Podcasts about adam10

Adam Posener is an undefeated Canadian mixed martial artist, one of my brown belt students, and is becoming known for his dominant grappling performances inside the cage. Representing On Guard BJJ and Posener's Pankration/MMA, Adam is coming off of a spectacular 3rd round buzzer-beater armbar victory in Montreal over Trukon Carson and improves his professional record to 4-0 with 4 stoppages. We talk about his dominant rise in MMA, his recent fight in Montreal (including gripes about the Quebec Athletic Commission), and potential future match-ups. Please leave a review, subscribe, like, share, and comment if you can. It really helps to grow the show!Adam's IG Contacts:@primetime_era@simonposener@onguardbjj  Adam's Sponsors: -Sente Athletics: https://senteathletics.comPromo code: "primetime10" -Combat Cartel Clothing Co.:https://combatcartel.caPromo code: "Primetime" -Sweet Success protein doughnuts:https://www.sweetsuccesstreats.comPromo code: "Adam10"Contact/Support The Show:Website: ejjp.showInstagram: https://www.instagram.com/theeverydayjiujitsupodcast/TikTok: https://www.tiktok.com/@ejjpodEmail: ejjpod@gmail.com On Guard Online Academy: https://onguardbjj.com/p/online-academy Zara Can Do Jiu Jitsu! https://books.friesenpress.com/store/title/119734000253392052/Matt-Kwan-Zara-Can-Do-Jiu-Jitsu%21 The Everyday Jiu Jitsu Podcast Store: https://my-store-ee3230.creator-spring.com/ Make a donation to my PayPal account: matt@onguardbjj.com

Love Island: All-Stars - Married At First Sight expert Paul Brunson rates Molly and Callum's reunion chances on our pod ahead of their 'date' on tonight's showJoin Amanda Devlin and Felicity Cross as they recap the latest drama from Love Island! In this episode, they discuss:The awkwardness between Joanna and Chris after being dumpedTheir thoughts on Eve leaving while Jess staysArabella moving on quickly to AdamPredictions for the upcoming heart rate challengeWhether Molly and Callum could rekindle thingsSpecial guest love expert Paul Brunson shares his wisdom on finding love on reality shows0:00 Intro0:30 Thoughts on dumped islanders3:00 Joanna and Chris not on the same page5:00 Eve leaving while Jess stays7:00 Arabella moves on quickly to Adam10:15 Interview with Paul Brunson20:00 Molly and Callum's potential25:00 Tom uses recycled chat on Molly27:00 Heart rate challenge predictions31:00 Theo Campbell almost joined the show40:30 What's coming up on the podcast Hosted on Acast. See acast.com/privacy for more information.

Timestamps: 0:00 - Intro 0:38 - Will's competitive history & struggles gaining weight & how he overcame that barrier to keep pursuing his bodybuilding goals 13:44 - Leviathan Nutrition's reputation & why Will chooses different marketing strategy for Leviathan 16:38 - Why Will started Leviathan Nutrition 23:42 - What goes into running a supplement company like Leviathan Nutrition & why these supplements aren't just for people using PEDs 37:18 - What Will is most proud of with Leviathan Nutrition 39:32 - Leviathan NAC product breakdown 43:01 - Leviathan Tudca product breakdown 46:57 - Leviathan GI Support product breakdown 50:41 - Leviathan HemoFlow product breakdown 54:29 - Leviathan Kidney Support product breakdown 57:23 - Leviathan IRE product breakdown 1:02:11 - Where people can buy Leviathan Nutrition supplements & find Will Will's Instagram - https://www.instagram.com/thetudcaking/ Leviathan Nutrition (code: Adam10) - https://leviathan-nutrition.com/ Leviathan's Instagram - https://www.instagram.com/leviathannutrition/ Leviathan's YouTube - https://www.youtube.com/@leviathannutrition2821 Apply For Coaching - https://adampeeler1.typeform.com/to/elvzT31W My Instagram - https://www.instagram.com/adamdpeeler/ MacroFactor Diet Tracking App (Use code PEELER for a 2-Week FREE Trial!) - https://macrofactorapp.com/?fbclid=IwAR1nWSMgA6aaao72V40gYRnOGNl_N40XhTy7ze_Tv6qaN2bpVUVZrXUh6WY Leviathan Nutrition (Code: ADAM10) - https://leviathan-nutrition.com/ Built Bar (code PEELER for 10% off) - https://builtbar.com/

James from Plant Surge - Harnessing the Power of Lightning Now usually you'd hear me talking to a gardener, a houseplant expert or someone else directly linked to the plant world. However, this time is a little different. Because, in this conversation I'm joined by someone from a company that I use and love and I think you'll also enjoy too. This is our chance to discuss their products and tell you exactly why they're worth talking about. In this episode I'm joined by James from a company called Plant Surge⁠. Plant Surge have created something that I think, is taking the gardening world by storm. But, we think it needs some explanation! Now, you may have seen PlantSurge on Instagram or at various flower shows over the last few years but not fully understand their product. Their device is set to revolutionise the gardening industry and this is mine and James' chance to explain just how that's going to happen. This is one that you need to hear to believe….! Now you've listened you'll be wanting to get your own. Luckily I've got an exclusive discount code for you to buy your very own to give your plants a boost! You can use the code ADAM10 on plantsurge.co.uk to get 10% off AND Free Postage! Links

