Podcasts about modulator

Michael Armstrong is a 25-year-old pre-law student. He loves to read, paint, play card games and video games. He was diagnosed with CF as an infant. We're going to talk about his CF journey and how life took a turn when he was being evaluated for a lung transplant in 2023 and 2024.   Michael was featured in the 2025 Portraits of cystic fibrosis calendar and our first or second  calendar he was featured when he was about five with his  brother.  Michaels dad, Tom was on our Board of Directors for many years…and I was lucky to see him just the other day.Thanks for sharing your story Michael. Please like, subscribe, and comment on our podcasts!Please consider making a donation: https://thebonnellfoundation.org/donate/The Bonnell Foundation website:https://thebonnellfoundation.orgEmail us at: thebonnellfoundation@gmail.com Thanks to our sponsors:Vertex: https://www.vrtx.comViatris: https://www.viatris.com/en

Larry and Les discuss their recent hunting trip, the guys chat about their Las Vegas adventure, and finally touch on the recent Oliver Anthony controversy. 

A new CF modulator could be on the horizon. Professor Dr. Bhanu Jena is exciting to tell us all about it. Dr. Jena was born in a small town in Odisha, India. He got his love for science and medicine from his father and grandfather. He majored in Chemistry, Zoology, and Botany at BJB College in Bhubaneswar, Odisha, India,  He got his masters in zoology. He received the Peasant Ku. Memorial Prize and the Utkal University Gold Medal. He also got his doctorate in zoology (Molecular Endocrinology). His resume is lengthy and impressive. He was a fellow at Yale Univeristy of Medicine and worked as on the faculty there. He also worked in the Department of Physiology at Wayne State Univeristy. Dr. Jena was conferred the title of Distinguished Professor, and the George E. Palade University Professorship by the Board of Governors at Wayne State.Dr. Jena is a cell biologist and chemist. He unraveled understanding of cell secretion with his pioneering discovery of the 'porosome', the secretory machinery in cells. This short bio doesn't even touch the surface of his contributions. To read more about him: https://static.s123-cdn-static- d.com/uploads/5744411/secure/normal_6539c9b2a5bef.pdfHIs company website: https://www.porosome.comA great porosome video, and a short one, explaining: https://www.youtube.com/watch?v=5y0Hset6gNw Please like, subscribe, and comment on our shows, wherever you get your podcasts.Please consider making a donation: https://thebonnellfoundation.org/donate/The Bonnell Foundation website:https://thebonnellfoundation.orgEmail us at: thebonnellfoundation@gmail.com Thanks to our sponsors:Vertex: https://www.vrtx.comViatris: https://www.viatris.com/en

Evan Cohen & Hembo (in for Greeny) recap a wild night at MSG as the 76ers come back to beat the Knicks and avoid elimination. Is Tyrese Maxey now the face of the 76ers? Would Embiid accept being a Robin? As for LeBron's future... will the Lakers draft Bronny James? Learn more about your ad choices. Visit megaphone.fm/adchoices

Poolbeg Pharma PLC (AIM:POLB, OTCQB:POLBF) chief legal officer John McEvoy joins Proactive's Stephen Gunnion with news that POLB 001's Immuno-modulator II has received the fully granted patent from the US Patent Office. McEvoy explained the patent encompasses a class of drugs for treating and preventing hypercytokinemia (cytokine storms) in patients triggered by an immune response, applicable across multiple disease indications. The granted patent further solidifies Poolbeg Pharma's robust intellectual property portfolio for POLB 001, potentially increasing the asset's value and making it more attractive to potential partners. McEvoy highlighted the company's ongoing efforts to strengthen and expand their IP portfolio, noting existing patents covering p38 MAP kinase inhibitors for influenza treatment and hypercytokinemia. Additional patents have been filed, particularly focusing on cancer immunotherapy applications of POLB 001. The company has also applied for patents concerning dosage regimens based on results from their recent LPs trial, aiming to protect innovations and maintain a competitive edge in the pharmaceutical market. This strategic IP protection is crucial for safeguarding the company's products and ensuring shareholder value, particularly as they seek partnerships to further develop POLB 001. #PoolbegPharma, #POLB001, #Immunomodulator, #USPatentOffice, #IntellectualProperty, #Pharmaceuticals, #CytokineStorm, #Hypercytokinemia, #PatentGranted, #DrugDevelopment, #MedicalInnovation, #CancerImmunotherapy, #InfluenzaTreatment, #PharmaIndustry, #JohnMcEvoy, #HealthcareNews, #Biotech, #ClinicalTrials, #PharmaPartnerships, #MedicalResearch #ProactiveInvestors #invest #investing #investment #investor #stockmarket #stocks #stock #stockmarketnews

In this video, we dive deep into the fascinating world of neuroscience to explore the powerful effects that exercise has on mental health. We explore the endorphin theory of exercise, why exercise has an antidepressant effect, the role of neurotrophins in exercise, how exercise can normalise the HPA Axis and much more… Professor Henning Budde is a Professor for Sport Science & Research Methodology at the Medical School Hamburg. He has taught and researched at universities throughout Europe, in South Korea and Australia, all the while publishing over 120 peer-reviewed articles on Ex Neuroscience. He has achieved these remarkable feats whilst also having a neurological disease, which affects his speaking.  Chapters 0:00 Show Intro 3:09 Monoamine Hypothesis 18:30 Measurement Difficulties 25:55 Endorphin Theory  43:55 HPA Axis 50:05 Exercise Effects on the Brain 1:05:50 Future of Exercise Neuroscience Research The Endocannabinoid System and Physical Exercise by Matei et al. (2023) The Endocannabinoid System as Modulator of Exercise Benefits in Mental Health by Amatriain-Fernandez et al (2021) Lessons in exercise neurobiology: The Case of Endorphins by Dishman and O'Connor (2009) Exercise-induced euphoria and anxiolysis do not depend on endogenous opioids in humans by Siebers et al. (2021) Physical activity, fitness, and gray matter volume by Erickson et al. (2015) Brain monoamines, exercise, and behavioral stress: animal models by Dishman et al. (1997)The runner's high: opioidergic mechanisms in the human brain by Boeker et al. (2008) Effect of exercise for depression: systematic review and network meta-analysis of randomised controlled trials by Noetel et al. (2024) The Exercise Effect on Mental Health: Neurobiological Mechanisms by Budde and Wegner (2018)

Watch Here : https://www.youtube.com/watch?v=49Cbkx4JsGE Website: https://vigoroussteve.com/ Consultations: https://vigoroussteve.com/consultations/ eBooks: https://vigoroussteve.com/shop/ YouTube Channel: http://www.youtube.com/user/VigorousSteve/ Workout Clips Channel: https://www.youtube.com/channel/UCWi2zZJwmQ6Mqg92FW2JbiA Instagram: https://instagram.com/vigoroussteve/ TikTok: https://www.tiktok.com/@vigoroussteve Reddit: https://www.reddit.com/r/VigorousSteve/ PodBean: https://vigoroussteve.podbean.com/ Spotify: https://open.spotify.com/show/2wR0XWY00qLq9K7tlvJ000 Patreon: https://www.patreon.com/vigoroussteve

As the topic of mental health has gained attention over the past several years, you've no doubt heard a couple of related phrases you're not familiar with. One is the vagus nerve. The other is heart rate variability. Here, we'll delve into the vagus nerve and what it's all about. What is the Vagus Nerve? The vagus nerve, also known as the 10th cranial nerve or cranial nerve X, is the longest and most complex of the cranial nerves. It is also known as the "wanderer nerve" due to its long, winding course through the body, connecting various organs and systems. It is a key part of the parasympathetic nervous system, which controls involuntary body functions such as digestion, heart rate, and immune response.“Vagus Nerve: What It Is, Function, Location & Conditions.” Cleveland Clinic, https://my.clevelandclinic.org/health/body/22279-vagus-nerve. Accessed 6 Feb. 2024. The vagus nerve originates in the medulla oblongata, a part of the brain that connects to the spinal cord, and extends down through the neck to the vital abdominal organs.Segal, Dayva. “Vagus Nerve: What to Know.” WebMD, https://www.webmd.com/brain/vagus-nerve-what-to-know. Accessed 6 Feb. 2024. It contains both motor and sensory fibers, which means it can send and receive information.Kenny BJ, Bordoni B. Neuroanatomy, Cranial Nerve 10 (Vagus Nerve) [Updated 2022 Nov 7]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK537171/ The vagus nerve carries signals between the brain, heart, and digestive system. It is responsible for various bodily functions, including digestion, heart rate, and breathing. It also plays a role in controlling mood, immune response, and the regulation of food intake, satiety, and energy homeostasis.Breit S, Kupferberg A, Rogler G, Hasler G. Vagus Nerve as Modulator of the Brain-Gut Axis in Psychiatric and Inflammatory Disorders. Front Psychiatry. 2018 Mar 13;9:44. doi: 10.3389/fpsyt.2018.00044. PMID: 29593576; PMCID: PMC5859128. Vagus nerve stimulation (VNS) is a treatment method that uses electrical impulses to stimulate the nerve. It's used to treat some cases of epilepsy and depression that don't respond to other treatments. Damage to it can lead to conditions like gastroparesis, where food does not move into the intestines, and vasovagal syncope, a condition where people faint from low blood pressure. Vagal Tone Vagal tone is often used to assess heart function, emotional regulation, and other processes that alter or are altered by changes in parasympathetic activity. A higher resting vagal tone means you have a reserve capacity for stress. You're more stress resilient.Laborde S, Mosley E, Thayer JF. Heart Rate Variability and Cardiac Vagal Tone in Psychophysiological Research - Recommendations for Experiment Planning, Data Analysis, and Data Reporting. Front Psychol. 2017 Feb 20;8:213. doi: 10.3389/fpsyg.2017.00213. PMID: 28265249; PMCID: PMC5316555. Vagal tone is typically measured indirectly by heart rate variability (HRV), which is the variation in time between each heartbeat. HRV is considered a marker of the body's resilience and adaptability to stress, with higher HRV (indicating greater variability in the intervals between heartbeats) generally associated with better health and fitness, greater resilience to stress, and lower risk of disease. The Vagus Nerve and the Gut-Brain Axis The vagus nerve plays a pivotal role in the gut-brain axis, a complex communication network that links the central nervous system (CNS) with the gastrointestinal (GI) tract. This bidirectional pathway allows for the exchange of signals between the gut and the brain, influencing a wide range of bodily functions, including mood, immune response, digestion, and heart rate. Here's how the vagus nerve affects the gut-brain axis: Direct and Indirect Sensing The vagus nerve can directly or indirectly sense a variety of signals from t...

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Bernie Martin is a Writer, Creative Consultant and, most importantly, Mother of a CF Fighter. After 15 years working as a Copywriter and Creative Director in some of Ireland's top advertising agencies, she started her own consultancy called The Salty Pen in 2018. This move was born out of a desire to have more flexibility around caring for her little lady with CF, who she describes as her muse, her strength, her drive, her everything! Bernie has written about the challenges facing CF families on her blog My Little Miss Salty, and she has written for The M Word and MummyPages. She has worked on a voluntary basis as a CF patient advocate in CHI Temple Street and as a campaigner during the #YesOrkambi campaign in 2016/17, with the support of Rothco, the advertising agency she worked with at the time. She has been a speaker at the Cystic Fibrosis Ireland Conference and at the new parent information day in Temple Street, as well as featuring in Humans of Dublin by Peter Varga.Bernie and her daughter, Eva, recently collaborated with the University of Notre Dame in the 100th episode of their long running series, ‘What would you fight for?' In this case, the fight is for new Cystic Fibrosis treatments. Bernie and her husband Dave live in Dublin, Ireland.Please consider making a donation: https://thebonnellfoundation.org/donate/The Bonnell Foundation website: https://thebonnellfoundation.orgBonnell Foundation email: thebonnellfoundation@gmail.comThanks to our sponsors:Vertex:  https://www.vrtx.comGenentech: https://www.gene.comViatris: https://www.viatris.com/en

Dr. Jennifer Taylor-Cousar is an amazing woman I can't wait to meet in person one day.  She is a Board Certified Pediatric and adult pulmonologist at National Jewish Health in Colorado. She's a rock star in the world of CF, and she's doing incredible work raising awareness about systemic and individual bias and racism in medicine. She also talks about the importance of representation in the field of medicine. I hope after you hear this podcast you are more inspired to speak up and do more to change the world.About Dr. Taylor-Cousar:Dr. Taylor-Cousar is a tenured professor of adult and pediatric pulmonary medicine at NationalJewish Health (NJHhttps://www.nationaljewish.org/home), where she serves as the Medical Director of Clinical Research Services,President of the Medical Staff, and is co-director of the Adult Cystic Fibrosis (CF) Program andDirector of the CF Therapeutics Development Network (TDN) center. She received herundergraduate degree in human biology from Stanford University, and completed her doctoratein medicine, combined residency in internal medicine and pediatrics, and her combinedfellowship in adult and pediatric pulmonary medicine at Duke University. She obtained herMaster of Clinical Science from the University of Colorado.Dr. Taylor-Cousar's expertise is clinical trial design and conduct; she has been national/globalprimary investigator on multiple CF TDN trials. Her investigator-initiated research focuses onthe development and evaluation of novel therapies for the treatment of CF, and on sexual andreproductive health in people with CF. Additionally, she serves on a number of nationalscientific advisory committees for the Cystic Fibrosis Foundation, American Thoracic Societyand the National Institutes of Health. She is an Associate Editor for the Journal of Cystic Fibrosisand a member of the International Advisory Board for the Lancet Respiratory Medicine.Dr. Taylor-Cousar is an elected member of the American Society for Clinical Investigation(ASCI). Her recent awards include the American Thoracic Society's Distinguished AchievementAward (2023,) the American Thoracic Society William J. Martin II Public Advisory RoundTable Distinguished Achievement Award (2022), the Emily's Entourage CF Trailblazer Award(2022) and the Cystic Fibrosis Research Incorporated CF Champion Award (2021).Michele and Terry Wright screening tool: https://noaacf.org/the-wright-cystic-fibrosis-screening-tool/Please consider making a donation: https://thebonnellfoundation.org/donate/The Bonnell Foundation website: https://thebonnellfoundation.orgBonnell Foundation email: thebonnellfoundation@gmail.comThanks to our sponsors:Vertex:  https://www.vrtx.comGenentech: https://www.gene.comViatris: https://www.viatris.com/en

In this episode, I share the findings from my PhD research and introduce the Ecology of Change in Outdoor Therapy (ECO-Therapy) Model developed from my research. The ECO-Therapy Model is a grounded theory to explain the mechanisms of change at work in the nature-based therapy process with children. The model was developed in the field of occupational therapy but may inform any pediatric therapist's work with children outdoors in nature. I'd love to hear your thoughts after you listen! It may be helpful to SEE a picture of the model while you listen to this episode. I describe a bit of what it looks like but a picture says a thousand words. You can find the image pinned at the top of my Instagram profile @lauraparkfig and it is also the thumbnail for this episode. (You may have to zoom in to see the details...) Here's what you'll learn: 00:01:27 The funny story about how I decided to share the model on this podcast episode. 00:02:42 Background of my research; what grounded theory is. 00:06:11 Why I named it The Ecology of Change in Outdoor Therapy (ECO-Therapy Model) 00:08:42 Names of the actors in the nature-based therapy process: Nature as the Continual Context and Blameless Co-Therapist; Child as the Motivated Adventurer; Therapist as the Attuned Analyzer and Modulator; Caregivers as the Contributing Beneficiaries 00:12:42 Six iterative phases in the nature-based therapy process: Longing for Freedom, Embarking on Adventure, Dancing with Nature, Claiming Self-Agency, Braving Real-Life Challenges, & Growing Adaptive Capacity. 00:29:09 The concept of hormesis and the hormetic effect of real-life challenges in nature 00:30:54 Real-life challenge compared to just-right challenge I would LOVE to hear your thoughts after listening to this episode. There is a lot more I could share from my research (there were 3 research questions and lots of data other than what I shared here)...so if this is interesting to you, please let me know! You can share your thoughts inside the Therapy in the Great Outdoors Community here. I always want these episodes to support your work with children to help you grow a thriving nature-based practice! xoxo Laura

In today's episode, Dr Shannon takes the prenatal chiropractic conversation down a different avenue.  A lot of times, she deals with patients who are seeking care for aches and pains related to pregnancy and fetal malposition issues (and we have tons of episodes about how adjustments impact those issues), but chiropractic care impacts how our nervous system functions - it's not just a pain reliever.  She uses her own birth stories to highlight how important nervous system regulation is for mom's preparing for birth.  Birth can bring about lots of feeling and emotions such as fears and issues with control which can impact the birthing process.  Chiropractic adjustments can take us from sympathetic dominance into parasympathetic calmness and facilitate the normal birthing process. Resources mentioned in the show:Ep 61: Finding your breath - 5 breathing exercises for pregnancy and postpartum Ep 103: Processing the emotions of pregnancy and birth through chiropractic care Ep 73: Five benefits of prenatal chiropractic care Ep 45: Top reasons to seek chiropractic care during pregnancy The Polyvagal TheoryVagus Nerve as a Modulator of the Brain-Gut Axis Breath of Life: The Respiratory Vagal Stimulation Model of Contemplative Activity Heart Rate Variability to Assess the Changes in Autonomic Nervous System Function Associated with Vertebral SubluxationSupport the showWant to show your support? Want to help us continue doing this important and impactful work: Support the Show (we greatly appreciate it!)Don't miss new episodes: Join the Aligned Birth CommunityInstagram: Aligned Birth Email: alignedbirthpodcast@gmail.com Find us online:Sunrise Chiropractic and Wellness North Atlanta Birth Services Editing: Godfrey SoundMusic: "Freedom” by RoaDisclaimer: The information shared, obtained, and discussed in this podcast is not intended as medical advice and should not be relied upon as a substitute for professional consultation with a qualified healthcare provider familiar with your individual medical needs. By listening to this podcast you agree not to use this podcast as medical advice to treat any medical condition in either yourself or others. Consult your own physician for any medical issues that you may be having. This disclaimer includes all guests or contributors to the podcast.

Diese Folge findest du auch im Videoformat beim Hauptsponsor der Show hier. Hier findest du im übrigen die aktuell umfangreichste DNA Analyse und Auswertung Deutschlands myGenes von EpiGenes. Du bist total begeistert von der Themenwelt der Epigenetik und möchtest Epigenetic Coach werden? Hier findest du alle Informationen dazu. Epi Food ist die neue gesunde Küche ohne Weizen, Zucker und Kuhmilch, welche sich epigenetisch negativ auf die Zellgesundheit und somit auf die DNA auswirken würden. Die Gründerinnen von Epi Food, Alex und Felix, sind schon seit 2014 in der Welt der Epigenetik unterwegs und haben 2019 ihr Buch „Epi Food“ veröffentlicht.   Auf ihrer Website gibt es eine jede Menge epische Rezepte, eine App und Workshops, die nicht nur darauf abzielen die DNA zu schützen sondern auch das ganze genetische Potential auszuschöpfen. Das gleichnamige Kochbuch basiert im Grunde ebenso auf dieser Idee, ich kann es nur empfehlen sich hier etwas Inspiration für eine leckere gesunde Küche abzuholen. Im Interview geht es um viele Küchentricks, „Do's“ and „Dont's“, Rezepte, Tee, Kaffee, Olivenöl und vieles mehr.  Inhalte: 4:40 min: Alexs persönliche Geschichte und Weg aus der Bulimie  8:35 min: Zucker, Bulimie, Magersucht und „Binge Eating“  12:45 min: Felis Bachelor Arbeit Geusndheitstrend Epigenetik 16:00 min: keine Milch, Weizen und Zucker? Vs. individuelle Ernährung 17:05 min: Intervallfasten in Menopause  18:00 min: Laktoseverträglichkeit, DNA und Anpassung von Europäern & Unverträglichkeiten  19:55 min: Was aus seiner Küche eliminieren sollte 24:05 min: Step by Step Verhaltensveränderung vs. All-In Eliminierung 24:45 min: Nährwerttabellen und Fehlerabweichung 25:30 min: Yoghurt selber machen und Alternativen  26:00 min: Tee vs. Kaffee, die Qualität machts 27:20 min: Olivenöl ist Motoröl!  30:00 min: Oleuropin als epigenetischer Modulator, Biolabel und gepunchte Öle 32:00 min: Nährwerttabelle vs. Zutatenliste 33:40 min: David Asprey und Studien zu Kaffee Qualität 35:20 min: fünf Gerichte kocht man im Durchschnitt  36:15 min: Hormone und Kräuter 36:50 min: Ausbleiben der Periode und Ernährungsumstellung  44:20 min: Bockshornklee, Bittermelone und Ceylon Zimt 44:45 min: Timing der Nahrungsaufnahme und Blutzuckermanagement 47:05 min: Stress, Supplements, Lifestyle und Ernährung  49:15 min: Ernährungsumstellung ist Verhaltensveränderung  52:05 min: Trigger als Urasche/Unterstützung für Verhalten 53:05 min: „gesunde“ süsse Alternativen 57:25 min: organische Lebensmittel günstig beziehen  1:00:45 min: Lebensmittel für die Libido  1:04:25 min: Maca, Austern, Zink, Selen 1:06:00 min: Zink und Testosteron   Links: www.epi-food.com Epi Food Kochbuch

Can brain-gut behavioral therapies reduce IBS symptoms, not just mood and psychological symptoms? Drs Lin Chang and Laurie Keefer discuss why incorporating this therapy in your practice works. Relevant disclosures can be found with the episode show notes on Medscape (https://www.medscape.com/viewarticle/987262). The topics and discussions are planned, produced, and reviewed independently of advertisers. This podcast is intended only for US healthcare professionals. Resources Irritable Bowel Syndrome (IBS) https://emedicine.medscape.com/article/180389-overview Benson-Henry Institute for Mind Body Medicine https://bensonhenryinstitute.org/mission-history/ Microbiome https://www.genome.gov/genetics-glossary/Microbiome Vagus Nerve as Modulator of the Brain-Gut Axis in Psychiatric and Inflammatory Disorders https://pubmed.ncbi.nlm.nih.gov/29593576/ Burden of Anxiety and Depression Among Hospitalized Patients With Irritable Bowel Syndrome: A Nationwide Analysis https://pubmed.ncbi.nlm.nih.gov/36593438/ A Rome Working Team Report on Brain-Gut Behavior Therapies for Disorders of Gut-Brain Interaction https://pubmed.ncbi.nlm.nih.gov/34529986/ Cognitive-Behavioral Therapy for IBS and Other FGIDs https://iffgd.org/resources/publication-library/cognitive-behavioral-therapy-for-ibs-and-other-fgids/ App-Delivered Gut-Directed Hypnotherapy Program Nerva Improves Symptoms in Patients With Irritable Bowel Syndrome but How Can We Ensure Users Are Compliant? https://gi.org/media/press-info-scientific-meeting/featured-science/oral-15 The Role of Resilience in Irritable Bowel Syndrome, Other Chronic Gastrointestinal Conditions, and the General Population https://pubmed.ncbi.nlm.nih.gov/32835842/

