Podcasts about ewas

DNA methylation, a cornerstone of epigenetic research, is vital for understanding gene regulation and its implications in health and disease. In this week's episode of the Everything Epigenetics podcast, I speak with David Goldberg and Nicole Renke about the latest advancements in DNA methylation tools, including Illumina's groundbreaking Methylation Screening Array (MSA).We explore the history and evolution of methylation microarrays, why they remain the gold standard for Epigenome-Wide Association Studies (EWAS), and the design process behind the MSA array. David and Nicole provide insight into the practical applications of these tools for research in aging, neurodegenerative disorders, and environmental exposures.You'll learn about:•⁠  ⁠What methylation microarrays are and why they're essential for EWAS•⁠  ⁠The market need and vision for Illumina's new MSA array•⁠  ⁠Key features and benefits of the MSA array for researchers•⁠  ⁠The role of cell-specific methylation in advancing epigenetic studies•⁠  ⁠Insights into the technical and biological validation of the MSA arrayChapters:00:00 Welcome and Introduction02:30 History of Methylation Microarrays10:45 Applications of EWAS in Research20:15 Unveiling the MSA Array: Vision and Design35:00 Technical Validation and Biological Insights45:30 Future Directions in DNA Methylation Research50:00 Closing RemarksSupport the showWhere to Find Us:Instagram Twitter Facebook Follow us on:Apple Podcast Spotify YouTube Visit our website for more information and resources: everythingepigenetics.com Thank you for joining us at the Everything Epigenetics Podcast and remember you have control over your Epigenetics, so tune in next time to learn more about how to harness this knowledge for your benefit.

Ewa Wisnierska wurde 2007 von einem Gewitter bis in 10.000 Meter Höhe gerissen. Wie hat das ihr Leben verändert? +++ Ewa Wiśnierska-Lubawska ist eine der erfolgreichsten Gleitschirmpilotinnen. Vier Jahre lang flog die Deutsch-Polin von Podium zu Podium und errang 2008 schließlich den Europameistertitel. In die Geschichtsbücher des Paraglidens ist sie aber mit einem unglaublichen, wenn auch unfreiwilligen Rekord eingegangen. 2007 geriet sie bei einem Trainingsflug im Vorfeld der Gleitschirm-Weltmeisterschaft in Australien in ein Gewitter. Mit Aufwinden von mehr als 40 Meter pro Sekunde wurde sie nach oben gerissen – bis in rund 10.000 Meter Höhe. Eigentlich gilt das als Todeszone, in der ein Mensch wegen der Kälte und ohne Zusatz-Sauerstoff keine 30 Sekunden überlebt. Ewa hat aber überlebt – wohl auch weil sie im Flug ohnmächtig geworden war und ihr unterkühlter Körper längere Zeit auf absoluter Sparflamme lief. Die unglaubliche Geschichte dieses Gewitterfluges wurde schon häufiger erzählt und wird bis heute in Medien immer wieder aufgegriffen. Mich hat für diese Podcast-Folge eine andere Frage interessiert: Was hat dieses zwangsläufig erschütternde Erlebnis mit Ewa gemacht? Und so erzählt die heute 54-jährige in dieser Episode 151 von Podz-Glidz von den Jahren vor dieser Zäsur – und von dem, was danach folgte. Es geht um Träume, Freiheit, Ehrgeiz, Erfolg und schließlich Ewas größte Lektion: zu sich zu stehen, auch mal Nein zu sagen und gerade damit für andere ein Vorbild zu sein. +++ Wenn Du Podz-Glidz und den Blog Lu-Glidz fördern möchtest, so findest Du alle zugehörigen Infos unter: https://lu-glidz.blogspot.com/p/fordern.html +++ Musik dieser Folge: Track: Frolic | Künstler: E's Jammy Jams Youtube Audio Library https://www.youtube.com/watch?v=xasb1I0Mxss +++ Lu-Glidz Links: + Blog: https://lu-glidz.blogspot.com + Facebook: https://www.facebook.com/luglidz + Instagram: https://www.instagram.com/luglidz/ + Whatsapp-Kanal: https://whatsapp.com/channel/0029VaBVs05CHDynzdlJlU34 + Youtube: https://youtube.com/@Lu-Glidz + Soundcloud: https://soundcloud.com/lu-glidz + Spotify: https://open.spotify.com/show/6ZNvk83xxGHHtfgFjiAHyJ + Apple-Podcast: https://itunes.apple.com/de/podcast/podz-glidz-der-lu-glidz-podcast/id1447518310?mt=2 + Linktree: https://linktr.ee/luglidz +++ LINKS zu Ewa Wisnierska: + Ewas Homepage: http://www.ewawisnierska.com/ + Ewa auf Facebook: https://www.facebook.com/ewa.wisnierska + Wikipedia-Eintrag zu Ewa: https://de.wikipedia.org/wiki/Ewa_Wi%C5%9Bnierska + Galileo-Filmbeitrag: Gefangen in einer Gewitterwolke: https://www.youtube.com/watch?v=MIZ5e1G_vBw + Spiegel-TV Reportage: Flug in die Todeszone: https://www.spiegel.de/video/wendepunkte-todeszone-video-99012447.html + Wondery-Podcast: Gefangen über den Wolken | Nomadin der Lüfte: https://open.spotify.com/episode/3Dc6IuSzw06rW9sHuzTWHz

Today's podcast, which repurposes a recent webinar, is the conclusion of a two-part examination of the CFPB's use of a proposed interpretive rule, rather than a legislative rule, to expand regulatory requirements for earned wage access (EWA) products. Part One, which was released last week, focused on the CFPB's use of an interpretive rule to expand regulatory requirements for buy-now, pay-later (BNPL) products. We open with a discussion of EWA products, briefly describing and distinguishing direct-to-consumer EWAs and employer-based EWAS. We review some of the consumer-friendly features that are common to EWAs, including that there is no interest charged and they are typically non-recourse, and discuss expedited funding fees and tips, neither of which is required to access EWAs. We also provide an overview of how some states have attempted to regulate (or specifically not regulate) EWAs. We then transition into a discussion of the CFPB's history with EWA products, including the Bureau's advisory opinion in 2020 that took a markedly different approach to EWAs, essentially taking the position that a certain subset of EWAs fell outside of the definition of “credit” under the Truth in Lending Act (TILA) and Regulation Z. The CFPB's proposed interpretive rule, on the other hand, states that EWAs are “credit” and that expedited funding fees and optional tips, in most circumstances, are part of the finance charge that must be disclosed under TILA and Regulation Z. We explore the Bureau's reasoning in support of these conclusions and some of the compliance difficulties that the proposed interpretive rule would create were it to go into effect as written. Since this recording took place, the CFPB has posted over 148,000 comment letters that it has received on the proposed interpretive rule, many of which are from consumers who use EWAs to access a portion of their earned wages prior to their scheduled payday and are concerned that the proposed interpretive rule could limit or jeopardize their access to EWAs. The high number of responses demonstrates the level of interest that the CFPB's proposed interpretive rule has generated. We conclude with thoughts about vulnerabilities with both the proposed interpretive rule for EWAs and the interpretive rule for BNPLs that we described in Part One of this podcast, as well as how these rules could potentially be challenged. One notable development that has occurred since our recording is that the Financial Technology Association has filed a complaint asking a D.C. federal court to strike down the interpretive rule for BNPLs because of the alleged violations of the Administrative Procedure Act that we discuss in this episode. Alan Kaplinsky, former Practice Leader and Senior Counsel in Ballard Spahr's Consumer Financial Services Group, moderates today's episode, and is joined by John Culhane and Michael Guerrero, Partners in the Group, and John Kimble, Of Counsel in the Group.

In this week's episode of the Everything Epigenetics podcast, I'm joined by Dr. Charles Breeze, an expert in computational epigenetics. We talk about his inspiring journey into the field of epigenetics, his trailblazing research on kidney function across diverse ethnic groups, and the innovative tools he's developed to push the boundaries of epigenetic research.Dr. Breeze shares how his fascination with the complex interaction between environmental and genetic factors shaped his path into epigenetics. This passion led him to focus on understanding why certain populations are at higher risk for diseases like chronic kidney disease. His work has uncovered insights into the disparities in kidney disease risk among different ethnic groups, shedding light on genetic and environmental factors that had previously been overlooked.To address the challenges of inclusivity and precision in epigenetic studies, Dr. Breeze developed specialized tools that enhance the accuracy of Epigenome-Wide Association Studies (EWAS). These tools aim to improve how we analyze the impact of genetics and environment on health, helping researchers study epigenetic patterns across populations more effectively. His contributions are making it easier to identify how factors like diet, stress, and pollution affect gene expression, paving the way for more inclusive and equitable health research.Dr. Breeze earned his Ph.D. in computational epigenetics and genomics from University College London, where he was a Marie Curie fellow. He has also worked at top institutions like the University of Oxford, the European Bioinformatics Institute, and the Altius Institute for Biomedical Sciences in Seattle. There, he led the analysis and creation of important mouse genome data. Dr. Breeze has developed bioinformatics tools like eFORGE and FORGE2, which help analyze data from studies on how genes and the environment affect health (EWAS and GWAS). Dr. Breeze is a member of the Encyclopedia of DNA Elements (ENCODE) and the International Human Epigenome Consortium (IHEC).You'll learn about:  - Dr. Breeze's early interest in genomics, sparked by reading "Genome" by Matthew Ridley  - His significant findings from the 2021 study titled “Epigenome-wide association study of kidney function identifies trans-ethnic and ethnic-specific loci,” which revealed ethnic disparities in kidney function  - The challenges faced in epigenetic research due to the lack of diversity in reference data and how this impacts research outcomes  - Proposed solutions to increase diversity in epigenomic data, including community involvement and targeted data generation  - How his bioinformatics tools, eFORGE and FORGE2, assist researchers in understanding the complex data from EWAS and GWAS studies  - His future research directions, including studies on kidney cancer and the expansion of pathway analysis toolsSupport the showWhere to Find Us:Instagram Twitter Facebook Follow us on:Apple Podcast Spotify YouTube Visit our website for more information and resources: everythingepigenetics.com Thank you for joining us at the Everything Epigenetics Podcast and remember you have control over your Epigenetics, so tune in next time to learn more about how to harness this knowledge for your benefit.

BUFFALO, NY- May 8, 2024 – A new research paper was published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 16, Issue 8, entitled, “The association between neighborhood deprivation and DNA methylation in an autopsy cohort.” Previous research has found that living in a disadvantaged neighborhood is associated with poor health outcomes. Living in disadvantaged neighborhoods may alter inflammation and immune response in the body, which could be reflected in epigenetic mechanisms such as DNA methylation (DNAm). In this new study, researchers Lindsay Pett, Zhenjiang Li, Sarina Abrishamcar, Kenyaita Hodge, Todd Everson, Grace Christensen, Marla Gearing, Michael S. Kobor, Chaini Konwar, Julia L. MacIsaac, Kristy Dever, Aliza P. Wingo, Allan Levey, James J. Lah, Thomas S. Wingo, and Anke Hüls from Emory University, University of British Columbia, BC Children's Hospital Research Institute, Centre for Molecular Medicine and Therapeutics, and Atlanta VA Medical Center used robust linear regression models to conduct an epigenome-wide association study examining the association between neighborhood deprivation (Area Deprivation Index; ADI), and DNAm in brain tissue from 159 donors enrolled in the Emory Goizueta Alzheimer's Disease Research Center (Georgia, USA). “We found one CpG site (cg26514961, gene PLXNC1) significantly associated with ADI after controlling for covariates and multiple testing (p-value=5.0e-8).” Effect modification by APOE ε4 was statistically significant for the top ten CpG sites from the EWAS of ADI, indicating that the observed associations between ADI and DNAm were mainly driven by donors who carried at least one APOE ε4 allele. Four of the top ten CpG sites showed a significant concordance between brain tissue and tissues that are easily accessible in living individuals (blood, buccal cells, saliva), including DNAm in cg26514961 (PLXNC1). This study identified one CpG site (cg26514961, PLXNC1 gene) that was significantly associated with neighborhood deprivation in brain tissue. PLXNC1 is related to immune response, which may be one biological pathway how neighborhood conditions affect health. “The concordance between brain and other tissues for our top CpG sites could make them potential candidates for biomarkers in living individuals.” DOI - https://doi.org/10.18632/aging.205764 Corresponding author - Anke Hüls - anke.huels@emory.edu Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.205764 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts About Aging-US Aging publishes research papers in all fields of aging research including but not limited, aging from yeast to mammals, cellular senescence, age-related diseases such as cancer and Alzheimer's diseases and their prevention and treatment, anti-aging strategies and drug development and especially the role of signal transduction pathways such as mTOR in aging and potential approaches to modulate these signaling pathways to extend lifespan. The journal aims to promote treatment of age-related diseases by slowing down aging, validation of anti-aging drugs by treating age-related diseases, prevention of cancer by inhibiting aging. Cancer and COVID-19 are age-related diseases. Please visit our website at https://www.Aging-US.com​​ and connect with us: Facebook - https://www.facebook.com/AgingUS/ X - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Spotify - https://open.spotify.com/show/1X4HQQgegjReaf6Mozn6Mc MEDIA@IMPACTJOURNALS.COM

The reliability of testing epigenetic DNA methylation using Illumina beadchips is of paramount importance due to the specific intricacies of this technology. Illumina beadchips are widely used platforms for high-throughput epigenetic analysis, employing thousands of probes to measure DNA methylation levels at specific genomic loci. In this week's Everything Epigenetics podcast, Dr. Karen Sugden and I talk about how the reliability of these probes directly impacts the accuracy and validity of the results obtained.Keep in mind that in the context of Illumina beadchips, reliability refers to the consistent and accurate performance of each individual probe across multiple samples and experimental replicates. Each probe is designed to target a specific CpG site, and the methylation signal it generates must be dependable and reproducible.We discuss how reliable probes ensure the accuracy of DNA methylation measurements and how the reliability of probes becomes crucial for reproducibility when conducting large-scale studies using Illumina beadchips, such as epigenome-wide association studies (EWAS).Dr. Sugden and I also discuss how the reliability of probes on Illumina beadchips has implications for cross-study comparisons. For example, if the probes exhibit inconsistent behavior across different experiments or cohorts, it becomes challenging to compare results and draw meaningful insights from combined analyses.Furthermore, we chat about the efficient utilization of resources being linked to probe reliability. Unreliable probes might necessitate repeating experiments or allocating additional resources to validate results, potentially delaying research progress and increasing costs.In the context of epigenetic research, where subtle changes in DNA methylation can hold profound biological significance, the accuracy and consistency of data generated by Illumina beadchips are pivotal. Lastly, we explore Dr. Sugden's current research which includes how epigenetic clocks are associated with cognitive impairment and dementia and marijuana use. In this episode of Everything Epigenetics, you'll learn about: Dr. Karen Sugden's career Reliability and why it mattersHow unreliability arises in epigenetic researchThe process of measuring DNA methylation on Illumina beadchips (or microarrays) Technical errors that could arise when looking at DNA methylationKaren's paper titled “Patterns of Reliability: Assessing the Reproducibility and Integrity of DNA Methylation Measurement”How to untangle data from different beadchips (27K vs. 450K vs. EPIC 850K)What constitutes a reliable probe vs. an unreliable probe How to handle unreliable probesWho is at fault for unreliable probes If reliability is the same for every beadchipHow unreliability impacts epigenetic research How we can deal with unreliabilityThe value of repeated data Creating a “gold standard” work flow for processing epigenetic data How epigenetic clocks associate with cognitive impairment and dementia The connection between epigenetic clocks and marijuanaDr. Sugden's current research investigations Karen Sugden's profile at Duke - https://moffittcaspi.trinity.duke.edu/karen-sugden-0Support the showThank you for joining us at the Everything Epigenetics Podcast and remember you have control over your Epigenetics, so tune in next time to learn more about how.

