Podcasts about mitogen

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.30.526325v1?rss=1 Authors: El, K., Bauer, B. M., Chen, Y.-C., Jeong, J.-W., Fueger, P. T. Abstract: Type 1 Diabetes (T1D) is caused by autoimmune-mediated beta cell destruction. Following beta cell injury, the pancreas attempts to launch a cellular repair and regenerative program, yet it fails to completely restore functional beta cell mass. One component of this regenerative program is epidermal growth factor receptor (EGFR) signaling. However, upon irreparable beta cell damage, EGFR signaling is dampened, disrupting attempts to restore functional beta cell mass and maintain normoglycemia. We previously demonstrated that the negative feedback inhibitor of EGFR, Mitogen-inducible gene 6 (Mig6), is induced by the pro-inflammatory cytokines central to the autoimmune-mediated beta cell destruction. We also established that pro-inflammatory cytokines suppress EGFR activation, and siRNA-mediated suppression of Mig6 restores EGFR signaling. Thus, we hypothesized that pro-inflammatory cytokines induce nitric oxide production and that in turn induced Mig6, disrupting EGFR repair mechanisms. We determined that NO induces Mig6, attenuating EGFR signaling, and NO synthase inhibition blocks the cytokine-mediated induction of Mig6, thereby restoring cytokine-impaired EGFR signaling. To that end, we treated mice lacking pancreatic Mig6 and control mice with a streptozotocin (STZ) to induce beta cell death and diabetes in a way that mimics the onset and progression of T1D. Whereas STZ-treated control mice became hyperglycemic and had reduced beta cell mass, STZ-treated Mig6 pancreas-specific knock out (PKO) mice remained euglycemic and glucose tolerant due to preserved beta cell mass. The restoration of beta cell mass in PKO mice was accompanied by enhanced beta cell proliferation. Thus, our work suggests that Mig6 is a promising target to preserve beta cell mass before overt T1D. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.17.387191v1?rss=1 Authors: Niu, J., Holland, S. M., Ketschek, A., Collura, K. M., Hayashi, T., Smith, G. M., Gallo, G., Thomas, G. Abstract: Dual Leucine-zipper Kinase (DLK, a MAP3K) mediates neuronal responses to diverse injuries and insults via c-Jun N-terminal Kinase (JNK) family Mitogen-activated Protein Kinases (MAPKs). It is unclear why DLK couples to JNKs in mammalian neurons versus other MAPKs, especially because some invertebrate DLK orthologs couple instead to the related p38 family MAPKs. Here we identify two mechanisms that potentially explain this DLK-JNK coupling. First, neural-specific JNK3, but not p38-MAPK, catalyzes positive feedback phosphorylation of DLK that further activates DLK and locks the DLK-JNK3 module in a highly active state. Furthermore, the pro-degenerative JNK2 and JNK3, but not the related JNK1, are endogenously palmitoylated. Moreover, palmitoylation targets both DLK and JNK3 to the same axonal vesicles and JNK3 palmitoylation is essential for pro-degenerative axonal retrograde signaling in vivo. These findings provide insights into DLK-JNK signaling relevant to multiple neuropathological conditions and answer long-standing questions regarding the selective pro-degenerative roles of JNK2/3. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.31.276253v1?rss=1 Authors: Blackwood, C. A., McCoy, M. T., Ladenheim, B., Cadet, J. L. Abstract: To identify signaling pathways activated by oxycodone self-administration (SA), Sprague-Dawley rats self-administered oxycodone for 20 days using short-access (ShA, 3 h) and long-access (LgA, 9 h) paradigms. Animals were euthanized two hours after SA cessation and dorsal striata were used in post-mortem molecular analyses. LgA rats escalated their oxycodone intake and separated into lower (LgA-L) or higher (LgA-H) oxycodone takers. LgA-H rats showed increased striatal protein phosphorylation of ERK1/2 and MSK1/2. Histone H3, phosphorylated at serine 10 and acetylated at lysine 14 (H3S10pK14Ac), a MSK1/2 target, showed increased abundance only in LgA-H rats. RT-qPCR analyses revealed increased AMPA receptor subunits, GluA2 and GluA3 mRNAs in the LgA-H rats. GluA3, but not GluA2, expression correlated positively with changes in pMSK1/2 and H3S10pK14Ac. Our findings indicate that escalated oxycodone SA results in MSK1/2-dependent histone phosphorylation, which promoted increases in striatal gene expression. Our observations offer novel avenues for pharmacological interventions against oxycodone addiction. Copy rights belong to original authors. Visit the link for more info

"Optimists tend to be stronger responders to placebos. The placebo effect is a pervasive phenomenon; in fact, it is part of the response to any active medical intervention. The placebo effect points to the importance of perception and the brain's role in physical health. The opposite of a Placebo Effect is a Nocebo Effect. A Nocebo effect causes the perception that the phenomenon will have a negative outcome to actively influence the result. Pessimism may now be correlated with the Nocebo Effect.' - Jesse Lawler on WFR 097    Brainpower Upgrade   For anyone who's ever been interested in increasing their brainpower and learning more about what their body is capable of and how to get started, this is a great Wellness Force Radio podcast episode for you to listen to! What an amazing time for all of us to be alive with all of this technology to help us enhance and improve our minds and bodies. On this week's episode, I had an incredible conversation with previous WFR guest, Axon Labs Founder, and Smart Drug Smarts (SDS) Podcast Host, Jesse Lawler about smart drugs, meditation, the placebo effect, and how we can take that next step forward to learning more about ourselves. If you tuned into last week's episode with Daniel Schmachtenberger, we dive even deeper this week to uncover how smart drugs like nootropics not only alter or state of consciousness, but how they can help benefit our lives and wellness as well.   