Diese Folge findest du auch im Videoformat unter ww.epi-genes.com Raphael ist NLP Advanced Master, NLP Master Coach, NLP Trainer, Lehrtrainer und Lehrcoach. Er hat zudem Ausbildungen als Professional Neuro Rhetoriker und Master Neuro Rhetoriker. Er ist psychologischer Berater, systemischer integraler Coach, Sales Coach und Sales Trainer.  Das klingt nach ihr viel Coaching und Erfahrung in Persönlichkeitsentwicklung. Tatsächlich hat Raphael etliche Menschen aus den unterschiedlichsten Bereichen als Coach in ihrer Entwicklung begleitet. Er hat ca. 14.000 Coachinggespräche geführt und 16.000 Stunden Seminare in der Erwachsenenbildung gehalten und Ausbildungen durchgeführt. Als NLP Practicioner durfte ich selbst ein bisschen die Welt der Persönlichketsentwicklung kennenlernen, weshalb ich mich ganz besonders gefreut habe mit Raphael noch tiefer in die Materie einzutauchen. Vor allem über Themen zu sprechen, die unser Mindest und somit auch unsere Epigenetik und Gesundheit beeinflussen. Insbesondere, welche Techniken man praktizieren kann, um positiv darauf einzuwirken.  Der thematische Zusammenhang zur vorhergehenden Episode mit Andreas Krüger und auch zu den drei folgenden Episoden ist nicht nur gegeben, sonder ergänzt und vervollständigt sich sogar inhaltlich sehr schön.  Im Interview sprechen wir über die epigenetischen Auswirkungen unseres Mindsets. In wie fern Glaubenssätze unser Verhalten und unsere Gesundheit bestimmen und wie gewisse Techniken, wie die Hypnose hier hilfreich sein können. Inhalte: 3:25 min: die dunkle Seite von Neurolinguistischem Programmieren (NLP) 7:25 min: wir werden von Medien, unseren Ummenschen und unserer Kommunikation beeinflusst und manipuliert 10:15 min: warum sich manche Menschen entwickeln und manche Menschen nicht 12:25 min: Spiral Dynamics, biopsychosoziales Bewusstsein und Wendeltreppe des Bewusstseins 17:05 min: 3 Bewusstseinszustände, 8 Stufen des Bewusstseins & Erleuchtung 18:55 min: Glaubenssätze auflösen in unterschiedlichen Bewusstseinszuständen 22:05 min: Quantenphysik, Verbundenheit und Erleuchtung 24:15 min: wie Kommunikation das Epigenom prägt 27:58 min: Neurotransmitter, Hormone und Kommunikation & Katia Trost und Episode 6 29:15 min: Glaubenssätze als epigenetischer Modulator  33.14 min: Elon Musk: „es ist einfacher Menschen zu beeinflussen, als Menschen aufzuzeigen, dass sie beeinflusst wurden“ 34:00 min: toxische Glaubenssätze 36:45 min: Glaubenssätze sind im Unterbewusstsein & Glaubenssätze über Glaubenssätze 38:30 min: Unverträglichkeiten und Glaubenssätze  43:55 min: wie lange es dauert einen Glaubenssatz aufzulösen & Glaubenssätze als Stütze des Lebens 47:03 min: Techniken um Glaubenssätze aufzulösen 52:20 min: Glaubenssätze positiv nutzen 56:05 min: meine Mindest Techniken: Dankbarkeit, Journaling und Priming 1:01:00 min: Trauma und Glaubenssätze 1:04:50 min: Glaubenssätze steuern unser gesamtes Leben 1:06:30 min: wie funktioniert die Hypnose? 1:08:40 min: gibt es die „TV-Hypnose“ auf schnippen? 1:09:45 min: Hypnose vs. Trance 1:14:15 min: Hypnose und Priming, Gehirnschwingungen und Flow 1:17:45 min: Abschirmen, Fremdenergien und das „gelbe“ Chakra 1:18:32 min: Mindsettechniken für zuhause  Links: https://training-supervision-coaching.de/

Today's Discussion Is... Reviewing and Discussing Resident Evil 4 (2023) Join your hosts: Wolf (@BoneKingTV) and Special Guest Co-Host Signal Modulator (aka @BrawlingBarb) as they tackle the remade, remixed, and revised story of Resident Evil 4 (2023)! With some comparisons to the original, first impressions, character examinations, personal experiences, speculations and more! Do you like thrill rides? Strap in, because today's episode is a long one!   @BoneKingTV|@BrawlingBarb Yell at us on Twitter! Theme: Opening/The Drive by Capcom

In this episode of the Business Broken to Smokin' Podcast: Lodestone True North's Head Coach Mark Whitmore and his right hand man Shane Kardos discuss digging down into the roots of issues. 0:00 Intro 8:00 At the root of all issues, at the end of the day, it basically goes back to the owner. 10:00 Reference to our S.M.A.C.K.! Tool (Check out our free course here: https://lodestone.thinkific.com/courses/smack ) 11:25 There are a handful of suspects for roots of issues 12:35 Places to look for potential roots on the “They Own” side: 13:25 Our People/Culture/Core Values - Attitude - Work Ethic - Ability or Talent - Availability 15:40 Clients 16:50 Vendors 17:50 On the We side (the leadership team) - Core Values - Strategy - Vision or where are we going - Purpose (why we exist) - Structure - Putting talented people in the right seats - Communication - Processes (behaviors, how we do things) - Systems (pipes and wires) - Tangibles (buildings, trucks, equipment, gear) **Credits** Music - Digging in the Dirt by Peter Gabriel on the album US Website: https://www.lodestonetruenorth.com Website: https://www.bigeasydesk.com (The best co-working space in Northeast Ohio!) LinkedIn Book Club Group: https://www.linkedin.com/groups/14158790/ LinkedIn Mark: https://www.linkedin.com/in/mark-whitmore-lodestone/ LinkedIn Lodestone: https://www.linkedin.com/company/lodestone-true-north Lodestone Online Courses: https://lodestone.thinkific.com Podcast: YouTube (video) https://youtube.com/@lodestonetruenorth Spotify (video or audio) https://open.spotify.com/show/3QCsZ7fyKr4z804oTac3FU Apple Podcasts (audio) https://apple.co/3O4uv4H Other Podcast Platforms https://lodestonetruenorth.com/podcast/

In this episode, host Dr. Amber Luong speaks with Dr. Devyani Lal and Dr. Tripti Brar. They discuss their recently published article: Biological sex as a modulator in rhinologic anatomy, physiology, and pathology: A scoping review. Read the article in the International Forum of Allergy and Rhinology. Listen and subscribe for free on Apple Podcasts , Google Podcasts and Subscribe […]

Diesen Podcast findest du auch im Videoformat auf www.epi-genes.com. Alexander ist Gründer von Natugena und Epi Genes. Wir sind schon seit Jahren befreundet und arbeiten zusammen. Unser Drive so vielen Menschen wie möglich die Informationen über holistische Gesundheit näher zu bringen, hat uns dazu gebracht den Epigenetik Podcast ins Leben zu rufen, bei dem wir die namhaftesten Gesundheitsexperten im deutschsprachigen Raum einladen und Ihre Ansichten und Behandlungsmethoden zu verbreiten. Um so mehr free mich heute die erste Folge mit Alex zu starten, um über seine Expertise im Bereich Mikronährstoffe zu sprechen. Alexander Martens ist Sportwissenschaftler, Mikronährstoffexperte und Gründer von NatuGena, einem Unternehmen, das sich auf die Herstellung von natürlichen Nahrungsergänzungsmitteln spezialisiert hat. Die Idee für NatuGena entstand aus seiner eigenen Erfahrung mit gesundheitlichen Problemen und der Suche nach natürlichen Lösungen, um seine Gesundheit zu verbessern. Das Ziel von NatuGena ist es, hochwertige Nahrungsergänzungsmittel auf Basis von natürlichen Inhaltsstoffen anzubieten, die das Wohlbefinden und die Gesundheit unterstützen sollen. Die Produkte von NatuGena werden unter strengen Qualitätsstandards hergestellt und enthalten keine künstlichen Farbstoffe, Aromen oder Konservierungsmittel. Zu den Produkten von NatuGena gehören unter anderem Nahrungsergänzungsmittel zur Unterstützung des Immunsystems, zur Verbesserung der Verdauung und zur Steigerung der Energie. Das Unternehmen legt großen Wert darauf, dass die Inhaltsstoffe in seinen Produkten auf natürliche Weise gewonnen werden und von höchster Qualität sind. Inhalte: 4:30 min: unser Drive im Gesundheitswesen 7:00 min: Nährstoffmängel, Genetik und warum Supplements? 10:50 min: „An apple a day keeps the doctor away“ stimmt das? 12:05 min: Unterschied Discounter Produkte vs. Qualitätsprodukt 16:50 min: Trennstoffe und was soll nicht in Nahrungsergänzungsmitteln auftauchen 21:35 min: Bioverfügbarkeit Pflanzenstoffe 25:50 min: Nährstoffbedarf vs. Information 28:55 min: Bioverfügbarkeit von Nährstoffen 35:00 min: Vitamin D3 als epigenetischer Modulator 36:15 min: Aufgaben Vitamin D3 39:30 min: Vitamin D3 Stoffwechelprozess 42:30 min: Vitamin D3 Ratio 25 OH:1,25 OH 45:45 min: Rezeptorblockaden, genetische Polymorphismen und Heterodimerität 51:45 min: Bor und Vitamin D3 53:15 min: Vitamin K2 und Knochenstoffwechel 58:55 min: Vorausschau, wohin bewegt sich die Industrie Natugena GmbHNatuGena ist nicht nur auf die Herstellung von Nahrungsergänzungsmitteln spezialisiert, sondern engagiert sich auch für Nachhaltigkeit und Umweltschutz. Das Unternehmen setzt sich für den Schutz der Umwelt ein und verwendet nachhaltige Verpackungsmaterialien, um seinen ökologischen Fußabdruck zu reduzieren. 2021 hat Alexander Martens dann noch Epi Genes ins Leben gerufen und schließt damit die Lücke zur genbasierten Lifestyle und Nährstoffberatung.

Episode 89 The Theremin Part 2: Recordings After 1970 Playlist Ultimate Spinach, “(Ballad of The) Hip Death Goddess” from Ultimate Spinach (1968 MGM Records). This American psychedelic rock band was from Boston, Massachusetts, although they had a sound that had more an affinity with the free spirit of San Francisco. The Theremin has a prominent part in this song, following the vocalist and filling in some interesting instrumental parts. Bass and Feedback, Richard Nese; Vocals, Drums, Tabla, Bass Drum, Bells, Chimes, Keith Lahteinen; Vocals, Electric Guitar, Guitar, Kazoo, Barbara Hudson; Vocals, Electric Piano, Electric Harpsichord, Organ, Harpsichord, Twelve-String Guitar, Sitar, Harmonica, Wood Flute, Theremin, Celesta, Ian Bruce-Douglas; Vocals, Lead Guitar, Guitar Feedback, Sitar Drone, Electric Sitar, Geoffrey Winthrop. 8:11 Hawkwind, “Paranoia Part 2” from Hawkwind (1970 Liberty). Hawkwind was a pioneering space-rock and psychedelic group from the UK. They were known to use a theremin during their early years—1969 to 1973 and revived its use on stage in later performances using a Moog Etherwave model in the 2000s. This first album features a theremin added to much of the sonic textures, sometimes overtly but often run through effects to provide a looming background, as in this song. It is sometimes difficult to distinguish, but I think there is a theremin providing some of the droning background and then sporadic bursts of tones beginning around 4:25. 14:54 McKendree Spring, “God Bless the Conspiracy” from 3 (1972 Decca). Electric Violin, Viola, Theremin, Michael Dreyfuss; Electronics (Ring Modulator), Tom Oberheim; Vocals, Acoustic Guitar, Dulcimer, Fran McKendree; Electric Bass, Larry Tucker; Electric Guitar, Martin Slutsky. This progressive band with experimental leanings was a quartet without a drummer. Dreyfus later said, “In God Bless the Conspiracy and No Regrets I was able to play viola and Theremin at the same time by bringing my body closer to the Theremin (to change pitch) while playing a harmony part on the viola,”(2006). He played a Theremin beginning 1969. He may have used a Moog theremin, such as the Troubadour. 6:53 Linda Cohen, “Horizon Jane” from Lake Of Light (1973 Poppy). Folky album from Philadelphia featuring several electronic musicians. Acoustic Guitar, Bass, Piano, Polytonic Modulator, Jefferson Cain; Classical Guitar, Composer, Linda Cohen; Flute, Stan Slotter; Producer, Electric Guitar, Matrix Electronic Drums, Modulator, Sitar, Synthesizer, Craig Anderton; Minimoog, Theremin, Charles Cohen. 3:36 Ronnie Montrose, “Space Station #5” from Montrose (1973 Warner Brothers). Ronnie Montrose added a custom-built Theremin to his equipment with the pitch antenna mounted on his aluminum (silver) Velano guitar so that he could play both at the same time. Volume for the theremin was controlled by a black box mounted on a mike stand, to which he stood nearby. He was recording with it throughout the 1970s. Here is a great live clip you where you can see how he played it. Note the end of the clip where he put the theremin guitar up against the speaker and wails on the volume control of the theremin control box. Bass, Bill Church; Drums, Denny Carmassi; Guitar, Theremin-Guitar, Ronnie Montrose; Vocals, Sam Hagar. 5:36 Arthur Brown's Kingdom Come, “Time Captives” from Journey (1974 Passport). Fender Bass, Percussion, Vocals, Phil Shutt; Bentley Rhythm Ace, Vocals, Arthur Brown; Electric Guitar, Vocals, Andy Dalby; Mellotron, ARP 2600, EMS VCS 3, Piano, Theremin, Percussion, Vocals, Victor Peraino. 8:37 Michael Quatro, “Get Away” from In Collaboration with The Gods (1975 United Artists Records). Brother of Detroit rockers Suzi and Patti Quatro, he had a flare for progressive rock and electronic keyboards in the 1970s. The Theremin makes frequent appearances on this album, this track in particular. Arranger, Piano Baldwin, Electric Piano Gretsch Electro, Piano Tack Piano, Sonic Six Synthesizer, Effects Univox Phaser, Univox Stringman, EC-80 Echo, Elka Electric Piano, Hammond Organ, Minimoog Synthesizer, Univox Mini-Korg, Electroharmonix Boxes, Mellotron Violin, Cello, Flute, Effects Wah-Wah Pedals, Effects Syntha-Pedal, Bass Nova Bass, Horns, Organ Pipe Organ, Sounds Ring Modulation, Maestro Theremin, Electronic Effects, Percussion , Michael Quatro;Bass, Lead Vocals, Arranged By Arranging Assistance, Dave Kiswiney; Drums, Kirk (Arthur) Trachsel; Guitar, Teddy Hale. 4:04 Melodic Energy Commission, “Revise The Scene” from Stranger In Mystery (1979 Energy Discs). This is the first album from this Canadian space-rock, psychedelic and folk troupe from British Columbia. The Theremin was a key instrument in their ensemble and was custom-built by group member George McDonald. His Theremin would eventually be known as the Galactic Stream Theremin and would take some 25 years to build and evolve into a six antennae instrument for “tuning into the performers body motions.” During this recording, a simpler, more traditional version was used. Gas & Steam Bass, Bells, Tambourine, Mark Franklin; Dulcimer, Bowed Dulcimer, Khaen, Gongs, Flute, Randy Raine-Reusch; Hydro-electric Guitar, Custom-made Theremin, Aura, Wall Of Oscillation, George McDonald; Percussion, Tablas, Brass Tank, Glockenspiel, Roland SH5 Synthesizer, Organ, Paul Franklin; EMS Synthi AKS, Delatronics, Electric Guitar, Del Dettmar; Wordy Voice, Guitar, Piano, Organ, Roland SH 1000 Synthesizer, Gongs, Vibraphone, Kalimba, Stone Drum, Egyptian Shepherd's Pipe, Xaliman. 6:13 The Nihilist Spasm Band, “Elsinore” from Vol. 2 (1979 Music gallery Editions). Canadian group that used all hand-made instruments, including the kit-made Theremin by Bill Exley. Bass, Hugh McIntyre; Drums, Greg Curnoe; Guitar, John Clement, Murray Favro; Kazoo, John Boyle; Pratt-a-various, Art Pratten; Vocals, Theremin, Bill Exley. Recorded live at the Toronto Music Gallery, February 4th 1978. 5:14 Yuseff Yancy, Garret List, “Sweetness” Garrett List / A-1 Band, “Sweetness” from ‎Fire & Ice (1982 Lovely Music). Alto Saxophone, Byard Lancaster; Maestro Theremin, Electronics, Youseff Yancy; Vocals, Genie Sherman. 4:11. Todd Clark, “Into the Vision” from Into The Vision (1984 T.M.I. Productions). Guitar, Cheetah Chrome; Theremin, Bat-wing Guitar with ARP Avatar, Todd Clark; Found Vocals, William Burroughs. 8:38 Danielle Dax, “Yummer Yummer Man” from Yummer Yummer Man (1985 Awesome). UK artist Danielle Dax. Wah Guitar, Steve Reeves; Guitar, Slide Guitar, Organ, David Knight; Producer, arranger, lyrics, Vocals, Theremin, Tapes, Danielle Dax; Drums, Martyn Watts; Music by Danielle Dax, David Knight. Dax is an experimental English musician, artist, and producer, born as Danielle Gardner. 3:16 Mars Everywhere, “Attack of the Giant Squid” from Visitor Parking (1989 Audiofile Tapes). Cassette release from this space-rock band from the 1980s. Electric Guitar, Electronics, Tape, Ernie Falcone; Synthesizer, Theremin, Keyboards, Tom Fenwick. 5:03 Jon Spencer Blues Explosion, “Vacuum of Loneliness” from The Jon Spencer Blues Explosion (1992 Caroline). This NY band uses an original Moog Vanguard (circa 1960). This rock and blues band was active from 1991 until 2016. Baritone Saxophone, John Linnell; Drums, Russell Simins; Guitar, Vocals, Judah Bauer; Tenor Saxophone, Kurt Hoffman; Trumpet, Frank London; Vocals, Guitar, Moog Vanguard Theremin, Jon Spencer. Here is a video of a live performance of The Jon Spencer Blues Explosion with a Moog Vanguard Theremin (just after the 39-minute mark). 3:02 Calvin Owens and His Blues Orchestra, “Vincent Van Gogh” from That's Your Booty (1996 Sawdust Alley). Trumpet solo and vocals, Calvin Owens; Maestro Theremin, Youseff Yancy; Alto Saxophone, Tenor Saxophone, Eddy De Vos, Kurt van Herck, Peter Vandendriessche; Backing Vocals, B. J. Scott, Frank Deruytter, Mieke Belange, Yan De Bryun; Baritone Saxophone, Bo Vander Werf, Johan Vandendriessche; Bass, Ban Buls, Roman Korohek; Cello, B. Piatkowski, X. Gao; Drums, Cesar Janssens, Laurent Mercier; Guitar, Marty Townsend, Yan De Bryun; Keyboards, Rafael Van Goubergen; Organ, Peter Van Bogart; Saxophone, Jimmy Heath; Tenor Saxophone, David "Fathead" Newman, Shelly Caroll Paul; Trombone, Marc Godfroid, Yan De Breker; Trumpet, Andy Haderer, Rüdiger Baldauf; Violin, D. Ivanov, E. Kouyoumdjian; Vocals, Archie Bell, Otis Clay, Ruby Wilson. 6:23. David Simons, “Music For Theremin And Gamelan (1998-1999), parts I and II” from Fung Sha Noon (2009 Tzadik). Theremin, Rob Schwimmer; Gamelan, Theremin, Sampler, MIDI Controller, Percussion, Marimba, Zoomoozophone, 43 Pitch Zither, Harmonic Canon, Slide Guitar, Chromelodeon harmonium, David Simons; Gamelan, Barbara Benary, Denman Maroney, John Morton, Laura Liben. 6:09 (part I) and 6:29 (part II) Lydia Kavina, “Voice of the Theremin,” composed by Vladimir Komarov from Music from The Ether, Original Works For Theremin (1999 Mode). TVox Tour model theremin, Lydia Kavina. Arranged, mixed, performed by Lydia Kavina. 8:11 Lydia Kavina, “Free Music #1,” composed by Percy Grainger from Music from The Ether, Original Works For Theremin (1999 Mode). TVox Tour model theremin, Lydia Kavina; mixed and spatialized, Steve Puntolillo. This work was originally written for theremin although Grainger had many ideas around how this type of “free music” should be played. This native Australian was fascinated by the sounds of the real world and invented a mechanical machine for making such sounds. In 1938, Grainger said, "...Out in nature we hear all kinds of lovely and touching 'free' (non-harmonic) combinations of tones, yet we are unable to take up these beauties and expressiveness into the art of music because of our archaic notions of harmony.” His adaptation of free music for theremin was an attempt to create sounds that were new to music. This version was multitracked by Kavina and an old acquaintance of mine, sound engineer Steve Puntolillo, to recreate the parts for four theremins. 1:19 The Kurstins, “Sunshine” from Gymnopedie (2000 Rouge Records). Composed by Roy Ayers; Minimoog, ARP String Ensemble, Organ, Guitar, Sampler, Drums, Rhodes Electric Piano, Greg Kurstin; Moog Theremin, Theremin Vocoder, Moogerfoogers, Pamelia Kurstin. 3:47 The Kurstins, “Outside” from Gymnopedie (2000 Rouge Records). Composed by Greg Kurstin; Minimoog, ARP String Ensemble, Organ, Guitar, Sampler, Drums, Rhodes Electric Piano, Greg Kurstin; Moog Theremin, Theremin Vocoder, Moogerfoogers, Pamelia Kurstin. 3:55 Hecate's Angels, “Shrink-Wrapped Soul” from Saints And Scoundrels (2004 redFLY Records). Los Angeles-based Pietra Wexstun is a composer, singer, keyboard and theremin player. Vocals, Farfisa organ, piano, theremin, sound effects, Pietra Wexstun; bass, Bill Blatt; guitar, Stan Ridgway; drums, Elmo Smith. 3:52 Pamelia Kurstin, “Barrow In Furness” from Thinking Out Loud (2007 Tzadik). From Kurstin first solo record. Composed, Produced, Theremin With L6 Looping Pedals and Microsynth Pedal, Guitar, Piano, Pamelia Kurstin. She played the Etherwave Pro Theremin by Moog fo this recording. Pamelia Kurstin, video with she and Bob Moogdiscussing the Etherwave Pro when it was introduced. Kurstin uses the Etherwave Pro Theremin by Moog Music. 5:12 Barbara Bucholtz, “SixEight” from Moonstruck (2008 Intuition Records). Bucholtz was a German theremin player and composer. She played a TVox Tour model theremin. Drums, Sebastian Merk; Music By, Contrabass Flute, Sampler, programmed, engineered, produced, and recorded by Tilmann Dehnhard; Trumpet, Arve Henriksen. 4:01 Herb Deutsch, “Longing” from Theremin One Hundred Years (2020 Electronic Sound). Composer, Herb Deutsch; Piano, Nancy Deutsch; Moog Melodia Theremin, Daryl Kubian. Recording from 2012. The beloved Herb Deutsch, who died recently at age 90, was an early collaborator with Bob Moog on the creation of the synthesizer. Herb became acquainted with Bob by purchasing a Theremin kit—a Moog Melodia model, in the early 1960s. He was primarily responsible for convincing Moog to add a keyboard to his modular unit. Also, this is taken from a terrific compilation of modern Theremin artists to benefit the New York Theremin Society. Check it out. 3:38 M83, “Sitting” from M83 (2016 Lowlands Festival). This is a live recording from Holland. “Sitting” was a song on M83's first album in 2001. But it didn't have a theremin part until they decided to spice-up the live interpretation of the song in 2016. Jordan Lawlor uses a Moog Theremini when M83 performs this in concert. He puts down his guitar, grabs some drum sticks, beats a rhythm on some electronic drums while dancing in place and moving his hands around a theremin. You can hear the theremin in this track but don't mistake it for the keyboard tones that Gonzalez is playing on his modular system. A longer sequence of theremin begins at 1:38 in the audio. You can view the video here, beginning at 26:54 into the show. M83 is a French electronica band founded in 1999 by Anthony Gonzalez, who remains the only sole member from the original outfit. Performing members on this live tour included: Anthony Gonzalez, lead vocals, modular synthesizers, keyboards, guitars, piano, bass, drums, percussion, programming, arrangement, mixer, production; Loïc Maurin, drums, percussion, guitar, bass, keyboards; Jordan Lawlor, guitars, vocals, multi-instrumentalist; Kaela Sinclair, Dave Smith and M-Audio keyboards, vocals; Joe Berry, piano, synthesizers, electronic wind instrument, saxophone. 4:03 Radio Science Orchestra, “Theme from Doctor Who” (2019). This UK-based band unites theremin, ondes martenot, Moog and modular electronics, for its performances. They've played such events as the TEDSummit, the British Library, and Glastonbury Festival. They made a concert recording with Lydia Kavina in 2009 of the Theme from Doctor Who. This version was made more recently and appears to also include Kavina. She plays the TVox Tour model theremin made by her husband G. Pavlov. 2:18 Thorwald Jørgensen, Kamilla Bystrova, “Moderato” from Air électrique: Original Music For Theremin And Piano (2020 Zefir). Jørgensen is an accomplished Dutch classical theremin player. Piano, Kamilla Bystrova; Liner Notes, Design, Moog Etherwave Pro Theremin, Thorwald Jørgensen. 2:10 Dorit Chrysler, “A Happy Place” from Theremin One Hundred Years (2020 Electronic Sound). Issued with the magazine's 7” vinyl and magazine bundle Electronic Sound Magazine, issue 70. Written, produced, and performed by Dorit Chrysler. 2:06 Dorit Chrysler, “Calder Plays Theremin Side A” from Calder Plays Theremin (2023 NY Theremin Society/Fridman Gallery) Written for Theremin Orchestra in 5 Movements, Chrysler's work is based on a commissioned sound piece by The Museum of Modern Art in conjunction with the exhibition Alexander Calder: Modern from the Start. Chrysler identified two of Alexander Calder's sculptures, Snow Flurry, I (1948) and Man-Eater with Pennants (1945), to interact and “play” multiple Theremins on site. I believe the Theremin are various Moog models. Calder Plays Theremin is a co-release of the NY Theremin Society and Fridman Gallery. 8:48   Opening background tracks: Ronnie Montrose, “Open Fire” (excerpt) from Open Fire (1978 Warner Brothers). Bass, Alan Fitzgerald; Drums, Rick Shlosser; Guitar, Custom-built Theremin mpounted to his electric guitar, Ronnie Montrose; composed by Edgar Winter, Ronnie Montrose. 2:09 Hooverphonic, “‎L'Odeur Animale” from The Magnificent Tree (2000 Columbia). Guitar, Raymond Geerts; Keyboards, Bass, Programmed by Alex Callier; Vocals, Geike Arnaert; Maestro Theremin, trumpet, Youseff Yancy; Fairlight, Effects, Dan Lacksman. 3:46. Opening and closing sequences voiced by Anne Benkovitz. Additional opening, closing, and other incidental music by Thom Holmes. See my companion blog that I write for the Bob Moog Foundation: For additional notes, please see my blog, Noise and Notations.

