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I'm without words. I offer to you that the end has commenced, the digital oversight is being being made operational, the sheep and goats are and will be separated, our shelves/our money/our normal will all be affected. Cling for dear life to daily Bible reading, prayer, fellowship and fasting. Crazy will intensify - increasingly impressing upon us the need for a closer walk with the One who offers peace. May the Lord bless us all. (Sorry the sound isn't better. With the usual platform gone, I/we are searching for a substitute.) VAXX UCSF Study re Covid vaxxes – “cure” worse than the disease: https://dreddymd.com/2025/04/22/study-vaccinated-6x-more-likely-hospitalized-than-unvaccinated/ “Replicon” bird flu vaxx coming: https://slaynews.com/news/fda-advances-bill-gates-replicon-mrna-bird-flu-vaccine/ RFK Jr. fast-tracks “self amplifying” bird flu vaxx: https://thewashingtonstandard.com/self-amplifying-modified-mrna-gene-therapy-bioweapon-shots-coming-for-bird-flu-video/ WHERE ARE THE ARRESTS? DOJ – Where are the arrests?!: https://rumble.com/v6sfgjf-glenn-beck-and-steve-bannon-where-are-the-arrests-we-are-burning-daylight.html Last summer, Trump insiders promise arrests: https://thepeoplesvoice.tv/insider-trump-to-shatter-un-into-a-thousand-pieces-and-arrest-covid-plandemic-criminals/ After RFK Jr appointed Health Sec., he promised Fauci et al would be prosecuted: https://www.medicine.news/2024-11-17-rfk-tony-fauci-bill-gates-arrested-trump.html Trump promises to get USA out of WHO day one of presidency: https://www.rvmnews.com/2024/12/trump-plans-to-pull-u-s-out-of-who-on-day-one-of-his-administration/ Trump signs paperwork to start process of withdrawal, takes 1 year: https://news.northeastern.edu/2025/01/23/us-withdrawn-from-who/ JAILED FOR CHRISTIAN PRAYER Australia – jail if you pray for release from unwanted same-sex attraction: https://www.lifesitenews.com/news/australian-state-could-send-christians-to-jail-if-they-pray-for-people-with-unwanted-same-sex-attraction/ 6 year-olds forced to write same-sex love letters in UK: https://www.lifesitenews.com/news/bbc-highlights-6-year-olds-forced-to-write-gay-love-letter-to-teach-accepti/ Australia – perversion tolerant: https://en.wikipedia.org/wiki/LGBTQ_rights_in_Australia This is why the transgender perversion is acceptable only to small children: https://citizenwatchreport.com/wow-this-womans-parents-should-be-arrested/ Concomitantly in India …: https://www.lifesitenews.com/news/proposed-change-to-india-anti-conversion-law-could-see-christians-put-to-death-for-evangelizing/?utm_source=daily-usa-2025-05-01&utm_medium=email AIPAC AND CONGRESS AIPAC controls some in Congress?: https://needtoknow.news/2025/04/elliott-brandt-ceo-of-the-aipac-israel-lobby-confirms-it-controls-congress-and-key-federal-leaders/ AIPAC's influence in Congress: https://newstarget.com/2024-11-11-aipac-brags-increasing-influence-over-us-congress.html Trump decides against supporting Israeli attack on Iran: https://www.nytimes.com/2025/04/16/us/politics/trump-israel-iran-nuclear.html Hegseth to Trump – don't invade Iran: https://www.theinteldrop.org/2025/04/26/report-that-trump-waved-off-israeli-strike-on-iran-inflames-the-lobby/ Israeli lobby to fire Hegseth?: https://www.youtube.com/watch?v=Uc153bFmTbQ&t=5s Trump to replace Hegseth?: https://www.npr.org/2025/04/21/nx-s1-5371312/trump-white-house-pete-hegseth-defense-department Jeffrey Sachs - Middle East to be modified?: https://youtu.be/tGz5MXPozcs?si=UITJP-ZgCPOhhS2g Turnaround, Trump blames Iran for Houthi attacks: https://halturnerradioshow.com/index.php/news-selections/world-news/uh-oh-trump-publicly-blames-iran-for-houthi-yemen-attacks-will-hold-iran-responsible-form-this-day-forward AND … talks with Iran postponed: https://halturnerradioshow.com/index.php/news-selections/world-news/next-round-of-u-s-iran-talks-suddenly-postponed AND … Nat.
Looking to enhance your interventional oncology practice with renal tumor ablation? In this episode, host Dr. Don Garbett is joined by Dr. AJ Gunn to discuss the current landscape of renal tumor ablation and Dr. Gunn's procedural tips for successful outcomes. Dr. Gunn is an interventional radiologist at the University of Alabama at Birmingham, with extensive experience in building service lines, including renal tumor management. --- This podcast is supported by: RADPAD® Radiation Protection https://www.radpad.com/ --- SYNPOSIS The doctors review various scoring systems to predict the risks associated with renal ablation. Dr. Gunn emphasizes that tumor size is the most consistent predictor of procedural complications, local recurrence, and metastasis. He also discusses ablation techniques and proactive steps to avoid complications, such as hydrodissection and the selection of appropriate ablation technology. He employs cryoablation for central renal tumors and large tumors to minimize damage to the collecting system, while using microwave ablation for smaller peripheral lesions. Additionally, prior literature and his personal experience suggest that preoperative embolization may be beneficial for larger hypervascular tumors. Finally, Dr. Gunn speaks about the ongoing Embolization Before Ablation of Renal Cell Carcinoma (EMBARC) study and the importance of sharing knowledge and experiences within the interventional oncology community. --- TIMESTAMPS 00:00 - Introduction 04:24 - Practice Building Philosophy 09:29 - Importance of Clinical Follow Up 12:17 - Predictive Factors of Ablation Success 23:30 - Renal Ablation Technique 31:41 - Embolization Before Ablation 44:13 - The Future of Renal Tumor Treatments --- RESOURCES Percutaneous Cryoablation of Stage T1b Renal Cell Carcinoma: Safety, Technical Results, and Clinical Outcomes (Gunn et al, 2019): https://pmc.ncbi.nlm.nih.gov/articles/PMC8983093/ Should Renal Mass Biopsy Be Performed prior to or Concomitantly with Thermal Ablation? (Chung et al, 2018): https://pubmed.ncbi.nlm.nih.gov/30075976/ EMBARC Trial: https://med.stanford.edu/ir/clinical-trials/embarc.html Society for Interventional Oncology (SIO) Conference: https://www.sio-central.org/Events/Annual-Scientific-Meeting
Listen to Dr. Anna Fuks, a leader in our profession, talks about her new book on pulp therapy for children. In this great podcast, Dr. Fuks discusses her amazing journey and career in pediatric dentistry, the history of pulp therapy for children, past to present, and why there was a need for the new textbook. Dr. Fuks describes the differing perspectives in Europe. She also talks about MTA use and how we need to grow it. She discusses the teaching FMC and FS treatments as well as describing her takes on the exciting future ahead in pediatric dentistry.Bio:Prof. Anna B. Fuks was born in Curitiba, Brazil, and graduated in Dentistry by the Federal University of the State of Parana. She completed her post-graduate course in Pediatric Dentistry at the University of Alabama, USA. and did her residency at the Children's Hospital of the same University. She returned to Brazil, where she practiced and taught Pediatric Dentistry at the University of Parana until 1973 when she immigrated to Israel and joined the Department of Pediatric Dentistry of the Hebrew University of Jerusalem, reaching the degree of Professor. Upon her retirement she received the grade of Professor Emeritus, that she maintains until the present date.Concomitantly to teaching and clinical practice Prof. Fuks dedicated herself to clinical and laboratory research. Being fluent in several languages, she has lectured in several countries worldwide.Dr. Fuks was President of the International Association of Pediatric Dentistry and is an honorary member of several Pediatric Dental Associations. She has published over 160 articles and 85 abstracts in many international journals, wrote 18 chapters in Pediatric Dentistry books, and continues serving actively as a member of the Editorial Board of several dental journals.Dr. Fuks has received several international prizes in research. In 2013 she received the Distinguished Service Award from the American Academy of Pediatric Dentistry (AAPD) and in 2015 became an Honorary Member of the International Association of Pediatric Dentistry (IAPD).Dr. Fuks worked par-time in clinical Pediatric Dentistry till 2017, when she completed 80. She continued clinical teaching at the Post-Graduate Clinic of the Hadassah Faculty of Dental Medicine until 2020 when, with the eruption of COVID, and being considered “high-risk”, she stopped clinical instruction. Presently she participates as mentor at the post graduate students' seminars at the Department of Pediatric Dentistry of the Hadassah School of Dental Medicine in Jerusalem. Also, in 2020Dr. Fuks made her first presentation onlinegiving a complete course for the Russian Society of Pediatric Dentistry. Since then, she has made several presentations and webinars online.Dr. Fuks is the Principal Editor of the Pediatric Endodontics, the only book specialized in endodontic treatment for primary and young permanent teeth. The book has already been translated into Chinese and the Turkish version is soon appearing in the market. She has now completed the publication of Contemporary Endodontics for Children and Adolescents, launched at the AAPD 2023 Annual Session, where this podcast was recorded.See Privacy Policy at https://art19.com/privacy and California Privacy Notice at https://art19.com/privacy#do-not-sell-my-info.
