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BUFFALO, NY- December 17, 2024 – A new #research paper was #published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 16, Issue 21 on November 29, 2024, entitled, “Thermotherapy has sexually dimorphic responses in APP/PS1 mice.” Researchers Samuel A. McFadden, Mackenzie R. Peck, Lindsey N. Sime, MaKayla F. Cox, Erol D. Ikiz, Caleigh A. Findley, Kathleen Quinn, Yimin Fang, Andrzej Bartke, Erin R. Hascup, and Kevin N. Hascup from Southern Illinois University School of Medicine, found that raising body temperature through heat therapy improved memory in male mice with Alzheimer's disease but worsened memory in females. These findings emphasize the importance of personalized treatments based on sex-specific responses to therapy. Alzheimer's disease (AD) is a progressive brain disorder characterized by memory loss and confusion. It is caused by the buildup of harmful proteins like beta-amyloid, which damages brain cells over time. In this study, genetically modified mice predisposed to develop Alzheimer disease (APP/PS1 mice) were kept in warmer environments for six months to explore the effects of heat therapy on memory and metabolism. The results revealed that male mice benefited from the therapy, with improved memory and reduced levels of beta-amyloid in their brains. Female mice, however, experienced a worsening of memory, likely due to increased inflammation triggered by the heat therapy. Inflammation, where the immune system is hyperactivated, can harm brain cells and worsen Alzheimer's disease symptoms. “Thermotherapy improved spatial navigation in male C57BL/6 and APP/PS1 mice, with the later attributed to reduced hippocampal soluble amyloid-β (Aβ)42. Female APP/PS1 mice exhibited worse spatial memory recall after chronic thermotherapy.” Heat therapy is already known to provide general health benefits, such as improving heart health and regulating blood sugar. This study suggests it could also offer a simple, non-drug approach to slowing Alzheimer's progression, particularly for men. Unlike exercise, which offers similar benefits, heat therapy is accessible for people who are weak or unable to engage in physical activity. While these findings are promising, the researchers emphasize the need for more studies to understand why men and women respond so differently to heat therapy. Future research should also investigate whether the results can be replicated in humans and how the therapy can be tailored to individual needs. In conclusion, heat therapy could present a safe and practical option for managing Alzheimer's disease, particularly in men. However, the observed gender differences highlight the importance of further research to refine its therapeutic potential and ensure it benefits everyone. DOI - https://doi.org/10.18632/aging.206156 Corresponding author - Kevin N. Hascup - khascup49@siumed.edu Video short - https://www.youtube.com/watch?v=IeMPHss4vj8 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts About Aging-US The mission of the journal is to understand the mechanisms surrounding aging and age-related diseases, including cancer as the main cause of death in the modern aged population. The journal aims to promote 1) treatment of age-related diseases by slowing down aging, 2) validation of anti-aging drugs by treating age-related diseases, and 3) prevention of cancer by inhibiting aging. (Cancer and COVID-19 are age-related diseases.) Please visit our website at https://www.Aging-US.com​​ and connect with us: Facebook - https://www.facebook.com/AgingUS/ X - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Spotify - https://open.spotify.com/show/1X4HQQgegjReaf6Mozn6Mc MEDIA@IMPACTJOURNALS.COM

Crossref is a non-profit organization that logs and updates citations for scientific publications. Each month, Crossref identifies a list of the most popular Aging (Aging-US) papers based on the number of times a DOI is successfully resolved. Below are Crossref's Top 10 Aging DOIs in 2023. 10: Old-age-induced obesity reversed by a methionine-deficient diet or oral administration of recombinant methioninase-producing Escherichia coli in C57BL/6 mice DOI: https://doi.org/10.18632/aging.204783 Authors: Yutaro Kubota, Qinghong Han, Jose Reynoso, Yusuke Aoki, Noriyuki Masaki, Koya Obara, Kazuyuki Hamada, Michael Bouvet, Takuya Tsunoda, and Robert M. Hoffman 9: Metformin use history and genome-wide DNA methylation profile: potential molecular mechanism for aging and longevity DOI: https://doi.org/10.18632/aging.204498 Authors: Pedro S. Marra, Takehiko Yamanashi, Kaitlyn J. Crutchley, Nadia E. Wahba, Zoe-Ella M. Anderson, Manisha Modukuri, Gloria Chang, Tammy Tran, Masaaki Iwata, Hyunkeun Ryan Cho, and Gen Shinozaki 8: Age prediction from human blood plasma using proteomic and small RNA data: a comparative analysis DOI: https://doi.org/10.18632/aging.204787 Authors: Jérôme Salignon, Omid R. Faridani, Tasso Miliotis, Georges E. Janssens, Ping Chen, Bader Zarrouki, Rickard Sandberg, Pia Davidsson, and Christian G. Riedel 7: Characterization of the HDAC/PI3K inhibitor CUDC-907 as a novel senolytic DOI: https://doi.org/10.18632/aging.204616 Authors: Fares Al-Mansour, Abdullah Alraddadi, Buwei He, Anes Saleh, Marta Poblocka, Wael Alzahrani, Shaun Cowley, and Salvador Macip 6: Potential reversal of biological age in women following an 8-week methylation-supportive diet and lifestyle program: a case series DOI: https://doi.org/10.18632/aging.204602 Authors: Kara N. Fitzgerald, Tish Campbell, Suzanne Makarem, and Romilly Hodges 5: Leukocyte telomere length, T cell composition and DNA methylation age DOI: https://doi.org/10.18632/aging.101293 Authors: Brian H. Chen, Cara L. Carty, Masayuki Kimura, Jeremy D. Kark, Wei Chen, Shengxu Li, Tao Zhang, Charles Kooperberg, Daniel Levy, Themistocles Assimes, Devin Absher, Steve Horvath, Alexander P. Reiner, and Abraham Aviv 4: DNA methylation GrimAge strongly predicts lifespan and healthspan DOI: https://doi.org/10.18632/aging.101684 Authors: Ake T. Lu, Austin Quach, James G. Wilson, Alex P. Reiner, Abraham Aviv, Kenneth Raj, Lifang Hou, Andrea A. Baccarelli, Yun Li, James D. Stewart, Eric A. Whitsel, Themistocles L. Assimes, Luigi Ferrucci, and Steve Horvath 3: Deep biomarkers of aging and longevity: from research to applications DOI: https://doi.org/10.18632/aging.102475 Authors: Alex Zhavoronkov, Ricky Li, Candice Ma, and Polina Mamoshina 2: An epigenetic biomarker of aging for lifespan and healthspan DOI: https://doi.org/10.18632/aging.101414 Authors: Morgan E. Levine, Ake T. Lu, Austin Quach, Brian H. Chen, Themistocles L. Assimes, Stefania Bandinelli, Lifang Hou, Andrea A. Baccarelli, James D. Stewart, Yun Li, Eric A. Whitsel, James G Wilson, Alex P Reiner, Abraham Aviv, Kurt Lohman, Yongmei Liu, Luigi Ferrucci, and Steve Horvath 1: Chemically induced reprogramming to reverse cellular aging DOI: https://doi.org/10.18632/aging.204896 Authors: Jae-Hyun Yang, Christopher A. Petty, Thomas Dixon-McDougall, Maria Vina Lopez, Alexander Tyshkovskiy, Sun Maybury-Lewis, Xiao Tian, Nabilah Ibrahim, Zhili Chen, Patrick T. Griffin, Matthew Arnold, Jien Li, Oswaldo A. Martinez, Alexander Behn, Ryan Rogers-Hammond, Suzanne Angeli, Vadim N. Gladyshev, and David A. Sinclair Aging is an open-access, traditional, peer-reviewed journal that has published high-impact papers in all fields of aging research since 2009. All papers are available to readers (at no cost and free of subscription barriers) in bi-monthly issues at Aging-US.com. For media inquiries, please contact media@impactjournals.com.

BUFFALO, NY- November 7, 2023 – A new #researchpaper was #published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 15, Issue 20, entitled, “Deciphering reproductive aging in women using a NOD/SCID mouse model for distinct physiological ovarian phenotypes.” Female fertility is negatively correlated with age, with noticeable declines in oocyte quantity and quality until menopause. To understand this physiological process and evaluate human approaches for treating age-related infertility, preclinical studies in appropriate animal models are needed. In this new study, researchers María Marchante, Noelia Ramirez-Martin, Anna Buigues, Jessica Martinez, Nuria Pellicer, Antonio Pellicer, and Sonia Herraiz from IVIRMA, University of Valencia and Instituto Investigación Sanitaria La Fe aimed to characterize an immunodeficient physiological aging mouse model displaying ovarian characteristics of different stages during women's reproductive life. “The main purpose of our study was to establish a physiological ovarian aging mouse model that could be employed to evaluate potential therapeutic interventions derived from human origin.” NOD/SCID mice of different ages (8-, 28-, and 36–40-week-old) were employed to mimic ovarian phenotypes of young, Advanced Maternal Age (AMA), and old women (~18–20-, ~36–38-, and >45-years-old, respectively). Mice were stimulated, mated, and sacrificed to recover oocytes and embryos. Then, ovarian reserve, follicular growth, ovarian stroma, mitochondrial dysfunction, and proteomic profiles were assessed. Age-matched C57BL/6 mice were employed to cross-validate the reproductive outcomes. The quantity and quality of oocytes were decreased in AMA and Old mice. These age-related effects associated spindle and chromosome abnormalities, along with decreased developmental competence to blastocyst stage. Old mice had less follicles, impaired follicle activation and growth, an ovarian stroma inconducive to growth, and increased mitochondrial dysfunctions. Proteomic analysis corroborated these histological findings. Based on that, NOD/SCID mice can be used to model different ovarian aging phenotypes and potentially test human anti-aging treatments. “In summary, in this study we characterized the quality of the ovarian microenvironment and reproductive outcomes of an immunodeficient murine model of physiological ovarian aging by evaluating fertility outcomes, ovarian reserve and stroma, mitochondrial dysfunctions, and the ovarian proteome at different stages. This model adequately mimicked the characteristics of the reproductive stages in women, without external agents compromising folliculogenesis, or disrupting molecular mechanisms and ovarian function, which could mask the processes of physiological aging.” DOI - https://doi.org/10.18632/aging.205086 Corresponding author - Sonia Herraiz - sonia_herraiz@iislafe.es About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at https://www.Aging-US.com​​ and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ X - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

Dr. Corey Watson is an Associate Professor at the University of Louisville. His work focuses on characterising and cataloguing antibody genetic diversity in human and mouse to better understand disease susceptibility and clinical health outcomes. Dr. William Lees is a researcher at University of London. His work focuses on developing Adaptive Immune Receptor (AIR) reference sets for diverse species and the annotation of experimental sequence data. In this episode we talk about the recent work by the Germline Database Working Group of the AIRR-Community. The accuracy of V and J gene segment assignment improves with the quality of the reference germline set. The accurate assignment is critical for characterization of somatic hypermutation. We discuss the challenges in creating a database to hold all relevant and potentially relevant germline information, especially in the light of increased discovery rate through technological advances and improved analysis pipelines. We also reflect on the complexity in handling personalised germline reference sets. The episode is hosted by Dr. Ulrik Stervbo and Dr. Zhaoqing Ding. Comments are welcome to the inbox of onairr@airr-community.org  or on social media under the tag #onAIRR. Further information can be found here: https://www.antibodysociety.org/the-airr-community/airr-c-podcast.  Website of the AIRR-C Germline Database Working Group https://www.antibodysociety.org/the-airr-community/airr-working-groups/germline_database/  Papers mentioned Collins, Andrew M., Mats Ohlin, Martin Corcoran, James M. Heather, Duncan Ralph, Mansun Law, Jesus Martínez-Barnetche, et al. 2023. “AIRR-C Human IG Reference Sets: Curated Sets of Immunoglobulin Heavy and Light Chain Germline Genes.” BioRxiv. https://doi.org/10.1101/2023.09.01.555348  Rodriguez, Oscar L., Yana Safonova, Catherine A. Silver, Kaitlyn Shields, William S. Gibson, Justin T. Kos, David Tieri, et al. 2023. “Genetic Variation in the Immunoglobulin Heavy Chain Locus Shapes the Human Antibody Repertoire.” Nature Communications 14 (1). https://doi.org/10.1038/s41467-023-40070-x  Lees, William D., Scott Christley, Ayelet Peres, Justin T. Kos, Brian Corrie, Duncan Ralph, Felix Breden, et al. 2023. “AIRR Community Curation and Standardised Representation for Immunoglobulin and T Cell Receptor Germline Sets.” Immunoinformatics (Amsterdam, Netherlands) 10 (100025): 100025. https://doi.org/10.1016/j.immuno.2023.100025  Jackson, Katherine J. L., Justin T. Kos, William Lees, William S. Gibson, Melissa Laird Smith, Ayelet Peres, Gur Yaari, et al. 2022. “A BALB/c IGHV Reference Set, Defined by Haplotype Analysis of Long-Read VDJ-C Sequences From F1 (BALB/c x C57BL/6) Mice.” Frontiers in Immunology 13. https://doi.org/10.3389/fimmu.2022.888555  Ford, Easton E., David Tieri, Oscar L. Rodriguez, Nancy J. Francoeur, Juan Soto, Justin T. Kos, Ayelet Peres, et al. 2023. “FLAIRR-Seq: A Method for Single-Molecule Resolution of near Full-Length Antibody H Chain Repertoires.” The Journal of Immunology 210 (10): 1607–19. https://doi.org/10.4049/jimmunol.2200825  Omer, Aviv, Ayelet Peres, Oscar L. Rodriguez, Corey T. Watson, William Lees, Pazit Polak, Andrew M. Collins, and Gur Yaari. 2022. “T Cell Receptor Beta Germline Variability Is Revealed by Inference from Repertoire Data.” Genome Medicine 14 (1). https://doi.org/10.1186/s13073-021-01008-4  Rodriguez, Oscar L., Catherine A. Silver, Kaitlyn Shields, Melissa L. Smith, and Corey T. Watson. 2022. “Targeted Long-Read Sequencing Facilitates Phased Diploid Assembly and Genotyping of the Human T Cell Receptor Alpha, Delta, and Beta Loci.” Cell Genomics 2 (12): 100228. https://doi.org/10.1016/j.xgen.2022.100228  Tools mentioned TIgGER (Immcantation) https://tigger.readthedocs.io/en/stable  IgDiscover https://github.com/NBISweden/IgDiscover  Partis https://github.com/psathyrella/partis MiXCR https://mixcr.com

