Podcasts about tnfr

What does it really take to grow a profitable service business? In this episode of The New Flat Rate podcast, President Danielle Putnam breaks down what “money in the bank” actually means for contractors—and why growing your company the right way starts with a solid financial foundation. From simple savings strategies to smart marketing moves and service call tactics that actually work, Danielle shares the exact steps contractors can take today to build a stronger, more secure business.0:00 - Introduction
0:30 - Money in the bank1:05 - Growing from a position of strength 2:52 - Rules to grow your savings5:22 - Let's go back to the basics6:36 - The discipline to save9:07 - Story time with Rodney Koop10:23 - Start small11:51 - Generating extra money - service call options12:22 - So, where do you start15:52 - Your techs don't need to upsell17:19 - Securing the base - marketing18:25 - 3 simple marketing tips20:17 - Track your results20:43 - TNFR gift21:35 - Start small, think big22:31 - ClosingLinks and Recourses:To learn more about The New Flat Rate- thenewflatrate.comFun-bound kit- https://app.hubspot.com/payments/tYZ4sz9TgZ9bYkdJ?referrer=PAYMENT_LINKProfit First by Mike Michalowicz- https://a.co/d/gEFpilhFoundation Wealth- https://foundationwealth.com/

A new research perspective was published in Oncotarget's Volume 14 on June 19, 2023, entitled, “Targeting GITR in cancer immunotherapy – there is no perfect knowledge.” In this new perspective, researchers Diwakar Davar and Roberta Zappasodi from the University of Pittsburgh Medical Center (UPMC), University of Pittsburgh, Weill Cornell Medical College, and Weill Cornell Graduate School of Medical Sciences discuss the glucocorticoid-induced TNFR-related protein (GITR), belonging to the TNFR superfamily (TNFRSF) and stimulating both the acquired and innate immunity. GITR is broadly expressed on immune cells, particularly regulatory T cells (Tregs) and natural killer (NK) cells. “Given its potential to promote T effector function and impede Treg immune suppression, GITR is an attractive target for cancer immunotherapy.” Preclinically, GITR agonists have demonstrated potent anti-tumor efficacy singly and in combination with a variety of agents, including PD-1 blockade. Multiple GITR agonists have been advanced into the clinic, although the experience with these agents has been disappointing. Recent mechanistic insights into the roles of antibody structure, valency, and Fc functionality in mediating anti-tumor efficacy may explain some of the apparent inconsistency or discordance between preclinical data and observed clinical efficacy. Overall, the clinical results obtained so far with GITR agonist agents have demonstrated specific immune effects in the expected immune cell populations based on preclinical studies. However, these effects have not produced substantial therapeutic activity in human cancer patients. A maturing understanding of the immune responses to GITR agonism in human cancer has clarified novel issues specific to drug development in this space including Ab structure (monospecific and bispecific mAbs and co-stimulatory GITR ligands), Ab valency, and Fc functionality. “This improved understanding of the immune responses to GITR agonism in patients should be kept in consideration for the design of novel rational combinations or treatment regimens in earlier disease settings where immunotherapy is gradually becoming the treatment of choice.” DOI - https://doi.org/10.18632/oncotarget.28461 Correspondence to - Diwakar Davar - davard@upmc.edu Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28461 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, immunotherapy, programmed death-1 (PD-1), cytotoxic T-lymphocyte Antigen-4 (CTLA-4), glucocorticoid-induced TNFR-related protein (GITR) About Oncotarget Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

In this episode of The New Flat Rate podcast, Matt talks to Online Access Director of Sales and Marketing Colleen Keyworth about why having a positive Google profile is crucial to your company. Questions? info@menupricing.com | 706.259.8892 Show Notes: [02:21] How is it that Online Access is able to specialize in home service industries? [06:08] What is the relevance of these members to have a positive Google business profile? [12:33] Why is it important to respond to every Google review? [16:45] What can company's do proactively to start helping their company build a bridge over the valley's they run through? [28:27] Is there a golden number that they know they could start with? [39:24] How can company's like Online Access help you find techs? [29:16] What should you be focusing on and be aware of in the world of pay per click right now? Links and Resources: WWW.TNFR.us WWW.HVACWebsites.com

