Podcasts about rnf

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Best podcasts about rnf

Latest podcast episodes about rnf

Rozmowy Na Fundamencie
#70 Gościnnie u Pogody. Nowelizacja Ustawy O Planowaniu I Zagospodarowaniu Przestrzennym

Rozmowy Na Fundamencie

Play Episode Listen Later Apr 7, 2025 46:43


70 odcinek Rozmów Na Fundamencie to skrócona wersja rozmowy, jaką miałem z Radkiem Pogodą z kanału "Pogodne shorty". Program dotyka tematyki związanej z nowelizacją ustawy o planowaniu i zagospodarowniu przestrzennym.Pełma wersja programu znajduje się pod poniższym linkiem:https://www.youtube.com/watch?v=mNY3Sekaqk8&t=1222sJeśli chciałbyś się ze mną skontaktować pisz na adres: pkielar.poczta@gmail.com

Rozmowy Na Fundamencie
#69 Woda Wcieka Do Piwnicy. A Co Na To Prawnik?

Rozmowy Na Fundamencie

Play Episode Listen Later Mar 23, 2025 33:26


Hydroizolacje to nie tylko materiały oraz zasady wywodzące się ze sztuki budowlanej oraz ze zdrowego rozsądku. Hydroizolacje jako wyrób budowalny, osadzone są w kontekście prawnym. O tym jak on wygląda, o tym jak prawo zaciemnia nam obraz prawdziwej sztuki budowlanej, opowiadam w 69 odcinku Rozmów Na Fundamencie.Zapraszam do wysłuchania i komentowania!A jeśli chciałbyś się ze mną skontaktować - pisz na adres: pkielar.poczta@gmail.com

Rozmowy Na Fundamencie
#68 Brązowa Wanna

Rozmowy Na Fundamencie

Play Episode Listen Later Feb 16, 2025 39:47


"Brązowa wanna" to rodzaj zabezpieczenia przed wodą gruntową, jaki stosowali nasi dziadowie. Genialny w swojej prostocie, inteligentny sposób, wykorzystujący lokalmie występujące materiały. Ten odcinek otwiera cykl jaki chciałbym poświęcić hydroizoacjom.Zapraszam do wysłuchania!A jeśli chciałbyś się ze mną skontaktować - pisz na adres pkielar.poczta@gmail.com

Rozmowy Na Fundamencie
#67 Skok Na Działki Budowlane

Rozmowy Na Fundamencie

Play Episode Listen Later Jan 18, 2025 40:37


67 odcinek Rozmów Na Fundamencie, to wersja audio programu jaki ukazał się w dniu 10.01.2025r. w telewizji internetowej PL1TV. Link do programu znajduje sie poniżej.Głównym tematem omawianym w  programie, jest nowelizacja ustawy o planowaniu i zagospodarowniu przestrzennym.Link do prgramy na PL1TV:https://pl1.tv/title/czy-zmiana-w-ustawie-ma-doprowadzic-do-drastycznego-spadku-wartosci-polskiej-ziemi/Jeśli chciałbyś skontaktować się ze mną - pisz na adres: pkielar.poczta@gmail.com

Rozmowy Na Fundamencie
#66 Rok 2024 - Najgorszy Rok W Budownictwie Od 20 Lat

Rozmowy Na Fundamencie

Play Episode Listen Later Jan 5, 2025 35:57


66 Odcinek Rozmów Na Fundamencie to mała retrospekcja. To spojrzenie wstecz co przyniósł rok 2024 i czego możemy się spodziewać w roku 2025.Zapraszam do wysłuchania!A jeśli chciałbyś / chciałabyś się ze mną skonatktować - pisz na adres: pkielar.poczta@gmail.com

Rozmowy Na Fundamencie
#65 Czynsze.Podatki. Opłaty. Lepiej w Polsce, Czy w Kanadzie

Rozmowy Na Fundamencie

Play Episode Listen Later Dec 8, 2024 37:15


Kanada kojarzy nam się z krajem w którym żyje się dostatnio i dobrze. W 65 odcinku Rozmów Na Fundamencie, Leszek Szostak opowie o podatkach, czynszach oraz cenach nieruchomości. Wraz z Leszkiem zapraszam do wysłuchania odcinka!Kontakt na Leszka znajdziesz poniżej:Telegram: t.me/ JosephConrad62YouTube: youtube.com/@LeszekSzostaktvRumble: rumble. com/user/LszostakFacebook: Leszek Szostak aka Joseph Conrad aka Citizen KaneA jeśli chciałbyś skonatktować się ze mną, pisz na adres: pkielar.poczta@gmail.com

Rozmowy Na Fundamencie
#64 Domy Kanadyjskie. Czyli Jak Buduje Się W Kanadzie

Rozmowy Na Fundamencie

Play Episode Listen Later Nov 17, 2024 43:48


O tym jakie są różnice w technologiach budowania domów stosowane w Kanadzie i w Polsce, czym ogrzewa się domy w Kanadzie, oraz czy certyfikacja energetyczna zawitała również do Kanady Rozmawiam z Leszkiem Szostakiem.64 odcinek Rozmów Na Fundamencie dedykuję wszystkim, którzy rozważają budowę domu drewnianego. Kontakt na Leszka Szostaka znajduje się poniżej:Telegram: t.me/ JosephConrad62YouTube: youtube.com/@LeszekSzostaktvRumble: rumble. com/user/LszostakFacebook: Leszek Szostak aka Joseph Conrad aka Citizen KaneJeśli chciałbyś skontaktować się ze mną - pisz na adres: pkielar.poczta@gmail.com

Rozmowy Na Fundamencie
#62 Osuszanie Oczami Eksperta Część 1

Rozmowy Na Fundamencie

Play Episode Listen Later Oct 27, 2024 38:09


Ekspercka wiedza z zakresu osuszania budynków. Pierwszy z dwóch odcinków, w których Marcin Hetman, zawodowo związany z firmą Dantherm, opowiada o tym jak powinno się w fachowy sposób osuszać budynki.Rozmowa z Marcinem dotyczy zarówno budynków zalanych powodzią jak i budynków zalanych z tytułu np. nieszczelnej instalacji. Wraz z Marcinem zapraszam do wysłuchania rozmowy.Jeśli chciałbyś skontaktować się z marcinem, pisz na adres: marcin.hetman@danthermgroup.comJeśli chciałbyś skontaktować się ze mną, pisz na adres: pkielar.poczta@gmail.com

Rozmowy Na Fundamencie
#63 Osuszanie Oczami Eksperta Część 2

Rozmowy Na Fundamencie

Play Episode Listen Later Oct 27, 2024 32:52


Ekspercka wiedza z zakresu osuszania budynków. Drugi odcinek, w których Marcin Hetman, zawodowo związany z firmą Dantherm, opowiada o tym jak powinno się w fachowy sposób osuszać budynki.Rozmowa z Marcinem dotyczy zarówno budynków zalanych powodzią jak i budynków zalanych z tytułu np. nieszczelnej instalacji. Wraz z Marcinem zapraszam do wysłuchania rozmowy.Jeśli chciałbyś skontaktować się z marcinem, pisz na adres: marcin.hetman@danthermgroup.comJeśli chciałbyś skontaktować się ze mną, pisz na adres: pkielar.poczta@gmail.com

Rozmowy Na Fundamencie
#61 Jak Poddać Renowacji Zalany Powodzią Dom

Rozmowy Na Fundamencie

Play Episode Listen Later Oct 2, 2024 55:38


61 odcinek budcastu "Rozmowy Na Fundamencie" to skomasowana wersja dwóch programów jakie zostały nagrane pod koniec września na kanale "Pogodne Shorty" Radka Pogody.Cały odcinek to nic innego jak porady dla wszystkich, którzy ucierpieli podczas powodzi i będą poddawali swoje domy renowacjom.Jeśli chciałbyś się ze mną skontaktować - pisz na adres: pkielar.poczta@gmail.com

Rozmowy Na Fundamencie
#60 Gra Zespołowa

Rozmowy Na Fundamencie

Play Episode Listen Later Sep 22, 2024 16:40


60 odcinek Rozmów Na Fundamencie to krótka opowieść o grze zespołowej. O tym, że relacje w życiu są bardzo ważne. A pomoc jaką możemy udzielić komuś w potrzebie, ma wartość bezcenną. Pamiętajmy o tym szczególknie teraz, kiedy tak wielu Polaków poszkodowanych zostało w wyniku powodzi.Jeśli chcesz się ze mną skontaktować pisz na adres: pkielar.poczta@gmail.com