The show's back! We've got a new format for the pod. Let us know what you think! ARTISTS: Pineapple Willows: pineapplewillows.bandcamp.com/album/pixelated-memories Silver Car Crash: silvercarcrash.bandcamp.com/album/shattered-shine C57BL/6: c57bl6.bandcamp.com/album/lp-1 Ames: ames1.bandcamp.com/track/taking-up-the-bed Beth Bombara: bethbombara.bandcamp.com/album/it-all-goes-up Viv & Riley: vivandriley.bandcamp.com/album/imaginary-people Be sure to follow us @campscoutspod on Instagram! Josh is @jwfreeman_ on Instagram Artwork by @madisonn_rrose on Twitter and Instagram

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.21.549983v1?rss=1 Authors: Jantzen, L., Dumontoy, S., Ramadan, B., Houdayer, C., Haffen, E., Hichami, A., Khan, N., Van Waes, V., Cabeza, L. Abstract: Obesity is a major risk factor for neuropsychiatric alterations. Fatty regimes lead to systemic and cerebral inflammation, the latest acting through lipotoxicity on hypothalamic structures controlling energy homeostasis. Since literature points to a protective effect of linoleic acid (LA) on mood disorders through the regulation of systemic inflammation, we investigated how five weeks of LA supplementation modulates emotional behaviour and microglia-related neuroinflammation. C57BL/6j mice were fed with either a high-fat (HFD) or a standard diet for 12 weeks, underwent a battery of behavioural tests and were subsequently sacrificed for immunofluorescence staining targeting microglia-specific calcium-binding proteins (IBA-1). Neuroinflammation severity was approximated in multiple hypothalamic, cortical and subcortical regions. Our results show an anxio-depressive-like effect of sustained HFD that neither was alleviated nor worsen with LA supplementation. Increased IBA-1 expression in the HFD group was substantially reversed with LA supplementation. Thus, our results suggest anti-neuroinflammatory properties of LA not restricted to hypothalamic areas, but also evident at the cortical and subcortical level. This study is therefore relevant in the frame of obesity and neuropsychiatric disorders with a neuroinflammatory basis. Further investigation may provide more information to justify dietary strategies aiming at reducing the impact of obesity associated comorbidities. 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/2023.07.19.549693v1?rss=1 Authors: Zhu, S., Waeckel-Enee, E., Moser, A., Bessard, M.-A., Roger, K., Lipecka, J., Yilmaz, A., Bertocci, B., Diana, J., Saintpierre, B., Guerrera, I. C., Francesconi, S., Mauvais, F.-X., van Endert, P. Abstract: Appropriate tuning of protein homeostasis through mobilization of the unfolded protein response (UPR) is key to the capacity of pancreatic beta cells to cope with highly variable demand for insulin synthesis. An efficient UPR ensures a sufficient beta cell mass and secretory output but can also affect beta cell resilience to autoimmune aggression. The factors regulating protein homeostasis in the face of metabolic and immune challenges are insufficiently understood. We examined beta cell adaptation to stress in mice deficient for insulin-degrading enzyme (IDE), a ubiquitous protease with high affinity for insulin and genetic association with type 2 diabetes. IDE deficiency induced a low-level UPR in both C57BL/6 and autoimmune non-obese diabetic (NOD) mice, associated with rapamycin-sensitive beta cell proliferation strongly enhanced by proteotoxic stress. Moreover, in NOD mice, IDE deficiency protected from spontaneous diabetes and triggered an additional independent pathway, conditional on the presence of islet inflammation but inhibited by proteotoxic stress, highlighted by strong upregulation of regenerating islet-derived protein 2, a protein attenuating autoimmune inflammation. Our findings establish a key role of IDE in islet cell protein homeostasis, identify a link between low-level UPR and proliferation, and reveal an UPR-independent anti-inflammatory islet cell response uncovered in the absence of IDE of potential interest in autoimmune diabetes. 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/2023.07.12.548754v1?rss=1 Authors: Adamson, A., Ilieva, N., Stone, J., De Miranda, B. R. Abstract: Trichloroethylene (TCE) is one of the most pervasive environmental contaminants in the world and is associated with Parkinson disease (PD) risk. Experimental models in rodents show that TCE is selectively toxic to dopaminergic neurons at high doses of ingestion, however, TCE is a highly volatile toxicant, and the primary pathway of human exposure is inhalation. As TCE is a highly lipophilic, volatile organic contaminant (VOC), inhalation exposure results in rapid diffusion throughout the brain, avoiding first-pass hepatic metabolism that necessitated high doses to recapitulate exposure conditions observed in human populations. We hypothesized that inhalation of TCE would induce significantly more potent neurodegeneration than ingestion and better recapitulate environmental conditions of vapor intrusion or off gassing from liquid TCE. To this end, we developed a novel, whole-body passive exposure inhalation chamber in which we exposed 10-month-old male and female Lewis rats to 50 ppm TCE (time weighted average, TWA) or filtered room air (control) over 8 weeks. In addition, we exposed 12-month-old male and female C57Bl/6 mice to 100 ppm TCE (TWA) or control over 12 weeks. Both rats and mice exposed to chronic TCE inhalation showed significant degeneration of nigrostriatal dopaminergic neurons as well as motor and gait impairments. TCE exposure also induced accumulation of pSer129-Syn in dopaminergic neurons as well as microglial activation within the substantia nigra of rats. Collectively, these data indicate that TCE inhalation causes highly potent dopaminergic neurodegeneration and recapitulates some of the observed neuropathology associated with PD, providing a future platform for insight into the mechanisms and environmental conditions that influence PD risk from TCE exposure. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Episode 401... Coming down from the milestone 400 show. It's National 7 Eleven Day! So, we naturally have a 7 Eleven themed batch to get those nostalgic Slurpee and Big Gulp memories flowing. Plus a set of new Bandcamp grabs and another brand new one from our upcoming Brothers Grim Punk release on Bandcamp to start the show! Mad Ax has remastered several of our old bands and put them up on the Bros Grim Punk Bandcamp page. This week, an old high school gem of a band that DD was in, Vertigo. Some post dead Kurdt vibes, if we do say. Enjoy!Download and stream here:BROS GRIM 401!!! Bros Grim Archive here:BROS GRIM ARCHIVEAiring Wednesdays 7pm PST on PUNK ROCK DEMONSTRATION & Fridays/Saturdays 7pm PST on RIPPER RADIO.Send us stuff to brothersgrimpunk@gmail.com.Punkerdown...Don't Need You 0:53  Brothers Grim Punk One Small Step For A Punk NO EXCUSE 1:15 CAVEMAN S/T AU All Went Too Well 1:03 Arsenico Reign Of Fear UK Toilet Terrorist 1:58 Chaotic Dischord Our Mental Health Is Fucking Mental  With A Whimper & A Bang (bkgrd) 5:26 VERTIGO UPPERDOWN 7-11    1:15 Screeching Weasel Screeching Weasel 711 1:13 Couch Sex I Can't Swim 7-11 0:12 Sick Of Stupidity One Shot, One Kill Seven Eleven 0:27 The Dwarves Greedy Boot 1 Stairway To 711 1:29 Rubix Skate & Destroy 7-Eleven Nachos 1:48 Froggy 7-Eleven Nachos Fuck 7-11! 1:22 ONiON We Are What You Eat 7-11 (bkgrd)    3:34    Ramones    Pleasant Dreams Mr. Quench (bkgrd) 3:51 Longboard Ranch Longboard Ranch Rides Again!  Ill Commute 2:46 Fight Music Robo Dick UK Dogwhistle 1:18 Perp Walk The Chain of Infection L.A. I Am Your Phantom 2:14 War Ghoul I Am Your Phantom/We Suffer But Why? Double Single AL Conquest 1:48 B.O.R.N. Belligerent Onslaught Relentless Noise GA VICIOUS CYCLE 1:22 FUNERAL MESS S/T Portland Right To Live 2:10 Malakili Demo 2023 L.A. $3.00 On Pump 6 0:53 C57BL/6 LP 1 Liquid Chaos (bkgrd) 4:15 The Detonators Liquid Chaos Syphon & Destroy 1:41 Common Enemy Living the Dream? LA after midnight 1:21 Dead City banned from LA Dalton 0:53 Neverland Ranch Hands Plastic Fact Eaters Volume 1 Stand Up 0:54 Minor Threat Complete Discography Waste No Time 0:36 The Fartz Because This Fuckin' World Stinks... Saturday Truck Fever 2:16 Guttermouth The Whole Enchilada Anarchy in the U . K. (bkgrd) 3:46 The Jimmy Psycho Experience Mosh Pits & Mai Tais: The Ultimate Punk Rock Lounge Party 8 More Times 2:24 VERTIGO UPPERDOWN

According to a recent survey by the National Institute of Mental Health (2017), Anxiety is the most common mental illness, with over 40 million adults in the US alone being diagnosed every year. The American Psychological Association (2013) defines anxiety as a future-oriented concern that may lead people to avoid situations that trigger or worsen their distress. Do you have experience with anxiety? Do you know someone who is often anxious? What other symptoms of anxiety do you recognize? There are in fact many types of anxiety disorders, including generalized anxiety disorder, Obsessive-compulsive Disorder (OCD), Panic Disorder, Post-Traumatic Stress Disorder (PTSD) and Social Phobia or Social Anxiety Disorder. #anxiety #anxietydisorders Credits Script Writer: Chloe Avanasa Script Editors: Kelly Soong VO: Amanda Silvera Animator: Napiart YouTube Manager: Cindy Cheong Our sources: National Institute of Mental Health. (November 2017). What Are Anxiety Disorders?. Retrieved from nimh.nih.gov/health/statistics/any-anxiety-disorder.shtml Nolen-Hoeksema, S. (2000). The role of rumination in depressive disorders and mixed anxiety/depressive symptoms. Journal of abnormal psychology, 109(3), 504. Laux, L., & Krohne, H. W. (Eds.). (1982). Achievement, stress, and anxiety. Hemisphere Publishing Corporation. Caplan, S. E. (2006). Relations among loneliness, social anxiety, and problematic Internet use. CyberPsychology & behavior, 10(2), 234-242. Stearns, P. N. (2012). American fear: The causes and consequences of high anxiety. Routledge. Greenson, R. R. (1959). Phobia, anxiety, and depression. Journal of the American Psychoanalytic Association, 7(4), 663-674. Reiss, S. (1991). Expectancy model of fear, anxiety, and panic. Clinical psychology review, 11(2), 141-153. Kinsey, S. G., Bailey, M. T., Sheridan, J. F., Padgett, D. A., & Avitsur, R. (2007). Repeated social defeat causes increased anxiety-like behavior and alters splenocyte function in C57BL/6 and CD-1 mice. Brain, behavior, and immunity, 21(4), 458-466.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.06.30.547216v1?rss=1 Authors: Obeidat, A. M., Ishihara, S., Li, J., Lammlin, L., Junginger, L., Maerz, T., Miller, R. J., Miller, R., Malfait, A.