Podcasts about modulated

Markus Loerner, Market Segment Manager, RF & Microwave Components at Rohde & Schwarz, talks with Pat Hindle and Del Pierson about a new, simplified setup for wideband modulated load pull including some background about load pull measurements.

"I'm the man in the arena." Ray Lewis and Shannon Sharpe have words, Billy votes on the AP Poll, Dan beats a 'Stat of the Day' into the ground, and the secret voice behind our show-long voice modulation is exposed. Learn more about your ad choices. Visit podcastchoices.com/adchoices

Edith HeardCollège de FranceEpigénétique et mémoire cellulaireAnnée 2024-2025Colloque - L'inactivation du chromosome X : Escape from X-inactivation is directly modulated by Xist RNA levelsOrganisation : Pre Edith Heard (Collège de France, chaire Épigénétique et mémoire cellulaire) et Pre Claire Rougeulle (Institut Curie)Agnese LodaEMBL, Allemagne

This episode features Prof. Malú Tansey PhD and colleague Dr. Andrea Merchak PhD from the University of Florida, USA, discussing neuroinflammation and the role of gut microbes in Parkinson's disease (PD) and other neurodegenerative diseases. “Inflammaging” tends to occur as aging progresses, but the links that have been made between the gut and the brain in PD have led their group to the hypothesis that PD may be an age-acquired autoimmune condition. Genetic factors are relevant, although not everyone with PD has the predisposing genes. Those with a certain genetic mutation have a different immune phenotype from normal. Furthermore, the gut microbiota influences the immune system and the inflammatory environment within the body, with some metabolites known to cross the blood-brain barrier and influence the immune cells of the brain. Currently the group is focusing on using the gut microbiome, blood, and colonic biopsies to gain insights into the brain. A combination of diet and probiotics is promising as an intervention to prevent neurodegeneration as people age. Episode abbreviations and links: Review on the fundamental role of neuroinflammation in Parkinson's disease: Inflammation and immune dysfunction in Parkinson disease Post on bioRxiv showing immune similarities in people with PD and people with IBD: Peripheral Blood Immune Cells from Individuals with Parkinson's Disease or Inflammatory Bowel Disease Share Deficits in Iron Storage and Transport that are Modulated by Non-Steroidal AntiInflammatory Drugs Review on the gut dysfunction in PD and whether it precedes brain pathology, with links to dysregulated immune activity: The gut-brain axis: is intestinal inflammation a silent driver of Parkinson’s disease pathogenesis? About Prof. Malú Tansey PhD: Malú Gámez Tansey, Ph.D. is the Norman and Susan Fixel Chair in Neuroscience and Neurology and former Director of the Center for Translational Research in Neurodegenerative Disease at the University of Florida. Her lab focuses on the role of inflammation and immune system responses in brain health and neurodegenerative disease, with particular focus on central-peripheral neuroimmune crosstalk and the gut-brain axis, with the long-term goal of developing better therapies to prevent and/or delay these diseases. Dr. Tansey obtained her B.S/M.S in Biological Sciences from Stanford University and her Ph.D. in Cell Regulation from UT Southwestern followed by post-doctoral work in neuroscience at Washington University. As head of Chemical Genetics at Xencor, she co-invented novel soluble TNF inhibitors that have now advanced to clinical trials in Alzheimer's disease. She returned to academia as an Assistant Professor of Physiology at UT Southwestern in 2002 and was recruited to Emory University School of Medicine as a tenured Associate Professor in 2009. After 10 year at Emory and rising to the rank of Full Professor where she earned several mentoring awards from students and faculty for her efforts in championing early-stage investigators, women and other under-represented groups in STEM, she was recruited to the Department of Neuroscience in the College of Medicine at the University of Florida, where she served on the executive committees for the McKnight Brain Institute and the Fixel Institute for Neurological Diseases. She will be moving to the Stark Neuroscience Research Institute at Indiana University in Indianapolis in January of 2025 as the first Director of Neuroimmunology Research and Executive Associate Director of Education at the Stark NRI. About Dr. Andrea Merchak PhD: Andrea Merchak, Ph.D. is a Gator Neuroscholar Postdoctoral Associate at the University of Florida. She obtained her B.S. at Centre College with a focus on behavioral neuroscience and her Ph.D. from the University of Virginia. There, her thesis work explored the link between the gut microbiota and the brain in mood disorders and multiple sclerosis. Her current work explores the relationship between gut health and genetic predispositions for neurodegeneration. She has received recognition for her work through the Young Scientist Award from the International Prebiotics, Probiotics, and Gut Microbiome Conference, the Outstanding Graduate Student Award from the University of Virginia, as well as a track record of funding from the NIH. She will be moving to the Stark Neuroscience Research Institute at Indiana University in Indianapolis in March of 2025 as an Assistant Professor of Neurology.

References Nature 2024.volume 635, pages 1010–1018 Trad. 1923. "Midnight Special" CCR https://open.spotify.com/track/5jRQvcl66ovRTjUwzXziZA?si=b15d07dc2d1448db Hunter-Garcia 1979 "Althea" Grateful Dead https://open.spotify.com/track/7M7AwtGvWdMYudqx5Iuh1m?si=bd3d661d47d14992 Mozart, WA. 1779. Sinfonia Concertante K364. https://youtu.be/_0hTDZ0whpU?si=K3PDAEJUz08t6i-L Bruce, Jack 1968. "Train Time" Live. Wheels of Fire lp. Cream https://open.spotify.com/track/7cJgHvkMpSkZDw9aYWYTWm?si=eff3eaa37fb8440d --- Support this podcast: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/support

SoftlySteph's The Friction of a Modulated Soul took home the Best Dance Experience at Raindance Immersive in a groundbreaking performance that tells the "story about the different cages that bind us from our authentic truth." It's a piece that completely blew me away with it's technological innovations, her fluid and emotionally-driven dance, a moving story that takes you on guided journey towards authentic identity, and an excellent curation of music from other VRChat creators. The piece manages to tie together so many different strands of technical innovation, storytelling, and performance, and it was one of my highlights from the entire Raindance Immersive festival this year. https://www.youtube.com/watch?v=OAUjJ_ozldM The crux of the innovations within The Friction of a Modulated Soul are from the new holographic shader (aka the "Apple Global Illumination") developed in partnership with SNR Labs' Apple Blossom, A://DDOS, and namoron (covered in great detail in the previous episode #1413) that both plays back recorded holographic objects that are a part of a timed dance performance, but also replicates and mirrors her dance performance at different scales in real-time. There's also real-time lighting effects on the 1.4 million point-cloud pixels that are utterly awe-inspiring, and took lots of black magic shader wizardry pull it all off by encoding and decoding information from video streams (again many of the more technical details are covered in episode #1413). I saw this piece as a live performance during Raindance, but they're also working on a replayable VRChat world that should be ready within the next month or so. SoftlySteph also curated a soundtrack of independent music by VRChat creators with five of the songs specifically composed for this piece. Everything in this piece was designed around story, which takes the audience on a journey from resisting internal disconnections, to achieving authentic connection to self, to then resisting collective pressures to disconnect, and then finally culminating with authentic connection. https://twitter.com/SoftlySteph/status/1807125937819148769 Overall, this was a beautifully-executed piece that is pushing into new forms of dance genre and performance, and was well-deserving of the best dance performance at Raindance Immersive. I had a chance to catch up with SoftlySteph to get a bit more context about how this project came about, her journey into VR via the stage dance and dance performance scene, and then her intentions with architecting this story about authentic self. This is a listener-supported podcast through the Voices of VR Patreon. Music: Fatality

After two guests cancel, Kristen & Sylvia fill the void with a fun-filled and informative conversation ranging from the lessons learned from the Adam Grant book "Think Again," to a discussion about the people in our lives, including "illuminators" and "diminishers," all brought to you by our new sponsors: Naked Attraction, Yellow Legal Pads & No. 2 Pencils, Coach and Tumi (not really).

BUFFALO, NY- April 9, 2024 – A new #researchpaper was #published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 16, Issue 6, entitled, “CMS121: a novel approach to mitigate aging-related obesity and metabolic dysfunction.” Modulated by differences in genetic and environmental factors, laboratory mice often show progressive weight gain, eventually leading to obesity and metabolic dyshomeostasis. The geroneuroprotector CMS121 has a positive effect on energy metabolism in a mouse model of type 2 diabetes. In this new study, researchers Alcir L. Dafre, Saadia Zahid, Jessica Jorge Probst, Antonio Currais, Jingting Yu, David Schubert, and Pamela Maher from Salk Institute for Biological Studies, National University of Sciences and Technology (NUST) and Federal University of Santa Catarina investigated the potential of CMS121 to counteract the metabolic changes observed during the ageing process of wild type mice. “This comprehensive analysis aimed to further understand how CMS121 influences the metabolic landscape, paving the way for potential therapeutic applications beyond its established geroneuroprotective benefits.” Control or CMS121-containing diets were supplied ad libitum for 6 months, and mice were sacrificed at the age of 7 months. Blood, adipose tissue, and liver were analyzed for glucose, lipids, and protein markers of energy metabolism. The CMS121 diet induced a 40% decrease in body weight gain and improved both glucose and lipid indexes. Lower levels of hepatic caspase 1, caspase 3, and NOX4 were observed with CMS121 indicating a lower liver inflammatory status. Adipose tissue from CMS121-treated mice showed increased levels of the transcription factors Nrf1 and TFAM, as well as markers of mitochondrial electron transport complexes, levels of GLUT4 and a higher resting metabolic rate. Metabolomic analysis revealed elevated plasma concentrations of short chain acylcarnitines and butyrate metabolites in mice treated with CMS121. “The diminished de novo lipogenesis, which is associated with increased acetyl-CoA, acylcarnitine, and butyrate metabolite levels, could contribute to safeguarding not only the peripheral system but also the aging brain. By mimicking the effects of ketogenic diets, CMS121 holds promise for metabolic diseases such as obesity and diabetes, since these diets are hard to follow over the long term.” DOI - https://doi.org/10.18632/aging.205673 Corresponding authors - Pamela Maher - pmaher@salk.edu and Alcir L. Dafre - alcir.dafre@ufsc.br Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.205673 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts About Aging-US Aging publishes research papers in all fields of aging research including but not limited, aging from yeast to mammals, cellular senescence, age-related diseases such as cancer and Alzheimer's diseases and their prevention and treatment, anti-aging strategies and drug development and especially the role of signal transduction pathways such as mTOR in aging and potential approaches to modulate these signaling pathways to extend lifespan. The journal aims to promote treatment of age-related diseases by slowing down aging, validation of anti-aging drugs by treating age-related diseases, prevention of cancer by inhibiting aging. Cancer and COVID-19 are age-related diseases. Please visit our website at https://www.Aging-US.com​​ and connect with us: Facebook - https://www.facebook.com/AgingUS/ X - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Spotify - https://open.spotify.com/show/1X4HQQgegjReaf6Mozn6Mc MEDIA@IMPACTJOURNALS.COM

Thomas Rockwell, San Diego State University The Salton Basin was free of significant water between about 100 BCE and 950 CE but has filled to the sill elevation of +13 m six times between ca 950 and 1730 CE. Based on a dense array of cone penetrometer (CPT) soundings across a small sag pond, the Imperial fault is interpreted to have experienced an increase in earthquake rate and accelerated slip in the few hundred years after re-inundation, an observation that is also seen on the southern San Andreas and San Jacinto faults. This regional basin-wide signal of transient accelerated slip in interpreted to result from the effects of increased pore pressure on fault strength resulting from the ~100 m of water load during full lake inundations. If the relationship between co-seismic subsidence in the sag depression and horizontal slip through the sag is even close to constant, the slip rate on the Imperial fault may have exceeded the plate rate for a few hundred years due to excess stored elastic strain that accumulated during the extended dry period prior to ca 950 CE.

Mong-Han Huang, University of Maryland The Ross Ice Shelf (RIS) in Antarctica is the largest ice shelf in the world. As the RIS flows toward the Ross Sea, a buildup of tensile stress due to increasing ice flow velocity develops a series of flow-perpendicular rift zones. Although these rifts are essential in contributing to future calving and reduction in size of the ice shelf, their material properties and mechanical response to external stress in the rift zone scale (~10-100 km) are poorly understood, partly due to a lack of high spatial-temporal scale in-situ observations to characterize key rift processes. Using a deployment of seismometers and GPS stations from the NSF DRRIS project and recently by our team, we further explore the link between seismicity, tidal cycles, and air temperature at two rifts of different ages. We found that icequakes along the major rift zones on RIS are modulated with the oscillating tidal stressing rate, and icequakes have a stronger modulation with stress rate in older rifts. We adopted the theory proposed by Heimisson and Avouac (2020) about seismicity rate due to oscillating stresses for icequakes. On RIS, the characteristic time scale from elevated icequake seismicity rate to background rate is much shorter than the periodicity of the tidal stresses, and therefore the seismicity rate is proportional to the stressing rate. This also suggests that how stress varies in time, rather than the total quantity of stress, has a higher contribution to brittle fractures in ice shelves. Constraining the current behavior of ice shelf rifts and their modulation by oscillating stresses will help inform their future stability in a changing climate.

References Nat Commun. 2022; 13: 4435. Virchows Archiv: European Journal of Pathology, 2020. Vol. 476, Issue 2 Cell Death Differ. 2015 Apr; 22(5): 703–718 Pentangle.1971. Hunting Song. https://youtu.be/CwvpMGc_J-w?si=s6pS2agc5s1N0H2z Falconieri , Cima, Uccellini, Turini, Merula, et al. 1600-1650. Early Italian Baroque Ensemble. https://music.youtube.com/playlist?list=OLAK5uy_mQznM05seareQTK-s3j-1VgS4DHblD5po&si=3mJts6TW3-T2g7k5 --- Send in a voice message: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/message Support this podcast: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/support

