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Our friend and scribe supreme FRED VAN LENTE returns to discuss some torturous theme parks! Fred has a new trade coming out as this episode drops, collecting his series Murder Kingdom… and we're gonna pair that with a delicious chilled glass of Forever People issue 4 (DC Comics, December 1971), featuring diabolical Desaad's Happyland! Oh what fun! Plus, we discuss his BRAND new book, The Future Is ******! You can find FVL on Instagram: @fredvanlente And his LinkTree has links to all of his doings, books, writing lessons and more! www.linktr.ee/fredvanlente For all things Jacked Kirby, including links to listen everywhere, our social media pages, and a place to buy yourself a swell Jacked Kirby t-shirt, visit our FlowPage: www.flow.page/jackedkirby If you like the show, share the show! Spread the word, tell a buddy, tag a friend! And make sure you rate and review us wherever you can! Thanks, kids!
Baby-making is more complicated than it might seem, and any couple struggling to conceive and achieve a successful pregnancy is faced with a confusing maze of fertility optimization measures.This is where whole genome personal genotyping can be very helpful. Your genes obviously have everything to do with fertility, and your genes are unique. Personal genotyping can illuminate what you might be doing wrong in the fertility optimization department. It empowers you and your partner to practice precision Biohacking by identifying the medicine, supplements, therapies, and lifestyle changes you need to bring a beautiful baby into the world.This deep-dive presentation will elucidate 17 problematic fertility genes you may have, how to find them, which conditions they are associated with, and give you a jumping-off point for addressing them...2:45 Important disclaimer: your genes don't have to be your destiny4:00 How to search your genome8:11 Single gene disorders10:18 On procrastination12:57 Polygenetic complexes17:22 MTHFR21:38 SLC19A122:04 DHFR23:25 MTR and MTT26:30 TCN27:00 PAI/SERPINE131:37 PEMT32:38 APEO34:18 FVL and F235:30 NOS37:05 GST/GPX42:04 PON43:20 VDR44:50 Male factor infertility51:40 Stress management hacks57:55 Folic Acid - The New Smoking?59:25 Niacin/Vitamin B31:00:30 Acupuncture1:04:50 Conclusion and inspirationRead: Decode Your Genome with Personal Genotyping for Precision Fertility Optimization
FVL scored the final 14 points to defeat Winneconne in an exciting season opener 35-26. Tony Giordana and Dick Knipinski had the call from Appleton.
FVL jumped out to a quick 3-0 lead but the Mustangs stormed back to defeat the Foxes 6-4 in game 1 of a Double Header Saturday afternoon. Tony Giordana had the call.
Little Chute scored five runs in the top of the 7th to break open a 5-5 tie but had yo hang on as FVL scored 3 runs in the bottom of the inning. Little Chute gets the doubleheader sweep with a 10-8 win. Tony Giordana had the call.
Noticias desde el último episodio Recordad que tenemos un patreon en www.patreon.com/portierramaryaire para el crecimiento de la comunidad. Inicio: (0:00:00) 9 de enero: Centenario del primer vuelo del autogiro de De la Cierva: (0:10:25) Publicado el inventario mundial World Air Forces 2023 de FlightGlobal: (0:24:39) Nuevas declaraciones del JEMA español: (0:28:36) Falta de aviones electrónicos en el EA: (0:56:04) Más PC-21 para el EA: (1:00:55) Rafale. Colombia y presunta compra, pero falsa noticia: (1:09:03) FCAS: (1:13:11) GCAP (ex-FCAS Tempest inglés): (2:03:39) F-22: (2:22:29) Ponen a prueba el Rapid Dragon: (2:28:35) Nuevos misiles AA de EEUU: (2:33:49) Compras de misiles novedoso para las FAS españolas: (2:41:40) Eurofighter EFA: (3:05:13) B-21 desvelado el 2 de diciembre: (3:56:29) Último AH-1 entregado: (4:04:49) MAH del KUH-1 y LAH: (4:06:58) NMH de RU: (4:08:45) NH90: (4:23:25) USAF: (4:27:47) F-35: (4:38:31) Vuelan segundo y tercer prototipos de KF-21 Boramae: (5:00:21) Rumanía compra 32 F-16 ex-noruegos y Bulgaria 8 F-16C/D Block 70: (5:01:38) A400M: (-1078507:0-15:0-19) Bell-Textron y su V-280 Valor ganan el FLRAA del FVL del US Army: (-1078507:0-15:0-19) NGRC: (-1078507:0-15:0-19) Tigre en Alemania: (-1078507:0-15:0-19)
Os traemos las últimas noticias desde los episodios anteriores de cada tema. Recordad que tenemos un patreon en www.patreon.com/portierramaryaire para el crecimiento de la comunidad. Inicio: (0:00:00) Ucrania, Mig-29 y HARM y la FA rusa sigue ausente: (0:19:54) Noticias de aeronáutica rusa: (0:47:47) Segundo prototipo del J-20 biplaza chino: (0:57:60) F-35 Lightning II : (1:03:52) MRTT: tras Brasil, Canadá compra 2 + 4 y certificación automática: (2:02:47) Fotones, fotazas o fotacas de nuestros F-18 en Lituania: (2:24:48) El USSOCOM selecciona sorprendentemente la fumigadora atómica para su Armed Overwatch: (2:28:19) The Japan Ground Self-Defense Force (JGSDF) has received the first UH-2 : (2:46:41) Polonia confirma la compra de 32 AW149 multirol para sustituir sus Mi-2 y Mi-8/17: (2:48:24) NH-90, más mal que bien: (2:51:07) Leonardo dice que espera volar pronto su AW249: (3:03:15) Sobre el FVL: (3:19:26) A400M: (3:30:32) La “MLU” del F-22: (3:35:31) Agilidad de desarrollo y Sistemas de arquitectura abierta OSA (Open Systems Architecture): (3:40:40) EC-130H por EC-37B: (4:03:09) C-101: (4:05:02) USAF inventario y disponibilidad: (4:06:48) B-21: (4:10:38) MPA o MPRA: (4:13:38) FCAS y Tempest. Y NGAD: (4:17:38) KF-21 Boramae: (4:24:14) FA-50: (4:33:32) Eurofighter Typhoon: (4:44:50) F-15 new EW suite: (4:56:04) F-16 y Grecia: (5:04:58) Despedida del SH-3 Morsa en la Armada Española: (5:13:11)
What Up With Rob and Chris The 65 Sports Series: Cole Alva- Dominated at Lincoln High School for the football team in 2021 earning him all league honors, all metro honors and and currently many college offers to play football at the next level. Cole also is a dominant wrestler at the 220 weight class. Just recently he won 1st place in the FVL championship tournament. What we love most about Cole is that he is more excited to talk about the support and other people in his life, family, teammates, community than he is comfortable talking about himself. Come hear from Cole about his wonderful career at Lincoln high school and where his future may land him. Subscribe To What Up! https://bit.ly/3qRR69T More What Up Videos
FVL rallied from a 12 point second half deficit to defeat Green Bay SW 53-47. With the win, the Foxes advance to the Regional final to take on West DePere. Dick Knapinski had the call.
