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Don't miss out on the Father's Day sales extended 1 last day:SAVE ON TRENDSPIDER - $9 TRIALS
Companies like Rocket Lab (RKLB), Archer Aviation (ARCH) and Joby Aviation (JOBY) saw up to double-digits percent rallies after President Trump signed executive orders that aim to boost drone security and electric air taxi aircraft. Diane King Hall gives more insight on why these stocks launched on the news and talks about headwinds and tailwinds the executive orders present for the industry.======== Schwab Network ========Empowering every investor and trader, every market day. Subscribe to the Market Minute newsletter - https://schwabnetwork.com/subscribeDownload the iOS app - https://apps.apple.com/us/app/schwab-network/id1460719185Download the Amazon Fire Tv App - https://www.amazon.com/TD-Ameritrade-Network/dp/B07KRD76C7Watch on Sling - https://watch.sling.com/1/asset/191928615bd8d47686f94682aefaa007/watchWatch on Vizio - https://www.vizio.com/en/watchfreeplus-exploreWatch on DistroTV - https://www.distro.tv/live/schwab-network/Follow us on X – https://twitter.com/schwabnetworkFollow us on Facebook – https://www.facebook.com/schwabnetworkFollow us on LinkedIn - https://www.linkedin.com/company/schwab-network/ About Schwab Network - https://schwabnetwork.com/about
Join your hosts Rhydon and Rachael for another action-packed bonus episode where we dive into top HVAC headlines before taking you through the recent Imola & Monaco Grand Prix recaps and previewing the Spanish Grand Prix. What's Inside: HVAC News & Industry Catch-Up (0:00–20:00) Top Distributors of 2025: A look at ACHR's Top-30 list and how Carrier Enterprise helped WATSCO, Inc. clinch the #1 spot. Inside the Modern HVAC Work Van: Smart storage solutions, strong branding on the move—and Rachael's go-to van setup and must-have tools. Improper HVAC Installation Lawsuits: Why a wave of litigation is sweeping the industry as states ramp up enforcement—and how to avoid becoming the next headline. Imola & Monaco Grand Prix Recaps (20:00–42:00) Imola Highlights: Standout overtakes, tire strategies, and surprise performances on the historic Italian circuit. Monaco Breakdown: Navigating the tight streets, key technical takeaways, and who emerged unscathed from the world's most challenging street race. Spanish Grand Prix Preview (42:00–End) What to watch for at Circuit de Barcelona-Catalunya: team strategies, driver matchups, and how track evolution could shake up qualifying—and the race. Enjoyed the blend of HVAC insights and F1 action?
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Joe Tigay includes 2 members of the Mag 7 in today's Big 3: Alphabet (GOOGL) and Nvidia (NVDA). But, his first pick is an overlooked aviation play in Archer Aviation (ACHR). Joe discusses the reasons why he's watching this group of stocks. Rick Ducat provides the chart analysis of each company's stock performance over the last year.======== Schwab Network ========Empowering every investor and trader, every market day.Subscribe to the Market Minute newsletter - https://schwabnetwork.com/subscribeDownload the iOS app - https://apps.apple.com/us/app/schwab-network/id1460719185Download the Amazon Fire Tv App - https://www.amazon.com/TD-Ameritrade-Network/dp/B07KRD76C7Watch on Sling - https://watch.sling.com/1/asset/191928615bd8d47686f94682aefaa007/watchWatch on Vizio - https://www.vizio.com/en/watchfreeplus-exploreWatch on DistroTV - https://www.distro.tv/live/schwab-network/Follow us on X – https://twitter.com/schwabnetworkFollow us on Facebook – https://www.facebook.com/schwabnetworkFollow us on LinkedIn - https://www.linkedin.com/company/schwab-network/About Schwab Network - https://schwabnetwork.com/about
George Tsilis examines this week's move higher in Archer Aviation (ACHR). The stock hit new 52-week highs after earnings, in which they did not report any revenue. George notes its partnership with Stellantis (STLA) as key to the company's cash reserves, Additionally, he spotlights its 2028 Olympics status as the Games' official air taxi provider. Shares are up over 260% over the last 52-weeks.======== Schwab Network ========Empowering every investor and trader, every market day.Subscribe to the Market Minute newsletter - https://schwabnetwork.com/subscribeDownload the iOS app - https://apps.apple.com/us/app/schwab-network/id1460719185Download the Amazon Fire Tv App - https://www.amazon.com/TD-Ameritrade-Network/dp/B07KRD76C7Watch on Sling - https://watch.sling.com/1/asset/191928615bd8d47686f94682aefaa007/watchWatch on Vizio - https://www.vizio.com/en/watchfreeplus-exploreWatch on DistroTV - https://www.distro.tv/live/schwab-network/Follow us on X – https://twitter.com/schwabnetworkFollow us on Facebook – https://www.facebook.com/schwabnetworkFollow us on LinkedIn - https://www.linkedin.com/company/schwab-network/About Schwab Network - https://schwabnetwork.com/about
The best gifts are the ones that keep on giving, and that's what this episode is all about! Today's show highlights the things you've told us that you learned from David, called out and amplified to help us all navigate another challenging year. Now that's an awesome birthday present. Thanks! Companies mentioned: AAPL, ACHR, AMZN, CMG, DIS, MELI, MSFT, NFLX, NVDA, ODFL, SHOP, TSLA Host: David Gardner Producer: Rick Engdahl
Archer Aviation (ACHR) reports earnings after the bell, which John Jannarone expects to be "speculative" due to its long path to profitability. The biggest concern on John's radar is FAA certification that keeps getting "kicked further and further out." Michael Boyd notes Archer's "exciting concept" but worries about the company's outlook. As Michael says, "no one's asking the hard questions" about aircraft demand.======== Schwab Network ========Empowering every investor and trader, every market day.Subscribe to the Market Minute newsletter - https://schwabnetwork.com/subscribeDownload the iOS app - https://apps.apple.com/us/app/schwab-network/id1460719185Download the Amazon Fire Tv App - https://www.amazon.com/TD-Ameritrade-Network/dp/B07KRD76C7Watch on Sling - https://watch.sling.com/1/asset/191928615bd8d47686f94682aefaa007/watchWatch on Vizio - https://www.vizio.com/en/watchfreeplus-exploreWatch on DistroTV - https://www.distro.tv/live/schwab-network/Follow us on X – https://twitter.com/schwabnetworkFollow us on Facebook – https://www.facebook.com/schwabnetworkFollow us on LinkedIn - https://www.linkedin.com/company/schwab-network/About Schwab Network - https://schwabnetwork.com/about
空の移動をもっと身近にしたいと思ってしまった4人のパパたち&1人のリケジョが、夜な夜なこっそり繰り広げる、eVTOL(=空飛ぶクルマ)に対する興味、好奇心、社会実装への情熱を語り合うラジオです。イヴ・エア・モビリティ、プロトタイプの初飛行を2025年中ごろに計画！エンブラエル系eVTOL企業！初飛行は少し延期？受注数もトップクラス！公開される初飛行は初飛行じゃない？ヴァージン・アトランティック、バーティカル・エアロスペースとの提携を解消！ジョビー・アビエーションと提携！振られたバーティカルには痛手？二股はダメよ、別れてから言って？ヴァージン塗装のJOBYの機体も！ヨーロッパ企業全滅の危機？サフランのEngineUsエンジン、アセンダンスのAtea eVTOL機に採用！ってなんて読むの？名前はエンジンだけど電動モーター！EASAから世界初の型式証明を取ったメーカー！空冷と水冷に違い？実は大事なサーマルマネジメント？万博バーティポート完成！スカイドライブの機体がチラ見え？…チラ？大阪港バーティポートも完成！JAL×住友商事のソラクル社、万博での飛行を断念ARCHER実機は日本では見れない！…などなど。気になるeVTOL関連ニュースピックアップです！メッセージはこちらから https://forms.gle/mib37UcseFvpzyGa8関連リンク■The Vertical Flight Society: The Electric VTOL Newshttps://evtol.news/■ Eve Planning First Flight With Prototype By Midyear, Aviation Week, March 12https://news.us4.list-manage.com/track/click?u=0bd0403bfc17d80346b4f2455&id=f719be0c2a&e=44a5123185■ Virgin Drops Vertical Aerospace; Partners With Joby, Aviation Week, March 17https://news.us4.list-manage.com/track/click?u=0bd0403bfc17d80346b4f2455&id=d94b3d1d95&e=44a5123185■ Safran's EngineUs Engines Will Power Atea eVTOL Aircraft, AIN, March 12https://news.us4.list-manage.com/track/click?u=0bd0403bfc17d80346b4f2455&id=e2ee54f43d&e=44a5123185■ 産経新聞 空飛ぶクルマの万博会場内の離着陸ポートが完成 複数機体の売り入れ施設は国内初https://www.sankei.com/article/20250328-ZOVNK7MYAVMTBB2NEB5QCOQM5Y/■ 日経新聞 JAL・住商、万博「空飛ぶクルマ」断念 事業化は継続https://www.nikkei.com/nkd/company/us/ACHR/news/?DisplayType=1&ng=DGXZQOUC288UM028032025000000SNSリンク ■X/Twitter https://twitter.com/evtolradio
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CME credits: 1.00 Valid until: 02-04-2026 Claim your CME credit at https://reachmd.com/programs/cme/autoantibodies-explained-anti-achr-anti-musk-and-their-diagnostic-role/32728/ While traditional therapies for generalized myasthenia gravis (gMG) have proven beneficial in the short term, new treatment options with fewer debilitating side effects and longer-term benefit are needed. The emergence of targeted inhibitors of the neonatal Fc receptor (FcRn) have demonstrated in clinical trials and real-world experience that they address both of these needs. Join Drs. Vera Bril, Nicholas Silvestri, and Hans Katzberg as they discuss this exciting new therapeutic option and how it may change the treatment landscape of gMG.