50 years ago, television manufacturer Magnavox launched a revolutionary new device that allowed users, for the first time, to manipulate the images on their home television sets.  How did this technological wonder come to be?  How did its development evolve?  Find out with our own resident Warden of the Department of Corrections, Ethan Johnson.   Links: https://www.mobygames.com/game/super-breakout/cover-art/gameCoverId,20988/ https://restaurant-ingthroughhistory.com/2014/07/13/the-browning-of-mcdonalds/ https://en.wikipedia.org/wiki/Magnavox_Odyssey https://twitter.com/j_ljunggren/status/1573688288661180416 https://en.wikipedia.org/wiki/Breakout_(video_game) https://thehistoryofhowweplay.wordpress.com/2022/09/16/the-first-video-game-console-a-new-history/   Timeline: August 31, 1966 - Baer conceptualizes the TV Gaming Display.     -He was supposedly in New York and was meeting somebody before going back up to New Hampshire.   September 1, 1966 - “Disclosure Backup DATA - TVGD” is drafted by Ralph Baer, witnessed by Bob Solomon.     -Game types: Action games, board games, artistic games, instructional games, board chase games     -”Example: ‘Steering' a wheel to control random drift of color (hue) over the CRT face”     -Pumping game mentioned     -”Bar, line, or dot generation - players control selective blanking, blinking, color coding of lines, bars, dots, fields via generator”   September 6, 1966 - TV Mode Data Entry Device, witnessed by Bob Solomon, Baer mocks up a schematic of the basic technical idea of driving signals to the screen.     -”Etch-a-sketch” drawing gives misleading impression of the vision of the system at present   December 1966 - Mocking up of screen splitting   December 20, 1966 - Herbert Campman approves the exploration of TVGD, “NBDA - Low Cost TV Data Entry Devices”     -$2000 for development, $500 for materials   January 2, 1967 - Robert Solomon joins “TVTY - NBD”     -His mockups show the screen split into even grids via an overlay or of two lines crossing each other like a cursor   February 6, 1967 - Robert Tremblay writes a schematic.   February 11, 1967 - “Discussion w/ R. Solomon Future planning - TV Gaming”     -Heathkit generator being used for driving objects, “to allow generation of a vertical bar, movable across the TV CRT face, & adjustable color”     -Modulator is set to Channel 3     -Next objective is to split the tv into two independent colors     -Pumping contest mentioned   February 12, 1967 - “List of possible games” using horizontal split of the screen, best illustration of their possibilities at this time     -Scoring, Bucket Filling, Game Timer, Skill Games     -Joystick controller sketched   February 17, 1967 - Bill Harrison sketches up electronics for the gun controller, “Odd-Even TV Game”   May 2, 1967 - Harrison writes up a spec on how TV color and video signals work     -Indicates them going back to square one     -Subsequent days see a number of schematics   May 4, 1967 - “TV Gaming”, illustration of split screen idea -“One major problem exist due to the inability to pass a 60 cps square through the picture tube. [...] This is at least partially due to poor low frequency response of the Heath IG-62.”   May 8, 1967 - “TV Generator” custom hardware for running through the Heath generator.     -Tested first on a RCA Model GH 560W   May 9, 1967 - Various game elements are toyed around with     -Diagrams for two pots to act as a “joystick” and a different implementation of the pumping game     -”1 Sound, 2 Pot [Circle drawing] Color Wheel, 3 Bars Vert & Hor”   May 10, 1967 - “Misc. Ideas for T.V.G.” by Bill Rusch to Ralph Baer     -1. Picture Drawing, pots or joysticks plus buttons for choosing color, “Need memory scheme, of course”     -2. Car Steering, movable road, top down or first person     -3. “Same as 2, but skiing”     -4. Chase Game, “Use ships, dots ot probably best two old “dog fighting” type WWI planes… or, up-to-date, plane and missile… or ship and torpedo.”     -5. Maze Game, “if hits line of maze, “rat” disappears and reappears back at the starting point”     -6. Rotating Spiral, “Maybe have 2nd player control instantaneous rotation speed”     -7. Racing game, disappearing if touching bounds, “if car in rear runs into car in front, rear offending car disappears and other one wins”     -8. “Roulette” (in quotations), with arrow at the top of the wheel     -9. “Baseball” Guessing Game, different colored strips, “Batter selects strip in which bat will appear. Pitch pushes “pitch” button, bell rings and ball appears on screen [...] If both appear in same strip, “HIT” Sign flashes [...] otherwise, “Strike” lights up.”     -10. Baseball “Skill Game” #1, “As above, except “ball” stays on for brief period only”     -11. “Map” Game - 1 or 2 Players, “”Teacher” (Player #1 or the “machine”) pushes button which lights up one state and starts timer displayed on screen”, timed with right and wrong buttons     -12. “Tracer Bullet Shooting Game”, player adjust briefly flashing bullets with the joystick to hit a plane then timer stops, “Could also make into single player game by having planes' movements controlled automatically and semi-randomly”     -13. “Baseball Skill Game” #2, selectable skill levels, pitching game Holy Baseballs, Batman!”     -14. Skeet Shooting #1, similar to plane game     -15. ESP Game, players try to guess each other's numbers represented by colors (showing that they couldn't do alphanumerics)     -16. “Hares and Hounds” Game, hares are numerous and small and move quickly whereas hounds are large and move slowly     -17. “Bullfight”, same as above with singular dots and using color for the cape     -18. “Soccer, Hockey, Polo, etc.”, would have team number players, “When displayed ball (puck, etc.) is touched by a man it moves in direction man was going”     -19. Skeet (Airplane) Shooting #2, “Probably best to have “stored” random target program so each player gets same choice of targets for score comparison”     -20. Golf Putting, two controls for choosing angle and power of the ball     -21. “Horse Racing”, another guessing game with color, features the bell again, “Note: The above would make an interesting “Non-TV” Board Game… perhaps could sell idea to someone like Parker Brothers”     -Pings Baer, J Mason, Bill Rusch, and Bob Solomon   May 15, 1967 - Games listed include a game with a telephone dial using the bar up the screen method, and a double bar graph game     -”To Produce Moveable Dot”, “To Produce Lines” outlines   May 16, 1967 - Several games outlined     -1st game, “Pumping Contest”, with a board featuring two buttons. Player one presses the fill the bucket, player two presses to lower the bucket.     -2nd game, “Firefighter's Pump Test”, color shifts from red to blue as player uses a two-sided pump mechanism. Interestingly the controller is atop a similar one to the pumping contest controller with “S2 not used” suggesting a modular controller.     -3rd game, “Color Catching Contest”. Players have to stop a cycling color on the screen that they call out. A variation using a “Flywheel or phonograph turntable” with a stop button, players have to select their color on the turning device after selecting the color on the overlay. Players have a +30/-30 score table on the overlay.     -4th game, “Roulette”. Physical roulette wheel, same as color guessing game. Implies color may switch on screen according to where the ball is on the reel.     -TVG #5, “Car Ride (Race)”. Shifting driving game with special controller. Includes a wheel, a shift, and an accelerator. Harrison suggests giving player 2 control of the shifting road via a joystick.   May 18, 1967 - First game of “Pumping Contest” is played.     -”Winners name will be withheld”   May 19, 1967 - “Car Ride” may be successfully implemented     -May 22, Baer suggests it be made two player who both use joysticks rather than the drive setup.   May 24, 1967 - “TV Generator”, successful production of two independent spots.   May 31, 1967 - Attempts to add on-TV audio. Schematic is crossed out for unknown reason.   June 1, 1967 - Ralph Baer toys with a checkerboard chase game with obstacles. Subsequent pages show maze-like design patterns.     -Bill Harrison toys with circular switches for changing game functionality and audio again.   June 5, 1967 - “Target Shooting Game” is revived. Gun barrel is made with a cardboard tube with a photocell at the other end.   June 7, 1967 - Archives two independent dots, a line, and a color background. Both background and one dot are green.     -Only able to switch between two colors for things like the Color game, green and blue.   June 14 - “Cludge” introduced for generating random numbers through “a digitally coded card is inserted in the dismatchy”.     -Use of “cludge”, an MIT hacker term.     -Said it would be a way to player a monopoly-type game.   June 14/15 1967 - Presentation of the games and funding proposal.     -14th show for Herbert Campman, 15th show for Royden Sanders, Harold Pope, and D Chisholm -Proposal for “Special Display Techniques”, “To investigate the feasibility of using Raster Scan Displays for low-data-rate graphic display applications”    -Requires three engineers, six techs, and 0-3 admins.         -Expected completion in January 1968. Design Aug-Sept, Breadboarding Sept-December, Final Report in January -Total budget of $17,240 -”Summary of Major Games”     -”Chess Board Game”, chase game where the player can only move orthogonally.     -”Fox Hunt”, three player game with fox, hunter, and scorekeeper. Fox is red.     -”Fox & Hounds Chase”, two players with three hounds and one fox. Fox tries to get from upper right to lower left.     -”Target Shooting”, stationary or moving targets     -”Color Guessing Game”, physical spinner and score kept with TV     -”Bucket Filling Game”, Pumping Contest   June 15, 1967 - “Items for Coverage” new list of games ideas     -”Analogic (Sleep Inducing) Application”, pattern generator, would have an automatic TV shutoff.     -”Child & Adult Psychology Test”, building blocks, “Textile, wallpaper design generation”     -”Warship vs Torpedo Boat”, animated streak flies towards the warship. IMPORTANT     -”Use of phonograph record to explain game”, prior use of cassette tape.     -”Target Shooting”, given new feature targets. “Add Sound, Limit Ammunition Available, Adjustable Sights”     -”Drawing Games”, said to use “optical memory”. Would have a phosphorescent painted overlay “For use in dark room only”     -Plan to use a phonograph to alter the game state     -A game for learning binary   June 15, 1967 - “Alternate Course for TV Game”, reordering of the technology     -So much happening on this day indicates a worry over the project future.   June 16, 1967 - Circuit card concept presented by Bill Harrison, cards essentially act the same as pin connectors would   June 17, 1967 - “TV Gaming - Status Report & Brief Review of TVG Applications”     -1. Decision of separate unit or integrated into TV set, “Note: Type 1A above could be provided in KIT form” (with a rectangle around KIT form)     -2. They would build a stand alone unit, circuit cards for Target Shooting and Chess games specifically     -3. A full list of applications: “Games for Entertainment, Skill, Chance, Artistic Games, Instructional Games, Bar graphs and lines, Card Games, Sports Games, Wargames, Probability games/study, Clinical Psychology Tool, Analogic”         -”Special effects” including disappearing, blinking, and phonograph/tape recording   July 7, 1967 - When the next batch of documents pick up.     -Parts testing, a switch to monochrome, focus on the light gun.   August 3, 1967 - Harrison conducts a test of the power with batteries.     -Giant RCA 9 volt battery.   September 15, 1967 - R&D Plan, summary     -Notes on approach and scope         -”Paper study and demonstration of applications for reaction and feedback”         -”Attempt circuit simplifications, aiming toward cost dedication”         -”Find source of contact overlays”         -”Create additional minimum cost functions for increased versatility” What could this mean?         -”Creation additional applications for system”     -New cost estimate of $8101, running through November         -”Develop added applications for existing equipment”         -”Modify equipment for added applications”         -”Demonstrate equipment and rework applications”   September 29, 1967 - Bill Rusch begins to try and come up with more applications for the two hardware dots.   October 4, 1967 - Special Sales Order for TVG project.     -Ralph Baer, Equipment Design, William Rusch, Task Manager. No Harrison.     -Pings a huge number of people in the company for the first time   October 10, 1967 - Harrison plays around with field shapes, not as complicated as the mazes but with rectangular variations.   October 12, 1967 - Bill Rusch works on circuit simplification.   October 18, 1967 - “Moving Spot for TVG”, the idea of something which could bounce around various spots on the screen. The spots would be predetermined and controlled via a push button to cycle through the various spots.     -First idea was a batting game which would send the ball back to its thrown position     -Second idea was Ping Pong, “coincidence” is introduced     -”Gun Ping Pong” as a target shooting game with predetermined paths set by off screen dots   October 31, 1967 - “TV Gaming Device” schematics are drawn up.     Game Sequence (10 games): Checker Games, Chase Games, Ping Pong, Hockey, Volly Ball, Checkers with Obstacle, Hand Ball, Target Shooting, Pumping Game, Golf   November 3, 1967 - William Rusch proposing circular ball for a soccer game   November 7, 1967 - Monthly status report by Bill Rusch for October, “A new system concept has been implemented. It offers cost savings and permits new classes of applications.”   November 15, 1967 - “Create New Fields” by Rusch, paths and tracks for games like racing, ‘collision' games (like orbiting planet lines), and missile game.   November 20, 1967 - Checkerboard generation by Rusch, Pool and golf game ideas with ricochet shots   November 21, 1967 - With a “Breakthru” that appears to be a trigger of the coincidence circuit, Rusch comes up with a list of several “APPLICATIONS”     -Pool, Ping Pong (with direction and speed determined by player object), Soccer, Ping Pong (over a center net, like TfT), “Ski Ball”, “Golf shot to elevated green”, Football Kick (forward facing), “Golf Putting Several (dark) holes”, “Better Football (Field Goal) Kick” (side view), Soccer/Hockey, Race Car with bumping vehicles, Volley Ball, “Doubles Ping Pong or Tennis), Golf with Five Spots     -Implementation of shadows     -”Penny Arcade Hockey” with spinning shapes as the bats, similar to Chicago Coins' Goalee   December 4, 1967 - More illustrated game ideas by Rusch. New semi star-like shape to represent player     -”Ball on a Band/Balloon Bounce”, bouncing a ball off a paddle to see how many times it can be hit     -”Dart Throwing” with gravitational pull     -”Basket Shooting”, 1 or 2 players     -”Plane + Ship Shooting + Bombing”, plane circles above and bombs hip below. Both move on set paths.     -”Two Planes shooting at each other”, basically Jet Fighter     -”RACE GAME with Int. joysticks, Obstacles and Bouncing!”, bouncing around an environment with walls     -”Boxing”, rudimentary humans, undecided if top or bottom view     -”Handball”, bounces off sides of the screen and drains on bottom     -”Pinball Game”, gains points if it hits dots on overlays as it ricochets. Drains through black box on overlay.     “Hands Off Bounce-Chase”, players bounce around until they collide with each other, marking the time   December 6-12 1967 - Harrison and Rusch investigate pool and hockey. Initially the circuits seem to be a no go, but success is reported on the 12.   December 13, 1967 - Rusch proposes new TVG ideas     -”Ouija Board TV set Game”     -”Puzzles - kids can ‘build' pictures with visual multi-shaped ‘blocks' etc” Demonstration visual is a pentomino         -Rusch outlines a vase-like figure “Silhouette”     -”Puppet Shows”     -Presuming a battery powered TV, ”Cheap Radar for Boats? Car tuner etc, In Planes?”   December 18, 1967 - “Mirror system on piano, organ”   December 20, 1967 - Other Rusch ideas     -”Combine TV and Telephone”     -”Shooting Galley with moving ducks and spinning hills”     -”Use TV as Oscilloscope”   January 2, 1968 - Report for December 1967     -”Additional operating modes (rebounding, shrinking target size) display circuitry was developed and demonstrated”     -Patent applications to be submitted   January 4, 1968 - Rusch, “MUST PERSEVERE FOR CREATIVE IDEAS”   January 11, 1968 - Harison to do list for gun, now in its rifle form     -”Finish pistol”     -”Put function from PC board into chassis”     -Photocell sync   January 17, 1968 - “Cost Estimate (Electronics Only)” by Harrison     -”Gun, $2.60”     -”Antenna Crowbar, $.51”     -”3 spot function box, $12.00”, 24 transistors, 1 Silicon controlled rectifier, 1 photocell, 1 inductive pick-up coil, 8 thin potentiometers, 8 long shaft potentiometers, 30 diodes, 60 resistors, 20 capacitores, 8 electrolytic capacitors. 161 parts, 10 individual parts.     -Total, $15.11   January 18, 1968 to February 19 - Meetings with Teleprompter/CATV about licensing the device.   January 26, 1968 - “CATV Demo Box”, for using a direct broadcast signal   January 31, 1968 - Herbert Campman issues a stop order for the project   February 20, 1968 - Harrison works on gun electronics     -Indications by numbering on the documents suggests there may have been other interim activity on either side   August 11, 1968 - Harrison resumes schematic work     -Creates general layouts for their functionality at present         -Includes generation of several spot types: Round ball, a diamond shape, the star-like shape, a vertical rounded rectangle, and a wide rounded rectangle   September 6-17, 1968 - Harrison is given the task to use Rusch's circuits to do five important functions:     -”Video ?”, “Coincidence detectors”, “Gated Differentiator”, “Wall Bounce”, “DMV Voltage Controlled”   October 26, 1968 - “LIST OF GAMES Playable w/ Various Configuations ”Games are prepared split into four categories. 2 spots with coincidence, 3 spots with reciprocate, 3 spots with Net/Wall line, 3 spots + ball and coincidence     -”Overlay Checker Games, Maze Games”     -”Chase Games”     -”Ping Pong, w/o net, w/ net”     -”Hockey (with overlay goals)     -”Handball, single handed, doubles”     -”Gun Games (gun added), single spot stationary or manually moved, ball intercept (auto or manual)”'     -”Golf Putting Game”     -Color still a noted feature of system   January 1969 - Noted as an approximate date, new games list     -”Handball”, “Ping Pong”, “Volley Ball”, “Hockey”, “Golf Putting”, “checkers Games”, “Chase”, “Target”, “Pumping Game”, “Coed Square Games - Add code generator”     -Controller with two potentiometers and one button is created     -Games currently toggled with a switch         -”1st position - table tennis or hockey”         -”2nd position - Chase or Overlay games + rifle”         -”3rd position - Hand Ball (incomplete)”   January 14, 1969 - Meeting with RCA.   March 1969 - New “TVG - DigBox” “Conservative estimate” of parts and price     -Without two players, case, controllers, gun, or connectors     -$12.65 total. 35 diodes, 30 transistors, 90 resistors, 1 silicon controlled rectifier, 10 large capacitors, 15 small capacitors, 10 potentiometers, 1 PC Board   March 10, 1969 - Meeting with Zenith.   March 12, 1969 - Meeting with GE.   March 18, 1969 - Meeting with Sylvania.   April 2, 1969 - Meeting with RCA.   May 7, 1969 - Meeting with GE.   May 26, 1969 - “Hockey ADD ON for TVG” by Bill Rusch     -Would allow for ball to move in the direction of the hit, with velocity, and bounce off walls     -Two separate generators for square and round ball spots     -Cost $12.00 for the electronics, plus $5.00 for the joysticks   May 28, 1969 - Meeting with GE and a representative from the Institute for Analytical Research.   May 29, 1969 - “Round Spot for TVG ??” by Harrison, seeming to express disbelief that they are still trying     Meeting with Motorola. (Warwick was demonstrated to at some point and Sony was considered, if not strictly demonstrated)   July 1970 - Magnavox representatives, encouraged by Bill Enders formerly of RCA, come for a demonstration of the Brown Box.   August 26, 1970 - Baer and Lou Etlinger travel to Magnavox's headquarters in Fort Wayne to demonstrate the Brown Box.   1971 - Bill Harrison creates a game list with the logic gates denoted as well as a currently unused color switch     -Ping Pong. Hockey, Hand Ball, “Volley Ball (also checkers with obstacle)”, “Pumping Game ?”, Target Shooting, Chase Game, Checker Games, Golf Putting, Code Gen   March 11th, 1971 - Sanders and Magnavox sign their initial licensing agreement for the technology of the Brown Box.   March 30, 1971 - Visit to Magnavox in Fort Wayne report by Baer     -In attendance: Gerry Martin (Console Product Dev), Bob Sanders (VP Engineering), Bob Wiles (Color TV Product Mfg), Bob Grant (TV Engineer Manager), Paul Knauer (Chief Color TV Engineer), George Kent (Section Chief, Color TV Engineering), Clarence Graef (Color Engineer), Gene Kile (Manager of Design), Clyde “Wiley” Welbaum (Design Director)     -Baer went with Kile and Welbaum. Harrison met with Kanuer, Kent, Graef, and Grant.         -Baer group was taped, 4 hour discussion         -”It was pointed out that product introduction in the TV business occurs in April & May”, unlikely for 1972     -”There was a positive attitude displayed by all attendees to the demo and at subsequent sessions with the exception of Bob Saunders who refused to enter into the spirit of the TV, as he did on our prior visit - cannot ‘read' his real position as yet.”     -”All parties recognize the need for an engineering team supported by at least one non-engineering, creative, imaginative software man”     -The control would have two controllers with 4-6 ft wires, use circuit cards, to look like a portable cassette recorder   June 10, 1971 - Bill Harrison does more schematics on “Chroma Gen for Magnavox”   June 28, 1971 - Harrison produces notes on a Magnavox meeting     -”gun not so good”     -Meeting happening in New York to discuss saleability of machine, marketing of the games such as names and whatnot     -George Kent is optimistic   July 20, 1971 - “Skill-O-Vision” by Bob Wiles outlines their plans for a market test     -Idea was discussed in San Diego with a man named Ken Crane     -Test would be conducted from Monday the 26 to Thursday the 29th     -Bob Wiles, Clarence Graef, and Vern Parnell would demonstrate the device   Provided Questionnaire outlines both a script and a set of questions     -”Under no circumstances will the electronic games impair your television reception”     -Game cards are used, English control is implemented, Reset button     -Games are Ping Pong, Checkerboard I, States and Capitals, Baseball, Rifle Range Questions, filled out in a California and a Michigan (October) test, 82 respondents:     -Interest         -89% Very much     -Like and dislike         -Top likes: competitive, Unique, Educational     -Preference of game card or a dial selector     -Demographic: Adults, Teens, Preteends, Grade Schoolers, Preschoolers         -Adults     -Other toys     -”Do you Presently Own a Color TV Set?”         -78% yes     -Preference on Skill-O-Vision name         -65% like     -”Would you buy this product if it were offered for sale at $75? If no, what price do you think the product should sell for?”         -80% yes     -Married or single     -Age of head of house     -Education level of head of house     -Income bracket   October 1971 - A decision is made to market the console   October 15, 1971 - Robert Fritsche memo on Skill-O-Vision, interprets data from the initial tests to push for family marketing and a new name   February 2nd, 1972 - Magnavox signs the final agreement to put the Brown Box system out on the market imminently.   April 25, 1972 - Odyssey patents accepted.   May 3, 1972 - The first Magnavox Profit Caravan show is held in Phoenix, Arizona.   May 23-25, 1972 - The Magnavox show in Burlingame.   August 1, 1972 - Another agreement is signed between Magnavox and Sanders.   September 1972 - Odyssey from Magnavox is released.     -Materials and labor costs are $35 for the console, $99.95 general cost.   November 28, 1972 - Robert Fritsche sends out a memo about Odyssey survey cards, letters, and interesting reports on Odyssey's use     -LA Air Traffic Control purchased two units for a training program with modification     -Veterans Administration in NY (Bioengineering Research Service), created qudrapalegic accessible version with a microswitch behind the head     -University of Kentucky testing motor responses with two units     -Optometrist in NJ, “He has modified the conditions under which Odyssey is used to better develop binocular, hand-eye, and other ocular skills.”     -High schools to use Odyssey in “Visual Training programs”     -”Head Start” in Maryland studying Odyssey   November 27, 1972 - A Bally lawyer calls Magnavox over the question of licensing     -Magnavox says they are not current in the position to designate sub-licensees.   April 1973 - Magnavox begins sending out legal probes.     -Terms of license are 7% on net sales, $5000 advance, no less than $1000 per year.         -Later reduced to 6% and $500 minimum.   April 15, 1974 - Bally files suit in New York, Magnavox files suit in Chicago. The former files for invalidation of the patents, the other files for infringement.     -Seeburg Industries Inc, The Seeburg Corporation, Williams Electronics Inc, World Wide Distributors are added.   September 1974 - Magnavox bought by Philips.   July 1975 - Atari files suit against Magnavox for invalidation.     -Quickly incorporated into the main case.   September 1975 - Sears gets added due to Home Pong.   January 1976 - Standard license agreement     -$100,000 advance     -5% for the first 250,000 units     -4% for the second 250,000 units     -3% in excess of 500,000 units   June 1976 - Atari, Bally, and Sears settle.     -Atari licensing agreement. $1.5 million in installments. 4% first 20,000 units, 3% after.     -”ATARI hereby grants to MAGNAVOX and SANDERS, subject to the reservations [...] a fully paid non-exclusive license to make, have made, use, sell and lease LICENSED PRODUCTS under the ATARI PATENTS, without the right to sublicense. ATARI further grants to MAGNAVOX and to SANDERS an option to grant non-exclusive sublicenses in foreign countries outside the United States under ATARI PATENTS provided that a payment is made to ATARI of 1% of the Net selling Price of the sub-licensed products.”   January 1977 - Initial case finalized in Magnavox's favor.   September 1977 - APF Electronics, Unisonic, Executive Games, URL, Taito America, Control Sales, Jewel Co, Osco Drug, Turn-Style, Jay-Kay Distributors, K-Mart, Bennet Bros, Venture Electronic International all sued by Magnavox.     -Fairchild, Allied Leisure, and Radio Shack also sued.     -Appears to be piecemealed off in settlements.     -URL does go bankrupt and Magnavox sues for settlement.   1978 - Bally is sued again over Bally Professional Arcade.   1980 - Magnavox v Mattel is filed     -Ends in 1982 after a 9 day trial, settlement at the 11th hour.     -Establishes precedent for programmable games.   1982 - Magnavox v Activision   1982 - APF and MIT jointly sue Magnavox     -Bolkow patents   1984 - Bally sued AGAIN   1986 - Magnavox v Nintendo     -Over both the original patents and the light gun   1992 - Magnavox v Sega of America   1993 - American Vending Sales, Inc, Atlas Distributing, Inc, Capcom U.S.A. Inc, Coin Machine Corporation of America, Data East U.S.A. Inc, Konami America Inc, Leland Corporation, Romstar Inc, Snk Corporation of America, Temco, Inc, Tradewest Inc, World Wide Distributors Inc, Taito America Corporation sued.   February 15, 1994 - “Konami agreed to pay North American Philips $495,000.  This amount represented a 3% royalty for each game Konami sold between June 1987 and April 1989 that incorporated the patented device”  