Detta avsnitt innehåller utdrag ur två långa samtal där Ewa Glimsand och jag pratade om hennes liv och hur det utformade sig efter makens plötsliga död strax innan deras tredje barn skulle födas. Nu när det har gått snart 14 år har Ewa fått perspektiv på allt som hänt och är i dag djupt tacksam över det liv hon har nu. Under den svåra tiden efter dödsfallet upplevde Ewa makens närvaro väldigt tydligt, parallellt med att hon hade ett starkt stöd av sina föräldrar, bröder och vänner. Detta innebar att hon orkade leva vidare och ta hand om sina tre barn. Jag har använt mig av hennes astrologiska karta under våra samtal och när jag går tillbaka i tiden så kan jag utläsa att de svåra åren innehöll viktiga upplevelser på hennes livsväg. Så småningom skulle hon möta en ny man som liksom hennes första man också blev hennes stora kärlek, en man som matchar henne perfekt, som jag kan se i deras jämförelsehoroskop. Paret har även fått ett gemensamt barn, som ur ett astrologiskt perspektiv har ett otroligt stark själsligt band till båda sina föräldrar. Ewa Glimstads hemsida: https://hspmamma.se Instagram: hsp_mamma

Socker och kolhydrater är ju ett ämne som det pratats mycket om de senaste åren, och trots att vi vet vad vi bör äta är det många som kämpar med ett starkt sug efter sötsaker och en fixering av mat. I det här avsnittet snackar vi om vad socker är och hur det fungerar i din kropp. Varför är det så viktigt att balansera ditt blodsocker? Hur hänger dina hormoner och signalsubstanser ihop med sötsug? Och vad är egentligen den bästa kosten för att gå ner i vikt? Allt det här och lite till hjälper hälsoingenjören Ewa Meurk oss att reda ut i dagens avsnitt. Du kommer även få tips på hur du kan minska ditt sötsug genom din kost och livsstil, men också vart du kan vända dig om du upplever att du har problem med sug efter socker och kolhydrater som du inte kommer tillrätta med. Ett viktigt avsnitt där du får fördjupad kunskap hur din kropp fungerar! Varmt välkommen att lyssna och ta del av Ewas fantastiska kunskap när det gäller metabol hälsa. ********** Tusen tack för att du lyssnar på Bodywisepodden – en podd som vill inspirera och ge dig redskap att leva ett starkt, friskt och energifyllt liv i en hållbar kropp! Tyckte du avsnittet var givande? Jag blir väldigt glad om du vill prenumerera, dela och ge mig 5 stjärnor

Chris O'Neill ses av många som kungafamiljens udda fågel, men faktum är att han får betraktas som den normale i sin egen släkt. Här får du den ocensurerade historien om O'Neill-familjen, komplett med mamman Ewas påstådda affär med kung Charles och syskondotterns experiment med hallucinogena droger.En podd från Aller Media. Hosted on Acast. See acast.com/privacy for more information.

Maintaining muscle mass is crucial for healthy aging, as it is closely linked to overall physical function and quality of life. As we age, our bodies naturally experience a decline in muscle mass and strength, known as sarcopenia. This loss of muscle mass can lead to a range of negative health outcomes, including decreased mobility, increased risk of falls and fractures, and decreased metabolic rate. Additionally, loss of muscle mass can contribute to chronic conditions such as obesity, diabetes, and cardiovascular disease. By developing an epigenetic clock for skeletal muscle, Dr. Voisin and her colleagues have identified specific methylation patterns that are associated with muscle aging. This research not only sheds light on the biological mechanisms behind sarcopenia, but may also provide new targets for interventions aimed at preserving muscle mass and function in older adults.In this week's Everything Epigenetics podcast, Dr. Sarah Voisin and I focus on her 2020 paper which describes her development of a human muscle-specific epigenetic clock that predicts age with better accuracy than the pan-tissue clock. Yes - you heard that right… better accuracy than Dr. Steve Horvath's 2013 clock. Dr. Voisin and I also chat about the importance of skeletal muscle and how this relates to epigenetics and aging, the power of machine learning, and how identifying which methylation positions change as we age may give us insight into the underlying reason as to WHY we age rather than just HOW. She is now focused on creating an atas of epigenetics for all human tissues at the cellular level by combining 75,000 DNA methylation profiles across 18 tissues. In this episode of Everything Epigenetics, you'll learn about: How Dr. Voisin got her start in statistics and biology The importance of skeletal muscle tissue and how this relates to Epigenetics and AgingWhen to start exercising and moving your bodyThe importance of weight lifting How often we should be moving our body Why Dr. Voisin decided to develop this type of Epigenetic ClockThe limitations of the Horvath 2013 Clock as it relates to skeletal muscle The complications of data miningThe importance of collaboration and data sharing  How Dr. Voisin created her muscle-specific Epigenetic Clock The power of machine learningHow the muscle clock outperforms Dr. Steve Horvath's 2013 pan-tissue ClockDr. Voisin's epigenetic wide association studies (EWAS) she performedDifferentiated methylated positions (DMPs) in this studyDifferentiated methylation regions (DMRs) in this studyThe utility/application of the skeletal muscle Epigenetic ClockDr. Voisin's next big project (I'm so excited about her next project!!!) MEAT (muscle epigenetic age test)Where to find Dr. Voisin:Email: sarah.voisin@vu.edu.au Twitter: https://www.vu.edu.au/research/sarah-voisinGitHub account:https://github.com/sarah-voisinSupport the showThank you for joining us at the Everything Epigenetics Podcast and remember you have control over your Epigenetics, so tune in next time to learn more about how.

Hinter der zeitgenössischen Bodywear Brand Opaak steht der Kopf der Gründerin und Kreativdirektorin Agathe D. Dzialocha, die Opaak 2017 auf den Markt lancierte. Nachdem sie als Designer im Bereich der Luxusmode in den Metropolen Stockholm und Amsterdam gearbeitet hatte, beschloss sie sich näher mit den Themen Sinn und Nachhaltigkeit in der Textilbranche zu beschäftigen und das Gespräch mit ihrer ständigen Inspirationsquelle aufzunehmen: den Frauen. Heute stehen die Entwürfe von Opaak für selbstbewussten Ausdruck und bestärken eine stetig wachsende internationale Community.Wir sprechen unter anderem  über:den  USP von OpaakVertriebswege wie B2B / B2C /D2Cdurch welche Maßnahmen Opaak für Nachhaltigkeit steht Lieferantenstrukturen und Herausforderungen PreissegmentKollektionsauswahl und -größeWas die Gründerin Agathe für die Zukunft von Opaak beschäftigtund vieles Spannende mehr.Es lohnt sich reinzuhören.Hier geht's zu den ShownotesWOMEN IN FASHION MENTORINGMöchtest auch Du mit Deinen vorhandenen Potenzialen, Fähigkeiten und Kenntnissen Deine unverwechselbare Marke im Fashion- und Lifestyle-Segment aufbauen? Ich helfe Dir gerne bei der Gründung Deiner eigenen Marke, und biete Dir meine Erfahrungen, meine Plattform, und den Zugang zu meinem exklusiven Netzwerk.TRIFF JETZT DEINE ENTSCHEIDUNG und vereinbare Dein kostenfreies Vorgespräch mit mir. Vielen Dank für Deine Treue!Herzlichst,Sibel Brozathttps://womeninfashion.de/www.linkedin.com/womeninfashion.dewww.instagram.com/womeninfashion.dewww.facebook.com/womeninfashion.deTelegram Gruppenchathttps://www.youtube.com/c/womeninfashiongermany

EXTREAM WILD AZZ SPECULATION WARNING! We discuss how the FBI in conjunction with Moscow PD are using a data upload data base to debunk rumors. We read an email about a (EWAS) extreme wild azz speculation (that we don't believe) that is going around regarding Ethan Chapin. Dylan Rounds still missing (probable homicide) the apparent lack of charges is more mysterious than his disappearance. We hear from Athena Strands mother about her precious little girl and the monster who took her. Arizona man kidnaps pregnant real-estate agent causing her to lose her baby. Princeton student dies under mysterious circumstances, University not forthcoming with answers. We also listen to an EVP a listener sent in. Can you hear the voice? We take you calls live! Program this number into your phone we want to talk with you. (325)261-0892 If you are driving down the road (we want you to be safe) you can listen to our audio only live stream here: https://www.radioking.com/play/midnight-radio2 If you are overseas leave us an audio message here: https://anchor.fm/midnightrad/message Idaho murders: Police say they're getting 'good tips' 4 weeks in despite lack of reward and suspect STILL SEARCHING Missing Dylan Rounds' body may be hidden in unmarked mineshaft Dylan Rounds' parents share new details about their missing son's boots, phone, pistol and more Earthworm Infertainment Athena Strand's mother speaks about her daughters abduction and murder | LiveNOW from FOX Arizona man arrested in Texas related to alleged assault, attempted kidnapping of pregnant real estate agent A Princeton Student Died, Misrach Ewunetie. Her Classmates Want to Know What Happened. EVP: "Joe are you here?" Disclaimer! This is a place to discuss your WAS (wild azz speculation), WAT (wild azz theories) and TAT (tame azz theories) safely without judgment. We encourage you give your tips; anything you have seen with your own eyes or heard with your own ears to law enforcement. Clips are played under the conditions of FAIR USE. This show is for entertainment and or information purposes only. No literal meaning should be taken or inferred. We do not encourage anyone mentioned in this video to be contacted or harassed. We would love to hear from you! Call and leave us up to a 3 min message. Call Us: (325)261-0892 Contact us by email: midnightrad.io101@gmail.com Visit our Website for episodes, articles and merch: www.midnightrad.io Leave us an audio message here: https://anchor.fm/midnightrad/message If you live overseas the option above is the best way to contact us . --- Send in a voice message: https://podcasters.spotify.com/pod/show/midnightrad/message Support this podcast: https://podcasters.spotify.com/pod/show/midnightrad/support

Wealth Without Bay Street EPISODE 142: Joining us on today's episode of Wealth Without Bay Street is Brittany Anderson. Brittany Anderson is the President and Shareholder of a top-ranked financial services firm, Sweet Financial Partners. Having more than a decade's worth of experience in her field, she has taken her business building and team engaging insights, and has worked with CEO's, Entrepreneurs, Business Owners, and Authors. Brittany is also the co-creator of the Ultimate Advisor Coaching and Ultimate Advisor Mastermind Platforms. Her insights have been featured in national media outlets such as the Huffington Post, Barron's, Private Wealth Magazine, Soar to Success & Forbes magazine. She has shared her expertise through her contribution to three published books and will continue on with her love for writing as she is set to publish two additional books in 2022. As an influential speaker and author, Brittany Anderson has spoken at Million Dollar Round Table, Raymond James National Conference, EWAS and others on showing up each day to be more than a title, more than a label, and pursuing a life that fulfils their purpose.

Mediet Ewa Olsson ser sådant som de flesta av oss inte ser. Hon är övertygad om att det finns liv efter döden, men hur det livet ser ut vet hon inte. Till henne kommer alla typer av människor för att få rådgivning om olika saker i livet – läkare, präster och vetenskapsmän lika ofta som andra. Ewas råd när du är ledsen: titta på en tecknad Walt Disney-film! Och vem är den gamla damen som kommer på besök i studion?

My guest on today's episode is passionate about helping women achieve not just financial independence, but the peace and security that comes with it. Brittany learned at a very young age the stress of not having enough as the oldest child in a single-parent home, and decided she would devote her life to helping women avoid that fate.Being successful with our money means we need to think differently about money, and its role in our lives. It takes time and effort, but with the right amount of coaching and a lot of patience, it is doable. Brittany Anderson will help you get started toward that if that's something you desire!Here's a bit of what you'll hear in today's episode:-What is a dream architect, and how to adopt a "shift in" mindset...02:55-How the natural human mindset trips us up in realizing our greatest potential...06:05-Financial advice for those who (think) they have no money to invest...10:25-What to say to those stuck in a "victim" mentality (tough love)...16:08-How to both identify, and achieve your own dream for your life...20:23-How Brittany feels called to minister to women and the unique challenges women face...26:01-The importance of living "now" vs. the perpetual stay on "Someday Isle"...31:10-How to connect with Brittany and take the first step on your journey of financial success!...34:00Resources mentioned:FacebookTwitterLinkedIn (Brittany)LinkedIn (Sweet Financial Partners)Sweet Financial Partners websiteMy Sweet Financial websiteThe Compound Effect by Darren HardyConnect with today's guest!Brittany Anderson is the President and Shareholder of a top-ranked financial services firm, Sweet Financial Partners. Having more than a decade's worth of experience in her field, she has taken her business building and team engaging insights, and has worked with CEO's, Entrepreneurs, Business Owners, and Authors. Brittany is also the co-creator of the Ultimate Advisor Coaching and Ultimate Advisor Mastermind Platforms. Her insights have been featured in national media outlets such as the Huffington Post, Barron's, Private Wealth Magazine, Soar to Success & Forbes magazine. She has shared her expertise through her contribution to four published books and will continue on with her love for writing as she is set to publish an additional book in 2023. As an influential speaker and author, Brittany Anderson has spoken at Million Dollar Round Table, Raymond James National Conference, EWAS and others on showing up each day to be more than a title, more than a label, and pursuing a life that fulfills their purpose._______To learn more and for free resources go to www.wendiepett.com. If you haven't listened to the Introduction and the first 5 episodes of the Visibly Fit Podcast make sure you do. You will be encouraged that becoming Visibly Fit is actually within REACH. You can download the worksheets at www.wendiepett.com/visiblyfitpodcast

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.21.513088v1?rss=1 Authors: Fodder, K., Murthy, M., Rizzu, P., Toomey, C. E., Hasan, R., Humphrey, J., Raj, T., Lunnon, K., Mill, J., Heutink, P., Lashley, T., Bettencourt, C. Abstract: Frontotemporal lobar degeneration (FTLD) is an umbrella term describing the neuropathology of a clinically, genetically and pathologically heterogeneous group of diseases, including frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). Among the major FTLD pathological subgroups, FTLD with TDP-43 positive inclusions (FTLD-TDP) and FTLD with tau positive inclusions (FTLD-tau) are the most common, representing about 90% of the cases. Although alterations in DNA methylation have been consistently associated with neurodegenerative diseases, namely Alzheimer's disease, little is known for FTLD and its heterogeneous subgroups and subtypes. The main goal of this study was to investigate DNA methylation variation in FTLD-TDP and FTLD-tau. We used frontal cortex genome-wide DNA methylation profiles from three FTLD cohorts (228 individuals), generated using the Illumina 450K or EPIC arrays. We performed epigenome-wide association studies (EWAS) for each cohort followed by meta-analysis to identify shared differential methylated loci across FTLD subgroups/subtypes. Additionally, we used weighted gene correlation network analysis to identify co-methylation signatures associated with FTLD and other disease-related traits. Wherever possible, we also incorporated relevant gene/protein expression data. The EWAS meta-analysis revealed four differentially methylated loci in FTLD, some of which showed altered gene and protein expression in FTLD. Two of the meta-analysis hits, OTUD4 and CEBPZ, were found to be co-methylated within signatures strongly associated with FTLD. These signatures were enriched for genes implicated in the ubiquitin system, RNA/stress granule formation and glutamatergic synaptic signalling. Altogether, our findings identified novel FTLD-associated loci, and support a role for DNA methylation as a mechanism involved in the dysregulation of biological processes relevant to FTLD, highlighting novel potential avenues for therapeutic development. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