Archer Aviation's (ACHR) stock continues to fly, this time after the FAA granted certification for a pilot training academy. George Tsilis notes the approval will help bring more attention to the technology, but will add more pressure to post profits. He says Archer Aviation needs to reverse its earnings yield from red to black to hold investor confidence.======== Schwab Network ========Empowering every investor and trader, every market day.Subscribe to the Market Minute newsletter - https://schwabnetwork.com/subscribeDownload the iOS app - https://apps.apple.com/us/app/schwab-network/id1460719185Download the Amazon Fire Tv App - https://www.amazon.com/TD-Ameritrade-Network/dp/B07KRD76C7Watch on Sling - https://watch.sling.com/1/asset/191928615bd8d47686f94682aefaa007/watchWatch on Vizio - https://www.vizio.com/en/watchfreeplus-exploreWatch on DistroTV - https://www.distro.tv/live/schwab-network/Follow us on X – https://twitter.com/schwabnetworkFollow us on Facebook – https://www.facebook.com/schwabnetworkFollow us on LinkedIn - https://www.linkedin.com/company/schwab-network/About Schwab Network - https://schwabnetwork.com/about
George Tsilis turns to companies with their eyes on the sky. Archer Aviation (ACHR) and Joby Aviation (JOBY) are both trading near their year-highs on their goal of advancing electric air vehicles. George discusses the headwinds that lie ahead for both companies. ======== Schwab Network ======== Empowering every investor and trader, every market day. Subscribe to the Market Minute newsletter - https://schwabnetwork.com/subscribe Download the iOS app - https://apps.apple.com/us/app/schwab-network/id1460719185 Download the Amazon Fire Tv App - https://www.amazon.com/TD-Ameritrade-Network/dp/B07KRD76C7 Watch on Sling - https://watch.sling.com/1/asset/191928615bd8d47686f94682aefaa007/watch Watch on Vizio - https://www.vizio.com/en/watchfreeplus-explore Watch on DistroTV - https://www.distro.tv/live/schwab-network/ Follow us on X – https://twitter.com/schwabnetwork Follow us on Facebook – https://www.facebook.com/schwabnetwork Follow us on LinkedIn - https://www.linkedin.com/company/schwab-network/ About Schwab Network - https://schwabnetwork.com/about
In this episode we look at the last companies to report earnings. Which stocks still have room left to run for the remainder of the year and beyond? After much of the market has already moved as some of the uncertainty settles down, is there anything left to buy at a reasonable valuation? I think we have found a few that deserve a closer look! Sold TSLA covered calls at $300 Closed NVDA calls @ $170 UMAC and ACHR rally higher on drone talks-- WEEK 50 1. AMD 2. DELL 3. GOOGL 4. LHX 5. LMT WEEK 1 SELL $PLUG, $HNST, $SHOP. BUY $DVN, $MPW, $NEE, WEEK 2 $NVDA, WEEK 3 $HASI, WEEK 4 $CRSP, WEEK 5 $TSM, WEEK 6 $MSFT, WEEK 7 $XOM, WEEK 8 $BMY, WEEK 9 $O, WEEK 10 $KO, WEEK 11 $SOUN, WEEK 12 $IRM and $AAPL WEEK 13 $AMD, WEEK 14 $CVX, WEEK 15 $AMZN, WEEK 16 $INTC/$X, WEEK 17 $V, WEEK 18 $O, WEEK 19 $META, WEEK 20 $CIVI, WEEK 21 $BRCC, WEEK 22 $WBA, WEEK 23 $COST, WEEK 24 $CVX, WEEK 25 $MO, WEEK 26 $AMZN, WEEK 27$UPS, WEEK 28 $JNJ, WEEK 29 $V, WEEK 30 $SOFI, WEEK 31 $XOM, WEEK 32 $NEE, WEEK 33 $MPW, WEEK 34 $PLTR, WEEK 35 $IBIT, WEEK 36 $DVN, WEEK 37 $S, WEEK 38 $UPS, WEEK 39 $CVX, WEEK 40 $C, WEEK $41 COST, WEEK 42 $DVN, WEEK 43 $PFE, WEEK 44 $CELH, WEEK 45 $C, WEEK 46 $UPS, WEEK 47 $CIVI, WEEK 48 $LLY, WEEK 49 $CELH As always, I thank each and every one of you for listening in, voting, and following along to the podcast and group! It has been a fun journey gathering info and sharing it with you all every week. Please make sure to subscribe, share and should you have questions, please feel free to ask and I'll do my best to cover them. ***Not investing advice, simply what I am looking to do in my own portfolio while understanding my risks, timeline, age, income, debt and other factors!!*** As always, thank you for continuing to support the page and podcast, by liking, subscribing and sharing! www.1stphorm.com/letitgrow https://barbellapparel.com/?rstr=Letitgrowbarbellapparel FB GROUP: https://www.facebook.com/groups/3149013668660459/ E-Trade Referral code https://refer.etrade.net/jsebastian1987 https://accounts.binance.us/en/register?ref=53539239 Use my referral link https://crypto.com/app/3jsnadjrsq to sign up for Crypto.com and we both get $25 USD. Open an account on webull, make a deposit and get a free share valued between $8-$2000!! https://a.webull.com/iq6NLY31wXgKyPlM1g If anyone is reading down here, you are the real MVP!! Thanks for your support and making our community a better place and for making me a better investor. I hope you've learned something; I certainly have! Let's get out there and "LET IT GROW" --- Support this podcast: https://podcasters.spotify.com/pod/show/letitgrow/support
Insider Financial recaps today's stock market action and discusses the stocks to watch ahead of Fed Day. To get our FREE reports and eBook: https://www.insiderfinancial.com/lp/youtube This video covers SPY, QQQ, DIA, IWM, TLT, BTC, NVDA, NRDY, RNAC, ALHC, DTC, ACHR, NCMI, JWN, SPIR, HOTH, ATOS, ATNM. The Stocks To Watch This Week Disclosure: Insider Financial has not been compensated for this video. Insider Financial is not an investment advisor; this video does not provide investment advice. Always do your research, make your own investment decisions, or consult with your nearest financial advisor. This video is not a solicitation or recommendation to buy, sell, or hold securities. This video is our opinion, is meant for informational and educational purposes only, and does not provide investment advice. Past performance is not indicative of future performance. For more information, please read our full disclaimer: https://insiderfinancial.com/disclaimer/ S&p 500, Dow, Nasdaq, SPY ETF, QQQ ETF, quantum computing stocks, Spac stocks, AI stocks, Bitcoin, crypto, Bitcoin stocks, crypto stocks, short squeeze, short squeeze stocks, low float, low float stocks, lithium stocks, ev stocks, small caps, trading, otc stocks, otc stocks list, penny stocks, penny stocks list, NASDAQ penny stocks, NYSE stocks, NYSE penny stocks, biotech stocks #smallcapstocks #stockstowatch #stockmarketnews
PODCASTER SENIOR: Prof. Francesco Saccà;PODCASTER JUNIOR: Dr.ssa Giulia Greco;RAZIONALE:La Miastenia Gravis (MG) è una patologia neuromuscolare autoimmune caratterizzata principalmente da faticabilità muscolare post-esercizio, generalizzata o confinata alla sola muscolatura estrinseca oculare, determinata dalla presenza di autoanticorpi rivolti contro diverse componenti della giunzione neuromuscolare, quali gli anti-AChR, anti-MuSK o anti-LRP4. Pazienti clinicamente affetti in cui non sia riscontrata positività per nessuno dei suddetti anticorpi, vengono considerati sieronegativi.Fino a qualche anno fa, l'approccio terapeutico per i pazienti affetti da MG era limitato all'utilizzo, talora combinato, di farmaci sintomatici (es. piridostigmina bromuro), corticosteroidi e/o immunosoppressori non steroidei, con estrema variabilità nella risposta clinica.Negli ultimi anni, grazie all'avvento di nuovi farmaci lo scenario è finalmente cambiato, permettendo di trattare in maniera efficace anche pazienti non responsivi ai trattamenti di prima linea.
Welcome to this special episode of the NeurologyLive® Mind Moments® podcast. Tune in to hear leaders in neurology sound off on topics that impact your clinical practice. For major FDA decisions in the field of neurology, we release short special episodes to offer a snapshot of the news, including the main takeaways for the clinical community, as well as highlights of the efficacy and safety profile of the agent in question. In this episode, we're covering the recent approval of zilucoplan (Zilbrysq; UCB Pharma) for the treatment of patients with acetylcholine receptor antibody–positive generalized myasthenia gravis. We spoke with James F. “Chip” Howard, MD, Distinguished Professor of Neuromuscular Disease and professor of neurology and medicine at The University of North Carolina at Chapel Hill School of Medicine, and the lead global investigator of the phase 3 RAISE study (NCT04115293), who discussed the downstream effects of this approval for myasthenia gravis, the available data from clinical studies, and the advantages for patients and physicians. For more of NeurologyLive®'s coverage of zilucoplan's approval, head here: FDA Approves Complement C5 Inhibitor Zilucoplan as Treatment for Myasthenia Gravis Episode Breakdown: 0:30 – Zilucoplan approved for AChR+ myasthenia gravis 1:40 – James F. Howard, MD, on his immediate reaction 3:30 – Safety data from the RAISE trial 4:25 – Howard on the potential advantages of zilucoplan 6:50 – Phase 3 efficacy data for zilucoplan 7:55 – Howard with context on the efficacy and the challenges with therapeutic availability in myasthenia gravis 12:10 – Howard, on the future of therapeutic development Thanks for listening to the NeurologyLive® Mind Moments® podcast. To support the show, be sure to rate, review, and subscribe wherever you listen to podcasts. For more neurology news and expert-driven content, visit neurologylive.com. REFERENCES 1. UCB announces US FDA approval of Zilbrysq (zilucoplan) for the treatment of adults with generalized myasthenia gravis. News release. October 17, 2023. Accessed October 17, 2023. https://www.ucb.com/stories-media/Press-Releases/article/UCB-announces-US-FDA-approval-of-ZILBRYSQR-zilucoplan-for-the-treatment-of-adults-with-generalized-myasthenia-gravis 2. Howard JF, Bresch S, Genge A, et al. Safety and efficacy of zilucoplan in patients with generalized myasthia gravis (RAISE): a randomized, double-blind, placebo-controlled, phase 3 study. 2023;22(5):395-406. doi:10.1016/S1474-4422(23)00080-7 3. Genge A, Hussain Y, Kaminski HJ, et al. Safety and tolerability of zilucoplan in RAISE-XT: a multicenter, open-label extension study in patients with myasthenia gravis. Presented at: MDA 2023; February 19-22; Dallas, TX. Abstract 145.
