a cell as follows: SARS-CoV-2 Spike undergoes a conformational change where the S1 trimers flip up and extend, locking onto ACE2 bound to the surface of a cell. TMPRSS2, or transmembrane protease serine 2, comes along and cuts off the heads of the Spike, exposing the S2 stalk-shaped subunit inside. The remainder of the Spike undergoes a conformational change that causes it to unfold like an extension ladder, embedding itself in the cell membrane. Then, it folds back upon itself, pulling the viral membrane and the cell membrane together. The two membranes fuse, with the virus's proteins migrating out onto the surface of the cell. The SARS-CoV-2 nucleocapsid enters the cell, disgorging its genetic material and beginning the viral replication process, hijacking the cell's own structures to produce more virus. SARS-CoV-2 Spike proteins embedded in a cell can actually cause human cells to fuse together, forming syncytia/MGCs (multinuclear giant cells). They also have other pathogenic, harmful effects. SARS-CoV- 2's viroporins, such as its Envelope protein, act as calcium ion channels, introducing calcium into infected cells. The virus suppresses the natural interferon response, resulting in delayed inflammation. SARS-CoV-2 N protein can also directly activate the NLRP3 inflammasome. Also, it suppresses the Nrf2 antioxidant pathway. The suppression of ACE2 by binding with Spike causes a buildup of bradykinin that would otherwise be broken down by ACE2. This constant calcium influx into the cells results in (or is accompanied by) noticeable hypocalcemia, or low blood calcium, especially in people with Vitamin D deficiencies and pre-existing endothelial dysfunction. Bradykinin upregulates cAMP, cGMP, COX, and Phospholipase C activity. This results in prostaglandin release and vastly increased intracellular calcium signaling, which promotes highly aggressive ROS release and ATP depletion. NADPH oxidase releases superoxide into the extracellular space. Superoxide radicals react with nitric oxide to form peroxynitrite. Peroxynitrite reacts with the tetrahydrobiopterin cofactor needed by endothelial nitric oxide synthase, destroying it and “uncoupling” the enzymes, causing nitric oxide synthase to synthesize more superoxide instead. This proceeds in a positive feedback loop until nitric oxide bioavailability in the circulatory system is depleted. Dissolved nitric oxide gas produced constantly by eNOS serves many important functions, but it is also antiviral against SARS-like coronaviruses, preventing the palmitoylation of the viral Spike protein and making it harder for it to bind to host receptors. The loss of NO allows the virus to begin replicating with impunity in the body. Those with endothelial dysfunction (i.e. hypertension, diabetes, obesity, old age, African-American race) have redox equilibrium issues to begin with, giving the virus an advantage. Due to the extreme cytokine release triggered by these processes, the body summons a great deal of neutrophils and monocyte-derived alveolar macrophages to the lungs. Cells of the innate immune system are the first-line defenders against pathogens. They work by engulfing invaders and trying to attack them with enzymes that produce powerful oxidants, like SOD and MPO. Superoxide dismutase takes superoxide and makes hydrogen peroxide, and myeloperoxidase takes hydrogen peroxide and chlorine ions and makes hypochlorous acid, which is many, many times more reactive than sodium hypochlorite bleach. Cytokine Storm Compilation: Covid-19 Vaccine Side Effects Neutrophils have a nasty trick. They can also eject these enzymes into the extracellular space, where they will continuously spit out peroxide and bleach into the bloodstream. This is called neutrophil extracellular trap formation, or, when it becomes pathogenic and counterproductive, NETosis. In severe and critical COVID-19, there is actually rather severe NETosis. Hypochlorous acid building up in the bloodstream begins to bleach the iron out of heme and compete for O2 binding sites. Red blood cells lose the ability to transport oxygen, causing the sufferer to turn blue in the face. Unliganded iron, hydrogen peroxide, and superoxide in the bloodstream undergo the Haber- Weiss and Fenton reactions, producing extremely reactive hydroxyl radicals that violently strip electrons from surrounding fats and DNA, oxidizing them severely. This condition is not unknown to medical science. The actual name for all of this is acute sepsis. We know this is happening in COVID-19 because people who have died of the disease have noticeable ferroptosis signatures in their tissues, as well as various other oxidative stress markers such as nitrotyrosine, 4-HNE, and malondialdehyde. When you intubate someone with this condition, you are setting off a free radical bomb by supplying the cells with O2. It's a catch-22, because we need oxygen to make Adenosine Triphosphate (that is, to live), but O2 is also the precursor of all these damaging radicals that lead to lipid peroxidation. The correct treatment for severe COVID-19 related sepsis is non-invasive ventilation, steroids, and antioxidant infusions. Most of the drugs repurposed for COVID-19 that show any benefit whatsoever in rescuing critically-ill COVID-19 patients are antioxidants. N-acetylcysteine, melatonin, fluvoxamine, budesonide, famotidine, cimetidine, and ranitidine are all antioxidants. Indomethacin prevents iron- driven oxidation of arachidonic acid to isoprostanes. There are powerful antioxidants such as apocynin that have not even been tested on COVID-19 patients yet which could defang neutrophils, prevent lipid peroxidation, restore endothelial health, and restore oxygenation to the tissues. Scientists who know anything about pulmonary neutrophilia, ARDS, and redox biology have known or surmised much of this since March 2020. In April 2020, Swiss scientists confirmed that COVID-19 was a vascular endotheliitis. By late 2020, experts had already concluded that COVID-19 causes a form of viral sepsis. They also know that sepsis can be effectively treated with antioxidants. None of this information is particularly new, and yet, for the most part, it has not been acted upon. Doctors continue to use damaging intubation techniques with high PEEP settings despite high lung compliance and poor oxygenation, killing an untold number of critically ill patients with medical malpractice. Because of the way they are constructed, Randomized Control Trials will never show any benefit for any antiviral against COVID-19. Not Remdesivir, not Kaletra, not HCQ, and not Ivermectin. The reason for this is simple; for the patients that they have recruited for these studies, such as Oxford's ludicrous RECOVERY study, the intervention is too late to have any positive effect. The clinical course of COVID-19 is such that by the time most people seek medical attention for hypoxia, their viral load has already tapered off to almost nothing. If someone is about 10 days post-exposure and has already been symptomatic for five days, there is hardly any virus left in their bodies, only cellular damage and derangement that has initiated a hyperinflammatory response. It is from this group that the clinical trials for antivirals have recruited, pretty much exclusively. In these trials, they give antivirals to severely ill patients who have no virus in their bodies, only a delayed hyperinflammatory response, and then absurdly claim that antivirals have no utility in treating or preventing COVID-19. These clinical trials do not recruit people who are pre-symptomatic. They do not test pre-exposure or post-exposure prophylaxis. This is like using a defibrillator to shock only flatline, and then absurdly claiming that defibrillators have no medical utility whatsoever when the patients refuse to rise from the dead. The intervention is too late. These trials for antivirals show systematic, egregious selection bias. They are providing a treatment that is futile to the specific cohort they are enrolling. India went against the instructions of the WHO and mandated the prophylactic usage of Ivermectin. They have almost completely eradicated COVID-19. The Indian Bar Association of Mumbai has brought criminal charges against WHO Chief Scientist Dr. Soumya Swaminathan for recommending against the use of Ivermectin. Ivermectin is not “horse dewormer”. Yes, it is sold in veterinary paste form as a dewormer for animals. It has also been available in pill form for humans for decades, as an antiparasitic drug. The media have disingenuously claimed that because Ivermectin is an antiparasitic drug, it has no utility as an antivirus. This is incorrect. Ivermectin has utility as an antiviral. It blocks importin, preventing nuclear import, effectively inhibiting viral access to cell nuclei. Many drugs currently on the market have multiple modes of action. Ivermectin is one such drug. It is both antiparasitic and antiviral. In Bangladesh, Ivermectin costs $1.80 for an entire 5-day course. Remdesivir, which is toxic to the liver, costs $3,120 for a 5-day course of the drug. Billions of dollars of utterly useless Remdesivir were sold to our governments on the taxpayer's dime, and it ended up being totally useless for treating hyperinflammatory COVID-19. The media has hardly even covered this at all. The opposition to the use of generic Ivermectin is not based in science. It is purely financially and politically-motivated. An effective non-vaccine intervention would jeopardize the rushed FDA approval of patented vaccines and medicines for which the pharmaceutical industry stands to rake in billions upon billions of dollars in sales on an ongoing basis. The majority of the public are scientifically illiterate and cannot grasp what any of this even means, thanks to a pathetic educational system that has miseducated them. You would be lucky to find 1 in 100 people who have even the faintest clue what any of this actually means. COVID-19 Transmission: COVID-19 is airborne. The WHO carried water for China by claiming that the virus was only droplet- borne. Our own CDC absurdly claimed that it was mostly transmitted by fomite-to-face contact, which, given its rapid spread from Wuhan to the rest of the world, would have been physically impossible. The ridiculous belief in fomite-to-face being a primary mode of transmission led to the use of surface disinfection protocols that wasted time, energy, productivity, and disinfectant. The 6-foot guidelines are absolutely useless. The minimum safe distance to protect oneself from an aerosolized virus is to be 15+ feet away from an infected person, no closer. Realistically, no public transit is safe. Surgical masks do not protect you from aerosols. The virus is too small and the filter media has too large of gaps to filter it out. They may catch respiratory droplets and keep the virus from being expelled by someone who is sick, but they do not filter a cloud of infectious aerosols if someone were to walk into said cloud. The minimum level of protection against this virus is quite literally a P100 respirator, a PAPR/CAPR, or a 40mm NATO CBRN respirator, ideally paired with a full-body tyvek or tychem suit, gloves, and booties, with all the holes and gaps taped. Live SARS-CoV-2 may potentially be detected in sewage outflows, and there may be oral-fecal transmission. During the SARS outbreak in 2003, in the Amoy Gardens incident, hundreds of people were infected by aerosolized fecal matter rising from floor drains in their apartments. COVID-19 Vaccine Dangers: The vaccines for COVID-19 are not sterilizing and do not prevent infection or transmission. They are “leaky” vaccines. This means they remove the evolutionary pressure on the virus to become less lethal. It also means that the vaccinated are perfect carriers. In other words, those who are vaccinated are a threat to the unvaccinated, not the other way around. All of the COVID-19 vaccines currently in use have undergone minimal testing, with highly accelerated clinical trials. Though they appear to limit severe illness, the long-term safety profile of these vaccines remains unknown. Some of these so-called “vaccines” utilize an untested new technology that has never been used in vaccines before. Traditional vaccines use weakened or killed virus to stimulate an immune response. The Moderna and Pfizer-BioNTech vaccines do not. They are purported to consist of an intramuscular shot containing a suspension of lipid nanoparticles filled with messenger RNA. The way they generate an immune response is by fusing with cells in a vaccine recipient's shoulder, undergoing endocytosis, releasing their mRNA cargo into those cells, and then utilizing the ribosomes in those cells to synthesize modified SARS-CoV-2 Spike proteins in-situ. These modified Spike proteins then migrate to the surface of the cell, where they are anchored in place by a transmembrane domain. The adaptive immune system detects the non-human viral protein being expressed by these cells, and then forms antibodies against that protein. This is purported to confer protection against the virus, by training the adaptive immune system to recognize and produce antibodies against the Spike on the actual virus. The J&J and AstraZeneca vaccines do something similar, but use an adenovirus vector for genetic material delivery instead of a lipid nanoparticle. These vaccines were produced or validated with the aid of fetal cell lines HEK-293 and PER.C6, which people with certain religious convictions may object strongly to. SARS-CoV-2 Spike is a highly pathogenic protein on its own. It is impossible to overstate the danger presented by introducing this protein into the human body. It is claimed by vaccine manufacturers that the vaccine remains in cells in the shoulder, and that SARS- CoV-2 Spike produced and expressed by these cells from the vaccine's genetic material is harmless and inert, thanks to the insertion of prolines in the Spike sequence to stabilize it in the prefusion conformation, preventing the Spike from becoming active and fusing with other cells. However, a pharmacokinetic study from Japan showed that the lipid nanoparticles and mRNA from the Pfizer vaccine did not stay in the shoulder, and in fact bioaccumulated in many different organs, including the reproductive organs and adrenal glands, meaning that modified Spike is being expressed quite literally all over the place. These lipid nanoparticles may trigger anaphylaxis in an unlucky few, but far more concerning is the unregulated expression of Spike in various somatic cell lines far from the injection site and the unknown consequences of that. Messenger RNA is normally consumed right after it is produced in the body, being translated into a protein by a ribosome. COVID-19 vaccine mRNA is produced outside the body, long before a ribosome translates it. In the meantime, it could accumulate damage if inadequately preserved. When a ribosome attempts to translate a damaged strand of mRNA, it can become stalled. When this happens, the ribosome becomes useless for translating proteins because it now has a piece of mRNA stuck in it, like a lace card in an old punch card reader. The whole thing has to be cleaned up and new ribosomes synthesized to replace it. In cells with low ribosome turnover, like nerve cells, this can lead to reduced protein synthesis, cytopathic effects, and neuropathies. Certain proteins, including SARS-CoV-2 Spike, have proteolytic cleavage sites that are basically like little dotted lines that say “cut here”, which attract a living organism's own proteases (essentially, molecular scissors) to cut them. There is a possibility that S1 may be proteolytically cleaved from S2, causing active S1 to float away into the bloodstream while leaving the S2 “stalk” embedded in the membrane of the cell that expressed the protein. SARS-CoV-2 Spike has a Superantigenic region (SAg), which may promote extreme inflammation. Anti-Spike antibodies were found in one study to function as autoantibodies and attack the body's own cells. Those who have been immunized with COVID-19 vaccines have developed blood clots, myocarditis, Guillain-Barre Syndrome, Bell's Palsy, and multiple sclerosis flares, indicating that the vaccine promotes autoimmune reactions against healthy tissue. SARS-CoV-2 Spike does not only bind to ACE2. It was suspected to have regions that bind to basigin, integrins, neuropilin-1, and bacterial lipopolysaccharides as well. SARS-CoV-2 Spike, on its own, can potentially bind any of these things and act as a ligand for them, triggering unspecified and likely highly inflammatory cellular activity. SARS-CoV-2 Spike contains an unusual PRRA insert that forms a furin cleavage site. Furin is a ubiquitous human protease, making this an ideal property for the Spike to have, giving it a high degree of cell tropism. No wild-type SARS-like coronaviruses related to SARS-CoV-2 possess this feature, making it highly suspicious, and perhaps a sign of human tampering. SARS-CoV-2 Spike has a prion-like domain that enhances its infectiousness. The Spike S1 RBD may bind to heparin-binding proteins and promote amyloid aggregation. In humans, this could lead to Parkinson's, Lewy Body Dementia, premature Alzheimer's, or various other neurodegenerative diseases. This is very concerning because SARS-CoV-2 S1 is capable of injuring and penetrating the blood-brain barrier and entering the brain. It is also capable of increasing the permeability of the blood-brain barrier to other molecules. SARS-CoV-2, like other betacoronaviruses, may have Dengue-like ADE, or antibody-dependent enhancement of disease. For those who aren't aware, some viruses, including betacoronaviruses, have a feature called ADE. There is also something called Original Antigenic Sin, which is the observation that