Podcasts about mtorc1

Play Episode Listen Later Oct 23, 2024 37:12

In this installment of the Longevity & Aging Series, Dr. Jon Berner from the Woodinville Psychiatric Associates in Woodinville, WA, joined host Dr. Evgeniy Galimov to discuss a research paper he co-authored that was published in Volume 16, Issue 14 of Aging (Aging-US), entitled, “mTORC1 activation in presumed classical monocytes: observed correlation with human size variation and neuropsychiatric disease.” DOI - https://doi.org/10.18632/aging.206033 Corresponding author - Jon Berner - jonbernermd@gmail.com Video interview - https://www.youtube.com/watch?v=45L89MaJ7qA Abstract Background: Gain of function disturbances in nutrient sensing are likely the largest component in human age-related disease. Mammalian target of rapamycin complex 1 (mTORC1) activity affects health span and longevity. The drugs ketamine and rapamycin are effective against chronic pain and depression, and both affect mTORC1 activity. Our objective was to measure phosphorylated p70S6K, a marker for mTORC1 activity, in individuals with psychiatric disease to determine whether phosphorylated p70S6K could predict medication response. Methods: Twenty-seven females provided blood samples in which p70S6K and phosphorylated p70S6K were analyzed. Chart review gathered biometric measurements, clinical phenotypes, and medication response. Questionnaires assessed anxiety, depression, autism traits, and mitochondrial dysfunction, to determine neuropsychiatric disease profiles. Univariate and multivariate statistical analyses were used to identify predictors of medication response. Results: mTORC1 activity correlated highly with both classical biometrics (height, macrocephaly, pupil distance) and specific neuropsychiatric disease profiles (anxiety and autism). Across all cases, phosphorylated p70S6K was the best predictor for ketamine response, and also the best predictor for rapamycin response in a single instance. Conclusions: The data illustrate the importance of mTORC1 activity in both observable body structure and medication response. This report suggests that a simple assay may allow cost-effective prediction of medication response. Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.206033 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, ketamine, lithium, monocyte, mTORC1, rapamycin About Aging-US The mission of the journal is to understand the mechanisms surrounding aging and age-related diseases, including cancer as the main cause of death in the modern aged population. The journal aims to promote 1) treatment of age-related diseases by slowing down aging, 2) validation of anti-aging drugs by treating age-related diseases, and 3) 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

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mTORC1 in Classical Monocytes: Links to Human Size Variation & Neuropsychiatric Disease

Play Episode Listen Later Aug 7, 2024 2:24

BUFFALO, NY- August 7, 2024 – A new #research paper was #published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science), Volume 16, Issue 14 on July 26, 2024, entitled, “mTORC1 activation in presumed classical monocytes: observed correlation with human size variation and neuropsychiatric disease.” In this new study, researchers Karl Berner, Naci Oz, Alaattin Kaya, Animesh Acharjee, and Jon Berner from Woodinville Psychiatric Associates, Virginia Commonwealth University, University of Birmingham, University Hospitals Birmingham, and MRC Health Data Research UK, aimed to measure phosphorylated p70S6K, a marker for mTORC1 activity, in individuals with psychiatric disease to determine whether phosphorylated p70S6K could predict medication response. Their results showed that mTORC1 activity correlated highly with classical biometrics (height, macrocephaly, pupil distance) and specific neuropsychiatric disease profiles (anxiety and autism). “Our data suggest that human variability of mTORC1 gain of function observed during the differentiation of stem-like monocytes into vascular tissue-resident macrophages correlates with physical size, subsets of neuropsychiatric disease, and clinical ketamine or rapamycin response.” DOI - https://doi.org/10.18632/aging.206033 Corresponding author - Jon Berner - jonbernermd@gmail.com Video short - https://www.youtube.com/watch?v=EXzX6CjtAHc Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.206033 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, ketamine, lithium, monocyte, mTORC1, rapamycin About Aging-US The mission of the journal is to understand the mechanisms surrounding aging and age-related diseases, including cancer as the main cause of death in the modern aged population. The journal aims to promote 1) treatment of age-related diseases by slowing down aging, 2) validation of anti-aging drugs by treating age-related diseases, and 3) 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

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What the heck is mTOR?

The Lab Report

Play Episode Listen Later Aug 6, 2024 24:58

There are a lot of terms bantered about in the biohacker and longevity space. With that, you've likely heard of mTOR – mechanistic (mammalian) target of rapamycin. But what exactly is it? mTOR is a key regulator in your body's metabolic and growth processes. It integrates various signals, including nutrients and growth factors, to control processes like protein synthesis, autophagy, and lipid metabolism. Because it regulates growth, dysregulation of mTOR has been implicated in various diseases, including cancer. In today's episode, we simplify the science behind mTOR – mechanistic target of rapamycin. This crucial enzyme may be the key to unlocking groundbreaking advancements in wellness, anti-aging, disease prevention, and health optimization. Today on The Lab Report: 3:00 mTOR – Why are we even covering this topic? 4:40 What is it? Muscle growth vs. autophagy 6:25 Why is it called mTOR? 9:00 Highly conserved and in every cell, every organ 10:30 mTORC1 and mTORC2 11:25 Influences and sensors – it's more than leucine 14:25 Dysregulation of mTOR – does protein cause cancer? 17:30 Should people take rapamycin for longevity? 20:20 Question of the Day Where does mTOR work in muscle protein synthesis? Additional Resources: Genova Connect **PROMO CODE TheLabReport20 for 20% off your purchase** Subscribe, Rate, & Review The Lab Report Thanks for tuning in to this week's episode of The Lab Report, presented by Genova Diagnostics, with your hosts Michael Chapman and Patti Devers. If you enjoyed this episode, please hit the subscribe button and give us a rating or leave a review. Don't forget to visit our website, like us on Facebook, follow us on Twitter, Instagram, and LinkedIn. Email Patti and Michael with your most interesting and pressing questions on functional medicine: podcast@gdx.net. And, be sure to share your favorite Lab Report episodes with your friends and colleagues on social media to help others learn more about Genova and all things related to functional medicine and specialty lab testing. To find a qualified healthcare provider to connect you with Genova testing, or to access select products directly yourself, visit Genova Connect. Disclaimer: The content and information shared in The Lab Report is for educational purposes only and should not be taken as medical advice. The views and opinions expressed in The Lab Report represent the opinions and views of Michael Chapman and Patti Devers and their guests.See omnystudio.com/listener for privacy information.

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GZ17-6.02 With Proteasome Inhibitors Kills Multiple Myeloma Cells

Play Episode Listen Later Mar 6, 2024 3:38

BUFFALO, NY- March 6, 2024 – A new #researchpaper was #published in Oncotarget's Volume 15 on March 5, 2024, entitled, “GZ17-6.02 interacts with proteasome inhibitors to kill multiple myeloma cells.” In this new study, researchers Laurence Booth, Jane L. Roberts, Cameron West, and Paul Dent from Virginia Commonwealth University and Genzada Pharmaceuticals investigated GZ17-6.02, a synthetically manufactured compound containing isovanillin, harmine and curcumin, in multiple myeloma cells. GZ17-6.02 has undergone phase I evaluation in patients with solid tumors (NCT03775525) with a recommended phase 2 dose (RP2D) of 375 mg PO BID. GZ17-6.02 was more efficacious as a single agent at killing multiple myeloma cells than had previously been observed in solid tumor cell types. “GZ17-6.02 interacted with proteasome inhibitors in a greater than additive fashion to kill myeloma cells and alone it killed inhibitor-resistant cells to a similar extent.” The drug combination of GZ17-6.02 and bortezomib activated ATM, the AMPK and PERK and inactivated ULK1, mTORC1, eIF2α, NFκB and the Hippo pathway. The combination increased ATG13 S318 phosphorylation and the expression of Beclin1, ATG5, BAK and BIM, and reduced the levels of BCL-XL and MCL1. GZ17-6.02 interacted with bortezomib to enhance autophagosome formation and autophagic flux, and knock down of ATM, AMPKα, ULK1, Beclin1 or ATG5 significantly reduced both autophagy and tumor cell killing. Knock down of BAK and BIM significantly reduced tumor cell killing. The expression of HDACs1/2/3 was significantly reduced beyond that previously observed in solid tumor cells and required autophagy. This was associated with increased acetylation and methylation of histone H3. Combined knock down of HDACs1/2/3 caused activation of ATM and the AMPK and caused inactivation of ULK1, mTORC1, NFκB and the Hippo pathway. HDAC knock down also enhanced ATG13 phosphorylation, increased BAK levels and reduced those of BCL-XL. “Collectively, our present studies support performing additional in vivo studies with multiple myeloma cells.” DOI - https://doi.org/10.18632/oncotarget.28558 Correspondence to - Paul Dent - paul.dent@vcuhealth.org Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28558 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, autophagy, ER stress, GZ17-6.02, bortezomib, proteasome inhibitor About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

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GZ17-6.02 With Bexarotene Kills Mycosis Fungoides Cells

Play Episode Listen Later Feb 26, 2024 3:32

BUFFALO, NY- February 26, 2024 – A new #research paper was #published in Oncotarget's Volume 15 on February 8, 2024, entitled, “GZ17-6.02 interacts with bexarotene to kill mycosis fungoides cells.” In this new study, researchers Michael R. Booth, Laurence Booth, Jane L. Roberts, Cameron West, and Paul Dent from Virginia Commonwealth University and Genzada Pharmaceuticals investigated the therapeutic agent GZ17-6.02, composed of curcumin, harmine and isovanillin. “Combined with our curcumin findings, we believe that isovanillin can complex with curcumin and harmine to create an entity with unique biology when compared to the three individual agents.” GZ17-6.02 has undergone phase I evaluation in patients with solid tumors (NCT03775525) with an RP2D of 375 mg PO BID. The biology of GZ17-6.02 in malignant T cells and in particular those derived from mycosis fungoides (MF) patients, has not previously been studied. The researchers found that GZ17-6.02 alone and in combination with standard-of-care agents was effective in killing MF cells. “All three components are necessary for optimal killing of MF cells.” GZ17-6.02 activated ATM, the AMPK, NFκB and PERK and inactivated ERK1/2, AKT, ULK1, mTORC1, eIF2α, and reduced the expression of BCL-XL and MCL1. GZ17-6.02 increased ATG13 S318 phosphorylation and the expression of Beclin1, ATG5, BAK and BIM. GZ17-6.02 in a dose-dependent fashion enhanced autophagosome formation and autophagic flux, and tumor cell killing. Signaling by ATM and AMPK were both required for efficient killing but not for the dose-response effect whereas ER stress (eIF2α) and macroautophagy (Beclin1, ATG5) were required for both efficient killing and the dose-response. Knock down of the death receptor CD95 reduced killing by ~20% and interacted with autophagy inhibition to further reduce killing, collectively, by ~70%. Inhibition of autophagy and knock down of death-mediators downstream of the mitochondrion, AIF and caspase 3, almost abolished tumor cell killing. Hence in MF cells, the team wrote that GZ17-6.02 is a multi-factorial killer, utilizing ER stress, macroautophagy, death receptor signaling and directly causing mitochondrial dysfunction.” “We discovered that GZ17-6.02 containing harmine, isovanillin and curcumin caused more tumor cell killing than any of the agents individually or in pairs, and that it could interact in an additive fashion with standard of care MF drugs such as bexarotene and vorinostat to cause additional tumor cell death.” DOI - https://doi.org/10.18632/oncotarget.28557 Correspondence to - Paul Dent - paul.dent@vcuhealth.org Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28557 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, autophagy, ER stress, GZ17-6.02, bexarotene, vorinostat About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

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Biochemical Mosaic I.c.11. Glycerolipid metabolism coupled to mTORC1 enzyme phosphorylation necessarily involves a complete analysis of membrane lipid molecular species distribution.DJGPhD.20.2.24

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Play Episode Listen Later Feb 20, 2024 29:56

References Nature . 2019 Nov;575(7782):361-365. Adv Biol Regul. 2017 May:64:39-48 J Biol Chem. 2013 Apr 5; 288(14): 9933–9945 Redox Biology.2017. Volume 11, April. Pages 622-630 Biochim Biophys Acta. 2011 Jun;1811(6):377-85 Dr Guerra: lipid lectures archives Schubert, F. 1816. Symphony #5 https://youtu.be/OHkot1TmvZU?si=uYtQfxUegl3KrkRK Newman, L Darby K. 1954. Marilyn Monroe. The River of No Return https://youtu.be/dLzeHkEQe9g?si=nXMd20gstc3vVdgl --- 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

Biochemical Mosaic I c.10. Is PE depletion reversed by mTORC1 phosphorylation of LIPIN1 or is DAG authentically activating CCT via membrane association thus obtaining robust PL synthesis? DJGPhD.

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Play Episode Listen Later Feb 19, 2024 30:00

References Biochim Biophys Acta. 2011 Jun;1811(6):377-85 Am J Physiol Lung Cell Mol Physiol 2001. 281: L98–L107. Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism 1997. Volume 1348, Issues 1–2, 4 Pages 79-90. Am J Physiol Lung Cell Mol Physiol 2001. Volume 281. Issue 1July Pages L108-L118 JBC 1991. Volume 266, Issue 36, 25 December. Pages 24503-24508 Progress in Lipid Research. 2015. Volume 59, ages 147-171 Nature 2019. volume 575, pages 361–365 --- 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

Biochemical Mosaic Event Ontologies I. Phosphatidic Acid Phosphatase. Autophagy commitment is linked to mTORC1 v. AMPK oppostional kinase networks maintaining proteostasis and lipid homeostasis.DJGPhD

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Play Episode Listen Later Feb 9, 2024 30:00

References Nature 2019.volume 575, pages 361–365 Cells 2022, 11(21), 3339 Guerra: Polypeptide, endomembranous lipid homeostasis, and bioenergetics lecture archives. --- 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

Dr. Keith Baar - Rethinking Tendon Management, Treatment & Pathophysiology

The Sports Medicine Project

Play Episode Listen Later Nov 16, 2023 90:03

Dam! You're all going to love this!Welcome Dr Keith Baar. If you see tendons in clinic, you need to listen to this!What does Keith do? (In his own words)The goal of my laboratory is to understand the molecular determinants of musculoskeletal development and the role of exercise in improving health and performance. To achieve this goal, we work on muscle, tendon, and ligaments from 2- and 3-dimensional tissue culture, in vivo wild type and genetically modified animals, and humans. Of particular interest are: 1) the interplay between nutrition and exercise and the mammalian target of rapamycin complex 1 (mTORC1) in the maintenance of muscle mass; 2) the role of the amino acid transceptor LAT1 in the activation of protein synthesis and maintenance of muscle mass; 3) the mechanism of ER stress-induced loss of protein synthesis and how this leads to anabolic resistance in muscle; and 4) the role of growth factors and loading on the activation of the Egr-1 transcription factor and the development and mechanics of ligaments. Our laboratory discovered that mTORC1 was activated by resistance exercise and that this correlates with the degree of skeletal muscle hypertrophy. Since then, we have focused on mTORC1 and its regulation by loading and nutrients. We have shown that: 1) mTORC1 is activated directly by load in a growth factor-independent manner; 2) a1-AMPK regulates mTORC1 activity during overload; 3) following a high fat diet the unfolded protein response, through inhibition of PKB, can attenuate mTORC1 activation; and 4) muscle signaling and protein synthesis after exercise are modified by nutritional interventions that are rich in leucine. Our laboratory has also developed a number of 2- and 3-dimensional tissue culture assays that can be used to study the effects of genes and nutrients on muscle, tendon, and ligament function. These studies have a direct clinical application and we work closely with colleagues in orthopedics, internal medicine, and the cancer center to develop resistance exercise, nutritional, and novel small molecule interventions that prevent muscle wasting from cachexia and sarcopenia and improve muscle function and quality of life.https://www.daverenfrew.comUpgrade your clinical skills and become a patreon:https://patreon.com/SportsMedicineProject?utm_medium=clipboard_copy&utm_source=copyLink&utm_campaign=creatorshare_creator&utm_content=join_linkSign up for a free weekly Research review about topics related to Sports Medicine straight to your email: https://gmail.us14.list-manage.com/subscribe?u=c3dca95db0740390c605a128e&id=b41f1293caRead through our already written blogs:https://achievepodiatry.com.au

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Episode 82 with Keith Baar, Ph.D.: How to Support & Maintain Healthy Tendons & Ligaments

Nutritional Revolution Podcast

Play Episode Listen Later Sep 26, 2023 61:10

In this week's episode, we talk to researcher and professor Keith Baar, Ph,D., about:What to do when you have injuries to your tendons/ligamentsHow to support and maintain healthy tendons and ligamentsCollagen use - does it work?Pro tip - watch this on our YouTube channel!Keith is the head of the Functional Molecular Biology Laboratory in the Department of Neurobiology, Physiology, and Behavior at the University of California, Davis. He is a molecular exercise physiologist and is leading a team of researchers attempting to develop ways to improve muscle, tendon, and ligament function.The goal of his laboratory is to understand the molecular determinants of musculoskeletal development and the role of exercise and nutrition in improving health and performance. To achieve this goal, he and his team work on muscle, tendon, and ligaments from 2- and 3-dimensional tissue culture, in vivo wild type and genetically modified animals, and humans.His study interests include the interplay between nutrition and exercise and the mechanistic target of rapamycin complex 1 (mTORC1) in the maintenance of muscle mass; the role of a ketogenic diet in improving age-related declines in muscle and brain function; and the role of different types of loading on the development and mechanics of ligaments.Please note that this podcast is created strictly for educational purposes and should never be used for medical diagnosis and treatment.See you in the next episode!***1:1 Coaching: Through 10/1/23, NEW CUSTOMERS can get $300 off 1:1 support! (Must pay 3 months in advance) Book your session today.Supplements That Improve Performance Mini CourseMentioned:Stay up-to-date with all of Keith Baar's exciting research and workTwitter: @MuscleScienceKeith's Google ScholarThe Burden and Risk Factors of Patellar and Achilles Tendinopathy in Youth BasketballAncient Egyptians & wooden splints/castsStress shielding of patellar tendon: effect on small-diameter collagen fibrils in rabbit modelMORE NR New customers save 10% off all products on our website with the code NEWNR10 If you would like to work with our practitioners, click here: https://nutritional-revolution.com/work-with-us/ Save 20% on all supplements at our trusted online source: https://us.fullscript.com/welcome/kchannell Join Nutritional Revolution's The Feed Club to get $20 off right away with an additional $20 Feed credit drop every 90 days.: https://thefeed.com/teams/nutritional-revolution If you're interested in sponsoring Nutritional Revolution Podcast, shoot us an email at nutritionalrev@gmail.com.

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#272 ‒ Rapamycin: potential longevity benefits, surge in popularity, unanswered questions, and more | David Sabatini, M.D., Ph.D. and Matt Kaeberlein, Ph.D.

The Peter Attia Drive

Play Episode Listen Later Sep 25, 2023 170:40

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter's Weekly Newsletter In this episode of The Drive, Peter welcomes guests David Sabatini and Matt Kaeberlein, two world-leading experts on rapamycin and mTOR. David and Matt begin by telling the fascinating story of the discovery of rapamycin and its brief history as a pharmacological agent in humans. They then unravel the function of mTOR, a central regulator of numerous biological processes, and they discuss the pathways through which rapamycin exerts its potential benefits on lifespan. They touch upon initial studies that suggested rapamycin may have geroprotective effects and the ongoing research that continues to shed light on this unique molecule. Furthermore, they discuss the elusive details surrounding the frequency and dosing of rapamycin use in humans, and Peter emphasizes his reservations about indiscriminately prescribing rapamycin as a longevity drug for patients. We discuss: David and Matt's expertise in mTOR and rapamycin [3:00]; The discovery of rapamycin and its first use in humans as an immunosuppressant [13:15]; The emergence of rapamycin as a molecule with the potential to prolong lifespan [19:30]; The groundbreaking rapamycin study on mouse lifespan extension and the open questions about the timing and frequency of dosing [26:00]; Explaining mTOR and the biology behind rapamycin's effects [35:30]; Differences in how rapamycin inhibits mTOR complex 1 (MTORC1) versus mTOR complex 2 (MTORC2) [45:15]; Reconciling the biochemical mechanism of rapamycin with its longevity benefit [49:15]; Important discoveries about the interplay of amino acids (leucine in particular) and mTOR [54:15]; Reconciling rapamycin-mediated mTOR inhibition with mTOR's significance in building and maintaining muscle [1:01:30]; Unanswered questions around the tissue specificity of rapamycin [1:08:30]; What we know about rapamycin's ability to cross the blood-brain barrier and its potential impacts on brain health and neurodegeneration [1:13:45]; Rapamycin may act as an immune modulator in addition to immunosuppressive effects [1:21:30]; Might rapamycin induce changes in T cell methylation patterns, potentially reversing biological aging? [1:34:15]; Rapamycin side effects and impacts on mental health: fascinating results of Matt's survey on off-label rapamycin use [1:42:00]; The impact of taking rapamycin in people who contracted COVID-19: more insights from Matt's survey [1:51:15]; What David would like to study with mTOR inhibitors [1:54:45]; Joan Mannick's studies of RTB101 and other ATP-competitive inhibitors of mTOR [2:00:30]; The impact of mTOR inhibition on autophagy and inflammation and a discussion of biomarkers [2:10:00]; The Dog Aging Project: what we've learned and what's to come from testing rapamycin in companion dogs [2:17:30]; Preliminary results of primate studies with rapamycin [2:24:45]; Dosing of rapamycin [2:27:45]; The effect of rapamycin on fertility [2:36:45]; The outlook for future research of rapamycin and the development of rapalogs [2:39:00]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

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Dectin-1 Stimulation Promotes Distinct Inflammatory Signature in HIV and Aging

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Play Episode Listen Later Aug 31, 2023 4:10

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 16, entitled, “Dectin-1 stimulation promotes a distinct inflammatory signature in the setting of HIV-infection and aging.” Dectin-1 is an innate immune receptor that recognizes and binds β-1, 3/1, 6 glucans on fungi. In this new study, researchers Archit Kumar, Jiawei Wang, Allen Esterly, Chris Radcliffe, Haowen Zhou, Brent Vander Wyk, Heather G. Allore, Sui Tsang, Lydia Barakat, Subhasis Mohanty, Hongyu Zhao, Albert C. Shaw, and Heidi J. Zapata evaluated Dectin-1 function in myeloid cells in a cohort of HIV-positive and HIV-negative young and older adults. “The HIV-positive and HIV-negative groups were comparable in age and gender distribution, incidence of comorbidities such as diabetes, metabolic syndrome, cardiovascular disease and pulmonary disease.” Stimulation of monocytes with β-D-glucans induced a pro-inflammatory phenotype in monocytes of HIV-infected individuals that was characterized by increased levels of IL-12, TNF-α, and IL-6, with some age-associated cytokine increases also noted. Dendritic cells showed a striking HIV-associated increase in IFN-α production. These increases in cytokine production paralleled increases in Dectin-1 surface expression in both monocytes and dendritic cells that were noted with both HIV and aging. Differential gene expression analysis showed that HIV-positive older adults had a distinct gene signature compared to other cohorts characterized by a robust TNF-α and coagulation response (increased at baseline), a persistent IFN-α and IFN-γ response, and an activated dendritic cell signature/M1 macrophage signature upon Dectin-1 stimulation. Dectin-1 stimulation induced a strong upregulation of MTORC1 signaling in all cohorts, although increased in the HIV-Older cohort (stimulation and baseline). In sum, this study demonstrates that the HIV Aging population has a distinct immune signature in response to Dectin-1 stimulation. This signature may contribute to the pro-inflammatory environment that is associated with HIV and aging. “Overall, this study demonstrates that age, HIV-infection and co-morbidities can alter the individual immune response. In particular our study showed a unique immune signature in the setting of both HIV and aging in response to Dectin-1 stimulation.” DOI - https://doi.org/10.18632/aging.204927 Corresponding author - Heidi J. Zapata - heidi.zapata@yale.edu Video short - https://www.youtube.com/watch?v=MpMBDvv0dDI Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204927 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, immune response, innate immune cells, HIV-infection, dectin-1 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

Stimulation of mRNA translation rescues hippocampal synaptic plasticity and memory in mouse models of Alzheimer's disease

