Podcasts about Inflammasome

From the 2024 Society for Leukocyte Biology meeting, Immune talks with Amy Hise about her career in science, her current research using mouse models for investigating fungal immunity and navigating the challenges of being a mom in science. Hosts: Cindy Leifer and Brianne Barker Guest: Amy Hise MicrobeTV Discord Server Mouse model for testing drugs to treat Candida fungal infection Inflammasomes in Aspergillosis Society for Leukocyte Biology Subscribe (free): Apple Podcasts, RSS, email Become a patron of Immune! Music by Tatami. Logo image by Blausen Medical Send your immunology questions and comments to immune@microbe.tv Content in this podcast should not be construed as medical advice.

References Guerra, D. 2024 Previous Mosaic III lectures and content. https://podcasts.apple.com/us/podcast/authentic-biochemistry/id1454408625 Hayward, J. 1969. "Never Comes the Day" from Moody Blues lp. Threshold of a Dream. https://youtu.be/8u1zH11yqFQ?si=xtXp1SWm8rF1RdFS Mozart, WA.1785. String Quartet No. 19 in C Major, K. 465 https://youtu.be/f3oK4XVMARs?si=FMypvP8O_WCII7vR Page, J.1972. "The Rain Song" Led Zeppelin Houses of the Holy lp. https://youtu.be/g8VduT7aR2c?si=zB2oS2kCV2t4WtEb --- 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

References J Lipid Res. 2022 Dec; 63(12): 100298. Mol Cells. 2020 Aug 31; 43(8): 749–762. Bach J.S. 1727. St Matthew Passion, BWV 244. https://www.youtube.com/live/3fP-rET0kFI?si=ZX-edMPg1wBA_5mh Squire, Chris. 1978. "You Can Be Saved" Yes. https://youtu.be/0TNzPHoVlz8?si=bFMp6w4T2SL6XxS4 --- 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

References Redox Biol. 2020 Apr; 31: 101482 Nat Rev Microbiol. 2009 Feb; 7(2): 99–109. J Neuroinflammation. 2019; 16: 236. Front Pharmacol. 2021; 12: 643254. Biber, H. 1676. "Passagalia" por solo violin https://youtu.be/sgcR183f8gA?si=ovfSbdg6WsfuIiTw McBroom, A. 1976. "The Rose" Conway Twitty https://youtu.be/cO59ITNCxzk?si=ueMmXtzMNH4YeQ_w Hunter-Weir. 1970. "Sugar Magnolia" American Beauty L.P. https://youtu.be/ei5EmN2HmVI?si=6ZrBBPmu3cMyMOAO --- 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

References Int J Mol Sci. 2021 Jul; 22(14): 7580. Trends Biochem Sci. 2023 Apr;48(4):331-344 Immunology. 2020;159:142–155 Curr. Opin. Immunol. 2020;62:39–44. Nat. Rev. Mol. Cell Biol. 2019;20:569–570. Lennon-McCartney. 1963. "This Boy" https://youtu.be/lW5D7HpYhBU?si=mHyiFng3rd3pukob Lennon-McCartney.1966. "And your Bird Can Sing" https://youtu.be/sOUlbredoUM?si=nPB64c8GS4joYx9G Lennon-McCartney 1969. "Let it Be" https://youtu.be/QDYfEBY9NM4?si=H6t6bwrv3vUNWoDj Vivaldi, A. 1715 "Gloria" https://youtu.be/RMHguvZPcqQ?si=igPXLKL9O0YbRWKz --- 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

References Front Immunol. 2019; 10: 1309 Immunity. 2018 Sep 18; 49(3):413–426.e5. Front Immunol. 2020; 11: 621733 Infect Immun. 2013 Dec; 81(12): 4478–4489. Immunity. 2023 Nov 14;56(11):2523-2541.e8. Harrison, G. 1969. "Here Comes the Sun" Abbey Road Lp. Beatles https://youtu.be/GKdl-GCsNJ0?si=xUqwi3Q7Ne694ruD Mozart, WA. 1775. Violin Concerto No.3 in G major, K. 216 https://youtu.be/j7Z6gouAVCc?si=xVwtNKAWDEDdtKMV Parsons, G. 1965 "Brass Buttons" Poco: Crazy Eyes Lp. https://youtu.be/CpFytplzLhI?si=vw08Gut3E-otgA9x --- 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

References Infect Immun. 2013 Dec; 81(12): 4478–4489 Cell Cycle. 2022; 21(11): 1121–1139. The Journal of Nutritional Biochem.2023.Volume 112, 109217 Lightfoot, G. 1964. "Early Morning Rain" https://youtu.be/ZFJ5Bj_put0?si=m1Ue7rFfk_ggSLR3 Simon ,P. 1968. "Old Friends" SImon and Garfunkle Bookends LP. https://youtu.be/7A76lTte8qE?si=rfk3Q6wTA6Nsiok7 Mozart, WA. 1782 Serenade in C. Minor K.388. https://youtu.be/R6iSGBNdqSw?si=S2eGPmcySUhw4uvU --- 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

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

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

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

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

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

Was your psoriasis caused by the Black Death? Learn more than you might have wanted to know about the Black Death and delve into the data on the immunologic/autoimmune ramifications of wiping out nearly half of Europe. ·       Intro 0:11 ·       In this episode 1:09 ·       The Black Death 1:24 ·       The History of IV Immunoglobulin episode 2:07 ·       How the Black Death happened 4:07 ·       How many people died from the Black Death? 6:49 ·       Record keeping 6:53 ·       The modern immune system, the Black Death and HIV 8:43 ·       What is CCR5? 8:55 ·       Current data on autoimmune diseases 10:35 ·       ERAP2 15:55 ·       How yersinia pestis kills you 21:04 ·       The inflammasome 22:03 ·       The Inflammasome for Dunces episode 22:09 ·       Mediterranean fever and mouse model 24:49 ·       Takeaways 30:20 ·       Summary 30:59 Disclosures: Brown reports no relevant financial disclosures. We'd love to hear from you! Send your comments/questions to Dr. Brown at rheuminationspodcast@healio.com. Follow us on Twitter @HRheuminations @AdamJBrownMD @HealioRheum. References: Wheelis M. Emerg Infect Dis. 2002;doi:10.3201/eid0809.100536. Ratner D, et al. PLoS Pathog. 2016;doi:10.1371/journal.ppat.1006035. Park YH, et al. Nat Immunol. 2020;doi:10.1038/s41590-020-0705-6. Patin E. Nat Immunol. 2020;doi:10.1038/s41590-020-0724-3. Galvani AP, et al. Proc Natl Acad Sci USA. 2003;doi:10.1073/pnas.2435085100.

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

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

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

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

Commentary by Dr. Valentin Fuster

References Chem Biol Interact. 2019 Dec 12; 316: 108917 J Neuroinflammation. 2019; 16: 236. --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message Support this podcast: https://anchor.fm/dr-daniel-j-guerra/support

The TWiM folk explore disruption of a Burkholderia intracellular niche by a cell death program, and an increase in Brucella infectiousness after intracellular passage. Become a patron of TWiM. Links for this episode: Disrupting intracellular niche (mBio) Intracellular passage increases infectiousness (Infect Immun) Type IV secretion systems (Front Micro) Music used on TWiM is composed and performed by Ronald Jenkees and used with permission. Send your microbiology questions and comments to twim@microbe.tv

In this episode of AwardsCast, the 2020 recipient of the Newcomer Helping Hand Award, Dr. Regina Vontell, sits down with Konnie Zeitner, NSH Speaker of the House and fellow past award recipient, to discuss Dr. Vontell's work with visualizing inflammasome structure in the brain. Applications for the 2021 Newcomer Helping Hand Award, sponsored by Newcomer Supply, are open until June 4th. Apply today! 

