Podcast appearances and mentions of Ken Walsh

This month on Episode 65 of Discover CircRes, host Cindy St. Hilaire highlights articles featured in the September 27th and October 11th issues of Circulation Research. This Episode also includes a discussion with Dr Ken Walsh and Dr Ariel Polizio about their study, Experimental TET2 Clonal Hematopoiesis Predisposes to Renal Hypertension Through an Inflammasome-Mediated Mechanism.   Article highlights: Ju, et al. NAE1 Crotonylation Regulates Cardiac Hypertrophy Pirri, et al. EPAS1 Atheroprotection via Fatty Acid Metabolism Saleem, et al. Myeloid CD11c+ Cells and JAK2/STAT3/SMAD3 in SSBP Pietsch, et al. Chronic Activation of Tubulin Tyrosination

First - As jury selection in the Trump Manhattan Criminal trial resumes - we'll be joined by Harvard University law professor Ronald Sullivan -- to break down the process and challenges in finding impartial jurors. Then – Brookings Institution's Ryan Hass will discuss President Biden's call this week for higher tariffs on Chinese steel and aluminum products -- and key policy differences between him and his predecessor on U.S. trade with China. Plus – journalist and author Ken Walsh discusses his new book "The Architects of Toxic Politics in America: Venom and Vitriol" Learn more about your ad choices. Visit megaphone.fm/adchoices

In episode #291 of Shut Up and Grind with Robert B. Foster, we hear the incredible story of Ken Walsh, who turned his life around from battling drug addiction to embracing the power of CrossFit. Ken shares his emotional journey, from the pain of losing his father to lung cancer to finding solace and strength in fitness. His transformation not only led to personal sobriety and well-being but also to a mission to help high school students navigate the challenges of addiction, mental health, and trauma through the discipline of fitness. Join us as Ken recounts how replacing drug highs with CrossFit highs has reshaped his life and how he's now dedicated to guiding youth on a path to resilience and health. --- Support this podcast: https://podcasters.spotify.com/pod/show/shutupandgrind/support

Sermon by Rev. Ken Walsh 1 Samuel 3:1-20 (NRSV) John 1:43-51

Not many of us have spent near as much time below the Earth's surface as Dr. Ken Walsh has.  Ken is a Senior Environmental Engineer at Leidos Inc., but that is not who he is.  Ken is an Everyday Explorer at hear.  He started his love of exploration under ground early in his life, and it has taken him deeper and deeper in to exploring the beauty that exists above and below ground.  It also has been a mode for him to explore the reaches of his own limits. We weave our way through a wide ranging conversation that will expose Ken's intelligence, creativity and natural curiosity, all of which are used by him to find wonder and awe no matter where he finds himself. 

This is the final episode of Perfectly Pan!cked in 2022 and we're going out with a bang!

It's time for your favourite podcast again folks. We have a small change to the starting panel as Stuart has gone to Germany searching for gas to heat his massive penthouse in the sleepy suburbs of Kathmandu. So, wearing one of Stuart's off the shoulder numbers is the wonderful Clodagh. Ooh la la…   We kick off this week with Jan and his new video doorbell. Yes, it appears Jan's wife is getting a bit sick and tired of Larry bursting through the front door for playtime with Sjef. So the Bloem household now features a First Security video doorbell which Jan thinks is the business. The great news is that it is not a subscription service but rather has an SD card for recording locally instead of on the cloud, like Ring doorbells. Check it out here: www.firstsecurityserviceinc.com/video-doorbell.html   Now that the security is sorted, it's time to move onto a great discussion on mental health. Clodagh is joined by Peter O'Toole, Head of Counselling, Wellbeing & Emotional Support with NCBI; Kathryn Sinnott, Senior Fundraising Executive and Insight Counselling Service Insight Groups Coordinator in Fighting Blindness; and Ken Walsh, who is visually impaired and is a guide dog owner. The panel talk about how to recognise when you might benefit from some support with your mental health, what support groups are available, and the difference between counselling and support groups, and much more besides.   We have compiled a list of supports available from Fighting Blindness and NCBI which you can access here: tinyurl.com/BGCsupports. We will add to this list as time goes on. If you would like to add information about these kinds of services from your country, please send the info to blindguyschat@gmail.com.   So, throw caution to the wind, throw frisbees to the dog, and settle in for the number 1 podcast as voted by COP27 delegates: Blind Guys Chat. 27 out of 27 attendees prefer it to overpriced sandwiches and desalinated water. Support Blind Guys Chat by contributing to their tip jar: https://tips.pinecast.com/jar/blind-guys-chat

1st Lt Kenneth Walsh was the first F4U Corsair ace and a pilot in VMF-124 during the Solomon Islands campaign. He would earn his Medal of Honor over the course of two missions in August of 1943 and finish the war with 21 victories. In addition to Ken Walsh and VMF-124, this episode covers the development of the F4U Corsair and the initial moves of Admiral Halsey up the Solomon Island chain. Selected readings: Harnessing the Sky: Frederick "Trap" Trapnell, the US Navy's Aviation Pioneer, 1923-1952 by Frederick Trapnell Jr and Dana Tibbitts Corsair, the F4U in World War II and Korea by Barrett Tillman History of Marine Corps Aviation in World War II by Robert Sherrod Time of Aces: Marine Pilots in the Solomons, 1942-1944 by Cdr Peter Mersky I can be reached at aviationmoh@gmail.com Feedback and reviews are appreciated. Semper Fi, Kelly "Beavis" Ramshur

Steve talks with the consummate historian of the modern American presidency, Kenneth T. Walsh, about daily life for those who work in the White House, including the President.  Ken Walsh is the author of three books: [...]

Steve talks with the consummate historian of the modern American presidency, Kenneth T. Walsh, about daily life for those who work in the White House, including the President.  Ken Walsh is the author of three books: [...]

Ken Walsh, CEO of AYCC, YMCA, Boys & Girls Club of Waterville, Maine, discusses how their organization serves the community and how the organization has transformed over the past 29-years under his direction. Ken's describes his vision of collaboration amongst non-profits to achieve greater efficiencies and greater benefits .