Becky Winslow, BS, PharmD Host and Pharmacogenomics Medical Science Liaison; Behnaz Sarrami, MS, PharmD, Host and Pharmacogenomics Medical Science Liaison; Thierry Dervieux, PharmD, PhD, Chief Scientific Officer at Prometheus Laboratories Disclaimer: Behnaz Disclaimer: These are my personal views and opinions, and I am not speaking on behalf of Castle Biosciences, Inc. Becky Disclaimer: These are my personal views and opinions, and I am not speaking on behalf of any other entity.   Transcription:  1 00:00:06,190 --> 00:00:19,620 You're listening to the Pharmacy podcast Network in a world where one size fits all medications dominate the pharmaceutical industry. 2 00:00:20,079 --> 00:00:24,750 Precision medicine brings a ray of hope for those seeking customized health care. 3 00:00:25,350 --> 00:00:32,830 Pharmacists have a unique opportunity to help people in need of specialized testing to ensure medications work as intended. 4 00:00:33,540 --> 00:00:44,680 Welcome to PGX for pharmacists where we unravel the wonders of precision medicine and its potential to revolutionize the way we approach pharmacy care. 5 00:00:45,169 --> 00:00:52,790 Get ready to uncover the secrets behind pharmacogenomics and how it's transforming lives one genome at a time. 6 00:00:52,799 --> 00:00:53,189 Hello, 7 00:00:53,200 --> 00:00:53,950 everyone. 8 00:00:54,159 --> 00:00:55,080 I'm your host, 9 00:00:55,090 --> 00:00:56,389 Doctor Becky Winslow. 10 00:00:56,409 --> 00:01:09,860 And you're listening to the PGX for Pharmacist podcast that we magazine recognized in 2021 as the ninth most listened to genetics podcasts in the world on the PGX for Pharmacist podcast. 11 00:01:09,870 --> 00:01:16,690 We explore all things pharmacogenomics related and our mission is to educate and advocate for PGX. 12 00:01:16,769 --> 00:01:23,849 We accomplish this mission through exclusive interviews with highly qualified and well experienced pharmacogenomics. 13 00:01:23,860 --> 00:01:29,720 Industry leaders such as today's special guest and my name is Baas Sami, 14 00:01:29,730 --> 00:01:32,739 the co-host of PGX for Pharms podcast, 15 00:01:32,750 --> 00:01:33,860 Pharmacogenomics, 16 00:01:33,870 --> 00:01:36,819 medical science liaison and a mentor to pharmacist. 17 00:01:36,889 --> 00:01:40,239 Connect with us on linkedin and let's get a conversation going. 18 00:01:40,269 --> 00:01:46,720 We want to hear from you and how you're impacting pharmacogenomic stakeholders and what you have learned throughout your journey. 19 00:01:48,510 --> 00:01:49,010 Ok. 20 00:01:49,019 --> 00:01:50,819 So without any further ado, 21 00:01:50,839 --> 00:01:54,769 I'm extremely pleased to introduce to our audience. 22 00:01:54,919 --> 00:01:56,059 Doctor Theory Devo, 23 00:01:57,239 --> 00:02:01,129 the Chief Scientific Officer at Prometheus Laboratories, 24 00:02:01,139 --> 00:02:08,139 and Perme Prometheus Laboratories is a reference clinical laboratory that's focused on the diagnosis, 25 00:02:08,149 --> 00:02:13,330 prognosis and monitoring of immune mediated inflammatory diseases. 26 00:02:13,970 --> 00:02:14,229 So, 27 00:02:14,240 --> 00:02:14,649 thank you, 28 00:02:14,660 --> 00:02:17,759 Doctor De for joining us on the podcast. 29 00:02:17,770 --> 00:02:18,589 Today. 30 00:02:18,600 --> 00:02:23,190 I'm excited to share your and Prometheus's story with our audience. 31 00:02:23,649 --> 00:02:25,630 Um in particular, 32 00:02:25,639 --> 00:02:45,369 I'm excited about you sharing your career journey as a farm D phd and Chief scientific officer and designer of the Predictor PK AD A which is a precision guided dosing test for the optimization of Humira Remicade and their bio cylinders. 33 00:02:46,119 --> 00:02:46,449 So, 34 00:02:46,460 --> 00:03:04,220 one of Bana's and my main goals for this episode of the PGX for Pharmacist podcast is to expand our audience's notion of what a PGX test looks like and to inspire them to think bigger than the traditional box PGX test. 35 00:03:04,229 --> 00:03:08,020 Most of them or most of you are uh familiar with. 36 00:03:09,020 --> 00:03:09,429 So, 37 00:03:09,440 --> 00:03:22,179 Doctor D uh I'd like to start the podcast by having our guests um introduce themselves and elaborate on how you are a pharmacogenomics expert. 38 00:03:23,619 --> 00:03:23,800 Yeah, 39 00:03:23,809 --> 00:03:24,250 thank you, 40 00:03:24,259 --> 00:03:25,759 Becky for having me. 41 00:03:25,770 --> 00:03:26,850 Uh uh Yes. 42 00:03:26,860 --> 00:03:27,289 So I am a, 43 00:03:27,300 --> 00:03:30,820 I am a pharmacist uh with uh a family who is a, 44 00:03:30,830 --> 00:03:33,039 a doctorate in pharmacokinetics. 45 00:03:33,539 --> 00:03:44,520 Uh I completed my studies in France and I came as a postdoc uh fellow uh to work in the United States about 20 years ago to work on the pharmacogenomic of anti cancer agents, 46 00:03:44,929 --> 00:03:49,160 uh primarily uh six Maturin as well as methotrexate. 47 00:03:49,169 --> 00:03:50,550 After my post doc, 48 00:03:50,770 --> 00:03:52,960 uh I moved uh in industry for promet. 49 00:03:53,490 --> 00:04:01,429 So I have a large experience in uh uh the implementation of pharmacogenetics testing in immune mediated inflammatory disease. 50 00:04:01,509 --> 00:04:12,550 Our lab Rome was the first uh clinical laboratory in the United States to offer the fin uh metyl transfer genotyping as well as the thin metabolites. 51 00:04:12,559 --> 00:04:13,029 So, 52 00:04:13,050 --> 00:04:21,989 uh uh of uh of 70 publications in the field and uh I'm very uh very excited to have uh to be on the postcard with you uh uh today. 53 00:04:23,660 --> 00:04:24,220 All right. 54 00:04:24,230 --> 00:04:27,359 So thank you for qualifying yourself as an expert. 55 00:04:27,369 --> 00:04:27,619 So, 56 00:04:27,630 --> 00:04:32,839 let's jump right in and delve into your current PGX work. 57 00:04:32,850 --> 00:04:33,279 So, 58 00:04:33,489 --> 00:04:36,540 if you'll tell us um a little about Prometheus, 59 00:04:36,549 --> 00:04:38,000 specifically, 60 00:04:38,010 --> 00:04:40,350 what is Prometheus's mission? 61 00:04:40,359 --> 00:04:43,799 And how are you guys going about accomplishing your mission? 62 00:04:44,760 --> 00:04:44,980 Yeah, 63 00:04:44,989 --> 00:04:45,700 sure. 64 00:04:45,709 --> 00:04:47,459 Uh So Promet is a, 65 00:04:47,470 --> 00:04:52,790 is a reference uh clinical laboratory based in Southern California in San Diego. 66 00:04:53,230 --> 00:04:56,809 Uh The company has been there for uh over 25 years. 67 00:04:56,820 --> 00:05:03,950 We are uh specialize in the differential diagnosis of autoimmune G I disease uh disorders, 68 00:05:04,059 --> 00:05:06,019 uh gastrointestinal disorder, 69 00:05:06,230 --> 00:05:08,619 uh and inflammatory bowel disease. 70 00:05:08,980 --> 00:05:10,299 And over the years, 71 00:05:10,309 --> 00:05:16,600 we have developed a portfolio of a differentiated solution to facilitate the diagnosis, 72 00:05:16,609 --> 00:05:17,470 the prognosis, 73 00:05:17,480 --> 00:05:18,429 the monitoring, 74 00:05:18,660 --> 00:05:21,910 as well as therapy selection with pharmacogenetics testing, 75 00:05:21,920 --> 00:05:24,730 which we are offering to our clinical laboratory. 76 00:05:24,829 --> 00:05:26,350 And most importantly, 77 00:05:26,410 --> 00:05:27,299 uh recently, 78 00:05:27,309 --> 00:05:35,660 we are uh uh developing some uh uh testing solution with the credit topic care test to optimize treatment to uh biologics. 79 00:05:36,470 --> 00:05:37,130 Ok. 80 00:05:37,140 --> 00:05:37,329 Well, 81 00:05:37,339 --> 00:05:37,450 that, 82 00:05:37,459 --> 00:05:38,049 that's great. 83 00:05:38,059 --> 00:05:46,100 Can you also tell us uh about the Prois Library of Precision Medicine Tests for inflammatory bowel disease for patients? 84 00:05:46,109 --> 00:05:49,230 how they benefit medication therapy management. 85 00:05:49,239 --> 00:05:56,429 Stakeholders across the IB DS patients journey from diagnosis to treatment to disease, 86 00:05:56,440 --> 00:06:02,049 monitoring through remission and how they differ from other lab tests for IBD and his treatments. 87 00:06:02,709 --> 00:06:03,209 Yes. 88 00:06:03,220 --> 00:06:03,369 So, 89 00:06:03,380 --> 00:06:04,399 so we uh our, 90 00:06:04,410 --> 00:06:10,100 our clinical laboratory offers some uh highly specialized test to facilitate the, 91 00:06:10,109 --> 00:06:16,779 the diagnostic of uh to facilitate the differential diagnosis of uh uh inflammatory bowel disease. 92 00:06:16,790 --> 00:06:22,359 So we are following uh testing solution with uh serological testing, 93 00:06:22,529 --> 00:06:23,799 for example, 94 00:06:23,809 --> 00:06:38,410 uh uh piana as as as well as uh macro microbial uh uh antibodies that are present uh uh in Crohn's disease as well as uh over uh auto uh auto antibodies that are present in er colitis. 95 00:06:39,339 --> 00:06:43,684 These are conditions that are uh uh somewhat difficult to treat. 96 00:06:43,704 --> 00:06:49,994 Uh And uh we are uh uh offering those tests to uh help uh gastroenterologist. 97 00:06:50,015 --> 00:06:51,114 Uh uh first of all, 98 00:06:51,125 --> 00:07:03,434 to establish a differential diagnosis of IBD as compared to other uh condition typically uh uh irritable bowel syndrome as well as over gastrointestinal disorder. 99 00:07:03,445 --> 00:07:05,635 When the diagnostic is established, 100 00:07:05,910 --> 00:07:31,839 uh we offer uh testing to uh establish a prognosis where we're gonna in inform the clinician that the patient has a more aggressive uh disease that will require more aggressive treatment where uh we can uh provide the testing solution to initiate uh uh the most appropriate therapy for uh for the patient uh with uh a testing where we are uh basically uh you know, 101 00:07:31,850 --> 00:07:36,559 establish de determining some genotyping with the fit transferal genotyping. 102 00:07:36,570 --> 00:07:37,279 For example, 103 00:07:37,290 --> 00:07:40,250 where we can uh indicate that the patient is, 104 00:07:40,260 --> 00:07:45,079 is likely uh to present with a side effect to those medication. 105 00:07:45,399 --> 00:07:46,170 And once you know, 106 00:07:46,179 --> 00:07:47,799 the the treatment is initiative, 107 00:07:47,809 --> 00:08:16,089 we have a portfolio of solution uh to facilitate the monitoring of the disease of the inflammatory bowel disease as well as the dosing optimization with uh uh the answer test which uh measure blood level uh for uh uh monoclonal antibodies that are indicated in the treatment of IB start with starting with Infliximab Adalimumab as well as uh Tein and vidal. 108 00:08:16,980 --> 00:08:24,040 So we have a comprehensive portfolio to uh to surround the clinician with uh a variety of testing solution. 109 00:08:24,049 --> 00:08:30,250 With our goal being to improve the uh the outcome uh of patients with uh with diabetes. 110 00:08:30,260 --> 00:08:34,520 And I think that the pharmacist has a very important role to play from that perspective. 111 00:08:35,179 --> 00:08:36,039 So theory, 112 00:08:36,049 --> 00:08:40,239 could you elaborate for us more on the predictor test? 113 00:08:40,249 --> 00:08:42,758 Um especially since you designed that test, 114 00:08:42,768 --> 00:08:44,218 we'd really like to know, 115 00:08:44,489 --> 00:08:45,039 um you know, 116 00:08:45,049 --> 00:08:49,638 what did that take and what role does it play in your suite of testing? 117 00:08:51,049 --> 00:08:51,270 Yeah. 118 00:08:51,280 --> 00:08:51,890 Sure. 119 00:08:51,900 --> 00:08:52,510 So the, 120 00:08:52,520 --> 00:08:52,570 the, 121 00:08:52,580 --> 00:08:52,989 the, 122 00:08:53,000 --> 00:08:53,229 the, 123 00:08:53,239 --> 00:08:59,960 the predictor test is uh uh is uh is utilized when the patient is receiving treatment. 124 00:09:00,280 --> 00:09:18,190 It's been speci specifically designed to optimize uh biological uh uh disease modifiers such as Infliximab adalimumab that are co therapies in the treatment of inflammatory bowel disease as well as other immune uh mediated inflammatory. 125 00:09:18,200 --> 00:09:21,549 This is what the test does is to you connect the blood specimen, 126 00:09:22,229 --> 00:09:23,049 uh you know, 127 00:09:23,059 --> 00:09:24,750 with dosing information. 128 00:09:25,039 --> 00:09:41,989 And what we do is to uh uh provide guidance uh to clinician with uh respect of the best dose to give in order to achieve the best the level which is the most consistent with uh uh the disease control that needs to be achieved for the patient. 129 00:09:42,169 --> 00:09:43,729 Typically a vast majority, 130 00:09:43,739 --> 00:09:46,159 about two third of a third to two third, 131 00:09:46,169 --> 00:09:54,669 a third of patient uh tend to be uh uh unresponsive uh to this uh very expensive medication. 132 00:09:54,989 --> 00:09:57,960 Uh Not because they don't have the uh you know, 133 00:09:57,969 --> 00:09:59,289 typically because they have a, 134 00:09:59,299 --> 00:09:59,590 you know, 135 00:09:59,599 --> 00:10:05,599 pharmacokinetic uh suboptimal pharmacokinetic uh that makes them uh you know, 136 00:10:05,609 --> 00:10:09,440 unresponsive because uh not enough drug has been given. 137 00:10:09,450 --> 00:10:18,469 So what we do with a predictor test is to basically estimate the pa the pharmacokinetic uh parameter for the patient. 138 00:10:18,750 --> 00:10:24,729 And from then uh re report the best dose uh to give in order to achieve the, 139 00:10:24,760 --> 00:10:31,570 the level which is consistent with the uh the most uh uh effective disease control to be achieved for the patient. 140 00:10:32,169 --> 00:10:33,059 So we are offering, 141 00:10:33,070 --> 00:10:38,049 we have developed a test for the Infliximab as well as Adalimumab which is Humira, 142 00:10:38,909 --> 00:10:41,309 but these are antimony causes factor. 143 00:10:41,460 --> 00:10:49,549 And we are also developing the test for vidur as well as uh is that are widely used also in the treatment of, 144 00:10:49,559 --> 00:10:51,969 of uh inflammatory bubble disease. 145 00:10:51,979 --> 00:10:52,669 Wow, 146 00:10:52,679 --> 00:10:55,450 uh for MET is a suite of tests. 147 00:10:55,460 --> 00:11:00,940 Goes well beyond um the PGX testing that our audience is most familiar with, 148 00:11:01,299 --> 00:11:08,679 uh which typically only includes snips for cyp genes and some pharmacodynamic genes. 149 00:11:08,690 --> 00:11:31,424 This is really exciting um genes and biomarkers related to immunology are not commonly found in what I call the box PGX tests such as those uh made by large uh laboratory manufacturing companies um where the panel has a set number of genes and uh you know, 150 00:11:31,434 --> 00:11:36,054 it was developed by a larger laboratory for maybe smaller laboratories use. 151 00:11:36,729 --> 00:11:39,010 So my understanding, 152 00:11:39,020 --> 00:11:53,729 having talked with you extensively theory is that immunology has fewer PGX test available because it's actually more difficult say than oncology to research and develop tests. 153 00:11:53,739 --> 00:11:54,119 So, 154 00:11:54,130 --> 00:12:00,729 could you elaborate for our audience on the difficulties that are associated with immunology, 155 00:12:00,739 --> 00:12:05,830 research and developing tests uh for immunology versus say oncology? 156 00:12:06,330 --> 00:12:06,530 Yeah, 157 00:12:06,539 --> 00:12:07,049 sure. 158 00:12:07,059 --> 00:12:09,969 So in uh in immunology, 159 00:12:09,979 --> 00:12:11,590 as compared to oncology, 160 00:12:11,599 --> 00:12:17,169 there is no such a thing such as a somatic mutation where for example, 161 00:12:17,179 --> 00:12:18,429 you're gonna have a behalf, 162 00:12:18,440 --> 00:12:18,659 you know, 163 00:12:18,669 --> 00:12:20,349 that indicates that the patient, 164 00:12:20,679 --> 00:12:20,919 you know, 165 00:12:20,929 --> 00:12:25,239 is likely to benefit or not from some treatment in immunology. 166 00:12:25,250 --> 00:12:26,750 This is far more complicated, 167 00:12:26,760 --> 00:12:28,830 complicated for the reason, 168 00:12:29,239 --> 00:12:31,020 starting with uh the fact that, 169 00:12:31,030 --> 00:12:31,179 you know, 170 00:12:31,190 --> 00:12:36,219 the response to this uh medication uh are multifactorial. 171 00:12:36,260 --> 00:12:37,820 And the fact that uh you know, 172 00:12:37,830 --> 00:12:39,380 the mutation that uh the, 173 00:12:39,390 --> 00:12:39,619 the, 174 00:12:39,630 --> 00:12:45,190 the single nucleotide polymorphism in the GM line which uh uh you know, 175 00:12:45,200 --> 00:12:52,429 can potentially associate with uh with outcome uh uh uh uh a lo in advance, 176 00:12:52,440 --> 00:12:58,359 meaning that uh they're gonna have a weak association uh with a response to those medications. 177 00:12:58,369 --> 00:13:09,609 So there is a necessity in immunology to combine multiple genetic polymorphism together in order to achieve uh some uh performances characteristics that will make uh you know, 178 00:13:09,619 --> 00:13:09,859 the, 179 00:13:09,869 --> 00:13:10,380 the, 180 00:13:10,390 --> 00:13:10,520 the, 181 00:13:10,530 --> 00:13:13,219 the clinician uh you know, 182 00:13:13,419 --> 00:13:15,619 uh order the test and most importantly, 183 00:13:15,630 --> 00:13:15,840 the, 184 00:13:15,849 --> 00:13:16,179 the, 185 00:13:16,190 --> 00:13:17,739 the payer to pay for the test. 186 00:13:17,750 --> 00:13:20,469 So this field has been uh you know, 187 00:13:20,479 --> 00:13:20,679 is, 188 00:13:20,690 --> 00:13:21,705 is moving for, 189 00:13:21,715 --> 00:13:21,994 you know, 190 00:13:22,005 --> 00:13:24,575 there are some tests that are being developed right now. 191 00:13:24,924 --> 00:13:39,034 But the biggest challenge is to be able to achieve again the the threshold of uh of performance that makes the test is variable enough uh to be uh again ordered by the clinician and the utilize uh to the benefit of the patient. 192 00:13:39,659 --> 00:13:41,200 I couldn't agree with you more. 193 00:13:41,210 --> 00:13:53,489 Um I've worked on the payer side or market access side of pharmacogenomics and even uh with a box test for which there's um a lot of research data available, 194 00:13:53,500 --> 00:13:55,119 even with those, 195 00:13:55,130 --> 00:13:59,760 it's sometimes difficult uh to get payers um to see the value. 196 00:13:59,770 --> 00:14:01,640 So I absolutely agree with you. 197 00:14:01,940 --> 00:14:03,679 Um The fact that you guys are, 198 00:14:03,690 --> 00:14:11,789 are uh investing in producing the data necessary says a lot about your laboratory. 199 00:14:11,979 --> 00:14:12,559 Um you know, 200 00:14:12,570 --> 00:14:15,380 and how committed you are to this testing and, 201 00:14:15,390 --> 00:14:17,320 and how you believe in the testing. 202 00:14:18,039 --> 00:14:23,640 So I just want to make sure that our audience recognizes that, 203 00:14:24,359 --> 00:14:24,619 you know, 204 00:14:24,630 --> 00:14:31,820 Prometheus doesn't simply provide tests to determine if drugs for IBD will be effective and safe. 205 00:14:32,190 --> 00:14:36,900 Um And maybe what the dose of the drug should be for the patient, 206 00:14:36,909 --> 00:14:40,219 but you have that whole suite of tests. 207 00:14:40,229 --> 00:14:47,380 Um the diagnostic test for the differential diagnosis all the way through remission. 208 00:14:48,030 --> 00:14:53,390 So can you elaborate you elaborated on it some in the previous question? 209 00:14:53,400 --> 00:15:01,229 But um can you tell us the difference between how you had to actually develop the test? 210 00:15:01,520 --> 00:15:02,530 Um You didn't, 211 00:15:02,539 --> 00:15:03,059 in other words, 212 00:15:03,070 --> 00:15:10,659 purchase a test from another manufacturer with the biomarkers that you include in your testing. 213 00:15:10,669 --> 00:15:16,830 Can you elaborate on how much more difficult it is to to develop a test from scratch? 214 00:15:18,169 --> 00:15:18,320 Yeah, 215 00:15:18,330 --> 00:15:18,659 sure. 216 00:15:18,669 --> 00:15:18,809 I mean, 217 00:15:18,820 --> 00:15:22,070 this is this is challenging for multiple and first of all, 218 00:15:22,080 --> 00:15:23,130 you need to have the, 219 00:15:23,419 --> 00:15:27,450 you need to have a clinical data set available with specimen available. 220 00:15:27,460 --> 00:15:28,159 Uh you know, 221 00:15:28,169 --> 00:15:28,780 in front, 222 00:15:28,859 --> 00:15:29,770 obviously, 223 00:15:29,859 --> 00:15:30,890 available. 224 00:15:31,200 --> 00:15:35,890 Uh So we are leveraging a pro meters a large bi bank of specimen. 225 00:15:36,299 --> 00:15:37,190 Uh as I said, 226 00:15:37,200 --> 00:15:39,719 Prometheus has been founded 25 years ago. 227 00:15:39,729 --> 00:15:40,599 So over the, 228 00:15:40,760 --> 00:15:41,919 the past two decades, 229 00:15:41,929 --> 00:15:54,849 we have been able to assemble a large uh substrate of data and specimen which we are uh uh using to uh uh establish our proof of concept if you will. 230 00:15:54,859 --> 00:16:07,559 And then when we have uh identify some genetic polymorphism that are uh adequately uh associated with uh uh disease outcome and disease progression as well as uh toxicity. 231 00:16:07,969 --> 00:16:11,469 Then we are entering validation phase where we are uh you know, 232 00:16:11,570 --> 00:16:14,789 using validation cohorts where we are again, 233 00:16:14,969 --> 00:16:22,630 combining multiple modalities together uh patient demographic as well as genetic marker together with theological marker. 234 00:16:22,640 --> 00:16:23,190 Actually, 235 00:16:23,500 --> 00:16:27,419 to come up with some Multivariate models that are uh again, 236 00:16:27,429 --> 00:16:39,250 bringing the performances characteristics of the pharmacogenomic test or its combination with our marker to the level where it's supposed to be in the first place to meet uh uh payer. 237 00:16:39,650 --> 00:16:41,190 And uh obviously, 238 00:16:41,200 --> 00:16:41,760 again, 239 00:16:41,770 --> 00:16:45,320 the patient uh to the benefit of the patient and to, 240 00:16:45,330 --> 00:16:46,619 to improve its outcome, 241 00:16:46,739 --> 00:16:47,429 the outcome. 242 00:16:48,340 --> 00:16:53,380 I think what you're describing really is the future of pharmacogenomics. 243 00:16:53,390 --> 00:16:54,599 Um In other words, 244 00:16:54,609 --> 00:17:03,419 not singing out pharmacogenomics as you know the end all and be all in the treatment paradigm. 245 00:17:03,559 --> 00:17:08,040 But using a PGX test in combination with, 246 00:17:08,050 --> 00:17:09,069 like you mentioned, 247 00:17:09,250 --> 00:17:11,160 other serological tests, 248 00:17:11,170 --> 00:17:12,959 maybe other genetic tests. 249 00:17:13,290 --> 00:17:14,890 Um But you know, 250 00:17:14,900 --> 00:17:25,869 I think what we want our audience to really wrap their heads around is that PGX is just a piece of that larger puzzle um from diagnosis to treatment to, 251 00:17:25,880 --> 00:17:26,910 to remission. 252 00:17:27,239 --> 00:17:29,880 So I think you guys are absolutely, 253 00:17:29,890 --> 00:17:31,579 you're already in the future. 254 00:17:31,589 --> 00:17:32,849 In other words, 255 00:17:32,859 --> 00:17:33,130 you know, 256 00:17:33,140 --> 00:17:39,689 you're already providing all these different uh tests um like you mentioned to, 257 00:17:39,699 --> 00:17:44,310 to facilitate from diagnosis to remission to remission. 258 00:17:44,660 --> 00:17:45,520 That's correct. 259 00:17:45,530 --> 00:17:45,829 Yeah. 260 00:17:46,349 --> 00:17:55,089 So um you've given us so much great information about uh the tests that that you guys offer. 261 00:17:55,329 --> 00:18:02,060 Can you explain to our audience um your newest test? 262 00:18:02,069 --> 00:18:03,859 Uh the responder test. 263 00:18:04,150 --> 00:18:12,979 And um what role it will play in the paradigm from the diagnosis of IBD to remission? 264 00:18:14,050 --> 00:18:14,260 Yeah, 265 00:18:14,270 --> 00:18:14,760 sure. 266 00:18:14,770 --> 00:18:15,569 So we, 267 00:18:15,579 --> 00:18:18,069 we are doing things a little bit different than other. 268 00:18:18,079 --> 00:18:19,489 We do believe that uh you know, 269 00:18:19,500 --> 00:18:21,449 the it has to be simple. 270 00:18:21,459 --> 00:18:24,189 Uh uh We can obviously construct some very, 271 00:18:24,199 --> 00:18:33,530 very complex algorithm and there are some tests that do that with a very sophisticated machine learning based tools that are available using neural networks, 272 00:18:33,540 --> 00:18:33,729 you know, 273 00:18:33,739 --> 00:18:34,790 those sorts of things. 274 00:18:34,800 --> 00:18:39,729 But we have taken on a different approach where with the responder test, 275 00:18:39,739 --> 00:18:40,329 we are basically, 276 00:18:40,339 --> 00:18:45,160 we are taking an approach which is very simple to address the first and foremost. 277 00:18:45,170 --> 00:18:53,020 Most important aspect of responding uh predicting response to uh to medication is the pharmacokinetics. 278 00:18:53,280 --> 00:19:03,250 Uh You cannot be responding to a drug if the drug is not given and you obviously cannot respond to a drug if the drug is not metabolized adequately. 279 00:19:03,359 --> 00:19:06,349 And this is what we are doing with the responder test. 280 00:19:06,579 --> 00:19:09,010 We are addressing some uh uh you know, 281 00:19:09,020 --> 00:19:11,630 fundamental issues with those uh biologist, 282 00:19:11,640 --> 00:19:12,410 for example, 283 00:19:12,660 --> 00:19:15,170 uh the anti tumor necrosis factors. 284 00:19:15,180 --> 00:19:15,650 So, 285 00:19:15,750 --> 00:19:19,199 such as uh Infliximab and Adalimumab, 286 00:19:19,209 --> 00:19:23,050 it is well known uh that uh uh those drugs, 287 00:19:23,060 --> 00:19:25,689 first of all are prone to immunization. 288 00:19:25,989 --> 00:19:36,949 Uh Meaning that uh uh the drug itself uh is recognized by the immune system uh and digested by the antigen presenting cells. 289 00:19:36,959 --> 00:19:42,209 If you will uh where you gonna have uh uh an immune uh uh response, 290 00:19:42,380 --> 00:19:56,979 uh mounted a cancer drug to produce uh immunogen that will severely impact its pharmacokinetics where the labels will be inadequate to produce uh the desired uh anti-inflammatory effects. 291 00:19:56,989 --> 00:19:57,150 So, 292 00:19:57,160 --> 00:19:58,890 we are with the risk conductors, 293 00:19:58,900 --> 00:20:01,040 we are combining two things together. 294 00:20:01,189 --> 00:20:07,959 First of all is the genetic test itself which uh predicts the risk of immun immunization. 295 00:20:07,969 --> 00:20:18,010 The name of the test is on HL A uh DQ A 105 ali uh that uh uh promotes the presentation of the, 296 00:20:18,020 --> 00:20:19,130 of the, 297 00:20:19,140 --> 00:20:19,910 of Infliximab, 298 00:20:20,010 --> 00:20:20,750 for example, 299 00:20:20,760 --> 00:20:32,130 to the T cell repertoire in order to uh promote the Ronon expansion and the formation of the anti antibodies together with uh another dimension which is the clearance, 300 00:20:32,140 --> 00:20:33,670 which is as important. 301 00:20:33,949 --> 00:20:36,209 Uh One of the key issue is the, 302 00:20:36,219 --> 00:20:36,770 the, 303 00:20:36,780 --> 00:20:41,239 the monoclonal antibodies and uh such as Infliximab or Adalimumab. 304 00:20:41,329 --> 00:20:42,280 But in fact, 305 00:20:42,290 --> 00:20:45,890 a neon antibodies that those drugs are uh you know, 306 00:20:45,900 --> 00:20:49,010 cleared and consumed uh from the, 307 00:20:49,020 --> 00:20:50,949 from the central compartment if you will, 308 00:20:50,959 --> 00:20:54,520 since we are doing a little bit of uh uh pharmacokinetics here. 309 00:20:54,530 --> 00:20:56,020 And uh uh you know, 310 00:20:56,030 --> 00:21:06,670 if the patient present who is uh a high degree of inflammatory burden is gonna have uh the patient will have a high clearance and that's gonna worsen uh in the, 311 00:21:06,680 --> 00:21:13,939 in the presence again of the HL AD Q A 105 genetic marker that uh associate with uh immunization. 312 00:21:13,949 --> 00:21:16,859 So I but this is a combination of both, 313 00:21:17,199 --> 00:21:19,359 these are the predictive factors of pharmacokinetic, 314 00:21:20,359 --> 00:21:38,209 which we combine together where the patient presenting with a risk of immunization as well as accelerated clearance due to the fact that the patient has high inflammation or due to the fact that they are so intrinsic pharmacokinetic properties that makes that the patient, 315 00:21:38,219 --> 00:21:38,300 you know, 316 00:21:38,310 --> 00:21:39,479 will clear the drug very, 317 00:21:39,489 --> 00:21:40,260 very fast. 318 00:21:40,560 --> 00:21:41,670 For example, 319 00:21:41,680 --> 00:21:46,819 due to the inefficient uh recirculation of the drug itself with the new, 320 00:21:46,869 --> 00:21:46,930 the, 321 00:21:46,939 --> 00:21:50,599 the the in the reticular on the system. 322 00:21:50,920 --> 00:21:51,619 Together, 323 00:21:51,630 --> 00:22:02,109 those patients presenting with uh uh together these uh poor prognostic factor of pharmacokinetic origin will tend to be severely underdose, 324 00:22:02,380 --> 00:22:06,719 will not be responding to the drug uh adequately as and they, 325 00:22:06,729 --> 00:22:10,719 and they probably should in the first place if you are able to address uh you know, 326 00:22:10,729 --> 00:22:12,270 the the the exposure. 327 00:22:12,439 --> 00:22:14,079 So what we do with this test, 328 00:22:14,089 --> 00:22:21,640 we will be able to inform uh the clinic that the patient is at risk of achieving, 329 00:22:21,650 --> 00:22:30,829 of achieving suboptimal pharmacokinetics and therefore being able to adjust the dose uh uh to start with more adequately. 330 00:22:30,839 --> 00:22:38,650 So that the the the proper uh exposure is achieved uh during induction to again to, 331 00:22:38,660 --> 00:22:39,040 to, 332 00:22:39,050 --> 00:22:39,380 to, 333 00:22:39,390 --> 00:22:40,890 to achieve a better outcome. 334 00:22:41,040 --> 00:22:47,270 And I think the pharmacist will have a very important role to play here in terms of absolutely, 335 00:22:47,280 --> 00:22:51,239 that information is priceless in the management of these medications. 336 00:22:51,250 --> 00:22:54,930 So thanks for elaborating on that. 337 00:22:56,010 --> 00:22:59,040 And if I may add in our previous conversation, 338 00:22:59,050 --> 00:23:00,810 uh before the recording of podcast, 339 00:23:00,819 --> 00:23:08,869 we had discussed um you guys' robust platform for collaborating with payers to obtain market access and reimbursements for the test. 340 00:23:09,109 --> 00:23:14,109 But without stealing the Thunder from uh Prometheus market access and reimbursement team, 341 00:23:14,199 --> 00:23:22,619 can you please uh briefly detail how Prometheus has proactively worked with payers to solve the problem. 342 00:23:22,920 --> 00:23:27,349 Um the population health problem by building the evidence payers want, 343 00:23:27,359 --> 00:23:41,170 want to see um about your test before you go to the market and then build the test and then hope the payers will see the value and the result and then that will improve the market access and reimbursement for your um precision medicine test. 344 00:23:42,160 --> 00:23:42,339 Yeah. 345 00:23:42,349 --> 00:23:43,180 So briefly I can, 346 00:23:43,189 --> 00:23:43,579 I'm, 347 00:23:43,589 --> 00:23:46,619 I'm probably not the right person to answer that question. 348 00:23:46,630 --> 00:23:47,369 We have a very, 349 00:23:47,380 --> 00:23:52,400 very efficient market access group uh uh pro meters that does a splendid job. 350 00:23:52,410 --> 00:23:59,780 But uh uh uh what I can tell you that we have an evidence uh uh development plan in place where we, 351 00:23:59,790 --> 00:24:14,000 we are establishing the clinical utility of our testing solution by demonstrating uh the payer value uh with respect of uh patient management and uh uh and the, 352 00:24:14,010 --> 00:24:16,630 and the impact of our technology on the, 353 00:24:16,640 --> 00:24:18,119 on physician behavior. 354 00:24:18,430 --> 00:24:21,319 Uh We have uh uh already uh you know, 355 00:24:21,329 --> 00:24:25,160 commercialized uh two of those tests for which we have initiated, 356 00:24:25,170 --> 00:24:29,040 initiated the Power studies uh that uh uh you know, 357 00:24:29,050 --> 00:24:32,000 already provide uh you know, 358 00:24:32,104 --> 00:24:34,484 differentiated and the value to, 359 00:24:34,494 --> 00:24:35,915 to the payer where we are, 360 00:24:35,925 --> 00:24:36,025 the, 361 00:24:36,035 --> 00:24:46,005 the clinicians are basically using our technology to make treatment decision uh as well as uh some prospective clinicality study which we are initiating, 362 00:24:46,145 --> 00:24:47,555 initiating to. 363 00:24:47,564 --> 00:24:48,574 Um uh again, 364 00:24:48,584 --> 00:24:49,425 demonstrate the, 365 00:24:49,435 --> 00:24:49,915 the, 366 00:24:49,925 --> 00:24:50,244 the, 367 00:24:50,255 --> 00:24:53,594 the payer value you uh uh we can certainly follow up with, 368 00:24:53,604 --> 00:24:58,755 uh you can certainly follow up with our market access group uh uh as appropriate there. 369 00:24:58,765 --> 00:25:00,765 Uh They can fill you with more information. 370 00:25:01,349 --> 00:25:01,589 No, 371 00:25:01,599 --> 00:25:02,520 that totally makes sense. 372 00:25:02,530 --> 00:25:03,310 That totally makes sense. 373 00:25:03,319 --> 00:25:10,890 But um we're excited that you're also farm d So how did you get to this role of outside the box path? 374 00:25:10,900 --> 00:25:11,550 There? 375 00:25:11,640 --> 00:25:17,530 There may be a pharmacist student or pharmacist wanting to switch or transition into a role such as yours, 376 00:25:17,540 --> 00:25:19,609 which is a Chief Scientific Officer. 377 00:25:19,619 --> 00:25:20,609 I want to learn more. 378 00:25:20,619 --> 00:25:23,920 So how would you um can you talk a little bit about that? 379 00:25:24,560 --> 00:25:24,780 Well, 380 00:25:24,790 --> 00:25:26,270 we are clinical laboratories. 381 00:25:26,280 --> 00:25:29,400 So in order to uh uh to be in my role, 382 00:25:29,410 --> 00:25:34,020 you need to have uh uh you need to have expertise in clinical laboratory science. 383 00:25:34,030 --> 00:25:36,140 So for the students is basically, 384 00:25:36,150 --> 00:25:36,300 you know, 385 00:25:36,310 --> 00:25:40,770 to do the family degree and then complete the family degree with uh a doctorate, 386 00:25:40,780 --> 00:25:40,930 you know, 387 00:25:40,939 --> 00:25:44,260 which is uh focus on clinical laboratory science. 388 00:25:44,270 --> 00:25:46,079 So you can achieve uh uh you know, 389 00:25:46,089 --> 00:25:47,640 the all the elements you need to be, 390 00:25:47,650 --> 00:25:48,219 for example, 391 00:25:48,229 --> 00:25:53,189 board certified uh as uh as as medical laboratory director. 392 00:25:53,199 --> 00:25:55,160 So you can uh uh so, 393 00:25:55,170 --> 00:25:55,589 uh yeah, 394 00:25:55,599 --> 00:25:56,030 this is, 395 00:25:56,040 --> 00:25:56,400 this is, 396 00:25:56,410 --> 00:25:57,209 this is uh you know, 397 00:25:57,219 --> 00:25:59,160 a great opportunity I think for pharmacies, 398 00:25:59,170 --> 00:26:10,800 there is an absolute need to uh have the clinical pharmacist provide uh uh drug information to healthcare professional as well as uh assist patient with the monitoring of their disease, 399 00:26:10,810 --> 00:26:15,229 the effectiveness of the therapy and um and uh you know, 400 00:26:15,239 --> 00:26:16,060 monitoring the, 401 00:26:16,069 --> 00:26:20,969 the side effect and the toxicity from uh from those uh those medication. 402 00:26:24,650 --> 00:26:24,959 Well, 403 00:26:24,969 --> 00:26:32,119 the I know our audience is going to have uh additional questions for you. 404 00:26:32,130 --> 00:26:32,540 I mean, 405 00:26:32,989 --> 00:26:35,609 you've provided them with so much great information, 406 00:26:35,619 --> 00:26:44,959 but it's only the beginning of what they could possibly learn um about um the testing that you do for IBD and, 407 00:26:44,969 --> 00:26:46,729 and even your career path. 408 00:26:47,050 --> 00:26:47,530 So, 409 00:26:47,540 --> 00:26:49,300 if you wouldn't mind telling us, 410 00:26:49,310 --> 00:26:51,359 um because we have to wrap up, 411 00:26:51,369 --> 00:26:52,670 unfortunately, 412 00:26:53,150 --> 00:26:55,810 this episode of the podcast, 413 00:26:55,819 --> 00:27:00,250 uh could you tell us how our audience members might be able to contact you directly. 414 00:27:01,260 --> 00:27:01,449 Yeah, 415 00:27:01,459 --> 00:27:07,079 I can be contacted on my uh on my email at TT W at como slab dot com. 416 00:27:07,949 --> 00:27:08,810 All right. 417 00:27:09,069 --> 00:27:09,300 Well, 418 00:27:09,310 --> 00:27:14,290 thank you again so much uh for joining us on this episode. 419 00:27:14,300 --> 00:27:15,290 We really, 420 00:27:15,300 --> 00:27:29,530 really hope that our listeners um ideas of not only what PGX can be but how PGX can be utilized in a comprehensive testing suite. 421 00:27:29,709 --> 00:27:35,670 We really hope that our a our audience will um listen in and learn this information. 422 00:27:36,280 --> 00:27:37,869 Um And to our audience, 423 00:27:37,880 --> 00:27:39,439 thank you for tuning in. 424 00:27:39,449 --> 00:27:42,619 We really hope that you've learned from this episode. 425 00:27:43,130 --> 00:27:46,339 Uh We do a whole lot of PG Xing here on this podcast. 426 00:27:46,349 --> 00:27:48,380 We talk about PGX Science, 427 00:27:48,390 --> 00:27:52,030 clinical application and the business of PGX. 428 00:27:52,260 --> 00:27:54,880 So we'd love to hear about from you. 429 00:27:55,099 --> 00:27:56,479 I love to hear from you. 430 00:27:56,489 --> 00:27:58,439 Um What can we teach you? 431 00:27:58,449 --> 00:28:00,920 What more can we teach you through our podcast? 432 00:28:00,930 --> 00:28:12,349 So please drop us a message on linkedin and let us know and please share this link to this podcast link episode with everyone so they can tune in and listen to the PGX for promises podcast. 433 00:28:12,520 --> 00:28:15,369 Leave us a review on Apple podcast or Spotify. 434 00:28:15,459 --> 00:28:18,130 And you can also visit us on PGX four, 435 00:28:18,140 --> 00:28:22,989 the number four Rx dot com to listen to all our other episodes. 436 00:28:23,000 --> 00:28:23,079 Well, 437 00:28:23,089 --> 00:28:23,790 thank you. 438 00:28:24,199 --> 00:28:28,750 Thanks for your interest in PGX and for spending some time with us. 439 00:28:28,760 --> 00:28:35,670 Please share this podcast and leave us a review on Apple podcasts or Spotify for all of our episodes. 440 00:28:35,680 --> 00:28:39,390 Please visit PGX for Rx dot com. 441 00:28:39,569 --> 00:28:43,380 That's PGX for Rx dot com.  