Enhance Your Brainpower With Smart Drugs   "Smart drugs are a part of a wide family that doesn't really have a common starting point." - Jesse Lawler   Jesse explains that there is one main, common misconception about the origins of smart drugs. It's a popular disbelief that all of the smart drugs that are out there just operate in the same way. Many believe that they're similar to the drugs (Ritalin and Adderall ) that are used to help ADHD. However, there's so much more to smart drugs than we originally thought was possible.  Smart drugs don't have one common root and each one individually helps us to enhance different cognitive senses: Memory Mood Energy Focus How to Choose the Perfect Smart Drug for You If you're curious in trying a smart drug, don't rush into taking anything immediately without giving yourself enough time to think if it's right for you. A lot of us already take a common cognitive enhancer: Coffee. Consider if coffee already helps you achieve what you want more of: energy, focus, or mood. A lot of us already know our limits with coffee and we can only drink so much of it before we become over anxious and jittery. If the right amount of coffee (1-3 cups or more if need be) already gives you what you want when you need it, do you really need to add a nootropic to the combination? Today it's quite popular to add different substances to your coffee and Bulletproof Coffee is a great example of that.  Some people like adding aniracetam, coconut oil, and grass-fed butter to their coffee, but it might not be for everyone. When trying a new smart drug, you have to take it one step at a time to see how different combinations affect you. Keep in mind that  you don't have to try everything to see what affect it will have on you. If you already have a good idea of what can happen when you take a smart drug and you don't think it will benefit you, then you can avoid taking it without the trial period. Alternatives to Taking Smart Drugs As already mentioned, coffee is a great cognitive enhancer without someone needing to take additional smart drugs. Another one is green tea. Green tea contains ethylene and GABA which has the same effect on the body as coffee does except it's much more gentler. Green tea doesn't have caffeine so it will help you be focused and calm without the jittery side effects.   Achieve a New State of Consciousness   "Stay curious and be open to exploring different states of consciousness. Look for anything that will help you improve your health." - Josh Trent   Today, we are discovering that there is a large variety of different ways that we can achieve a new state of consciousness. How can smart drugs help us achieve consciousness? Specific smart drugs have been created help us improve our memory, creativity, and attentiveness. Jess said that in general, our brain is able to keep track of 7 ideas in our working memory at a time (some people are able to take on between 5-9 ideas, but 7 is the average). But if you're able to add just one more working memory to the mix, think about what else you could achieve! Why are tech CEOs in Silicon Valley microdosing on LSD? Psychedelics have been used regularly to help people be more creative in their field and it's certainly gaining momentum for top executives in Silicon Valley. This might appear to be just a hippie phenomenon, but CEOs are finding that small doses of LSD are helping them do more than they could have done before. Even former Apple CEO, Steve Jobs, credited LSD to influencing his progress in the world of technology. We're not supporting the use of LSD, but it's fascinating that psychedelic use is now encouraging further research into how LSD affects the mind and our state of consciousness. Learn more in Jesse's interview with Dr. James Fadiman on the use of psychedelics to achieve a new state of consciousness. Using Oxygen to Enhance Our Consciousness: Holotropic & Wim-hof Breathing Believe it or not, oxygen is a natural drug that can take you to a new state of consciousness. There are two types of breathing techniques that you can use to get you to the state that you want to achieve: Grof's Holotropic Breathwork and the Wim-hof breathing technique. Ayahuasca: A Natural Smart Drug Jesse discussed the uses of Ayahuasca with Dr. Rick Strassman on the SDS episode, Breakthrough Work With "The Spirit Molecule." Ayahuasca is a DMT (di-methyl-triptamine). DMTs are actually all around us and they're even a naturally occurring psychedelic made in the body! Yes, you read that correctly. DMT is naturally found in small amounts in every living thing. Ayahuasca can have a negative effect on the body such as nausea and diarrhea, but plants can have an overall positive impact on our consciousness. In fact, Jesse believes that more people should be more open to experimentation. If something can lead to a positive outcome like it can for Post Traumatic Stress Disorder (PTSD) survivors, then it could be worth giving it a shot.   "If you have a condition like PTSD, then almost nothing should be off the table as a potential therapy. There are plenty of success stories with people treating depression, PTSD, and things like that with psychedelic therapies. If you've got a significant problem that you're trying to solve, it seems like it should be one of the things that you certainly can consider. " - Jesse Lawler on using plant medicines and psychedelics to help us heal our minds.    Achieve Mindfulness Through Meditation One of the easiest ways to naturally get to a different state of consciousness everyday is through the power of meditation. From beginners to the advanced, there's not just one way to meditate and you can use different apps or pieces of technology like the MUSE Headband. Silent meditation Vipassana Focusing on breathing Listening to be in the present moment A lot of people tend to go too fast, too quickly with meditation. Meditation won't be very effective for you if rush into doing hours of meditation compared to just a couple of minutes when you're a beginner. Meditation that helps to quiet the mind can be good for someone who is depressed. It helps to get rid of nagging negative thoughts inside the mind and shut out everything.   "The style of meditation that a person chooses is really going to affect what they're practicing and getting their brain to be better at. So to be aware of what your meditation goal is, you will gravitate towards a certain style."  - Jesse Lawler   When it comes to meditation, there is no one size fits all. Just try different forms of meditation until you come cross the best way for you to become more mindful.   The Connection Between Placebo Effect & Willpower   "You're either an abstainer or a moderator." - Gretchen Rubin on willpower   Can our willpower fatigue with too much use (like a muscle) or is it just something that we're born with?   "Willpower is probably something that does get exhaustive in a person, but I think that something that looks like willpower to an outsider might not actually be willpower to that person. A person can train themselves to avoid Doritos to the point that it takes zero willpower to avoid it now. Willpower's just not an option to that person." - Jesse Lawler   It can be very difficult for some people to control themselves and have the willpower to prevent themselves from eating unhealthy foods. Both the optimistic and negative mindset on health can impact our willpower. Those with a negative mindset will believe less in their own health and wellness than people who are overly optimistic that something like a smart drug or meditation can help them. Having an optimistic mindset will help you find something that works for you, but a negative  mindset can hinder your progress to look for something that can help you.   "Optimists tend to be stronger responders to placebos. The Placebo Effect is when we put thoughts into our mind that we do something or there will be a positive outcome. The opposite of a Placebo Effect is a Nocebo Effect in which case things will be bad and get worse. Pessimism might be correlated with the Nocebo Effect." - Jesse Lawler   Jesse's Own N=1 Self Experiment   "One of the greatest advantages of experimentation is just realizing that you can do it. It's a continuous reminder of our power to start changes in our own lives when you're just screwing with something to see if it works in your own life. It's a constant reminder that we're always in flux and flux can't change but at least you can direct it." - Jesse Lawler   An N=1 self experiment is understanding what works for you through a process of elimination or a process of strategic testing. During the experiment you might use self quantifying devices such as wearable trackers, apps, and more that allow for self-optimization. Josh shared his own N=1 self experiment on last week's episode, Emotional Resilience, Nootropics & Outsmarting the Modern World with Daniel Schmachtenberger Jesse's N=1 experiment ended up being a total crash and burn for him. He participated in the Uberman Sleep Schedule which meant he had to break up his sleep into 20 minute blocks that were separated by 3.5 hours throughout the day. However, that's way less hours of sleep than what the majority of us need in 24 hours!  The Uberman Sleep Schedule is for people who want to be more productive during the day. The main idea is that you train your brain to drop into REM really quickly, but it's not a restorative way to sleep at all.  Even though Jesse doesn't recommend this intense sleep schedule, he has been using the Oura Ring to keep track of his health. Why a ring instead of a bracelet? It's because the blood vessels are closer to the surface of the skin. Therefore, the ring is supposed to collect more accurate data than a bracelet. Whatever you may decide to purchase, make sure you invest in something that is: Safe Can help improve your health Usable for long term results Worth the investment Become your own citizen scientist. It's not about the app, bracelet, tracker etc. or anything you're using as long as it lines up with your main intentions. As a citizen scientist, begin your own N=1 self experiement by having a clear goal that something is going to help you perform better.   