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Insider Financial recaps last week's stock market action, discusses our trading plan for the coming week, and previews our new research report on a potential short squeeze stock. To get our FREE reports and eBook, go to: https://signup.insiderfinancial.com/ To get FREE stocks and trade from 4 am to 8 pm on WeBull, visit: https://a.webull.com/i/insiderfinancial. This video covers PGY, SMLR, RGTI, ACHR, GNS, VFF, IDAI, APRN, GRPN. Get Ready For A Potential Short Squeeze! Disclosure: Insider Financial has not been compensated for this video. Insider Financial is not an investment advisor; this video does not provide investment advice. Always do your research, make your own investment decisions, or consult with your nearest financial advisor. This video is not a solicitation or recommendation to buy, sell, or hold securities. This video is our opinion, is meant for informational and educational purposes only, and does not provide investment advice. Past performance is not indicative of future performance. For more information, please read our full disclaimer: https://insiderfinancial.com/disclaimer/ S&p 500, Dow, Nasdaq, SPY ETF QQQ ETF, PGY stock SMLR stock, RGTI stock, ACHR stock, GNS stock, VFF stock, IDAI stock, APRN stock, GRPN stock, quantum computing stocks, Spac stocks, AI stocks, Bitcoin stocks, crypto stocks, short squeeze, short squeeze stocks, low float, low float stocks, lithium stocks, ev stocks, small caps, trading, otc stocks, otc stocks list, penny stocks, penny stocks list, NASDAQ penny stocks, NYSE stocks, NYSE penny stocks #smallcapstocks #pennystocks #shortsqueeze
Insider Financial recaps the day's stock market action and discusses our current trading plan for this challenging market. To get our FREE reports and eBook, go to: https://signup.insiderfinancial.com/ To get FREE stocks and trade from 4 am to 8 pm on WeBull, visit: https://a.webull.com/i/insiderfinancial. This video covers PGY, SMLR, RGTI, ACHR, IONQ, YELL, TLRY, TUP, W, WE. More Pain In Store For Bulls? How To Trade This Market! Disclosure: Insider Financial has not been compensated for this video. Insider Financial is not an investment advisor; this video does not provide investment advice. Always do your research, make your own investment decisions, or consult with your nearest financial advisor. This video is not a solicitation or recommendation to buy, sell, or hold securities. This video is our opinion, is meant for informational and educational purposes only, and does not provide investment advice. Past performance is not indicative of future performance. For more information, please read our full disclaimer: https://insiderfinancial.com/disclaimer/ S&p 500, Dow, Nasdaq, SPY ETF QQQ ETF, TUP stock, Tupperware stock, stock, YELL stock, Yellow stock, TLRY stock, Tilray stock, PGY stock SMLR stock, RGTI stock, ACHR stock, IONQ stock, W stock, Wayfair stock, WE stock, WeWork stock, quantum computing stocks, Spac stocks, AI stocks, Bitcoin stocks, crypto stocks, short squeeze, short squeeze stocks, low float, low float stocks, lithium stocks, ev stocks, small caps, trading, otc stocks, otc stocks list, penny stocks, penny stocks list, NASDAQ penny stocks, NYSE stocks, NYSE penny stocks #smallcapstocks #tradingplan #tradingstrategy
Half way through June and here's the list of winners I've had so far $coin $shop $nvda $baba $tsla $Orcl $clf $pxd $snow $panw $tqqq A description of all the moving averages I use and why I use them 2 rules from Strategis Research Motley Fool recommends $ENPH 5 all time high stocks yesterday FREE NEWSLETTER WITH CHARTS - subscribe at dailystockpick.substack.com SPONSORED BY VISIBLE - Check out this page: https://www.visible.com/get/?3MFGCRG, it has all the info you need to know about joining Visible. When you use my friend code, 3MFGCRG, you'll get your first month of service for $20-off! Use code DSP25 for 25% off Trendspider's platform - https://trendspider.com/?_go=gary93 Sign up for Webull and get free stocks like I did - WEBULL LINK Support the podcast - HERE Social Links and more - https://linktr.ee/dailystockpick NOTES Newsletter paid subs - I turned it on last night and some folks may have been charged so if you want a refund just ask. Poll in the What is confirmation 6-15 pod - should I upload video podcasts to Spotify? ANSWER YES! 2 rules at Strategis research Don't fight the fed Don't fight the tape MTD winners that I've picked $coin under $50 $shop under $60 $nvda under $400 $baba under $80 $tsla under $200 $Orcl under $90 $clf under $15 $pxd under $200 - with that big dividend $snow at $150 $panw under $200 $tqqq at $32 Ones I've missed $sofi $pltr $dpst Play video of crypto trading Moving averages I have on my screen and why China is stimulating their economy which has been EXTREMELY stalled. That announcement moved the US market. But the 2-10 year bond inversion is coming up to the Oct low high spread. Bitcoin going nuts because $blk files for Bitcoin etf with $coin as the custodian Motley Fool chose $ENPH - I posted the text in the Facebook group All time highs yesterday $NVDA $LEN $ORCL $AAPL $MSFT $UBER was up 5% $SNOW was up 5% $RBLX went under $40 and then over $40 $QCOM was $105 when I pointed out it was just too low. It's now at $123 $pypl $rkt $nvda $CAVA IPO - I didn't bring it up because in no way were you going to get in on this one. Wait for it - it's going to crash. $jepi and $qyld Getting messages from folks that they found me after they blew up accounts or lost money. That's why I started this whole journey. Just know I won't charge you anything that's out there today. I do get a commission on TrendSpider but that's such a small fee for a tool like that. $ADBE up 5% after hours after beating earnings and offering mixed guidance. Great article on $ADBE if you want to invest https://www.investors.com/news/technology/adbe-stock-adobe-beats-q2-goals-on-cloud-software-demand/?src=A00220 $BOIL MOVING $MU setting up india factory and $intc setting up a factory in Poland Melissa - FB $JOBY $ACHR I'm up almost 25% on each of these stocks. My initial thought was to keep holding, but the 2nd thought was to sell because I was done. Corey's analysis of $aci in the Facebook group - solid Brandon - FB $SPCE - announced the first space flight on June 27-30 of this year. The stock moved HUGE on the news - all hype. SCANS $CRWD $PXD $META $UCO $COIN $MELI --- Support this podcast: https://podcasters.spotify.com/pod/show/dailystockpick/support
Joakim Achrén, “the gaming startup guy”, is a games investor, and founder of Elite Game Developers, which provides advice for game founders. He co-founded Next Games (which was acquired by Netflix), and worked as Director of Analytics at Supercell.
4.08 Myasthenia Gravis and Lambert Eaton Syndrome MSK/Rheumatology review for the USMLE Step 1 Exam Introduction: Review of neuromuscular junction and its components: presynaptic part, postsynaptic part, synaptic cleft. Cascade of events leading to the release of acetylcholine into the synaptic cleft. Myasthenia Gravis: Autoimmune neuromuscular junction disease. Fluctuating muscle weakness, especially ocular and eyelid weakness, distal limb weakness. Antibodies target nicotinic acetylcholine receptors (n-AChR's). Association with thymic hyperplasia and enlarged thymus. Treatment: Acetylcholinesterase inhibitors (AChE inhibitors), immunosuppressants. Lambert Eaton Syndrome: Autoimmune neuromuscular junction disease associated with cancer. Fluctuating muscle weakness, autonomic dysfunction, decreased reflexes. Antibodies target presynaptic calcium channels on nerve terminals. Autonomic manifestations due to calcium channels also present in smooth muscle. Around 50% of cases associated with an underlying malignancy. Treatment: Immunosuppression, addressing underlying malignancy if present.
Featuring ACHR AMD BEKE BORR CHPT CHWY CRM CRWD DDOG IMMX IMUX JOBY LEVI MDB NU NVDA PATH PLAB PSTG RPTX Trading Risk Disclaimer All the information shared in this video is provided for educational purposes only. Any trades placed upon reliance of SharperTrades.com are taken at your own risk for your own account. Past performance is no guarantee. While there is great potential for reward trading stocks, commodities, options and forex, there is also substantial risk of loss. All trading operations involve high risks of losing your entire investment. You must therefore decide your own suitability to trade. Trading results can never be guaranteed. This is not an offer to buy or sell stocks, forex, futures, options, commodity interests or any other trading security.
Featuring BORR BP CPRI CRM CRWD DDOG GLD HRB JOBY (ACHR) LEVI MSFT NIO SBUX SPXS SWIR VSCO ZM Trading Risk Disclaimer All the information shared in this video is provided for educational purposes only. Any trades placed upon reliance of SharperTrades.com are taken at your own risk for your own account. Past performance is no guarantee. While there is great potential for reward trading stocks, commodities, options and forex, there is also substantial risk of loss. All trading operations involve high risks of losing your entire investment. You must therefore decide your own suitability to trade. Trading results can never be guaranteed. This is not an offer to buy or sell stocks, forex, futures, options, commodity interests or any other trading security.
Featuring ACCD ACHR AMZN ASC ATER CYN FB HCDI INVZ MX NKTX NUTX PINS RCMT RDBX ROKU TDOC UNG Trading Risk Disclaimer All the information shared in this video is provided for educational purposes only. Any trades placed upon reliance of SharperTrades.com are taken at your own risk for your own account. Past performance is no guarantee. While there is great potential for reward trading stocks, commodities, options and forex, there is also substantial risk of loss. All trading operations involve high risks of losing your entire investment. You must therefore decide your own suitability to trade. Trading results can never be guaranteed. This is not an offer to buy or sell stocks, forex, futures, options, commodity interests or any other trading security.
Shaun Weiss is a head coach and trainer for Business Development Resources, a training and coaching authority in the home service industry. He was named as one of the Top 40 Under 40 in the ACHR news list. In this episode, we talked about sales, company structures, home services…
James Howard Jr., MD, Distinguished Professor of Neuromuscular Disease and Professor of Neurology and Medicine at UNC School of Medicine, reviews the treatment landscape for myasthenia gravis. Myasthenia gravis is a chronic autoimmune neuromuscular disease characterized by weakness of the skeletal muscles. Common symptoms include weakness of the muscles that control the eyes, eyelids, facial expressions, chewing, talking, and swallowing. The condition is usually due to the presence of antibodies against acetylcholine receptors in the neuromuscular junction.As Dr. Howard explains, due to the variety of ways this rare disease can present, treatment of myasthenia gravis is individualized to each patient based on their specific symptoms and unique comorbidities. In addition, the financial situation of each patient is taken into account.Acetylcholinesterase inhibitors are often used as bridge therapies. Corticosteroids are also common bridge therapies in younger patients, while steroid sparing agents are more common in older patients or in patients with contraindications to steroids. In patients under the age of 60 with generalized disease and who are anti-acetylcholine receptor (AChR) antibody positive, the removal of the thymus gland is common. Dr. Howard goes on to discuss approved treatments for myasthenia gravis. In 2017, eculizumab, a complement inhibitor, was approved by the U.S. Food and Drug Administration (FDA) for the treatment of generalized myasthenia gravis in adult patients who are anti-acetylcholine receptor (AChR) antibody positive. More recently, in December 2021, the FDA approved efgartigimod alfa, an FcRn inhibitor, for the treatment of this same patient population. This approval was based on positive results from the global phase 3 ADAPT trial, which were published in the July 2021 issue of The Lancet Neurology. While Dr. Howard stresses the need for individualized treatment for all myasthenia gravis patients, he is optimistic about the future of FcRn inhibitors in the treatment of myasthenia gravis.