the body prefers to produce antibodies based on previously-encountered strains of a virus over newly- encountered ones. In ADE, antibodies from a previous infection become non-neutralizing due to mutations in the virus's proteins. These non-neutralizing antibodies then act as trojan horses, allowing live, active virus to be pulled into macrophages through their Fc receptor pathways, allowing the virus to infect immune cells that it would not have been able to infect before. This has been known to happen with Dengue Fever; when someone gets sick with Dengue, recovers, and then contracts a different strain, they can get very, very ill. If someone is vaccinated with mRNA based on the Spike from the initial Wuhan strain of SARS-CoV-2, and then they become infected with a future, mutated strain of the virus, they may become severely ill. In other words, it is possible for vaccines to sensitize someone to disease. There is a precedent for this in recent history. Sanofi's Dengvaxia vaccine for Dengue failed because it caused immune sensitization in people whose immune systems were Dengue-naive. In mice immunized against SARS-CoV and challenged with the virus, a close relative of SARS-CoV-2, they developed immune sensitization, Th2 immunopathology, and eosinophil infiltration in their lungs. We have been told that SARS-CoV-2 mRNA vaccines cannot be integrated into the human genome, because messenger RNA cannot be turned back into DNA. This is false. There are elements in human cells called LINE-1 retrotransposons, which can indeed integrate mRNA into a human genome by endogenous reverse transcription. Because the mRNA used in the vaccines is stabilized, it hangs around in cells longer, increasing the chances for this to happen. If the gene for SARS-CoV-2 Spike is integrated into a portion of the genome that is not silent and actually expresses a protein, it is possible that people who take this vaccine may continuously express SARS-CoV-2 Spike from their somatic cells for the rest of their lives. By inoculating people with a vaccine that causes their bodies to produce Spike in-situ, they are being inoculated with a pathogenic protein. A toxin that may cause long-term inflammation, heart problems, and a raised risk of cancers. In the long-term, it may also potentially lead to premature neurodegenerative disease. Absolutely nobody should be compelled to take this vaccine under any circumstances, and in actual fact, the vaccination campaign must be stopped immediately. COVID-19 Criminal Conspiracy: The vaccine and the virus were made by the same people. In 2014, there was a moratorium on SARS gain-of-function research that lasted until 2017. This research was not halted. Instead, it was outsourced, with the federal grants being laundered through NGOs. Ralph Baric is a virologist and SARS expert at UNC Chapel Hill in North Carolina. This is who Anthony Fauci was referring to when he insisted, before Congress, that if any gain-of-function research was being conducted, it was being conducted in North Carolina. This was a lie. Anthony Fauci lied before Congress. A felony. Ralph Baric and Shi Zhengli are colleagues and have co-written papers together. Ralph Baric mentored Shi Zhengli in his gain-of-function manipulation techniques, particularly serial passage, which results in a virus that appears as if it originated naturally. In other words, deniable bioweapons. Serial passage in humanized hACE2 mice may have produced something like SARS-CoV-2. The funding for the gain-of-function research being conducted at the Wuhan Institute of Virology came from Peter Daszak. Peter Daszak runs an NGO called EcoHealth Alliance. EcoHealth Alliance received millions of dollars in grant money from the National Institutes of Health/National Institute of Allergy and Infectious Diseases (that is, Anthony Fauci), the Defense Threat Reduction Agency (part of the US Department of Defense), and the United States Agency for International Development. NIH/NIAID contributed a few million dollars, and DTRA and USAID each contributed tens of millions of dollars towards this research. Altogether, it was over a hundred million dollars. EcoHealth Alliance subcontracted these grants to the Wuhan Institute of Virology, a lab in China with a very questionable safety record and poorly trained staff, so that they could conduct gain-of-function research, not in their fancy P4 lab, but in a level-2 lab where technicians wore nothing more sophisticated than perhaps a hairnet, latex gloves, and a surgical mask, instead of the bubble suits used when working with dangerous viruses. Chinese scientists in Wuhan reported being routinely bitten and urinated on by laboratory animals. Why anyone would outsource this dangerous and delicate work to the People's Republic of China, a country infamous for industrial accidents and massive explosions that have claimed hundreds of lives, is completely beyond me, unless the aim was to start a pandemic on purpose. In November of 2019, three technicians at the Wuhan Institute of Virology developed symptoms consistent with a flu-like illness. Anthony Fauci, Peter Daszak, and Ralph Baric knew at once what had happened, because back channels exist between this laboratory and our scientists and officials. December 12th, 2019, Ralph Baric signed a Material Transfer Agreement (essentially, an NDA) to receive Coronavirus mRNA vaccine-related materials co-owned by Moderna and NIH. It wasn't until a whole month later, on January 11th, 2020, that China allegedly sent us the sequence to what would become known as SARS-CoV-2. Moderna claims, rather absurdly, that they developed a working vaccine from this sequence in under 48 hours. Stephane Bancel, the current CEO of Moderna, was formerly the CEO of bioMerieux, a French multinational corporation specializing in medical diagnostic tech, founded by one Alain Merieux. Alain Merieux was one of the individuals who was instrumental in the construction of the Wuhan Institute of Virology's P4 lab. The sequence given as the closest relative to SARS-CoV-2, RaTG13, is not a real virus. It is a forgery. It was made by entering a gene sequence by hand into a database, to create a cover story for the existence of SARS-CoV-2, which is very likely a gain-of-function chimera produced at the Wuhan Institute of Virology and was either leaked by accident or intentionally released. The animal reservoir of SARS-CoV-2 has never been found. This is not a conspiracy “theory”. It is an actual criminal conspiracy, in which people connected to the development of Moderna's mRNA-1273 are directly connected to the Wuhan Institute of Virology and their gain-of-function research by very few degrees of separation, if any. The paper trail is well- established. The lab-leak theory has been suppressed because pulling that thread leads one to inevitably conclude that there is enough circumstantial evidence to link Moderna, the NIH, the WIV, and both the vaccine and the virus's creation together. In a sane country, this would have immediately led to the world's biggest RICO and mass murder case. Anthony Fauci, Peter Daszak, Ralph Baric, Shi Zhengli, and Stephane Bancel, and their accomplices, would have been indicted and prosecuted to the fullest extent of the law. Instead, billions of our tax dollars were awarded to the perpetrators. The FBI raided Allure Medical in Shelby Township north of Detroit for billing insurance for “fraudulent COVID-19 cures”. The treatment they were using? Intravenous Vitamin C. An antioxidant. Which, as described above, is an entirely valid treatment for COVID-19-induced sepsis, and indeed, is now part of the MATH+ protocol advanced by Dr. Paul E. Marik. The FDA banned ranitidine (Zantac) due to supposed NDMA (N-nitrosodimethylamine) contamination. Ranitidine is not only an H2 blocker used as antacid, but also has a powerful antioxidant effect, scavenging hydroxyl radicals. This gives it utility in treating COVID-19. The FDA also attempted to take N-acetylcysteine, a harmless amino acid supplement and antioxidant, off the shelves, compelling Amazon to remove it from their online storefront. This leaves us with a chilling question: did the FDA knowingly suppress antioxidants useful for treating COVID-19 sepsis as part of a criminal conspiracy against the American public? The establishment is cooperating with, and facilitating, the worst criminals in human history, and are actively suppressing non-vaccine treatments and therapies in order to compel us to inject these criminals' products into our bodies. This is absolutely unacceptable. COVID-19 Vaccine Development and Links to Transhumanism: This section deals with some more speculative aspects of the pandemic and the medical and scientific establishment's reaction to it, as well as the disturbing links between scientists involved in vaccine research and scientists whose work involved merging nanotechnology with living cells. On June 9th, 2020, Charles Lieber, a Harvard nanotechnology researcher with decades of experience, was indicted by the DOJ for fraud. Charles Lieber received millions of dollars in grant money from the US Department of Defense, specifically the military think tanks DARPA, AFOSR, and ONR, as well as NIH and MITRE. His specialty is the use of silicon nanowires in lieu of patch clamp electrodes to monitor and modulate intracellular activity, something he has been working on at Harvard for the past twenty years. He was claimed to have been working on silicon nanowire batteries in China, but none of his colleagues can recall him ever having worked on battery technology in his life; all of his research deals with bionanotechnology, or the blending of nanotech with living cells. The indictment was over his collaboration with the Wuhan University of Technology. He had double- dipped, against the terms of his DOD grants, and taken money from the PRC's Thousand Talents plan, a program which the Chinese government uses to bribe Western scientists into sharing proprietary R&D information that can be exploited by the PLA for strategic advantage. Charles Lieber's own papers describe the use of silicon nanowires for brain-computer interfaces, or “neural lace” technology. His papers describe how neurons can endocytose whole silicon nanowires or parts of them, monitoring and even modulating neuronal activity. Charles Lieber was a colleague of Robert Langer. Together, along with Daniel S. Kohane, they worked on a paper describing artificial tissue scaffolds that could be implanted in a human heart to monitor its activity remotely. Robert Langer, an MIT alumnus and expert in nanotech drug delivery, is one of the co-founders of Moderna. His net worth is now $5.1 billion USD thanks to Moderna's mRNA-1273 vaccine sales. Both Charles Lieber and Robert Langer's bibliographies describe, essentially, techniques for human enhancement, i.e. transhumanism. Klaus Schwab, the founder of the World Economic Forum and the architect behind the so-called “Great Reset”, has long spoken of the “blending of biology and machinery” in his books. Since these revelations, it has come to the attention of independent researchers that the COVID-19 vaccines may contain reduced graphene oxide nanoparticles. Japanese researchers have also found unexplained contaminants in COVID-19 vaccines. Graphene oxide is an anxiolytic. It has been shown to reduce the anxiety of laboratory mice when injected into their brains. Indeed, given SARS-CoV-2 Spike's propensity to compromise the blood-brain barrier and increase its permeability, it is the perfect protein for preparing brain tissue for extravasation of nanoparticles from the bloodstream and into the brain. Graphene is also highly conductive and, in some circumstances, paramagnetic. In 2013, under the Obama administration, DARPA launched the BRAIN Initiative; BRAIN is an acronym for Brain Research Through Advancing Innovative Neurotechnologies®. This program involves the development of brain-computer interface technologies for the military, particularly non-invasive, injectable systems that cause minimal damage to brain tissue when removed. Supposedly, this technology would be used for healing wounded soldiers with traumatic brain injuries, the direct brain control of prosthetic limbs, and even new abilities such as controlling drones with one's mind. Various methods have been proposed for achieving this, including optogenetics, magnetogenetics, ultrasound, implanted electrodes, and transcranial electromagnetic stimulation. In all instances, the goal is to obtain read or read-write capability over neurons, either by stimulating and probing them, or by rendering them especially sensitive to stimulation and probing. However, the notion of the widespread use of BCI technology, such as Elon Musk's Neuralink device, raises many concerns over privacy and personal autonomy. Reading from neurons is problematic enough on its own. Wireless brain-computer interfaces may interact with current or future wireless GSM infrastructure, creating neurological data security concerns. A hacker or other malicious actor may compromise such networks to obtain people's brain data, and then exploit it for nefarious purposes. However, a device capable of writing to human neurons, not just reading from them, presents another, even more serious set of ethical concerns. A BCI that is capable of altering the contents of one's mind for innocuous purposes, such as projecting a heads-up display onto their brain's visual center or sending audio into one's auditory cortex, would also theoretically be capable of altering mood and personality, or perhaps even subjugating someone's very will, rendering them utterly obedient to authority. This technology would be a tyrant's wet dream. Imagine soldiers who would shoot their own countrymen without hesitation, or helpless serfs who are satisfied to live in literal dog kennels. BCIs could be used to unscrupulously alter perceptions of basic things such as emotions and values, changing people's thresholds of satiety, happiness, anger, disgust, and so forth. This is not inconsequential. Someone's entire regime of behaviors could be altered by a BCI, including such things as suppressing their appetite or desire for virtually anything on Maslow's Hierarchy of Needs. Anything is possible when you have direct access to someone's brain and its contents. Someone who is obese could be made to feel disgust at the sight of food. Someone who is involuntarily celibate could have their libido disabled so they don't even desire sex to begin with. Someone who is racist could be forced to feel delight over cohabiting with people of other races. Someone who is violent could be forced to be meek and submissive. These things might sound good to you if you are a tyrant, but to normal people, the idea of personal autonomy being overridden to such a degree is appalling. For the wealthy, neural laces would be an unequaled boon, giving them the opportunity to enhance their intelligence with neuroprosthetics (i.e. an “exocortex”), and to deliver irresistible commands directly into the minds of their BCI-augmented servants, even physically or sexually abusive commands that they would normally refuse. If the vaccine is a method to surreptitiously introduce an injectable BCI into millions of people without their knowledge or consent, then what we are witnessing is the rise of a tyrannical regime unlike anything ever seen before on the face of this planet, one that fully intends to strip every man, woman, and child of our free will. Our flaws are what make us human. A utopia arrived at by removing people's free will is not a utopia at all. It is a monomaniacal nightmare. Furthermore, the people who rule over us are Dark Triad types who cannot be trusted with such power. Imagine being beaten and sexually assaulted by a wealthy and powerful psychopath and being forced to smile and laugh over it because your neural lace gives you no choice but to obey your master. The Elites are forging ahead with this technology without giving people any room to question the social or ethical ramifications, or to establish regulatory frameworks that ensure that our personal agency and autonomy will not be overridden by these devices. They do this because they secretly dream of a future where they can treat you worse than an animal and you cannot even fight back. If this evil plan is allowed to continue, it will spell the end of humanity as we know it. Conclusions: The current pandemic was produced and perpetuated by the establishment, through the use of a virus engineered in a PLA-connected Chinese biowarfare laboratory, with the aid of American taxpayer dollars and French expertise. This research was conducted under the absolutely ridiculous euphemism of “gain-of-function” research, which is supposedly carried out in order to determine which viruses have the highest potential for zoonotic spillover and preemptively vaccinate or guard against them. Gain-of-function/gain-of-threat research, a.k.a. “Dual-Use Research of Concern”, or DURC, is bioweapon research by another, friendlier-sounding name, simply to avoid the taboo of calling it what it actually is. It has always been bioweapon research. The people who are conducting this research fully understand that they are taking wild pathogens that are not infectious in humans and making them more infectious, often taking grants from military think tanks encouraging them to do so. These virologists conducting this type of research are enemies of their fellow man, like pyromaniac firefighters. GOF research has never protected anyone from any pandemic. In fact, it has now started one, meaning its utility for preventing pandemics is actually negative. It should have been banned globally, and the lunatics performing it should have been put in straitjackets