Play Episode Listen Later Aug 3, 2023

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.08.03.551808v1?rss=1 Authors: Ribeiro, F. C., Cozachenco, D., Argyrousi, E. K., Staniszewski, A., Wiebe, S., Calixtro, J. D., Soares-Neto, R., Al-Chami, A., El Sayegh, F., Bermudez, S., Arsenault, E., Cossenza, M., Lacaille, J.-C., Nader, K., Sun, H., De Felice, F. G., Lourenco, M. V., Arancio, O., Aguilar-Valles, A., Sonenberg, N., Ferreira, S. T. Abstract: Impaired synaptic plasticity and progressive memory deficits are major hallmarks of Alzheimer's disease (AD). Hippocampal mRNA translation, required for memory consolidation, is defective in AD. Here, we show that genetic reduction of the translational repressors, Fragile X messenger ribonucleoprotein (FMRP) or eukaryotic initiation factor 4E (eIF4E)-binding protein 2 (4E-BP2), ameliorated the inhibition of hippocampal protein synthesis and memory impairment induced by AD-linked amyloid-b; oligomers (AbOs) in mice. Furthermore, systemic treatment with (2R,6R)-hydroxynorketamine (HNK), an active metabolite of the antidepressant ketamine, prevented deficits in hippocampal mRNA translation, long-term potentiation (LTP) and memory induced by AbOs in mice. HNK activated hippocampal signaling by extracellular signal-regulated kinase 1/2 (ERK1/2), mechanistic target of rapamycin (mTOR), and p70S6 kinase 1 (S6K1)/ribosomal protein S6 (S6), which promote protein synthesis and synaptic plasticity. S6 phosphorylation instigated by HNK was mediated by mTOR in hippocampal slices, while rescue of hippocampal LTP and memory in HNK-treated AbO-infused mice depended on ERK1/2 and, partially, on mTORC1. Remarkably, treatment with HNK corrected LTP and memory deficits in aged APP/PS1 mice. RNAseq analysis showed that HNK reversed aberrant signaling pathways that are upregulated in APP/PS1 mice, including inflammatory and hormonal responses and programmed cell death. Taken together, our findings demonstrate that upregulation of mRNA translation corrects deficits in hippocampal synaptic plasticity and memory in AD models. The results raise the prospect that HNK could serve as a therapeutic to reverse memory decline in AD. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Excitatory neuron-specific suppression of the integrated stress response pathway contributes to autism-related phenotypes in a mouse model of fragile X syndrome

Play Episode Listen Later Apr 24, 2023

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.24.538123v1?rss=1 Authors: Hooshmandi, M., Sharma, V., Perez, C. T., Sood, R., Simbriger, K., Wong, C., Lister, K. C., Guzman, A. U., Bartley, T. D., Rocha, C., Maussion, G., Nadler, E., Roque, P. M., Gantois, I., Popic, J., Levesque, M., Kaufman, R. J., Avoli, M., Sanz, E., Nader, K., Hagerman, R. J., Durcan, T. M., Costa-Mattioli, M., Lacaille, J.-C., Martinez-Cerdeno, V., Gibson, J. R., Huber, K., Sonenberg, N., Gkogkas, C. G., Khoutorsky, A. Abstract: Dysregulation of protein synthesis is one of the key mechanisms underlying autism spectrum disorder (ASD). However, the role of a major pathway controlling protein synthesis, the integrated stress response (ISR), in ASD remains poorly understood. Here, we demonstrate that the main arm of the ISR, eIF2 phosphorylation (p-eIF2), is suppressed in excitatory but not inhibitory neurons in a mouse model of fragile X syndrome (FXS; Fmr1-/y). We further show that the decrease in p-eIF2 is mediated via activation of the mTORC1. Genetic reduction of p-eIF2 only in excitatory neurons is sufficient to increase general protein synthesis and cause autism-like behavior. In Fmr1-/y mice, genetic restoration of p-eIF2 solely in excitatory neurons reverses elevated protein synthesis and rescues autism-related phenotypes. Thus, we reveal a previously unknown causal relationship between excitatory neuron-specific translational control via the ISR pathway, general protein synthesis and core phenotypes reminiscent of autism in a mouse model of FXS. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

When ketones will kill you & when they'll protect you | Episode 30

vlmd rounds

Play Episode Listen Later Apr 11, 2023 56:45

Title: When ketones will kill you & when they'll protect youIt's important to know when ketones are good for you and when they are bad for you. What do we know about heart function on chronic ketone body exposure? What do ketones have to do with mTORC1 and v-ATPases? How did amino acids sneak into this episode??? Check out Episode 30 of vlmd rounds. For more info, visit www.VyvyaneLohMD.com

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The human acetylcholinesterase c-terminal T30 peptide activates neural growth through an alpha 7 nicotinic acetylcholine receptor mTOR pathway

Play Episode Listen Later Apr 7, 2023

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.07.536081v1?rss=1 Authors: Graur, A., Kabbani, N. Abstract: Acetylcholinesterase (AChE) is a highly conserved enzyme responsible for the regulation of acetylcholine signaling within the brain and periphery. AChE has also been shown to participate in non-enzymatic activity and contributing to development and aging. In particular, enzymatic cleavage of the carboxy terminal region of the synaptic AChE isoform, AChE-T, is shown to generate a bioactive T30 peptide that binds to the 7 nicotinic acetylcholine receptor (nAChR) at synapses. Here, we explore intracellular mechanisms of T30 signaling within the human cholinergic neural cell line SH-SY5Y using high performance liquid chromatography (HPLC) coupled to electrospray ionization mass spectrometry (ESI-MS/MS). Proteomic analysis of cells exposed to (100nM) T30 for 3-days reveals significant changes within proteins important for cell growth. Specifically, bioinformatic analysis identifies proteins that converge onto the mammalian target of rapamycin (mTOR) pathway signaling. Functional experiments confirm that T30 regulates neural cell growth via mTOR signaling and 7 nAChR activation. In addition, T30 was found promote mTORC1 pro-growth signaling through an increase in phosphorylated elF4E, and a decrease in autophagy LC3B-II level. Taken together, our findings define mTOR as a novel pathway activated by the T30 cleavage peptide of AChE and suggest a role for mTOR signaling in cholinergic aspects of brain development, as well as disease. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

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Efficient genetic editing of human intestinal organoids using ribonucleoprotein-based CRISPR

Play Episode Listen Later Mar 31, 2023

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.31.535108v1?rss=1 Authors: Skoufou-Papoutsaki, N., Adler, S., D'Santos, P., Mannion, L., Mehmed, S., Kemp, R., Smith, A., Perrone, F., Nayak, K., Russell, A., Zilbauer, M., Winton, D. J. Abstract: Organoids are currently one of the most widely used ex vivo models in epithelial biology. Combined with genetic editing strategies, organoids offer a promise of rapid and efficient investigation of gene function in many models of human disease. However, to date, the editing efficiency of organoids with the use of non-viral electroporation methods has been only up to 30%, with implications for the subsequent need for selection including including turnaround time and exhaustion or adaptation of the organoid population. Here, we describe an efficient method of intestinal organoid editing using a Ribonucleoprotein CRISPR-based approach. Editing efficiencies of up to 98% in target genes were robustly achieved across different anatomical gut locations and developmental timepoints from multiple patient samples with no off-target editing. The method allowed us to study the effect of the loss of the tumour suppressor gene, PTEN, in normal human intestinal cells. Analysis of PTEN deficient organoids defined phenotypes that likely relate to its tumour suppressive function in vivo, such as a proliferative advantage and increased organoid budding. Transcriptional profiling revealed differential expression of genes in pathways commonly known to be associated with PTEN loss including mTORC1 activation. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

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Quantitative proteomics and phosphoproteomics of PPP2R5D variants reveal deregulation of RPS6 phosphorylation through converging signaling cascades

Play Episode Listen Later Mar 27, 2023

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.27.534397v1?rss=1 Authors: Smolen, K. A., Papke, C. M., Swingle, M. R., Musiyenko, A., Li, C., Camp, A. D., Honkanen, R. E., Kettenbach, A. N. Abstract: Variants in the phosphoprotein phosphatase-2 regulatory protein-5D gene (PPP2R5D) cause the clinical phenotype of Jordan's Syndrome (PPP2R5D-related disorder), which includes intellectual disability, hypotonia, seizures, macrocephaly, autism spectrum disorder and delayed motor skill development. The disorder originates from de novo single nucleotide mutations, generating missense variants that act in a dominant manner. Pathogenic mutations altering 13 different amino acids have been identified, with the E198K variant accounting for ~40% of reported cases. Here, we use CRISPR-PRIME genomic editing to introduce a transition (c.592G greater than A) in the PPP2R5D allele in a heterozygous manner in HEK293 cells, generating E198K-heterozygous lines to complement existing E420K variant lines. We generate global protein and phosphorylation profiles of wild-type, E198K, and E420K cell lines and find unique and shared changes between variants and wild-type cells in kinase- and phosphatase-controlled signaling cascades. As shared signaling alterations, we observed ribosomal protein S6 (RPS6) hyperphosphorylation, indicative of increased ribosomal protein S6-kinase activity. Rapamycin treatment suppressed RPS6 phosphorylation in both, suggesting activation of mTORC1. Intriguingly, our data suggest AKT-dependent (E420K) and -independent (E198K) activation of mTORC1. Thus, although upstream activation of mTORC1 differs between PPP2R5D-related disorder genotypes, treatment with rapamycin or a p70S6K inhibitor warrants further investigation as potential therapeutic strategies for patients. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Dual impact of PTEN mutation on CSF dynamics and cortical networks via the dysregulation of neural precursors and their interneuron descendants

Play Episode Listen Later Mar 19, 2023

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.18.533275v1?rss=1 Authors: DeSpenza, T., Kiziltug, E., Allington, G., Barson, D., O'Connor, D., Robert, S. M., Mekbib, K. Y., Nanda, P., Greenberg, A., Singh, A., Duy, P. Q., Mandino, F., Zhao, S., Lynn, A., Reeves, B. C., Marlier, A., Getz, S. A., Nelson-Williams, C., Shimelis, H., Zhang, J., Walsh, L. K., Wang, W., Smith, H., OuYang, A., Deniz, E., Lake, E., Jin, S. C., Luikart, B. W., Kahle, K. T. Abstract: Expansion of the cerebrospinal fluid (CSF)-filled cerebral ventricles (ventriculomegaly) is the quintessential feature of congenital hydrocephalus (CH) but also seen in autism spectrum disorder (ASD) and several neuropsychiatric diseases. PTEN is frequently mutated in ASD; here, we show PTEN is a bona fide risk gene for the development of ventriculomegaly, including neurosurgically-treated CH. Pten-mutant hydrocephalus is associated with aqueductal stenosis due to the hyperproliferation of periventricular Nkx2.1+ neural precursors (NPCs) and CSF hypersecretion from inflammation-dependent choroid plexus hyperplasia. The hydrocephalic Pten-mutant cortex exhibits ASD-like network dysfunction due to impaired activity of Nkx2.1+ NPC-derived inhibitory interneurons. Raptor deletion or post-natal Everolimus corrects ventriculomegaly, rescues cortical deficits, and increases survival by antagonizing mTORC1-dependent Nkx2.1+ cell pathology. These results implicate a dual impact of PTEN mutation on CSF dynamics and cortical networks via the dysregulation of NPCs and their interneuron descendants. These data identify a non-surgical treatment target for hydrocephalus and have implications for other developmental brain disorders. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

AAV1.NT-3 Gene Therapy Prevents Age-Related Sarcopenia

Play Episode Listen Later Mar 15, 2023 4:02

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 5, entitled, “AAV1.NT-3 gene therapy prevents age-related sarcopenia.” Sarcopenia is progressive loss of muscle mass and strength occurring during normal aging with significant consequences on the quality of life for elderly. Neurotrophin 3 (NT-3) is an important autocrine factor supporting Schwann cell survival and differentiation and stimulating axon regeneration and myelination. NT-3 is involved in the maintenance of neuromuscular junction (NMJ) integrity, restoration of impaired radial growth of muscle fibers through activation of the Akt/mTOR pathway. In this new study, researchers Burcak Ozes, Lingying Tong, Morgan Myers, Kyle Moss, Alicia Ridgley, and Zarife Sahenk from Nationwide Children's Hospital and The Ohio State University used a triple muscle-specific creatine kinase (tMCK) promoter to restrict NT-3 expression to the skeletal muscle and self-complimentary adeno-associated virus serotype 1 (scAAV1) as vector to assess the therapeutic efficacy of AAV1.NT-3 in wild type-aged C57BL/6J mice, a model for natural aging and sarcopenia. “Quantitative histopathologic parameters served to address age-related changes in muscle, peripheral nerve and NMJ.” The treatment efficacy was assessed at 6 months post-injection using run to exhaustion and rotarod tests, in vivo muscle contractility assay, and histopathological studies of the peripheral nervous system, including NMJ connectivity and muscle. AAV1.NT-3 gene therapy in WT-aged C57BL/6 mice resulted in functional and in vivo muscle physiology improvements, supported by quantitative histology from muscle, peripheral nerves and NMJ. Hindlimb and forelimb muscles in the untreated cohort showed the presence of a muscle- and sex-dependent remodeling and fiber size decrease with aging, which was normalized toward values obtained from 10 months old WT mice with treatment. The molecular studies assessing the NT-3 effect on the oxidative state of distal hindlimb muscles, accompanied by western blot analyses for mTORC1 activation were in accordance with the histological findings. “When considering the burden of sarcopenia on the lifestyle of elderly, and on the healthcare system, we believe this preclinical study is providing strong support for AAV.NT-3 gene therapy in the successful management of sarcopenia, as a serious and plausible option in the future.” DOI: https://doi.org/10.18632/aging.204577 Corresponding Author: Zarife Sahenk - zarife.sahenk@nationwidechildrens.org Keywords: sarcopenia, gene therapy, aging, NT-3, muscle remodeling Sign up for free Altmetric alerts about this article: https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204577 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

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A Deeper Dive on Dairy, Acne, Prostate Cancer and Laron syndrome

Keto Naturopath

Play Episode Listen Later Mar 10, 2023 50:23

Taking a deeper look at dairy and why it is not only such a problem for so many but a near definitive cause for cancer. Acne and prostate cancer having a strong association with dairy consumption. Also, will be looking at a group of people who have a genetic defect (Laron syndrome) that blunts the effects of IGF-1 and the insulin increasing effects of whey. Reference Links:Linking diet to acne metabolomics, inflammation, and comedogenesis: an update.https://www.ncbi.nlm.nih.gov/pubmed/26203267Evidence for acne-promoting effects of milk and other insulinotropic dairy products.https://www.ncbi.nlm.nih.gov/pubmed/21335995The impact of cow's milk-mediated mTORC1-signaling in the initiation and progression of prostate cancer.https://www.ncbi.nlm.nih.gov/pubmed/22891897/Over-stimulation of insulin/IGF-1 signaling by western diet may promote diseases of civilization: lessons learnt from laron syndromehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3141390/Insulin-like growth factor 1https://en.wikipedia.org/wiki/Insulin-like_growth_factor_1—————————COME SAY HI!!! —————————— Facebook Group about Keto: https://www.facebook.com/groups/ketonaturopath/ ------ OUR NEW MEMBERSHIP GROUP FOR EVERYTHING KETO --------------------- Labs, Research and cooking, Implementation www.ketonaturopathmembers.com Weekly Live Zoom Q&A Sessions and private FB group BLOG: https://ketonaturopath.com/ Pinterest: https://www.pinterest.com/ketonaturopath YYouTube channel www.youtube.com/ketonaturopath Podcast: https://www.buzzsprout.com/482971/episodes Our Youtube Podcasts https://studio.youtube.com/channel/UC6LBX8_RDaXtzF_Z02jvl0QJudi's NEW cooking channel Keto Naturopath Kitchen https://www.youtube.com/c/KetoNaturopathKitchen ——————————— OUR COURSE —————————— PSMF 30 day course: https://www.thebiointegrationcode.com/courses/PSMFChallenge ———————— WHERE WE GET OUR WINE (an affiliate link) —————————— Dry farm wines www.dryfarmwines.com/ketonaturopath —————WHERE WE GET OUR Uric ACID FORA 6 METER ———————— https://www.fora-shop.com/ (that measures Glucose, Ketones, and Cholesterol together with Uric Acid) Get a 10% discount with this Discount Code: Ketonaturopath10 How we use the Fora 6 Meter https://youtu.be/0V5B_SXR6qM ————WHERE WE GET OUR GENOME SNP ANALYSIS DONE——————————— Strategene https://bit.ly/3iqCfka ——————————WHERE WE GET YOUR LABS DONE—————————————— https://www.UltaLabTests.com/ketonaturopath ———————

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Spatiotemporal regulation of de novo and salvage purine synthesis during brain development

llc regulation copy de novo salvage cns synthesis brain development yamada s6 biorxiv spatiotemporal mtorc1

Play Episode Listen Later Mar 2, 2023

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.01.530588v1?rss=1 Authors: MIzukoshi, T., Yamada, S., Sakakibara, S.-i. Abstract: The levels of purines, essential molecules to sustain eukaryotic cell homeostasis, are regulated by the coordination of the de novo and salvage synthesis pathways. In the embryonic central nervous system (CNS), the de novo pathway is considered crucial to meet the requirements for the active proliferation of neural stem/progenitor cells (NSPCs). However, how these two pathways are balanced or separately utilized during CNS development remains poorly understood. In this study, we showed a dynamic shift in pathway utilization, with greater reliance on the de novo pathway during embryonic stages and on the salvage pathway at postnatal-adult stages. The pharmacological effects of various purine synthesis inhibitors in vitro and the expression profile of purine synthesis enzymes indicated that NSPCs in the embryonic cerebrum mainly utilize the de novo pathway. Simulatenously, NSPCs in the cerebellum require both the de novo and the salvage pathways. In vivo administration of de novo inhibitors resulted in severe hypoplasia of the forebrain cortical region, indicating a gradient of purine demand along the anteroposterior axis of the embryonic brain, with cortical areas of the dorsal forebrain having higher purine requirements than ventral or posterior areas such as the striatum and thalamus. This histological defect of the neocortex was accompanied by strong downregulation of the mechanistic target of rapamycin complex 1 (mTORC1)/ribosomal S6 kinase (S6K)/S6 signaling cascade, a crucial pathway for cell metabolism, growth, and survival. These findings indicate the importance of the spatiotemporal regulation of both purine pathways for mTORC1 signaling and proper brain development. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

mTORC1-mediated acquisition of reward-related spatial representations by hippocampal somatostatin interneurons

llc reward copy acquisition spatial representations mediated laplante robitaille biorxiv bidirectional ca2 lacaille bosson hippocampal mtorc1 ca1 somatostatin

Play Episode Listen Later Feb 24, 2023

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.24.529922v1?rss=1 Authors: Michon, F.-X., Laplante, I., Bosson, A., Robitaille, R., Lacaille, J.-C. Abstract: Plasticity of principal cells and inhibitory interneurons underlies hippocampal memory. Bidirectional modulation of somatostatin cell mTORC1 activity, a crucial translational control mechanism in synaptic plasticity, causes parallel changes in hippocampal CA1 somatostatin interneuron (SOM-IN) long-term potentiation and hippocampus-dependent memory, indicating a key role in learning. However, SOM-IN activity changes and behavioral correlates during learning, and the role of mTORC1 in these processes, remain ill-defined. To address these questions, we used two-photon Ca2+ imaging from SOM-INs during a virtual reality goal-directed spatial memory task in head-fixed control mice (SOM-IRES-Cre mice) or in mice with conditional knockout of Rptor (SOM-Rptor-KO mice) to block mTORC1 activity in SOM-INs. We found that control mice learn the task, but SOM-Raptor-KO mice exhibit a deficit. Also, SOM-IN Ca2+ activity became increasingly related to reward localization during learning in control mice but not in SOM-Rptor-KO mice. Four types of SOM-IN activity patterns related to reward location were observed, "reward off sustained", "reward off transient", "reward on sustained" and "reward on transient", and these responses showed global remapping after reward relocation in control but not SOM-Rptor-KO mice. Thus, SOM-INs develop mTORC1-dependent spatial coding related to learning reward localization. This coding may bi-directionally interact with pyramidal cells and other structures to represent and consolidate reward location. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Maturation of Nucleus Accumbens Synaptic Transmission Signals a Critical Period for the Rescue of Social Deficits in a Mouse Model of Autism Spectrum Disorder

Play Episode Listen Later Feb 8, 2023

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.08.527742v1?rss=1 Authors: Matthiesen, M., Khlaifia, A., Steininger, C. F. D., Dadabhoy, M., Mumtaz, U., Arruda-Carvalho, M. Abstract: Social behavior emerges early in development, a time marked by the onset of neurodevelopmental disorders featuring social deficits, including autism spectrum disorder (ASD). Although deficits in social interaction and communication are at the core of the clinical diagnosis of ASD, very little is known about their neural correlates at the time of clinical onset of the disorder. The nucleus accumbens (NAc), a brain region extensively implicated in social behavior, undergoes synaptic, cellular and molecular alterations in early life, and is particularly affected in ASD mouse models. To explore a link between the maturation of the NAc and neurodevelopmental deficits in social behavior, we compared age-dependent changes in spontaneous synaptic transmission in NAc shell medium spiny neurons (MSNs) between the highly social C57BL/6J mouse strain and the idiopathic ASD mouse model BTBR T+ Itpr3tf/J at postnatal day (P) 4, P6, P8, P12, P15, P21 and P30. We found that MSNs from both C57BL/6J and BTBR mice display age-dependent increases in spontaneous excitatory and inhibitory synaptic currents between P4 and P30. Comparison of NAc spontaneous transmission between strains showed that BTBR MSNs display increased excitatory transmission during the first postnatal week, and increased inhibition across the first, second and fourth postnatal weeks, suggesting accelerated maturation of excitatory and inhibitory synaptic inputs onto BTBR MSNs compared to C57BL/6J mice. These early life changes in synaptic transmission are consistent with a potential critical period in the maturation of the NAc, which could maximize the efficacy of interventions affecting social behavior. To test this possibility, we treated BTBR mice in either early life (P4-P8) or adulthood (P60-P64) with the mTORC1 antagonist rapamycin, a well-established rescue intervention for ASD-like behavior. We found that rapamycin treatment rescued social interaction deficits in BTBR mice when injected in infancy, but not in adulthood. These data emphasize the importance of studying brain regions involved in the pathophysiology of neurodevelopmental disorders at clinically-relevant time points, which may offer novel insight into the timing and targets of therapeutic interventions to maximize positive outcomes. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Interplay between PLEKHG3-regulated actin dynamics and lysosomal trafficking in cell motility

Play Episode Listen Later Feb 1, 2023

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.01.526449v1?rss=1 Authors: Ettelt, R., Didusch, S., Vucak, G., Riemelmoser, B., Ehrenreiter, K., Hartl, M., Huber, L., Baccarini, M. Abstract: Lysosomes are highly dynamic organelles regulating numerous metabolic signaling pathways by recruiting cytosolic proteins to their membrane-bound protein platforms. To identify new proteins recruited to the lysosomal membrane, we performed a proximity-dependent labelling (PDL) screen using as bait a component of the late endosomal/lysosomal adaptor and MAPK and mTOR activator (LAMTOR) complex, which regulates lysosome positioning as well as mTORC1, AMPK and MEK/ERK signaling. The screen identified a network of proteins involved in actin remodelling, the most prominent of which was Pleckstrin homology domain-containing family G member 3 (PLEKHG3), a Rho guanine nucleotide exchange factors (GEF) that binds to actin filaments and is enriched in the protrusions formed by migrating cells. We show that GFP-PLEKHG3 accumulates in focal adhesion sites (FAs), where it colocalizes with peripheral lysosomes independently of LAMTOR3 (L3). By altering the intracellular position of lysosomes, we demonstrate that the accumulation of lysosomes in the periphery concentrates PLEKHG3 below the plasma membrane (PM) while inhibiting the formation of protrusions and also limiting cell motility. Overall, this study reveals that the subcellular positioning of lysosomes plays a role in the intracellular distribution of PLEKHG3 and in the cell's protrusion activity, shape, and motility. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

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Autophagy Disruption Reduces mTORC1 Activation Leading to Retinal Ganglion Cell Neurodegeneration Associated with Glaucoma