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.11.527059v1?rss=1 Authors: Ge, W.-p., Wang, Y., Liang, Y., Ai, D., Li, J.-L., Feng, Z., Guo, Z., Chen, X.-j., Zhang, T., zou, X., Gao, J.-L., Gao, X., Hu, X.-L., Wu, L.-J., Sun, W., Zhu, S., Duan, S., Wang, W. Abstract: ADAMs (a disintegrin and metalloproteinase) are transmembrane proteins with cell adhesion and protease activities that contain disintegrin and metalloproteinase domains. ADAM10, a member of the ADAM family, is widely expressed in the brain. There are greater than 40 substrates reported for ADAM10, including Notch, Delta-like ligand-1 (Dll1), and N-cadherin. To date, however, its function in the brain has been largely unknown. We used genetic manipulation to delete Adam10 specifically from glial progenitors in developing brains and observed that conditional knockout mice showed locomotor abnormalities. They all died within 4 months with apparent defects in the cerebellum. By comprehensively analyzing data from bulk RNA sequencing, single-cell RNA sequencing, and staining of the cerebellum, we found that ADAM10 promoted astrocyte generation under physiological conditions. Upon the removal of Adam10 in glial progenitors, the production of oligodendrocytes vastly increased, whereas the generation of astrocytes was substantially inhibited. Our results showed that ADAM10 plays a critical role in macroglial cell fate decisions during brain development. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.05.522934v1?rss=1 Authors: Rakotomamonjy, J., Rylaarsdam, L., Fares-Taie, L., McDermott, S., Davies, D., Yang, G., Fagbemi, F., Epstein, M., Guemez-Gamboa, A. Abstract: Protocadherins (PCDHs) are cell adhesion molecules that regulate many essential neurodevelopmental processes related to neuronal maturation, dendritic arbor formation, axon pathfinding, and synaptic plasticity. Bi-allelic loss-of-function variants in PCDH12 are associated with several neurodevelopmental disorders (NDDs) such as diencephalic-mesencephalic dysplasia syndrome, cerebral palsy, cerebellar ataxia, and microcephaly. Despite the highly deleterious outcome resulting from loss of PCDH12, little is known about its role during brain development and disease. Here, we show that PCDH12 loss severely impairs cerebral organoid development with reduced proliferative areas and disrupted laminar organization. 2D models further show that neural progenitor cells lacking PCDH12 prematurely exit cell cycle and differentiate earlier when compared to wildtype. Furthermore, we show that PCDH12 regulates neuronal migration through a mechanism requiring ADAM10-mediated ectodomain shedding and membrane recruitment of cytoskeleton regulators. Our data demonstrate a critical and broad involvement of PCDH12 in cortical development, revealing the pathogenic mechanisms underlying PCDH12-related NDDs. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

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

See all the Healthcasts at https://www.biobalancehealth.com/healthcast-blog/ At a get together of friends, I was pulled aside by a good friend who asked me how she could prevent dementia, because the mother she loves is in a memory care facility and she never wants that to be her future!  My answer was brief, but I can now think of so many other things I could have recommended for her, and I thought I would share them with you, and I will give her a copy of the blog that goes along with these suggestions. I read research every day that tells doctors what causes dementia and increases risk of getting dementia at the middle or latter part of life.  When I get to the basis of all the findings in the medical articles, it is detailed as I will discuss, But the basic qualities and problems to treat include INFLAMMATION, ATHEROSCLEROTIC VASCULAR DISEASE, OBESITY, HIGH SUGAR DIET, HIGH BP SMOKING AND ALCOHOL AND POOR DIET. Risk of Dementia Includes the following categories of Modifiable Risk factors:  Low Testosterone and estradiol Chronic inflammation Obesity Diabetes High BP Depression Cigarette/cigar smoking Hearing loss Binge Drinking and excessive alcohol intake Sedentary lifestyle Lack of sunlight High carb diet—sodas, sugar Aging= low sex hormones, poor production of nitric oxide and poor absorption of oral vitamin Bs Chronic injuries and pain that cause chronic inflammation—get that knee or shoulder fixed! Chronic heart disease---arrythmia, atherosclerotic heart disease   Foods to Eat Prevent Dementia Eggs in moderation Cumin Anything with protein Yogurt and other foods (Kambucho) with probiotics and lactobacciluus Clean fresh foods Meats and fish that are fresh or frozen, not preserved, or processed Steamed or fresh vegetables (not canned or processed) Seeds and nuts (raw and roasted without salt preferable) Foods to avoid to prevent dementia: Inflammatory foods and soy products Milk, especially cow's milk. (High carb content) especially skin milk! Soy All phytoestrogens Wheat Food with preservatives (all processed foods have preservatives) Modifiable risk factors        Replace hormones that are missing with bio-identical hormones, non-oral delivery system Estradiol pellets, patches, gels, for women Progesterone for women who miss it or who have a uterus Testosterone pellets, creams, gels Thyroid replacement. Armour Thyroid for women and levothyroxine for men Neurotransmitters by taking probiotics       Suppress LH and FSH –high levels increase risk of dementia and osteoporosis (new study) Take estradiol and testosterone for women—enough to suppress FSH and LH to pre-menopausal levels Replace Testosterone for men Keep Blood Sugar Normal Eat a low sugar and low carb diet— Treat prediabetes with meds Treat diabetes with meds Decease alcohol; intake to 1 4 oz glass of wine a day and < 1.5 oz of alcohol/day Get to ideal weight   Achieve Ideal Weight –Obesity and Overweight Increases Inflammation That Increases Dementia, so Decrease Inflammation             Eat properly--Eat your base caloric intake or less daily Low carb diet Eat ½ X -1 X your body weight in protein daily Drink clear water equivalent to your weight in ounces (you weight 130—drink 130 oz of water a day) No Soda No alcohol until you achieve ideal weight No desserts or baked goods, rice, wheat products until achieve id3al weight Supplements—see below     Exercise Daily Aerobic exercise--for > 40 minutes a day Weight training 3-4 times a week Red Light Therapy especially in the evenings—activate your mitochondria! Directed toward skin for 20 minutes a day Specific red-light therapy –to face or area of pain Natural light in AM Step outside at sunrise or early morning for 15-30 minutes—no sunglasses  Sleep in a dark room with quiet at least 7 hours a night OK to take melatonin at bedtime to sleep      Supplements -Take a multi vitamin every day like Thorne daily Nutrients 2/day + Antioxidants: Vitamins C, A, and E Vitamin D3 Vitamin Bs—Methyl B12, Methyl Folate oral or injections Anti-inflammatory supplements: Aspirin 81 mg/day Milk thistle Curcumin Omega 3 and 6 oils DHA NAC DIM Arteriorisol Minerals: Zinc 30-60/day Magnesium 300-600/day Electrolytes: especially in summer during exercise NUUN supplement Increase Nitric oxide and keep BP less than 140/90 Neo 40 RX Cialis daily 2.5- 5 mg/day Eat beets—lots of them Non-modifiable risk factors: Race (Am Indians and Blacks have a higher risk) Early age of menopause (without hormone replacement) Genetics: HLA-DR15 tissue type, APO-E ¾. And 4/4 Less than high school education Just a word about genetics. We now know that even if you carry genes for dementia, you can modify your genetics…there is hope!  This new concept is called epigenetics, and it shows that the factors we employ above can put certain dementia genes “to sleep” and activate other genes that are going to make you healthier!  We are no longer a puppet of our genes! Genetic Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10−7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education. If you're a doc you probably understood this abstract from a recent article ..if not.. disregard.