SHR # 2995:: The Intersection Between Toxicology and Aging - Dr. John Wise, PhD - I discussed the problem with keeping people alive longer as the US Government sees it back in 2008. Today we are imminently faced with the challenges of an increasingly aging population and longer lifespans due to improved health care. Concomitantly, we are faced with ubiquitous environmental pollution linked with various health effects and age-related diseases which contribute to increased morbidity with age. Geriatric populations are rarely considered in the development of environmental regulations or in toxicology research. Today, life expectancy is often into one's 80s or beyond, which means multiple decades living as a geriatric individual. Hence, adverse health effects and late-onset diseases might be due to environmental exposures as a geriatric, and we currently have no way of knowing. Considering aging from a different perspective, the term “gerontogen” was coined in 1987 to describe chemicals that accelerate biological aging but has largely been left out of toxicology research. - CARL RECOMMENDS: superhumanradio.net/carl-recommends - - View and download all shows at https://superhumanradio.net - Visit us on Instagram: @superhumanradio - Support SHR - https://superhumanradio.net/make-a-donation
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.27.534410v1?rss=1 Authors: Shi, S. X., Li, Y.-J., Wendt, T. S., Shi, K., Jin, W., Liu, Q., Gonzales, R. J. Abstract: Sphingosine-1-phosphate receptor 1 (S1PR1) is highly expressed in endothelial cells and receptor activation plays an important role in mediating endothelial function and health, thus showing promise as a pharmacologic target for acute ischemic stroke (AIS) treatment. Here, we examined the effect of a selective S1PR1 ligand, RP101075, on infarct volume and neurological outcome in adult male mice subjected to transient middle cerebral artery occlusion (tMCAO). Concomitantly, we examined S1PR1 expression profile in the ischemic mouse brain, as well as S1PR1 expression and impact of receptor activation on human brain microvascular endothelial cell (HBMEC) proliferation and survival following hypoxia plus glucose deprivation (HGD). We observed that RP101075 administration at onset of reperfusion reduced infarct volume and lessened neurological deficits in tMCAO mice and these responses were S1PR1 dependent. Additionally, we observed that tMCAO increased brain S1PR1 protein levels and flow cytometry revealed increases in S1PR1 levels are greatest in brain endothelial cells compared to other brain cell types (astrocyte, neuron, microglia). In cultured HBMECs, RP101075 increased cell proliferation and ozanimod, parent compound of RP1010175, increased live cell count during HGD; this response was S1PR1 dependent. In conclusion, S1PR1 activation improves neuroprotection/outcome post-stroke and preserves brain endothelial cell survival following ischemia-like injury. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.14.532654v1?rss=1 Authors: Poirier, G., Mourey, F., Sirandre, C., Papaxanthis, C., Gaveau, J. Abstract: Several sensorimotor control studies have provided evidence supporting that the central nervous system optimizes gravity effects to minimize muscle effort. Recently, this hypothesis has been supported by the consistent observation of direction-specific negative epochs in the phasic electromyographic signal of antigravity muscles during vertical arm movements. This suggests that gravity torque is harvested to produce some of the arm motion. However, further investigation is needed to more finely understand how the CNS integrates gravity effects into muscle commands. Here, we aimed to analyze the phasic muscular activity across varying movement speeds during horizontal and vertical arm movements. We quantified the amount of negativity during acceleration and deceleration phases for all movement directions during fast, natural, and slow movements. We found that the negativity was more important during the acceleration phase of downward movements and during the deceleration phase of upward movements, resulting in diminished phasic activity compared to horizontal movements. Concomitantly, we found direction-specific effects of movement speed on phasic EMG activity of gravity muscles. This resulted in altered EMG to kinematics relationships in vertical movements compared to horizontal ones. These results support the Effort-minimization hypothesis and confirm that the negativity of phasic EMG is an important aspect of the motor command. Furthermore, the present results reveal that the CNS finely tunes this feature across a range of movement speeds and directions. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.09.523229v1?rss=1 Authors: Rey, S., Ohm, H., Moschref, F., Zeuschner, D., Klämbt, C. Abstract: Neuronal information conductance depends on transmission of action potentials. The conductance of action potentials is based on three physical parameters: The axial resistance of the axon, the axonal insulation by glial membranes, and the positioning of voltage-gated ion channels. In vertebrates, myelin and channel clustering allow fast saltatory conductance. Here we show that in Drosophila melanogaster voltage-gated sodium and potassium channels, Para and Shal, co-localize and cluster in an area of motor axons resembling the axon initial segment. Para but not Shal localization depends on peripheral glia. In larvae, relatively low levels of Para channels are needed to allow proper signal transduction and nerves are simply wrapped by glial cells. In adults, the concentration of Para at the axon initial segment increases. Concomitantly, these axon domains are covered by a mesh of glial processes forming a lacunar structure that serves as an ion reservoir. Directly flanking the voltage-gated ion channel rich axon segment, the lacunar structures collapse forming a myelin-like insulation. Thus, Drosophila development may reflect the evolution of myelin which forms in response to increased levels of clustered voltage-gated ion channels. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.01.518561v1?rss=1 Authors: Vantler, M., Schorscher, M., Berghausen, E. M., Moore, J. B., Wong, D., Zhaolong, L., Wissmueller, M., Gnatzy-Feik, L., Zierden, M., Mehrkens, D., Adam, M., Zhao, X., Odenthal, M., Sengle, G., Boor, P., Maegdefessel, L., Baldus, S., Rosenkranz, S. Abstract: Background: Catalytic class IA PI 3-kinase isoform p110alpha is a crucial regulator of cellular proliferation and survival in numerous cell types. While p110alpha is critically involved in pathogenic vascular remodeling, its physiological role for vascular integrity under stress conditions has not been studied. We report a protective function of smooth muscle p110alpha against abdominal aortic aneurysm (AAA) formation. Methods & Results: In mice lacking p110alpha in smooth muscle cells (sm-p110alpha-/-), perfusion of the infrarenal aorta with porcine pancreatic elastase (PPE) yielded substantially enhanced AAA formation compared to wild type controls. This disease phenotype is partly attributable to a subtle preexisting vascular phenotype under basal conditions, as sm-p110alpha-/- mice displayed a smaller media area, deranged aortic wall structure (detached smooth muscle cells, increased apoptotic cell death), and a diminished functional responsiveness of aortic rings to vasodilators. Furthermore, p110alpha is also implicated in regenerative processes during AAA development: Whereas wild type mice showed increased media hypertrophy, neointima formation and proliferation upon PPE intervention, these vascular remodeling processes were diminished in sm-p110alpha-/- mice. Concomitantly, increased numbers of elastic fiber breaks and ECM degradation were detected in sm-p110alpha-/- aorta. Mechanistically, we found that lack of p110alpha expression impaired smooth muscle cell proliferation, expression of contractile marker genes and production of elastin fibers. This phenotype largely depended on reduced phosphorylation and inactivation of FOXO1, as specific FOXO1 inhibition fully rescued proliferation of p110alpha-/- smooth muscle cells, and knockdown of FOXO1 increased expression of calponin and elastin. Conclusions: Smooth muscle p110alpha protects against AAA disease by maintaining aortic wall homoeostasis and promoting SMC proliferation to compensate for cell loss during AAA development. Our findings have potential implications for current approaches aimed at p110alpha inhibition for cancer therapy and suggest new pharmacological strategies to activate p110alpha signaling in AAA disease. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
A new research paper was published in Oncotarget's Volume 13 on September 14, 2022, entitled, “Site of analysis matters – Ongoing complete response to Nivolumab in a patient with HIV/HPV related metastatic anal cancer and MLH1 mutation.” Anal cancer is a rare disease with increasing incidence. In patients with locally recurrent or metastatic disease, which cannot be treated with chemoradiotherapy or salvage surgery, systemic first-line chemotherapy with carboplatin and paclitaxel is standard of care. For patients who progress after first-line therapy and are still eligible for second-line therapy, programmed cell death protein 1 (PD-1) antibodies are potential therapeutic options. However, prediction of response to immunotherapy is still challenging, including in patients with anal cancer. “Altogether, there is little data on PD-1 treatment in HIV infected patients.” In a new study, researchers Melanie Demes, Ursula Pession, Jan Jeroch, Falko Schulze, Katrin Eichler, Daniel Martin, Peter Wild, and Oliver Waidmann from Universitätsklinikum Frankfurt and Centrum für Hämatologie und Onkologie reported a case of an HIV infected patient with anal cancer, microsatellite instability (MSI) high status, a high mutation frequency regarding tumor mutational burden (TMB) and an ongoing response to Nivolumab. “We report here to our knowledge the first anal cancer case with microsatellite instability (MSI) due to MLH1 mutation and a deep and ongoing response to Nivolumab treatment.” Thorough analysis of the primary tumor as well as metastatic sites by next generation sequencing (NGS) revealed that MSI was formally only found in the metastatic sites but not in the primary tumor. Concomitantly, tumor mutational burden (TMB) was higher in the metastatic site than in the primary tumor. The researchers concluded that all anal cancer patients should be tested for MSI and whenever possible molecular analysis should be performed rather from metastatic sites than from the primary tumor. “According to our results, we propose to assess mutational status in tissue from metastasis rather than from the primary site when additional molecular analyses are performed for treatment decisions.” DOI: https://doi.org/10.18632/oncotarget.28274 Correspondence to: Oliver Waidmann – Emails: oliver.waidmann@kgu.de Keywords: anal cancer, microsatellite instability, immunotherapy, high-throughput nucleotide sequencing, nivolumab 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. 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/OncotargetYouTube 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
Webcast URL: https://knowledgewebcasts.com/know-portfolio/sanctions-trends-cle/ The U.S. Department of the Treasury's Office of Foreign Assets Control (OFAC) continues to administer and enforce strict scrutiny on U.S. and non-U.S. companies. Several settlement agreements have been noted in the past months that signal the broad reach of U.S. sanctions regulations. Concomitantly, the US government has continued to utilize economic sanctions to fight corruption and other criminal activity around the world. U.S. and non-U.S. companies alike engaged in global transactions must implement a rigorous and effective compliance program to mitigate legal liabilities, including for the transfer or the facilitation of the transfer of the proceeds of corruption. Join key thought leaders in OFAC and financial institution compliance Javier Coronado (Diaz Reus International Law Firm) and Stanley Foodman (Foodman CPAs and Advisors), as they provide a discussion of the latest and significant issues surrounding OFAC recent enforcement actions. This course will guide you in implementing necessary compliance measures to avoid risks and sanctions. For any more information please click on the webcast URL at the top of this description.
Article: Oxygen uptake rates have contrasting responses to temperature in the root meristem and elongation zone Journal: Physiologia Plantarum Year: 2022 Guest: Maura Zimmermann Host: Arif Ashraf Abstract Growing at either 15 or 25°C, roots of Arabidopsis thaliana, Columbia accession, produce cells at the same rate and have growth zones of the same length. To determine whether this constancy is related to energetics, we measured oxygen uptake by means of a vibrating oxygen-selective electrode. Concomitantly, the spatial distribution of elongation was measured kinematically, delineating meristem and elongation zone. All seedlings were germinated, grown, and measured at a given temperature (15 or 25°C). Columbia was compared to lines where cell production rate roughly doubles between 15 and 25°C: Landsberg and two Columbia mutants, er-105 and ahk3-3. For all genotypes and temperatures, oxygen uptake rate at any position was highest at the root cap, where mitochondrial density was maximal, based on the fluorescence of a reporter. Uptake rate declined through the meristem to plateau within the elongation zone. For oxygen uptake rate integrated over a zone, the meristem had steady-state Q10 values ranging from 0.7 to 2.1; by contrast, the elongation zone had values ranging from 2.6 to 3.3, implying that this zone exerts a greater respiratory demand. These results highlight a substantial energy consumption by the root cap, perhaps helpful for maintaining hypoxia in stem cells, and suggest that rapid elongation is metabolically more costly than is cell division. Cover art design and audio editing: Ragib Anjum --- Send in a voice message: https://anchor.fm/no-time-to-read-podcast/message
This Podcast introduces the concept of the “Great Reset”. Many of us have been hearing the word “reset” for several years now. Concomitantly, we hear the word “rebirth”. What is meant by the term “reset”. The answer to that question depends on who you are talking to. This podcast is a discussion with Dave Henderson, the most well read, self-educated man I know, about this topic. We start from the beginning of life and the beginning of creation itself to obtain an understanding of the foundations on which everything is built. If we don't understand the foundation of something, anything, how can we discuss what it will be “reset' to? Come listen to our very deep discussion of the Foundation of the earth and how the Fibonacci Sequence can be found in all created things. How the Golden Ratio appears in everything from brainwaves to electricity to the Parthenon! It's absolutely amazing that our Dad and Father, the One and Only Uncreated Being created everything out of nothing but the sound of His Voice, using a specific mathematical formula as one of only two constants! It's unbelievable! And why should you and I care? Because our own Dad is Sovereign, He runs everything perfectly and He has promised us in His Word that the Final Solution is in His Hands: The Great Reset! We have nothing to fear; what a relief. So if you are going nuts trying to make heads or tales out of the news and how the Globalists, Central Bankers and Cabalists are claiming there is going to be a “reset” that is a New World Order. Put your mind and heart at ease; they don't know what they are talking about. The “Great Reset” is in our Father's Hands would you want anyone else to be in charge of this whole enchilada?