Rozmowy Na Fundamencie
#59 Wakacyjne Opowieści - 4 Lata Przed Klęską

Rozmowy Na Fundamencie

Play Episode Listen Later Aug 31, 2024 25:35


Ten odcinek to ostatnia w tym roku wakacyjna opowieść. Nieco oderwana od tematyki, którą zwykle poruszam na swoim kanale. Ale chyba dość dobrze pasująca do obecnych, jakże niepewnych czasów.59 odcinek Rozmów Na Fundamencie nosi tytuł: "4 lata przed klęską".Zapraszam do wysłuchania i komentowania.A jeśli chciałbyś się ze mną skontaktować - pisz na adres: pkielar.poczta@gmail.com

Paddock Pass Podcast - Motorcycle Racing - MotoGP - World Superbike
Episode 430: Ai Ogura speaks! And your post-Austrian Grand Prix Qs

Paddock Pass Podcast - Motorcycle Racing - MotoGP - World Superbike

Play Episode Listen Later Aug 21, 2024 71:13


David has been to KTM, Neil has interviewed Ai Ogura on MotoGP, Honda, Moto2 and more, Steve has come back from the golf course and Adam is AWOL with his book but here is the latest show with exclusive content and some excellent questions from Patreon subscribers. Join us for special and exclusive content on Patreon. Become a Paddock Insider for just 10 dollars a month: https://www.patreon.com/paddockpasspodcast Find us here: https://twitter.com/PaddockPassPod Chapters 00:00 – Introduction and Dave's trip to KTM 05:15 – Rider of the week Poll 05:45 – Have Trackhouse improved over RNF? 12:12 – Interviewing Ai Ogura 31:40 – Marc Marquez is the bigger draw than anyone else? 33:30 – Too much Marquez hype? 35:15 – Ducati GP23 vs GP24 and where can they level? 37:40 – Rider movements for 2025 and failing Fermin? 46:00 – Teams dealing with riders? 47:45 – Marquez and Bagnaia in 2025? A match made in… 50:00 – Japanese dry patch 52:00 – The timing of Jorge Martin's move to Aprilia 55:55 – The age of MotoGP fans and the spread of the sport

Rozmowy Na Fundamencie
#58 Wakacyjne Opowieści - Zemsta

Rozmowy Na Fundamencie

Play Episode Listen Later Aug 16, 2024 32:00


Ten podcast - to podobnie jak poprzedni odcinek - mała podróż do przeszłości.Luźne wspomnienia z zamierzchłych czasów. Z budowlanką i z ... korporacją w tle.A motywem przewodnim jest: zemsta. Zapraszam do wysłuchania i komentowania!A jeśli chciałbyś się ze mną skontaktować  - pisz na adres: pkielar.poczta@gmail.com

Rozmowy Na Fundamencie
#57 Wakacyjne Opowieści - Imieniny Krzysztofa

Rozmowy Na Fundamencie

Play Episode Listen Later Jul 27, 2024 28:54


Ten podcast - to mała podróż do przeszłości.Luźne wspomnienia z zamierzchłych czasów. Z budowlanką i z ... alkoholem w tle.Zapraszam do wysłuchania i komentowania!A jeśli chciałbyś się ze mną skontaktować  -pisz na adres: pkielar.poczta@gmail.com

Rozmowy Na Fundamencie
#56 Od Budowy Panela Do Drenażu Portfela

Rozmowy Na Fundamencie

Play Episode Listen Later Jul 20, 2024 36:09


56 odcinek Rozmów Na Fundamencie to wersja audio programu nagranego dla kanału PS TV o tytule: "Od budowy panela do drenażu portfela". W rozmowie z Piotrem Szlachtowiczem odpowiadam na komentarze słuchaczy, jakie pojawiły się pod ostatnim, wspólnie nagranym programem.Wraz z Piotrem Szlachtowiczem zapraszam do wysłuchania!Jeśli chiałbyś się ze mną skontaktować - pisz na adres: pkielar.poczta@gmail.com

Rozmowy Na Fundamencie
#55 Fotowoltaika Czy To Działa

Rozmowy Na Fundamencie

Play Episode Listen Later Jul 5, 2024 36:52


55 odcinek Rozmów Na Fundamencie to wersja audio rozmowy jaką miałem w programie PS TV u Piotra Szlachtowicza. Fotowoltaika - czy to w ogóle działa? W związku z wieloma programami, w których tylko zachwala się instalacje fotowoltaiczne, ten program przedstawia nieco inne oblicze energii pozyskiwanej ze słońca.Jeśli chciałbyś się ze mną skontaktować - pisz na adres: pkielar.poczta@gmail.com

Rozmowy Na Fundamencie
#54 Dyrektywa Budynkowa

Rozmowy Na Fundamencie

Play Episode Listen Later Jun 22, 2024 39:40


Odcinek 54 podcastu Rozmowy Na Fundamencie dotyczy dyrektywy budynkowej, zwanej jako dyrektywa EPBD. Odcinek jest wersją audio programu jaki ukazał się na kanale Piotra Szlachtowicza PS TV w dniu 01.06.2024. Zapraszam do wysłuchania i komentowania.Jeśli chcoiałbyś się ze mną skontaktować, pisz na adres: pkielar.poczta@gmail.com

Rozmowy Na Fundamencie
#53 Budujemy Na Księżycu

Rozmowy Na Fundamencie

Play Episode Listen Later Jun 16, 2024 32:40


Odlecieliśmy w kosmos. Niemal nikogo nie jest już stać na swój własny dom, na swoje własne mieszkanie. Na budowach brakuje fachowców. A my bierzemy się za budowowanie na księżycu. O kosmicznych pomysłach i nie tylko, opowiadam w 53 odcinku Rozmów Na Fundamencie. Zapraszam do wysłuchania i komentowania.A jeśli chciałbyś się ze mną skontaktować - pisz na adres: pkielar.poczta@gmail.com

Rozmowy Na Fundamencie
#52 Dom Komfortowy

Rozmowy Na Fundamencie

Play Episode Listen Later Jun 1, 2024 25:51


Gonimy za komfortem a ten odbiera nam kawałek po kawałku nasze prawdziwe życie, nasze człowieczeństwo. 52 odcinek Rozmów Na Fundamencie to moje luźne skojarzenia z domem bezobsługowym, z domem komfotowym. Zapraszam do wysłuchania!Jeśli chciałbyś się ze mną skontaktować - pisz na adres: pkielar.poczta@gmail.com

Rozmowy Na Fundamencie
#51 Moralność Budowlańca

Rozmowy Na Fundamencie

Play Episode Listen Later Apr 28, 2024 31:24


Odcinek jubileuszowy nawiązujący do pierwszego odcinka Rozmów Na Fundamencie. W odcinku skupiam się na morolności ludzi, którzy pracują w budownictwie. Pod koniec odcinka przywołuję program Radka Pogody, na którego link znjdziesz poniżej:https://youtu.be/9QmYhDa7D1M?si=NohFy5zgxVTfPjUkA jeśli chcesz się ze mną skontaktować pisz na adres: pkielar.poczta@gmail.com

Rozmowy Na Fundamencie
#49 Zielona Trylogia Część 1 - Wielka Płyta

Rozmowy Na Fundamencie

Play Episode Listen Later Mar 23, 2024 67:32


Pierwsza część cyklu "Zielona Trylogia" jaki nagrałem wraz z Radosławem Pogodą z kanału "Pogodne szorty". Odcinek dotyczy zmian jakie będą dotykały mieszkańców tzw. wielkiej płyty. Pełna wersja odcinka (również w wersji wizualnej) znajduje się pod poniższym linkiem:https://youtu.be/JivF-nTB1dw?si=1Bh8TQvlXn4YyBuWJeśli chcesz się ze mną skontaktować pisz na adres: pkielar.poczta@gmail.com

Lap 76
Lap 76 395 MotoGP sezona veka je tu! Kome ide čelični tron? Pecco, Martin, Bezz, MM, Bestia, Acosta?

Lap 76

Play Episode Listen Later Mar 5, 2024 233:16


+Celokupan izveštaj i analiza konačnih predsezonski testova u 2024. iz Katara.+Ducati i dalje neprikosnoven. Honda i Yamaha nisu postigle ciljeve još.Link za zvaničnu Fantasy Lap 76 MotoGP ligu za 2024: https://fantasy.motogp.com/leagues/join/4WEEP7HUKod za ligu: 4WEEP7HUPodrška Infinity Lighthouse ekipi!

Rozmowy Na Fundamencie
#48 O Fundamencie Raz Jeszcze

Rozmowy Na Fundamencie

Play Episode Listen Later Feb 25, 2024 21:05


Kilka dodatkowych informacji dotyczących prac związanych z fundamentem i fundamentowaniem. Ten odcinek to rozszerzenie odcinka 47. Na co zwracać uwagę? Co zrobić z nadmiarowym betonem? Zapraszam do kolejnego odcinka "Rozmów Na Fundamencie"Jeżeli chcesz się ze mną skontaktować - pisz na adres: pkielar.poczta@gmail.com

Rozmowy Na Fundamencie
#47 Fundament To Podstawa

Rozmowy Na Fundamencie

Play Episode Listen Later Feb 1, 2024 27:33


Fundament jest najważniejszą częścią budynku. To na nim bowiem spoczywa cała konstrukcja. To fundament przecież przekazuje wszystke obciążenia z budynku na grunt. Jak konstruowano fundamnety kiedyś i jak to wygląda obecnie - o tym wszystkim w 47 odcinku Rozmów Na Fundamencie. Zapraszam do wysłuchania!Jeśli chcesz się ze mną skontaktować pisz na adres: pkielar.poczta@gmail.com

Rozmowy Na Fundamencie
#46 Czy Zmierzamy W Stronę Bezdomności?