This month on Episode 20 of the Discover CircRes podcast, host Cindy St. Hilaire highlights four featured articles from the January 8 and January 22 issue of Circulation Research. This episode features an in-depth conversation with Drs Stefanie Dimmeler and Wesley Abplanalp from Goethe University in Frankfurt, Germany, regarding their study titled Clonal Hematopoiesis-Driver DNMT3A Mutations Alter Immune Cells in Heart Failure.   Article highlights:   Li, et al. FA Scaffold Genes Are Novel TAA Genes   Z Perestrelo, et al. ECM Structure and Mechanics in Heart Failure   Castranova, et al. Zebrafish Intracranial Lymphatics   Rogers, et al. Computational Phenotypes for VT/VF Risk     Cindy St. Hilaire:              Hi, and welcome to Discover CircRes, the podcast with the American Heart Association's journal, Circulation Research. I'm your host, Dr Cindy St. Hilaire, from the Vascular Medicine Institute at the University of Pittsburgh. Today I'll be highlighting four articles selected from the January 8’th and January 22’nd issues of Circ Res. After the highlights, Dr Stephanie Dimmeler and Wesley Abplanalp at Goethe University in Frankfurt, Germany will join me to discuss their study, Clonal Hematopoiesis-Driver DNMT3A Mutations Alter Immune Cells in Heart Failure.   Cindy St. Hilaire:              The first article I want to share is Variants of Focal Adhesion Scaffold Genes Cause Thoracic Aortic Aneurysm. The first authors are Yang Li and Shijuan Gao, and the corresponding authors are Jie Du and Yulin Li from Beijing Institute of Heart, Blood and Lung Vessel Disease in Beijing, China. Thoracic aortic aneurysm is the localized expansion of the blood vessel. This expansion causes weakening of the vessel wall, causing it to rupture, which is a life-threatening emergency. Although there are several genetic mutations that lead to thoracic aortic aneurysms, more often thoracic aortic aneurysms occur as an isolated event with no known cause or family history. To gain greater insight into the genetic underpinnings of isolated thoracic aortic aneurysms, Li and Gao and colleagues performed whole exome sequencing of DNA from 551 patients and 1070 healthy controls. They found that five percent of the patients screened harbored mutations in previously identified genes associated with TAA. Importantly, they identified a number of novel candidate gene variants in the remaining 95%. In four patients they discovered mutations in a gene named Testin. Testin is a scaffold protein found at focal adhesions, which are the points of connection between the extracellular matrix and the cell’s intracellular cytoskeletal framework. Mice that lacked Testin, or carried a mutant version of it, had dilated aortas and impaired contractility of vascular smooth muscle cells. Moreover, the team found additional focal adhesion gene variants present in the patient cohort, suggesting weakening or dysfunction of the structural elements may be a driving force in thoracic aortic aneurysm pathology. Cindy St. Hilaire:              The second article I want to share is titled Multi-scale Analysis of Extracellular Matrix Remodeling in the Failing Heart. The first author is Ana Rubina Perestrelo, and the corresponding author is Giancarlo Forte, and they're from St. Anne's University Hospital in the Czech Republic. After a myocardial infarction, when a lack of blood supply causes injury to the cardiac muscle, the damaged muscle tissue is patched by proliferating fibroblasts and the remodeling of the extracellular matrix. This is a process that is called fibrosis. However, this fibrotic process often continues after the initial repair and itself causes progressive loss of cardiac function. To better understand how cardiac fibrosis progresses, Perestrelo and colleagues examined cardiac extracellular matrix and fibroblasts from patients with and without heart failure. Using both microscopy and mass spectrometry, they found that the extracellular matrix from heart failure patients had a larger content of collagen and other extracellular matrix proteins, as well as more compact and less elastic fibers than non-heart failure controls. Cindy St. Hilaire:              RNA analysis of fibroblasts from patient and control hearts revealed heart failure patients had increased transcription of genes involved in assembling both the extracellular matrix and focal adhesions, which, as we just learned, are the points of connection between extracellular matrix and the cell's cytoskeleton. One such gene encoded the transcription factor yes-associated protein, or YAP. In cardiac fibroblasts, high levels of YAP drove expression of extracellular matrix factors. Similarly, extracellular matrix material from heart failure patients was particularly potent in triggering YAP activity. In highlighting this positive feedback of extracellular matrix remodeling, the work suggests that blocking this YAP-driven process may be an effective strategy for slowing heart failure pathogenesis. Cindy St. Hilaire:              The third article I want to share is titled Live Imaging of Intracranial Lymphatics in the Zebrafish. The first author is Daniel Castronova and the corresponding author is Brant Weinstein from the National Institutes of Health in Bethesda, Maryland Until recently it was believed that the mammalian central nervous system lacked a classical lymphatic system. However, that belief was overturned a few years ago when canonical lymphatic vessels were discovered in the mouse brain. The discovery has implications for the understanding of the brains inflammatory and protein clearance processes, as well as disorders associated with these processes, such as in Alzheimer's disease. Because in vivo analysis of the mammalian brain lymph system is hindered by the thickness of the skull, Castronova and colleagues turned to a recently engineered zebrafish that has practically transparent tissues. Visualizing the fish brain through the top of the animal’s skull, the team found a complex network of lymphatic vessels covering much of the brain, particularly the cerebellum and the optical areas. The team confirmed the identity of the vessels with a series of lymph markers and showed that the vessels both carried out tissue drainage and contained trafficking neutrophils. The work introduces the fish as a valuable model for studying intercranial lymphatics in both health and disease states. Cindy St. Hilaire:              The last article I want to share before we switch to our interview with Dr Dimmeler is titled Machine Learned Cellular Phenotypes Predict Outcome in Ischemic Cardiomyopathy. The first authors are Albert Rogers and Anojan Selvalingam. The corresponding author is Sanjiv Narayan from Stanford University in Palo Alto, California. Sudden cardiac arrest affects over 300,000 people per year in the US alone. Individuals with reduced left ventricular ejection fraction are at an elevated risk for sudden cardiac arrest. Many of these patients qualify for implantable cardiac defibrillators. However, in the first year of implantation, these devices are rarely needed to deliver life-saving therapy, and identifying means to further risk stratify these patients has been elusive. The authors of this study hypothesized that the morphology of individual ventricular monophasic action potentials in patients with ischemic cardiomyopathy could possibly identify tissue or cellular electrophysiological phenotypes that can be identified by machine learning and then be used to predict long-term outcomes for patients. Cindy St. Hilaire:              Using 42 patients with coronary artery disease, the team recorded 5,706 ventricular monophasic action potentials and left ventricular ejection fraction during steady state pacing. Patients were then randomly allocated to independent training and testing cohorts. Support vector machines and convolutional neural networks were trained to two end points. The first, sustained ventricular arrhythmia, and the second, mortality at three years. Patient level predictions in independent test cohorts yielded a strong concordance statistic and were the most significant multivariate predictors. This machine learning of action potential recordings in patients revealed novel phenotypes for long term outcomes in ischemic cardiomyopathy. These computational phenotypes may reveal cellular mechanisms for clinical outcomes and could be applied to other conditions. Cindy St. Hilaire:              Today, Dr Stephanie Dimmeler and her postdoctoral fellow Wesley Abplanalp, from the Goethe University in Frankfurt, Germany, are here to discuss their study, Clonal Hematopoiesis-Driver DNMT3A Mutations Alter Immune Cells in Heart Failure. This article is in our January 22nd issue, the second issue of 2021. Thank you both very much for joining me here today. I know it's the evening where you are, so I appreciate you taking the time to sit with me. Wesley Abplanalp:         Of course. Thank you. Cindy St. Hilaire:              I think I want to start with the definition of clonal hematopoiesis. Just to get every listener on the same page. Our bone marrow produces billions of blood cells every day and the traditional view is that maybe 10 to 20,000 of these hematopoietic STEM and progenitor cells create all the progeny blood cells. This idea of multiple hematopoietic and progenitor cells, or HSPCs, is in contrast to this phenomenon called clonal hematopoiesis. That is where a sizable portion of the differentiated blood cells at a given time in a human has been derived from a