PODCAST A Novel Is Culture A Symbolic Universal Language? © 2020 Volume 1 ISBN 978-976-96531-5-3From time in memorial there is has been a perception that anthropologists and linguists through their lens held conversations regarding the “effect of culture on language vice versa compounded by the fact that how language affects society and the way we global citizens think. Concomitantly, since the aforesaid seems plausible then the five fundamental characteristics of language include cultural relevance, symbolism, flexibility, variation, and social importance is critical to this discourse. However, logically speaking, in the scheme of things language therefore is perceived as a vital part of human connection. William Anderson GittensAuthor, Cinematographer,Dip., Com., Arts. B.A. Media Arts Specialists’ Editor in Chief Devgro Media Arts Services Publishing ®2015 License Cultural Practitioner, Publisher, CEO Devgro Media Arts Services®2015WORKS CITED "Language definition and meaning | Collins English Dictionary". www.collinsdictionary.com. Retrieved 10 December 2019. "syntax". Oxford Dictionaries UK Dictionary. Oxford University Press. Retrieved 2016-01-22. A Novel Is Culture A Symbolic Universal Language? © 2020 Volume 1 ISBN 978-976-96531-5-3 Anderson, Stephen R. (n.d.). "Morphology". Encyclopedia of Cognitive Science. Macmillan Reference, Ltd., Yale University. Retrieved 30 July 2016. Arnauld, Antoine (1683). La logique (5th ed.). Paris: G. Desprez. p. 137. "Nous avons emprunté...ce que nous avons dit...d'un petit Livre...sous le titre de Grammaire générale." Brown, Dunstan (December 2012) [2010]. "Morphological Typology" (PDF). In Jae Jung Song (ed.). The Oxford Handbook of Linguistic Typology. pp. 487–503. doi:10.1093/oxfordhb/9780199281251.013.0023. Retrieved 30 July 2016. Cassin, Barbara. Dictionary of Untranslatables: A Philosophical Lexicon, Princeton University Press, 2014.Chomsky, Noam (2002) [1957]. Syntactic Structures. p. 11. Clotaire R. The Culture Code: An Ingenious Way to Understand Why People Around the World Live and Buy as They Do. New York, 2006. ISBN 978-0-7679-2056-8Darrow, A.; Haack, P.; Kuribayashi, F. (1987). "American Nonmusic Majors Descriptors and Preferences for Eastern and Western Musics by Japanese and". Journal of Research in Music Education. 35 (4): 237–248. doi:10.2307/3345076. JSTOR 3345076.Demorest, S. M.; Morrison, S. J.; Beken, M. N.; Jungbluth, D. (2008). "Lost in translation: An enculturation effect in music memory performance". Music Perception. 25 (3): 213–223. doi:10.1525/mp.2008.25.3.213. Fortson IV, Benjamin W. (2004). Indo-European Language and Culture: An Introduction. Blackwell. p. 186. ISBN 978-1405188968. "[The Aṣṭādhyāyī] is a highly precise and thorough description of the structure of Sanskrit somewhat resembling modern generative grammar...[it] remained the most advanced linguistic analysis of any kind until the twentieth century."Giorgio, Graffi (2001). 200 Years of Syntax: A Critical Survey (googlebook preview). John Benjamins Publishing. ISBN 9789027284570.Gittens,William Anderson ,Author, Cinematographer,Dip., Com., Arts. B.A. Media Arts Specialists’ Editor-in-Chief Devgro Media Arts Services Publishing ®2015 License Cultural Practitioner, Publisher, CEO Devgro Media Arts Services®2015Gittens,William Anderson,Author, Cinematographer, Dip., Com., Arts. B.A. Media Arts Specialists’ Editor in Chief Devgro Media Arts Services Publishing ®2015 License Cultural Practitioner, Publisher, CEO Devgro Media Arts Services®2015 http://changingminds.org/techniques/questioning/open_cloSupport the show (http://www.buzzsprout.com/429292)
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.06.327742v1?rss=1 Authors: Kliche, J., Ali, M., Ivarsson, Y. Abstract: The spike protein of the SARS-CoV-2 interacts with angiotensin converting enzyme 2 (ACE2) and enters the host cell by receptor-mediated endocytosis. Concomitantly, evidence is pointing to the involvement of additional host cell receptors, such as integrins. The cytoplasmic tails of ACE2 and integrin beta3 contain a plethora of predicted binding motifs. Here, we confirm the functionality of some of these motifs through affinity measurements. The class I PDZ binding motif in the ACE2 cytoplasmic tail binds the first PDZ domain of the scaffold protein NHERF3. The clathrin-adaptor subunit AP2 Mu2 interacts with an endocytic motif in the ACE2 with low affinity and the interaction is abolished by phosphorylation of Tyr781. Furthermore, the C-terminal region of integrin beta3 contains a LC3-interacting region, and its interaction with ATG8 domains is enhanced by phosphorylation. Together, our data provides possible molecular links between host cell receptors and endocytosis and autophagy Copy rights belong to original authors. Visit the link for more info
So folks think that illegalizing a commonly abused drug like marijuana actually solves the conundrum. On the flip side, the reality has been a mess, so far. Drug use among the youth is on an upward trajectory. Concomitantly, criminal activities are at an all-time high, thanks partly to drug abuse and addiction. Paradoxically, making marijuana illegal only serves to exercerbate the sprouting security concerns stemming from drug use. In this episode, I invite you to think with me; how legalising weed is the path we should tread!!!
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.26.221770v1?rss=1 Authors: Cao, E., Zhao, Y., Zhou, M., Shen, J., Wang, Q. Abstract: Secondary active cation-chloride cotransporters (CCCs) catalyze electroneutral symport of Cl- with Na+ and/or K+ across membranes1,2. CCCs are fundamental in cell volume homeostasis, transepithelia ion movement, maintenance of intracellular Cl- concentration, and inhibitory synaptic transmission3-6. K+-Cl- cotransport 1 (KCC1) was first characterized in red blood cells and later in many other cell types as a crucial player in regulatory volume decrease in defense against cell swelling upon hypotonic challenges7,8. Here we present two cryo-EM structures of human KCC1: one captured in an inward-open state and another arrested in an outward-open state by a small molecule inhibitor. KCC1 can surprisingly adopt two distinct dimeric architectures via homotypic association of different protein domains and conversion between these two forms of dimers may entail dynamic formation and rupture of two interdigitating regulatory cytoplasmic domains. The inhibitor wedges into and forces open an extracellular ion permeation path and arrests KCC1 in an outward-open conformation. Concomitantly, the outward-open conformation involves inward movement of the transmembrane helix 8 and occlusion of the intracellular exit by a conserved short helix within the intracellular loop 1. Our structures provide a blueprint for understanding the mechanisms of CCC transporters and their inhibition by small molecule compounds. Copy rights belong to original authors. Visit the link for more info
Ostensibly,Silence is the absence of ambient audible sound, the emission of sounds of such low intensity that they do not draw attention to themselves, or the state of having ceased to produce sounds; this latter sense can be extended to apply to the cessation or absence of any form of communication, whether through speech or other medium.Professor Margaret Montoya purports that silence has many meanings.It signifies different things in different cultures. It also changes depending on the context. Concomitantly, one thing for sure Silence can mean many things especially in interpersonal relationships. It's ambiguous. It can express lots of different emotions ranging from joy, happiness, grief, embarrassment to anger, denial, fear, withdrawal of acceptance or love. WILLIAM Anderson GittensAuthor, Cinematographer,Dip., Com., Arts. B.A. Media Arts Specialists’ Editor-in-Chief License Cultural Practitioner, Publisher, Student of Film, CEO Devgro Media Arts ServicesiMovie and Devgro Media Arts ServicesPresent A Devgro Media Arts Services Production In Association With iMovie A William Anderson Gittens Podcast The Silence In Culture©2020Directed,Edited,Produced, Shoot on Location, Scripted, and Narrated By William Anderson Gittens Author, Dip. Com. Art, Editor-In-Chief, Media Arts Specialist Publisher, License Cultural Practitioner PodcasterCEO Devgro Media Arts ServicesSome of the digital flowers Filmed on Location Thorsby Barbados-WORKS CITED"Messiah Part II". May 16, 2020. Retrieved May 25, 2020 – via Wikipedia."Silence | Define Silence at Dictionary.com". Dictionary.reference.com. Retrieved 2013-08-15."Silent Films on JSTOR". www.jstor.org. Retrieved October 29, 2019.Ann Mullen (November 8, 2000). "Breaking the blue code". Metro Times. Retrieved December 29, 2014.Armstrong, P. (2007, July). Cultures of silence: Giving voice to marginalized communities. Paper presented at the meeting of the Standing Conference on University Research and Teaching in the Education of Adults, Belfast, Northern Ireland.Bartje Bartmans (1 August 2015). "Igor Stravinsky - Les Noces (1923)" – via YouTubBlack 2006, xvi.Britain Yearly Meeting, "Quaker Faith and Practice"Bromberg, Serge; Lang, Eric (directors) (2012). The Extraordinary Voyage (DVD). MKS/Steamboat Films.Brookfield, S. (2006). The Skillful Teacher: On Techniques, Trust, and Tesponsiveness in theBrownlow, Kevin (1968a). The Parade's Gone By... New York: Alfred A. Knopf.Busoni, Ferruccio (1911). Sketch of a New Esthetic of Music. New York: G. Schirmer. p. 23.Cage, J.(1952), 4’33", Published by Edition Peters (PE.P06777)Charles Darwin (2004). The Descent of Man. London: Penguin Books. pg. 123.Chin, Gabriel; Wells, Scott (1998). "The "Blue Wall of Silence" and "the Blue Curtain of Secrecy" as Evidence of Bias and Motive to Lie: A New Approach to Police Perjury". University of Pittsburgh Law Review. 59: 233. SSRN 1810012.Christalyn Brannen (2002), Going to Japan on Business: Protocol, Strategies, and Language for the Corporate Traveler, Stone Bridge Press, p. 73, ISBN 978-1-880656-73-0Classroom (2nd edition), Jossey-Bass, 2006.Cook, David A. (1990). A History of Narrative Film (2nd ed.). New York: W.W. Norton. ISBN 978-0-393-95553-8.Cooper, Barry (Spring 2011). "Beethoven's Uses of Silence". The Musical Times. 152 (1914): 25–43. JSTOR 23039954.Cox, Christoph; Warner, Daniel (2004). Audio Culture: Readings in Modern Music.:Current, Richard Nelson; CuSupport the show (http://www.buzzsprout.com/429292)
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.09.194704v1?rss=1 Authors: Paulina G. Eusebi, Natalia Sevane, Manuel Pizarro, Marta Valero-Lorenzo, Susana Dunner Abstract: Aggressive behavior is an ancient and conserved trait considered habitual and essential for most animals in order to eat, protect themselves from predators and also to compete for mating and defend their territories. Genetic factors have shown to play an important role in the development of aggression both in animals and humans, displaying moderate to high heritability estimates. However, although such types of conducts have been studied in different animal models, the molecular architecture of aggressiveness remains poorly understood. This study compared gene expression profiles of 16 prefrontal cortex (PFC) samples from aggressive and non-aggressive cattle breeds: Lidia, selected for agonistic responses, and Wagyu, specialized on meat production and selected for tameness. RNA sequencing was used to identify 918 up and 278 down-regulated differentiated expressed genes (DEG). The functional interpretation of the up-regulated genes in the aggressive cohort revealed enrichment of pathways such as the Alzheimer disease-presenilin, integrins or the ERK/MAPK signaling cascade, all implicated in the development of abnormal aggressive behaviors and neurophysiological disorders. Moreover, gonadotropins, leading to testosterone release, are also up-regulated as natural mechanisms enhancing aggression. Concomitantly, heterotrimeric G-protein pathways, associated with low reactivity mental states, and the GAD2 gene, a repressor of agonistic reactions at PFC, are down-regulated, guaranteeing the development of the adequate responses required by the aggressive Lidia cattle. We also identified six upstream regulators, whose functional activity fits with the etiology of abnormal behavioral responses associated with aggression. These results provide valuable insights into the complex architecture that underlie naturally developed agonistic behaviors. Copy rights belong to original authors. Visit the link for more info
The Torah's message differs from the prophets': the former focuses on law, the latter on morals. Concomitantly, the prophets taught knowledge of God, while the Torah indicates that this is an impossibility: He is utterly unknowable. If you can know Hashem, then you should emulate Him; if you cannot, then you should obey the fixed, inflexible, and sometimes inscrutable law. Explore how these contradictory teachings are both true – on different levels of consciousness. Together, these diametrically opposed philosophies comprise one great system that allows for both negative theology and anthropomorphism. Please take a moment to subscribe and leave a review on Apple Podcasts. Thanks for listening! You can email Rabbi Burton with questions or comments at oros.yaakov@gmail.com
It is commonly thought that violence, injustice, and discrimination against religious minorities, especially in the Middle East, are a product of religious fundamentalism and myopia. Concomitantly, it is often argued, that more of secularism and less of religion represents the solution to this problem. In her stunning new book Religious Difference in a Secular Age: A Minority Report (Princeton University Press, 2015), Saba Mahmood, Professor of Anthropology at the University of California at Berkeley, brings such a celebratory view of secularism into fatal doubt. Through a careful and brilliant analysis, Mahmood convincingly shows that far from a solution to the problem of interreligious strife, political secularism and modern secular governance are in fact intimately entwined to the exacerbation of religious tensions in the Middle East. Focusing on Egypt and the experience of Egyptian Copts and Bahais, Mahmood explores multiple conceptual and discursive registers to highlight the paradoxical qualities of political secularism, arguing that majority/minority conflict in Egypt is less a reflection of the failure of secularism and more a product of secular discourses and politics, both within and outside the country. In our conversation, we touched on the salient features of this book such as the concept of political secularism and its applicability to a context such as Egypt, the genealogy of minority rights and religious liberty in the Middle East, discourses of minority rights and citizenship in relation to the Egyptian Copts, the discourse of public order and the regulation of Bahai religious identity and difference in Egypt, secularism, family law, and sexuality and the category of secularity and particular understandings of time, history, and scripture brought into view by the controversy generated in Egypt by the novel Azazeel. This theoretically rigorous book is also wonderfully written, making it particularly suitable for graduate and undergraduate courses on Islam, the Middle East, secularism, religion and politics, gender and sexuality, and theories and methods in religion. Learn more about your ad choices. Visit megaphone.fm/adchoices
It is commonly thought that violence, injustice, and discrimination against religious minorities, especially in the Middle East, are a product of religious fundamentalism and myopia. Concomitantly, it is often argued, that more of secularism and less of religion represents the solution to this problem. In her stunning new book Religious...