Martin Luther King Jr. - Letter From Birmingham Jail - Episode 1 - Dr. King Reaches Out Of His Jail Cell To Touch The Heart Of A Nation! I'm Christy Shriver and we're here to discuss books that have changed the world and have changed us. I'm Garry Shriver and this is the How to Love Lit Podcast. Today we are going to start a three part series on a man who changed the landscape of political protesting- demonstrating that positive change can occur without massive loss of life. He won the Nobel Peace Prize when he was 35 years old, at the time he was the youngest to ever receive the award. His life became synonymous with civil disobedience- taking it farther than Thoreau ever dreamed possible. He radically and controversially claimed the role of a Christian political resister was not only the role to resist injustice. This was not enough, to be successful one must accompany resistance with love- loving the persecutor- a claim that would be put to the test over and over and for which he would be martyred. On Jan 20, 1986, the US Federal Government proclaimed a national holiday commemorating his life and message. Today over 955 (that number is likely small), but there are at least 955 major street, boulevards and thoroughfares that carry his name not only across the United States but across the world. If you haven't figured it out yet, we are talking about the life, literature and legacy of Dr. Martin Luther King, Jr. Specifically, the iconic letter that moved a nation from apathy to change, the “Letter from Birmingham Jail.” It was written on April 16, 1963 and famously addressed to “My Dear Fellow Clergyman.” Indeed, and yet, so many students or really people, who hear that name know so little about the movement itself. Growing up first in our nation's capital, Washington DC and then Brazil, I'd heard of Dr. King. I knew he stood for non-violence, but I ignorantly thought he literally just walked around preaching and protesting, carrying signs, singing and marching. I had NO idea how calculated the entire Civil Rights moment was. I had no idea the amount of strategy and genius that went into the planning and execution of one of the most effective non-violent movements in the world- or even how many years it was in the making. I just thought, Dr. King got up one day and just started protesting. Well, I think most people don't, even people of good faith who try to mimic some of his basic strategies. It's really difficult to wrap our minds around the complexity involved, not to mention the sheer power of King's personal rhetorical charisma that carried the movement from a few thousand African-American Christian protesters in Montgomery, Alabama to 250,000 people of all ethnicities and faith and the steps of the Lincoln Memorial. The changes in legislation and the implementation of laws that had been allowed to be ignored for a century were a direct result of this movement we are discussing over the next few episodes. So, let's get started beginning with some terminology that we hear when it comes to Civil Rights, words that many of us who aren't originally from the South may not be familiar with- for example what are Jim Crow laws. Who was Jim Crow and what are his laws? Sure. Jim Crow was not a real person. He was a character created by a famous white comedian in the 1850s. This white comedian painted his face black with charcoal and called himself Jim Crow and did comedy- it's what today we call black face and, of course, is derogatory and highly offensive. That term later was adopted to refer to the laws that went into effect starting in the 1880s-these laws, of course, are also derogatory and highly offensive- so the term remains appropriate. They refer to legislation that specifically targeted African-Americans to keep them from upward social mobility and fully participating in American life with the rest of the mostly white population. Let me remind you that all of this occurred AFTER the end of the Civil War and after the Union troops left the South where they had been forcing Southern cities to integrate against their will under the direction of President Ulysses Grant- this period has been called Reconstruction. After 1877 Reconstruction ended partly because the North was exhausted from trying to enforce the rights guaranteed by the 14th and 15th amendments. The north abandoned the South and the south will remain a third world part of the country for decades to come. Jim Crow laws stayed in effect literally all the way until success of the Civil Rights Movement in the 1960s. Let me give you an example, in 1891, 25 years after the Civil War,Georgia became the first Southern state to pass a Jim Crow law. The Georgia legislature passed a law that railroads had to provide equal but separate accommodations for black and white passengers. In other words, the African Americans would not be allowed to sit with the white Americans. After this first attempt at dividing the races was allowed- there soon were others- there began to be black and white bathrooms, black and white water fountains, hospitals, schools, swimming pools, prisons, barber shops, parks, movie theaters, sports arenas, telephone booths, lunch counters, libraries even graveyards. In his letter Dr. King refers to these signs as “nagging”- that of course is an understatement. They were degrading and psychologically damaging. Racism in the United States during the Jim Crow period was worse than in any other period of history, including today. There was a famous case, Plessy versus Ferguson in 1896- five years after that first sign in Georgia- that created a legal precedent saying that these laws were okay- The courts said that if the facilities were equal then it was not illegal for people to be separated by race. This was a blow to African-Americans as well as the railroad industry actually, which didn't want to segregate their railcars. It was an enormous financial burden- beyond being offensive and unnecessary- they now had to provide two of everything. But Jim Crow laws went on for years, and of course the facilities were never equal, but even if they had been, the message was still derogatory, and the entire system obviously unjust which caused many advocates of social equality both African-American as well as white to continue to mobilize and advocate for change. During WW2, President Harry Truman desegregated the US military in 1947, which was a huge advance in Civil Rights. Jackie Robinson broke the color barrier in professional sports in 1947, but it wasn't until 1954 that there would be another landmark ruling of the Supreme Court that would address this issue. In 1954, in a case known as Brown versus Topeka Board of Education, lawyers Richard Ellis and Michael Birzer successfully argued that things were separate but not equal, and in fact, the facilities for black children in schools were always inferior. In a unanimous decision, the court agreed saying that separate learning facilities were by their very definition unequal and this had a detrimental effect on minority children because it is interpreted as a sign of inferiority. This was a big deal. The legal precedent had been set. This was the finally justice in the courts, but now, how does that play out in classrooms across the country. Who is going to force almost half the schools in the United States to integrate students of both races? And when would they be required to make this happen? In every state in the South, Segregation was actually the law- a school couldn't have been integrated even if they had wanted to. Central High School in Little Rock Arkansas was the first southern school to even attempt integration in 1957. So, The short answer is -not immediately. Well, and as Dr. King pointed out in his letter, entire African nations were being decolonized faster than American students were being allowed to integrate in local schools. And it is here that Dr. Martin Luther King Jr. rise to national recognition emerges. At the young age of 26, he is newly married and has recently moved to accept a job as the pastor of the Dexter Street Baptist Church in the southern town of Montgomery, Alabama. It would be here that he would meet another seemingly inconspicuous woman but powerful woman by the name of Rosa Parks. Together, they were about to change their world. So as we set this up, let's introduce Dr. King's life before entering the political scene in 1956- and let's try to keep the dates straight- that's kind of hard for those of us for whom numbers don't come naturally. So, Dr. King was born in 1929 in an upper-middle class African-American family in Atlanta, Georgia. One interesting detail was that his birth name was Michael. That's right, his father later changed his name to Martin Luther, perhaps because of a trip he made to Germany to study the great theologian who also changed the political landscape of his day during the ProtestantReformation, but that is still slightly speculative. His father was a very popular Baptist pastor, the pastor of the successful and well-established Ebenezer Baptist Church. King was privileged to have received a high level of education- likely one of the most educated Southern African-Americans at this time period. He attended the very elite Morehouse College there in Atl, and then Crozer Theological Seminary in Chester, Pennsylvania and finally Boston University. So, you can see, he had the opportunity to ignore the plight of the majority of African-Americans. He had job offers at various universities in prestigious locations. Another important point to notice is that while in Boston he met a rising star vocalist by the name of Coretta Scott, and he fell in love with her. They got married in 1955. It wasn't long after that, he took the pastorate in the much smaller town of Montgomery, Alabama and moved their with Coretta and their baby, _______. Dexter Avenue Baptist Church, btw, is located just a stone's throw from the state capitol building in Montgomery- the heart of state government. Then, on December 1, 1955, something happened that changed Dr. King's life forever as well as the entire world. A woman by the name of Rosa Parks was arrested for not giving up her seat to a white gentleman on a bus. She had entered the bus through the front door instead of the back door, as required by those Jim Crow laws. This hadn't been an accident, the practice of forcing women to give up their seats had been going on for years, and several women protested to no avail, but for the highly and morally reputable Rosa Parks, it would be different. The national spot light was heading her way- but it wasn't accidental. This was a highly intentional and strategic play. Let me go back and say, Dr. King had personal experience with being forced to stand against his will on a bus. When he was in high school, he won a speaking contest in a town 90 miles outside of Atlanta. He and the teacher who went with him to the contest were riding on a bus back to Atlanta, super excited when white passenger got on. The white bus driver ordered King and his teacher to give up their seats, and cursed them. King wanted to stay seated, but his teacher urged him to obey the law. They had to stand in the aisle for the 90 miles back home. King stated later that that was the angriest he had ever felt in his life. If you can imagine. So, of course he could understand emotionally as well as cognitively what was happening every day in buses in Montgomery, Alabama as well as across the South. But what do you do? That's the question. Later on in Dr. King's life, someone asked him that very question- how do you manage your anger. I want to quote King here, "A destructive passion is harnessed by directing that same passion into constructive channels." And that's what he did in this case. Yes- next very next day, after Park's arrest, on December 2 ministers, including a man by the name of Rev. Ralph Abernathy who would be the one to go to jail with Dr. King, met at King's church to organize and publicize a bus boycott. Relying in part on Dr. King's eloquence, they mobilized the African-American community almost in full. On December 5, 90 percent of Montgomery's African-American citizens stayed off the buses. Dr. King was also elected as the president of the Montgomery Improvement Association or the MIA- the organization spearheading the boycott. According to Rosa Parks, the reason they chose King to be the president of the MIA was because he was so new to Montgomery, no one knew him. He had no friends but also no enemies. The evening that Dr. King spoke at Holt Street Baptist Church, this is what he said. “I want it to be known that we're going to work with grim and bold determination to gain justice on the buses in this city. And we are not wrong.… If we are wrong, the Supreme Court of this nation is wrong. If we are wrong, the Constitution of the United States is wrong. If we are wrong, God Almighty is wrong”. And what is striking is that when you see what they were demanding, these demands are not crazy, they are not even unrealistic or difficult to implement. They wanted courteous treatment by bus operators, first come first serve seating on public buses, and they wanted African-American bus drivers to be hired to work the routes that were in areas where mostly African-Americans were living. The demands were not met, and the boycott went on for 13 months- now think about that, even in the South, that is a lot of walking in a lot of bad weather for a long time. And this came at a huge personal cost to the thousands of African-Americans who were working or studying all over Birmingham but living across town in the segregated section for African Americans. Large complex carpool systems were created of over 300 cars to support the boycotters. People with cars offered rides to the walkers. The city government resisting, going so far as to punish African-American taxi drivers for offering rides at reduced rates. 