single, kind of dominant HSPC. This idea of clonal hematopoiesis can really best, I think, be conceptualized when we think about cancers, like leukemia, but a lot of clonal hematopoiesis has been linked to what is called clonal hematopoiesis of indeterminate potential, or CHIP. I was wondering if you could kind of give us a little bit of details about what is known regarding the drivers of CHIP, this clonal hematopoiesis of indeterminate potential, and what's the genesis of exploring the role of CHIP and how it affects cardiovascular health, and specific to your study, heart failure? Stephanie Dimmeler:     Well, thank you very much. Maybe I start with the more general question, actually the CHIP refers to the occurrence of mutations in hematopoietic STEM cells, which leads to the extension of these mutated cells. Initially it was thought that this is correctly linked to cancer and the development of the leukemia, but it turned out that the occurrence of such mutation is not exclusively seen in patients with leukemia, but actually also healthy persons can acquire such mutation, and has such mutations of blood. So it's an age-dependent phenomenon and with increasing age, up to 20% of the people have such mutations. Cindy St. Hilaire:              Wow, 20%. Stephanie Dimmeler:     If they are old enough. There are a few of such mutations, particularly in these enzymes, which we are also studying in MTCA, or type two, this doesn’t lead to leukemia, but still subject to such mutations die earlier. So they have a poor prognosis. As said it was not linked to leukemia or cancer, but it was shown by Eisner and colleagues and Dr Libby also  that such mutation have a higher risk of dying from coronary artery disease. We have added to this information, and our group is actually working together with the hematology department, that also heart failure patients with such mutations have a very poor prognosis. Cindy St. Hilaire:              Interesting. Maybe when we're talking about clonal hematopoiesis I know in your paper you mentioned, I think it was three or four commonly found mutants. Is there something shared between these genes that are mutated? I know in this study we're focusing on DNMT3A, but what does that do normally and what are some of these other drivers of clonal hematopoiesis, and is there a similar theme to the mutations? Wesley Abplanalp:         Well, I guess I could jump in a little bit. We're looking at DNMT3A, and the other very commonly found gene that's often mutated is TED2, and I think what's really interesting about these two genes is that they can both epigenetically control gene regulation, of course. So one is a DNA methyltransferase and of course the other has the opposite effect. This is not true necessarily for all CHIP-associated mutations, but I do think it is quite interesting that these tend to be the two most abundantly found mutated genes, especially in the context of CHIP, and especially within these heart failure cohorts. Cindy St. Hilaire:              So how common are these mutations? I guess we can specifically talk about DNMT3A. How common is that in the general population as a whole? Do we know that yet? Stephanie Dimmeler:     Yeah, some studies, it's a clear age dependent phenomenon. It depends on the age. In young subjects only very few subjects have such mutations, but with increased age, like 80, for example, you have a significant number and it's even higher if you look at heart failure patients, who have up to 40% of heart failure patients with high age having such mutations. Also, of course I have to say it depends a bit how you count the mutations. It depends where you set the cut off. We, for example, set the cutoff at two percent of mutations carrying DNA in the blood, and it depends with the numbers, depending with how low or how high you set the cut off. Cindy St. Hilaire:              Wow. So really it could be quite high. I guess I didn't realize it was that high. So could you maybe walk us through the study? What did you start with and what analysis did you perform? Wesley Abplanalp:         So with this study, we enrolled subjects with chronic ischemic heart failure. We were beginning there because we'd already found that the patients who have chronic ischemic heart failure and harbored these mutations have a worse prognosis. So our question is clearly there's something in the blood that's happening that's maybe facilitating this. We wanted to know more about this. It was already understood that these cells might be associated with inflammation, but the real question is we wanted to know what the transcriptional signatures would be in these patients. We enrolled six heart failure patients with a DNMT3A mutation. Wesley Abplanalp:         We had already screened through subjects before, and another four subjects with heart failure, with no known CHIP associated mutation. So we screened for 56 mutations that are associated with CHIP or other hematological malignancies. Then this is how we began our cohort. From this, then we took the peripheral blood from these subjects and use the peripheral blood mononuclear cells. So basically it'd be immune cells, which are circulating from these subjects and then performed a droplet single cell RNA sequencing analysis on just these circulating cells. We didn't necessarily enrich any cell type. We were trying to take an unbiased approach to really capture what was happening in the landscape. Then from here, we really dove down into some of the most abundant cell types that are there. For example, the monocytes and the T cells. Cindy St. Hilaire:              That's great. I think I read you found there were no significant changes in the actual types of cells. So both mutant and control populations had similar numbers of different types of cells, but what you did find that was significantly different, was the gene expression profiles within the cells of the mutant versus the controls. Can you talk a little bit about these changes? What was the same and what was different between your groups? Wesley Abplanalp:         Right. So one thing that I think that was really striking, like you're saying, or important, we're not seeing the change in the relative shifts in the abundances of cells. So therefore we can ask what's really happening within the cell. That's where the strength of the technology really has its full effect, I guess. What we're seeing is we were able to kind of add and confirm that the hallmark inflammatory cytokines, like IL-Beta and IL-6, IL-8, for example, were upregulating, this gives us great insights for potential interventions for these subjects, for example. These were quite different. We were also seeing, so we found this in the monocytes, we were also seeing an increase in resistin. So this was at this point, unknown. In resisitin, I think is a really interesting molecule because this is a secreted protein. It's been shown that when endothelial cells are exposed to this, that they become activated. Wesley Abplanalp:         We could also take this in vitro and silence DNTM3A in monocytes, and then we could add the supernatant. So what's secreted from these monocytes and add them to otherwise naive endothelial cells. We could see indices of endothelial cells becoming activated through increases in IL-Beta and BK-1.. We are additionally showing increasing interactions between endothelial cells and monocytes, which had otherwise not been shown before. We are also kind of showing these novel interactions between monocytes and T-cells, which I think is really cool because then you wind up having this capacity for a small number of cells enriching the impact on the greater blood and population. Through the interactions with T-cells and endothelial cells, we wind up seeing strong evidence, for example, for a potential bystander effect. So that for a few rogue cells to really have a much broader impact on these cells in the greater milieu. Cindy St. Hilaire:              Yeah. I found that graphic, your graphical abstract, it was something just really neat to think about in terms of there's this clonal hematopoiesis, but it's not a hundred percent, right? Is that correct? These mutations aren't in every single one of these circulating cells. I was wondering, could you find evidence that the inflammatory, maybe this would be an in vitro study, the inflammatory activation or cytokine release or activation of endothelial cells is better, worse, the same if the monocyte has it versus the T-cell has it, versus both? Are they equal contributors? What, I guess what, in terms of a stepwise progression, where do you think these mutants are more potent? Wesley Abplanalp:         Oh, this is a good question. Cindy St. Hilaire:              If you can speculate. Maybe you can't speculate yet. Wesley Abplanalp:         Yeah, I think at this point, I think it's a lot of speculation. With the monocytes we wind up seeing, I think some of the biggest changes we wind up seeing are just in these cytokine, they turn into kind of a cytokine factory. They just really push out these cytokines. There's a much more mixed response, I think from the T-cells, but inherently the T-cells are a much more diverse population. So it begins to become a little bit difficult to compare because they all have different roles and different functions. Unfortunately, I think it's finding a good T-cell model in vitro, for example, is a little more difficult than recapitulating some of this for monocytes, for example. Cindy St. Hilaire:              