Commentary by Dr. Douglas Mann

This week’s episode features author Jaime Layland and Associate Editor Dharam Kumbhani as they discuss the ariticle "Colchicine in Patients with Acute Coronary Syndrome: The Australian COPS Randomized Clinical Trial." TRANSCRIPT BELOW: Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast, summary, and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center, VCU Health, in Richmond, Virginia. Dr. Carolyn Lam: Greg, for our feature discussion we're talking about a very hot topic these days, the role of colchicine, this time in patients with acute coronary syndrome, with Australian data. I cannot wait to get to that, but I'm going to make you wait because I want to tell you about a whole lot of other really cool papers in today's issue. Dr. Carolyn Lam: First, have you ever wondered what is the association between risk factor control and cardiovascular disease risk in type 2 diabetes? Well, today's paper answers that. It's from Dr. Wright from University of Manchester and her colleagues who looked at a retrospective cohort using data from the English practices from Clinical Practice Research Datalink, or CPRD, and the Scottish Care Information diabetes dataset. They also linked to hospital and mortality data and identified more than 101,000 patients with type 2 diabetes in CPRD matched with almost 379,000 controls without diabetes and almost 331,000 patients with type 2 diabetes in the Scottish Care Information diabetes database between 2006 and 2015. The main exposure was a number of optimized risk factors, and these are: (1) Nonsmoker; (2) total cholesterol less than 4 mmol/L; (3) triglycerides less than or equal to 1.7 mmol/L; (4) HB A1c less than 7%; and (4) systolic blood pressure less than 140 or less than 130 mmHg of high risk. Dr. Greg Hundley: Carolyn, I am very curious. Lots of data here. What did they find? Dr. Carolyn Lam: So the key findings were: Dr. Carolyn Lam: First, even with optimally managed risk factors, people with type 2 diabetes still had a 21% higher risk for all cardiovascular disease events and non-fatal coronary heart disease, and a 31% higher risk of heart failure hospitalization compared to patients without diabetes. Dr. Carolyn Lam: 2. Only 6% of people with type 2 diabetes had optimal risk factor controls, so a very low percent. Dr. Carolyn Lam: 3. The association between the number of elevated risk factors and cardiovascular disease events and mortality was much stronger in patients with type 2 diabetes but without cardiorenal disease compared to those with established cardiorenal disease. People without cardiorenal disease were also younger and more likely to have suboptimal risk factor control and fewer prescriptions for risk-factor-modifying medication. Dr. Carolyn Lam: So take-home message: Greater use of guideline-driven care, clinical decision support, drug intervention, and self-management support should be encouraged for risk factor control, and people with type 2 diabetes and without cardiorenal disease may especially benefit greatly from cardiovascular disease risk factor intervention. Dr. Greg Hundley: Very nice, Carolyn. Dr. Greg Hundley: Well, my first study comes from Dr. Gregory Lewis from Mass General Hospital in Boston, Massachusetts. Carolyn, another quiz: Have you wondered about differences in metabolism in those who exercise versus those that do not? Dr. Carolyn Lam: Greg, I wonder about that all the time when I'm running out there. Dr. Greg Hundley: In this study, cardiopulmonary exercise testing, or CPET, and metabolite profiling was performed on Framingham heart study participants aged about 54 years with 63% of them being women with blood drawn at rest in 471 subjects and then again at peak exercise in 411. Dr. Carolyn Lam: Nice, and kudos for the majority women. So what were the results? Dr. Greg Hundley: The authors observed changes including reductions in metabolites implicated in insulin resistance and increases in metabolites associated with lipolysis, nitric oxide bioavailability, and adipose browning. Exercise-induced metabolite changes were variably related to the amount of exercise performed, peak workload, sex, and body mass index. There was attenuation of favorable exercise excursions in some metabolites in individuals with higher BMI and greater excursions in select cardioprotective metabolites in women despite less exercise being performed. Four metabolite signatures of exercise response patterns were analyzed in a separate cohort. The Framingham offspring study of 2,045 were about age 55 years and 51% were women, two of which were associated with overall mortality over a median follow-up at 23 years. Dr. Greg Hundley: So Carolyn, in conclusion, the authors found acute exercise elicits widespread changes in the circulating metabolome. These findings provide a detailed map of the metabolic response to acute exercise in humans and identify potential mechanisms responsible for the beneficial cardiometabolic effects of exercise that could be useful in future studies. Dr. Carolyn Lam: Beautiful. I'm going to keep exercising and I bet you will, too, Greg. Dr. Carolyn Lam: So this next paper is a mechanistic study that revealed a special population of tissue regulatory T-cells in the heart with a unique phenotype and pro-repair function. So this comes from corresponding author Dr. Cheng from Tongji Medical College of Huazhong University of Science and Wuhan Hubei, China. He and his colleagues studied the dynamic accumulation of regulatory T-cells in the injured myocardium in mouse models of myocardial infarction, myocardial ischemia re-perfusion injury, or cardiac cryo injury, and using state-of-the-art methods such as bulk RNA sequencing, photo conversion, parabiosis, single-cell TCR sequencing, adoptive transfer, and functional assays. Dr. Greg Hundley: Carolyn, interesting. What did they find? Dr. Carolyn Lam: They showed that regulatory T-cells that accumulate in the injured myocardium after myocardial infarction or myocardial ischemia re-perfusion injuries had a distinct transcriptome which differs from lymphoid organ regulatory T-cells and other non-lymphoid tissue, and this represents a novel population of tissue regulatory T-cells in the heart. These heart regulatory T-cells were mainly thymus driven and recruited from the circulation showed active local proliferation with the IL-33/ST2 axis promoting their expansion. With the phenotype of promoting tissue repair, heart regulatory T-cells over-expressing spark contributed to elevated collagen content and enhanced maturation in infarct scars to prevent cardiac rupture and improve survival after myocardial infarction. Dr. Carolyn Lam: So in summary, this paper identified and characterized a phenotypically and functionally unique population of heart regulatory T-cells, which may lay the foundation to harness these cells for cardiac protection in myocardial infarction or other cardiac diseases. Dr. Greg Hundley: Wow, Carolyn. Very interesting. Dr. Greg Hundley: Well, my next paper comes from Dr. Michael Rubart from Indiana University School of Medicine, and as some background it's going to discuss calmodulin. So calmodulin mutations are associated with arrhythmia syndromes in humans. Exome sequencing previously identified a de novo mutation in CALM1 resulting in a P.N98S substitution in a patient with sinus bradycardia and stress-induced bidirectional ventricular ectopy. The objectives of the present study were to determine if mice carrying this N98S mutation knocked into CALM1 replicate the human arrhythmia phenotype and then to examine some of the arrhythmia mechanisms. Dr. Carolyn Lam: Okay. So what did they find? Dr. Greg Hundley: Carolyn, several techniques were used in this study. Mouse lines heterozygous for the CALM1 N98S allele generated using CRISPR and caspase 9 technology. Also, adult mutant mice and their wild-type litter mates underwent electrocardiographic monitoring. Ventricular D and re-polarization was assessed in isolated hearts using optical voltage mapping, and action potentials in wholesale currents as well as calcium influx were measured in single ventricular myocytes using patch-clamp techniques and fluorescence microscopy, respectively. Microelectrode techniques were employed for in situ membrane voltage monitoring of ventricular conduction fibers. Carolyn, it was really a comprehensive study. Dr. Greg Hundley: So what did the authors find? Heterozygosity for the CALM1 N9S mutation was causative of an arrhythmia syndrome characterized by sinus bradycardia, QRS widening, adrenergically mediated QTC interval prolongation, and bidirectional ventricular tachycardia. Second, beta adrenergically induced calcium influx L dysregulation contributed to the long QT phenotype. And finally third, they found that pause dependent early after depolarizations and tachycardia induced delayed after depolarizations originating in the His-Purkinje network and ventricular myocytes, respectively, constituted potential sources of arrhythmia in the CALM1 N98S positive hearts. Dr. Carolyn Lam: Wow. Sounds like a really comprehensive study. Thanks, Greg. Dr. Carolyn Lam: Let's talk about some other papers in this issue, shall we? There is a Perspective piece by Dr. Klassen on the COVID-19 pandemic, a massive threat for those living with cardiovascular disease among the poorest billion. There's an ECG challenge by Dr. Littman on a malignant electrocardiogram. Here's a hint: It's a pseudo-infarct pattern with important learnings. They're in an exchange of letters between Drs. Packard and Schwartz regarding the role of lipoprotein A and modification by alirocumab, a pre-specified analysis of ODYSSEY Outcomes randomized clinical trial. Dr. Greg Hundley: Oh thanks, Carolyn. I've got a couple other papers. Dr. Venkateswaran Subramanian has a Research Letter entitled Lysyl Oxidase Inhibition Ablates Sexual Dimorphism of Abdominal Aortic Aneurysm Formation in Mice. Professor Jan Cornell has another research letter entitled Colchicine Attenuates Inflammation Beyond the Inflammasome in Chronic Coronary Artery Disease. The LoDoCo2 proteomic substudy. And then finally, Dr. Sanjay Kaul from Cedars-Sinai Medical Center has a white paper reviewing the benefit/risk trade-offs in assessment of new drugs and devices. Dr. Greg Hundley: Well, Carolyn, how about we get on to that feature discussion and learn more about colchicine and acute coronary syndromes. Dr. Carolyn Lam: Yeah. Let's go, Greg. Today's feature discussion is all about colchicine, that commonly used treatment for gout that has recently emerged as a novel therapeutic option in cardiovascular medicine. I am so pleased to have with us the corresponding author of today's paper, Dr. Jamie Layland from Monash University, as well as our associate editor, Dharam Kumbhani, from UT Southwestern to discuss this very important trial data from Australia. Jamie, could you start us off by telling us all about this Australian COPS trial? Dr. Jamie Layland: We performed the Australian COPS trial back in 2015, and it finished recruiting in 2018. Essentially the trial was a trial to look at the safety and efficacy of colchicine being used in acute coronary syndromes, and this was prior to the release of important trial COLCOT. So essentially we randomized patients who presented to the hospital with an acute coronary syndrome to receive colchicine twice daily for one month followed by colchicine once a day for 11 months, and we followed these patients up for a minimum of 12 months. This was performed across 17 sites across Australia, and we looked at a composite endpoint of total death, acute coronary syndromes, unplanned urgent revascularization, and stroke. Dr. Carolyn Lam: Nice. So Jamie, could I first clarify that this was an investigator-led trial, I'll bet, and man, first of all, applause for doing this. I can only imagine how much work this took and maybe then tell us about the results. Dr. Jamie Layland: Yeah. So this was an investigator-initiated trial through a network of academic investigators across Australia on limited research funding, so through philanthropic and institutional support. So it was a huge effort over a number of years, and I'm very thankful to the support of Circulation and Dharam in supporting the paper, which I think was a great success. Dr. Jamie Layland: So the results of this trial were a surprise to us all, but essentially this was a negative trial in the sense that colchicine did not improve the primary outcome, so there was no improvement in the rate of the COLCOT outcome. And interestingly, there was an increase in total mortality, in particular non-cardiovascular deaths were higher at five compared to the placebo at one. That was over a 12-month follow-up period. Dr. Carolyn Lam: Interesting. So Jamie, I'm going to ask the question that's on everyone's mind then: What's the difference between your trial and COLCOT? Dr. Jamie Layland: That's a great question. Obviously, COLCOT was a much larger trial. COLCOT was an international trial of over 4,000 patients. Similar patient demographics, similar patient subgroup of acute coronary syndromes. However, importantly, COPS was a trial of inpatient initiation of colchicine. So patients when they had their STEMI, or non-STEMI most commonly, they were given colchicine usually within 72 hours of their index hospitalization and sometimes sooner, and this was given prior to discharge. With COLCOT, the median time of administration of colchicine was around 14 days, so slightly different groupings there. However, in COLCOT you were allowed to administer colchicine as an inpatient. You can see obviously from the European side of cardiology the impressive data when colchicine was given earlier in COLCOT how this translated to improved outcomes. So clearly, there is a potential benefit there for early administration of colchicine when you look at these two trials. Dr. Jamie Layland: But we administered colchicine acutely when patients presented in their index hospitalization. We also importantly used a different dosing schedule to COLCOT. So COLCOT was 0.5 mg daily and we used 0.5 twice daily. This was for the first 30 days, and this was based on early data from the group from western Australia who showed that when colchicine was given to patients at a BD dosing in those patients who were already on aspirin and high-potency statins, there was a significant reduction in hsCRP, obviously a commonly used marker of inflammation at four weeks, and also based on data showing that there was a heightened inflammatory response in the early days following an acute coronary syndrome. So we felt that using this twice-daily dose would be advantageous and potentially helpful for our patients. So they're the two main differences between the studies. Dr. Carolyn Lam: Thanks for explaining that so clearly. Dharam, could I have your thoughts? This was, of course, discussed heavily, right, by the editors. Could you give us a sneak peek of what else was discussed? Dr. Dharam Kumbhani: The trial is very important, although it is smaller perhaps in sample size and kind of done with less resources than COLCOT. I do think this adds to the body of literature on colchicine for secondary prevention of CAD. And one of the interesting things is that we see we also have the LoDoCo2 trial, which was a slightly different population, Jamie, which was the chronic coronary artery disease patients, but also still looking at secondary prevention. What is really striking to me is that a very similar signal in non-CV death was noted in that trial as well. Again, it was not seen in COLCOT and LoDoCo1, but it was very interesting that a similar finding was there. So I do think this is something that the field will need to investigate more and really try to understand is this just noise and by chance alone, or is this something that that's a real signal for. Dr. Carolyn Lam: Jamie, what are your thoughts about that and in LoDoCo differences with your trial? Dr. Jamie Layland: Good question, and a very important topic that obviously is currently under discussion amongst the colchicine community. As I said, it was a surprising result. We weren't anticipating this non-CV death signal, but as Dharam said when LoDoCo2 came out, a fantastic trial again, but this signal of non-CV death. I don't know whether it's merely just a noise as you say or whether it's a significant finding, but clearly we need to do more research in this field to understand the mechanism and whether this is a real signal or not. It seems a little bit discordant with previously published work. So if you look at the literature in patients with gout from across the world, there's no real signal of increased non-CV death in those patients. However, with patients with acute coronary syndrome as we are administering the colchicine on a daily basis and then commonly this isn't used for gout, so that is a slight difference. But certainly, there was no signal in the non-CV literature to support the findings that we had and the signal in LoDoCo2. Dr. Jamie Layland: The other thing to note is in a cohort of five non-CV deaths, three out of those five patients were actually not taking colchicine at the time of their death. They stopped the drug prematurely. So I think we just need to take a step back and really await the results. Obviously, we've got two-year and five-year data coming out from the COPS trial which will be interesting to look at, but also the Clear Synergy trial from the McMaster team, that would be a very important trial providing more data on this potential signal. But reassuringly, and I feel more reassured knowing the COLCOT data, which is a slightly similar cohort to ours, showing that there was no trend towards increased non-CV deaths. So I think it's something that we have to be aware of and there will be lots of metro-analysis I'm sure being published in the coming months looking at this specifically. But yeah, I think we shouldn't cast any aspersions on colchicine yet. I think that's too early, but I do think we need more data. Dr. Carolyn Lam: Thanks, Jamie. Speaking of looking deeper in your data and looking at those who died and were they taking the medication and so on, you did some other post-hoc analysis, right? And maybe you could just describe briefly, for example, the 400-day followup. Dr. Jamie Layland: Yes. So the interesting thing with our data, and I had mentioned this before, is that we had limited resources, so we really wanted to do this trial, and obviously competitive funding is tricky at the best of times, but we were really committed to doing this trial and we had a group of investigators who were all committed to doing this trial. But for this to work, we had a single research nurse and a fellow performing the follow-up. So at times, there was a little lag between the timing of the follow-up. So we ended up getting follow-up which was slightly prolonged over the 12-month window. On average, it was around 400 days. When we looked at the 400-day data, we saw that there was an increasing separation of the biomarkers after 365 days. Dr. Jamie Layland: The results, this was obviously not the primary outcome, this was a sensitivity analysis, but there was a suggestion or a significance out to 400 days with an improvement with colchicine. However, this is the primary composite outcome, so revascularization, acute coronary syndrome, stroke, and total death notwithstanding this positive outcome, there was still this trend to high rate of mortality, so that has to be taken into consideration. But there was a suggestion that the longer the duration of colchicine was given for, it culminated into these lights affect. And we see from CT data that colchicine actually has some plaque-modulating effects and reduces high-risk or low-attenuation plaque. So you could hypothesize that as the majority of the benefits seen in colchicine in LoDoCo2, in COLCOT, and in COPS was the reductions in urgent revascularization, stroke, and acute coronary syndromes. Dr. Jamie Layland: So perhaps there is this effect that colchicine is having on plaque stabilization so we're seeing less longer-term events, but this is just hypothesis generated and we need more data to support that. But it is a very interesting finding nonetheless. Dr. Carolyn Lam: Thank you. Dharam, could I hand you the last word on where you think this field is going or where you think it should go? Dr. Dharam Kumbhani: I think Jamie put it really nicely. I think he outlined the study nicely with its strengths and its limitations, and I think this is obviously a debate between perhaps the colchicine believers and the ones that are still perhaps trying to understand a little bit more about its true role, because as was mentioned I think there's really a benefit in ischemia-driven revasc. I think we've seen that in almost all the colchicine trials. There is no reduction in mortality, and as we saw in the COPS data maybe it goes the other way. So I think from a pathophysiological standpoint it makes sense. I think there's good translational data to suggest that it would be beneficial in this patient population, but I think that's the beauty of having clinical trials and the ones that are done by different investigators and perhaps in different settings, because they help us answer the truth. And whether colchicine becomes a stable part of our armamentarium for secondary prevention of CAD going forward, I think the jury is still out and as was mentioned I think Clear Synergy would probably be very helpful in hopefully tying all this together. Dr. Dharam Kumbhani: So again, I want to congratulate Jamie and his team for really providing us with a very interesting trial done in a very pragmatic setting, and I think the field is very thankful to them for providing us with this information. Dr. Carolyn Lam: Thank you, audience, for joining us today. You've been listening to Circulation on the Run. Don't forget to join me and Greg again next week. Dr. Greg Hundley: This program is copyright the American Heart Association 2020.  