long ago. Either through a leak or an intentional release from the Wuhan Institute of Virology, a deadly SARS strain is now endemic across the globe, after the WHO and CDC and public officials first downplayed the risks, and then intentionally incited a panic and lockdowns that jeopardized people's health and their livelihoods. This was then used by the utterly depraved and psychopathic aristocratic class who rule over us as an excuse to coerce people into accepting an injected poison which may be a depopulation agent, a mind control/pacification agent in the form of injectable “smart dust”, or both in one. They believe they can get away with this by weaponizing the social stigma of vaccine refusal. They are incorrect. Their motives are clear and obvious to anyone who has been paying attention. These megalomaniacs have raided the pension funds of the free world. Wall Street is insolvent and has had an ongoing liquidity crisis since the end of 2019. The aim now is to exert total, full-spectrum physical, mental, and financial control over humanity before we realize just how badly we've been extorted by these maniacs. The pandemic and its response served multiple purposes for the Elite: Concealing a depression brought on by the usurious plunder of our economies conducted by rentier-capitalists and absentee owners who produce absolutely nothing of any value to society whatsoever. Instead of us having a very predictable Occupy Wall Street Part II, the Elites and their stooges got to stand up on television and paint themselves as wise and all-powerful saviors instead of the marauding cabal of despicable land pirates that they are. Destroying small businesses and eroding the middle class. Transferring trillions of dollars of wealth from the American public and into the pockets of billionaires and special interests. Engaging in insider trading, buying stock in biotech companies and shorting brick-and-mortar businesses and travel companies, with the aim of collapsing face-to-face commerce and tourism and replacing it with e-commerce and servitization. Creating a casus belli for war with China, encouraging us to attack them, wasting American lives and treasure and driving us to the brink of nuclear armageddon. Establishing technological and biosecurity frameworks for population control and technocratic- socialist “smart cities” where everyone's movements are despotically tracked, all in anticipation of widespread automation, joblessness, and food shortages, by using the false guise of a vaccine to compel cooperation. Any one of these things would constitute a vicious rape of Western society. Taken together, they beggar belief; they are a complete inversion of our most treasured values. What is the purpose of all of this? One can only speculate as to the perpetrators' motives, however, we have some theories. The Elites are trying to pull up the ladder, erase upward mobility for large segments of the population, cull political opponents and other “undesirables”, and put the remainder of humanity on a tight leash, rationing our access to certain goods and services that they have deemed “high-impact”, such as automobile use, tourism, meat consumption, and so on. Naturally, they will continue to have their own luxuries, as part of a strict caste system akin to feudalism. Why are they doing this? Simple. The Elites are Neo-Malthusians and believe that we are overpopulated and that resource depletion will collapse civilization in a matter of a few short decades. They are not necessarily incorrect in this belief. We are overpopulated, and we are consuming too many resources. However, orchestrating such a gruesome and murderous power grab in response to a looming crisis demonstrates that they have nothing but the utmost contempt for their fellow man. To those who are participating in this disgusting farce without any understanding of what they are doing, we have one word for you. Stop. You are causing irreparable harm to your country and to your fellow citizens. To those who may be reading this warning and have full knowledge and understanding of what they are doing and how it will unjustly harm millions of innocent people, we have a few more words. Damn you to hell. You will not destroy America and the Free World, and you will not have your New World Order. We will make certain of

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CWRW #194 Conversation

Play Episode Listen Later Nov 9, 2021 115:02

This is the Morning Show that Makes you Hate All Morning Shows. Don't forget to follow https://twitter.com/https://linktr.ee/Theralphwilliam If you want a place to voice your opinions to all platforms sign up to podbean with this affiliate link https://www.podbean.com/GetCoffee Link for business hosting https://www.podbean.com/pro/GetCoffee Get some Merchandise TearzESC Shop | Redbubble Join us on Twitch! theralphwilliampodcast - Get 10% off when you use promo code RW at checkout Fromthedoctors.com Download our internet radio station in your App Store W-ESN Epic Strategies Network Epicstrategiesnetwork.com Rumble https://rumble.com/vh7g39-doggy-handling-competition.html If you are interested being apart of the discord server shoot us a DM on the social media's and joint the crew! Please Read the Rules: By calling in the show you are aware that the show will be published and that you are responsible for your own words and comments. Your opinions and commments does not reflect the views of the show. Say hello and acknowledge those in the chat when entering. Mute yourself when not talking or I will Mute You. Allow others to speak before speaking. Not a requirement but would appreciate it if you would SHARE the show Hello, My name is Spartacus, and I've had enough. We have been forced to watch America and the Free World spin into inexorable decline due to a biowarfare attack. We, along with countless others, have been victimized and gaslit by propaganda and psychological warfare operations being conducted by an unelected, unaccountable Elite against the American people and our allies. Our mental and physical health have suffered immensely over the course of the past year and a half. We have felt the sting of isolation, lockdown, masking, quarantines, and other completely nonsensical acts of healthcare theater that have done absolutely nothing to protect the health or wellbeing of the public from the ongoing COVID-19 pandemic. Now, we are watching the medical establishment inject literal poison into millions of our fellow Americans without so much as a fight. We have been told that we will be fired and denied our livelihoods if we refuse to vaccinate. This was the last straw. We have spent thousands of hours analyzing leaked footage from Wuhan, scientific papers from primary sources, as well as the paper trails left by the medical establishment. What we have discovered would shock anyone to their core. First, we will summarize our findings, and then, we will explain them in detail. References will be placed at the end. Summary: COVID-19 is a blood and blood vessel disease. SARS-CoV-2 infects the lining of human blood vessels, causing them to leak into the lungs. Current treatment protocols (e.g. invasive ventilation) are actively harmful to patients, accelerating oxidative stress and causing severe VILI (ventilator-induced lung injuries). The continued use of ventilators in the absence of any proven medical benefit constitutes mass murder. Existing countermeasures are inadequate to slow the spread of what is an aerosolized and potentially wastewater-borne virus, and constitute a form of medical theater. Various non-vaccine interventions have been suppressed by both the media and the medical establishment in favor of vaccines and expensive patented drugs. The authorities have denied the usefulness of natural immunity against COVID-19, despite the fact that natural immunity confers protection against all of the virus's proteins, and not just one. Vaccines will do more harm than good. The antigen that these vaccines are based on, SARS-CoV- 2 Spike, is a toxic protein. SARS-CoV-2 may have ADE, or antibody-dependent enhancement; current antibodies may not neutralize future strains, but instead help them infect immune cells. Also, vaccinating during a pandemic with a leaky vaccine removes the evolutionary pressure for a virus to become less lethal. There is a vast and appalling criminal conspiracy that directly links both Anthony Fauci and Moderna to the Wuhan Institute of Virology. COVID-19 vaccine researchers are directly linked to scientists involved in brain-computer interface (“neural lace”) tech, one of whom was indicted for taking grant money from China. Independent researchers have discovered mysterious nanoparticles inside the vaccines that are not supposed to be present. The entire pandemic is being used as an excuse for a vast political and economic transformation of Western society that will enrich the already rich and turn the rest of us into serfs and untouchables. COVID-19 Pathophysiology and Treatments: COVID-19 is not a viral pneumonia. It is a viral vascular endotheliitis and attacks the lining of blood vessels, particularly the small pulmonary alveolar capillaries, leading to endothelial cell activation and sloughing, coagulopathy, sepsis, pulmonary edema, and ARDS-like symptoms. This is a disease of the blood and blood vessels. The circulatory system. Any pneumonia that it causes is secondary to that. In severe cases, this leads to sepsis, blood clots, and multiple organ failure, including hypoxic and inflammatory damage to various vital organs, such as the brain, heart, liver, pancreas, kidneys, and intestines. Some of the most common laboratory findings in COVID-19 are elevated D-dimer, elevated prothrombin time, elevated C-reactive protein, neutrophilia, lymphopenia, hypocalcemia, and hyperferritinemia, essentially matching a profile of coagulopathy and immune system hyperactivation/immune cell exhaustion. COVID-19 can present as almost anything, due to the wide tropism of SARS-CoV-2 for various tissues in the body's vital organs. While its most common initial presentation is respiratory illness and flu-like symptoms, it can present as brain inflammation, gastrointestinal disease, or even heart attack or pulmonary embolism. COVID-19 is more severe in those with specific comorbidities, such as obesity, diabetes, and hypertension. This is because these conditions involve endothelial dysfunction, which renders the circulatory system more susceptible to infection and injury by this particular virus. The vast majority of COVID-19 cases are mild and do not cause significant disease. In known cases, there is something known as the 80/20 rule, where 80% of cases are mild and 20% are severe or critical. However, this ratio is only correct for known cases, not all infections. The number of actual infections is much, much higher. Consequently, the mortality and morbidity rate is lower. However, COVID-19 spreads very quickly, meaning that there are a significant number of severely-ill and critically-ill patients appearing in a short time frame. In those who have critical COVID-19-induced sepsis, hypoxia, coagulopathy, and ARDS, the most common treatments are intubation, injected corticosteroids, and blood thinners. This is not the correct treatment for COVID-19. In severe hypoxia, cellular metabolic shifts cause ATP to break down into hypoxanthine, which, upon the reintroduction of oxygen, causes xanthine oxidase to produce tons of highly damaging radicals that attack tissue. This is called ischemia-reperfusion injury, and it's why the majority of people who go on a ventilator are dying. In the mitochondria, succinate buildup due to sepsis does the same exact thing; when oxygen is reintroduced, it makes superoxide radicals. Make no mistake, intubation will kill people who have COVID-19. The end-stage of COVID-19 is severe lipid peroxidation, where fats in the body start to “rust” due to damage by oxidative stress. This drives autoimmunity. Oxidized lipids appear as foreign objects to the immune system, which recognizes and forms antibodies against OSEs, or oxidation-specific epitopes. Also, oxidized lipids feed directly into pattern recognition receptors, triggering even more inflammation and summoning even more cells of the innate immune system that release even more destructive enzymes. This is similar to the pathophysiology of Lupus. COVID-19's pathology is dominated by extreme oxidative stress and neutrophil respiratory burst, to the point where hemoglobin becomes incapable of carrying oxygen due to heme iron being stripped out of heme by hypochlorous acid. No amount of supplemental oxygen can oxygenate blood that chemically refuses to bind O2. The breakdown of the pathology is as follows: SARS-CoV-2 Spike binds to ACE2. Angiotensin Converting Enzyme 2 is an enzyme that is part of the renin-angiotensin-aldosterone system, or RAAS. The RAAS is a hormone control system that moderates fluid volume in the body and in the bloodstream (i.e. osmolarity) by controlling salt retention and excretion. This protein, ACE2, is ubiquitous in every part of the body that interfaces with the circulatory system, particularly in vascular endothelial cells and pericytes, brain astrocytes, renal tubules and podocytes, pancreatic islet cells, bile duct and intestinal epithelial cells, and the seminiferous ducts of the testis, all of which SARS-CoV-2 can infect, not just the lungs. SARS-CoV-2 infects a cell as follows: SARS-CoV-2 Spike undergoes a conformational change where the S1 trimers flip up and extend, locking onto ACE2 bound to the surface of a cell. TMPRSS2, or transmembrane protease serine 2, comes along and cuts off the heads of the Spike, exposing the S2 stalk-shaped subunit inside. The remainder of the Spike undergoes a conformational change that causes it to unfold like an extension ladder, embedding itself in the cell membrane. Then, it folds back upon itself, pulling the viral membrane and the cell membrane together. The two membranes fuse, with the virus's proteins migrating out onto the surface of the cell. The SARS-CoV-2 nucleocapsid enters the cell, disgorging its genetic material and beginning the viral replication process, hijacking the cell's own structures to produce more virus. SARS-CoV-2 Spike proteins embedded in a cell can actually cause human cells to fuse together, forming syncytia/MGCs (multinuclear giant cells). They also have other pathogenic, harmful effects. SARS-CoV- 2's viroporins, such as its Envelope protein, act as calcium ion channels, introducing calcium into infected cells. The virus suppresses the natural interferon response, resulting in delayed inflammation. SARS-CoV-2 N protein can also directly activate the NLRP3 inflammasome. Also, it suppresses the Nrf2 antioxidant pathway. The suppression of ACE2 by binding with Spike causes a buildup of bradykinin that would otherwise be broken down by ACE2. This constant calcium influx into the cells results in (or is accompanied by) noticeable hypocalcemia, or low blood calcium, especially in people with Vitamin D deficiencies and pre-existing endothelial dysfunction. Bradykinin upregulates cAMP, cGMP, COX, and Phospholipase C activity. This results in prostaglandin release and vastly increased intracellular calcium signaling, which promotes highly aggressive ROS release and ATP depletion. NADPH oxidase releases superoxide into the extracellular space. Superoxide radicals react with nitric oxide to form peroxynitrite. Peroxynitrite reacts with the tetrahydrobiopterin cofactor needed by endothelial nitric oxide synthase, destroying it and “uncoupling” the enzymes, causing nitric oxide synthase to synthesize more superoxide instead. This proceeds in a positive feedback loop until nitric oxide bioavailability in the circulatory system is depleted. Dissolved nitric oxide gas produced constantly by eNOS serves many important functions, but it is also antiviral against SARS-like coronaviruses, preventing the palmitoylation of the viral Spike protein and making it harder for it to bind to host receptors. The loss of NO allows the virus to begin replicating with impunity in the body. Those with endothelial dysfunction (i.e. hypertension, diabetes, obesity, old age, African-American race) have redox equilibrium issues to begin with, giving the virus an advantage. Due to the extreme cytokine release triggered by these processes, the body summons a great deal of neutrophils and monocyte-derived alveolar macrophages to the lungs. Cells of the innate immune system are the first-line defenders against pathogens. They work by engulfing invaders and trying to attack them with enzymes that produce powerful oxidants, like SOD and MPO. Superoxide dismutase takes superoxide and makes hydrogen peroxide, and myeloperoxidase takes hydrogen peroxide and chlorine ions and makes hypochlorous acid, which is many, many times more reactive than sodium hypochlorite bleach. Cytokine Storm Compilation: Covid-19 Vaccine Side Effects Neutrophils have a nasty trick. They can also eject these enzymes into the extracellular space, where they will continuously spit out peroxide and bleach into the bloodstream. This is called neutrophil extracellular trap formation, or, when it becomes pathogenic and counterproductive, NETosis. In severe and critical COVID-19, there is actually rather severe NETosis. Hypochlorous acid building up in the bloodstream begins to bleach the iron out of heme and compete for O2 binding sites. Red blood cells lose the ability to transport oxygen, causing the sufferer to turn blue in the face. Unliganded iron, hydrogen peroxide, and superoxide in the bloodstream undergo the Haber- Weiss and Fenton reactions, producing extremely reactive hydroxyl radicals that violently strip electrons from