War has engulfed the Twin Galaxies! The evil Overlord Araklial has returned from banishment. He has brought turmoil and grief to the known universe for the past seven years. During that time, Khalen Daedark and his Arranger companions have worked tirelessly to root out Tritonus infiltrators. Their efforts are aided by a mysterious source known only as the Modulator. But the war is not going well for the Major and Perfect races. Outer planets have fallen to the enemy, and even the core worlds are now threatened. In a desperate attempt to halt the advance of the invading forces, Khalen and the others must make questionable alliances and undertake dangerous covert missions into the heart of enemy territory. Now they must seek out the Lost Ensemble of Harmony in order to strike a counterpoint to Araklial's dissonance and drive back his army. March of the Free revisits the themes and motifs from Movements I and II and brings the Master Symphony to a rousing conclusion. Enter one final time into a universe of alien technologies and exotic worlds – a universe where music flows through creation as a spiritual energy shaped by powerful maestros for either harmony or discord. Enter the thrilling climax of this symphony as I chat with my returning guest co-host and contributor Keith Robinson about the third movement on Tuesday, September 20th at 7:00 PM Eastern time. You can listen in at 646-668-8485. Follow PJC Media on podcast platforms everywhere. Or, click on the link here: http://tobtr.com/12131903.

CME credits: 1.50 Valid until: 30-08-2023 Claim your CME credit at https://reachmd.com/programs/cme/mezigdomide-cc-92480-a-potent-novel-cereblon-e3-ligase-modulator-combined-with-dexamethasone-in-patients-with-relapsedrefractory-multiple-myeloma-preliminary-results-from-the-dose-expansion-phase-of-the-cc-92480-mm-001-trial/14335/ With the introduction of both immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide, and the use of these in combination with drugs from other classes, IMiDs have made a dramatic progress in the treatment of multiple myeloma (MM). However, despite improvement in outcomes, patients with MM ultimately relapse and must undergo further treatment. Early studies show that Cereblon E3 Ligase Modulators (CELMoDs®) iberdomide and CC-92480 show similar trends in activity in patients refractory to IMiDs. This new next generation of IMIDs have shown enhanced tumoricidal and immune-stimulatory effects compared with first-generation IMiDs and have the potential to replace the current standard of care in both frontline and RRMM. This program covers the benefits as well as current challenges with the use of first-generation IMiDs while exploring the MOA, clinical, and safety activity to date of selective CELMoD® therapy in MM.

In this weeks TBO Danny fucks up and has a voice mod on the whole episode so enjoy this weird ass episode.

We all know breathing is good for you and a vital process of life. Today, Bianca and Emilia talk about the importance of practicing breathwork, their experiences, and how it changed their mindset and overall health. Just like your heart beats on its own, breathing is an automatic function that you don't need to learn how to do or constantly focus on. It's also one of the cheapest and most effective ways to optimize your well-being.Here's the list of episodes related to today's discussion, and we highly recommend listening to them as well:#9 | How to Develop an All-Star Mindset https://apple.co/3MDKJjY#14 | Your Unique Energetic Dualism with Shawna Pelton https://apple.co/37Nj5Co#15 | How to Gauge Your Mental Health https://apple.co/3rWBzHL#24 | How to Honor (Personal) Boundaries https://apple.co/37NsSsh#81 | Bridging the Gap Between Medicine, Brain & Mental Health https://apple.co/37oUDqH#86 | Brainwashing: Is Personal Development a Cult? https://apple.co/3rWBILjAdditional resources:How Breath-Control Can Change Your Life: A Systematic Review on Psycho-Physiological Correlates of Slow Breathing https://bit.ly/3KosdusVagus Nerve as Modulator of the Brain–Gut Axis in Psychiatric and Inflammatory Disorders https://bit.ly/3y6tyn8The Effect of Diaphragmatic Breathing on Attention, Negative Affect and Stress in Healthy Adultshttps://bit.ly/37Nsx8YBreathing Exercises https://bit.ly/3rTkFcHMindful Breathing Exercises https://bit.ly/3rXKGYp[NATURAL HIGH!] DMT Breathing - 50s Breathholds (3 Guided Rounds) https://bit.ly/3rWs9MkHolotropic Breathwork Benefits and Risks https://bit.ly/39cfpKQHOLOTROPIC BREATHWORK THEORY https://bit.ly/3OH8cCQ_________________________________Connect with Emilia, Bianca & the EVOLVE VENTURES Community:Click HERE to Register for our next Virtual FREE EventWebsite: www.evolveventurestech.com@EvolveVentures on Instagram@EvolveVenturesTech on Facebook (Public Page)Evolve Ventures Society (Private Facebook Group)@EvolvewithEmilia on Instagram / @Evolvewith Emilia on TikTok@EvolvewithBianca on InstagramShow notes:[2:29] What has been your health journey?[4:53] Your breath: the ultimate wellness pill[10:31] Bianca on practicing breathwork[16:04] Breathing is the most crucial practice you can do[22:15] Key takeaways[23:18] Outro***Leave them a 5-star review if you felt their energy, became inspired, or felt as though value was added to your life in your EVOLUTION.(Stay tuned for next Thursday's Episode!)

Tim Dyer is the Co-Founder and CEO of Addex Therapeutics, which is focusing on the pharmacology known as allosteric modulation. This emerging class of small molecule drugs known as allosteric modulators is being explored for treating central nervous system and neurologic disorders, particularly movement disorders like dyskinesia associated with Parkinson's and dystonia. Addex did not invent allosteric modulation but is pioneering the screening technologies to find these difficult to locate molecules. Tim explains, "In the conventional world, which people probably know a lot about, are the orthosteric agonists and antagonists. These molecules are binding to the active site. The way to understand, in simple terms, the difference between an allosteric and an orthosteric drug is to use an analogy of the dimmer light switch." "If you think about the dimmer light switch, you're initially turning the light on-- that would be the orthosteric agonist. Turning the light off would be the orthosteric antagonist, and what Addex is, is the dimmer. We leave the body in charge of turning the light on, so to speak, and then the Addex, allosteric modulator, if it's a positive modulator, we are really turning up the intensity of the light. If it is a negative modulator, we are turning down the intensity, so we're really modulating the intensity of the signal." @AddexPharma #AllostericModulators #CNSDrugDiscovery #NeurologicDrugDiscovery #DrugDevelopment #ParkinsonsDisease #Dyskinesia #Dystonia #Blepharospasm #MovementDisorders Addextherapeutics.com Listen to the podcast here  

Tim Dyer is the Co-Founder and CEO of Addex Therapeutics, which is focusing on the pharmacology known as allosteric modulation. This emerging class of small molecule drugs known as allosteric modulators is being explored for treating central nervous system and neurologic disorders, particularly movement disorders like dyskinesia associated with Parkinson's and dystonia. Addex did not invent allosteric modulation but is pioneering the screening technologies to find these difficult to locate molecules. Tim explains, "In the conventional world, which people probably know a lot about, are the orthosteric agonists and antagonists. These molecules are binding to the active site. The way to understand, in simple terms, the difference between an allosteric and an orthosteric drug is to use an analogy of the dimmer light switch." "If you think about the dimmer light switch, you're initially turning the light on-- that would be the orthosteric agonist. Turning the light off would be the orthosteric antagonist, and what Addex is, is the dimmer. We leave the body in charge of turning the light on, so to speak, and then the Addex, allosteric modulator, if it's a positive modulator, we are really turning up the intensity of the light. If it is a negative modulator, we are turning down the intensity, so we're really modulating the intensity of the signal." @AddexPharma #AllostericModulators #CNSDrugDiscovery #NeurologicDrugDiscovery #DrugDevelopment #ParkinsonsDisease #Dyskinesia #Dystonia #Blepharospasm #MovementDisorders Addextherapeutics.com Download the transcript here  

Host: Patty Cason, RN, MS, FNP-BC Guest: Joely Pritzker, RN, MS, FNP-C Are you ready to apply the latest counseling techniques to address the contraceptive revolution? Join nurse practitioners Patty Cason and Joely Pritzker as they briefly review the history of contraceptive counseling and then use case vignettes to illustrate how shared decision-making techniques will support the appropriate use of nonhormonal contraceptive options, such as the vaginal pH modulator (VPM). Participating in this activity will ensure that you are ready to effectively counsel patients on their many options so that each patient's reproductive and sexual health goals can be met.

CME credits: 0.25 Valid until: 25-03-2023 Claim your CME credit at https://reachmd.com/programs/cme/strategies-to-improve-patient-communication-about-the-vaginal-ph-modulator/13300/ Are you ready to apply the latest counseling techniques to address the contraceptive revolution? Join nurse practitioners Patty Cason and Joely Pritzker as they briefly review the history of contraceptive counseling and then use case vignettes to illustrate how shared decision-making techniques will support the appropriate use of nonhormonal contraceptive options, such as the vaginal pH modulator (VPM). Participating in this activity will ensure that you are ready to effectively counsel patients on their many options so that each patient's reproductive and sexual health goals can be met.

CME credits: 0.25 Valid until: 25-03-2023 Claim your CME credit at https://reachmd.com/programs/cme/strategies-to-improve-patient-communication-about-the-vaginal-ph-modulator/13300/ Are you ready to apply the latest counseling techniques to address the contraceptive revolution? Join nurse practitioners Patty Cason and Joely Pritzker as they briefly review the history of contraceptive counseling and then use case vignettes to illustrate how shared decision-making techniques will support the appropriate use of nonhormonal contraceptive options, such as the vaginal pH modulator (VPM). Participating in this activity will ensure that you are ready to effectively counsel patients on their many options so that each patient's reproductive and sexual health goals can be met.

Host: David J. Portman, MD Guest: Patty Cason, RN, MS, FNP-BC Guest: David L. Eisenberg, MD, MPH, FACOG Are you ready for the contraceptive revolution? Are you applying the latest information on contraceptive efficacy, recent clinical trial data, and sexual satisfaction when counseling your patients on contraceptive options? Join Dr. David Portman, Dr. David Eisenberg, and Ms. Patty Cason as they discuss the novel mechanisms of action of cutting-edge, non-hormonal contraceptive options, such as the vaginal pH modulator (VPM). Participating in this activity will ensure that you are prepared to discuss sexual and reproductive goals with your patients and confirm that your patients' goals are being met.

CME credits: 0.25 Valid until: 11-02-2023 Claim your CME credit at https://reachmd.com/programs/cme/the-vaginal-ph-modulator-a-revolutionary-approach-to-contraception/13299/ Are you ready for the contraceptive revolution? Are you applying the latest information on contraceptive efficacy, recent clinical trial data, and sexual satisfaction when counseling your patients on contraceptive options? Join Dr. David Portman, Dr. David Eisenberg, and Ms. Patty Cason as they discuss the novel mechanisms of action of cutting-edge, non-hormonal contraceptive options, such as the vaginal pH modulator (VPM). Participating in this activity will ensure that you are prepared to discuss sexual and reproductive goals with your patients and confirm that your patients' goals are being met.

CME credits: 0.25 Valid until: 11-02-2023 Claim your CME credit at https://reachmd.com/programs/cme/the-vaginal-ph-modulator-a-revolutionary-approach-to-contraception/13299/ Are you ready for the contraceptive revolution? Are you applying the latest information on contraceptive efficacy, recent clinical trial data, and sexual satisfaction when counseling your patients on contraceptive options? Join Dr. David Portman, Dr. David Eisenberg, and Ms. Patty Cason as they discuss the novel mechanisms of action of cutting-edge, non-hormonal contraceptive options, such as the vaginal pH modulator (VPM). Participating in this activity will ensure that you are prepared to discuss sexual and reproductive goals with your patients and confirm that your patients' goals are being met.

When Babe goes all Squircle on us

CHEST January 2022, Volume 161, Issue 1 Dr Damian G. Downey and Dr Rebecca M. Thursfield join CHEST Podcast Moderator Dr Gretchen Winter to discuss the treatment goals of cystic fibrosis transmembrane regulator protein therapy in adults vs children. DOI: https://doi.org/10.1016/j.chest.2021.05.070 DOI: https://doi.org/10.1016/j.chest.2021.06.018 DOI: https://doi.org/10.1016/j.chest.2021.06.019 DOI: https://doi.org/10.1016/j.chest.2021.03.073

Host: David L. Eisenberg, MD, MPH, FACOG Many women prefer to use a nonhormonal contraceptive. They also want the freedom to self-administer on demand and want assurances that the contraceptive is safe, effective, and has received FDA approval. One such contraceptive is a self-administered, hormone-free gel that functions as a vaginal pH modulator. Join Dr. David Eisenberg as he describes the evolution of this vaginal pH modulator and the clinical trials leading to FDA approval. Even more significant is patient acceptance, which was remarkably high for this contraceptive. In fact, approximately 9 out of 10 women participating in the clinical trials indicated they would continue using the vaginal pH modulator and also recommend this novel method to their friends.

CME credits: 0.50 Valid until: 30-11-2022 Claim your CME credit at https://reachmd.com/programs/cme/expanding-contraceptive-choices-for-women-the-vaginal-ph-modulator/13055/ Many women prefer to use a nonhormonal contraceptive. They also want the freedom to self-administer on demand and want assurances that the contraceptive is safe, effective, and has received FDA approval. One such contraceptive is a self-administered, hormone-free gel that functions as a vaginal pH modulator. Join Dr. David Eisenberg as he describes the evolution of this vaginal pH modulator and the clinical trials leading to FDA approval. Even more significant is patient acceptance, which was remarkably high for this contraceptive. In fact, approximately 9 out of 10 women participating in the clinical trials indicated they would continue using the vaginal pH modulator and also recommend this novel method to their friends.

CME credits: 0.50 Valid until: 30-11-2022 Claim your CME credit at https://reachmd.com/programs/cme/expanding-contraceptive-choices-for-women-the-vaginal-ph-modulator/13055/ Many women prefer to use a nonhormonal contraceptive. They also want the freedom to self-administer on demand and want assurances that the contraceptive is safe, effective, and has received FDA approval. One such contraceptive is a self-administered, hormone-free gel that functions as a vaginal pH modulator. Join Dr. David Eisenberg as he describes the evolution of this vaginal pH modulator and the clinical trials leading to FDA approval. Even more significant is patient acceptance, which was remarkably high for this contraceptive. In fact, approximately 9 out of 10 women participating in the clinical trials indicated they would continue using the vaginal pH modulator and also recommend this novel method to their friends.

