Podcasts about abc1

In this episode of Dyer's Daily, Jamie Dyer remembers ABC1.

This mentions the city of Samaria, and is part of a larger corpus of Babylonian writings. God bless you! Thank you for listening! Please share and leave a 5 star review! Subscribe! See you tomorrow!

This month on Episode 34 of Discover CircRes, host Cynthia St. Hilaire highlights four original research articles featured in the March 4 and March 18th issues of Circulation Research. This episode also features a conversation with Dr Mireille Ouimet and Sabrina Robichaud from the University of Ottawa Heart Institute to discuss their study, Autophagy is Differentially Regulated in Leukocyte and Non-Leukocyte Foam Cells During Atherosclerosis.   Article highlights:   Pauza, et al. GLP1R in CB Suppress Chemoreflex-Mediated SNA   Lim, et al. IL11 in Marfan Syndrome   Hohl, et al. Renal Denervation Prevents Atrial Remodeling in CKD   Liu, et al. Smooth Muscle Cell YAP Promotes Arterial Stiffness   Cindy St. Hilaire:        Hi and welcome to Discover CircRes, the podcast of the American Heart Association's journal, Circulation Research. I'm your host, Cindy St. Hilaire from the Vascular Medicine Institute at the University of Pittsburgh, and today I'm going to be highlighting articles from our March issues of Circulation Research. I'm also going to speak with Dr Mireille Ouimet and Sabrina Robichaud from the University of Ottawa Heart Institute, and they're with me to discuss their study, Autophagy is Differentially Regulated in Leukocyte and Non-Leukocyte Foam Cells During Atherosclerosis.   The first article I want to share is titled GLP1R Attenuates Sympathetic Response to High Glucose via Carotid Body Inhibition. The first author is Audrys Pauza, and the corresponding authors are Julian Paton and David Murphy at the University of Bristol.   Cindy St. Hilaire:        Hypertension and diabetes are risk factors for cardiovascular disease. And yet, for many patients with these two conditions, lowering blood pressure and blood sugar is insufficient for eliminating the risk. The carotid body is a cluster of sensory cells in the carotid artery, and it regulates sympathetic nerve activity. Because hypertension and diabetes are linked to increased sympathetic nerve activation, this group investigated the role of the carotid body in these disease states. They performed a transcriptome analysis of crowded body tissue, from rats with and without spontaneous hypertension. And they found among many differentially-expressed genes that the transcript encoding glucagon-like peptide-1 receptor or GLP1R, was considerably less abundant in hypertensive animals.   Cindy St. Hilaire:        This was of particular interest because the gut hormone GLP-1 promotes insulin secretion and tends to be suppressed in Type 2 diabetes. Moreover, GLP1R agonists are already used as diabetic treatments. This group showed that treating rat carotid body with GLP1R agonist suppresses sympathetic nerve activation and arterial blood pressure, suggesting that these drugs may provide benefits in more than one way. Perhaps the carotid body could be a novel target for lowering cardiovascular disease risk in metabolic syndrome.   Cindy St. Hilaire:        The second article I want to share is titled Inhibition of IL11 Signaling Reduces Aortic Pathology in Murine Marfan syndrome. The first author is Wei-Wen Lim, and the corresponding author is Stuart Cook and they're from the National Heart Center in Singapore. People with the genetic connective tissue disorder Marfan syndrome, are typically tall and thin with long limbs and are prone to skeletal, eye and cardiovascular problems, including a life-threatening weakening of the aorta. While Marfan syndrome patients commonly take blood pressure-lowering treatments to minimize risk of aortic aneurysm and dissection, there's currently no cure for Marfan syndrome or targeted therapy.   Cindy St. Hilaire:        The cytokine IL11 is strongly induced in vascular smooth muscle cells upon treatment with the growth factor TGF-beta, which is over activated in Marfan syndrome patients. And TGF-beta is also considered a key feature of the syndrome's molecular pathology. This study found that IL11 is strongly upregulated in the aortas of Marfan syndrome model mouse, and that genetically eliminating IL11 in these animals protected them against aortic dilation, fibrosis, inflammation, elastin degradation and loss of smooth muscle cells. Treating Marfan syndrome mice with anti-IL11 neutralizing antibodies exhibited the same beneficial effects. These results suggest that perhaps inhibiting IL11's activity could be a novel approach for protecting the aortas of Marfan syndrome patients.   Cindy St. Hilaire:        The next article I want to mention is titled Renal Denervation Prevents Atrial Arrhythmogenic Substrate Development in Chronic Kidney Disease. The first authors are, Mathias Hohl, Simina-Ramona Selejan and Jan Wintrich, and the corresponding authors also Mathias Hohl, and they're from Saarland University. People with chronic kidney disease have a two to three fold higher risk than the general population of developing atrial fibrillation, which is a common form of arrhythmia that can be life-threatening. Chronic kidney disease is associated with activation of the sympathetic nervous system, which can be damaging to the heart. Thus, this group examined myocardial tissues from atrial fibrillation patients with and without chronic kidney disease to see how they differ. They found that atrial fibrosis was more pronounced in patients with both conditions than in patients with atrial fibrillation alone, suggesting that chronic kidney disease perhaps exacerbates or even drives arterial remodeling.   Cindy St. Hilaire:        Sure enough, induction of chronic kidney disease in rats led to greater atrial fibrosis and incidence of atrial fibrillation than seen in the control animals. Renal denervation is a treatment in which the sympathetic nerves are ablated, and it's a medical procedure that's used for treating uncontrolled hypertension, and it has also been shown in animals to reduce atrial fibrillation. Performing renal denervation in the rats with chronic kidney disease reduced atrial fibrosis and atrial fibrillation susceptibility. This study not only shows that chronic kidney disease induces atrial fibrosis and in turn atrial fibrillation, but also suggests that renal denervation may be used in chronic kidney disease patients to break this pathological link and prevent potentially deadly arrhythmias.   Cindy St. Hilaire:        The last article I want to highlight is titled YAP Targets the TGFβ Pathway to Mediate High-Fat/High-Sucrose Diet-Induced Arterial Stiffness. First author is Yanan Liu and the corresponding author is Ding Ai from Tianjin Medical University. Metabolic syndrome is characterized as a collection of conditions that increase the risk of cardiovascular diseases, such as obesity, hypertension and diabetes. Among the tissue pathologies associated with metabolic syndrome is arterial stiffness, which itself is a predictor of cardiovascular disease incidence and mortality. To specifically investigate how arterial stiffness develops in metabolic syndrome, this group fed mice a high-fat, high-sugar diet, which is known to induce metabolic syndrome and concomitant arterial stiffness.   Cindy St. Hilaire:        After two weeks on the diet, the animals' aorta has exhibited significant upregulation of TGF-beta signaling, which is a pathway known for its role in tissue fibrosis, and the aorta has also exhibited increased levels of yes-associated protein, or YAP, which has previously been implicated in vascular remodeling, collagen deposition and inflammation. YAP gain and loss of function experiments in transgenic mice revealed that while knockdown of protein in the animals' smooth muscle cells attenuated arterial stiffness, increased expression exacerbated the condition.   Cindy St. Hilaire:        The team went on to show that YAP interacted with and prevented the activation of PPM-1 B, which is a phosphatase that normally inhibits TGF-beta signaling and thus fibrosis. Together the results suggest that targeting the YAP, PPM-1 B pathway, could be a strategy for reducing arterial stiffness and associated cardiovascular disease risk in metabolic syndrome.   Cindy St. Hilaire:        Today, Sabrina Robichaud and Dr Mireille Ouimet from University of Ottawa Heart Institute are with me to discuss their study Autophagy is Differentially Regulated in Leukocyte and Non-Leukocyte Foam Cells During Atherosclerosis, which is in our March 18 issue of Circulation Research. So thank you both for joining me today.   Sabrina Robichaud:    Thank you so much for having us. It's a pleasure.   Mireille Ouimet:         Thank you for having us.   Cindy St. Hilaire:        Yeah, and congrats on the study. So we know that LDL particles contain cholesterol and fats, and these are the initiating factors in atherosclerosis. And it's also really now appreciated that inflammation in the vessel wall is a secondary consequence to this lipid accumulation. Macrophages are an immune cell that, in the context of the plaque, gobble up this cholesterol to the point that they become laden with lipids and exhibit this foamy appearance, which we now call foam cells. And these foam cells can exhibit atheroprotective properties, one of them called reverse cholesterol transport, and that's really one of the focuses of your paper. So before we dig into what your paper is all about, could you give us a little bit of background about what reverse cholesterol transport is in the context of the atherosclerotic plaque? And maybe introduce how it links to this cellular recycling program, autophagy, which is also a big feature of your study.   