Two papers published this month in JASN provide new insights into these unsolved questions: Why is the risk of atherosclerotic cardiovascular disease so high in kidney patients? Why is the podocyte slit diaphragm so vulnerable to immunological injury?

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.   

Mark opens this week's episode of Reasonable Doubt remembering his mother who passed away at the age of 91. Then, Mark gives an update on his lawsuit against Los Angeles County over their outdoor dining restrictions. This leads to longer conversation about the COVID spikes in Los Angeles and more efficient ways precautions could be handled. Before they wrap, Adam responds to some online criticism. Please Support Our Sponsors: TommyJohn.com/RD NetSuite.com/Doubt MadisonReedMr.com use code ADAM10

Goldberg and Matt chat about Matt driving different McLarens all week and Bill gives an update on his new garage build. Geico: Visit Geico.com Dodge: Visit Dodge.com or your local dealer today MadisonReedMr.com use code Adam10

Goldberg and Matt chat about Matt driving different McLarens all week and Bill gives an update on his new garage build.Geico: Visit Geico.comDodge: Visit Dodge.com or your local dealer todayMadisonReedMr.com use code Adam10

Goldberg and Matt chat about Matt driving different McLarens all week and Bill gives an update on his new garage build. Geico: Visit Geico.com Dodge: Visit Dodge.com or your local dealer today MadisonReedMr.com use code Adam10

Goldberg and Matt welcome Nic Ashby of Rockstar Garage to the show to talk about their one-off Quadra Custom Mustang build. The guys also chat about the McLaren 765LT and Romain Grosjean's F1 crash.Geico: Visit Geico.comDodge: Visit Dodge.com or your local dealer todayMadisonReedMr.com use code Adam10

Goldberg and Matt welcome Nic Ashby of Rockstar Garage to the show to talk about their one-off Quadra Custom Mustang build. The guys also chat about the McLaren 765LT and Romain Grosjean's F1 crash. Geico: Visit Geico.com Dodge: Visit Dodge.com or your local dealer today MadisonReedMr.com use code Adam10

Goldberg and Matt welcome Nic Ashby of Rockstar Garage to the show to talk about a one-off Quadra Custom Mustang build. The guys also chat about the McLaren 765LT and Romain Grosjean's F1 crash. Geico: Visit Geico.com Dodge: Visit Dodge.com or your local dealer today MadisonReedMr.com use code Adam10

Adam and Mark are live from the Improv in West Palm Beach, Florida for this week's Best Hour In The Universe. The 1942 is flowing as they discuss California Governor Gavin Newsom's curfew & Rudy Giuliani's now infamous press conference and Mark's theory behind the Republican strategy. Adam also recounts his recent appearance on Tucker Carlson and goes over the process of appearing on that show remotely. As the show winds down, the guys turn to the audience and take questions live from the audience on topics including Kyle Rittenhouse making bail & the chances that the Presidential election finding its way to the United States Supreme Court. Please Support Our Sponsors: NetSuite.com/Doubt TommyJohn.com/RD MadisonReedMr.com use code Adam10

Goldberg and Matt welcome NHRA Funny Car Champion Matt Hagan to the program to talk about winning his third series title over the weekend. The guys also chat about Matt's Ford Lightning heading back to the shop and the SSC Tuatara speed record being challenged by the public. Geico: Visit Geico.com Dodge: Visit Dodge.com or your local dealer today Avery Dennison: Visit AveryDennison.com/color MadisonReedMr.com use code Adam10