VIDEOS: COVID-19 VACCINATED PEOPLE SUFFERING STRANGE HALLUCINATIONS BEFORE COLLAPSING – 7:15 WHISTLEBLOWER NURSE IN WASHINGTON DESCRIBES VACCINE INJURIES FROM EMPLOYMENT MANDATE – 1:45 FUNERAL EMBALMER: 85% OF DEAD BODIES NOW HAVE STRANGE BLOOD CLOTS SINCE COVID VACCINE ROLL-OUTS – 15:20 “UNEXPLAINED DEATHS” BECOMING #1 CAUSE OF DEATH IN 2022 IN CANADA, AUSTRALIA, AND EUROPE – 5:26 Jay Bhattacharya: The legal case against Anthony Fauci    Rhodiola found to be an effective herbal medicine for treating fatigue and weakness National Academy of Medical Sciences of Ukraine, September 28, 2022 With everything that's going on in life, it's normal to feel tired at some point. Fatigue is a condition characterized by extreme feelings of either physical or mental tiredness. One study shows that rhodiola (Rhodiola rosea) can be used as an herbal medicine for fatigue. People who are experiencing fatigue can have symptoms like sore muscles, lack of motivation, headaches, drowsiness, and irritability. If fatigue lasts for one to six months it can be classified as prolonged fatigue. However, if it goes beyond that it is already classified as chronic fatigue. Studies show that a third of the adult population has experienced chronic fatigue at least once in their life. With the high prevalence of chronic fatigue, it is unfortunate that there is still no standard medication available for it. Previous studies have shown that rhodiola can reduce symptoms in people suffering from mental fatigue. In addition to this, animal studies have also revealed that rhodiola can stimulate physical work capacity. For this study, which was published in Complementary Medicine Research, the researchers looked at rhodiola as a potential medication for prolonged and chronic fatigue. Researchers performed a clinical trial with 100 participants suffering from either prolonged or chronic fatigue. Although the trial lasted for eight weeks, significant improvements in fatigue symptoms were already observable after just one week. Further improvements could still be observed throughout the trial period. Furthermore, no adverse effects were observed with rhodiola intake. Parenting practices in teen years set the stage for closeness, warmth later on Penn State University, October 5, 2022 High-quality parenting practices in adolescence lay the foundation for close parent-child relationships when the children become young adults, according to new research from Penn State. The study is one of the first to examine how changes in parental involvement, parental warmth, and effective discipline during adolescence predict the quality of the relationships between parents and their young adult children, said Greg Fosco, professor of human development and family studies and associate director of the Edna Bennett Pierce Prevention Research Center at Penn State, who was co-principal investigator on the study. The study's findings were published recently in Developmental Psychology. The research team surveyed 1,631 participants in a long-term research study of families in rural and semi-rural Pennsylvania and Iowa who completed surveys between sixth and 12th grades and again at age 22. “Our research showed that parenting can change a lot during the teenage years: parents often express less warmth and affection, spend less time with their teens, and become more harsh in their discipline. Parents that were able to maintain positive parenting and involvement laid the foundation for a close relationship when their teens became adults,” said Fosco. Staying involved in teens' lives may look different than when they were younger, and it can be challenging to stay close with teens as they seek greater independence and autonomy, Fosco acknowledged. Based on the study's findings, he suggested these activities: Do something together, like playing sports, bike riding, exercising, going for a walk, gaming, cooking, attending events, or going out for a meal or dessert. Work on a project together around the house. Talk about what's going on at school. Discuss what you want to do in the future. Further, adolescents who experienced higher levels of parental warmth in the early teen years reported feeling more closeness and warmth with mothers and fathers when they were in their 20s, Fosco said. The study also found that parents who were skilled at using effective discipline with their sixth grade children — and maintained these effective practices over the course of adolescence — had less conflictual relationships when their children were in their 20s. Lifestyle Influences Metabolism Via DNA Methylation Helmholtz Zentrum Munchen (Germany) September 20, 2022 An unhealthy lifestyle leaves traces in the DNA. These may have specific effects on metabolism, causing organ damage or disease. Scientists of Helmholtz Zentrum München have now identified 28 DNA alterations associated with metabolic traits. This world-first epigenome-wide association study (EWAS) of modified genes and metabolites has been now published in the journal Human Molecular Genetics. In the course of life, aging processes, environmental influences and lifestyle factors such as smoking or diet induce biochemical alterations to the DNA. Frequently, these lead to DNA methylation, a process in which methyl groups are added to particular DNA segments, without changing the DNA sequence. Such processes can influence gene function and are known as epigenetics. To this end, the team analyzed blood samples from more than 1800 participants of the KORA study *. In doing so, they analyzed more than 457,000 loci in the DNA as to biochemical alterations and compared them with the concentrations of 649 different metabolites. The analysis showed that the methylation of 28 DNA segments changed a number of important metabolic processes. In the relevant DNA regions there were also already known disease-related genes: for example, the TXNIP gene that regulates glucose metabolism and is associated with the development of diabetes mellitus. Appropriately, with the methylated TXNIP there were altered concentrations of metabolites from the lipid and glucose metabolism. Also genes that are known to be biochemically altered due to smoking affect different metabolic activities, and specifically those with corresponding biological functions. “This study gives us new insights into how lifestyle factors can influence metabolism via the resulting alterations in the DNA,” said Gieger, research group leader at the IGE. “We can now use these results to develop new diagnostic and therapeutic approaches for lifestyle-related diseases such as diabetes.” Exposure to fluoridated water and attention deficit hyperactivity disorder prevalence among children and adolescents in the United States: an ecological association York University (Ontario), September 30, 2022 Epidemiological and animal-based studies have suggested that prenatal and postnatal fluoride exposure has adverse effects on neurodevelopment. The aim of this study was to examine the relationship between exposure to fluoridated water and Attention-Deficit Hyperactivity Disorder (ADHD) prevalence among children and adolescents in the United States. Methods: Data on ADHD prevalence among 4-17 year olds collected in 2003, 2007 and 2011 as part of the National Survey of Children's Health, and state water fluoridation prevalence from the Centers for Disease Control and Prevention (CDC) collected between 1992 and 2008 were utilized. Results: State prevalence of artificial water fluoridation in 1992 significantly positively predicted state prevalence of ADHD in 2003, 2007 and 2011, even after controlling for socioeconomic status. A multivariate regression analysis showed that after socioeconomic status was controlled each 1% increase in artificial fluoridation prevalence in 1992 was associated with approximately 67,000 to 131,000 additional ADHD diagnoses from 2003 to 2011. Overall state water fluoridation prevalence (not distinguishing between fluoridation types) was also significantly positively correlated with state prevalence of ADHD for all but one year examined. Conclusions: Parents reported higher rates of medically-diagnosed ADHD in their children in states in which a greater proportion of people receive fluoridated water from public water supplies. The relationship between fluoride exposure and ADHD warrants future study.

Brittany Anderson is the President & Partner at Sweet Financial Partners. She is also the Co-Founder of Dare to Dream Enterprises and the co-host of ‘The Ultimate Advisor' podcast. As the President and Partner of a top-ranked financial services firm, she has taken her business building and team engaging insights, and has worked with CEO's, Entrepreneurs, Business Owners, and Authors. With over a decade of industry experience, Brittany is the co-creator of the Ultimate Advisor Coaching and Ultimate Advisor Mastermind Platforms. Her insights have been featured in national media outlets such as the Huffington Post, Women, Inc & Forbes magazine. As an influential speaker and author, Brittany Anderson has spoken at Million Dollar Round Table, Raymond James National Conference, EWAS and others on showing up each day to be more than a title, more than a label, and pursuing a life that fulfills their purpose. Links and Notes Website https://daretodreaminspired.com/ https://sweetfinancial.com/ LinkedIn https://www.linkedin.com/in/brittany-anderson/ Email brittany@sweetfinancial.com Podcast https://sweetfinancial.com/where-money-and-mindset-meet-podcast/

"Ask ourselves, is this gonna matter in a week, a year or five years from now?" - Brittany AndersonBrittany Anderson is the President and Shareholder of a top-ranked financial services firm, Sweet Financial Partners. Having more than a decade's worth of experience in her field, she has taken her business building and team engaging insights, and has worked with CEO's, Entrepreneurs, Business Owners, and Authors. Brittany is also the co-creator of the Ultimate Advisor Coaching and Ultimate Advisor Mastermind Platforms. Her insights have been featured in national media outlets such as the Huffington Post, Women, Inc, Barron's, Private Wealth & Forbes magazine. She has shared her expertise through her contribution to three published books and will continue on with her love for writing as she is set to publish two additional books in 2022. As an influential speaker and author, Brittany Anderson has spoken at Million Dollar Round Table, Raymond James National Conference, EWAS and others on showing up each day to be more than a title, more than a label, and pursuing a life that fulfills their purpose.Please enjoy!Click here to subscribe to The Sell My Business Podcast to save time and effort.SELECTED LINKS FOR THIS EPISODEbrittany@sweetfinancial.comSweet FinancialBrittany Anderson (@thebrittanyanderson) • Instagram photos and videosLog into FacebookSweet Financial Partners - YouTubehttps://www.linkedin.com/in/brittany-anderson/https://www.amazon.com/gp/product/B09RKQG7NM/The Deep Wealth Sell My Business PodcastCockroach Startups: What You Need To Know To Succeed And ProsperFREE Deep Wealth eBook on Why You Suck At Selling Your Business And What You Can Do About It (Today)Book Your FREE Deep Wealth Strategy Call

Brittany Anderson is the President and Shareholder of a top-ranked financial services firm, Sweet Financial Partners. Having more than a decade's worth of experience in her field, she has taken her business-building and team-engaging insights and has worked with CEO's, Entrepreneurs, Business Owners, and Authors. Brittany is also the co-creator of the Ultimate Advisor Coaching and Ultimate Advisor Mastermind Platforms. Her insights have been featured in national media outlets such as the Huffington Post, Women, Inc & Forbes Magazine. She has shared her expertise through her contribution to three published books and will continue on with her love for writing as she is set to publish two additional books in 2022. As an influential speaker and author, Brittany Anderson has spoken at Million Dollar Round Table, Raymond James National Conference, EWAS and others on showing up each day to be more than a title, more than a label, and pursuing a life that fulfills their purpose.To learn more about Brittany, please visit her website:  https://www.sweetfinancial.com or listen to her guest episode on 10X Advisor Podcast. Social Links:https://www.facebook.com/brittany.anderson.25 https://www.facebook.com/sweetfinancial https://www.instagram.com/thebrittanyanderson/ https://www.linkedin.com/in/brittany-anderson/Connect with Mike:Website: https://mikemalatesta.com/LinkedIn: https://www.linkedin.com/in/mikemalatesta/ Please LIKE

Brittany Anderson is the President and Shareholder of a top-ranked financial services firm, Sweet Financial Partners. Having more than a decade's worth of experience in her field, she has taken her business-building and team-engaging insights and has worked with CEO's, Entrepreneurs, Business Owners, and Authors. Brittany is also the co-creator of the Ultimate Advisor Coaching and Ultimate Advisor Mastermind Platforms. Her insights have been featured in national media outlets such as the Huffington Post, Women, Inc & Forbes Magazine. She has shared her expertise through her contribution to three published books and will continue on with her love for writing as she is set to publish two additional books in 2022. As an influential speaker and author, Brittany Anderson has spoken at Million Dollar Round Table, Raymond James National Conference, EWAS and others on showing up each day to be more than a title, more than a label, and pursuing a life that fulfills their purpose.To learn more about Brittany, please visit her website:  https://www.sweetfinancial.com or listen to her guest episode on 10X Advisor Podcast. Social Links:https://www.facebook.com/brittany.anderson.25 https://www.facebook.com/sweetfinancial https://www.instagram.com/thebrittanyanderson/ https://www.linkedin.com/in/brittany-anderson/Connect with Mike:Website: https://mikemalatesta.com/LinkedIn: https://www.linkedin.com/in/mikemalatesta/ Please LIKE

In this episode, Dale and Brittany explore her story of coming from a small town and the traditional path mindset, to that of becoming the true visionary and leader of her life, and how things changed for her in doing so.  It's a great conversation, and you're going to love it...   About Brittany: Brittany is the President and Shareholder of a top-ranked financial services firm, Sweet Financial Partners. Having more than a decade's worth of experience in her field, she has taken her business building and team engaging insights, and has worked with CEO's, Entrepreneurs, Business Owners, and Authors. Her insights have been featured in national media outlets such as the Huffington Post, Women, Inc & Forbes magazine. She has shared her expertise through her contribution to three published books and will continue on with her love for writing as she is set to publish two additional books in 2022. As an influential speaker and author, Brittany Anderson has spoken at Million Dollar Round Table, Raymond James National Conference, EWAS and others on showing up each day to be more than a title, more than a label, and pursuing a life that fulfills their purpose.   Links for Brittany: www.sweetfinancial.com Brittanyanderson.com Facebook: https://www.facebook.com/brittany.anderson.25/ LinkedIn: https://www.linkedin.com/in/brittany-anderson/ Insta: https://www.instagram.com/thebrittanyanderson/     Lions Guide Links: Join The Lions Guide Community:  www.lionsguide.com   Subscribe to the Podcast: Podcast on Apple:  https://podcasts.apple.com/us/podcast/lions-guide-podcast/id1569364934 Podcast on Spotify:  https://open.spotify.com/show/2ZVKZ93jnqsXUDQcMdE4LO Podcast on Google:  https://podcasts.google.com/feed/aHR0cHM6Ly9saW9uc2d1aWRlcG9kY2FzdC5saWJzeW4uY29tL3Jzcw Podcast on Facebook:  www.facebook.com/groups/lionsguidecommunity Podcast on YouTube:  www.youtube.com/channel/UC_4paeQ1EaPFMTyPUNt75jg     Connect with Lions Guide: Facebook Page:  www.facebook.com/lionsguide Instagram:  www.instagram.com/lionsguide LinkedIn:  www.linkedin.com/lionsguide

In this episode, Dale and Brittany explore her story of coming from a small town and the traditional path mindset, to that of becoming the true visionary and leader of her life, and how things changed for her in doing so. It's a great conversation, and you're going to love it... About Brittany: Brittany is the President and Shareholder of a top-ranked financial services firm, Sweet Financial Partners. Having more than a decade's worth of experience in her field, she has taken her business building and team engaging insights, and has worked with CEO's, Entrepreneurs, Business Owners, and Authors. Her insights have been featured in national media outlets such as the Huffington Post, Women, Inc & Forbes magazine. She has shared her expertise through her contribution to three published books and will continue on with her love for writing as she is set to publish two additional books in 2022. As an influential speaker and author, Brittany Anderson has spoken at Million Dollar Round Table, Raymond James National Conference, EWAS and others on showing up each day to be more than a title, more than a label, and pursuing a life that fulfills their purpose. Links for Brittany: www.sweetfinancial.com Brittanyanderson.com Facebook: https://www.facebook.com/brittany.anderson.25/ LinkedIn: https://www.linkedin.com/in/brittany-anderson/ Insta: https://www.instagram.com/thebrittanyanderson/ Lions Guide Links: Join The Lions Guide Community: www.lionsguide.com Subscribe to the Podcast: Podcast on Apple: https://podcasts.apple.com/us/podcast/lions-guide-podcast/id1569364934 Podcast on Spotify: https://open.spotify.com/show/2ZVKZ93jnqsXUDQcMdE4LO Podcast on Google: https://podcasts.google.com/feed/aHR0cHM6Ly9saW9uc2d1aWRlcG9kY2FzdC5saWJzeW4uY29tL3Jzcw Podcast on Facebook: www.facebook.com/groups/lionsguidecommunity Podcast on YouTube: www.youtube.com/channel/UC_4paeQ1EaPFMTyPUNt75jg Connect with Lions Guide: Facebook Page: www.facebook.com/lionsguide Instagram: www.instagram.com/lionsguide LinkedIn: www.linkedin.com/lionsguide

Brittany Anderson is the President and Shareholder of a top-ranked financial services firm, Sweet Financial Partners. Having more than a decade's worth of experience in her field, she has taken her business building and team engaging insights, and has worked with CEO's, Entrepreneurs, Business Owners, and Authors. Brittany is also the co-creator of the Ultimate Advisor Coaching and Ultimate Advisor Mastermind Platforms. Her insights have been featured in national media outlets such as the Huffington Post, Women, Inc & Forbes magazine. She has shared her expertise through her contribution to three published books and will continue on with her love for writing as she is set to publish two additional books in 2022. As an influential speaker and author, Brittany Anderson has spoken at Million Dollar Round Table, Raymond James National Conference, EWAS and others on showing up each day to be more than a title, more than a label, and pursuing a life that fulfills their purpose. Learn more about your ad choices. Visit megaphone.fm/adchoices

In this episode of The Ultimate Advisor Podcast, we discuss why Bryan Sweet started EWAS (Elite Wealth Advisor Symposium) and the impact we made to thousands of Financial Advisors and how Bryan and his partners helped Financial Advisors Achieve their dreams. So push PLAY and join us as we discuss why and how Bryan Sweet built this Unique Event to help Financial Advisors be more successful and achieve their dreams.