-M. Abstract: Objective: Knee joints are densely innervated by nociceptors. Sprouting of nociceptors has been reported in late-stage osteoarthritis (OA), both in human knees and in rodent models. Here, we sought to describe progressive nociceptor remodeling in four mouse models of knee OA, capturing early and late-stage disease. Methods: Sham surgery, destabilization of the medial meniscus (DMM), partial meniscectomy (PMX), or non-invasive anterior cruciate ligament rupture (ACLR) was performed in the right knee of 10-12-week old male C57BL/6 NaV1.8-tdTomato mice. Mice were euthanized (1) 4, 8 or 16 weeks after DMM or sham surgery; (2) 4 or 12 weeks after PMX or sham; (3) 1 or 4 weeks after ACLR injury or sham. Additionally, a cohort of naive male wildtype mice was evaluated at 6 and 24 months. Twenty-m thick mid-joint cryosections were assessed qualitatively and quantitatively for NaV1.8+ and PGP9.5+ innervation. Cartilage damage (using a modified OARSI score), synovitis, and osteophytes were assessed blindly. Results: Progressive OA developed in the medial compartment after DMM, PMX, and ACLR. Synovitis and associated neo-innervation by nociceptors peaked in early-stage OA. In the subchondral bone, channels containing sprouting nociceptors appeared early, and progressed with worsening joint damage. Two-year old mice developed primary OA in both the medial and the lateral compartment, accompanied with neuroplasticity in the synovium and the subchondral bone. All 4 models had an increased nerve signal in osteophytes. Conclusion: Anatomical neuroplasticity of nociceptors was observed in association with joint damage in 4 distinct mouse models, suggesting that it is intrinsic to OA pathology. 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 Aging (Aging-US) Volume 15, Issue 11, entitled, “Old-age-induced obesity reversed by a methionine-deficient diet or oral administration of recombinant methioninase-producing Escherichia coli in C57BL/6 mice.” Obesity increases with aging. Methionine restriction affects lipid metabolism and can prevent obesity in mice. In this new study, researchers Yutaro Kubota, Qinghong Han, Jose Reynoso, Yusuke Aoki, Noriyuki Masaki, Koya Obara, Kazuyuki Hamada, Michael Bouvet, Takuya Tsunoda, and Robert M. Hoffman from AntiCancer Inc., University of California San Diego and Showa University School of Medicine observed C57BL/6 mice double their body weight from 4 to 48 weeks of age and become obese. The team then evaluated the efficacy of oral administration of recombinant-methioninase (rMETase)-producing E. coli (E. coli JM109-rMETase) or a methionine-deficient diet to reverse old-age-induced obesity in C57BL/6 mice. “In the present study we tested a low-methionine diet to reverse old-age-induced obesity. [...] E. coli JM109-rMETase was also tested in the present study to reverse old-age-induced obesity.” Fifteen C57BL/6 male mice aged 12–18 months with old-age-induced obesity were divided into three groups. Group 1 was given a normal diet supplemented with non-recombinant E. coli JM109 cells orally by gavage twice daily; Group 2 was given a normal diet supplemented with recombinant E. coli JM109-rMETase cells by gavage twice daily; and Group 3 was given a methionine-deficient diet without treatment. The administration of E. coli JM109-rMETase or a methionine-deficient diet reduced the blood methionine level and reversed old-age-induced obesity with significant weight loss by 14 days. There was a negative correlation between methionine levels and negative body weight change. Although the degree of efficacy was higher in the methionine-deficient diet group than in the E. coli JM109-rMETase group, the present findings suggested that oral administration of E. coli JM109-rMETase, as well as a methionine-deficient diet, are effective in reversing old-age-induced obesity. “In conclusion, the present study provides evidence that restricting methionine by either a low-methionine diet or E. coli JM109-rMETase has clinical potential to treat old-age-induced obesity.” DOI - https://doi.org/10.18632/aging.204783 Corresponding author - Robert M. Hoffman - all@anticancer.com Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204783 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, obesity, methionine restriction, methionine-deficient diet, recombinant methioninase (rMETase), Escherichia coli, microbiome, weight-loss About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at https://www.Aging-US.com​​ and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.06.24.546367v1?rss=1 Authors: Nagel, M., Niestroj, M., Bansal, R., Fleck, D., Lampert, A., Stopkova, R., Stopka, P., Ben-Shaul, Y., Spehr, M. Abstract: In most mammals, conspecific chemosensory communication relies on semiochemical release within complex bodily secretions and subsequent stimulus detection by the vomeronasal organ (VNO). Urine, a rich source of ethologically relevant chemosignals, conveys detailed information about sex, social hierarchy, health and reproductive state, which becomes accessible to a conspecific via vomeronasal sampling. So far, however, numerous aspects of social chemosignaling along the vomeronasal pathway remain unclear. Moreover, since virtually all research on vomeronasal physiology is based on secretions derived from inbred laboratory mice, it remains uncertain whether such stimuli provide a true representation of potentially more relevant cues found in the wild. Here, we combine a robust low-noise VNO activity assay with comparative molecular profiling of sex- and strain-specific mouse urine samples from two inbred laboratory strains as well as from wild mice. With comprehensive molecular portraits of these secretions, VNO activity analysis now enables us to (i) assess whether and, if so, how much sex- / strain-selective raw chemical information in urine is accessible via vomeronasal sampling; (ii) identify which chemicals exhibit sufficient discriminatory power to signal animal sex, strain, or both; (iii) determine the extent to which wild mouse secretions are unique; and (iv) analyze whether vomeronasal response profiles differ between strains. We report both sex- and, in particular, strain-selective VNO representations of chemical information. Within the urinary secretome, both volatile compounds and proteins exhibit sufficient discriminative power to provide sex- and strain-specific molecular fingerprints. While total protein amount is substantially enriched in male urine, females secrete a larger variety at overall comparatively low concentrations. Surprisingly, the molecular spectrum of wild mouse urine does not dramatically exceed that of inbred strains. Finally, vomeronasal response profiles differ between C57BL/6 and BALB/c animals, with particularly disparate representations of female semiochemicals. 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/2023.05.03.539254v1?rss=1 Authors: Meloni, E. G., Carlezon, W. A., Bolshakov, V. Y. Abstract: The natural alignment of animals into social dominance hierarchies produces adaptive, and potentially maladaptive, changes in the brain that influence health and behavior. Aggressive and submissive behaviors assumed by animals through dominance interactions engage stress-dependent neural and hormonal systems that have been shown to correspond with social rank. Here, we examined the impact of social dominance hierarchies established within cages of group-housed laboratory mice on expression of the stress peptide pituitary adenylate cyclase-activating polypeptide (PACAP) in areas of the extended amygdala comprising the bed nucleus of the stria terminalis (BNST) and central nucleus of the amygdala (CeA). We also quantified the impact of dominance rank on corticosterone (CORT), body weight, and behavior including rotorod and acoustic startle response. Weight-matched male C57BL/6 mice, group-housed (4/cage) starting at 3 weeks of age, were ranked as either most-dominant (Dominant), least-dominant (Submissive) or in-between rank (Intermediate) based on counts of aggressive and submissive encounters assessed at 12 weeks-old following a change in homecage conditions. We found that PACAP expression was significantly higher in the BNST, but not the CeA, of Submissive mice compared to the other two groups. CORT levels were lowest in Submissive mice and appeared to reflect a blunted response following social dominance interactions. Body weight, motor coordination, and acoustic startle were not significantly different between the groups. Together, these data reveal changes in specific neural/neuroendocrine systems that are predominant in animals of lowest social dominance rank, and implicate PACAP in brain adaptations that occur through the development of social dominance hierarchies. 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/2023.05.01.538951v1?rss=1 Authors: Baumgartner, N. E., Biraud, M. C., Lucas, E. K. Abstract: 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/2023.04.21.537724v1?rss=1 Authors: Cerroni, C., Steiner, A., Seanez, L., Kwon, S., Lewis, A. S. Abstract: Glucagon-like peptide-1 receptor (GLP-1R) agonists are common type 2 diabetes medications that have been repurposed for adult chronic weight management. Clinical trials suggest this class may also be beneficial for obesity in pediatric populations. Since several GLP-1R agonists cross the blood-brain barrier, it is important to understand how postnatal developmental exposure to GLP-1R agonists might affect brain structure and function in adulthood. Toward that end, we systemically treated male and female C57BL/6 mice with the GLP-1R agonist exendin-4 (0.5 mg/kg, twice daily) or saline from postnatal day 14 to 21, then allowed uninterrupted development to adulthood. Beginning at 7 weeks of age, we performed open field and marble burying tests to assess motor behavior and the spontaneous location recognition (SLR) task to assess hippocampal-dependent pattern separation and memory. Mice were sacrificed, and we counted ventral hippocampal mossy cells, as we have recently shown that most murine hippocampal neuronal GLP-1R is expressed in this cell population. We found that GLP-1R agonist treatment did not alter P14-P21 weight gain, but modestly reduced adult open field distance traveled and marble burying. Despite these motor changes, there was no effect on SLR memory performance or time spent investigating objects. Finally, we did not detect any changes in ventral mossy cell number using two different markers. These data suggest developmental exposure to GLP-1R agonists might have specific rather than global effects on behavior later in life and that extensive additional study is necessary to clarify how drug timing and dose affect distinct constellations of behavior in adulthood. 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/2023.04.17.537179v1?rss=1 Authors: Stewart, A. N., Kumari, R., Bailey, W. M., Glaser, E. P., Hammers, G. V., Wireman, O. H., Gensel, J. C. Abstract: Restoring function in chronic stages of spinal cord injury (SCI) has often been met with failure or reduced efficacy when regenerative strategies are delayed past the acute or sub-acute stages of injury. Restoring function in the chronically injured spinal cord remains a critical challenge. We found that a single injection of retrogradely transported adeno-associated viruses (AAVrg) to knockout the phosphatase and tensin homolog protein (PTEN) in chronic SCI can effectively target both damaged and spared axons and restore locomotor functions in near-complete injury models. AAVrgs were injected to deliver cre recombinase and/or a red fluorescent protein (RFP) under the human Synapsin 1 promoter (hSyn1) into the spinal cords of C57BL/6 PTENFlox mice to knockout PTEN (PTEN-KO) in a severe thoracic SCI crush model at both acute and chronic time points. PTEN-KO improved locomotor abilities in both acute and chronic SCI conditions over a 9-week period. Regardless of whether treatment was initiated at the time of injury (acute), or three months after SCI (chronic), mice with limited hindlimb joint movement gained hindlimb weight support after treatment. Interestingly, functional improvements were not sustained beyond 9 weeks coincident with a loss of RFP reporter-gene expression and a near-complete loss of treatment-associated functional recovery by 6 months post-treatment. Treatment effects were also specific to severely injured mice; animals with weight support at the time of treatment lost function over a 6-month period. Retrograde tracing with Fluorogold revealed viable neurons throughout the motor cortex despite a loss of RFP expression at 9 weeks post-PTEN-KO. However, few Fluorogold labeled neurons were detected within the motor cortex at 6 months post-treatment. BDA labeling from the motor cortex revealed a dense corticospinal tract (CST) bundle in all groups except chronically treated PTEN-KO mice indicating a potential long-term toxic effect of PTEN-KO to neurons in the motor cortex. PTEN-KO mice had significantly more B-tubulin III labeled axons within the lesion when treatment was delivered acutely, but not chronically post-SCI. In conclusion, we have found that using AAVrgs to knockout PTEN is an effective manipulation capable of restoring motor functions in chronic SCI and can enhance axon growth of currently unidentified axon populations when delivered acutely after injury. However, the long-term consequences of PTEN-KO may exert neurotoxic effects. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