Goldberg and Matt welcome NHRA Funny Car Champion Matt Hagan to the program to talk about winning his third series title over the weekend. The guys also chat about Matt's Ford Lightning heading back to the shop and the SSC Tuatara speed record being challenged by the public. Geico: Visit Geico.com Dodge: Visit Dodge.com or your local dealer today Avery Dennison: Visit AveryDennison.com/color MadisonReedMr.com use code Adam10

Goldberg and Matt welcome NHRA Funny Car Champion Matt Hagan to the program to talk about winning his third series title over the weekend. The guys also chat about Matt's Ford Lightning heading back to the shop and the SSC Tuatara speed record being challenged by the public.Geico: Visit Geico.comDodge: Visit Dodge.com or your local dealer todayAvery Dennison: Visit AveryDennison.com/colorMadisonReedMr.com use code Adam10

Adam and Mark open this week's episode of Reasonable Doubt criticizing California, and especially the city of Burbank who are enacting unconstitutional rules surrounding masks. This leads to a conversation on how misinformation from the media led to a missed opportunity to properly educate and protect people from the virus. After that, Mark gives an update on some recent Scott Peterson news. Before they wrap, Adam and Mark analyze the latest information coming out from the Breonna Taylor case and how it's been mischaracterized over the past few months. Please Support Our Sponsors: TommyJohn.com/RD Upstart.com/Doubt MadisonReedMr.com use code Adam10

Matt and Goldberg chat about the Ford Mustang Mach 1. Matt also shares some updates on his Ford Lightning pickup and the guys talk about the C8 Corvette production hiccups. Geico: Visit Geico.com Dodge: Visit Dodge.com or your local dealer today MadisonReedMr.com use code Adam10

Matt and Goldberg chat about the Ford Mustang Mach 1. Matt also shares some updates on his Ford Lightning pickup and the guys talk about the C8 Corvette production hiccups.Geico: Visit Geico.comDodge: Visit Dodge.com or your local dealer todayMadisonReedMr.com use code Adam10

Matt and Goldberg chat about the Ford Mustang Mach 1. Matt also shares some updates on his Ford Lightning pickup and the guys talk about the C8 Corvette production hiccups. Geico: Visit Geico.com Dodge: Visit Dodge.com or your local dealer today MadisonReedMr.com use code Adam10

Today’s show opens with Dr. Drew in studio for a Covid-19 update and statements made by the World Health Organization about the ineffectiveness of lockdowns. The guys also listen back on some absurd comments made by Gavin Newsom, and Adam goes on to share some Mike August stories from the previous day’s crazy travel schedule. Ravi Patel then joins the show, and Adam talks with him about his birthday cocktail party, as well as his new international travel docuseries, ‘Ravi Patel’s Pursuit of Happiness’. Later, Adam recalls his mom’s terrible house in North Hollywood, and the guys go on to talk about Coronavirus restrictions, as well as Ravi’s role in the upcoming Wonder Woman movie. Please support today’s sponsors: BetOnline enter PODCASTONE Geico.com Lifelock.com enter ADAM SimpliSafe.com/ADAM TruNiagen.com/ADAM TruckerTab.com MadisonReedMr.com enter ADAM10

Ravi Patel is still on the line for Part 2 of today’s show. To begin the news, Gina plays Kanye West’s first official Presidential Campaign Ad. The group also talk about the announcement that Gal Gadot is being cast a Cleopatra, people being offended by the word ‘dreadlocks’, and the vetting of Amy Coney Barrett. Another news story involves wedding ring finders, and the conversation changes to Adam’s relationship with his kids, and why he thinks being fair is more important than being nice. In the last part of the pod, Jeff Cesario joins for All Balls All Sports with stories about Dak Prescott’s recovery from ankle surgery, the first Dodgers-Braves playoff game, and today’s Bet Online Line. Please support today’s sponsors: BetOnline enter PODCASTONE Geico.com Lifelock.com enter ADAM SimpliSafe.com/ADAM TruNiagen.com/ADAM TruckerTab.com MadisonReedMr.com enter ADAM10

Goldberg and Matt chat about the new McLaren hybrid sports car, Ken Block gifting his daughter with a Fox-Body Mustang, and drag racer Lea Pruett’s unbelievable crash in St. Louis. And thanks for supporting our sponsors: Geico.com, MadisonReedMr.com enter ADAM10, and visit Dodge.com or your local dealer today.

Goldberg and Matt chat about the new McLaren hybrid sports car, Ken Block gifting his daughter with a Fox-Body Mustang, and drag racer Lea Pruett’s unbelievable crash in St. Louis. And thanks for supporting our sponsors: Geico.com, MadisonReedMr.com enter ADAM10, and visit Dodge.com or your local dealer today.

Goldberg and Matt chat about the new McLaren hybrid sports car, Ken Block gifting his daughter with a Fox-Body Mustang, and drag racer Lea Pruett’s unbelievable crash in St. Louis. And thanks for supporting our sponsors: Geico.com, MadisonReedMr.com enter ADAM10, and visit Dodge.com or your local dealer today.