Brain Boost: Explore Nexus or Mitogen                                   Use code WELLFX to get 15% off both NEXUS and Mitogen from AXON Labs at http://smartdrugsmarts.com/wellnessforce/ About Jesse Lawler Jesse Lawler is the Founder of AXON Labs and the Host of Smart Drug Smarts. Smart Drug Smarts is a top ranked podcast that brings you actionable insights from world-leading experts in neuroscience and psychopharmacology — for the enhancement and protection of your greatest asset: your own brain. SmartDrugSmarts Podcast explores a range of health, wellness, fasting, cognitive enhancement, smart drugs, meditation, altered states of consciousness and basically anything or anyone that supports human and brain optimization.   Resources Mentioned by Jesse & Josh Listen to WFR episode #036 with Jesse Lawler: How to Build a Bulletproof Brain Dive right in with Smart Drug Smarts Podcast with this starter kit to enhance your mind Get started on smart drugs Enhance your mind with WFR episode #096 Emtional Resilience, Nootropics, & Outsmarting the Modern World with Daniel Schmachtenberger Check out the Smart Drug Smarts Podcast Learn more about Axon Labs Join the community to learn more about nootropics Discover how to do the Wim Hof breathing exercise Find out how to do the Grof breathing technique  Learn more about Vipassana Meditation with Josh Trent- WFR Tune into WFR episode no. 86 with Mark Divine: Creating the Unbeatable Mind Listen to SDS episode no. 162- The "Gut-Brain Axis" with Scott Anderson Listen to the SDS episode no. 155-Microdosing LSD with Dr. James Fadiman Find out more about Holotropic Breathwork – DIY Psychedelia with the SDS episode no. 89 Check out SDS episode no. 137- DMT: Dr. Rick Strassman’s Breakthrough Work With “The Spirit Molecule” Check out SDS episode no. 164- Placebo: The Power of the Mind to Heal Listen to SDS episode no. 145- Dennis McKenna: A 30-Year Psychedelic Education Check out this Forbes article, LSD Microdosing: The New Job Enhancer In Silicon Valley And Beyond? Learn more about Ayahuasca and DMT Track your wellness with the Oura Ring Read this article on 10 Interesting Facts About Caffeine Learn more about the Uberman Sleep Schedule Start meditating today with the MUSE Headband Go to the MAPS official website: Multidisciplinary Association for Psychedelic Studies Read Catching Fire: How Cooking Made Us Human by Richard Wrangham Learn more about Gretchen Rubin   Rate & Review Wellness Force Aloha! Josh here. Listen, I deeply value your thoughts, now let your voice be heard. I live to serve the Wellness Force even better based on your words, feedback, and requests. (including how the WFR episodes can support you in forming new, healthy, wellness habits) Ask A Live Question For The Next Episode Click here to leave a voicemail directly to Josh Trent to be read live on the air.  You May Also Like These Episodes Food Freedom Forever With Melissa Hartwig Nir Eyal:Breaking Bad Habits, Technology Addiction, & Emotional Triggers Healthy, Happy & Harder To Kill w/ Steph Gaudreau of Stupid Easy Paleo Beyond Meditation: How To Get A Better Brain With Ariel Garten Living A Healthy Lifestyle In A Modern World With Dan Pardi Creating A Life Worth Living With Michael Strasner Get More Wellness In Your Life Download Your Free Wellness Technology Guide: wellnessforce.com/radio Don't miss next week's show: Subscribe and stay updated Did you like this show? Rate and review Wellness Force on iTunes You read all the way to the bottom? That's what I call love! I do the same thing for the people, things, and movements I care about as well. PS: Looks like you and I share the same passion. I'm grateful for you and want to extend you my email address. Write to me and let me know what you'd like to have to get more wellness in your life. Lauren Bryant, Podcast Production Lauren Bryant is the Podcasting Assistant and Show Notes Writer for Wellness Force Radio. She has a BBA in both Marketing and Spanish for Business as well as certificates in Advanced Business Communications and International Business from the University of Wisconsin- Eau Claire. Lauren’s wellness journey began at a young age when she joined her local YMCA swim team, The Wave, of La Crosse, WI. One of the most profound views on wellness that anyone has said to her was when she was an assistant swim coach for that same YMCA swim team. One day during a practice, former head swim coach, Jon Brenner, shared with her that the most important thing about coaching the swimmers was that “It doesn’t matter if they become the best athletes in the world. What’s important is that we give them the tools and guidance they need to live a healthy, active lifestyle for the rest of their lives.” Since hearing those words, she has taken it to heart to not only focus on continuously living her own healthy lifestyle, but to help others pursue their wellness goals as well. Lauren’s not only an avid swimmer, but a fan of running, yoga, cooking, and doing any activity outside that involves being surrounded by nature. In the Fall of 2014, she completed a long-awaited goal of walking the Camino de Santiago in Spain. According to Lauren, wellness is about finding gratitude and joy in doing any type of physical or self-care activity that we love. Wellness means providing ourselves with self-love, good nutrition, and the inner peace that our individual minds and bodies need.