Becky Winslow, BS, PharmD Host and Pharmacogenomics Medical Science Liaison; Behnaz Sarrami, MS, PharmD, Host and Pharmacogenomics Medical Science Liaison; Thierry Dervieux, PharmD, PhD, Chief Scientific Officer at Prometheus Laboratories In this episode of the PGX for Pharmacists Podcast, Dr. Thierry Dervieux, Dr. Behnaz Sarrami, and I discuss Dr. Dervieux's career as a PharmD, PhD, and chief scientific officer who has designed a pharmacogenomics test prescribers may use to optimize biosimilars for autoimmune gastrointestinal diseases. Dr. Dervieux will illustrate to our audience pharmacogenomics' potential beyond Tier 1 and 2 genetic testing by describing the clinical validity and utility of his laboratory's suite of tests in the autoimmune gastrointestinal disease diagnosis and treatment market. Behnaz and I hope this episode will inspire pharmacists interested in pharmacogenomics to think beyond the boxed PGx test most laboratories offer when they think about PGx and consider all the biological systems in which genetics impacts drugs' efficacy and safety. Disclaimer: Behnaz Disclaimer: These are my personal views and opinions, and I am not speaking on behalf of Castle Biosciences, Inc. Becky Disclaimer: These are my personal views and opinions, and I am not speaking on behalf of any other entity.   Transcription: 1 00:00:06,190 --> 00:00:19,620 You're listening to the Pharmacy podcast Network in a world where one size fits all medications dominate the pharmaceutical industry. 2 00:00:20,079 --> 00:00:24,750 Precision medicine brings a ray of hope for those seeking customized health care. 3 00:00:25,350 --> 00:00:32,830 Pharmacists have a unique opportunity to help people in need of specialized testing to ensure medications work as intended. 4 00:00:33,540 --> 00:00:44,680 Welcome to PGX for pharmacists where we unravel the wonders of precision medicine and its potential to revolutionize the way we approach pharmacy care. 5 00:00:45,169 --> 00:00:52,790 Get ready to uncover the secrets behind pharmacogenomics and how it's transforming lives one genome at a time. 6 00:00:52,799 --> 00:00:53,189 Hello, 7 00:00:53,200 --> 00:00:53,950 everyone. 8 00:00:54,159 --> 00:00:55,080 I'm your host, 9 00:00:55,090 --> 00:00:56,389 Doctor Becky Winslow. 10 00:00:56,409 --> 00:01:09,860 And you're listening to the PGX for Pharmacist podcast that we magazine recognized in 2021 as the ninth most listened to genetics podcasts in the world on the PGX for Pharmacist podcast. 11 00:01:09,870 --> 00:01:16,690 We explore all things pharmacogenomics related and our mission is to educate and advocate for PGX. 12 00:01:16,769 --> 00:01:23,849 We accomplish this mission through exclusive interviews with highly qualified and well experienced pharmacogenomics. 13 00:01:23,860 --> 00:01:29,720 Industry leaders such as today's special guest and my name is Baas Sami, 14 00:01:29,730 --> 00:01:32,739 the co-host of PGX for Pharms podcast, 15 00:01:32,750 --> 00:01:33,860 Pharmacogenomics, 16 00:01:33,870 --> 00:01:36,819 medical science liaison and a mentor to pharmacist. 17 00:01:36,889 --> 00:01:40,239 Connect with us on linkedin and let's get a conversation going. 18 00:01:40,269 --> 00:01:46,720 We want to hear from you and how you're impacting pharmacogenomic stakeholders and what you have learned throughout your journey. 19 00:01:48,510 --> 00:01:49,010 Ok. 20 00:01:49,019 --> 00:01:50,819 So without any further ado, 21 00:01:50,839 --> 00:01:54,769 I'm extremely pleased to introduce to our audience. 22 00:01:54,919 --> 00:01:56,059 Doctor Theory Devo, 23 00:01:57,239 --> 00:02:01,129 the Chief Scientific Officer at Prometheus Laboratories, 24 00:02:01,139 --> 00:02:08,139 and Perme Prometheus Laboratories is a reference clinical laboratory that's focused on the diagnosis, 25 00:02:08,149 --> 00:02:13,330 prognosis and monitoring of immune mediated inflammatory diseases. 26 00:02:13,970 --> 00:02:14,229 So, 27 00:02:14,240 --> 00:02:14,649 thank you, 28 00:02:14,660 --> 00:02:17,759 Doctor De for joining us on the podcast. 29 00:02:17,770 --> 00:02:18,589 Today. 30 00:02:18,600 --> 00:02:23,190 I'm excited to share your and Prometheus's story with our audience. 31 00:02:23,649 --> 00:02:25,630 Um in particular, 32 00:02:25,639 --> 00:02:45,369 I'm excited about you sharing your career journey as a farm D phd and Chief scientific officer and designer of the Predictor PK AD A which is a precision guided dosing test for the optimization of Humira Remicade and their bio cylinders. 33 00:02:46,119 --> 00:02:46,449 So, 34 00:02:46,460 --> 00:03:04,220 one of Bana's and my main goals for this episode of the PGX for Pharmacist podcast is to expand our audience's notion of what a PGX test looks like and to inspire them to think bigger than the traditional box PGX test. 35 00:03:04,229 --> 00:03:08,020 Most of them or most of you are uh familiar with. 36 00:03:09,020 --> 00:03:09,429 So, 37 00:03:09,440 --> 00:03:22,179 Doctor D uh I'd like to start the podcast by having our guests um introduce themselves and elaborate on how you are a pharmacogenomics expert. 38 00:03:23,619 --> 00:03:23,800 Yeah, 39 00:03:23,809 --> 00:03:24,250 thank you, 40 00:03:24,259 --> 00:03:25,759 Becky for having me. 41 00:03:25,770 --> 00:03:26,850 Uh uh Yes. 42 00:03:26,860 --> 00:03:27,289 So I am a, 43 00:03:27,300 --> 00:03:30,820 I am a pharmacist uh with uh a family who is a, 44 00:03:30,830 --> 00:03:33,039 a doctorate in pharmacokinetics. 45 00:03:33,539 --> 00:03:44,520 Uh I completed my studies in France and I came as a postdoc uh fellow uh to work in the United States about 20 years ago to work on the pharmacogenomic of anti cancer agents, 46 00:03:44,929 --> 00:03:49,160 uh primarily uh six Maturin as well as methotrexate. 47 00:03:49,169 --> 00:03:50,550 After my post doc, 48 00:03:50,770 --> 00:03:52,960 uh I moved uh in industry for promet. 49 00:03:53,490 --> 00:04:01,429 So I have a large experience in uh uh the implementation of pharmacogenetics testing in immune mediated inflammatory disease. 50 00:04:01,509 --> 00:04:12,550 Our lab Rome was the first uh clinical laboratory in the United States to offer the fin uh metyl transfer genotyping as well as the thin metabolites. 51 00:04:12,559 --> 00:04:13,029 So, 52 00:04:13,050 --> 00:04:21,989 uh uh of uh of 70 publications in the field and uh I'm very uh very excited to have uh to be on the postcard with you uh uh today. 53 00:04:23,660 --> 00:04:24,220 All right. 54 00:04:24,230 --> 00:04:27,359 So thank you for qualifying yourself as an expert. 55 00:04:27,369 --> 00:04:27,619 So, 56 00:04:27,630 --> 00:04:32,839 let's jump right in and delve into your current PGX work. 57 00:04:32,850 --> 00:04:33,279 So, 58 00:04:33,489 --> 00:04:36,540 if you'll tell us um a little about Prometheus, 59 00:04:36,549 --> 00:04:38,000 specifically, 60 00:04:38,010 --> 00:04:40,350 what is Prometheus's mission? 61 00:04:40,359 --> 00:04:43,799 And how are you guys going about accomplishing your mission? 62 00:04:44,760 --> 00:04:44,980 Yeah, 63 00:04:44,989 --> 00:04:45,700 sure. 64 00:04:45,709 --> 00:04:47,459 Uh So Promet is a, 65 00:04:47,470 --> 00:04:52,790 is a reference uh clinical laboratory based in Southern California in San Diego. 66 00:04:53,230 --> 00:04:56,809 Uh The company has been there for uh over 25 years. 67 00:04:56,820 --> 00:05:03,950 We are uh specialize in the differential diagnosis of autoimmune G I disease uh disorders, 68 00:05:04,059 --> 00:05:06,019 uh gastrointestinal disorder, 69 00:05:06,230 --> 00:05:08,619 uh and inflammatory bowel disease. 70 00:05:08,980 --> 00:05:10,299 And over the years, 71 00:05:10,309 --> 00:05:16,600 we have developed a portfolio of a differentiated solution to facilitate the diagnosis, 72 00:05:16,609 --> 00:05:17,470 the prognosis, 73 00:05:17,480 --> 00:05:18,429 the monitoring, 74 00:05:18,660 --> 00:05:21,910 as well as therapy selection with pharmacogenetics testing, 75 00:05:21,920 --> 00:05:24,730 which we are offering to our clinical laboratory. 76 00:05:24,829 --> 00:05:26,350 And most importantly, 77 00:05:26,410 --> 00:05:27,299 uh recently, 78 00:05:27,309 --> 00:05:35,660 we are uh uh developing some uh uh testing solution with the credit topic care test to optimize treatment to uh biologics. 79 00:05:36,470 --> 00:05:37,130 Ok. 80 00:05:37,140 --> 00:05:37,329 Well, 81 00:05:37,339 --> 00:05:37,450 that, 82 00:05:37,459 --> 00:05:38,049 that's great. 83 00:05:38,059 --> 00:05:46,100 Can you also tell us uh about the Prois Library of Precision Medicine Tests for inflammatory bowel disease for patients? 84 00:05:46,109 --> 00:05:49,230 how they benefit medication therapy management. 85 00:05:49,239 --> 00:05:56,429 Stakeholders across the IB DS patients journey from diagnosis to treatment to disease, 86 00:05:56,440 --> 00:06:02,049 monitoring through remission and how they differ from other lab tests for IBD and his treatments. 87 00:06:02,709 --> 00:06:03,209 Yes. 88 00:06:03,220 --> 00:06:03,369 So, 89 00:06:03,380 --> 00:06:04,399 so we uh our, 90 00:06:04,410 --> 00:06:10,100 our clinical laboratory offers some uh highly specialized test to facilitate the, 91 00:06:10,109 --> 00:06:16,779 the diagnostic of uh to facilitate the differential diagnosis of uh uh inflammatory bowel disease. 92 00:06:16,790 --> 00:06:22,359 So we are following uh testing solution with uh serological testing, 93 00:06:22,529 --> 00:06:23,799 for example, 94 00:06:23,809 --> 00:06:38,410 uh uh piana as as as well as uh macro microbial uh uh antibodies that are present uh uh in Crohn's disease as well as uh over uh auto uh auto antibodies that are present in er colitis. 95 00:06:39,339 --> 00:06:43,684 These are conditions that are uh uh somewhat difficult to treat. 96 00:06:43,704 --> 00:06:49,994 Uh And uh we are uh uh offering those tests to uh help uh gastroenterologist. 97 00:06:50,015 --> 00:06:51,114 Uh uh first of all, 98 00:06:51,125 --> 00:07:03,434 to establish a differential diagnosis of IBD as compared to other uh condition typically uh uh irritable bowel syndrome as well as over gastrointestinal disorder. 99 00:07:03,445 --> 00:07:05,635 When the diagnostic is established, 100 00:07:05,910 --> 00:07:31,839 uh we offer uh testing to uh establish a prognosis where we're gonna in inform the clinician that the patient has a more aggressive uh disease that will require more aggressive treatment where uh we can uh provide the testing solution to initiate uh uh the most appropriate therapy for uh for the patient uh with uh a testing where we are uh basically uh you know, 101 00:07:31,850 --> 00:07:36,559 establish de determining some genotyping with the fit transferal genotyping. 102 00:07:36,570 --> 00:07:37,279 For example, 103 00:07:37,290 --> 00:07:40,250 where we can uh indicate that the patient is, 104 00:07:40,260 --> 00:07:45,079 is likely uh to present with a side effect to those medication. 105 00:07:45,399 --> 00:07:46,170 And once you know, 106 00:07:46,179 --> 00:07:47,799 the the treatment is initiative, 107 00:07:47,809 --> 00:08:16,089 we have a portfolio of solution uh to facilitate the monitoring of the disease of the inflammatory bowel disease as well as the dosing optimization with uh uh the answer test which uh measure blood level uh for uh uh monoclonal antibodies that are indicated in the treatment of IB start with starting with Infliximab Adalimumab as well as uh Tein and vidal. 108 00:08:16,980 --> 00:08:24,040 So we have a comprehensive portfolio to uh to surround the clinician with uh a variety of testing solution. 109 00:08:24,049 --> 00:08:30,250 With our goal being to improve the uh the outcome uh of patients with uh with diabetes. 110 00:08:30,260 --> 00:08:34,520 And I think that the pharmacist has a very important role to play from that perspective. 111 00:08:35,179 --> 00:08:36,039 So theory, 112 00:08:36,049 --> 00:08:40,239 could you elaborate for us more on the predictor test? 113 00:08:40,249 --> 00:08:42,758 Um especially since you designed that test, 114 00:08:42,768 --> 00:08:44,218 we'd really like to know, 115 00:08:44,489 --> 00:08:45,039 um you know, 116 00:08:45,049 --> 00:08:49,638 what did that take and what role does it play in your suite of testing? 117 00:08:51,049 --> 00:08:51,270 Yeah. 118 00:08:51,280 --> 00:08:51,890 Sure. 119 00:08:51,900 --> 00:08:52,510 So the, 120 00:08:52,520 --> 00:08:52,570 the, 121 00:08:52,580 --> 00:08:52,989 the, 122 00:08:53,000 --> 00:08:53,229 the, 123 00:08:53,239 --> 00:08:59,960 the predictor test is uh uh is uh is utilized when the patient is receiving treatment. 124 00:09:00,280 --> 00:09:18,190 It's been speci specifically designed to optimize uh biological uh uh disease modifiers such as Infliximab adalimumab that are co therapies in the treatment of inflammatory bowel disease as well as other immune uh mediated inflammatory. 125 00:09:18,200 --> 00:09:21,549 This is what the test does is to you connect the blood specimen, 126 00:09:22,229 --> 00:09:23,049 uh you know, 127 00:09:23,059 --> 00:09:24,750 with dosing information. 128 00:09:25,039 --> 00:09:41,989 And what we do is to uh uh provide guidance uh to clinician with uh respect of the best dose to give in order to achieve the best the level which is the most consistent with uh uh the disease control that needs to be achieved for the patient. 129 00:09:42,169 --> 00:09:43,729 Typically a vast majority, 130 00:09:43,739 --> 00:09:46,159 about two third of a third to two third, 131 00:09:46,169 --> 00:09:54,669 a third of patient uh tend to be uh uh unresponsive uh to this uh very expensive medication. 132 00:09:54,989 --> 00:09:57,960 Uh Not because they don't have the uh you know, 133 00:09:57,969 --> 00:09:59,289 typically because they have a, 134 00:09:59,299 --> 00:09:59,590 you know, 135 00:09:59,599 --> 00:10:05,599 pharmacokinetic uh suboptimal pharmacokinetic uh that makes them uh you know, 136 00:10:05,609 --> 00:10:09,440 unresponsive because uh not enough drug has been given. 137 00:10:09,450 --> 00:10:18,469 So what we do with a predictor test is to basically estimate the pa the pharmacokinetic uh parameter for the patient. 138 00:10:18,750 --> 00:10:24,729 And from then uh re report the best dose uh to give in order to achieve the, 139 00:10:24,760 --> 00:10:31,570 the level which is consistent with the uh the most uh uh effective disease control to be achieved for the patient. 140 00:10:32,169 --> 00:10:33,059 So we are offering, 141 00:10:33,070 --> 00:10:38,049 we have developed a test for the Infliximab as well as Adalimumab which is Humira, 142 00:10:38,909 --> 00:10:41,309 but these are antimony causes factor. 143 00:10:41,460 --> 00:10:49,549 And we are also developing the test for vidur as well as uh is that are widely used also in the treatment of, 144 00:10:49,559 --> 00:10:51,969 of uh inflammatory bubble disease. 145 00:10:51,979 --> 00:10:52,669 Wow, 146 00:10:52,679 --> 00:10:55,450 uh for MET is a suite of tests. 147 00:10:55,460 --> 00:11:00,940 Goes well beyond um the PGX testing that our audience is most familiar with, 148 00:11:01,299 --> 00:11:08,679 uh which typically only includes snips for cyp genes and some pharmacodynamic genes. 149 00:11:08,690 --> 00:11:31,424 This is really exciting um genes and biomarkers related to immunology are not commonly found in what I call the box PGX tests such as those uh made by large uh laboratory manufacturing companies um where the panel has a set number of genes and uh you know, 150 00:11:31,434 --> 00:11:36,054 it was developed by a larger laboratory for maybe smaller laboratories use. 151 00:11:36,729 --> 00:11:39,010 So my understanding, 152 00:11:39,020 --> 00:11:53,729 having talked with you extensively theory is that immunology has fewer PGX test available because it's actually more difficult say than oncology to research and develop tests. 153 00:11:53,739 --> 00:11:54,119 So, 154 00:11:54,130 --> 00:12:00,729 could you elaborate for our audience on the difficulties that are associated with immunology, 155 00:12:00,739 --> 00:12:05,830 research and developing tests uh for immunology versus say oncology? 156 00:12:06,330 --> 00:12:06,530 Yeah, 157 00:12:06,539 --> 00:12:07,049 sure. 158 00:12:07,059 --> 00:12:09,969 So in uh in immunology, 159 00:12:09,979 --> 00:12:11,590 as compared to oncology, 160 00:12:11,599 --> 00:12:17,169 there is no such a thing such as a somatic mutation where for example, 161 00:12:17,179 --> 00:12:18,429 you're gonna have a behalf, 162 00:12:18,440 --> 00:12:18,659 you know, 163 00:12:18,669 --> 00:12:20,349 that indicates that the patient, 164 00:12:20,679 --> 00:12:20,919 you know, 165 00:12:20,929 --> 00:12:25,239 is likely to benefit or not from some treatment in immunology. 166 00:12:25,250 --> 00:12:26,750 This is far more complicated, 167 00:12:26,760 --> 00:12:28,830 complicated for the reason, 168 00:12:29,239 --> 00:12:31,020 starting with uh the fact that, 169 00:12:31,030 --> 00:12:31,179 you know, 170 00:12:31,190 --> 00:12:36,219 the response to this uh medication uh are multifactorial. 171 00:12:36,260 --> 00:12:37,820 And the fact that uh you know, 172 00:12:37,830 --> 00:12:39,380 the mutation that uh the, 173 00:12:39,390 --> 00:12:39,619 the, 174 00:12:39,630 --> 00:12:45,190 the single nucleotide polymorphism in the GM line which uh uh you know, 175 00:12:45,200 --> 00:12:52,429 can potentially associate with uh with outcome uh uh uh uh a lo in advance, 176 00:12:52,440 --> 00:12:58,359 meaning that uh they're gonna have a weak association uh with a response to those medications. 177 00:12:58,369 --> 00:13:09,609 So there is a necessity in immunology to combine multiple genetic polymorphism together in order to achieve uh some uh performances characteristics that will make uh you know, 178 00:13:09,619 --> 00:13:09,859 the, 179 00:13:09,869 --> 00:13:10,380 the, 180 00:13:10,390 --> 00:13:10,520 the, 181 00:13:10,530 --> 00:13:13,219 the clinician uh you know, 182 00:13:13,419 --> 00:13:15,619 uh order the test and most importantly, 183 00:13:15,630 --> 00:13:15,840 the, 184 00:13:15,849 --> 00:13:16,179 the, 185 00:13:16,190 --> 00:13:17,739 the payer to pay for the test. 186 00:13:17,750 --> 00:13:20,469 So this field has been uh you know, 187 00:13:20,479 --> 00:13:20,679 is, 188 00:13:20,690 --> 00:13:21,705 is moving for, 189 00:13:21,715 --> 00:13:21,994 you know, 190 00:13:22,005 --> 00:13:24,575 there are some tests that are being developed right now. 191 00:13:24,924 --> 00:13:39,034 But the biggest challenge is to be able to achieve again the the threshold of uh of performance that makes the test is variable enough uh to be uh again ordered by the clinician and the utilize uh to the benefit of the patient. 192 00:13:39,659 --> 00:13:41,200 I couldn't agree with you more. 193 00:13:41,210 --> 00:13:53,489 Um I've worked on the payer side or market access side of pharmacogenomics and even uh with a box test for which there's um a lot of research data available, 194 00:13:53,500 --> 00:13:55,119 even with those, 195 00:13:55,130 --> 00:13:59,760 it's sometimes difficult uh to get payers um to see the value. 196 00:13:59,770 --> 00:14:01,640 So I absolutely agree with you. 197 00:14:01,940 --> 00:14:03,679 Um The fact that you guys are, 198 00:14:03,690 --> 00:14:11,789 are uh investing in producing the data necessary says a lot about your laboratory. 199 00:14:11,979 --> 00:14:12,559 Um you know, 200 00:14:12,570 --> 00:14:15,380 and how committed you are to this testing and, 201 00:14:15,390 --> 00:14:17,320 and how you believe in the testing. 202 00:14:18,039 --> 00:14:23,640 So I just want to make sure that our audience recognizes that, 203 00:14:24,359 --> 00:14:24,619 you know, 204 00:14:24,630 --> 00:14:31,820 Prometheus doesn't simply provide tests to determine if drugs for IBD will be effective and safe. 205 00:14:32,190 --> 00:14:36,900 Um And maybe what the dose of the drug should be for the patient, 206 00:14:36,909 --> 00:14:40,219 but you have that whole suite of tests. 207 00:14:40,229 --> 00:14:47,380 Um the diagnostic test for the differential diagnosis all the way through remission. 208 00:14:48,030 --> 00:14:53,390 So can you elaborate you elaborated on it some in the previous question? 209 00:14:53,400 --> 00:15:01,229 But um can you tell us the difference between how you had to actually develop the test? 210 00:15:01,520 --> 00:15:02,530 Um You didn't, 211 00:15:02,539 --> 00:15:03,059 in other words, 212 00:15:03,070 --> 00:15:10,659 purchase a test from another manufacturer with the biomarkers that you include in your testing. 213 00:15:10,669 --> 00:15:16,830 Can you elaborate on how much more difficult it is to to develop a test from scratch? 214 00:15:18,169 --> 00:15:18,320 Yeah, 215 00:15:18,330 --> 00:15:18,659 sure. 216 00:15:18,669 --> 00:15:18,809 I mean, 217 00:15:18,820 --> 00:15:22,070 this is this is challenging for multiple and first of all, 218 00:15:22,080 --> 00:15:23,130 you need to have the, 219 00:15:23,419 --> 00:15:27,450 you need to have a clinical data set available with specimen available. 220 00:15:27,460 --> 00:15:28,159 Uh you know, 221 00:15:28,169 --> 00:15:28,780 in front, 222 00:15:28,859 --> 00:15:29,770 obviously, 223 00:15:29,859 --> 00:15:30,890 available. 224 00:15:31,200 --> 00:15:35,890 Uh So we are leveraging a pro meters a large bi bank of specimen. 225 00:15:36,299 --> 00:15:37,190 Uh as I said, 226 00:15:37,200 --> 00:15:39,719 Prometheus has been founded 25 years ago. 227 00:15:39,729 --> 00:15:40,599 So over the, 228 00:15:40,760 --> 00:15:41,919 the past two decades, 229 00:15:41,929 --> 00:15:54,849 we have been able to assemble a large uh substrate of data and specimen which we are uh uh using to uh uh establish our proof of concept if you will. 230 00:15:54,859 --> 00:16:07,559 And then when we have uh identify some genetic polymorphism that are uh adequately uh associated with uh uh disease outcome and disease progression as well as uh toxicity. 231 00:16:07,969 --> 00:16:11,469 Then we are entering validation phase where we are uh you know, 232 00:16:11,570 --> 00:16:14,789 using validation cohorts where we are again, 233 00:16:14,969 --> 00:16:22,630 combining multiple modalities together uh patient demographic as well as genetic marker together with theological marker. 234 00:16:22,640 --> 00:16:23,190 Actually, 235 00:16:23,500 --> 00:16:27,419 to come up with some Multivariate models that are uh again, 236 00:16:27,429 --> 00:16:39,250 bringing the performances characteristics of the pharmacogenomic test or its combination with our marker to the level where it's supposed to be in the first place to meet uh uh payer. 237 00:16:39,650 --> 00:16:41,190 And uh obviously, 238 00:16:41,200 --> 00:16:41,760 again, 239 00:16:41,770 --> 00:16:45,320 the patient uh to the benefit of the patient and to, 240 00:16:45,330 --> 00:16:46,619 to improve its outcome, 241 00:16:46,739 --> 00:16:47,429 the outcome. 242 00:16:48,340 --> 00:16:53,380 I think what you're describing really is the future of pharmacogenomics. 243 00:16:53,390 --> 00:16:54,599 Um In other words, 244 00:16:54,609 --> 00:17:03,419 not singing out pharmacogenomics as you know the end all and be all in the treatment paradigm. 245 00:17:03,559 --> 00:17:08,040 But using a PGX test in combination with, 246 00:17:08,050 --> 00:17:09,069 like you mentioned, 247 00:17:09,250 --> 00:17:11,160 other serological tests, 248 00:17:11,170 --> 00:17:12,959 maybe other genetic tests. 249 00:17:13,290 --> 00:17:14,890 Um But you know, 250 00:17:14,900 --> 00:17:25,869 I think what we want our audience to really wrap their heads around is that PGX is just a piece of that larger puzzle um from diagnosis to treatment to, 251 00:17:25,880 --> 00:17:26,910 to remission. 252 00:17:27,239 --> 00:17:29,880 So I think you guys are absolutely, 253 00:17:29,890 --> 00:17:31,579 you're already in the future. 254 00:17:31,589 --> 00:17:32,849 In other words, 255 00:17:32,859 --> 00:17:33,130 you know, 256 00:17:33,140 --> 00:17:39,689 you're already providing all these different uh tests um like you mentioned to, 257 00:17:39,699 --> 00:17:44,310 to facilitate from diagnosis to remission to remission. 258 00:17:44,660 --> 00:17:45,520 That's correct. 259 00:17:45,530 --> 00:17:45,829 Yeah. 260 00:17:46,349 --> 00:17:55,089 So um you've given us so much great information about uh the tests that that you guys offer. 261 00:17:55,329 --> 00:18:02,060 Can you explain to our audience um your newest test? 262 00:18:02,069 --> 00:18:03,859 Uh the responder test. 263 00:18:04,150 --> 00:18:12,979 And um what role it will play in the paradigm from the diagnosis of IBD to remission? 264 00:18:14,050 --> 00:18:14,260 Yeah, 265 00:18:14,270 --> 00:18:14,760 sure. 266 00:18:14,770 --> 00:18:15,569 So we, 267 00:18:15,579 --> 00:18:18,069 we are doing things a little bit different than other. 268 00:18:18,079 --> 00:18:19,489 We do believe that uh you know, 269 00:18:19,500 --> 00:18:21,449 the it has to be simple. 270 00:18:21,459 --> 00:18:24,189 Uh uh We can obviously construct some very, 271 00:18:24,199 --> 00:18:33,530 very complex algorithm and there are some tests that do that with a very sophisticated machine learning based tools that are available using neural networks, 272 00:18:33,540 --> 00:18:33,729 you know, 273 00:18:33,739 --> 00:18:34,790 those sorts of things. 274 00:18:34,800 --> 00:18:39,729 But we have taken on a different approach where with the responder test, 275 00:18:39,739 --> 00:18:40,329 we are basically, 276 00:18:40,339 --> 00:18:45,160 we are taking an approach which is very simple to address the first and foremost. 277 00:18:45,170 --> 00:18:53,020 Most important aspect of responding uh predicting response to uh to medication is the pharmacokinetics. 278 00:18:53,280 --> 00:19:03,250 Uh You cannot be responding to a drug if the drug is not given and you obviously cannot respond to a drug if the drug is not metabolized adequately. 279 00:19:03,359 --> 00:19:06,349 And this is what we are doing with the responder test. 280 00:19:06,579 --> 00:19:09,010 We are addressing some uh uh you know, 281 00:19:09,020 --> 00:19:11,630 fundamental issues with those uh biologist, 282 00:19:11,640 --> 00:19:12,410 for example, 283 00:19:12,660 --> 00:19:15,170 uh the anti tumor necrosis factors. 284 00:19:15,180 --> 00:19:15,650 So, 285 00:19:15,750 --> 00:19:19,199 such as uh Infliximab and Adalimumab, 286 00:19:19,209 --> 00:19:23,050 it is well known uh that uh uh those drugs, 287 00:19:23,060 --> 00:19:25,689 first of all are prone to immunization. 288 00:19:25,989 --> 00:19:36,949 Uh Meaning that uh uh the drug itself uh is recognized by the immune system uh and digested by the antigen presenting cells. 289 00:19:36,959 --> 00:19:42,209 If you will uh where you gonna have uh uh an immune uh uh response, 290 00:19:42,380 --> 00:19:56,979 uh mounted a cancer drug to produce uh immunogen that will severely impact its pharmacokinetics where the labels will be inadequate to produce uh the desired uh anti-inflammatory effects. 291 00:19:56,989 --> 00:19:57,150 So, 292 00:19:57,160 --> 00:19:58,890 we are with the risk conductors, 293 00:19:58,900 --> 00:20:01,040 we are combining two things together. 294 00:20:01,189 --> 00:20:07,959 First of all is the genetic test itself which uh predicts the risk of immun immunization. 295 00:20:07,969 --> 00:20:18,010 The name of the test is on HL A uh DQ A 105 ali uh that uh uh promotes the presentation of the, 296 00:20:18,020 --> 00:20:19,130 of the, 297 00:20:19,140 --> 00:20:19,910 of Infliximab, 298 00:20:20,010 --> 00:20:20,750 for example, 299 00:20:20,760 --> 00:20:32,130 to the T cell repertoire in order to uh promote the Ronon expansion and the formation of the anti antibodies together with uh another dimension which is the clearance, 300 00:20:32,140 --> 00:20:33,670 which is as important. 301 00:20:33,949 --> 00:20:36,209 Uh One of the key issue is the, 302 00:20:36,219 --> 00:20:36,770 the, 303 00:20:36,780 --> 00:20:41,239 the monoclonal antibodies and uh such as Infliximab or Adalimumab. 304 00:20:41,329 --> 00:20:42,280 But in fact, 305 00:20:42,290 --> 00:20:45,890 a neon antibodies that those drugs are uh you know, 306 00:20:45,900 --> 00:20:49,010 cleared and consumed uh from the, 307 00:20:49,020 --> 00:20:50,949 from the central compartment if you will, 308 00:20:50,959 --> 00:20:54,520 since we are doing a little bit of uh uh pharmacokinetics here. 309 00:20:54,530 --> 00:20:56,020 And uh uh you know, 310 00:20:56,030 --> 00:21:06,670 if the patient present who is uh a high degree of inflammatory burden is gonna have uh the patient will have a high clearance and that's gonna worsen uh in the, 311 00:21:06,680 --> 00:21:13,939 in the presence again of the HL AD Q A 105 genetic marker that uh associate with uh immunization. 312 00:21:13,949 --> 00:21:16,859 So I but this is a combination of both, 313 00:21:17,199 --> 00:21:19,359 these are the predictive factors of pharmacokinetic, 314 00:21:20,359 --> 00:21:38,209 which we combine together where the patient presenting with a risk of immunization as well as accelerated clearance due to the fact that the patient has high inflammation or due to the fact that they are so intrinsic pharmacokinetic properties that makes that the patient, 315 00:21:38,219 --> 00:21:38,300 you know, 316 00:21:38,310 --> 00:21:39,479 will clear the drug very, 317 00:21:39,489 --> 00:21:40,260 very fast. 318 00:21:40,560 --> 00:21:41,670 For example, 319 00:21:41,680 --> 00:21:46,819 due to the inefficient uh recirculation of the drug itself with the new, 320 00:21:46,869 --> 00:21:46,930 the, 321 00:21:46,939 --> 00:21:50,599 the the in the reticular on the system. 322 00:21:50,920 --> 00:21:51,619 Together, 323 00:21:51,630 --> 00:22:02,109 those patients presenting with uh uh together these uh poor prognostic factor of pharmacokinetic origin will tend to be severely underdose, 324 00:22:02,380 --> 00:22:06,719 will not be responding to the drug uh adequately as and they, 325 00:22:06,729 --> 00:22:10,719 and they probably should in the first place if you are able to address uh you know, 326 00:22:10,729 --> 00:22:12,270 the the the exposure. 327 00:22:12,439 --> 00:22:14,079 So what we do with this test, 328 00:22:14,089 --> 00:22:21,640 we will be able to inform uh the clinic that the patient is at risk of achieving, 329 00:22:21,650 --> 00:22:30,829 of achieving suboptimal pharmacokinetics and therefore being able to adjust the dose uh uh to start with more adequately. 330 00:22:30,839 --> 00:22:38,650 So that the the the proper uh exposure is achieved uh during induction to again to, 331 00:22:38,660 --> 00:22:39,040 to, 332 00:22:39,050 --> 00:22:39,380 to, 333 00:22:39,390 --> 00:22:40,890 to achieve a better outcome. 334 00:22:41,040 --> 00:22:47,270 And I think the pharmacist will have a very important role to play here in terms of absolutely, 335 00:22:47,280 --> 00:22:51,239 that information is priceless in the management of these medications. 336 00:22:51,250 --> 00:22:54,930 So thanks for elaborating on that. 337 00:22:56,010 --> 00:22:59,040 And if I may add in our previous conversation, 338 00:22:59,050 --> 00:23:00,810 uh before the recording of podcast, 339 00:23:00,819 --> 00:23:08,869 we had discussed um you guys' robust platform for collaborating with payers to obtain market access and reimbursements for the test. 340 00:23:09,109 --> 00:23:14,109 But without stealing the Thunder from uh Prometheus market access and reimbursement team, 341 00:23:14,199 --> 00:23:22,619 can you please uh briefly detail how Prometheus has proactively worked with payers to solve the problem. 342 00:23:22,920 --> 00:23:27,349 Um the population health problem by building the evidence payers want, 343 00:23:27,359 --> 00:23:41,170 want to see um about your test before you go to the market and then build the test and then hope the payers will see the value and the result and then that will improve the market access and reimbursement for your um precision medicine test. 344 00:23:42,160 --> 00:23:42,339 Yeah. 345 00:23:42,349 --> 00:23:43,180 So briefly I can, 346 00:23:43,189 --> 00:23:43,579 I'm, 347 00:23:43,589 --> 00:23:46,619 I'm probably not the right person to answer that question. 348 00:23:46,630 --> 00:23:47,369 We have a very, 349 00:23:47,380 --> 00:23:52,400 very efficient market access group uh uh pro meters that does a splendid job. 350 00:23:52,410 --> 00:23:59,780 But uh uh uh what I can tell you that we have an evidence uh uh development plan in place where we, 351 00:23:59,790 --> 00:24:14,000 we are establishing the clinical utility of our testing solution by demonstrating uh the payer value uh with respect of uh patient management and uh uh and the, 352 00:24:14,010 --> 00:24:16,630 and the impact of our technology on the, 353 00:24:16,640 --> 00:24:18,119 on physician behavior. 354 00:24:18,430 --> 00:24:21,319 Uh We have uh uh already uh you know, 355 00:24:21,329 --> 00:24:25,160 commercialized uh two of those tests for which we have initiated, 356 00:24:25,170 --> 00:24:29,040 initiated the Power studies uh that uh uh you know, 357 00:24:29,050 --> 00:24:32,000 already provide uh you know, 358 00:24:32,104 --> 00:24:34,484 differentiated and the value to, 359 00:24:34,494 --> 00:24:35,915 to the payer where we are, 360 00:24:35,925 --> 00:24:36,025 the, 361 00:24:36,035 --> 00:24:46,005 the clinicians are basically using our technology to make treatment decision uh as well as uh some prospective clinicality study which we are initiating, 362 00:24:46,145 --> 00:24:47,555 initiating to. 363 00:24:47,564 --> 00:24:48,574 Um uh again, 364 00:24:48,584 --> 00:24:49,425 demonstrate the, 365 00:24:49,435 --> 00:24:49,915 the, 366 00:24:49,925 --> 00:24:50,244 the, 367 00:24:50,255 --> 00:24:53,594 the payer value you uh uh we can certainly follow up with, 368 00:24:53,604 --> 00:24:58,755 uh you can certainly follow up with our market access group uh uh as appropriate there. 369 00:24:58,765 --> 00:25:00,765 Uh They can fill you with more information. 370 00:25:01,349 --> 00:25:01,589 No, 371 00:25:01,599 --> 00:25:02,520 that totally makes sense. 372 00:25:02,530 --> 00:25:03,310 That totally makes sense. 373 00:25:03,319 --> 00:25:10,890 But um we're excited that you're also farm d So how did you get to this role of outside the box path? 374 00:25:10,900 --> 00:25:11,550 There? 375 00:25:11,640 --> 00:25:17,530 There may be a pharmacist student or pharmacist wanting to switch or transition into a role such as yours, 376 00:25:17,540 --> 00:25:19,609 which is a Chief Scientific Officer. 377 00:25:19,619 --> 00:25:20,609 I want to learn more. 378 00:25:20,619 --> 00:25:23,920 So how would you um can you talk a little bit about that? 379 00:25:24,560 --> 00:25:24,780 Well, 380 00:25:24,790 --> 00:25:26,270 we are clinical laboratories. 381 00:25:26,280 --> 00:25:29,400 So in order to uh uh to be in my role, 382 00:25:29,410 --> 00:25:34,020 you need to have uh uh you need to have expertise in clinical laboratory science. 383 00:25:34,030 --> 00:25:36,140 So for the students is basically, 384 00:25:36,150 --> 00:25:36,300 you know, 385 00:25:36,310 --> 00:25:40,770 to do the family degree and then complete the family degree with uh a doctorate, 386 00:25:40,780 --> 00:25:40,930 you know, 387 00:25:40,939 --> 00:25:44,260 which is uh focus on clinical laboratory science. 388 00:25:44,270 --> 00:25:46,079 So you can achieve uh uh you know, 389 00:25:46,089 --> 00:25:47,640 the all the elements you need to be, 390 00:25:47,650 --> 00:25:48,219 for example, 391 00:25:48,229 --> 00:25:53,189 board certified uh as uh as as medical laboratory director. 392 00:25:53,199 --> 00:25:55,160 So you can uh uh so, 393 00:25:55,170 --> 00:25:55,589 uh yeah, 394 00:25:55,599 --> 00:25:56,030 this is, 395 00:25:56,040 --> 00:25:56,400 this is, 396 00:25:56,410 --> 00:25:57,209 this is uh you know, 397 00:25:57,219 --> 00:25:59,160 a great opportunity I think for pharmacies, 398 00:25:59,170 --> 00:26:10,800 there is an absolute need to uh have the clinical pharmacist provide uh uh drug information to healthcare professional as well as uh assist patient with the monitoring of their disease, 399 00:26:10,810 --> 00:26:15,229 the effectiveness of the therapy and um and uh you know, 400 00:26:15,239 --> 00:26:16,060 monitoring the, 401 00:26:16,069 --> 00:26:20,969 the side effect and the toxicity from uh from those uh those medication. 402 00:26:24,650 --> 00:26:24,959 Well, 403 00:26:24,969 --> 00:26:32,119 the I know our audience is going to have uh additional questions for you. 404 00:26:32,130 --> 00:26:32,540 I mean, 405 00:26:32,989 --> 00:26:35,609 you've provided them with so much great information, 406 00:26:35,619 --> 00:26:44,959 but it's only the beginning of what they could possibly learn um about um the testing that you do for IBD and, 407 00:26:44,969 --> 00:26:46,729 and even your career path. 408 00:26:47,050 --> 00:26:47,530 So, 409 00:26:47,540 --> 00:26:49,300 if you wouldn't mind telling us, 410 00:26:49,310 --> 00:26:51,359 um because we have to wrap up, 411 00:26:51,369 --> 00:26:52,670 unfortunately, 412 00:26:53,150 --> 00:26:55,810 this episode of the podcast, 413 00:26:55,819 --> 00:27:00,250 uh could you tell us how our audience members might be able to contact you directly. 414 00:27:01,260 --> 00:27:01,449 Yeah, 415 00:27:01,459 --> 00:27:07,079 I can be contacted on my uh on my email at TT W at como slab dot com. 416 00:27:07,949 --> 00:27:08,810 All right. 417 00:27:09,069 --> 00:27:09,300 Well, 418 00:27:09,310 --> 00:27:14,290 thank you again so much uh for joining us on this episode. 419 00:27:14,300 --> 00:27:15,290 We really, 420 00:27:15,300 --> 00:27:29,530 really hope that our listeners um ideas of not only what PGX can be but how PGX can be utilized in a comprehensive testing suite. 421 00:27:29,709 --> 00:27:35,670 We really hope that our a our audience will um listen in and learn this information. 422 00:27:36,280 --> 00:27:37,869 Um And to our audience, 423 00:27:37,880 --> 00:27:39,439 thank you for tuning in. 424 00:27:39,449 --> 00:27:42,619 We really hope that you've learned from this episode. 425 00:27:43,130 --> 00:27:46,339 Uh We do a whole lot of PG Xing here on this podcast. 426 00:27:46,349 --> 00:27:48,380 We talk about PGX Science, 427 00:27:48,390 --> 00:27:52,030 clinical application and the business of PGX. 428 00:27:52,260 --> 00:27:54,880 So we'd love to hear about from you. 429 00:27:55,099 --> 00:27:56,479 I love to hear from you. 430 00:27:56,489 --> 00:27:58,439 Um What can we teach you? 431 00:27:58,449 --> 00:28:00,920 What more can we teach you through our podcast? 432 00:28:00,930 --> 00:28:12,349 So please drop us a message on linkedin and let us know and please share this link to this podcast link episode with everyone so they can tune in and listen to the PGX for promises podcast. 433 00:28:12,520 --> 00:28:15,369 Leave us a review on Apple podcast or Spotify. 434 00:28:15,459 --> 00:28:18,130 And you can also visit us on PGX four, 435 00:28:18,140 --> 00:28:22,989 the number four Rx dot com to listen to all our other episodes. 436 00:28:23,000 --> 00:28:23,079 Well, 437 00:28:23,089 --> 00:28:23,790 thank you. 438 00:28:24,199 --> 00:28:28,750 Thanks for your interest in PGX and for spending some time with us. 439 00:28:28,760 --> 00:28:35,670 Please share this podcast and leave us a review on Apple podcasts or Spotify for all of our episodes. 440 00:28:35,680 --> 00:28:39,390 Please visit PGX four Rx dot com. 441 00:28:39,569 --> 00:28:43,380 That's PGX four Rx dot com.  