Mireille Ouimet:         Yes, so the reverse cholesterol transport pathway is a pathway that's very highly anti-atherogenic. It's linked to HDL function and the HDL protective effects, in that HDL can serve as a cholesterol acceptor for any excess cholesterol from arterial cells or other cells of the body and return this excess cholesterol to the liver for excretion into the feces. There is also trans-intestinal cholesterol efflux that can help eliminate any excess bodily cholesterol. Mireille Ouimet:         So reverse cholesterol transport is a way that we can eliminate excess cholesterol from foam cells in the vascular wall, and that's why we're really interested in the process. But the rate-limiting step of cholesterol efflux out of foam cells in plaques is actually, they have to be mobilized in the form of free cholesterol to be pumped out of the cells through the action of the ATP-binding cassette transporters. And so the rate-limiting step of the process is the hydrolysis of the cholesterol esters and the lipid droplets, because that's where the excess cholesterol is stored in foam cells.   Mireille Ouimet:         And so for years, people investigated the actions of cytosol like lipases in mobilizing free cholesterol from lipid droplets, although the identity of those lipases are not well-known and in macrophage themselves, but our recent work showed a role for autophagy in the catabolism of lipid droplets. And in fact, in macrophage foam cells, 50% of lipid droplet hydrolysis is attributable to autophagy while the other half is mediated by neutral lipases, which makes it really important to investigate the mechanisms of autophagy-mediated lipid droplet catabolism.   Cindy St. Hilaire:        That is so interesting. I guess I didn't realize it was that significant a component in that kind of rate-limiting step. That's so cool. So really, a lot of the cholesterol efflux studies, and maybe this is just limited to my knowledge of a lot of these cholesterol efflux studies, but to my knowledge, it's been really focused on the foam cell itself, the macrophage foam cell. However, there's been a lot of recent work that has now implicated vascular smooth muscle cells in this process. So could you share some of the research specific to smooth muscle cells and smooth muscle-derived foam cells that led you to want to investigate the contributions of smooth muscle cell-derived foam cells in cholesterol efflux?   Mireille Ouimet:         Yeah, so you're right in the sense that macrophages have always been the culprit foam cells in the atherosclerotic plaques but pioneering work from several groups, including Edward Fisher and Gordon Francis, they've shown that the smooth muscle cells can actually acquire a macrophage-like phenotype becoming lipid-loaded and foamy. And there's been work specifically looking at the ABC transporters, and their ability to efflux cholesterol from these vascular smooth muscle cell-derived foam cells, because as they trans-differentiate into macrophage-like cells, they acquire the expression of ABCA1, but this is to a lower extent, as compared to their macrophage counterparts.   Mireille Ouimet:         And the efflux is defective because there's an impairment in liposomal cholesterol processing of the lipoproteins that's really important to activate a like cell, and the expression of the ABC transporters, so vascular smooth muscle cell-derived foam cells are very poor effluxes.   Sabrina Robichaud:    There's very few studies that look at the vascular smooth muscle cell foam cells, and the very few that did look at it mostly focused on the ABCA1 transporters, and did show that they were poor effluxes. And as we all know, ABC1 is not the only cholesterol transporters that can transport cholesterol out of cells, there's also ABCG1 which is also one of our major findings in our paper.   Cindy St. Hilaire:        Can you tell us a little bit about the models you chose in the study and why you picked them? And also maybe a step back in terms of, what are the pros and cons of using mouse models in atherosclerotic studies?   Sabrina Robichaud:    So we chose to use the GFP-LC3 reporter mouse model because it allows us to track in lifestyle the movement of LC3, which is the main component of the autophagosome which is involved in pathology. So by using this reporter model, we could infer whether or not the cells had high autophagy or low autophagy. And to induce atherosclerosis in these mice, instead of backcrossing them to either an LDLR knockout or an ApoE knockout, we chose to do the adeno-associated virus that encode the gain of function PCSK9 instead to kind of minimize the time for breeding. It did have the effect that we needed in terms of raising plasma cholesterol to induce the atherosclerosis. So that was one of the models that we used in our paper.   Mireille Ouimet:          There's not very many good mouse models to study autophagy flux in vivo and GFP-LC3 is kind of the main one currently. We're working on developing some other tools to track lipophagy in vivo, but these things take time to put in place. So in the future, we hope to have some better tools to track lipophagy in real-time in vivo.   Cindy St. Hilaire:        How difficult is it to measure autophagy flux in vivo? I know there's certain part like LC3 or P62, a lot of people use a western blot and it's like, oh, it's high, it must be active, but it's a flux. So it's a little bit more... There's more subtleties to that, dynamic than that. So how difficult is it to really measure this flux in in vivo tissues?   Mireille Ouimet:         Yes, so now there are more recent mouse models that have been developed more recently to replace kind of the GFP-LC3 is the Rosella LC3. So it has both a red and a green tag, and so two LC3, so when autophagosomes are fused to lysosomes and are degraded, then there's preferential quenching of the GFP first, and then you have the red appearance that predominates so we know that then it's kind of like it a live flux measurements. Because we use the GFP-LC3 mouse, Sabrina treated her cells ex vivo. When we dissected out the aortic arches, digested the cells then we divided those into two components and added bafilomycin so that we can inhibit lysosome acidification to see the changes in the flux. And that's really to get the differences in untreated versus bafilomycin-treated.   Mireille Ouimet:         When we inhibit the lysosome, then we're sure that it is a functional flux or not. But it's kind of an indirect way of measuring it, and it reads very complex when we're talking about P62 and LC3 degradation with or without lysosome inhibition, but you really need that lysosomal inhibition, to show that if you block the degradation of the autophagosomes that fuse in with a lysosome, then you get an increase in the LC3 and the P62, and that's when you know that the flux is you intact.   Mireille Ouimet:         Because you could get an increase in LC3, that's just related to a defect in the breakdown of the autophagosome. But in our study, we've used phosphorylated ATG16L1, which is a now better marker of active autophagy. And I would recommend researchers to begin to use that rather than the combination of P62 and LC3 together with or without a lysosome inhibitors such as- Cindy St. Hilaire:        Oh, interesting. So let's repeat that, phosphorylated ATG-   Mireille Ouimet:         16L1, yes. So there's been an antibody that was developed by a colleague at the University of Ottawa, Dr Ryan Russell, and it's commercially available through cell signaling now, and it really has been a great tool to track active autophagy.   Cindy St. Hilaire:        That's great. I remember my lab was looking at that at one point, and I was trying to explain the flux as... I don't know if people are going to remember this, but there's this amazing, I Love Lucy skit, where her and Ethel are working on a chocolate factory conveyor belt, and it picks up speed. And because she can't get it all done quick, she starts stuffing them in her mouth. And it's like, if you just took a snapshot of that, you would not know whether it's going too fast, or not functioning properly. And so I equate the flux experiments to that. Which are probably aging myself a lot on so.   Cindy St. Hilaire:        All right, so sticking to kind of the autophagy angle, what were the differences you found in autophagy in early and late atherosclerotic plaques? Because I know you looked at those two time points, but also, importantly, between the macrophage foam cells and the smooth muscle cell-derived foam cells?   Sabrina Robichaud:    So surprisingly, there weren't that big of a difference between each time point when we were looking at the individual cell type by themselves. Surprisingly, we did find that the macrophages did have a functional autophagy flux, even at the later stages of atherosclerosis, which was kind of interesting in itself. But when we looked at the vascular smooth muscle cell foam cells, though, that was a whole other story, and we found that these were actually defective at a very early stage and stayed defective up until the very late stage of atherosclerosis.   Cindy St. Hilaire:        And what is the very early stage like? What's that definition with the smooth muscle cell?   Sabrina Robichaud:    So we did a six-week time points in terms of our atherosclerosis study, and then a 25-week time point. So there are far apart, which shows like the very early, early stage and what would be considered the most effective autophagy at that point with the necrotic core and everything. So surprisingly, the two phenotype were quite similar at early and both late stages for both cell types, but were functional in the macrophages but dysfunctional in the smooth muscle cells.   Cindy St. Hilaire:        So you mentioned at one point in the discussion that you observed inconsistent lipid loading of the smooth muscle cells, and you mentioned that a lipase, which is excreted from the foam cells can then be internalized by, I assume kind of neighboring or in the vicinity, smooth muscle cells. And so the question I had it's kind of one of those chicken-and-egg question, and it's, is the smooth muscle cell-derived foam cell an independent process? Does it happen alone or de novo as a function of a smooth muscle-mediated process? Or is it really dependent first on this macrophage foam cell providing this lipid that is efflux that is then internalized by a smooth muscle cell that kind of goes on to become a foam cells. It's kind of a question of like the continuum of an atherosclerotic plaque and what do you think is happening, either based on your data or just kind of a hunch?   