In this week's episode, our hosts get to chat with a leader who knows leadership well. Danielle Putnam, recognized by The News as The Top 40 Under 40, and Service World Expo as the 2021 Woman of the Year, is President of The New Flat Rate, Advisory Board Member and Past President of Women in HVACR, and is the Executive Director of her non-profit, Family Frameworks.Danielle has a personal connection with the home service industry. Her first job was passing out flyers door-to-door for her father's electrical business. She was 7 years old. In high school, she moved up to being an office dispatcher and parts runner. After college, she became the marketing director for an HVAC company in Oregon.Danielle knows home service, but she is also no stranger to big business. Before co-founding TNFR, she was the director of business development for a large digital services firm, pitching to C-level executives for big-name companies. As part of her job, she also stood before multi-million-dollar investors, seeking capital for the publicly-owned company that she worked for.Danielle is dedicated to helping grow the industry she grew up in and loves. As a public speaker, she promotes careers in the home service industry. When not in the office, she spends time with her husband and three children and enjoys hiking, snowboarding, reading, and fine wines.It was a pleasure to chat with Danielle and hear all about her take and advice for leadership. In this episode Danielle hits on:-Leadership is about making others better due to your presence and making sure that impact lasts in your absence.-Most successful founders and business leaders have likened the start-up phase to waging war against an industry on behalf of underserved customers. -To lead yourself, use your head - to lead others, use your heart - this is where boundaries need to step into the picture. **FREE Download**Email Danielle at: Danielle@menupricing.comMention this episode in the Subject, and receive your FREE Process Writing Kit!If you enjoyed this chat From the Yellow Chair, please rate, review, and subscribe from wherever you're listening. We'd love to hear from you; what are you liking, what are you loving? What do you want more of!Interested in being a guest on our show? Click >>HERE

We have all been there...we struggle with not having enough good talent on our team, and it is easy to blame the reduction of skilled labor in the workforce for this struggle. But in reality, it is our own fault that we do not have every person on our team that we dream of having. We, as business owners and managers, are quick to make excuses as to why we can't find any amazing team members.  Well, on today's episode, we sit down with Danielle Putnam & Rosalyn Guerra of The New Flat Rate, and they set us straight on this myth surrounding the hiring issues that we feel like we are facing each day! One day, Danielle is sharing with her team about complaints that she is dealing with from her clients pertaining to hiring issues. She shares the way that she has found success hiring some of the brightest minds within our industry, people such as Rosalyn!! And it doesn't take Rosalyn very long before she is building a working model of the "Hiring Cycle!"  On this episode of the Service Business Mastery podcast, these two fabulous women in HVACr explain this "Hiring Cycle," and how we can use it within our business to continuously hire amazing talent both inside and outside of our home service industry!  Also, listen closely as Danielle shares some golden nuggets when it comes to tax rebates that will make your employees jump for joy!  Learn more and connect with the crew at TNFR by emailing Danielle@menupricing.com  Service Business Mastery Podcast www.servicebusinessmastery.com

We have all been there...we struggle with not having enough good talent on our team, and it is easy to blame the reduction of skilled labor in the workforce for this struggle. But in reality, it is our own fault that we do not have every person on our team that we dream of having. We, as business owners and managers, are quick to make excuses as to why we can't find any amazing team members.  Well, on today's episode, we sit down with Danielle Putnam & Rosalyn Guerra of The New Flat Rate, and they set us straight on this myth surrounding the hiring issues that we feel like we are facing each day! One day, Danielle is sharing with her team about complaints that she is dealing with from her clients pertaining to hiring issues. She shares the way that she has found success hiring some of the brightest minds within our industry, people such as Rosalyn!! And it doesn't take Rosalyn very long before she is building a working model of the "Hiring Cycle!"  On this episode of the Service Business Mastery podcast, these two fabulous women in HVACr explain this "Hiring Cycle," and how we can use it within our business to continuously hire amazing talent both inside and outside of our home service industry!  Also, listen closely as Danielle shares some golden nuggets when it comes to tax rebates that will make your employees jump for joy!  Learn more and connect with the crew at TNFR by emailing Danielle@menupricing.com  Service Business Mastery Podcast www.servicebusinessmastery.com