surrounding fats and DNA, oxidizing them severely. This condition is not unknown to medical science. The actual name for all of this is acute sepsis. We know this is happening in COVID-19 because people who have died of the disease have noticeable ferroptosis signatures in their tissues, as well as various other oxidative stress markers such as nitrotyrosine, 4-HNE, and malondialdehyde. When you intubate someone with this condition, you are setting off a free radical bomb by supplying the cells with O2. It's a catch-22, because we need oxygen to make Adenosine Triphosphate (that is, to live), but O2 is also the precursor of all these damaging radicals that lead to lipid peroxidation. The correct treatment for severe COVID-19 related sepsis is non-invasive ventilation, steroids, and antioxidant infusions. Most of the drugs repurposed for COVID-19 that show any benefit whatsoever in rescuing critically-ill COVID-19 patients are antioxidants. N-acetylcysteine, melatonin, fluvoxamine, budesonide, famotidine, cimetidine, and ranitidine are all antioxidants. Indomethacin prevents iron- driven oxidation of arachidonic acid to isoprostanes. There are powerful antioxidants such as apocynin that have not even been tested on COVID-19 patients yet which could defang neutrophils, prevent lipid peroxidation, restore endothelial health, and restore oxygenation to the tissues. Scientists who know anything about pulmonary neutrophilia, ARDS, and redox biology have known or surmised much of this since March 2020. In April 2020, Swiss scientists confirmed that COVID-19 was a vascular endotheliitis. By late 2020, experts had already concluded that COVID-19 causes a form of viral sepsis. They also know that sepsis can be effectively treated with antioxidants. None of this information is particularly new, and yet, for the most part, it has not been acted upon. Doctors continue to use damaging intubation techniques with high PEEP settings despite high lung compliance and poor oxygenation, killing an untold number of critically ill patients with medical malpractice. Because of the way they are constructed, Randomized Control Trials will never show any benefit for any antiviral against COVID-19. Not Remdesivir, not Kaletra, not HCQ, and not Ivermectin. The reason for this is simple; for the patients that they have recruited for these studies, such as Oxford's ludicrous RECOVERY study, the intervention is too late to have any positive effect. The clinical course of COVID-19 is such that by the time most people seek medical attention for hypoxia, their viral load has already tapered off to almost nothing. If someone is about 10 days post-exposure and has already been symptomatic for five days, there is hardly any virus left in their bodies, only cellular damage and derangement that has initiated a hyperinflammatory response. It is from this group that the clinical trials for antivirals have recruited, pretty much exclusively. In these trials, they give antivirals to severely ill patients who have no virus in their bodies, only a delayed hyperinflammatory response, and then absurdly claim that antivirals have no utility in treating or preventing COVID-19. These clinical trials do not recruit people who are pre-symptomatic. They do not test pre-exposure or post-exposure prophylaxis. This is like using a defibrillator to shock only flatline, and then absurdly claiming that defibrillators have no medical utility whatsoever when the patients refuse to rise from the dead. The intervention is too late. These trials for antivirals show systematic, egregious selection bias. They are providing a treatment that is futile to the specific cohort they are enrolling. India went against the instructions of the WHO and mandated the prophylactic usage of Ivermectin. They have almost completely eradicated COVID-19. The Indian Bar Association of Mumbai has brought criminal charges against WHO Chief Scientist Dr. Soumya Swaminathan for recommending against the use of Ivermectin. Ivermectin is not “horse dewormer”. Yes, it is sold in veterinary paste form as a dewormer for animals. It has also been available in pill form for humans for decades, as an antiparasitic drug. The media have disingenuously claimed that because Ivermectin is an antiparasitic drug, it has no utility as an antivirus. This is incorrect. Ivermectin has utility as an antiviral. It blocks importin, preventing nuclear import, effectively inhibiting viral access to cell nuclei. Many drugs currently on the market have multiple modes of action. Ivermectin is one such drug. It is both antiparasitic and antiviral. In Bangladesh, Ivermectin costs $1.80 for an entire 5-day course. Remdesivir, which is toxic to the liver, costs $3,120 for a 5-day course of the drug. Billions of dollars of utterly useless Remdesivir were sold to our governments on the taxpayer's dime, and it ended up being totally useless for treating hyperinflammatory COVID-19. The media has hardly even covered this at all. The opposition to the use of generic Ivermectin is not based in science. It is purely financially and politically-motivated. An effective non-vaccine intervention would jeopardize the rushed FDA approval of patented vaccines and medicines for which the pharmaceutical industry stands to rake in billions upon billions of dollars in sales on an ongoing basis. The majority of the public are scientifically illiterate and cannot grasp what any of this even means, thanks to a pathetic educational system that has miseducated them. You would be lucky to find 1 in 100 people who have even the faintest clue what any of this actually means. COVID-19 Transmission: COVID-19 is airborne. The WHO carried water for China by claiming that the virus was only droplet- borne. Our own CDC absurdly claimed that it was mostly transmitted by fomite-to-face contact, which, given its rapid spread from Wuhan to the rest of the world, would have been physically impossible. The ridiculous belief in fomite-to-face being a primary mode of transmission led to the use of surface disinfection protocols that wasted time, energy, productivity, and disinfectant. The 6-foot guidelines are absolutely useless. The minimum safe distance to protect oneself from an aerosolized virus is to be 15+ feet away from an infected person, no closer. Realistically, no public transit is safe. Surgical masks do not protect you from aerosols. The virus is too small and the filter media has too large of gaps to filter it out. They may catch respiratory droplets and keep the virus from being expelled by someone who is sick, but they do not filter a cloud of infectious aerosols if someone were to walk into said cloud. The minimum level of protection against this virus is quite literally a P100 respirator, a PAPR/CAPR, or a 40mm NATO CBRN respirator, ideally paired with a full-body tyvek or tychem suit, gloves, and booties, with all the holes and gaps taped. Live SARS-CoV-2 may potentially be detected in sewage outflows, and there may be oral-fecal transmission. During the SARS outbreak in 2003, in the Amoy Gardens incident, hundreds of people were infected by aerosolized fecal matter rising from floor drains in their apartments. COVID-19 Vaccine Dangers: The vaccines for COVID-19 are not sterilizing and do not prevent infection or transmission. They are “leaky” vaccines. This means they remove the evolutionary pressure on the virus to become less lethal. It also means that the vaccinated are perfect carriers. In other words, those who are vaccinated are a threat to the unvaccinated, not the other way around. All of the COVID-19 vaccines currently in use have undergone minimal testing, with highly accelerated clinical trials. Though they appear to limit severe illness, the long-term safety profile of these vaccines remains unknown. Some of these so-called “vaccines” utilize an untested new technology that has never been used in vaccines before. Traditional vaccines use weakened or killed virus to stimulate an immune response. The Moderna and Pfizer-BioNTech vaccines do not. They are purported to consist of an intramuscular shot containing a suspension of lipid nanoparticles filled with messenger RNA. The way they generate an immune response is by fusing with cells in a vaccine recipient's shoulder, undergoing endocytosis, releasing their mRNA cargo into those cells, and then utilizing the ribosomes in those cells to synthesize modified SARS-CoV-2 Spike proteins in-situ. These modified Spike proteins then migrate to the surface of the cell, where they are anchored in place by a transmembrane domain. The adaptive immune system detects the non-human viral protein being expressed by these cells, and then forms antibodies against that protein. This is purported to confer protection against the virus, by training the adaptive immune system to recognize and produce antibodies against the Spike on the actual virus. The J&J and AstraZeneca vaccines do something similar, but use an adenovirus vector for genetic material delivery instead of a lipid nanoparticle. These vaccines were produced or validated with the aid of fetal cell lines HEK-293 and PER.C6, which people with certain religious convictions may object strongly to. SARS-CoV-2 Spike is a highly pathogenic protein on its own. It is impossible to overstate the danger presented by introducing this protein into the human body. It is claimed by vaccine manufacturers that the vaccine remains in cells in the shoulder, and that SARS- CoV-2 Spike produced and expressed by these cells from the vaccine's genetic material is harmless and inert, thanks to the insertion of prolines in the Spike sequence to stabilize it in the prefusion conformation, preventing the Spike from becoming active and fusing with other cells. However, a pharmacokinetic study from Japan showed that the lipid nanoparticles and mRNA from the Pfizer vaccine did not stay in the shoulder, and in fact bioaccumulated in many different organs, including the reproductive organs and adrenal glands, meaning that modified Spike is being expressed quite literally all over the place. These lipid nanoparticles may trigger anaphylaxis in an unlucky few, but far more concerning is the unregulated expression of Spike in various somatic cell lines far from the injection site and the unknown consequences of that. Messenger RNA is normally consumed right after it is produced in the body, being translated into a protein by a ribosome. COVID-19 vaccine mRNA is produced outside the body, long before a ribosome translates it. In the meantime, it could accumulate damage if inadequately preserved. When a ribosome attempts to translate a damaged strand of mRNA, it can become stalled. When this happens, the ribosome becomes useless for translating proteins because it now has a piece of mRNA stuck in it, like a lace card in an old punch card reader. The whole thing has to be cleaned up and new ribosomes synthesized to replace it. In cells with low ribosome turnover, like nerve cells, this can lead to reduced protein synthesis, cytopathic effects, and neuropathies. Certain proteins, including SARS-CoV-2 Spike, have proteolytic cleavage sites that are basically like little dotted lines that say “cut here”, which attract a living organism's own proteases (essentially, molecular scissors) to cut them. There is a possibility that S1 may be proteolytically cleaved from S2, causing active S1 to float away into the bloodstream while leaving the S2 “stalk” embedded in the membrane of the cell that expressed the protein. SARS-CoV-2 Spike has a Superantigenic region (SAg), which may promote extreme inflammation. Anti-Spike antibodies were found in one study to function as autoantibodies and attack the body's own cells. Those who have been immunized with COVID-19 vaccines have developed blood clots, myocarditis, Guillain-Barre Syndrome, Bell's Palsy, and multiple sclerosis flares, indicating that the vaccine promotes autoimmune reactions against healthy tissue. SARS-CoV-2 Spike does not only bind to ACE2. It was suspected to have regions that bind to basigin, integrins, neuropilin-1, and bacterial lipopolysaccharides as well. SARS-CoV-2 Spike, on its own, can potentially bind any of these things and act as a ligand for them, triggering unspecified and likely highly inflammatory cellular activity. SARS-CoV-2 Spike contains an unusual PRRA insert that forms a furin cleavage site. Furin is a ubiquitous human protease, making this an ideal property for the Spike to have, giving it a high degree of cell tropism. No wild-type SARS-like coronaviruses related to SARS-CoV-2 possess this feature, making it highly suspicious, and perhaps a sign of human tampering. SARS-CoV-2 Spike has a prion-like domain that enhances its infectiousness. The Spike S1 RBD may bind to heparin-binding proteins and promote amyloid aggregation. In humans, this could lead to Parkinson's, Lewy Body Dementia, premature Alzheimer's, or various other neurodegenerative diseases. This is very concerning because SARS-CoV-2 S1 is capable of injuring and penetrating the blood-brain barrier and entering the brain. It is also capable of increasing the permeability of the blood-brain barrier to other molecules. SARS-CoV-2, like other betacoronaviruses, may have Dengue-like ADE, or antibody-dependent enhancement of disease. For those who aren't aware, some viruses, including betacoronaviruses, have a feature called ADE. There is also something called Original Antigenic Sin, which is the observation that the body prefers to produce antibodies based on previously-encountered strains of a virus over newly- encountered ones. In ADE, antibodies from a previous infection become non-neutralizing due to mutations in the virus's proteins. These non-neutralizing antibodies then act as trojan horses, allowing live, active virus to be pulled into macrophages through their Fc receptor pathways, allowing the virus to infect immune cells that it would not have been able to infect before. This has been known to happen with Dengue Fever; when someone gets sick with Dengue, recovers, and then contracts a different strain, they can get very, very ill. If someone is vaccinated with mRNA based on the Spike from the initial Wuhan strain of SARS-CoV-2, and then they become infected with a future, mutated strain of the virus, they may become severely ill. In other words, it is possible for vaccines to sensitize someone to disease. There is a precedent for this in recent history. Sanofi's Dengvaxia vaccine for Dengue failed because it caused immune sensitization in people whose immune systems were Dengue-naive. In mice immunized against SARS-CoV and challenged with the virus, a close relative of SARS-CoV-2, they developed immune sensitization, Th2 immunopathology, and eosinophil infiltration in their lungs. We have been told that SARS-CoV-2 mRNA vaccines cannot be integrated into the human genome, because messenger RNA cannot be turned back into DNA. This is false. There are elements in human cells called LINE-1 retrotransposons, which can indeed integrate mRNA into a human genome by endogenous reverse transcription. Because the mRNA used in the vaccines is stabilized, it hangs around in cells longer, increasing the chances for this to happen. If the gene for SARS-CoV-2 Spike is integrated into a portion of the genome that is not silent and actually expresses a protein, it is possible that people who take this vaccine may continuously express SARS-CoV-2 Spike from their somatic cells for the rest of their lives. By inoculating people with a vaccine that causes their bodies to produce Spike in-situ, they are being inoculated with a pathogenic protein. A toxin that may cause long-term inflammation, heart problems, and a raised risk of cancers. In the long-term, it may also potentially lead to premature neurodegenerative disease. Absolutely nobody should be compelled to take this vaccine under any circumstances, and in actual fact, the vaccination campaign must be stopped immediately. COVID-19 Criminal Conspiracy: The vaccine and the virus were made by the same people. In 2014, there was a moratorium on SARS gain-of-function research that lasted until 2017. This research was not halted. Instead, it was outsourced, with the federal grants being laundered through NGOs. Ralph Baric is a virologist and SARS expert at UNC Chapel Hill in North Carolina. This is who Anthony Fauci was referring to when he insisted, before Congress, that if any gain-of-function research was being conducted, it was being conducted in North Carolina. This was a lie. Anthony Fauci lied before Congress. A felony. Ralph Baric and Shi Zhengli are colleagues and have co-written papers together. Ralph Baric mentored Shi Zhengli in his gain-of-function manipulation techniques, particularly serial passage, which results in a virus that appears as if it originated naturally. In other words, deniable bioweapons. Serial passage in humanized hACE2 mice may have produced something like SARS-CoV-2. The funding for the gain-of-function research being conducted at the Wuhan Institute of Virology came from Peter Daszak. Peter Daszak runs an NGO called EcoHealth Alliance. EcoHealth Alliance received millions of dollars in grant money from the National Institutes of Health/National Institute of Allergy and Infectious Diseases (that is, Anthony Fauci), the Defense Threat Reduction Agency (part of the US Department of Defense), and the United States Agency for International Development. NIH/NIAID contributed a few million dollars, and DTRA and USAID each contributed tens of millions of dollars towards this research. Altogether, it was over a hundred million dollars. EcoHealth Alliance subcontracted these grants to the Wuhan Institute of Virology, a lab in China with a very questionable safety record and poorly trained staff, so that they could