Flying On Top... Most Beautiful Airplane... What Could Go Wrong?... Mars Ingenuity... Is NASA GA?... Illudium Q-36 Explosive Space Modulator. All this and more on Uncontrolled Airspace Podcast. Recorded Sept 9, 2021. (1:00:06) [#663]

# 59-A: "The Ring Modulator Can Not Handle It!" by Spoken Word with Electronics

# 59-A: "The Ring Modulator Can Not Handle It!" by Spoken Word with Electronics

Focus: Logic of Sense “22nd Series – Porcelain and Volcano” and “23rd Series of the Aion” With: Nate DeProspo, John Muckelbauer, and Nathaniel Street Hard Times with Time (Start – 5:45) Derrida and the Deconstructed Present; Vulgar Time (6:00-11:48) Kant, Time/Space, Faculties; Heidegger and the relationship of change to bodies (12:00-25:40) Deleuze's book on Kant; Sublime: Limits of Representation, “'God', for example” (25:50-33:30) (Failed) Representation: What's the point of language?; Freedom, choice, and self-transformation; Events and Spacing (33:40-43:05) "Crossing the Rubicon," for example; Language – Container or Modulator?; (43:15-51:40) Emergence of Language; Wait, is language a thing? Do we have it? Do we speak it?; Molar, Molecular, the Trope (51:50-1:07:08) Burping and Talking; The Logic of Sense and the Sense of Logic; (1:07:15-end)

Another awesome modulator bay show for ya today! Mr. Basic, Haze and AudiosErgeon on the move to find out what's been going on with each others music space lately in the heat of summer. So enjoy! Mr. Basic's YouTube : https://www.youtube.com/channel/UCPP621crLuge7qTEpJ2kkqA Haze Anderson's YouTube : https://www.youtube.com/channel/UC8Az20K6S9qnE73yG_ZHyKw

NHERI's University of Florida wind hazards facility is one of the world's largest and most diverse suites of experimental infrastructure. Funded by the National Science Foundation, the UF's boundary layer wind tunnel is located within the Powell Family Structures and Materials Laboratory. In June and July 2021, the DesignSafe Radio podcast features interviews with NHERI at UF facility director and principal investigator Jennifer Bridge, who details the capabilities UF wind tunnel and the research it makes possible. In this episode, Bridge discusses more research possibilities with the flow field modulator (FFM). As well as revealing effects of transient wind events on structures, it allows researchers to combine BLWT terrain-condition measurements with the FFM. So you could, for example, insert a structural model in realistic terrain and discover its performance during downbursts. Also, the FFM enables researchers to test larger models in the urban setting, called the urban canopy layer. Lastly, Bridge discusses the difference between NHERI's two complementary wind-research laboratories. The UF facility enables fine-tuning of models, and the Wall of Wind at Florida International University enables full-scale testing. Bridge notes the importance of collaborations between facilities and funding agencies — for designing more a more resilient civil infrastructure.“How are we going to design resilient infrastructure of the future? It's going to take all of us.”-Jennifer BridgeRelated links:NHERI's University of Florida experimental facilityVideo overview of the wind tunnel facility located within the University of Florida's Powell Family Structures and Materials Laboratory.Work at UF helps engineers design structures that enable Floridians to survive extreme wind events. Video interview with UF professor Forrest Masters.Listen to the podcast on the DesignSafe Radio website, or subscribe via Apple Podcasts, Spotify or Stitcher. Interested in natural hazards research? Follow DesignSafe Radio on Facebook and Twitter. DesignSafe Radio highlights ways that NSF-supported research renders infrastructure and communities more resilient to natural hazards like earthquakes, hurricanes, tsunamis and storm surge. The podcast is produced by NHERI, the Natural Hazards Engineering Research Infrastructure, NSF award CMMI 1612144. Any statements in this material are those of the presenter(s) and do not necessarily reflect the views of the National Science Foundation.

NHERI's University of Florida wind hazards facility is one of the world's largest and most diverse suites of experimental infrastructure. Funded by the National Science Foundation, the UF's boundary layer wind tunnel is located within the Powell Family Structures and Materials Laboratory. In June and July 2021, the DesignSafe Radio podcast features interviews with NHERI at UF facility director and principal investigator Jennifer Bridge, who details the capabilities UF wind tunnel and the research it makes possible. Professor Jennifer Bridge describes the flow field modulator, a new piece of equipment at the facility that greatly enhances the capabilities of the BLWT. The FFM is a bank of 319 very fast, individually controlled fans that can simulate transient events like wind gusts, downbursts, and thunderstorm winds. It can also replay wind events (called time histories) with data collected in the field, for example by the UF's “storm chaser” team and its mobile weather towers. The facility is unique in its scale. Bridge explains how the FFM opens up wind engineering research to many new questions, with many new possibilities for discovering how different wind profiles affect structures. Click here for a view of the flow field modulator (FFM).“What's unique about our facility is the scale, these 319 fans, but it's really the degrees of freedom that we have. There are just endless possibilities with what we can do, because of the number of fans, because of their flexibility and responsiveness. There's just alot that we can do in this facility now that we weren't able to do before.”-Jennifer BridgeRelated links:NHERI's University of Florida experimental facilityVideo overview of the wind tunnel facility located within the University of Florida's Powell Family Structures and Materials Laboratory.Work at UF helps engineers design structures that enable Floridians to survive extreme wind events. Video interview with UF professor Forrest Masters.Listen to the podcast on the DesignSafe Radio website, or subscribe via Apple Podcasts, Spotify or Stitcher. Interested in natural hazards research? Follow DesignSafe Radio on Facebook and Twitter. DesignSafe Radio highlights ways that NSF-supported research renders infrastructure and communities more resilient to natural hazards like earthquakes, hurricanes, tsunamis and storm surge. The podcast is produced by NHERI, the Natural Hazards Engineering Research Infrastructure, NSF award CMMI 1612144. Any statements in this material are those of the presenter(s) and do not necessarily reflect the views of the National Science Foundation.