FVL opened the second half on a 20-0 run, as they defeat the Menasha Bluejays 54-38. Joey Dee had the call.
In nonconference football action, Fox Valley Lutheran travelled to Little Chute. FVL defeated Little Chute by a score of 22-21. Jonathan Krause and Jonathan Dinse were on the call.
Noticias aéreas desde el 12 de agosto de 2021, con Alejandro-Orel a los mandos. Recordad que tenemos abierto un Patreon para apoyar el crecimiento de la comunidad: https://www.patreon.com/portierramaryaire . Tras el corte, el guión y minutado: Inicio: (0:00:00) Sobre el A400M: (0:09:18) China: H-20, J-35, J-16D J-20: (0:32:37) NH-90 Lobo del Ejército del Aire (EA): (0:58:03) F-117 oficialmente operando desde Fresno.: (0:58:37) Grecia comprará otros 6 Rafale para complementar los 18: (0:59:59) Sobre la cierta autonomía aeronáutica española: (1:12:55) y AFJT...: (1:22:26) Se firman las especificaciones y requisitos del FCAS y el reparto del pastel : (1:39:58) Sobre el FVL: (1:59:24) Sobre arquitectura abierta, ingeniería digital, etc.: (2:17:56) Futuro helo medio OTAN: NGRC: (2:25:17) Las PC-21 llegan a España: (2:25:43) Sobre el EFA: (2:30:26) El Rapid Dragon sigue ensayándose: (2:38:04) Generaciones de armas según la USNavy: (2:49:20) Ataque antibuque “barato”: (2:51:18) KF-X e IF-X surcoreano e indonesio: (2:51:38) TF-X turco: (2:57:38) F-18 canadiense alargado: (3:15:50) ¿El futuro de los cazas biplazas?: (3:21:22) Pérdida de la MPA en España: (3:27:27) MRTT para España: (3:38:45) Sobre F-35: (3:45:49) Cositas de la USAF: (3:56:15) Primera entrega de F-18E Block III: (4:18:24) C295 e India: (4:24:41) CH-47, Tigre y FAMET-AVIET en general: (4:56:45)
En este episodio os vamos a dar las noticias más relevantes aéreas y de drones del último mes y medio. Recordad que tenemos abierto un Patreon para apoyar el crecimiento de la comunidad: https://www.patreon.com/portierramaryaire . Tras el corte, el guión y minutado: Inicio: (0:00:00) Su-75 Checkmate ruso: (0:15:28) Tomas aire Su-57 : (1:00:56) Noticias del F-35, Suiza, etc.: (1:02:08) FCAS inglés: (1:42:02) F-X japonés (F3): (1:46:15) España aprueba financiación para 2ª fase del FCAS, MRTT y helos: (1:47:02) Mala pinta: parece que los 4 C295 MPA no salen adelante: (2:00:06) Sin embargo la base de Morón...: (2:15:25) Aviones MPA y SIGINT/ELINT para Alemania, Italia y Corea del Sur... ¿y para España?: (2:18:18) Sobre el Airbus AFJT: (2:25:04) Sobre el EFA: (2:26:43) El OFP-08E de nuestros F-18: (3:00:40) MLU de los Mirage 2000D franceses: (3:01:48) Primeras PC-21 a mediados de septiembre: (3:07:14) Los 3 NH-90 españoles del ET en Malí y más: (3:08:39) Novedades del FVL: (3:20:18) ¿T-129 ATAK turcos para Marruecos?: (3:36:02) B-21: (3:44:30) Nuevo fallo del Arrow: (3:48:04) Nuevo reactor de entrenamiento para la USNavy: (3:50:55) Indonesia confirma que seguirá con Corea del Sur para el KF-X/IF-X: (3:56:58) Skyborg autonomy core system flew onboard MQ-20 Avenger : (4:01:46) Francia selecciona el Aliaca para sus buques de combate: (4:15:41) US Navy eyes programme of record for cargo drones to resupply ships: (4:18:14) El Euromalo: (4:30:16) Necesidades de drones del ET español: (4:36:35) Láser antidrón francés: (4:41:48) El Orion ruso sigue la estela MQ-1/MQ-9 armándose: (4:45:16) Sobre MQ-9 incluida la situación española: (4:45:57) Escuela española militar de drones: (4:58:38) Coyote C-UAS: (4:59:17) Drones desde drones...: (5:04:28) LongShot: (5:07:09) Ya yendo a museos...: (5:09:14) Skyborg: (5:09:37) MQ-25: (5:12:42) Skydweller: (5:15:12) Conceptos de Bell VTOL muy rápidos: (5:19:40) Turquía quiere UCAS embarcado a falta de F-35B: (5:23:28) En EEUU los primeros drones furtivos sacrificables (attritable) serán agresores: (5:41:12)
In the Apple Bowl, Xavier took on Fox Valley Lutheran. Xavier defeated Fox Valley Lutheran by a score of 54-18. B.J. DeGroot was on the call.