Play Episode Listen Later Jan 7, 2023

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.04.522687v1?rss=1 Authors: Huang, K.-C., Gomes, C., Shiga, Y., Belforte, N., VanderWall, K. B., Lavekar, S. S., Fligor, C. M., Harkin, J., Di Polo, A., Meyer, J. S. Abstract: Autophagy dysfunction has been associated with several neurodegenerative diseases including glaucoma, characterized by the degeneration of retinal ganglion cells (RGCs). However, the mechanisms by which autophagy dysfunction promotes RGC damage remain unclear. Here, we hypothesized that perturbation of the autophagy pathway results in increased autophagic demand, thereby downregulating signaling through mammalian target of rapamycin complex 1 (mTORC1), a negative regulator of autophagy, contributing to the degeneration of RGCs. We identified an impairment of autophagic-lysosomal degradation and decreased mTORC1 signaling via activation of the stress sensor adenosine monophosphate-activated protein kinase (AMPK), along with subsequent neurodegeneration in RGCs differentiated from human pluripotent stem cells (hPSCs) with a glaucoma-associated variant of Optineurin (OPTN-E50K). Similarly, the microbead occlusion model of glaucoma resulting in ocular hypertension also exhibited autophagy disruption and mTORC1 downregulation. Pharmacological inhibition of mTORC1 in hPSC-derived RGCs recapitulated disease-related neurodegenerative phenotypes in otherwise healthy RGCs, while the mTOR-independent induction of autophagy reduced protein accumulation and restored neurite outgrowth in diseased OPTN-E50K RGCs. Taken together, these results highlight an important balance between autophagy and mTORC1 signaling essential for RGC homeostasis, while disruption to these pathways contributes to neurodegenerative features in glaucoma, providing a potential therapeutic target to prevent neurodegeneration. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

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Cell migration CRISPRi screens in human neutrophils reveal regulators of context-dependent migration and differentiation state

Play Episode Listen Later Dec 16, 2022

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.16.520717v1?rss=1 Authors: Belliveau, N. M., Footer, M. J., Akdogan, E., van Loon, A. P., Collins, S. R., Theriot, J. A. Abstract: Neutrophils are the most abundant leukocyte in humans and provide a critical early line of defense as part of our innate immune system. Their exquisite sensitivity to chemical gradients and ability to rapidly migrate make them especially suited to protect against infection. However, their terminal differentiation status and short lifetime (on the order of days) have hindered their study. Furthermore, while modern CRISPR-based gene perturbation strategies now allow comprehensive, genome-scale screens in human cells, their application to complex and dynamic processes like cell migration remain limited. Using HL-60 cells, a leukemia cell line that can be differentiated into neutrophil-like cells, we have developed multiple cell migration screen strategies that provide comprehensive, genome-wide discovery of molecular factors that are critical for directed (chemotaxis), undirected (chemokinesis), and 3D amoeboid cell migration in these fast-moving cells. Combining these assays with additional, pooled, genome-wide CRISPR interference dropout screens of cell proliferation and neutrophil differentiation, we have identified a comprehensive set of genes that are important across the processes of cellular growth, differentiation, and migration. This combined dataset highlights a particular reliance upon mTORC1 signaling that alters neutrophil lifetime, migration phenotype, and sensitivity to chemotactic cues. Across our cell migration screens, we identified several hundred genes important for migration including those with specific roles only in particular migratory contexts. This genome-wide screening strategy, therefore, provides an invaluable approach to the study of neutrophils and provides a resource that will inform future studies of cell migration in these and other rapidly migrating cells. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

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Non-Canonical Functions of a Mutant TSC2 Protein in Mitotic Division

Play Episode Listen Later Dec 7, 2022

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.07.519401v1?rss=1 Authors: Chalkley, M.-B. L., Mersfelder, R. B., Sundberg, M., Armstrong, L., Sahin, M., Ihrie, R. A., Ess, K. Abstract: Tuberous Sclerosis Complex (TSC) is a debilitating neurodevelopmental disorder characterized by a variety of clinical manifestations including epilepsy, autism, and intellectual disability. TSC is caused by mutations in the TSC1 or TSC2 genes, which encode the hamartin/tuberin proteins respectively. These proteins function as a heterodimer that negatively regulates mechanistic Target of Rapamycin Complex 1 (mTORC1). TSC research has focused on the effects of mTORC1, a critical signaling hub, on regulation of diverse cell processes including metabolism, cell growth, translation, and neurogenesis. However, non-canonical functions of TSC2 are not well studied, and the potential disease-relevant biological mechanisms are not well understood. We observed aberrant multipolar mitotic division, a novel phenotype, in TSC2 mutant iPSCs. The multipolar phenotype is not meaningfully affected by treatment with mTORC1 inhibition, suggesting that multipolar division is an mTORC1-independent phenotype. We further observed dominant negative activity of the mutant form of TSC2 in producing the multipolar division phenotype. These data expand the knowledge of TSC2 function and pathophysiology which will be highly relevant to future treatments for patients with TSC. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

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AUTS2 gene dosage affects synaptic AMPA receptors via a local dendritic spine AUTS2-TTC3-AKT-mTORC1 signaling dysfunction

Play Episode Listen Later Dec 1, 2022

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.01.518705v1?rss=1 Authors: Bestel, A.-M., Duchon, A., Viard, J., Kvajo, M., Daudin, R., Khelfaoui, M., Haziza, S., Loe-Mie, Y., Aime, M., Suizu, F., Birling, M.-C., Bensaid, M., Jacquot, S., Koebel, P., Reverdy, C., Rain, J.-C., Noguchi, M., Marques, X., Triller, A., Humeau, Y., Herault, Y., Karayiorgou, M., Gogos, J., Simonneau, M. Abstract: The Human 1.2-Mb AUTS2 locus on chromosome 7q11.22 encodes a 1259-aa full-length protein, and a 711-aa C-terminal isoform. Functions of these AUTS2 proteins are only partly known. The major traits found in patients displaying AUTS2 locus mutations are Intellectual Disabilities, microcephaly attention deficit hyperactivity disorder (ADHD) (54%), and autistic traits. Furthermore, AUTS2 common variants were recently found associated to alcohol consumption and dyslexia using GWAS approaches. Auts2 localizes mainly in cell nuclei. We evidenced by super-resolution that Auts2 is present in dendritic spines. Auts2 interacts with Ttc3, the Akt2 E3 ligase, and negatively regulates Akt2 ubiquitination. Auts2 haploinsufficiency affects Akt/mTorc1 pathway with a decrease in AMPA and NMDA receptor subunits and in synaptic currents. Akt2 injection in postsynaptic neurons is sufficient to reverse changes in synaptic currents generated by Auts2 haploinsufficiency. Using chromosome engineering based on targeted meiotic recombination, we generated two mouse models with Auts2 locus deletion and duplication. Deleted Auts2 locus mice display stereotypies (rearing), perseveration and abnormal recognition memory. Duplicated Auts2 locus mice display similar perseveration and abnormal recognition memory but also a decrease in cued and contextual fear memory. Gene dosage induce changes in brain sub-region neuronal networks. In the thalamo-lateral amygdala pathway linked to cued fear memory, we found synaptic impairments linked to AMPA receptors, with a specific decrease in pAKT/total AKT ratio in duplicated Auts2 mice. Altogether, our study thereby provides a novel mechanistic and potentially therapeutic understanding of synaptic AKT/mTORC1 deregulated signaling and its related behavioral and cognitive phenotypes. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Lysosomes mediate the mitochondrial UPR via mTORC1-dependent ATF4 phosphorylation

Play Episode Listen Later Nov 15, 2022

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.11.14.516427v1?rss=1 Authors: Li, T. Y., Wang, Q., Gao, A. W., Li, X., Mottis, A., Shong, M., Auwerx, J. Abstract: Lysosomes are central platforms for not only the degradation of macromolecules but also the integration of multiple signaling pathways. However, whether and how lysosomes mediate the mitochondrial stress response (MSR) remain largely unknown. Here, we demonstrate that lysosomal acidification via the vacuolar H+-ATPase (v-ATPase) is essential for the transcriptional activation of the mitochondrial unfolded protein response (UPRmt). Mitochondrial stress stimulates v-ATPase-mediated lysosomal activation of the mechanistic target of rapamycin complex 1 (mTORC1), which then directly phosphorylates the MSR transcription factor, activating transcription factor 4 (ATF4). Disruption of mTORC1-dependent ATF4 phosphorylation blocks the UPRmt, but not other similar stress responses, such as the UPRER. Finally, ATF4 phosphorylation downstream of the v-ATPase/mTORC1 signaling is indispensable for sustaining mitochondrial redox homeostasis and protecting cells from reactive oxygen species (ROS)-associated cell death upon mitochondrial stress. Thus, v-ATPase/mTORC1-mediated ATF4 phosphorylation via lysosomes links mitochondrial stress to UPRmt activation and mitochondrial function resilience. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

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Malonyl-CoA is an ancient physiological ATP-competitive mTORC1 inhibitor

Play Episode Listen Later Nov 6, 2022

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.11.06.515351v1?rss=1 Authors: Nicastro, R., Brohee, L., Alba, J., Nuechel, J., Figlia, G., Kipschull, S., Gollwitzer, P., Romero-Pozuelo, J., Fernandes, S. A., Lamprakis, A., Vanni, S., Teleman, A. A., De Virgilio, C., Demetriades, C. Abstract: Cell growth is regulated primarily by the mammalian/mechanistic Target of Rapamycin Complex 1 (mTORC1) that functions both as a nutrient sensor and a master controller of virtually all biosynthetic pathways 1. This ensures that cells are metabolically active only when conditions are optimal for growth. Notably, although mTORC1 is known to regulate fatty acid (FA) biosynthesis, how and whether the cellular lipid biosynthetic capacity signals back to fine-tune mTORC1 activity remains poorly understood. Here, we show that mTORC1 senses the capacity of a cell to synthesize FAs by detecting the levels of malonyl-CoA, an intermediate of this biosynthetic pathway. We find that, in both yeast and mammalian cells, this regulation is very direct, with malonyl-CoA binding to the mTOR catalytic pocket and acting as a specific ATP-competitive inhibitor. When ACC1 (acetyl-CoA carboxylase 1) is hyperactive or FASN (fatty acid synthase) is downregulated/inhibited, elevated malonyl-CoA levels are channelled to proximal mTOR molecules that form direct protein-protein interactions with ACC1 and FASN. Our findings represent a conserved, unique, homeostatic mechanism whereby impaired FA biogenesis leads to reduced mTORC1 activity to coordinatively link this metabolic pathway to the overall cellular biosynthetic output. Moreover, they reveal the first-described example of a physiological metabolite that directly inhibits the activity of a signalling kinase by competing with ATP for binding. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

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Intracellular calcium elevations drive the nucleation of FIP200- and ATG13-containing pre-autophagosomal structures that become omegasomes

Play Episode Listen Later Nov 2, 2022

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.11.02.514842v1?rss=1 Authors: Smith, M., Schoenfelder, P., Manifava, M., Polson, H., Tooze, S., Roderick, L., Ktistakis, N. Abstract: Ca2+ modulates autophagy at multiple steps including the induction and maturation of autophagosomes, but the magnitude and spatiotemporal properties of this calcium signal and its ultimate effect on the autophagic machinery are unclear. Focusing on the induction step leading to omegasome formation, we report that low but sustained elevations in cytosolic calcium levels induce omegasome formation but treatments that only transiently elevate calcium do not. The calcium-induced structures are early intermediates that mature into omegasomes but do not constitute full autophagosomes because they are partially devoid of late autophagy proteins ATG16 and LC3. In addition to omegasomes, all four components of the ULK complex (ULK1, FIP200, ATG13, ATG101) respond to calcium modulation: they translocate to early autophagy puncta in complete medium upon calcium elevation, and are inhibited from translocation during starvation by calcium chelation with BAPTA-2 AM. The principal early step affected by calcium lies downstream of mTORC1 inactivation and upstream of VPS34 activation, coinciding biochemically with phosphorylation of ATG13 at serine 318, which is known to require ULK1 activity. However, although the calcium-mediated step requires ATG9, FIP200 and ATG13, it does not require ULK1/2, suggesting that calcium does not directly regulate ULK1 activity but rather it regulates the mechanism by which the ULK complex components ATG13 and FIP200, together with ATG9, nucleate pre-autophagosomal precursors. This calcium-induced nucleation is sufficient to drive autophagy induction up to the omegasome step, but not beyond it. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

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Intracellular BAPTA directly inhibits PFKFB3, thereby impeding mTORC1-driven Mcl-1 translation and killing Mcl-1-addicted cancer cells

Play Episode Listen Later Nov 1, 2022

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.31.512457v1?rss=1 Authors: Sneyers, F., Kerkhofs, M., Welkenhuyzen, K., Speelman-Rooms, F., Shemy, A., Voet, A. R., Eelen, G., Dewerchin, M., Tait, S., Ghesquiere, B., Bootman, M. D., Bultynck, G. Abstract: Intracellular Ca2+ signals control several physiological and pathophysiological processes. The main tool to chelate intracellular Ca2+ is intracellular BAPTA (BAPTAi), usually introduced into cells as a membrane-permeant acetoxymethyl ester (BAPTA-AM). We previously demonstrated that BAPTAi enhanced apoptosis induced by venetoclax, a Bcl-2 antagonist, in diffuse large B-cell lymphoma (DLBCL). These findings implied a novel interplay between intracellular Ca2+ signaling and anti-apoptotic Bcl-2 function. Hence, we set out to identify the underlying mechanisms by which BAPTAi enhances cell death in B-cell cancers. We observed that BAPTAi induced apoptosis in lymphoma cell models that were highly sensitive to S63845, an Mcl-1 antagonist. BAPTAi provoked a rapid decline in Mcl-1-protein levels by inhibiting mTORC1-driven MCL-1 translation. Overexpression of nondegradable Mcl-1 rescued BAPTAi-induced cell death. We further examined how BAPTAi diminished mTORC1 activityand found that BAPTAi impaired glycolysis by directly inhibiting 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) activity, an up to now unappreciated effect of BAPTAi. All aforementioned effects of BAPTAi were also elicited by a BAPTAi analog with low affinity for Ca2+. Thus, our work reveals PFKFB3 inhibition as an unappreciated Ca2+-independent mechanism by which BAPTAi impairs cellular metabolism and ultimately the survival of Mcl-1-dependent cancer cells. Our work has two important implications. First, direct inhibition of PFKFB3 emerged as a promising target in cancer treatment. Second, cellular effects caused by BAPTAi are not necessarily related to Ca2+ signaling. Our data support the need for a reassessment of the role of Ca2+ in cellular processes when findings were based on the use of BAPTAi. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

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Uterine histotroph and conceptus development. III. Adrenomedullin stimulates proliferation, migration and adhesion of porcine trophectoderm cells via AKT-TSC2-MTOR cell signaling pathway.

Play Episode Listen Later Oct 11, 2022

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.10.511652v1?rss=1 Authors: Liu, B., Paudel, S., Flowers, W. L., Piedrahita, J. A., Wang, X. Abstract: Adrenomedullin (ADM) as a highly conserved peptide hormone has been reported to increase significantly in the uterine lumen during the peri-implantation period of pregnancy in pigs, but its functional roles in growth and development of porcine conceptus (embryonic/fetus and its extra-embryonic membranes) as well as underlying mechanisms remain largely unknown. Therefore, we conducted in vitro experiments using our established porcine trophectoderm cell line (pTr1) isolated from Day-12 porcine conceptuses to test the hypothesis that porcine ADM stimulates cell proliferation, migration and adhesion via AKT-TSC2-MTOR cell signaling pathway in pTr1 cells. Porcine ADM at 10-7 M stimulated (P less than 0.05) pTr1 cell proliferation, migration and adhesion by 1.4-, 1.5- and 1.2-folds, respectively. These ADM-induced effects were abrogated (P less than 0.05) by siRNA-mediated knockdown of ADM (siADM) and its shared receptor component calcitonin-receptor-like receptor (CALCRL; siCALCRL), as well as by rapamycin, the inhibitor of mechanistic target of rapamycin (MTOR). Using siRNA mediated knockdown of CALCRL coupled with Western blot analyses, ADM signaling transduction was determined in which ADM binds to CALCRL to increase phosphorylation of MTOR, its downstream effectors (4EBP1, P70S6K, and S6), and upstream regulators (AKT and TSC2). Collectively, these results suggest that porcine ADM in histotroph act on its receptor component CALCRL to activate AKT-TSC2-MTOR, particularly MTORC1 signaling cascade, leading to elongation,migration and attachment of conceptuses. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

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Enhanced mTORC1 signaling and Protein Synthesis in Parkinson Disease Pathogenesis

The Tailored Life Podcast

Play Episode Listen Later Oct 6, 2022

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.03.510455v1?rss=1 Authors: Khan, M. R., Yin, X., Kang, S.-u., Mitra, J., Wang, H., Brahmachari, S., Karuppagounder, S. S., Kimura, Y., Jhaldiyal, A., Kim, H. H., Gu, H., Chen, R., Redding-Ochoa, J., Troncoso, J., Ha, T., Dawson, V. L., Dawson, T. M. Abstract: Pathological alpha-synuclein (alpha-syn) plays an important role in the pathogenesis of alpha-synucleinopathies such as Parkinson disease (PD). Disruption of protein homeostasis is thought be central to PD pathogenesis, however the molecular mechanism of this deregulation is poorly understood. Here we report that pathologic alpha-syn binds to tuberous sclerosis protein (TSC) 2 and destabilizes the TSC1-TSC2 complex leading to activation of the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) and enhanced mRNA translation. Dopamine neuron loss, behavioral deficits and aberrant biochemical signaling in the alpha-syn preformed fibril (PFF) and Drosophila alpha-syn transgenic models of pathologic alpha-syn induced degeneration were attenuated by genetic and pharmacologic inhibition of mTOR and protein translation. Our findings establish a potential molecular mechanism by which pathologic alpha-syn activates mTORC1 leading to enhanced protein translation and concomitant neurodegeneration in PD. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

712 - Does Concurrent Training Really Work..? (with Dr.Brandon Roberts)

Play Episode Listen Later Feb 10, 2022 15:28

Concurrent training may compromise strength, power, and/or hypertrophic adaptations, which is commonly referred to as the interference effect. Some results indicated that there might be a decrease in adaptation to resistance training when it is combined with an aerobic training program. It seems that resistance training enhances aerobic training, but not vice versa (Hickson 1980; Hakkinen et al., 1993; Kraemer et al., 2005). The first meta-analysis on concurrent training in 2012 found that concurrent training limited (by about ~20%) the amount of strength, power, and hypertrophy that could occur compared to strength training alone. A few years later some different scientists looked at a very similar data set, and what they found was that when you compared concurrent to strength training, the farther you separated the endurance component from the strength component, the better. There's actually a nice dose-response up to about 24 hours of separation between training types. Endurance exercise primarily increases the number of mitochondria (aka mitochondrial biogenesis). Resistance training mainly increases the size of the muscle. These are somewhat competing pathways. Endurance training stimulates molecular pathways such as PGC-1, CaMK, calcineurin, AMPK, and MAPK which underly the cellular processes that promote mitochondrial biogenesis and angiogenesis, which lead to an increase in endurance capacity. AMPK is a key energy sensor of the cells and is an inhibitor of the AKT-mTOR pathway. Even though the animal studies have been impressive at showing that AMPK can directly inhibit mTORC1 activity and muscle growth, acute studies in humans are not definitive. Plus, most studies have examined acute molecular responses up to 4 h post-exercise, whereas mTORC1 signaling persists for up to 24 h post-exercise while AMPK is active for a much shorter period (~3h). There was a more recent meta-analysis in 2018 that found HIIT and RT does not negatively impact hypertrophy or upper body strength, but does have a possible negative effect on lower body strength. However, the negative effect can be ameliorated by incorporating running based HIIT and increasing time between exercise modes. Finally, the newest meta-analysis found that concurrent aerobic and strength training did not interfere with the development of maximal strength and muscle hypertrophy compared with strength training alone. Yet, the development of explosive strength was reduced by concurrent training. The subgroup analysis was only significant within the explosive strength measurements, indicating that there was a detrimental effect of doing concurrent training within the same session, but if separated by 3 hours the effect disappeared. —- To Download The Tailored Trainer and Gain Unlimited Access To Expert Programming, Sign Up Here: Tailored Trainer Sign Up Page To Get Your Questions Answered On The Podcast: Ask Us Here! 1st Phorm Supps: To Get FREE PRIORITY SHIPPING and Support The Podcast, Get Your Supplements At 1st Phorm Using Our Link: www.1stphorm.com/tailoredcoachingmethod To Apply For Coaching: Click Here Download 1 (or ALL) Of Our FREE GUIDES: www.tailoredcoachingmethod.com/guides Private Podcast FB Community: Be Part Of The Conversation and Community, RIGHT HERE. —- Extra Content For You: How We Coach: Client Case Study Article Top 4 Podcast Episodes: - Nutritional Periodization - Nutrition FAQ - Training FAQ - My Story ---- Social Links: Blog – http://www.tailoredcoachingmethod.com/blog  Facebook - https://www.facebook.com/tailoredcoachingmethod  Instagram -https://www.instagram.com/codymcbroom YouTube - https://www.youtube.com/TailoredCoachingMethod Email – info@tailoredcoachingmethod.com Cody McBroom Has Also Been Featured On: Huffington Post, Bodybuilding.com, The PTDC, Dr. John Rusin, Muscle For Life, Barbell Shrugged, Strong By Design, OPEX Fitness and More…

202: Dairy Linked to Acne, Diabetes, and Cancer According to Revolutionary Study by Switch4Good.org

Plant Based Briefing

Play Episode Listen Later Feb 1, 2022 9:54

Dairy is linked to acne, diabetes, and cancer says new study pinpointing a causation, not just correlation. From Switch4Good.org. Original post: https://switch4good.org/dairy-acne-diabetes-cancer-new-study/ Switch4Good is an evidence-based nonprofit dedicated to rattling accepted norms around dairy and health. They're working to abolish the current system of dietary racial oppression, and promoting solutions for climate change. They have a fantastic podcast hosted by Olympic medalist Dotsie Bausch and Baywatch actress/health coach Alexandra Paul - they'll inspire and educate you to start living better and feeling better. How to support the podcast: Share with others. Buy some merch: https://www.plantbasedbriefing.com/shop Leave 5-star rating and review on Apple: https://podcasts.apple.com/us/podcast/plant-based-briefing/id1562925866 Spotify: https://open.spotify.com/show/2GONW0q2EDJMzqhuwuxdCF Amazon: https://www.amazon.com/Plant-Based-Briefing/dp/B08K59CRM4/ref=sr_1_3?crid=18XNAH6UMO9L5&keywords=plant+based+briefing&qid=1643393899&sprefix=plant+based+briefi%2Caps%2C168&sr=8-3 Follow Plant Based Briefing on social media: Twitter: @PlantBasedBrief YouTube: YouTube.com/PlantBasedBriefing Facebook: Facebook.com/PlantBasedBriefing LinkedIn: Plant Based Briefing Podcast Instagram: @PlantBasedBriefing #vegan #plantbased #veganpodcast #plantbasedpodcast #plantbasedbriefing #DairyFree #Switch4Good #ditchdairy #dairyisscary #acne #diabetes #cancer #breastcancer #prostatecancer #lungcancer #mTORC1 #insulin #IGF-1 #BCAAs #neurodegeneration #milk

Unconventional Method Effectively Targets NSCLC

Play Episode Listen Later Oct 1, 2021 7:34

The mammalian target of rapamycin (mTOR) operates within two distinct protein complexes—mTOR complex 1 (mTORC1) and complex 2 (mTORC2). These protein complexes are not yet fully understood, as they were only recently identified in humans in 1994. What researchers do know is that mTORC1 is involved in the regulation of many cellular processes and is a key mediator of cell growth and proliferation. mTORC1 is activated by growth factor receptor signals through the PI3K–AKT and RAS–ERK mitogen-activated protein kinase (MAPK) pathways. The PI3K/AKT/mTOR pathway may be an efficacious target in the treatment of patients with non-small cell lung cancer (NSCLC). This theory is based on the identification of particular gene mutations in NSCLC that are associated with the PI3K/AKT/mTOR pathway. However, previous studies have not yet succeeded in defining an effective monotherapy or combination of therapies that targets this pathway while improving NSCLC patient outcome. Researchers from Institut Curie, PSL University, Xentech, BioPôle Alfort, Hôpital Foch, and Centre Léon Bérard designed a study using a new methodology to test treatment combinations based on specific targets identified as biomarkers of resistance to PI3K-targeting treatments, and not based on the NSCLC mutations themselves. Their trending research paper was published by Oncotarget in 2021 and entitled, “High in vitro and in vivo synergistic activity between mTORC1 and PLK1 inhibition in adenocarcinoma NSCLC.” Full blog - https://www.oncotarget.org/2021/09/30/trending-with-impact-unconventional-method-effectively-targets-nsclc/ Press release - https://www.oncotarget.com/news/pr/mtorc1-and-plk1-inhibition-in-adenocarcinoma-nsclc/ Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.27930 DOI - https://doi.org/10.18632/oncotarget.27930 Full text - https://www.oncotarget.com/article/27930/text/ Correspondence to - Didier Decaudin - Didier.decaudin@curie.fr Keywords - NSCLC, Pi3K signalling pathway, mTORC1, RAD001 (everolimus), PLK1 About Oncotarget Oncotarget is a bi-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit https://www.oncotarget.com or connect with: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget YouTube - https://www.youtube.com/c/OncotargetYouTube/ LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Oncotarget is published by Impact Journals, LLC please visit https://www.ImpactJournals.com or connect with @ImpactJrnls Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