Mireille Ouimet:         That's an excellent question. And there's no doubt that macrophages really drive the initiating events of atherosclerosis. So I don't think that without the macrophage there would ever be a vascular smooth muscle cell, or there would be minimal vascular smooth muscle cell-derived foam cells. Definitely the inconsistencies that we observed in our study, were if we added like aggregated LDL on its own to a primary mouse vascular smooth muscle cell, we would get poor lipid loading and a very low percentage of those cells that would become foamy, relative to treating them with cyclodextrin complex cholesterol, for instance.   Mireille Ouimet:         So free cholesterol, that's cell permeable, will go into the vascular smooth muscle cell, no problem, and generate the foaminess and then allow that cell to acquire the macrophage-like phenotype. But aggregated LDL on its own in our hands, just gave very poor loading. And when we treated the vascular smooth muscle cells with aggregated LDL along with macrophage-derived condition media, we got some improvements, but it was still kind of inconsistent. But then we thought if we treat the vascular smooth muscle cells with aggregated LDL in the presence of conditioned media from macrophage foam cells that were preloaded with the aggregated LDL, would that promote their foaminess to a greater extent? And it did.   Mireille Ouimet:         So, there have been studies from Gordon Francis's lab that showed that adding recombinant lysosomal acid lipase to vascular smooth muscle cells that contained aggregated LDL, promoted the lysosomal hydrolysis of the aggregated LDL and to generate the foamy macrophages and allow the lysosomal processing. So we know that that vascular smooth muscle cells take up lysosomal acid lipase, and we know that macrophages undergo lysosome exocytosis and they can secrete lysosome acid lipase and acidify the extracellular milieu.   Mireille Ouimet:         So work from Fred Maxfield group has shown the presence of these cell surface connected compartments that are acidified, containing macrophage-derived lysosomal acid lipase, that even hydrolyze extra cellularly-aggregated LDL for macrophages. So we're not sure whether there's probably a local production of free cholesterol in the plaque by macrophages, this free cholesterol could be taken up by the vascular smooth muscle cell. And also the vascular smooth muscle cells do express some scavenger receptors, whether the expression of these scavenger receptors like LRP or CD36 even goes up when they've taken up a little bit of the free cholesterol. And then that allows the aggregated LDL to come in and then there would be some lysosomal acid lipase secreted by the macrophage foam cells that would promote the lysosomal processing of this aggregated LDL. All of those are very complex questions that will require some addressing in vivo models.     Cindy St. Hilaire:        You also mentioned in the paper that studies... There's a handful of them now. Studies have shown that between 30% and 70% of the cells that are staining positively for macrophage markers, meaning they're foam cells, are of the smooth muscle cell lineage. And so I believe people have seen that in mouse plaques with lineage tracing, but they've also used newer techniques to really see this also in human atherosclerotic plaques. So we know it's not just from a mouse, we know that smooth muscle cells can turn into a macrophage-like foam cell, and it's 30% to 70%, which is a huge range. Cindy St. Hilaire:        So do we know the factors that dictate whether a specific plaque is going to have more or less smooth muscle cell derived foam cells? And I guess more important to what you found in your paper is, how important would it be to know whether a plaque is on the 30% end or on the 70% end in terms of therapeutic strategies?   Sabrina Robichaud:    Yeah, most of these studies, the range can be attributed to the different time points at which these studies have been collected early on will be a little bit more macrophage understanding would be at a later time point. Now of course in terms of therapeutics, as we saw in our paper, metformin actually will positively increase cholesterol efflux in the vascular smooth muscle cell foam cells, but not in the macrophages. So obviously, being able to know at which point there's a majority of macrophages versus vascular smooth muscle cells, definitely going to determine which therapeutic we're going to be able to use.   Sabrina Robichaud:    Ideally, we would be able to find a therapeutic that would work in both foam cell, but from what we've seen, the mechanistic behind the autophagy dysfunction between both cell types are so different, that I'm not entirely sure that that would be possible, we would need some sort of combination therapy. But again, we need to be a little bit more targeted depending on the percentage of the foam cells that are comprising the plaque at that particular moment in time.   Cindy St. Hilaire:        Yeah, so you mentioned there's a function of time there. If you look earlier, there's more macrophage, if you look later, the percent of smooth muscle cell-derived foam cell increases. Is there a point in a very advanced atherosclerotic plaque where it's just mostly smooth muscle cells? Or do those macrophage foam cells stay, and it's just the increasing number of smooth muscle cell-derived foam cells? Do we know?   Mireille Ouimet:         This is an excellent question, and I was going to bring up the topic of clonal expansion of the vascular smooth muscle cells. So it's a very heterogeneous population and understanding that might be some of the differences that we see in different studies. It could be the model has one type of a smooth muscle cell that's expanding more than another, what are the factors that govern that? Does one clone take over at the later stages versus the earlier stages? We don't know.   Mireille Ouimet:         But we were surprised in our studies to see that the macrophages that are present at least on the lumen of the plaques were very active in autophagy. They had the highest staining for the phospho-ATG16L1 in that late stage. So we're not sure if it's newly-recruited macrophages that come in, that are more active and in autophagy, and then have good lysosomal capacity that keeps degrading the lipid present in the plaque and tries to ingest it, but also as a consequence keeps releasing some of the degraded cholesterol into the milieu where the smooth muscle cells that are proliferating are internalizing it and becoming more foamy. So these are really great open questions that need to be addressed in the field.   Cindy St. Hilaire:        So drug-eluting stents are coated with rapamycin or the various chemical compositions that are derived from rapamycin. And rapamycin itself induces autophagy. So while the thought behind using this coating on stents was to prevent smooth muscle cell proliferation, and thus restenosis or ingrowing of the stent, your study suggests that this could also help to promote autophagy in the cells underlying the stent. So has anyone gone in and looked at plaques that have been stented and either failed or not, and investigated the foam cell content or markers for autophagy activity?   Mireille Ouimet:         Not to my knowledge, and this has been something we've definitely... We think that this is what's happening. Some of the protective effects of these drug-eluting stents that have everolimus or sirolimus or the rapamycin or rapamycin analogs, we do believe that some of their protective effect can be attributed to autophagy activation, but this remains to be demonstrated. We think that autophagy activation locally would promote reverse cholesterol transport and would be one of the processes that prevents restenosis because we can promote the efflux of cholesterol out.   Cindy St. Hilaire:        Great. So I guess stemming from my question on the stents, what are the other translational implications of the findings of your study? And what would you like to see come out of this?   Mireille Ouimet:         So one of the things is, as Sabrina mentioned, would be to target both foam cell populations because it seems as though the vascular smooth muscle cell foam cells are very much defective in their autophagy capacity, and they're very poor effluxes, but we could potentially restore autophagy in the cell population to promote reverse cholesterol transport.   And looking at prevention of atherosclerosis is a bit different than looking at regression, because regression is at a later stage where the plaques are more advanced. And if they're mostly vascular smooth muscle cell-derived, maybe then those drugs that we're considering that protect against the development of atherosclerosis are effective on the macrophage themselves early on, but might not be mimicking what we would see in the clinic where the patients that present are older.   Cindy St. Hilaire:        Yeah, it's kind of really reminiscent of like the CANTOS trial and like, where do we want to target the therapy? It's going to be very different if it's an early smaller plaque, versus a late-stage possibly pro close to rupturing type of plaque. Well, Sabrina Robichaud and Dr Ouimet, thank you so much for joining me today. Congratulations again on a wonderful study, and I'm really looking forward to hearing more about this from your group.   Sabrina Robichaud:    Thank you.   Mireille Ouimet:         Thank you very much. And we also want to thank all the co-authors on the study, specifically also Adil Rasheed, who is co-first author on the work and Katey Rayner's group for all the support and involvement in this study.   Cindy St. Hilaire:        That's it for the highlights from the March 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, Sabrina Robichaud and Dr Mireille Ouimet Sabrina. This podcast is produced by Ashara Ratnayaka, edited by Melissa Stoner and supported by the editorial team of Circulation Research. Some of the copy text for highlighted articles was provided by Ruth Williams. I'm your host, Dr Cindy St. Hilaire and this is Discover CircRes, you're on-the-go source for the most up-to-date and exciting discoveries in basic cardiovascular research. This program is copyright of the American Heart Association 2022, The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more information, visit ahajournals.org.