A new research paper was published on the cover of Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 15, Issue 5, entitled, “AAV1.NT-3 gene therapy prevents age-related sarcopenia.” Sarcopenia is progressive loss of muscle mass and strength occurring during normal aging with significant consequences on the quality of life for elderly. Neurotrophin 3 (NT-3) is an important autocrine factor supporting Schwann cell survival and differentiation and stimulating axon regeneration and myelination. NT-3 is involved in the maintenance of neuromuscular junction (NMJ) integrity, restoration of impaired radial growth of muscle fibers through activation of the Akt/mTOR pathway. In this new study, researchers Burcak Ozes, Lingying Tong, Morgan Myers, Kyle Moss, Alicia Ridgley, and Zarife Sahenk from Nationwide Children's Hospital and The Ohio State University used a triple muscle-specific creatine kinase (tMCK) promoter to restrict NT-3 expression to the skeletal muscle and self-complimentary adeno-associated virus serotype 1 (scAAV1) as vector to assess the therapeutic efficacy of AAV1.NT-3 in wild type-aged C57BL/6J mice, a model for natural aging and sarcopenia. “Quantitative histopathologic parameters served to address age-related changes in muscle, peripheral nerve and NMJ.” The treatment efficacy was assessed at 6 months post-injection using run to exhaustion and rotarod tests, in vivo muscle contractility assay, and histopathological studies of the peripheral nervous system, including NMJ connectivity and muscle. AAV1.NT-3 gene therapy in WT-aged C57BL/6 mice resulted in functional and in vivo muscle physiology improvements, supported by quantitative histology from muscle, peripheral nerves and NMJ. Hindlimb and forelimb muscles in the untreated cohort showed the presence of a muscle- and sex-dependent remodeling and fiber size decrease with aging, which was normalized toward values obtained from 10 months old WT mice with treatment. The molecular studies assessing the NT-3 effect on the oxidative state of distal hindlimb muscles, accompanied by western blot analyses for mTORC1 activation were in accordance with the histological findings. “When considering the burden of sarcopenia on the lifestyle of elderly, and on the healthcare system, we believe this preclinical study is providing strong support for AAV.NT-3 gene therapy in the successful management of sarcopenia, as a serious and plausible option in the future.” DOI: https://doi.org/10.18632/aging.204577 Corresponding Author: Zarife Sahenk - zarife.sahenk@nationwidechildrens.org Keywords: sarcopenia, gene therapy, aging, NT-3, muscle remodeling Sign up for free Altmetric alerts about this article: https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204577 About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at https://www.Aging-US.com​​ and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.17.529003v1?rss=1 Authors: Sutter, P. A., Willis, C. M., Menoret, A., Nicaise, A. M., Sacino, A. V., Sikkema, A. H., Jellison, E. R., Win, K. K., Han, D. K., Church, W., Baron, W., Vella, A. T. J., Crocker, S. J. Abstract: Astrocyte activation is associated with neuropathology and the production of tissue inhibitor of metalloproteinase-1 (TIMP1). TIMP1 is a pleiotropic extracellular protein that functions both as a protease inhibitor and as a growth factor. We have previously demonstrated that murine astrocytes that lack expression of Timp1 do not support rat oligodendrocyte progenitor cell (rOPC) differentiation, and adult global Timp1 knockout (Timp1KO) mice do not efficiently remyelinate following a demyelinating injury. To better understand the basis of this, we performed unbiased proteomic analyses and identified a fibronectin-derived peptide called anastellin that is unique to the murine Timp1KO astrocyte secretome. Anastellin was found to block rOPC differentiation in vitro and enhanced the inhibitory influence of fibronectin on rOPC differentiation. Anastellin is known to act upon the sphingosine-1-phosphate receptor 1 (S1PR1), and we determined that anastellin also blocked the pro-myelinating effect of FTY720 (or fingolimod) on rOPC differentiation in vitro. Further, administration of FTY720 to wild-type C57BL/6 mice during MOG35-55-EAE ameliorated clinical disability while FTY720 administered to mice lacking expression of Timp1 in astrocytes (Timp1cKO) had no effect. Analysis of human TIMP1 and fibronectin (FN1) transcripts from healthy and multiple sclerosis (MS) patient brain samples revealed an inverse relationship where lower TIMP1 expression was coincident with elevated FN1 in MS astrocytes. Lastly, we analyzed proteomic databases of MS samples and identified anastellin peptides to be more abundant in the cerebrospinal fluid (CSF) of human MS patients with high versus low disease activity. The prospective role for anastellin generation in association with myelin lesions as a consequence of a lack of astrocytic TIMP-1 production could influence both the efficacy of fingolimod responses and the innate remyelination potential of the the MS brain. 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/2023.01.12.523788v1?rss=1 Authors: Rocchetti, J., Fasano, C., Dal-Bo, G., Guma, E., El Mestikawy, S., Wong, T. P., Fakhfouri, G., GIROS, B. Abstract: Evidence suggests that subcortical hyperdopaminergia alters cognitive function in schizophrenia and antipsychotic drugs (APD) fail at rescuing cognitive deficits in patients. In a previous study, we showed that blocking D2 dopamine receptors (D2R), a core action of APD, led to profound reshaping of mesohippocampal fibers, deficits in synaptic transmission and impairments in learning and memory in the mouse hippocampus (HP). However, it is currently unknown how excessive dopamine affects HP-related cognitive functions, and how APD would impact HP functions in such a state. After verifying the presence of DAT-positive neuronal projections in the ventral (temporal), but not in the dorsal (septal), part of the HP, GBR12935, a blocker of dopamine transporter (DAT), was infused in the CA1 of adult C57Bl/6 mice to produce local hyperdopaminergia. Chronic GBR12935 infusion in temporal CA1 induced a mild learning impairment in the Morris Water Maze and abolished long-term recognition memory in novel-object (NORT) and object-place recognition tasks (OPRT). Deficits were accompanied by a significant decrease in DAT+ mesohippocampal fibers. Intrahippocampal or systemic treatment with sulpiride during GBR infusions improved the NORT deficit but not that of OPRT. In vitro application of GBR on hippocampal slices abolished long-term depression (LTD) of fEPSP in temporal CA1. LTD was rescued by co-application with sulpiride. In conclusion, chronic DAT blockade in temporal CA1 profoundly altered mesohippocampal modulation of hippocampal functions. Contrary to previous observations in normodopaminergic mice, antagonising D2Rs was beneficial for cognitive functions in the context of hippocampal hyperdopaminergia. 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/2022.12.22.521569v1?rss=1 Authors: Sharma, N., Sharma, M., Thakkar, D., Kumar, H., Smetanova, S., Buresova, L., Andrla, P., Khairnar, A. Abstract: Background: The contribution of gastrointestinal (GI) inflammation and local exposure to neurotoxins in the gut offers the most in-depth explanation of Parkinson's disease (PD) etiopathogenesis through abnormal accumulation and spreading of alpha-synuclein (-syn) aggregates from the gut to the brain. Objectives: This study was designed to investigate whether dextran sodium sulfate (DSS)-mediated colitis may have lasting effects on dopaminergic pathways in the brain and whether or not colitis exacerbated susceptibility to later exposure to the neurotoxin rotenone. Methods: To induce chronic colitis, 10 months old C57BL/6 mice were pre-exposed to 3 cycles of 7 days of 1% (w/v) DSS administration in drinking water followed by 14 days of regular drinking water. After colitis-induction, animals received a low dose of intragastric rotenone for the next 8 weeks, followed by testing for Parkinsonian behavior and GI phenotypes of inflammation. At the end of the 8th week after colitis, colon, brain stem, and midbrain tissue were isolated and analyzed for -syn, inflammatory markers, and dopaminergic neuronal loss. Gut microbial composition was assessed by 16S rRNA sequencing analysis. Results: We found that local rotenone exposure for 8 weeks did not affect colitis severity and colonic tight junction (TJ) protein expression (ZO-1, Occludin, and Claudin-1). On the other hand, we found that while eight weeks of chronic rotenone administration led to an increase in inflammatory markers, the presence of pre-existing colitis resulted in a considerable change in gut microbiota composition and a decrease in TJ's protein expression. In addition, the administration of rotenone in mice post-colitis caused gastrointestinal function impairment and poor behavioral performances. Itworsened rotenone-induced -syn pathology in the colon, which extended upward and resulted in severe dopaminergic neuron loss and significant astroglia activation in the dorsal motor nucleus of the vagus (DMV), locus coeruleus, substantia nigra as well as in striatum. Interestingly, in the case of rotenone alone, we found that -syn induced ChAT+ neuronal death is restricted to the DMV. These findings indicate that long-term rotenone exposure in conjunction with early inflammatory intestinal milieu exacerbates the progression of -syn pathology and aggravates neurodegeneration in the intragastric mouse PD model. Conclusions: This work provides detailed insight into the involvement of GI inflammation triggered after a neurotoxic insult in the colon and explores their potential to impact central dopaminergic degeneration in PD. This way, we can identify potential therapeutic targets that stop the enteric inflammatory processes involved in progressing PD. 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/2022.10.28.514233v1?rss=1 Authors: Kanold-Tso, Z., Plenz, D. Abstract: Environmental enrichment (EE) has been increasingly used to enhance and support the physiological fitness and natural behavior of research animals. For mice, which are known to be highly active nocturnal animals that live in large social groups, the introduction of running wheels is a particularly promising approach in EE. When wheels are introduced to their home cage, mice increase their nocturnal locomotion activity by orders of magnitude. However, little is known about how mice share such a readily adopted EE. Here, we studied wheel running in single-housed and group-housed mice. We hypothesized that group-housed mice will compete over the scarce resource of a running wheel leading to a change in overall wheel usage compared to single-housed mice that have exclusive wheel access. We measured wheel locomotion in two strains of single-housed and group-housed mice over multiple 24h periods at sub-second temporal resolution using a custom-designed data acquisition system. We observed both sex- and housing-specific differences in wheel usage. In single-housed C57Bl/6 mice, mice ran at consistent speeds and females ran larger distances. In group housing, periods of slow locomotion speeds as well as speed transitions emerged with fewer breaks in wheel usage. This group effect was less pronounced in a genetic mouse model (parvalbumin-Cre on C57Bl/6 background). Our results demonstrate a change in wheel usage during group housing which supports competition over EE resources while enhancing overall locomotion in mice. 