Danielle Putnam, recognized by The News as The Top 40 Under 40, and Service World Expo as the 2021 Woman of the Year, is President of The New Flat Rate, Advisory Board Member and Past President of Women in HVACR, and is the Executive Director of her non-profit, Family Frameworks. Danielle has a personal connection with the home service industry. Her first job was passing out flyers door-to-door for her father's electrical business. She was 7 years old. In high school, she moved up to being an office dispatcher and parts runner. After college, she became the marketing director for an HVAC company in Oregon.Danielle knows home service, but she is also no stranger to big business. Before co-founding TNFR, she was the director of business development for a large digital services firm, pitching to C-level executives for big name companies. As part of her job, she also stood before multi-million-dollar investors, seeking capital for the publicly-owned company that she worked for.Danielle is dedicated to help grow the industry she grew up in and loves. As a public speaker, she promotes careers in the home service industry. When not in the office, she spends time with her husband and three children and enjoys hiking, snowboarding, reading and fine wines.Here's a glimpse of what you'll learn:How Danielle started The New Flat Rate in her father's garageHow entrepreneurial guilt at time off manifests in leaders and CEOsWhy Danielle views not delegating certain things as enabling complacent behaviorsMartin's advice surround the four cardinal rules of leadershipWhat Danielle's parents instilled in her and what she hopes to instill in her childrenHow to carve out and retain important family timeWhat Martin's immediate ‘no' isWhat “stagecoach leadership” means and how it can be used in your businessWhat Danielle hopes her immediate ‘no' will be in 2022In this episode….Danielle Putnam is no stranger to the home service industry or big business and she puts all that earned knowledge to work as President of The New Flat Rate. She started TNFR quite literally in her father's garage. She grew up in the family business of contracting before leaving for 11 years. She returned with solid training in business work environments and she credits that time with founding a solid peer aspect to her relationship with her father, respect that served both well in working together.From a young age Danielle learned to hone her entrepreneurial spirit; she got a job cleaning for a neighbor at age 12 so she could buy her own clothes, a move encouraged by her mother. Now with her tech company, The New Flat Rate, she provides the sales platform needed to increase cash flow for small businesses in the heating, air, electrical and plumbing home services industries. TNFR is rolling out beta for chimneys and launched an indoor air quality app last year. But Danielle is looking to learn more about leadership and wants to lean in to saying no to distracting opportunities so she can focus on enabling employees with challenges and zeroing in on what her business truly needs to grow. In this episode of What CEOs Talk About, host Martin Hunter and Danielle Putnam explore all the ways in which saying yes to too many things, such a necessary attribute in the starting years of business, must evolve into saying no to more things once the business is stable. They discuss how they keep devoted family time in balance while leading busy work lives and Danielle shares her recent gains in the art of saying ‘no' for the right reasons. Resources mentioned in this episode:URGEOContact email: info@urgeo.comMartin Hunter on LinkedInDanielle Putnam on LinkedInThe New Flat Rate WebsiteThe New Flat Rate on LinkedInJohn Maxwell‘The 7 Habits of Highly Effective People' by Stephen R. Covey‘How To Win Friends and Influence People' by Dale CarnegieMoneyball Master and CommanderSponsor for this episode...This episode is brought to you by URGEO.URGEO is the Latin for urge: A strong desire to drive change, stimulate thought, incite feeling, and encourage action. Martin Hunter and his team provide liberation for the CEO and Board of a company through their fractional COO services.URGEO's fractional COO services help to move you through growing pains so that your company can flourish and improve its profits.They have worked with a multitude of companies in SaaS, CPG, mining, and transportation, from start-ups to large multinational corporations. They specialize in helping companies avoid roadblocks and stay on the right strategic and operational track for growth.If you are a visionary and want an integrator to get everything done for you, then you need to get in touch with URGEO today.To learn more about their services, visit https://www.URGEO.com or email them directly at info@urgeo.com