Perspectives Podcast - Tony Nash[00:00:00] Hey, everyone. Welcome to this episode of  Perspectives. It's such a pleasure to join you. And I want to thank you for being with us. I really appreciate you. I got interviewed the other day and I got to brag about our view is, and I think you're fantastic. So it's great that you're here today. We have a very special guest, especially if you're Australian centric.So his name is Tony Nash. You may know him as the man who co-founded Booktopia. It is a very large online book seller here in Australia. It's massive. It's where I do my business, which I didn't get to tell Tony in the interview, but Tony is just a great guy. He's a real pragmatist. You're going to enjoy.He's very down to earth approach and nature. When it comes to building such a successful business, it is the world's largest online and offline book retailer. In the world, which is quite the achievement. I think it's fantastic because obviously everybody's minds go to Amazon, but Amazon's focus as Tony reveals is an inbox now.So they've [00:01:00] carved out this phenomenal niche themselves with some entrepreneurial thinking, pragmatism seeing gaps in the market and just figuring out obsessing about what the customers want. He created the business with his brother, Simon and friend, Steve. And they're starting budget on Google ads was $10 a day.They deliberately did not make a profit until 2016. They started in 2004 did not make any profit to two 16. We talk about that in the interview, and that was deliberate because what they wanted to do was to keep funding the growth that was required to take care of their customer demands. It turns over in exists.I think it's over $200 million a year. Now it's been listed in the AFI Bow's fast hundred, eight times the only company ever to achieve this feat from 2009 to 2017, it's been voted bookstore of the year. They've moved into publishing as well. We didn't get to talk about that as much as I'd liked, but that's a really interesting new niche they're carving out for themselves.It has [00:02:00] won the New South Wales Telstra Business  of the Year the Australian Telstra Business Award People's  choice Award we were a finalist in that. I remember that. They've been a finalist seven times in the Telstra business awards and they are state, it stated that Australian authors and titles are a key focus for this company.And you'll hear that come through. When we talk with him, they completed an IPO in 2020 during the first year. Did you believe he'd ever say this the first year of this global pandemic and our response to it? They did an IPO. So initial public offering, they went public and their capital raised successfully.They did an 11 week launch from decision to IPO, which I think is fantastic. They hold nearly 200,000 books in stock, ready to ship. They sell an item every 4.8 seconds. Their warehouses in excess of 10,000 square meters. Their main rival apparently is Amazon. Even though Amazon is in Australia, Booktopia is just doing gangbusters, going from strength to [00:03:00] strength.We talk about teams, culture. We talk about what it takes to build a business very much this theme of pragmatism and keeping your head and focusing on the customer and figuring out where the sale is going to be made because everything else up until then is talk and with no further talk from him.Here is Tony Nash. So you've been going now, you began in 2004. How would you say if you were to describe right now, how you got here? Rather than telling me what you did. How did you get here to be in this position where you are now with Booktopia mostly, for me, it feels like one thing led to another. So I'm very horizon point driven.That means that I have a clear picture of where I want to get to. And I may not necessarily know that that's. How to get there, but by having that horizon point to me it's more like a mountain range beyond the mountain range that I can see in the [00:04:00] distance and going, right. We've got to get to X and at the moment we're turning over 200 million.So therefore, what have I got to do to get to 300 million? But before that, of course it was getting from 100 to 200, from 20 to a hundred and so on and so forth. So if you work your way back then that's that's quite often when I think about the driving force, it's like, if someone said to me, come on, let's, let's get on a boat and go for a trip.And, and, and where do you want to go? And I say, look, let's go east. Well, we can end up in Alaska. We could end up in Antarctica and you got, what can you be a bit more specific? And it's like, well, New Zealand, north or south island and north, so Wellington or Auckland, Oakland, Ryan and I were in Oakland.Well, you know, the where the marina is, where we're going to where they had the America's cup, that's where we're going. And all of a sudden everything gets clear. And, and that to me is a lot about having that destination that then creates a level of [00:05:00] thinking, which gets you into action. Okay. So you start with the end in mind, which is what anybody who's an entrepreneur who's successful and not successful starts with that's.I imagine that's part of it, but there must be more to the soup because. It's not as simple as just set the intention and the horizon line cause a new horizon line keeps presented itself and that horizon line is always further away and to get to their new horizon line, the challenge is always unique because the once you've conquered one horizon line, you've conquered those challenges.The next horizon line is completely different. Challenges are required for you to overcome. Can you talk about that? Yep. So where the Where the engine sits in terms of how we fire up and what we do comes from asking one question every day, what do our customers want? So even though there's an end point in mind, it's still coming from the point of what do they want, because that will determine what we do to get where we need to get to, to the horizon point.So that's how it feels to me. In [00:06:00] terms of, I guess, if you were to use the New Zealand metaphor, it's kind of like, oh, we're going to go in a cruiser or you're going to go on a sailing boat. Are we, how are we going to get there? And, and so that, that would be the next unpicking of the, you know, taking the layers of the onion away.There are many, many other things though that make up the. You know, who who's on your crew what sort of roles do you need to have or the other we can't afford to have passengers. So who's doing what that comes, that comes into play. If I think about it I've never really used it in this kind of metaphor before, but that makes sense to me.How are we funding it? So are we, do we want to have more month left at the end of the money or do we want to have more money left at the end of the month? We focused more on cashflow statements in the beginning that we did in profit and loss. There was a very clear growth strategies that I had in mind in terms of, in terms of getting, you know, I didn't want to overgrow.I didn't want to under, but I didn't want to grow too quickly. So it's slow down there. So it's talking about capital raising [00:07:00] or not capital raising. How did you decide what your sweet spot was for over or under growing? How did you, was it an intuition? Did you have numbers to base it on? How did you go?Yeah, kind of felt to me, like by growing at around 25 to 30% a year was was a, a stretch that was manageable. But not exhaustive. And so, and what I liked about that, it wasn't lumpy. So every year people were used to beat in the distribution center and customer service, sales, marketing, whoever, like, they just knew that we were growing at a very steady, right.And I found that to be really helpful in terms of people getting used to, if we were jumped, like. 80% one year with the pandemic, which some companies would have. And then it's only 10% the next year. Overall over two years, you've increased by about 40% a year, 35% a year. But for us having that steady growth all the time, Pru proved that we could bring on [00:08:00] people that we could fulfill the orders that we were getting, that we can manage our cashflow, that we weren't spiraling out of control.That's how it felt for me. And I imagine if you had overreach, you would have been in danger of not getting the capital funding you needed to bail you out of the overreach. So it wasn't as simple as finding the sweet spot, really the business relied on it because you were profit net, nothing for how many years.That was extraordinary. Part of the story. Yeah, that was, that was intentional. So to me it was about pushing, putting back into the business, everything that we were accumulating. So having started the business off a $10 note back in. 2004. We we had another business at a time and when I say we I've been in business with my brother and my sister and my brother-in-law and we had another business, internet marketing.So we were doing consulting work and Booktopia was a little side project for me that got bigger and bigger. So it was about, it was just about getting old that And the beautiful thing for us, of course, it customers paid upfront. [00:09:00] So they, they transacted, they gave us their money. We then hustled as hard as we could.And then our suppliers, mostly in the book industry is, is that it's 30 days end of month. So in some instances we may have sold the book on the first, second, third, fourth of the month. We didn't have to pay that for, you know, almost 60 days later. So there was an aspect of using our customer's money. They were our investors, they, they handed over their money and we, we worked hard to hire more people hold more stock, write more software, buy more automation.Yeah. But there were times when we when we moved, when we change facilities, we invested in automation and our suppliers were, were stretched to we, we were late in paying them. We had to continue selling more books to then eventually pay them. And, and then we got to the next level and we finally were able to.Kind of get some clean air again. And once we'd done through that light not make money for that was until 2016 and that was incredible, but that was on par. [00:10:00] So it was on purpose. It was on purpose. And what happened was we tried to IPO in 2016 we had got to 80 million in revenue and we we went through the whole journey and it was basically like going down to Bondai beach and Sydney on a mid winter's day to try and sell ice greens with a southerly coming in from the Antarctic.And it was eight degrees because temple and Webster were trading at 15 cents. Then now at $10, a Kogan had flatline over the six months since they had listed SurfStitch was going off. The market red bubble had gone backwards. And so it was there. And then the, the week that we were trying to firm up the price and do our management roadshow, Amazon announced they were coming to Australia and the fund managers all said, well, they're going to annihilate you.So we're not interested. And, and we had to go away and do go from 80 million to 200 million in the meantime. And so Amazon didn't annihilate, but the one thing I took away from. From that particular process, was that okay. Growth has been great and, and putting all the money [00:11:00] back in has been terrific, but I think we now need to become a little bit more sustainable and, and focus on revenue and profit.And, and so we, we started to focus on profit and build that up as well. So that then type it out our growth. So we didn't put as much money back in, but we had we still had high double digit growth. We just didn't have as much, but we were then is no one gave us money. If we couldn't raise money ever, ever, ever, ever.Then we still had our own business too, and we were still funding it then. So they put us in a stronger position and that's why we, we shifted. And I shifted from being a revenue based business. And in the early days of the internet, people really didn't care about profit. They just wanted to know that you were growing.Yes. But it'd be, I, it was clear to me that especially talking to fund managers, they wanted to know that if they put the money in it, wasn't, it wasn't only going to be potentially capital growth, but it was also going to be dividends as well. In long-term yeah. When you're talking about sustainability, you talk about in terms of the needs to be the cashflow and the [00:12:00] profit.Isn't sustainability though. Also about stabilizing your supply chains and stabilizing distribution in Australia. Tell me about it. So you had to not invest as much money back in your business, as you had to stabilize a sustainable distribution network. How did you do both? How did you do all of that?Nope. The way that most people do that is they, they understand their supply chain model and where they can get their product from and how that works. And then they start to order and and build up a level of capacity that Takes into consideration the slowness of whoever whoever's supplying you.So in our case the, the algorithms that we write to, to order the stock that we needed for the. 150,000 titles that we had in stock was to make sure that yeah, we would buy them out and have zero for a little while, but then it was coming back in now algorithms, cause we've got the funding is to hold as much as we can.So we, our low tide is well above the zero [00:13:00] point. And so then you do that. What I'm doing now though, is which is more exciting for me having moved from online retailing about four or five years ago, we got into distribution. Now the publishers are appointing us as their Australian distributor. So we go to ourselves, but we also sell to Amazon and Dimmick's and QBD and all the little indie bookstores, whether they buy from us, buy from us.So we've actually, we've actually addressed that supply chain by saying, Hey. We can hold your books. We can actually sell more if you keep less. And of course for Booktopia we get better discounts because we are the distributor now. And so that's one of the areas. Okay. Thank you. And, and then also we are we're talking to printers, like for example there, there are printers, there's a legal publisher here in Australia.They print in Sydney, their warehouses in Canberra, which is three and a half hour drive away. So they drive all the stock and all the product down to Canberra, put it in the warehouse. Some PR obviously gets sold in Canberra, but it's mostly in Sydney and [00:14:00] Melbourne. So then it all comes back to Sydney, into Melbourne, right?What the hell? Like my company is making money out of that. And there's yeah, there's even at the last semester we were very big on academic books and one of the PhD students ordered a book from us, which John Wiley is the publisher. So we ordered it from Wiley. It's a. PhD books are not many are needed.So it was print on demand. It was printed in Singapore, which is the PID partner. They then ship it to Queensland. Where there John Wiley shed is their distribution center is they then freight it down to us and Sydney and we sent it to the customer. What the hell, how much it's all going to the freight companies?So my goal over the next 10 years is really to address that Leia historically in the book industry. Cause it's been going for 570 years and certainly for the last several decades, it's very siloed. So the printers did the printing and the publishers did the publishing. The distributors held the books, the authors write, then the literary agents represented them and so forth.It's very, very silent and I'm looking [00:15:00] at it addressing that without investment in logistics and publishing which we've also stabbed in the last couple of years. And and, and just kind of see if we can remove some of that and have that profitability. Sit with us, give more to the author.And, and hopefully make the price very compelling to the customer. What you're also doing is taking over proud of the market. That's never been addressed. You're doing something you're making a unique offering that hasn't been available to authors until now. Yeah. And one of the reasons for that is The lucky thing for me is I'm not really a reader.I actually do. I listen to audio books. I listened to a lot of audio books, but to sit down or because I have ADHD is that I I don't, I was never much of a Raider. So I came into the book industry as, as an outsider, looking at it from a very different perspectives. They had a very, like, this is the way it always was the way it always is.We're looking across the valley of, of publishing in the book, industry gain, look at our valley and I'm going well, [00:16:00] I'm in a helicopter looking from up here. Or I went over to the other side of the valley, or I sat down through the river through the middle of it and I got a different perspective. And so from my view, I just didn't see it the way that they saw it.And I just saw other opportunities within that. One of the things that you saw was a belief in a business model. I'm going to say it. Perhaps Amazon may have been on your mind in a couple of those meetings. How did you know to keep going? When this monolith had decimated the U S book market and the publishing industry around the world, how did you, I want to know your thinking.Cause it's more than a punch that you've done. This is well, in the beginning though, the thing was, is that Booktopia was started with no light bulb moment or insight, or there's a gap in the market. It was just a side project, $10 a day. We used another company to manage our site and fulfill our orders because they had done it for one of our internet marketing clients, Angus and Robertson.So they built the site for you as well, the first ever ordering. [00:17:00] Yeah, they, we got through our internet marketing consulting business. We got Angus and Robertson. One of Australia's oldest bookstores, their website to the top of Google as a project. And they use this company in Sydney to manage their site and fulfill their orders.And this company managed 80 bookstores websites. So my brother who had done that project set up a meeting and Christmas of 2003 pitched the idea of, of of us. Being introduced to their other clients and getting them all to the top of Google so they can make more money. And the owner of that company said not interested.I said, you're not interested in making more money. I said, seriously. And he goes, he goes, no, we build websites. We manage you. We've got this platform that we can, we can get a bookstore website up and running within 10 minutes, 10 minutes. There's a million books on there. And if you sell anything, we pay a commission.I said, well, that sounds interesting. Yeah. And he goes, yeah, I know, but no internet, only businesses have made anything out of it's all been off the back of a traditional bookstore. So I went away from that meeting. I [00:18:00] said to my brother, he said, what? Wouldn't mind giving that book thing a bit of a guy.Cause I could see there was very little cost from outside other than driving traffic and, and getting a commission. And, and so I kind of went away from that, came up with the name, Booktopia registered the business and sure enough, this company got the Booktopia website up and running within 10 minutes with a million books on there.And my brother handled the finances, said. You can stop Booktopia it's gotta be outside of hours. Cause we're doing all this consulting work. And I said, sure. Yeah. So you was selling your time for money as a consultant, not even. Visualizing the vision of what God's hope you could become. No, we had no idea my brother, right.My brother read the sales plan. You'll you'll sell one book for the first three months and then it'll go to two and then it'll go, right. This is awesome. This is awesome. And my brother finances gave me a budget of $10 per day to start. What did you spend the $10 on? I've been dying to ask you that question.Google ad words. I was a Google ads, Google ads, but I didn't [00:19:00] go for search terms like books or bookshop or, or or, you know, those kinds of generic terms. I went for authors and titles and sent them deep into the site because they had already used Google to do a search. So I sent them to where those books were and it took me three days to sell my first book.And that was the total sales for the day one book. At the end of the month, I had done $2,000, but by the fourth month, I was up to 30,000 a month by the end of the year, a hundred thousand dollars a month by the end of two years, $200,000 a month. So We kept publishing distribution back then they, so that, that company that managed our site amazing, they took care of it all for a commission.That's all right. Yeah. Well, they, we got a commission for generating a sale, so it was a white label system. They had 80 odd stores that they were managing and they, they did Angus and Robertson, Collins books bunch of other independent bookstores. And, you know, we were one of them and then we quickly became one of their largest and it was once we got to [00:20:00] around 2 million in revenue we could see that there was something going on here.And I went through the Australian booksellers association annual conference in 2006, and we were still doing the internet marketing. We were still using this other company. And I came back from that and I said to the family, these guys have no idea what's going on. We got to go out and do this ourselves.And because of my background before internet marketing I was, I. Sorry. I was a recruitment consultant for the competing industry. And before that I was a computer programmer and my brother-in-law was an IBM software engineer. And so we had the confidence to build our own site, which we did. And in 2007 beginning of 2007, three is after we had started Booktopia.We parted ways with the other company when it moved into a small warehouse in Sydney, 500 square meters, next door, a brothel. And not that we knew that when we moved in, we had found out later and then bought some shelves on eBay. Hi, hi to warehouse manager rang the publishers and we said, it's assets.Booktopia, we're [00:21:00] turning over 2 million a year. Never heard of you. Because all our orders have been going through this other company. So we've got basic terms, basic discounts, and we still did our consulting work. So it wasn't until two years later that we could finally say, all right, Booktopia is turning over.I think it was around 7 million. So we could stop doing the recruitment or the internet marketing. So we could focus on the, the Booktopia business. What were the publishers saying to discuss, to offer you such lousy terms? When you clearly, the volume you were moving was bigger than any one bookstore or brand in Australia, we were only doing 2 million, so there was nothing there.In fact, I remember getting a letter from PSM, the education publishers to say, as you're an online retailer and have no overheads, your discount will be 10%. Now at that stage, I think we had about 10 people working in the business. I looked around at our warehouse and our shows and our people. What do you mean no overheads?I just think that it's some sort of smoke happens by magic. And so [00:22:00] it took quite a while. It took I would say another five or six years for them to really get their head around what was going on. And they started to shift because it was a very archaic industry where you know, where they they controlled everything.And, and so w once we got to 30 or 40 million in revenue, we were starting to you might've negotiated a little differently, probably. Yeah. I just got some discounts, improved terms improved once we, of course, you know, paid our bills and, and, and put more volume. Yeah. What was it like signing that first contract on the first warehouse, still working in your other job that wasn't too scary?It was $1,500 a month. Yeah, I think so. It was not much more than what we're paying for an office in, in north Sydney. But it was. We didn't hold any stock in the beginning. So we literally took orders from customers. And we would order it from the supplier would come in, you know, a few weeks later, five weeks later, eight weeks later, and people were [00:23:00] bitching and complaining saying, you don't like you guys suck.I should have bought from Amazon. And it was about a year after we had gone out on our own. So almost four years of being in the business, there's one book had been selling really well at because the author had been on Oprah and it was the wife of Jerry Seinfeld, Jessica Seinfeld and, and America had sold out of its 300,000 copies and HarperCollins in Australia had 200 copies left.So I said to my brother and brother-in-law, we shouldn't buy all of them then no one left, but except us. So we did, and it arrived into our warehouse. And imagine what keen to a bookshop where there's only like one book on the shelf or that yeah, that's how a bookshop looked at that time. So, so when this order, when an audit would come through the site, we just pick it, pack it and ship it.And the feedback from everyone was, wow. What great service you guys are really quick. And I, I said to the others, you know, to kill a Mockingbird is sold every single month for 50 years. Why, why are we ordering it in? And what else is there? How to win friends and influence people, power positive thinking, thinking very rich Harry Potter, Dr.Zeus. So a little warehouse that was supposed to be more of a cross-docking kind of thing [00:24:00] really started to fill up. And then after a couple of years, by 2009, we had to move out of there to, to 2000 square meters. And we thought, well, this will last us five years, the five years that ran out of space after two years.And then we take another 2000 square meters. And at this stage it's all manual handling of every book. Yeah. Yeah. Except we had, we bought one packing machine that in the middle and someone would have the one in, just put it through and we'll come out with a package wrapped around. And it was in 2014, seven, seven years ago when we moved to 10,000 square meters.And that was a pretty big league. We were turning over 40 million. And we moved here. And that was where we invested initially 5 million in automation and then, which was conveyed as in more packing things. And then, and then over the next few years we invested another 5 million in, in automation to improve our capabilities.And then that got us to around 150 million in revenue by the beginning of 20 [00:25:00] 2020. And that's when we did our first raise, how, how did you come to the decision to do the crowdfunding? Can you talk a little bit about that? I think our listeners would be really interesting interest in how Boulder moved.That was to even consider it. Was it over a glass of red that you came to that decision when you're on MBMA how did you crowd go to crowdfund? Talk about that. So what happened was when the IPI didn't happen and we had when you do an IPO, there was there's a lot of costs involved and we accumulated those costs and then we never raised the money to pay our first costs.What I recommend to the listeners, if they are looking at it is definitely. Accumulate the money for the capital raise rather than trying use it out of the proceeds of your business, because that really stretched us. We had a couple of million dollars in costs that needed to be paid down and that put pressure on our suppliers, which meant that we were putting, being put on stock because we couldn't pay them.We had to sell so more and it was a very tricky period to navigate and our way through to get that's not how you want to do an IPO. Yes. Well we [00:26:00] didn't have much 80 million in turnover, so we didn't have many other options, but yeah, that was our learning, our lessons and learnings on that period. So then once that didn't happen, we didn't look at a trade sale.So we, we engaged a company from Seattle to go around the world and talk to companies who might be interested in buying us because we were on track to under a million in revenue. We got no interest there, so then, okay. That's that was done. And then we the business was continuing to grow and I felt well, you know, one of the reasons why we wanted to IPO in the first place is that our customers are our hugest fans.They've been our investors all the way through buying books from us. And that's why we wanted to list. So I knew some guys who did had the crowdfunding platform and I reached out to them and I said, look, how about we do raise some capital through you guys. And so we we had some conversations and we said, we already had a prospectus that could be used reused to go to market with.And, and so we, we did that and we were going to be able to raise a few million dollars out of that. [00:27:00] And the reason why we didn't was because we also did a road show with a guy who has a company called wholesale investor. And we went to Sydney, Brisbane, and Singapore presenting ourselves to to invest at the investor community.So this was alongside the crowd funding and through those. Those events I did end up at the top of the Sheraton at 11:30 PM, edging my way to the back of the room. Cause it was so noisy standing next to this guy who we get into a conversation and he came out to Booktopia gave him a tour, told him where we were at and he goes, I think I know a guy who might be able to help you out raise some capital.Yeah. And then this guy, mark Peyton from ifs G capital came out. We really liked each other. He came into the business three to four days a week working inside. And that's the one thing I feel at that time, it felt like the problem or the reason why we weren't getting any any results in terms of raising capital is we didn't come from the capital markets and other companies who had been [00:28:00] succeeding, had someone there.Either an investor or a CEO or something who had come from the capital markets and can talk the talk of the, of that part of the world. And so, so he came on and there was things that were missing in terms of some of the modeling that we had within our books. That's helpful, more profits. So we've made some changes to some of the things that we've been doing in terms of postage and so forth, and made sure that we upped our profits slightly.And then within six months we had completed an $8 million raise. And then we also added to that $12 million of some senior debt that we had had for, we ended up having for about 11 months until the IPO, and that enabled us to, to invest in the automation that we needed to get to the next level. So that was, that was how come the crowdfunding came into play.I still won. 10 11. I wanted to have our customers own a piece of booklet. Exactly. I love that. It's a really inspiring message. How was it received by your customers? [00:29:00] W well pissed off in the end because we, we closed it off and and, and went through the traditional because we were going to raise a lot more money, which is what the business actually needed rather than, you know, three to 5 million.But they, they loved it. And those that were going to invest More than most people that were investing 5,000 and more we're invited to be on the priority offer for the IPO. Yeah. And that, that would have been great. The head away to have P feel part of the story that was unfolding. I'm interested that when you went looking around the world, there were no potential buyers.Was that because you feel you were under in terms of what those potential investors may have been looking for, what weren't they seeing that this is a stable, sustainable replicable completely. It can only scale up because all you're doing is supplying to customers, not consulting clients. So the scalability is obvious.What was the gap? That's a tricky one to [00:30:00] answer. Cause there's two types. There's obviously private equity firms who have got a specific mandate and they'll, they'll be looking at businesses in a very. Two dimensional way going, okay, where are they geographically, geographically? Are they based? What's what vertical or sector are they in?And a variety of other things and being Australian and growth, they care about growth trajectories, tremendously. They're going to show how they can make the money in five years. Yeah. The Australia was not part of their geographical mandate or, you know, what, what they were looking for for those that were in publishing.Because we're e-commerce and because of the value that we, and Amazon and others at LaSeon and so many other businesses that are out there based on it's a very different valuation than a publisher or a traditional business is based on. So they, they struggled to get their head around the multiples.So the multiples are higher. Yeah. Yeah, because not according to them though, no [00:31:00] traditional businesses there was there was little appetite there, so it just, I mean, interestingly for me after the IPO didn't happen because many reasons, but one was because Amazon was announced that we're coming to Australia.So I reached out to the Amazon through that process. And personally, directly, I reached out to the Amazon M and a team and I said, are, you know, here we are, we're turning over a hundred million a you interested in. I said we only buy businesses that we don't care what revenue you're doing. We don't care how much profit you make.They just have to be aligned to our three to five year goals. And I said, well, where Australia's biggest online book retailer, you guys sell books with turning over a hundred million and we're on track to get a 200 million. And you're saying that we're not aligned to your three to five year goals. I said, To myself, not to them.Thank you for that insight information. I will take that away and on. That was really helpful because we were seeing that Amazon was moving away from books and have been doing that globally. And [00:32:00] even though they're still the biggest book retailer, the publishers and the evidence was there, that they actually were moving more into a tech company rather than a supply chain and logistics fulfillment business.That was a very inspirational conversation to have had. So that's led you to decide then and there to do IPO again, or what was your thinking that time just to, were you always going to keep it in the family? What led you to decide to IPO again? Was that a turning point moment or what was the turning point for you?For us, it was always about how do we get money off the table? So we build a business and my brother is always, he's two years younger than me. I'm the CEO and have been he was, once we got past 50 million, it was big enough. He was happy to still leave it at 50 million revenue, pay a dividend lovely business.Thank you very much, but that's not what our, it, he may say. That's not what I wanted, but it's actually not what our customers were wanting from us. And to be fair. And yeah. And when you say that, can you just slow down? So I assume you mean by that you had to [00:33:00] provide a bigger range and faster. Is that what you mean by what our customers wanted?No, it's just that more people were transitioning online and therefore more people were coming to us. What do you do say we don't want you to buy from us. We, you need to stay at 50 million. No, they, they continued to To want to transact with us. And that's what was fundamentally, we kept doing what we were doing.More people were moving online. We were, and we did it well. So, so Simon, my brother, he, he was ready to retire, which he did just before the IPO. But part of that whole that whole journey, that goal was to how do we get money off the table? How do we convert the value of the business? So the family can know, can be set for, you know, how many generations who knows.We knew that we had done the hard work. There were many ways to, would have been happy to sell it to someone if the price was right. But that, that wasn't the way it worked out. So when we did the capital raise at the beginning of 2020, which is quite funny because I'm assuming one who is the founder and chairman of champ [00:34:00] benches and He was it wasn't through champ.It wasn't through private equity is to resign personal investment and a consortium of people who came in with him to make the $8 million investment. Six weeks later, the pandemic hit. And I remember meeting out with him and looking at his very grave and grey face going, what have I just done? I've just put what was money into a company.And we're being hit with a global restructure and, and it turned out to be one of the best investments that he's been the best investment. He made that. If you're online and you must've known it at the time, I'm going to throw that credit to you. Everyone has to go home. They have to have things to do.Now. That's not in the moment. In those days. When I, when I reflect on it, there was no guarantees who knew with the postal service stay open with, would we be able to deliver, how, how devastating was it? How, how did it, was it transmittable by, by a book? All these things, [00:35:00] there was still a lot of dust had to settle.Got it. So but things very quickly, we worked out that we were on the right track and sales kicked in excuse me. So, so what happened was we we were never planning to IPO. In that year we were going to wait a whole year because the investment that we had that they had made in us was to, to, for us to.Increase our capacity by adding more automation. We want it to go from our capacity of 30,000 books in and out per day to 60,000 out per day and an hour. That, that was a project that we'd been working on for some time and why we did the raise and that wasn't going to go live until the end of the year.So pandemic hit and we didn't have that in place. So we wanted to we wanted to get that deployed, get it optimized, and then be able to say to the market look how much profitability we have now. Look at the scale, look at everything else and, and have, have the runs on the board, but everything was very [00:36:00] uncertain and.E-commerce had moved from the wings to send a stage theater had been darkened and the spotlight was on e-commerce and we decided in August let's do it. And basically we did an 11 week IPO. Yeah, it was bloody quick. And that helped actually it helped so well because we could nothing was as long as a piece of string, everything goes, no, no, don't worry about that.We'll just, you know, just do this, do this. And so we stripped a lot of a way decisions were made quicker. And we, we were fortunate to a degree because we tried to IPO four years before and we still have that Pathfinder, which is the pre prospectus document we have We had, we had appointed out chairman four years before and we, he and I liked each other and he stayed on for those four years as our unlisted chair of Booktopia.So he'd been to our monthly board meetings. He had heard us discuss everything. I'm assuming Wong had joined us as a board member [00:37:00] already at the beginning of the year and had met with me already. Well, before that, as we discuss the plans for the business and he was on as a director. So, so there was already quite a bit of.Knowledge about our business quite often, when you try to IPO, which is what happened last time, you're appointing your, your non-executive directors. They're going into the due diligence process and the DDC meetings which is due to the due diligence committee meetings with the lawyers and with the accountants and so forth, doing all of the due diligence to then get their head around what your business is.They have a cultural match or a philosophical match about how to, how to do it. Exactly. So you had, so your feeling is, and your perception is it was successful this time around partly because you had the right people around you who already up to speed with how you were doing it. No, because it was like going down the Bondai beach on a mid day.So ice creams, right. We were oversubscribed four or five times. The value survey on the valuation of the business is [00:38:00] 300 in 15 million. And when we started probably four or five months before, it was probably more like 200 million. So e-commerce was e-commerce was really hot and we had the product and to be fair, even though a businesses value today at around 350 360 million, we're very similar in size to temple and Webster who have got a market cap of 1 billion.We've got a, we're much bigger than Adobe beauty and their market cap is in the mid 400. So we, we knew we had a very, very good business. And, and so what we've been able to do is get some money off the table. Like we had planned the school that the family still owns at this stage, I think over 40%, 45% of the companies, which is, which is Terrific.And we were able to sell down and, and and bought some and great institutional funds onto the register and very passionate about a business we're in for the long term and also the retail customers as well, who are now. So we, we did accomplish, it was very helpful to have the pandemic [00:39:00] accelerate.E-commerce exactly. What was the biggest challenge you've faced in your first 10 years when you had made a conscious decision not to make profit? It was 12 years. What was the mental challenge? Not the physical challenge of making sure you had enough money and money, but what was the biggest challenge you faced for you?I never feel like I haven't like them. The question I get asked often as, you know, what keeps you up at night? Nothing. I hit the bed, I got to sleep. So I'm I don't feel like that. It's this, you make it sound like it's it's you know, it was a big burden or that it was heavy or that it was like, oh my God, I, you know, I don't know how I'm going to do this, but we did it.It's it's never been like that. I don't think that way, I think, okay, this is what you've thrown at me out of left field. Never expected it. Okay. How are we going to deal with this? Because we will, and, and that's, that's one of the attributes that I have, I think, [00:40:00] I think so, which is quite helpful. I think maybe the things that I don't, and this is the way that I explain it when I do my keynotes to entrepreneurs and, and hopefully anyone can get this you know, through this, just through talking about it, is that Yeah, I've got a, I've got a good friend of mine.She's she's in credible talent, but she rides the highs. Like she, she has a great month or like win an award and like, she's just not there. Right. And then something doesn't work out and it's just like, blah, she's just bitching, incompliance. Right. And then she's up again. And she said, you know, I get exhausted just watching her go along this journey of like a roller coaster.Like we, we list on the, on the ASX. So we win the Telstra business award of the year or whatever. It's like, I, yeah. That's how I celebrate very little, you know, a fist pump and we're on track. And then when something doesn't work out, so the distance that I travel, right. Modulator is very flat. It's very modulator.[00:41:00] Very rolling. Rolling Hills. Yeah. And so I'm not, I'm a peaks in the valleys. And I think for me that, that. Solid being solid and, and not being. And actually she and I caught up only the last couple of weeks because I told her exactly what I what I tell people in, in I gave her that and she goes, you know, I've, I listened to that and I I've stopped myself sometimes and going, I don't need to get that pissed off or agitated or aggravated.And she, even, she, she heard me, she listened. So that was but I that's the way that I do it. And I think anyone that is in business, particularly as a business owner you get stuff thrown at you out of left field that you do not expect. The government will contact you. The regulations will change.The ASX will have a view. Yeah. In our, in our warehouse, the first time we moved in here, we moved in mid winter. It was called, of course it's a warehouse, but then it hit summer and it was 42 degrees in the warehouse. And then everyone struggled and it got to winter and everyone was fine. And then it was coming around to summer and they [00:42:00] were going to complain to fair work and it was okay, what do we have to do?Well, we're going to have to strengthen the stress into the ceiling and we've got to put these big jet engines. Two of them that are going to cost $600,000 and that'll keep it at 28 degrees and get all the hot air out. Okay. That's what we've got to do. You didn't expect it was an extra cost, but that's what you do.And you, you, you just keep pushing through that. That's that's that's what it is to be in business. You've got to say, bring it on. You also gotta be pragmatic. So the biggest challenge I faced, so you didn't really face my, my biggest challenge when I built my business in the first 10 years was my inability to trust others.As much as I trusted myself, I could do everything better all the time. And that was my biggest thing to get over. It's just that I know best. So therefore I should do best or interfere and just learning how, when to let go when it's not abdication, but delegation, which taught me systems. That was my biggest challenge.And is the only way we go. We're nothing like you. We do [00:43:00] over eight, we do eight figures, but to get to my first eight fears, I had to overcome my own BS about what others could do around me and how to build a team and what culture means. Yeah. That's interesting. So I do talk about that in my keynotes about Shlomo.So he, he also had an online bookstore and Booktopia, and his company started a similar time and we were turning over about, I don't know, five, $7 million. And I keep in touch and I called him. I said, man, how you going? And he goes, all tidy, terrible. I said, what's the matter? And he goes, well, I've had 18 angina or texts in the last three months.Wow. You're kidding mate. What's why. And he goes, well, you know, my wife and I were working 18 hours a day, six days a week. And and I said, how many people have you got working there? Cause he was turning over 2 million and we had, I don't know, maybe 12, 14 people. And he goes, oh, and there's my wife and I, and two casuals.You're joking. He goes, why don't you hire more people? [00:44:00] He goes, well, they just never do it as good as us. I said exactly, but at least they're doing part of it and they're taking it away. So if it's at 80 or 90% or 70%, but that's more because I'd come from a recruitment background. And I 14 years in recruitment, I understood hiring people.I understood what it took to bring people on board and let people go and so forth. So it was, it's been very much part of me as bringing people on and empowering them to, to give them the opportunity to grow with the business. So that was not one of the things that that I had to, that I, I had to NGO or challenge like you, you had to do.But I will share one thing with you, which I think has been really valuable to me when I was a recruitment consultant. I had contractors it contractors working for me and. I had 15 of them. And I went and did this course with Robert Kiyosaki, the guy that wrote rich dad, poor dad, about seven years before you wrote that book in the course called money in you, I did that.Or you did that. Okay, [00:45:00] great. You know what I'm talking about? 1992. And, and what happened was it was actually, I went in there because it said money, but in the end it was more about you. You probably have the same experience. And so, so I came back from that course, having had some great insights about myself, because the problem I had with my recruiting was that I got to 15 and then.I would drop back down to 11 contracts and then I came back up to 15 and then I dropped back down to 10 to eight and it just, I was stuck at this invisible ceiling. And then I had some breakthrough realizations about myself that I realized how I was self sabotaging or my thinking was not this certain.Right. And I went from 15 to 30 contractors in three months. Yeah. And then I got stuck there and I'd got back down to 24, 25 that got to 30 and then down to 20. So then I went back and did another one of these courses called creating wealth. And I had another breakthrough and I got to 45 contractors and I'd get back then.[00:46:00] And I was stuck at 45 and then I did business school for entrepreneurs in Hawaii in 93. And then I had more breakthroughs. And then I ended up with about 110 contractors working for me. Now, the reason why I share that story with you in particular for entrepreneurs, because I talk about, and I make up, I make up the scenario.And if you can hear me out, imagine if you owned them as Alrighty. I actually. Was presenting to a group of jewelers. My friend is in the jewelry business and I S I said that, you know, imagine you're in a Maserati and they all looked around the room. Yeah,well, that was quite a, that was not the normal reaction, but imagine you're in a Maserati and Maserati being an Italian sports car, quite often, it needs to end up in the workshop. And, and this particular day, there it is. You've got to drop it off and a mechanic needs to work on it. He gives you the loan and the loan is a 15 year old to Dorothy it.And you've got this very important meeting that you need to get to. And it's [00:47:00] in double bay or it's in Toorak if you're in Melbourne. All right. And you've got to get to this meeting and, and you, you get there and when you arrive there, It's a little restaurant cafe that you're meeting this new, big client that you're going to pitch to.And, and you think, well, I'll just pack in the back straight and I'll walk around and there's no parking spots and the light is light. And if you do not get there on time, right? It's a reflection on the opportunities, but there's only one spot available in front of the cafe restaurant. So you pack 15 year old two-door theater in front of the restaurant and you get out and you look at the client and they're looking at you and you're looking at the car and they're looking at the car and you're going, I mess it, rati.This is not, this is not my car. It's not, this is not who I am. Right. You got to get out of that car as you is not. About the car, right? You are not your car. You are not your wife. You are not your husband or boyfriend or girlfriend. You are not your kids. You're not your kids' academic results or their [00:48:00] sporting results.You are not your footie team. Even though one of my best mates thinks he's the Richmond tigers. He is not the Richmond tight, the Richmond tigers. And, and with Booktopia. Right. I am not. Booktopia. OPR is listed it's Booktopia that was listed when it wins the Telstra business awards. It's Booktopia. And I remember when I started it and I was walking through the apartment and pass the room where I was doing my work in, and I stopped all of a sudden in front of the door because I felt this boom, boom, boom.I felt the baby. Like I could feel the hopper business. I remember when it crowed. I remember when it took it to the steps. I remember when we went to daycare for the first day, I remember when it went to primary school and high school and went to university and went out on its own. And because I see it as a separate organism and I'm thinking all the time, what does it need?What does it need right now? Who does it need to have in its team? What funding does it need? What nourishment does it need? What [00:49:00] space does it need? Right. I am not. I have not overlaid my own ego and my own belief systems about myself onto my company, which is for me. I honestly, I can honestly say to your listeners that one of the reasons why Booktopia has had for from 2008 to 2000, 20, 30% plus company, and you guys, right.And its revenue is because of that is because I have not identified myself as the business. It's its own organism, it's its own thing. And I I'm sure that that's how Jeff Bezos and others think about their business. It's unencumbered is enabled to, to flourish, overturn a core because if it, if it was me and I had to overlay my own ego on it maybe we'd be at 60 or 70 million because that's all I could.You know, imagine of myself, it's been a very interesting aspect to the growth and the success of the business. Have you made mistakes with hiring with someone has brought their ego or their own [00:50:00] insecurity into it and tried to move it in a different direction or a bad direction or a self-serving direction?Not that because I'm, maybe I'm waiting. Maybe I'm just way too dominant in terms of my vision. I do empower people to get on with it. They, if they know what they need to do, and I'm not saying I'm, I'm not micromanaging. I think people who've worked here will attest to that. So this is what we need to do.Go away and make it manifest it, make it happen. So they have a lot of scope there, but I, I don't feel like I've been. Now that we have a board there's that aspect in terms of being listed, of course, non-executive, they can have their inputs, but I think one of the reasons that's the beauty of the Booktopia business versus say an adore beauty is that you know adore beauty, Kate has stepped back new CEO.She's very talented actually to kneel. But it's a, it was an IPO led it was a private equity led IPO. They already own quadrant owned 60% of the business. That's not the situation here, so people are investing in [00:51:00] Booktopia and see Booktopia because of the vision that I am the executive have not necessarily that it's transitioned more towards, towards you know, a, an investor led business.So You know, Jeff Bezos owns 10% of Amazon. That means 90% is owned by everyone else. It's still quite a large number, 180 billion us in, in personal wealth. But it's yeah, it's, it's I think that's one of the things, so I don't, I didn't experience that. And I, I understand the question that you asked, but I've never felt like I've been.Railroad I've certainly made mistakes. I've certainly learnt from certain things where I've been able to pivot and change and, and go, yeah. Okay. That didn't work. So let's, let's move on and let's do this. I'm sure you get a lot of questions about your mistakes. I'm generally pretty interested to know what are you most pleased about in terms of strategic thinking?People will say you only learn from your mistakes. You don't learn from your successes. That is not true. I've learned stacks from when I'd make a good strategic decision, and I'm going to keep doing [00:52:00] that. Where did your strategy really serve for you to get to where you are now? As you look back in hindsight, you can think, ah, I see now why that really contributed.It's asking that one question over and over. What do our customers through through asking that and exploring that and be curious, curious around it, holding stock, investing in automation all the things that we've done to, to. Complish that has, has led us to here. So I think that that has been one of the the most insightful and valuable things that we were able to hold onto as a, as a, a guide along the journey people ask me, is they all the time, the same thing, actually oddly enough I give them the tour of the facility.So they see all the automation and the robots and the automatic packing machines, conveyors, you know, hundreds and hundreds of thousands of books everywhere. It's like, they go crazy. And as we were walking back towards the office, they say, oh, you must be so proud how proud you must be. And I say, [00:53:00] I say to me, I said to them, this is pride to me.Imagine yourself in a pitch black room where you can't even see the hand in front of your face, that you. You know, when you take a step forward that you're on track or off track, simply by the way that your foot strikes the ground. Nah, that doesn't feel right. That that's where I'm going to be. That is pride to me.So it's very, very internal. It's very internal. It's a very, yeah. Internal sense of knowing they say that in the money in you, I remember that flip chat that height was on track only 3% of the time and 97% on you know, correcting and re and reconnecting back to be on track. So it's a bit like that.So yeah, I'm the successes to me in terms of some of the things that have come that have come through is, is like, is that knowing that you're on track? Knowing that that, and that, that you're not, you're not there yet. Like one of the thing with the IPO people asking me, oh, you must be, you must feel fantastic.It must be [00:54:00] great to list. And like I could tell by the way they were asking, it's like, this is kind of feels like you finally made it. And I said at the ASX, in my, in a speech to the people that were there, I said, I said, here it is. This is the way it feels to me. It's like being on the tour, de France you're on the 10th stage.And the IPO is the 40 kilometer go banner, where you've got still 40 Ks to get to the top of the mountain to finish the stage. And after that, you got an another 11 more stages before you get to the sharps Elisa. When you get to drink champagne with your mates, go 20 kilometers an hour and, and make it to the finish line.I said I said, this is just assigned to say, you're on track and you want that in your revision mirror really quick, because it's focused on whatever you got to do next. And that that's how that the IPO and many of the other things that we've accomplished as well, Telstra business awards, so forth, I'm sensing from you.And I'm sure it's coming through to our viewers. You ha you've become more of you through this process. And not [00:55:00] less of you. I see a lot of business owners have success. I would call a successful or a business that's in the public eye and they seem to magnify aspects of themselves that perhaps they wouldn't be pleased with.As they look back, I have a sense that you're pleased with. As you look back of you becoming more review in the aspects of you that you like about yourself. It's I would, I would put more of that down to marriage. Nice. Yeah. You know, my wife and I have been together for almost 10 years. My son is 18, so yeah.I never got married, but I I'm a father and and my ex works in the business. My wife was married before, I've got a 15 year old stepdaughter and, and I, I would say that re you've got a lot of hope and you've got a lot of you know, imagination about why you want to marry that person and be in that relationship.But I can assure you it is at times you do not feel like you're going to be married the next day. And that [00:56:00] divorce lawyers are going to be, I going to be cold in, but you talk it through and you love each other and you keep discovering, you know, how you're, how you're connected and you know, what's not working for you and why what's going on for you.And it's it's businesses. Life is like that. It's, it's a, it's a, an emotional. Marriage of, of, of achiever accomplishing something together and, and that it's easy to bail out and go, you know, I'm pulling the rip cord and I'll see you back down on the ground. You know, I'm out of this one, it's going to crash and burn or you're in it for the longterm.So, so I have no there's no guarantees that cath Catherine and I are going to be together. We just are in it every day. And Y that's how businesses is as well. It's like, you've got, you've got, you're dealing with issues and you're being, you're being asked to step up and learn and challenge yourself.And, [00:57:00] and and that that's, you know, that you're either, you're either invested in your own personal yeah, that's what I'm sensing in. You, you either are invest in becoming the best of you and you bring that and business requires that. So does marriage. You've got to want to bring your best to it for the best of it to flourish, or it's not going to be the best.It's going to be some facsimile that just can't sustain. That's right. Add on top of that parenting, would you even take you at a whole nother level? But I think, I think for me that even one of my best mates product from when I went to high school, he goes, Tony, I know you from, I know you from high school Chatswood high school, just a typical, you know, public school.And he goes, how the hell did you end up here? Like what? I know that kid. Right. It's impossible to think that you're the guy, but it's just that personal mission that voyage of discovery to find out more and ask those questions and to go deeper and [00:58:00] understand yourself and unpack. I liked, I liked to do personal development workshops.I did many of them just with Robert. I did tons of different ones to me now being in businesses like a personal development workshop, being in a marriage and being a parent is like a personal development workshop to act like it's not it's to let down the other team, you'll let down your business. You let down your wife or your husband, you let down your kids.If you don't see this moment as an opportunity for ourselves to grow, cause then we put it on them and it's up to them to change it's up to them to do bad, or it's up to them to stop it rather than saying, what can I own in this? That's what I got from my personal development. How much of this can I look within rather than.I can easily point don't get me wrong, but how much can I look within myself? If there was an entrepreneur starting out today, what would you be talking with them or mentoring that mentoring them about other than the basics and getting the fundamentals in play? Most of the time when I meet entrepreneurs what's missing [00:59:00] is that the point of cash?Where is someone going to hand over the money to that's something. And I'll share with you a story. When I was at business school with Robert Kiyosaki in 1993, I The course of 16 days, it was incredible. You at 7:00 AM and you're running team, you finished at 2:00 AM and your marketing teams. He flew people in a crisis, many different subjects all through the, through the 16 days.I learned so much and it was three years before I started my own company. But during, on one of the days as a, just as a process, as a, as a challenge at the break, he sent us out and said, what I want you to do is I want you to go out there. And we were in Hawaii on the big island of Hawaii, and I want you to go out there and sell.And if you got a dollar bill in your pocket, just take it out. That was 150 in the course, just go around and sell it. And if you, for the point of integrity of the process, if you could be the, the one being sold to, if you feel like you want that, then you got to hand over your dollar. And I went out and I was in recruitment.So I went out hard and strong. Like we've got the [01:00:00] best business, we've got the biggest, we advertise more in marketing than anyone else, Ellison in the newspapers. And we, we attract more candidates and so on and so forth. And I was just saying all these. You know, it was really intense. And I came, I came back in after that, I had not made one back test as a really hopeless, you know, I'm the best salesman in my company that that really sucks.And so I walked back into the room and the course goes on the next break. He does the same thing. I changed my tactic and I, I'm more loving, you know, I listened, we listened to our candidates. We, we understand what they need. We talk to our clients really looking for what they want. And we, we do, it's like a matchmaking service and people were much kinder in the feedback this time around tenure.I really love what you're saying, but no, I don't think so. I went back into the room and go that price that's really sucks. I hate that prices I'm in the best salesman in my company. And so of course goes on. Then we take the next break [01:01:00] and I do something completely different. I sit in the corner with my arms folded and my legs crossed and I said, well, you can go and get stuffed.Right. That didn't work either. Can't believe it. Yeah. While I was sitting there and got into myself, you know what? I just, this is not right. What am I not thinking? What am I doing here? That's this is, I've got, something's got to change. And while I'm sitting there, I realized, oh my God, two years ago, I remember I did that.That remedial massage course, I can go out and offer a massage. So the next break, I offered three minute massages for a dollar. I made four backs. And seriously, when you ask that question, in terms of entrepreneurs, it's about really understanding where the Kashi is. So when, when we had our before our internet marketing business, we had a chat software company and the.com crash.And we were not, no one was interested in putting chat software in the website. We couldn't pay ourselves a salary. My son had just been born. My [01:02:00] brother and brother-in-law his families. They, I mean, they did, they couldn't earn any money. My parents were giving us a bit of money to make it through. And I was speaking to a web designer asking them.How do you, how do you get to the top of Google? Like if we were at the top of Google for the software that we had, which was chat software for the internet, how do you get to the top of Google as someone does a search? Cause they'd been goin