BUFFALO, NY- October 16, 2023 – A new research paper was published on the cover of Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 15, Issue 19, entitled, “BMAL1 modulates senescence programming via AP-1.” Cellular senescence and circadian dysregulation are biological hallmarks of aging. Whether they are coordinately regulated has not been thoroughly studied. In this new study, researchers Sarah K. Jachim, Jian Zhong, Tamas Ordog, Jeong-Heon Lee, Aditya V. Bhagwate, Nagaswaroop Kengunte Nagaraj, Jennifer J. Westendorf, João F. Passos, Aleksey V. Matveyenko, and Nathan K. LeBrasseur from the Mayo Clinic in Rochester, Minnesota, hypothesized that BMAL1, a pioneer transcription factor and master regulator of the molecular circadian clock, plays a role in the senescence program. “Here, we demonstrate BMAL1 is significantly upregulated in senescent cells and has altered rhythmicity compared to non-senescent cells.” Through BMAL1-ChIP-seq, they showed that BMAL1 is uniquely localized to genomic motifs associated with AP-1 in senescent cells. Integration of BMAL1-ChIP-seq data with RNA-seq data revealed that BMAL1 presence at AP-1 motifs is associated with active transcription. Finally, the researchers showed that BMAL1 contributes to AP-1 transcriptional control of key features of the senescence program, including altered regulation of cell survival pathways, and confers resistance to drug-induced apoptosis. “Overall, these results highlight a previously unappreciated role of the core circadian clock component BMAL1 on the molecular phenotype of senescent cells.” DOI - https://doi.org/10.18632/aging.205112 Corresponding authors - Nathan K. LeBrasseur - lebrasseur.nathan@mayo.edu Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.205112 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, AP-1, circadian clock, cellular senescence, senolytic, transcription regulation About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at https://www.Aging-US.com​​ and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