Questions about the integration? Email or give us a call at 706.259.8892 / info@menupricing.com 50% off your first two months for Housecall Pro members when joining TNFR! – https://thenewflatrate.com/housecallpro/ 50% off your first two months for TNFR members when you sign up for Housecall Pro – https://www.housecallpro.com/thenewflatrate SHOW NOTES Introducing Roland Ligtenberg [00:59] What is the integration between apps? [3:15] Automation to eliminate human error [4:32] Booming economy = more calls [6:28] How to tackle the hiring crisis in the booming economy [12:53] Trade Academy Scholarship and Program [16:11] Book and Podcast Recommendations from Roland and Danielle [23:20] Pro-tip from Roland [28:29] Discounts and special offers [32:17] LINKS & RESOURCES 50% off your first two months for Housecall Pro members when joining TNFR! – https://thenewflatrate.com/housecallpro/ 50% off your first two months for TNFR members when you sign up for Housecall Pro – https://www.housecallpro.com/thenewflatrate Trade Academy with Housecall Pro: https://tradeacademy.com/ Danielle's Book Recommendation- Three Feet from Gold Roland's Book Recommendation – The Daily Stoic Ask Danielle for your hiring matrix: Email info@menupricing.com

Are you afraid to implement changes in your business because you don't want to lose employees? If so, you're not alone. In this episode, a contractor friend of ours Don Hilderbrand of PlumbSmart Technologies has innovative ideas you can use right away. Questions? Email us at info@menupricing.com www.TheNewFlatRate.com Show Notes: Introducing Don Hilderbrand [1:24] How to find new employees [7:50] Overcoming the fear of losing employees [13:50] Thinking outside the box with TNFR [17:30] How to implement changes [20:35] Customizing performance incentives [25:11] Giving options to clients [30:19] Building a unified, loyalty team [35:45] Links and Resources: PlumbSmart Tech Skills USA PHCC Apprentice Program TNFR's Menu Pricing System

Danielle Putnam sat down with contractor, consultant, author, and business coach, Rob Matheny on TNFR Podcast to discuss the million-dollar question: How can you build freedom in your business? In other words, how can you build a business that makes enough money while still allowing you to take time off, to feel free, and to enjoy your job and family more? Show Notes: Introducing Rob Matheny [1:42] Finding good people [5:40] Working with family members [10:07] Automating processes [15:31] Learning to be organized [20:05] Being a good communicator [24:48] Links and Resources: Be a Service Ninja by Rob Matheny Two Second Lean by Paul Akins The Founder's Mentality by Chris Zook and James Allen Never Split the Difference by Chris Voss Email danielle@menupricing.com to receive TNFR's Process Writing Kit

Every month, The New Flat Rate hosts a member day webinar for our members! We love to share them on our podcast so that our members can review them at their convenience. TOPIC: Getting Started/Back Engaged with The New Flat Rate. In this 30-minute, high level, FREE Member Day Webinar, Danielle Putnam, Jessica Cox, and Suzanne Wedeven discuss the best practices in Getting Started or Back Engaged with TNFR! Questions? Feel free to contact us any time. 706.259.8892 / info@menupricing.com / www.TheNewFlatRate.com

¡Gracias por escuchar! La inhibición de TNF mediante moléculas pequeñas recientemente descubiertas se da como un antagonismo de señalización proinflamatoria de TNF mediante el aprovechamiento exclusivo de la plasticidad conformacional del TNF trimérico. El desarrollo de este mecanismo de acción podría marcar un resurgimiento de moduladores no biológicos de interacciones proteína-proteína clínicamente relevantes en reumatología, como se revisará en este episodio.Les pido amablemente dejen sus calificaciones a este y otros episodios en iTunes así como sus  sugerencias en la sección de comentarios.He aquí las referencias revisadas:Kalliolias, G. D. & Ivashkiv, L. B. TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat. Rev. Rheumatol. 12, 49–62 (2016)Davis, J. M. & Colangelo, J. Small- molecule inhibitors of the interaction between TNF and TNFR. Future Med. Chem. 5, 69–79 (2013)He, M. M. et al. Small- molecule inhibition of TNF-alpha. Science 310, 1022–1025 (2005)He, M. M. et al. Small- molecule inhibition of TNF-alpha. Science 310, 1022–1025 (2005)Jairath, V. & Feagan, B. G. Global burden of inflammatory bowel disease. Lancet Gastroenterol. Hepatol. 5, 2–3 (2020)Kingsmore, K. M., Grammer, A. C. & Lipsky, P. E. Drug repurposing to improve treatment of rheumatic autoimmune inflammatory diseases. Nat. Rev. Rheumatol. 16, 32–52 (2020)Mak, K. K. & Pichika, M. R. Artificial intelligence in drug development: present status and future prospects. Drug Discov. Today 24, 773–780 (2019)Nair, N. & Wilson, A. G. Can machine learning predict responses to TNF inhibitors? Nat. Rev. Rheumatol. 15, 702–704 (2019)Steeland, S., Libert, C. & Vandenbroucke, R. E. A new venue of TNF targeting. Int. J. Mol. Sci. 19, 1442 (2018)O’Connell, J. et al. Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer. Nat. Commun. 10, 5795 (2019)Scott, D. E., Bayly, A. R., Abell, C. & Skidmore, J. Small molecules, big targets: drug discovery faces the protein- protein interaction challenge. Nat. Rev. Drug Discov. 15, 533–550 (2016)