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Novo spoznanje v razumevanju biokemije celične smrti

Pogled v znanost

Play Episode Listen Later Aug 30, 2021 24:02

Imunska sposobnost organizma, tako pa tudi celic, je temeljno prirojena, precej pa jo pridobimo z razvojem od rojstva naprej. Ob vsaki poškodbi v telo oziroma v celice vdrejo mikrobi, torej molekule, ki sprožijo obrambne mehanizme za odstranitev tujkov. Ob tem umre tudi mnogo okuženih celic, in če jih je preveč, za telo to ni dobro, saj kronično vnetje dolgoročno škoduje. Zato raziskovalci skušajo razumeti biokemične procese t.im. celične smrti. V oddaji bomo pobliže spoznali raziskovalni interes, kako se ob okužbi, ki povzroči specifično in programirano celično smrt, t.im. piroptozo, obnaša prirojena imunost celice. Dr. Iva Hafner Bratkovič s Kemijskega inštituta (D12- Odsek za sintezno biologijo in imunologijo) bo opisala nov kamenček v mozaiku razumevanja teh procesov, ki se je odmevno zgostil v objavi v reviji CELL. To spoznanje bo pomembno za medicinsko pomoč pri nevrodegenerativnih in srčno-žilnih boleznih. Povod za pogovor je nedavna objava članka v omenjeni reviji, kjer je sogovornica podpisana kot soprva avtorica, s Kemijskega inštituta pa je sodelovala tudi njena doktorska študentka Elvira Boršić. Slovenski del raziskave je omogočila ARRS, začetek pa program Fullbright. Na sliki: Metabolna signalna pot mTORC1 preko oksidativnega stresa okrepi piroptozo. Vir: Kemijski inštitut, D12

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mTOR in Aging Ep6 - Life interventions Dr Sabatini Interview Series Ep 6

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Play Episode Listen Later Aug 9, 2021 9:31

In this video Dr. Sabatini discusses some of the life style interventions that affect our longevity and his personal regimen. This is the last episode of Dr. Sabatani Interview Series. Dr. David Sabatini is an American scientist and Professor of Biology at the Massachusetts Institute of Technology as well as a member of the Whitehead Institute for Biomedical Research. He is known for his important contributions in the areas of cell signaling and cancer metabolism, most notably the discovery of mTOR, more than 20 years ago. Since then Dr. Sabatini has continued to work on better understanding this complex regulator of our metabolism Some key references. Genome-wide CRISPR screens reveal multitiered mechanisms through which mTORC1 senses mitochondrial dysfunction https://www.biorxiv.org/content/10.1101/2020.10.22.351361v1.full.pdf Twenty-five years of mTOR: Uncovering the link from nutrients to growth https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5692607/ mTOR introduction YouTube Series with Dr. Sabatini https://www.youtube.com/watch?v=EnIerDljc7g https://www.youtube.com/watch?v=defOfBEuw_M https://www.youtube.com/watch?v=tGA9RALG66s

mTOR in Aging Ep5 - Diet & mTOR Dr Sabatini Interview Series

american technology professor diet twenty biology crispr massachusetts institute genome mtor sabatini biomedical research whitehead institute mtorc1

Play Episode Listen Later Aug 1, 2021 14:41

Dr. David Sabatini is an American scientist and Professor of Biology at the Massachusetts Institute of Technology as well as a member of the Whitehead Institute for Biomedical Research. He is known for his important contributions in the areas of cell signaling and cancer metabolism, most notably the discovery of mTOR, more than 20 years ago. Since then Dr. Sabatini has continued to work on better understanding this complex regulator of our metabolism In this video Dr. Sabatini discusses how diet effects mTOR activation. He also talks about calorie restriction and intermittent fasting. Some key references. Genome-wide CRISPR screens reveal multitiered mechanisms through which mTORC1 senses mitochondrial dysfunction https://www.biorxiv.org/content/10.1101/2020.10.22.351361v1.full.pdf Twenty-five years of mTOR: Uncovering the link from nutrients to growth https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5692607/

mTOR in Aging Ep4 - Rapamycin and Rapalogs Dr David Sabatini Interview Series

Play Episode Listen Later Jul 11, 2021 8:43

In this video Dr. Sabatini discusses rapamycin, how it acts on mTORC1 and mTORC2 and the rapalogs, drugs which are similar to rapamycin but may be more clinically effective. Dr. David Sabatini is an American scientist and Professor of Biology at the Massachusetts Institute of Technology as well as a member of the Whitehead Institute for Biomedical Research. He is known for his important contributions in the areas of cell signaling and cancer metabolism, most notably the discovery of mTOR, more than 20 years ago. Since then Dr. Sabatini has continued to work on better understanding this complex regulator of our metabolism Some key references. Genome-wide CRISPR screens reveal multitiered mechanisms through which mTORC1 senses mitochondrial dysfunction https://www.biorxiv.org/content/10.1101/2020.10.22.351361v1.full.pdf Twenty-five years of mTOR: Uncovering the link from nutrients to growth https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5692607/ mTOR introduction YouTube Series with Dr. Sabatini https://www.youtube.com/watch?v=EnIerDljc7g https://www.youtube.com/watch?v=defOfBEuw_M https://www.youtube.com/watch?v=tGA9RALG66s

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mTOR in Aging Ep 3 - Mitochondria Effects on mTOR Study Dr David Sabatini Interview Series

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Play Episode Listen Later Jul 4, 2021 6:45

In this video Dr. Sabatini discusses his recent paper and in particular how the health of the mitochondria impact the activation of mTOR and how this is signaled. Dr. David Sabatini is an American scientist and Professor of Biology at the Massachusetts Institute of Technology as well as a member of the Whitehead Institute for Biomedical Research. He is known for his important contributions in the areas of cell signaling and cancer metabolism, most notably the discovery of mTOR, more than 20 years ago. Since then Dr. Sabatini has continued to work on better understanding this complex regulator of our metabolism Some key references. The paper discussed in the video. Genome-wide CRISPR screens reveal multitiered mechanisms through which mTORC1 senses mitochondrial dysfunction https://www.biorxiv.org/content/10.1101/2020.10.22.351361v1.full.pdf Twenty-five years of mTOR: Uncovering the link from nutrients to growth https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5692607/

mTOR in Aging Ep1 - The Role of mTOR Dr David Sabatini Interview Series

Play Episode Listen Later Jun 13, 2021 11:04

In this video Dr. Sabatini discusses the role of mTOR as the master regulator of the cell and distinguishes between mTORC1 and mTORC2. Dr. David Sabatini is an American scientist and Professor of Biology at the Massachusetts Institute of Technology as well as a member of the Whitehead Institute for Biomedical Research. He is known for his important contributions in the areas of cell signaling and cancer metabolism, most notably the discovery of mTOR, more than 20 years ago. Since then Dr. Sabatini has continued to work on better understanding this complex regulator of our metabolism

american technology professor biology massachusetts institute mtor sabatini biomedical research whitehead institute mtorc1 mtorc2

Table of Contents: Oncotarget Volume 12, Issue #8

Play Episode Listen Later Apr 14, 2021 9:31

Listen to short summaries of the latest oncology-focused research published in this week's issue of Oncotarget. https://www.oncotarget.com/archive/v12/i8/ Oncotarget Volume 12, Issue 8 features: COVER PAPER: “Prognostic and therapeutic value of the Hippo pathway, RABL6A, and p53-MDM2 axes in sarcomas” https://doi.org/10.18632/oncotarget.27928 NEWS: “Immunotherapy and fatigue: what we know and what we don’t know” https://doi.org/10.18632/oncotarget.27946 (PDF Download) EDITORIAL: “Drug exposure: still relevant after all these years” https://doi.org/10.18632/oncotarget.27899 (PDF Download) EDITORIAL: “Up to your NEK2 in CIN” https://doi.org/10.18632/oncotarget.27918 (PDF Download) RESEARCH PAPER: “Analytic validation and clinical utilization of the comprehensive genomic profiling test, GEM ExTra®” https://doi.org/10.18632/oncotarget.27945 RESEARCH PAPER: “Insulin-like growth factor 1/Child-Turcotte-Pugh composite score as a predictor of treatment outcomes in patients with advanced hepatocellular carcinoma treated with sorafenib” https://doi.org/10.18632/oncotarget.27924 RESEARCH PAPER: “Controlling for cellular heterogeneity using single-cell deconvolution of gene expression reveals novel markers of colorectal tumors exhibiting microsatellite instability” https://doi.org/10.18632/oncotarget.27935 RESEARCH PAPER: “Urine protein biomarkers of bladder cancer arising from 16-plex antibody-based screens” https://doi.org/10.18632/oncotarget.27941 RESEARCH PAPER: “The acylfulvene alkylating agent, LP-184, retains nanomolar potency in non-small cell lung cancer carrying otherwise therapy-refractory mutations” https://doi.org/10.18632/oncotarget.27943 RESEARCH PAPER: “Loss of CPAP causes sustained EGFR signaling and epithelial-mesenchymal transition in oral cancer” https://doi.org/10.18632/oncotarget.27932 RESEARCH PAPER: “Carcinoma cells that have undergone an epithelial-mesenchymal transition differentiate into endothelial cells and contribute to tumor growth” https://doi.org/10.18632/oncotarget.27940 RESEARCH PAPER: “Predicting clinical outcomes using cancer progression associated signatures” https://doi.org/10.18632/oncotarget.27934 RESEARCH PAPER: “High in vitro and in vivo synergistic activity between mTORC1 and PLK1 inhibition in adenocarcinoma NSCLC” https://doi.org/10.18632/oncotarget.27930 About Oncotarget: Oncotarget is a bi-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit https://www.oncotarget.com/ or follow us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget LinkedIn - https://www.linkedin.com/company/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/oncotargetyoutube Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget Oncotarget is published by Impact Journals , LLC. Please visit https://www.impactjournals.com/ or connect with us @ImpactJrnls Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

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Table of Contents: Oncotarget Volume 12, Issue #7

Play Episode Listen Later Apr 2, 2021 10:15

Listen to short summaries of the latest oncology-focused research published in this week's issue of Oncotarget. https://www.oncotarget.com/archive/v12/i7/ Oncotarget Volume 12, Issue 7 features: COVER PAPER: "Caloric restriction creates a metabolic pattern of chronological aging delay that in budding yeast differs from the metabolic design established by two other geroprotectors" https://doi.org/10.18632/oncotarget.27926 EDITORIAL: "The long road to TRAIL therapy: a TRAILshort detour" https://doi.org/10.18632/oncotarget.27902 RESEARCH PERSPECTIVE: "The role of immune surveillance in malignant transformation of benign salivary gland tumors" https://doi.org/10.18632/oncotarget.27900 RESEARCH PAPER: "Differential expression of Vitamin D binding protein in thyroid cancer health disparities" https://doi.org/10.18632/oncotarget.27920 RESEARCH PAPER: "Inhibition of resistant triple-negative breast cancer cells with low-dose 6-mercaptopurine and 5-azacitidine" https://doi.org/10.18632/oncotarget.27922 RESEARCH PAPER: "Mutually exclusive lymphangiogenesis or perineural infiltration in human skin squamous-cell carcinoma" https://doi.org/10.18632/oncotarget.27915 RESEARCH PAPER: "Decreased expression of the translation factor eIF3e induces senescence in breast cancer cells via suppression of PARP1 and activation of mTORC1" https://doi.org/10.18632/oncotarget.27923 RESEARCH PAPER: "[18F]FDG and [18F]FES positron emission tomography for disease monitoring and assessment of anti-hormonal treatment eligibility in granulosa cell tumors of the ovary" https://doi.org/10.18632/oncotarget.27925 RESEARCH PAPER: "Effect of cell microenvironment on the drug sensitivity of hepatocellular cancer cells" https://doi.org/10.18632/oncotarget.27910 RESEARCH PAPER: "Landscape of somatic mutations in breast cancer: new opportunities for targeted therapies in Saudi Arabian patients" https://doi.org/10.18632/oncotarget.27909 RESEARCH PAPER: "The presence of polymorphisms in genes controlling neurotransmitter metabolism and disease prognosis in patients with prostate cancer: a possible link with schizophrenia" https://doi.org/10.18632/oncotarget.27921 CASE REPORT: "Prognostic significance of isochromosome 17q in hematologic malignancies" https://doi.org/10.18632/oncotarget.27914 About Oncotarget: Oncotarget is a bi-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit https://www.oncotarget.com/ or follow us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget LinkedIn - https://www.linkedin.com/company/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/oncotargetyoutube Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget Oncotarget is published by Impact Journals , LLC. Please visit https://www.impactjournals.com/ or connect with us @ImpactJrnls Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

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The Gary Null Show - 02.02.21

The Gary Null Show

Play Episode Listen Later Feb 2, 2021 61:53

Gary takes on the real issues that the mainstream media is afraid to tackle. Tune in to find out the latest about health news, healing, politics, and the economy. George Orwell and 1984: How Freedom Dies Orwell's final warning - Picture of the future The Efficacy of Olive Leaf Extract on Healing Herpes Simplex Virus: A Randomized Double-blind Study Lorestan University of Medical Sciences (Iran), January 29, 2021 Herpes simplex virus (HSV), as a common infection in healthy individuals, is treated symptomatically, but drug resistance and the side effects of drugs have drawn the attention of researchers to complementary medicine. Olive Leaf Extract (OLE) has antiviral effects that may treat HSV. The current study aimed to compare the clinical effects of OLE and Acyclovir on HSV-1. Methods This randomized double-blind clinical trial was conducted on 66 patients who had already been diagnosed with HSV-1. The participants were randomized into two groups, receiving 2% OLE cream or 5% acyclovir cream five times a day for six days. The symptoms were evaluated before, and three and six days after the interventions. Data were analyzed using the SPSS software through the Kolmogorov-Smirnov test, chi-squared, t-test, and repeated measures ANOVA. Results The results showed clinical symptoms decreased in both groups during the study and both medications were effective in the treatment of HSV-1. However, the OLE group experienced less bleeding (P=0.038), itching (P=0.002), and pain (P=0.001) on the third day as well as less irritation (P=0.012), itching (P=0.003) and color change (P=0.001) on the sixth day compared to the acyclovir group. The treatment course for participants in the OLE group was shorter than in the acyclovir group (P = 0.001). Conclusion The evidence from these trials suggests the OLE cream is superior in the healing of episodes of HSV-1 over the acyclovir cream. Future studies are recommended to investigate if OLE could be an adjunct to acyclovir treatment. How vitamins, steroids and potential antivirals might affect SARS-CoV-2 Study indicates that some vitamins, steroids and antivirals could bind to the Spike protein, and may inhibit virus infectivity, whereas high cholesterol may enable the virus University of Bristol (UK), January 29, 2021 Evidence is emerging that vitamin D - and possibly vitamins K and A - might help combat COVID-19. A new study from the University of Bristol published in the journal of the German Chemical Society Angewandte Chemie has shown how they - and other antiviral drugs - might work. The research indicates that these dietary supplements and compounds could bind to the viral spike protein and so might reduce SARS-CoV-2 infectivity. In contrast, cholesterol may increase infectivity, which could explain why having high cholesterol is considered a risk factor for serious disease. Recently, Bristol researchers showed that linoleic acid binds to a specific site in the viral spike protein, and that by doing so, it locks the spike into a closed, less infective form. Now, a research team has used computational methods to search for other compounds that might have the same effect, as potential treatments. They hope to prevent human cells becoming infected by preventing the viral spike protein from opening enough to interact with a human protein (ACE2). New anti-viral drugs can take years to design, develop and test, so the researchers looked through a library of approved drugs and vitamins to identify those which might bind to this recently discovered 'druggable pocket' inside the SARS-CoV-2 spike protein. The team first studied the effects of linoleic acid on the spike, using computational simulations to show that it stabilizes the closed form. Further simulations showed that dexamethasone - which is an effective treatment for COVID-19 - might also bind to this site and help reduce viral infectivity in addition to its effects on the human immune system. The team then conducted simulations to see which other compounds bind to the fatty acid site. This identified some drugs that have been found by experiments to be active against the virus, suggesting that this may be one mechanism by which they prevent viral replication such as, by locking the spike structure in the same way as linoleic acid. The findings suggested several drug candidates among available pharmaceuticals and dietary components, including some that have been found to slow SARS-CoV-2 reproduction in the laboratory. These have the potential to bind to the SARS-CoV-2 spike protein and may help to prevent cell entry. The simulations also predicted that the fat-soluble vitamins D, K and A bind to the spike in the same way making the spike less able to infect cells. Dr Deborah Shoemark, Senior Research Associate (Biomolecular Modelling) in the School of Biochemistry, who modelled the spike, explained: "Our findings help explain how some vitamins may play a more direct role in combatting COVID than their conventional support of the human immune system. "Obesity is a major risk factor for severe COVID. Vitamin D is fat soluble and tends to accumulate in fatty tissue. This can lower the amount of vitamin D available to obese individuals. Countries in which some of these vitamin deficiencies are more common have also suffered badly during the course of the pandemic. Our research suggests that some essential vitamins and fatty acids including linoleic acid may contribute to impeding the spike/ACE2 interaction. Deficiency in any one of them may make it easier for the virus to infect." Pre-existing high cholesterol levels have been associated with increased risk for severe COVID-19. Reports that the SARS-CoV-2 spike protein binds cholesterol led the team to investigate whether it could bind at the fatty acid binding site. Their simulations indicate that it could bind, but that it may have a destabilising effect on the spike's locked conformation, and favour the open, more infective conformation. Dr Shoemark continued: "We know that the use of cholesterol lowering statins reduces the risk of developing severe COVID and shortens recovery time in less severe cases. Whether cholesterol de-stabilises the "benign", closed conformation or not, our results suggest that by directly interacting with the spike, the virus could sequester cholesterol to achieve the local concentrations required to facilitate cell entry and this may also account for the observed loss of circulating cholesterol post infection." Professor Adrian Mulholland, of Bristol's School of Chemistry, added: "Our simulations show how some molecules binding at the linoleic acid site affect the spike's dynamics and lock it closed. They also show that drugs and vitamins active against the virus may work in the same way. Targeting this site may be a route to new anti-viral drugs. A next step would be to look at effects of dietary supplements and test viral replication in cells." Alison Derbenwick Miller, Vice President, Oracle for Research, said: "It's incredibly exciting that researchers are gaining new insights into how SARS-CoV-2 interacts with human cells, which ultimately will lead to new ways to fight COVID-19. We are delighted that Oracle's high-performance cloud infrastructure is helping to advance this kind of world-changing research. Growing a globally-connected community of cloud-powered researchers is exactly what Oracle for Research is designed to do." Researchers find melatonin is effective against polycystic kidney disease Concordia University (Canada), January 26, 2021 A hormone commonly associated with sleep-wake regulation has been found to reduce cysts in fruit flies, according to Concordia researchers. It's a finding that may affect the way we treat some kidney diseases and reduce the need for kidney transplants. In a new paper published in the journal Molecules, alum Cassandra Millet-Boureima(MSc 19) and Chiara Gamberi, affiliate assistant professor of biology, write that melatonin was found to reduce cysts in the renal tubules of fruit flies. These tubules are also found in more complex mammals, including humans, where they are called nephrons. This study, which builds on previous studies by Millet-Boureima and Gamberi, was co-authored by Roman Rozencwaig and Felix Polyak of BH Bioscience in Montreal. The researchers hope that their findings can be applied to treating people suffering from autosomal dominant polycystic kidney disease. ADPKD is a genetic chronic and progressive disease characterized by the growth of dozens of cysts in the nephrons. It is incurable and affects approximately 12.5 million worldwide. Similarities big and small Because nephrons in vertebrates are embedded in other tissue, the researchers experimented on Drosophila -- the common fruit fly. "Drosophila conserves many of the renal pathway components found in vertebrates and have anatomically isolated renal tubes," Gamberi explains. "With microdissection, we can isolate the tubules and conduct biochemical and molecular analysis." The researchers bred fruit flies bearing the Bicaudal C gene mutation. It is known to cause kidney cysts in all manner of living beings, from flies to frogs to mice to humans. Over 18 days, Millet-Boureima administered melatonin to 50 Drosophila and ethanol to a control group. She then dissected the flies and scored their cysts, a process yielding a cystic index. She found that the melatonin-treated flies had much fewer and smaller cysts than the control. Because Millet-Boureima was skilled at dissecting the insects and evaluating the recovered renal tubules, she was able to avoid bias in the count. She was also able to distinguish three separate sections of the Drosophila tubule, each with its own unique function, and assign the cysts to a particular section. After testing several compounds on the same family of cells, she observed different activities along the length of the tubule. The researchers realized that they could potentially develop targeted treatment depending on the location of the cysts in a patient's nephrons. "Biologically speaking, this has a lot of potential that we will obviously develop," Gamberi says. Helping without harming Though Gamberi says melatonin has not been previously used to treat PKD, she does think it holds some promise. PKD is a chronic disease, so treatment cannot include any toxic components. This rules out chemotherapy and tumour-killing antineoplastics used in oncology, for instance. However, melatonin is entirely non-toxic and shares certain properties with antineoplastics and anti-inflammatory agents. "We know from oncology that melatonin has two effects when it is administered with chemotherapy," Gamberi explains. "First, it acts as a drug adjuvant to the chemotherapy, making it work more effectively against cancer cells. Second, it appears to protect healthy cells from the toxicity of the chemotherapy. Basically, melatonin increases the specificity of the chemotherapy. We hope that it can have a similar positive effect when used with an anti-ADPKD drug like tolvaptan, which can damage the liver." The researchers are keen to share their findings as quickly as possible. "I hope there will be more research on the drugs we tested and that we get more results that will help the PKD community," Millet-Boureima says. Gallic acid is a dual alpha/beta-secretase modulator that reverses cognitive impairment and remediates pathology in Alzheimer Saitama Medical Center (Japan), January 20, 2021 According to news reporting from Saitama, Japan, research stated, “Several plant-derived compounds have demonstrated efficacy in pre-clinical Alzheimer’s disease (AD) rodent models. Each of these compounds share a gallic acid (GA) moiety, and initial assays on this isolated molecule indicated that it might be responsible for the therapeutic benefits observed.” Higher concentrations of GA are found in blueberry, blackberry, strawberry, plums, grapes, mango, cashew nut, hazelnut, walnut and tea. The news correspondents obtained a quote from the research from Saitama Medical Center, “To test this hypothesis in a more physiologically relevant setting, we investigated the effect of GA in the mutant human amyloid beta-protein precursor/presenilin 1 (APP/PS1) transgenic AD mouse model. Beginning at 12 months, we orally administered GA (20 mg/kg) or vehicle once daily for 6 months to APP/PS1 mice that have accelerated Alzheimer-like pathology. At 18 months of age, GA therapy reversed impaired learning and memory as compared with vehicle, and did not alter behavior in nontransgenic littermates. GA-treated APP/PS1 mice had mitigated cerebral amyloidosis, including brain parenchymal and cerebral vascular beta-amyloid deposits, and decreased cerebral amyloid beta-proteins. Beneficial effects co-occurred with reduced amyloidogenic and elevated nonamyloidogenic APP processing. Furthermore, brain inflammation, gliosis, and oxidative stress were alleviated. We show that GA simultaneously elevates alpha- and reduces beta-secretase activity, inhibits neuroinflammation, and stabilizes brain oxidative stress in a pre-clinical mouse model of AD. We further demonstrate that GA increases abundance of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10, Adam10) proprotein convertase furin and activates ADAM10, directly inhibits beta-site APP cleaving enzyme 1 (BACE1, Bace1) activity but does not alter Adam10 or Bace1 transcription. Thus, our data reveal novel post-translational mechanisms for GA.” According to the news reporters, the research concluded: “We suggest further examination of GA supplementation in humans will shed light on the exciting therapeutic potential of this molecule.” This research has been peer-reviewed. Black cumin’s anti-inflammatory potential may have airways/asthma benefits: RCT University College London, January 27, 2021 Supplements containing oil from black cumin (Nigella sativa) may improve asthma control and lung function, says a new study. The seed and oil of Nigella sativa have been used extensively in traditional medicine in many Middle Eastern and Asian countries for the treatment of a range of conditions, including some immune and inflammatory disorders. The new study, published in Phytotherapy Research , found that one gram per day of the oil for four weeks led to significant improvements in scores of asthma control and a “remarkable reduction of peripheral blood eosinophil count,” wrote the authors “Eosinophil cell plays a major role in asthma inflammation, and blood eosinophil count is considered to be a vital biomarker in asthma trials. To our knowledge, this is the first [randomized, double-blind, placebo-controlled trial] that showed a significant reduction of blood eosinophilia by [Nigella sativa oil (NSO)] among asthmatic patients.” Scientists from University College London (UK) and King Abdulaziz University (Saudi Arabia) recruited 80 asthmatics and randomly assigned them to one of two equal groups. The participants received either capsules containing 500 mg of NSO twice per day or placebo for four weeks. Data from the 60 people who completed the study (10 dropouts in each group) indicated that the black cumin supplement was associated with significant improvements in mean score on the Asthma Control Test, compared to placebo. Black cumin oil products are commercially available through brands such as Life Extension. Structure-function claims made on the products include: “Modulates key regulators of inflammation” In addition, the black cumin group also experienced a significant decrease in blood eosinophils: −50 versus 15 cells/microliter. A non-statistically significant improvement in lung function, measured as forced expiratory volume in 1 second, was also associated with the black cumin supplements. “The NSO supplementation appeared to be effective in enhancing the control of asthma symptoms with a trend in pulmonary function improvement,” wrote the researchers. “These findings may provide an evidence for the potential benefits of NSO supplementation in the clinical management of asthma. “Future studies should follow patients for a longer period and use additional outcomes to validate the benefits of NSO in asthma.” LSD may offer viable treatment for certain mental disorders McGill University (Quebec), January 26, 2021 Researchers from McGill University have discovered, for the first time, one of the possible mechanisms that contributes to the ability of lysergic acid diethylamide (LSD) to increase social interaction. The findings, which could help unlock potential therapeutic applications in treating certain psychiatric diseases, including anxiety and alcohol use disorders, are published in the journal PNAS. Psychedelic drugs, including LSD, were popular in the 1970s and have been gaining popularity over the past decade, with reports of young professionals claiming to regularly take small non-hallucinogenic micro-doses of LSD to boost their productivity and creativity and to increase their empathy. The mechanism of action of LSD on the brain, however, has remained a mystery. Studies in mice provide clues To conduct their study, the researchers administered a low dose of LSD to mice over a period of seven days, resulting in an observable increase in the sociability of the mice. "This increased sociability occurs because the LSD activates the serotonin 5-HT2A receptors and the AMPA receptors -- which is a glutamate receptor, the main brain excitatory neurotransmitters -- in the prefrontal cortex and also activates a cellular protein called mTORC 1," explains Danilo De Gregorio, PharmD, PhD, who is a postdoctoral fellow in the Neurobiological Psychiatry Unit at McGill and the study's first author. "These three factors, taken together, promote social interaction in mice, which is the equivalent of empathy and social behaviour in humans." The researchers note that the main outcome of their study is the ability to describe, at least in rodents, the underlying mechanism for the behavioural effect that results in LSD increasing feelings of empathy, including a greater connection to the world and sense of being part of a large community. "The fact that LSD binds the 5-HT2A receptor was previously known. The novelty of this research is to have identified that the prosocial effects of LSD activate the 5-HT2 receptors, which in-turn activate the excitatory synapses of the AMPA receptor as well as the protein complex mTORC1, which has been demonstrated to be dysregulated in diseases with social deficits such as autism spectrum disorder," as specified by Prof. Nahum Sonenberg, Professor at the Department of Biochemistry of McGill University, world renowned expert in the molecular biology of diseases and co-lead author of the study. Using the cutting-edge technique of optogenetics, a technique where genes for light-sensitive proteins are introduced into specific types of brain cells in order to monitor and control their activity precisely using light signals, the researchers observed that when the excitatory transmission in the prefrontal cortex is de-activated, the prosocial effect of LSD was nullified, highlighting the importance of this brain region on the modulation of the behavioural effects of LSD. Moving forward to apply the findings to humans Having found that LSD increases social interaction in mice, the researchers are hoping to continue their work and to test the ability of LSD to treat mutant mice displaying the behavioural deficits similar to those seen in human pathologies including autism spectrum disorders and social anxiety disorders. The hope is to eventually explore whether micro-doses of LSD or some novel derivates might have a similar effect in humans and whether it could also be a viable and safe therapeutic option. "Social interaction is a fundamental characteristic of human behaviour," notes the co-lead author Dr. Gabriella Gobbi, Professor in the Department of Psychiatry at McGill and psychiatrist at the McGill University Health Centre. "These hallucinogenic compounds, which, at low doses, are able to increase sociability may help to better understand the pharmacology and neurobiology of social behavior and, ultimately, to develop and discover novel and safer drugs for mental disorders." Polyphenol-rich virgin olive oil reduces insulin resistance and liver inflammation and improves mitochondrial dysfunction University of Naples (Italy), January 28, 2021 Studies from University of Naples Federico II Describe New Findings in Insulin Resistance (Polyphenol-rich virgin olive oil reduces insulin resistance and liver inflammation and improves mitochondrial dysfunction in high-fat diet fed rats) A new study on Endocrine System Diseases and Conditions - Insulin Resistance is now available. According to news reporting originating in Naples, Italy, research stated, "Virgin olive oil is an essential component of the Mediterranean diet. Its antioxidant and anti-inflammatory properties are mainly linked to phenolic contents." The news reporters obtained a quote from the research from the University of Naples Federico II, "This study aims to evaluate the beneficial effects of a polyphenol-rich virgin olive oil (HPCOO) or olive oil without polyphenols (WPOO) in rats fed high-fat diet (HFD). Male Sprague-Dawley rats were divided into four groups based on the different types of diet: (I) standard diet (STD); (II) HFD; (III) HFD containing WPOO, and (IV) HFD containing HPCOO. HPCOO and WPOO induced a significant improvement of HFD-induced impaired glucose homeostasis (by hyperglycemia, altered oral glucose tolerance, and HOMA-IR) and inflammatory status modulating pro-and anti-inflammatory cytokines (TNF-a, IL-1, and IL-10) and adipokines. Moreover, HPCOO and less extensively WPOO, limited HFD-induced liver oxidative and nitrosative stress and increased hepatic fatty acid oxidation. To study mitochondrial performance, oxidative capacity and energy efficiency were also evaluated in isolated liver mitochondria. HPCOO, but not WPOO, reduced H O release and aconitase activity by decreasing degree of coupling, which plays a major role in the control of mitochondrial reactive oxygen species emission." According to the news reporters, the research concluded: "HPCOO limits HFD-induced insulin resistance, inflammation, and hepatic oxidative stress, preventing nonalcoholic fatty liver disease progression." For more information on this research see: Polyphenol-rich virgin olive oil reduces insulin resistance and liver inflammation and improves mitochondrial dysfunction in high-fat diet fed rats.