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/2022.10.26.513830v1?rss=1 Authors: Gulner, B. R., Navabi, Z. S., kodandaramaiah, S. B. Abstract: Morphometric studies have provided crucial insights into the skull anatomy of commonly used wildtype (WT) laboratory mice strains such as the C57BL/6. With the increasing use of transgenic (TG) animals in neuroscience research, it is important to determine whether the results from morphometric studies performed on WT strains can be extended to TG strains derived from these WT strains. We report a new computer vision-based analysis pipeline for surveying mouse skull morphology using microcomputed tomography (micro-CT) scans. We applied this pipeline to study and compare eight cohorts of adult mice from two strains, including both male and female mice at two age points. We found that the overall skull morphology was generally conserved between cohorts, with only 13% of landmark distance differences reaching statistical significance. In addition, we surveyed the dorsal skull bone thickness differences between cohorts. We observed significantly thicker dorsal, parietal, and/or interparietal bones in WT, male, or older mice for 53% of thickness comparisons. This knowledge of dorsal skull bone thickness has potential implications for surgical planning through skull imaging and has applications in automating cranial microsurgeries on mice. 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/2022.10.12.511923v1?rss=1 Authors: Swift-Gallant, A., Hinks, M. E., Martin, Y., Burke, F., Bambico, F. Abstract: Major depressive disorder (MDD) is a leading cause of non-fatal global disease burden, with females being two-fold more likely than males to be diagnosed with the disorder. Despite this distinct sex-linked disparity of diagnosis, it is unclear what underlies the sex bias of MDD prevalence. Recent findings suggest a role for the gut in mediating affective disorders through the gut-brain-axis (GBA). However, few studies have included sex as a biological variable. For this study, cross-sex transfer of cecal microbiota was performed between male and female C57Bl/6 mice to elucidate the effects of sex and the gut microbiome on a standard battery of tests measuring depressive-like behaviours. Specifically, regardless of sex, recipients of male cecal content had a greater sucrose preference than controls and recipients of female cecum. Conversely, in the splash test, recipients of female cecum displayed a decrease in grooming behaviour compared to both controls and recipients of male cecum, suggestive of an increase in depressive-like behaviour. These results support a role for female-specific gut microbes in contributing to female vulnerability to depression, while male-specific gut microbes may protect in part against an anhedonia-like phenotype. 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/2022.09.22.508924v1?rss=1 Authors: Dahiya, D., Smith, J., Strickland, T., Morris, D., Reschke, C., Engel, T., Henshell, D., McCoy, C. E., Dowling, J. K. Abstract: Hypoxic ischaemic injury (HIE) in the neonatal brain has significant consequences on neurodevelopment and increases the occurrence of neurological deficits in infants. HIE is also a leading cause of neonatal seizures. Therapeutic options for the treatment of HIE are very limited. Hypoxia-ischemia directly damages brain tissue in a primary-wave of injury which activates a cascade of events triggering local and systemic inflammatory responses, driven by the innate immune system, which contribute to a significant secondary-wave of injury taking place as early as 6 hours post-hypoxia-ischaemia. Levels of the well documented inflammatory microRNA, miR-155 are elevated in rodent seizure and epilepsy models. Here, we assessed the impact of, miR-155 deletion in myeloid cells , on regulating inflammation and seizure severity in a preclinical model of neonatal hypoxia-induced seizures (Hypoxia-Sz). Wildtype miR-155 (miR-155+/+LysMCre) mice were compared to a mouse line in which miR-155 was deleted in myeloid cells (miR-155fl/fl LysMCre). We demonstrate significant upregulation of miR-155 target genes, brain-derived neurotrophic factor (bdnf), arginase-2 (arg-2), ship-1 and socs-1 in miR-155fl/fl LysMCre mice compared to controls at various time points following Hypoxia-Sz. Conversely, we report decreased mRNA levels of pro-inflammatory cytokines IL-1[beta]; and IL-6 and lower protein levels of IL-1[beta]; in miR-155fl/fl LysMCre mice as compared to WTs. Myeloid miR-155 deletion significantly reduced behavioural seizure severity score, reduced electrographically (EEG) measured seizure frequency and seizure burden as compared to mice to wildtypes, suggesting miR-155 regulation of seizure occurrence in this model. Behavioural tests for motor functions at 5 weeks post Hypoxia-Sz demonstrated differences between genotypes. Excitingly this work highlights that inhibition of miR-155, specifically in myeloid cells, may hold therapeutic benefit for both seizures and comorbidities associated with hypoxic brain injury. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.07.506981v1?rss=1 Authors: Parks, S. Z., Rutter, G. A., Leclerc, I. Abstract: Background: Soluble Resistance Related Calcium Binding Protein (sorcin) is a calcium (Ca2+) binding protein which has been shown to play a role in maintaining intracellular endoplasmic reticulum (ER) Ca2+ stores and lowering ER stress. Recently, our lab has demonstrated that sorcin expression was downregulated in the islets of Langerhans of mice fed a high-fat diet or in human islets incubated with the saturated fatty acid palmitate. We also showed that overexpression of sorcin under control of the rat insulin promoter (RIP7) in C57BL/6J mice, or whole body sorcin deletion in 129S1/SvImJ mice, improves or impairs insulin secretion and pancreatic {beta}-cell function respectively. The mechanisms behind this beneficial role of sorcin in the pancreatic {beta}-cell might depend on protection against lipotoxic endoplasmic reticulum (ER) stress through improved ER Ca2+ dynamics and activation of the Activating Transcription Factor 6 (ATF6) branch of the unfolded protein response (UPR). Whether sorcin is also implicated in hypothalamic ER stress during the progression of obesity is unknown. This could potentially contribute to the diminished satiety typically observed in overweight individuals. Aim: To investigate a potential role of sorcin in hypothalamic ER stress, leptin resistance, hyperphagia and obesity. Methods: Whole-body sorcin null mice, backcrossed onto the C57BL/6J genetic background, were used. Body weight, food intake and EchoMRI body composition were measured in vivo whereas qRT-PCR analysis of sorcin and ER stress markers expression were performed on the arcuate nucleus of the hypothalamus. Leptin signalling through STAT3 phosphorylation was measured by Western blots on sorcin-null HEK293 cells, engineered by CRISPR/Cas9, and transfected with leptin receptor (LepRb). Results: Sorcin expression was not influenced in the arcuate nucleus (ARC) of the hypothalamus by diet-induced obesity. Whole-body sorcin ablation did not cause ARC ER stress nor changes in body weight, body composition or food intake in C57BL/6 male mice exposed to a high-fat, high-sugar diet. STAT3 phosphorylation (Y705) in response to leptin was not impaired in sorcin-null HEK293 cells. Conclusion: In our model, whole body sorcin ablation did not increase hypothalamic ER stress nor influenced food intake or body weight. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.08.505352v1?rss=1 Authors: Foster, W., Beach, K. F., Carson, P. F., Harris, K. C., Alonso, B. L., Costa, L. T., Simamora, R. C., Corbin, J. E., Hoag, K. F., Mercado, S. I., Bernhard, A. G., Leung, C. H., Nestler, E. J., Been, L. E. Abstract: In placental mammals, estradiol levels are chronically elevated during pregnancy, but quickly drop to prepartum levels following birth. This may produce an estrogen withdrawal state that has been linked to changes in affective states in humans and rodents during the postpartum period. The neural mechanisms underlying these affective changes, however, are understudied. We used a hormone-simulated pseudopregnancy (HSP), a model of postpartum estrogen withdrawal, in adult female C57BL/6 mice to test the impact of postpartum estrogen withdrawal on several behavioral measures of anxiety and motivation. We found that estrogen withdrawal following HSP increased anxiety-like behavior in the elevated plus maze, but not in the open field or marble burying tests. Although hormone treatment during HSP consistently increased sucrose consumption, sucrose preference was generally not impacted by hormone treatment or subsequent estrogen withdrawal. In the social motivation test, estrogen withdrawal decreased the amount of time spent in proximity to a social stimulus animal. These behavioral changes were accompanied by changes in the expression of {Delta}FosB, a transcription factor correlated with stable long-term plasticity, in the nucleus accumbens (NAc). Specifically, estrogen-withdrawn females had higher {Delta}FosB expression in the nucleus accumbens core. Using transgenic reporter mice, we found that this increase in {Delta}FosB occurred in both D1- and D2-expressing cells in the NAc core. Together, these results suggest that postpartum estrogen withdrawal impacts anxiety and motivation and increases {Delta}FosB in the NAc core. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.05.506665v1?rss=1 Authors: Torteli, A., Toth, R., Berger, S. D., Samardzic, S., Bari, F., Menyhart, A., Farkas, E. Abstract: Background: Despite successful recanalization to treat acute ischemic stroke, reperfusion failure associated with poor functional outcomes develops in half of the patients. The cause of reperfusion failure remains the subject of intensive research. Here, we explore the possibility that spreading depolarization (SD), a potent ischemic injury mechanism is a significant contributor and reliable predictor of reperfusion failure. Methods: Young adult male and female C57BL/6 mice (n=69) were anesthetized with isoflurane (0.6-0.9%) and prepared for transcranial optical imaging. After 10 min of baseline, incomplete global forebrain ischemia was induced by transient (45 min) bilateral common carotid artery (CCA) occlusion, followed by 75 min reperfusion. SD and cerebral blood flow (CBF) changes were visualized with intrinsic optical signal imaging and laser speckle contrast imaging. To block SD, the irreversible NMDA receptor antagonist MK801 was applied (0.3 mg/kg, i.p., n=29). Neurological deficit was evaluated at baseline and post-ischemia with a composite Garcia Neuroscore scale. Collaterals of the circle of Willis were examined after loading the vasculature with carbon black ink. Ischemic neuronal injury was evaluated in hematoxylin-eosin-stained brain sections. Results: SD emerged after ischemia onset in one or both hemispheres under a perfusion threshold (CBF drop to 21.1+-4.6 vs. 33.6+-4.4 %, SD vs. no SD). The failure of later reperfusion (44.4+-12.5 %) was invariably linked to previous ischemic SD. In contrast, reperfusion was adequate (98.9+-7.4 %) in hemispheres devoid of SD during ischemia. CBF reduced below the perfusion threshold of SD, when the P1 segment was absent in the circle of Willis. SD occurrence and the linked reperfusion failure were associated with poor neurologic function, and greater neuronal necrosis. The inhibition of SD with MK801 significantly improved reperfusion. Conclusions: SD occurrence during ischemia impairs later reperfusion, prognosticating poor functional outcomes. The increased likelihood of SD occurrence is predicted by inadequate collaterals. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

Dr. Yustein is a pediatric oncologist and physician-scientist with significant training in molecular and cellular biology. During his time as the Director of the Faris D. Ewing Sarcoma Center at Texas Children's Hospital, he recognized the need for improving our understanding of the molecular pathogenesis of sarcomas and the identification of new therapeutic avenues, especially for patients with therapeutic resistant and/or metastatic disease. His laboratory has tremendous interest and experience in merging innovative murine models and patient-derived resources towards garnering molecular insights into sarcoma initiation, development/resistance and metastatic progression and translating these findings towards testing novel therapeutic interventions for these aggressive malignancies. His laboratory has developed and characterized robust metastatic genetically engineered mouse models (GEMM) for pediatric sarcomas, including osteosarcoma (OS), which recapitulate the human disease initiation and progression. Subsequently, his lab has derived primary sarcoma lines from the GEMM tumors that can be orthotopically transplanted into wild type C57BL/6 mice and monitored using in vivo imaging for further characterization of sarcoma development and progression. He recently moved to Atlanta to join Emory University as a Professor in the Department of Pediatrics, Hematology-Oncology Division and the Director of Solid Tumor Translational Research Children's Healthcare of Atlanta and the Aflac Cancer and Blood Disorders Center. --- What We Do at MIB Agents: PROGRAMS: ✨ End-of-Life MISSIONS ✨ Gamer Agents ✨ Agent Writers ✨ Prayer Agents ✨ Healing Hearts - Bereaved Parent Support ✨ Ambassador Agents - Peer Support ✨ Warrior Mail ✨ Young Adult Survivorship Support Group ✨ EDUCATION for physicians, researchers and families: ✨ OsteoBites, weekly webinar & podcast with thought leaders and innovators in Osteosarcoma ✨ MIB Book: Osteosarcoma: From our Families to Yours ✨ RESEARCH: Annual MIB FACTOR Research Conference ✨ Funding $100,000 annually for OS research ✨ MIB Testing & Research Directory ✨ The Osteosarcoma Project partner with Broad Institute of MIT and Harvard ... Kids are still dying with 40+ year old treatments. Help us MakeItBetter.