In this week’s episode, special guests Joshua Lowcock (EVP, Chief Digital & Global Brand Safety Officer of UM Worldwide) and Alison Pepper (EVP, Government Relations of 4A’s) discuss the issues surrounding Section 230, arguably the most important law for online speech and social media — what it is, its unexpected origin, how it benefit brands and marketers, and why it has been popping up recently in the news.0:58— weekly news roundup with co-hosts Scott and Adam10:46 — a conversation about Section 230 and what it means for marketersAdditional resources for more information:ITIF - Information Technology & Innovation Foundation - https://itif.org/EFF - Electronic Frontier Foundation - https://www.eff.org/Professor Eric Goldman, Santa Clara University School of Law - https://blog.ericgoldman.org/We welcome your honest feedback! Find our co-hosts Adam and Scott on Twitter at @adamjsimon & @tippier. See acast.com/privacy for privacy and opt-out information.

Ira Pastor, ideaXme life sciences ambassador, interviews Dr. Rudolph Tanzi, Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard University, Vice-Chair of Neurology, Director of the Genetics and Aging Research Unit, and Co-Director of the Henry and Allison McCance Center for Brain Health at Massachusetts General Hospital. Ira Pastor Comments: On this episode we are going to journey back to the topic of Alzheimer’s disease (AD), projected to affect over a 100 million people worldwide by mid century.  Dr. Rudolph Tanzi: Dr. Rudolph Tanzi is the Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard University, Vice-Chair of Neurology, Director of the Genetics and Aging Research Unit, and Co-Director of the Henry and Allison McCance Center for Brain Health at Massachusetts General Hospital (MGH), and has been investigating the genetics of neurological disease since the 1980s when he participated in the first study that used genetic markers to find a disease gene for Huntington's disease. In 1990, Dr. Tanzi received his Ph.D. in neurobiology at Harvard Medical School, where his doctoral thesis was on the discovery and isolation of the first Alzheimer's disease gene - the amyloid precursor protein (APP), published in 1987 in Science. Dr. Tanzi's work in Alzheimer's disease research: Dr Tanzi co-discovered all three familial early-onset Alzheimer's disease (FAD) genes and several other neurological disease genes including those responsible for Wilson’s disease. Dr Tanzi also serves as Chair of the Cure Alzheimer's Fund Research Leadership Group and leader of the Cure Alzheimer's Fund Alzheimer’s Genome Project, where he has carried out multiple genome wide association studies (GWAS) of thousands of Alzheimer’s families leading to the identification of novel AD candidate genes, including CD33, and ADAM10 genes. Dr Tanzi has also worked on the role of zinc and copper in AD, on gamma secretase modulators for the prevention and treatment of Alzheimer's, and on human stem cells to create an “Alzheimer’s-in-a-Dish”, three-dimensional neural culture system, that was the first to recapitulate both pathological hallmarks of Alzheimer’s disease. Dr. Tanzi has published over 500 scientific papers, including the top three most cited papers in the field of Alzheimer's disease research. Dr. Tanzi also co-authored the books "Decoding Darkness: The Search the Genetic Causes of Alzheimer's Disease", the New York Times Best Selling book “Super Brain: Unleashing the Explosive Power of Your Mind to Maximize Health, Happiness, and Spiritual Well-Being”, "Super Genes: Unlock the Astonishing Power of Your DNA for Optimum Health and Well-Being", and "The Healing Self: A Revolutionary New Plan to Supercharge Your Immunity and Stay Well for Life" with Deepak Chopra. Dr. Tanzi in the Media Dr. Tanzi has made numerous television appearances on shows such as CBS This Morning and Dr. Oz. He also hosts the shows "Super Brain with Dr. Rudy Tanzi", "Super Genes with Dr. Rudy Tanzi" and "The Brain Body Mind Connection with Dr. Rudy Tanzi and Dr. Deepak Chopra" on PBS television. In addition to his work in AD and brain health, Dr. Tanzi has wide ranging musical pursuits. Dr Tanzi professionally plays keyboards, most recently with Joe Perry and Aerosmith. He also co-wrote the song tribute to Alzheimer's patients called "Remember Me", performed by singer Chris Mann. He plays keyboards on the albums: "Aerosmith: Music from Another Dimension", and "Joe Perry: Switzerland Manifesto." On this episode we will hear from Dr Tanzi about: His background; how he developed an interest in neurobiology and the domain of AD. His work on the Alzheimer's Disease - Infectious Disease connection and the Alzheimer's Disease - Neuro-inflammation connection. His work with stem cells and regenerative medicine. His work in the area of aging, brain health and the "psycho-biologic" aspects of health and wellness. About mental health and self care during the COVID-19 crisis. Credits: Ira Pastor interview video, text, and audio. Follow Ira Pastor on Twitter:@IraSamuelPastor If you liked this interview, be sure to check out ourinterviewexploring the viral causes of Alzheimer's! Follow ideaXme on Twitter:@ideaxm On Instagram:@ideaxme Find ideaXme across the internet including on iTunes,SoundCloud,Radio Public,TuneIn Radio,I Heart Radio, Google Podcasts, Spotify and more. ideaXme is a global podcast, creator series and mentor programme. Our mission: Move the human story forward!™ ideaXme Ltd.