¡Me muero en verdá! En #La210Cuica nos forzamos a revelar cuáles eran nuestros gustos más ABC1, además de repasar en más de una oportunidad a toda la clase alta de este país. También nos acompañaron los cabros de "Revolver" para conversar sobre los fenómenos musicales de la TV. Si no te das besos con tus primos, dale play a este episodio.

Giants, this is episode #84 – today's guest is an Australian Comedian, Writer, TV and movie Actor – and Dancing With The Stars Australia – 2020 winner. Winning the mirrorball trophy and $50,000 for her charity, the Safe Steps Family Violence and Support Centre. She is in fact the first Comedian I've interviewed on the show. And has brought so much joy and laughter to millions of households.   She won the Best Supporting Actress at the AACTA awards (The Australian Academy of Cinema and Television Arts) for her role as Dolly Faraday in the acclaimed ABC1 drama ‘The Beautiful Lie'. She's also starred in the award-winning TV series ‘Laid', Logie Award winning drama ‘Offspring' and in all five seasons of Working Dog's show ‘Utopia', for which she won another AACTA Award for Best Performance in a Television Comedy in 2015. Comedy audiences would also know her from her appearances on Spicks and Specks, The Project and is a regular on the hilarious show; ‘Have You Been Paying Attention?' one of my favourites. Internationally, she's been a guest on Never Mind The Buzzcocks, Chelsea Lately and The Rob Brydon Show. In 2016 she also co-created, co-wrote and starred in the smash hit comedy Rosehaven with Luke McGregor, for which she won the 2017 award for Best Performance in a Television Comedy at the AACTAs, has been nominated twice for Most Popular Actress at the Logies, as well as two nominations for her writing at the AWGIEs (Australian Writers Guild). Season five of Rosehaven by the way, is out now – definitely give it a watch, it is brilliant.   Some of the topics we spoke about include: How she grew up, including her big break Her creative writing process How she manages the different hats (on and off the stage) And very candidly and vulnerably, shares some of her experiences with anxiety, depression and all things mental health and wellness from her vantage point..   So if you're someone that's interested in unpacking the journey of a high-performing, multi-faceted creative professional, in a way that might help you forge your own creative identity – and want to listen to something both funny and real, then this episode is for you. Now a quick note, if we aren't connected yet on Instagram, I invite you to follow me on my handle @TheGiantThinker as I share daily posts and stories on helping decision-makers, business owners and leaders get unstuck lightning fast through human-centred design methodologies, creative strategies and personal experiences. Send me a DM I'd love to hear from you! You can find me on my handle @TheGiantThinker.   Alright, on with the show. I present to you … the quick-witted, courageous and insanely talented ... Celia Pacquola!     More on Celia can be found via the links below: https://www.instagram.com/celia_pacquola https://twitter.com/celiapacquola Celia on IMDB Subscribe to The Giant Thinkers Podcast on iTunes.     Want to know the most productive tool that has helped me accelerate my progress? It's the Five-Minute Journal; the simplest, most effective thing you can do everyday to be happier. It's a physical journal that gives you a positive quote, followed by three questions you answer in the morning and two questions to answer in the evening before bed. It basically anchors your mind in a positively focused, intentional and grateful mindset, in less than 5 minutes a day. Grab yours here: GiantThinkers.com/fiveminutejournal