Ingen har väl missat dramat mellan den svartsjuka Christopher och Hannas nya bögbästis Joshua, även kallad Deskpen. Joshua verkar trött på detta och har därför skickat en fredsgåva till studion. Hanna har skaffat sig en skäggagam som ska heta Skäggis och är på jakt efter ett terrarium till honom. I Vardagsfilosofiska rummet gästas vi av den ursnygga duon Daniel Hallberg och Ewa Fröling. Daniels moral är urusel och Ewas är väl inte så bra den heller. Får man fisa i en hiss full med folk? Får man ljuga för sin partner? Och är det så fel att avboka sin andra vaccindos för att man är rädd att få biverkningar precis före helgen? Dagens avsnitt får ni inte missa! Programledare: Christopher Garplind och Hanna Hellquist

Du möchtest ganz unverbindlich mit mir sprechen, damit wir herausfinden können, ob wir zusammenpassen? Bitte hier entlang: => hier geht´s zum Erstgespräch - im Juli 2021 gibt es auf alle Coachingprogramme 10% Nachlass + eine Extrawoche Coaching geschenkt! Du willst nicht lange fackeln und direkt starten? Dann bitte hier entlang (Umbuchungen jeder Zeit auch nach Start möchtlich!): => direkt zum Kurs "Abnehmen mit der 5-Klick-Methode von Anke" Hier findest Du meine Facebookgruppe nur für Frauen: www.facebook.com/groups/abnehmenalsfrau/ Zu meiner öffentlichen Facebookgruppe zum Podcast: https://www.facebook.com/groups/abnehmenalltagstauglich Zum Download der Liste mit Lebensmitteln für unterwegs + Zusammenfassung meiner Tipps aus Episoden #171 und #172 => bitte hier entlang (klick): Liste mit Lebensmitteln, die Du unterwegs kaufen kannst + alltagstaugliche Abnehmtipps Zur heutigen Episode: Gewohnheiten, die sich jahrzehntelang in unser Gehirn eingebrannt haben, lassen sich nicht so einfach abstellen. Das ist klar! Die Frage, die Du Dir jedoch stellen darfst: Tun meine Gewohnheiten mir gut, oder schaden sie mir? Möchte ich einfach nur jammern, oder habe ich ein klares Ziel vor Augen? Bist Du bereit, wirklich etwas zu verändern? Hör dir dazu diese Podcastepisode an... Musik: Awaken by Mrpetelee Rzd5 | soundcloud.com/mrpeteleerzd5official Music promoted by www.free-stock-music.com Creative Commons Attribution-ShareAlike 3.0 Unported creativecommons.org/licenses/by-sa/3.0/deed.en_US

Alejandro Badia, MD, FACS, FRCSI is a hand and upper extremity surgeon, author and healthcare entrepreneur in Doral (Miami), Florida.Badia studied physiology at Cornell University and obtained his medical degree at NYU, where he also trained in orthopedics. A hand fellowship at Alleghany General Hospital in Pittsburgh was followed by an AO trauma fellowship in Freiburg, Germany. He runs an international hand fellowship, served on the review board of a hand surgery techniques journal, and previously organized a yearly Miami meeting for surgeons /therapists devoted to upper limb arthroscopy and arthroplasty. This international meeting was held at the renowned Miami Anatomical Research Center  ( M.A.R.C. ) which Badia co-founded in 2005.In 2008 he created the Badia Hand to Shoulder Center, having previously co-founded the Miami Hand Center, and Surgery Center at Doral.In 2010 he launched OrthoNOW®, the first immediate orthopedic care center in south Florida, later franchising the concept which can now be licensed to orthopedic colleagues and healthcare systems and currently seeking the optimal strategic healthcare partner.He is past president of the International Society for Sport Traumatology of the Hand (ISSPORTH) is a member of several orthopedic societies (AAOS, ASSH, AAHS, EWAS), honorary member of more than 10 international hand surgery and arthroscopy associations, and served as honored professor at the prestigious Philadelphia Hand Course in 2012. Having lectured in all seven continents he is currently focused on improving healthcare delivery in the orthopedics and sports medicine realm.Dr Badia has outlined his journey and delved into the major challenges and hurdles of delivering healthcare in the U.S. through his Amazon best-selling book, “Healthcare from the Trenches” published during the Covid19 pandemic.Follow Knowledgeable Aging:Facebook: https://www.facebook.com/Knowledgeable-Aging-102638398162823Twitter: https://twitter.com/KnowledgeAgingInstagram: https://www.instagram.com/knowledgeableaging/LinkedIn: https://www.linkedin.com/company/knowledgeable-aging/?viewAsMember=trueSpotify: https://open.spotify.com/show/05OHF9FkmhzCO5PDsyGfGqNewsletter: https://www.knowledgeableaging.com/newsletter/

Twin studies, GWAS, TWAS, EWAS and more - In this episode, Joseph takes you through 20 papers published in February 2021 that explore novel genes or variants associated with Alzheimer's Disease, studied associations of novel pathways to AD or link molecular pathways of other diseases to AD.  Sections in this episode:  Comorbidities and other conditions (1:28)  Identification and Validation of Risk Genes and Loci (9:10)  Changes in the Brain (21:02)  New Tools Development (26:01)  Miscellaneous (29:42) --------------------------------------------------------------You can find the bibliography for this episode by clicking here. To access the folder with all the bibliographies for 2021 so far, follow this link (it will be updated as we publish episodes and process bibliographies), or click the following link below:https://drive.google.com/drive/folders/1N1zx_itPkCDNYE1yFGZzQxDDR-NiRx3p?usp=sharingYou can also join our mailing list to receive a newsletter once per month by filling this form. Or tweet at us: @AMiNDR_podcast  --------------------------------------------------------------We would appreciate your feedback so we can better cater to your needs.  You can fill our feedback form here:    https://forms.gle/5aq2JyrT6g4P1m8v6 You can also share your thoughts and suggestions by contacting us:  Email: amindrpodcast@gmail.com  Facebook:  AMiNDR  Twitter: @AMiNDR_podcastInstagram: @AMiNDR.podcastYoutube: AMiNDR Podcast--------------------------------------------------------------We would like to thank our amazing team for all of the work that goes into every episode of AMiNDR. Today's episode was scripted, hosted and edited by Joseph Liang. The bibliography was created by Jacques Ferreira and the wordcloud was generated by Sarah Louadi (www.wordart.com). Big thanks to sorting manager Elyn Rowe and the rest of the sorting team for sorting all the papers published in January into themes for our episodes, and to our managers Sarah Louadi, Ellen Koch and Anusha Kamesh, for keeping everything running smoothly.Our music is from "Journey of a Neurotransmitter" by musician and fellow neuroscientist Anusha Kamesh; you can find the original piece and her other music on soundcloud under Anusha Kamesh or on her YouTube channel, AKMusic.   https://www.youtube.com/channel/UCMH7chrAdtCUZuGia16FR4w   -------------------------------------------------------------- If you are interested in joining the team, send us your CV by email. We are specifically looking for help with sorting abstracts by topic, abstract summaries and hosting, creating bibliographies, and promotions. However, if you are interested in helping in other ways, don't hesitate to apply anyways.  --------------------------------------------------------------*About AMiNDR: *  Learn more about this project and the team behind it by listening to our first episode: "Welcome to AMiNDR!"  

Wir sprechen über verschiedene Wege, ein "IT-Fuzzy" zu werden.

This episode’s Community Champion Sponsor is Ensemble Health Partners. To learn more about their inspiring work: https://www.ensemblehp.com/ (CLICK HERE) --- Americans are facing serious problems with our healthcare system- skyrocketing costs, a lack of patient access, and inefficient delivery. Despite all the political debates and media coverage on healthcare policy and reform, there is typically one glaring omission: feedback from the people in the trenches- the doctors, nurses and other healthcare professionals who provide care to the patients. To shed light on these critically important issues, we are joined by Dr. Alejandro Badia, Chief Medical Officer of OrthoNow and author of the acclaimed book, Healthcare from the Trenches. Dr. Badia shares his personal journey of becoming a national-leading orthopedic surgeon and why he is so dedicated to scaling his healthcare delivery model.  Join us to hear Dr. Badia’s powerful message for every American to understand the root causes of our healthcare crisis and demand meaningful reform. Episode Highlights: Dr. Badia’s dreams of being a surgeon as a child Dr. Badia’s journey in orthopedics The faults in the US Healthcare system The lack of innovation and healthy competition in healthcare Red tape holding back healthcare from patients Why Alejandro wrote his book, “Healthcare from the Trenches” About our Guest:  Alejandro Badia, MD, FACS, FRCSI is a hand and upper extremity surgeon at Badia Hand to Shoulder Center in Doral, Florida. Badia studied physiology at Cornell University and obtained his medical degree at NYU, where he also trained in orthopedics. A hand fellowship at Alleghany General Hospital in Pittsburgh was followed by an AO trauma fellowship in Freiburg, Germany. He runs an international hand fellowship, served on the review board of a hand surgery techniques journal, and previously organized a yearly Miami meeting for surgeons /therapists devoted to upper limb arthroscopy and arthroplasty. This international meeting was held at the renowned Miami Anatomical Research Center ( M.A.R.C. ) which Badia co-founded in 2005.  In 2008 he created the Badia Hand to Shoulder Center and Surgery Center at Doral while in 2010, he launched OrthoNOW®, the first immediate orthopedic care center in South Florida, later franchising the concept which can now be licensed to orthopedic colleagues and healthcare systems. He is past president of the International Society for Sport Traumatology of the Hand (ISSPORTH) is a member of several orthopedic societies (AAOS, ASSH, AAHS, EWAS), honorary member of more than 10 international hand surgery and arthroscopy associations, and served as an honored professor at the prestigious Philadelphia Hand Course in 2012. Having lectured in all seven continents he is currently focused on improving healthcare delivery in the orthopedics and sports medicine realm. Dr. Badia has outlined his journey and delved into the major challenges and hurdles of delivering healthcare in the U.S. through his Amazon best-selling book, “Healthcare from the Trenches” published during the Covid19 pandemic.  Links Supporting This Episode: “Healthcare from the Trenches” website: https://healthcarefromthetrenches.com/ (CLICK HERE) Dr. Alejandro Badia LinkedIn page: https://www.linkedin.com/in/drbadia/ (CLICK HERE) Dr. Alejandro Badia Twitter page: https://twitter.com/drbadia (CLICK HERE) Visit our website: https://www.passionatepioneers.com/ (CLICK HERE) Subscribe to newsletter: https://forms.gle/PLdcj7ujAGEtunsj6 (CLICK HERE) Guest nomination form: https://docs.google.com/forms/d/e/1FAIpQLScqk_H_a79gCRsBLynkGp7JbdtFRWynTvPVV9ntOdEpExjQIQ/viewform (CLICK HERE) Support this podcast

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.22.215939v1?rss=1 Authors: van Dongen, J., Hagenbeek, F. A., Suderman, M., Roetman, P. J., Sugden, K., Chiocchetti, A. G., Ismail, K., Mulder, R. H., Hafferty, J., Adams, M. J., Walker, R., Morris, S., Lahti, J., Kupers, L. K., Escaramis, G., Alemany, S., Bonder, M. J., Meijer, M., Ip, H. F., Jansen, R., Baselmans, B. M. L., Parmar, P., Lowry, E., Streit, F., Sirignano, L., Send, T., Frank, J., Jylhava, J., Wang, Y., Mishra, P. P., Colins, O. F., Corcoran, D., Poulton, R., Mill, J., Hannon, E., Arseneault, L., Korhonen, T., Vuoksimaa, E., Felix, J., Bakermans-Kranenburg, M., Campbell, A., Czamara, D., Binder, E., Corpel Abstract: DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N=15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha=1.2x10-7; Bonferroni correction). In cord blood samples of 2,425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r=0.74, p=0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripherl blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range=3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits. Copy rights belong to original authors. Visit the link for more info