Neuregulin-1 (NRG1) type III is a growth factor on the surface of neurons in the peripheral nervous system (PNS). It is required for initial myelination of nerves by Schwann cells after birth and for remyelination after injury. Neuregulin-1 type III is activated by cleavage (shedding) in its extracellular juxtamembrane region generating a membrane-bound N-terminal fragment (NTF) that contains a bioactive epidermal growth factor (EGF)-like domain. This domain signals to neighboring Schwann cells in a contact-dependent manner prompting the cells to initiate myelination. The β-site APP cleaving enzyme 1 (BACE1) was identified as the enzyme that cleaves NRG1 type III and promotes myelination. Consequently, loss of BACE1 cleavage results in dramatically reduced myelin sheaths around nerves in the PNS of BACE1 knockout mice. Besides its role in myelination, BACE1, better known as β-secretase, is also involved in the generation of the neurotoxic amyloid β-peptide (Aβ) which is the main component of amyloid plaques in the brain of patients suffering from Alzheimer’s disease (AD). The Aβ peptide is derived through sequential cleavage of the amyloid precursor protein APP, first by BACE1 in the extracellular domain and subsequently by the γ-secretase in the transmembrane domain (TMD). Inhibition of BACE1 and γ-secretase is therefore considered a promising therapeutic strategy for AD. However, this approach harbors the risk of mechanism-based side effects due to impaired processing of substrates beside APP such as NRG1 type III which is not only a substrate for BACE1 but like APP is also cleaved in its TMD by the γ-secretase. Adding another layer of complexity, ADAM10 and ADAM17, the so-called α-secretases of AD, also cleave NRG1 type III. In the first part of this study, the proteolytic processing of NRG1 type III in its ectodomain was investigated in detail. The precise juxtamembrane shedding sites of BACE1, ADAM10 and ADAM17 were determined by mass spectrometry and two novel cleavage sites of BACE1 and ADAM17 N-terminal of the EGF-like domain were discovered. Cleavage at these novel sites by ADAM17 and BACE1 results in the secretion of the EGF-like domain from NRG1 type III as α-sEGF and β-sEGF, respectively. Using novel monoclonal antibodies generated against the identified cleavage sites the processing of NRG1 type III could also be confirmed in primary neurons. The soluble EGF-like domains were found to be functionally active and induced signaling pathways required for myelination in cultured Schwann cells. Furthermore, β-sEGF rescued the myelination deficit in the PNS of a zebrafish model lacking BACE1, thereby demonstrating its activity in vivo. Using cell culture and the zebrafish model the effects of BACE1- and ADAM17-mediated shedding on the activity of the soluble EGF-like domains were carefully dissected. In contrast to published evidence, however, both the BACE1- as well as the ADAM17-shed sEGF were found to be equally active and to promote myelination in vivo. Together this suggests that NRG1 type III dependent myelination is not only controlled by membrane-retained NRG1 type III but also in a contact-independent manner via proteolytic liberation of the EGF-like domain. The second part of this study investigates the processing of the C-terminal fragment (CTF) which remains after shedding of NRG1 type III. Intramembranous cleavage of the CTF by the γ-secretase was previously shown to release the NRG1 intracellular domain, which acts as transcriptional regulator of proteins involved in neuronal maturation and brain plasticity. Interestingly, a mutation within the TMD of NRG1 type III is associated with an increased risk of schizophrenia linking γ-secretase processing of NRG1 type III to this neurological disorder. Using a novel antibody against the N-terminus of the NRG1 CTF it was possible to detect a NRG1 β-peptide that is secreted during γ-secretase cleavage and could potentially serve as marker for this processing. Moreover, by means of mass spectrometry, the precise cleavage sites within the TMD of NRG1 could be identified. Strikingly, the ɛ-like cleavage site was found to be located exactly at the position of the schizophrenia-associated mutation providing a possible mechanism for the reported interference of this mutation with γ-secretase cleavage. The evidence presented unambiguously establishes NRG1 type III as a γ-secretase substrate and provides a basis for further investigation of the mechanisms which link its processing to the development of schizophrenia. In summary and with regard to BACE1 and γ-secretase being prime targets for a potential AD therapy, the results of this work call for further careful investigation of the consequences of altered NRG1 type III signaling due to chronic treatment with inhibitors.

Thu, 12 Jun 2014 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/17073/ https://edoc.ub.uni-muenchen.de/17073/1/Renner_Sonja.pdf Renner, Sonja ddc:610, ddc:600, Medizinische Fakultät