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.08.332007v1?rss=1 Authors: Palomino-Antolin, A., Narros-Fernandez, P., Farre-Alins, V., Sevilla-Montero, J., Decouty-Perez, C., Lopez-Rodriguez, A. B., Fernandez, N., Monge, L., Casas, A. I., Calzada, M. J., Egea, J. Abstract: Background and purpose: Post-ischemic inflammation contributes to worsening of ischemic brain injury and in this process, the inflammasomes play a key role. Inflammasomes are cytosolic multiprotein complexes which upon assembly activate the maturation and secretion of the inflammatory cytokines IL-1{beta} and IL-18. However, participation of the NLRP3 inflammasome in ischemic stroke remains controversial. Our aims were to determine the role of NLRP3 in ischemia and to explore the mechanism involved in the potential protective effect of the neurovascular unit. Methods: WT and NLRP3 knock-out mice were subjected to ischemia by middle cerebral artery occlusion (60 minutes) with or without treatment with MCC950 at different time points post-stroke. Brain injury was measured histologically with 2,3,5-triphenyltetrazolium chloride (TTC) staining. Results: We identified a time-dependent dual effect of NLRP3. While neither the pre-treatment with MCC950 nor the genetic approach (NLRP3 KO) proved to be neuroprotective, post-reperfusion treatment with MCC950 significantly reduced the infarct volume in a dose-dependent manner. Importantly, MCC950 improved the neuro-motor function and reduced the expression of different pro-inflammatory cytokines (IL-1{beta}, TNF-), NLRP3 inflammasome components (NLRP3, pro-caspase-1), protease expression (MMP9) and endothelial adhesion molecules (ICAM, VCAM). We observed a marked protection of the blood-brain barrier (BBB), which was also reflected in the recovery of the tight junctions proteins (ZO-1, Claudin-5). Additionally, MCC950 produced a reduction of the CCL2 chemokine in blood serum and in brain tissue, which lead to a reduction in the immune cell infiltration. Conclusions: These findings suggest that post-reperfusion NLRP3 inhibition may be an effective acute therapy for protecting the blood-brain barrier in cerebral ischemia with potential clinical translation. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.08.288043v1?rss=1 Authors: Cosker, K., Mallach, A., Limaye, J., Piers, T. M., Staddon, J., Neame, S. J., Hardy, J., Pocock, J. M. Abstract: The R47H variant of the microglial membrane receptor TREM2 is linked to increased risk of late onset Alzheimers disease. Human induced pluripotent stem cell derived microglia, iPS-Mg, from patient iPSC lines expressing the AD-linked R47Hhet TREM2 variant, common variant, Cv, or an R47Hhom CRISPR edited line and its isogeneic control, demonstrated that R47H-expressing iPS-Mg expressed a deficit in signal transduction in response to the TREM2 endogenous ligand phosphatidylserine with reduced pSYK-pERK1/2 signalling and a reduced NLRP3 inflammasome response, including ASC speck formation, Caspase-1 activation and IL-1beta secretion. Apoptotic cell phagocytosis and soluble TREM2 shedding were unaltered, suggesting a disjoint between these pathways and the signalling cascades downstream of TREM2 in R47H-expressing iPS-Mg, whilst metabolic deficits in glycolytic capacity and maximum respiration were reversed when R47H expressing iPS-Mg were exposed to PS+ expressing cells. These findings suggest that R47H-expressing microglia are unable to respond fully to cell damage signals such as phosphatidylserine, which may contribute to the progression of neurodegeneration in late-onset AD. Copy rights belong to original authors. Visit the link for more info