Jane Ferguson:                  Hi there. Welcome to Getting Personal: Omics of the Heart, the podcast from Circulation: Genomic and Precision Medicine. I'm Jane Ferguson, and this is Episode 36 from February 2020.                                                 First up, we have “Identification of Circulating Proteins Associated with Blood Pressure Using Mendelian Randomization” from Sébastien Thériault, Guillaume Paré, and colleagues from McMaster University in Ontario. They set out to assess whether they could identify protein biomarkers of hypertension using a Mendelian randomization approach. They analyzed data from a genome-wide association study of 227 biomarkers which were profiled on a custom Luminex-based platform in over 4,000 diabetic or prediabetic participants of the origin trial.                                                 They constructed genetic predictors of each protein and then used these as instruments for Mendelian randomization. They obtained systolic and diastolic blood pressure measurements in almost 70,000 individuals, in addition to mean arterial pressure and pulse pressure in over 74,000 individuals, all European ancestry with GWAS data, as part of the International Consortium for Blood Pressure.                                                 Out of the 227 biomarkers tested, six of them were significantly associated with blood pressure traits by Mendelian randomization after correction for multiple testing. These included known biomarkers such as NT-proBNP, but also novel associations including urokinase-type plasminogen activator, adrenomedullin, interleukin-16, cellular fibronectin and insulin-like growth factor binding protein-3. They validated all of the associations apart from IL-16 in over 300,000 participants in UK Biobank. They probed associations with other cardiovascular risk markers and found that NT-proBNP associated with large artery atherosclerotic stroke, IGFBP3 associated with diabetes, and CFN associated with body mass index.                                                 This study identified novel biomarkers of blood pressure, which may be causal in hypertension. Further study of the underlying mechanisms is required to understand whether these could be useful therapeutic targets in hypertensive disease.                                                 The next paper comes from Sony Tuteja, Dan Rader, Jay Giri and colleagues from the University of Pennsylvania and it's entitled, “Prospective CYP2C19 Genotyping to Guide Antiplatelet Therapy Following Percutaneous Coronary Intervention: A Pragmatic Randomized Clinical Trial”.                                                 They designed a pharmacode genomic trial to assess effects of CYP2C19 genotyping on antiplatelet therapy following PCI. Because loss of function alleles in CYP2C19 impair the effectiveness of clopidogrel, the team were interested in understanding whether knowledge of genotype status would affect prescribing in a clinical setting. They randomized 504 participants to genotype guided or usual care groups and assessed the rate of prasugrel or ticagrelor prescribing in place of clopidogrel within each arm. As a secondary outcome, they assessed whether prescribers adhere to genotype guided recommendations. Of genotyped individuals, 28% carried loss of function alleles. Within the genotype guided group overall, there was higher use of prasugrel or ticagrelor with these being prescribed to 30% of patients compared with only 21% in the usual care group. Within genotype individuals carrying loss of function alleles, 53% were started on prasugrel or ticagrelor, demonstrating some adherence to genotype guided recommendations.                                                 However, this also meant that 47% of people whose genotype suggested reduced effectiveness were nevertheless prescribed clopidogrel. This study highlights that even when genotype information is available, interventional cardiologists consider clinical factors such as disease presentation and may weight these more highly than genotype information when selecting antiplatelet therapy following PCI.                                                 The next paper is about “Deep Mutational Scan of an SCN5A Voltage Sensor and comes to us from Andrew Glazer, Dan Roden and colleagues from Vanderbilt University Medical Center. In this paper, the team aim to characterize the functional consequences of variants and the S4 voltage sensor of domain IV and the SCN5A gene using a high throughput method that they developed. SCN5A encodes the major voltage gated sodium channel in the heart and variants in SCN5A can cause multiple distinct genetic arrhythmia syndromes, including Brugada syndrome, long QT syndrome, atrial fibrillation, and dilated cardiomyopathy, and have been linked to sudden cardiac death.                                                 Because of this, there's considerable interest in understanding the functional and clinical consequences of different variants, but previous approaches were time consuming and results were often inconclusive with many variants being classified as uncertain significance. This newly developed deep mutational scanning approach allows for simultaneous assessment of the function of thousands of variants, making it much more efficient than low throughput patch clamping. The team assessed the function of 248 variants using a triple drug assay in HEK293T cells expressing each variant and they identified 40 putative gain of function and 33 putative loss of function variants. They successfully validated eight of nine of these by patch clamping data. Their study highlights the effectiveness of this deep mutational scanning approach for investigating variants in the cardiac sodium channel SCN5A gene and suggests that this may also be an effective approach for investigating putative disease variants and other ion channels.                                                 The next article is a research letter from Connor Emdin, Amit Khera, and colleagues from Mass General Hospital in the Broad Institute entitled, “Genome-Wide Polygenic Score and Cardiovascular Outcomes with Evacetrapib in Patients with High-Risk Vascular Disease: A Nested Case-Control Study”. In this study, the team set out to probe the utility of using polygenic risk scores to predict the risk of major adverse cardiovascular events within individuals already known to be at high cardiovascular risk and to assess whether genetic scores can identify individuals who would benefit from the use of a CETP inhibitor such as Evacetrapib. They analyze data from the ACCELERATE trial which had tested Evacetrapib in a high risk population, and they found no effect on the incidents of major adverse cardiovascular events overall. Within a nested case-control sample of individuals experiencing major CVD events versus no events, they applied a polygenic risk score and found that the score predicted major cardiovascular events.                                                 Patients in the highest quintile of the risk score were at 60% higher risk of a major cardiovascular event than patients in the lowest quintile. There was no evidence of any interaction between the genetic risk score and Evacetrapib. These data suggest that genetic risk scores may have utility in identifying individuals at high risk events but may not have utility in identifying individuals who may derive more benefit from CETP inhibition. The next letter concerns “Epigenome-Wide Association Study Identifies a Novel DNA Methylation in Patients with Severe Aortic Valve Stenosis” and comes from Takahito Nasu, Mamoru Satoh, Makoto Sasaki and colleagues from Iwate Medical University in Japan. They were interested in understanding whether differences in DNA methylation could underlie the risk of aortic valve stenosis. They conducted an EWAS or epigenome-wide association study of peripheral blood mononuclear cells or PBMCs from 44 individuals with aortic stenosis and 44 disease free controls.                                                 They collected samples at baseline before a surgical intervention in the individuals with aortic stenosis and collected a follow-up sample one year later. They found that DNA methylation at a site on chromosome eight mapping to the TRIB1, or tribbles homolog one gene, was lower in the aortic stenosis group than in the controls at baseline. They replicated the association in an independent sample of 50 cases and 50 controls. TRIB1 MRNA levels were higher in the aortic stenosis group than the controls. When they looked at methylation status one year after aortic valve replacement or a transcatheter aortic valve implantation in patients with stenosis, they found that DNA methylation had increased in the cases while TRIB1 MRNA decreased. These data suggests that methylation status of TRIB1 and expression of TRIB1 may relate to the disease processes in aortic stenosis such as hemodynamic dysregulation and they can be reversed through surgical intervention. Changes in the methylation status of TRIB1 could be a novel biomarker of response to aortic valve replacement.                                                 The next letter comes from Niels Grote Beverborg, Pim van der Harst, and colleagues from University Medical Center Groningen and is entitled, “Genetically Determined High Levels of Iron Parameters Are Protective for Coronary Artery Disease”. Their study addresses the conflicting hypotheses that high iron status is either deleterious or protective against cardiovascular disease. The team constructed genetic predictors of serum iron status using 11 previously identified snips and tested the genetic association with CAD in UK Biobank data from over 408,000 white participants. Overall, the genetic score for higher iron status was associated with protection against CAD. Ten of the snips suggested individual neutral or protective effects of higher iron status on CAD, while one iron increasing snip was associated with increased risk of disease but this was thought to be likely through an iron independent mechanism. Overall, these data suggest that a genetic predisposition to higher iron status does not increase risk of CAD and is actually protective against disease.                                                 The final letter is entitled, “Confidence Weighting for Robust Automated Measurements of Popliteal Vessel Wall MRI” and comes from Daniel Hippe, Jenq-Neng Hwang, and colleagues from the University of Washington. They were interested in assessing whether images of popliteal artery wall incidentally obtained during knee MRI as part of an osteoarthritis study could be used to study the development and progression of atherosclerosis. They developed an automated deep learning based algorithm to segment and quantify the popliteal artery wall in images obtained over 10 years in over 4,700 individuals. Their approach, which they named FRAPPE, or fully automated and robust analysis technique for popliteal artery evaluation, was able to reduce the average time required for segmentation analysis from four hours to eight minutes per image. They applied weights based on confidence for each segment to automatically improve the accuracy of aggregate measurements such as mean wall thickness or mean lumen area. Their data suggest that this automated method can rapidly generate useful information on atherosclerosis from MRI images obtained as part of other studies. When combined with other data. This approach may facilitate novel discovery in secondary analyses of existing studies in an efficient and cost effective way.                                                 And that's all for issue one of 2020. Come back next time for more of the latest papers from Circulation: Genomic and Precision Medicine. Speaker 2:                           This podcast is copyright American Heart Association 2020.  