Rozmowy Na Fundamencie

Play Episode Listen Later Jan 13, 2024 79:34


Niemal wszystko co dzieje się w budownictwie od niemal 30 lat, przybliża nas do bezdomności. Ciężko to zauważyć bo kolejne zmiany w przepisach i technologiach, wdrażane są na przestrzeni nie tyle lat, co dziesięcioleci. O tym, w którą stronę zmierza współczesny świat, w 46 odcinku Rozmów Na Fundamencie rozmawiam z Radkiem Pogodą. Radek jest autorem podcastu "Pogodne Szorty".Link do programu Radka znajduje się poniżej:https://www.youtube.com/@RadoslawPogoda/featuredJeśli chcesz się ze mną skontaktować pisz na adres: pkielar.poczta@gmail.com

Rozmowy Na Fundamencie
#45 Polska Rzeczpospolita Budowa

Rozmowy Na Fundamencie

Play Episode Listen Later Jan 1, 2024 27:08


Polskość to nie tylko język, kultura, historia. To również sposób budowania. Polski dom oraz polski sposób budowania w jasny sposób wskazują, że nasze budownictwo jest charakterystyczne, indywidualne i niepowtarzalne.Polska Rzeczpospolita Budowa - to odcinek, w którym koncentruję się na tym, jak wygląda budowanie "po polsku". Zapraszam do wysłuchania 45 odcinka Rozmów Na Fundamencie.Jeśli chcesz się ze mną skontaktować pisz na adres: pkielar.poczta@gmail.com

MotoWeek - MotoGP, Motorcycle and Racing News
Can Trackhouse Succeed in MotoGP?

MotoWeek - MotoGP, Motorcycle and Racing News

Play Episode Listen Later Dec 29, 2023 44:38


What is a Trackhouse, and what is it doing in MotoGP? The U.S. racing team is headed to the Premiere Class - I discuss the unprecedented demise of RNF, why Trackhouse was chosen, and whether they can succeed in MotoGP!The Rundown:- RNF: How did they get into trouble?- Dorna makes an unprecedented decision - was it right?- Who is Trackhouse? What makes them different?- Why was a U.S. owner chosen?- Aprilia is on-board- Can they make an impact this year and compete?Stay tuned for upcoming episodes on the other big stories heading into the 2024 season: new concession rules, Marc Marquez going to Ducati, and more!Find all of the latest episodes at Motoweek.net, follow on Twitter @Motoweek and Instagram @motoweekusa – and you can support the show on Patreon at patreon.com/motoweekThanks for listening!

Everything Moto Racing
EMR Podcast #122 - RNF Out, Trackhouse In, 2023 Season Predictions, Marquez To Lenovo Ducati? + More!

Everything Moto Racing

Play Episode Listen Later Dec 28, 2023 78:52


Welcome to Episode 122 of the Everything Moto Racing podcast! We hope you enjoy it! In this episode, we discussed RNF being kicked out of MotoGP, Trackhouse replacing them, Marti leaving Ducati, and the 2023 season predictions!

Rozmowy Na Fundamencie
#44 Kierownik Budowy

Rozmowy Na Fundamencie

Play Episode Listen Later Dec 17, 2023 29:39


Nadzór na budowie jest kluczowy. Kierownik budowy pełni bardzo ważną funkcję i z pewnością dobry kierownik nie będzie tani. O tym jaką odpowiedzialność ma osoba nadzorująca cały proces budowy domu, opowiadam w 44 odcinku Rozmów Na Fundamencie. Tytuł tego odcinka to: "Kierownik Budowy"Jeśli chcesz się ze mną skontaktować, pisz na adres pkielar.poczta@gmail.com

Paddockast
INVASÃO AMERICANA! MotoGP corre risco de ser conquistada como Fórmula 1? | Paddock Sprint

Paddockast

Play Episode Listen Later Dec 11, 2023 38:38


Com a chegada da Trackhouse para substituir a barrada RNF, a MotoGP começou a falar em uma segunda corrida nos Estados Unidos, já que quer conquistar o que considera ser um “mercado importante”. O Mundial de Motovelocidade, porém, vive um período de entressafra, já que não tem pilotos nativos dos Estados Unidos como titulares na classe rainha desde a aposentadoria de Ben Spies. O país comandado por Joe Biden, todavia, tem um passado glorioso no esporte, com campeões como Eddie Lawson, Kevin Schwantz, Wayne Rainey, Freddie Spencer, Kenny Roberts, Kenny Roberts Jr. e Nicky Hayden. Bom ressaltar, também, que em um passado não muito distante, a MotoGP corria três vezes no país, o que mudou com a saída de Laguna Seca e Indianápolis. Desde 2016, o GP das Américas, em Austin, é o único na programação.

JKMoto
America Returns to Moto GP

JKMoto

Play Episode Listen Later Dec 6, 2023 71:40


We're back once again for an exciting week of two-wheeled news, but it's not just your favorite podcast that is back. Americans are once again in Moto GP, not with a new rider but with an entire team. Trackhouse Racing is taking over what used to be the RNF team as Aprilia satellite team sponsor. With some amazing looking Nicky Hayden livery on the bike, we are more than excited to see what that brings for the future of Americans in Moto GP. On top of that great news, of course, we couldn't go a week without mentioning Marc Marquez, who left the Valencia test leaving everyone giddy and nervous about what lies in store for the Ducati stable next year. Extreme levels of talent and bike performance mixed up with some intense drama leave us headed for winter wishing the new season could start immediately. So hold onto your seats and stick around for a wild episode and a wild Moto GP 2024!!

Rozmowy Na Fundamencie
#43 Zmiany W Prawie Budowlanym

Rozmowy Na Fundamencie

Play Episode Listen Later Nov 15, 2023 29:18


Zmiany w prawie budowlanym stały się ulubionym zajęciem rządu. Czy faktycznie chodzi o uproszczenie procedur i ułatwienie nam życia? O tym wszystkim opowiadam w 43 odcinku Rozmów Na Fundamencie. Zapraszam do wysłuchania, komentowania i subskrybowania.Jeżeli chcesz się ze mną skontaktować pisz na adres: pkielar.poczta@gmail.com

GPOne MotoGP Podcast
BAR SPORT, MANDALIKA: Aprilia vola, ma è cortocircuito Oliveira-Rivola!

GPOne MotoGP Podcast

Play Episode Listen Later Oct 14, 2023 51:56


L'Aprilia sta andando fortissimo sul circuito Indonesiano di Mandalika ma a stupire è il cortocircuito fra le dichiarazioni di Massimo Rivola, Ceo della casa di Noale, e Oliveira. Il Ceo dichiara di non avere notizia di un interessamento della Honda aggiungendo che il pilota del team RNF ha un contratto di ferro, mentre Miguel lo smentisce.Parliamo ovviamente anche della situazione sportiva in Ducati, con Bagnaia apparentemente in difficoltà, di mercato e di quanto sta accandeo in Indonesia.