T cell metabolic Dialectics : deriving bioenergetic supremecy from glycolysis through fatty acid and lipid synthesis to ultimate fatty acid oxidation and ATP generation. Dr Daniel J. Guerra

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Play Episode Listen Later Dec 30, 2020 29:41

Authentic Biochemistry Podcast 29 December 2020 Daniel J. Guerra Ph.D. •All scientific inquiry should start with dialectical method that uses the current knowledge base to generate various specific Theses and then follow each with the counter-argument by employing the Square of Opposition thus producing Anti-theses and then, making the third movement, which allows for a Synthesis that has the flavor of rejection, acceptance or indifference. *Downstream of co-stimulation and PI3K-AKT, the mammalian target of Rapamycin (mTOR) kinase pathway integrates multiple signals and regulates anabolic metabolic reprogramming in T cells exiting quiescence. mTOR complex 1 (mTORC1) is required for cell cycle entry and coordination of early metabolic changes that occur upon T cell activation. *T cells deficient in Raptor, an essential component of mTORC1, fail to upregulate the expression of Glut1 and other glycolytic enzymes when activated. *Raptor-deficient T cells also exhibit defects in de novo lipid synthesis and oxidative phosphorylation, suggesting the mTOR pathway is a global regulator of T cell metabolic programs. *mTORC1-mediated signaling is also required for proteomic remodeling of pathways including one-carbon metabolism(SAM and Folic acid), FAO, and the electron transport chain (ETC) that occurs early in activating T cells. --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message Support this podcast: https://anchor.fm/dr-daniel-j-guerra/support

Modulating a Gatekeeper of Cellular Metabolism to Treat a Range of Diseases

The Bio Report

Play Episode Listen Later Nov 12, 2020 36:28

A gatekeeper of cellular metabolism known as mTORC1 underlies a wide range of age-related diseases. Navitor Pharmaceuticals is developing therapies that can modulate the mTORC1 complex and allow for a new approach to treating a wide range of diseases including autosomal dominant polycystic kidney disease and major depressive disorders. We spoke to Tom Hughes, president and CEO of Navitor, about mTORC1, the company's platform technology, and why it has implications for a wide range of seemingly unrelated conditions.

Brain-Specific Inhibition of mTORC1 by a Dual Drug Strategy: A Novel Approach for the Treatment of Alcohol Use Disorder

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Play Episode Listen Later Oct 12, 2020

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.12.336701v1?rss=1 Authors: Ehinger, Y., Zhang, Z., Phamluong, K., Soneja, D., Shokat, K., Ron, D. Abstract: Alcohol Use Disorder (AUD) is a devastating psychiatric disorder affecting a large portion of the population. Unfortunately, efficacious medications to treat the disease are limited and thus AUD represents an area of unmet medical need. mTORC1 plays a crucial role in neuroadaptations underlying alcohol use. mTORC1 also contributes to alcohol craving, habit, and relapse. Thus, mTORC1 inhibitors are promising therapeutic agents to treat AUD. However, chronic inhibition of mTORC1 in the periphery produces undesirable side effects in humans, which limit their potential clinical use for the treatment of AUD. To overcome these limitations, we utilized a binary drug strategy in which mice were co-administered the mTORC1 inhibitor RapaLink-1 together with a novel small molecule (RapaBlock) to protect mTORC1 activity in the periphery. We show that the dual administration of RapaLink-1 with RapaBlock, abolishes RapaLink-1-dependent mTORC1 inhibition in the liver and blocks adverse side effects detected in humans including body weight loss, glucose intolerance and liver toxicity. Importantly, we show that co-administration of RapaLink-1 and RapaBlock inhibits alcohol-dependent mTORC1 activation in the Nucleus Accumbens and robustly moderates the level of alcohol use. Our data present a novel approach that could be used to treat individuals suffering from AUD . Copy rights belong to original authors. Visit the link for more info

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Rapamycin and Muscle Aging: Stronger for Longer

Super Human Radio

Play Episode Listen Later Sep 16, 2020 86:52

SHR # 2589 :: Rapamycin and Muscle Aging: Stronger for Longer - Dr. Daniel Ham, PhD - With life expectancy increasing, age-related diseases are also on the rise, including sarcopenia, the loss of muscle mass due to aging. Researchers from the University of Basel's Biozentrum have demonstrated that a well-known drug can delay the progression of age-related muscle weakness. Already in our best years, our muscles begin to shrink and their strength dwindles. Unfortunately, this is a natural part of aging. For some people, the decline in muscle mass and function is excessive. This condition, called sarcopenia, affects every second or third person over 80, reducing mobility, autonomy and quality of life. Rapamycin helps to reduce senescent cell accumulation and extend lifespan by modulating mTORc1 activity and has been thought to also reduce muscle mass and protein synthesis. But is this true? Database web app discussed during the interview can be found here https://sarcoatlas.scicore.unibas.ch/ . mTORC1 signaling is not essential for the maintenance of muscle mass and function in adult sedentary mice https://pubmed.ncbi.nlm.nih.gov/31697050/

Rapamycin and Muscle Aging: Stronger for Longer

Super Human Radio

Play Episode Listen Later Sep 16, 2020 86:52

SHR # 2589 :: Rapamycin and Muscle Aging: Stronger for Longer - Dr. Daniel Ham, PhD - With life expectancy increasing, age-related diseases are also on the rise, including sarcopenia, the loss of muscle mass due to aging. Researchers from the University of Basel's Biozentrum have demonstrated that a well-known drug can delay the progression of age-related muscle weakness. Already in our best years, our muscles begin to shrink and their strength dwindles. Unfortunately, this is a natural part of aging. For some people, the decline in muscle mass and function is excessive. This condition, called sarcopenia, affects every second or third person over 80, reducing mobility, autonomy and quality of life. Rapamycin helps to reduce senescent cell accumulation and extend lifespan by modulating mTORc1 activity and has been thought to also reduce muscle mass and protein synthesis. But is this true? Database web app discussed during the interview can be found here https://sarcoatlas.scicore.unibas.ch/ . mTORC1 signaling is not essential for the maintenance of muscle mass and function in adult sedentary mice https://pubmed.ncbi.nlm.nih.gov/31697050/

university longer stronger researchers muscle databases basel shr rapamycin mtorc1

GTPBP1 resolves paused ribosomes to maintain neuronal homeostasis

Play Episode Listen Later Sep 4, 2020

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.03.281675v1?rss=1 Authors: Terrey, M., Adamson, S. I., Gibson, A. L., Deng, T., Ishimura, R., Chuang, J. H., Ackerman, S. L. Abstract: Ribosome-associated quality control pathways respond to defects in translational elongation to recycle arrested ribosomes and degrade aberrant polypeptides and mRNAs. Loss of an individual tRNA gene leads to ribosomal pausing that is resolved by the translational GTPase GTPBP2, and in its absence causes neuron death. Here we show that loss of the homologous protein GTPBP1 during tRNA deficiency in the mouse brain also leads to codon-specific ribosome pausing and neurodegeneration, suggesting that these non-redundant translational GTPases function in the same pathway to mitigate ribosome pausing. Ribosome stalling in the mutant brain led to activation of the integrated stress response (ISR) mediated by GCN2 and decreased mTORC1 signaling. However, in contrast to the ISR, which enhanced neuron survival, reduced mTORC1 signaling increased neuronal death. Our data demonstrate that GTPBP1 functions as an important quality control mechanism during translation elongation and suggest that translational signaling pathways intricately interact to regulate neuronal homeostasis during defective translation elongation. Copy rights belong to original authors. Visit the link for more info

loss maintain copy ackerman deng adamson paused isr homeostasis neuronal resolves chuang biorxiv mrnas trna ribosome mtorc1 ishimura gtpases

mTOR inhibition in primary neurons and the developing brain represses transcription of cholesterol biosynthesis genes and alters cholesterol levels

Play Episode Listen Later Sep 4, 2020

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.04.282772v1?rss=1 Authors: Schuele, M., Butto, T., Dewi, S., Strand, S., Gerber, S., Endres, K., Schweiger, S., Winter, J. Abstract: Dysregulated mammalian target of rapamycin (mTOR) activity is associated with various neurodevelopmental disorders ranging from idiopathic autism spectrum disorders to monogenic syndromes as for example Tuberous sclerosis complex. Thus, maintaining mTOR activity levels in a physiological range is essential for brain development and functioning. Upon activation, mTOR regulates a variety of cellular processes such as cell growth, autophagy and metabolism. On a molecular level, however, the consequences of mTOR activation are not well understood, especially in the brain. Thus, while it was shown that in cells outside the central nervous system mTORC1 activity is necessary for activating gene transcription of different metabolic pathways this mechanism is ill defined in the brain. By combining mTORC1 inhibition with RNA-sequencing we identified numerous genes of the sterol/cholesterol biosynthesis pathway to be downstream targets of mTORC1 in vitro in primary neurons and in vivo in the developing cerebral cortex of the mouse. Of note, reduced expression of these genes upon mTORC1 inhibition translated into reduced cholesterol levels. We further show that while mTORC1 does not regulate chromatin accessibility or RNA stability of these genes it drives transcription of their DNA. Using a bioinformatics approach, we identified binding sites for the transcription factors SREBP, SP1 and NF-Y to be enriched in the promoters of mTORC1 target genes and confirmed binding of NF-YA by ChIP-qPCR. Altogether, our results indicate that mTORC1 is an important regulator of the expression of sterol/cholesterol biosynthesis genes in the developing brain. Altered expression of these genes may be an important contributing factor in the pathogenesis of neurodevelopmental disorders associated with dysregulated mTOR signaling. Copy rights belong to original authors. Visit the link for more info

Aberrant DJ-1 expression underlies L-type calcium channel hypoactivity in tuberous sclerosis complex and Alzheimer's disease

dj alzheimer's disease craft copy expression mrna rna ts calcium keene deficits aberrant biorxiv ca2 tuberous sclerosis complex mtorc1

Play Episode Listen Later Aug 27, 2020

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.26.267260v1?rss=1 Authors: Niere, F., Cacheaux, L. P., Uneri, A., Reynoldson, C., Penaranda, J., Taylor, W. C., Craft, S., Keene, C. D., Ma, T., Raab-Graham, K. F. Abstract: L-type voltage-dependent Ca2+ channels (L-VDCC) integrate synaptic signals to facilitate a plethora of cellular mechanisms. L-VDCC dysfunction is implicated in several neurological and psychiatric diseases. Despite their importance, signals upstream of L-VDCC activity that regulate their channel density, however, are poorly defined. In disease models with overactive mammalian target of rapamycin complex 1 (mTORC1) signaling (or mTORopathies), including tuberous sclerosis (TS) and Alzheimer's disease (AD), we report a novel mechanism downstream of mTORC1 signaling that results in a deficit in dendritic L-VDCC activity. Deficits in L-VDCC activity are associated with increased expression of the mTORC1-regulated RNA-binding protein DJ-1. DJ-1 binds the mRNA coding the auxiliary Ca2+ channel subunit 2{delta}2 responsible for shuttling L-VDCC to the membrane and represses its expression. Moreover, this novel DJ-1/2{delta}2/L-VDCC pathway is disrupted in human AD and preclinical models of AD and TS. Our discovery that DJ-1 directs L-VDCC activity and L-VDCC-associated protein 2{delta}2 at the synapse suggests that DJ-1/2{delta}2/L-VDCC is a common, fundamental pathway disrupted in TS and AD that can be targeted in clinical mTORopathies. Copy rights belong to original authors. Visit the link for more info

Episode 585 IronRadio - Topic Chat, Mail, Breaking Science News

Iron Radio

Play Episode Listen Later Aug 2, 2020

Listener mail and breaking science news bring on PLENTY of discussion on a wide range of topics. Join in for talk on... - Creatine use and potential confusion during a doctor's visit - Planning and logging training programs - High protein diets - Metformin and longevity - mTORC1 stimulation vs. suppression - Top nutrition podcasts - Red flags for fraud and bro science - Carb challenges for predicting your chance of diabetes - A molecule in oranges that may help control obesity - A newly identified gene that may be a linchpin for staying lean - CBD oil and COVID-19 severity Pull up a bench and get in on this! Lastly, you're invited to pre-buy and follow along with our next taste tests on YouTube - Shrooms original mushroom jerky and Jack Links bacon jerky. https://podcasts.apple.com/podcast/id308382038 and https://www.youtube.com/watch?v=ZSdCiZtvcB0

covid-19 planning mail cbd carb creatine metformin science news jack links mtorc1

Episode 585 IronRadio - Topic Chat, Mail, Breaking Science News

Iron Radio

Play Episode Listen Later Aug 2, 2020

Listener mail and breaking science news bring on PLENTY of discussion on a wide range of topics. Join in for talk on... - Creatine use and potential confusion during a doctor's visit - Planning and logging training programs - High protein diets - Metformin and longevity - mTORC1 stimulation vs. suppression - Top nutrition podcasts - Red flags for fraud and bro science - Carb challenges for predicting your chance of diabetes - A molecule in oranges that may help control obesity - A newly identified gene that may be a linchpin for staying lean - CBD oil and COVID-19 severity Pull up a bench and get in on this! Lastly, you're invited to pre-buy and follow along with our next taste tests on YouTube - Shrooms original mushroom jerky and Jack Links bacon jerky. https://podcasts.apple.com/podcast/id308382038 and https://www.youtube.com/watch?v=ZSdCiZtvcB0

covid-19 planning mail cbd carb creatine metformin science news jack links mtorc1

Structural mechanism for amino acid-dependent Rag GTPase switching by SLC38A9

PaperPlayer biorxiv biochemistry

Play Episode Listen Later Jul 29, 2020

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.28.225524v1?rss=1 Authors: Fromm, S., Lawrence, R. E., Hurley, J. H. Abstract: The mechanistic target of rapamycin complex 1 (mTORC1) couples cell growth to nutrient, energy and growth factor availability1-3. mTORC1 is activated at the lysosomal membrane when amino acids are replete via the Rag guanosine triphosphatases (GTPases)4-6. Rags exist in two stable states, an inactive (RagA/BGDP:RagC/DGTP) and active (RagA/BGTP:RagC/DGDP) state, during low and high cellular amino acid levels4,5. The lysosomal folliculin (FLCN) complex (LFC) consists of the inactive Rag dimer, the pentameric scaffold Ragulator7,8, and the FLCN:FNIP (FLCN-interacting protein) GTPase activating protein (GAP) complex9, and prevents activation of the Rag dimer during amino acid starvation10,11. How the LFC is released upon amino acid refeeding is a major outstanding question in amino-acid dependent Rag activation. Here we show that the cytoplasmic tail of the lysosomal solute carrier family 38 member 9 (SLC38A9), a known Rag activator12-14, destabilizes the LFC. By breaking up the LFC, SLC38A9 triggers the GAP activity of FLCN:FNIP toward RagC. We present the cryo electron microscopy (cryo-EM) structures of Rags in complex with their lysosomal anchor complex Ragulator and the cytoplasmic tail of SLC38A9 in the pre and post GTP hydrolysis state of RagC, which explain how SLC38A9 destabilizes the LFC and so promotes Rag dimer activation. Copy rights belong to original authors. Visit the link for more info

switching copy gap dependent hurley structural mechanism rags rag amino acids lfc gtp biorxiv mtorc1 gtpase gtpases

Brain transcriptome analysis reveals subtle effects on mitochondrial function and iron homeostasis of mutations in the SORL1 gene implicated in early onset familial Alzheimers disease

Play Episode Listen Later Jul 17, 2020

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.17.207787v1?rss=1 Authors: Barthelson, K., Pederson, S. M., Newman, M., Lardelli, M. Abstract: Background: To prevent or delay the onset of Alzheimers disease (AD), we must understand its molecular basis. The great majority of AD cases arise sporadically with a late onset after 65 years of age (LOAD). However, rare familial cases of AD can occur due to dominant mutations in a small number of genes that cause an early onset prior to 65 years of age (EOfAD). As EOfAD and LOAD share similar pathologies and disease progression, analysis of EOfAD genetic models may give insight into both subtypes of AD. Sortilin-related receptor 1 (SORL1) is genetically associated with both EOfAD and LOAD and provides a unique opportunity to investigate the relationships between both forms of AD. Currently, the role of SORL1 mutations in AD pathogenesis is unclear. Methods: To understand the molecular consequences of SORL1 mutation, we performed targeted mutagenesis of the orthologous gene in zebrafish. We generated an EOfAD-like mutation, V1482Afs, and a putatively null mutation, to investigate whether EOfAD-like mutations in sorl1 display haploinsufficiency by acting through loss-of-function mechanisms. We performed mRNA-sequencing on whole brains comparing normal (wild type) fish with their siblings heterozygous for EOfAD-like or complete loss-of-function mutations in sorl1 or transheterozygous for these mutations. Differential gene expression and gene set enrichment analyses identified, respectively, changes in young adult zebrafish brain transcriptomes, and putative effects on neural subcellular functions. Results: We identified subtle effects on expression of genes involved in energy production, mRNA translation and mTORC1 signalling in both the EOfAD-like and null mutant brains, implying that these effects are due to sorl1 haploinsufficiency. Surprisingly, we also observed changes to expression of genes occurring only in the EOfAD-mutation carrier brains, suggesting gain-of-function effects. Transheterozygosity for the EOfAD-like and null mutations (i.e. lacking wild type sorl1), caused apparent effects on iron homeostasis and other transcriptome changes distinct from the single-mutation heterozygous fish. Conclusions: Our results provide insight into the possible early brain molecular effects of an EOfAD mutation in human SORL1. Differential effects of heterozygosity and complete loss of normal SORL1 expression are revealed. Copy rights belong to original authors. Visit the link for more info