Vielversprechende Therapieansätze für die Alzheimer Erkrankung basieren auf der Amyloid-Hypothese und beinhalten die Inhibition der β-Sekretase BACE1 und des γ-Sekretase-Komplexes sowie die Aktivierung der α-Sekretase ADAM10. Für die Einschätzung und Minimierung von Nebenwirkungsprofilen ist die Kenntnis weiterer Substrate dieser Sekretasen essentiell. Als ein solches Substrat wurde Typ I Neuregulin1-β (Typ I NRG1-β), ein Mitglied der EGF-Familie von Wachstumsfaktoren, vermutet. In der vorliegenden Arbeit konnte in vitro gezeigt werden, dass Typ I NRG1-β ein Substrat für den γ-Sekretase-Komplex darstellt. Nach erfolgtem Shedding von Typ I NRG1-β katalysiert der γ-Sekretase-Komplex die intramembranäre Proteolyse durch einen Schnitt innerhalb der Transmembrandomäne. Ferner konnte in vitro gezeigt werden, dass BACE1 das Shedding der Isoformen Typ I NRG1-β1 und Typ I NRG1-β4 katalysiert, wobei die β1-Isoform das bevorzugte Substrat von BACE1 darstellt. Typ I NRG1-β2 wird dagegen nicht oder nur in sehr geringem Ausmaß durch BACE1 prozessiert. Für die β1-Isoform wurde die BACE1-Schnittstelle innerhalb der juxtamembranären Region zwischen der Aminosäure-Position Glu236-Phe237 und Met238-Glu239 (EF-ME) von humanem Typ I NRG1-β1 charakterisiert. Es konnte gezeigt werden, dass diese Schnittstelle spezifisch für BACE1 ist und dass keine weiteren BACE1-Schnittstellen innerhalb der juxtamembranären Region von Typ I NRG1-β1 existieren. Neben BACE1 wird das Shedding der β1-Isoform durch α-Sekretasen katalysiert, wobei das Shedding der β1-Isoform hauptsächlich durch ADAM10 erfolgt. Im Gegensatz zur β1-Isoform werden die Isoformen β2 und β4 nicht durch ADAM10 geschnitten. Für die β2-Isoform konnte jedoch ein Shedding durch andere α-Sekretasen in vitro nachgewiesen werden. Die vorliegenden Ergebnisse ermöglichen allerdings keine Aussage dazu, um welche spezifischen α-Sekretasen es sich handelt. Für α-Sekretasen wird kontrovers eine fehlende Schnittstellen-Sequenzspezifität diskutiert. Vermutlich sind für die Substraterkennung neben einer spezifischen Schnittstellensequenz weitere Faktoren von Bedeutung. So konnte in dieser Arbeit gezeigt werden, dass die Länge der juxtamembranären Region von Typ I NRG1-β einen entscheidenden Einfluss auf das Shedding durch α-Sekretasen hat. Dabei stellen die Isoformen mit einer kürzeren juxtamembranären Region das bevorzugte Substrat für α-Sekretasen dar. Diese Arbeit zeigt, dass Typ I NRG1-β ein Substrat von allen drei Sekretasen ist, die vielversprechende Therapieansatzpunkte in der Alzheimertherapie darstellen. Durch die Beeinflussung der Aktivität dieser Sekretasen wird somit auch die Proteolyse von Typ NRG1-β beeinflusst und damit letztendlich auch die physiologischen Funktionen von Typ NRG1-β. Im Hinblick auf daraus resultierende Nebenwirkungen ist es daher essentiell, die physiologische Bedeutung der Sekretasen ADAM10, BACE1 und des γ-Sekretase-Komplexes bezüglich der Funktionen von Typ NRG1-β weiter zu analysieren.

The processing of APP occurs in two alternative ways: upon release of the ectodomain by α-secretase, the neuroprotective APPsα-fragment is produced. But if APP is cleaved by the β-secretase the Aβ-peptide can be produced. To be able to influence the production of Aβ-peptides, it is essential to understand how it is decided if cleavage occurs by α- or β-secretase. At present little is known about the control of the alternate processing. Until now, the molecular mechanisms and especially the responsible cellular modulators are not understood in detail or not yet identified. To get a better understanding of cellular regulatory processes and to identify novel cellular modulators of APP ectodomain shedding, the present work chose two approaches: on the one hand cellular mechanisms of TMEM59-mediated inhibition ectodomain shedding of APP were investigated. On the other hand a genome-wide RNAi screening in Drosophila cells was performed in order to identify novel cellular modulators of APP ectodomain shedding in human cells. TMEM59 was identified as a novel modulator of APP ectodomain shedding in a cDNA expression screening in the lab (Neumann et al., 2006; Schobel et al., 2008; Schobel et al., 2006). TMEM59 is a Golgi protein that inhibits on the one hand processing and maturation of APP and on the other hand Golgi glycosylation reactions (Fischer, 2008). My own work could verify these effects of TMEM59 and its homolog TMEM59L on processing and maturation of APP. In particular, it was shown that these effects are not only true for transiently expressed APP but also for endogenous levels of APP. In detailed immunofluorescence studies it was shown that TMEM59 colocalizes with different markers of the Golgi subcompartments and that therefore TMEM59 is present throughout the whole Golgi apparatus. This finding points to a more general modulation of Golgi glycosylation reactions by TMEM59. To test if TMEM59-dependet modulation of Golgi glycosylation reactions also affects APP secretases ADAM10 and BACE1, which are also glycosylated proteins, the activities of these proteases were investigated. It was shown that proteolytic activities were not changed, ruling out that impairment of secretase activities by TMEM59 could cause the observed inhibition of APP processing. But interestingly, studies of intracellular APP transport could show that TMEM59 caused retention of APP in the Golgi apparatus and blockage of transport towards the cell surface and into endosomal compartments. Since APP is cleaved by α-secretase at the plasma membrane and by β-secretase in endosomes it is likely that a TMEM59-dependent APP transport block causes the observed inhibition of APP ectodomain shedding. For further validation of TMEM59 and its homolog TMEM59L as modulators of APP ectodomain shedding, a double knockdown study was performed. In this approach effects on APP ectodomain shedding could also be established, affirming TMEM59 and its homolog TMEM59L as modulators of APP ectodomain shedding with novel cellular mechanisms. In order to identify novel cellular modulators of APP ectodomain shedding a genome wide RNAi screening in Drosophila cells was performed and candidate genes were investigated in human cells in present work. Initially a suitable Drosophila reporter cell line expressing a reporter construct of APP ectodomain shedding (HRP-APP) was established. Other constructs were used to monitor general secretion (GLuc) and transfection efficiency (FLuc). Using Kuzbanian, the α-secretase in Drosophila (Sapir et al., 2005), as a positive control guaranteed that transfection of cDNAs into Drosophila cells did not interfere with uptake of dsRNAs or efficiency of RNAi and that the reporter construct HRP-APP is normally produced and processed in reporter cells. After successful establishment of the reporter cell line the genome wide RNAi was performed in two steps: a primary screening revealed approx. 300 candidate genes out of which 43 could be confirmed in a secondary screening to be modulators of APP ectodomain shedding. The RNAi screening was verified by the several-fold appearance of Kuzbanian among the top modulators. For further investigation of the top candidates human ortholog genes were identified. The 30 human candidate genes were investigated in RNAi studies in human SH-SY5Y cells. In these cells, APP is processed by α-secretase ADAM10 as well as by β-secretase BACE1. Therefore effects on both shedding products (APPsα and APPsβ) were investigated upon depletion of candidate genes using siRNAs. It is known that siRNAs produce a high rate of off target effects, to this end a robust validation strategy was developed. Candidate genes were first depleted with two different siRNA pools and their effects on APP shedding were compared. Afterwards the remaining 12 candidate genes were depleted using single siRNA sequences and the effects were compared to those of the siRNA pool. Only when a reproduction of effects was obtained in a next step correlation of knockdown and phenotype were assessed. Using these steps of validation 5 candidate genes could be verified as modulators of APP shedding in human cells: next to genes coding for a histone protein (HIST1H4C), a ribosomal protein (RPL36AL), a protein of the minor spliceosom (ZMAT5), an unknown gene (METTL16) and the gene VPS24 („vacuolar protein sorting-associated protein 24“), coding for a protein of intracellular protein transport, were identified. VPS24 was chosen for further validation by a pathway analysis. VPS24 belongs to the ESCRT machinery („endosomal sorting complex required for transport“) and therefore participates in endosomal-lysosomal protein transport. In further RNAi studies other members of the ESCRT machinery were depleted in human cells and effects on APP shedding were compared to VPS24 depletion. For most of the ESCRT members a consistent reduction in APPsβ production could be observed. To engross these results VPS24 was depleted by using an alternative RNAi system. With this stable knockdown approach, the knockdown phenotype could be confirmed. This stepwise validation strategy for candidate genes of the initial Drosophila RNAi screening verified VPS24 as a modulator of APP ectodomain shedding in human cells.