In the Apple Bowl, Xavier took on Fox Valley Lutheran. Xavier defeated Fox Valley Lutheran by a score of 54-18. B.J. DeGroot was on the call.
FVL took an early lead on the road and never trailed as they cruised past Appleton East 72-53 in a Big Apple Classic game at East. Nick Brandl had the call.
FVL took an early lead on the road and never trailed as they cruised past Appleton East 72-53 in a Big Apple Classic game at East. Nick Brandl had the call.
This week we’re joined by the CEO of Vinturas, Jon Kuiper. Jon was the former head of Koopman Logistics Group and has years of experience as a senior executive and a CEO in the Finished Vehicle Logistics (FVL) industry. He joins us to talk about how Vinturas is using blockchain technology to revolutionise the FVL industry. What is blockchain? Jon Kuiper explains what blockchain technology means in the FVL industry. Blockchain technology or distributed ledger technology allows Vinturas to create an infrastructure which fosters collaboration between FVL companies and all other stakeholders in the ecosystem. This in depth collaboration allows for a single source of truth amongst all players in the FVL ecosystem, which in turn can bring huge benefits for all network participants. The finished vehicle logistics industry According to The Association of European Vehicle Logistics, Finished Vehicle Logistics (FVL) are the activities that take place after a new vehicle leaves the factory until the point when it reaches the customer. The FVL industry is a highly specialised sub-section of the transportation industry with dedicated storage warehouses and skilled drivers to ensure smooth delivery without damages to the high-value product. FVL is part of the automotive logistics market which according to a study by Global Market Insights is valued at over USD 115 billion in 2018 and is estimated to grow to USD 170 billion by 2025. The key 3 challenges in the finished vehicle supply chain industry Supply chain visibility In 2017 Supply Chain Worldwide Survey surveyed 623 supply chain professionals across 17 different countries and concluded that only 6% of firms were able to offer any type of supply chain visibility. This, more than ever presents a huge problem across supply chains which need to be addressed. Complexity The finished vehicle supply chain is very complex and the complexity is only increasing. Cars can be transported from the original equipment manufacturer (OEM) through potentially 4 modes of transport road, rail, maritime and river before it reaches the car dealership further increasing the complexity. FVL often spans different countries and these countries have their regulations and rules which will need to be abided to. Also, it’s not one firm which controls the whole supply chain. Products are often passed between 3 or 4 LSP’s in the supply chain before it reaches the car dealership creating multiple handover points between different logistic service providers. Customer demands Amazon certainly leads the way in producing extremely efficient supply chains having spent billions in R&D in the last 20 years perfecting their supply chain. The ‘Amazon Effect’ has meant that expectations of supply chains in many industries have risen in recent years. Now consumers expect shorter delivery times, are less tolerant of mistakes or late deliveries. Importantly customers expect to know where their product is and how long it’ll take to reach them so like Jon Kuiper says they know ‘if he can use it to go on holiday or not." Forecasting A problem with opaque supply chains is that it removes OEM’s ability to forecast or plan. This means that they are not able to update customers, nor are they able to execute last mile processes. The fleet owners have no information on the vehicles and the reasoning behind their vehicles being held up. If it’s because of damage it will have a large impact on their business. The overarching problem with the inability to forecast is that all stakeholders in the supply chain can’t manage the process. Inefficient operations and processes in the finished vehicle supply chain industry Before the supply chain process begins a tendering process occurs to see who can cover the supply chain service at the lowest price but there are well-known disadvantages of this process. The tendering process means that profit margins reduce.
Excited tonight as the #HSBBGOTW crew heads to Roseville to see @OakmontVikings host @PlacerAthletics in FVL action. Both teams are thinking postseason, this game may decide who gets there. http://mixlr.com/stonesradionetworks–2… 6:50 Coaches Corner 7:00 Tip Off sponsored by @lincolnpotters
It’s time for the #PCHSBBGOTW presented by your #LincolnPotters !! Tonight is @BballPondo at the @OakmontVikings live at 7p with the coaches corner sponsored by Asto Air Design at 6:50! Join us for some awesome #FVL action!
Victor Sanchez is a young, easy to talk guy. He currently runs two businesses, Kiovic and FVL entertainment in Stamford,CT. In this podcast, we talk about his digital marketing company, Kiovic, and how he first started working with local businesses in Stamford.FVL entertainment is a production organization that produces music videos and implements digital marketing strategies to maximize exposure and results for music artists.