A new research paper was published in Aging (Aging-US) on the cover of Volume 14, Issue 12, entitled, “Time makes histone H3 modifications drift in mouse liver.” Aging is known to involve epigenetic histone modifications, which are associated with transcriptional changes, occurring throughout the entire lifespan of an individual. “So far, no study discloses any drift of histone marks in mammals which is time-dependent or influenced by pro-longevity caloric restriction treatment.” To detect the epigenetic drift of time passing, researchers—from Istituto di Ricovero e Cura a Carattere Scientifico, University of Urbino ‘Carlo Bo', University of Milan, and University of Padua—determined the genome-wide distributions of mono- and tri-methylated lysine 4 and acetylated and tri-methylated lysine 27 of histone H3 in the livers of healthy 3, 6 and 12 months old C57BL/6 mice. “In this study, we used chromatin immunoprecipitation sequencing technology to acquire 108 high-resolution profiles of H3K4me3, H3K4me1, H3K27me3 and H3K27ac from the livers of mice aged between 3 months and 12 months and fed 30% caloric restriction diet (CR) or standard diet (SD).” The comparison of different age profiles of histone H3 marks revealed global redistribution of histone H3 modifications with time, in particular in intergenic regions and near transcription start sites, as well as altered correlation between the profiles of different histone modifications. Moreover, feeding mice with caloric restriction diet, a treatment known to retard aging, reduced the extent of changes occurring during the first year of life in these genomic regions. “In conclusion, while our data do not establish that the observed changes in H3 modification are causally involved in aging, they indicate age, buffered by caloric restriction, releases the histone H3 marking process of transcriptional suppression in gene desert regions of mouse liver genome most of which remain to be functionally understood.” DOI: https://doi.org/10.18632/aging.204107 Corresponding Author: Marco Giorgio - marco.giorgio@unipd.it Keywords: epigenetics, aging, histones, ChIP-seq, diet Sign up for free Altmetric alerts about this article: https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204107 About Aging-US: Launched in 2009, Aging (Aging-US) publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Follow Aging on social media: SoundCloud – https://soundcloud.com/Aging-Us Facebook – https://www.facebook.com/AgingUS/ Twitter – https://twitter.com/AgingJrnl Instagram – https://www.instagram.com/agingjrnl/ YouTube – https://www.youtube.com/agingus​ LinkedIn – https://www.linkedin.com/company/aging/ Pinterest – https://www.pinterest.com/AgingUS/ For media inquiries, please contact media@impactjournals.com

Videos :  2. Fake Cases: The Fraudulent PCR Test Is at the Heart of This Entire Plandemic – Dr. Reiner Fuellmich With Judy Mikovits & More   3.  Over 17,000 Physicians and Scientists Agree: “There Is No Medical Emergency” – Dr. Robert Malone   4. Honest Government Ad | Julian Assange   Cranberry juice may slash cardiometabolic risk factors: RCT study USDA Agriculture Research Center, April 30, 2022 Daily consumption of a low-calorie cranberry juice may improve certain risk factors of heart disease, including blood pressure and triglycerides, says a new study from the Agricultural Research Service at the USDA. Eight weeks of supplementing the diet with a cranberry juice containing 173 mg of phenolic compounds per serving was associated with significant reductions in C-reactive protein (CRP), diastolic blood pressure, and blood sugar levels, according to findings published in the Journal of Nutrition . While the majority of the science supporting the health benefits of cranberries is for urinary tract health, a growing body of data supports the cardiovascular potential of the berries. For example, a study by scientists at the Mayo Clinic and College of Medicine found that two glasses of cranberry juice a day may protect against the development of hardening of the arteries. Writing in the European Journal of Nutrition (Vol. 52, pp 289-296), the Mayo Clinic researchers reported that no effect was observed on the function of the cells lining the arteries (endothelial cells), but cranberry juice may reduce the number of endothelial cells that produce a compound called osteocalcin, which has been linked to hardening of the arteries.     Vitamin D toxicity rare in people who take supplements, researchers report Mayo Clinic, April 30, 2022   Over the last decade, numerous studies have shown that many Americans have low vitamin D levels and as a result, vitamin D supplement use has climbed in recent years. In light of the increased use of vitamin D supplements, Mayo Clinic researchers set out to learn more about the health of those with high vitamin D levels. They found that toxic levels are actually rare. A vitamin D level greater than 50 nanograms per milliliter is considered high. Vitamin D levels are determined by a blood test called a serum 25-hydroxyvitamin D blood test. A normal level is 20-50 ng/mL, and deficiency is considered anything less than 20 ng/mL, according the Institute of Medicine (IOM). The researchers analyzed data collected over 10 years from patients in the Rochester Epidemiology Project, a National Institutes of Health-funded medical records pool , one of the few places worldwide where scientists can study virtually an entire geographic population to identify health trends. Of 20,308 measurements, 8 percent of the people who had their vitamin D measured had levels greater than 50 ng/mL, and less than 1 percent had levels over 100 ng/mL. "We found that even in those with high levels of vitamin D over 50 ng/mL, there was not an increased risk of hypercalcemia, or elevated serum calcium, with increasing levels of vitamin D," says study co-author Thomas D. Thacher, M.D., a family medicine expert at Mayo Clinic. Only one case over the 10-year study period was identified as true acute vitamin D toxicity; the person's vitamin D level was 364 ng/mL. The individual had been taking 50,000 international units (IU) of vitamin D supplements every day for more than three months, as well as calcium supplements. The IOM-recommended upper limit of vitamin D supplementation for people with low or deficient levels is 4,000 IU a day.     Reducing sedentary time mitigates the risk of type 2 diabetes and cardiovascular diseases University of Turku (Finland), May 2, 2022 A new study suggests that reducing daily sedentary time can have a positive effect on the risk factors of lifestyle diseases already in three months. Spending just one hour less sitting daily and increasing light physical activity can help in the prevention of these diseases. In an intervention study of the Turku PET Centre and the UKK Institute in Finland, the researchers investigated whether health benefits can be achieved by reducing daily sedentary time during a three-month intervention period. The research participants were sedentary and physically inactive working-age adults with an increased risk of type 2 diabetes and cardiovascular diseases. The intervention group managed to reduce sedentary time by 50 minutes per day on average, mainly by increasing the amount of light- and moderate-intensity physical activity. In the three-month period, the researchers observed benefits in health outcomes related to blood sugar regulation, insulin sensitivity and liver health in the intervention group.     Study Finds Cannabis May Be A “Miracle” Treatment For Autistic Kids Shaare Zedek Medical Center (Israel), April 26, 2022 Autism could now be added to the lengthy and perpetually-expanding list of afflictions and symptoms treatable with the one product of nature shamefully prohibited by the federal government — the “miracle” palliative, cannabis. In a recent article titled, “Marijuana may be a miracle treatment for children with autism,” Israeli researchers began a new study comprised of 120 children ranging in age from five to 29 years, who have been diagnosed with mild to severe autism. Study participants are given one of two cannabis oil treatments or a placebo, drops of which can be mixed into a meal — none contain high levels of THC, the ingredient which gives users a ‘high.' Myriad scientific studies and innumerable anecdotal cases have proven cannabis to treat everything from PTSD to ADHD, various cancers to the painful pressure of glaucoma — but the plant's miraculous quality has been most apparent in treating severe seizures of childhood epilepsy. Now, it appears, cannabis — specifically, the non-psychoactive compound, cannabidiol or CBD — may offer improved quality of life for children with autism, and the families providing their care. In an observational study, the doctor found 70 patients with autism experienced positive results from cannabis — so the clinical trial was launched for in-depth study.     Resveratrol and pinostilbene provide neuroprotectoin against age-related deficits. Duquesne University, April 27, 2022 According to news, research stated, "Age-related declines in motor function may be due, in part, to an increase in oxidative stress in the aging brain leading to dopamine (DA) neuronal cell death. In this study, we examined the neuroprotective effects of natural antioxidants resveratrol and pinostilbene against age-related DAergic cell death and motor dysfunction using SH-SY5Y neuroblastoma cells and young, middle-aged, and old male C57BL/6 mice." The news reporters obtained a quote from the research from Duquesne University, "Resveratrol and pinostilbene protected SH-SY5Y cells from a DA-induced decrease in cell viability. Dietary supplementation with resveratrol and pinostilbene inhibited the decline of motor function observed with age. While DA and its metabolites (DOPAC and HVA), dopamine transporter, and tyrosine hydroxylase levels remain unchanged during aging or treatment, resveratrol and pinostilbene increased ERK1/2 activation in vitro and in vivo in an age-dependent manner. Inhibition of ERK1/2 in SH-SY5Y cells decreased the protective effects of both compounds." "These data suggest that resveratrol and pinostilbene alleviate age-related motor decline via the promotion of DA neuronal survival and activation of the ERK1/2 pathways." Study sheds light on the benefits of exercise in fatty liver disease University of Eastern Finland, May 3, 2022 Exercise supports the treatment of non-alcoholic fatty liver (NAFLD) disease by impacting on several metabolic pathways in the body, a new study from the University of Eastern Finland shows Regular high-intensity interval training (HIIT) exercise over a period of 12 weeks significantly decreased the study participants' fasting glucose and waist circumference, and improved their maximum oxygen consumption rate and maximum achieved workload. These positive effects were associated with alterations in the abundance of a number of metabolites. In particular, exercise altered amino acid metabolism in adipose tissue. The study was published in Scientific Reports. Exercise had a beneficial effect on fasting glucose concentrations, waist circumference, maximum oxygen consumption rate, and maximum achieved workload. These factors were also associated with many of the observed alterations in the abundance of various metabolites in the exercise intervention group. The most significant alterations were observed in amino acids and their derivatives, lipids, and bile acids. In particular, exercise increased the levels of amino acids, which are the building blocks of proteins, in adipose tissue. According to the researchers, their higher accumulations in adipose tissue may be associated with improved lipid and glucose metabolism, as well as with reduced insulin resistance. The levels of various gut microbial metabolites were altered as a result of exercise, which is suggestive of changes in the composition of gut microbes, or in their function. Among these metabolites, increased amount of indolelactic acid, for example, can strengthen the intestinal mucosa, immune defense, and glucose balance.    