How to provide the best pricing & service to your clients. Rodney Koop is the father of 9 and grandfather of 10. He purchased a HVAC company in 1995 and expected an easy life with lots of easy money. After 6 years, he began to feel the real struggles of being an entrepreneur. Signed up with Nextar, and loved that people would share information with him. Entrepreneurs stop growing when the money runs out, but Business people have a plan and they stick to it. Joined Airtime 500...one page pricing sheet… That is when he realized all of the flat rate programs are the same… He ran off many technicians because he wanted them to upsell and sell equipment. Found an increase of $200 per service ticket after creating The New Flat Rate program for each business owner that implements TNFR. Search Menu Pricing and you will find The New Flat Rate or email them at info@thenewflatrate.com Rodney@menupricing.com or call them at (706)226-2055

How to provide the best pricing & service to your clients. Rodney Koop is the father of 9 and grandfather of 10. He purchased a HVAC company in 1995 and expected an easy life with lots of easy money. After 6 years, he began to feel the real struggles of being an entrepreneur. Signed up with Nextar, and loved that people would share information with him. Entrepreneurs stop growing when the money runs out, but Business people have a plan and they stick to it. Joined Airtime 500...one page pricing sheet… That is when he realized all of the flat rate programs are the same… He ran off many technicians because he wanted them to upsell and sell equipment. Found an increase of $200 per service ticket after creating The New Flat Rate program for each business owner that implements TNFR. Search Menu Pricing and you will find The New Flat Rate or email them at info@thenewflatrate.com Rodney@menupricing.com or call them at (706)226-2055