In episode 10 of the Fredrickson Health Show friend and fellow functional medicine consultant-Alex Tollington dissect and interpret the recommended botanicals and nutraceuticals from IFM.org's website. "Health professionals and the public must be well informed about the SARS-CoV-2 virus, the disease it causes (COVID-19), and how it spreads. This information is readily available and not within the scope of this document. At this time, there are no specific vaccines or uniformly successful treatments for COVID-19. In this context of insufficient evidence, the scope of this document will be to assess the scientific plausibility of promising prevention approaches and therapeutic (nutraceutical and botanical) interventions and then to offer clinical recommendations. This article is part one of a series. Click here to view part two."-IFM.ORG In episode 10 of the Fredrickson Health Show friend and fellow functional medicine consultant-Alex Tollington dissect and interpret the recommended botanicals and nutraceuticals from IFM.org's website. Show notes below. 2:25 Alex Tollington transition in career from Engineer to Functional Medicine Nutrition consultant. 3:35 How finding cures takes time. 5:45 Cytokine Storm, Inflammasome complex description. 7:45 Inflammation and Disease. 8:16 acute vs chronic inflammation 9:16 Quercitin benefits-mast cell stabilizer, inflammation, ionophore. 12:19 Quercitin comes from the name Oak Forest 13:30 Alex's personal story with high dose quercetin for relief from a bee sting. 14:40 Quercitin and absorption. 15:30 Curcumin/Turmeric intro 19:50 Benefits of Full spectrum Turmeric 21:27 EGCG-Green Tea Extract modulating the inflammasome 22:27-NR2 modulation-genetic shifts to less inflammatory state. 25:32 4 cups daily of green tea recommended!? 25:57 NAC-N-ACETYL-CYSTEINE 29:22 NAC STUDY on elderly patients on influenza 29:50 Resveratrol as an immune product? 30:32 Resveratrol and alzheimers 31:38 Vitamin D and Covid 37:23 New York Attorney General study with Vit D. Finding a reputable brand is key. 37:58 Melatonin as anti inflammatory 41:27 Vitamin A and secretory igA 44:46 Elderberry and it's anti-viral effects 46:00 Elderberry study showing it doesn't contribute to cytokine storm. 47:15 PEA part of endocannaboid system

This episode is about the pathophysiology on crystallopathies. The cellular pathways involved unify multiple concepts and multiple branches of medicine, from toxicology to cardiology to rheumatology and oncology. Heme Review YouTube Channel: https://www.youtube.com/channel/UCNSoNc9s67nfOGlCXSu5VsA References: [0] Crystallopathies. N Engl J Med 2016; 374:2465-2476. https://www.nejm.org/doi/full/10.1056/NEJMra1601611 [1] Recent advances in the mechanisms of NLRP3 inflammasome activation and its inhibitors. Cell Death & Disease. Volume 10, Article number: 128 (2019). https://www.nature.com/articles/s41419-019-1413-8 [2] The Inflammasome. Molecular Cell. VOLUME 10, ISSUE 2, P417-426, AUGUST 01, 2002. https://www.cell.com/molecular-cell/fulltext/S1097-2765(02)00599-3 [3] Silica crystals and aluminum salts mediate NALP-3 inflammasome activation via phagosomal destabilization. Nat Immunol. 2008 Aug; 9(8): 847–856. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834784/ [4] Tumor Cell–Derived IL1β Promotes Desmoplasia and Immune Suppression in Pancreatic Cancer. Cancer Res 2020;80:1088–101. https://cancerres.aacrjournals.org/content/80/5/1088 --- Support this podcast: https://anchor.fm/chubbyemu/support

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.05.135228v1?rss=1 Authors: Poh, L., Fann, D., Wong, P., Lim, H. M., Foo, S. L., Kang, S.-W., Rajeev, V., Selvaraji, S., Vinaya, R. I., Parathy, N., Khan, M. B., Jo, D.-G., Drummond, G. R., Sobey, C. G., Lai, M. K. P., Chen, C. L.-H., Lim, L. H. K., Arumugam, T. V. Abstract: Chronic cerebral hypoperfusion is associated with vascular dementia (VaD). Cerebral hypoperfusion may initiate complex molecular and cellular inflammatory pathways that contribute to long term cognitive impairment and memory loss. Here we used a bilateral common carotid artery stenosis (BCAS) mouse model of VaD to investigate its effect on the innate immune response particularly the inflammasome signaling pathway. Comprehensive analyses revealed that chronic cerebral hypoperfusion induces a complex temporal expression and activation of inflammasome components and their products (IL1b and IL18) in different brain regions, and promotes activation of apoptotic and pyroptotic cell death pathways. Glial cell activation, white matter lesion formation and hippocampal neuronal loss also occurred in a spatiotemporal manner. Moreover, in AIM2 knockout mice we observed attenuated inflammasome-mediated production of proinflammatory cytokines, apoptosis and pyroptosis, as well as resistance to chronic microglial activation, myelin breakdown, hippocampal neuronal loss, and behavioural and cognitive deficits following BCAS. Hence, we have demonstrated that activation of the AIM2 inflammasome substantially contributes to the pathophysiology of chronic cerebral hypoperfusion-induced brain injury and may therefore represent a promising therapeutic target for attenuating cognitive impairment in VaD. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.12.090654v1?rss=1 Authors: Zhang, Z., Ma, Q., Velagapudi, R., Barclay, W. E., Rodriguiz, R. M., Wetsel, W. C., Shinohara, M. L., Terrando, N. Abstract: Neuroinflammation is a growing hallmark of perioperative neurocognitive disorders (PNDs), including delirium and longer-lasting cognitive deficits. We have developed a clinically-relevant orthopedic mouse model to study the impact of a common surgical procedure on the vulnerable brain. The mechanism underlying PNDs remain unknown. Here we evaluated the impact of surgical trauma on the NLRP3 inflammasome signaling, including the expression of apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1, and IL-1{beta} in the hippocampus of C57BL6/J male mice, adult (3-months) and aged (>18-months). Surgery triggered ASC specks formation in CA1 hippocampal microglia, but without inducing significant morphological changes in NLRP3 and ASC knockout mice. Since no therapies are currently available to treat PNDs, we assessed the neuroprotective effects of a biomimetic peptide derived from the endogenous inflammation-ending molecule, Annexin-A1 (ANXA1). We tested the hypothesis that this peptide (ANXA1sp) inhibits NLRP3 inflammasome activation, thus preventing microglial activation and hippocampal-dependent memory deficits. Together these results uncover a previously underrecognized role of the NLRP3 inflammasome in triggering postoperative neuroinflammation and offer a new target for advancing treatment of PNDs through resolution of inflammation. Copy rights belong to original authors. Visit the link for more info