Denise made an audio recording of one of her lessons, and is sharing it part of it with you.  This portion of the the lesson focuses on the ABCs:  Arms, Base of support, and Connection.In this episode:A trot warm up exercise to lengthen and secure the riders leg.Arm awareness and its effect on the horse's carriage and balance.Connection: riding the horse "from back to front".How the rider's  seat, hips and legs create a solid "base of support". Effect of Base and Arms on posture and security of rider as well as the movement of the horse.Denise Youell, a USHJA certified hunter/jumper horse trainer and barn owner, draws on her experiences from over 30 years of professional work in the industry by sharing knowledge and ideas to help with riding and caring for horses.Do you have a question or an idea for the show?Interact on FB and IG @barnaislepodcast, Twitter @barnaislepod  Music: DriftMaster by Shane Ivers - https://www.silvermansound.com

Motivados por la experiencia vital de la paternidad ABC1, decidimos preguntarle a les auditories por sus grandes experiencias de vida. Desde el live, el formulario anonimatus y los audios de whatsapp nos supieron compartir un pedazo de su sabiduría. Quédese hasta el final para su sección favorita... Besitos bye!

The first UFC event of 2021 and it did not disappoint. First round KO's and 5 round wars, this event set a high bar! Listen along to Mags and Carlos breaking down the action!!

On todays BTLT, the fellas catch up on what was a hectic weekend. Logan turned 28 and they talk about how he feels being so close to 30. Pete Davidson and Machine Gun Kelly's friendship is brought up as Logan tells Tristen about the lie detector test video he saw them in. UFC featured their first fight card on ABC networks over the weekend and the fellas talked about the main event of the night going viral on the internet. Also, current events take center stage with controversial parenting decisions, NFL football news, and TikTok viral prank bomb.

The first UFC event of 2021 and it did not disappoint. First round KO's and 5 round wars, this event set a high bar!Listen along to Mags and Carlos breaking down the action!! Listen, share, subscribe!Follow on Twitter @dejkirkby, @kirkby_carlos, @FiveRoundsPod and @shootsportsish 

Dans ce chapitre ABC1, Le grand maître des jeux est Nega Ninja.