This month on the Discover CircRes podcast, host Cindy St. Hilaire highlights three featured articles from recent issues of Circulation Research and talks with Denisa Wagner and Nicoletta Sorvillo about their article on how PAD4 in blood promotes VWF strings and thrombosis. Article highlights: Goodyer et al: ScRNA-seq of the Cardiac Conduction System Xiong et al: Chemotaxis Mediated Second Heart Field Deployment Ranchoux et al: Pulmonary Hypertension and Metabolic Syndrome Rühl et al. Thrombin/APC Response in FVL and FII 20210G>A Mahmoud et al. LncRNA SMILR’s Mechanism and Therapeutic Potential Transcript Cindy St. H: Hi, welcome to Discover CircRes, the monthly podcast of the American Heart Association's Journal, Circulation Research. I'm your host, Cindy St. Hilaire, and I'm an assistant professor at the University of Pittsburgh. My goal as host of this podcast is to share with you some highlights from the recent articles published in the August 2nd and August 16th issues of Circulation Research. Cindy St. H: After I discuss some highlights, we'll also have an in-depth conversation with Drs. Denisa Wagner and Nicoletta Sorvillo, from Boston Children's Hospital and Harvard Medical School, who are the lead authors of one of the exciting discoveries from the August 16th issue. Cindy St. H: The first article I want to share with you today is titled Transcriptomic Profiling of the Developing Cardiac Conduction System at Single-Cell Resolution. The first author is William R. Goodyer, and the corresponding author is Sean Wu. They are both located at the Cardiovascular Institute and the Department of Pediatrics at Stanford University. Cindy St. H: Have you ever wondered how your heart beats, and why there's always this glub-glub pattern, and where did it come from? How is the heart able to initiate that pattern, from cells that don't contract to cells that contract? Well, the beating of the heart is regulated by what's called the cardiac conduction system, and this is an area in the heart of specialized cells, and these cells establish the rhythmic beating by coordinating the contraction of the chambers of the heart. Cindy St. H: There's several components to the CSS. The sinoatrial node acts as the pacemaker in the right atrium. The arterial ventricle node is the electrical relay that slows down the pulse from the SA node. A His bundle helps to transmit those impulses, and the Purkinjie fibers are the terminus of the electrical signal. Between all of these different components are a heterogeneous population of what are called transitional cells. There are several studies that have linked these somewhat amorphous or heterogeneous transitional cells to different arrhythmic disorders. Cindy St. H: For the normal function of the heart, all of these parts must come together, and when they don't, there's severe clinical manifestations such as arrhythmias, like I said, but also you can get decreased cardiac output and even sudden cardiac death. While important, the cells of the CSS are rather elusive, and that's because they're in a relatively small number compared to the rest of the cells in the heart, and there also aren't very clear markers to identify the cells in the CSS. Cindy St. H: To address this, Goodyer and colleagues harvested cells from embryonic mouse hearts and performed single-cell RNA sequencing on 22,000 individually barcoded cells. What they were looking for is learning what type of cells they are, but more importantly, they had the goal of identifying what these elusive transitional cells are, and can we find a marker for these cells to study them? And in some, yes. Together, the sequencing and spatial data provided gene expression atlas of the mouse CSS. Hopefully, this atlas will guide future studies into the essential electrical system that regulates the heartbeat. Cindy St. H: The next article I'd like to highlight is titled Single-Cell Transcriptomics Reveals Chemotaxis-Mediated Intra-Organ Crosstalk During Cardiogenesis. We're really going to hit you over the head with some single-cell transcriptomics in this month's podcast. The first authors of this article are Halqing Xiong, Yingjie Lou, Yanzhu Yue, Jiejie Zhang and the corresponding author is Aibin He and they're all from the Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine and the Peking-Tsinghua Center for Life Sciences, all at Peking University in Beijing, China. Cindy St. H: During development, the mammalian heart originates from two distinct areas in the early embryo and they're called the first heart field and the second heart field. Progenitor cells from these regions give rise to very different structures. From the first heart field comes the atria and the left ventricle, and the second heart field forms the right ventricle and the outflow tract. While we know the outcomes of these different developmental layers, a full understanding of how the first and second heart fields are regulated and how they actually interact with one another is actually lacking a lot of detail and we're not exactly sure how those structures can influence one another. Cindy St. H: So to learn more, Xiong and colleagues utilized two different murine models that were engineered to label cells coming from either the first or second heart fields red, and by labeling these cells red, it allows for their very pure isolation and then downstream studying at the single-cell level. So from each of these two models, they collected about 600 red-labeled cells and they collected these cells at four different time points, that were essentially at 12 hour intervals, and they did this starting at embryonic day 7.5, and that's because that's the time point in the mouse where these second and first heart fields are starting to develop. Cindy St. H: What they found, by using single-cell RNA sequencing, is that the first heart field cells differentiated into cardiomyocytes, in what they called a gradual, wave-like manner, while the second heart field cells differentiated in what they referred to as a more stepwise, defined pattern. The team also found high expression of migration factor MIF in first heart field cells and they found MIF's receptor CXCR2 in the second heart field progenitor cells. This suggests that perhaps the first heart field cells could regulate the migration of the second heart field cells. Sure enough, blocking MIF- CXCR2 interaction in cultured mouse embryos prevented second heart field cell migration and also prevented normal development of the right ventricular outflow tract structures. So together these results provide insight into both normal heart development and also suggest what might go awry in certain congenital heart malformations. Cindy St. H: The next paper I want to highlight is titled Metabolic Syndrome Exacerbates Pulmonary Hypertension due to Left Heart Disease. The first author is Benoit Ranchoux and the corresponding author is Francois Potus, and they are from the Pulmonary Hypertension Research Group at Laval University in Quebec City in Quebec, Canada. The disease pulmonary hypertension can arise from a number of causes, but one of the main drivers of what's called group two pulmonary hypertension is left heart disease. Left heart disease itself is caused by several conditions, such as diastolic dysfunction, aortic stenosis, which is a disease that I study, or mitral valve disease. All of these pathologies result in the left heart not beating efficiently or exerting too much energy. Cindy St. H: More than half of all group 2 PH patients also have metabolic syndrome, and metabolic syndrome is a condition that is ever increasing in the modern