I'm not an immunologist, I guess, being a vascular biologist, you're a little bit immunologist always, but what are our abilities to model this in a mouse system? Are these cell types very easily translatable between mouse and human? I know there's different cytokine profiles when we're talking macrophages and things like that, is it similar for T-cells also? Or is that more translatable? Stephanie Dimmeler:     The  proton signature have been observed in type two hetero zygote STEM cell transplants in mice as well. Also, DNTM3A editing has been shown in actually, a very nice Circulation Research paper by Ken Walsh to have an effect also on heart failure. These studies suggest that at least the pro-inflammatory signature in monocytes can be recapitulated as well, can be the phenotypes that grows its development, as shown by [Ken Walsh, and the heart failure phenotypes. I think Cynthia, you've touched upon a very interesting question. Mainly, to what extent is the transcription we are seeing related directly to the mutation of the cell? To what extent can you explain and understand that so many of the cells have this changed signature? I think our data clearly suggests, at least for the monocytes, that it's not only the mutated cell alone. Stephanie Dimmeler:     They have also a channel effect on the other, non-mutated cell, because our percentage of cells which has the mutation is between maybe 2% and 10% to 30% to 40%. We have many more cells which have the inflammatory signature. In the T-cells it's a bit different maybe, but also we have excessive activation. I think we don't know yet the reason. It could be many, but we are really doing, what we are currently doing is to try to target which cell is mutated and which cell is not mutated in humans. Then we can distinguish biochemically between the mutation carriers and the biotype cells, and then we can tell more what happens directly, and what happens secondarily, because of course, if you have an inflammatory cell, this inflammation can influence the neighboring cell as well. In the STEM cell niche, the cells are also in the same environment, so] how much your environment in STEM cell niche, this may also affect the neighboring other hematopoietic STEM cells. This is what I think is the next step to do. Cindy St. Hilaire:              Yeah, that's one thing I was actually thinking about is obviously the clonal hematopoiesis aspect means there is a STEM cell harboring a mutation that is selecting or allowing that population to grow much more efficiently or faster than the non mutant cells. What is that doing to the other STEM cells in that area? Is it inflammation just in the periphery once these cells are differentiated in little packets of cytokine releasing cells, but yeah, what's happening at the level of the niche in terms of these mutations? Stephanie Dimmeler:     A very interesting question. I think it's so far understudied, at least we have no insights, but what is known is that for some heart failure, and acute myocardial infarction also had an impact on the STEM cell niche, so there is activation of the osteogenic niche, there is a change in the vascular niche. So this are maybe effects, which may link also hematopoiesis and the cardiovascular and heart disease on some level, but to know what is he and egg need some more studies to do. Cindy St. Hilaire:              Yeah, yeah. As always, I have that same problem with calcification stuff. What is the cause? What is the consequence? I guess it's ripe for funding and studies. The schematic, your graphical summary is really focusing in on this monocyte T-cell interaction on the endothelium, which is obviously not the heart tissue itself. So how do you envision, this is kind of easy to conceptualize or picture when we're talking about an atherosclerotic plaque, right? It's right at that interface where these blood cells are touching the vasculature, but what do you think is happening to exacerbate or drive the heart failure component regarding clonal hematopoiesis and specifically this mutation? Wesley Abplanalp:         So one thing that we are seeing, and I think that's particularly interesting, is perhaps this interaction between the endothelium, like you were saying, and monocytes. Ken Walsh, and I think others have shown, but Ken Walsh I think had shown that with a DNMT3A loss of function study, that they could see an increase in the extra visation, or these monocytes coming in to the myocardial tissue. That there seemed to be some kind of indices of heart failure that then accompanied this. How or why this was happening I think people didn't really know, but I think there are many ways in which this could happen. If, for example, if these cells are secreting resistin, and there's increased adhesion molecules, and of course there's increased chances for extra visation where these cells can leave the blood and then go into the heart. Cindy St. Hilaire:              Has anyone ever looked at cardiac tissue from patients harboring these mutations and seen differences in either the cardiomyocytes or the cardiac fibroblasts or anything like that? Or is that what you're doing next perhaps, or- Wesley Abplanalp:         Stephanie's smiling. Stephanie Dimmeler:     We tried to, the problem is there's difficulties in these biopsies to get enough material to study the mutation. Cindy St. Hilaire:              Of course. Stephanie Dimmeler:     So far, the problem with the patients also incomparison to mice models that we have to clean off the circulating blood, which may also be stuck in the tissue. Therefore, we have some results, but not yet for publishing because the reviewers will make us pass time to make this more confusing. So, as soon as we can detect by single cell on a sequencing or nuclear sequencing, the mutated cells and the non-mutated cells, then we have a chance to get more insights. So far, we cannot distinguish really the cardiac monocytes versus the circulating monocytes, which makes our study a bit more difficult. Really I can add one more point to your previous question. Cindy St. Hilaire:              Sure. Stephanie Dimmeler:     I think one, an interesting message of our paper would also be that if you have proinflammatory monocytes coming from the circulation into the heart, and our study will claim that they are more likely to hold through the heart tissue and then invade, because endothelial affects the capacity. Then they may replace the cardiac macrophages, which would be seen as a more physiological and protected type of cell, which is involved, as we know in electrical continuation and so on. Then we have these bone marrow cells, which are increasing in holding and this of course could aggravate all the heart failure in addition to the cytokines they are producing. I think, finally, also one shouldn't neglect the T-cell. T-cells are known to play a role in heart failure, and if we have activation of T-cells, which we have to prove now in the cardiac tissue, but at least in the circulation here, I would assume that this is the case. This could have also consequences of course, and could link hematopoiesis to heart failure phenotypes as well. Cindy St. Hilaire:              So where do you think this will go in the future? How could this knowledge, and possibly even single cell sequencing technology, be leveraged for therapies in the future? Stephanie Dimmeler:     So my wish would be that our data would be leading to a type of guided therapy. If we understand better which mutation affects which pathways, or which genes, we may use specific anti-inflammatory treatments, not global anti-inflammatory treatments, but more specified or specific treatment strategies to target patients with mutations. I think single cell sequencing is a very good way to start it. Followed by proteomics and then other -omic technologies. This is actually what I would wish we could do with it, which other people hopefully start some pilot trials with patients and try some treatments, but we could maybe get even further insights by the single cell data. Then the responses also of the treatments, the single cell sequencing, you can see, but it can normalize the phenotype, which would be, of course, the wish. Cindy St. Hilaire:              That would be amazing because we tried in the Cantos Trial to just, let's block inflammation and see what happens. There were certain populations where it seemed to have a much greater effect than others, and maybe targeting clonal hematopoiesis could help tweak or tighter those therapies. This was a great study. I want to commend you both on this excellent story and thank you so much for joining me today. Stephanie Dimmeler:     Thank you very much. Nice to see you again. Wesley Abplanalp:         Thank you. Cindy St. Hilaire:              That's it for the highlights from the January 8th and January 22nd issues of Circulation Research. Thank you for listening. Please check out the CircRes Facebook page and follow us on Twitter and Instagram with the handle @CircRes and #DiscoverCircRes. Thank you to our guests, Doctors Stephanie Dimmeler and Wesley Abplanalp. This podcast is produced by Rebecca McTavish and Ashara Ratnayaka, edited by Melissa Stoner, and supported by the Editorial Team of Circulation Research. Some of the copy text for the highlighted articles is provided by Ruth Williams. I'm your host, Dr Cindy St. Hilaire, and this is Discover CircRes, your on-the-go source for the most exciting discoveries in basic cardiovascular research.  