Regulated intramembrane proteolysis of the amyloid precursor protein (APP) by the protease activities α-, β- and γ-secretase controls the generation of the neurotoxic amyloid β peptide. APLP2, the amyloid precursor-like protein 2, is a homolog of APP, which shows functional overlap with APP, but lacks an amyloid β domain. Compared to APP, less is known about the proteolytic processing of APLP2, in particular in neurons, and the cleavage sites have not yet been determined. APLP2 is cleaved by the β-secretase BACE1 and additionally by an α-secretase activity. The two metalloproteases ADAM10 and ADAM17 have been suggested as candidate APLP2 α-secretases in cell lines. Here, we used RNA interference and found that ADAM10, but not ADAM17, is required for the constitutive α-secretase cleavage of APLP2 in HEK293 and SH-SY5Y cells. Likewise, in primary murine neurons knock-down of ADAM10 suppressed APLP2 α-secretase cleavage. Using mass spectrometry we determined the proteolytic cleavage sites in the APLP2 sequence. ADAM10 was found to cleave APLP2 after arginine 670, whereas BACE1 cleaves after leucine 659. Both cleavage sites are located in close proximity to the membrane. γ-secretase cleavage was found to occur at different peptide bonds between alanine 694 and valine 700, which is close to the N-terminus of the predicted APLP2 transmembrane domain. Determination of the APLP2 cleavage sites enables functional studies of the different APLP2 ectodomain fragments and the production of cleavage-site specific antibodies for APLP2, which may be used for biomarker development.

Proteolytic processing of the amyloid precursor protein (APP) by α-secretase prevents the formation of the amyloid β-peptide (Aβ), which is the main constituent of amyloid plaques in brains of Alzheimer's disease (AD) patients. In AD α-Secretase activity is decreased, and overexpression of the α-secretase ADAM10 (a disintegrin and metalloprotease 10) in an AD animal model prevents amyloid pathology. ADAM10 features a 444-nucleotide-long, very GC-rich 5′-untranslated region (5′UTR) with two upstream open reading frames. Because similar properties of 5′UTRs are found in transcripts of many genes, which are regulated by translational control mechanisms, we asked whether ADAM10 expression is translationally controlled by its 5′UTR. Here we demonstrate that the 5′UTR of ADAM10 represses the rate of ADAM10 translation. In the absence of the 5′UTR, we observed a significant increase of ADAM10 protein levels in HEK293 cells, whereas mRNA levels were unchanged. Moreover, the 5′UTR of ADAM10 inhibits translation of a luciferase reporter in an in vitro-transcription/-translation assay. Successive deletion of the first half of the ADAM10 5′UTR revealed a striking increase in ADAM10 protein expression in HEK293 cells, suggesting that this part of the 5′UTR contains inhibitory elements for translation. In contrast, the deletion of the 3'-part of the 5'UTR led to significantly reduced protein levels. Thus, we provide evidence that the 5′UTR of ADAM10 may have an important role for post-transcriptional regulation of ADAM10 expression. Therefore these findings might be of significant importance for future research in Alzheimer's disease and the development of novel therapeutic strategies of this devastating disorder.