Die von intrinsichen renalen Zellen und infiltrierenden Leukozyten exprimierten Zytokine sind zentrale Vermittler entzündlicher Nierenerkrankungen. Tumor Nekrose Faktor-α (TNF) ist ein solches proinflamatorisches Zytokin, das in der glomerulären Entzündungsreaktion involviert ist. Die funktionelle Rolle von TNF wurde in Tiermodellen der Glomerulonephritis belegt. Die biologischen Effekte von TNF werden durch die beiden funktionell eigenständigen TNF-Rezeptoren TNFR1 (CD120a) und TNFR2 (CD120b) vermittelt. Neuere Daten zeigen, dass in Modellen einer Immunkomplex-Glomerulonephritis wie der nephrotoxische Serumnephritis die beiden TNF-Rezeptoren in vivo unterschiedliche Funktionen bei der glomerulären Entzündung vermitteln können. Der vorliegenden Arbeit liegt die Hypothese zugrunde, dass Tnfr1 und Tnfr2 unterschiedliche inflammatorische TNF-Effekte in Glomeruli vermitteln. Daher war das Ziel dieser Arbeit, Expression und Funktion der beiden TNF-Rezeptoren in Maus-Glomeruli zu charakterisieren und die Tnfr-abhängig exprimierten Entzündungsmediatoren in Maus-Glomeruli zu identifizieren. Aufbauend auf den Ergebnissen dieser Arbeit könnten selektive, Tnfr-spezifische Therapien zur Hemmung der glomerulären Entzündungsreaktion entwickelt werden. Zudem wurde in dieser Arbeit die funktionelle Rolle der beiden TNF-Rezeptoren im MRL/lpr-Mausmodell der Lupusnephritis untersucht, um eine selektive Tnfr-Blockade als mögliche Therapiestrategie zu charakterisieren. Hierfür war eine Rückkreuzung von Tnfr1- und Tnfr2-defizienten C57BL/6J-Mäusen in den MRL/lpr-Hintergrund erforderlich. Um TNF-Rezeptor-1- und 2-vermittelte inflammatorische Signalwege in Glomeruli zu identifizieren wurde die Expression und die Funktion der beiden TNF-Rezeptoren in Mausnieren, in isolierten Glomeruli ex vivo und murinen glomerulären Endothel- und Mesangialzellen in vitro untersucht. In normaler Mausniere konnte eine Tnfr1- und Tnfr2-mRNA- und Protein-Expressionen präferentiell in Glomeruli im Vergleich zum Tubulointerstitium nachgewiesen werden. Die Expression von beiden TNF-Rezeptoren und die TNF-induzierte Induktion von Tnfr2-mRNA-Expression wurde auch in vitro sowohl in murinen glomerulären Endothel- als auch Mesangialzelllinien bestätigt. Die prominente glomeruläre TNF-Rezeptor-Expression korrelierte mit einer konstitutiven glomerulären mRNA-Expression von Adhäsionsmolekülen wie Icam-1, Vcam-1, E- und P-Selektin und Chemokinen wie Ccl2, Ccl3 und Ccl5. Eine intraperitoneale TNF-Injektion induzierte die Expression dieser Mediatoren präferentiell in Glomeruli. Diese in vivo TNF-Exposition führte zu einer raschen glomerulären Akkumulation von Leukozyten einschließlich Neutrophilen und mononukleären Phagozyten, die mittels einer kompartimentspezifischer Durchflußzytometrie analysiert wurden. Um Tnfr-abhängige inflammatorische Effekte in intrinsischen glomerulären Zellen unabhängig von infiltrierenden Leukozyten zu untersuchen, wurde eine Microarray-Gene-Expressionsanalyse an intakten Glomeruli durchgeführt, die aus Wildtyp und Tnfr-defizienten Mäusen isoliert und anschließend mit TNF ex vivo stimuliert wurden. Die meisten TNF-Effekte wurden ausschließlich durch Tnfr1 vermittelt, unter anderem die induzierte mRNA-Expression von Adhäsionsmolekülen, proinflammatorischen Chemokinen, Komplement-Faktoren und proapoptotischen Molekülen. Im Gegensatz dazu fanden wir nur vier Tnfr2-abhängig exprimierte Gene, einschließlich einer kleinen GTPase der Rab-Familie (Rab6b). Diese Ergebnisse wurden durch quantitative RT-PCR-Analysen von TNF-stimulierten Glomeruli und primären Mesangialzellen bestätigt. Weitere Untersuchungen zeigten allerdings auch einen Beitrag von Tnfr2 bei der gesteigerten glomerulären Expression von Adhäsionsmolekülen und Chemokine nach Stimulation mit niedrigen TNF-Konzentrationen auf. Im Gegensatz zur Wildtyp-Kontrolle fehlte in TNF-stimulierten Tnfr1-defizienten Glomeruli die Sekretion verschiedener proinflammatorischer Chemokine beinahe vollständig. Interessanterweise war die Proteinexpression auch in Tnfr2-defizienten Glomeruli signifikant herunterreguliert. Folglich sind die meisten inflammatorischen TNF-Effekte in Glomeruli via Tnfr1 durch die induzierte Expression von proinfammatorischen Mediatoren wie Adhäsionsmolekülen und Chemokinen vermittelt. Darüber hinaus dürfte Tnfr2 zu dieser inflammatorischen Antwort beitragen, wenn Glomeruli niedrigen TNF-Konzentrationen ausgesetzt sind. Ferner scheint Tnfr2 posttranskriptionell die Chemokinsekretion in Glomeruli nach einer TNF-Exposition zu beeinflussen, möglicherweise durch die Tnfr2-abhängig exprimierte Rab GTPase Rab6b, die am intrazellulären Transport und der Sekretion von inflammatorischen Molekulen beteiligt sein könnte. In Bezug auf Tnfr-spezifische, anti-inflammatorische Therapien weisen die hier präsentierten Ergebnisse somit darauf hin, dass eine selektive Tnfr1-Blockade eine glomeruläre, insbesondere durch Granulozyten und Makrophagen vermittelte Entzündung verbessern könnte, möglicherweise bei geringer Hemmung immunregulatorischer und antimikrobieller Funktionen von TNF, die redundant durch Tnfr2 vermittelt werden könnten. Dagegen erscheint aufgrund der erhobenen Daten im MRL/lpr-Mausmodell eine Blockade von TNF oder beider Rezeptoren bei der Lupusnephritis, in der glomeruläre Neutrophileninfiltrate keine entzündliche Rolle spielen, weniger erfolgversprechend. Gleichzeitig weisen die vorliegenden Ergebnisse auf eine immunsuppressive, die systemische Immunreaktivität beim SLE begrenzende Funktion von Tnfr2 hin.