Dans ce chapitre ABC1, Le grand maître des jeux est Nega Ninja.

Me entrevistaron en el programa santafesino #ABC1, que se emite por #SomosRosario. ¡Te invito a ver la nota!

No viven en el barrio alto Ni estudiarion en colegio ABC1 tampoco pertenecen a algun partido instrumental y ni siquiera tienen cuenta Rut Felipe Rodriguez y Mauricio Palazzo se rien del projimo para no andar de malas pulgas y desnudan las contradicciones de un pais siempre acosado por terremotos, incendios, tsunamis y de faltos de politicos y uniformados. Esto es ideologicamente falsos, por radioqueleo.cl

No viven en el barrio alto Ni estudiarion en colegio ABC1 tampoco pertenecen a algun partido instrumental y ni siquiera tienen cuenta Rut Felipe Rodriguez y Mauricio Palazzo se rien del projimo para no andar de malas pulgas y desnudan las contradicciones de un pais siempre acosado por terremotos, incendios, tsunamis y de faltos de politicos y uniformados. Esto es ideologicamente falsos, por radioqueleo.cl

No viven en el barrio alto Ni estudiarion en colegio ABC1 tampoco pertenecen a algun partido instrumental y ni siquiera tienen cuenta Rut Felipe Rodriguez y Mauricio Palazzo se rien del projimo para no andar de malas pulgas y desnudan las contradicciones de un pais siempre acosado por terremotos, incendios, tsunamis y de faltos de politicos y uniformados. Esto es ideologicamente falsos, por radioqueleo.cl

No viven en el barrio alto Ni estudiarion en colegio ABC1 tampoco pertenecen a algun partido instrumental y ni siquiera tienen cuenta Rut Felipe Rodriguez y Mauricio Palazzo se rien del projimo para no andar de malas pulgas y desnudan las contradicciones de un pais siempre acosado por terremotos, incendios, tsunamis y de faltos de politicos y uniformados. Esto es ideologicamente falsos, por radioqueleo.cl

No viven en el barrio alto Ni estudiarion en colegio ABC1 tampoco pertenecen a algun partido instrumental y ni siquiera tienen cuenta Rut Felipe Rodriguez y Mauricio Palazzo se rien del projimo para no andar de malas pulgas y desnudan las contradicciones de un pais siempre acosado por terremotos, incendios, tsunamis y de faltos de politicos y uniformados. Esto es ideologicamente falsos, por radioqueleo.cl

Luke McGregor was a 25 year old virgin. Now has become the hero of all our sex lives. He joins Rosie Waterland and Laura Brodnick for a hard chat about putting your sex life on national TV.  The Seven Year Switch drew massive ratings but Laura is calling on us all to stop watching. And Xena fans rejoice: the warrior princess is the latest reboot to hit our screens.  Show notes Your hosts are  Rosie Waterland,and Laura Brodnick With thanks to special guest Luke McGregor whose brilliant show, Luke Warm Sex, is on ABC1 on Wednesdays at 9pm, or anytime on  iview. Rosie recommends Frasier  Laura recommends Big Love. Contact the show on the Facebook page, via twitter, or by emaling podcast@mamamia.com.au This show was produced by... Monique Bowley and Holly Wainwright for the Mamamia Women's Network. This show was brought to you by the Nescafe Red Mug Machine, the perfect friend to keep us awake as we watch more TV.

Luke McGregor was a 25 year old virgin. Now has become the hero of all our sex lives. He joins Rosie Waterland and Laura Brodnick for a hard chat about putting your sex life on national TV.  The Seven Year Switch drew massive ratings but Laura is calling on us all to stop watching. And Xena fans rejoice: the warrior princess is the latest reboot to hit our screens.  Show notes Your hosts are  Rosie Waterland,and Laura Brodnick With thanks to special guest Luke McGregor whose brilliant show, Luke Warm Sex, is on ABC1 on Wednesdays at 9pm, or anytime on  iview. Rosie recommends Frasier  Laura recommends Big Love. Contact the show on the Facebook page, via twitter, or by emaling podcast@mamamia.com.au This show was produced by... Monique Bowley and Holly Wainwright for the Mamamia Women's Network. This show was brought to you by the Nescafe Red Mug Machine, the perfect friend to keep us awake as we watch more TV.

Remembrance Day services after an assassination plot against Queen Elizabeth II was foiled, Prince Charles' tribute to Countdown's host, Ian "Molly" Meldrum, news of another royal wedding in Stockholm and Prince Edward visits Sydney.See more in this week's show.Visit our website http://rightroyalroundup.com.au.Like us on Facebook https://www.facebook.com/RightRoyalRoundup, follow us on Twitter @RightRoyalRound and Instagram rightroyalroundup

Peter Helliar chats to the executive producer of It's A Date, Laura Waters about the final instalment of ABC1's comedy, It's A Date. Listen to this podcast after watching episode 8. It's A Date is a comedy series exploring the trials and tribulations of the world of dating.

Peter Helliar chats to the executive producer of It's A Date, Laura Waters about the final instalment of ABC1's comedy, It's A Date. Listen to this podcast before watching episode 8. It's A Date is a comedy series exploring the trials and tribulations of the world of dating.

Peter Helliar chats to star and co-writer of episode 7, Lawrence Mooney about the 7th installment of ABC1's comedy, It's A Date. Listen to this podcast after watching episode 7. It's A Date is a comedy series exploring the trials and tribulations of the world of dating.

Peter Helliar chats to star and co-writer of episode 7, Lawrence Mooney about the 7th installment of ABC1's comedy, It's A Date. Listen to this podcast before watching episode 7. It's A Date is a comedy series exploring the trials and tribulations of the world of dating.

Peter Helliar and Ryan Shelton chat about episode 6 of ABC1's comedy, It's A Date. Listen to this podcast before watching episode 6. It's A Date is a comedy series exploring the trials and tribulations of the world of dating.

Peter Helliar and Ryan Shelton chat about episode 6 of ABC1's comedy, It's A Date. Listen to this podcast before watching episode 6. It's A Date is a comedy series exploring the trials and tribulations of the world of dating.