Discover CircRes
April 2023 Discover CircRes

Discover CircRes

Play Episode Listen Later Apr 20, 2023 34:07


This month on Episode 47 of Discover CircRes, host Cynthia St. Hilaire highlights three original research articles featured in the March 31 issue of Circulation Research. We'll also provide an overview of the Compendium on Increased Risk of Cardiovascular Complications in Chronic Kidney Disease published in the April 14 issue. Finally, this episode features an interview with Dr Elizabeth Tarling and Dr Bethan Clifford from UCLA regarding their study, RNF130 Regulates LDLR Availability and Plasma LDL Cholesterol Levels.   Article highlights:   Shi, et al. LncRNAs Regulate SMC Phenotypic Transition   Chen, et al. Bilirubin Stabilizes Atherosclerotic Plaque   Subramaniam, et al. Mapping Non-Obvious cAMP Nanodomains by Proteomics   Compendium on Increased Risk of Cardiovascular Complications in Chronic Kidney Disease   Cindy St. Hilaire:              Hi, and welcome to Discover CircRes, the podcast of the American Heart Association's Journal, Circulation Research. I'm your host, Dr Cindy St. Hilaire, from the Vascular Medicine Institute at the University of Pittsburgh, and today I'm going to share three articles selected from our March 31st issue of Circulation Research and give you a quick summary of our April 14th Compendium. I'm also excited to speak with Dr Elizabeth Tarling and Dr Bethan Clifford from UCLA regarding their study, RNF130 Regulates LDLR Availability and Plasma LDL Cholesterol Levels.   So first the highlights. The first article we're going to discuss is Discovery of Transacting Long Noncoding RNAs that Regulates Smooth Muscle Cell Phenotype. This article's coming from Stanford University and the laboratory of Dr Thomas Quertermous. Smooth muscle cells are the major cell type contributing to atherosclerotic plaques. And in plaque pathogenesis, the cells can undergo a phenotypic transition whereby a contractile smooth muscle cell can trans differentiate into other cell types found within the plaque, such as macrophage-like cells, osteoblast-like cells and fibroblast-like cells. These transitions are regulated by a network of genetic and epigenetic mechanisms, and these mechanisms govern the risk of disease.   The involvement of long non-coding RNAs, or Lnc RNAs as they're called, has been increasingly identified in cardiovascular disease. However, smooth muscle cell Lnc RNAs have not been comprehensively characterized and the regulatory role in the smooth muscle cell state transition is not thoroughly understood. To address this gap, Shi and colleagues created a discovery pipeline and applied it to deeply strand-specific RNA sequencing from human coronary artery smooth muscle cells that were stressed with different disease related stimuli. Subsequently, the functional relevancy of a few novel Lnc RNAs was verified in vitro.   From this pipeline, they identified over 4,500 known and over 13,000 unknown or previously unknown Lnc RNAs in human coronary artery smooth muscle cells. The genomic location of these long noncoding RNAs was enriched near coronary artery disease related transcription factor and genetic loci. They were also found to be gene regulators of smooth muscle cell identity. Two novel Lnc RNAs, ZEB-interacting suppressor or ZIPPOR and TNS1-antisense or TNS1-AS2, were identified by the screen, and this group discovered that the coronary artery disease gene, ZEB2, which is a transcription factor in the TGF beta signaling pathway, is a target for these Lnc RNAs. These data suggest a critical role for long noncoding RNAs in smooth muscle cell phenotypic transition and in human atherosclerotic disease.   Cindy St. Hilaire:              The second article I want to share is titled Destabilization of Atherosclerotic Plaque by Bilirubin Deficiency. This article is coming from the Heart Research Institute and the corresponding author is Roland Stocker. The rupture of atherosclerotic plaque contributes significantly to cardiovascular disease. Plasma concentrations of bilirubin, a byproduct of heme catabolism, is inversely associated with risk of cardiovascular disease, but the link between bilirubin and atherosclerosis is unknown.   Chen et el addressed this gap by crossing a bilirubin knockout mice to a atherosclerosis prone APOe knockout mouse. Chen et el addressed this gap by crossing the bilirubin knockout mouse to the atherosclerosis-prone APOE knockout mouse, and used the tandem stenosis model of plaque instability to address this question. Compared with their litter mate controls, bilirubin-APOE double knockouts showed signs of increased systemic oxidative stress, endothelial dysfunction, as well as hyperlipidemia. And they had higher atherosclerotic plaque burden.   Hemeatabolism was increased in unstable plaques compared with stable plaques in both of these groups as well as in human coronary arteries. In mice, the bilirubin deletion selectively destabilized unstable plaques and this was characterized by positive arterial remodeling and increased cap thinning, intra plaque hemorrhage, infiltration of neutrophils and MPO activity. Subsequent proteomics analysis confirmed bilirubin deletion enhanced extracellular matrix degradation, recruitment and activation of neutrophils and associated oxidative stress in the unstable plaque. Thus, bilirubin deficiency generates a pro atherogenic phenotype and selectively enhances neutrophil-mediated inflammation and destabilization of unstable plaques, thereby providing a link between bilirubin and cardiovascular disease risk.   Cindy St. Hilaire:              The third article I want to share is titled Integrated Proteomics Unveils Regulation of Cardiac Monocyte Hypertrophic Growth by a Nuclear Cyclic AMP Nano Domain under the Control of PDE3A. This study is coming from the University of Oxford in the lab of Manuela Zaccolo. Cyclic AMP is a critically important secondary messenger downstream from a myriad of signaling receptors on the cell surface. Signaling by cyclic AMP is organized in multiple distinct subcellular nano domains, regulated by cyclic AMP hydrolyzing phosphodiesterases or PDEs.   The cardiac beta adrenergic signaling has served as the prototypical system to elucidate this very complex cyclic AMP compartmentalization. Although studies in cardiac monocytes have provided an understanding of the location and the properties of a handful of these subcellular domains, an overview of the cellular landscape of the cyclic AMP nano domains is missing.   To understand the nanodynamics, Subramanian et al combined an integrated phospho proteomics approach that took advantage of the unique role that individual phosphodiesterases play in the control of local cyclic AMP. They combined this with network analysis to identify previously unrecognized cyclic AMP nano domains associated with beta adrenergic stimulation. They found that indeed this integrated phospho proteomics approach could successfully pinpoint the location of these signaling domains and it provided crucial cues to determine the function of previously unknown cyclic AMP nano domains.   The group characterized one such cellular compartment in detail and they showed that the phosphodiesterase PDE3A2 isoform operates in a nuclear nano domain that involves SMAD4 and HDAC1. Inhibition of PDE3 resulted in an increased HDAC1 phosphorylation, which led to an inhibition of its deacetylase activity, and thus derepression of gene transcription and cardiac monocyte hypertrophic growth. These findings reveal a very unique mechanism that explains the negative long-term consequences observed in patients with heart failure treated with PDE3 inhibitors.   Cindy St. Hilaire:              The April 14th issue is our compendium on Increased Risk of Cardiovascular Complications in Chronic Kidney Disease. Dr Heidi Noels from the University of Aachen is our guest editor of the 11 articles in this issue. Chronic kidney disease is defined by kidney damage or a reduced kidney filtration function. Chronic kidney disease is a highly prevalent condition affecting over 13% of the population worldwide and its progressive nature has devastating effects on patient health. At the end stage of kidney disease, patients depend on dialysis or kidney transplantation for survival. However, less than 1% of CKD patients will reach this end stage of chronic kidney disease. Instead, most of them with moderate to advanced chronic kidney disease will prematurely die and most often they die from cardiovascular disease. And this highlights the extreme cardiovascular burden patients with CKD have.   The titles of the articles in this compendium are the Cardio Kidney Patient Epidemiology, Clinical Characteristics, and Therapy by Nicholas Marx, the Innate Immunity System in Patients with Cardiovascular and Kidney Disease by Carmine Zoccali et al. NETs Induced Thrombosis Impacts on Cardiovascular and Chronic Kidney disease by Yvonne Doering et al. Accelerated Vascular Aging and Chronic Kidney Disease, The Potential for Novel Therapies by Peter Stenvinkel et al. Endothelial Cell Dysfunction and Increased Cardiovascular Risk in Patients with Chronic Kidney Disease by Heidi Noels et al. Cardiovascular Calcification Heterogeneity in Chronic Kidney Disease by Claudia Goettsch et al. Fibrosis in Pathobiology of Heart and Kidney From Deep RNA Sequencing to Novel Molecular Targets by Raphael Kramann et al. Cardiac Metabolism and Heart Failure and Implications for Uremic Cardiomyopathy by P. Christian Schulze et al. Hypertension as Cardiovascular Risk Factor in Chronic Kidney Disease by Michael Burnier et al. Role of the Microbiome in Gut, Heart, Kidney crosstalk by Griet Glorieux et al, and Use of Computation Ecosystems to Analyze the Kidney Heart Crosstalk by Joachim Jankowski et al.   These reviews were written by leading investigators in the field, and the editors of Circulation Research hope that this comprehensive undertaking stimulates further research into the path flow of physiological kidney-heart crosstalk, and on comorbidities and intra organ crosstalk in general.   Cindy St. Hilaire:              So for our interview portion of the episode I have with me Dr Elizabeth Tarling and Dr Bethan Clifford. And Dr Tarling is an associate professor in the Department of Medicine in cardiology at UCLA, and Dr Clifford is a postdoctoral fellow with the Tarling lab. And today we're going to be discussing their manuscript that's titled, RNF130 Regulates LDLR Availability and Plasma LDL Cholesterol Levels. So thank you both so much for joining me today.   Elizabeth Tarling:             Thank you for having us.   Bethan Clifford:               Yeah, thanks for having us. This is exciting.   Cindy St. Hilaire:              I guess first, Liz, how did you get into this line of research? I guess, before we get into that, I should disclose. Liz, we are friends and we've worked together in the ATVB Women's Leadership Committee. So full disclosure here, that being said, the editorial board votes on these articles, so it's not just me picking my friends. But it is great to have you here. So how did you enter this field, I guess, briefly?   Elizabeth Tarling:             Yeah, well briefly, I mean my training right from doing my PhD in the United Kingdom in the University of Nottingham has always been on lipid metabolism, lipoprotein biology with an interest in liver and cardiovascular disease. So broadly we've always been interested in this area and this line of research. And my postdoctoral research was on atherosclerosis and lipoprotein metabolism. And this project came about through a number of different unique avenues, but really because we were looking for regulators of LDL biology and plasma LDL cholesterol, that's sort of where the interest of the lab lies.   