conduct gain-of-function research, not in their fancy P4 lab, but in a level-2 lab where technicians wore nothing more sophisticated than perhaps a hairnet, latex gloves, and a surgical mask, instead of the bubble suits used when working with dangerous viruses. Chinese scientists in Wuhan reported being routinely bitten and urinated on by laboratory animals. Why anyone would outsource this dangerous and delicate work to the People's Republic of China, a country infamous for industrial accidents and massive explosions that have claimed hundreds of lives, is completely beyond me, unless the aim was to start a pandemic on purpose. In November of 2019, three technicians at the Wuhan Institute of Virology developed symptoms consistent with a flu-like illness. Anthony Fauci, Peter Daszak, and Ralph Baric knew at once what had happened, because back channels exist between this laboratory and our scientists and officials. December 12th, 2019, Ralph Baric signed a Material Transfer Agreement (essentially, an NDA) to receive Coronavirus mRNA vaccine-related materials co-owned by Moderna and NIH. It wasn't until a whole month later, on January 11th, 2020, that China allegedly sent us the sequence to what would become known as SARS-CoV-2. Moderna claims, rather absurdly, that they developed a working vaccine from this sequence in under 48 hours. Stephane Bancel, the current CEO of Moderna, was formerly the CEO of bioMerieux, a French multinational corporation specializing in medical diagnostic tech, founded by one Alain Merieux. Alain Merieux was one of the individuals who was instrumental in the construction of the Wuhan Institute of Virology's P4 lab. The sequence given as the closest relative to SARS-CoV-2, RaTG13, is not a real virus. It is a forgery. It was made by entering a gene sequence by hand into a database, to create a cover story for the existence of SARS-CoV-2, which is very likely a gain-of-function chimera produced at the Wuhan Institute of Virology and was either leaked by accident or intentionally released. The animal reservoir of SARS-CoV-2 has never been found. This is not a conspiracy “theory”. It is an actual criminal conspiracy, in which people connected to the development of Moderna's mRNA-1273 are directly connected to the Wuhan Institute of Virology and their gain-of-function research by very few degrees of separation, if any. The paper trail is well- established. The lab-leak theory has been suppressed because pulling that thread leads one to inevitably conclude that there is enough circumstantial evidence to link Moderna, the NIH, the WIV, and both the vaccine and the virus's creation together. In a sane country, this would have immediately led to the world's biggest RICO and mass murder case. Anthony Fauci, Peter Daszak, Ralph Baric, Shi Zhengli, and Stephane Bancel, and their accomplices, would have been indicted and prosecuted to the fullest extent of the law. Instead, billions of our tax dollars were awarded to the perpetrators. The FBI raided Allure Medical in Shelby Township north of Detroit for billing insurance for “fraudulent COVID-19 cures”. The treatment they were using? Intravenous Vitamin C. An antioxidant. Which, as described above, is an entirely valid treatment for COVID-19-induced sepsis, and indeed, is now part of the MATH+ protocol advanced by Dr. Paul E. Marik. The FDA banned ranitidine (Zantac) due to supposed NDMA (N-nitrosodimethylamine) contamination. Ranitidine is not only an H2 blocker used as antacid, but also has a powerful antioxidant effect, scavenging hydroxyl radicals. This gives it utility in treating COVID-19. The FDA also attempted to take N-acetylcysteine, a harmless amino acid supplement and antioxidant, off the shelves, compelling Amazon to remove it from their online storefront. This leaves us with a chilling question: did the FDA knowingly suppress antioxidants useful for treating COVID-19 sepsis as part of a criminal conspiracy against the American public? The establishment is cooperating with, and facilitating, the worst criminals in human history, and are actively suppressing non-vaccine treatments and therapies in order to compel us to inject these criminals' products into our bodies. This is absolutely unacceptable. COVID-19 Vaccine Development and Links to Transhumanism: This section deals with some more speculative aspects of the pandemic and the medical and scientific establishment's reaction to it, as well as the disturbing links between scientists involved in vaccine research and scientists whose work involved merging nanotechnology with living cells. On June 9th, 2020, Charles Lieber, a Harvard nanotechnology researcher with decades of experience, was indicted by the DOJ for fraud. Charles Lieber received millions of dollars in grant money from the US Department of Defense, specifically the military think tanks DARPA, AFOSR, and ONR, as well as NIH and MITRE. His specialty is the use of silicon nanowires in lieu of patch clamp electrodes to monitor and modulate intracellular activity, something he has been working on at Harvard for the past twenty years. He was claimed to have been working on silicon nanowire batteries in China, but none of his colleagues can recall him ever having worked on battery technology in his life; all of his research deals with bionanotechnology, or the blending of nanotech with living cells. The indictment was over his collaboration with the Wuhan University of Technology. He had double- dipped, against the terms of his DOD grants, and taken money from the PRC's Thousand Talents plan, a program which the Chinese government uses to bribe Western scientists into sharing proprietary R&D information that can be exploited by the PLA for strategic advantage. Charles Lieber's own papers describe the use of silicon nanowires for brain-computer interfaces, or “neural lace” technology. His papers describe how neurons can endocytose whole silicon nanowires or parts of them, monitoring and even modulating neuronal activity. Charles Lieber was a colleague of Robert Langer. Together, along with Daniel S. Kohane, they worked on a paper describing artificial tissue scaffolds that could be implanted in a human heart to monitor its activity remotely. Robert Langer, an MIT alumnus and expert in nanotech drug delivery, is one of the co-founders of Moderna. His net worth is now $5.1 billion USD thanks to Moderna's mRNA-1273 vaccine sales. Both Charles Lieber and Robert Langer's bibliographies describe, essentially, techniques for human enhancement, i.e. transhumanism. Klaus Schwab, the founder of the World Economic Forum and the architect behind the so-called “Great Reset”, has long spoken of the “blending of biology and machinery” in his books. Since these revelations, it has come to the attention of independent researchers that the COVID-19 vaccines may contain reduced graphene oxide nanoparticles. Japanese researchers have also found unexplained contaminants in COVID-19 vaccines. Graphene oxide is an anxiolytic. It has been shown to reduce the anxiety of laboratory mice when injected into their brains. Indeed, given SARS-CoV-2 Spike's propensity to compromise the blood-brain barrier and increase its permeability, it is the perfect protein for preparing brain tissue for extravasation of nanoparticles from the bloodstream and into the brain. Graphene is also highly conductive and, in some circumstances, paramagnetic. In 2013, under the Obama administration, DARPA launched the BRAIN Initiative; BRAIN is an acronym for Brain Research Through Advancing Innovative Neurotechnologies®. This program involves the development of brain-computer interface technologies for the military, particularly non-invasive, injectable systems that cause minimal damage to brain tissue when removed. Supposedly, this technology would be used for healing wounded soldiers with traumatic brain injuries, the direct brain control of prosthetic limbs, and even new abilities such as controlling drones with one's mind. Various methods have been proposed for achieving this, including optogenetics, magnetogenetics, ultrasound, implanted electrodes, and transcranial electromagnetic stimulation. In all instances, the goal is to obtain read or read-write capability over neurons, either by stimulating and probing them, or by rendering them especially sensitive to stimulation and probing. However, the notion of the widespread use of BCI technology, such as Elon Musk's Neuralink device, raises many concerns over privacy and personal autonomy. Reading from neurons is problematic enough on its own. Wireless brain-computer interfaces may interact with current or future wireless GSM infrastructure, creating neurological data security concerns. A hacker or other malicious actor may compromise such networks to obtain people's brain data, and then exploit it for nefarious purposes. However, a device capable of writing to human neurons, not just reading from them, presents another, even more serious set of ethical concerns. A BCI that is capable of altering the contents of one's mind for innocuous purposes, such as projecting a heads-up display onto their brain's visual center or sending audio into one's auditory cortex, would also theoretically be capable of altering mood and personality, or perhaps even subjugating someone's very will, rendering them utterly obedient to authority. This technology would be a tyrant's wet dream. Imagine soldiers who would shoot their own countrymen without hesitation, or helpless serfs who are satisfied to live in literal dog kennels. BCIs could be used to unscrupulously alter perceptions of basic things such as emotions and values, changing people's thresholds of satiety, happiness, anger, disgust, and so forth. This is not inconsequential. Someone's entire regime of behaviors could be altered by a BCI, including such things as suppressing their appetite or desire for virtually anything on Maslow's Hierarchy of Needs. Anything is possible when you have direct access to someone's brain and its contents. Someone who is obese could be made to feel disgust at the sight of food. Someone who is involuntarily celibate could have their libido disabled so they don't even desire sex to begin with. Someone who is racist could be forced to feel delight over cohabiting with people of other races. Someone who is violent could be forced to be meek and submissive. These things might sound good to you if you are a tyrant, but to normal people, the idea of personal autonomy being overridden to such a degree is appalling. For the wealthy, neural laces would be an unequaled boon, giving them the opportunity to enhance their intelligence with neuroprosthetics (i.e. an “exocortex”), and to deliver irresistible commands directly into the minds of their BCI-augmented servants, even physically or sexually abusive commands that they would normally refuse. If the vaccine is a method to surreptitiously introduce an injectable BCI into millions of people without their knowledge or consent, then what we are witnessing is the rise of a tyrannical regime unlike anything ever seen before on the face of this planet, one that fully intends to strip every man, woman, and child of our free will. Our flaws are what make us human. A utopia arrived at by removing people's free will is not a utopia at all. It is a monomaniacal nightmare. Furthermore, the people who rule over us are Dark Triad types who cannot be trusted with such power. Imagine being beaten and sexually assaulted by a wealthy and powerful psychopath and being forced to smile and laugh over it because your neural lace gives you no choice but to obey your master. The Elites are forging ahead with this technology without giving people any room to question the social or ethical ramifications, or to establish regulatory frameworks that ensure that our personal agency and autonomy will not be overridden by these devices. They do this because they secretly dream of a future where they can treat you worse than an animal and you cannot even fight back. If this evil plan is allowed to continue, it will spell the end of humanity as we know it. Conclusions: The current pandemic was produced and perpetuated by the establishment, through the use of a virus engineered in a PLA-connected Chinese biowarfare laboratory, with the aid of American taxpayer dollars and French expertise. This research was conducted under the absolutely ridiculous euphemism of “gain-of-function” research, which is supposedly carried out in order to determine which viruses have the highest potential for zoonotic spillover and preemptively vaccinate or guard against them. Gain-of-function/gain-of-threat research, a.k.a. “Dual-Use Research of Concern”, or DURC, is bioweapon research by another, friendlier-sounding name, simply to avoid the taboo of calling it what it actually is. It has always been bioweapon research. The people who are conducting this research fully understand that they are taking wild pathogens that are not infectious in humans and making them more infectious, often taking grants from military think tanks encouraging them to do so. These virologists conducting this type of research are enemies of their fellow man, like pyromaniac firefighters. GOF research has never protected anyone from any pandemic. In fact, it has now started one, meaning its utility for preventing pandemics is actually negative. It should have been banned globally, and the lunatics performing it should have been put in straitjackets long ago. Either through a leak or an intentional release from the Wuhan Institute of Virology, a deadly SARS strain is now endemic across the globe, after the WHO and CDC and public officials first downplayed the risks, and then intentionally incited a panic and lockdowns that jeopardized people's health and their livelihoods. This was then used by the utterly depraved and psychopathic aristocratic class who rule over us as an excuse to coerce people into accepting an injected poison which may be a depopulation agent, a mind control/pacification agent in the form of injectable “smart dust”, or both in one. They believe they can get away with this by weaponizing the social stigma of vaccine refusal. They are incorrect. Their motives are clear and obvious to anyone who has been paying attention. These megalomaniacs have raided the pension funds of the free world. Wall Street is insolvent and has had an ongoing liquidity crisis since the end of 2019. The aim now is to exert total, full-spectrum physical, mental, and financial control over humanity before we realize just how badly we've been extorted by these maniacs. The pandemic and its response served multiple purposes for the Elite: Concealing a depression brought on by the usurious plunder of our economies conducted by rentier-capitalists and absentee owners who produce absolutely nothing of any value to society whatsoever. Instead of us having a very predictable Occupy Wall Street Part II, the Elites and their stooges got to stand up on television and paint themselves as wise and all-powerful saviors instead of the marauding cabal of despicable land pirates that they are. Destroying small businesses and eroding the middle class. Transferring trillions of dollars of wealth from the American public and into the pockets of billionaires and special interests. Engaging in insider trading, buying stock in biotech companies and shorting brick-and-mortar businesses and travel companies, with the aim of collapsing face-to-face commerce and tourism and replacing it with e-commerce and servitization. Creating a casus belli for war with China, encouraging us to attack them, wasting American lives and treasure and driving us to the brink of nuclear armageddon. Establishing technological and biosecurity frameworks for population control and technocratic- socialist “smart cities” where everyone's movements are despotically tracked, all in anticipation of widespread automation, joblessness, and food shortages, by using the false guise of a vaccine to compel cooperation. Any one of these things would constitute a vicious rape of Western society. Taken together, they beggar belief; they are a complete inversion of our most treasured values. What is the purpose of all of this? One can only speculate as to the perpetrators' motives, however, we have some theories. The Elites are trying to pull up the ladder, erase upward mobility for large segments of the population, cull political opponents and other “undesirables”, and put the remainder of humanity on a tight leash, rationing our access to certain goods and services that they have deemed “high-impact”, such as automobile use, tourism, meat consumption, and so on. Naturally, they will continue to have their own luxuries, as part of a strict caste system akin to feudalism. Why are they doing this? Simple. The Elites are Neo-Malthusians and believe that we are overpopulated and that resource depletion will collapse civilization in a matter of a few short decades. They are not necessarily incorrect in this belief. We are overpopulated, and we are consuming too many resources. However, orchestrating such a gruesome and murderous power grab in response to a looming crisis demonstrates that they have nothing but the utmost contempt for their fellow man. To those who are participating in this disgusting farce without any understanding of what they are doing, we have one word for you. Stop. You are causing irreparable harm to your country and to your fellow citizens. To those who may be reading this warning and have full knowledge and understanding of what they are doing and how it will unjustly harm millions of innocent people, we have a few more words. Damn you to hell. You will not destroy America and the Free World, and you will not have your New World Order. We will make certain of that.