Ryley Hill, San Diego State University Both natural and anthropogenic hydrologic loads have been associated with stimulating seismicity. However, there are few documented examples that hydrologic loads can trigger large earthquakes. The southern San Andreas Fault (SSAF) in Southern California lies next to the Salton Sea, a successor of ancient Lake Cahuilla that periodically filled and desiccated over the past millennium. Here we use new geologic and paleoseismic data to demonstrate that the past six major earthquakes on the SSAF likely occurred during highstands of Lake Cahuilla. To investigate possible causal relationships, we computed time-dependent Coulomb stress changes produced by lake level fluctuations over the last ~1100 years. Using a fully coupled model of a poroelastic crust overlying a viscoelastic mantle, we find that hydrologic loads increased Coulomb stress on the SSAF by several hundred kilopascals and fault-stressing rates by more than a factor of 2, likely sufficient for triggering. Stress perturbations are dominated by pore pressure changes, but are enhanced by the poroelastic “memory" effect whereby increases in pore pressure due to previous lake high stands do not completely vanish by diffusion and constructively interfere with the undrained response in subsequent high stands. The destabilizing effects of lake inundation are enhanced by a nonvertical fault dip, the presence of a fault damage zone, and lateral pore pressure diffusion. Our model provides physical insights into relations between lake level and time-dependent seismic hazard, and may be applicable to other regions with hydrologic loading from either natural or anthropogenic sources.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.31.551234v1?rss=1 Authors: Kern, S., Nagel, J., Gerchen, M. F., Gürsoy, C., Meyer-Lindenberg, A., Kirsch, P., Dolan, R. J., Gais, S., Feld, G. B. Abstract: Declarative memory retrieval is thought to involve reinstatement of the neuronal activity patterns elicited and encoded during a prior learning episode. Recently, it has been suggested that two mechanisms operate during reinstatement, dependent on task demands: individual memory items can be reactivated simultaneously as a clustered occurrence or, alternatively, replayed sequentially as temporally separate instances. In the current study, participants learned associations between images that were embedded in a directed graph network and retained over a brief 8-minute consoli-dation period. During a subsequent cued recall session, participants retrieved the learned infor-mation while undergoing magnetoencephalographic (MEG) recording. Using a trained stimulus de-coder, we found evidence for clustered reactivation of learned material. Reactivation strength of individual items during clustered reactivation decreased as a function of increasing graph distance, an ordering present solely for successful retrieval but not with retrieval failure. In line with previous research, we found evidence that sequential replay was dependent on retrieval performance and limited to low performers. The results provide further evidence for the existence of different perfor-mance-dependent retrieval mechanisms suggesting graded clustered reactivation as a plausible mechanism to search within abstract cognitive maps. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.06.26.546615v1?rss=1 Authors: Tang, D.-l., Parrell, B., Beach, S., Niziolek, C. Abstract: When individuals make a movement that produces an unexpected outcome, they learn from the resulting error. This process, essential in both acquiring new motor skills and adapting to changing environments, critically relies on error sensitivity, which governs how much behavioral change results from a given error. Although behavioral and computational evidence suggests error sensitivity can change in response to task demands, neural evidence regarding the flexibility of error sensitivity in the human brain is lacking. Critically, the sensitivity of the nervous system to auditory errors during speech production, a complex and well-practiced motor behavior, has been extensively studied by examining the prediction-driven suppression of auditory cortical activity. Here, we tested whether the nervous system's sensitivity to errors, as measured by this suppression, can be modulated by altering speakers' perceived variability. Our results showed that error sensitivity was increased after exposure to an auditory perturbation that increased participants' perceived variability, consistent with predictions generated from previous behavioral data and state-space modeling. Conversely, we observed no significant changes in error sensitivity when perceived variability was unaltered or artificially reduced. The current study establishes the validity of behaviorally modulating the nervous system's sensitivity to errors. As sensitivity to sensory errors plays a critical role in sensorimotor adaptation, modifying error sensitivity has the potential to enhance motor learning and rehabilitation in speech and, potentially, more broadly across motor domains. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.15.537013v1?rss=1 Authors: O'Leary, J. D., Bruckner, R., Autore, L., Ryan, T. J. Abstract: Memories are stored as ensembles of engram neurons and their successful recall involves the reactivation of these cellular networks. While progress has been made in understanding the biology of engrams, significant gaps remain in connecting these cell ensembles with the process of forgetting. Here, we examine whether forgetting is governed by changes in engram plasticity and suggest that it helps animals prioritize relevant memory representations for adaptive behavior. We utilized a mouse model of object memory and investigated the conditions in which a memory could be preserved, retrieved, or forgotten. The results indicate that engram activity correlated with the rate of forgetting. Direct modulation of engram activity via optogenetic stimulation or inhibition either facilitated or prevented the recall of an object memory. In addition, the modulation of engram activity was able to prevent forgetting itself. Moreover, through pharmacological and behavioral interventions, we successfully prevented or accelerated forgetting of an object memory. Finally, we show that these results can be explained by a computational model in which engrams that are subjectively less relevant for adaptive behavior are more likely to be forgotten. Together, these findings suggest that forgetting is an adaptive form of engram plasticity that involves circuit remodeling, which allows engrams to switch from an accessible state to an inaccessible state. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.07.535979v1?rss=1 Authors: Chowdhury, D., Dhabal, S., Bhatt, M., Maity, D., Chakraborty, S., Priyadarshi, S., Haldar, S. Abstract: Methotrexate is a well-known antineoplastic drug used to prevent cancer aggravation. Despite being a targeted therapeutic approach, its administration comes with the risk of cancer recurrence, plausibly through its proven off-target effect on focal adhesions. Since FA dynamics is dependent on force transmission through its constituent proteins, including talin, methotrexate might affect the mechanical activity of these proteins. Here we have combined single-molecule studies, computational dynamics, cell-based assays, and genomic analysis to unveil the focal adhesion-regulating role of methotrexate central to its effect on talin dynamics and downstream pathways. Interestingly, our single-molecule force spectroscopic study shows that methotrexate modulates the bimodal force distribution of talin in a concentration-dependent manner. Steered molecular dynamics reveal that methotrexate-talin interactions alter talin mechanical stability exposing their vinculin binding sites. Finally, we found that methotrexate-regulated talin-dynamics remodel cancer cell mechanical phenotypes like cell polarity, adhesion, and migration by regulating talin-vinculin association-mediated YAP signaling. These results further correlate with genomic analysis of methotrexate-treated patients, demonstrating its clinical importance. Taken together, these findings disseminate the effects of methotrexate-modulated mechanosensitivity of adhesion proteins on cellular events. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.06.535865v1?rss=1 Authors: Rowies, F. T., Batalha, C. M. P. F., Nakahara, T. S., Malnic, B., de Souza-Pinto, N. C. Abstract: Olfactory dysfunction is considered a biomarker of several pathological conditions, including age-associated neurodegenerations, glioblastoma and COVID-19. Olfactory sensory neurons (OSNs) are specialized neurons that detect odorants and send olfactory information to the brain through the olfactory bulb. To perform their function, they are in direct contact with the environment, where they are exposed to several environmental toxins such as atmospheric levels of O2 and volatile molecules. Nonetheless, very little is known about DNA damage levels and expression of DNA repair pathways in these cells. Here we measured nuclear and mitochondrial DNA damage in olfactory epithelium (OE) and compared with levels detected in olfactory bulb (OB) and temporal cortex (TC), as a non-olfactory related central nervous system region. Surprisingly, DNA damage was lower in OE and OB when compared with TC, both for nuclear and mitochondrial genomes. Accordingly, expression of representative genes for all excision repair pathways was detected in OSNs. Moreover, expression of most evaluated DNA repair genes was lower in mature versus OSN progenitors, suggesting that DNA repair is downregulated during differentiation. Analysis of single cell expression data confirmed that expression of the most differentially expressed DNA repair genes decreased from progenitor to mature OSNs. Finally, in situ hybridization data showed that APE1 mRNA levels are lower in the mature OSNs layer of the olfactory epithelium, closest to the nasal cavity lumen. Altogether, we show here that DNA repair pathways are relevant in protecting OSNs against DNA damage accumulation and that differentiation through the OE is accompanied by changes in the expression levels of DNA repair genes. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.31.534952v1?rss=1 Authors: Ghibaudo, V., Juventin, M., Buonviso, N., Peter-Derex, L. Abstract: Coupling of sleep spindles with cortical slow waves and hippocampus sharp-waves ripples is crucial for sleep-related memory consolidation. Recent literature evidenced that nasal respiration modulates neural activity in large-scale brain networks. In the rodent, this respiratory drive strongly varies according to vigilance states. Particularly, during sleep, respiration promotes the coupling between hippocampal sharp-wave ripples and cortical DOWN/UP state transitions. However, no study has examined whether sleep spindles could be respiration-modulated in humans. In this work, we aimed to investigate the influence of breathing on brain oscillations during non-rapid-eye-movement stage 2 sleep (N2) in humans by examining the coupling between sleep spindles and respiration cycle. Full night polysomnography of twenty healthy participants were analysed. Spindles and slow waves were detected during N2 sleep stage. Spindle-related sigma power as well as spindle and slow waves events were analysed according to the respiratory phase. We found a significant coupling between slow and fast spindles with respiration cycle, with enhanced sigma activity and probability of occurrence of spindles during the middle part of the expiration phase. A different coupling was observed between breathing and slow waves that were more distributed around both respiration phase transitions. Our findings suggest that breathing cycle influences the dynamics of brain activity during non-rapid-eye-movement sleep. This may enable sleep spindles to synchronize with other brain rhythms including hippocampus sharp wave ripples and facilitate information transfer between distributed brain networks. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.22.533752v1?rss=1 Authors: Dennis, C., Pouchin, P., Richard, G., Mirouse, V. Abstract: The basement membrane (BM) is an essential structural element of tissues, and its diversification participates in organ morphogenesis. However, the traffic routes associated with BM formation and the mechanistic modulations explaining its diversification are still poorly understood. Drosophila melanogaster follicular epithelium relies on a BM composed of oriented BM fibrils and a more homogenous matrix. Here, we determined the specific molecular identity and cell exit sites of BM protein secretory routes. First, we found that Rab10 and Rab8 define two parallel routes for BM protein secretion. When both routes were abolished, BM production was fully blocked; however, genetic interactions revealed that these two routes competed. Rab10 promoted lateral and planar-polarized secretion, whereas Rab8 promoted basal secretion, leading to the formation of BM fibrils and homogenous BM, respectively. We also found that the dystrophin-associated protein complex (DAPC) associated with Rab10 and both were present in a planar-polarized tubular compartment containing BM proteins. DAPC was essential for fibril formation and sufficient to reorient secretion towards the Rab10 route. Moreover, we identified a dual function for the exocyst complex in this context. First, the Exo70 subunit directly interacted with dystrophin to limit its planar polarization. Second, the exocyst complex was also required for the Rab8 route. Altogether, these results highlight important mechanistic aspects of BM protein secretion and illustrate how BM diversity can emerge from the spatial control of distinct traffic routes. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.20.533578v1?rss=1 Authors: Gu, L., Liu, L., Shao, W., Gu, J., Xu, Q., Wang, Y., Yu, Q., Lian, X., Zhang, H. Abstract: Generation of the unconsciousness associated with arousal during the initial stage of anesthesia by midazolam is critical for general anesthesia, however, the exact mechanism remains unknown. Here, firstly, we found that the destruction of noradrenergic neurons in the locus coeruleus (LCNE) could prolong the emergence time of midazolam-induced anesthesia. Secondly, the same results were found by activation of the noradrenergic pathway between the LC and the ventrolateral preoptic nucleus (VLPO) using optogenetics and chemogenetics approaches, respectively. Thirdly, this effect was mediated by alpha 1 and beta adrenergic receptors rather than alpha2 adrenergic receptors in the VLPO. Moreover, the noradrenergic pathway to modulate the arousal between the LC and VLPO was controlled by GABAA receptors in the LC and VLPO in our models. Our data demonstrate that activation of the NEergic pathway between the LC and VLPO can promote arousal to prevent delayed recovery from midazolam-induced anesthesia. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.28.530397v1?rss=1 Authors: Verma, A., Asthana, S., Saini, D. K., Ayappa, K. G. Abstract: CXCR4 is a G-protein coupled receptor which mediates signalling for diverse functions such as cell proliferation and migration, hematopoiesis and plays a role in embryogenesis and development. Signal transduction occurs primarily through transmembrane helices that function in the multicomponent lipid environment of the plasma membrane. Elevated levels of plasma membrane oxysterols occur in cardiovascular and metabolic disorders, physiological stress and inflammatory conditions. We use experimental and simulation approaches to study the impact of oxysterol chemistry and composition on CXCL12-mediated CXCR4 signalling. Experiments on HeLa cells show a pronounced decrease in calcium oscillation response for the tail oxidized sterols in comparison with the ring oxidized sterols with 22(R) hydroxycholesterol showing a near complete loss of signalling followed by 27-hydroxycholesterol and 25-hydroxycholesterol. All-atom molecular dynamics simulations reveal that tail oxidized, 27-hydroxycholesterol, displaces cholesterol and ubiquitously binds to several critical signalling residues, as well as the dimer interface. Enhanced 27-hydroxycholesterol binding alters CXCR4 residue conformations, disrupts the toggle switch and induces secondary structure changes at both N and C termini. Our study provides a molecular view of the observed mitigated CXCR4 signalling in the presence of oxysterols revealing that disruption of cholesterol-protein interactions, important for regulating the active state, is a key factor in the loss of CXCR4 signalling. Additionally, a signalling class switching from Gi to Gs as revealed by increased CREB and ERK phosphorylation is observed in the experiments. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.07.527584v1?rss=1 Authors: Qiu, Z., Jiang, J., Becker, S. I., Pegna, A. J. Abstract: In the current EEG study, we used a dot-probe task in conjunction with backward masking to examine the neural activity underlying awareness and spatial processing of fearful faces and the neural processes for subsequent cued spatial targets. We presented face images under different viewing conditions (subliminal and supraliminal) and manipulated the relation between a fearful face in the pair and a subsequent target. Through both mass univariate analysis and multivariate pattern analysis, we found that fearful faces can be processed to an extent where they attract spatial attention only when they are presented supraliminally and when they are task-relevant. The spatial attention capture by fearful faces also modulated the processing of subsequent lateralised targets that were spatially congruent with the fearful face, in both behavioural and neural data. There was no evidence for nonconscious processing of the fearful faces in the current paradigm. We conclude that spatial attentional capture by fearful faces requires visual awareness and it is modulated by top-down task demands. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Ralph trained in mineral surveying, but became a computer analyst. But after a change in profession he entered aviation as a flying instructor, and an airline captain. Thus he has studied and observed climate and weather for 40 years in the real world, as a part of his profession. Slides for this presentation: https://tomn.substack.com/p/ralph-ellis-on-ice-ages “Modulation of ice ages via precession and dust-albedo feedbacks”: https://www.sciencedirect.com/science/article/pii/S1674987116300305 —— https://linktr.ee/tomanelson1 Tom Nelson's Twitter: https://twitter.com/tan123 Substack: https://tomn.substack.com/ About Tom: https://tomnelson.blogspot.com/2022/03/about-me-tom-nelson.html Notes for climate skeptics: https://tomn.substack.com/p/notes-for-climate-skeptics ClimateGate emails: https://tomnelson.blogspot.com/p/climategate_05.html