For Episode 315 we have Jesse Lawler of Smart Drug Smarts on to talk with us about nootropics (smart drugs) and ways to enhance cognition.   Guest: Jesse Lawler   For a discount on nootropics from Jesse, and links to topics discussed on the show check out http://smartdrugsmarts.com/robbwolf/   Links to topics Robb and Jesse discussed: Infographic: What is a Nootropic?  http://smartdrugsmarts.com/what-are-nootropics/ Episode 105: The Racetam Family - http://smartdrugsmarts.com/episode-105-racetams/   Jesse discussed two of his personal favorite nootropics: aniracetam and sulbutiamine.   These two feature prominently in the smart drug stacks we sell -- Nexus and Mitogen -- which are each geeked out on at length (along with all the other ingredients) in these two episodes... Episode 85: The Story of Mitogen http://smartdrugsmarts.com/episode-85-story-of-mitogen/ Episode 92: Nexus - The Nitty Gritty http://smartdrugsmarts.com/episode-92-nexus/   Other episodes: Episode 90: GHB The Good, the Bad the Sleepy  http://smartdrugsmarts.com/?s=GHB Episode 120:  Intermittent Fasting and Cognition with Mark Mattson http://smartdrugsmarts.com/episode-120-intermittent-fasting/ Episode 37: David Nutt and the Obstacles to Rational Drug Research http://smartdrugsmarts.com/?s=david+nutt

Hosts: Vincent Racaniello, Dickson Despommier, and Daniel Griffin The doctors TWiP solve the case of the Woman with White Worms, and explain the role of a secreted growth factor from a carcinogenic parasite in wound healing and angiogenesis.   Links for this episode: Wound healing growth factor from carcinogenic parasite (PLoS Path) Opisthorchis (CDC) Opisthorchis life cycle (CDC) Image credit Letters read on TWiP 101 Listener Pick Ramon - Ancient Rome was infested with parasites Case study for TWiP 101 This week's case involves an uncommon parasite. Young girl,

**Summary:** In Episode #180 Ari – joined by special guest hosts Nick Sonnenberg, founder of [Calvin App](http://www.calvinapp.com/) and co-founder of [Less Doing Virtual Assistants](http://www.lessdoing.com/VA) – interviews Abelard Lindsay, the creator of CilTep, a powerful, over-the-counter nootropic. Listen as Ari and Abelard talk brain chemistry, memory development, and cognitive function. **Special Announcements:** ## [Rockefeller Roundtable](http://helmsociety.com/ari-meisel-ceo-roundtable-nc/) Come watch Ari regale a roundtable of avid [Helm Society](http://helmsociety.com/) listeners with the lessons of Less Doing on September 9th from 10AM to 2PM in New York City. ## [Freeing Finland](http://www.biohackersummit.com) Come watch Ari and a collection of other well-renowned biohackers free the people of Finland from their bodily limitations at the 2015 Biohacker Summit being held in Helsinki, Finland from September 23rd through September 24th. Those interested in attending can [buy tickets here](http://biohackersummit.com/#pl_areauf9k2sm). ## [Leave Us a Review!](https://geo.itunes.apple.com/us/podcast/ari-meisel-less-doing/id605938952?mt=2&uo=6) Hey Less Doing Podcast Listeners, we want to hear from YOU! Visit us on iTunes and leave a review or subscribe to the podcast if you're not already a dedicated follower. **Time Stamped Show Notes:** - 18:34 – Introduction of Abelard Lindsay—Director of Research Development for Natural Stacks - 20:40 – Talking about CilTep - 21:20 – Coming up with the foundational ingredients - 21:53 – PDE4 inhibitors - 22:26 – There's a long cascade from short-term memory to long-term memory - 24:50 – Abelard basically conducted self-study with supplements to find the basis of CilTep - 26:20 – CilTep prolongs a state of wonder—it makes studying pleasurably addictive - 27:28 – When dopamine receptors are activated, they release CAMP into the neuron which causes memory encoding to increase - 29:08 – PDE5 is closely related to PDE4 but it drives sexual rather than mental arousal - 30:30 – Developing the pathway to improvement and problem solving - 33:10 – What Abelard takes regularly - 34:25 – Can you overdo it on nootropics? - 35:58 – Hard to clearly say because everyone is different - 36:45 – Nexus, CilTep, and Mitogen all work on different systems - 38:35 – None of Abelard's stacks feature caffeine - 39:10 – Abelard's _Top 3 Tips to be More Effective_ - 39:18 – Get to know your brain - 39:54 – Try to argue without using logical fallacies - 40:28 – Write down ideas - 41:38 – [www.AbelardResearch.com](http://www.AbelardResearch.com) and [www.NaturalStacks.com](http://www.NaturalStacks.com) and [www.axonlabs.io](http://www.axonlabs.io) and @CilTep **5 Key Points:** 1. Memory isn't a singular concept—there are different kinds of memory 2. Keep a written log of your ideas 3. Don't necessarily be opposed to self-experimentation. 4. Become close friends with your brain—get to know it. 5. Nootropic can help you create and prolong a natural state of wonder. **Resources Mentioned:** - [The MiFold](https://www.indiegogo.com/projects/mifold-the-grab-and-go-booster-seat#/story?utm_source=mifold.com&utm_medium=mifold.com&utm_term=hero_cta&utm_content=pre-order_now&utm_campaign=click-thru%20from%20mifold%20website) – A grab and go Car booster seat - [Drones for Blood Testing](http://www.vocativ.com/news/216434/bloody-good-drones-actually/) – Exploring the use of drones for blood transfer, testing, etc. - [The Slack Post](https://theslackpost.com/?ref=producthunt) – A simple online newspaper for the posting of all Slack integrations - [Chronic Inflammation and Behavior](http://www.medicaldaily.com/chronic-inflammatory-diseases-sometimes-cause-behavioral-problems-probiotics-might-345092) – From Medical Daily, an article highlighting how probiotics can help with mental illness - [Make a Game Out of Eating](http://www.yumit.io/?ref=producth --- Send in a voice message: https://anchor.fm/lessdoing/message

Einleitung: Zur in-vitro Diagnostik der Tuberkulose (TB) und latenten TB Infektion (LTBI) im Kindesalter werden derzeit zunehmend „Interferon-gamma (IFN-γ) release assays“ (IGRA) verwendet. Die Sensitivität der IGRA insbesondere im Kindesalter ist umstritten. Auch eine diagnostische Unterscheidung zwischen TB und LTBI ist mittels IGRA und anderen bisherigen basierten Testverfahren nicht möglich. In vorangegangen Studien zeigte sich der Biomarker „IFN-γ-inducible-protein-10“ (IP-10) als viel versprechend zur Diagnose der TB und LTBI. Ziele: In der vorliegenden Dissertationsschrift wurden die IP-10-Plasmakonzentrationen von Kindern mit TB, LTBI, Atemwegsinfektion (AWI) oder nicht-tuberkulöse Mykobakterien (NTM)-Erkrankung ohne Stimulation der Proben, nach unspezifischer Mitogen-Stimulation und nach spezifischer Mycobacterium tuberculosis (M. tuberculosis)-Antigen-Stimulation bestimmt. Die Antigen-stimulierten IP-10-Plasmakonzentrationen der TB- und LTBI-Gruppe wurden mit denen der NTM- und AWI-Gruppe verglichen. Darüberhinaus wurde beurteilt, ob eine Unterscheidung zwischen TB und LTBI anhand der IP-10-Plasmakonzentration möglich ist. Außerdem wurde die Konkordanz und Korrelation zwischen dem IP-10-ELISA und QuantiFERON® -TB Gold In-Tube (QFT-IT) Test beurteilt und untersucht, ob der Biomarker IP-10 altersabhängig sezerniert wird. Material & Methoden: 48 Kinder wurden in die Studie eingeschlossen. Das mittlere Alter der Studienteilnehmer war 54 Monate. Alle Studienteilnehmer wurden zuvor in Deutschland entweder mit einer TB (n=11), LTBI (n=14), NTM (n=8) oder AWI (n=15) diagnostiziert. Unabhängig von der vorliegenden Studie wurden bei allen teilnehmenden Kindern IFN-γ-Werte mittels des QFT-IT-Testes bestimmt. Im Rahmen des QFT-IT wurden die für den Test notwendigen Blutproben entweder nicht stimuliert, mit einer unspezifischen Mitogenen-Substanz oder mit spezifischen M.tuberculosis-Antigenen stimuliert. Die jeweiligen Plasma-Überstände wurden asserviert und zur Bestimmung von IP-10 verwendet. Die IP-10-Konzentrationen wurden, in Zusammenarbeit mit dem Klinischen Forschungszentrums der Universität von Kopenhagen, mittels einem zu