Cindy St. Hilaire:              Excellent. And Bethan, you came to UCLA from the UK. Was this a topic you were kind of dabbling in before or was it all new for you?   Bethan Clifford:               It was actually all completely new for me. So yeah, I did my PhD at the same university as Liz and when I started looking for postdocs, I was honestly pretty adamant that I wanted to stay clear away from lipids and lipid strategy. And then it wasn't until I started interviewing and meeting people and I spoke to Liz and she really sort of convinced me of the excitement and that the interest and all the possibilities of working with lipids and well now I won't go back, to be honest.   Cindy St. Hilaire:              And now here you are. Well-   Bethan Clifford:               Exactly.   Cindy St. Hilaire:              ... congrats on a wonderful study. So LDLR, so low density lipoprotein receptor, it's a major determinant of plasmid LDL cholesterol levels. And hopefully most of us know and appreciate that that is really a major contributor and a major risk for the development of atherosclerosis and coronary artery disease. And I think one thing people may not really appreciate, which your study kind of introduces and talks about nicely, is the role of the liver, right? And the role of receptor mediated endocytosis in regulating plasma cholesterol levels. And so before we kind of chat about the nitty-gritty of your study, could you just give us a brief summary of these key parts between plasma LDL, the LDL receptor and where it goes in your body?   Elizabeth Tarling:             Yeah. So the liver expresses 70% to 80% of the body's LDL receptor. So it's the major determinant of plasma lipoprotein plasma LDL cholesterol levels. And through groundbreaking work by Mike Brown and Joe Goldstein at the University of Texas, they really define this receptor mediated endocytosis by the liver and the LDL receptor by looking at patients with familial hypercholesterolemia. So those patients have mutations in the LDL receptor and they either express one functional copy or no functional copies of the LDL receptor and they have very, very large changes in plasma LDL cholesterol. And they have severe increases in cardiovascular disease risk and occurrence and diseases associated with elevated levels of cholesterol within the blood and within different tissues. And so that's sort of how the liver really controls plasma LDL cholesterol is through this receptor mediated endocytosis of the lipoprotein particle.   Cindy St. Hilaire:              There's several drugs now that can help regulate our cholesterol levels. So there's statins which block that rate limiting step of cholesterol biosynthesis, but there's this new generation of therapies, the PCSK9 inhibitors. And can you just give us a summary or a quick rundown of what are those key differences really? What is the key mechanism of action that these therapies are going after and is there room for more improvement?   Bethan Clifford:               Yeah, sure. So I mean I think you've touched on something that's really key about the LDR receptor is that it's regulated at so many different levels. So we have medications available that target the production of cholesterol and then as you mentioned this newer generation of things like PCSK9 inhibitors that sort of try and target LDL at the point of clearance from the plasma.   And in response to your question of is there room for more regulation, I would say that given the sort of continual rate of increased cholesterol in the general population and the huge risks associated with elevated cholesterol, there's always capacity for more to improve that and sort of generally improve the health of the population. And what we sort of found particularly exciting about RNF130 is that it's a distinct pathway from any of these regulatory mechanisms. So it doesn't regulate the level of transcription, it doesn't regulate PCSK9. Or in response to PCSK9, it's a completely independent pathway that could sort of improve or add to changes in cholesterol.   Cindy St. Hilaire:              So your study, it's focusing on the E3 ligase, RNF130. What is an E3 ligase, and why was this particular one of interest to you? How did you come across it?   Elizabeth Tarling:             is predTates Bethan joining the lab. This is, I think, again for the listeners and those people in training, I think it's really important to note this project has been going in the lab for a number of years and has really... Bethan was the one who came in and really took charge and helped us round it out. But it wasn't a quick find or a quick story. It had a lot of nuances to it. But we were interested in looking for new regulators of LDL cholesterol and actually through completely independent pathways we had found the RNF130 locus as being associated with LDL cholesterol in animals. And then it came out in a very specific genome-wide association study in the African American care study, the NHLBI care study. And so really what we started looking at, we didn't even know what it was.   Elizabeth Tarling:             So we asked ourselves, well what is this gene? What is this protein? And it's RNF, so that's ring finger containing protein 130 and ring stands for really interesting new gene. Somebody came up with the glorious name. But proteins that contain this ring domain are very characteristic and they are E3 ubiquitin ligases. And so they conjugate the addition of ubiquitin to a target protein and that signals for that protein to either be internalized and/or degraded through different decorative pathways within the cell. And so we didn't land on it because we were looking at E3 ligases, we really came at it from an LDL cholesterol perspective. And it was something that we hadn't worked on before and the study sort of blossomed from there.   Cindy St. Hilaire:              That's amazing and a beautiful, but also, I'm sure, heartbreaking story because these long projects are just... They're bears. So what does this RNF130 do to LDLR? What'd you guys find?   Bethan Clifford:               As Liz said, this is a long process, but one of the key factors of RNF130 is it's structurally characteristically looked like E3 ligase. So the first thing that Liz did and then I followed up with in the lab is to see is this E3 ligase ubiquitinating in vitro. And if it is going to ubiquitinate, what's it likely to regulate that might cause changes in plasma cholesterol that would explain these human genetic links that we saw published at the same time.   And so because the LDL cholesterol is predominantly regulated by the LDL receptor and the levels of it at the surface of the parasites in the liver, the first question we wanted to see is does RNF130 interact in any way with that pathway? And I'm giving you the brief view here of the LDL receptor. We obviously tested lots of different receptors. We tested lots of different endocytose receptors and lipid regulators, but the LDL receptor is the one that we saw could be ubiquitinated by RNF130 in vitro. And so then we wanted to sort of go on from there and establish, okay, if this E3 ubiquitin ligase, is it regulating LDL receptor? What does that mean in an animal context in terms of regulating LDL cholesterol?   Cindy St. Hilaire:              Yeah, and I guess we should also explain, ubiquitination, in terms of this receptor, and I guess related to Goldstein and Brown and receptor mediated endocytosis, like what does that actually mean for the liver cell and the cholesterol in the LDLR that is binding the receptor?   Bethan Clifford:               So yes, ubiquitination is a really common regulatory mechanism actually across all sorts of different cells, all sorts of different receptors and proteins. And basically what it does is it signals for degradation of a protein. So a ubiquitin molecule is conjugated to its target such as in our case the LDL receptor and that ubiquitin tells the cell that this protein is ready for proteasomal degradation. And that's just one of the many things ubiquitination can do. It can also signal for a trafficking event, it can signal for a protein to protein interaction, but it's most commonly associated with the proteasomal degradation.     Cindy St. Hilaire:              So in terms of... I guess I'm thinking in terms of PCSK9, right? So those drugs are stemming from observations in humans, right? There were humans with gain and loss of function mutations, which caused either more or less of this LDLR receptor internalization. How is this RNF130 pathway different from the PCSK9 activities?   Elizabeth Tarling:             Yeah, so PCSK9 is a secreted protein, so it's made by hepatocyte and actually other cells in the body and it's secreted and it binds to the LDL particle, LDL receptor complex, and signals for its internalization and degradation in the proteasome. So this is not ubiquitination event, this is a completely different trafficking event. And so the RNF130, actually what Bethan showed, is it directly ubiquitinates the LDL receptor itself, signaling for an internalization event and then ultimately degradation of the LDR receptor through a decorative pathway, which we also define in the study.   So these are two unique mechanisms and actually some key studies that we did in the paper were to modulate RNF130 in animals that do not have PCSK9. And so in that system where in the absence of PCSK9 you have a lot of LDR receptor in the liver that's internalizing cholesterol. What happens when you overexpress RNF130? Do you still regulate at the LDL receptor? And you absolutely do. And so that again suggests that they're two distinct mechanisms and two distinct pathways.   Cindy St. Hilaire:              That was one thing I really loved about your paper is every kind of figure or section, the question that would pop up in my head, even ones that didn't pop in my head were beautifully answered with some of these really nice animal models, which is never an easy thing, right? And so one of the things that you brought up was difficulty in making one of the animal models. And so I'm wondering if you could share a little bit for that challenge. I think one thing that we always tend to hide is just science is hard and a lot of what we do doesn't work. And I really think especially for the trainees and really everyone out there, if we kind of share these things more, it's better. So what was one of the most challenging things in this study? And I guess I'm thinking about that floxed animal.   Elizabeth Tarling:             Yeah, so I'll speak a bit about that and then I'll let Bethan address because she was really the one on the ground doing a lot of the struggles. But again, we actually weren't going to include this information in the paper. And upon discussion and actually prompted by the reviewers of the paper and some of the questions that they asked us, we realized, you know what? It's actually really important to show this and show that this happens and that there are ways around it.   And so the first story is before Bethan even arrived in the lab, we had purchased embryonic stem cells that were knockout first condition already. And so this is a knockout strategy in which the exon of interest is flanked with lots of P sites so that you can create a flox animal, but also so you can create a whole body knockout just by the insertion of this knockout first cassette.   Elizabeth Tarling:             And so we got those mice actually in the first year of Bethan joining the lab. We finally got the chimeric mice and we were able to stop reading those mice. And at the same time we tried to generate our flox animals so that we could move on to do tissue-specific studies. And Bethan can talk about the pain associated with this. But over two years of breeding, we never got the right genotypes from the different crosses that you need to do to generate the flox animal.   