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.31.526457v1?rss=1 Authors: Funamizu, A., Marbach, F., Zador, A. M. Abstract: The activity of neurons in the auditory cortex is driven by both sounds and non-sensory context. To investigate the neuronal correlates of non-sensory context, we trained head-fixed mice to perform a two-alternative choice auditory task in which either reward or stimulus expectation (prior) was manipulated in blocks. Using two-photon calcium imaging to record populations of single neurons in auditory cortex, we found that both sensory and reward expectation modulated the activity of these neurons. Interestingly, the optimal decoder was stable even in the face of variable sensory representations. Neither the context nor the mouse's choice could be reliably decoded from the recorded auditory activity. Our findings suggest that in spite of modulation of auditory cortical activity by task priors, auditory cortex does not represent sufficient information about these priors to exploit them optimally and that decisions in this task require that rapidly changing sensory information be combined with more slowly varying task information extracted and represented in brain regions other than auditory cortex. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.28.522133v1?rss=1 Authors: Rathod, M., Franz, H., Beyersdorfer, V., Wanuske, M.-T., Fischer, K. L., Stüdle, C., Zimmermann, A., Spindler, V. Abstract: Glycosylation is an essential mediator of cell-cell adhesion and epidermal differentiation. We used CRISPR/Cas9-based gene editing to determine the role of dolichol phosphate mannosyltransferase 1 (DPM1), a key enzyme for N- and O-glycosylation. DPM1 loss resulted in weakening of cell-cell adhesion, impaired localization of the desmosome components desmoplakin and desmoglein 2, and cytoskeletal organization defects in human keratinocytes. In a 3D organotypic human epidermis model, loss of DPM1 resulted in impaired differentiation with abnormally increased cornification, reduced thickness of non-corneal layers, and the formation of intercellular gaps in the epidermis. Using proteomic approaches, SERPINB5 was identified as novel interaction partner of desmoplakin, ameliorating the effects of DPM1 loss on cell-cell adhesion and epidermal differentiation. Further analysis showed that the changes induced by DPM1 and SERPINB5 loss were at least in part dependent on elevated TGF-{beta} signalling. Together, we identify DPM1 through SERPINB5 as a novel regulator of cell-cell adhesion and differentiation. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Dive into Magnetohydrodynamic (MHD) simulations of the HD 189733 star-planet system in order to predict radio transit modulations of exoplanets. Learn how MHD simulations can model electromagnetic field interactions between local stars and exoplanet magnetospheres at varying planetary radii, and field intensities to generate synthetic radio images (10MHz-1GHz), EM field strength, viewing phase angles, and local star parameters. Topics include: Alfven Wave Solar Atmosphere Model (AWSOM),ray tracing algorithm,Plasma Physics Absorption coefficient,imaging Modulated waves, spacebased instruments, Scar telescope mission, and future research with radio, EUV, and Xray transits to run algorithms on datasets to classify 1,000 Earth-sized planets within 50ly Soumitra Hazra, Post-Doctoral Research Associate, Lowell Center for Space Science and Technology Exoplanet Radio Transits as a Probe for Exoplanetary Magnetic Fields -- Time-dependent MHD Simulations Soumitra Hazra, et al, 2022, Earth and Planetary Astrophysics, https://doi.org/10.48550/arXiv.2208.06006 --- Support this podcast: https://anchor.fm/frontierspace/support