Dr. Pastore discusses the vital role sleep plays in immunity, how lack of sleep and poor quality sleep can lower your immune system, sleep duration guidelines for optimal health and steps you can take to improve your sleep.    What is “poor” sleep [1:00] Quality sleep for adults 7-9 continuous, uninterrupted hours of sleep per night  Likely not possible for parents, like Dr. Pastore  Teenagers require 8-10 continuous, uninterrupted hours of sleep per night  6.5 - 7 hours for teenagers can have same effect as being inebriated  Sleep science still needs much more research  Those staying home & safe during COVID-19 can cause COVID-19 dreams Intense/horror dreams due to inability to normalize stress/anxiety during the day   Lack of quality sleep mentioned above is directly associated with higher likelihood of being sick after being exposed to a virus [3:55] Studies on common cold  Lack of sleep or disrupted sleep increases risk of getting a virus    Lack of sleep impacted how fast you recover if you do get sick [4:40] Dr. Pastore treating patients & working with other doctors treating patients with COVID-19, those recovering slower & have the virus longer have worse sleep  21 & 23 days of having the active COVID-19 infection  Seen faster COVID-19 recovery of 9 days with better, quality sleep    Quality sleep needs to be uninterrupted [7:05] Difficult for parents waking up for children 7-9 for adults, 8-10 hours for teenager straight    Long-term poor quality sleep increase risk of obesity & diseases that further the risk for infections [9:05]   Medical fact: poor sleep causes cardiovascular disease, diabetes & obesity  Cardiovascular disease, diabetes & obesity increase risk for infections such as COVID-19 or regular flu  Inflammasome is byproduct of being overweight & obesity  Proinflammatory response that can lower immune system  Quality sleep drastically improves fat loss progress  Lack of sleep (as little as 2-3 nights in a row) - cells become temporarily insulin resistant which causes elevation in glucose, can lead to weight gain & fat storage  Chronic lack of sleep can make cells permanently insulin resistant  Quality sleep improves cell-signalling communication between insulin receptor cells & GLUT receptors to let glucose into the cells    Poor sleep lowers your immune system, makes it longer to recover from a virus, increases risk of diseases that can further lower the immune system, and can worsen health if pre-existing disease exists [13:00]  We're all biochemically & genetically unique  Knowing genetics, medical history, biological markers, calcium score    Why does decreased sleep lower the immune system? [14:55] Sleep supports & enhances the initiation of an adaptive immune system response  Adaptive immune system response process: Trouble maker / invading antigen / virus invading body Human immune system takes up antigen & appropriates it Breaks apart the antigen & presents fragments of antigen to T Helper Cells T Helper Cells signal cytokines Interleukin 12 Interleukin 12 calls in T-Helper Cell One Response, supports antigen specific T-Cells T-Helper Cell 1 Response starts B-Cell production of antibodies to always be able to recognize the invading antigen / virus  If the invading antigen is presented in the body again, the body will attack it  Produced in the lymph nodes  Vaccines are a great example of adaptive immunity, producing herd immunity  Sleep turns this response on, lack of sleep turns it off Immune cannot identify the invading antigen  Sleep deprived hepatitis A vaccine patients vs quality sleep hepatitis A vaccine patients Poor sleep patients did not have amplified adaptive immune system response to vaccine Parents typically lose hundreds of hours of sleep    Prescription medications to improve sleep quality [21:05] Dr. James Maas, “Father of Sleep” & other sleep doctors confirm prescription sleep medications will not lead to a perfect night's sleep or “sleep saviours” Have seductive-type affects Can affect memory & perception of sleep quality  Our Neurochemistry of Sleep Podcast  LINK Be aware of side effects Rebound insomnia Dizziness Headaches Difficult swallowing or breathing Worsening depression & suciride ideation Study showed those with highest sleep medication prescriptions had highest risk of all-cause mortality  Study showed increased risk of various cancers, increased risk of dementia  Not getting into a deep sleep, interferes with glucose & cell receptor response    Could be underlying issue or health concern causing lack of sleep [24:20] Chronic pain & arthritis  Breathing disorders  Dietary supplements & stimulants (caffeine) close to bed  Gastoresophorefluz disorder Hypothyroidism, Graves Disease Chronic back pain  Sinus disorder or allergies  Medications can disrupt sleep Birth control Cold medicine  Asthma medication High blood pressure medication  Depression  Thyroid medication Talk to your doctor to find the underlying cause  Pharmacogenetics - PGX  Test genetics to determine drug response based on individual genetics  Medications aren't a one-size fits all Could be nutritional deficiency  Magnesium, Vitamin D Request bloodwork from physician  40% population at risk for low magnesium  Undiagnosed sleep apnea  Temporarily stop breathing, adrenaline wakes you up    Lifestyle changes to implement to improve sleep [29:30] Address stress  Get regular physical activity & exercise  Exercise helps lower stress Caffeine consumption Genetic variations to process caffeine faster/slower Avoid caffeine after 3-4PM  Green tea, diet cola, soft drinks with caffeine  Exposure to artificial light Disrupts normal neurological signalling for sleep, turns off melatonin production Can upregulate alert/excitatory neurotransmitters to keep you awake Blue light blocking glasses Night mode on electronics reducing blue light Limit alcohol  Sedative effect - can help you fall asleep initially  Later in night, causes dopamine rush & interferes with adaptive immune response More consistent alcohol consumption will continue to lower immune system nightly Limit or eliminate nicotine  Vaping, chewing tobacco  Nicotine neurotoxin, extremely addictive Makes it difficult to fall asleep  Sleep in a cool bedroom  Lower temperature helps with sleep   Melatonin for sleep [35:30] Melatonin is both a hormone and neurotransmitter Excreted from penial gland  Exposure to natural light during day, as sun sets, darkness cues melatonin production Helps stimulate our sleep - high affinity melatonin receptors in SCN  MTA & MT1A, MT2 & MT2B receptors - absorbs melatonin & slows excitatory function to prepare for sleep  Promotes sleep by stimulating acute inhibition of neurological firing of awake neurotransmitters in SCN Helps initiate sleep process, but won't benefit rest of sleep cycle  Helps regulate circadian rhythm (sleep/wake cycles) Taking a “low” dose of 1mg of melatonin is still incredibly high compared to what the brain produces naturally   Can produce “hangover” in the morning Fatigued, tired, brain fog, delayed responses Suppressing dopamine responses  Receptors of SCN turned off way past sleep period  Up to 18 hours of hangover Walking wounded: feel better at 8-10PM and take another dose High-dose (1mg+) melatonin should not be a nightly supplement for sleep    Effective natural products for sleep do exist [40:50] Dr. Pastore's poor sleep practicing as a doctor, then being a father Developed sleep supplement Power OFF for his own sleep issues as nothing else worked https://poweronpoweroff.com/products/power-off We can provide you with the scientific paper Dr. Pastore wrote  Help turn off excitatory neurotransmitters before bed to fall asleep Help stay asleep without waking up   Studies on theanine + 5 hydroxytryptophan shown to keep you asleep GABA to help you fall asleep  Most GABA can't cross blood-brain barrier Blood-brain barrier: only allows certain nutrients/neurotransmitters into the brain from the bloodstream to protect the brain  Dr. Pastore used his PhD in nanomedicine to make GABA pass the blood brain barrier  Magnolia plant - honokiol   Studies show honokiol primes receptor for GABA uptake Combination of ingredients address mechanism of turning off cellular stress response constantly being fired by ephedrine (excitatory / awake neurotransmitter) at night  Requires sulphur enzyme system - enzyme phenalethol…..help :)  Cysteine & dimer to create cystine Helps fall back asleep after interrupted sleep Won't prevent you from waking up if needed Formula evolves as new studies & research comes out    Antihistamines / Benadryl before bed [52:55] Dangerous for long-term health Harvard in 2005 urged doctors to advise patients to stop using antihistamines for sleep Antihistamines reduce acetylcholine, which over time increases risk of age-related mental decline Disrupts memory, cognitive sharpness, more forgetful    Wrap-Up [55:15] Aim for 7-9 hours per night Work with physician to find underlying cause for lack of sleep  Stay away from prescription sleep aids & over the counter sleep aids as much as possible Be mindful of melatonin  help@poweronpoweroff.com & https://poweronpoweroff.com/products/power-off www.drrobetpastore.com & @drrobetpastore

In this Authentic Biochemistry Podcast, Dr. Dan Guerra explains the roles of acid sphingomyelinases and associated ceramide production on the NLRP3 inflammasome activation as linked to coronavirus pathogen molecular patterns and the production of proinflammatory cytokines 19 February 2020. --- Support this podcast: https://anchor.fm/dr-daniel-j-guerra/support

We are having a nasty influenza season, in addition to the coronavirus problem; Dietary support to induce bacteriophages, viruses that attack bad bacteria; Bacteriophages used to treat stunted growth in children; Hope for Chinese herbs treatment for Coronavirus, but detailed biochemistry analysis says otherwise; A generous but elderly blood donor asks if he should have a colonoscopy; Electroacupuncture technique to treat stroke effects by increasing brain blood flow; Can we guess your age based on your skin microbes? A green algae can treat irritable bowel disease; The first influenza strains you are exposed to influences your reactions to future strains; Dealing with death of a loved one -- sometimes the anxiety reaction is a real cardiac condition; Possible treatment of Schizophrenia using MicroRNA to regulate gene transcription; A new strategy for antibiotics prevents the growth of bacterial cell walls; Reversing inflammation that causes aging -- turning off the inflammasome!

We are having a nasty influenza season, in addition to the coronavirus problem; Dietary support to induce bacteriophages, viruses that attack bad bacteria; Bacteriophages used to treat stunted growth in children; Hope for Chinese herbs treatment for Coronavirus, but detailed biochemistry analysis says otherwise; A generous but elderly blood donor asks if he should have a colonoscopy; Electroacupuncture technique to treat stroke effects by increasing brain blood flow; Can we guess your age based on your skin microbes? A green algae can treat irritable bowel disease; The first influenza strains you are exposed to influences your reactions to future strains; Dealing with death of a loved one -- sometimes the anxiety reaction is a real cardiac condition; Possible treatment of Schizophrenia using MicroRNA to regulate gene transcription; A new strategy for antibiotics prevents the growth of bacterial cell walls; Reversing inflammation that causes aging -- turning off the inflammasome!