And it was actually in discussions with Bethan where we decided we need to go back. We need to go back to those ESLs that we purchased five years ago and we need to figure out if all of the elements that the quality control step had told us were in place are actually present. And so Bethan went back and sequenced the whole locus and the cassette to figure out what pieces were present and we found that one of the essential locks P sites that's required for every single cross from the initial animal was absent and therefore we could actually never make the mouse we wanted to make.   And so that's sort of just a lesson for people going down that route and making these tools that we need in the lab to answer these questions is that despite paying extra money and getting all of the sort of QCs that you can get before you receive the ESLs, we should have gone back and done our own housekeeping and sort of a long journey told us when we went back that we didn't have what we thought we had at the beginning. And that was a real sticking point as Bethan can-   Cindy St. Hilaire:              Yeah. And so you know you're not alone. My very first postdoc that I did, I went with a mouse that they had also bought and were guaranteed that it was a knockout and it was not. And it is a painful lesson, but it is critical to... You get over it.   So Bethan, maybe you can also tell us a little bit about what are the other kind of next things you tried? You pivoted and you pivoted beautifully because all the models you used I thought were quite elegant in terms of exactly asking the question you wanted to ask in the right cells. So can you maybe explain some of the in vivo models you used for this study?   Bethan Clifford:               Sure, there are definitely a lot. So I mean I think Liz sort of encapsulated the trouble we have with the knockout really succinctly, but actually I want to just take this moment to sort of shout out to another postdoc in the Tarling lab, Kelsey Jarrett, who was really instrumental in the pivoting to a different model. So for the knockouts when we sort of established we didn't have exactly what we thought we did and then to compound that we also weren't getting the DeLiAn ratios breeding this whole body knockout.   We wanted to sort of look at a more transient knockout model. And that's where Kelsey really stepped in and sort of led the way and she generated AAV-CRISPR for us to target RNF130 specifically in the liver. And that had the added beauty of, one, not requiring breeding to get over this hurdle of the knockout being somewhat detrimental to breeding. But it also allowed us to ask the question of what RNF130 is doing specifically in the liver where the liver regulates LDL receptor and LDL cholesterol.   And so that was one of the key models that really, really helped get this paper over the finish line. But we did a whole barrage of experiments, as you've seen. We wanted to make sure... One of the key facets of the Tarling lab is whenever you do anything, no matter what you show Liz, it will always be, "Okay, you showed it to me one way, now show it to me a different way." Can you get the same result coming at it from different ways? And if you can't, why is that? What is the regulation behind that? And so that's really what the paper is doing is asking the same question in as many ways as we can accurately and appropriately probe what RNF130 does to the LDR receptor.   So we tried gain of function studies without adenovirus overexpression. We tried transient knockdown with antisense oligonucleotides, and then we did, as I said, the AAV-CRISPR knockdown with the help of Kelsey and our whole body knockout. And then we also repeated some of these studies such as the adenovirus and the ASO in specific genetic backgrounds. So in the absence of PCSK9, can we still regulate the LDL receptor? And then we also, just to really confirm this, in the absence of the LDL receptor, do we see a difference? And the answer is no, because this effect was really dependent on that LDL receptor being present. So there was a big combination.   Cindy St. Hilaire:              It was really nice, really a beautiful step-wise progression of how to solidly answer this question. But a lot of, I think, almost all you did was in mice. And so what is the genetic evidence for relevancy in humans? Can you discuss a little bit about those databases that you then went to to investigate, is this relevant in humans?   Bethan Clifford:               I think Liz might be better off answering that question.   Elizabeth Tarling:             And I think this sort of pivots on what Bethan was saying. So when we had struggles in the lab, it was a team environment and a collaboration between people in the lab that allowed us to make that leap and make those next experiments possible to then really answer that question. And to be able to include the antisense oligonucleotides required a collaboration with industry. We were very lucky to have a longstanding collaboration with Ionis, who provided the antisense oligonucleotides.   And for the human genetics side of things, that also was a collaboration with Marcus Seldin, who was a former postdoc with Jake Lusis and is now our PI at UC Irvine. And what he helped us do is dive into those summary level databases and ask from that initial study in the NHLBI care population, do we see associations of RNF130 expression in humans with LDL cholesterol with cardiovascular outcomes. And so one database which I would recommend everybody use, it's publicly available, is the StarNet database. And it's in the paper and the website is there. And that allowed us to search for RNF130.   Elizabeth Tarling:             And what it does is it asks how RNF130 expression in different tissues is associated with cardiometabolic outcomes and actual in CAD cases and controls, so people with and without heart disease. And we found that expression of RNF130 in the liver was extremely strongly correlated with the occurrence of cardiovascular disease in people with CAD. So in cases versus controls. And then we were also able to find many other polymorphisms in the RNF130 locus that were associated with LDL cholesterol in multiple different studies.   And I think the other message from this paper is this, unlike PCSK9 and unlike LDR receptor itself, which are single gene mutations that cause cardiovascular disease, there are many sub genome-wide significant loci that contribute to this multifactorial disease, which is extremely complex. And I think RNF130 falls within that bracket that those sort of just on the borderline of being genome-wide significant still play significant biological roles in regulating these processes. And they don't come up as a single gene hit for a disease, but combinatorialy they are associated with increased risk of disease and they have a molecular mechanism that's associated with the disease. And so that's what Marcus helped us do in terms of the human genetics is really understand that and get down to that level of data.   Cindy St. Hilaire:              Yeah. Yeah, it really makes you want to go back and look at those. Everyone always focuses on that really high peak and those analyses, but what are all those other ones above the noise, right? So it's really important.   Elizabeth Tarling:             I think it's really hard to do that. I think that's one where people... Again, it comes down to team science and the group of people that we brought together allowed us to ask that molecular question about how that signal was associated with the phenotype. I think by ourselves we wouldn't have been able to do it.   Cindy St. Hilaire:              Yeah. So your antisense oligonucleotide experiments, they were really nice. They showed, I think it was a four-week therapy, they showed that when you injected them expression of RNF130 went down by 90%. I think cholesterol in the animals was lowered by 50 points or so. Is this kind of a next viable option? And I guess related to that, cholesterol's extremely important for everything, right? Cell membrane integrity, our neurons, all sorts of things. Is it possible with something that is perhaps really as powerful as this to make cholesterol too low?   Elizabeth Tarling:             I think that what we know from PCSK9 gain and loss of function mutations is that you can drop your plasma cholesterol to very low levels and still be okay because there are people walking around with mutations that do that. I think RNF130 is a little different in that it's clearly regulatory in a homeostatic function in that it's ubiquitously expressed and it has this role in the liver to regulate LDL receptor availability, but there are no homozygous loss of function mutants people walking around, which tells us something else about how important it is in potentially other tissues and in other pathways. And we've only just begun to uncover what those roles might be.   So I think that as a therapy, it has great potential. We need to do a lot more studies to sort of move from rodent models into more preclinical models. But I do think that the human data tell us that it's really important in other places too. And so yeah, we need to think about how best it might work as a therapy. If it's combinatorial, if it's dosed. Those are the types of things that we need to think about.   Cindy St. Hilaire:              Yeah, it's really exciting. Do you know, are there other protein targets of RNF130? Is that related to my next question of what is next?   Elizabeth Tarling:             I mean, so I should point out, so Bethan unfortunately left the lab last year for a position at Amgen where she's working on obesity and metabolic disease. But before she left, she did two very, very cool experiments searching for new targets or additional targets of RNF130. Starting in the liver, but hopefully we'll move those into other tissues. And so she did gain of function RNF130 versus what loss of function we have of RNF130, and she did specific mass spec analysis of proteins that are ubiquitinated in those different conditions. And by overlaying those data sets, we're hoping to carve out new additional targets of RNF130. And there are some, and they're in interesting pathways, which we have yet to completely test, but definitely there are additional pathways, at least when you overexpress and reduce expression. Now, whether they turn out to be, again, bonafide in vivo, actual targets that are biologically meaningful is sort of the next step.   Cindy St. Hilaire:              Yeah. Well, I'm sure with your very rigorous approach, you are going to find out and hopefully we'll see it here in the future. Dr Elizabeth Tarling and Dr Bethan Clifford, thank you so much for joining me today. I really enjoyed this paper. It's a beautiful study. I think it's a beautiful example, especially for trainees about kind of thoroughly and rigorously going through and trying to test your hypothesis. So thanks again.   Elizabeth Tarling:             Thank you.   Bethan Clifford:               Thank you very much.   Cindy St. Hilaire:              That's it for the highlights from the March 31st and April 14th issues of Circulation Research. Thank you for listening. Please check out the Circulation Research Facebook page and follow us on Twitter and Instagram with the handle @CircRes, and #DiscoverCircRes. Thank you to our guests, Dr Liz Tarling and Dr Bethan Clifford.   This podcast is produced by Ishara Ratnayaka, edited by Melissa Stoner, and supported by the editorial team of Circulation Research. I'm your host, Dr Cindy St. Hilaire, and this is Discover CircRes, you're on-the-go source for the most exciting discoveries in basic cardiovascular research.   This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more information, visit ahajournals.org.  