Wisconsin voters were told to stay home because of the coronavirus and then told to go out and vote in the state's primary. We discuss what put voters in the Badger State in this predicament. Plus, a personal account of New York Gov. Andrew Cuomo, who is getting high marks for keeping his state informed. And journalist Ken Walsh discusses his new book about how presidents (going back to FDR) have dealt with crises during their tenure. The post Episode #323: Presidents and Crises appeared first on Ken Rudin's Political Junkie.

sermon by Rev. Ken Walsh

sermon by Rev. Ken Walsh based on John 11:1-45

sermon by Rev. Ken Walsh based on Matthew 21:1-11

sermon by Rev. Ken Walsh based on Matthew 4:1-11

sermon by Rev. Ken Walsh based on Matthew 17:1-9

sermon by Rev. Ken Walsh based on Deuteronomy 30:15-20; 1 Corinthians 3:1-9

sermon by Rev. Ken Walsh based on 1 Corinthians 2:1-16; Matthew 5:13-20

sermon by Rev. Ken Walsh 1 Corinthians 1:10-18 Matthew 4:12-23

Set sail through the South Pacific with journalist, author and historian, Ken Walsh. He’s authored eight books, was president of the White House Correspondents’ Association and is currently the White House and Political Analyst for U.S. News & World Report. But what sparked his passion for communication was actually a childhood motivation for dessert. Tune in now! Read more about this episode.