Things get a little nerdy in this episode, which focuses on the basic science of what makes the inflammasome tick in CAPS, as well as data on the use of interleukin 1 inhibition. Hint: Listen to “The Inflammasome for Dunces” episode first, and this one will make more sense. Intro :20 Recap of Part 1 :33 Overview of this episode 1:56 Familial cold autoinflammatory syndrome 3:04 Muckle-Wells syndrome 6:34 The two checkpoint problem 8:36 What do we know about the inhibition of the inflammasome? 11:13 Back to the trebuchet analogy 11:48 Brought to you by GSK. Considering a treatment change for patients with active SLE? Learn about a treatment option for your patients at treatfortodayandtomorrow.com A paper on CARD8 in the setting of CAPS 13:50 Let’s talk about prostaglandins 15:27 There are over 100 mutations in CAPS 18:15 Let’s talk about treatment 18:42 One caveat 25:41 That’s CAPS 26:45 Reach out to me via email and on Twitter 27:03 Episode recap 27:41 We’d love to hear from you! Send your comments/questions to rheuminationspodcast@healio.com. Follow us on Twitter @HRheuminations @AdamJBrownMD @HealioRheum Brought to you by GSK. Consider the long-term impact of disease activity, flares and corticosteroid use on patients with active SLE. Learn more now at treatfortodayandtomorrow.com. Disclosure: Brown reports no relevant financial disclosures. References: Agostini L, et al. Immunity. 2004;20:319-325. Brogan PA, et al. Arthritis Rheum. 2019;71:1955-1963. Marsaud C, et al. J Rheumatol. 2014;41:1721-1722. Hawkins PN, et al. NEJM. 2003;348:2583-2584. Hoffman HM, et al. Lancet. 2004;364:1779-1785. Hoffman HM, et al. Clin Ther. 2012;34:2091-2103. Ito S, et al. Arthritis Res Ther. 2014;16:doi:10.1186/ar4483. Kuemmerle-Deschner JB, et al. Ann Rheum Dis. 2011;70:2095-2102. Lachmann HJ, et al. NEJM. 2009;360:2416-2425. Mamoudjy N, et al. Orphanet J Rare Dis. 2017;12:doi:10.1186/s13023-017-0589-1. Rosengren S, et al. J Allergy Clin Immunol. 2007;119:991-996. Ross JB, et al. J Cutan Med Surg. 2008;12:8-16. Tassi S, et al. Proc Natl Acad Sci USA. 2010;107:9789-9794. Thornton BD, et al. Am J Kidney Dis. 2007;49:477-481.

A quick take on one of the little-appreciated engines of the innate immune system.  Intro :10 A little about this episode :25 The inflammasome is a component of the innate immune system 3:12 Remember NLRP3 4:12 The toll-like receptors 5:05 Triggering the inflammasome 7:05 The proteins 8:04 A medieval battle and a trebuchet 9:56 A disclosure 17:00 I hope you enjoyed this episode 18:06 We’d love to hear from you! Send your comments/questions to rheuminationspodcast@healio.com. Follow us on Twitter @HRheuminations @AdamJBrownMD @HealioRheum References: Booshehri LM, Hoffman HM. J Clin Immunol. 2019;39:277-286. Hasudungan A. Immunology – NOD like receptors and the inflammasome [Video]. YouTube. https://www.youtube.com/watch?v=biunM2iD8qM&t=4s. Published March 29, 2015. Accessed September 4, 2019.

Dr Wang:             Welcome to the monthly podcast, On the Beat, for Circulation: Arrhythmia and Electrophysiology. I'm Dr Paul Wang, Editor-in-Chief, with some of the key highlights from this month's issue.                                 In our first paper, Ying Tian and associates examine the effects and long-term outcomes of percutaneous stellate ganglion blockade in the setting of drug refractory electrical storm due to ventricular arrhythmia. They studied 30 consecutive patients over nearly a five-year period. They used bupivacaine alone, or in combination with lidocaine injected into the neck with good local anesthetic spread in the vicinity of the left stellate ganglion in 15 patients, or both stellate ganglion in 15 patients.                                 The mean left ventricular ejection fraction was 34%. At 24 hours, 60% of patients were free of ventricular arrhythmia. Patients whose ventricular arrhythmia was controlled had a lower hospital mortality rate than patients whose ventricular arrhythmia continued. 5.6 versus 50%, P equals 0.009. Implantable cardioverter-defibrillator interrogation showed a significant 92% reduction in ventricular arrhythmia episodes from 26 to 2 in the 72 hours after stellate ganglion blockade, P less than 0.001.                                 Patients who died during the same hospitalization, N equals 7, were more likely to have ischemic cardiomyopathy, 100% versus 43.5%. And recurrent ventricular arrhythmias within 24 hours, 85.7% versus 26.1%. There were no procedure related complications.                                 In our next paper, Zachi Attia and associates hypothesized that a convolutional neural network could be trained through a process called 'deep learning' to predict a person's age and gender using only 12-lead electrocardiogram signals. They trained convolutional neural network using 10 second samples of 12-lead ECG signals from 499,727 patients to predict gender and age. The networks were tested on a separate cohort of 275,056 patients. For gender classification, the model obtained 90.4% classification accuracy with an area under the curve of 0.97. In the independent test data, age was estimated as a continuous variable with an average error of 6.9 years, R squared equals 0.7.                                 Among 100 hundred patients with multiple ECGs over the course of at least two decades of life, most patients, 51%, had an average error between real age and convolutional neural network predicted age of less than seven years. Major factors seen amongst patients with convolutional neural network predicted age that exceeded chronologic age by greater than seven years included low ejection fraction, hypertension, and coronary disease, P less than 0.1. In the 27% of patients whose correlation was greater than 0.8, between convolutional neural network predicted and chronological age, no incident events occurred over follow up 30 years.                                 The authors concluded that applying artificial intelligence to the ECG allows prediction of patient, gender, and estimation of age. The ability of artificial intelligent algorithm to determine physiological age with further validation may serve as a measure of overall health.                                 In our next paper, Zain Ul Abideen Asad and associates performed a meta-analysis of randomized control trials in order to compare the efficacy and safety of catheter ablation with medical therapy for atrial fibrillation with the primary outcome being all-cause mortality. They examined 18 randomized controlled trials comprising 4,464 patients. Catheter ablation resulted in significant reduction in all-cause mortality, relative risk of 0.69 that was driven by patients with atrial fibrillation and heart failure in reduced ejection fraction, relative risk 0.52.                                 Catheter ablation resulted in significantly fewer cardiovascular hospitalizations, hazard ratio of 0.56, and fewer recurrences of atrial arrhythmia, relative risk 0.42. Subgroup analysis suggested that younger patients, age less than 65 years, and men derived more benefit from catheter ablation compared to medical therapy.                                 In our next paper, Felipe Kazmirczak, Ko-Hsuan Amy Chen, and associates examined patients with cardiac sarcoidosis meeting guideline criteria for implantable defibrillator implantation in a large retrospective cohort study of patients with biopsy proven sarcoidosis and known or suspected cardiac sarcoidosis undergoing cardiovascular magnetic resonance imaging. The authors found that in 290 patients, the class one and class 2A recommendation identified all patients who experienced a composite endpoint of significant ventricular arrhythmia or sudden cardiac death over a mean follow-up of three years.                                 Patients meeting class one recommendations had a significantly higher incidence of composite endpoint than those meeting class 2A recommendations. Left ventricular ejection fraction greater than 35% with greater than 5.7% late gadolinium enhancement and cardiovascular negative residence imaging was as sensitive as or significantly more specific than left trigger ejection frack greater than 35% with any late gadolinium enhancement. Patients meeting two class 2A recommendations left ventricular ejection fraction greater than 35% would need for a pacemaker, and left ventricle rejection at greater than 35% with late gadolinium enhancement. Greater than 5.7% had high annualized event rates. Excluding two class 2A recommendations, left ventricular ejection fraction greater than 35% with syncope, and left ventricular ejection fraction greater than 35% with inducible ventricular [inaudible] resulted in improved discrimination for the composite endpoint.                                 In our next paper, Kenji Okubo, Antonio Frontera, and associates examined the ability of a new grid mapping catheter for performing substrate and ventricular tachycardia activation mapping during ventricular tachycardia ablation procedures, identifying the low voltage areas and visualizing diastolic pathways. The authors studied 41 consecutive patients undergoing ventricular tachycardia ablation procedure. The grid mapping catheter was used to create three different maps with three bipolar configurations along the spine, across the spine, high density wave solution.                                 The median low voltage area drawn by the high-density wave configuration was 28.9 centimeters squared, but it was 13% and 15% smaller with a low voltage area identified by along and across. The late potential areas identified by the three configurations did not differ. Ventricular tachycardia activation mapping visualizes the full diastolic pathway in 22 out of 40, or 55%. The authors found that identifying the full diastolic pathway led to a higher ongoing VT termination rate during the ablation than in the case of partial recordings, 88% versus 45%, P equals 0.03. In addition, when the full diastolic pathway's identified, the targeted VTS were always non-inducible.                                 In our next paper, Masateru Takigawa, and associates examined whether the spacing orientation, the bipoles of high-density mapping catheters impacts the accuracy of scar detection. The authors analyze the electrograms using high-density HD grid catheter and determine the optimal cutoff for scar detection in six infarcted sheep. For using bipolar voltages to detect MRI defined scar, the area under the receiver operating curve dependent on the spacing and orientation of the bipoles and range from 0.89 to 0.923. The area under the receiver operating curve was significantly larger, P less than 0.01, when only the best points on each site were selected for analysis compared to when all points were used.                                 In our next paper, Darren Tsang and associates examine the impact of prior sternotomy on transvenous lead extraction outcomes. Of 1,480 patients, 455 had prior sternotomy. When compared to patient with no prior sternotomy, those with prior tsunami were more likely to be older, male, and present with more comorbidities and leads targeted for extraction. No statistical difference was identified in major and minor complication rates, clinical success rates, or in hospital mortality.                                 In patients with prior sternotomy, there were no instances of pericardial effusion following extraction. Patients with sternotomies prior to lead extraction experienced vascular cardiac perforation, presented clinically with hemothoraces rather than pericardial effusions.                                 In our next paper, Babak Nazer and associates highlight the electrophysiologic properties in sites of ablation for manifest nodofascicular and nodoventricular accessory pathways that connect the atrial ventricular node and the Purkinje system or ventricular myocardium respectively. Concealed nodoventricular and nodofascicular pathways participate as the retrograde limb of supraventricular tachycardia. Manifest nodofascicular and nodoventricular accessory pathways comprise the antegrade limb of wide complex supraventricular tachycardia but are quite rare.                                 The authors report on eight patients who underwent electrophysiologic studies for wide complex tachycardia three, narrow complex tachycardia one, and for pre-excitation in four patients. The authors found nodofascicular and nodoventricular accessory pathways were an integral part of the supraventricular tachycardia in three patients. In these three cases, cases one and two revealed wide complex tachycardia due to manifest supraventricular tachycardia. Case three with a bi-directional nodofascicular and nodoventricular accessory pathway that conducted retrograde during supraventricular tachycardia, and antegrade causing pre-excitation during atrial pacing.                                 The nodofascicular or nodoventricular accessory pathway with a bystander during AV nodal reentry and tachycardia, atrial fibrillation, atrial flutter, and orthodromic AV reentrant tachycardia in four cases, and caused only pre-excitation in one. Successful accessory pathway ablation was achieved empirically in the slow pathway region in one case. In five cases, the ventricular insertion was mapped to the slow pathway region in two cases, or septal right ventricle in three cases. The accessory pathway was not mapped in cases five and seven due to its bystander role. The QRS morphology of pre-excitation predicted the right ventricular insertion sites in four to five cases in which it was mapped. During follow-up, one patient noted recurrent palpitations but no documented supraventricular tachycardia. The authors recommend that ablation should initially target the slow pathway region with mapping of the right ventricular insertion site if slow pathway ablation is not successful, and that the QRS morphology of maximal pre-excitation may be used to predict the successful right ventricular ablation site.                                 In our next paper, Constanze Schmidt and associates sought to determine if gene therapy targeting TASK-1 atrial specific potassium channel gene would suppress atrial fibrillation and correct cellular electrophysiological modeling in a porcine model of atrial fibrillation. The authors induced atrial fibrillation in pigs using atrial burst stimulation via implanted pacemakers and injected into both atria adeno-associated viral vectors carrying anti TASK-1 SIRNA for gene transfer to suppress TASK-1 channel expression.                                 After 14 days, porcine cardiomyocytes were isolated from the right and left atrium. The authors found that anti TASK-1 adeno-associated viral vector application significantly reduced atrial fibrillation burden in comparison to pigs. Arrhythmic effects of anti TASK-1 SIRNA were associated with reduction of TASK-1 currents and prolongation of action potential durations in cardiomyocytes to sinus rhythm values. The authors concluded that suppression of atrial fibrillation through selective reduction of TASK-1 currents may represent a new option for anti-arrhythmic therapy.                                 We have two excellent research letters this month. Jordana Kron and associates reported the presence of Inflammasome within the granulomas in hearts of three cardiac sarcoidosis patients. Providing additional support for the role of IL-1 in the pathogenesis of cardiac sarcoidosis and raising the possibility of ion targeted therapies to treat cardiac sarcoidosis.                                 Walid Barake and associates examine 549 patients with left bundle branch block, left ventricular ejection fraction greater than 50% at baseline, and a follow-up echocardiogram. Of these, 134, 24.4% had a greater than 10% drop in left ventricular ejection fraction. The patients with possible left bundle branch block induced cardiomyopathy were more likely to be younger and male.                                 That's it for this month. We hope that you'll find the journal to be the go-to place for everyone interested in the field. See you next time.                                 This program is copyright American Heart Association 2019.  