It is commonly thought that violence, injustice, and discrimination against religious minorities, especially in the Middle East, are a product of religious fundamentalism and myopia. Concomitantly, it is often argued, that more of secularism and less of religion represents the solution to this problem. In her stunning new book Religious Difference in a Secular Age: A Minority Report (Princeton University Press, 2015), Saba Mahmood, Professor of Anthropology at the University of California at Berkeley, brings such a celebratory view of secularism into fatal doubt. Through a careful and brilliant analysis, Mahmood convincingly shows that far from a solution to the problem of interreligious strife, political secularism and modern secular governance are in fact intimately entwined to the exacerbation of religious tensions in the Middle East. Focusing on Egypt and the experience of Egyptian Copts and Bahais, Mahmood explores multiple conceptual and discursive registers to highlight the paradoxical qualities of political secularism, arguing that majority/minority conflict in Egypt is less a reflection of the failure of secularism and more a product of secular discourses and politics, both within and outside the country. In our conversation, we touched on the salient features of this book such as the concept of political secularism and its applicability to a context such as Egypt, the genealogy of minority rights and religious liberty in the Middle East, discourses of minority rights and citizenship in relation to the Egyptian Copts, the discourse of public order and the regulation of Bahai religious identity and difference in Egypt, secularism, family law, and sexuality and the category of secularity and particular understandings of time, history, and scripture brought into view by the controversy generated in Egypt by the novel Azazeel. This theoretically rigorous book is also wonderfully written, making it particularly suitable for graduate and undergraduate courses on Islam, the Middle East, secularism, religion and politics, gender and sexuality, and theories and methods in religion. Learn more about your ad choices. Visit megaphone.fm/adchoices
It is commonly thought that violence, injustice, and discrimination against religious minorities, especially in the Middle East, are a product of religious fundamentalism and myopia. Concomitantly, it is often argued, that more of secularism and less of religion represents the solution to this problem. In her stunning new book Religious Difference in a Secular Age: A Minority Report (Princeton University Press, 2015), Saba Mahmood, Professor of Anthropology at the University of California at Berkeley, brings such a celebratory view of secularism into fatal doubt. Through a careful and brilliant analysis, Mahmood convincingly shows that far from a solution to the problem of interreligious strife, political secularism and modern secular governance are in fact intimately entwined to the exacerbation of religious tensions in the Middle East. Focusing on Egypt and the experience of Egyptian Copts and Bahais, Mahmood explores multiple conceptual and discursive registers to highlight the paradoxical qualities of political secularism, arguing that majority/minority conflict in Egypt is less a reflection of the failure of secularism and more a product of secular discourses and politics, both within and outside the country. In our conversation, we touched on the salient features of this book such as the concept of political secularism and its applicability to a context such as Egypt, the genealogy of minority rights and religious liberty in the Middle East, discourses of minority rights and citizenship in relation to the Egyptian Copts, the discourse of public order and the regulation of Bahai religious identity and difference in Egypt, secularism, family law, and sexuality and the category of secularity and particular understandings of time, history, and scripture brought into view by the controversy generated in Egypt by the novel Azazeel. This theoretically rigorous book is also wonderfully written, making it particularly suitable for graduate and undergraduate courses on Islam, the Middle East, secularism, religion and politics, gender and sexuality, and theories and methods in religion. Learn more about your ad choices. Visit megaphone.fm/adchoices
It is commonly thought that violence, injustice, and discrimination against religious minorities, especially in the Middle East, are a product of religious fundamentalism and myopia. Concomitantly, it is often argued, that more of secularism and less of religion represents the solution to this problem. In her stunning new book Religious Difference in a Secular Age: A Minority Report (Princeton University Press, 2015), Saba Mahmood, Professor of Anthropology at the University of California at Berkeley, brings such a celebratory view of secularism into fatal doubt. Through a careful and brilliant analysis, Mahmood convincingly shows that far from a solution to the problem of interreligious strife, political secularism and modern secular governance are in fact intimately entwined to the exacerbation of religious tensions in the Middle East. Focusing on Egypt and the experience of Egyptian Copts and Bahais, Mahmood explores multiple conceptual and discursive registers to highlight the paradoxical qualities of political secularism, arguing that majority/minority conflict in Egypt is less a reflection of the failure of secularism and more a product of secular discourses and politics, both within and outside the country. In our conversation, we touched on the salient features of this book such as the concept of political secularism and its applicability to a context such as Egypt, the genealogy of minority rights and religious liberty in the Middle East, discourses of minority rights and citizenship in relation to the Egyptian Copts, the discourse of public order and the regulation of Bahai religious identity and difference in Egypt, secularism, family law, and sexuality and the category of secularity and particular understandings of time, history, and scripture brought into view by the controversy generated in Egypt by the novel Azazeel. This theoretically rigorous book is also wonderfully written, making it particularly suitable for graduate and undergraduate courses on Islam, the Middle East, secularism, religion and politics, gender and sexuality, and theories and methods in religion. Learn more about your ad choices. Visit megaphone.fm/adchoices
It is commonly thought that violence, injustice, and discrimination against religious minorities, especially in the Middle East, are a product of religious fundamentalism and myopia. Concomitantly, it is often argued, that more of secularism and less of religion represents the solution to this problem. In her stunning new book Religious Difference in a Secular Age: A Minority Report (Princeton University Press, 2015), Saba Mahmood, Professor of Anthropology at the University of California at Berkeley, brings such a celebratory view of secularism into fatal doubt. Through a careful and brilliant analysis, Mahmood convincingly shows that far from a solution to the problem of interreligious strife, political secularism and modern secular governance are in fact intimately entwined to the exacerbation of religious tensions in the Middle East. Focusing on Egypt and the experience of Egyptian Copts and Bahais, Mahmood explores multiple conceptual and discursive registers to highlight the paradoxical qualities of political secularism, arguing that majority/minority conflict in Egypt is less a reflection of the failure of secularism and more a product of secular discourses and politics, both within and outside the country. In our conversation, we touched on the salient features of this book such as the concept of political secularism and its applicability to a context such as Egypt, the genealogy of minority rights and religious liberty in the Middle East, discourses of minority rights and citizenship in relation to the Egyptian Copts, the discourse of public order and the regulation of Bahai religious identity and difference in Egypt, secularism, family law, and sexuality and the category of secularity and particular understandings of time, history, and scripture brought into view by the controversy generated in Egypt by the novel Azazeel. This theoretically rigorous book is also wonderfully written, making it particularly suitable for graduate and undergraduate courses on Islam, the Middle East, secularism, religion and politics, gender and sexuality, and theories and methods in religion. Learn more about your ad choices. Visit megaphone.fm/adchoices
It is commonly thought that violence, injustice, and discrimination against religious minorities, especially in the Middle East, are a product of religious fundamentalism and myopia. Concomitantly, it is often argued, that more of secularism and less of religion represents the solution to this problem. In her stunning new book Religious Difference in a Secular Age: A Minority Report (Princeton University Press, 2015), Saba Mahmood, Professor of Anthropology at the University of California at Berkeley, brings such a celebratory view of secularism into fatal doubt. Through a careful and brilliant analysis, Mahmood convincingly shows that far from a solution to the problem of interreligious strife, political secularism and modern secular governance are in fact intimately entwined to the exacerbation of religious tensions in the Middle East. Focusing on Egypt and the experience of Egyptian Copts and Bahais, Mahmood explores multiple conceptual and discursive registers to highlight the paradoxical qualities of political secularism, arguing that majority/minority conflict in Egypt is less a reflection of the failure of secularism and more a product of secular discourses and politics, both within and outside the country. In our conversation, we touched on the salient features of this book such as the concept of political secularism and its applicability to a context such as Egypt, the genealogy of minority rights and religious liberty in the Middle East, discourses of minority rights and citizenship in relation to the Egyptian Copts, the discourse of public order and the regulation of Bahai religious identity and difference in Egypt, secularism, family law, and sexuality and the category of secularity and particular understandings of time, history, and scripture brought into view by the controversy generated in Egypt by the novel Azazeel. This theoretically rigorous book is also wonderfully written, making it particularly suitable for graduate and undergraduate courses on Islam, the Middle East, secularism, religion and politics, gender and sexuality, and theories and methods in religion. Learn more about your ad choices. Visit megaphone.fm/adchoices
Fakultät für Physik - Digitale Hochschulschriften der LMU - Teil 05/05
Chirped pulse amplification in solid-state lasers is currently the method of choice for producing high-energy ultrashort pulses, having surpassed the performance of dye lasers over 20 years ago. The third generation of femtosecond technology based on short-pulse-pumped optical parametric chirped pulse amplification (OPCPA) holds promise for providing few-cycle pulses with terawatt-scale peak powers and kilowatt-scale-average powers simultaneously, heralding the next wave of attosecond and femtosecond science. OPCPA laser systems pumped by near-1-ps pulses support broadband and efficient amplification of few-cycle pulses due to their unrivaled gain per unit length. This is rooted in the high threshold for dielectric breakdown of the nonlinear crystals for even shorter pump pulse durations. Concomitantly, short pump pulses simplify dispersion management and improve the temporal contrast of the amplified signal. This thesis covers the main experimental and theoretical steps required to design and operate a high-power, high-energy, few-cycle OPCPA. This includes the generation of a broadband, high-contrast, carrier envelope phase (CEP)-stable seed, the practical use of a high-power thin-disk regenerative amplifier, its efficient use for pumping a multi-stage OPCPA chain and compression of the resulting pulses. A theoretical exploration of the concept and its extension to different modes of operation, including widely-tunable, high-power multi-cycle pulse trains, and ultrabroadband waveform synthesis is presented. Finally, a conceptual design of a field synthesizer with multi-terawatt, multi-octave light transients is discussed, which holds promise for extending the photon energy attainable via high harmonic generation to several kiloelectronvolts, nourishing the hope for attosecond spectroscopy at hard-x-ray wavelengths.