sermon by Rev. Ken Walsh based on Isaiah 60:1-6; Ephesians 1:3-14

This month on Episode 6 of the Discover CircRes podcast, host Cindy St. Hilaire highlights five featured articles from the October 25 and November 8, 2019 issues of Circulation Research and talks with Coleen McNamara and Aditi Upadhye about their article, Diversification and CXCR4-Dependent Establishment of the Bone Marrow B-1a Cell Pool Governs Atheroprotective IgM Production Linked To Human Coronary Atherosclerosis.   Article highlights:   Omura, et al. ADAMTS8 in Pulmonary Hypertension.   Rödel, et al. Blood Flow Suppresses CCM Phenotypes in Zebrafish   Cai, et al. Proteomics Assessment of hPSC-CM Maturation   Shin, et al. Leptin Causes Hypertension Via Carotid Body Trpm7   Lin , et al. Cellular Heterogeneity in Elastin Deposition   Transcript Dr Cindy St. Hilaire:          Hi. Welcome to Discover CircRes, the monthly podcast of the American Heart Association's journal, Circulation Research. I'm your host, Dr Cindy St. Hilaire and I'm an assistant professor of medicine at the University of Pittsburgh. In this episode I'm going to share with you some highlights from recent articles that were published in the October 25th and our November 8th issues of Circulation Research. We're also going to have an in-depth conversation with doctors Coleen McNamara and Aditi Upadhye, who are the lead authors in one of the exciting discoveries from our October 25th issue. The first article I want to share with you is titled ADAMTS8 promotes the development of pulmonary arterial hypertension and right ventricular failure, a possible novel therapeutic target. The first author is Junichi Omura and the corresponding author is Hiroaki Shimokawa, and the work was conducted at Tohoku University, Sendai, Japan. Pulmonary hypertension is caused from the excessive proliferation of the vasculature in the lungs. It has contributions from smooth muscle cells, endothelial cells, inflammatory cells, and these cells proliferate and occlude the small vessels in the lungs. And this occlusion leads ultimately to failure of the right heart ventricle. Current therapies only treat the symptoms, not the underlying pathology. So there really is a big push right now to try to discover novel therapeutic targets. The authors of this study performed a gene expression screen, and in this screen, they compared pulmonary artery smooth muscle cells from pulmonary hypertension patients to those same cells from healthy controls. The research has found numerous differentially-expressed genes. However, they chose to focus on one called ADAMTS8. And they focused on this because the protein is expressed specifically in the lungs and heart tissues, and it was significantly upregulated in the patient's cells. So ADAMTS8 is a secreted zinc dependent protease, and this protease function makes it potentially a druggable target. So similar to human cells, ADAMTS8 was also found to be upregulated in the lungs of mice with pulmonary hypertension and a lack of vascular ADAMTS8 attenuated the disease symptoms. Conversely, overexpression of ADAMTS8 in pulmonary artery smooth muscle cells from both mice and humans prompted increased proliferation. They performed a high throughput screen to try and identify compounds that would suppress ADAMTS8 and pulmonary artery smooth muscle cell proliferation. And in this screen, they found mebendazole, which is a drug that is already in clinical use for parasitic worm infections. Thus, the study not only pins ADAMTS8 as a driver of pulmonary hypertension, but also suggests a potential existing drug might be useful for treating it. The next manuscript I want to share with you is titled Blood Flow Suppresses Vascular Anomalies In a Zebrafish Model of Cerebral Cavernous Malformations. The first author is Claudia Jasmin Rödel, and the corresponding author is Salim Abdelilah-Seyfried, and they are from the University of Potsdam in Potsdam, Germany. Vessel diameter and geometry as well as blood velocity and flow speed, all affect how the flow of blood impacts biomechanical forces that are received by the endothelial cells that line the lumen of vessels. Pathological changes in biomechanical signaling pathways or abnormal patterns of blood flow have been implicated in the etiology of various vascular diseases, and this manuscript is focusing on one: cerebral cavernous malformations, or CCMs. There are various genetic causes of CCMs, and this combined with several lines of evidence, point to a role for blood flow in CCM lesion development. Specifically, patients typically develop CCM lesions only in low perfused venous capillaries. Those are slow flow vessels. Rarely are high flow vessels affected. The authors want to answer the question, why do CCMs develop in low flow areas and more broadly, what is the role of hemodynamic forces in CCM pathology? To explore the role of blood flow and vascular remodeling, they use a zebrafish model. This is a great model to study this specific type of malformation, because the zebrafish itself is transparent and you can do an amazing way of imaging and I highly recommend that you go online and check out some of the videos that are supplemental figures for this paper. They're beautiful, they're neat, and you can really see the blood flow in these zebrafish models that they use. Okay, so which models did they use? They used ones that had normal levels of blood flow or normal speeds of blood flow, and then a zebrafish that is actually absent of any blood flow. Which is crazy that it can live for any amount of time. And so they use these zebrafish and looked at the lateral dorsal aorta, which is a high shear stress vascular bed. They found that blood flow induces a protective response in endothelial cells. This finding helps to explain why CCM patients never suffer from vascular anomalies within highly perfused blood vessels since these vessels are protected by the flow itself. The next paper I want to highlight is titled An Unbiased Proteomics Method to Assess the Maturation of Human Pluripotent Stem Cell-Derived Cardiomyocytes. The first author is Wenxuan Cai and the corresponding author is Ying Ge, and they are from the University of Wisconsin Madison in Madison, Wisconsin. Cardiomyocytes are the beating cells of the heart and they're very difficult to work with in culture as they don't proliferate very well. As such, scientists are moving to use human induced pluripotent STEM cells as means to create cardiomyocytes. So cardiomyocytes derived from human pluripotent stem cells are a valuable resource for drug discovery and screening and disease modeling. While useful, these pluripotent stem cell-derived cardiomyocytes remain immature compared to their natural adult counterparts, and this immaturity slightly reduces their utility. So there are now several methods that people use to promote maturation of cardiomyocytes, but currently there's no consensus on the best way to assess cardiomyocyte maturity, or rather, IPS cardiomyocyte maturity. In this manuscript, Cai and colleagues have established a straightforward yet comprehensive mass spectrometry approach to ensure cardiomyocyte maturity. This method combines analysis of a subset of intact proteins with an unbiased screen of digested peptide fragments. The team used the method to examine early and late stage maturation of cardiomyocytes derived from embryonic, as well as human induced pluripotent stem cell sources, validating their findings against cells from mouse hearts. For the intact protein analysis, sarcomeres were isolated from cell samples which enabled the identification of the major sarcomeric proteins, as well as any post-translational modifications on these proteins that can fine tune our assessment of maturity. The unbiased screen further identified both known and novel maturation markers. This study not only provides a handy tool for assessing IPS-derived cardiomyocyte maturity, but it also defines a set of maturity markers for cross reference in future studies. The next paper I want to discuss is titled Leptin Induces Hypertension Acting on Transient Receptor Potential Melastatin 7, Trpm7, Channel In the Carotid Body. The first author is Mi-Kyung Shin, and the corresponding author is Vsevolod Polotsky, and they are from the Johns Hopkins University in Baltimore, Maryland. Leptin is a hormone that is secreted from fatty tissue, and it's secreted in response to eating something fatty and delicious. Leptin signaling increases metabolism and blood pressure, and it also helps to reduce appetite. That is, if you don't eat the fatty food too fast. So, obese individuals can exhibit high levels of leptin, yet their metabolism and appetite may be unaltered, while hypertension may still develop. Leptin's effects on appetite metabolism are mediated via signaling in the brain, while its effects on blood pressure are thought to be mediated elsewhere. In this manuscript, the authors suspected that the carotid body has something to do with this. The carotid body is a cluster of cells in the neck that detect blood levels of oxygen and other substrates, and the carotid body cells can communicate the information to the brain via the carotid sinus nerve. The carotid body has abundant expression of leptin receptor, and moreover, leptin has been shown to increase carotid sinus nerve firing. So in this manuscript, the authors now show that infusions of leptin into mice increased hypertension in the animals only when the carotid sinus nerve was intact. They also showed that hypertension in these mice was dependent on the iron channel Trpm7, which is very abundant in the carotid body. Inhibition of Trpm7 prevented the leptin-induced hypertension. Together, these results begin to explain why obese individuals' leptin still induces hypertension when the hormone's other effects on appetite and metabolism are diminished. They suggest that inhibition of Trpm7 could perhaps be a way to treat the hypertension seen in obese individuals. The last paper I want to highlight before we move over to our interview is titled Heterogeneous Cellular Contributions to Elastic Laminae Formation and Arterial Wall Development. The first author is Chien-Jung Lin, and the corresponding author is Jessica Wagenseil from the Washington University in St. Louis. Elastin is the extracellular matrix protein that provides structure to both large and small arteries. Vascular smooth muscle cells are known to produce the layered elastic laminae found in elastic arteries. However, they synthesize very little elastin in more muscular arteries. Muscular arteries also have well-defined internal elastic laminae that separates the smooth muscle cells from the endothelial cells, but the source of the elastin in these muscular arteries is not well-defined. The goal of this study was to define the extent to which endothelial cells can contribute to elastin in the eternal elastic laminae of various arteries. To address this question, they created several new strains of mice in which elastin is deleted specifically in a smooth muscle or an endothelial cell. They found that smooth muscle cells and endothelial cells can both independently form an internal elastic lamina in elastic arteries. In muscular and resistance arteries, however, endothelial cells are the major source of elastin. Further, in the ascending aorta, it was noted that ill-formed internal elastic laminae was associated with neointimal formation, confirming that the internal elastic laminae is a critical physical barrier for smooth muscle cells and endothelial cells in large elastic arteries. This study provides new information about how smooth muscle cells and endothelial cells contribute to elastin production in the artery wall, and also how local elastic laminae defects may contribute to cardiovascular disease. I'm here with Dr Coleen McNamara and Aditi Upadhye, and we'll be discussing their paper titled Diversification and CXCR4-Dependent Establishment of the Bone Marrow B-1a Cell Pool Governs Atheroprotective IgM Production Linked to Human Coronary Atherosclerosis. And this paper is was published in our October 25th edition of the journal. So thank you both so much for joining me today. Dr Coleen McNamara:    Thank you for having us. Dr Aditi Upadhye:            Thank you. Dr Cindy St. Hilaire:          I'm really looking forward to learning more about this paper. First, I'm wondering if you could just please introduce yourselves and give us a little bit about your background. Dr Coleen McNamara:    Well, I'm Coleen McNamara. I'm a physician scientist in the Cardiovascular Research Center at the University of Virginia in cardiovascular medicine. And my laboratory studies B cells and atherosclerosis predominantly. And that's the topic of Aditi's paper. Dr Aditi Upadhye:            And I'm Aditi Upadhye. I'm a PhD student in Coleen's lab and my project in Coleen's lab has focused on the role of CXCR4 in B-1 cell IgM production in atherosclerosis. Dr Cindy St. Hilaire:          If this is your project, you must be nearing the end of graduate school then. Dr Aditi Upadhye:            Yes, very close. Dr Cindy St. Hilaire:          Excellent. And congratulations on a beautiful paper. Dr Aditi Upadhye:            Thank you so much. Dr Cindy St. Hilaire:          So I was just reading the paper and I did see that you stated the objective of the paper, was that you wanted to characterize bone marrow IgM repertoire and determine whether CXCR4 regulated the B-1 cell production of this atheroprotective IgM. Could you maybe just give us a quick primer on what all those words mean? What is a B-1 cell, what is IgM, and what is this atheroprotectiveness, and why is this important