covid-19 america ceo american amazon conversations china technology japan americans french doctors chinese reading simple brain elon musk japanese dna north carolina western mit dm recovery barack obama current detroit twitch congress african americans harvard defense fbi vaccines camp wall street elite concerns oxford independent math alzheimer's disease scientists engaging traditional cdc fda republic naturally rico establishing swiss parkinson pfizer serial daniels national institutes anthony fauci moderna spike ngo billions usd bangladesh references destroying world economic forum wuhan ngos mumbai vitamin d hierarchy doj makes astrazeneca existing us department morning show new world order sars cov mrna nih cells sars sag infectious diseases dod cox neuralink usaid allergy maslow wireless great reset atp mute r d surgical lupus elites rna nda s2 transferring international development peep ivermectin darpa o2 spartacus s1 fenton ade unc chapel hill dengue pla sanofi virology envelope klaus schwab free world prc p4 j j mitre pfizer biontech enos palsy graphene gsm bci rw pathophysiology sod ards vaccine development wuhan institute c6 dengue fever dissolved dark triad raas united states agency vili paul e hek lewy body dementia gof guillain barre syndrome mpo marik cgmp nrf2 zantac oses peter daszak th2 hne brain initiative onr messenger rna wuhan university wiv robert langer nlrp3 oxidized soumya swaminathan nadph shelby township defense threat reduction agency moderna's mrna bradykinin intravenous vitamin c stephane bancel superoxide shi zhengli furin biomerieux dengvaxia indomethacin health national institute indian bar association

CWRW #193 Norway Say What??

Play Episode Listen Later Nov 8, 2021 119:28

This is the Morning Show that Makes you Hate All Morning Shows. Don't forget to follow https://twitter.com/https://linktr.ee/Theralphwilliam If you want a place to voice your opinions to all platforms sign up to podbean with this affiliate link https://www.podbean.com/GetCoffee Link for business hosting https://www.podbean.com/pro/GetCoffee Get some Merchandise TearzESC Shop | Redbubble Join us on Twitch! theralphwilliampodcast - Get 10% off when you use promo code RW at checkout Fromthedoctors.com Download our internet radio station in your App Store W-ESN Epic Strategies Network Epicstrategiesnetwork.com Rumble https://rumble.com/vh7g39-doggy-handling-competition.html If you are interested being apart of the discord server shoot us a DM on the social media's and joint the crew! Please Read the Rules: By calling in the show you are aware that the show will be published and that you are responsible for your own words and comments. Your opinions and commments does not reflect the views of the show. Say hello and acknowledge those in the chat when entering. Mute yourself when not talking or I will Mute You. Allow others to speak before speaking. Not a requirement but would appreciate it if you would SHARE the show Hello, My name is Spartacus, and I've had enough. We have been forced to watch America and the Free World spin into inexorable decline due to a biowarfare attack. We, along with countless others, have been victimized and gaslit by propaganda and psychological warfare operations being conducted by an unelected, unaccountable Elite against the American people and our allies. Our mental and physical health have suffered immensely over the course of the past year and a half. We have felt the sting of isolation, lockdown, masking, quarantines, and other completely nonsensical acts of healthcare theater that have done absolutely nothing to protect the health or wellbeing of the public from the ongoing COVID-19 pandemic. Now, we are watching the medical establishment inject literal poison into millions of our fellow Americans without so much as a fight. We have been told that we will be fired and denied our livelihoods if we refuse to vaccinate. This was the last straw. We have spent thousands of hours analyzing leaked footage from Wuhan, scientific papers from primary sources, as well as the paper trails left by the medical establishment. What we have discovered would shock anyone to their core. First, we will summarize our findings, and then, we will explain them in detail. References will be placed at the end. Summary: COVID-19 is a blood and blood vessel disease. SARS-CoV-2 infects the lining of human blood vessels, causing them to leak into the lungs. Current treatment protocols (e.g. invasive ventilation) are actively harmful to patients, accelerating oxidative stress and causing severe VILI (ventilator-induced lung injuries). The continued use of ventilators in the absence of any proven medical benefit constitutes mass murder. Existing countermeasures are inadequate to slow the spread of what is an aerosolized and potentially wastewater-borne virus, and constitute a form of medical theater. Various non-vaccine interventions have been suppressed by both the media and the medical establishment in favor of vaccines and expensive patented drugs. The authorities have denied the usefulness of natural immunity against COVID-19, despite the fact that natural immunity confers protection against all of the virus's proteins, and not just one. Vaccines will do more harm than good. The antigen that these vaccines are based on, SARS-CoV- 2 Spike, is a toxic protein. SARS-CoV-2 may have ADE, or antibody-dependent enhancement; current antibodies may not neutralize future strains, but instead help them infect immune cells. Also, vaccinating during a pandemic with a leaky vaccine removes the evolutionary pressure for a virus to become less lethal. There is a vast and appalling criminal conspiracy that directly links both Anthony Fauci and Moderna to the Wuhan Institute of Virology. COVID-19 vaccine researchers are directly linked to scientists involved in brain-computer interface (“neural lace”) tech, one of whom was indicted for taking grant money from China. Independent researchers have discovered mysterious nanoparticles inside the vaccines that are not supposed to be present. The entire pandemic is being used as an excuse for a vast political and economic transformation of Western society that will enrich the already rich and turn the rest of us into serfs and untouchables. COVID-19 Pathophysiology and Treatments: COVID-19 is not a viral pneumonia. It is a viral vascular endotheliitis and attacks the lining of blood vessels, particularly the small pulmonary alveolar capillaries, leading to endothelial cell activation and sloughing, coagulopathy, sepsis, pulmonary edema, and ARDS-like symptoms. This is a disease of the blood and blood vessels. The circulatory system. Any pneumonia that it causes is secondary to that. In severe cases, this leads to sepsis, blood clots, and multiple organ failure, including hypoxic and inflammatory damage to various vital organs, such as the brain, heart, liver, pancreas, kidneys, and intestines. Some of the most common laboratory findings in COVID-19 are elevated D-dimer, elevated prothrombin time, elevated C-reactive protein, neutrophilia, lymphopenia, hypocalcemia, and hyperferritinemia, essentially matching a profile of coagulopathy and immune system hyperactivation/immune cell exhaustion. COVID-19 can present as almost anything, due to the wide tropism of SARS-CoV-2 for various tissues in the body's vital organs. While its most common initial presentation is respiratory illness and flu-like symptoms, it can present as brain inflammation, gastrointestinal disease, or even heart attack or pulmonary embolism. COVID-19 is more severe in those with specific comorbidities, such as obesity, diabetes, and hypertension. This is because these conditions involve endothelial dysfunction, which renders the circulatory system more susceptible to infection and injury by this particular virus. The vast majority of COVID-19 cases are mild and do not cause significant disease. In known cases, there is something known as the 80/20 rule, where 80% of cases are mild and 20% are severe or critical. However, this ratio is only correct for known cases, not all infections. The number of actual infections is much, much higher. Consequently, the mortality and morbidity rate is lower. However, COVID-19 spreads very quickly, meaning that there are a significant number of severely-ill and critically-ill patients appearing in a short time frame. In those who have critical COVID-19-induced sepsis, hypoxia, coagulopathy, and ARDS, the most common treatments are intubation, injected corticosteroids, and blood thinners. This is not the correct treatment for COVID-19. In severe hypoxia, cellular metabolic shifts cause ATP to break down into hypoxanthine, which, upon the reintroduction of oxygen, causes xanthine oxidase to produce tons of highly damaging radicals that attack tissue. This is called ischemia-reperfusion injury, and it's why the majority of people who go on a ventilator are dying. In the mitochondria, succinate buildup due to sepsis does the same exact thing; when oxygen is reintroduced, it makes superoxide radicals. Make no mistake, intubation will kill people who have COVID-19. The end-stage of COVID-19 is severe lipid peroxidation, where fats in the body start to “rust” due to damage by oxidative stress. This drives autoimmunity. Oxidized lipids appear as foreign objects to the immune system, which recognizes and forms antibodies against OSEs, or oxidation-specific epitopes. Also, oxidized lipids feed directly into pattern recognition receptors, triggering even more inflammation and summoning even more cells of the innate immune system that release even more destructive enzymes. This is similar to the pathophysiology of Lupus. COVID-19's pathology is dominated by extreme oxidative stress and neutrophil respiratory burst, to the point where hemoglobin becomes incapable of carrying oxygen due to heme iron being stripped out of heme by hypochlorous acid. No amount of supplemental oxygen can oxygenate blood that chemically refuses to bind O2. The breakdown of the pathology is as follows: SARS-CoV-2 Spike binds to ACE2. Angiotensin Converting Enzyme 2 is an enzyme that is part of the renin-angiotensin-aldosterone system, or RAAS. The RAAS is a hormone control system that moderates fluid volume in the body and in the bloodstream (i.e. osmolarity) by controlling salt retention and excretion. This protein, ACE2, is ubiquitous in every part of the body that interfaces with the circulatory system, particularly in vascular endothelial cells and pericytes, brain astrocytes, renal tubules and podocytes, pancreatic islet cells, bile duct and intestinal epithelial cells, and the seminiferous ducts of the testis, all of which SARS-CoV-2 can infect, not just the lungs. SARS-CoV-2 infects a cell as follows: SARS-CoV-2 Spike undergoes a conformational change where the S1 trimers flip up and extend, locking onto ACE2 bound to the surface of a cell. TMPRSS2, or transmembrane protease serine 2, comes along and cuts off the heads of the Spike, exposing the S2 stalk-shaped subunit inside. The remainder of the Spike undergoes a conformational change that causes it to unfold like an extension ladder, embedding itself in the cell membrane. Then, it folds back upon itself, pulling the viral membrane and the cell membrane together. The two membranes fuse, with the virus's proteins migrating out onto the surface of the cell. The SARS-CoV-2 nucleocapsid enters the cell, disgorging its genetic material and beginning the viral replication process, hijacking the cell's own structures to produce more virus. SARS-CoV-2 Spike proteins embedded in a cell can actually cause human cells to fuse together, forming syncytia/MGCs (multinuclear giant cells). They also have other pathogenic, harmful effects. SARS-CoV- 2's viroporins, such as its Envelope protein, act as calcium ion channels, introducing calcium into infected cells. The virus suppresses the natural interferon response, resulting in delayed inflammation. SARS-CoV-2 N protein can also directly activate the NLRP3 inflammasome. Also, it suppresses the Nrf2 antioxidant pathway. The suppression of ACE2 by binding with Spike causes a buildup of bradykinin that would otherwise be broken down by ACE2. This constant calcium influx into the cells results in (or is accompanied by) noticeable hypocalcemia, or low blood calcium, especially in people with Vitamin D deficiencies and pre-existing endothelial dysfunction. Bradykinin upregulates cAMP, cGMP, COX, and Phospholipase C activity. This results in prostaglandin release and vastly increased intracellular calcium signaling, which promotes highly aggressive ROS release and ATP depletion. NADPH oxidase releases superoxide into the extracellular space. Superoxide radicals react with nitric oxide to form peroxynitrite. Peroxynitrite reacts with the tetrahydrobiopterin cofactor needed by endothelial nitric oxide synthase, destroying it and “uncoupling” the enzymes, causing nitric oxide synthase to synthesize more superoxide instead. This proceeds in a positive feedback loop until nitric oxide bioavailability in the circulatory system is depleted. Dissolved nitric oxide gas produced constantly by eNOS serves many important functions, but it is also antiviral against SARS-like coronaviruses, preventing the palmitoylation of the viral Spike protein and making it harder for it to bind to host receptors. The loss of NO allows the virus to begin replicating with impunity in the body. Those with endothelial dysfunction (i.e. hypertension, diabetes, obesity, old age, African-American race) have redox equilibrium issues to begin with, giving the virus an advantage. Due to the extreme cytokine release triggered by these processes, the body summons a great deal of neutrophils and monocyte-derived alveolar macrophages to the lungs. Cells of the innate immune system are the first-line defenders against pathogens. They work by engulfing invaders and trying to attack them with enzymes that produce powerful oxidants, like SOD and MPO. Superoxide dismutase takes superoxide and makes hydrogen peroxide, and myeloperoxidase takes hydrogen peroxide and chlorine ions and makes hypochlorous acid, which is many, many times more reactive than sodium hypochlorite bleach. Cytokine Storm Compilation: Covid-19 Vaccine Side Effects Neutrophils have a nasty trick. They can also eject these enzymes into the extracellular space, where they will continuously spit out peroxide and bleach into the bloodstream. This is called neutrophil extracellular trap formation, or, when it becomes pathogenic and counterproductive, NETosis. In severe and critical COVID-19, there is actually rather severe NETosis. Hypochlorous acid building up in the bloodstream begins to bleach the iron out of heme and compete for O2 binding sites. Red blood cells lose the ability to transport oxygen, causing the sufferer to turn blue in the face. Unliganded iron, hydrogen peroxide, and superoxide in the bloodstream undergo the Haber- Weiss and Fenton reactions, producing extremely reactive hydroxyl radicals that violently strip electrons from surrounding fats and DNA, oxidizing them severely. This condition is not unknown to medical science. The actual name for all of this is acute sepsis. We know this is happening in COVID-19 because people who have died of the disease have noticeable ferroptosis signatures in their tissues, as well as various other oxidative stress markers such as nitrotyrosine, 4-HNE, and malondialdehyde. When you intubate someone with this condition, you are setting off a free radical bomb by supplying the cells with O2. It's a catch-22, because we need oxygen to make Adenosine Triphosphate (that is, to live), but O2 is also the precursor of all these damaging radicals that lead to lipid peroxidation. The correct treatment for severe COVID-19 related sepsis is non-invasive ventilation, steroids, and antioxidant infusions. Most of the drugs repurposed for COVID-19 that show any benefit whatsoever in rescuing critically-ill COVID-19 patients are antioxidants. N-acetylcysteine, melatonin, fluvoxamine, budesonide, famotidine, cimetidine, and ranitidine are all antioxidants. Indomethacin prevents iron- driven oxidation of arachidonic acid to isoprostanes. There are powerful antioxidants such as apocynin that have not even been tested on COVID-19 patients yet which could defang neutrophils, prevent lipid peroxidation, restore endothelial health, and restore oxygenation to the tissues. Scientists who know anything about pulmonary neutrophilia, ARDS, and redox biology have known or surmised much of this since March 2020. In April 2020, Swiss scientists confirmed that COVID-19 was a vascular endotheliitis. By late 2020, experts had already concluded that COVID-19 causes a form of viral sepsis. They also know that sepsis can be effectively treated with antioxidants. None of this information is particularly new, and yet, for the most part, it