The Corps of the Finality (345.1) 31:0.1 THE Corps of Mortal Finaliters represents the present known destination of the ascending Adjuster-fused mortals of time. But there are other groups who are also assigned to this corps. The primary finaliter corps is composed of the following: (345.2) 31:0.2 1. Havona Natives. (345.3) 31:0.3 2. Gravity Messengers. (345.4) 31:0.4 3. Glorified Mortals. (345.5) 31:0.5 4. Adopted Seraphim. (345.6) 31:0.6 5. Glorified Material Sons. (345.7) 31:0.7 6. Glorified Midway Creatures. (345.8) 31:0.8 These six groups of glorified beings compose this unique body of eternal destiny. We think we know their future work, but we are not certain. While the Corps of the Mortal Finality is mobilizing on Paradise, and while they now so extensively minister to the universes of space and administer the worlds settled in light and life, their future destination must be the now-organizing universes of outer space. At least that is the conjecture of Uversa. (345.9) 31:0.9 The corps is organized in accordance with the working associations of the worlds of space and in keeping with the associative experience acquired throughout the long and eventful ascendant career. All the ascendant creatures admitted to this corps are received in equality, but this exalted equality in no way abrogates individuality or destroys personal identity. We can immediately discern, in communicating with a finaliter, whether he is an ascendant mortal, Havona native, adopted seraphim, midway creature, or Material Son. (345.10) 31:0.10 During the present universe age the finaliters return to serve in the universes of time. They are assigned to labor successively in the different superuniverses and never in their native superuniverses until after they have served in all the other six supercreations. Thus may they acquire the sevenfold concept of the Supreme Being. (345.11) 31:0.11 One or more companies of the mortal finaliters are constantly in service on Urantia. There is no domain of universe service to which they are not assigned; they function universally and with alternating and equal periods of assigned duty and free service. (345.12) 31:0.12 We have no idea as to the nature of the future organization of this extraordinary group, but the finaliters are now wholly a self-governing body. They choose their own permanent, periodic, and assignment leaders and directors. No outside influence can ever be brought to bear upon their policies, and their oath of allegiance is only to the Paradise Trinity. (346.1) 31:0.13 The finaliters maintain their own headquarters on Paradise, in the superuniverses, in the local universes, and on all the divisional capitals. They are a separate order of evolutionary creation. We do not directly manage them or control them, and yet they are absolutely loyal and always co-operative with all our plans. They are indeed the accumulating tried and true souls of time and space — the evolutionary salt of the universe — and they are forever proof against evil and secure against sin. 1. The Havona Natives (346.2) 31:1.1 Many of the Havona natives who serve as teachers in the pilgrim-training schools of the central universe become greatly attached to the ascending mortals and still more intrigued with the future work and destiny of the Corps of Mortal Finaliters. On Paradise there is maintained, at the administrative headquarters of the corps, a registry for Havona volunteers presided over by the associate of Grandfanda. Today, you will find millions upon millions of Havona natives upon this waiting list. These perfect beings of direct and divine creation are of great assistance to the Mortal Corps of Finality, and they will undoubtedly be of even greater service in the far-distant future. They provide the viewpoint of one born in perfection and divine repleteness. The finaliters thus embrace both phases of experiential existence — perfect and perfected. (346.3) 31:1.2 Havona natives must achieve certain experiential developments in liaison with evolutionary beings which will create reception capacity for the bestowal of a fragment of the spirit of the Universal Father. The Mortal Finaliter Corps has as permanent members only such beings as have been fused with the spirit of the First Source and Center, or who, like the Gravity Messengers, innately embody this spirit of God the Father. (346.4) 31:1.3 The inhabitants of the central universe are received into the corps in the ratio of one in a thousand — a finaliter company. The corps is organized for temporary service in companies of one thousand, the ascendant creatures numbering 997 to one Havona native and one Gravity Messenger. Finaliters are thus mobilized in companies, but the finality oath is administered individually. It is an oath of sweeping implications and eternal import. The Havona native takes the same oath and becomes forever attached to the corps. (346.5) 31:1.4 The Havona recruits follow the company of their assignment; wherever the group goes, they go. And you should see their enthusiasm in the new work of the finaliters. The possibility of attaining the Corps of the Finality is one of the superb thrills of Havona; the possibility of becoming a finaliter is one of the supreme adventures of these perfect races. (346.6) 31:1.5 The Havona natives are also received, in the same ratio, into the Corps of Conjoint Trinitized Finaliters on Vicegerington and into the Corps of Transcendental Finaliters on Paradise. The Havona citizens regard these three destinies as constituting the supreme goals of their supernal careers, together with their possible admission to the Corps of Havona Finaliters. 2. Gravity Messengers (346.7) 31:2.1 Wherever and whenever Gravity Messengers are functioning, the finaliters are in command. All Gravity Messengers are under the exclusive jurisdiction of Grandfanda, and they are assigned only to the primary Corps of the Finality. They are invaluable to the finaliters even now, and they will be all-serviceable in the eternal future. No other group of intelligent creatures possesses such a personalized messenger corps able to transcend time and space. Similar types of messenger-recorders attached to other finaliter corps are not personalized; they are absonitized. (347.1) 31:2.2 Gravity Messengers hail from Divinington, and they are modified and personalized Adjusters, but no one of our Uversa group will undertake to explain the nature of one of these messengers. We know they are highly personal beings, divine, intelligent, and touchingly understanding, but we do not comprehend their timeless technique of traversing space. They seem to be competent to utilize any and all energies, circuits, and even gravity. Finaliters of the mortal corps cannot defy time and space, but they have associated with them and subject to their command all but infinite spirit personalities who can. We presume to call Gravity Messengers personalities, but in reality they are superspirit beings, unlimited and boundless personalities. They are of an entirely different order of personality as compared with Solitary Messengers. (347.2) 31:2.3 Gravity Messengers may be attached to a finaliter company in unlimited numbers, but only one messenger, the chief of his fellows, is mustered into the Mortal Corps of the Finality. This chief however has assigned to him a permanent staff of 999 fellow messengers, and as occasion may require, he may call upon the reserves of the order for assistants in unlimited numbers. (347.3) 31:2.4 Gravity Messengers and glorified mortal finaliters achieve a touching and profound affection for one another; they have much in common: One is a direct personalization of a fragment of the Universal Father, the other a creature personality existent in the surviving immortal soul fused with a fragment of the same Universal Father, the spirit Thought Adjuster. 3. Glorified Mortals (347.4) 31:3.1 Ascendant Adjuster-fused mortals compose the bulk of the primary Corps of the Finality. Together with the adopted and glorified seraphim they usually constitute 990 in each finaliter company. The proportion of mortals and angels in any one group varies, though the mortals far outnumber the seraphim. The Havona natives, glorified Material Sons, glorified midway creatures, the Gravity Messengers, and the unknown and missing member make up only one per cent of the corps; each company of one thousand finaliters has places for just ten of these nonmortal and nonseraphic personalities. (347.5) 31:3.2 We of Uversa do not know the “finality destiny” of the ascendant mortals of time. At present they reside on Paradise and temporarily serve in the Corps of Light and Life, but such a tremendous course of ascendant training and such lengthy universe discipline must be designed to qualify them for even greater tests of trust and more sublime services of responsibility. (347.6) 31:3.3 Notwithstanding that these ascendant mortals have attained Paradise, have been mustered into the Corps of the Finality, and have been sent back in large numbers to participate in the conduct of local universes and to assist in the administration of superuniverse affairs — in the face of even this apparent destiny, there remains the significant fact that they are of record as only sixth-stage spirits. There undoubtedly remains one more step in the career of the Mortal Corps of the Finality. We do not know the nature of that step, but we have taken cognizance of, and here call attention to, three facts: (348.1) 31:3.4 1. We know from the records that mortals are spirits of the first order during their sojourn in the minor sectors, and that they advance to the second order when translated to the major sectors, and to the third when they go forward to the central training worlds of the superuniverse. Mortals become quartan or graduate spirits after reaching the sixth circle of Havona and become spirits of the fifth order when they find the Universal Father. They subsequently attain the sixth stage of spirit existence upon taking the oath that musters them forever into the eternity assignment of the Corps of the Mortal Finality. (348.2) 31:3.5 We observe that spirit classification, or designation, has been determined by actual advancement from one realm of universe service to another realm of universe service or from one universe to another universe; and we surmise that the bestowal of seventh-spirit classification upon the Mortal Corps of the Finality will be simultaneous with their advancement to eternal assignment for service on hitherto unrecorded and unrevealed spheres and concomitant with their attainment of God the Supreme. But aside from these bold conjectures, we really know no more about all this than you do; our knowledge of the mortal career does not go beyond present Paradise destiny. (348.3) 31:3.6 2. The mortal finaliters have fully complied with the injunction of the ages, “Be you perfect”; they have ascended the universal path of mortal attainment; they have found God, and they have been duly inducted into the Corps of the Finality. Such beings have attained the present limit of spirit progression but not finality of ultimate spirit status. They have achieved the present limit of creature perfection but not finality of creature service. They have experienced the fullness of Deity worship but not finality of experiential Deity attainment. (348.4) 31:3.7 3. The glorified mortals of the Paradise Corps of Finality are ascendant beings in possession of experiential knowledge of every step of the actuality and philosophy of the fullest possible life of intelligent existence, while during the ages of this ascent from the lowest material worlds to the spiritual heights of Paradise, these surviving creatures have been trained to the limits of their capacity respecting every detail of every divine principle of the just and efficient, as well as merciful and patient, administration of all the universal creation of time and space. (348.5) 31:3.8 We deem that human beings are entitled to share our opinions, and that you are free to conjecture with us respecting the mystery of the ultimate destiny of the Paradise Corps of Finality. It seems evident to us that the present assignments of the perfected evolutionary creatures partake of the nature of postgraduate courses in universe understanding and superuniverse administration; and we all ask, “Why should the Gods be so concerned in so thoroughly training surviving mortals in the technique of universe management?” 4. Adopted Seraphim (348.6) 31:4.1 Many of the faithful seraphic guardians of mortals are permitted to go through the ascendant career with their human wards, and many of these guardian angels, after becoming Father fused, join their subjects in taking the finaliter oath of eternity and forever accept the destiny of their mortal associates. Angels who pass through the ascending experience of mortal beings may share the destiny of human nature; they may equally and eternally be mustered into this Corps of the Finality. Large numbers of the adopted and glorified seraphim are attached to the various nonmortal finaliter corps. 