age, especially in America, and it's characterized by obesity coupled with pathology such as dyslipidemia, type 2 diabetes and high blood pressure. Metabolic syndrome is also marked by elevated levels of the inflammatory cytokine IL6. Rat studies have shown that IL6 can induce proliferation of the pulmonary artery smooth muscle cells and consequently, pulmonary hypertension. Cindy St. H: In this study Ranchoux and colleagues pulled together all these different pieces in a rat model and essentially want to test left heart disease coupled with metabolic syndrome coupled with does pulmonary hypertension happen or get worse? What they found was really interesting. Left heart disease was induced in a rat model using super coronary aortic banding and then metabolic syndrome was induced with a high fat diet feeding, or with treatment with Olanzapine, which is a second generation anti-psychotic agent, and it's known to induce metabolic syndrome not only in rats, but also in humans. The data from this paper show that inducing metabolic syndrome in rats coupled with left heart disease resulted in elevated IL6 levels and also greatly exacerbated pulmonary hypertension. Cindy St. H: Digging into this mechanism, they found that inhibition of IL6, using either an anti-IL6 antibody or by reducing IL6 secretion from macrophages, using the diabetes drug Metformin, ameliorated the pulmonary hypertension in the rats. They then went on and looked at human samples and they found that IL6 was higher in the lungs of pulmonary hypertension patients and that this IL6 could induce proliferation of human pulmonary artery smooth muscle cells. So together these data suggest that the observation in rats holds true for humans, but further goes on to suggest that perhaps Metformin, which is a well-known, well-used diabetic drug, could perhaps be used for the potential treatment of Group 2 pulmonary hypertension patients. Cindy St. H: In the August 16th issue, we have an article titled Increased Activated Protein C Response Rates Reduce the Thrombotic Risk of Factor V Leiden Carriers but not of Prothrombin 20210G>A Carriers. That is some title. The first authors are Heiko Rühl, and Christina Berens, and Dr Rühl is also the corresponding author, and they are at the Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, in Bonn, Germany. Genetic studies have found two mutations that convey particularly increased risk for venous thrombo-embolism, and VTE is also more commonly referred to as deep vein thrombosis. These mutations are called factor five Leiden mutations, or FVL, and the prothrombin 20210G>A mutation we're just going to call F2. Interestingly, the penetrance of these mutations, or how likely they are to exhibit a phenotype, is variable. Some individuals with mutations never experience deep vein thrombosis, while others experience multiple episodes. Cindy St. H: As a group, the FVL carriers produce a higher than normal level of an anticoagulation factor called APC, or activated protein c. They also produce high levels of the pro-coagulation factor thrombin, and the authors of this study wondered if it was the balance, or rather perhaps an imbalance, of these factors that could explain the phenotypic variations in the patients that harbor the same mutation. To test this, they collected 58 patients. 30 were FVL and 28 were F2 carriers, and they injected these patients with clotting factors and examined their response rates. In both of the groups, about half of the individuals had no history of deep vein thrombosis, while the other half had had at least one episode. Cindy St. H: The team found that while both types of mutations were associated with increased APC and thrombin levels after coagulant injection compared with a control group, in the FVL group lower APC levels correlated with a much higher risk of deep vein thrombosis. In other words, the FVL carriers who had never experienced deep vein thrombosis produced higher levels of APC. Translating this to the clinic, perhaps APC testing could help identify individuals who are carriers of the FVL mutation and determine which of them are at higher risk due to lower levels of APC. Cindy St. H: The last paper we're going to highlight before switching to our interview is titled The Human- and Smooth Muscle Cell Enriched lncRNA, SMILR, Promotes Proliferation by Regulating Mitotic CENPF mRNA and Drives Cell Cycle Progression Which Can Be Targeted to Limit Vascular Remodeling. Now that is a crazy title! We’ve got to limit these names here this is difficult. The first authors are Amira Mahmoud and Margaret Ballantyne and the corresponding author is Andrew Baker, and they're all from Queens Medical Research Institute, BHF Center for Cardiovascular Sciences at University of Edinburgh in Edinburgh, UK. Cindy St. H: Before we dive into this article, I think it's important that we give a quick explanation of what is a lncRNA? lncRNA, or L-N-C RNA, stands for long non-coding RNA, and these are described as being transcripts which are made into RNA that are in lengths exceeding 200 nucleotides. So that differs them from micro RNAs or peewee RNAs or snRNAs, and they are classically or, I guess originally, considered not to be translated into protein. However, I think now more and more studies are finding that perhaps they are made into peptide sequences. However it's not fully clear what the function of those sequences are. Similar to micro RNAs, they also harbor regulatory functions that can control cellular functions by helping to fine tune the regulation of gene transcription and translation. Cindy St. H: Largely speaking, vascular smooth muscle cells are quiescent, but they can be stimulated to proliferate and migrate following injury to the vessel wall. While such activation of smooth muscle cells is essential for wound healing, these same processes are operative in vascular disease or after a cardiovascular procedure. Often what happens is an excess of proliferation of the smooth muscle cell wall can lead to dangerous occlusion of the blood vessel. The long non-coding RNA, SMILR, was recently identified as a promoter of smooth muscle cell proliferation and now in this article, Mahmoud and colleagues have defined its mechanism of action. Through transcriptome analysis of human smooth muscle cells, in which the levels of SMILR were either modulated to be increased or suppressed, the team found that lncRNA regulated expression of several genes involved in mitosis, or cell division. Furthermore, RNA interaction experiments revealed that the messenger RNA encoding the mitotic centromere protein, CENPF, was a direct interaction partner of SMILR. So just like the suppression of SMILR, the inhibition of CENPF resulted in reduced mitosis of the smooth muscle cells. Cindy St. H: The team then went on to show the inhibition of SMILR via RNA interference could block the smooth muscle cell proliferation ex-vivo, and they did this using intact sections of human saphenous vein. These results suggest that targeting this lncRNA could be a potential clinical treatment in situations where vessel occlusion is at risk. Cindy St. H: Okay, so now we're going to switch and have our interview with Drs Denisa Wagner and Nicoletta Sorvillo, and we're going to discuss their paper entitled Plasma Peptidylarginine Deiminase IV Promotes VWF-Platelet String Formation and Accelerates Thrombosis after Vessel Injury. Thank you Drs. Wagner and Sorvillo for joining us today. I think a funny thing is that between Nicoletta in Switzerland, me and you on the East coast and my producer on the West coast, I think we're spanning about nine