80 leaders of the boycott were jailed under an old law from the twenties for “conspiracy that interfered with lawful business.” King himself was tried, convicted and ordered to pay $500 or serve 386 days in jail. King's house was bombed while he was at church. On the day of the bombing, King rushed home to see that Coretta and his baby were okay. This would not be the last big test on his ability to remain non-violent, but it was an important moment in his public career. Many people were outraged that someone had cowardly tried to murder the family of their leader, and they showed up on his porch with weapons ready to defend King and go after the assailant. King, although still personally affected, famously and calmly stood on his front porch and told everyone to go home. The mandate of Jesus was to love their enemies. So, when he talks about loving your enemies in his letter, he's. not just saying these things. He lived this idea and practiced it risking his own life, the life of his wife and the lives of his children. He believed so deeply in the life of Jesus Christ in the power of redemptive love through Jesus Christ that he put his life on the line. A point I want to make because it is something that I have thought about and he speaks to is what to do with the anger. How do you avoid the inevitable hate that has to emerge in your heart? I don't care who you are or what your religious faith is- the hate and rage and anger are justifiable and unavoidable. Of course, I'm not the first person to have this question and Dr. King spoke about that many many times later on during his life. I'm not sure he had a working theory at the age of 26. But by the time he was writing books, he did have an articulate vision on how this could work. For Dr. King, anger was a part of a process. It IS part of the process. He said you have anger then forgiveness then redemption then love. That was the order. It is what he believed and that is what he practiced to the best of his ability- although, and he speaks to this honestly in his biographical work, he struggled with anger his whole life. Well, the Montgomery Boycott as well as King's trial got national new coverage. A man by the name of Glenn Smiley visited Montgomery and offered King advice and training on Gandhian techniques of nonviolence. These two men discussed how to apply Ghandian techniques to American race relations. King later said, ““Christ showed us the way, and Gandhi in India showed it could work”. King and his team would combine Ghandhi's methods with Christian ethics to create a model for challenging segregation all over the South. So, follow the chronology- On June 5th, 1956, remember, Parks was arrested on Dec 1st, but by the beginning of June, the federal district court ruled that bus segregation was unconstitutional. That's HUGE but not the last word- in the United States, people have a right to go up the chain to the next court to see if a different court will overrule the first one. Since this was a possibility, The boycott could not nor did not end until December 20, 1956 when the case made its all through the appeal process all the way to the final court- the Supreme Court- when the decision was NOT overturn- then the boycott ended. The boycott lasted for a total of 381 days, if you can imagine. And here's a fun side- note- The day after it ended- Ralph Abernathy, Ed Nixon and Glenn Smiley- now let me add that Glenn Smiley is white- but these three men got on an integrated bus together- for the very first time- how satisfying would that have been. King famously had this to say about the boycott: “We came to see that, in the long run, it is more honorable to walk in dignity than ride in humiliation. So … we decided to substitute tired feet for tired souls, and walk the streets of Montgomery”. You can already see that metaphorical language that he's so famous for in both his speaking and writing. True and speaking of writing, he wrote up his experiences from Montgomery in a book called Stride to Freedom and in 1958, set out on a book tour across the United States. He wasn't as famous obviously as he would eventually become, but he was a well-known figure. On September 20, 1958, a 42 year old apparently deranged African-American woman plunged a letter-opener into his chest. So, Dr. King's methods were not always well-received by either side. No- Non-violence is controversial because it's obviously unfair. Why do I have to practice non-violence when the opposing side is not? It's a fair question and one which King spent his lifetime discussing. Non-violence is paradoxical – it doesn't seem like it would work. Its power lies in its ability to contrast so sharply with violence that you strip away any pretense that the violence is justified. It's also very slow. You have to have a tremendous amount of patience, trust, and stubbornness. And King was moving forward- but he was absolutely fed up with the pace of the federal court system. Remember, the courts mandated that schools be integrated in 1954, but still, here they were in 1963, nine years after Brown vs. Board of Education, and only 9% of African-American students were attending integrated schools. 1963 was going to be the year. 1963 was the 100 year anniversary of the Emancipation Proclamation- the day Lincoln pronounced that slaves were no longer slaves- for Dr. King, Rosa Parks, Fred Abernathy and the thousands of others willing to put their lives on the line- 100 years was enough time- and the chosen place for this confrontation of forces and will would be Birmingham, Alabama. Garry, why Birmingham? This was not a coincidence. This movement was not spontaneous; it did not just blow up. It was planned and as Julius Caesar would tell you - selecting the location for the confrontation is key to success. is Well, Dr. King tells us in his writings. The whole thing was highly orchestrated. Birmingham was the largest industrial city of the South. It had been a symbol of bloodshed in the past when African-American trade unions tried to form there. Because it was an industrial city, the financial interests and the political interests were intertwined. Birmingham was one of the most segregated cities in the United States- the entire city was an expression of Jim Crow- from hospitals to schools to parks to jobs to everything. Brutality towards African-Americans was an undisputed reality headed up by a man who prided on keeping African Americans, to use his words, “in their place.” His name was Eugene, but this man, the Commissioner of Public Safety went by the nick Name, Bull- Mr. Bull Connor. Under his reign or leadership depending on how you view his leadership, between 1957-1963 there had been 17 unsolved bombings of African-American churches and homes of Civil Rights leaders. Bull Connor was so radical that one time a white United States Senator visited Birmingham to give a give a speech and was arrested because he walked through the door marked, “Colored.” This guy was ruthless, and he ruled both African-Americans and whites alike with fear. He was accompanied and supported by a segregationist governor- Governor George Wallace who is famous for saying at his inauguration, “Segregation now; segregation tomorrow; segregation forever!” Goodness, history likely does not shine favorably on these remarks. No, nor on any of these defenders of segregation, of which Bull Connor was one of the most publicly vicious, but I will say, Bull Connor played a very important role in disrupting segregation because he played the part of the villain so well and so predictably. He was the perfect foil. After it was all over, JFK famously told MLK at the White House following the signing of the Birmingham agreement, “Our judgement of Bull Connor should not be too harsh, after all, in his way, he has done a good deal for civil-rights legislation this year.” Connor was the absolute perfect foil for nonviolent protest. Meaning, he was so terrible, it became morally obvious to any fool who was right and who was wrong. Exactly, and after it was all said and done, President Kennedy could say that, but in April of 1963, that was not so obvious. Bull was on a rampage; he was in control; and he was winning. On the third of April in 1963, segregationist Albert Boutwell became the new mayor of Birmingham. Mr. Boutwell was a likeable person; he was not like Bull Connor so some people thought he was the better choice. They were even glad he had won, but in the words of Fred Shuttlesworth, he was nothing but a “dignified Bull Connor.” Now, you're starting to throw out some names that will show up in the letter. Yes, Reverend Fred Shuttlesworth was one of the local leaders of the Civil Rights Movement in Alabama. Remember, he had been involved in Montgomery. He had organized an organization called the Alabama Christian Movement for Human Rights, otherwise known as the ACHR. Now, this becomes important because as we're going to read in a minute, Dr. King is accused of being an outsider and meddling into somebody else's business and starting trouble. To which he is going to respond that he was invited to come, and Reverend Shuttlesworth is one of the local leaders who had invited him. All of this becomes very important in understanding the context of the letter. So, at this time, the ACHR was holding weekly meeting in churches all over Birmingham. At these meetings they were mobilizing African-Americans to boycott business that displayed jim crow signs, or refused to hire African American workers except as janitorial staff. As a result, many stores and businessess around town were losing as much as 40% of their business. Shuttlesworth, became a problem for the status quo, and as a result, he had been jailed, his home AND his church both had been bombed. In the now famous room 30 of the Gaston hotel, Abernathy and King among others launched what they called “Project C”. The goal was to pressure Birmingham businesses to integrate and remove those horrible Jim Crow signs that said “White Only” or “Colored”. The intense boycotts and demonstrations were to start on the first week of March and would continue all until April 14, which was Easter and the Easter season is a big season for shopping, especially for clothes. What is interesting to me, and something I think is lost on a lot of students, is that they didn't just go around and drum up angry people to hold up signs and such, they required them to participate in workshops and daily evening meetings. Everything that happened in these weekly and later nightly meetings was intentional. Everything had a purpose. They would start the mass meetings by singing old negro spirituals they called freedom songs. These songs were adaptations from the same negro spirituals slaves had sung 100 years previously. These songs were old and inspirational, they had been transformed from songs of sorrow song by one's great-grandparents to becoming battle hymns. Singing together is psychologically bonding under any circumstances, but the power of the history of the music as well as the spirituality of the songs is difficult to explain in words. Every single volunteer was required to sign a commitment card where they would pledge their body and soul to nonviolence in the face of violence. This was explained in full. They developed ten commandments. The first commandment was to daily meditate on the teachings of Jesus Christ. The 8th was to refrain from violence of fist, tongue or heart. Yes, the idea was the prepare every person psychologically to expect and withstand abuse. When they started to march, when they entered a restaurant labled whites only in a to sit-in, when they were arrested, they needed to be prepared to do what they had been trained to do- resist peacefully. It is counter-intuitive to human nature. On April 6th, they marched orderly two by two without banners or singing. Bull Connor, right on cue, emerged and arrested 42 marchers for “parading without a permit”. And this became the pattern. After ten days, between 400-500 people were sitting in jail. Dr. King and Ralph Abernathy decided that on Good Friday, they would lead the demonstration and submit to being arrested, as they most assuredly would be. They left their church and walked with around 50 others – they had been denied a permit to march, so they were guilty of parading without a permit. Of course, that day when Dr. King and Rev. Abernathy began walking down the street in Birmingham, Alabama, many bystanders lined the streets. The marchers began to sing. The bystanders joined in the singing and sometimes burst into applause. As if on cue, Bull Connor emerged, his officers grabbed Dr. King and Rev. Abernathy by the back of their shirts and hauled them off to jail. Dr. King was held in solitary confinement for over 24 hours. Not