This month on Episode 9 of the Discover CircRes podcast, host Cindy St. Hilaire highlights four featured articles from the January 31 and February 14, 2020 issues of Circulation Research and talks with Dr Joe Miano and DrThomas Quertermous about their article Coronary Disease-Associated Gene TCF21 Inhibits Smooth Muscle Cell Differentiation by Blocking the Myocardin-Serum Response Factor Pathway.   Article highlights:   Wang, et al. Multi-Omics Integration Study of AF   Heianza, et al. Antibiotics and Risk of Mortality   Dikalova, et al. Sirt3 Reduces Hypertension and Vascular Dysfunction   Hu, et al. Lipid Overload Acetylates Drp1 in the Heart Transcript Dr St. Hilaire: Hi, welcome to Discover CircRes, the podcast of the American Heart Association's journal, Circulation Research. I'm your host, Dr Cindy St. Hilaire, and I'm from the Vascular Medicine Institute at the University of Pittsburgh. Today I'm going to share with you four articles that we selected from the January 31st and February 14th issues of Circulation Research. I'm also going to have a discussion with corresponding authors, Drs. Joe Miano and Thomas Quertermous about their study on the role of TCF21 and smooth muscle cell lineage specificity in coronary artery disease. So first, the highlights. The first article I'm sharing with you is titled, Integrative Omics Approach to Identifying Genes Associated with Atrial Fibrillation. First author is Biqi Wang, and the corresponding author is Honghuang Lin from Boston University School of Medicine in Boston, Massachusetts. Atrial fibrillation, or Afib, is the most common form of heart arrhythmia and in the US alone there's somewhere between three and six million individuals with this condition. AFib can be either idiopathic or inherited, and genome-wide association studies, or GWAS studies, have identified hundreds of genetic loci that are linked to AFib. However, these loci explained only a small percentage of inherited cases. This suggests that there are many more AF related genes yet to be discovered. To try and identify these elusive a-fibrillated loci, this study integrated data from previously performed transcriptome, epigenome and GWAS studies. The TWAS and EWAS, as the transcriptome and epigenome-wide studies are short-handedly called, was collected from more than 150 Afib patients, and over 2,000 control individuals. While existing GWAS data, that's genomic data, was collected from tens of thousands of AFib and control participants. By combining and analyzing the data from these TWAS, EWAS, AND GWAS studies, the team was able to identify an additional 1700 genes that were associated with AFib. Now this is compared to the original 206 loci that were identified by the GWAS studies alone. Many of these new genes are involved in cardiac development as well as the regulation of the heart and the muscle cells. The additional gene hunting power afforded by co-analyzing multiple Omics data is not only helpful for approaching AFib but is really setting a platform upon which future studies might be done to provide novel insights for numerous other diseases of complex ideology. The second article I will highlight is titled, Duration and Life-Stage of Antibiotic Use and Risks of All-Cause and Cause-Specific Mortality, a Prospective Cohort Study. The first author is Yoriko Heianza, and the corresponding author is Lu Qi from Tulane University in New Orleans, Louisiana. So microbiome is a word that is used to describe all of the microbes; the bacteria, the fungi, the protozoa, and the viruses that live on and also live inside the human body. And how our microbiome influences human health as well as disease state is a new and hot research topic. Alterations to the gut microbiome have been suggested to influence the risk of developing certain chronic diseases, including cancer and cardiovascular disease. There are many factors that influence the constituents of the gut microbiome; things such as your diet, your environment, your stress level, but another factor that can significantly alter the gut microbiome is the use of antibiotics. So there's preliminary evidence that suggests long-term antibiotic use may be linked to increased mortality in adult women, and now this study defined that link in more detail. The authors performed a large-scale population study of antibiotic use in middle aged and older women with a follow up period of 10 years. Over 37,000 women who were in middle age or in late age at the start of the study show that long durations of antibiotic use, which was defined as using antibiotics over two or more months, was associated with increased risk of all-cause mortality and of cardiovascular disease-related mortality in late adulthood, even after adjusting for risk factors such as age, lifestyle, diet and obesity. While no such association was apparent in middle-aged women, the risk for older women was more pronounced if they had also used antibiotics during middle life. And middle life is defined as between the age of 40 and 59 years of age. This suggests that risk of mortality due to antibiotic use may be cumulative. While antibiotics are unquestionably beneficial for saving lives, the link is not necessary causative, and the results indicate a potential risk may exist that could be factored into prescription decisions. Obviously, there's much more details that need to be worked out, but this is quite a provocative study. While antibiotics unquestionably saved lives and the link is not necessarily causative, the results indicate a potential risk may exist that could be factored into prescription decisions. Moving to a metabolism theme, the next article I want to share with you is titled, Mitochondrial Deacetylase Sirt3 Reduces Vascular Dysfunction and Hypertension While Sirt3 Depletion in Essential Hypertension Is Linked to Vascular Inflammation and Oxidative Stress. The first author is Anna Dikalova and the corresponding author is Sergey Dikalov, and the work was completed at Vanderbilt University. Hypertension affects about a third of the global adult population. That's a huge number of individuals. It's a risk factor for stroke, myocardial infarction and heart failure. Although blood pressure lowering treatments are widely available, hypertension remains uncontrolled in about 30% of patients who are on those treatments. A thorough understanding of the complex pathophysiology of the condition would facilitate the search for much needed alternate treatments for this third of patients with hypertension. To that end, these investigators studied the role of Sirt3, which is an enzyme that tends to be at the lower than usual levels in blood vessels of patients with hypertension. Sirt3 regulates metabolic and antioxidant functions, and alterations in either of these functions can contribute to cardiovascular disease and vascular dysfunction. The team showed that mice genetically engineered to over express Sirt3 had healthier blood vessels and lower blood pressure than control animals who were subjected to experimentally induced hypertension. By contrast, Sirt3 depletion was shown to cause vascular inflammation and increased signs of vascular aging in mice. The team also confirmed that humans with hypertension exhibit low levels of Sirt3; however, the mechanism causing Sirt3 to be low in certain people is not clear. These data suggest that boosting Sirt3 may be potential therapy for hypertension; however, of course, more studies must be conducted to thoroughly investigate this. The last article I want to share with you before we switch to our interview is titled, Increased Drp1 Acetylation by Lipid Overload Induces Cardiomyocyte Death and Heart Dysfunction. The first author is Qingxun Hu and the corresponding author is Wang from the University of Washington School of Medicine in Seattle, Washington. In the heart, fat molecules are the main energy source. However, excessive lipids caused from diet induced dyslipidemia, AKA eating too much fat, can lead to cardiomyocyte dysfunction. It's known that lipid overload in the heart can cause increased activity of dynamin-related protein one, or Drp1. Drp1 is an enzyme that regulates mitochondrial fission, but exactly how Drp1 becomes activated due to lipid overload is entirely unclear. The authors of this paper confirmed that Drp1 activity and mitochondrial fission are abnormally increased in the hearts of mice fed a high-fat diet, and these mice also exhibit signs of heart dysfunction. They show similar effects in monkeys who were fed a high-fat diet. Interestingly, Drp1 mRNA was not altered in the hearts of mice. However, Drp1 protein acetylation was increased. So this suggests post-translational modifications are regulating its activity in dyslipidemia. The team went on to perform experiments on cultured rat cardiomyocytes, and they found that incubation with saturated fatty acid palmitate led to the acetylation of Drp1, and thus its activation. And this activation resulted in an excess of mitochondrial fission, which reduced cell viability. By contrast, mutation of Drp1 to prevent its acetylation protected the cells. Together, the results reveal the mechanism of how dyslipidemia can contribute to heart cell dysfunction. Further, this data suggests that Drp1 activity or acetylation state could be novel targets for treating obesity-related heart disease. Okay, we're now going to switch over to the interview portion of the podcast. I have with me Dr Thomas Quertermous, the William G Erwin Professor of Medicine and the Director of Research in the division of cardiovascular medicine at Stanford University. And Dr Joe Miano, Professor and Jay Harold Harrison Distinguished University Chair in vascular biology at the Medical College of Georgia at Augusta University. And today we're going to be discussing their manuscript titled Coronary Disease Associated Gene TCF21 Inhibits Smooth Muscle Cell Differentiation by Blocking the Myocardin-Serum Response Factor Pathway. So welcome to both of you. Thank you for joining me. Dr Miano: Thank you. Dr Quertermous: Thank you. Dr St. Hilaire: So I'm going to start with you, Dr Quertermous. You've been taking a genomics approach to identify factors that contribute to coronary artery disease. And I'm wondering if you could just give us a brief summary of your work thus far and how it brought you to this current study? Dr Quertermous: Well, as you know, the classical risk factors for coronary artery disease and vascular disease in general really only contribute about 30% of the total risk and the remainder has not been studied, and not been investigated, and can't currently be targeted by therapeutics. So the goal is to try and better understand what are the molecular mechanisms in the blood vessel wall that must contribute the remainder of the risk. And so with the advent of genome-wide association studies and the identification of genes and loci, we've been able to begin to uncover the signaling pathways and mechanisms of disease risk. Dr St. Hilaire: And so the one we're most interested in today, this TCF21, you pulled that up out of one of your GWA studies, or how did we get to this? Dr Quertermous: Well, it's an interesting story. I first cloned that gene about 15 years ago when I was trying to understand vascular development, and it's a basic helix loop helix factor, and I was, well, a number of labs at that point in time were cloning this class of transcription factor to try and better understand developmental processes, and so it was one of a number of bHLH proteins that we cloned at the time. I did some work on it and then named it Pod-1 at that point in time, and then lost interest, and went away from it. And then I was involved in the cardiogram genome-wide association study for coronary artery disease, and I was sitting at my desk one night, and I was watching the hits coming in, you know, as we were doing the association, as we were doing the analysis, and I saw this gene, TCF21, and I thought, "Well, I don't really know what the heck that gene is." And so I was going back and forth between our data and a spreadsheet on the web, and I saw that I had published on this gene, and I was like, "Wow, I didn't even know that I had written a paper about this gene." And then it became clear that it was the bHLH factor I'd cloned some time ago. And then knowing what I knew about the development, that this gene is involved in early processes that lead to the formation of the coronary artery, and in particular the development of smooth muscle cells, then I became super interested, and I said, "Okay, my gene, I'm coming back to you. You and me are going to have a great future together." And that was really how I got started. Dr St. Hilaire: It re-found you. Dr Quertermous: It found me, I guess in this case, yes, and so I began then to work very seriously, because it's hard to try and understand mechanisms. And so we had a good starting point. We had a transcription factor so I could quickly identify the targets downstream of that, and I can link it into some cell biology that I already had some insights into. Dr St. Hilaire: That's a really neat story. I like that. It's kind of penicillin-esque. Dr Quertermous: Thank you. Dr St. Hilaire: Dr Miano, those of us familiar with smooth muscle cells appreciate that they are plastic, that they have this ability to kind of switch their phenotypes per se, and those of us familiar with that also then know about the myocardin and serum response factor pathway. But for our listeners who are less familiar with that, could you maybe give a brief background about what myocardin SRF pathway is and what smooth muscle cell phenotype modulation is? Dr Miano: Sure. I wish I could say, as my colleague said, that I cloned one of those factors, but I didn't. I've been interested in SRF since I was a graduate student actually. Actually went to Eric Olson's lab to look for what we affectionately called back then SmyoD, which stands for smooth muscle myo D. So at that time, we didn't understand what the factors were, even the signaling, that directed cells to become differentiated smooth muscle cells. So I went to Eric's lab looking for SmyoD. Of course I didn't find it. I found some other things. Worked a little bit on SRF, but it was actually Daiju Wong in 2000 or 2001 who in a Cell paper described an elegant a way of finding myocardin, what he called myocardin. So SRF myocardin is a transcriptional switch that is necessary and sufficient to make just about any cell a smooth muscle cell. So when myocardin is not present, then smooth muscle cells lose their differentiated state and they become another cell type, depending on who SRF talks to. And so how does a factor that binds a very discrete element like the CArG box, how does it confer cell identity or specific cell states? And it does so through its interaction with these cofactors, one of which is myocardin. And as this paper describes so elegantly, what Tom did in his lab, is that this TCF1 transcription factor, which is DNA binding, unlike myocardin, it does a similar thing in that it competes for SRF binding with myocardin, so it binds myocardin, prevents myocardin's ability to bind SRF, and thereby directs a new program of gene expression. Dr St. Hilaire: Interesting. So it's kind of helping to fine tune that transcriptional regulation. So I always think of smooth muscle cells, they're kind of always in a contractile state when they're healthy, and it's when they're in either unhealthy, or diseased, or a stress state that they're in that more proliferative-like state. And Dr Quertermous, your previous studies have shown that TCF21 is required for the De-differentiation, and proliferation, and migration of smooth muscle cells. However, there was one sentence in the paper that I was slightly confused on and I'm hoping that you can expand about the bigger role of TCF21. And what it said was that TCF21 expression is protective towards human coronary artery disease. And so the data in the paper show that TCF21 inhibits smooth muscle cell contractility. So can you maybe reconcile the bigger mutations or things you identified in the GWAS with the functional activities you're seeing that you presented in the paper, and maybe talk about the timeline in the continuum of atherosclerosis where TCF is maybe good or maybe bad? Dr Quertermous: So this paper is one of a duo of papers, honestly, that the other paper being published in Nature Medicine almost exactly the same time, and so that paper sort of described some of the aspects of TCF21 at a population level and shows that if you look at all of the single base pairs in the genome that regulate disease risk at 6q23.2 and also regulate expression, you can gain an idea of what's the directionality of the expression of TCF21. And those data suggests that the more TCF21 you have, the less your risk of developing coronary artery disease. And Joe and other scientists have worked for a long, long time to characterize this process and characterize the plasticity of this cell type. And note that one can switch the cell back and forth between being a contractile0differentiated cell to a de-differentiated cell, and elegant work by Gary Owens and a number of investigators have profiled the phenotype of the cells that the smooth muscle cell can become if it undergoes this differentiation process. It's not been able to know though up until this point in time whether that's a good process or a bad process. I mean, 15, 10 years ago we thought smooth muscle cells are proliferating, they're creating a space-occupying lesion, they're decreasing the lumen of the blood vessel, and that's got to be a bad thing. And in honesty, I think over the past three or four years, it's been increasingly clear that perhaps the smooth muscle cells are actually doing a good thing. They are stabilizing the lesion, they're creating the fibrous cap, and there's been some nice work correlating the number of smooth muscle cells in the plaque to the risk that that plaque is going to rupture. Dr St. Hilaire: Yeah, that was kind of my next question. Do you think there's more nuance to it's not just contractile, and synthetic? There's much more broader scope and it's not so much a good or a bad smooth muscle cell. Dr Quertermous: I think it depends on the circumstances I guess, but it's important that the smooth muscle cell be able to migrate into the plaque, and begin to produce matrix components which stabilize the plaque, and to form the fibrous cap, and I think if the smooth muscle cell remains in the media as a contractile cell, it's really not able to do those things, right? And so the human genetics data, looking at the directionality, the expression, the different alleles and their expression patterns, and what is the risk allele at? In this region of the genome, it's pretty clear that more TCF21 is good, and what TCF21 does is to promote this phenotypic modulation. And so that suggests that the process as a whole is good. Not just the gene, but what it does. It's really not possible that TCF21 does anything else in the blood vessel wall. It's primarily restricted to the smooth muscle cell. It's not expressed in macrophages, or endothelial cells, or the other cell types that we think are important in the pathophysiology of the disease process. So putting everything together, it looks for the most part, like this is a positive force in the blood vessel wall, this gene and this process. Dr St. Hilaire: Interesting. And speaking to the vessel wall, I thought one of the very cool and really key experiments in the paper was taking your mechanistic in vitro studies into the mouse, and Dr Miano, maybe you could tell us a little bit about how you were able to do that and mutate these smooth muscle specific CArG boxes in a mouse model. Dr Miano: Well, that's a really good question. Again, it's a history. We've wanted to edit CArG boxes, well, mutate back then, for a long, long time, but it wasn't until the CRISPR craze took a foothold that we really recognize now the power of harnessing that and doing the experiments we wanted to do for so long. And so we've previously published on a CArG box in the first intron of the calponin locus, and found that, to our surprise, that a subtle mutation in that element completely abolished expression of calponin into the smooth muscle. So Tom and I were working in parallel and unbeknownst to me, Tom was working on this SRF enhancer in the second intron, and we've known for quite a while that SRF is auto regulated by itself, and there's CArG boxes in it 5-prime promoter, and there's CArG boxes in the interior of the locus as well, including the one in the second intron that Tom describes in the paper here. And so what we've been doing is using CRISPR in the mouse to make these subtle edits in these CArG boxes around the SRF locus. And unlike the affirmation calponin model I just described, if we mutate the two proximal CArG boxes of SRF, we don't see a lot of change in SRF expression. That was really surprising to us, because studies from Bob Schwartz' lab in Houston two decades ago showed those were important, at least in an artificial reporter assay for the autoregulatory loop that he first described. So we moved interior to this CArG box that's really the focus of this paper, highly conserved, much more so than other CArG boxes, and we first deleted the region, which we often do with CRISPR, and found there was a decrease. But we'd like to do more subtle things with CRISPR, which is really the power of this new editing technology. And so we went in and made just, I think it was like four or five base substitutions to create a novel restriction cipher ease in genotyping. And we reported in the paper, you can see that, to compliment Tom's group's data, that in vivo, indeed, that CArG box by itself, nothing else altered within the locus, did cause a, I would call, a substantial decrease in expression of this important regulator. And so that was really our main contribution to this paper. Dr St. Hilaire: Yeah. I know the opportunities are endless, but also complicated and expensive, and I thought this was a beautiful addition to really confirming those mechanistic studies. So I think my next big question is, if TCF21 is,  so important and protective, and perhaps it's upregulation is beneficial, what is regulating it, and do we know how we can potentially modulate this? Dr Quertermous: That's a great question. That's a great question. And so we know a few things; we certainly know that platelet-derived growth factor stimulation of smooth muscle cells will upregulate TCF21, which is sort of surprising. I mean, it's not so surprising, I guess. So we've spent a little time working on that, and there's a micro RNA which regulates the expression level of TCF21, but we haven't spent a lot more time than that, honestly. We spent a lot more time downstream trying to figure out what's the mechanism by which TCF21 works to suppress the smooth muscle contractile phenotype and activate this more de-differentiated migratory phenotype that the smooth muscle cell adopts. So we've not gone upstream, but your question's a really, really good one. We certainly mapped where TCF21 binds across the genome and we've mapped the variation that regulates its expression, and so we've made progress in that direction, and as I said, identified things which are downstream. But we definitely need to spend more time upstream, and I think that's the area of this intersection of molecular science and genomic science, that there are not many groups that really spend much time up above the gene trying to understand. And so we've not spent enough time doing that, and I think that as a community we've not spent enough time doing that, because I think that's where the big payoff can come in terms of therapeutics. Dr St. Hilaire: To that end, I think I'll end with that question. What do you think is the best way that we could leverage your findings in the clinic? Would it be to focus more on the downstream or to try to identify these more upstream factors in TCF21? Dr Quertermous: Well, I think both open up opportunities, right? If we can understand how TCF21 works and what's downstream, and we can activate those processes and activities, then that's good. If we can figure out what's above TCF21, that would be good as well. The danger there is that TCF21 does a lot of things in a lot of different cells in the body. Dr St. Hilaire: So it'd be a little bit harder to focus onto a smooth muscle cell in a plaque than perhaps some of the downstream effects of TCF21? Dr Quertermous: Correct. Right. That's my worry. It's sort of like thinking about TGF beta and you wouldn't really want to try and manipulate TGF beta. Dr St. Hilaire: That's a whole another can of worms. Dr Quertermous: Yeah, it gets you into a lot of difficulties, I think. So we're really pretty focused downstream now and thinking that we can find specific opportunities there that are resident in that smooth muscle cell in the blood vessel that may not be active in other cell types. So that's really our thinking and that's the way we're going. Dr St. Hilaire: Wonderful. Well, thank you so much to both of you for joining me today. I learned a lot and I really thought this was a beautiful, complex, but well-done study, so thank you very much. Dr Miano: Thank you, Cindy. Dr Quertermous: Thank you so much for calming us down, I guess. Dr St. Hilaire: Well, that's it for our highlights from the January 31st and February 14th issues of Circulation Research. Thank you so much for listening. This podcast is produced by Rebecca McTavish, edited by Melissa Stoner, and supported by the Editorial team of Circulation Research. Some of the copy texts for the highlighted articles was provided by Ruth Williams. Thank you to our guests, Drs Thomas Quertermous and Joseph Miano. I'm your host, Dr Cindy St. Hilaire, and this is Discover CircRes, your source for the most up-to-date and exciting discoveries in basic cardiovascular research.    