The Immune trio explains how activation of the inflammasome by a bacterial protein causes blood clotting through a programmed cell death process called pyroptosis.   Subscribe (free): iTunes, Google Podcasts. RSS, email Become a patron of Immune! Links for this episode Inflammasome activation triggers blood clotting (Immunity) Rotavirus and Nlrp9b inflammasome (Nature) Societal Amnesia and vaccines by Cindy Leifer Image credit Letters read on Immune 20 Time stamps by Jolene. Thanks! Weekly Science Picks Steph- iBiology Immunology Course Cindy- Changing vaccine hesitancy Vincent- Bad Advice by Paul Offit (and Vaccines and Your Child) Listener Pick Steve- An Elegant Defense Music by Steve Neal. Immune logo image by Blausen Medical. Send your immunology questions and comments to immune@microbe.tv

RheumNow Podcast TNF's Role With The Inflammasome (1.25.19) by Dr. Cush

The TWiM team considers the state of the world’s fungi as revealed by a report from the Kew Royal Botanical Gardens, and how Salmonella loses motility to evade host defenses. Hosts: Vincent Racaniello, Michael Schmidt, Elio Schaechter, and Michele Swanson Take our listener survey. Thanks! asm.org/twimpoll Subscribe to TWiM (free) on iTunes, Google Podcasts, Stitcher, Android, RSS, or by email. You can also listen on your mobile device with the Microbeworld app. Become a Patron of TWiM! Links for this episode: Subscribe to MicrobeTV on YouTube State of the World’s Fungi 2018 Salmonella loses motility to avoid inflammasome activation (Cell Rep) Music used on TWiM is composed and performed by Ronald Jenkees and used with permission. Send your microbiology questions and comments to twim@microbe.tv

Vincent and Daniel solve the case of the Panamanian Farmer with Three Weeks of Diarrhea, and discuss how microbes egested during bites of sand flies exacerbate the severity of leishmaniasis. Hosts: Vincent Racanielloand Daniel Griffin Become a patron of TWiP. Links for this episode: Sand fly microbesand leishmaniasis severity (Cell Host Micr) Letters read on TWiP 153 Case Study for TWiP 153 Man in clinic, in city recently, developed rash in groin area, concerned about this. Lives in open relationship with male partner, had sexual encounter with another male. Few weeks. Rash is in the pubic hair, is very itchy. Mostly around umbilicus, can see blue spots in this area. These are skin changes. Buys magnifying glass to look and describes seeing things which we see as well. No notable medical history. Send your case diagnosis, questions and comments to twip@microbe.tv Music by Ronald Jenkees

Commentary by Dr. Valentin Fuster

Synaptic activity shifts dendritic lysosomes Invading pathogens or other toxic agents can trigger the assembly of the inflammasome adaptor ASC into large, intracellular specks that activate caspase-1 to initiate a proinflammatory cell death called pyroptosis. Kuri et al. follow the dynamics of ASC speck formation in live zebrafish, revealing their lethal effects on epidermal keratinocytes and their subsequent engulfment and degradation by macrophages. This biosights episode presents the paper by Kuri et al. from the September 4th, 2017, issue of The Journal of Cell Biology and includes an interview with two of the paper's authors, Paola Kuri and Maria Leptin (EMBL). Produced by Caitlin Sedwick and Ben Short. See the associated paper in JCB for details on the funding provided to support this original research.

Neonatal sepsis is a common cause of mortality in newborns. Often, it is the inflammation in response to the pathogen, rather than the pathogen itself, that causes the most harm to the sick patient. Neonatal sepsis is currently treated with corticosteroids but they come with a significant number of adverse effects. One promising new anti-inflammatory drug is a phosphodiesterase inhibitor called pentoxyfylline. Esther Speer, a pediatrician specialized in neonatology at Stony Brook Children's Hospital, carried out an in vitro study using cord blood from healthy-term neonates, providing further evidence that pentoxyfylline represents a promising alternative to corticosteroids. See acast.com/privacy for privacy and opt-out information.

WFIRM talks to Doris Taylor, PhD about maximizing regenerative medicine strategies.

Hosts: Vincent Racaniello, Dickson Despommier, Alan Dove and Kathy Spindler Guests: Nels Elde and Edward Chuong Nels and Ed join the TWiV team to talk about their observation that regulation of the human interferon response depends on regulatory sequences that were co-opted millions of years ago from endogenous retroviruses.   Links for this episode Endogenous retroviruses and regulation of innate immunity (Science) Placenta is viral (Nature) An ERV that maintains pluripotency of human embryonic stem cells (TWiV 279) Letters read on TWiV 382 This episode is sponsored by ASM Agar Art Contest and ASV 2016 Weekly Science Picks Nels - Don't Get Me Started - Matt GiorgianniAlan - Sun's magnetic field (paper)Dickson - Most realistic dinosaur terrifiesVincent - Top secret!Kathy - Zika virus risk for US 50 cities (paper)Ed - Watching comb jellies poop Listener Picks Asal - Lost paper of Gregor MendelDennis - PhysicsGirlJacob - Second (XKCD) and ACI blogger interview Send your virology questions and comments to twiv@microbe.tv

The This Week in Microbiology team, Vincent, Elio, and Michele meet with Harry Mobley, Mary O'Riordan, and Vince Young at the University of Michigan, during the designation of the Department of Microbiology and Immunology as a Milestones in Microbiology site. They discuss how the laboratory has advanced the science and teaching of microbiology, and discuss faculty work on uropathogenic E. coli, induction of stress by bacterial infection, and the gut microbiome.

The This Week in Microbiology team, Vincent, Elio, and Michele meet with Harry Mobley, Mary O’Riordan, and Vince Young at the University of Michigan, during the designation of the Department of Microbiology and Immunology as a Milestones in Microbiology site. They discuss how the laboratory has advanced the science and teaching of microbiology, and discuss faculty work on uropathogenic E. coli, induction of stress by bacterial infection, and the gut microbiome.

Vincent, Elio, and Michele meet with Harry Mobley, Mary O’Riordan, and Vince Young at the University of Michigan, during the designation of the Department of Microbiology and Immunology as a Milestones in Microbiology site. They discuss how the laboratory has advanced the science and teaching of microbiology, and discuss faculty work on uropathogenic E. coli, induction of stress by bacterial infection, and the gut microbiome.