I always thought there was something to the New Finland Radicals.  Sure, the music isn't exactly mainstream, but it isn't so far off the beaten path that it's inaccessible.  Their talents as musicians and composers (I'll use that word here in lieu of something as simplistic as "songwriters") is not in question.  Their production skills show imagination and creativity, and their ability to try new approaches and incorporate new styles into their music is certainly an asset.  They're well loved by fellow bands and usually have no trouble winning over at least a few fans in a crowd that may not have heard of them before.  So, why aren't these guys bigger than they are?  Well, after looking at how far they've come in the two years since they were last on, I'd say they're getting there, and dammit, I'm going to keep inviting them back until everybody sees my way on this. I had a lot of fun the first time I met TNFR.  After recording the show, we sat around and talked for another hour or so, at least, completely commandeering the jukebox at the in Broad Ripple (much to the grumblings of the patrons, who just didn't get the intricacies of Asia's progressive pop sensibilities, I suppose).  Contrary to popular belief, I rarely get the chance to geek out about music with the guests on the show.  Generally they've got to play a set or trot off to their jobs, or what have you, as the guys did this night.  Fortunately, as is typical with second interviews, we got the chance to do it on mic this time.  Also, as is typical, we had to edit out a lengthy discussion of the merits of Yes and Styx for fear of alienating the majority of our audience.  If anybody wants to hear that discussion, buy me (or the New Finland Radicals) a round next time you see us and we'll be sure to talk your ear off about our passion for pretentious prog rock. Links referenced in the show:   New Finland Radicals can be found here | |   They were last heard on back in 2009. Their latest CD, The Brian Sessions, came out in may 2009 was recorded at the by Chris Wodoc.  This release features several re-recordings of tracks that were first demoed on the "Green CD" and played during their previous Indy In-Tune appearance. Many of the tracks can be found on their websites listed above.  The CD can be purchased at their shows.   They recently opened for the at the Tonight's drinks were courtesy of Brian from Brownsburg and Jeff from Greenwood, who graciously donated to the "Guest Entertainment and Waitress Tip Fund" via our . You can catch them at the You can catch an old interview from on their .  And of course the one accolade I forgot to attribute (and pay them for) was coming in third place in our first back in 2010

A growth factor that antagonizes signaling by tumor necrosis factor α relieves symptoms of inflammatory arthritis.

Thu, 27 Jul 2006 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/5766/ https://edoc.ub.uni-muenchen.de/5766/1/Hauer_Julia.pdf.pdf Hauer, Julia ddc:610, ddc:600, M