hours of time zones here. Thank you all for taking the time, whatever time of day it is, wherever you are. Dr Wagner: Thank you. Cindy St. H: I was wondering, Denisa, if you could please introduce yourself and tell us a little bit about your background. Dr Wagner: I am a vascular biologist. I was always interested in platelets, endothelial cells, and leukocyte. I started with a background of von Willebrand factor research. Von Willebrand factor is the most important adhesion molecule for platelets and it is stored in endothelial cells as we have found very early on, in an organelle called Weibel-Palade bodies. So my work on this paper is actually related to the first observation I ever made scientifically of showing that von Willebrand factor is released from endothelium. Cindy St. H: Wow, that's wonderful. And Nicoletta, could you please introduce yourself and tell us a little bit about your background? Nicoletta: I'm Italian, I studied in Italy and I did my PhD in the Netherlands, and I've always worked on inflammation and thrombosis during my PhD. One of the major proteins I was working on is ADAMTS13. That is again a protagonist of our paper. Then I moved to Boston, where I had the pleasure to be able to work in Denisa Wagner's lab, and there I continued working on inflammation and ADAMTS13 and now currently I moved here to Bern and I'm bringing my expertise here, but I moved a little bit towards ischemia and reperfusion injury and transplantation. Cindy St. H: Interesting. Wow. Denisa, I want to circle back to this factor being one of the first findings that you worked on. How does it feel to still be working on it? Is it still exciting? Dr Wagner: It is nice and it's refreshing to come back to it. I did a lot of stuff in between. We did a lot of adhesion molecule work, leukocyte rolling. We made the early knockouts like b-selectin, p-selectin, and von Willebrand factor knockout as well. So it's fun. And by the way, since Nicoletta said that she was Italian, I am originally Czech, from Prague. Cindy St. H: Interesting. I did not know that. And actually, Denisa, I don't know if you remember, but when I was a graduate student in Katya Ravid’s lab, we collaborated with you to use some of this intravital imaging on one of our JCI papers. Dr Wagner: Oh right, right. I was wondering where I knew your name from. That's funny. Cindy St. H: Yes. Yeah, yeah. So it's wonderful to speak to you again. Really I wanted to interview you because I loved this paper, not only because it was a really interesting mechanism that actually I wasn't very well aware of, this citrullination and also because of the beautiful intravital imaging you could do and then link it to patient disease states. Maybe you can start by telling me what's the clinical unmet need or the question that your paper was trying to address? Nicoletta: So Denisa Wagner's lab always has worked on neutrophils and NETs and it has been shown that these NETs are involved in thrombosis. So we were curious what happens when even the enzyme that is important to make these NETs, this extracellular DNA, does when it's in the circulation. And this enzyme is of course PAD4 and it is known that it can modify our [inaudible] residues on protein through this process of citrullination. So we went to see if it could modify plasma proteins and as Denisa already said, an important molecule that initiates thrombotic processes is vWF that can be released during inflammation or when there's a damage to the endothelium . So we went to see what happens if the enzyme that is involved in removing this vWF that is ADAMTS13 happens if it gets modified by this enzyme path. So our question was more like what happens if you have the release of an enzyme that is normally intracellular? What would happen if it gets outside of the cell? Cindy St. H: Interesting. So before we get too deep in the weeds, what is citrullinization and why is it important? What do these modifications do? Nicoletta: It changes the charge of a protein. It goes and modifies arginine, and it transforms it into citrulline. It changes the charge of a protein and therefore you can imagine if you change a charge of protein it can change even the structure of a protein and if you change the structure then you can change the function. So this is what this modification can do. Cindy St. H: And that's what it's doing on the ADAMTS13? It's essentially altering or inhibiting its function? Nicoletta: Yes. What we saw is that we can find these citrullinated residues on ADAMTS13 and we identify them by mass spectrometry and then we saw that if it is modified by citrullination, it loses its activity so it doesn't function anymore. Cindy St. H: Interesting. Very neat. Could you talk a little bit about the process of where this is happening naturally and where it goes wrong in a diseased state such as either sepsis or aging or just general clotting? Dr Wagner: These neutrophil extracellular traps are generated often more during a disease state when there is either an infection or exacerbated inflammation that would be like in sepsis or for example, in a metabolic disorder like diabetes. So there is a lot more of them being generated. Also, for example, in diabetes, PAD4 is elevated inside the neutrophil four-fold. If it's released from diabetic neutrophils , then there would be really a lot more of it. And in aging also, then a NETosis becomes much more prominent. We have done this only with mice, but I believe that it will be also, unfortunately, the case with humans that old mice make a lot more NETs than young mice. Therefore this is relevant to look. Since thrombosis increases both with aging, the incidence of thrombosis, thrombosis increases with a disease like diabetes or in sepsis, you will have micro thrombosis. We thought it would be interesting to study those processes as well, then. Cindy St. H: That's really neat. One of the techniques that you utilize heavily in this paper and several of your papers that I'm familiar with is this intravital imaging or intravital microscopy. Just so people can get a sense of what it is you're actually doing, could you maybe describe what that experiment is? Maybe Nicoletta, you could describe that for us? Nicoletta: During intravital microscopy, we are able to image in vivo, a vessel in a live mouse. And in this case we use mice and we can label leukocytes and platelets and then look at them in the vessel in vivo and you can then look for a thrombus forming or you can look at the [inaudible 00:23:43] already had leukocyte rolling and you can see what is happening inside the vessel during a proper blood flow and you can damage the vessel in some cases. In our case, in our paper, we do a ferric chloride injury where we damaged the vessel with ferric chloride and therefor you initiate a thrombus development and you can visualize it in vivo and real time. Cindy St. H: Excellent. Yes. And hopefully our listeners will look and see the beautiful pictures because those are some serious clots you get forming in the vessels. Yeah. Yeah. And so the other thing that you did was confirming the modification on ADAMTS13, you use mass spectrometry. How difficult was it to confirm that what you thought was happening was happening using that technique? Nicoletta: It was very difficult and challenging, I have to say. Dr Wagner: See, I would love to hear more about it because you often read, Oh, then we did mass spec and we got this beautiful whatever. Could you tell us a little bit about the struggles? Nicoletta: It was quite a struggle. I mean I think trying to identify such a modification that is very, first of