has not been acted upon. Doctors continue to use damaging intubation techniques with high PEEP settings despite high lung compliance and poor oxygenation, killing an untold number of critically ill patients with medical malpractice. Because of the way they are constructed, Randomized Control Trials will never show any benefit for any antiviral against COVID-19. Not Remdesivir, not Kaletra, not HCQ, and not Ivermectin. The reason for this is simple; for the patients that they have recruited for these studies, such as Oxford's ludicrous RECOVERY study, the intervention is too late to have any positive effect. The clinical course of COVID-19 is such that by the time most people seek medical attention for hypoxia, their viral load has already tapered off to almost nothing. If someone is about 10 days post-exposure and has already been symptomatic for five days, there is hardly any virus left in their bodies, only cellular damage and derangement that has initiated a hyperinflammatory response. It is from this group that the clinical trials for antivirals have recruited, pretty much exclusively. In these trials, they give antivirals to severely ill patients who have no virus in their bodies, only a delayed hyperinflammatory response, and then absurdly claim that antivirals have no utility in treating or preventing COVID-19. These clinical trials do not recruit people who are pre-symptomatic. They do not test pre-exposure or post-exposure prophylaxis. This is like using a defibrillator to shock only flatline, and then absurdly claiming that defibrillators have no medical utility whatsoever when the patients refuse to rise from the dead. The intervention is too late. These trials for antivirals show systematic, egregious selection bias. They are providing a treatment that is futile to the specific cohort they are enrolling. India went against the instructions of the WHO and mandated the prophylactic usage of Ivermectin. They have almost completely eradicated COVID-19. The Indian Bar Association of Mumbai has brought criminal charges against WHO Chief Scientist Dr. Soumya Swaminathan for recommending against the use of Ivermectin. Ivermectin is not “horse dewormer”. Yes, it is sold in veterinary paste form as a dewormer for animals. It has also been available in pill form for humans for decades, as an antiparasitic drug. The media have disingenuously claimed that because Ivermectin is an antiparasitic drug, it has no utility as an antivirus. This is incorrect. Ivermectin has utility as an antiviral. It blocks importin, preventing nuclear import, effectively inhibiting viral access to cell nuclei. Many drugs currently on the market have multiple modes of action. Ivermectin is one such drug. It is both antiparasitic and antiviral. In Bangladesh, Ivermectin costs $1.80 for an entire 5-day course. Remdesivir, which is toxic to the liver, costs $3,120 for a 5-day course of the drug. Billions of dollars of utterly useless Remdesivir were sold to our governments on the taxpayer's dime, and it ended up being totally useless for treating hyperinflammatory COVID-19. The media has hardly even covered this at all. The opposition to the use of generic Ivermectin is not based in science. It is purely financially and politically-motivated. An effective non-vaccine intervention would jeopardize the rushed FDA approval of patented vaccines and medicines for which the pharmaceutical industry stands to rake in billions upon billions of dollars in sales on an ongoing basis. The majority of the public are scientifically illiterate and cannot grasp what any of this even means, thanks to a pathetic educational system that has miseducated them. You would be lucky to find 1 in 100 people who have even the faintest clue what any of this actually means. COVID-19 Transmission: COVID-19 is airborne. The WHO carried water for China by claiming that the virus was only droplet- borne. Our own CDC absurdly claimed that it was mostly transmitted by fomite-to-face contact, which, given its rapid spread from Wuhan to the rest of the world, would have been physically impossible. The ridiculous belief in fomite-to-face being a primary mode of transmission led to the use of surface disinfection protocols that wasted time, energy, productivity, and disinfectant. The 6-foot guidelines are absolutely useless. The minimum safe distance to protect oneself from an aerosolized virus is to be 15+ feet away from an infected person, no closer. Realistically, no public transit is safe. Surgical masks do not protect you from aerosols. The virus is too small and the filter media has too large of gaps to filter it out. They may catch respiratory droplets and keep the virus from being expelled by someone who is sick, but they do not filter a cloud of infectious aerosols if someone were to walk into said cloud. The minimum level of protection against this virus is quite literally a P100 respirator, a PAPR/CAPR, or a 40mm NATO CBRN respirator, ideally paired with a full-body tyvek or tychem suit, gloves, and booties, with all the holes and gaps taped. Live SARS-CoV-2 may potentially be detected in sewage outflows, and there may be oral-fecal transmission. During the SARS outbreak in 2003, in the Amoy Gardens incident, hundreds of people were infected by aerosolized fecal matter rising from floor drains in their apartments. COVID-19 Vaccine Dangers: The vaccines for COVID-19 are not sterilizing and do not prevent infection or transmission. They are “leaky” vaccines. This means they remove the evolutionary pressure on the virus to become less lethal. It also means that the vaccinated are perfect carriers. In other words, those who are vaccinated are a threat to the unvaccinated, not the other way around. All of the COVID-19 vaccines currently in use have undergone minimal testing, with highly accelerated clinical trials. Though they appear to limit severe illness, the long-term safety profile of these vaccines remains unknown. Some of these so-called “vaccines” utilize an untested new technology that has never been used in vaccines before. Traditional vaccines use weakened or killed virus to stimulate an immune response. The Moderna and Pfizer-BioNTech vaccines do not. They are purported to consist of an intramuscular shot containing a suspension of lipid nanoparticles filled with messenger RNA. The way they generate an immune response is by fusing with cells in a vaccine recipient's shoulder, undergoing endocytosis, releasing their mRNA cargo into those cells, and then utilizing the ribosomes in those cells to synthesize modified SARS-CoV-2 Spike proteins in-situ. These modified Spike proteins then migrate to the surface of the cell, where they are anchored in place by a transmembrane domain. The adaptive immune system detects the non-human viral protein being expressed by these cells, and then forms antibodies against that protein. This is purported to confer protection against the virus, by training the adaptive immune system to recognize and produce antibodies against the Spike on the actual virus. The J&J and AstraZeneca vaccines do something similar, but use an adenovirus vector for genetic material delivery instead of a lipid nanoparticle. These vaccines were produced or validated with the aid of fetal cell lines HEK-293 and PER.C6, which people with certain religious convictions may object strongly to. SARS-CoV-2 Spike is a highly pathogenic protein on its own. It is impossible to overstate the danger presented by introducing this protein into the human body. It is claimed by vaccine manufacturers that the vaccine remains in cells in the shoulder, and that SARS- CoV-2 Spike produced and expressed by these cells from the vaccine's genetic material is harmless and inert, thanks to the insertion of prolines in the Spike sequence to stabilize it in the prefusion conformation, preventing the Spike from becoming active and fusing with other cells. However, a pharmacokinetic study from Japan showed that the lipid nanoparticles and mRNA from the Pfizer vaccine did not stay in the shoulder, and in fact bioaccumulated in many different organs, including the reproductive organs and adrenal glands, meaning that modified Spike is being expressed quite literally all over the place. These lipid nanoparticles may trigger anaphylaxis in an unlucky few, but far more concerning is the unregulated expression of Spike in various somatic cell lines far from the injection site and the unknown consequences of that. Messenger RNA is normally consumed right after it is produced in the body, being translated into a protein by a ribosome. COVID-19 vaccine mRNA is produced outside the body, long before a ribosome translates it. In the meantime, it could accumulate damage if inadequately preserved. When a ribosome attempts to translate a damaged strand of mRNA, it can become stalled. When this happens, the ribosome becomes useless for translating proteins because it now has a piece of mRNA stuck in it, like a lace card in an old punch card reader. The whole thing has to be cleaned up and new ribosomes synthesized to replace it. In cells with low ribosome turnover, like nerve cells, this can lead to reduced protein synthesis, cytopathic effects, and neuropathies. Certain proteins, including SARS-CoV-2 Spike, have proteolytic cleavage sites that are basically like little dotted lines that say “cut here”, which attract a living organism's own proteases (essentially, molecular scissors) to cut them. There is a possibility that S1 may be proteolytically cleaved from S2, causing active S1 to float away into the bloodstream while leaving the S2 “stalk” embedded in the membrane of the cell that expressed the protein. SARS-CoV-2 Spike has a Superantigenic region (SAg), which may promote extreme inflammation. Anti-Spike antibodies were found in one study to function as autoantibodies and attack the body's own cells. Those who have been immunized with COVID-19 vaccines have developed blood clots, myocarditis, Guillain-Barre Syndrome, Bell's Palsy, and multiple sclerosis flares, indicating that the vaccine promotes autoimmune reactions against healthy tissue. SARS-CoV-2 Spike does not only bind to ACE2. It was suspected to have regions that bind to basigin, integrins, neuropilin-1, and bacterial lipopolysaccharides as well. SARS-CoV-2 Spike, on its own, can potentially bind any of these things and act as a ligand for them, triggering unspecified and likely highly inflammatory cellular activity. SARS-CoV-2 Spike contains an unusual PRRA insert that forms a furin cleavage site. Furin is a ubiquitous human protease, making this an ideal property for the Spike to have, giving it a high degree of cell tropism. No wild-type SARS-like coronaviruses related to SARS-CoV-2 possess this feature, making it highly suspicious, and perhaps a sign of human tampering. SARS-CoV-2 Spike has a prion-like domain that enhances its infectiousness. The Spike S1 RBD may bind to heparin-binding proteins and promote amyloid aggregation. In humans, this could lead to Parkinson's, Lewy Body Dementia, premature Alzheimer's, or various other neurodegenerative diseases. This is very concerning because SARS-CoV-2 S1 is capable of injuring and penetrating the blood-brain barrier and entering the brain. It is also capable of increasing the permeability of the blood-brain barrier to other molecules. SARS-CoV-2, like other betacoronaviruses, may have Dengue-like ADE, or antibody-dependent enhancement of disease. For those who aren't aware, some viruses, including betacoronaviruses, have a feature called ADE. There is also something called Original Antigenic Sin, which is the observation that the body prefers to produce antibodies based on previously-encountered strains of a virus over newly- encountered ones. In ADE, antibodies from a previous infection become non-neutralizing due to mutations in the virus's proteins. These non-neutralizing antibodies then act as trojan horses, allowing live, active virus to be pulled into macrophages through their Fc receptor pathways, allowing the virus to infect immune cells that it would not have been able to infect before. This has been known to happen with Dengue Fever; when someone gets sick with Dengue, recovers, and then contracts a different strain, they can get very, very ill. If someone is vaccinated with mRNA based on the Spike from the initial Wuhan strain of SARS-CoV-2, and then they become infected with a future, mutated strain of the virus, they may become severely ill. In other words, it is possible for vaccines to sensitize someone to disease. There is a precedent for this in recent history. Sanofi's Dengvaxia vaccine for Dengue failed because it caused immune sensitization in people whose immune systems were Dengue-naive. In mice immunized against SARS-CoV and challenged with the virus, a close relative of SARS-CoV-2, they developed immune sensitization, Th2 immunopathology, and eosinophil infiltration in their lungs. We have been told that SARS-CoV-2 mRNA vaccines cannot be integrated into the human genome, because messenger RNA cannot be turned back into DNA. This is false. There are elements in human cells called LINE-1 retrotransposons, which can indeed integrate mRNA into a human genome by endogenous reverse transcription. Because the mRNA used in the vaccines is stabilized, it hangs around in cells longer, increasing the chances for this to happen. If the gene for SARS-CoV-2 Spike is integrated into a portion of the genome that is not silent and actually expresses a protein, it is possible that people who take this vaccine may continuously express SARS-CoV-2 Spike from their somatic cells for the rest of their lives. By inoculating people with a vaccine that causes their bodies to produce Spike in-situ, they are being inoculated with a pathogenic protein. A toxin that may cause long-term inflammation, heart problems, and a raised risk of cancers. In the long-term, it may also potentially lead to premature neurodegenerative disease. Absolutely nobody should be compelled to take this vaccine under any circumstances, and in actual fact, the vaccination campaign must be stopped immediately. COVID-19 Criminal Conspiracy: The vaccine and the virus were made by the same people. In 2014, there was a moratorium on SARS gain-of-function research that lasted until 2017. This research was not halted. Instead, it was outsourced, with the federal grants being laundered through NGOs. Ralph Baric is a virologist and SARS expert at UNC Chapel Hill in North Carolina. This is who Anthony Fauci was referring to when he insisted, before Congress, that if any gain-of-function research was being conducted, it was being conducted in North Carolina. This was a lie. Anthony Fauci lied before Congress. A felony. Ralph Baric and Shi Zhengli are colleagues and have co-written papers together. Ralph Baric mentored Shi Zhengli in his gain-of-function manipulation techniques, particularly serial passage, which results in a virus that appears as if it originated naturally. In other words, deniable bioweapons. Serial passage in humanized hACE2 mice may have produced something like SARS-CoV-2. The funding for the gain-of-function research being conducted at the Wuhan Institute of Virology came from Peter Daszak. Peter Daszak runs an NGO called EcoHealth Alliance. EcoHealth Alliance received millions of dollars in grant money from the National Institutes of Health/National Institute of Allergy and Infectious Diseases (that is, Anthony Fauci), the Defense Threat Reduction Agency (part of the US Department of Defense), and the United States Agency for International Development. NIH/NIAID contributed a few million dollars, and DTRA and USAID each contributed tens of millions of dollars towards this research. Altogether, it was over a hundred million dollars. EcoHealth Alliance subcontracted these grants to the Wuhan Institute of Virology, a lab in China with a very questionable safety record and poorly trained staff, so that they could conduct gain-of-function research, not in their fancy P4 lab, but in a level-2 lab where technicians wore nothing more sophisticated than perhaps a hairnet, latex gloves, and a surgical mask, instead of the bubble suits used when working with dangerous viruses. Chinese scientists in Wuhan reported being routinely bitten and urinated on by laboratory animals. Why anyone would outsource this dangerous and delicate work to the People's Republic of China, a country infamous for industrial accidents and massive explosions that have claimed hundreds of lives, is completely beyond me, unless the aim was to start a pandemic on purpose. In November of 2019, three technicians at the Wuhan Institute of Virology developed symptoms consistent with a flu-like illness. Anthony Fauci, Peter Daszak, and Ralph Baric knew at once what had happened, because back channels exist between this laboratory and our scientists and officials. December 12th, 2019, Ralph