We’re back with new faces, new voices, new innovations and more great TV chat. We welcome Marian Blythe, Rachel Howe and Chris Rankine to the fold and immediately get down to the nitty gritty with a review of ABC1’s family drama, The Time Of Our Lives. Marian gives us a bit of a rundown on […]

Peter Helliar and co-writer of episode 5, Steven Gates chat about the fifth installment of ABC1's comedy, It's A Date. Listen to this podcast before watching episode 5. It's A Date is a comedy series exploring the trials and tribulations of the world of dating.

Peter Helliar and Steven Gates chat about episode 5 of ABC1's comedy, It's A Date. Listen to this podcast after watching episode 5. It's A Date is a comedy series exploring the trials and tribulations of the world of dating.

Peter Helliar and Kate McLennan chat about episode 4 of ABC1's comedy, It's A Date. Listen to this podcast after watching episode 4. It's A Date is a comedy series exploring the trials and tribulations of the world of dating. Contains coarse language and adult themes.

Peter Helliar and Kate McLennan chat about episode 4 of ABC1's comedy, It's A Date. Listen to this podcast then watch episode 4. It's A Date is a comedy series exploring the trials and tribulations of the world of dating.

Peter Helliar and Asher Keddie chat about episode 3 of ABC1's comedy, It's A Date. Listen to this podcast after watching episode 3. It's A Date is a comedy series exploring the trials and tribulations of the world of dating.

The Sidekicks are back to bring you the latest in geeky news, reviews and anything else they can get their grubby little hands on. Welcome to the new companion to Australia's #1 geek culture podcast and TV series, Geek Speak Live!Geek Speak Sidekick Issue 7:-- Working on the Show Holiday? The things these boys do. -- What's Brendan been reading? --  The Sidekicks chat about 'Comic Book Heroes', the ABC1 documentary on Gestalt Comics. -- Steve gives the lowdown on ZICS, the Zine and Indy Comic Symposium coming up in Brisbane. -- Which guests have already been announced for Oz Comic Con next year? -- The Sidekicks give a spoiler-ridden review of 'The Wolverine'. Did we mention there are spoilers? Well there are. Sthpoilers. You have been warned. -For more coverage on all things geeky head along to http://www.facebook.com/geekspeaktv

John Clarke is, without hyperbole, one of the most important figures in Australian TV comedy. His latest project was a documentary series about Australia’s great sporting history called Sporting Nation, which appeared on ABC1 as a lead-up to the Olympics to which the ABC doesn’t have rights. He tells us all about The Games, Farnarkelling, […]

Frank Woodley comes in to talk to us about doing physical comedy on Australian television and how it really hasn’t been done before. He has a new show starting on ABC1 on Wednesday 22 Feb. Then, Glenn Peters has seen two foreign language series, Spiral and The Killing. He sets them head to head in […]

We talk to Penny Chapman, the producer of the new ABC1 series, The Straits. There’s a review of Grimm vs Once Upon a Time and a Raywatch about Channel 9’s coverage of Australia Day protests. Notes One Thing The Straits: 8:30pm Thursday, ABC1 The Office – BBC version: DVD Raywatch You can play along at […]