Motorsport101
Episode #424: MotoGP 2023 Season Preview

Motorsport101

Play Episode Listen Later Mar 20, 2023 103:04


It's the final episode of Season Preview Season here on Motorsport101, and with MotoGP back in Portimao to kick off their 2023 season on Sunday, Dre and Cam sit down for a feature-length deep dive on the state of the sport heading into the new year. Now, we're going to be honest here, things look a little bleak. Ducati are set to dominate with eight bikes, a GP23 that broke Portimao's lap record in testing, and and a super-team with Enea Bastianini joining from Gresini. Can anyone stop them? Especially when their 7th best rider in their ranks is... Alex Marquez? Honda gets featured heavily at the start, as they're throwing EVERYTHING at the wall to keep Marc Marquez happy, including brining in Suzuki's former head of development, and outsourcing an entire chassis to Moto2 kings Kalex. A last roll of the dice to keep the legend happy? What about Aprilia? ALL the aero onboard with Aleix Espargaro already going under the knife with a fibrosis diagnosis, and now a second team with RNF, Raul Fernandez and Miguel Oliveira joining. Can they stay at the front in a post-concession world? What about a revamped KTM? Jack Miller joins Brad Binder, and Pol Espargaro returning home after a horror stint with Honda. Is this really worth all the talent squandered, and can they develop their way into serious contenders of being just a flash in the pan? Yamaha are also all by themselves now, and Fabio Quartararo looks set to be their own challenger. Can be bounce back after the biggest title choke in the sport's history. And is there any hope for Franco Morbidelli? This and so much more in a feature-length season preview on Motorsport101!

MotoGP España
72: ¿Quién se juega más en los test de Sepang?

MotoGP España

Play Episode Listen Later Feb 7, 2023 42:22


Arranca, por fin, la pretemporada MotoGP 2023 con la celebración de los test de Sepang, unos ensayos en los que algunos fabricantes se juegan más que otros a la hora de dar con la tecla. Este fin de semana arrancan en el circuito malasio de Sepang los primeros test oficiales de la pretemporada MotoGP 2023, unos ensayos en los que se podrá comprobar si el trabajo realizado en las fábricas durante el largo invierno ha dado los frutos esperados. Uri Puigdemont y Germán García Casanova analizan en nuestro habitual podcast MotoGP qué constructores se juegan más este año en unos test que para todos los fabricantes serán cruciales, aunque algunos, seguramente, se juegan más que otros. Los casos más claros, sin duda, son los de Honda y Yamaha. Las dos casas japonesas arrastran un claro retroceso respecto al gran dominador de 2022, Ducati, que ganó la triple corona con una moto que todo el mundo convino que está muy por encima del resto. Para HRC la temporada 2023 y su nuevo prototipo RC213V tiene tintes de ser un 'ahora o nunca', con Marc Márquez completamente recuperado de sus problemas físicos demandando una moto que sea suficientemente competitiva como para volver a luchar por el campeonato. Algo similar pasa con Yamaha, que tras ganar el título en 2021 con Fabio Quartararo, el pasado año vivió un paso atrás que el francés no piensa tolerar por segunda vez. Tanto Marc como Fabio son los pilotos franquicia de sus respectivos equipos y no tener las armas necesarias para demostrar su potencial podría llevarles a pensar en cambiar de aires más pronto que tarde. Desde su atalaya de tricampeón, Ducati observa con absoluta tranquilidad las cuitas de sus rivales, aunque con la inquietud de saber que este año han colocado a dos gallos en el mismo gallinero. Pecco Bagnaia defenderá la corona conquistada en 2022 y su primer y, posiblemente, más duro rival será su nuevo compañero de box, Enea Bastianini, que ya el año pasado empezó a dar muestras, en la parte final del curso, que no se conformará con nada que no sea luchar por el campeonato. Para Aprilia 2023 será el primer año completo sin concesiones, con un equipo satélite y con el cartel de moto que puede competir por el título, como ya hizo el año pasado con Aleix Espargaró. Para Maverick Viñales se acaba el crédito de la adaptación y esta temporada debe empezar a demostrar que puede ganar carreras como hizo con Suzuki y Yamaha en el pasado. Todo ello con la llegada de un Miguel Oliveira al equipo satélite que será competitivo desde el principio, no en vano en Aprilia han apostado por equipar a RNF con las motos de 2022 que demostraron ser ganadoras. KTM, que ha llevado a un ejército de probadores al shakedown de Sepang, sigue presentando soluciones aerodinámicas que le permitan equipararse a Ducati y, sobre todo, Aprilia de la que se ha inspirado para hacer un nuevo carenado. El fabricante austríaco, tras unos años de crecimiento, busca en 2023 empezar a demostrar que no están en MotoGP como meras comparsas.

The Race MotoGP Podcast
Ducati picks Bastianini - so what now for Martin?

The Race MotoGP Podcast

Play Episode Listen Later Aug 30, 2022 62:39


Ducati completing its MotoGP works line-up for 2023 and other silly season developments are the topic of conversation in the latest edition of The Race MotoGP Podcast.Host Toby Moody is joined by Valentin Khorounzhiy and Simon Patterson to talk about Enea Bastianini getting the nod over Jorge Martin to replace Jack Miller at the factory Ducati team.The crew ponder the upsides and downsides of the choice, and discuss whether it may set Martin on a course for a Ducati exit down the line.They also touch upon KTM's decision-making in light of the revelation that Remy Gardner expects to drop off the grid for 2022, and debate whether Raul Fernandez is likely to succeed in course-correcting his MotoGP career with his switch to Aprilia.Finally, they discuss Honda-related matters - like the hold-up in confirming Joan Mir for 2023 and the MotoGP outlook for protege Ai Ogura - and tackle a batch of listener questions.*NOTE - This episode was recorded before Mir's move to Honda and RNF's line-up of Miguel Olivera and Raul Fernandez were made official.Follow The Race on Instagram, Twitter and FacebookCheck out our latest videos on YouTubeDownload our brand-new app on iOS or AndroidFor MotoGP news, analysis and must-read features visit the-race.com Hosted on Acast. See acast.com/privacy for more information.

The Race MotoGP Podcast
Ducati picks Bastianini - so what now for Martin?

The Race MotoGP Podcast

Play Episode Listen Later Aug 30, 2022 66:24


Ducati completing its MotoGP works line-up for 2023 and other silly season developments are the topic of conversation in the latest edition of The Race MotoGP Podcast. Host Toby Moody is joined by Valentin Khorounzhiy and Simon Patterson to talk about Enea Bastianini getting the nod over Jorge Martin to replace Jack Miller at the factory Ducati team. The crew ponder the upsides and downsides of the choice, and discuss whether it may set Martin on a course for a Ducati exit down the line. They also touch upon KTM's decision-making in light of the revelation that Remy Gardner expects to drop off the grid for 2022, and debate whether Raul Fernandez is likely to succeed in course-correcting his MotoGP career with his switch to Aprilia. Finally, they discuss Honda-related matters - like the hold-up in confirming Joan Mir for 2023 and the MotoGP outlook for protege Ai Ogura - and tackle a batch of listener questions. *NOTE - This episode was recorded before Mir's move to Honda and RNF's line-up of Miguel Olivera and Raul Fernandez were made official. Follow The Race on Instagram, Twitter and Facebook Check out our latest videos on YouTube For MotoGP news, analysis and must-read features visit the-race.com

MotoWeek - MotoGP, Motorcycle and Racing News
Dovi Retirement, Marc Marquez Recovering

MotoWeek - MotoGP, Motorcycle and Racing News

Play Episode Listen Later Aug 13, 2022 40:28


Andrea Dovizioso is making an exit from RNF - we talk about his hasty Yamaha departure, give an update on Marc Marquez, review your comments on MotoGP at Silverstone - and more!The Rundown- Andrea Dovizioso is retiring after Misano- Portugal will officially be starting off the 2023 MotoGP season- Aleix Espargaro did get hurt in that Silverstone wreck- Marc Marquez update - things are looking promising- Comments!: Silverstone, Ducati dodging controversy, the Stegosaurus Tail - and more- Pics and Video!Get the latest episodes at Motoweek.net, follow on Twitter @motoweek and Instagram @motoweekusa, and like the show and leave your comments on Facebook at facebook.com/motoweek.net or on the Reddit Sub at r/motoweekAnd you can support the show on Patreon at patreon.com/motoweekThanks for listening!