Neurotrophine sind für die Entwicklung und Funktion des Nervensystems von Wirbeltieren unabdingbar. Sie entfalten ihre vielfältigen Funktionen über zwei Typen von Transmembranrezeptoren. Einerseits binden sie an die Trk-Rezeptoren, andererseits an den Neurotrophinrezeptor p75NTR. Obwohl p75NTR der erste klonierte Neurotrophinrezeptor war, wird die Wirkungsweise von Trk-Rezeptoren heute besser verstanden als von p75NTR. Erstens besitzen Trk-Rezeptoren als Rezeptortyrosinkinasen im Gegensatz zu p75NTR eine intrinsische enzymatische Aktivität, was die Aufklärung ihrer Signaltransduktionsmechanismen bedeutend erleichtert hat. Zweitens vermitteln Trk-Rezeptoren die klassische trophische Funktion der Neurotrophine, p75NTR hingegen neuartige Funktionen von Neurotrophinen, die zuvor noch nicht bekannt waren. Diese nicht-klassischen Funktionen, wie beispielsweise die Zelltod auslösende Wirkung von NGF, werden erst seit den letzten Jahren untersucht. Drittens konnte die Funktion der Trk-Rezeptoren in vollständigen Deletionsmutanten der Maus analysiert werden, wohingegen von p75NTR erst seit kurzem ein vollständiger Knockout existiert. In unserem Labor war nämlich gefunden worden, dass eine Spleißvariante von p75NTR in der bereits beschriebenen Deletionsmutante noch exprimiert wird. Am Beginn dieser Doktorarbeit stand die nähere Charakterisierung dieser Spleißvariante im Vordergrund. Um ihre physiologische Relevanz zu klären, wurde zunächst versucht, die Spleißvariante als endogenes Protein zu detektieren. Dies gelang in Kulturen aus primären Schwannzellen. Wie zudem gezeigt wurde, ist diese Rezeptorisoform in einer in unserem Labor generierten Deletionsmutante von p75NTR nicht mehr vorhanden. Darüber hinaus wurde ein erheblich stärkerer Schwannzellphänotyp in der neuen Deletionsmutante gefunden im Vergleich zur bereits beschriebenen. Letztere stellt somit einen Hypomorph dar. Die Funktion von p75NTR konnte nunmehr erstmals mit Hilfe eines vollständigen Knockouts untersucht werden. Wurde p75NTR zunächst lediglich eine die Trk-Rezeptoren modulierende Funktion zugeschrieben, war bei Beginn dieser Doktorarbeit in mehreren Ansätzen gezeigt worden, dass p75NTR unabhängig von den Trk-Rezeptoren eigenständige Signalaktivität besitzt, die zudem derjenigen der Trk-Rezeptoren entgegengerichtet sein kann. Für eine detaillierte molekulare Analyse der Funktion von p75NTR ist ein In-vitro-Assay unverzichtbar. Ein zentrales Ziel dieser Arbeit war deshalb die Etablierung eines solchen Assays. Ein In-vitro-Assay für p75NTR unter Verwendung der vollständigen Deletionsmutante konnte in cerebellären Körnerzellen etabliert werden. Aktivierung von p75NTR mit NGF führt zu einer Erhöhung der RhoA-Aktivität. Darüber hinaus konnte gezeigt werden, dass auch TNFR, wie p75NTR ein Mitglied der TNFR-Überfamilie, RhoA aktiviert, obgleich mit einer klar unterschiedlichen Kinetik. Die TNFa-vermittelte Regulation von RhoA hemmte das Auswachsen von Neuriten. Im cerebellären Kultursystem konnte jedoch kein Effekt von NGF auf das Neuritenwachstum festgestellt werden. Weil Rho aber auch die Transkription steuern kann, wurde die Wirkung von NGF auf das Genexpressionsmuster von Körnerzellen mit einem ‘Gene-Profiling’-Experiment analysiert. Es wurden 69 Gene, die durch NGF entweder hoch- oder hinunterreguliert werden und zum Teil ‘Cluster’ bilden, gefunden. Mit Hilfe der vollständigen Deletionsmutante wurden bisher GAP-5 und GluR2 als neue Zielgene von p75NTR identifiziert. GluR2 kodiert für eine der vier AMPA-Rezeptor-Untereinheiten und spielt eine zentrale Rolle für die synaptische Plastizität. Da in einem unabhängigen Ansatz ein Defekt bei der Ausprägung von hippocampalem LTD (‘long term depression’), einer Form von synaptischer Plastizität, im vollständigen Knockout von p75NTR gefunden worden war, wurde der weitere Schwerpunkt dieser Arbeit auf den AMPA-Rezeptor gelegt. Die weitere Untersuchung aller AMPA-Rezeptor-Untereinheiten im Hippocampus ergab, dass neben GluR2 auch GluR3 ein Zielgen von p75NTR ist und dass zudem GluR2 wie auch GluR3, jedoch nicht GluR1 und GluR4, in vivo im p75NTR-Knockout im Vergleich zum Wildtyp in ihrer Expression signifikant verändert sind. Diese Befunde legen eine veränderte Stöchiometrie des AMPA-Rezeptors im p75NTR-Knockout nahe und liefern einen Erklärungsansatz für das veränderte LTD in der p75NTR-Deletionsmutante. Zudem erweitern sie das Konzept der Bedeutung von Neurotrophinen für die synaptische Plastizität im Allgemeinen und der von p75NTR im Speziellen.