to research? Dr Aditi Upadhye:            Sure. So research over the past few decades has shown that the role of B cells in atherosclerosis is subset specific. So in mice there are two broad categories of B cells. B-1 and B-2. And B-2 cells are the ones you typically learn about in immunology classes. They're the ones that produce really high affinity class-switched antibodies in a T-cell dependent manner. And there is evidence that B-2 cells are atherogenic. So either through their ability to modulate T-cells through cytokine production, or through their production of IgG and IgE antibodies, they may have atherogenic capability. B-1 cells are very, very different. They produce what are called these natural IgM antibodies. So they're present even in germ-free mice that don't have any prior antigen exposure, exogenous antigen exposure. And the kind of paradigm in the field thus far had been that B-1 cells produce germline-encoded antibodies. So they don't acquire quite as much diversity as their B-2 cell counterparts do. And really importantly, it has been shown that B-1 cells are an atheroprotective cell subset, primarily through their ability to produce IgM. So our coauthor, Dr Joseph Witztum, previously demonstrated that B-1 cells produced IgM antibodies against oxidation specific epitopes that arise on oxidized LDL in atherosclerosis. But really the mechanisms that regulate IgM production and what these IgMs are targeted against is less known. And that's something that we were trying to get at with this paper. Dr Cindy St. Hilaire:          One of the things you talked about in one of the earlier figures in your paper was that there's differences in the chemokine expression between these B cells that are in the spleen versus when they're in the bone marrow. And these differences are apparent at baseline, but also under hyperlipidemic conditions. Is there a cause or a consequence angle to asking this question about B-1 cells and atheroprotectiveness? Dr Aditi Upadhye:            Yeah, I think so. One of the points of this paper is that B-1 cells are very heterogeneous and so they may be going to multiple locations, not just the bone marrow, which we focus on in our paper, but also the spleen, also the perivascular adipose tissue, are sites that we're also interested in looking at. So the fact that there is different chemokine ligand expression level on these different sites might guide them to these different places and might help with their function. Dr Cindy St. Hilaire:          Yeah, and I guess that's a perfect segue for my next question. And it seems that the CXCR4 expression on the cells is really key to their proper migration and then the subsequent secretion of the IgM. Do we know what's happening to CXCR4 expression either as we age or as atherosclerosis progresses? Is there any evidence of environmental or behavioral or genetic angles that might predispose an individual to having more or less CXCR4 on their B cells? Dr Aditi Upadhye:            That's a great question. So there are a lot of things that regulate chemokine receptor expression, including expression of the ligands too. I don't know that much about how CXCR4 expression changes with age or with atherosclerosis. At least in mice, it seems that CXCR4 doesn't change during hyperlipidemia. So for example, in C57 black 6 mice versus a ApoE knockout mice, either child fed or Western diet fed, CXCR4 doesn't seem to change on the one cell subsets. Dr Cindy St. Hilaire:          Interesting. Maybe a future project then. Dr Aditi Upadhye:            Yeah. Yeah. Dr Cindy St. Hilaire:          So I found it really interesting, I think it was in figure five, I always like to try to pick out my favorite figures. My favorite figures of this paper are three, five, and seven. And so... Are those your favorite? But so I guess one of the things that I thought was interesting is that you made a mouse, a multiple knockout mouse that had ApoE knockout and it also was not able to make IgM antibodies. Is that correct? So when you took that mouse and then you looked at it, I think at 80 weeks of age, you could see differences in the atherosclerosis on these mice, but then you couldn't see it on kind of the standard model of what probably most atherosclerosis labs use. And that is a younger mouse that's put on a high fat diet for a shorter window of time. And so could you maybe talk about what that difference means, what your study shows, and then how do we move forward with studying the role of inflammation and atherosclerosis in younger versus older mice? Dr Aditi Upadhye:            Yeah, that's a great question. And I think that every model has its caveats that, and that's something that we ran into when we were trying to show whether B-1 cell CXCR4 is important in atheroprotection. But I think what our findings suggest is that there is a very delicate balance between the amount of IgM that you have and the lipid burden that you have. And in any given model, these might be factors to consider when it comes to studying atherosclerosis. Just taking those factors into consideration when you're analyzing your atherosclerosis results. Dr Cindy St. Hilaire:          Absolutely. Dr Coleen McNamara:    One of the reasons we liked this 100-week-old, or the 80-week-old mouse is the one where if it doesn't have IgM, there's significantly more atherosclerosis even on a chow diet. And so that's a cholesterol of about 300 or 400, and then an 80 to a 100-week old mouse is about the equivalent of a 70-year-old person, which is sort of more akin to the human situation. And so in that setting, the IgMs matter, whereas it didn't look like the IgMs as Aditi said were really capable of blocking the oxidized lipids that were generated in younger mice that had cholesterols well over a thousand. So we felt like that that was really relevant, which is why we use that same model for when we did the single cell sorting and sequenced the antibody repertoire. Thinking that that would give us more insight into the role of age and modest hyperlipidemia, which is more the clinical scenario. Dr Cindy St. Hilaire:          Do you think that has implications for how humans with familial hypercholesterolemia are treated versus someone with just a lower level but still elevated lipid profile? Dr Coleen McNamara:    Yeah, I do, and I think that's really an important point, Cindy, because the vast majority of people that suffer from cardiovascular disease, have heart attacks, die of cardiovascular disease, are typically older people with modest cholesterol levels. Familial hypercholesterolemia, obviously in those patients, they get significant cardiovascular disease at young ages. But that's certainly in a relative sense, a much less common occurrence. So I think that the model and the mechanisms that we were looking at are more applicable than garden variety atherosclerosis. Dr Cindy St. Hilaire:          Interesting. That's something I haven't really thought about. We always just kind of use these mice to model athero and try to do it in the quickest way possible to get the papers out. But it's really interesting. Dr Coleen McNamara:    We use a lot of mouse models and we use young models with hypercholesterolemia in our laboratory as well. So I think that there's a real role for doing that. And a lot of people have really advanced the field with those types of models as well because they allow you to ask mechanistic questions. Dr Cindy St. Hilaire:          One of the things you mentioned in the paper was the variability of the IgMs produced, that there's not just one IgM, there's different flavors, I guess is a way to put it. Can you maybe just talk about that a little bit, what that might mean? And then I have another follow-up question after that. Dr Aditi Upadhye:            Sure. So B-1 cells, the B cell receptor, it's different on different B cells. And so that is made through a process called VDJ recombination. And the B cell receptor determines what your antibody is going to be specific for. There's a lot of different IgMs present within a given B cell repertoire because the differential combination of all these genes makes up the repertoire. Dr Cindy St. Hilaire:          What is it about the IgM that makes it atheroprotective, what's it actually targeting? Dr Aditi Upadhye:            That's a great question. So Dr Witztum and colleagues and others have shown that these IgMs target oxidation specific epitopes. And for example, one of them that we focus on in this paper is malondialdehyde-modified LDL. And so these IgMs can recognize MDA and either facilitate its clearance or prevent it from being bound to macrophages and prevent inflammatory processes within those macrophages downstream. Dr Cindy St. Hilaire:          So essentially this IgM is kind of working to prevent foam cell formation? Dr Aditi Upadhye:            Yes. Dr Cindy St. Hilaire:          Excellent. Dr Coleen McNamara:    So these are, these modified lipids are danger associated molecular patterns, as you've heard about before. So not only are these modified lipids taken up into the macrophage by scavenger receptors, which we know is an atherogenic, a process that leads to atherosclerosis, but they can also activate inflammatory pathways through toll-like receptors. Dr Cindy St. Hilaire:          So in light of the variability, I guess what I'm wondering is, is there more variability in these IgMs based on atherosclerotic state or in humans, healthy or control, and then also how are these heterogeneous populations of cells, how does your finding coincide with the recent studies on clonal hematopoiesis? And I was wondering if you could talk a little bit about that. Actually, for people who don't know, the idea... I guess I should explain the idea of clonal hematopoiesis. So essentially there was a recent paper in Science by Ken Walsh, who's actually at UVA now, where they found that there's acquired mutations in hematopoietic stem cells, and as we age, those mutations can become enriched and therefore somewhat clonal, hence the term clonal hematopoiesis. So how does the variability of the B cell population kind of work with this clonal hematopoiesis theory? Dr Coleen McNamara:    Well, it's interesting that you ask that because that's actually another direction within the lab. So we're collaborating with Dr Walsh and Jose Fuster, who was the first author on that Science paper. And we think, and in particular related to Aditi's work, that this particular subset of B cells has quite a propensity for clonality. And what she was actually able to show is, in terms of the B-1a cells within the peritoneal cavity, when their complementarity determining region three was sequenced, which is the main region responsible for recognizing the antigen-in 70% of the single cells that were sequenced, it was identical. So that actually is quite clonal. Dr Cindy St. Hilaire:          Yeah. So essentially if it was random, you would expect those numbers to be much lower. Much more variable. Dr Coleen McNamara:    Absolutely. But yet in the bone marrow, we saw much less of any given sequence being overrepresented. And in addition, there was evidence that there was modification in the antibody repertoire in adult life. Sort of suggesting and getting back to your earlier questions, that it actually may be atherogenic stimuli or hyperlipidemia that could be stimulating selection of other B cell clones. Dr Cindy St. Hilaire:          Interesting. So we have a lot of chicken and egg questions to ask for the future. Dr Coleen McNamara:    Yeah, exactly. And we're really getting into that space because we do think that the subtype of immune cell lends itself to clonal expansion. Dr Cindy St. Hilaire:          I guess I want to end with one question about the translatability of some of your findings. So the last figure, figure seven, you show an inverse relationship between the level of CXCR4 on these B-1 cells with increasing plaque burden. And essentially I think the analysis you did suggests that it was actually very predictive, even more so than lipid levels. So is there base for this as a biomarker of sorts do you think moving forward? Dr Aditi Upadhye:            Yeah, I think that's how we'd like to move forward in the lab is to look at how CXCR4 might be atheroprotective on these B-1 cells. And if we can find a good preclinical model to test that and see how it's atheroprotective in a more mechanistic way, that would be great. I think also that our ability to show that increasing CXCR4 on mouse B-1 cells and getting them to increase their localization to the bone marrow and increase IgM production, that also indicates that this could be feasible. But whether or not that can be atheroprotective is a question for the future. Dr Cindy St. Hilaire:          That's great. Well thank you so much for taking the time speaking with me today. This was an amazing story with very cool implications for the future, and Aditi, I look forward to following your bright career in the future. Dr Aditi Upadhye:            Thank you so much for the opportunity. Dr Coleen McNamara:    Thank you. Dr Cindy St. Hilaire:          Thank you. Well, that's it for our highlights from the October 25th and November 8th issues of Circulation Research. Thank you so much for listening. This podcast is produced by Rebecca McTavish, edited by Melissa Stoner, and supported by the Editorial team of Circulation Research. Some of the copy texts for the highlighted articles was provided by Ruth Williams, and I'm your host, Dr Cindy St. Hilaire, and this is Discover CircRes, your source for the most up to date and exciting discoveries in basic cardiovascular research.  