MotoWeek - MotoGP, Motorcycle and Racing News
MW: Marc Is Out - Again. Aprilia Kicks Off Silly Season!

MotoWeek - MotoGP, Motorcycle and Racing News

Play Episode Listen Later May 31, 2022 42:02


Mugello featured as much action off the track as there was on it! In this Bonus Episode, we discuss Marc Marquez' surprise announcement, Aprilia's official start to the MotoGP Silly Season, and more!The Rundown- MotoGP News:- Marc Marquez - out again. Why, for how long, and how does this affect Honda?- Max Biaggi becomes a MotoGP Legend- Valentino Rossi has his number retired - what do you think of number retirements?- Silly Season News:- Aprilia decides on their '23 Factory lineup - did they make the right decision?- RNF defects to Aprilia - what does it mean for Yamaha?What do you think of the Marc and Aprilia announcements? Let me know on Facebook.com/motoweek.net or on the Reddit Sub at r/motoweekFind all of the latest episodes at Motoweek.net, follow on Twitter @Motoweek and Instagram @motoweekusa – and you can support the show on Patreon at patreon.com/motoweekThanks for listening!

The Race MotoGP Podcast
Bagnaia's Mugello win reviewed + reaction to Marquez surgery news

The Race MotoGP Podcast

Play Episode Listen Later May 30, 2022 69:46


The Italian Grand Prix weekend at Mugello - and the huge Marc Marquez announcement that came in during it - is the subject of the latest episode of The Race MotoGP Podcast.Marquez and his employer Honda announced that the six-time MotoGP champion would be going in for a fourth operation on his right humerus bone, requiring another lengthy spell on the sidelines - and prompting a striking admission that without this surgery Marquez felt he was headed for a swift retirement.Host Toby Moody is joined by Valentin Khorounzhiy and Simon Patterson to discuss the Marquez news, Francesco Bagnaia's Sunday triumph and the flatter-than-usual atmosphere at an under-attended Mugello.They also touch upon Suzuki's horror weekend, Fabio Quartararo's continued brilliance, Aprilia's 'Leicester-like' title push and its 2023 signing of Yamaha satellite team RNF.Follow The Race on Instagram, Twitter and FacebookCheck out our latest videos on YouTubeFor MotoGP news, analysis and must-read features visit the-race.com Hosted on Acast. See acast.com/privacy for more information.

The Race MotoGP Podcast
Bagnaia's Mugello win reviewed + reaction to Marquez surgery news

The Race MotoGP Podcast

Play Episode Listen Later May 30, 2022 73:31


The Italian Grand Prix weekend at Mugello - and the huge Marc Marquez announcement that came in during it - is the subject of the latest episode of The Race MotoGP Podcast. Marquez and his employer Honda announced that the six-time MotoGP champion would be going in for a fourth operation on his right humerus bone, requiring another lengthy spell on the sidelines - and prompting a striking admission that without this surgery Marquez felt he was headed for a swift retirement. Host Toby Moody is joined by Valentin Khorounzhiy and Simon Patterson to discuss the Marquez news, Francesco Bagnaia's Sunday triumph and the flatter-than-usual atmosphere at an under-attended Mugello. They also touch upon Suzuki's horror weekend, Fabio Quartararo's continued brilliance, Aprilia's 'Leicester-like' title push and its 2023 signing of Yamaha satellite team RNF.

Reals&Feels
Kid Intervention ft DudeInDaCorner

Reals&Feels

Play Episode Listen Later Mar 28, 2022 114:31


This week the RnF team is joined by a familiar face to tackle the wild news segments and touchy subject. Intro Cut: After Ashes- "Dante's Peak" (music video on youtube) Outro Cut: Sean Davey - "Lose"

MotoGP España
45: Marc Márquez está de vuelta

MotoGP España

Play Episode Listen Later Jan 28, 2022 22:29


La noticia más esperada del invierno se confirmó esta misma semana: Marc Márquez está de vuelta, y con él el podcast de MotoGP de Motorsport.com. La total recuperación de la lesión ocular sufrida por Marc Márquez en la recta final de la pasada temporada y la confirmación de que va a estar desde el primer momento en los test de Sepang con Honda es el punto de partida del primer podcast ‘Por Orejas' de 2022, en el que, como siempre, Uri Puigdemont y Germán Garcia Casanova analizaran semanalmente la actualidad del Mundial de MotoGP. Un campeonato que tras perder a Valentino Rossi, que se retiró tras la carrera de Valencia, la última del pasado curso, necesitaba mantener en las mejores condiciones posibles a la que es, seguramente, su máxima estrella ahora mismo, el español Marc Márquez. Nuestros especialistas debaten qué supone para el piloto, para Honda y para el campeonato que Márquez pueda recuperar un nivel lo más parecido posible al que nos tenía acostumbrados antes de su lesión en el brazo derecho, en julio de 2020, y cómo afectará al resto de la parrilla. A falta de poco más de una semana para el inicio de la pretemporada en Sepang, los equipos de la clase reina han empezado a hacer sus presentaciones, repasamos también los estrenos de Gresini, del nuevo RNF o la presentación de KTM y Tech3, a la espera todavía de que el resto de las formaciones hagan su puesta de largo.

Rich Not Famous
Setting Intentions and Getting Our Sh*t Together

Rich Not Famous

Play Episode Listen Later Nov 14, 2021 40:33


This week, the girls catch up on the recent adventures of their lives and talk about the importance of setting positive intentions for the coming week. Sit back, listen, and set your weekly intentions alongside Mari and Naomi! Please follow us on Spotify and Apple Podcasts and leave a rating and review! Follow us on Instagram @_richnotfamous_ and join the RNF fam!

The Race MotoGP Podcast
Quartararo's sudden coronation steals spotlight from rare Honda 1-2

The Race MotoGP Podcast

Play Episode Listen Later Oct 25, 2021 62:40


The post-Emilia Romagna Grand Prix edition of The Race MotoGP podcast discusses Fabio Quartararo's day of glory at Misano and the riders who are best poised to challenge him in 2022.Simon Patterson and Valentin Khorounzhiy join host Toby Moody for a customary overview of the weekend's premier-class action, as well as the extravagant title celebrations that were due to be postponed until Francesco Bagnaia's sudden late-race crash.There is also a discussion of Bagnaia's star-making season, as well as an assessment of where MotoGP's former king Marc Marquez is on his road to recovery and what Pol Espargaro's second-place should tell his employer Honda.Enea Bastianini earns plaudits for his second podium appearance, as does Miguel Oliveira despite his podium-denying crash, while in the final part the crew talks about the one-year deal handed to the new Yamaha satellite team RNF.

Rich Not Famous
You Can Be a Badass at Making Money|Book Club Ep.1

Rich Not Famous

Play Episode Listen Later Aug 30, 2021 43:02


Naomi and Mari are back this week with an exciting new segment to the podcast! In this episode they dive in to the book, You Are a Badass at Making Money by Jen Sincero. The girls share their biggest takeaways and get deep about how to change your mindset, your life, and your preconceived notions about money. As always, share this podcast, join the RNF family on Instagram @_richnotfamous_ and let us know what you think!

Rich Not Famous
Get To Know Us! 21 Questions With a Twist

Rich Not Famous

Play Episode Listen Later Aug 2, 2021 26:43


Your RNF hosts take a twist on 21 questions! Naomi and Mari share everything from their dream cars to their most embarrassing moment. Follow us on Instagram and share this podcast with your friends so we can grow the RNF fam!!! Let us know what you think over on Instagram @_richnotfamous_

Rich Not Famous
What No One Tells You About Graduating College + Welcome to RNF!!

Rich Not Famous

Play Episode Listen Later Jul 26, 2021 25:44


Naomi and Mari sit down for their first ever episode of Rich Not Famous to introduce themselves and chat about how they met, what recent post-grad life is really like, and what this podcast will be all about. It's a bit of a mess but we promise we're getting the hang of this podcasting thing! Follow us on Instagram and share this podcast with your friends so we can grow the RNF fam!! Let us know what you think over on Instagram @_richnotfamous_