From Wikipedia, the free encyclopedia224 – "The Doctor, the Widow and the Wardrobe"Doctor Who episodeCastDoctor    Matt Smith (Eleventh Doctor)ProductionWriter     Steven MoffatDirector     Farren Blackburn[1]Executive producer(s)         Steven Moffat    Piers Wenger    Caroline Skinner[2]Series     Specials (2011)Length     60 minOriginally broadcast     25 December 2011[3]Chronology← Preceded by     Followed by →"The Wedding of River Song"     Series 7"The Doctor, the Widow and the Wardrobe" is an episode of the British science fiction television series Doctor Who, in which the Doctor visits Earth and an alien forest. The episode was shown in the United Kingdom on Christmas Day on BBC One,[4] BBC America in the United States[5] Space in Canada,[6] and on ABC1 in Australia.[7] It is the seventh Christmas special since the show's revival in 2005.The episode features Claire Skinner, Bill Bailey, Arabella Weir and Alexander Armstrong. A sneak preview was aired on 18 November 2011 for Children in Need.[8]Contents [hide]     1 Plot        1.1 Prequel        1.2 Episode        1.3 Continuity    2 Production        2.1 Cast notes    3 References    4 External links[edit] Plot[edit] PrequelOn 6 December, a prequel to the episode was released online.[9] The Doctor is seen on a spaceship holding a red button which, when he lets go, will cause the space ship to explode. While holding the button, he has phoned the TARDIS to speak to Amy Pond asking her to rescue him, although he does not have his co-ordinates. Amy cannot fly the TARDIS, and she is not on the TARDIS. The Doctor wishes Amy a Merry Christmas before letting go of the button, and the spaceship explodes.[10][edit] EpisodeDuring the Christmas season of 1938, the Doctor finds himself on a damaged alien spacecraft in Earth's orbit. He escapes the exploding ship and the fall to Earth by rapidly donning an impact space suit, though in his haste, the helmet is put on backwards. On crashing to Earth, he is found by Madge Arwell, wife of Reg and mother of two children, Lily and Cyril. She helps the Doctor, stuck and unable to see while in the impact suit, to his TARDIS, and the Doctor promises to repay her for her kindness.Three years later, during World War II, Reg is reported killed in action when the Lancaster Bomber he was piloting disappeared over the English Channel. Madge is told this via telegraph just before Christmas, but decides not to tell her children, hoping to keep their spirits up through the holiday. Madge and the children evacuate London to a relative's house in Dorset, where they are greeted by the Doctor, calling himself "the Caretaker"; Madge does not recognise him from their previous encounter.The Doctor has prepared the house specially for the children and the holiday; though the children are pleased, Madge privately explains about Reg's death to the Doctor and insists he not overindulge the children. During the first night, Cyril is lured into opening a large glowing present under the Christmas tree, revealing a time portal to a snow-covered forest. The Doctor shortly discovers Cyril's absence and follows him with Lily; the two eventually track Cyril down to a strange lighthouse-like structure. Madge, finding her children missing, soon follows them into the forest, but is met by three miners in space suits from the planet Androzani Major.At the lighthouse, Cyril is met by a humanoid creature made of wood; it places a simple band of metal around his head like a crown. Lily and the Doctor arrive, followed by another wood creature, but find that they have rejected Cyril as he is "weak", as is the Doctor. The Doctor concludes that the life forces of the trees in the forest are trying to escape through a living creature, the crown acting as an interface. Meanwhile, Madge, holding the miners at gunpoint, is taken back to their excavation walker and told that the forest of the planet they are on is scheduled to be melted by acid rain within minutes, killing anything within it. The miners are teleported away safely before the rain starts after helping Madge to locate where her children are.Madge, using the little knowledge she knows of flying a plane from Reg, directs the walker to the lighthouse and safely reunites with her children as the acid rain starts. The wood creatures identify her as "strong", and the Doctor realises they consider her the "mothership", able to carry the life force safely. Donning the band, Madge absorbs the life force of the forest, allowing her to direct the top of the lighthouse as an escape pod away from the acid rain and into the time vortex. To get them home, the Doctor directs her to think of memories of home, allowing Madge to revisit her fond memories of Reg, shown on screens within the pod. She realises that she will have to recall the moment of Reg's death, but the Doctor forces her to continue to do so; Lily and Cyril come to learn the truth as they witness his last moments aboard the Lancaster bomber.Soon, the escape pod safely leaves the time vortex, landing just outside the house in Dorset, and the life force of the forest have converted themselves to ethereal beings within the time vortex. The Doctor steps outside while Madge starts to explain Reg's death to Lily and Cyril, but he returns to interrupt her and to tell her to come outside. There stands Reg and his Lancaster; he had followed the bright light of the escape pod into the time vortex and came out safely along with the pod at Dorset. The family has a tearful reunion as the Doctor watches.As Madge and her family turns to celebrate Christmas, the Doctor attempts to slip away, but Madge catches him, and as she sees the TARDIS realises that he is the man in the space suit from three years back. She insists on him staying for Christmas dinner, but when the Doctor reveals he has other friends out there that believe he is dead, Madge convinces him to go to see them at Christmas. The Doctor offers Madge his help if she ever needs it again.Later, the Doctor arrives outside Amy and Rory's home, two years since he left them there. Amy pretends to be angry at him for leaving them the way he did, but explains that River Song told them about his faked death, and Rory reveals that they have been setting a place for him at their Christmas dinner table every year. Having remarked earlier in the episode how "humany-wumany" it is to cry because of happiness, the Doctor finds himself shedding a tear of happiness in reaction to Rory's remark, and grins in wonder, and then steps inside to join them for dinner.[edit] Continuity    The three tree harvesters are from Androzani Major in the year 5345, a planet already featured in the serial The Caves of Androzani.    The Doctor also mentions the Forest of Cheem, which appeared in the Ninth Doctor episode The End of the World. He also mentioned that one of them fancied him, which was Jabe Ceth Ceth Jafe, who sacrificed her life for him.    Amy Pond tells the Doctor that two years have passed since Lake Silencio ("The Impossible Astronaut"/"The Wedding of River Song").[edit] ProductionThe Lincolnshire Aviation Heritage Centre's preserved Lancaster bomber Just Jane, used in the programmeThe BBC announced in September 2011 that production had started for the special and filming was due to be complete by mid October 2011.[11] However, filming was disrupted on 30 September due to a 24-hour protest at BBC Wales because of compulsory redundancies.[12] The story is partly inspired by The Lion, the Witch and the Wardrobe (from The Chronicles of Narnia) by C. S. Lewis.[13] C. S. Lewis died the day before the very first episode of classic Doctor Who aired. Filming of some scenes involving Alexander Armstrong took place in and around the Lancaster bomber 'Just Jane' at the Lincolnshire Aviation Heritage Centre on 3 October 2011.[14] External footage of the lighthouse building took place in the Forest of Dean, Gloucestershire.[15][edit] Cast notesAlexander Armstrong previously appeared in Doctor Who episodes "The Stolen Earth" and "Journey's End" as the voice of Mr Smith, an alien computer, his character from The Sarah Jane Adventures.Arabella Weir previously appeared as an alternate incarnation of the Third Doctor in the Doctor Who Unbound audio drama Exile.[16]Claire Skinner is placed in the opening titles instead of Karen Gillan and Arthur Darvill, whose appearance in the episode was not reported before broadcast. Gillan and Darvill are, however, credited above Skinner in the episode's end credits.[edit] References    ^ Golder, Dave (21 September 2011). "UPDATE: Doctor Who Christmas Special Director Revealed". SFX. Retrieved 15 December 2011.    ^ "Steven Moffat on the New Exec". BBC. 21 July 2011. Retrieved 21 July 2011.    ^ Seale, Jack (29 November 2011). "Christmas TV: scheduling confirmed for Doctor Who, Strictly and Downton". Radio Times. Immediate Media. Retrieved 29 November 2011.    ^ "Doctor Who: Christmas Day at 7:00pm". BBC. 29 November 2011. Retrieved 15 December 2011.    ^ "Doctor Who Christmas Special" (Press release). BBC America. Retrieved 15 December 2011.    ^ "Doctor Who: The Doctor, The Widow and the Wardrobe - December 25th at 9pm ET!". Space. Retrieved 28 December 2011.    ^ http://www.abc.net.au/tv/doctorwho/christmas2011/    ^ Golder, Dave (27 October 2011). "Doctor Who Christmas Special Clip During Children in Need". SFX. Retrieved 29 October 2011.    ^ "Adventure Calendar 2011". BBC. 1 December 2011. Retrieved 15 December 2011.    ^ "The Prequel to The Doctor, The Widow and The Wardrobe" (Video). BBC. 6 December 2011. Retrieved 15 December 2011.    ^ "Christmas Special: The Stars! The Story!". BBC. 20 September 2011. Retrieved 15 December 2011.    ^ Jeffery, Morgan (30 September 2011). "'Doctor Who' Christmas special filming disrupted by BBC Wales strike". Digital Spy. Retrieved 30 September 2011.    ^ "Doctor Who Christmas special cast to include Bill Bailey and Claire Skinner". Metro. 21 September 2011. Retrieved 22 September 2011.    ^ "Doctor Who Christmas Special role for Lincolnshire Aviation Heritage Centre". Skegness Standard. Retrieved 30 November 2011.    ^ who "Look what's landed for Dr Who Xmas special!". The Forester. 22 September 2011. Retrieved 26 December 2011.    ^ "Doctor Who Unbound — Exile". Big Finish. Retrieved 25 October 2011.