all, novel and it changes the math only of one thousandth it's very difficult. To identify you can confuse it with a deiminasion again because of the increase of mass is the same. And another problem was that ADAMTS13, our plasma protein, is low abundance in plasma compared to other plasma proteins like Fibrinogen, that is very, very much abundant. It was a challenge for this reason. So trying to pinpoint out a small, tiny modification already in a protein that is not so abundant in plasma and therefore we have to use this probe, this Biosyn PG program. And we did this in collaboration with Paul Thompson's lab and we were able to then fish out what was modified by the citrullination, but it was very challenging. We tried several different types of techniques that were different types of approaches before being able to show that in vivo. So in human samples we can find this modification. Dr Wagner: Nicoletta grew a lot of gray hair during that period. (laughs) Dr Wagner: It took us about a year to figure out how we could detect it in vivo because also some antibodies to ADAMTS13 don't work so well. It's a minor protein, but she figured it out. Cindy St. H: Wow. That's amazing. Well, congratulations on that. That's excellent. I guess what I'm wondering now is what are the next steps and what might your findings mean in terms of future potential therapeutic options or treatment strategies for different detrimental thrombotic events? Dr Wagner: I think what we have really verified that the PAD4 remains active when it circulates in circulation, when the release, and there are several diseases in which PAD4 levels were found to be elevated, like rheumatoid arthritis and what it means in general. That is PAD4 is actually causing havoc. It is citrullinating probably quite indiscriminately. Several proteins may be finding the exposed parts. Maybe it could have some binding sites, but I think it just affects proteins in general and for some of them like, ADAMTS13, this had a very detrimental effect. So in diseases where there is a lot of PAD4, one has to worry about the consequences of citrullinating things and perhaps spot for inhibitors should be used. What do you think, Nicolleta? Nicoletta: I totally agree with you. Yes, I totally agree. I mean PAD4 outside the cell could be dangerous, of course. However, we never know if there's something good that it can do that protects by citrullinating proteins so there's so much more to discover about extracellular PAD4 and its effect on the environment. Dr Wagner: However, Nicoletta when she wrote a paper at the end she decided to talk about ADAMTS13 as a therapeutic because both she and I, we are convinced that ADAMTS13 it's a possible future therapeutic and it's already given to patients who are lucky in ADAMTS13 and may be given to patients who have thrombotic events in the future, like stroke or myocardial infarction. And these situations are highly pro-inflammatory. Therefore, we would anticipate that in these situations, NETs, and we know NETs are released and therefore, what Nicolleta suggests at the end, is that introducing together with ADAMTS13 an inhibitor of citrullination would be a good thing so that the protein, the ADAMTS13, remains active in circulation. Cindy St. H: Wow. So a two-hit strategy. I mean I can think of a handful of potential diseases this would be good for. You know, patients with sickle cell, there's a lot of NETs released then thrombotic events or even stroke. I mean, do you see that this is a potential mechanism that's common to all thrombotic disease or just kind of specific subsets? Nicoletta: All is a big word I think, but I think that there are many disorders where together with a thrombotic event, you can find also low levels or low activity of ADAMTS13 and in many of these disorders, nobody knew really why you have a reduction of ADAMTS13 activity, what is happening? Why do you lose this ADAMTS13? What we believe, but of course further studies are needed, is that maybe in these disorders, what is causing the loss of ADAMTS13 is this release of PAD4 because in stroke or in some DIC sepsis, you can find patients or many patients who do have low levels of ADAMTS13 activity and we believe that it's due to maybe citrullination by PAD4. So in that case, I agree with you maybe then that this therapy can be used in different thrombotic events as you suggested. Cindy St. H: So what does PAD4 normally do when it's intracellular? What is its, I guess healthy role, in a cell, if it has one? Nicoletta: So what is known now is that it really regulates transcription. So that's very important because it citrullinates transcription factors to facilitate transcription. And what Denisa Wagner's lab has identified is that it's extremely important to form these NETs because it citrullinates histone and allows the unraveling of the chromatin and then the NET release. However, it's extremely interesting. We are very interested to understand what else does it do within the cell. Cindy St. H: Interesting. That is so neat. I love this story. Dr Sorvillo and Dr Wagner, thank you so much for joining us and congratulations again on a wonderful paper. Dr Wagner: Thank you. Nicoletta: Thank you for having us and inviting us. Thank you. Cindy St. H: So that's it for the highlights from our August issues of Circulation Research. Thank you for listening. This podcast is produced by Rebecca McTavish and edited by Melissa Stoner and supported by the editorial team of Circulation Research. Copy text for the highlighted articles is provided by Ruth Williams. I'm your host, Cindy St Hilaire and this is Discover CircRes, your source for the most up-to-date and exciting discoveries in basic cardiovascular research.
The Foxes began the season with back-to-back road wins last week starting with a 9-3 win Thursday (3/28) over Saint Mary Catholic in a game that saw pitcher Syd Birling strikeout 14 batters. FVL followed up that win with a 15-9 victory on Friday (3/29) over Winnebago Lutheran Academy.
The Foxes began the season with back-to-back road wins last week starting with a 9-3 win Thursday (3/28) over Saint Mary Catholic in a game that saw pitcher Syd Birling strikeout 14 batters. FVL followed up that win with a 15-9 victory on Friday (3/29) over Winnebago Lutheran Academy.
On this episode of the Business Podcast, sponsored by Bell, we discuss the week on world markets with guests “Rocket Ron” Epstein, PhD, of Bank of America Merrill Lynch, Richard Aboulafia of the Teal Group consultancy and Sash Tusa of Agency Partners. Topics: — Latest on Boeing 737 Max 8 and 9 grounding and efforts to return to flight — Impact of 737 design decisions on Boeing’s 777X and 797 programs — China’s decision to order nearly 300 airliners from Airbus — implications of Germany’s new arms export restrictions on Saudi Arabia — US Army aviation portfolio budget tradeoffs, including cut to CH-47 Chinook heavy lift helicopter to support Future Vertical Lift program— First flight of Boeing -Sikorsky SB-1 Defiant co-axial, compound helicopter that’s competing for the FVL contract against Bell’s V-280 Valor
Girls Basketball contest between FVL and Xavier. Fox Valley Lutheran defeated Xavier 57-33. Joey Dee and Brian Butch on the call.
Boys Basketball contest between FVL and Xavier. Xavier defeated Fox Valley Lutheran 73-49. Joey Dee and Brian Butch on the call.
Boys Basketball contest between FVL and Xavier. Xavier defeated Fox Valley Lutheran 73-49. Joey Dee and Brian Butch on the call.
Girls Basketball contest between FVL and Xavier. Fox Valley Lutheran defeated Xavier 57-33. Joey Dee and Brian Butch on the call.