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During this week’s episode, Justin plays with a new mixer, we talk about synthesizers, Star Dew Valley livestreams and try to tell a story about Mandy Patinkin perfectly.All that and more on Excellent Week.

This month’s podcast is another in the Remote  Variations series featuring Modulator ESP from Nottingham, UK. Its super-spacey, droney stuff! Modulator ESP is an adventurer in sound. He produces improvised experimental soundscapes, using synthesizers, sampling,sequencing, looping and processing to create strange worlds of sound somewhere between ambient, berlin school, drone, space music and noise. http://www.modulator-esp.co.uk/ If … Continue reading Errant Space Podcast Seventy One: Remote Variations 4 with Modulator ESP →

In this episode, we explore this one-stop modulation laboratory. Chorus. Check. Phaser. Check. Organ style octave. Check. Sonic goodness awaits with this pedal.

In todays episode were back again with Mr. Basic and the Modulator Bay Show for a special guest appearance with Haze Anderson of YouTube! We talk gear, sound, electronics and get a few pointers from the master himself Haze.. So pull up the old Easy computer chair or whatever chair you have and enjoy the Life In Space Broadcast of Modulator Bay! Mr. Basic's Channel: https://www.youtube.com/channel/UCPP621crLuge7qTEpJ2kkqA Haze Anderson on YouTube: https://www.youtube.com/user/hazeanderson AudiosErgeon's Website: https://moogcraft32.wixsite.com/audiosergeon

In this episode we have another talk with Mr. Basic and what cool things we have accomplished in the year 2020. We also look to the future with new ideas and ways to have fun with modular synthesizers and gear. Enjoy and as always stay creative friends! Mr. Basic On YouTube: www.youtube.com/channel/UCPP621crLuge7qTEpJ2kkqA Mr. Basic's Discord: discord.gg/8KPrNgG Mr. Basic On Twitch: www.twitch.tv/mellollama Official Website Of Modulator Bay: http://modulatorbay.com Mr. Basic On Bandcamp: mrbasic.bandcamp.com/releases AudiosErgeon's Website: https://moogcraft32.wixsite.com/audiosergeon

In this episode, Mark spits some filthy Grime lyrics, why quoting the Magna Carta in Lockdown is futile, who's strong enough to rip their shirt from their torso, some valuable chat around attitudes to money and the amazing link between your brain, your heart and your guts. ---- ** YOUR HOSTS ** Damo & Mark --- ** HOW TO LISTEN** Our Podcast is brilliantly hosted on Anchor. You can also listen and/or subscribe to us on the following platforms: Apple Podcasts / Google Podcasts / Pocket Casts / Spotify --- ** GET IN TOUCH ** Thanks for listening! Please drop us a line at imfinecast@gmail.com with any feedback or questions. You can follow us on social media: Instagram / Twitter / Facebook --- ** SHOW NOTES ** This is where we like to keep all the references and links to what we've talked about in this episode. --- One giant ... lie? Why so many people still think the moon landings were faked --- “Article 61” of Magna Carta doesn't allow you to ignore Covid-19 regulations --- Br3nya Ft Ivorian Doll - Bezerk (Official Music Video) --- Einstein's Last Desk --- Compound Interest: How Teens Can Become Millionaires --- Vagus Nerve as Modulator of the Brain-Gut Axis in Psychiatric and Inflammatory Disorders The Body Keeps the Score: Mind, Brain and Body in the Transformation of Trauma by Bessel van der Kolk --- Maslow's hierarchy of needs --- The Valsalva Maneuver --- ** MUSIC ** I'm Fine Theme Music and Stings by the Monkey Fighters Check them out on Spotify or follow them on social media: Instagram / Twitter / Facebook --- Send in a voice message: https://anchor.fm/imfinecast/message

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.15.383737v1?rss=1 Authors: Finney, C. A., Shvetcov, A., Westbrook, R. F., Morris, M. J., Jones, N. Abstract: Silent infarcts (SI) are subcortical cerebral infarcts that occur in the absence of typical symptoms associated with ischemia but are linked to cognitive decline and the development of dementia. There are no approved treatments for SI, but one potential treatment is tamoxifen, a selective estrogen receptor modulator. While SI can have long-term consequences, it is critical to establish whether treatments are able to selectively target its early consequences, to avoid progression to complete injury. We induced SI in the dorsal hippocampal CA1 of rats and assessed whether tamoxifen is protective 24 hours later against cognitive deficits and injury responses to SI including gliosis, apoptosis, inflammation and changes in estrogen receptors (ERs). Hippocampal SI led to subtle cognitive impairment on the object place recognition task, an effect ameliorated by tamoxifen administration. SI did not lead to detectable hippocampal cell loss but did increase apoptosis, astrogliosis, microgliosis and inflammation. Tamoxifen protected against the effects of SI on all measures except microgliosis. SI also increased ER and decreased ER{beta} in the hippocampus, which was again mitigated by tamoxifen. Exploratory data analyses using scatterplot matrices and principal component analysis indicated that the SI rats given tamoxifen were indistinguishable from sham controls. Further, SI rats were significantly different from all other groups, an effect produced by low levels of ER and increased apoptosis, gliosis, inflammation, ER{beta}, and time spent with the unmoved object. The results demonstrate that tamoxifen is protective against the early cellular and cognitive consequences of hippocampal SI as early as 24 hours after injury. This effect is driven by mitigation of apoptosis, gliosis, and inflammation and normalization of ER levels in the CA1, leading to improved cognitive outcomes after hippocampal SI. Copy rights belong to original authors. Visit the link for more info

CME credits: 0.25 Valid until: 23-10-2021 Claim your CME credit at https://reachmd.com/programs/cme/new-era-begins-contraception-vaginal-gel-ph-modulator/11931/ While the use of contraception is a nearly universal experience in the United States, unintended pregnancy rates remain high. With the recent approval of the nonhormonal vaginal pH modulator, there are now more contraceptive options than ever before. Join Drs. David Eisenberg and David Portman as they discuss how this new method fits into clinical practice and how it compares to other contraceptive methods.

CME credits: 0.25 Valid until: 23-10-2021 Claim your CME credit at https://reachmd.com/programs/cme/new-era-begins-contraception-vaginal-gel-ph-modulator/11931/ While the use of contraception is a nearly universal experience in the United States, unintended pregnancy rates remain high. With the recent approval of the nonhormonal vaginal pH modulator, there are now more contraceptive options than ever before. Join Drs. David Eisenberg and David Portman as they discuss how this new method fits into clinical practice and how it compares to other contraceptive methods.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.15.340851v1?rss=1 Authors: Perez-Sisques, L., Martin-Flores, N., Masana, M., Solana, J., Llobet, A., Romani-Aumedes, J., Canal, M., Campoy, G., Garcia, E., Sanchez, N., Fernandez, S., Gilbert, J. P., Rodriguez, M. J., Man, H., Feinstein, E., Williamson, D., Soto, D., Gasull, X., Alberch, J., Malagelada, C. Abstract: RTP801/REDD1 is a stress-regulated protein whose upregulation is necessary and sufficient to trigger neuronal death in in vitro and in vivo models of Parkinson's and Huntington's diseases and is up regulated in compromised neurons in human postmortem brains of both neurodegenerative disorders. Indeed, in both Parkinson's and Huntington's disease mouse models, RTP801 knockdown alleviates motor-learning deficits. Here, we investigated the physiological role of RTP801 in neuronal plasticity. RTP801 is found in rat, mouse and human synapses. The absence of RTP801 enhanced excitatory synaptic transmission in both neuronal cultures and brain slices from RTP801 knock-out (KO) mice. Indeed, RTP801 KO mice showed improved motor learning, which correlated with lower spine density but increased basal filopodia and mushroom spines in the motor cortex layer V. This paralleled with higher levels of synaptosomal GluA1 and TrkB receptors in homogenates derived from KO mice motor cortex, proteins that are associated with synaptic strengthening. Altogether, these results indicate that RTP801 has an important role modulating neuronal plasticity in motor learning. Copy rights belong to original authors. Visit the link for more info

Ed joins Richard "TalkToMeGuy" to discuss how breathwork can improve our immune function. This Fall, discover your "life with breath" applying "breath AS medicine" to improve not only your immunity but your overall health and well-being.

Ed Harrold is an author, inspirational leader, public speaker, coach and educator. Ed’s mastery in the science of mindful breathing has guided him to apply conscious breathing practices in corporate health & performance coaching, fitness & athletic training, healthcare continuing education courses, stress reduction and overall health and well-being.  He is the author of Life With Breath IQ + EQ = NEW YOU and BodyMindBusiness: The Business Of BE’ing Within. Ed blends the fields of neuroscience and the wisdom of contemplative traditions into effective strategies to improve health, well-being and performance.  His fluency in mindfulness-based strategies combined with the belief in the human potential gives him the depth and understanding to meet individuals and group needs across industries and platforms. He is here to share howbreathing rates and patterns influence your biochemistry, biomechanics, physiology and psychology, as well as how you can retrain your body to improve brain, heart and autonomic nervous system function. Ed is a contributing health & wellness editor for Thrive Global, MindBodyGreen & PTOnTheNet, HuffingtonPost and more.  Learn more about Ed Harrold at edharrold.com

Kyoto Geiko performance reimagined by Nick St. George. "OK Geiko is another step along my road towards more abstract composition, moving away from narrative and the use of spoken word.  "This is an exercise in pure sound (dare one even say "music"?!) and features a new piece of software (for me) which I learnt about via the Cities & Memory website. Cherry Audio's oddly-named 'Voltage Modular" (Modulator, surely?) has provided me with a whole host of synth sounds for the first time, and you will hear some of them in this piece.  "The starting point was the percussive sequence that came from the Geiko performance  - the field recording then reappears throughout with samples from the vocal elements of the show. A couple of Japanese instrumental 'flavours' and beds from our old friend Apple Loops were also added to the mix."

An in-depth look at the unique properties of Nutriferon for the all-important function of immune system modulation with Master Pharmacist, Rusty Ost.

Enjoy the next episode of Modulator Bay with Mr. Basic and I. We talk about Synthesis, Music and Games. This is apart of our series on Modular Gear and everything that we find interesting, Enjoy! Check out Mr. Basic and his awesome Music and Videos : YouTube: https://www.youtube.com/channel/UCPP6... Mr. Basic's Discord: https://discord.gg/8KPrNgG Twitch streams: https://www.twitch.tv/mrbasicsound Official Website: https://modulatorbay.com Bandcamp: https://mrbasic.bandcamp.com/releases

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.27.119552v1?rss=1 Authors: Xu, S., Li, G., Ye, X., Chen, D., Chen, Z., Xu, Z., Ye, L., Stimming, E. F., Marchionini, D., Zhang, S. Abstract: Perturbation of Huntingtin (HTT)s physiological function is one postulated pathogenic factor in Huntingtons disease (HD). However, little is known how HTT is regulated in vivo. In a proteomic study, we isolated a novel [~]40kDa protein as a strong binding partner of Drosophila HTT and demonstrated it was the functional ortholog of HAP40, an HTT associated protein shown recently to modulate HTTs conformation but with unclear physiological and pathologic roles. We showed that in both flies and human cells, HAP40 maintained conserved physical and functional interactions with HTT, loss of HAP40 resulted in similar phenotypes as HTT knockout, including animal viability and autophagy, and more strikingly, HAP40 depletion significantly reduced the levels of endogenous HTT, while HAP40 was mostly degraded via the proteasome in the absence of HTT. Interestingly, polyglutamine expansion in HTT did not affect its affinity for HAP40. However, HAP40 modulated HD pathogenesis in Drosophila model by regulating the overall protein levels and the toxicity of full-length mutant HTT. Together, our study uncovers a conserved mechanism governing the stability and in vivo functions of HTT, and demonstrates that HAP40 is a central and positive regulator of HTT, a potential modulator of HD pathogenesis and a promising candidate for "HTT-lowering" strategy against HD. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.10.087346v1?rss=1 Authors: Shields, L. Y., Li, H., Nguyen, K., Kim, H., Doric, Z., Gill, T. M., Haddad, D., Vossel, K., Calvert, M., Nakamura, K. Abstract: Alterations in mitochondrial fission may contribute to the pathophysiology of several neurodegenerative diseases, including Alzheimers disease (AD). However, we understand very little about the normal functions of fission, or how fission disruption may interact with AD-associated proteins to modulate pathogenesis. Here we show that loss of the central mitochondrial fission protein dynamin-related 1 (Drp1) in CA1 and other forebrain neurons markedly worsens the learning and memory of mice expressing mutant human amyloid-precursor protein (hAPP) in neurons. In cultured neurons, Drp1KO and hAPP converge to produce mitochondrial Ca2+ (mitoCa2+) overload, despite decreasing mitochondria-associated ER membranes (MAMs) and cytosolic Ca2+. This mitoCa2+ overload occurs independently of ATP levels. These findings reveal a potential mechanism by which mitochondrial fission protects against hAPP-driven pathology. Copy rights belong to original authors. Visit the link for more info