Listen to a blog summary of a trending research paper published by Oncotarget in Volume 13, entitled, "Transplantation of autologous bone marrow pre-loaded ex vivo with oncolytic myxoma virus is efficacious against drug-resistant Vk*MYC mouse myeloma.“ ______________________ Multiple myeloma (MM) is a currently incurable cancer of blood plasma cells. Autologous stem cell transplantation (ASCT) has had efficacious results among eligible patients. However, even after ASCT, a significant number of patients continue to relapse and become resistant to current standard therapies. A promising new method to treat blood cancers is a form of immunotherapy called virotherapy. Oncolytic viruses are uniquely capable of being reprogrammed to selectively infect and kill various cancer cells without infecting or damaging normal cells in host organisms, including mice and humans. Researchers from Arizona State University, Emory University and the Mayo Clinic (in Scottsdale, Arizona) had previously experimented with using the oncolytic myxoma virus (MYXV) to treat MM. In nature, MYXV only affects rabbits and is innocuous in mice and humans. They found that MYXVs delivered through stem cell transplantation can eliminate some residual MM cells in the Balb/c mouse model. “Recently, we reported that ex vivo virotherapy with oncolytic myxoma virus (MYXV) improved MM-free survival in an autologous-transplant Balb/c mouse model.” However, the researchers found that Balb/c mice may not be ideal models for MM. They observed that the behavior of MM in Balb/c mice did not quite reflect the development, clinical manifestation and localization of MM observed in human patients. Therefore, the team conducted a new study of MYXVs in the Vk*MYC transplantable C57BL/6 mouse MM model. Their trending research paper was published in Oncotarget on March 3, 2022, and entitled, “Transplantation of autologous bone marrow pre-loaded ex vivo with oncolytic myxoma virus is efficacious against drug-resistant Vk*MYC mouse myeloma.“ Full blog post - https://www.oncotarget.org/2022/03/17/trending-with-impact-adjunct-virotherapy-fights-multiple-myeloma/ DOI - https://doi.org/10.18632/oncotarget.28205 Correspondence to - Grant McFadden - grantmcf@asu.edu Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28205 Keywords - myxoma virus, multiple myeloma, combination therapy, autologous transplantation, oncolytic virus About Oncotarget Oncotarget is a peer-reviewed, open access biomedical journal covering research on all aspects of oncology. 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/ Oncotarget is published by Impact Journals, LLC: https://www.ImpactJournals.com Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

Dec 21 For our last episode of 2021, we're highlighting two important topics in refinement: sedation and euthanasia. Sedation is necessary for zebrafish during procedures such as imaging, biopsy, and surgery to ensure animal welfare and high-quality science. But the effects of sedation can last beyond the administration period and should also be carefully considered. A paper by Gressler et al. explores the use of eugenol and propofol during a 3-hour sedation and their subsequent effects after a 1 hour washout period. Both drugs had effects on behavior and physiology even after the washout period. For behavior, in a novel tank test, eugenol was found to amplify diving response while propofol induced anti-anxiety responses. For physiology, both drugs caused alterations in gill structure. Clearly, as with other species, sedation of zebrafish can significantly affect behavior and physiology beyond the administration period. Therefore, sedation procedures must be carefully designed and reported to refine experiments. Read more in Applied Animal Behavior Science.Next, let's look at euthanasia, an important consideration for any animal study, and those involving zebrafish are no exception. Despite zebrafish being widely used in research, there is no consensus on which method to use when euthanizing them. The most commonly-used method – an overdose of tricaine, or MS-222 – is versatile, readily available and, in fact, is the only legal option in some areas, but it is now known to be aversive. A new paper by von Krogh et al. describes work to address this discrepancy. It describes how the team screened overdoses of seven common alternative anaesthetics dissolved in water, to determine whether they led adult zebrafish to lose reflexes in a rapid, reliable, and non-aversive manner. Other substances were used to buffer the anaesthetics where needed, adjusting the pH of the water to avoid causing irritation. The authors found adding one gram of lidocaine hydrochloride per litre buffered with two grams of sodium bicarbonate per litre, was particularly effective, reliably inducing loss of all reflexes within two minutes and provoking little aversive behavior. Adding fifty milliliters of ethanol per liter further reduced these issues. While the authors recommend this method, they also stress the importance of further investigation, including for zebrafish at different developmental stages. You can read this important work now in Biology.Finally, let's shift focus to mice and how researchers are working to ensure they are euthanized humanely.Gradual exposure to carbon dioxide remains the most common method in use today for euthanising laboratory rodents. Although CO2 is generally considered an acceptable option when properly administered, there are concerns that CO2 is aversive to rodents and might cause distress and pain above certain concentrations. In a new study, Rodriguez-Sanchez and colleagues investigated using a voluntarily ingested sedative to reduce CO2 aversiveness. Cream cheese mixed with different doses of a rapid-acting anesthetic was provided to C57BL/6 mice before exposing the animals to CO2. Using a broad range of behavioural parameters, the team showed 20 mg/kg of sedative resulted in a mild sedation and likely reduced the aversiveness of CO2. While the investigators acknowledge more work is needed to determine the experience of the mice during sedation, they suggest voluntary oral administration of a sedative is potentially an effective, affordable, and easy way to minimise the stress of mice during CO2 euthanasia. Find out more about the study in Animals. See acast.com/privacy for privacy and opt-out information.