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.08.519576v1?rss=1 Authors: Ives, J., Labendzki, P., Perapoch Amado, M., Greenwood, E., Viswanathan, N., Northrop, T., Wass, S. V. Abstract: Previous infant entrainment research has shown neural entrainment to a wide range of stimuli and amplitude modulated frequencies. However, it is unknown if infants neurally entrain more strongly to some frequencies more than others, and to which low amplitude modulated frequency infants show the strongest entrainment. The current study seeks to address this by testing the neural entrainment of N=23 4-6-month-old infants and N=22 control group adult caregivers while they listened to a range of sinusoidally amplitude modulated beep stimuli at rest (no sound), 2, 4, 6, 8, 10 and 12 Hz. Analysis examined differences across power and phase, regions of interest predetermined by previous literature and by segmented time windows. Results showed that the strongest entrainment was at 2Hz for both adult and infant participants; that there was no significant difference in power and phase, entrainment was occipital temporal and slightly left fronto-central in adults and right fronto-central and left occipito-temporal in infants, leading to some regions of interest used in previous studies being significant in infants and all regions of interest being significant in adults. Segmenting by time window did not show any significant increase or decrease in entrainment over time, but longer time windows showed a stronger entrainment response. In conclusion, it is important to choose appropriate stimulation frequencies when investigating entrainment between stimulation frequencies or across ages; whole head recording is recommended to see the full extent of activation; there is no preference on power vs phase analyses; and longer recordings show stronger effects. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.11.23.517709v1?rss=1 Authors: Ivaldo, C., Passalacqua, M., Furfaro, A. L., d'Abramo, C., Ruiz, S., Chatterjee, P. K., Metz, C. N., Nitti, M., Marambaud, P. Abstract: Classical cadherins, including vascular endothelial (VE)-cadherin, are targeted by matrix metalloproteinases (MMPs) and {gamma}-secretase during adherens junction (AJ) disassembly, a mechanism that might have relevance for endothelial cell (EC) integrity and vascular homeostasis. Here, we show that oxidative stress triggered by H2O2 exposure induced efficient VE-cadherin proteolysis by MMPs and {gamma}-secretase in human umbilical endothelial cells (HUVECs). The cytoplasmic domain of VE-cadherin produced by {gamma}-secretase, VE-Cad/CTF2 - a fragment that has eluded identification so far - could readily be detected after H2O2 treatment. VE-Cad/CTF2, released into the cytosol, was tightly regulated by proteasomal degradation and was sequentially produced from an ADAM10/17-generated C-terminal fragment, VE-Cad/CTF1. Interestingly, BMP9 and BMP10, two circulating ligands critically involved in vascular maintenance, significantly reduced VE-Cad/CTF2 levels during H2O2 challenge, as well as mitigated H2O2- mediated actin cytoskeleton disassembly during VE-cadherin processing. Notably, BMP9/10 pretreatments efficiently reduced apoptosis induced by H2O2, favoring endothelial cell recovery. Thus, oxidative stress is a trigger of MMP- and {gamma}-secretase-mediated endoproteolysis of VE-cadherin and AJ disassembly from the cytoskeleton in ECs, a mechanism that is negatively controlled by the EC quiescence factors, BMP9 and BMP10. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.26.513851v1?rss=1 Authors: Krugliak, A., Draschkow, D., Vo, M. L.-H., Clarke, A. Abstract: We typically encounter objects in a context, for example, a sofa in a living room or a car in the street, and this context influences how we recognize objects. Objects that are congruent with a scene context are recognised faster and more accurately than objects that are incongruent. Furthermore, objects that are incongruent with a scene elicit a stronger negativity of the N300/N400 EEG component compared to objects that are congruent with the scene. However, exactly how context modulates access to semantic object information is unknown. Here, we used a modelling-based approach with EEG to directly test how context influences the processing of semantic object information. Using representational similarity analysis, we first asked whether EEG patterns dissociated objects in congruent or incongruent scenes, finding that representational differences between the conditions emerged towards 300 ms. Next, we tested the relationship between EEG patterns and a semantic model based on property norms, revealing that the processing of semantic information for both conditions started around 150 ms, while after around 275 ms, semantic effects were stronger and lasted longer for objects in incongruent scenes compared to objects in congruent scenes. The timing of these effects overlapped with known N300/N400, suggesting previous congruency effects might be explained by differences in processing semantic object information. This suggests that scene contexts can provide a prior expectation about what kind of objects could appear, which might allow for more efficient semantic processing if the object is congruent with the scene, and extended semantic effects for incongruent objects. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.25.512385v1?rss=1 Authors: Sheppard, P. A. S., Chandramohan, D., Lumsden, A., Vellone, D., Denley, M. C. S., Srivastava, D. P., Choleris, E. Abstract: Background: Social memory is essential to the functioning of a social animal within a group. Estrogens can affect social memory too quickly for classical genomic mechanisms. Previously, 17{beta}-estradiol (E2) rapidly facilitated short-term social memory and increased nascent synapse formation, these synapses being potentiated following neuronal activity. However, what mechanisms underlie and co-ordinate the rapid facilitation of social memory and synaptogenesis are unclear. Here, the necessity of extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K) signaling for rapid facilitation of short-term social memory and synaptogenesis was tested. Methods: Mice performed a short-term social memory task or were used as task-naive controls. ERK and PI3K pathway inhibitors were infused intra-dorsal hippocampally 5 minutes before E2 infusion. Forty minutes following intrahippocampal E2 or vehicle administration, tissues were collected for quantification of glutamatergic synapse number in the CA1. Results: Dorsal hippocampal E2 rapid facilitation of short-term social memory depended upon ERK and PI3K pathways. E2 increased glutamatergic synapse number (GluA1/bassoon colocalization) in task-performing mice but decreased synapse number in task-naive mice. Critically, ERK signaling was required for synapse formation/elimination in task-performing and task-naive mice, whereas PI3K inhibition blocked synapse formation only in task-performing mice. Conclusions: Whilst ERK and PI3K are both required for E2 facilitation of short-term social memory and synapse formation, only ERK is required for synapse elimination. This demonstrates previously unknown, bidirectional, rapid actions of E2 on brain and behaviour and underscores the importance of estrogen signaling in the brain to social behaviour. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.23.513371v1?rss=1 Authors: Huang, J.-Y., Hess, M., Bajpai, A., Barton, S. J., Li, X., Hobson, L. N., Lu, H.-C. Abstract: Neuronal subnetworks are common features of adult cortical circuits and serve as functional units for information processing and encoding. To determine when neuronal subnetworks are established, we employed in vivo calcium imaging to monitor neuronal activity in the primary somatosensory cortex (S1) of awake mice during early postnatal development. We found several striking developmental trajectories: (1) neuronal activity frequencies and network synchrony were sex-dependent; (2) neuronal subnetworks merged as early as P11; (3) the number of neurons in a subnetwork decreases with increasing age; (4) subnetwork neurons are initially spatially segregated, but become intermingled with other subnetworks neurons with increasing age; (5) neurons within the same subnetwork acquire a more cohesive activity pattern as age increases, and (6) enhancing GABAergic activity at P15 acutely increased female but not male subnetwork coherence. Together, our findings demonstrate that P11-P21 is the critical time for subnetwork assembly and GABAergic inputs strengthen subnetwork coherence. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.17.512498v1?rss=1 Authors: Douchamps, V., di Volo, M., Torcini, A., Battaglia, D., Goutagny, R. Abstract: The hippocampus and the entorhinal cortex display a rich oscillatory activity, believed to support neural information processing in key cognitive functions. In the hippocampal region CA1, a slow gamma rhythm (30-80 Hz) generated in CA3 would support memory retrieval whereas a medium gamma rhythm (60-120 Hz) generated in the entorhinal cortex would support memory encoding. However, descriptions involving discrete gamma sub-bands can only partially account for the haphazard diversity of oscillatory behaviors observed in individual recordings during spatial navigation behavior. Here, we stress that transient gamma oscillatory episodes at any frequency or phase relative to the ongoing theta (4-12 Hz) rhythm can be recorded at any layer within CA1. Eventually, the commonly reported averages are dominated by a minority of very strong power events overshadowing gamma heterogeneity. Nevertheless, we show that such gamma diversity can be naturally explained by a simple mechanistic model, and that behavior-related information (position within a maze) can be decoded from most individual gamma events, despite their low power and erratic-like nature. Our results indicate that behavior specifically shapes ensembles of irregular hippocampal gamma oscillations, in a way which evolves with learning, depends on the hippocampal layer and is hard to reconcile with the hypothesis of rigid, narrowly tuned gamma sub-bands. Beyond randomness, the pervasive gamma diversity may thus reflect complexity at the "fringe-of-synchrony" likely functional but invisible to classic average-based analyses. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.15.512353v1?rss=1 Authors: Lind, S., Wu, Y., Sundqvist, M., Forsman, H., Dahlgren, C. Abstract: Allosterically modulated free fatty acid receptor 2 (FFA2R/GPR43) can be activated without the involvement of any orthosteric FFA2R agonist, by signals generated for example by P2Y2R, the G protein coupled receptor for ATP. An FFA2R specific positive allosteric modulator (PAM; Cmp58) was used to disclose the molecular mechanism by which signals generated by ATP/P2Y2R transactivates FFA2R. The P2Y2R induced signal that transactivates the allosterically modulated FFA2R was generated downstream of the Gq containing G protein that couple to P2Y2R. A receptor induced rise in the cytosolic concentration of ionized calcium ([Ca2+]i) was hypothesized to be the receptor transactivation signal. The Gq dependent transient rise in [Ca2+]i induced by the ATP activated P2Y2Rs was not affected by Cmp58. The hypothesis gained, however, support from the finding that the modulator transferred FFA2R to a Ca2+sensitive state. The rise in [Ca2+]i induced by the Ca2+ specific ionophore ionomycin, activated the allosterically modulated FFA2R. The response induced by ionomycin was rapidly terminated and the FFA2Rs could then no longer be activated by the orthosteric FFA2R agonist propionate or be transactivated by the signal generated by the activated ATP receptor. The desensitized/non-responding state of FFA2R was, however, revoked by an earlier described cross-sensitizing/activating allosteric FFA2R modulator. The receptor transactivation of the allosterically modulated FFA2Rs, represent a unique regulatory receptor cross-talk mechanism by which the activity of a G protein coupled receptor is controlled by a signaling system operating from the cytosolic side of the plasma membrane. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.05.510949v1?rss=1 Authors: Watts, M. E., Oksanen, M., Lejerkrans, S., Mastropasqua, F., Gorospe, M., Tammimies, K. Abstract: Circular RNAs (circRNAs) are emerging as a key component of the complex neural transcriptome implicated in brain development. However, the specific expression patterns and functions of circRNAs in human neuronal differentiation have not been explored. Using total RNA sequencing analysis, we identified expressed circRNAs during the differentiation of human neuroepithelial stem (NES) cells into developing neurons and discovered that many circRNAs originated from host genes with synaptic functions. Interestingly, when assessing population data and rare de novo variants in autism spectrum disorder (ASD) candidate host genes, exons giving rise to circRNAs had a significantly higher frequency of genetic variants. Screening for RNA-binding protein sites identified enrichment of Splicing Factor Proline and Glutamine Rich (SFPQ) motifs in increased circRNAs, several of which we validated as being reduced by SFPQ knockdown and enriched in SFPQ ribonucleoprotein complexes. Our study provides an in-depth characterisation of circRNAs in a human neuronal differentiation model and highlights SFPQ as both a regulator and binding partner of circRNAs elevated during neuronal maturation. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