3/3/20: On today’s Titan Talk (broadcast live on Facebook, Instagram & Youtube!) Titan Medical Center CEO John Tsikouris talks about: Special Guest Rachel Daniels aka: The Real Lois lane Therapy of the week: Thymosin Alpha 1 - Immune system modulator peptide What it is & how it works. New athletes & ambassadors are coming on! Arnold testing athletes for coronavirus Blood testing amino acids & why? New events coming are going to be awesome & a variety of different things! March 7th- Luxe Lingerie Show March 13th (6-12pm) - World Class Fight League XXVI March 14th (Daytime) - Drop Zone Gunner III April 5th (10am-4pm) Mad Burger Fest - Madeira Beach May 16th (12-5pm) Tampa Bay Jeep Fest- Clearwater June 20th (9am) - Deke Warner’s NPC Mid Florida Classic St.Pete Art & Fashion Week 10-12th Sept 12th (9am-9pm) NPC Iron Bay Classic Titan TV Show on ABC in Florida from Sarasota to Crystal River. Tune in Sunday’s 11 AM! Titan Programs are ready: titanmedicalfitness.com Poll question: Have you done any preparation for the Coronavirus? CHOICES: “Yes”, “No”, “Why should I?” & “I don't know what the Coronavirus is” Don’t miss out on our Titan Weekly Newsletter that’s full of information about Titan’s therapies, events, & just about everything else! It includes direct links to all of our social media and website sections all in one email! 3/2/20 Weekly Newsletter: TA1 (Thymosin Alpha 1) & NEW UPCOMING EVENTS! Email Link https://conta.cc/3are6mR Just text the words: “titanmedical” to the number: 22828 to automatically be put on our emailing list. Follow us on our social media, YouTube, & listen to us on our Titan Medical podcast! (https://titanmedicallifestylepodcast.fireside.fm) Don’t forget to join us on Friday when we go live with Titan Athlete Big Dru! titanmedical #coronavirus #arnold #peptide #fitness #enhancement #medicalscience #health #aminos #tampa #therapy #medicalclinic #johntsikouris #weightloss #diet #talkshow #injectable b12 #antiaging #tvshow

In this episode Mr. Basic from YouTube has a discussion with me about modular gear the future of modular synthesizers and how cool it is to be in the technological time where we can communicate with each other on the internet to find other artist like ourselves. Enjoy and check out Mr. Basic on YouTube here: https://www.youtube.com/channel/UCPP621crLuge7qTEpJ2kkqA/featured

Добрый день уважаемые слушатели. Представляем новый выпуск подкаста RWpod. В этом выпуске: Ruby Rails 6 allows spaces in postgres table names, macOS to Remove Having Ruby Installed by Default, Direct instruction marking in Ruby 2.6 и Rails 6 boot sequence An overview of Redis::Distributed – Redis client side partitioning in Ruby, PostgreSQLCursor for handling large Result Sets, Modulator - a tool for adding HTTP layer on top of your application using AWS Lambda and API Gateway services и Truemail gem helps you validate emails by regex pattern, presence of domain mx-records, and real existence of email account on a current email server Web Optional Chaining for JavaScript - Stage 2 и Plot to steal cryptocurrency foiled by the npm security team Extract critical CSS, Variable fonts and quirky custom axes и Creating Animations Using React Spring

I interview a real SARMs manufacturer located in the United States. In this podcast I interview a real manufacturer of research peptides like SARMs, Ostarine, LGD-4033, BPC 157, PT 141, and more. He reveals how SARMs are made, what in a lot of SARMs that should not be, should you use powder or liquid SARMs, and more. You cannot afford to miss this podcast. Click the link below to go to the manufacturers website. SARMs For Sale

We've got synths coming out of both ends this episode, getting the lowdown on Softube Parallels, a closer look at Massive X, and loads more. Elsewhere, we score an exclusive interview with Aphex Twin about his work on the Bass Station II, and Tim chats to bass music father figure, Hervé. WEBSITE AND SHOW NOTES www.a4ppodcast.com TWITTER https://twitter.com/a4ppodcast FACEBOOK http://www.facebook.com/a4ppodcast/reviews *Aphex Twin may or may not be Aphex Twin

Commentary by Dr. Valentin Fuster

Topics Disscussed: Pineal Gland, Modulator of reality, DMT, DNA, Soul, Afterlife, Spirtual World, consciousness, Records of Life, Simulation Theory, Ayahuasca, Alien Race alterting our DNA We delve deep and discuss the pineal gland also known as the third eye with Anthony Peake. But, according to our guest today consciousness theorist, Anthony Peake, says that the pineal gland may very well just be the doorway to the sectects of the universe and its right in our heads. He is the author of some very fasnatintng books The Infinite Mindfield, Opening the Doors of Perception, the immortal mind, is there life after death, the daemon, The Labyrinth of Time: The Illusion of Past, Present and Future and the out of body experience….. In the Podcast, We talked about Our Pineal Gland and made the connection with DNA, he talked about his own first hand experience with the Hypnagogic Light Device, an invention theorised to stimulate DMT release. He also outlined evidence for the pineal gland’s veneration in religious tradition, beginning with the Sumerians and Egyptians, linking Zoroastrianism, Vedantistism, Tibetan Buddhism and the Ancient Greek Elusian mysteries. Peake ultimately draws a theoretical conclusion involving entheogens, bioluminescence, DNA and the Zero Point Field. Support the podcast: Via our Patreon page - https://www.patreon.com/Ascend Show Notes - http://ascendbodymind.com/ascend-podcast/

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Banging Techno sets :: 098 >> Kerstin Eden // Timao Subscribe to Banging Techno Sets on iTunes https://itunes.apple.com/us/podcast/banging-techno-sets/id1453474812?mt=2 www.bangingtechnosets.com _____________________ Kerstin Eden Twitter: https://twitter.com/kerstineden Soundcloud: https://soundcloud.com/kerstineden Facebook: https://www.facebook.com/kerstineden?_rdr City: Frankfurt / Germany KERSTIN EDEN In the beginning there was an ironing board…Kerstin Eden was not aware which huge impact it would have, as in 2003 she nicked her mother’s ironing board and placed her 1210s and a mixer on it. Today, some years later, she has not only inspired some guys with home booth architecture, but also provided sore leg muscles for many party freaks. In recent years her reputation as insatiable sound machine has grown continuously and an outstanding club history and large fan base have been established. From Berlin over Frankfurt, Ibiza over Hongkong; the live wire behind the decks is well-known in hot spotted techno clubs for special marathon sets up to 16 hours, but also on festivals like Nature One, Mayday, Winterworld, Soundtropolis, Syndicate, Echolot Festival, Ruhr in Love or Loveparade. The ingredients of her dark powerful sound are straight techno rhythms with fat dirty bass-lines, peppered with tribal and hypnotic sounds. You can actually see and hear her passion for music, when you experience how she infects the party crowd with one of her long mixing sessions – which has always a surprise to hold. Living a nerds life she´s spending most of her time in studio with producing sessions. After years of learning she finally started releasing tracks & remixes 2012 and has signed on Naked Lunch Recordings, Heavy Snatch Records, Citylife Records. _____________________ Timao Beatport: https://pro.beatport.com/artist/timao/417185 HearThis: https://hearthis.at/timao Soundcloud: https://soundcloud.com/timaotechno Facebook: https://www.facebook.com/TimBusch.Timao City: Herford / Germany TIM BUSCH aka TIMAO Born on the 18th May 1977, from Herford / Germany. 1996 his first contact with elektronic Music was due to frequent visits to his favorite Club, Stammheim / Aufschwung Ost in Kassel, he developed a predilection for minimalistic, house influenced electronical Music. Soon he aquired his own turntables and he thought himself how to mix tracks together, his love for Techno emerged. He began mixing on private partys, later he got gigs in several clubs. In 2009 he started to experiment with Abelton to produce his own electronic music. At this point some informal tracks of his experiments originated, at first they remained unpublished. To carry out his scheme he used various social networks for promotion purposes, at last his first track „Modulator“ was published in spring 2014 by Heftys Label „Darker Sounds“. Soon further releases followed through Record Labels like Subwoofer Records and Toxic Recordings. Timao - Construction EP will be released on Teksession Records (16.03.2015) and has been remixed by not nameless artists like Tonikattitude, Klangtronik, Primal Beat... Further productions are in progress… _______________________________ Banging Techno sets Subscribe to Banging Techno Sets on iTunes https://itunes.apple.com/us/podcast/banging-techno-sets/id1453474812?mt=2 Facebook: http://www.facebook.com/BangingTechnoSets Soundcloud: http://soundcloud.com/bangingtechno-sets Twitter: https://twitter.com/BangingTechno Google + https://plus.google.com/u/0/b/113379277795569248132/+BangingTechnosets1/posts Youtube: http://www.youtube.com/user/BangingTechnosets1 ______________________________ Subscribe to Banging Techno Sets on iTunes https://itunes.apple.com/us/podcast/banging-techno-sets/id1453474812?mt=2

In this work, techniques were developed and used to study the properties of molecules on a single-molecule level. Single-molecule techniques have the major advantage, that in contrast to ensemble measurements, they allow a detailed insight on the distribution and dynamics of single molecules without averaging over subpopulations. The use of Total Internal Reflection Fluorescence Microscopy (TIRFM) in combination with single-pair Förster Resonance Energy Transfer (spFRET) and Alternating Laser Excitation (ALEX) allows the identification of molecular-states by making quantitative measurements of distances in the Ångström range. The development of highly sensitive photon detectors and the use of versatile labeling techniques with photostable (synthetic or genetically-encoded) fluorophores, extended the application of TIRF microscopy to in vitro and live-cell experiments. Despite reducing the complexity of biological systems down to the single-molecule level, functions of individual molecules and interactions between them can be very sophisticated and challenging to analyze. Using information theory based methods, e.g. HMM, the dynamics extracted from single-molecule data was used to illuminate protein interactions and functions. The highly regulated process of gene transcription plays a central role in living organisms. The TATA-box Binding Protein (TBP) is a Transcription Factor (TF) that mediates the formation of the Pre-Initiation Complex (PIC). The lifetime of TBP at the promoter site is controlled by the Modulator of transcription 1 (Mot1), an essential TBP-associated ATPase involved in repression and in activation of transcription. Based on ensemble measurements, various models for the mechanism of Mot1 have been proposed. However, little is known about how Mot1 liberates TBP from DNA. Using TIRF microscopy, the conformation and interaction of Mot1 with the TBP/DNA complex were monitored by spFRET. In contrast to the current understanding of how Mot1 works, Mot1 bound to the TBP/DNA complex is not able to directly disrupt the TBP/DNA complexes by ATP hydrolysis. Instead, Mot1’s ATPase activity induces a conformational change in the complex. The nature of this changed, "primed", conformation is the change of the bending dynamics of the DNA. The results presented in this work suggest a model in which this primed conformation is a destabilized TBP/DNA complex. The interaction with an additional Mot1 molecule is required in order to liberate TBP from DNA. The effect of Mot1 on the DNA dynamics is TBP binding orientation specific. Mot1 effects on the DNA bending dynamics are strongest for molecules where TBP is bound in the inverted binding orientation. The specificity of Mot1’s regulation of DNA bending dynamics suggests that Mot1 preferably "primes" TBP bound in the inverted binding orientation. The mechanistic insight into the interaction of Mot1 with the TBP/DNA complex serves as a framework for understanding the role of Mot1 in gene up- and down-regulation. In a second project, the same single-molecule techniques were used to fabricate and evaluate self-assembled optically controllable, nanodevices. Based on the specificity of Watson-Crick base pairing, DNA was used as a scaffold to position different fluorophores with nanometer accuracy. The functionality of these nanodevices was expanded by making them optically addressable by incorporation of the switchable fluorescent protein Dronpa. Two functions have been demonstrated: Signal enhancement using Optical Lock-In Detection (OLID) and pH sensing in a live-cell environment.

Obwohl seit der erstmaligen Beschreibung der Alzheimer-Erkrankung vor über 100 Jahren eine Vielzahl der ursächlichen histopathologischen Veränderungen und der beteiligten molekularen Mechanismen erforscht werden konnte, ist noch unklar, welche Faktoren die Spaltung des ß-Amyloid Vorläuferproteins (APP) beeinflussen und zu der pathologischen ß-Amyloid (Aß) Bildung und Aggregation führen. In zahlreichen Studien ergaben sich Hinweise, dass Cholesterin einen wichtigen Modulator der Alzheimer-Erkrankung darstellt. Zusammen mit Sphingolipiden bildet Cholesterin laterale Membrandomänen, sogenannte Lipid Rafts, die bei der Bildung der ß-Amyloid Plaques entscheidend beteiligt sein könnten. In der vorliegenden Arbeit wurde die Struktur dieser Domänen spezifisch verändert. Durch Transfektion mit dem Scavenger Rezeptor Klasse B Typ I (SR-BI) der die selektive Cholesterin- und Phospholipidaufnahme in die Zelle erhöht, wurden neue Lipid Rafts generiert und bestehende Domänen vergrößert. SR-BI induzierte eine Abnahme des von der α-Sekretase gespaltenen APP, sowie eine Zunahme des von der ß-Sekretase gespaltenen APP. Gleichzeitig kam es zu einem Anstieg der Menge des Aß-Peptids. Somit wurde gezeigt, dass ein Anstieg der Cholesterin-reichen Membrandomänen zu einer Abnahme der α-Sekretase Spaltung, einer Erhöhung der ß-Sekretase Spaltung und einer Zunahme der pathologischen ß-Amyloid Bildung führt. Während APP in Wildtyp-Zellen nahezu ausschließlich in DSM lokalisiert war, kam es durch die SR-BI Expression zu einer Translokation in DRM, die weitgehend Lipid Rafts repräsentieren. In den DRM konnte BACE damit mit APP interagieren. Um das subzelluläre Kompartiment zu identifizieren, an dem die APP-Spaltung stattfinden könnte, wurde mit Hilfe der Konfokalen Laserscanmikroskopie die intrazelluläre Verteilung von APP und BACE vor und nach SR-BI Expression untersucht. Nach SR-BI Transfektion war die Kolokalisation von APP und BACE in der Umgebung der Zellmembran deutlich verstärkt. Zusammen mit früheren Arbeiten lassen diese Ergebnisse vermuten, dass die verstärkte APP-Prozessierung durch Induktion Cholesterin-reicher Domänen vorwiegend submembranös (Early Endosomes) und auf der Ebene der Plasmamembran stattfindet. Ob eine medikamentöse oder diätetische Cholesterin-Reduzierung, die den Lipid Raft Anteil der Zelle senkt und somit die Interaktion von APP mit BACE verhindert, als Therapiemöglichkeit für die Alzheimer-Erkrankung in Frage kommt, bedarf noch weiterer intensiver Forschung.

Thu, 28 Feb 2008 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/8354/ https://edoc.ub.uni-muenchen.de/8354/1/Siegmund_Annette.pdf Siegmund, Annette ddc:600, ddc:610, Medi

Die Familie der Sorting Nexine (SNX) umfasst 33 bekannte Mitglieder, jedoch ist der Funktionsmechanismus vieler Sorting Nexine bislang nicht aufgeklärt. Auf der Suche neuer Modulatoren der βAPP-Proteolyse konnte im Rahmen eines Expressionsklonierungs-Screens (Schobel et al., 2006) ein bislang nicht beschriebenes Protein, Sorting Nexin 33 (SNX33), als Aktivator der βAPP-Proteolyse identifiziert werden. SNX33 ist ein phosphoryliertes Protein, das ubiquitär exprimiert wird und zudem eine hohe Homologie zu den Proteinen SNX9 und SNX18 aufweist. SNX33 ist im Zytosol lokalisiert, kann jedoch auch Membran-assoziiert vorliegen. Es konnte gezeigt werden, dass Überexpression von SNX33 zu einer Inhibition Dynamin-abhängiger Endozytose und in Folge dessen zu einer etwa 50% -igen Reduktion der βAPP-Endozytose führt. Die von SNX33 induzierte Endozytosehemmung wird durch die SH3-Domäne des Proteins vermittelt. Im Rahmen dieser Doktorarbeit durchgeführte Koimmunpräzipitationsstudien zeigten, dass SNX33 mittels seiner SH3-Domäne mit Dynamin interagiert und auf diese Weise möglicherweise dessen Funktion moduliert. In Übereinstimmung mit den durchgeführten Zellkultur-Experimenten führte eine Überexpression von SNX33 im Modellorganismus Caenorhabditis elegans ebenfalls zu einem Dynamin-Funktionsverlust. Da SNX33 Expression zu einer generellen Inhibition Dynamin-abhängiger Endozytose führt, handelt es sich dabei nicht um einen spezifischen βAPP-Modulator. Konsequenz einer reduzierten βAPP-Internalisierung ist eine starke Zunahme der neurotrophen sAPPα-Bildung sowie - je nach verwendeter Zelllinie - ein leichter Anstieg bzw. eine geringe Reduktion der pathogenen sAPPβ-Generierung. Es konnte gezeigt werden, dass Überexpression der homologen Proteine SNX9 und SNX18 ebenfalls zu einer Zunahme der βAPP-Spaltung führt. Es handelt sich also um einen Effekt, der von der ganzen Sorting Nexin-Subgruppe (SNX33/SNX9/SNX18) vermittelt wird. Diese Beobachtung legt die Vermutung nahe, dass diese Funktion innerhalb dieser Subgruppe konserviert ist. Transfektion von SNX1 führte zu keiner Änderung der βAPP-Proteolyse, was bedeutet, dass dieser Effekt nicht von der gesamten Sorting Nexin-Familie vermittelt wird. Interessanterweise ist die Spaltung von βAPP besonders sensitiv bezüglich einer veränderten Endozytose-Rate, da die Proteolyse der Transmembranproteine L-Selektin und des Tumornekrosisfaktor-Rezeptors 2 (TNFR2) unter SNX33 Überexpressionsbedingungen nicht signifikant verändert war. Ein siRNA-vermittelter Knock-Down von SNX33 führte zu keiner generellen Endozytoseinhibition in HEK293 Zellen, es konnte keine veränderte βAPP-Endozytoserate beobachtet werden. Die Bildung von sAPPα- und sAPPβ war in Folge dessen unverändert. Auch ein lst-4/SNX33-Knock-Down in C. elegans führte überraschenderweise zu keiner Inhibition der Dynamin-Funktion, äußerte sich jedoch in einer Fehlfunktion der Insulin-Signaltransduktion. SNX33-Knock-Down in humanen Zellen brachte keine nachweisbare Beeinträchtigung des Insulinsignalweges mit sich, jedoch besteht die Möglichkeit, dass die Homologen SNX9 und SNX18 einen Verlust von SNX33 kompensieren können. Dabei gilt zu beachten, dass eine Funktionsübernahme durch homologe Proteine in C. elegans nicht möglich ist, da dieser Organismus nur ein einziges homologes Protein der SNX33/SNX9/SNX18-Subgruppe besitzt. Im Rahmen dieser Doktorarbeit präsentierten sowie diskutierten Daten zeigen, dass SNX33 in unterschiedliche zellulärer Prozesse involviert ist. SNX33 ist ein neu identifizierter Modulator der Zelle, der für zentrale Signalwege und Vorgänge, wie zum Beispiel der Insulinrezeptor-Signaltransduktion und Endozytose, von Bedeutung ist. Im Gegensatz zum Modellorganismus C. elegans kann im humanen Zellkultursystem ein durch siRNA induzierter Funktionsverlust von SNX33 durch die homologen Proteine SNX9 und SNX18 kompensiert werden.

An interview with Daniel Foster of LOGOS Bible Software, as well as a guest tech tip from Rev. Rick Anderegg and the continuing iPod-to-minivan saga!

Diese Arbeit konnte Oncostatin M als Modulator der Hypothalamus-Hypophysen-Nebennierenrinden-Achse näher charakterisieren. Es konnte gezeigt werden, dass Oncostatin M an hypophysärem Gewebe über den gp130/LIFR-Komplex zur Aktivierung der Jak-STAT-Kaskade mit folgender STAT-abhängiger POMC- und STAT3-Expression und schließlich zur ACTH-Ausschüttung führt. Da über den gp130/OSMR-Rezeptorkomplex keine Jak-STAT-Aktivierung mit konsekutiver POMC- und STAT3-Expression und ACTH-Sekretion nachgewiesen werden konnte, wird postuliert, dass Oncostatin M an der Modulation der corticotrophen Funktion über den gp130/LIFR-Komplex, nicht jedoch über den gp130/OSMR-Komplex beteiligt ist. Auf adrenocorticaler Zellebene konnte erstmals ein direkter stimulierender Effekt von Oncostatin M auf die Steroidsekretion gezeigt werden. Murines OSM führt über den gp130/OSMR-Rezeptor-Komplex, humanes OSM und murines LIF zur Aktivierung der Jak-STAT-Kaskade und zur Steroidausschüttung durch murine Y-1 Zellen. Damit konnte Onostatin M als potenter Modulator der adrenocorticalen Zellfunktion charakterisiert werden. Erstmals wurde hier die Induktion von Apoptose durch OSM an adrenocorticalen Tumorzellen beschrieben. Es bleibt zu zeigen, dass der an der murinen Zelllinie Y-1 nachgewiesen Effekt auch auf humane Tumorzellen übertragbar ist. Ein zellspezifischer apoptotischer Effekt von OSM auf adrenocorticale Tumorzellen könnte ein potentieller wertvoller Mechanismus zur Entwicklung einer spezifischen Therapie des hochmalignen Nebennierenrindencarcinoms darstellen.

Bakterielle Toxine aktivieren spezifische Signalwege in humanen Zellen und modulieren so deren Funktion und Morpholgie. Ein besseres Verständnis der Effekte von Toxinen auf humane Zellen könnte zur Aufklärung der Pathogenese bakterieller Erkrankungen beitragen. In dieser Arbeit wurde der Effekt des Exotoxins CNF-1 aus Escherichia coli auf die Morphologie humaner Endothelzellen (HUVEC) und die beteiligten Signalwege untersucht. CNF-1 führt in HUVEC zeitabhängig sowohl zur Bildung von Aktinfasern als auch zur Ausbildung von "membrane ruffles" und Filopodien. Diese Aktinstrukturen werden durch Aktivierung der GTPasen Rho, Rac und CDC42 induziert. Rho führt in Endothelzellen über Rho-Kinase zu einer Myosinleichtketten (MLC)- Phosphorylierung und dadurch zur Hemmung von MLC-Phosphatase. Stimulation der Endothelzellen mit CNF-1 führt hingegen abhängig von Rho und Rho-Kinase ohne Hemmung der MLC-Phosphataseaktivität zu einem Anstieg der MLC-Phosphorylierung und einer Zellkontraktion. Es konnte gezeigt werden, dass zwar Rac und CDC42 in den ersten Stunden durch CNF aktiviert werden, diese aber nicht für die MLC-Phosphorylierung verantwortlich sind. 24h nach CNF-Stimulation zeigt sich immer noch eine Aktivierung von RhoA, nicht aber von CDC42 und Rac. Trotzdem kommt es zu einem Anstieg der MLC-Phosphatase und dadurch zu einem Abfall der MLC-Phosphorylierung und Zellausbreitung. Diese Ergebnisse zeigen, dass CNF zu einer Entkopplung des Rho, Rho-Kinase, Myosinleichtketten-Phosphatase-Signalweges führt. Diese Entkopplung könnte eine Rolle bei der pathologischen Wirkung des Toxins spielen.