WFIRM talks to James Thacker, PhD about Inflammasome Regulation for Disease.

Das proinflammatorische Zytokin IL–1beta ist maßgeblich an der renalen Schädigung im Rahmen der Immunkomplex-Glomerulonephritis beteiligt. Für die Spaltung von pro-IL–1beta in seine extrazelluläre sezernierbare Form sind Inflammasome zuständig. Für das NLRP3-Inflammasom, das auf eine Vielzahl endogener Gefahrensignale (DAMPs) reagiert, wurde eine funktionelle Rolle bereits in tubulointerstitiellen Nephropathien gezeigt, wohingegen die Funktion in glomerulären Erkrankungen bis dato nicht geklärt ist. Um zu untersuchen,ob NLRP3 und sein Adaptermolekül ASC am Geschehen der Immunkomplex-vermittelten glomerulären Inflammation beteiligt sind, wurde ein T-Zell-abhängiges autologes NTN Modell induziert. Dies erfolgte in Mäusen mit einer Defizienz der Inflammasomkomponenten NLRP3 (C57BL/6-Nlrp3tm1Tsc) und ASC (C57BL/6-Pycardtm1V md). Die renale Expression von NLRP3/ASC Inflammasom-Komponenten und pro–IL–1beta stiegen während der NTN an und waren insbesondere in dendritischen Zellen (DC) vermehrt nachweisbar. Diese Tatsache war assoziiert mit der renalen Produktion von aktivem IL–1beta, was auf die Aktivierung des Inflammasoms hindeutet. Eine Defizienz für Nlrp3 oder Asc verringerte den renalen Schaden signifikant, ebenso die Leukozyteninfiltration und die T–Zell Aktivierung. Übereinstimmend mit einem ASC-abhängigen Verlust der inflammasomvermittelten IL–1beta-Aktivierung war die renale und lienale Produktion von aktivem IL–1beta in Asc-defizienten Mäusen vermindert. Überraschenderweise blieb die IL–1beta-Bildung bei Nlrp3-defizienten Tieren unverändert, was auf nicht-kanonische proinflammatorische NLRP3–abhängige Effekte im Modell der NTN hinweist. Ein solcher möglicher Effekt könnte die NLRP3-vermittelte Freisetzung von proinflammatorischem HMGB–1 als ein neuer nicht-kanonischer Mechanismus von NLRP3 und ASC während der Immunkomplex-Glomerulonephritis sein. Auf Grund dessen wäre die Blockade sowohl von NLRP3, als auch von ASC eine möglicher nutzbringender therapeutischer Ansatz im Rahmen der Behandlung von Immunkomplex-vermittelten Glomerulonephritiden.

Interferon-β therapy is only effective in treating a mouse model of multiple sclerosis when the disease is dependent upon the NLRP3 inflammasome.

Background: Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation due to dysregulation of the mucosal immune system. The cytokines IL-1 beta and IL-18 appear early in intestinal inflammation and their pro-forms are processed via the caspase-1-activating multiprotein complex, the Nlrp3 inflammasome. Previously, we reported that the uptake of dextran sodium sulfate (DSS) by macrophages activates the Nlrp3 inflammasome and that Nlrp3(-/-) mice are protected in the acute DSS colitis model. Of note, other groups have reported opposing effects in regards to DSS susceptibility in Nlrp3(-/-) mice. Recently, mice lacking inflammasomes were found to develop a distinct intestinal microflora. Methods: To reconcile the contradicting observations, we investigated the role of Nlrp3 deficiency in two different IBD models: acute DSS colitis and TNBS (2,4,6-trinitrobenzene sulfonic acid)-induced colitis. In addition, we in-vestigated the impact of the intestinal flora on disease severity by performing cohousing experiments of wild-type and Nlrp3(-/-) mice, as well as by antibiotic treatment. Results: Nlrp3(-/-) mice treated with either DSS or TNBS exhibited attenuated colitis and lower mortality. This protective effect correlated with an increased frequency of CD103+ lamina propria dendritic cells expressing a tolerogenic phenotype in Nlrp3(-/-) mice in steady state conditions. Interestingly, after cohousing, Nlrp3(-/-) mice were as susceptible as wild-type mice, indicating that transmission of endogenous bacterial flora between the two mouse strains might increase susceptibility of Nlrp3(-/-) mice towards DSS-induced colitis. Accordingly, treatment with antibiotics almost completely prevented colitis in the DSS model. Conclusions: The composition of the intestinal microflora significantly influences disease severity in IBD models comparing wild-type and Nlrp3(-/-) mice. This observation may - at least in part - explain contradictory results concerning the role of the inflammasome in different labs. Further studies are required to define the role of the Nlrp3 inflammasome in noninflamed mucosa under steady state conditions and in IBD. Copyright (C) 2012 S. Karger AG, Basel

On episode #13 of the podcast This Week in Microbiology, Stanley, Jo, Michael and Elio discuss how colonic microbial ecology and risk for colitis are regulated by an inflammasome, and amelioration of intestinal inflammation in mice by delivery of a probiotic-derived soluble protein to the colon.

Two related ligands that activate the same receptor have different effects on immune system stimulation and inflammation.

The use of antimycotic drugs in fungal infections is based on the concept that they suppress fungal growth by a direct killing effect. However, amphotericin and nystatin have been reported to also trigger interleukin-1β (IL-1β) secretion in monocytes but the molecular mechanism is unknown. Here we report that only the polyene macrolides amphotericin B, nystatin, and natamycin but none of the tested azole antimycotic drugs induce significant IL-1β secretion in-vitro in dendritic cells isolated from C57BL/6 mouse bone marrow. IL-1β release depended on Toll-like receptor-mediated induction of pro-IL-1β as well as the NLRP3 inflammasome, its adaptor ASC, and caspase-1 for enzymatic cleavage of pro-IL-1β into its mature form. All three drugs induced potassium efflux from the cells as a known mechanism for NLRP3 activation but the P2X7 receptor was not required for this process. Natamycin-induced IL-1β secretion also involved phagocytosis, as cathepsin activation as described for crystal-induced IL-1β release. Together, the polyene macrolides amphotericin B, nystatin, and natamycin trigger IL-1β secretion by causing potassium efflux from which activates the NLRP3-ASC-caspase-1. We conclude that beyond their effects on fungal growth, these antifungal drugs directly activate the host's innate immunity.

IL-1β and IL-18 are proinflammatory cytokines that contribute to renal immune complex disease, but whether IL-1β and IL-18 are mediators of intrinsic glomerular inflammation is unknown. In contrast to other cytokines the secretion of IL-1β and IL-18 requires a second stimulus that activates the inflammasome-ASC-caspase-1 pathway to cleave pro-IL-1β and -IL-18 into their mature and secretable forms. As the NLRP3 inflammasome and caspase-1 were shown to contribute to postischemic and postobstructive tubulointerstitial inflammation, we hypothesized a similar role for NLRP3, ASC, and caspase-1 in glomerular immunopathology. This concept was supported by the finding that lack of IL-1R1 reduced antiserum-induced focal segmental necrosis, crescent formation, and tubular atrophy when compared to wildtype mice. Lack of IL-18 reduced tubular atrophy only. However, NLRP3-, ASC- or caspase-1-deficiency had no significant effect on renal histopathology or proteinuria of serum nephritis. In vitro studies with mouse glomeruli or mesangial cells, glomerular endothelial cells, and podocytes did not reveal any pro-IL-1β induction upon LPS stimulation and no caspase-1 activation after an additional exposure to the NLRP3 agonist ATP. Only renal dendritic cells, which reside mainly in the tubulointerstitium, expressed pro-IL-1β and were able to activate the NLRP3-caspase-1 axis and secrete mature IL-1β. Together, the NLRP3-ASC-caspase-1 axis does not contribute to intrinsic glomerular inflammation via glomerular parenchymal cells as these cannot produce IL-1β during sterile inflammation.

Background The proinflammatory cytokines interleukin 1 beta (IL-1 beta) and IL-18 are central players in the pathogenesis of inflammatory bowel disease (IBD). In response to a variety of microbial components and crystalline substances, both cytokines are processed via the caspase-1-activating multiprotein complex, the NLRP3 inflammasome. Here, the role of the NLRP3 inflammasome in experimental colitis induced by dextran sodium sulfate (DSS) was examined. Methods IL-1b production in response to DSS was studied in macrophages of wild-type, caspase-1(-/-), NLRP3(-/-), ASC(-/-), cathepsin B(-/-) or cathepsin L(-/-) mice. Colitis was induced in C57BL/6 and NLRP3(-/-) mice by oral DSS administration. A clinical disease activity score was evaluated daily. Histological colitis severity and expression of cytokines were determined in colonic tissue. Results Macrophages incubated with DSS in vitro secreted high levels of IL-1b in a caspase-1-dependent manner. IL-1b secretion was abrogated in macrophages lacking NLRP3, ASC or caspase-1, indicating that DSS activates caspase-1 via the NLRP3 inflammasome. Moreover, IL-1b secretion was dependent on phagocytosis, lysosomal maturation, cathepsin B and L, and reactive oxygen species (ROS). After oral administration of DSS, NLRP3(-/-) mice developed a less severe colitis than wild-type mice and produced lower levels of proinflammatory cytokines in colonic tissue. Pharmacological inhibition of caspase-1 with pralnacasan achieved a level of mucosal protection comparable with NLRP3 deficiency. Conclusions The NLRP3 inflammasome was identified as a critical mechanism of intestinal inflammation in the DSS colitis model. The NLRP3 inflammasome may serve as a potential target for the development of novel therapeutics for patients with IBD.