Oncotarget - Indoximod Opposes The Immunosuppressive Effects Mediated By IDO And TDO

Play Episode Listen Later Jun 23, 2020 5:06

Volume 11 Issue 25 of @Oncotarget reported that Indoximod has shaped the understanding of the biology of IDO1 in the control of immune responses, though its mechanism of action has been poorly understood. Indoximod can have a direct effect on T cells, increasing their proliferation as a result of mTOR reactivation. Further, indoximod modulates the differentiation of CD4+ T cells via the aryl hydrocarbon receptor, which controls transcription of several genes in response to different ligands including kynurenine. Indoximod increases the transcription of RORC while inhibiting transcription of FOXP3, thus favoring differentiation to IL-17-producing helper T cells and inhibiting the differentiation of regulatory T cells. Indoximod can also downregulate expression of IDO protein in vivo in murine lymph node dendritic cells and in vitro in human monocyte-derived dendritic cells via a mechanism that involves signaling through the Ah R. Together, these data improve the understanding of how indoximod influences the effects of IDO, beyond and distinct from direct enzymatic inhibition of the enzyme. Dr. Erik L. Brincks from NewLink Genetics Corporation as well as Lumos Pharma, Inc. said "Indoleamine 2,3-dioxygenase (IDO1) plays an important role in the regulation of acquired local and peripheral immune tolerance in normal and pathological scenarios." In cancer, IDO1 can be expressed either directly by the tumor cells or induced indirectly in host antigen presenting cells by the tumor. IDO1 expression by tumor cells has been associated with significantly worse clinical prognosis and reduced survival in malignant melanoma, pancreatic cancer, ovarian cancer, both pediatric and adult acute myelogenous leukemia, colorectal cancer, prostate cancer, endometrial cancer, and others. The cellular pharmacodynamic effects of IDO1 activity include the inhibition of antigen-specific CD8+ T cell proliferation, stimulation of differentiation of na�ve CD4+ T cells to Fox P3+ regulatory T cells, the activation of Tregs, and the recruitment of MDSC to the tumor. Both isomers are capable of restoring T-cell proliferation in an MLR assay with IDO+ dendritic cells as the stimulator cells, or in syngeneic antigen-dependent T-cell proliferation assays using IDO+ dendritic cells isolated from tumor-draining lymph nodes. L1m T is a competitive inhibitor and substrate of IDO1 enzymatic activity in cell-free assays using purified recombinant IDO1 enzyme, and in tumor cells treated with INFγ or in tumor cell lines transfected with expression vectors that encode IDO1 under the control of an heterologous promoter. The Brincks Research Team concluded in their Oncotarget Research Paper that these effects are independent on the Trp metabolizing activity of IDO and/or TDO but happen to oppose the effects of the enzymatic activity of IDO and TDO by multiple mechanisms that act on cell types commonly affected by the IDO and TDO pathways. Indoximod creates a Trp-sufficiency signal which leads to reactivation of MAP4K3 which leads to activation of mTORC1 activity, thus opposing and bypassing the effects of Trp deprivation that lead to GCN2 activation and MAP4K3 and mTOR inactivation. This effect requires a relatively high concentration of indoximod, is observed in both CD4+ and CD8+ T cells and leads to an increase in the proliferative capacity of activated effector and helper T cells. This effect takes place at clinically relevant concentrations of indoximod and is independent of IDO/TDO activity or exogenous Kyn, though it happens to oppose the Kyn/Ah R effects on T cell differentiation. Full text - https://www.oncotarget.com/article/27646/text/

effects inf opposes mediated mtor trp mlr cd4 cd8 t t do cd4 t erik l kyn tregs immunosuppressive mtorc1 oncotarget foxp3

Do Sports Drinks Actually Work?

Lab Rats Podcast

Play Episode Play 42 sec Highlight Listen Later Jun 21, 2020 50:28

Gatorade, Vitamin Water, Body Armor, FitAid, Nuun tablets...these are just a few of the many sports drinks that have been a staple for refueling the body after physical activity. While the ingredients vary substantially among each drink, there are a few common components you'll find, a few being:ElectrolytesAmino Acids (BCAAs or EAAs)B VitaminsWhat purpose do these compounds serve in human nutrition? And are they necessary? Furthermore, are they worth the other ingredients that are also commonly found in sports drinks like sugar, synthetic dyes, and flavorings? Andy and Aaron break down key ingredients found in popular sports drinks, how they impact the recovery process, and what to look for before consuming.Learn more on InstagramWatch us on YouTubeVisit our WebsiteResources:How much water should you drink?Hydration 101: How Much Water Do You Really Need?"Drink at Least Eight Glasses of Water a Day." Really? Is There Scientific Evidence for "8 X 8"?Everything you need to know about electrolytesAmino acids: metabolism, functions, and nutritionLysineMethionine PhenylalanineThreonineTryptophanLeucineIsoleucineValineHistidineBranched-chain amino acids in health and disease: metabolism, alterations in blood plasma, and as supplementsBranched chain amino acid supplementation and exercise induced muscle damage in exercise recovery: a meta-analysis of randomized clinical trialsActivation of mTORC1 by leucine is potentiated by branched-chain amino acids and even more so by essential amino acids following resistance exerciseEssential amino acids and muscle protein recovery from resistance exerciseNiacinPantothenic acid (B5) in health and diseaseVitamin B12 in Health and DiseaseRiboflavin (B2) and Health: A Review of Recent Human ResearchInflammation, vitamin B6 and related pathways

health water recovery exercise workout hydration gatorade actually work health podcast b6 body armor b5 vitamin water nuun sports drinks fitaid mtorc1 indianapolis podcast

The Mammalian Target of Rapamycin (mTOR) Kinase Mediates Haloperidol-Induced Cataleptic Behavior

Play Episode Listen Later Jun 20, 2020

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.18.160416v1?rss=1 Authors: Ramirez-Jarquin, U. N., Shahani, N., Pryor, W., Usiello, A., Subramaniam, S. Abstract: The mammalian target of rapamycin (mTOR) is a ubiquitously expressed serine/threonine kinase protein complex (mTORC1 or mTORC2) that orchestrates diverse functions ranging from embryonic development to aging. However, its brain tissue-specific roles remain less explored. Here, we have identified that the depletion of the mTOR gene in the mice striatum completely prevented the extrapyramidal motor side-effects (catalepsy) induced by the dopamine 2 receptor (D2R) antagonist haloperidol, which is the most widely used typical antipsychotic drug. Conversely, a lack of striatal mTOR in mice did not affect catalepsy triggered by the dopamine 1 receptor (D1R) antagonist SCH23390. Along with the lack of cataleptic effects, the administration of haloperidol in mTOR mutants failed to increase striatal phosphorylation levels of ribosomal protein pS6 (S235/236) as seen in control animals. To confirm the observations of the genetic approach, we used a pharmacological method and determined that the mTORC1 inhibitor rapamycin has a profound influence upon post-synaptic D2R-dependent functions. We consistently found that pretreatment with rapamycin entirely prevented (in a time-dependent manner) the haloperidol-induced catalepsy in wild-type mice. Collectively, our data indicate that striatal mTORC1 blockade may offer therapeutic benefits with regard to the prevention of D2R-dependent extrapyramidal motor side-effects of haloperidol in psychiatric illness. Copy rights belong to original authors. Visit the link for more info

target behavior copy conversely collectively induced pryor mtor mammalian rapamycin kinase biorxiv shahani haloperidol mtorc1 d2r mtorc2

Más que Nutrición - Episodio #9 - Matías Monsalves - Suplementación con cuerpos cetónicos.

Más Que Nutrición

Play Episode Listen Later Jun 12, 2020 71:38

En nuestro octavo episodio tuvimos el honor de conversar con:

High Content Screening and Proteomic Analysis Identify the Kinase Inhibitor BX795 as a Potent Neuroprotective Compound in a Patient-Derived Model of Parkinson's Disease

Research To Practice | Oncology Videos

Play Episode Listen Later Jun 12, 2020

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.12.148031v1?rss=1 Authors: Antoniou, N., Prodromidou, K., Kouroupi, G., Samiotaki, M., Panayotou, G., Xilouri, M., Stefanis, L., Grailhe, R., Taoufik, E., Matsas, R. Abstract: Combining high throughput screening approaches with induced pluripotent stem cell (iPSC)-based disease models represents a promising unbiased strategy to identify therapies for neurodegenerative disorders. Here we applied high content imaging on iPSC-derived neurons from patients with familial Parkinson's disease bearing the G209A (p.A53T) lpha-synuclein mutation and launched a screening campaign on a small kinase inhibitor library. We thus identified the multi-kinase inhibitor BX795 that at a single dose effectively restores disease-associated neurodegenerative phenotypes. Proteomics profiling mapped the molecular pathways underlying the neuroprotective effects of BX795 that comprised a cohort of 118 protein-mediators of the core biological processes of RNA metabolism, protein synthesis, modification and clearance, and stress response, all linked to the mTORC1 signaling hub. In agreement, expression of human p.A53T-lpha-Synuclein in neuron-like cells affected key components of the mTORC1 pathway resulting in aberrant protein synthesis that was restored in the presence of BX795 with concurrent facilitation of autophagy. Taken together, we have developed an adaptable platform based on p.A53T iPSC-derived neurons for drug screening and identified a promising small molecule with potent neuroprotective actions as candidate therapeutic for PD and other protein conformational disorders. Copy rights belong to original authors. Visit the link for more info

Breast Cancer | Virginia Kaklamani, MD, DSc

Play Episode Listen Later Oct 28, 2019 71:33

Breast Cancer Update, Issue 3, 2019 — Part 2: Our interview with Dr Kaklamani highlights the following topics as well as cases from her practice: Efficacy and safety of the novel SERD elacestrant for ER-positive breast cancer; Phase III EMERALD trial evaluating elacestrant versus endocrine therapy (00:00) Incidence of ESR1 mutations; activity of elacestrant after disease progression on fulvestrant and a CDK4/6 inhibitor (02:14) Results from the Phase II ANETT trial of the mTORC1/2 inhibitor TAK-228 with tamoxifen as neoadjuvant therapy for ER-positive breast cancer (03:53) Novel approaches under investigation in the neoadjuvant setting (07:20) Perspective on the use of neoadjuvant therapy to optimize surgical outcomes for patients with ER-positive, HER2-negative breast cancer (09:43) Activity of CDK4/6 inhibitors for locally advanced ER-positive breast cancer (11:30) Case: A woman in her late 60s with ER-positive, HER2-negative breast cancer and 1 of 3 positive axillary lymph nodes receives a 21-gene assay RS of 18 (13:49) Role of the 21-gene expression assay in predicting chemotherapy benefit for patients with ER-positive breast cancer (15:56) Clinical and genomic risk to guide the use of adjuvant therapy for breast cancer (19:11) Case: A premenopausal woman in her late 40s with ER-positive, HER2-negative, node-negative breast cancer receives a RS of 19 (23:19) Clinical implications of the TAILORx trial comparing chemoendocrine therapy to endocrine therapy for patients with ER-positive, node-negative breast cancer and an intermediate RS (25:00) Tailoring adjuvant endocrine therapy for premenopausal women with ER-positive breast cancer (27:54) Benefit of endocrine therapy with or without chemotherapy for patients with ER-positive breast cancer and an intermediate RS; consideration of clinical and genomic risk in assessing the likelihood of disease recurrence (30:54) Case: A woman in her early 40s with ER-positive, HER2-negative breast cancer and metastases in the liver and bones attains a partial response to ribociclib in combination with endocrine therapy (35:24) Benefit with CDK4/6 inhibitors versus chemotherapy for ER-positive breast cancer with visceral metastases (37:57) Efficacy of ribociclib in premenopausal women; QT prolongation associated with ribociclib/tamoxifen (40:54) Comparison of the efficacy and toxicity profiles of abemaciclib, palbociclib and ribociclib for women with ER-positive mBC (42:24) Activity of CDK4/6 inhibitors as monotherapy; CNS penetration of CDK4/6 inhibitors (45:47) Monitoring and management of side effects associated with CDK4/6 inhibitors (48:07) Case: A woman in her mid-50s initially diagnosed with Stage II ER-positive breast cancer develops metastatic disease to the bone 8 years later and receives palbociclib and anastrozole (50:54) Perspective on the use of multiplex genomic assays to guide treatment decision-making for patients with ER-positive mBC (53:35) Results of the Phase III SOLAR-1 trial evaluating alpelisib for patients with ER-positive advanced breast cancer (55:54) Tolerability of alpelisib for patients with ER-positive breast cancer (57:54) Sequencing everolimus and alpelisib after disease progression on a CDK4/6 inhibitor (1:00:06) Case: A postmenopausal woman in her mid-30s with ER-positive mBC and BRCA2 and PIK3CA mutations receives talazoparib in the third-line setting (1:01:46) Choice of PARP inhibitor for patients with advanced breast cancer and BRCA mutations (1:04:58) Response and side-effect profiles of alpelisib (1:06:10) Selection and sequencing of therapy for patients with mBC and germline BRCA mutations (1:07:00) CME information and select publications

Episode 92: Megan Roberts discusses the potential of a ketogenic diet to extend healthspan and lifespan

Beast Fitness Radio's Podcast

Play Episode Listen Later Jul 16, 2019 45:30

Our guest today is Megan Roberts, a research scientist who conducted an interesting study that showeda ketogenic diet extended the longevity and healthspan of adult mice. This study has been discussed in several earlier episodes of STEM-Talk. Megan conducted her research while earning a master’s degree in nutritional biology at the University of California, Davis. Today, she is the scientific director at Nourish Balance Thrive, an online health-coaching company where Megan helps people optimize their heath and performance. Show notes: [00:02:53] Dawn begins the interview mentioning that Megan grew up in Northern California and asks Megan what she was like as a child. [00:03:20] Megan talks about how her interest in science started. [00:03:38] Dawn asks Megan how she became a martial arts instructor, teaching teen-agers as well as children as young as five years old. [00:04:02] Megan talks about her decision to attend the University of California, Davis. [00:04:16] Megan explains why she initially want to major in biochemistry, but decided toward the end of her freshman year to switch majors. [00:04:42] Ken asks Megan about her decision to stay at UC Davis to earn a master’s degree in nutritional biology. [00:05:08] Megan talks about the privilege of having open-minded professors and peers who were a part of her nutritional biology program at UC Davis. [00:06:07] Ken mentions that part of Megan’s thesis ended up in Cell Metabolism, in the form of a paper titeld, “A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice.”The paper, Ken points out, has been discussed in several episodes of STEM-Talk. He asks Megan about the motivations behind her study. [00:07:41] Megan describes the three different diets used for the mouse studies. [00:08:30] Dawn mentions that an important aspect of the study was that all of the mice were fed the same number of calories every day. She asks Megan to explain the significance of this parameter. [00:09:23] Megan describes the various markers of physiological function that were measured how the study yielded interesting results in terms of healthspan in the mice. [00:10:14] Dawn asks how the memories of the mice were tested. Dawn also asks Megan to go into detail on the finding that mice on the ketogenic diet were having their memories preserved for longer. [00:11:13] Ken asks Megan how she tested the grip strength of mice. [00:12:05] Megan talks about the two areas of healthspan that saw the most dramatic effects with the ketogenic diet: memory and the preservation of motor-function. [00:12:39] Ken asks if Megan and her colleagues were surprised by the finding that lifespan was increased by 14 percent in the mice fed a ketogenic diet. [00:13:08] Dawn mentions that the ketogenic diet came out on top in the study, followed by the low-carb diet. Dawn mentions that those mice on the low-carb diet, however, surprisingly gained weight asks Megan is she was surprised by this. [00:14:35] Ken asks what lead Megan to the idea of studying the ketogenic diet as an intervention in midlife, as opposed to being a habit throughout life. [00:15:27] Dawn asks how well Megan thinks these mouse models are likely to translate to humans. [00:17:05] Ken asks what experiments Megan would have done to extend her findings reported in the Cell Metabolism paper if she had managed to have more time, funding and resources. [00:17:52] Dawn mentions that Megan’s study suggests that the metabolic changes that accompany carbohydrate restriction might indeed help increase lifespan. However, Dawn asks Megan about ketone bodies themselves (AcAc and BhB) and their potential role in the extension of healthspan. [00:18:13] Ken asks about Megan’s findings in regards to a tissue dependent mTORC1 signaling, in the context of skeletal muscle and the ketogenic diet. [00:20:26] Dawn asks Megan for her take on the tissue specific effects of ketones that she ob...

university california northern california extend uc davis lifespan ketogenic diet healthspan bhb acac cell metabolism nourish balance thrive mtorc1 megan roberts stem talk

The NEW RAGING FULL Brief Overview (Intraworkout Nutrition Basics)

Play Episode Listen Later May 24, 2019 18:56

Episode 248 is a brief overview and breakdown on the all new formula for ProjectAD's RAGING FULL! This is their intra workout carbohydrate and hydration blend that has some awesome new aspects to it! This is a brief overview which should help you guys understand why I am a huge fan of this new formula! There will be an extreme in depth breakdown in the future for those science nerds like me that LOVE the details! INTRAWORKOUT CARBOHYDRATE/AMINO ACID REFERENCES Bird SP, et al. Liquid carbohydrates/essential amino acid ingestion during a short-term bout of resistance exercise suppresses myofibrillar protein degradation. Metabolism. 2006 May;55(5):570-7. Bloom PC, et al. Effect of different post-exercise sugar diets on the rate of muscle glycogen synthesis. Med Sci Sports Exerc. 1987 Oct;19(5):491-6. Desbrow B, et al. Carbohydrate-electrolyte feedings and 1h time trial cycling performance. Int J Sport Nutr Exerc Metab. 2004 Oct;14(5):541-9. Erith S, et al. The effect of high carbohydrate meals with different glycemic indices on recovery of performance during prolonged Haff GG, et al. Carbohydrate supplementation and resistance training. J Strength Cond Res. 2003 Feb;17(1):187-96. Ivy JL, et al. Muscle glycogen synthesis after exercise: effect of time of carbohydrate ingestion. J Appl Physiol. 1988 Apr;64(4):1480-5. Jentjens RL, et al. Oxidation of combined ingestion of glucose and fructose during exercise. J Apply Physiol. 2004 Apr;96(4):1277-84. Jentjens RL, et al. Oxidation of exogenous glucose, sucrose and maltose during prolonged cycling exercise. J Apply Physiol. 2004 Apr;96(4):1285-91. Jentjens RL, Jeukendrup AE. High rates of exogenous carbohydrate oxidation from a mixture of glucose and fructose ingested during prolonged cycling exercise. Br J Nutr. 2005 Apr;93(4):485-92 Jeukendrup AE. Carbohydrate during exercise and performance. Nutrition. 2004 Jul-Aug;20(7-8):669-77. Keizer HA, et al. Influence of liquid and solid meals on muscle glycogen resynthesis, plasma fuel hormone response, and maximal physical working capacity. Int J Sports Med. 1987 Apr;8(2):99-104. https://www.ncbi.nlm.nih.gov/pubmed/25080121 https://www.jstage.jst.go.jp/article/fstr/21/3/21_499/_html Ferrando, A.A., et al., Oral branched-chain amino acids decrease whole-body proteolysis. JPEN. Journal of parenteral and enteral nutrition, 1995. 19(1): p. 47-54. http://www.ncbi.nlm.nih.gov/pubmed/7658600 Ruderman, N.B., et al., Regulation of alanine formation and release in rat muscle in vivo: effect of starvation and diabetes. The American journal of physiology, 1977. 233(2): p. E109-14. http://www.ncbi.nlm.nih.gov/pubmed/888947 Shimomura, Y., et al., Exercise promotes BCAA catabolism: effects of BCAA supplementation on skeletal muscle during exercise. The Journal of nutrition, 2004. 134(6 Suppl): p. 1583S-1587S. http://www.ncbi.nlm.nih.gov/pubmed/15173434 Fujii, H., et al., Branched-chain alpha-keto acid dehydrogenase kinase content in rat skeletal muscle is decreased by endurance training. Biochemistry and molecular biology international, 1998. 44(6): p. 1211-6. http://www.ncbi.nlm.nih.gov/pubmed/9623776 Lamont, L.S., et al., Comparison of leucine kinetics in endurance-trained and sedentary humans. Journal of applied physiology, 1999. 86(1): p. 320-5. http://www.ncbi.nlm.nih.gov/pubmed/9887146 Wagenmakers, A.J., et al., Carbohydrate supplementation, glycogen depletion, and amino acid metabolism during exercise. The American journal of physiology, 1991. 260(6 Pt 1): p. E883-90. http://www.ncbi.nlm.nih.gov/pubmed/2058665 Louard, R.J., et al., Effect of infused branched-chain amino acids on muscle and whole-body amino acid metabolism in man. Clinical science, 1990. 79(5): p. 457-66. http://www.ncbi.nlm.nih.gov/pubmed/2174312 Gualano, A.B., et al., Branched-chain amino acids supplementation enhances exercise capacity and lipid oxidation during endurance exercise after muscle glycogen depletion. The Journal of sports medicine and physical fitness, 2011. 51(1): p. 82-8. http://www.ncbi.nlm.nih.gov/pubmed/21297567 Shimomura, Y., et al., Branched-chain amino acid supplementation before squat exercise and delayed-onset muscle soreness. International journal of sport nutrition and exercise metabolism, 2010. 20(3): p. 236-44. http://www.ncbi.nlm.nih.gov/pubmed/20601741 Coombes, J.S. and L.R. McNaughton, Effects of branched-chain amino acid supplementation on serum creatine kinase and lactate dehydrogenase after prolonged exercise. The Journal of sports medicine and physical fitness, 2000. 40(3): p. 240-6. http://www.ncbi.nlm.nih.gov/pubmed/11125767 Bolster, D.R., et al., Regulation of protein synthesis associated with skeletal muscle hypertrophy by insulin-, amino acid- and exercise-induced signalling. The Proceedings of the Nutrition Society, 2004. 63(2): p. 351-6. http://www.ncbi.nlm.nih.gov/pubmed/15294054 Atherton, P.J., et al., Distinct anabolic signalling responses to amino acids in C2C12 skeletal muscle cells. Amino acids, 2010. 38(5): p. 1533-9. http://www.ncbi.nlm.nih.gov/pubmed/19882215 Kimball, S.R. and L.S. Jefferson, Signaling pathways and molecular mechanisms through which branched-chain amino acids mediate translational control of protein synthesis. The Journal of nutrition, 2006. 136(1 Suppl): p. 227S-31S. http://www.ncbi.nlm.nih.gov/pubmed/16365087 Gran, P. and D. Cameron-Smith, The actions of exogenous leucine on mTOR signalling and amino acid transporters in human myotubes. BMC physiology, 2011. 11: p. 10. http://www.ncbi.nlm.nih.gov/pubmed/21702994 Greiwe, J.S., et al., Leucine and insulin activate p70 S6 kinase through different pathways in human skeletal muscle. American journal of physiology. Endocrinology and metabolism, 2001. 281(3): p. E466-71. http://www.ncbi.nlm.nih.gov/pubmed/11500301 Atherton, P.J., et al., Muscle full effect after oral protein: time-dependent concordance and discordance between human muscle protein synthesis and mTORC1 signaling. The American journal of clinical nutrition, 2010. 92(5): p. 1080-8. http://www.ncbi.nlm.nih.gov/pubmed/20844073 Matthews, D.E., Observations of branched-chain amino acid administration in humans. The Journal of nutrition, 2005. 135(6 Suppl): p. 1580S-4S. http://www.ncbi.nlm.nih.gov/pubmed/15930473 Paddon-Jones, D., et al., Amino acid ingestion improves muscle protein synthesis in the young and elderly. American journal of physiology. Endocrinology and metabolism, 2004. 286(3): p. E321-8. http://www.ncbi.nlm.nih.gov/pubmed/14583440 Wolfe, R.R., Effects of amino acid intake on anabolic processes. Canadian journal of applied physiology = Revue canadienne de physiologie appliquee, 2001. 26 Suppl: p. S220-7. http://www.ncbi.nlm.nih.gov/pubmed/11897897 Floyd, J.C., Jr., et al., Evidence That Insulin Release Is the Mechanism for Experimentally Induced Leucine Hypoglycemia in Man. J Clin Invest, 1963. 42: p. 1714-9. http://www.ncbi.nlm.nih.gov/pubmed/14083162 Chow, L.S., et al., Mechanism of insulin’s anabolic effect on muscle: measurements of muscle protein synthesis and breakdown using aminoacyl-tRNA and other surrogate measures. Am J Physiol Endocrinol Metab, 2006. 291(4): p. E729-36. http://www.ncbi.nlm.nih.gov/pubmed/16705065 Shimomura, Y., et al., Nutraceutical effects of branched-chain amino acids on skeletal muscle. The Journal of nutrition, 2006. 136(2): p. 529S-532S. http://www.ncbi.nlm.nih.gov/pubmed/16424141 •••SUPPORT OUR SPONSOR••• (COACHING) Alex - www.theprepcoach.com (FREE OPEN FORUM w/ EXCLUSIVE VIDEOS) http://www.theprepcoachforum.com (SUPPLEMENTS) www.projectad.me___use discount code “BFR25” to save off your order! www.maresearchchems.com___use discount code “alex15” to save off your order! www.masupps.com___use discount code “alex20” to save off your order! (INJECTABLE L-CARNITINE) www.synthetek.com___use discount code “alexkikel” to save off your order! (BULK SUPPLEMENTS) www.truenutrition.com___use discount code “AXK5” to save off your order! •••FIND THE EPISODES••• ITUNES:https://itunes.apple.com/us/podcast/beastfitness-radios-podcast/id1065532968 LIBSYN:http://beastfitnessradio.libsyn.com VIMEO: www.vimeo.com/theprepcoach YOUTUBE: https://www.youtube.com/c/ThePrepCoach •••PREP COACH APPAREL••• https://teespring.com/stores/the-prep-coach-apparel