Influence of fine structures on gyrosynchrotron emission of flare loops modulated by sausage modes by Mijie Shi et al. on Thursday 15 September Sausage modes are one leading mechanism for interpreting short period quasi-periodic pulsations (QPPs) of solar flares. Forward modeling their radio emission is crucial for identifying sausage modes observationally and for understanding their connections with QPPs. Using the numerical output from three-dimensional magnetohydrodynamic (MHD) simulations, we forward model the gyrosynchrotron (GS) emission of flare loops modulated by sausage modes and examine the influence of loop fine structures. The temporal evolution of the emission intensity is analyzed for an oblique line of sight crossing the loop center. We find that the low- and high-frequency intensities oscillate in-phase at the period of sausage modes for models with or without fine structures. For low-frequency emissions where the optically thick regime arises, the modulation magnitude of the intensity is dramatically reduced by the fine structures at some viewing angles. On the contrary, for high-frequency emissions where the optically thin regime holds, the effect of fine structures or viewing angle is marginal. Our results show that the periodic intensity variations of sausage modes are not wiped out by the fine structures, and sausage modes remains a promising candidate mechanism for QPPs even when flare loops are fine-structured. arXiv: http://arxiv.org/abs/http://arxiv.org/abs/2209.07176v1

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.31.506084v1?rss=1 Authors: Lugtmeijer, S., Geerligs, L., Tsvetanov, K. A., Mitchell, D. J., Campbell, K. L. Abstract: Working memory is critical to higher-order executive processes and declines throughout the adult lifespan. However, our understanding of the neural mechanisms underlying this decline is limited. Recent work suggests that functional connectivity between frontal control and posterior visual regions may be critical, but examinations of age differences therein have been limited to a small set of brain regions and extreme group designs (i.e., comparing young and older adults). In this study, we build on previous research by using a lifespan cohort and a whole-brain approach to investigate working memory load-modulated functional connectivity in relation to age and performance. The article reports on analysis of the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) data. Participants from a population-based lifespan cohort (N=111, age 23-86) performed a visual short-term memory task during functional magnetic resonance imaging. Visual short-term memory was measured with a delayed recall task for visual motion with three different loads. Whole-brain load-modulated connectivity was estimated using psychophysiological interactions in a hundred regions of interest, sorted into seven networks (Schaefer et al., 2018, Yeo et al., 2011). Results showed that load-modulated functional connectivity was strongest within the dorsal attention network followed by the visual network during encoding and maintenance. With increasing age, load-modulated functional connectivity strength decreased throughout the cortex. Within the dorsal attention network, increased load-modulated connectivity strength was related to better task performance in an age-invariant way. Our results demonstrate the widespread negative impact of age on the modulation of functional connectivity by working memory load. Older adults might already be close to ceiling in terms of their resources at the lowest load and therefore less able to further increase connectivity with increasing task demands. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

References Dr Guerra's synthesis of the relevant literature BioEssays, Volume: 39, Issue: 5, First published: 20 February 2017. Front Cardiovasc Med. 2020; 7: 2. --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

Bill and Jeff recap their Ep. 40 Youtube video - The Electro-Harmonix Blurst Modulated Filter, video out now.  Also, the guys discuss pedals in general, preferences and all kinds of interesting things related to guitars, pedal boards, bands and fan mail, while hanging out at The SoCal Riff Ranch!

The researchers recruited healthy older participants to two groups according to their history of tea drinking frequency and investigated both functional and structural networks to reveal the role of tea drinking on brain organization. The suppression of hemispheric asymmetry in the structural connectivity network was observed as a result of tea drinking. The authors did not observe any significant effects of tea drinking on the hemispheric asymmetry of the functional connectivity network. Dr. Junhua Li and Dr. Lei Feng said, "Tea has been a popular beverage since antiquity, with records referring to consumption dating back to the dynasty of Shen Nong (approximately 2700 BC) in China." Tea is consumed in diverse ways, with brewed tea and products with a tea ingredient extremely prevalent in Asia, especially in China and Japan. Although individual constituents of tea have been related to the roles of maintaining cognitive abilities and preventing cognitive decline, a study with behavioural and neurophysiological measures showed that there was a degraded effect or no effect when a constituent was administered alone and a significant effect was observed only when constituents were combined. The superior effect of the constituent combination was also demonstrated in a comparative experiment that suggested that tea itself should be administered instead of tea extracts; a review of tea effects on the prevention of Alzheimers disease, found that the neuroprotective role of herbal tea was apparent in eight out of nine studies. It is worth noting that the majority of studies thus far have evaluated tea effects from the perspective of neurocognitive and neuropsychological measures, with direct measurement of brain structure or function less-well represented in the extant literature. These studies focusing on brain regional alterations did not ascertain tea effects on interregional interactions at the level of the entire brain. The Li/Feng Research team concluded, "In summary, our study comprehensively investigated the effects of tea drinking on brain connectivity at both global and regional scales using multi-modal imaging data and provided the first compelling evidence that tea drinking positively contributes to brain structure making network organization more efficient." Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.102023 DOI - https://doi.org/10.18632/aging.102023 Full Text - https://www.aging-us.com/article/102023/text Correspondence to: Junhua Li email: junhua.li@essex.ac.uk and Lei Feng email: pcmfl@nus.edu.sg Keywords: tea drinking, brain efficiency, fMRI, DTI, default mode network, hemispheric asymmetry About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research as well as topics beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, cancer, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR among others), and approaches to modulating these signaling pathways. Please visit our website at http://www.Aging-US.com or connect with us on: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/agingus​ LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Aging-US is published by Impact Journals, LLC please visit http://www.ImpactJournals.com or connect with @ImpactJrnls Media Contact 18009220957x105 MEDIA@IMPACTJOURNALS.COM

Welcome to Balance and Moderation… A Wellness podcast, with some personality… Big love is the motto and our message is for everyone, so don't forget to share this with all the beautiful people in your life. Enjoy! Episode 33 is all about circadian rhythm. This is the 24-hour cycle in the physiological processes of human beings. Modulated by sleeping and eating are the daily patterns that affect brain wave activity, hormone production, cell regeneration, and other biological functions in the body. Check out our instagram @theBAMpodcast Send any questions and inquiries you have to balance.moderation@gmail.com Hosts: Sheridan Lee @TheSoulAndScience Rob Young @WellnessRob Show Links Circadian rhythm https://www.sciencedaily.com/terms/circadian_rhythm.htm The link between circadian rhythms and aging: Gene associated with longevity also regulates the body's circadian clock https://www.sciencedaily.com/releases/2013/06/130620132320.htm Disruption Of Circadian Rhythms Affects Both Brain And Body, Mouse Study Finds https://www.sciencedaily.com/releases/2009/10/091026225744.htm Disrupted circadian rhythms linked to later Parkinson's diagnoses https://www.sciencedaily.com/releases/2020/06/200615142802.htm Circadian rhythms help guide waste from brain https://www.sciencedaily.com/releases/2020/09/200902082326.htm Chronic drinking can disrupt circadian rhythms https://www.sciencedaily.com/releases/2010/08/100824161428.htm What is blue light? The effect blue light has on your sleep and more. https://www.health.harvard.edu/staying-healthy/blue-light-has-a-dark-side

Dr. Jasmin Jo interviews Dr. Caroline Chung about her paper: “A prospective phase II randomized trial of proton radiotherapy vs intensity modulated radiotherapy for patients with newly diagnosed GBM” published online in Neuro-Oncology in Feb 2021.

Gauge/Gravity Duality 2013

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.18.389106v1?rss=1 Authors: Jetta, D., Bahrani Fard, M. R., Sachs, F., Munechika, K., Hua, S. Z. Abstract: Adherent cells utilize local environmental cues to make decisions on their growth and movement. We have previously shown that HEK293 cells grown on the fibronectin stripe patterns were elongated. Here we show that Piezo1 function is involved in cell spreading. Inhibiting the Rho-ROCK pathway also reversibly inhibited cell extension indicating that myosin contractility is involved. Piezo1 expressing HEK cells plated on fibronectin stripes elongated, while a knockout of Piezo1 eliminated elongation. Inhibiting Piezo1 conductance using GsMTx4 or Gd3+ blocked cell spreading, but the cells grew thin tail-like extensions along the patterns. Images of GFP-tagged Piezo1 showed plaques of Piezo1 moving to the extrusion edges, co-localized with focal adhesions. Surprisingly, in non-spreading cells Piezo1 was located primarily on the nuclear envelope. The growth of thin extrusion tails did not occur in Piezo1 knockout cells suggesting that Piezo1 may have functions besides acting as a cation channel. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.10.376699v1?rss=1 Authors: Milne, A. E., Zhao, S., Tampakaki, C., Bury, G., Chait, M. Abstract: The brain is highly sensitive to auditory regularities and exploits the predictable order of sounds in many scenarios, from parsing complex auditory scenes to the acquisition of language. To understand the impact of stimulus predictability on perception it is important to determine how the discovery of predictable structure influences processing and attention. Here we use pupillometry to gain insight into the effect of sensory regularity on arousal. Pupillometry is a commonly used measure of salience and processing effort, with more perceptually salient or perceptually demanding stimuli consistently associated with larger pupil diameters. In two experiments we tracked human listeners' pupil dynamics while they listened to sequences of 50ms tone pips of different frequencies. The order of the tone pips was either random, or contained deterministic regularities (experiment 1, n = 18, 11 female) or a probabilistic structure (experiment 2, n = 20, 17 female). The sequences were rapid, preventing conscious tracking of sequence structure thus allowing us to focus on automatic extraction of different types of regularities. We hypothesized that if regularity facilitates processing, a smaller pupil diameter would be seen in response to regular relative to random patterns. Conversely, if regularity is associated with attentional capture (i.e. engages processing resources) the opposite pattern would be expected. In both experiments we observed a smaller sustained (tonic) pupil diameter for regular compared with random sequences, consistent with the former hypothesis and confirming that predictability facilitates sequence processing. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.11.378646v1?rss=1 Authors: Lee, W. H., Liu, W., Fan, J.-S., Yang, D. Abstract: The viral protease domain (NS3pro) of dengue virus is essential for virus replication and its cofactor NS2B is indispensable for the proteolytic function. Although several NS3pro-NS2B complex structures have been obtained, the dynamic property of the complex remains poorly understood. Using NMR relaxation techniques, here we found that NS3pro-NS2B exists in both closed and open conformations which are in dynamic equilibrium on a sub-millisecond timescale in aqueous solution. Our structural information indicates that the C-terminal region of NS2B is disordered in the open conformation but folded in the closed conformation. Using mutagenesis, we showed that the closed-open conformational equilibrium can be shifted by changing NS2B stability. Moreover, we revealed that the proteolytic activity of NS3pro-NS2B correlates well with the population of the closed conformation. Our results suggest that the closed-open conformational equilibrium can be used by both nature and man to control the replication of dengue virus. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.30.360990v1?rss=1 Authors: Peng, Y., Li, S., Onufriev, A., Landsman, D., Panchenko, A. R. Abstract: Despite histone tails' critical roles in epigenetic regulation, little is known about mechanisms of how histone tails modulate the nucleosomal DNA solvent accessibility and recognition of nucleosomes by other macromolecules. Here we generate extensive atomic level conformational ensembles of histone tails in the context of the full human nucleosome, totaling 26 microseconds of molecular dynamics simulations. We explore the histone tail binding with the nucleosomal and linker DNA and observe rapid conformational transitions between bound and unbound states allowing us to estimate kinetic and thermodynamic properties of the histone tail-DNA interactions. Different histone types exhibit distinct, although conformationally heterogeneous, binding modes and each histone type occludes specific DNA regions from the solvent. Using a comprehensive set of experimental data on nucleosome structural complexes, we find that majority of the studied nucleosome-binding proteins and histone tails target mutually exclusive regions on nucleosomal or linker DNA around the super-helical locations {+/-}1, {+/-}2, and {+/-}7. This finding is explained within the generalized competitive binding and tail displacement models of partners recruitment to nucleosomes. Finally, we demonstrate the crosstalk between different histone post-translational modifications, where charge-altering modifications and mutations typically suppress tail-DNA interactions and enhance histone tail dynamics. Copy rights belong to original authors. Visit the link for more info

The Ubercast EP40Connect with Uberjak'd:linktr.ee/uberjakd1. ID - ID2. The Spook Returns - B3nte. Badjack & KSHMR3. Bang Bang Boom - Krunk & Tommie Sunshine4. Accelerate - Eric Mendoza & Zerocool5. ID - ID6. Party Till We Die - Timmy Trumpet & MakJ7. When the Funk Drops [Uberjakd edit] - Uberjakd & Deorro f. Far East Movement8. Queef - Joel Fletcher & Deorro9. Jetfuel [Uberjakd intro edit] - Uberjakd & Joel Fletcher10. Shake it - Joey Dale & Maddix11. Disco Weapon - MOTi & Maurice West12. Muscular - Ibranvoski & Syzz13. Close [Brooks remix] - IZECOLD14. ILYSM - Autoerotique & Steve Aoki15. I Got my - Bougenvilla16. Blip - D.O.D17. Flute [Uberjakd remix] - New World Sound18. Get Down - Hardwell & W&W19. Pursuit of Love [Jaymac edit] - Kid Cudi Vs Dimitri Vegas and Like mike20. Big Fat Spotless [Uber edit] - Martin Garrix & Jay Hardway21. Certified - Morten22. Caribbean Rave - W&W23. Omnia - Hold me24. Amsterdam - Jay Hardway25. Acid Rain - Will Sparks & Joel fletcher26. 7 Nation Mumbai [Uber edit] - JDG & Samuel james27. Make it right [Ilan Bluestone remix] - Armin28. Modulated lions - Ilan Bluestone29. Mosquito - Neelix30. Colors - Avalon, Tristan & Vini Vici31. FTS (Ridvan edit] - Showtek32. Turn day to night - The Galaxy33. Turn up - EMME x Erotic Cafe34. Invisible Children [Jinco & Francis edit] - Tigerlilly & KSHMR35. Swords [Bad Royale remix] - M.I.A36. Mr Brightside [Two Friends remix] - The killers37. Fix You Up - Uberjakd f. Yton