Jane Ferguson: Hi everyone. Welcome to episode 20 of Getting Personal Omics of the Heart, the podcast brought to you by the Circulation: Genomic and Precision Medicine Journal and the American Heart Association Council on Genomic and Precision Medicine. I'm Jane Ferguson from Vanderbilt University. It's September 2018 and let's dive straight into the papers from this month's issue of Circulation: Genomic and Precision Medicine.                                 We're starting off with some pharmacogenomics. Bruce Peyser, Deepak Voora and colleagues from Duke University published an article entitled, "Effects of Delivering SLCO1B1 Pharmacogenetic Information in Randomized Trial and Observational Settings."                                 Although statins are generally well tolerated, 5-15% of patients taking statins for LDL lowering and cardiovascular protection end up developing statin associated muscular symptoms. Because onset of muscular symptoms associated with discontinuing statin use, as well as increased cardiovascular morbidity, there is a clear need to identify ways to prevent or reduce symptoms in these people. Variants affecting statin related myopathy have previously been discovered through GWAS, including a variant in the SLCO1B1 gene, which also has been shown to relate to statin myalgia and discontinuation of statin use. The risks appear to be greatest with simvastatin, indicating the people at risk of muscle complications may do better on either low-dose Simvastatin or another statin. However, there's still some uncertainty surrounding the risks and benefits of various statins as they pertain to risk of muscular symptoms.                                 The authors have previously shown that pharmacogenetics testing led to increased number of people reporting statin use, but effects of pharmacogenetic testing on adherence, prescribing, and LDL cholesterol had never been tested in a randomized control trial. In this study, they randomized 159 participants to either genotype informed statin therapy or usual care, and then followed them for months to eight months.                                 25% of participants were carriers of the SLCO1B1 star five genotype. The authors found that statin adherence was similar in both groups, but gene type guided therapy resulted in more new statin prescriptions and significantly lower LDL cholesterol at three months, and levels that were lower but no longer significantly different at eight months.                                 In individual's randomized to usual care who then crossed over to genotype informed therapy after the trial period ended, there was an additional decrease in LDL cholesterol. Overall, genotype informed statin therapy led to an increase in re-initiation of statins and decreases in LDL cholesterol, but did not appear to affect adherence.                                 The authors also examined the effects of commercial genetic testing for SLCO1B1 variants in an observational setting by looking at over 92000 individuals with data available in the EHR. They found the people who receive genetic testing results had a larger drop in LDL cholesterol compared to untested controls. Overall, the study indicates that carriers of the SLCO1B1 risk variant may benefit from genotype informed statin therapy, while for non-carriers receiving their results may has limited effects.                                 If you want to read more on this, Sony Tuteja and Dan Rader from UPenn wrote an editorial to accompany this article, which was published in the same issue.                                 We're staying on the topic of statins and LDL for our next paper. This article comes from Akinyemi Oni-Orisan, and Neil Risch and colleagues from the University of California and is entitled, "Characterization of Statin Low-Density Lipoprotein Cholesterol Dose-Response Utilizing Electronic Health Records in a Large Population-Based Cohort."                                 They were interested in understanding what determines variation in statin induced LDL reduction, particularly the genetic component, and they used a large EHR derived data set, the Kaiser Permanente Genetic Epidemiology research on adult health and aging cohort to address this important question. An EHR dataset does have intrinsic limitations, but also has some clear strengths, not only as a readily available and cost-effective data source for large sample sizes, but also because it reflects real world clinical care in diverse individuals, which is not always well represented within the selective constraints of a randomized trial.                                 There were over 33000 individuals who met their inclusion criteria. To account for differences in potency between different statins and doses, the authors generated a defined daily dose value, with one defined daily dose equal to 40 milligrams per day of Lovastatin. The slope of the dose response was similar across statin types and across different sex and race or ethnicity groups. But there were differences by statin type in the response independent of dose, as well as differences in absolute responses by sex, age, race, smoking, and diabetes.                                 Based on these differences, the authors revised the defined daily doses and they highlight how previously defined equivalencies between different statins may not be accurate. They found that individuals with East Asian ancestry had an enhanced response to therapy compared with individuals of European ancestry.                                 The authors identified related individuals within the data set and the estimated heritability of statin response using parent-offspring and sibling pairs. They found only modest heritability, indicating that non-genetic factors may be more important in determining variability in statin response. Overall, this large single cohort study adds to our knowledge on determinants of statin response and raises further questions on the relative effects of different statins and doses within patient subgroups.                                 Okay, so now let's talk about GWAS and Athero. Sander van der Lann, Paul de Bakker, Gerard Pasterkamp and coauthors from University Medical Center Utrecht published a paper entitled, "Genetic Susceptibility Loci for Cardiovascular Disease and Their Impact on Atherosclerotic Plaques."                                 Over the past decade, genome-wide association studies in large cohorts have been very successful in identifying cardiovascular risk loci. However, relating these to subclinical disease or two mechanisms has been more challenging. The authors were interested in understanding whether established GWAS loci for stroke and coronary disease are associated with characteristics of atherosclerotic plaque, the idea being that some of the risk loci may alter disease risk by determining the development and stability of plaque. They identified seven plaque characteristics to study and histological samples, including intraplaque fat, collagen content, smooth muscle cell percentage, macrophage percentage, calcification, intraplaque hemorrhage, and intraplaque vessel density.                                 They selected 61 known loci and examined association of those SNiPA with black phenotypes in over 1400 specimens from the athero express biobank study. Out of the 61 loci, 21 were associated with some black phenotype compared with zero of five negative control loci, which were chosen as established GWAS loci for bipolar disorder, which, presumably, should share limited mechanistic etiology with plaque. They used the software package VEGAS to run gene-based analyses. They also assessed SNiPA relationships with gene expression and methylation in multiple tissues derived from two independence Swedish biobanks, which included atherosclerotic arterial wall, internal mammary artery, liver, subcutaneous fat, skeletal muscle, visceral fat, and fasting whole blood.                                 One CAD locus on chromosome 7q22 that survived correction for multiple testing was associated with intraplaque fat, and was also an EQTL for expression of several genes across multiple tissues. In addition, it was also a methylation QTL.                                 The authors focused on this locus and looked at correlation of expression within the LDL receptor and noted associations with HDL and LDL cholesterol in the global lipids genetics contortion data, which suggests that this locus may have a role in the metabolism. At this locus, the HBP1 gene expressed foam cells may be an interesting candidate as a causal gene in determining plaque-lipid accumulation and cardiovascular risk.                                 So next up, we have a paper that is also about athero and is coauthored by many of the same group as did that previous study. So yeah, this group's productivity is kind of making the rest of us look bad this month. So Martin Siemelink, Sander van de Lann, and Gerard Pasterkamp and their colleagues published, "Smoking is Associated to DNA Methylation in Atherosclerotic Carotid Lesions."                                 Okay. So I think one of the few things we can all definitely agree on is that smoking is bad. But, does smoking exert any of its cardiovascular damage by altering within atherosclerotic plaques? That's the question this group set out to answer.                                 They carried out a two-stage epigenome-wide association study, or EWAS, with discovery and replication of differentially methylated loci with tobacco smoking within carotid arteriosclerotic plaques of a total of 664 patients undergoing carotid endarterectomy and enrolled in the arthero-expressed biobanks study. In discovery, they found 10 CpG loci within six genes that associated with smoking. Four of the CpG loci replicated. These four loci mapping within six genes showed reduced methylation in current smokers compared with former or never smokers.                                 However, there was no difference in specific plaque characteristics based on methylation at any of the four loci. There was also no significant difference in plaque gene expression at these loci based on smoking status. However, a SNiPA at a nearby locus located in the 3' UTR of the PLEKHGB4 Gene was associated with methylation at AHRR, and was a [inaudible 00:09:58] QTL for PLEKHGB4 of expression but not a AHRR expression. The authors speculate that PLEKHGB4 may co-regulate AHRR expression. The authors also examined blood methylation in a subset of the same subjects, and they were able to replicate previously identified CPG sites associated with smoking.                                 This is a really complex area, and it's hard to identify mechanisms and causality from these multiple layers of data, but the authors demonstrate the importance of using disease relevant tissues to start to understand how environmental factors interact with genetics and other underlying physiology to modify methylation and function within the vasculature.                                 Our final full-length research paper this issue from Brian Byrd and colleagues Michigan, is actually the subject of our interview today. So I won't go into too much detail on it right now, but keep listening for an interview with Brian about their paper, "Human Urinary mRNA as a Biomarker of Cardiovascular Disease: A Proof-of-Principle Study of Sodium-Loading in Prehypertension."                                 Our review article this month is about the "Dawn of Epitranscriptomic Medicine" from Konstantinos Stellos from Newcastle University and Aikaterini Gatsiou from Goethe-Universität Frankfurt. In this paper, they're taking us to the next level beyond just RNA, but towards RNA epigenetics. Given the large number of possible modifications that can and are made to RNA during RNA name metabolism, there's huge potential to gain a new biological and mechanistic understanding by studying the RNA epitranscriptome. I think we'll ignore this at our peril. So if you need to catch up on this new field, this comprehensive review will get you right up to speed.                                 Moving on, our research letters are short format papers that allow authors to present focused results. These are also a great avenue to submit findings from replication studies that might not necessitate a full-length paper. So if you have some data from a replication study that you've been procrastinating writing up, a short research letter is a great format to consider.                                 This month, Bertrand Favre, Luca Borradori and coauthors from Bern University Hospital published a letter entitled, "Desmoplakin Gene Variants and Risk for Arrhythmogenic Cardiomyopathy: Usefulness of a Functional Biochemical Assay." The desmoplakin is essential for the cell-cell adhesion complex's desmosomes. Mutations in this gene have been associated with a wide range of phenotypes, including some in skin and hair, but also in heart, which can manifest arrhythmogenic or dilated cardiomyopathy. This protein anchors intermediate filaments, so mutations that alter binding to intermediate filaments may pathogenicity.                                 The author selected seven reported amino acid altering mutations in desmoplakin, and they screened for effects on binding using a novel fluorescence binding assay. They found that three of the seven mutations had a clear impact on binding. This assay is a novel way to assess functional impact of desmoplakin variants, and may be useful to inform the severity of future phenotypes in individuals carrying a desmoplakin mutation.                                 Finally, if you want to stay up-to-date on the genetics of aortic disease and Marfan syndrome, you can find a letter from Christian Groth and colleagues and an author response from Norifumi Takeda and colleagues regarding their previously published paper on impact of pathogenic FBN1 variant types on the progression of aortic disease in patients with Marfan syndrome.                                 I am joined today by Dr. Brian Byrd from the University of Michigan, who is the senior author on a Manuscript published in this month's issue, entitled, "Human Urinary mRNA as a Biomarker of Cardiovascular Disease: A Proof-of-Principle Study of Sodium-Loading in Prehypertension."                                 So welcome Brian. Thanks so much for coming on the podcast. Brian Byrd:          Thank you for having me. Jane Ferguson: So before we get started, could you give a brief introduction of yourself to the listeners and maybe tell us a little bit about how you got into the field? Brian Byrd:          Absolutely. So I am a cardiologist and a physician scientist. I'm an assistant professor at the University of Michigan, where I have a laboratory engaged in clinical investigation. My background is that I did my Internal Medicine Residency at Vanderbilt University. And after I finished residency, I entered Nancy Brown's lab. She's the Chair of Medicine at Vanderbilt, as I know you're aware. And she had a laboratory focused, and still does have a laboratory focused, on the investigation of high blood pressure, with a lot of focus on understanding high blood pressure as it occurs in humans. And I got a Master of Science degree in clinical investigation while I was in her lab, and we did some work on a number of topics related to the renin-angiotensin-aldosterone system, which has been a long-standing interest of mine ever since then.                                 So, at the same time, I was learning how to take care of patients with very complex blood pressure problems, who required three, or four, or five, or six blood pressure medications, in some cases, to control. And it's with that background that I became very interested in the science that underlies treatment-resistant high blood pressure in people and what we might be able to do about that. Jane Ferguson: Wow. Nice. Yeah and I think that background of sort of the combination of clinical and experimental is really nice and really important. I think your paper actually exemplifies that really nicely, so using humans but also some basic science techniques and combining them to really have a very patient focused instead of mechanistic interrogation.                                 So as I mentioned, you just published this really nice manuscript using urine as a source of mRNA biomarkers, which has relevance to hypertension and potentially also to other diseases. But before we get sort of too much into the weeds on the specific details, for any of our listeners who didn't get a chance to read your paper yet, maybe you could briefly summarize what you did? Brian Byrd:          Okay, so the general overview of what we were interested in was that the patients who have treatment resistant high blood pressure tend to have a lot of activation of a receptor in the kidney called the mineralocorticoid receptor. And this receptor helps control salt in bladder in the body. Obviously the amount of salt in the blood stays very, very homeostatic, but we if eat more salt one day then the next and there needs to be a system to help regulate the homeostasis. And so, you waste more or less salt in the urine depending upon how much sodium you're taking in.                                 And one of the functions of the mineralocorticoid receptor is to control this salt and bladder regulation or to fine tune it anyway. And the reason we know that that's an important receptor in patients with treatment-resistant high blood pressure is because of a series of studies done by David Calhoun and Brian Williams and others, showing that mineralocorticoid receptor blockers, or antagonists, are very effective in the treatment of tough to control high blood pressure.                                 And so, we had some insight that there would be something interesting to study there, and one of the things that we knew was that the mineralocorticoid receptor is a ligand activated transcription factor. So when it gets activated by it's ligan which canonically is a steroid hormone from the adrenal gland aldosterone, the receptor, which is in the cytoplasm, ordinarily dimerizes and translocates to the nucleus, where it controls the regulation of a number of genes. We also were aware that cells secrete RNA, and others had the idea that it might be inside vesicles because there's a lot of ribonuclease and biofluids. And you would think it might be difficult to pass the RNA if it were sort of naked as it were.                                 And it turns out that that's right. If you, for example, introduced synthetic RNAs into biofluids, the RNAs will be gone very quickly in a matter of seconds. So, we had this idea that we might be able to look at RNA that was being secreted by cells probably in vesicles, and assay the activity of the receptor potentially. We weren't sure if that was going to be possible or not.                                 One of the things we did was we used part of the available data to look at the transcriptome of vesicles in the urine that had been isolated from 3300 milliliters of urine by ultracentrifugation [inaudible 00:18:57]. Jane Ferguson: So it's a big centrifusion. Brian Byrd:          Exactly. Jane Ferguson: Like you [inaudible 00:19:00] Brian Byrd:          It must have been some project. So that was the work of Kevin Miranda and colleagues, and we were able to compare that transcriptome to the transcriptome of human kidney cortex samples from the GTEx project, which a large consortium focused on human transcriptomics.                                 And that was sort of the first part of what we presented in this paper, and the second thing that we did was we looked within a crossover study in a collaboration with Scott Hummel, one of my close collaborators here at the University of Michigan. We looked at individuals who had been put on a low salt diet activating renin-angiotensin-aldosterone system and causing more activation of the mineralocorticoid receptor. And then, those same individuals underwent saline infusion, so salt loading, and we knew that that would suppress the renin-angiotensin-aldosterone system. And we measured the [inaudible 00:20:02] measures of the renin-angiotensin-aldosterone system, but we also took the urine samples that had been recently banked from that experiment and we centrifuged them to try to palette the cells. We took the supernatant and we extracted RNA after trying to enrich for extracellular vesicles.                                 And with that approach, we measure targets that we thought would be regulated my the mineralocorticoid receptor, as well as some things that we did not think would be regulated by mineralocorticoid receptor. So that's the general overview of what we undertook. Jane Ferguson: Great. Right. So it's very cool. I guess we can break it down into sort of the two different parts, because I think it was a really nice examples of using public data to sort of start addressing your question and then actually doing a human experiment. But so for the GTEx data and the urinary data, you looked at few different tissues, right? And was kidney the one that you were thinking upfront would sort of most likely to correlate, or were you also looking at bladder and other sort of tissues that could potentially be of relevance to urine? But what sort of the ... I guess sort of tell me more about those different tissues that you looked at and what you found and what surprised you or not. Brian Byrd:          Great question. So, the kidney was on our minds from the outset. We knew that Mark Knepper at the National Institute of Health had published in the [inaudible 00:21:25] National Academy of Sciences back in 2004 that there are urinary extracellular vesicles. And he had found proteins that are very characteristic of the aldosterone sensitive distal nephron, that part of the kidney that we're interested in, embedded in the vesicles.                                 So we became quite interested in the idea that it seemed that there was likely a population of vesicles in the urine that is of kidney origin. And that's not to say that there weren't also plenty of vesicles from other origins as well, and there could very well be RNA that is not vesicle enclosed, but is rather ribonucleic protein bound or even bound to other carriers potentially. That could be there as well, and it's possible that the origin of those things could be any number of tissues. I don't really think that we know yet where the possible tissue origins are.                                 But we were curious to know ... I guess the direct answer to your question is we thought from the outset that we probably would find some sort of signal related to the kidney. But we wanted to also consider the possibility that our findings were not very specific to the kidney. And so we thought that the brain would be an interesting negative control. If we say very high correlation with the brain, it would suggest that maybe what we're looking for is a signal that's not really coming from the kidney.                                 And we also wanted to look at the bladder just to try to understand whether or not the signals that we're detecting could be coming from the bladder. It's certainly true that some aspects of the system that we're interested in are present in the bladder, so I wondered whether that might even serve as a signal amplifier for what we were looking for since there's, presumably, quite a bit of bladder tissue right around the urine. It might be contributing vesicles.                                 So that's sort of the rationale for why we looked at those things. Jane Ferguson: And you found mostly enrichment for kidneys. So sort of I guess what you were hoping to find came true? That actually there was sort of evidence that even though there may be contribution from other tissues, that really kidney seem to be the predominant contributor to the expression of the genes in the urine. Brian Byrd:          I think there's a lot of truth to that. One of the things I would say is we found high correlation looking across all genes. But it occurred to us ... As soon as we thought that, we realized, wait a second, that could be driven by ubiquitously expressed genes. Housekeeping genes.                                 So we really wanted to stratify our analysis by things we thought would be expressed in the kidney as well as things that we thought would be ubiquitously expressed to make sure that we could see signals that correlate ... That the transcriptome of the kidney, per se, had a good correlation with those same in terms of the abundance of the gene counts or recounts. They said it was similar to what was in the vesicles.                                 And so, we looked in the literature, and we found that a group had already established a number, 55 genes actually, that were highly kidney enriched as well as over 8000 genes that were ubiquitously expressed. And so we started the analysis from this perspective of the stratification. We thought that was a very important aspect of the analysis. And it's definitely true that if you look at our findings with respect to the kidney enriched genes, as you might expect, they correlate quite well with what is in the urinary extracellular vesicles compared to the kidney cortex.                                 You look at the brain as you might expect the expression of those kidney enriched genes is not well correlated with what's happening in the urine. And then, with respect to the bladder, it's sort of somewhere in between. Jane Ferguson: Okay. Interesting. So I know that some people look at small non-coding RNAs in urine, but you were mostly focused on mRNAs. Is that right? Brian Byrd:          That's right. I thought of this as sort of frontier, something that I knew from some early publications was probably measurable. But I didn't know what it would signify, if anything, with respect to physiology. And I knew that there were quite a few papers about micro RNAs and I wanted to do something a little bit innovated, partly.                                 But the main reason that I was interested in the RNAs was because I could relatively easily tie those to the existing literature from animal models. Preclinical animal models and cell culture studies showing what happens when the mineralocorticoid receptor's activated. That was really the driving reason that I was interested in the RNA. Because if you think about what is the approximate event that might be a readout for activation of a new growth hormone receptor like the mineralocorticoid receptor, it's really the transcriptional events that happen when the receptors translocates to the nucleus and serves its ligan activated transcription factor role. Jane Ferguson: Right. So, [inaudible 00:26:43] sort of the first part of analysis, you saw these really nice correlations between expression and kidney and in urine. And then, a lot of the times when you tried to publish that kind of thing, people are like, "Okay, so what? So you didn't do any intervention. We don't really know what that means."                                 But I like that you took it to the next step and you did sort of a human intervention experimental model. So tell me more about that model and how that worked. Brian Byrd:          Right. Well, I'll just mention also that the work that was done in terms of RNA [inaudible 00:27:14] was done in collaboration with Mark Bertini in Italy as well as Dr. [inaudible 00:27:19]. They were fundamental to getting that work done.                                 With respect to the collaboration with Scott Hummel, one of my colleagues here at the University of Michigan, what we did in that setting was to look at whether or not we could identify within these urinary mRNA signals that are in the supernatant in the urine, whether we could identify changes in physiology. That was the question that was of greatest interest scientifically.                                 And for a very practical or blind perspective, the question was could we detect the activation of the receptor that might determine whether or not people should get a certain medication. Of course, we're not saying that that's an established fact yet, but this is sort of concept, that there's something here to explore further.                                 And so, what we found was that a number of genes that are regulated by the mineralocorticoid receptor, including genes encoding the subunits of the amiloride-sensitive epithelial sodium channel that regulates the salt that I was talking about earlier. We found that those genes changed with sodium loading in terms of their abundance in the expected direction.                                 We also found that several of the assays that we made changed ... I'm sorry. That they correlated with the serum aldosterone concentration. So the concentration of the ligan for the receptor whose readout we were looking for. And we also noticed an inverse correlation with urinary sodium excretion, which is what we would expect if we really identified a readout of the mineralocorticoid receptor's activity.                                 So this study supported the idea that we have identified a way to measure this nuclear hormone receptors activity in living humans. Jane Ferguson: Right. Which is really nice. So there's probably a huge amount of extra things you could do with this, some sort of different ways you could look at it. So how did you pick the time point? So, I suppose when you think about it, I mean the genes, they're transcribed and then that takes a little bit of time, and then it takes a little bit of time for that to sort of make its way into the urine and to be excreted.                                 So how did you decide on sort of what time points to use, and do you think you would see the same things or different things [inaudible 00:29:39] if you did repeated sampling or if you looked at different time points? Brian Byrd:          That's a fantastic question. So this was a study that had already been completed, and I had mentioned to Scott what we were working on. And he said, "You know, we have these samples from this study and it might be possible for us to collaborate."                                 So, we didn't get to pick the timeframes. Jane Ferguson: Right. Brian Byrd:          So, that's a great point. And what I would say is that, as you can imagine, we're very focused on exactly the questions you're asking now. What about sort of signal refinement? What about the chrono-biology of these signals, and how do we understand when we see what in the urine?                                 So, I'm actively pursuing those questions. Jane Ferguson: Right. So, I know as well, there was quite a lot of sort of technical challenges I think to doing this work. Sort of getting to be even able to amplify and get a signal from these RNAs that are really present, sort of pretty low abundance in urine compared to tissues or biofluids that we're used to working with.                                 So tell me maybe a little bit about that process and sort of how much optimization was required to get these essays to work? Brian Byrd:          Great question. So, I had known [inaudible 00:30:58] since 2014 when I took a course on isolation of extracellular vesicles in Heidelberg, Germany. And I had talked to him at a meeting in Washington DC, and I had mentioned what we were trying to do. And he said, "You know, if you were trying to do that, you might want to consider preamplification." You know, using something like 15 cycles of preamplification. And he was willing to share that protocol that he had with me, because they were interested in similar issues. So, I was able to use that protocol to evaluate these gene targets in the urine. And so that was immensely helpful.                                 And the other thing that we did was we used locked nucleic acid probes to try to increase the sensitivity and specificity of our assays. Finally, we just tried to use good logic in the design of the assays. So we were concerned that the RNA might be fragmented, so where it was possible to do so within the design constraints that I'll mention in a second, we made multiple assays per gene target just in case this was fragmented. Which makes the analysis a little more complicated, but I think it was probably the right thing to do, given the state of knowledge that we had then.                                 And one of the other things we did was we made sure that the primers either ... Within a primer, there was an intron or between the primers there was an intron, so that if we actually did try to amplify DNA, abundant amounts of DNA, with those primers just to make sure that our theorizing about the inability to amplify things was actually factual. And that turned out that we couldn't amplify anything at 40 cycles with those.                                 So, we spent a lot of time thinking about how not to get fooled, but also to have adequate signal detection. And have included in the supplement quite a bit of information about the technical merits of the assays and showing how close the technical replicates were. They tended to be very, very similar to one another. We didn't see a signal in every urine sample for every participant at both time points, and I think that was interesting to me about that there tended to be a very binary result, so that you'd either see three technical replicants for the QPCR assays, our QPCR assays that were extremely similar to each other, or you would see no CT value detected.                                 [inaudible 00:33:47] That these were valid assessments of very low copy numbers. Jane Ferguson: Right. And that's probably related to up front of what happens to urine right after it's collected and stored, or during that RNA extraction. But it seems like once you've got RNA, then downstream assays were sort of ... They held through, but I guess ... I mean, and you obviously didn't have necessarily a huge amount of control over how these urine samples were collected. So it's kind of nice that you were able to see something even though these were collected possibly in a way that was not optimized for preserving RNAs.                                 But do you think those ... Are there ways that you could make this even sort of more streamlined and better as far from the get go of how you collect the urine, whether you could be extracting stuff right away? Is that anything you sort of looked into of how this could be improved? Brian Byrd:          That's really been the focus of the labs work since we completed that project, is sort of understanding how would we do this in a prospective study in the best possible way so that the results are highly repeatable, that we get a CT value in everybody so that we're really ... I mean, as you can imagine, that actually has something to do with the input volume of urine that you use. So if you have too little input volume, then you won't be able to detect the targets that you might be interested in every person.                                 However, if you have more, then you can do more with that. But then you have to think about how you're going to deal with the larger volumes of urine. There are lots of questions that we've been interested in related to extract the RNA and the stability of the RNA. And so we have done some experiments of that type, and we continue to work in that area. And I do think that those questions you're asking are the right questions with respect to next steps. Jane Ferguson: All right. So you looked at sort of specific targets, which I think made a lot of sense. Sort of this proof of principle. But do you think this would work on a transcriptome wide level? I mean, could you look at all the genes, or do you think that's just sort beyond the possibility right now given sort of the RNA fragmentation and how you have to sort of amplify it before being able to detect anything? Brian Byrd:          I think it's possible. So the group that had preceded our work with 3300 mils of urine, isolating the vesicles from there, eight have showed that that's something that can be done. The question that's of interest to me is does it actually require such large volumes of urine? And I think the answer to that question is going to be no from what we're overseeing so far.                                 And so, we're thinking along exactly the lines that you are. And certainly some of the feedback we've gotten as we've discussed this project with people is, "Hey, could you look at everything rather than picking targets at [inaudible 00:36:41]."                                 I think there's advantages and disadvantages. I think we chose based on prior knowledge in a way that was rational. But at the same time, it may turn out that there are many things about activation of the mineralocorticoid receptor in humans, especially in the living in-tact human, that don't exactly mirror what's found in rabbits, rats, mice or cells, which are really the systems that have been evaluated the most thoroughly in the past.                                 So I'm very interested in exactly what you're proposing. Jane Ferguson: Yeah. I mean, I think it's exciting because it's obviously relevant for hypertension, but potentially a lot of other conditions, to be able to look at that sort of dynamic change. So I think it's really exciting. It's very cool. Brian Byrd:          And I appreciate your asking about this study. We were excited to do this work and very, very excited to see where we can in the future with this. And I agree with the point you were making, that here we've gone from a rather specific application driven question and we've, I think, made some insights that are probably useful outside the application that we had in mind. And it may turn out that the application where this is the most important is not even the one that we considered in the first place at all.                                 And so I'm pleased by that. I'm pleased by the fact that I think in a sense we're working in what Donald Stokes described as pasture's quadrant, which is a sense that the work is driven both by curiosity and by an intent to use the results. Jane Ferguson: Right. Brian Byrd:          And so that's really what gets me out of bed in the morning, is working that exact space. So that's what we were glad to have done and continue to do. Jane Ferguson: Yeah. No, I think it's grea.t and I feel like a lot of people will read this paper and be like, "Hey, I have urine stored in the freezer. What can I do with this now?" Brian Byrd:          Contact me. Let's talk. We'll see what we can do. But we certainly tried to describe the methods in such a way that people could easily follow in our footsteps if they want to apply these methods. Jane Ferguson: Yeah. Now having read through them, I think that ... Really thorough. I really liked the sort of attention to detail. It was definitely one of those ones where I was like, "Oh yeah. I can see exactly how I could do this if I wanted to. So I think that was great. Brian Byrd:          Thank you. Jane Ferguson: So yeah. Congratulations on the paper. Really nice work and thanks so much for talking to me. Brian Byrd:          Thank you. It was a delight. Jane Ferguson: That's it from me for September. If you haven't had enough yet, you can access all the papers online and you can choose to digest the papers in video format. Available on our website or the Circulation YouTube channel. Thank you for listening and subscribing. I look forward to bringing you more next month.  