Forschungszwecken entwickelten ELISAs gemessen. Ergebnisse: Die IP-10-Plasmakonzentrationen ohne Stimulation, mit unspezifischer Mitogen- und spezifischer Antigen-Stimulation betrug für die TB-Gruppe 704 pg/ml, 12.966 pg/ml und 12.702 pg/ml; für die LTBI-Gruppe 366,5 pg/ml, 10.232 pg/ml und 9.109 pg/ml; für die NTM-Gruppe 309 pg/ml, 11.197 pg/ml und 97 pg/ml; und für die AWI-Gruppe 694 pg/ml, 5.401 pg/ml und 84 pg/ml. Es konnte kein signifikanter Unterschied zwischen der IP-10-Konzentration der TB- und LTBI-Gruppe festgestellt werden (p-Wert= 0,24). Die IP-10- und IFN-γ- Plasmakonzentrationen der Kinder mit TB und LTBI korrelierten stark miteinander (rsp=0,65; p-Wert = 0,03 und rsp=0,79; p-Wert < 0,001). Der IP-10-ELISA und QFT-IT Test zeigten ebenso eine hohe Konkordanz (κ =0,96). Die IP-10-Sekretion war 18fach höher im Vergleich zur IFN-γ-Sekretion. Es konnte keine Korrelation zwischen dem Alter und der Mitogen-stimulierten IP-10-Konzentration nachgewiesen werden. Schlussfolgerungen: Die IP-10-Plasmakonzentration von Kindern mit TB und LTBI im Vergleich zu Kindern mit NTM und AWI ist signifikant nach spezifischer M.tuberculosis-Antigen-Stimulation erhöht (p-Wert > 0,001). Die qualitativen und quantitativen Testergebnisse des IP-10-ELISAs korrelieren stark mit denen des QFT-IT-Testes. Im Vergleich zu IFN-γ scheint IP-10 in höheren Konzentrationen und möglicherweise unabhängig vom Alter sezerniert zu werden. Das legt die Vermutung nahe, dass IP-10 zur Diagnose der TB und LTBI im Kindesalter in Zukunft Verwendung finden könnte.

Aktivierende Mutationen in Rezeptortyrosinkinasen spielen eine wichtige Rolle in der Pathogenese solider und hämatologischer Neoplasien, wie der akuten myeloischen Leukämie (AML). Im Rahmen dieser Arbeit wurden bislang nicht-charakterisierte Mutationen der Protoonkogene c-KIT und FLT3, die in der AML auftreten, in Zellkulturmodellen auf ihr transformierendes Potential hin untersucht. In-frame-Mutationen in Exon 8 des c-KIT-Gens, die aus kleinen Deletionen mit oder ohne Insertionen im extrazellulären Bereich bestehen, treten nahezu ausschließlich in Core-binding-Faktor-Leukämien auf und verschlechtern die Prognose der betroffenen Patienten. Drei repräsentative Exon-8-Mutationen wurden stabil in IL-3-abhängigen Ba/F3-Zellen exprimiert. Sie führten zur Hyperaktiverung des Rezeptors nach Ligandenstimulation, was sich in verstärkter Proliferation und Resistenz gegenüber Apoptose äußerte. In Rezeptor-Crosslinking-Experimenten zeigte eine repräsentative Exon-8-Mutante spontane und erhöhte liganden-induzierte Dimerisierung. Die biologischen Effekte konnten anhand einer erhöhten Phosphorylierung des nachgeordneten Signalmoleküls Mitogen-aktivierte Proteinkinase (MAPK) bestätigt werden. Im Gegensatz dazu hatte der FLT3-D324N-Single-Nukleotid-Polymorphismus, der in 6.4% von De-novo-AML-, 9.0% von CML- und 4.5% von ALL-Patientenproben detektiert wurde, keinerlei Auswirkungen auf die Prognose von AML-Patienten und wurde auch bei Kontrollpersonen gefunden (1.5%). Er wies keine funktionellen Unterschiede zu Wildtyp-FLT3 hinsichtlich Rezeptorphosphorylierung, Proliferation oder Apoptoseresistenz auf. Im Gegensatz zu Exon-8-Mutationen besitzen KIT-Mutationen in der Aktivierungsschleife, die – wie hier gezeigt wurde- die Prognose von Patienten mit günstigem Karyotyp verschlechtern, Resistenz gegenüber dem PTK-Inhibitor Imatinib. Zwei dem Imatinib nicht-verwandte Inhibitoren – PKC412 und SU5614 – wurden auf die Ansprechbarkeit von KIT-D816V getestet. Nur PKC412 war in der Lage, das spontane Wachstum von KIT-D816V-transduzierten Ba/F3-Zellen und die Rezeptorautophosphorylierung in HEK 293T-Zellen zu inhibieren. PKC412 führte überdies in den Ba/F3-Zellen zu einem deutlichen G0/G1-Arrest. Die beschriebenen In-vitro-Versuche können zwar einen ersten Einblick in die Rolle der untersuchten Mutationen in der AML bieten, tiefergehende Modelle sind jedoch vonnöten, um das Verständnis der Krankheitsentstehung in diesem Kontext zu erhöhen.