MIND MANIFEST EP 4 - GUILLERMO VELASCO DIEZ

Mind Manifest Podcast

Play Episode Listen Later May 20, 2019 42:50

Today Hannah Courtauld (Psychologist) and spoke to Guillermo Velasco Diez, (PhD). Guillermo is a biochemist heavily involved in the research of the therapeutic potential of cannabinoids in the treatment of Cancer. In this episode, Hannah and Guillermo Discuss: -Guillermo’s academic background and route into the world of cannabinoid research -The mechanisms of action of cannabinoids in terms of attenuating the physiological impact of carcinoma -Crowdsourced funding strategies including the medical cannabis bike tour -The current state of play with regards to clinical studies in this field -Glioblastoma and how cannabinoids are being used to treat this condition -His work with the Spanish Observatory of Medical Cannabis -Charitable and educational organisations like the canna foundation Guillermo Velasco Díez, PhD - BIO Guillermo Velasco was born in Madrid, studied Biology and obtained his PhD degree (1997) at the School of Biology of the Complutense University, Madrid, Spain. After defending his PhD, he got an EMBO long-term fellowship to work in Philip Cohen’s laboratory at the MRC Protein Phosphorylation Unit (Dundee, Scotland) on a project aimed at studying the regulation and of the Rho-activated protein kinase (ROCK). In 1999 he was awarded a position as an Assistant Teacher at the School of Chemistry of the Complutense University and in 2003 was awarded an associate professorship. In 2001 Guillermo started a line of research aimed at investigating the mechanisms underlying cannabinoid anti-tumour action as well as at optimising the potential clinical utilisation of these agents in cancer therapies. Many different avenues are currently been explored by in his group - they are currently investigating the role of endoplasmic reticulum stress, autophagy, apoptosis, intracellular trafficking of ceramide and regulation of mTORC1 and mTORC2 in cannabinoid anti-tumour action, as well as the participation of growth factor receptor-activated pathways in the resistance to the anti-neoplasic actions of cannabinoids. Guillermo Velasco was born in Madrid, studied Biology and obtained his PhD degree (1997) at the School of Biology of the Complutense University, Madrid, Spain. After defending his PhD, he got an EMBO long-term fellowship to work in Philip Cohen’s laboratory at the MRC Protein Phosphorylation Unit (Dundee, Scotland) on a project aimed at studying the regulation and of the Rho-activated protein kinase (ROCK). In 1999 he was awarded a position as an Assistant Teacher at the School of Chemistry of the Complutense University and in 2003 was awarded an associate professorship. In 2001 Guillermo started a line of research aimed at investigating the mechanisms underlying cannabinoid anti-tumour action as well as at optimising the potential clinical utilisation of these agents in cancer therapies. Many different avenues are currently been explored by in his group - they are currently investigating the role of endoplasmic reticulum stress, autophagy, apoptosis, intracellular trafficking of ceramide and regulation of mTORC1 and mTORC2 in cannabinoid anti-tumour action, as well as the participation of growth factor receptor-activated pathways in the resistance to the anti-neoplastic actions of cannabinoids.

school rock phd spain cancer scotland madrid manifest biology chemistry diez velasco glioblastoma rho crowdsourced embo complutense university mtorc1 assistant teacher mtorc2

David M. Sabatini Part 2: Regulation of mTORC1 by Nutrients

iBiology Videos

Play Episode Listen Later Apr 5, 2019 30:54

Sabatini explains that mTORC1 responds to many different upstream signals including a variety of growth factors, nutrients, and types of stress.

regulation nutrients david m sabatini mtorc1

David M. Sabatini Part 3: Ribophagy and Nucleotide Recycling

iBiology Videos

Play Episode Listen Later Apr 3, 2019 27:12

Sabatini focuses on a lysosomal membrane protein that his lab had found to interact with mTORC1 and to sense arginine levels inside the lysosome. In some cell types, the amino acids needed to build new proteins are not taken up as free amino acids but instead come from the breakdown of proteins in the lysosome. This led the lab to ask which arginine-rich proteins are being degraded in the lysosome, which led to the realization that ribosomal proteins are amongst the most arginine-rich proteins in mammalian cells. After many more experiments, they showed that mTORC1 regulates a balance between the biogenesis of ribosomes, and the breakdown of ribosomes (known as ribophagy), dependent on the nutritional state of the cell. Ribophagy seems to be particularly important for supplying the cell with nucleosides during nutrient starvation.

recycling david m sabatini nucleotide mtorc1

Ph.D. candidate Rosalie Lawrence on how our cells make decisions

Berkeley Talks

Play Episode Listen Later Jan 29, 2019 28:34

On Nov. 6, 2018, Ph.D. candidate in molecular and cell biology Rosalie Lawrence gave an interview on KALX's program, "The Graduates," about her research on how cells in our bodies make decisions. She studies mTORC1, a protein complex that interacts with cellular organelles called lysosomes and tells the cell when it has enough nutrients to grow. She is interested in the role mTORC1 plays in the development of cancer. "The Graduates," broadcast on the campus's community and student radio station KALX, features graduate student research at UC Berkeley. Listen or download past episodes on iTunes. This episode was hosted by Andrew Saintsing, a Ph.D. student in the Department of Integrative Biology. See acast.com/privacy for privacy and opt-out information.

candidate uc berkeley cells graduates make decisions integrative biology mtorc1 kalx

Episode 31: A Deeper Dive on Dairy, Acne, Prostate Cancer and Laron syndrome

Keto Naturopath

Play Episode Listen Later Sep 11, 2018 49:40

Taking a deeper look at dairy and why it is not only such a problem for so many but a near definitive cause for cancer. Acne and prostate cancer having a strong association with dairy consumption. Also, will be looking at a group of people who have a genetic defect (Laron syndrome) that blunts the effects of IGF-1 and the insulin increasing effects of whey. Reference Links:Linking diet to acne metabolomics, inflammation, and comedogenesis: an update.https://www.ncbi.nlm.nih.gov/pubmed/26203267Evidence for acne-promoting effects of milk and other insulinotropic dairy products.https://www.ncbi.nlm.nih.gov/pubmed/21335995The impact of cow's milk-mediated mTORC1-signaling in the initiation and progression of prostate cancer.https://www.ncbi.nlm.nih.gov/pubmed/22891897/Over-stimulation of insulin/IGF-1 signaling by western diet may promote diseases of civilization: lessons learnt from laron syndromehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3141390/Insulin-like growth factor 1https://en.wikipedia.org/wiki/Insulin-like_growth_factor_1 Buy C8Keto MCT Oil on AmazonOur Facebook Group Keto NaturopathUntil next time, Dr. Karl

research study diet syndrome diary keto dairy insulin acne prostate cancer naturopaths ketogenic deeper dive ketosis ketones igf ketone laron mtorc1

Episode 70: David Sabatini on the discovery of mTOR and its role in disease, longevity & healthspan

mit discovery fasting longevity nexus mtor gedankenexperiment sabatini rapamycin whitehead institute methionine mtorc1 peter attia md

Play Episode Listen Later Aug 14, 2018 76:18

Peter Attia, who was our very first guest on STEM-Talk, describes David Sabatini’s discovery of mTOR as one of his two favorite science stories. Today, Dr. David Sabatini joins us and gives us a first-hand account of how his research into rapamycin in 1994 as a graduate student led him to the discovery of mTOR, which we now know is a critical regulator of cellular growth. Our interview with David delves into his continuing research into mTOR, which has led to promising opportunities for the development of new treatments for debilitating diseases such as cancer, diabetes and neurological disorders. He also discusses mTOR’s role in healthspan and lifespan. David is a molecular cell biologist who, according to Reuters News Service, is on the short list for a Nobel Prize. David is on the faculty at MIT and heads up the Sabatini Lab at the Whitehead Institute. In today’s episode, we discuss: • Rapamycin, a macrolide antibiotic discovered in the soil of Easter Island • David’s discovery of mTOR while a grad student at Johns Hopkins • mTOR’s role as one of the major growth pathways in the body • mTOR’s role as a nutrient sensor • How mTOR inhibiton has become one of the hottest topics in longevity research • mTOR’s role in diseases, especially its connection to cancer • The role of RAG GTPases as key mTOR mediators • Protein intake and downstream mTOR activation • Research into ketogenic diets effect on longevity and healthspan • Whether David would take rapamycin as a means to enhance his longevity • And much, much more Show notes: [00:03:32] David talks about growing up in New York and having parents who immigrated to the United States from Argentina. [00:04:00] Dawn asks what David was like as a kid. [00:04:59] Dawn asks David about his decision to attend Brown University. [00:05:56] David talks about his decision to become a scientist and the time he spent in the lab of Al Dahlberg [00:06:53] Ken mentions that after his time at Brown, David headed off for Johns Hopkins to work in Sol Snyder’s lab, a professor known particularly for the work he and his colleagues did on the opioid receptor. Ken asks what drew David to Sol’s lab. [00:08:25] David talks about how as graduate student at Johns Hopkins in the M.D./Ph.D. program, he began trying to understand the molecular mechanism of rapamycin, a macrolide antibiotic discovered in the soil of Easter Island. Rapamycin was known as a potent antifungal, immunosuppressive with anti-tumorigenic properties. That research led David to the major discovery in 1994 of the protein to which rapamycin binds, now referred to as the mechanistic target of rapamycin, or mTOR. [00:11:46] Dawn asks David to give a high-level definition and overview of what mTOR does. [00:13:44] Dawn asks why the “m” in mTOR went from standing for “mammalian” to “mechanistic.” [00:14:11] Ken mentions that we now know mTOR is one of the major growth pathways in the body that is responsible for growth in both a positive sense and a pathologic sense. He goes on to mention that mTOR acts as a major switch between catabolism and anabolism, and asks David to explain why both of these processes are essential for survival. [00:16:10] Dawn asks how the two different mTOR protein complexes, mTORC1 and mTORC2, differ with regards to their activation and downstream function. [00:17:40] Dawn asks David about his decision to join the faculty atMIT and embark on a research-focused career there, starting his own lab at the Whitehead Institute rather than following the clinical path arising from his M.D. [00:20:50] Ken asks about how nutrients and other inputs are sensed and integrated by the mTOR complexes, given how one of the most fascinating aspects about mTORC1 is its role as a nutrient sensor. [00:23:46] Ken asks why both nutrients and growth factors are required to activate mTORC1. [00:25:54] Dawn mentions her interest in the connection of mTOR to aging,

#09 - David Sabatini, M.D., Ph.D.: rapamycin and the discovery of mTOR — the nexus of aging and longevity?

The Peter Attia Drive

Play Episode Listen Later Aug 13, 2018 71:22

In this episode, my good friend David Sabatini delves into his extensive work with the mechanistic target of rapamycin—better known as mTOR—and rapamycin. The compound rapamycin is the only known pharmacological agent to extend lifespan all the way from yeast to mammals—across a billion years of evolution. David, a professor of biology and a member of the Whitehead Institute at MIT, shares his remarkable journey and discovery of mTOR in mammalian cells and its central role in nutrient sensing and longevity. Fasting, rapamycin, mTOR, autophagy, gedankenexperiments: having this conversation with David is like being the proverbial kid in the world’s greatest candy store. We discuss: mTOR and David’s student years [4:30]; Rapamycin and the discovery of mTOR [8:15]; The connection between rapamycin, mTOR, and longevity [30:30]; mTOR as the cell’s general contractor [34:45]; The effect of glucose, insulin, and amino acids on mTORC1 [42:50]; Methionine sensing and restriction [49:45]; An intermittent approach to rapamycin [54:30]; Rapamycin’s effects on cancer, cardiovascular disease, and neurodegeneration [57:00]; Gedankenexperiment: couch potatoes on rapamycin vs perfectly behaved humans [1:03:15]; David’s dream experiment with no resource constraints [1:07:00]; and More. Learn more at www.PeterAttiaMD.com Connect with Peter on Facebook | Twitter | Instagram.

Episode 63: Keith Baar talks about collagen synthesis, ketogenic diet, mTORC1 signaling, autophagy, post strength training nutrition, and more…

Play Episode Listen Later May 8, 2018 62:47

Dr. Keith Baar joins Ken and Dawn today for the second of his two-part interview for STEM-Talk. Keith is a renowned scientist in the emerging field of molecular exercise physiology who has made fundamental discoveries on how muscles grow bigger, stronger, and more fatigue resistant. He is the head of the Functional Molecular Biology Laboratory in the Department of Neurobiology, Physiology, and Behavior at the University of California, Davis. In his lab, he leads a team of researchers attempting to develop ways to improve muscle, tendon and ligament function. Part one of our interview, episode 62, covered Keith’s childhood in Canada and his undergrad years at the University of Michigan as well as his time at the University of California, Berkeley, where he earned a master’s degree in human biophysics. We talked about Keith’s work at the University of Illinois, where he received a doctorate in physiology and biophysics. We also covered Keith’s time in the lab of John Holloszy, who is known as the father of exercise research in the United States, as well as the five years Keith spent at the University of Dundee in Scotland. Episode 63 picks up with Keith explaining his decision to return to the states and join the faculty at the University of California, Davis. Ken and Dawn then talk to Keith about his most recent research, some of which is looking at how to determine the best way to train, as well as what types of foods compliment training to decrease tendon and ligament injury and accelerate return to play. This work has the potential to improve muscle function not only in athletes, but also improve people’s quality of life as they age. Another key topic covered in part two of our interview is the research Keith is doing on a ketogenic diet and its potential to reduce cancer rates and improve cognition. Keith also provides his thoughts on what optimal workouts and nutrition should look like. Links: Baar’s UC Davis physiology department bio: https://www.ucdmc.ucdavis.edu/physiology/faculty/baar.html Baar’s UC Davis biology department bio: https://biology.ucdavis.edu/people/keith-baar Functional Molecular Biology Lab website: http://www.fmblab.com/ Molecular brakes regulating mTORC1 activation in skeletal muscle paper: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4137116/ Age-related Differences in Dystrophin article: https://www.ncbi.nlm.nih.gov/pubmed/27382038 Show notes: 2:54: Dawn begins part 2 of our interview by mentioning that for the past eight years, Keith has been working at the University of California Davis. She asks Keith what prompted him to return to the U.S. from Scotland and join the faculty at UC Davis. 3:37: Dawn points out that Keith’s Functional Molecular Biology Lab conducts research across a range of related topics, including musculoskeletal development and adaptation as well as methods for engineering functional musculoskeletal tissues in vitro. She asks Keith to give a high-level overview of some of that research. 4:16: Dawn comments that some of Keith’s recent work has shown that we can use specific nutrition and training strategies to optimize injury recovery and prevention. She goes on to say that musculoskeletal injuries are among the most common problems that active people have. 8:45: Ken talks about how Keith has noted that tendon stiffness is dependent upon collagen content, and the amount of crosslinks within. He goes on to mention that Keith has developed various training modalities, as well as nutritional protocols, that can increase and decrease tendon stiffness. Ken begins this line of inquiry by asking about the training methods for this purpose. 12:04: Following up on the previous question, Ken asks whether anyone has looked at how blood flow restriction training, which is increasing in popularity, affects tendon stiffness. 13:32: Dawn moves on to asking about nutrition. She mentions that Keith’s lab has done a great deal of...

Episode 62: Keith Baar talks about muscle and explains mTOR, PGC-1a, dystrophin, and the benefits of chocolate

Play Episode Listen Later Apr 24, 2018 63:27

Today’s episode is the first of a two-part interview with Dr. Keith Baar, the head of the Functional Molecular Biology Laboratory in the Department of Neurobiology, Physiology, and Behavior at the University of California, Davis. In his capacity as a researcher, Keith has made fundamental discoveries on how muscle grows bigger, stronger, and more fatigue resistant. He is a renowned scientist in the emerging field of molecular exercise physiology, and is leading a team of researchers attempting to develop ways to improve muscle, tendon and ligament function. Part one of our interview features our conversation with Keith about his background and his time time in the lab of John Holloszy, who is known as the father of exercise research in the United States. Episode 63 of STEM-Talk has Dawn and Ken talking to Keith about his most recent research, which is looking at how to determine the best way to train, as well as what types of foods compliment training to decrease tendon and ligament injury and accelerate return to play. This work has the potential to improve muscle function and people’s quality of life, especially as they age. Ken and Dawn also have a conversation with Keith about the research he is doing on a ketogenic diet and its potential to reduce cancer rates and improve cognition. Links: UC Davis physiology department bio: https://www.ucdmc.ucdavis.edu/physiology/faculty/baar.html UC Davis biology department bio” https://biology.ucdavis.edu/people/keith-baar Functional Molecular Biology Lab website: http://www.fmblab.com Molecular brakes regulating mTORC1 activation in skeletal muscle paper: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4137116/ Age-related Differences in Dystrophin article: https://www.ncbi.nlm.nih.gov/pubmed/27382038 Show notes: 3:14: Dawn opens the interview by mentioning that Keith grew up in Canada, and asks what he was like as a child. 4:02: Dawn asks if Keith was interested in science as a kid. 4:53: Dawn comments that after high school, Keith came to the U.S. to attend the University of Michigan, where he earned a bachelor’s degree in kinesiology. She Keith if Michigan was where he first became interested in the science of how muscles work. 7:54: Dawn asks Keith if he played any sports at Michigan. 8:34: Dawn asks what lead Keith to attend the University of California, Berkeley to pursue a master’s degree in human biophysics. 9:39: Dawn mentions that after his time at Berkeley, Keith returned to the Midwest to attend the University of Illinois where he received his doctorate in physiology and biophysics. She asks why he decided on Illinois for his doctoral work. 11:12: Ken mentions that Keith’s Ph.D. work focused on the effect of resistance exercise on specific molecular markers that are related to muscle growth. He goes on to say that Keith identified that mTOR complex 1 was activated in response to resistance exercise and that the activation was proportional to the load across the muscle. He asks Keith to talk about this work and its significance. 16:20: Ken comments how surprising that discovery must have been. 17:33: Ken asks Keith to explain the two basic ways of activating mTORC1 in skeletal muscle. Ken also asks whether these two are merely additive, or if together they elicit a greater muscle protein response than either would independently. 29:49: Dawn mentions that after Illinois, Keith went to work in the lab of John Holloszy at Washington University in St. Louis, a professor of medicine who is known as the father of exercise research in the United States. Dawn asks if is Holloszy is the one who discovered that when people do endurance exercise that their muscles accumulate more mitochondria. 32:24: Ken asks about the role of PGC-1a. 38:43: Ken comments that we know most sports require a combination of strength and endurance for optimal performance, bringing up the topic of concurrent training.

ECP #10 - Intermittent Fasting - der HEILIGE GRAL zum Fettabbau?

ELAE Coaching Podcast

Play Episode Listen Later Sep 30, 2017 18:10

In letzter Zeit hat ein relativ neuer Trend seinen Weg in die Fitnessszene gefunden, das sogenannte Intermittent Fasting – oder auf Deutsch: Intermittierendes Fasten. Wir gehen auf die Vor- und Nachteile des Intermittent Fasting ein und erklären wie es funktioniert und für wen es Sinn machen kann Intermittent Fasting zu nutzen. Quellen: Adechian, S. et al., 2012. Protein feeding pattern, casein feeding, or milk-soluble protein feeding did not change the evolution of body composition during a short-term weight loss program. American Journal of Physiology - Endocrinology and Metabolism, 15 October, 303(8), pp. 973-982. Adlouni, A. et al., 1997. Fasting during Ramadan induces a marked increase in high-density lipoprotein cholesterol and decrease in low-density lipoprotein cholesterol.. Annals of Nutrition & Metabolism, 1 January, 41(4), pp. 242-249. Anson, M. R. et al., 2003. Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake. Proceedings of the National Academy of Sciences of the United States of America, 13 May, 100(10), pp. 6216-6220. Arnal, M.-A.et al., 2000. Protein Feeding Pattern Does Not Affect Protein Retention in Young Women1. The Journal of Nutrition, 1 July, 130(7), pp. 1700-1704. Atherton, P. J. et al., 2010. Muscle full effect after oral protein: time-dependent concordance and discordance between human muscle protein synthesis and mTORC1 signaling. American Journal of Clinical Nutrition, November, 92(5), pp. 1080-1088. Martin, B., Mattson, M. P. & Maudsley, S., 2006. Caloric restriction and intermittent fasting: Two potential diets for successful brain aging. Ageing Research Reviews, August, 5(3), pp. 332-353. Moro, T. et al., 2016. Effects of eight weeks of time-restricted feeding (16/8) on basal metabolism, maximal strength, body composition, inflammation, and cardiovascular risk factors in resistance-trained males. Journal of Translational Medicine, 13 October, 14(1), pp. 1-10. Schoenfeld, B. J., Aragon, A. A. & Krieger, J. W., 2013. The effect of protein timing on muscle strength and hypertrophy: a meta-analysis. Journal of the International Society of Sports Nutrition, 3 December, 10(1), p. 1. Wan, R., Camandola, S. & Mattson, M. P., 2003. Intermittent fasting and dietary supplementation with 2-deoxy-D-glucose improve functional and metabolic cardiovascular risk factors in rats. The FASEB Journal, June, 17(9), pp. 1133-1134. World Health Organization, 2017. Cardiovascular diseases (CVDs). [Online] Available at: http://www.who.int/mediacentre/factsheets/fs317/en/ [Zugriff am 26 September 2017].

ECP #9 - Supplement CHECK - BCAA: Segen oder Fluch?