even a lawyer was allowed to visit with him. He was not allowed to telephone his wife. Several violations of civil liberties all at once. Coretta, by Monday, stressed out of her mind, placed a call to President Kennendy. It wasn't but a few minutes from her trying to contact the president that his brother Robert Kennedy, who was at that time the Attorney General of the United States, called her back promising to intervene. The president called himself a few hours later. He called the officials in Birmingham, and amazingly the conditions of Dr. King's imprisonment changed significantly. He was in jail for eight days, and it was during that time, that a public letter was written to him and signed by 8 leading clergyman in Alabama. Again, these men have their names signed on the wrong side of history and this has to be embarrassing at this point. But, oh well, they wrote a public letter- and on the surface this letter sounds so reasonable. It is another example of someone saying something cruel in the nicest way possible. It is accusatory- in a polite way- and it enrages Dr. King. We started the podcast today talking about what do you do when you are enraged- really righteously enraged- this is what Dr. King did- he channeled this energy to become this laser-sharp rhetorical monster and it became uncontainable. Let's read the public letter written by these fellow clergymen, and then let's begin Dr. King's response that changed the world. What are some of the things we need to highlight- first of all- what are their main points King is an outsider= he's come from the outside to agitate They acknowledge that they understand why he might feel impatience, but they are encouraging him to let the system work and not incite unrest. They should trust the courts. They go so far as to commend the police- remember that is Bull Connor. Yes- and this is to a man who's family has been targeted to be murdered and arrested unfairly. Exactly, before we read his response- let's look at who signed it. Read the names and where they are from When Dr. King responds to these ministers- he makes it a point to cite a theologian from each of these specific religious traditions, and may I point out that he does it from memory since he is in a jail cell. Next week, we will analyze and discuss how he systematically demolishes the specious arguments and challenges on principles of Judeo-Christian faith the inconsistencies in the words and lives of “My Dear fellow clergyman”. Okay, we have a lot to look forward to. I hope you have enjoyed this discussion on the background of this important piece of American literature and history. As always, thank you flr listening, if you feel so inspired, please give us a five star rating on your podcast app. Connect with us on social media be it fb, insta, twitter or linked in. Also, if you are an educator, check out our instructional materails on our website. Howtolovelitpodcast.com Peace Out
On this episode, we are joined by Nolan Sarandou from Jackson Comfort Services, based out of Akron, OH. We discuss advice for managing a team, what leadership looks like and we touch upon recruitment! Nolan was nominated as 40 under 40 by ACHR the News
Joakim Achrén is a gaming entrepreneur, with fifteen years of experience from two venture-backed gaming startups, including Next Games, which IPOed in 2107. Joakim is now running Elite Game Developers, a company that helps entrepreneurs start their first game company. He's also an angel investor in Skunkworks Games, Lightheart Entertainment, Savage Game Studios, and more. Joakim recently took on the role of Venture Partner at Play Ventures and hosts his own podcast, Elite Game Developers Podcast. Join us in this fascinating discussion with topics like: - How Joakim caught “the bug” for helping other founders - What comes between the early validation phase and obtaining data from user behavior within a playable version of your game - The most common trap mobile developers fall into - The biggest takeaways you should be gaining from your metrics - The key to building mobile games that make players want to come back - The balance between “stealing like an artist” and innovating - What the gaming industry can learn from Pixar's creative process For more resources head to www.playmakerspodcast.com
In this episode, Joakim and I cover how Elite Game Developers started: how the platform grew up to 3,000+ subscribers in 2 years, what was the reasoning behind the content creation, and what is the ambition with the platform going forward. Joakim shares few pieces of wisdom about his life values and priorities, why he decided to not start another company to create Elite Game Developers instead, a great platform of content for founders to not repeat the common mistakes and pitfalls in the industry. We also touch on the topic of angel investing, and why it is important to continue to support the ecosystem of founders. Joakim Achrén is a gaming entrepreneur, with fifteen years of experience from two venture-backed gaming startups, including Next Games, which IPO-ed in 2107. Joakim is now running Elite Game Developers, a company that helps entrepreneurs start their first games company. He's also an angel investor in Skunkworks Games, Lightheart Entertainment, Savage Game Studios, and more. Joakim recently took on the role of Venture Partner at Play Ventures. More about Elite Game Developers: https://elitegamedevelopers.com/
In this episode of the Smart HVAC Marketing podcast, we are joined by Kyle Gargaro from ACHR News. Kyle is the editorial director for the HVAC publication. We discuss how to set-up your HVAC business for success, and focus on the different outlets of achieving brand awareness. The Air Conditioning, Heating and Refrigeration NEWS is the HVACR contractor's weekly newsmagazine and is the industry's most trusted and utilized direct communications link to the HVACR buyer. The NEWS assists the decision-makers in all branches of the HVACR industry. In addition to contractors, our readers include manufacturers, distributors, parts and supply wholesalers, and service companies and their various departments.
In this video we chat with Chris Hunter about strategies for success when it comes to getting the most out of your career in the heating and cooling business. Your learn about top tips for daily peak performance and more! We hope you enjoy this one! Chris Hunter is an Author, Business Coach, Founder of Hunter Super Techs, and the Go Time Success Group. When he’s not leading workshops and seminars or giving keynote speeches at conferences around the nation, he’s spending time with his family and attending church. Chris is a devoted husband, father, and grandpa, and incorporates his family values and love of Christ into his business practices. Chris’s ability to effectively run his business comes from his humble origins as a small business owner. He has seen firsthand the importance of investing in personal growth, in the growth of your team, and watching these seeds grow into healthy relationships with customers. Chris has based his personal/business philosophy on the teachings of the most important book in history, the Bible. In one of his favorite verses, Colossians 3:23, it says, “...whatever you do, work at it with all your heart as to The Lord and not to men.” This type of mentality is what ultimately led to Chris seeking out the best teachers to learn from, finding the most willing students to form into his teams, as well as always finding new and innovative means to better serve his customers. Chris Hunter’s Awards/Accolades Include: * Tom McCart Consultant of the Year Award Winner * Nationally Recognized Contractor of the Year * 2016 ACHR the NEWS, Best Contractor to Work For * Top 40 under 40 in the HVAC industry * Inc 5000 fastest-growing private companies * PHC magazine Top 20 Contractors * Ron Smith Industry Trailblazer Award Winner Learn more about Chris Hunter at https://www.gotimesuccessgroup.com Follow us on the gram @betweentwofurnaces email us betweentwofurnaces@gmail.com
In this episode of Trade Talk, Stacy Jackson and Alanna Jackson from Jackson Marketing talk with Jenna Ochoa from JB Warranties about being listed as one of ACHR News Top 40 Under 40 and what it's like to be a woman in the HVAC industry. Jenna shares: details about her role at JB Warranties what it's like being named to the ACHR News Top 40 Under 40 list her thoughts on the strides women are making in HVAC what it's like working with family the JB Warranties' company culture how JB Warranties has grown challenges facing the HVAC industry Want to put the power of extended warranties to work for your HVAC or plumbing business? Register for a JB Warranties Premium Protection Plan today!
Chris Hunter is the founder of Hunter Super Techs and Go Time Success Group. He is also the Director of Customer Relations with ServiceTitan. Over the last two decades, he has delivered quality service and leadership in his industry, earning him over 3500+ positive online reviews and a plethora of awards and recognition. These include the Tom McCart Consultant of the Year Award, Nationally Recognized Contractor of the Year in 2016 by ACHR, and the Ron Smith Industry Trailblazer Award. In this episode, we talked about HVAC, entrepreneurship, leadership, customer service, team building, strategic planning...
Chris Hunter is the founder of Hunter Super Techs and Go Time Success Group. He is also the Director of Customer Relations with ServiceTitan. Over the last two decades, he has delivered quality service and leadership in his industry, earning him over 3500+ positive online reviews and a plethora of awards and recognition. These include the Tom McCart Consultant of the Year Award, Nationally Recognized Contractor of the Year in 2016 by ACHR, and the Ron Smith Industry Trailblazer Award. In this episode, we talked about HVAC, entrepreneurship, leadership, customer service, team building, strategic planning...
A strong company culture is where you have trust Joakim is the 1st entrepreneur I met in Finland. After 15 years experience as a business owner, he now dedicates his time helping other entrepreneurs build successful ventures. In this Inter:views, we talk a lot about the importance of company culture as well as the art of listening.
Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 05/06
Muscle spindles are complex stretch-sensitive mechanoreceptors that consist of 4-12 specialized muscle fibers. These intrafusal muscle fibers are innervated in the central (equatorial) region by an afferent sensory axon and in both peripheral (polar) regions by efferent γ-motoneurons. Until now little is known about muscle spindle development at the molecular level, especially about the development of cholinergic specializations. My study shows that nicotinic acetylcholine receptors (AChR) are concentrated at the γ-motoneuron endplate as well as in the equatorial region. Moreover, enzymes required for the synthesis and removal of acetylcholine, including choline acetyltransferase (ChAT) and acetylcholinesterase (AChE), as well as vesicular acetylcholine transporter (VAChT) and the AChR-associated protein rapsyn are all concentrated at the polar γ-motoneuron endplate and (with the exception of AChE) also at the equatorial region. Finally, the presynaptic protein bassoon, involved in synaptic vesicle exocytosis, is also present at the γ-motoneuron endplate and at the annulospiral sensory nerve ending. During postnatal development, the AChR subunit composition at the γ-motoneuron endplate changes from the γ-subunit containing fetal AChR to the ε-subunit containing adult AChR. This is similar to the postnatal change at the neuromuscular junction. In the equatorial region the ε-subunit expression starts around postnatal week two; however the γ-subunit persists in the central region despite the onset of the ε-subunit expression. Therefore, the γ- and ε-subunits are simultaneously present in the equatorial region. This result was confirmed using a mouse line in which the AChR γ-subunit was genetically labelled by green fluorescence protein (GFP). In this mouse, the GFP-labelled AChR γ-subunits are concentrated at the contact site of the intrafusal fiber with the sensory nerve ending. This result indicates different AChR maturation occurs within two areas of the same intrafusal fiber. I also show that agrin and the agrin receptor complex (consisting of LRP4 and MuSK) are present in muscle spindles in the region of the sensory and motor innervation. Moreover, agrin, MuSK, and LRP4 are expressed by proprioceptive neurons in dorsal root ganglia but only agrin and LRP4 were detected in the cell body of γ-motoneurons in the spinal cord. In mice with a targeted deletion of agrin, AChR aggregates are absent from the polar region and γ-motoneuron endplates do not form. By contrast, AChR aggregates remain detectable in the central part of intrafusal fibers. Moreover, muscle-specific re-expression of mini-agrin is sufficient to restore the formation of synaptic specializations at γ-motoneuron endplates. These results show an unusual AChR maturation at the annulospiral endings and confirm that agrin is a major determinant for the formation of γ-motoneuron endplates. Agrin on the other hand appears dispensable for the aggregation of AChRs in the central region of intrafusal fibers.
Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 07/19
Die kongenitalen myasthenen Syndrome (CMS) bilden klinisch und pathogenetisch eine heterogene Gruppe von relativ seltenen hereditären Erkrankungen des Kindesalters. Sie werden durch unterschiedliche genetische Defekte im Bereich der neuromuskulären Endplatte verursacht und manifestieren sich mit variabler Symptomatik, bei der eine ermüdbare Muskelschwäche das herausragende Kennzeichen ist. Bisher sind zehn verschiedene Gene bekannt, deren Defekte CMS verursachen können. Dazu gehören die Gene, die für Acetylchoilinrezeptor (AChR)-Untereinheiten kodieren, das CHAT-Gen, welches für die Cholin-Acetyltransferase kodiert, das RAPSN-Gen, das SCN4A-Gen, das DOK7-Gen, sowie das COLQ-Gen und das MUSK-Gen. Der Hauptschwerpunkt dieser Arbeit lag auf der molekulargenetischen Untersuchung des COLQ-Gens und des MUSK-Gens. Im COLQ-Gen konnten wir bei 8 Patienten aus 7 unanhängigen Familien 7 verschiedene Mutationen identifizieren, 4 davon waren noch nicht beschrieben worden. Eine Missens-Mutation des COLQ-Gens (T441A) fand sich homozygot in drei unabhängigen deutschen CMS-Familien mit insgesamt vier betroffenen Personen. Dabei führt ein homozygoter Austausch (1321 A>G) im Exon 17 dazu, dass die Aminosäure Threonin, die an dieser Position innerhalb der C-terminalen Region des ColQ-Proteins über viele Speziesgrenzen konserviert ist, durch Alanin ersetzt wird. Da diese Region für die Trimerisierung von ColQ und für die Insertion der AChE/ColQ-Komplexe in der Basallamina essentiell ist, führt der Aminosäurenaustausch zu einem vollständigen Fehlen von der im synaptischen Spalt verankerten Esterase. Die Abwesenheit von AChE im synaptischen Spalt bei den Patienten mit ColQ-CMS führt dazu, dass die klinischen Symptome bei allen Erkrankten auf eine Therapie mit AChE-Hemmern nicht ansprechen oder sich sogar dramatisch verschlechtern können. Deswegen ist die genaue molekulargenetische Charakterisierung bei diesen Patienten für die richtige Therapie sehr wichtig. Das MUSK-Gen spielt eine wichtige Rolle für die Ausbildung der postsynaptischen Strukturen. Die Phosphorylierung von MuSK ist essentiell für die Aggregation der AChR an der posysynaptischen Membran. Aus diesen Gründen kam MUSK als potentielles CMS-Kandidatengen in Betracht. Wir untersuchten 10 Patienten, bei denen die übrigen bekannten CMS-Gene zuvor ausgeschlossen worden waren und konnten bei 5 von ihnen insgesamt 6 Sequenzveränderungen feststellen. Diese erwiesen sich jedoch als Polymorphismen. Eine pathogene Mutation ließ sich nicht nachweisen. Erst im Jahr 2004 wurden von einer französischen Arbeitsgruppe die ersten zwei compound heterozygoten und bis jetzt einzigen MUSK-Mutationen beschrieben. Es scheint, dass Mutationen im MUSK-Gen sehr selten ein CMS verursachen, was sich durch die essentielle Rolle der Tyrosinkinase erklären lässt. Da CMS durch unterschiedliche strukturelle oder funktionelle Veränderungen an der neuromuskulären Endplatte bedingt sind, ist eine präzise klinische und genetische Charakterisierung des CMS wichtig für alle Patienten. Genetische Beratung und pränatale Diagnostik können nur durchgeführt werden, wenn eine exakte Diagnostik auf molekularer Ebene verfügbar ist. Außerdem hat die exakte molekulargenetische Charakterisierung kongenitaler myasthener Syndrome für die betroffenen Patienten große Bedeutung, da sich daraus unterschiedliche Konsequenzen hinsichtlich Prognose, Vererbbarkeit und Behandlungsmöglichkeiten ergeben. Zusätzlich bietet die molekulargenetische Analyse die Möglichkeit, das Verständnis der pathophysiologischen Zusammenhänge der neuromuskulären Übertragung zu erweitern.
Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 05/19
Die kongenitalen myasthenen Syndrome (CMS) bilden pathogenetisch und klinisch eine heterogene Gruppe von relativ seltenen hereditären Erkrankungen des Kindesalters, denen eine gestörte Erregungsübertragung im Bereich der neuromuskulären Endplatte zu Grunde liegt. Daher stellen diese Erkrankungen ein hervorragendes Modell zur Untersuchung synaptischer Prozesse dar. Ziel dieser Arbeit war die Identifizierung und Charakterisierung von genetischen Veränderungen, die zu einer gestörten Erregungsübertragung an der menschlichen neuromuskulären Endplatte und damit zu CMS führen. Die Analyse ursächlicher Mutationen und deren pathophysiologischer Bedeutung soll die Grundlage für eine sichere Einordnung von CMS bilden. Aus der Korrelation von Geno- und Phänotypen von CMS-Patienten sollen Daten gewonnen werden, die für den einzelnen CMS-Patienten hinsichtlich Diagnostik, Beratung und Therapie hilfreich sind. Es konnten über 250 nicht verwandte CMS-Patienten aus Deutschland und anderen europäischen Ländern molekulargenetisch analysiert werden. Dies führte zur Identifizierung und funktionellen Charakterisierung zahlreicher ursächlicher Mutationen in sechs verschiedenen CMS-Genen (Gene kodierend für Acetylcholinrezeptor (AChR)-Untereinheiten: CHRNE, CHRND, CHRNA1, sowie COLQ, CHAT und RAPSN). Ausgewählte Mutationen wurden in funktionellen Studien auf ihren pathogenetischen Effekt an der Endplatte hin untersucht. Auf diese Weise konnte bereits bei über 50% der Patienten des CMS-Kollektivs die molekulare Grundlage des CMS identifiziert werden. Übereinstimmend mit den Ergebnissen anderer Arbeitsgruppen wurden die meisten Mutationen (19 verschiedene Mutationen in 40 unabhängigen Familien) im CHRNE-Gen kodierend für die epsilon-Untereinheit des adulten AChR identifiziert, die zu einem postsynaptischen CMS führen. Im Bereich der übrigen AChR-Untereinheiten ist eine Missense-Mutation im CHRND-Gen kodierend für die delta-Untereinheit hervorzuheben. Für diese konnte ein für AChR-Mutationen neuartiger Pathomechanismus gezeigt werden: die Mutation reduziert die Fähigkeit der AChR, mit dem postsynaptischen Protein Rapsyn zu clustern. Als zweithäufigste Ursache eines CMS im Kollektiv stellten sich Mutationen des RAPSN-Gens heraus (10 verschiedene Mutationen in 22 unabhängigen Familien). Bei Patienten deutschen Ursprungs erwiesen sich diese sogar als häufigste ursächliche Mutationen. Neben verschiedenen anderen Mutationen trugen die meisten der Patienten dabei auf mindestens einem Allel die Mutation N88K. Die besondere Häufigkeit von N88K konnte auf einen Founder in der indoeuropäischen Bevölkerung zurückgeführt werden. Klinisch auffällig waren bei RAPSN- Patienten – ähnlich wie bei Patienten mit CHAT-Mutationen - im Rahmen von Infekten plötzlich auftretende, lebensbedrohliche Störungen der Atmung. Durch einen Schnelltest auf die Mutation N88K bei neuen Patienten können insgesamt etwa 10% aller CMS-Fälle genetisch diagnostiziert werden. Damit können weitere aufwendige und für die Patienten belastende Untersuchungen vermieden werden. Darüber hinaus gelang es, bei einer Reihe von Patienten des CMS-Kollektivs Mutationen im COLQ- sowie im CHAT-Gen nachzuweisen und zu charakterisieren: Mutationen im synaptisch exprimierten COLQ-Gen konnten bislang in insgesamt 11 CMS-Familien nachgewiesen werden. Die meisten genetischen Veränderungen waren als „private“ Mutationen jeweils nur in einzelnen Patienten bzw. Familien nachweisbar. Eine Missense-Mutation des COLQ-Gens (T441A) fand sich dagegen interessanterweise homozygot in drei unabhängigen deutschen CMS-Familien mit insgesamt vier betroffenen Personen. Krankheitsalter bei Erstmanifestation, Fortschreiten und Schweregrad der Erkrankung zeigten trotz der identischen Mutation eine bemerkenswerte Variabilität zwischen den einzelnen Patienten. Eine biochemische Charakterisierung der Mutation T441A mittels Dichtegradienten-Zentrifugation der aus Patientenmuskel extrahierten AChE zeigte ein Fehlen der ColQ-assoziierten, im synaptischen Spalt verankerten Esterase-Form. Im CHAT-Gen wurden bei sechs Index-Patienten des Kollektivs sieben unterschiedliche Mutationen identifiziert. Bei allen Patienten traten – ähnlich wie bei Patienten mit RAPSN-Mutationen - wiederholt plötzliche Apnoen auf. Im Schweregrad der myasthenen Symptomatik zeigten auch CHAT-Patienten deutliche Unterschiede, sogar bei Vorliegen einer identischen genetischen Ursache. Die klinische Beobachtung von zwei kroatischen Patienten mit identischen Mutationen des CHAT-Gens betont die Bedeutung plötzlicher Apnoen als Risikofaktor für die Entwicklung sekundärer hypoxischer Hirnschäden und einer psychomotorischen Retardierung. Die Größe des Patientenkollektivs ermöglichte es erstmals, Daten zu Vorkommen und Häufigkeit einzelner CMS-Mutationen in unterschiedlichen Bevölkerungsgruppen zu gewinnen. Darüber hinaus erbrachte die Analyse von Phänotyp und Genotyp wichtige Informationen zu klinischen Besonderheiten, Therapiemöglichkeiten und Prognose. Neben der Analyse bekannter CMS-Gene bilden die in dieser Arbeit charakterisierten Patienten und Familien die Grundlage, weitere CMS-Gene zu identifizieren.
Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 02/19
Die kongenitalen myasthenen Syndrome (CMS) bilden klinisch und pathogenetisch eine heterogene Gruppe von relativ seltenen hereditären Erkrankungen des Kindesalters. Sie werden durch unterschiedliche genetische Defekte im Bereich der neuromuskulären Endplatte verursacht und manifestieren sich mit variabler Symptomatik, bei der eine ermüdbare Muskelschwäche das herausragende Kennzeichen ist. Die exakte Klassifizierung eines CMS ist dabei neben dem wissenschaftlichem Interesse auch von klinischer Relevanz, da sich aus ihr für die betroffenen Patienten und ihre Familien unterschiedliche Konsequenzen hinsichtlich Prognose, Vererbbarkeit und pharmakologischer Therapie ergeben. In der vorliegenden Arbeit konnten post- und präsynaptische CMS verursachende genetische Defekte identifiziert werden. Dabei betreffen die meisten der nachgewiesenen Mutationen, analog zu anderen Untersuchungen, die epsilon-Untereinheit des nikotinergen Acetylcholinrezeptors (AChRepsilon). Einige Ergebnisse sind hierbei von besonderem wissenschaftlichem Interesse: Bei einer 1200bp großen Mikrodeletion auf dem ACHRepsilon-Gen handelte sich um die erste chromosomale Deletion, die bei CMS nachgewiesen werden konnte. Eine zusätzliche Mutation in der Promotorregion des ACHRepsilon-Gens (epsilon-154G/A) führt bei dem Patienten zur Manifestation des Krankheitsbilds. Bei einer Mutation an der Spleißakzeptorstelle von Intron 7 im ACHRepsilon-Gen (epsilonIVS7-2A/G), die bei insgesamt fünf Patienten aus drei unabhängigen Familien auftritt, konnte der fehlerhafte Spleißvorgang durch Analyse des resultierenden Transkripts aufgezeigt werden: Exon 7 wird, unter Verlust von Exon 8, direkt an Exon 9 gespleißt, aufgrund einer Leserahmenverschiebung entsteht ein vorzeitiges Stopcodon. Während die meisten Mutationen im ACHRepsilon-Gen nur bei einigen wenigen Patienten nachgewiesen werden, stellt die Mutation epsilon1267delG in der Volksgruppe der Roma die häufigste Ursache für CMS dar. Die relativ große Anzahl von Patienten mit dieser Mutation, die untersucht werden konnte, ermöglichte eine detaillierte Genotyp-Phänotyp-Korrelation. Zukünftig wird eine direkte Testung auf die Mutation epsilon1267delG die Diagnosestellung bei Patienten dieser Volksgruppe deutlich vereinfachen und beschleunigen. Darüber hinaus sollte diskutiert werden, ob aufgrund der hohen Carrier-Frequenz für diese Mutation ein Neugeborenen-Screening für die betroffenen Bevölkerungsgruppen angeboten werden sollte. Bei frühzeitiger Diagnosestellung können rechtzeitig Therapie- und Präventionsmaßnahmen eingeleitet werden, und bei entsprechender Medikation mit Acetylcholinesterase-Hemmern mögliche Komplikationen, wie Apnoe und plötzlicher Kindstod vermieden werden. Die Haplotypenanalyse von dieser Patienten mit der Mutation epsilon1267delG eröffnet neue Erkenntnisse über Ursprung und Verbreitung des mutierten Alleles in der Romabevölkerung. Es wurde ein Kernhaplotyp identifiziert, der auch bei Patienten aus Indien und Pakistan nachgewiesen werden konnte. Das gemeinsame Auftreten eines solchen Founder-Allels untermauert die, hauptsächlich auf sprachwissenschaftlichen Vergleichen beruhende These, daß die Vorfahren der Roma vom indischen Subkontinent stammen. Weitaus seltener als Mutationen im AChR treten Mutationen auf der präsynaptischen Seite der neuromuskulären Endplatte bei CMS auf. Im Gen für Cholin-Acetyltransferase (ChAT) konnte bei drei Patienten aus zwei unabhängigen Familien eine neue Mutation (CHAT I336T) homozygot nachgewiesen werden sind. Bei allen CHAT I336T Patienten wird, zusätzlich zu der myasthenen Symptomatik von einem, für Mutationen in diesem Gen typischen, gehäuften Auftreten von Apnoen, berichtet. Insgesamt bietet die molekulargenetische Analyse von CMS neben der Bedeutung, die sie für den einzelnen Patienten hat, die Möglichkeit das Verständnis der pathophysiologischen Zusammenhänge der neuromuskulären Übertragung zu erweitern.
Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 02/19
Die kongenitalen myasthenen Syndrome (CMS) bilden klinisch und pathogenetisch eine heterogene Gruppe von relativ seltenen hereditären Erkrankungen des Kindesalters. Sie werden durch unterschiedliche genetische Defekte im Bereich der neuromuskulären Endplatte verursacht und manifestieren sich mit variabler Symptomatik, bei der eine belastungs- und tageszeitabhängige Muskelschwäche das herausragende Kennzeichen ist. Man unterscheidet synaptische, prä- und postsynaptische CMS-Formen. Während der letzten Jahre hat sich gezeigt, dass die postsynaptischen Störungen bei weitem überwiegen, vor allem solche, bei denen die Mutationen in den Untereinheiten des Azetylcholinrezeptor (AChR) liegen. Dabei haben sich vor allem Mutationen im Gen, das für die Epsilon (e) -Untereinheit des AChR kodiert, als besonders häufig erwiesen. Der Hauptschwerpunkt dieser Arbeit lag deshalb auf der genauen Untersuchung des Gens kodierend für die e-Untereinheit bei unseren CMS-Patienten. Im Rahmen dieser Arbeit wurden 86 CMS-Patienten aus 71 nicht-verwandten Familien mit Hilfe eines Fragebogens rekrutiert und anschließend molekulargenetisch untersucht. Unter den 71 CMS-Familien waren 21 Familien, die aus Deutschland stammten, und 50 Familien nicht-deutscher Abstammung. Alle Patienten zeigten typische CMS-Symptome. Die zwölf Exons des Gens der e-Untereinheit des AChR einschließlich der Spleiß-Donor- und Spleiß-Akzeptor-Sequenzen sowie die Promotorregion wurden sequenziert. Bei 40 der 86 CMS-Patienten wurden unterschiedliche Frameshift-Mutationen entdeckt, die zu einer verminderten Expression des AChR führen. Die Frameshift-Mutation e1267delG wurde bei 33 Patienten aus 26 nicht-verwandten Familien entdeckt. Alle e1267delG-Patienten stammen aus der Volksgruppe der Roma oder kommen aus südosteuropäischen Ländern. Die Mutation e1267delG wurde bei 58% (26/45) der CMS-Familien, die nicht-deutscher Abstammung sind, gefunden im Vergleich zu 0% (0/26) der Familien mit deutscher Abstammung. Bei sechs CMS-Patienten zeigten sich Spleiß-Mutationen, deren Pathogenität aus Muskel-RNA bewiesen wurde. Bei zwei Patienten konnten Promotormutationen nachgewiesen werden, die ebenfalls zu einer beeinträchtigten AChR-Expression führen. Bei sechs Patienten fanden sich Missense-Mutationen, die nicht vorbeschrieben sind und deren pathophysiologische Konsequenzen noch geklärt werden müssen. Bei 36 CMS-Patienten aus unserer 86 CMS-Patienten umfassenden Population konnten keine Mutationen im Gen der e-Untereinheit des AChR gefunden werden. Mutationen anderer Gene könnten verantwortlich sein für CMS bei diesen Patienten. Die Mutations-suche in diesen Genen könnte, zumindest in geeigneten Familien mit mehreren betroffenen und nicht betroffenen Mitgliedern, mittels begrenzter Kopplungsanalyse durch Ausschluss oder nähere Eingrenzung einzelner Genloci vereinfacht werden. Wir finden bei Patienten mit Mutationen im e-Gen des AChR häufiger eine Ptose, eine Ophthalmoparese, ein als generalisiertes oder als bulbär und fazial beschriebenes Krankheitsbild, ein Dekrement, einen gutartigen Verlauf, sowie eine Krankheits-manifestion vor Vollendung des zweiten Lebensjahres. Krisenhafte Verschlechterungen findet man dagegen häufiger bei CMS-Patienten, die keine Mutationen im e-Gen haben. Mutationen im CHAT-Gen könnten dafür verantwortlich sein. Da CMS durch verschiedene strukturelle oder funktionelle Abnormalitäten an der Synapse bedingt sind, ist eine präzise elektrophysiologische und/oder genetische Klassifikation der CMS wichtig für Patienten. Genetische Beratung und pränatale Diagnostik können nur durchgeführt werden, wenn eine exakte Diagnostik auf molekularer Ebene verfügbar ist. Außerdem hat die exakte Klassifizierung kongenitaler myasthener Syndrome für die betroffenen Patienten große Bedeutung, da sich daraus unterschiedliche Konsequenzen hinsichtlich Prognose, Vererbbarkeit und Behandlungs-möglichkeiten ergeben. Die Analyse ursächlicher genetischer Defekte wird die Grundlage für eine sichere und verlässliche Einordnung von CMS bilden und möglicherweise die bisher erforderlichen invasiven Verfahren ablösen. Darüber hinaus sind durch die genaue Kenntnis des ursächlichen Defektes und der patho-physiologischen Zusammenhänge in Zukunft auch neue Therapiemöglichkeiten für CMS-Patienten zu erwarten.
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