sermon by Rev. Ken Walsh based on Luke 10:38-42

Ken Walsh, historian, author, and political journalist who's covered six presidencies, joins Melanie somewhere between Easter Island and Bora Bora for a non-partisan conversation about Trump, the "Distruptor in Chief." Ken's take on this president is thoughtful, considered, and wise. His latest book is: Ultimate Insiders: White House Photographers and How They Shape History. Ken Walsh: US News and World Report Want more how-to's for hope and happiness? Sign up for Melanie's free newsletter here: www.melanieharth.com.

Sermon by Rev. Ken Walsh

Ken's back! He joined us for a wide ranging chat on Christmas Eve about all sorts of incredible history. facebook: https://www.facebook.com/fellowpassengerspodcast/ twitter: https://twitter.com/Fellowpodcast instagram: https://instagram.com/fellowpassengerspodcast Produced By: http://www.displacestudios.com/ For all enquiries email: fellowpassengerspodcast@gmail.com

In this Christmassy episode we speak with Ken Walsh who studied German history in Berlin, and lives there working as a tour guide. facebook: https://www.facebook.com/fellowpassengerspodcast/ twitter: https://twitter.com/Fellowpodcast instagram: https://instagram.com/fellowpassengerspodcast Produced By: http://www.displacestudios.com/ For all enquiries email: fellowpassengerspodcast@gmail.com

Today is Father’s Day and for many families it is a happy occasion, but for those who have lost a child, it can be a very difficult day. Ken Walsh’s third child Caoimhe was stillborn after he and his wife Linda were told during the pregnancy that their daughter had Edward's syndrome, a life-limiting condition. After the birth, the family were helped through their trauma by the charity Feileacáin, who say it’s important that men are encouraged to speak about their feelings about the loss of a child. Róisín Ingle spoke to Ken about losing Caoimhe, how Feileacáin helped them and why it’s important for bereaved fathers to know that they don't always have stay strong. http://www.feileacain.ie/

Prussia, and one of the greatest vanishing acts of the 20th century. Co-host Ysanne Choksey. Thanks to Markus Colla, Steffen Bender of the Prussian Association Berlin Brandenburg, Stefan Görlich of the Association Berliner Schlosses Special thanks to Darren O’byrne, Ken Walsh and Hans Georg. Music by Mark Schilders and Svetnik, LY Foulidis, Svetnik. Image by Sbs-Hf (CC-BY-SA 4.0)

Many ecommerce merchants want to sell products to consumers in other countries. But the process is not as easy as selling domestically. The complexities can include tariffs, customs and export laws. But for United States’ based merchants, the U.S. Department of Commerce can help. That department has just published a free PDF guide to help merchants with export sales. And the official responsible for the guide is with us in this interview. He’s Ken Walsh, International Trade Specialist with the U.S. Commercial Service, an agency of the Department of Commerce. He joins Practical Ecommerce’s Kerry Murdock.

U.S. News Chief White House Correspondent Kenneth T. Walsh audio podcast

U.S. News Chief White House Correspondent Kenneth T. Walsh

Ken Walsh, Chief White House correspondent for U.S. News & World Report, says GOP resisters may be boxing the party into a corner.