ELAE Coaching Podcast

Play Episode Listen Later Sep 28, 2017 9:59

Das sehr häufig verwendete Nahrungsergänzungsmittel BCAA hat nun wieder einen besonderen Hype in der Fitness und Bodybuildingszene erfahren, daher stellen wir uns die Frage ob dieser Hype gerechtfertigt ist oder ob BCAA-Produkte doch wieder nur unnötige Supplemente sind. Quellen: Churchward-Venne, T. A. et al., 2012. Supplementation of a suboptimal protein dose with leucine or essential amino acids: effects on myofibrillar protein synthesis at rest and following resistance exercise in men. Journal of Physiology, June, 590(11), pp. 2751-2765. Jackman, S. R. et al., 2017. Branched-Chain Amino Acid Ingestion Stimulates Muscle Myofibrillar Protein Synthesis following Resistance Exercise in Humans. Frontiers in Physiology, 7 June.8(390). Karlsson, H. K. R. et al., 2004. Branched-chain amino acids increase p70S6k phosphorylation in human skeletal muscle after resistance exercise. American Journal of Physiology - Endocrinology and Metabolism, 10 Junge, 287(1), pp. E1-E7. Moberg, M. et al., 2014. Absence of leucine in an essential amino acid supplement reduces activation of mTORC1 signalling following resistance exercise in young females. Journal of Applied Physiology: Nutrition and Metabolism, 39(2), pp. 183-194. Sharp, C. P. M. & Pearson, D. R., 2010. Amino Acid Supplements and Recovery from High-Intensity Resistance Training. Journal of Strength & Conditioning Research, April, 24(4), pp. 1125-1130. Witard, O. C. et al., 2014. Myofibrillar muscle protein synthesis rates subsequent to a meal in response to increasing doses of whey protein at rest and after resistance exercise. American Journal of Clinical Nutrition, January, 99(1), pp. 86-95.

fitness strength recovery journal humans hype sharp absence pearson metabolism supplement physiology segen frontiers junge fluch american journal supplementation karlsson jackman clinical nutrition nahrungserg bcaa moberg supplemente conditioning research branched resistance exercise mtorc1 physiology endocrinology bodybuildingszene

Science Signaling Podcast for 28 February 2017: Balancing autophagy in the stressed heart

Multiple Sclerosis Discovery: The Podcast of the MS Discovery Forum

Play Episode Listen Later Feb 27, 2017 13:50

Saumya Das explains how the protein DDiT4L protects the heart from pathological hypertrophy.

science stress balancing stressed heart disease heart failure signaling autophagy cardiomyopathy mtorc1 mtorc2

biosights: February 6, 2017

biosights

Play Episode Listen Later Feb 6, 2017 7:59

Localizing mTORC2 activity The mTORC2 complex regulates cell growth and proliferation by phosphorylating the protein kinase Akt, but where in the cell mTORC2 is active, and how growth factors direct its activity towards Akt, remains unclear. Ebner et al. use a novel reporter to show that endogenous mTORC2 activity localizes to plasma membrane, mitochondrial, and endosomal pools with distinct sensitivities to PI3 kinase and growth factor signaling, and that growth factors induce Akt phosphorylation by promoting Akt's recruitment to the plasma membrane. This biosights episode presents the paper by Ebner et al. from the February 6th, 2017, issue of The Journal of Cell Biology and includes an interview with two of the paper's authors, Michael Ebner and Ivan Yudushkin (Max F. Perutz Laboratories and Medical University of Vienna, Vienna, Austria). Produced by Caitlin Sedwick and Ben Short. See the associated paper in JCB for details on the funding provided to support this original research. Subscribe to biosights via iTunes or RSS View biosights archive The Rockefeller University Press biosights@rockefeller.edu

journal austria akt medical university cell biology mtor ebner jcb pi3 mtorc1 mtorc2

Multiple Sclerosis Discovery -- Episode 64 with Dr. Helen Tremlett

Play Episode Listen Later Jan 5, 2016 13:33

[intro music] Host – Dan Keller Hello, and welcome to Episode Sixty-Three of Multiple Sclerosis Discovery, the Podcast of the MS Discovery Forum. I’m Dan Keller. We’ve just passed the winter solstice. What better time than the shortest daylight hours of the year to check in with research at the University of British Columbia on sunlight and MS? Today we talk with Dr. Helen Tremlett who is exploring sun exposure over a person’s life course and how that syncs with their MS risk and disease course. In the weekly papers section on the MS Discovery Forum, this week’s list includes nearly 150 newly published research reports that could lead to better understanding and treatment of MS and related disorders. We selected four papers as editor’s picks. In one paper, researchers think they may have the first experimental evidence that MS may start with damage or loss of myelin-making cells in the brain and spinal cord. In this new mouse model of progressive MS, experimentally damaged brain cells make it hard for the mice to walk. The mice recover when their brain cells repair on their own. Six months later, the MS-like disease returns. In the study, the team showed that nanoparticles targeting the autoimmune reaction prevent the second phase of the disease. The study shows support for an “inside-out” model of MS. That’s different from the “outside-in” model, in which some aspect about the immune system goes wrong and then initiates the attack on myelin-making cells. The paper is published in Nature Neuroscience by collaborating researchers from Northwestern University and the University of Chicago. To grow and be healthy, all human cells need a signaling molecule named mTOR, named for the mammalian target of rapamycin. That’s true for myelin-making cells, or oligodendrocytes, as listeners may remember from an earlier podcast interview with Dr. Wendy Macklin. The ability to make myelin seems to depend on a key part known as mTOR complex 1, also called its raptor subunit. In a very basic advance, scientists have determined the atomic architecture of the raptor, or mTORC1, piece. The details are reported in the journal Science and provide a structural basis for studying mTORC1 function. In another editor’s pick, a review of cases of pediatric neuromyelitis optica, or NMO, showed that new international diagnostic guidelines applied well to children. Unfortunately, they also found that children with NMO have delayed treatment and worse short-term outcomes compared to those with MS. The authors urged immediate adoption of the guidelines to select the best treatment and improve outcomes. In the fourth editor’s pick, researchers found a potential new target to protect axons in a mouse model of neurodegeneration in multiple sclerosis. The target is a pore in the mitochondria, the cellular battery that provides energy. They designed a molecule to block the pore and showed it helped protect neurons and improved the mice’s mobility, all with minimal immunosuppression. The paper by mostly UK researchers is published in the Journal of Biological Chemistry. Now, let’s take a look at the latest Drug Development Pipeline updates. The drugs with important additions and changes are dimethyl fumarate, fingolimod, glatiramer acetate, natalizumab, and rituximab. One update reflects findings from post-hoc analysis of clinical trial data showing that the positive effects of fingolimod are apparent quite soon –within months – after initiation of treatment. [transition music] And now to our interview. I spoke with Professor Helen Tremlett, Canada research chair in neuroepidemiology and multiple sclerosis at the University of British Columbia when we were at the ECTRIMS conference in Barcelona in October. She has been studying sun exposure over the course of the lifetime and its relation to MS risk. While MS may affect an individual's likelihood to go out in the sun, studies may also need to consider the influence of sun exposure before the disease develops. Interviewer – Dan Keller What are you doing in this area? Interviewee – Helen Tremlett So I was presenting at ECTRIMS yesterday on a really interesting study based out of the Nurses' Health Study, and this was a collaboration from my group in Vancouver and Harvard School of Public Health; and that's Alberto Ascherio's group and Sandy Munger. So we were looking at sun exposure over the life course and associations with multiple sclerosis. So here we were looking at both aspects of the spectrum, if you can imagine; we were looking at sun exposure and future risk of multiple sclerosis, but also once an individual has developed multiple sclerosis, we were looking at the impact that potentially has on an individual in terms of their propensity to go outdoors in the daylight hours, outdoors in the sun. MSDF Right. So it may be the cart is before the horse in that sense; not that sun exposure is causing it, but their disability is causing less sun exposure? Dr. Tremlett We were looking at both sides of the equation. And I think it is important, particularly in a disease such as MS where onset of MS is a little bit fuzzy, I think, to look at sun exposure of the life course is important, and certainly our findings are indicating that. Because you want to know sunlight exposure in MS risk, but you also want to know, once someone's developed multiple sclerosis, how that influences their behavior outdoors and what implications that has if you're then trying to design the study to look at what causes MS. You need to be really careful who you recruit, because if that person has already changed their behavior, then that may influence your findings, and you're not then actually looking at what causes MS at all, you're just looking at a consequence of the disease. So I guess that's the first part of why we wanted to do that. And the second part is if having MS, if having a chronic condition, does influence your propensity or ability or desire to go outside, what consequence could that have for your health in terms of maybe your serum vitamin D levels or your melatonin levels, and that may have a consequence in terms of long-term health. MSDF You segmented people by where they were and at what ages. Dr. Tremlett It was pretty interesting. So, first of all, over ages 5 to 15, we found there that there was a 48% lower risk of MS for women living in high, relative to low, ambient UVB areas during their sort of childhood and early adolescent years. So that was pretty interesting. But we found, kind of to our surprise because it goes against other studies that are out there, we found that time spent outdoors in summer or winter wasn't significantly associated with MS risk in that age group, 5 to 15 years. But what we didn't realize is that it wasn't until we combined that outdoor behavior with the UVB, then we could see that there was an association. So we found that less time spent outdoors in summer in low ambient UVB areas—that was associated with a two-fold increased risk of multiple sclerosis. That was an important step for us; I mean, it might, you know, sound obvious to combine those two, but it was an important step because other studies in smaller geographical areas such as Tasmania, or there's a study out of Norway in a small region of Norway, they can find an association between time spent outdoors in summer/winter and MS risk. But I think we couldn't find it in the US, because the US is at such a diversity of latitudes – the study spanned over 14 US states – so it wasn't until we looked at that outdoor behavior in context of ambient UVB that we could find the association. And then, I suppose, our next step was to look at outdoor behavior over the life course. And this was really interesting, that we found some avoidance behavior was apparent in later life in multiple sclerosis. And maybe that comes as no surprise to people, but I think our numbers are interesting to put a concrete figure on it. So, for instance, by age 50, our MS cases were 60% less likely to report high relative to low outdoor exposure compared to controls, and that was in winter and in summer. So the bottom line is people with MS, once they have MS, are not going outside as much, so they're not getting that UVB exposure, so potentially they're not making that vitamin D and serum vitamin D. And then the winter exposure's important as well, because potentially they're not getting the same melatonin production and inhibition, and that may have a really important role in terms of immunology, the circadian rhythm and your sleep cycle, which, again, all knocks back into overall health and immunology of MS. And there have been some presentations actually at this conference looking into melatonin and its association with relapses in MS, and that's pretty interesting. MSDF There's even some emerging thought that sleep is essential for good brain function in terms of taking out the garbage – glymphatics and things like that. So melatonin disturbances may actually have some further consequences in an inflammatory brain disease. Dr. Tremlett And there's some interesting studies, not that we did but others have done, looking at shift work and risk of MS. And shift work may be associated with increased risk of MS. Maybe melatonin ties into that as well. MSDF Is there also potentially an effect, besides on vitamin D and melatonin, that sun exposure itself has an effect on the immune system, maybe suppressing it? Dr. Tremlett Yeah, modulating it in some way. No, absolutely. We don't really know the mechanism. I mean, the obvious one would be sun on human skin at the right time of year on the right skin color can result in really high levels of serum vitamin D being produced. Sunlight exposure the minute it actually hits the skin surface can have a direct immunomodulatory effect. And then, obvious, sun hitting the eye. Melatonin is one of the pathways in there that may then impact the immune system. MSDF Is it possible to make any conclusions or even recommendations at this point? Dr. Tremlett No. It's an observational study, and we do actually need to do more analysis on this group of individuals. The main recommendations we could make from this study is informing how to design future studies, and also two things you could take from this in terms of recommendations. First of all, we saw sun avoidance behavior in individuals once they've developed multiple sclerosis. That's really important because it really means that if you want to look at what is causing MS, do not take serum vitamin D levels or look at skin cancer risk, for instance, in individuals who already have MS, because they've already changed in compare to controls, adding further somehow differences are related to what causes MS, because these individuals have already changed their behavior because they've got a chronic disease. So that's the first statement, which might be a no-brainer for some people, but it's amazing how many studies are still published like that in the MS literature at the moment. And I suppose the second piece is trying to understand if we are going to do an interventional study, what time period in an individual's life or within a population do you need to target in order to change the course and prevent the disease from occurring? And we're trying to understand that more, looking beyond the window age 5 to 15, look more into adulthood to see if ambient UVB is associated with MS risk later in life and into adulthood. And others have shown that there does seem to be an association even into adulthood, which is exciting because if you do want to do an intervention study, then you haven't necessarily missed the boat because you've not intervened during childhood. But, I mean, the real question is how do you intervene and what with? And that's another topic in itself. MSDF We'll leave that for another day. Thank you. Dr. Tremlett Thank you very much. [transition music] Next week, we'll continue our discussion with Professor Tremlett when she'll talk about her preliminary studies on pediatric MS patients and their gut microbiomes. Until then, thank you for listening to Episode Sixty-Three of Multiple Sclerosis Discovery. This Podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Heather McDonald curated the MSDF drug database updates. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations. Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances. We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org. For Multiple Sclerosis Discovery, I'm Dan Keller. [outro music]

ceo university canada president chicago science ms vice president united kingdom journal barcelona discovery vancouver norway public health british columbia northwestern university tasmania multiple sclerosis sunlight melatonin harvard school uvb mtor heather mcdonald nature neuroscience biological chemistry nmo mtorc1 nurses health study dan keller ectrims scientific operations accelerated cure project msdf carol cruzan morton

Multiple Sclerosis Discovery -- Episode 63 with Dr. Helen Tremlett

Multiple Sclerosis Discovery: The Podcast of the MS Discovery Forum

Play Episode Listen Later Dec 27, 2015 15:18

[intro music] Host – Dan Keller Hello, and welcome to Episode Sixty-Three of Multiple Sclerosis Discovery, the Podcast of the MS Discovery Forum. I’m Dan Keller. We’ve just passed the winter solstice. What better time than the shortest daylight hours of the year to check in with research at the University of British Columbia on sunlight and MS? Today we talk with Dr. Helen Tremlett who is exploring sun exposure over a person’s life course and how that syncs with their MS risk and disease course. In the weekly papers section on the MS Discovery Forum, this week’s list includes nearly 150 newly published research reports that could lead to better understanding and treatment of MS and related disorders. We selected four papers as editor’s picks. In one paper, researchers think they may have the first experimental evidence that MS may start with damage or loss of myelin-making cells in the brain and spinal cord. In this new mouse model of progressive MS, experimentally damaged brain cells make it hard for the mice to walk. The mice recover when their brain cells repair on their own. Six months later, the MS-like disease returns. In the study, the team showed that nanoparticles targeting the autoimmune reaction prevent the second phase of the disease. The study shows support for an “inside-out” model of MS. That’s different from the “outside-in” model, in which some aspect about the immune system goes wrong and then initiates the attack on myelin-making cells. The paper is published in Nature Neuroscience by collaborating researchers from Northwestern University and the University of Chicago. To grow and be healthy, all human cells need a signaling molecule named mTOR, named for the mammalian target of rapamycin. That’s true for myelin-making cells, or oligodendrocytes, as listeners may remember from an earlier podcast interview with Dr. Wendy Macklin. The ability to make myelin seems to depend on a key part known as mTOR complex 1, also called its raptor subunit. In a very basic advance, scientists have determined the atomic architecture of the raptor, or mTORC1, piece. The details are reported in the journal Science and provide a structural basis for studying mTORC1 function. In another editor’s pick, a review of cases of pediatric neuromyelitis optica, or NMO, showed that new international diagnostic guidelines applied well to children. Unfortunately, they also found that children with NMO have delayed treatment and worse short-term outcomes compared to those with MS. The authors urged immediate adoption of the guidelines to select the best treatment and improve outcomes. In the fourth editor’s pick, researchers found a potential new target to protect axons in a mouse model of neurodegeneration in multiple sclerosis. The target is a pore in the mitochondria, the cellular battery that provides energy. They designed a molecule to block the pore and showed it helped protect neurons and improved the mice’s mobility, all with minimal immunosuppression. The paper by mostly UK researchers is published in the Journal of Biological Chemistry. Now, let’s take a look at the latest Drug Development Pipeline updates. The drugs with important additions and changes are dimethyl fumarate, fingolimod, glatiramer acetate, natalizumab, and rituximab. One update reflects findings from post-hoc analysis of clinical trial data showing that the positive effects of fingolimod are apparent quite soon –within months – after initiation of treatment. [transition music] And now to our interview. I spoke with Professor Helen Tremlett, Canada research chair in neuroepidemiology and multiple sclerosis at the University of British Columbia when we were at the ECTRIMS conference in Barcelona in October. She has been studying sun exposure over the course of the lifetime and its relation to MS risk. While MS may affect an individual's likelihood to go out in the sun, studies may also need to consider the influence of sun exposure before the disease develops. Interviewer – Dan Keller What are you doing in this area? Interviewee – Helen Tremlett So I was presenting at ECTRIMS yesterday on a really interesting study based out of the Nurses' Health Study, and this was a collaboration from my group in Vancouver and Harvard School of Public Health; and that's Alberto Ascherio's group and Sandy Munger. So we were looking at sun exposure over the life course and associations with multiple sclerosis. So here we were looking at both aspects of the spectrum, if you can imagine; we were looking at sun exposure and future risk of multiple sclerosis, but also once an individual has developed multiple sclerosis, we were looking at the impact that potentially has on an individual in terms of their propensity to go outdoors in the daylight hours, outdoors in the sun. MSDF Right. So it may be the cart is before the horse in that sense; not that sun exposure is causing it, but their disability is causing less sun exposure? Dr. Tremlett We were looking at both sides of the equation. And I think it is important, particularly in a disease such as MS where onset of MS is a little bit fuzzy, I think, to look at sun exposure of the life course is important, and certainly our findings are indicating that. Because you want to know sunlight exposure in MS risk, but you also want to know, once someone's developed multiple sclerosis, how that influences their behavior outdoors and what implications that has if you're then trying to design the study to look at what causes MS. You need to be really careful who you recruit, because if that person has already changed their behavior, then that may influence your findings, and you're not then actually looking at what causes MS at all, you're just looking at a consequence of the disease. So I guess that's the first part of why we wanted to do that. And the second part is if having MS, if having a chronic condition, does influence your propensity or ability or desire to go outside, what consequence could that have for your health in terms of maybe your serum vitamin D levels or your melatonin levels, and that may have a consequence in terms of long-term health. MSDF You segmented people by where they were and at what ages. Dr. Tremlett It was pretty interesting. So, first of all, over ages 5 to 15, we found there that there was a 48% lower risk of MS for women living in high, relative to low, ambient UVB areas during their sort of childhood and early adolescent years. So that was pretty interesting. But we found, kind of to our surprise because it goes against other studies that are out there, we found that time spent outdoors in summer or winter wasn't significantly associated with MS risk in that age group, 5 to 15 years. But what we didn't realize is that it wasn't until we combined that outdoor behavior with the UVB, then we could see that there was an association. So we found that less time spent outdoors in summer in low ambient UVB areas—that was associated with a two-fold increased risk of multiple sclerosis. That was an important step for us; I mean, it might, you know, sound obvious to combine those two, but it was an important step because other studies in smaller geographical areas such as Tasmania, or there's a study out of Norway in a small region of Norway, they can find an association between time spent outdoors in summer/winter and MS risk. But I think we couldn't find it in the US, because the US is at such a diversity of latitudes – the study spanned over 14 US states – so it wasn't until we looked at that outdoor behavior in context of ambient UVB that we could find the association. And then, I suppose, our next step was to look at outdoor behavior over the life course. And this was really interesting, that we found some avoidance behavior was apparent in later life in multiple sclerosis. And maybe that comes as no surprise to people, but I think our numbers are interesting to put a concrete figure on it. So, for instance, by age 50, our MS cases were 60% less likely to report high relative to low outdoor exposure compared to controls, and that was in winter and in summer. So the bottom line is people with MS, once they have MS, are not going outside as much, so they're not getting that UVB exposure, so potentially they're not making that vitamin D and serum vitamin D. And then the winter exposure's important as well, because potentially they're not getting the same melatonin production and inhibition, and that may have a really important role in terms of immunology, the circadian rhythm and your sleep cycle, which, again, all knocks back into overall health and immunology of MS. And there have been some presentations actually at this conference looking into melatonin and its association with relapses in MS, and that's pretty interesting. MSDF There's even some emerging thought that sleep is essential for good brain function in terms of taking out the garbage – glymphatics and things like that. So melatonin disturbances may actually have some further consequences in an inflammatory brain disease. Dr. Tremlett And there's some interesting studies, not that we did but others have done, looking at shift work and risk of MS. And shift work may be associated with increased risk of MS. Maybe melatonin ties into that as well. MSDF Is there also potentially an effect, besides on vitamin D and melatonin, that sun exposure itself has an effect on the immune system, maybe suppressing it? Dr. Tremlett Yeah, modulating it in some way. No, absolutely. We don't really know the mechanism. I mean, the obvious one would be sun on human skin at the right time of year on the right skin color can result in really high levels of serum vitamin D being produced. Sunlight exposure the minute it actually hits the skin surface can have a direct immunomodulatory effect. And then, obvious, sun hitting the eye. Melatonin is one of the pathways in there that may then impact the immune system. MSDF Is it possible to make any conclusions or even recommendations at this point? Dr. Tremlett No. It's an observational study, and we do actually need to do more analysis on this group of individuals. The main recommendations we could make from this study is informing how to design future studies, and also two things you could take from this in terms of recommendations. First of all, we saw sun avoidance behavior in individuals once they've developed multiple sclerosis. That's really important because it really means that if you want to look at what is causing MS, do not take serum vitamin D levels or look at skin cancer risk, for instance, in individuals who already have MS, because they've already changed in compare to controls, adding further somehow differences are related to what causes MS, because these individuals have already changed their behavior because they've got a chronic disease. So that's the first statement, which might be a no-brainer for some people, but it's amazing how many studies are still published like that in the MS literature at the moment. And I suppose the second piece is trying to understand if we are going to do an interventional study, what time period in an individual's life or within a population do you need to target in order to change the course and prevent the disease from occurring? And we're trying to understand that more, looking beyond the window age 5 to 15, look more into adulthood to see if ambient UVB is associated with MS risk later in life and into adulthood. And others have shown that there does seem to be an association even into adulthood, which is exciting because if you do want to do an intervention study, then you haven't necessarily missed the boat because you've not intervened during childhood. But, I mean, the real question is how do you intervene and what with? And that's another topic in itself. MSDF We'll leave that for another day. Thank you. Dr. Tremlett Thank you very much. [transition music] Next week, we'll continue our discussion with Professor Tremlett when she'll talk about her preliminary studies on pediatric MS patients and their gut microbiomes. Until then, thank you for listening to Episode Sixty-Three of Multiple Sclerosis Discovery. This Podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Heather McDonald curated the MSDF drug database updates. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations. Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances. We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org. For Multiple Sclerosis Discovery, I'm Dan Keller. [outro music]

ceo university canada president chicago science ms vice president united kingdom journal barcelona discovery vancouver norway public health british columbia northwestern university tasmania multiple sclerosis sunlight melatonin harvard school uvb mtor heather mcdonald nature neuroscience biological chemistry nmo mtorc1 nurses health study dan keller ectrims scientific operations accelerated cure project msdf carol cruzan morton

Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma

EHA 2015

Play Episode Listen Later Aug 6, 2015 4:22

Dr Jessica Okosun (Barts Cancer Institute, London, UK) talks to ecancertv at EHA 2015 about her study on follicular lymphoma. The aim of the study was to identify novel gene mutations in follicular lymphoma that might serve as therapeutic targets. The RRAGC mutations lead to activation of mTORC1 in the absence of amino acids. Overall, the emergence of frequent, gain-of-function RRAGC mutations that are clonally represented and maintained during progression provides an excellent candidate to be therapeutically exploited.

united kingdom activating mutation recurrent follicular lymphoma eha mtorc1

Science Signaling Podcast, 28 October 2014

Play Episode Listen Later Oct 27, 2014 11:57

William Pryor and Srinivasa Subramaniam report that a mutant form of huntingtin that is associated with early-onset Huntington's disease promotes anabolic signaling that contributes to disease symptoms in mice.

science huntington signaling neurodegeneration huntington's disease mtorc1 striatum gtpase huntingtin

Science Signaling Podcast, 14 January 2014

science schizophrenia psychosis akt signaling mtor haloperidol mtorc1

Play Episode Listen Later Jan 13, 2014 10:18

Moses Chao and Eric Klann discuss how the antipsychotic drug haloperidol changes neuronal morphology.

Science Signaling Podcast, 3 April 2012

Play Episode Listen Later Apr 2, 2012 15:02

Rapamycin’s effects on longevity and insulin sensitivity are mediated by different molecular targets.

science tor metabolism signaling mtor insulin sensitivity rapamycin mtorc1 mtorc2

Science Signaling Podcast, 27 March 2012

science regeneration regulated signaling hypertrophy homeostasis atrophy mtor cachexia g protein mtorc1

Play Episode Listen Later Mar 26, 2012 14:37

Regulated protein synthesis and degradation mediate skeletal muscle homeostasis.

Science Signaling Podcast, 8 November 2011

Play Episode Listen Later Nov 7, 2011 10:40

The vacuolar ATPase is required for amino acid-mediated activation of mTORC1.

science rag signaling atpase mtorc1 gtpase lysosome

Science Signaling Podcast, 21 April 2009