5. Glorified Material Sons (349.1) 31:5.1 There is provision in the universes of time and space whereby the Adamic citizens of the local systems, when long delayed in receiving planetary assignment, may initiate a petition for release from permanent-citizenship status. And if granted, they join the ascending pilgrims on the universe capitals and thence proceed onward to Paradise and the Corps of the Finality. (349.2) 31:5.2 When an advanced evolutionary world attains the later eras of the age of light and life, the Material Sons, the Planetary Adam and Eve, may elect to humanize, receive Adjusters, and embark upon the evolutionary course of universe ascent leading to the Corps of Mortal Finaliters. Certain of these Material Sons have partially failed or technically defaulted in their mission as biologic accelerators, as Adam did on Urantia; and then are they compelled to take the natural course of the peoples of the realm, receive Adjusters, pass through death, and progress by faith through the ascendant regime, subsequently attaining Paradise and the Corps of the Finality. (349.3) 31:5.3 These Material Sons are not to be found in many finaliter companies. Their presence lends great potential to the possibilities of high service for such a group, and they are invariably chosen as its leaders. If both of the Edenic pair are attached to the same group, they are usually permitted to function jointly, as one personality. Such ascendant pairs are far more successful in the adventure of trinitizing than are the ascendant mortals. 6. Glorified Midway Creatures (349.4) 31:6.1 On many planets the midway creatures are produced in large numbers, but they seldom tarry on their native world subsequent to its being settled in light and life. Then, or soon thereafter, they are released from permanent-citizenship status and start on the ascension to Paradise, passing through the morontia worlds, the superuniverse, and Havona in company with the mortals of time and space. (349.5) 31:6.2 The midway creatures from various universes differ greatly in origin and nature, but they are all destined to one or another of the Paradise finality corps. The secondary midwayers are all eventually Adjuster fused and are mustered into the mortal corps. Many finaliter companies have one of these glorified beings in their group. 7. The Evangels of Light (349.6) 31:7.1 At the present time every finaliter company numbers 999 personalities of oath status, permanent members. The vacant place is occupied by the chief of attached Evangels of Light assigned on any single mission. But these beings are only transient members of the corps. (349.7) 31:7.2 Any celestial personality assigned to the service of any finaliter corps is denominated an Evangel of Light. These beings do not take the finaliter oath, and though subject to the corps organization they are not of permanent attachment. This group may embrace Solitary Messengers, supernaphim, seconaphim, Paradise Citizens, or their trinitized offspring — any being required in the prosecution of a transient finaliter assignment. Whether or not the corps is to have these beings attached to the eternal mission, we do not know. At the conclusion of attachment these Evangels of Light resume their former status. (350.1) 31:7.3 As the Mortal Corps of the Finality is at present constituted, there are just six classes of permanent members. The finaliters, as might be expected, engage in much speculation as to the identity of their future comrades, but there is little agreement among them. (350.2) 31:7.4 We of Uversa often conjecture respecting the identity of the seventh group of finaliters. We entertain many ideas, embracing possible assignment of some of the accumulating corps of the numerous trinitized groups on Paradise, Vicegerington, and the inner Havona circuit. It is even conjectured that the Corps of the Finality may be permitted to trinitize many of their assistants in the work of universe administration in the event they are destined to the service of universes now in the making. (350.3) 31:7.5 One of us holds the opinion that this vacant place in the corps will be filled by some type of being of origin in the new universe of their future service; the other inclines to the belief that this place will be occupied by some type of Paradise personality not yet created, eventuated, or trinitized. But we will most likely await the entrance of the finaliters upon their seventh stage of spirit attainment before we really know. 8. The Transcendentalers (350.4) 31:8.1 Part of the perfected mortal’s experience on Paradise as a finaliter consists in the effort to achieve comprehension of the nature and function of more than one thousand groups of the transcendental supercitizens of Paradise, eventuated beings of absonite attributes. In their association with these superpersonalities, the ascendant finaliters receive great assistance from the helpful guidance of numerous orders of transcendental ministers who are assigned to the task of introducing the evolved finaliters to their new Paradise brethren. The entire order of the Transcendentalers live in the west of Paradise in a vast area which they exclusively occupy. (350.5) 31:8.2 In the discussion of Transcendentalers we are restricted, not only by the limitations of human comprehension, but also by the terms of the mandate governing these disclosures concerning the personalities of Paradise. These beings are in no way connected with the mortal ascent to Havona. The vast host of the Paradise Transcendentalers have nothing whatever to do with the affairs of either Havona or the seven superuniverses, being concerned only with the superadministration of the affairs of the master universe. (350.6) 31:8.3 You, being a creature, can conceive of a Creator, but you can hardly comprehend that there exists an enormous and diversified aggregation of intelligent beings who are neither Creators nor creatures. These Transcendentalers create no beings, neither were they ever created. In speaking of their origin, in order to avoid using a new term — an arbitrary and meaningless designation — we deem it best to say that Transcendentalers simply eventuate. The Deity Absolute may well have been concerned in their origin and may be implicated in their destiny, but these unique beings are not now dominated by the Deity Absolute. They are subject to God the Ultimate, and their present Paradise sojourn is in every way Trinity supervised and directed. (351.1) 31:8.4 Although all mortals who attain Paradise frequently fraternize with the Transcendentalers as they do with the Paradise Citizens, it develops that man’s first serious contact with a Transcendentaler occurs on that eventful occasion when, as a member of a new finaliter group, the mortal ascender stands in the finaliter receiving circle as the Trinity oath of eternity is administered by the chief of Transcendentalers, the presiding head of the Architects of the Master Universe. 9. Architects of the Master Universe (351.2) 31:9.1 The Architects of the Master Universe are the governing corps of the Paradise Transcendentalers. This governing corps numbers 28,011 personalities possessing master minds, superb spirits, and supernal absonites. The presiding officer of this magnificent group, the senior Master Architect, is the co-ordinating head of all Paradise intelligences below the level of Deity. (351.3) 31:9.2 The sixteenth proscription of the mandate authorizing these narratives says: “If deemed wise, the existence of the Architects of the Master Universe and their associates may be disclosed, but their origin, nature, and destiny may not be fully revealed.” We may, however, inform you that these Master Architects exist in seven levels of the absonite. These seven groups are classified as follows: (351.4) 31:9.3 1. The Paradise Level. Only the senior or first-eventuated Architect functions on this highest level of the absonite. This ultimate personality — neither Creator nor creature — eventuated in the dawn of eternity and now functions as the exquisite co-ordinator of Paradise and its twenty-one worlds of associated activities. (351.5) 31:9.4 2. The Havona Level. The second Architect eventuation yielded three master planners and absonite administrators, and they have always been devoted to the co-ordination of the one billion perfect spheres of the central universe. Paradise tradition asserts that these three Architects, with the counsel of the pre-eventuated senior Architect, contributed to the planning of Havona, but we really do not know. (351.6) 31:9.5 3. The Superuniverse Level. The third absonite level embraces the seven Master Architects of the seven superuniverses, who now, as a group, spend about equal time in the company of the Seven Master Spirits on Paradise and with the Seven Supreme Executives on the seven special worlds of the Infinite Spirit. They are the superco-ordinators of the grand universe. (351.7) 31:9.6 4. The Primary Space Level. This group numbers seventy Architects, and we conjecture that they are concerned with the ultimate plans for the first universe of outer space, now mobilizing beyond the borders of the present seven superuniverses. (351.8) 31:9.7 5. The Secondary Space Level. This fifth corps of Architects numbers 490, and again we conjecture that they must be concerned with the second universe of outer space, where already our physicists have detected definite energy mobilizations. (352.1) 31:9.8 6. The Tertiary Space Level. This sixth group of Master Architects numbers 3,430, and we likewise infer that they may be occupied with the gigantic plans for the third universe of outer space. (352.2) 31:9.9 7. The Quartan Space Level. This, the final and largest corps, consists of 24,010 Master Architects, and if our former conjectures are valid, it must be related to the fourth and last of the ever-increasing-sized universes of outer space. (352.3) 31:9.10 These seven groups of Master Architects total 28,011 universe planners. On Paradise there is a tradition that far back in eternity there was attempted the eventuation of the 28,012th Master Architect, but that this being failed to absonitize, experiencing personality seizure by the Universal Absolute. It is possible that the ascending series of the Master Architects attained the limit of absonity in the 28,011th Architect, and that the 28,012th attempt encountered the mathematical level of the presence of the Absolute. In other words, at the 28,012th eventuation level the quality of absonity equivalated to the level of the Universal and attained the value of the Absolute. (352.4) 31:9.11 In their functional organization the three supervising Architects of Havona act as associate assistants to the solitary Paradise Architect. The seven Architects of the superuniverses act as co-ordinates of the three supervisors of Havona. The seventy planners of the universes of the primary outer space level are at present serving as associate assistants to the seven Architects of the seven superuniverses. (352.5) 31:9.12 The Architects of the Master Universe have at their disposal numerous groups of assistants and helpers, including two vast orders of force organizers, the primary eventuated and the associate transcendental. These Master Force Organizers are not to be confused with the power directors, who are germane to the grand universe. (352.6) 31:9.13 All beings produced by the union of the children of time and eternity, such as the trinitized offspring of the finaliters and the Paradise Citizens, become wards of the Master Architects. But of all other creatures or entities revealed as functioning in the present organized universes, only Solitary Messengers and Inspired Trinity Spirits maintain any organic association with the Transcendentalers and the Architects of the Master Universe. (352.7) 31:9.14 The Master Architects contribute technical approval of the assignment of the Creator Sons to their space sites for the organization of the local universes. There is a very close association between the Master Architects and the Paradise Creator Sons, and while this relationship is unrevealed, you have been informed of the association of the Architects and the grand universe Supreme Creators in the relationship of the first experiential Trinity. These two groups, together with the evolving and experiential Supreme Being, constitute the Trinity Ultimate of transcendental values and master universe meanings. 