In a must win situation last Friday (10/12) the Foxes punched their ticket into the WIAA playoffs with a 24-14 road win over Marinette. FVL is into the playoffs for the fourth consecutive year and did so by winning their final three games of the 2018 regular season.
In a must win situation last Friday (10/12) the Foxes punched their ticket into the WIAA playoffs with a 24-14 road win over Marinette. FVL is into the playoffs for the fourth consecutive year and did so by winning their final three games of the 2018 regular season.
FVL defeated Xavier 13-7 in Week 8 of the High School Football Season. Bill Scott and Tom Neises were on the call.
FVL defeated Xavier 13-7 in Week 8 of the High School Football Season. Bill Scott and Tom Neises were on the call.
The Mustangs capped off another perfect week with a win over FVL on Thursday (9/20) followed by a 5-0 showing Saturday (9/22) at the Appleton East Invitational to take home the title for the first time in school history. Little Chute ran their record to a perfect 25-0 on the year.
The Mustangs capped off another perfect week with a win over FVL on Thursday (9/20) followed by a 5-0 showing Saturday (9/22) at the Appleton East Invitational to take home the title for the first time in school history. Little Chute ran their record to a perfect 25-0 on the year.
Zach Morris talked to Little Chute Mustangs Coach Brian Ryczkowski after their win over FVL.
Zach Morris talked to Little Chute Mustangs Coach Brian Ryczkowski after their win over FVL.
Wrightstown defeated FVL 42-28 in Week 5 of the High School Football season. Bill Scott and Tom Neises were on the call.
Wrightstown defeated FVL 42-28 in Week 5 of the High School Football season. Bill Scott and Tom Neises were on the call.
The R&B Show - 102 - Riders On The Storm: The Three Amigos are back at it! Ricardo Arguello and Brett Christopherson discuss the ramifications of the big FVL win over Luxemburg-Casco. We look at surprise 2-0 football teams in the Post-Crescent area. We also delve into social media and high school athletes. We wonder why more soccer teams haven't made it to the WIAA state tournament. We give some love to the Neenah and Appleton North girls volleyball teams. Brett and Rosie talk music and The Doors for some reason. Rosie gives us an update on the Elite 11 football team and we all can't wait for Bill's Pizza in Stevens Point after the big Kimberly/SPASH tilt this Friday!
Community First Credit Union Game of the Week between FVL and Xavier.
Community First Credit Union Game of the Week between FVL and Xavier.
Community First Credit Union Game of the Week between FVL and Xavier.
Community First Credit Union Game of the Week between FVL and Xavier.
Community First Credit Union Game of the Week between FVL and Freedom.
Community First Credit Union Game of the Week between FVL and Tomahawk.
Community First Credit Union Game of the Week between FVL and Little Chute.
Community First Credit Union Game of the Week between FVL and Tomahawk.
Community First Credit Union Game of the Week between FVL and Tomahawk.
Community First Credit Union Game of the Week between FVL and Little Chute.
Community First Credit Union Game of the Week between FVL and Freedom.
Community First Credit Union Game of the Week between FVL and Tomahawk.
Community First Credit Union Game of the Week between FVL and Freedom.
Community First Credit Union Game of the Week between FVL and Freedom.
Community First Credit Union Game of the Week between FVL and Little Chute.
Community First Credit Union Game of the Week between FVL and Little Chute.
Community First Credit Union Game of the Week between Wrightstown and FVL.
Community First Credit Union Game of the Week between Wrightstown and FVL.
Community First Credit Union Game of the Week between Wrightstown and FVL.
Community First Credit Union Game of the Week between Wrightstown and FVL.
Community First Credit Union Game of the Week between Xavier and FVL.
Community First Credit Union Game of the Week between Xavier and FVL.
Community First Credit Union Game of the Week between Xavier and FVL.
Community First Credit Union Game of the Week between Xavier and FVL.
Community First Credit Union Game of the Week between Xavier and FVL.
Community First Credit Union Game of the Week between Xavier and FVL.
Community First Credit Union Game of the Week between Xavier and FVL.
Community First Credit Union Game of the Week between Xavier and FVL.
Game one of the Big Apple Classic between FVL and Appleton East.
Game one of the Big Apple Classic between FVL and Appleton East.
Game one of the Big Apple Classic between FVL and Appleton East.
Game one of the Big Apple Classic between FVL and Appleton East.
Community First Credit Union Game of the Week between FVL and Wrightstown.
Community First Credit Union Game of the Week between FVL and Wrightstown.
Community First Credit Union Game of the Week between FVL and Wrightstown.
Community First Credit Union Game of the Week between FVL and Wrightstown.
Community First Credit Union Game of the Week between FVL and Little Chute.
Community First Credit Union Game of the Week between FVL and Little Chute.
Community First Credit Union Game of the Week between FVL and Little Chute.
Community First Credit Union Game of the Week between FVL and Little Chute.
Community First Credit Union Game of the Week between FVL and Xavier.
Community First Credit Union Game of the Week between FVL and Xavier.
Community First Credit Union Game of the Week between FVL and Xavier.
Community First Credit Union Game of the Week between FVL and Xavier.
Reviews: Bigger Bang #1, Django/Zorro #1, The Kitchen #1 Jon Hoche returns to join Jimmy in studio to fill the rotating co-host chair. Jimmy shares his cameo appearance in his pal Grace Helbig's recent video and they wish a big happy 86th anniversary to Mickey and Minnie Mouse! Special guest Fred Van Lente also joins the guys to chat about his extensive writing career in comics. We cover much including his early work to his massive Marvel comics up to his current new Dark Horse series Resurrectionists. Fred also has great tips on writing for all of you budding writers out there. And we bring back the old CNI questionnaire to find out some of Fred's favorite superhero onomatopoeia and catch phrases. It's a lengthy episode but chock full of FVL goodness! Apologies for rushing at the end though. Jon and Jimmy had to bust out to go see an advanced screening of Kingsman: The Secret Service (Thanks Mark Millar!). Leave your iTunes comments! 5 stars and nothing but love! Thanks for listening!
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