Möt vår sockersyster Ewa Meurk som har levt 15 år i tillfrisknande från sockerberoendesjukdomen och är idag utbildad funktionsterapeut. Ewas barn har växt upp på LCHF och hon delar generöst med sig av alla de tips och trix som hon har lärt sig genom årets lopp. Hennes expertområde ligger i insulinets roll för övervikt och ohälsa och hon berättar vad du kan göra om du, trots LCHF, har svårt att tappa vikt. Avsnittet är fullt av skratt, kunskap och framförallt hopp om en fantastisk sockerfri framtid!

"Det skapande rummet är inget stängt rum. Du kliver in, upprättar kontakt till vad du än behöver och trots att det kanske finns väggar, öppnar det sig i oändlighet. O, lycka att stiga in!" Stina Söndagens gäst, Ewa J Sundberg, har upplevt begränsningar och instängdhet i sitt liv. Det fanns en tid då hon kände att något alltid kunde bli bättre, finare, renare. I den stränga religiösa miljön hon en gång levde i fanns en dubbelhet; både bestraffningar men också humor och innerlighet. En dag var hon ändå tvungen att bryta upp för att kunna leva ett eget liv, sannare mot den som hon var och är; en konstnärssjäl.Längtan efter att skapa blev också vägen till frihet, kärlek och till och med lycka.Ewa J Sundberg är numera pensionär men fortsätter att skapa och håller kurser i Vedic Art som handlar om att rikta kraft och uppmärksamhet inåt och våga vara sig själv i sin fulla potential. Hon är också kvinnan som vågar göra beställningar till universum och får leveranser. Hör Stina och Ewas samtal söndag kl 22-23.Du som lyssnar, hur ser dina beställningar ut och vad har konsekvenserna blivit av dom? Eller tror du inte på sånt alls? Vad är frihet för dig? Hur bröt du ditt fångenskap? Var fick du kraften ifrån? Vad betyder skapande för dig? Vad händer när du skapar? Ring på söndag kl 22-00 för att dela med dig! Numret till slussen är 018 - 17 40 20 och du kan också skicka ett mail till sondagsstina@sverigesradio.se eller skriva en kommentar i sociala medier.

Mycket intressant och informativ intervju med Ewa Berthagen, en av Sveriges mest insatta personer när det gäller sköldkörtelproblem. Vi diskuterar allt från problem i vården, till symtom, till hur man ska göra för att få hjälp, till vilka prover man behöver ta, till vilka tillskott som kan gynna sköldkörteln, och Ewas egna berättelse mm mm. En hel timme har du här! Verkligen värt att lyssna på. Så här gör du:… läs mer

Background: With the help of epigenome-wide association studies (EWAS), increasing knowledge on the role of epigenetic mechanisms such as DNA methylation in disease processes is obtained. In addition, EWAS aid the understanding of behavioral and environmental effects on DNA methylation. In terms of statistical analysis, specific challenges arise from the characteristics of methylation data. First, methylation beta-values represent proportions with skewed and heteroscedastic distributions. Thus, traditional modeling strategies assuming a normally distributed response might not be appropriate. Second, recent evidence suggests that not only mean differences but also variability in site-specific DNA methylation associates with diseases, including cancer. The purpose of this study was to compare different modeling strategies for methylation data in terms of model performance and performance of downstream hypothesis tests. Specifically, we used the generalized additive models for location, scale and shape (GAMLSS) framework to compare beta regression with Gaussian regression on raw, binary logit and arcsine square root transformed methylation data, with and without modeling a covariate effect on the scale parameter. Results: Using simulated and real data from a large population-based study and an independent sample of cancer patients and healthy controls, we show that beta regression does not outperform competing strategies in terms of model performance. In addition, Gaussian models for location and scale showed an improved performance as compared to models for location only. The best performance was observed for the Gaussian model on binary logit transformed beta-values, referred to as M-values. Our results further suggest that models for location and scale are specifically sensitive towards violations of the distribution assumption and towards outliers in the methylation data. Therefore, a resampling procedure is proposed as a mode of inference and shown to diminish type I error rate in practically relevant settings. We apply the proposed method in an EWAS of BMI and age and reveal strong associations of age with methylation variability that are validated in an independent sample. Conclusions: Models for location and scale are promising tools for EWAS that may help to understand the influence of environmental factors and disease-related phenotypes on methylation variability and its role during disease development.