Baric signed a Material Transfer Agreement (essentially, an NDA) to receive Coronavirus mRNA vaccine-related materials co-owned by Moderna and NIH. It wasn't until a whole month later, on January 11th, 2020, that China allegedly sent us the sequence to what would become known as SARS-CoV-2. Moderna claims, rather absurdly, that they developed a working vaccine from this sequence in under 48 hours. Stephane Bancel, the current CEO of Moderna, was formerly the CEO of bioMerieux, a French multinational corporation specializing in medical diagnostic tech, founded by one Alain Merieux. Alain Merieux was one of the individuals who was instrumental in the construction of the Wuhan Institute of Virology's P4 lab. The sequence given as the closest relative to SARS-CoV-2, RaTG13, is not a real virus. It is a forgery. It was made by entering a gene sequence by hand into a database, to create a cover story for the existence of SARS-CoV-2, which is very likely a gain-of-function chimera produced at the Wuhan Institute of Virology and was either leaked by accident or intentionally released. The animal reservoir of SARS-CoV-2 has never been found. This is not a conspiracy “theory”. It is an actual criminal conspiracy, in which people connected to the development of Moderna's mRNA-1273 are directly connected to the Wuhan Institute of Virology and their gain-of-function research by very few degrees of separation, if any. The paper trail is well- established. The lab-leak theory has been suppressed because pulling that thread leads one to inevitably conclude that there is enough circumstantial evidence to link Moderna, the NIH, the WIV, and both the vaccine and the virus's creation together. In a sane country, this would have immediately led to the world's biggest RICO and mass murder case. Anthony Fauci, Peter Daszak, Ralph Baric, Shi Zhengli, and Stephane Bancel, and their accomplices, would have been indicted and prosecuted to the fullest extent of the law. Instead, billions of our tax dollars were awarded to the perpetrators. The FBI raided Allure Medical in Shelby Township north of Detroit for billing insurance for “fraudulent COVID-19 cures”. The treatment they were using? Intravenous Vitamin C. An antioxidant. Which, as described above, is an entirely valid treatment for COVID-19-induced sepsis, and indeed, is now part of the MATH+ protocol advanced by Dr. Paul E. Marik. The FDA banned ranitidine (Zantac) due to supposed NDMA (N-nitrosodimethylamine) contamination. Ranitidine is not only an H2 blocker used as antacid, but also has a powerful antioxidant effect, scavenging hydroxyl radicals. This gives it utility in treating COVID-19. The FDA also attempted to take N-acetylcysteine, a harmless amino acid supplement and antioxidant, off the shelves, compelling Amazon to remove it from their online storefront. This leaves us with a chilling question: did the FDA knowingly suppress antioxidants useful for treating COVID-19 sepsis as part of a criminal conspiracy against the American public? The establishment is cooperating with, and facilitating, the worst criminals in human history, and are actively suppressing non-vaccine treatments and therapies in order to compel us to inject these criminals' products into our bodies. This is absolutely unacceptable. COVID-19 Vaccine Development and Links to Transhumanism: This section deals with some more speculative aspects of the pandemic and the medical and scientific establishment's reaction to it, as well as the disturbing links between scientists involved in vaccine research and scientists whose work involved merging nanotechnology with living cells. On June 9th, 2020, Charles Lieber, a Harvard nanotechnology researcher with decades of experience, was indicted by the DOJ for fraud. Charles Lieber received millions of dollars in grant money from the US Department of Defense, specifically the military think tanks DARPA, AFOSR, and ONR, as well as NIH and MITRE. His specialty is the use of silicon nanowires in lieu of patch clamp electrodes to monitor and modulate intracellular activity, something he has been working on at Harvard for the past twenty years. He was claimed to have been working on silicon nanowire batteries in China, but none of his colleagues can recall him ever having worked on battery technology in his life; all of his research deals with bionanotechnology, or the blending of nanotech with living cells. The indictment was over his collaboration with the Wuhan University of Technology. He had double- dipped, against the terms of his DOD grants, and taken money from the PRC's Thousand Talents plan, a program which the Chinese government uses to bribe Western scientists into sharing proprietary R&D information that can be exploited by the PLA for strategic advantage. Charles Lieber's own papers describe the use of silicon nanowires for brain-computer interfaces, or “neural lace” technology. His papers describe how neurons can endocytose whole silicon nanowires or parts of them, monitoring and even modulating neuronal activity. Charles Lieber was a colleague of Robert Langer. Together, along with Daniel S. Kohane, they worked on a paper describing artificial tissue scaffolds that could be implanted in a human heart to monitor its activity remotely. Robert Langer, an MIT alumnus and expert in nanotech drug delivery, is one of the co-founders of Moderna. His net worth is now $5.1 billion USD thanks to Moderna's mRNA-1273 vaccine sales. Both Charles Lieber and Robert Langer's bibliographies describe, essentially, techniques for human enhancement, i.e. transhumanism. Klaus Schwab, the founder of the World Economic Forum and the architect behind the so-called “Great Reset”, has long spoken of the “blending of biology and machinery” in his books. Since these revelations, it has come to the attention of independent researchers that the COVID-19 vaccines may contain reduced graphene oxide nanoparticles. Japanese researchers have also found unexplained contaminants in COVID-19 vaccines. Graphene oxide is an anxiolytic. It has been shown to reduce the anxiety of laboratory mice when injected into their brains. Indeed, given SARS-CoV-2 Spike's propensity to compromise the blood-brain barrier and increase its permeability, it is the perfect protein for preparing brain tissue for extravasation of nanoparticles from the bloodstream and into the brain. Graphene is also highly conductive and, in some circumstances, paramagnetic. In 2013, under the Obama administration, DARPA launched the BRAIN Initiative; BRAIN is an acronym for Brain Research Through Advancing Innovative Neurotechnologies®. This program involves the development of brain-computer interface technologies for the military, particularly non-invasive, injectable systems that cause minimal damage to brain tissue when removed. Supposedly, this technology would be used for healing wounded soldiers with traumatic brain injuries, the direct brain control of prosthetic limbs, and even new abilities such as controlling drones with one's mind. Various methods have been proposed for achieving this, including optogenetics, magnetogenetics, ultrasound, implanted electrodes, and transcranial electromagnetic stimulation. In all instances, the goal is to obtain read or read-write capability over neurons, either by stimulating and probing them, or by rendering them especially sensitive to stimulation and probing. However, the notion of the widespread use of BCI technology, such as Elon Musk's Neuralink device, raises many concerns over privacy and personal autonomy. Reading from neurons is problematic enough on its own. Wireless brain-computer interfaces may interact with current or future wireless GSM infrastructure, creating neurological data security concerns. A hacker or other malicious actor may compromise such networks to obtain people's brain data, and then exploit it for nefarious purposes. However, a device capable of writing to human neurons, not just reading from them, presents another, even more serious set of ethical concerns. A BCI that is capable of altering the contents of one's mind for innocuous purposes, such as projecting a heads-up display onto their brain's visual center or sending audio into one's auditory cortex, would also theoretically be capable of altering mood and personality, or perhaps even subjugating someone's very will, rendering them utterly obedient to authority. This technology would be a tyrant's wet dream. Imagine soldiers who would shoot their own countrymen without hesitation, or helpless serfs who are satisfied to live in literal dog kennels. BCIs could be used to unscrupulously alter perceptions of basic things such as emotions and values, changing people's thresholds of satiety, happiness, anger, disgust, and so forth. This is not inconsequential. Someone's entire regime of behaviors could be altered by a BCI, including such things as suppressing their appetite or desire for virtually anything on Maslow's Hierarchy of Needs. Anything is possible when you have direct access to someone's brain and its contents. Someone who is obese could be made to feel disgust at the sight of food. Someone who is involuntarily celibate could have their libido disabled so they don't even desire sex to begin with. Someone who is racist could be forced to feel delight over cohabiting with people of other races. Someone who is violent could be forced to be meek and submissive. These things might sound good to you if you are a tyrant, but to normal people, the idea of personal autonomy being overridden to such a degree is appalling. For the wealthy, neural laces would be an unequaled boon, giving them the opportunity to enhance their intelligence with neuroprosthetics (i.e. an “exocortex”), and to deliver irresistible commands directly into the minds of their BCI-augmented servants, even physically or sexually abusive commands that they would normally refuse. If the vaccine is a method to surreptitiously introduce an injectable BCI into millions of people without their knowledge or consent, then what we are witnessing is the rise of a tyrannical regime unlike anything ever seen before on the face of this planet, one that fully intends to strip every man, woman, and child of our free will. Our flaws are what make us human. A utopia arrived at by removing people's free will is not a utopia at all. It is a monomaniacal nightmare. Furthermore, the people who rule over us are Dark Triad types who cannot be trusted with such power. Imagine being beaten and sexually assaulted by a wealthy and powerful psychopath and being forced to smile and laugh over it because your neural lace gives you no choice but to obey your master. The Elites are forging ahead with this technology without giving people any room to question the social or ethical ramifications, or to establish regulatory frameworks that ensure that our personal agency and autonomy will not be overridden by these devices. They do this because they secretly dream of a future where they can treat you worse than an animal and you cannot even fight back. If this evil plan is allowed to continue, it will spell the end of humanity as we know it. Conclusions: The current pandemic was produced and perpetuated by the establishment, through the use of a virus engineered in a PLA-connected Chinese biowarfare laboratory, with the aid of American taxpayer dollars and French expertise. This research was conducted under the absolutely ridiculous euphemism of “gain-of-function” research, which is supposedly carried out in order to determine which viruses have the highest potential for zoonotic spillover and preemptively vaccinate or guard against them. Gain-of-function/gain-of-threat research, a.k.a. “Dual-Use Research of Concern”, or DURC, is bioweapon research by another, friendlier-sounding name, simply to avoid the taboo of calling it what it actually is. It has always been bioweapon research. The people who are conducting this research fully understand that they are taking wild pathogens that are not infectious in humans and making them more infectious, often taking grants from military think tanks encouraging them to do so. These virologists conducting this type of research are enemies of their fellow man, like pyromaniac firefighters. GOF research has never protected anyone from any pandemic. In fact, it has now started one, meaning its utility for preventing pandemics is actually negative. It should have been banned globally, and the lunatics performing it should have been put in straitjackets long ago. Either through a leak or an intentional release from the Wuhan Institute of Virology, a deadly SARS strain is now endemic across the globe, after the WHO and CDC and public officials first downplayed the risks, and then intentionally incited a panic and lockdowns that jeopardized people's health and their livelihoods. This was then used by the utterly depraved and psychopathic aristocratic class who rule over us as an excuse to coerce people into accepting an injected poison which may be a depopulation agent, a mind control/pacification agent in the form of injectable “smart dust”, or both in one. They believe they can get away with this by weaponizing the social stigma of vaccine refusal. They are incorrect. Their motives are clear and obvious to anyone who has been paying attention. These megalomaniacs have raided the pension funds of the free world. Wall Street is insolvent and has had an ongoing liquidity crisis since the end of 2019. The aim now is to exert total, full-spectrum physical, mental, and financial control over humanity before we realize just how badly we've been extorted by these maniacs. The pandemic and its response served multiple purposes for the Elite: Concealing a depression brought on by the usurious plunder of our economies conducted by rentier-capitalists and absentee owners who produce absolutely nothing of any value to society whatsoever. Instead of us having a very predictable Occupy Wall Street Part II, the Elites and their stooges got to stand up on television and paint themselves as wise and all-powerful saviors instead of the marauding cabal of despicable land pirates that they are. Destroying small businesses and eroding the middle class. Transferring trillions of dollars of wealth from the American public and into the pockets of billionaires and special interests. Engaging in insider trading, buying stock in biotech companies and shorting brick-and-mortar businesses and travel companies, with the aim of collapsing face-to-face commerce and tourism and replacing it with e-commerce and servitization. Creating a casus belli for war with China, encouraging us to attack them, wasting American lives and treasure and driving us to the brink of nuclear armageddon. Establishing technological and biosecurity frameworks for population control and technocratic- socialist “smart cities” where everyone's movements are despotically tracked, all in anticipation of widespread automation, joblessness, and food shortages, by using the false guise of a vaccine to compel cooperation. Any one of these things would constitute a vicious rape of Western society. Taken together, they beggar belief; they are a complete inversion of our most treasured values. What is the purpose of all of this? One can only speculate as to the perpetrators' motives, however, we have some theories. The Elites are trying to pull up the ladder, erase upward mobility for large segments of the population, cull political opponents and other “undesirables”, and put the remainder of humanity on a tight leash, rationing our access to certain goods and services that they have deemed “high-impact”, such as automobile use, tourism, meat consumption, and so on. Naturally, they will continue to have their own luxuries, as part of a strict caste system akin to feudalism. Why are they doing this? Simple. The Elites are Neo-Malthusians and believe that we are overpopulated and that resource depletion will collapse civilization in a matter of a few short decades. They are not necessarily incorrect in this belief. We are overpopulated, and we are consuming too many resources. However, orchestrating such a gruesome and murderous power grab in response to a looming crisis demonstrates that they have nothing but the utmost contempt for their fellow man. To those who are participating in this disgusting farce without any understanding of what they are doing, we have one word for you. Stop. You are causing irreparable harm to your country and to your fellow citizens. To those who may be reading this warning and have full knowledge and understanding of what they are doing and how it will unjustly harm millions of innocent people, we have a few more words. Damn you to hell. You will not destroy America and the Free World, and you will not have your New World Order. We will make certain of that.

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CWRW #192