10. The Ultimate Adventure (352.8) 31:10.1 The senior Master Architect has the oversight of the seven Corps of the Finality, and they are: (352.9) 31:10.2 1. The Corps of Mortal Finaliters. (352.10) 31:10.3 2. The Corps of Paradise Finaliters. (352.11) 31:10.4 3. The Corps of Trinitized Finaliters. (353.1) 31:10.5 4. The Corps of Conjoint Trinitized Finaliters. (353.2) 31:10.6 5. The Corps of Havona Finaliters. (353.3) 31:10.7 6. The Corps of Transcendental Finaliters. (353.4) 31:10.8 7. The Corps of Unrevealed Sons of Destiny. (353.5) 31:10.9 Each of these destiny corps has a presiding head, and the seven constitute the Supreme Council of Destiny on Paradise; and during the present universe age Grandfanda is the chief of this supreme body of universe assignment for the children of ultimate destiny. (353.6) 31:10.10 The gathering together of these seven finaliter corps signifies reality mobilization of potentials, personalities, minds, spirits, absonites, and experiential actualities that probably transcend even the future master universe functions of the Supreme Being. These seven finaliter corps probably signify the present activity of the Ultimate Trinity engaged in mustering the forces of the finite and the absonite in preparation for inconceivable developments in the universes of outer space. Nothing like this mobilization has taken place since the near times of eternity when the Paradise Trinity similarly mobilized the then existing personalities of Paradise and Havona and commissioned them as administrators and rulers of the projected seven superuniverses of time and space. The seven finaliter corps represent the divinity response of the grand universe to the future needs of the undeveloped potentials in the outer universes of future-eternal activities. (353.7) 31:10.11 We venture the forecast of future and greater outer universes of inhabited worlds, new spheres peopled with new orders of exquisite and unique beings, a material universe sublime in its ultimacy, a vast creation lacking in only one important detail — the presence of actual finite experience in the universal life of ascendant existence. Such a universe will come into being under a tremendous experiential handicap: the deprivation of participation in the evolution of the Almighty Supreme. These outer universes will all enjoy the matchless ministry and supernal overcontrol of the Supreme Being, but the very fact of his active presence precludes their participation in the actualization of the Supreme Deity. (353.8) 31:10.12 During the present universe age the evolving personalities of the grand universe suffer many difficulties due to the incomplete actualization of the sovereignty of God the Supreme, but we are all sharing the unique experience of his evolution. We evolve in him and he evolves in us. Sometime in the eternal future the evolution of Supreme Deity will become a completed fact of universe history, and the opportunity to participate in this wonderful experience will have passed from the stage of cosmic action. (353.9) 31:10.13 But those of us who have acquired this unique experience during the youth of the universe will treasure it throughout all future eternity. And many of us speculate that it may be the mission of the gradually accumulating reserves of the ascendant and perfected mortals of the Corps of the Finality, in association with the other six similarly recruiting corps, to administer these outer universes in an effort to compensate their experiential deficiencies in not having participated in the time-space evolution of the Supreme Being. (353.10) 31:10.14 These deficiencies are inevitable on all levels of universe existence. During the present universe age we of the higher levels of spiritual existences now come down to administer the evolutionary universes and minister to the ascending mortals, thus endeavoring to atone for their deficiencies in the realities of the higher spiritual experience. (354.1) 31:10.15 But though we really know nothing about the plans of the Architects of the Master Universe respecting these outer creations, nevertheless, of three things we are certain: (354.2) 31:10.16 1. There actually is a vast and new system of universes gradually organizing in the domains of outer space. New orders of physical creations, enormous and gigantic circles of swarming universes upon universes far out beyond the present bounds of the peopled and organized creations, are actually visible through your telescopes. At present, these outer creations are wholly physical; they are apparently uninhabited and seem to be devoid of creature administration. (354.3) 31:10.17 2. For ages upon ages there continues the unexplained and wholly mysterious Paradise mobilization of the perfected and ascendant beings of time and space, in association with the six other finaliter corps. (354.4) 31:10.18 3. Concomitantly with these transactions the Supreme Person of Deity is powerizing as the almighty sovereign of the supercreations. (354.5) 31:10.19 As we view this triune development, embracing creatures, universes, and Deity, can we be criticized for anticipating that something new and unrevealed is approaching culmination in the master universe? Is it not natural that we should associate this agelong mobilization and organization of physical universes on such a hitherto unknown scale and the personality emergence of the Supreme Being with this stupendous scheme of upstepping the mortals of time to divine perfection and with their subsequent mobilization on Paradise in the Corps of the Finality — a designation and destiny enshrouded in universe mystery? It is increasingly the belief of all Uversa that the assembling Corps of the Finality are destined to some future service in the universes of outer space, where we already are able to identify the clustering of at least seventy thousand aggregations of matter, each of which is greater than any one of the present superuniverses. (354.6) 31:10.20 Evolutionary mortals are born on the planets of space, pass through the morontia worlds, ascend the spirit universes, traverse the Havona spheres, find God, attain Paradise, and are mustered into the primary Corps of the Finality, therein to await the next assignment of universe service. There are six other assembling finality corps, but Grandfanda, the first mortal ascender, presides as Paradise chief of all orders of finaliters. And as we view this sublime spectacle, we all exclaim: What a glorious destiny for the animal-origin children of time, the material sons of space! (354.7) 31:10.21 [Jointly sponsored by a Divine Counselor and One without Name and Number authorized so to function by the Ancients of Days on Uversa.] ~ ~ ~ ~ ~* (354.8) 31:10.22 These thirty-one papers depicting the nature of Deity, the reality of Paradise, th
Adrenocortical carcinoma (ACC) is a rare and highly aggressive endocrine neoplasm, with limited therapeutic options. Activating β-catenin somatic mutations are found in ACC and have been associated with a poor clinical outcome. In fact, activation of the Wnt/β-catenin signaling pathway seems to play a major role in ACC aggressiveness, and might, thus, represent a promising therapeutic target. Similar to patient tumor specimen the H295 cell line derived from an ACC harbors a natural activating β-catenin mutation. We herein assess the in vitro and in vivo effect of β-catenin inactivation using a doxycyclin (dox) inducible shRNA plasmid in H295R adrenocortical cancer cells line (clone named shβ). Following dox treatment a profound reduction in β-catenin expression was detectable in shβ clones in comparison to control clones (Ctr). Accordingly, we observed a decrease in Wnt/βcatenin-dependent luciferase reporter activity as well as a decreased expression of AXIN2 representing an endogenous β-catenin target gene. Concomitantly, β-catenin silencing resulted in a decreased cell proliferation, cell cycle alterations with cell accumulation in the G1 phase and increased apoptosis in vitro. In vivo, on established tumor xenografts in athymic nude mice, 9 days of β-catenin silencing resulted in a significant reduction of CTNNB1 and AXIN2 expression. Moreover, continous β-catenin silencing, starting 3 days after tumor cell inoculation, was associated with a complete absence of tumor growth in the shβ group while tumors were present in all animals of the control group. In summary, these experiments provide evidences that Wnt/β-catenin pathway inhibition in ACC is a promising therapeutic target.
Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 05/06
Oxygenic photosynthesis converts light energy into chemical energy and is responsible for generating most of our atmosphere’s oxygen and biomass on earth. Several multimeric protein complexes are involved in the underlying photosynthetic electron transfer chain with photosystem II (PSII) representing the initial complex mediating the extraction of electrons from water molecules, thus generating molecular oxygen as a by-product. During recent years, the structural details and components of the PSII complex, including its inorganic and organic cofactors, have been elucidated in great detail. However, little is known about the assembly pathway of this at least 20 protein subunits containing machinery. Previous work indicated that PSII assembly occurs in a step-wise fashion and requires a number of facilitating factors, which interact transiently with nascent PSII complexes. Earlier studies of one of those assembly factors, the cyanobacterial PratA protein, suggested that PSII biogenesis does not only underlie a temporal order but is also organized at the spatial level, as PratA was shown to mark a special intermediate membrane subfraction (PDMs), hypothesized to represent regions for initial steps of PSII biogenesis. The presented work focused on a more detailed characterization of PDMs, clearly supporting their significance not only with regard to early protein assembly, but also concerning pigment synthesis and integration into the PSII precomplexes. The PDMs could further be allocated to special membrane regions, named biogenesis centers, at sites where thylakoid membranes converge to the plasma membrane, thus demonstrating the spatial organization of PSII assembly at the cellular level. Moreover, a novel function of PratA in preloading of PSII with Mn2+ ions, necessary for construction of the water-splitting complex, was discovered. Concomitantly with progression of the assembly, the nascent PSII complexes are transported from the PDMs to the thylakoid membrane system, where Sll0933 – a novel PSII assembly factor identified in this thesis – mediates the integration of the PSII inner antenna proteins followed by completion of the assembly process. Additionally, it could be shown that many of the so far identified facilitating factors interact with each other and, thus, form a complex network for PSII assembly. Especially the interaction between the two assembly factors YCF48 and Sll0933 was characterized in more detail, revealing a successive mode of action with YCF48 operating upstream of Sll0933. Taken together, the presented results enable the development of an extended and elaborated model of PSII assembly, which is a concerted process connecting protein and cofactor synthesis/integration in a spatiotemporal manner, and thus contribute to a more profound understanding of photosynthesis itself.
Restless legs syndrome (RLS) is a sensorimotor disorder with an age-dependent prevalence of up to 10% in the general population above 65 years of age. Affected individuals suffer from uncomfortable sensations and an urge to move in the lower limbs that occurs mainly in resting situations during the evening or at night. Moving the legs or walking leads to an improvement of symptoms. Concomitantly, patients report sleep disturbances with consequences such as reduced daytime functioning. We conducted a genome-wide association study (GWA) for RLS in 922 cases and 1,526 controls (using 301,406 SNPs) followed by a replication of 76 candidate SNPs in 3,935 cases and 5,754 controls, all of European ancestry. Herein, we identified six RLS susceptibility loci of genome-wide significance, two of them novel: an intergenic region on chromosome 2p14 (rs6747972, P = 9.03 x 10(-11), OR = 1.23) and a locus on 16q12.1 (rs3104767, P = 9.4 x 10(-19), OR = 1.35) in a linkage disequilibrium block of 140 kb containing the 59-end of TOX3 and the adjacent non-coding RNA BC034767.
Dendritic cells (DCs) are bone marrow-derived professional antigen-presenting cells that act as master regulators of acquired and innate immune responses. While descriptions of cells with dendritic morphology in rodent kidneys date back to the early 1970s, a network of DCs in the mouse kidney has only recently been described. DCs acquire distinct phenotypic and functional characteristics depending on the microenvironment and the disease stages. Concomitantly, their communication with cells of the adaptive immunity might have tissue-protective or tissue-deleterious consequences. This review summarizes results from recent studies on the role of DCs in experimental renal inflammation. Copyright (C) 2011 S. Karger AG, Basel
Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 02/19
Topical tacrolimus (FK506) leads to profound phenotypic and functional alterations of epidermal antigen-presenting dendritic cells in atopic dermatitis. BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease in which antigen-presenting epidermal dendritic cells (DCs), ie, Langerhans cells and the so-called inflammatory dendritic epidermal cells (IDECs) expressing the high-affinity receptor for IgE (FcepsilonRI) may play a significant pathophysiologic role. Therapeutic efficacy of the immunosuppressive macrolide tacrolimus (FK506) in AD has been demonstrated in clinical trials, but little is known of its mode of action. OBJECTIVE: The present study focused on the effects of topical tacrolimus treatment on epidermal CD1a+/FcepsilonRI+ DC populations in lesional AD. METHODS: Immunohistological analysis, epidermal DC phenotyping, and functional studies were performed on skin biopsy specimens from treated and untreated lesional skin of 10 patients with AD participating in a clinical trial with tacrolimus. RESULTS: Untreated lesional skin was characterized by a high proportion of CD1a+ cells, which was largely due to a high proportion of IDECs strongly expressing FcepsilonRI. Epidermal DCs isolated from untreated lesional skin exhibited high stimulatory activity toward autologous T cells, which was strongly reduced while clinical improvement was seen during application of tacrolimus. Concomitantly, a decreased FcepsilonRI expression was observed in both Langerhans cells and IDECs. Finally, topical tacrolimus led to a progressive decrease in the IDEC population within the pool of CD1a+ epidermal DCs and also to a decrease in their CD36 expression, which is indicative of lower local inflammation. CONCLUSION: Epidermal CD1a+ DCs may represent a target for topical tacrolimus in the treatment of AD.
Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 01/06
Due to enormous progress in recombinant DNA techniques and methodology, a multitude of biosynthetic, pharmaceutically relevant polypeptides and proteins became available in the past decade and have been employed in numerous pharmaceutical products. Concomitantly, substantial progress was made in pharmaceutical formulation development of peptides and proteins, inasmuch as many challenges in formulating these compounds in products with optimal therapeutic effects and shelf life were successfully approached. Additionally, new drug delivery systems – e.g., based on polymeric materials – will most likely enlarge the spectrum of future proteinic dosage forms, where today solutions and lyophilized products take center stage. Yet, due to the proneness of proteins to degradation - what can affect pharmaceutical relevant features such as biological activity and immunogenicity -, scrutinizing the homogeneity of protein formulations is of utmost importance. Hence, the development and implementation of new analytical techniques in order to keep pace is highly desired. It was the aim of this thesis to evaluate the applicability of asymmetrical flow field flow fractionation (AF4) in pharmaceutical protein analytics, to compare AF4 performance with established state-of-the-art methods and to reveal the effectivity of inherent AF4 characteristics in demanding analytical tasks. The Theoretical Section encompasses Chapter 2, wherein the family of field-flow fractionation techniques is introduced, as well as Chapter 3 (attending to protein aggregation) and Chapter 4, which provides an insight into multi-angle light scattering. The Theoretical Section is summarized in Chapter 5. Chapter 6 attends to the general applicability of (semi-)chromatographic AF4 in protein analysis. The correlation of cross flow progression with increased resolution was exemplified by the separation of human serum albumin (HSA), thereby rendering the (base-line) separation of HSA specimen into monomer, dimer, trimer and tetramer possible. Due to the AF4 feature to discretionarily alter the resolution power within one separation run, the fractionation of higherorder aggregates and insoluble, precipitated protein was successfully performed. System variables and parameters of fractionation were investigated, revealing that sample loads differing more than two orders of magnitude did not negatively affect data reproducibility. Whereas up to now cross flow intensity was deemed to predominantly account for contingent sample loss during AF4 experiments, analysis of proteins with varying hydrophilicity proved the preceding focusing step to contribute notably for that phenomenon. How to overcome potential drawbacks such as sample-membrane interactions by adequate choice of the ultrafiltration membrane as well as carrier liquid composition was illustrated. Chapter 11. Summary, conclusions and prospective 177 Given the background that effective AF4 fractionations are due to differences in analyte size – i.e., in diffusion coefficients -, the separation of equal-sized proteins is prima facie considered to be impractical. Yet, the retaining impact of sample-membrane interaction was evidenced to decrease the effective diffusion coefficient, resulting in successful fractionations of proteins differing ~1% in size (i.e., G-CSF, 19.6 kDa versus IFN-α2a, 19.4 kDa). In this realm, the normal mode elution order of smaller analytes eluting prior to larger ones was shown to be invertible, exemplified by the elution of a 40 kDa analyte prior to IFN-α2a. AF4 potency in analysis of insoluble high molecular weight (hmw) aggregates was compared with data derived by established methods such as light obscuration and Coulter technique, verifying the competitiveness of AF4. A comparative study of AF4 with size exclusion chromatography (SE-HPLC) unveiled SE-HPLC to inhere higher recovery rates and AF4 to exhibit greater resolution. Coupling both techniques with multi-angle light scattering (MALS) detection systems disclosed SE-HPLC to induce artifacts concerning hmw aggregate quantification. Moreover, in contrast to SE-HPLC, AF4 was capable of seizing undissolved and precipitated protein specimen, thus making AF4 a promising alternative in the analysis of protein pharmaceuticals. AF4´s ability to separate undissolved sample components proved to be an indispensable feature in the analysis of a pharmaceutical protein formulated within siliconized disposable syringes, which was attended to in Chapter 7. During long-term storage, visible particulate matter developed sporadically within the syringe volumes, raising the question of the particles´ origin. Since protein instabilities were not to be accounted for being the particle source – verified by several analytical methods -, silicone oil detachment and subsequent coalescence came into question, as the barrel siliconization process was lacking a final heat curing step. Thus, an AF4 application was developed, intending to separate μm sized silicone oil droplets. The task was approached by analysis of silicone oil emulsions, followed by the fractionation of ultrasoundstressed syringe volumes containing detached and coalesced silicone oil after stress exertion. Unambiguously, detached silicone oil was evidenced by AF4 to account for visible particulate matter in the syringe volumes, corroborated by MALS and refractive index detection as well as light microscopy and syringe frictional drag analysis. Subsequently to artificially induced protein aggregation of particle-containing syringe volumes, AF4 was able to separate silicone oil droplets, protein monomer and aggregates as individual fractions within one single run. Finally, AF4 enabled access to data on protein drug stability and insights into protein adsorption tendencies on coalesced silicone oil specimen – thereby providing valuable data which otherwise would have required a variety of various analytical techniques. Chapter 11. Summary, conclusions and prospective 178 In Chapter 8 the suitability of AF4 in overall-characterization of gelatin nanoparticles was explored. The efficacy of providing hmw gelatin bulk material by various desolvation steps was evaluated by SE-HPLC and AF4. Due to the absence of shear degradation phenomena, AF4 was demonstrated to enable more moderate separation conditions than SE-HPLC, verified by on-line determination of analyte molecular weight via MALS. Gelatin nanoparticles were characterized by means of AF4/MALS with respect to size and size distributions and the data were compared to results of photon correlation spectroscopy (PCS) and scanning electron microscopy (SEM). Because of the precedent separation step via AF4, data derived by MALS revealed a greater veracity than PCS results, where the size assessment of nanoparticles relied on batch experiments. Whereas PCS attributed unloaded and DNA plasmid loaded nanoparticles virtually unimodal size distributions, both AF4/MALS and SEM demonstrated the nanoparticles to span a broad size range. Furthermore, loaded and unloaded nanoparticles were unveiled to exhibit only minimal differences in size, thus providing information on the interplay of nanoparticles and plasmid strands. For the first time, the separation of nanocolloidal drug carrier and designated pharmaceutical payload was established. Additionally to drug carrier characteristics, data on the loading efficacy could be yielded. Furthermore, nanoparticle shelf life stability and extent of potential drug decomplexation could be determined. Bearing in mind colloidal, polymer-based drug delivery carriers gaining increasing importance, that very AF4 application is expected to accommodate the demand for accurate analytics, as the pharmaceutical product can be characterized in both qualitative and quantitative terms. In Chapter 9 a case study of particulate matter analysis of a pharmaceutical antibody solution is presented, wherein individual vials of one production lot developed visible components at random during long-term storage. In order to (a) provide evidence on the presence of the contamination, (b) to attempt particulate entitiy quantification and (c) to elucidate particles´ nature, a multiplicity of analytical techniques were applied, encompassing particle counting (optical inspection, light obscuration, light microscopy), protein characterization techniques (SE-HPLC, polyacrylamide gel electrophoresis, AF4, microcalorimetry) and particle separation techniques (sterile filtration, AF4). Attempts to isolate the particulate components by AF4 or filtration techniques provided no further indications of the particle´s origin. Virtually no alterations in protein characteristics were monitored between contaminated and particle-free vial volumes, respectively. Solely, microcalorimetric data of contaminated vial volumes resembled those of immunoglobulin solutions exposed to heat stress prior to analytics. Consequently, protein instabilities were assumed not to cause the visible contamination. Chapter 11. Summary, conclusions and prospective 179 The topic of liquid protein parenterals, protein instability and particulate matter was completed by presenting a formulation process of an immunoglobulin into a liquid formulation in Chapter 10. Prevalent strategies and mainstream trends of liquid protein formulation were introduced by reviewing latest publications on the issue. Parameters revealing decisive influence on the protein´s long-term stability such as solution pH as well as type and concentration of excipients were evaluated by means of accelerated stability studies at various storage temperatures. Additionally, processing parameters, e.g., freeze/thawing, were assessed evaluating criteria in terms of surfactant and buffer choice. The addition of NaCl was shown to detract from protein stability and to facilitate the formation of particulate matter. Non-deleterious alternatives of salt additives were discovered. On the other hand, the addition of polyols such as mannitol and sorbitol was demonstrated to notably contribute to the immunoglobulin stability. Preferential accumulation at the native state protein was thought to be the mechanism for reducing aggregation phenomena of the protein. Besides, the extent of fragmentation was reduced by polyols, indicating a second pathway of stabilization, which was hypothesized to be hampering of oxidation processes. Due to detailed investigations, a proposal pertaining an optimal formulation could be made in the course of that case study. This thesis has shown that asymmetrical flow field-flow fractionation (AF) can effectively be used to monitor protein stability in a broad variety of pharmaceutical formulations. Especially in the characterization of the most common outcome of physical instability – i.e., protein aggregation – the potential of AF4 has comprehensively been demonstrated. Moreover, AF4 applications and separation tasks within pharmaceutical analytics considered hitherto impractical or at least highly challenging were successfully performed. Facing increasingly complex liquid- or colloidal-based formulations, with this knowledge practice and research in pharmaceutical analytics can take a notable step forward.
Because fatty acid composition of biliary phospholipids influences cholesterol secretion into bile, we investigated whether replacement of n-1 monounsaturated or n-6 polyunsaturated fatty acids with n-3 polyunsaturated fatty acids in biliary phosphatidylcholines reduces supersaturation with cholesterol and prevents precipitation of cholesterol crystals in bile of gallstone patients. Seven patients with radiolucent gallstones in functioning gallbladders were studied before (control) and after 5 wk of dietary supplementation with marine fish oil (11.3 gm/day = 3.75 gm n-3 polyunsaturated fatty acids/day). Duodenal bile was collected for analysis during intravenous infusion of cholecystokinin. Gallbladder emptying in response to cholecystokinin was comparable before and during intake of n-3 polyunsaturated fatty acids. Intake of n-3 polyunsaturated fatty acids increased (p < 0.001) the fractions of eicosapentaenoic and docosahexaenoic acids and decreased the fractions of linoleic (p < 0.001) and arachidonic acids (p < 0.02) in biliary phospholipids. Concomitantly, the molar ratio of cholesterol to phospholipids decreased (-19%; p < 0.05). As a consequence, the cholesterol saturation index was reduced by -25% (p = 0.01), from 1.60 ± 0.44 to 1.24 ± 0.38. However, in vitro nucleation time of duodenal bile was not prolonged. The decrease in cholesterol saturation was not sufficient to prevent nucleation of cholesterol crystals in bile of gallstone patients. In conclusion, our data suggest that cholesterol saturation can be influenced by the fatty acid composition of the phosphatidylcholines secreted in bile.
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