Hepatocyte Growth Factor (HGF) is a pleiotropic factor acting on cells expressing the Met receptor tyrosine kinase. HGF/Met signaling has been described in detail and it is known to control cell migration, growth and differentiation in several embryonic organs and to be implicated in human cancer. Conversely, little is known about the transcriptional targets that lead to Met-mediated biological functions. Also, little is known about the physiological mechanisms that attenuate Met signaling. This work provides the results of a screen for genes transcriptionally regulated by Met in several cell lines and addresses the functions of the highly inducible gene Mig6 (Mitogen-inducible-gene6, also called Gene 33 and RALT). By the use of Met loss of function mutant mice Met is shown to be the major inducer of mig6 in hepatocytes and lungs of E13.5 embryos. Mig6 is shown in turn to negatively regulate HGF/Met-induced cell migration. The effect is observed by Mig6 overexpression and reversed by Mig6 siRNA knock down experiments indicating that endogenous Mig6 is part of a mechanism that inhibits Met signaling. Mig6 functions in cells of hepatic origin and in neurons suggesting a role for Mig6 in different cell lineages. Mechanistically, Mig6 requires an intact Cdc42/Rho interactive binding (CRIB) domain to exert its inhibitory action suggesting that Mig6 acts at least in part distally from Met possibly by sequestering Rho-like GTPases. Because Mig6 is also induced by HGF stimulation, this work provides evidence that Mig6 is part of a negative feedback loop that attenuates Met functions in different contexts and cell types.

Primary biliary cirrhosis (PBC) is considered an autoimmune disease characterized by destruction of small intrahepatic bile ducts by lymphocytes. Altered functions of these lymphocytes might reflect an abnormal immune response leading to tissue damage. We investigated lymphokine secretion by mitogen-stimulated T lymphocytes from the liver biopsies of patients with PBC and for comparison also peripheral blood. In PBC, diminished synthesis of lymphotoxin (TNFP), tumor necrosis factor (TNFa) and interferon-y (IFIVy) was found both in T-cell lines from liver tissue and in peripheral blood. The reduction was most prominent for TNFP in early histological stages of PBC, and appeared to be a stable phenomenon when T cells were tested after long-term tissue culture. Analysis of mRNA levels indicates a possible link between reduced TNFP production and a defect in interleukin-2 transcription. The data suggest that diminished lymphokine production in patients with PBC may play ;In important role in the immanopathogenesis of this disease.

Expression of the Q5k gene was examined by northern blot analysis and polymerase chain reaction (PCR) in the AKR mouse and various cell lines, each of the H-2k haplotype. Our results show that Q5k mRNA is present during the whole postimplantational development of the AKR embryo/fetus (gestation day 6 to 15). In the juvenile mouse (week 2 to 4) transcription of the Q5k gene persisted in all organs examined. In contrast, in the adult animal expression of the Q5k gene was limited to the thymus and uterus of the pregnant mouse. Upon malignant transformation, the amount of Q5k-specific mRNA increased dramatically in thymus and could also be observed in the spleen of thymoma bearing animals. Expression of the Q5k gene was also detectable in several transformed mouse cell lines. Mitogen stimulation or treatment with cytokines induced Q5k expression in primary spleen cell cultures. A possible explanation for the tissue-restricted expression in the adult AKR mouse is discussed.