Videos for Today: 1. DR Peter C. Gøtzsche Comments – 3 mins   2. PARENTS IN NY TAKE TO THE STREETS TO WARN IGNORANT PARENTS INJECTING THEIR CHILDREN WITH PFIZER SHOT   3, DANIEL NAGASE – EFFECTS OF CV VX ON THE IMMUNE SYSTEM DEVELOPMENT IN CHILDREN   4.The Great Narrative: A call to action speaker Freeke Heijman (start 3 min mark)    5. COMMERCIAL PILOT CODY FLINT: “I DON'T KNOW IF I WILL EVER BE ABLE TO FLY A PLANE AGAIN.”   6. Study, Experts: Vaccinated Are Spreading COVID-19 start 23 seconds in    7. RFK CLIP Start 50 seconds in    Everyone missed this one… vaccinated people are up to 9X more likely to be hospitalized than unvaccinated people Australian War Propaganda Keeps Getting Crazier Are we seeing some new form of Covid-19 Vaccine induced Acquired Immunodeficiency Syndrome? – Official Government data suggests the Fully Vaccinated are on the precipice of disaster as their Immune Systems are being decimated $285 Billion Tax Cut for the Rich Is Now 2nd Most Expensive Piece of Build Back Better Wall Street's Takeover of Nature Advances with Launch of New Asset Class  Court Deals New Blow to ‘Fatally Flawed' Biden Vaccine Mandates, But What Does That Mean?     Study: Sustainable eating is cheaper and healthier Oxford University, November 11, 2021 Oxford University research has today revealed that, in countries such as the US, the UK, Australia and across Western Europe, adopting a vegan, vegetarian, or flexitarian diet could slash your food bill by up to one-third. The study, which compared the cost of seven sustainable diets to the current typical diet in 150 countries, using food prices from the World Bank's International Comparison Program, was published in The Lancet Planetary Health. It found that in high-income countries: Vegan diets were the most affordable and reduced food costs by up to one third. Vegetarian diets were a close second. Flexitarian diets with low amounts of meat and dairy reduced costs by 14%. By contrast, pescatarian diets increased costs by up to 2%. “We think the fact that vegan, vegetarian and flexitarian diets can save you a lot of money is going to surprise people,” says Dr. Marco Springmann, researcher on the Oxford Martin Programme on the Future of Food. “When scientists like me advocate for healthy and environmentally-friendly eating, it's often said we're sitting in our ivory towers promoting something financially out of reach for most people. This study shows it's quite the opposite. These diets could be better for your bank balance as well as for your health and…the planet.” Miguel Barclay, author of the bestselling “One Pound Meals” series of cookbooks, says, “I definitely agree that cutting down your meat, or cutting it out completely, will save you money. I've written seven budget cookbooks and have costed up hundreds of recipes, and without doubt vegan and vegetarian meals consistently come in at a much lower price than recipes with meat.” The study focused on whole foods and did not include highly-processed meat replacements or eating at restaurants or takeaways. The study also found that in lower income countries, such as on the Indian subcontinent and in sub-Saharan Africa, eating a healthy and sustainable diet would be up to a quarter cheaper than a typical Western diet, but at least a third more expensive than current diets. To analyze what options could improve affordability and reduce diet costs, the study looked at several policy options. It found that making healthy and sustainable diets affordable everywhere is possible within the next 10 years when economic development, especially in lower income countries, is paired with reductions in food waste and a climate and health-friendly pricing of foods. “Affording to eat a healthy and sustainable diet is possible everywhere, but requires political will,” according to Dr. Springmann. “Current low-income diets tend to contain large amounts of starchy foods and not enough of the foods we know are healthy. And the western-style diets, often seen as aspirational, are not only unhealthy, but also vastly unsustainable and unaffordable in low-income countries. Any of the healthy and sustainable dietary patterns we looked at are a better option for health, the environment, and financially, but development support and progressive food policies are needed to make them both affordable and desirable everywhere.” The study, “The global and regional costs of healthy and sustainable dietary patterns: a modeling study,” is published in The Lancet Planetary Health on 10 November 2021. Country-level results are available here. Green One Pound Meals by Miguel Barclay is published on 30 December. It features planet-friendly recipes and includes tips and ideas for shopping smart and avoiding food waste. Meta-analysis concludes resveratrol beneficially modulates glycemic control in diabetics Zagazig University and Suez Canal University (Egypt), October 29 2021.  Findings from a meta-analysis of clinical trials published on October 16, 2021 in Medicina Clinica (Barcelona) revealed an association between supplementing with resveratrol and improvements in glycemic control. “Type 2 diabetes mellitus (T2DM) is a progressive meta-inflammatory disorder, which induces micro and macrovascular complications,” Ibrahim A. Abdelhaleem and colleagues wrote. “Resveratrol is a nutraceutical known to have antioxidant and anti-inflammatory properties.” “This systematic review and meta-analysis is the first to consider resveratrol's efficacy on glycemic and cardiometabolic parameters in patients with T2DM.” Sixteen randomized trials that included a total of 871 diabetic men and women were selected for the meta-analysis. The trials compared resveratrol to a placebo with or without concurrent antidiabetic medications or other drug treatment. Resveratrol doses of 500 milligrams or more were associated with lower fasting blood glucose, fasting serum insulin, insulin resistance, total cholesterol, LDL cholesterol and diastolic blood pressure in comparison with a placebo. Resveratrol was associated with a greater reduction in hemoglobin A1c (a marker of long-term glucose control) compared to a placebo in trials of three months duration. When HDL cholesterol levels were analyzed, resveratrol was superior to a placebo in trials of less than two months duration. Resveratrol was also associated with a reduction in systolic blood pressure compared to measurements obtained in the placebo group. Furthermore, triglycerides were lower in association with resveratrol in trials that lasted six to twelve months. “We concluded that resveratrol appropriately improved insulin sensitivity by decreasing insulin resistance, fasting blood glucose, fasting serum insulin, and hemoglobin A1c,” the authors concluded. “In addition, it improved other cardiometabolic parameters, including triglycerides, total cholesterol, LDL cholesterol, and systolic and diastolic blood pressure. The most appropriate glycemic control effect was fulfilled when consumed for at least one month with doses of 500 mg or more.” Exercise linked to better mental health Kaiser Permanente Research, November 11, 2021 Kaiser Permanente research published on November 11 in Preventive Medicine showed people who exercised more during the initial lockdown period of the COVID-19 pandemic experienced less anxiety and depression than those who didn't exercise. It also showed that people who spent more time outdoors typically experienced lower levels of anxiety and depression than those who stayed inside. More than 20,000 people participated in the survey-based study from 6 regions served by Kaiser Permanente across the United States, which included Hawaii, Colorado, Georgia, and the mid-Atlantic states, as well as Southern and Northern California. “What these study findings tell us is that even during an active pandemic or other public health crisis, people should be encouraged to be physically active to help maintain their physical and mental health,” said the study's lead author Deborah Rohm Young, PhD, the director of the Division of Behavioral Research for the Kaiser Permanente Southern California Department of Research & Evaluation. “Parks and other nature areas should remain open during public health emergencies to encourage outdoor physical activity.” In March 2020, COVID-19 developed into a worldwide pandemic. With no known treatment, public health officials attempted to reduce its spread by limiting human interactions through stay-at-home policies. Businesses temporarily closed or changed their practices to prevent the spread of the virus, affecting the economy and many people's jobs. These stressful factors, along with fewer opportunities to socialize with friends and family, increased symptoms of depression and anxiety for many people. Since it is known that physical activity and time spent in nature are associated with improved mental health, researchers at Kaiser Permanente in Southern California sought to determine how exercise and time outdoors was associated with people's mental health during the height of the pandemic. In April 2020, researchers sent a series of COVID-19 surveys to more than 250,000 participants in the Kaiser Permanente Research Bank — a collection of lifestyle surveys, electronic health record data, and biospecimens, which Kaiser Permanente members volunteered. People who reported COVID-19 symptoms were not included in this analysis, resulting in 20,012 respondents. They each completed at least 4 surveys between April and July 2020. White women older than 50 accounted for a high proportion of the respondents. Most respondents said they were retired and generally adhered to the “safer-at-home” orders during the period of the survey. The study found that: Reports of anxiety and depression decreased over time Anxiety and depression scores were higher for females and younger people, and lower for Asian and Black people compared with white respondents Participants who reported no physical activity reported the highest depression and anxiety compared to people who had exercised Spending less time outdoors was associated with higher depression and anxiety scores People who had increased their time outdoors the most reported the highest anxiety scores, but the research could not explain the finding “What we learned from these findings is that during future emergencies it will be important to carefully weigh the decisions to close parks and outdoor areas against the negative impact those closures may have on people's mental health,” said Dr. Young. Bedtime linked with heart health University of Exeter (UK), November 9, 2021 Going to sleep between 10:00 and 11:00 pm is associated with a lower risk of developing heart disease compared to earlier or later bedtimes, according to a study published today in European Heart Journal—Digital Health, a journal of the European Society of Cardiology (ESC). “The body has a 24-hour internal clock, called circadian rhythm, that helps regulate physical and mental functioning,” said study author Dr. David Plans of the University of Exeter, UK. “While we cannot conclude causation from our study, the results suggest that early or late bedtimes may be more likely to disrupt the body clock, with adverse consequences for cardiovascular health.” While numerous analyses have investigated the link between sleep duration and cardiovascular disease, the relationship between sleep timing and heart disease is underexplored. This study examined the association between objectively measured, rather than self-reported, sleep onset in a large sample of adults. The study included 88,026 individuals in the UK Biobank recruited between 2006 and 2010. The average age was 61 years (range 43 to 79 years) and 58% were women. Data on sleep onset and waking up time were collected over seven days using a wrist-worn accelerometer. Participants completed demographic, lifestyle, health and physical assessments and questionnaires. They were then followed up for a new diagnosis of cardiovascular disease, which was defined as a heart attack, heart failure, chronic ischaemic heart disease, stroke, and transient ischaemic attack. During an average follow-up of 5.7 years, 3,172 participants (3.6%) developed cardiovascular disease. Incidence was highest in those with sleep times at midnight or later and lowest in those with sleep onset from 10:00 to 10:59 pm. The researchers analyzed the association between sleep onset and cardiovascular events after adjusting for age, sex, sleep duration, sleep irregularity (defined as varied times of going to sleep and waking up), self-reported chronotype (early bird or night owl), smoking status, body mass index, diabetes, blood pressure, blood cholesterol and socioeconomic status. Compared to sleep onset from 10:00 to 10:59 pm, there was a 25% higher risk of cardiovascular disease with a sleep onset at midnight or later, a 12% greater risk for 11:00 to 11:59 pm, and a 24% raised risk for falling asleep before 10:00 pm. In a further analysis by sex, the association with increased cardiovascular risk was stronger in women, with only sleep onset before 10:00 pm remaining significant for men. Dr. Plans said: “Our study indicates that the optimum time to go to sleep is at a specific point in the body's 24-hour cycle and deviations may be detrimental to health. The riskiest time was after midnight, potentially because it may reduce the likelihood of seeing morning light, which resets the body clock.” Dr. Plans noted that the reasons for the observed stronger association between sleep onset and cardiovascular disease in women is unclear. He said: “It may be that there is a sex difference in how the endocrine system responds to a disruption in circadian rhythm. Alternatively, the older age of study participants could be a confounding factor since women's cardiovascular risk increases post-menopause—meaning there may be no difference in the strength of the association between women and men.” He concluded: “While the findings do not show causality, sleep timing has emerged as a potential cardiac risk factor—independent of other risk factors and sleep characteristics. If our findings are confirmed in other studies, sleep timing and basic sleep hygiene could be a low-cost public health target for lowering risk of heart disease.” Garlic compounds may boost cardio health indirectly via gut microbiota National Taiwan University, November 6 2021 Allicin from garlic may prevent the metabolism of unabsorbed L-carnitine or choline into TMAO, a compound linked to an increased risk of cardiovascular diseases, says a new study from the National Taiwan University. TMAO – or trimethylamine N-oxide – has been known to be generated from dietary carnitine through metabolism of gut microbiota, and was recently reported to be an “important gut microbiota-dependent metabolite to cause cardiovascular diseases,” explained Taiwanese researchers in the Journal of Functional Foods . While antibiotics have been found to inhibit TMAO production, concerns over side effects and resistance have limited their use. This has led researchers to examine the potential of natural alternatives. New data indicated that carnitine-fed lab mice showed a “remarkable increase in plasma TMAO levels”, compared with lab mice fed a control (no carnitine). However, when allicin supplements were provided with the carnitine diet, TMAO levels were significantly reduced. “Surprisingly, the plasma TMAO levels in the mice of ‘carnitine diet + allicin' treatment group were as low as that of chow diet [control] group,” wrote the researchers. “This result indicated that the metabolic capacity of mice gut microbiota to produce TMAO was completely inhibited by allicin supplement even though provided with carnitine-rich environment in the gut. “It means the functional alteration of gut microbiota induced by carnitine diet can be prevented by addition of another substance with antimicrobial potential derived from food, such as allicin.” Garlic and heart health The study adds to the body of scientific literature supporting the potential heart health benefits of garlic and the compounds it contains. Consumer awareness of the health benefits of garlic, mostly in terms of cardiovascular and immune system health, has benefited the supplements industry, particularly since consumers seek the benefits of garlic without the odors that accompany the fresh bulb. The benefits have been linked to the compound allicin, which is not found in fresh garlic: It is only formed when garlic is crushed, which breaks down a compound called diallyl sulphide. Study details “This may offer an opportunity to take advantage of plants' delicately designed defense system against microorganisms, to protect ourselves by modulating gut microbiota to a healthier status,” wrote the researchers The Taiwanese researchers divided male C57BL/6(B6) mice into four groups: One group received only the control chow diet; the second group received the carnitine diet (carnitine added to drinking water at a level of 0.02%); the third group received the carnitine diet with supplemental allicin; and the final group received the control diet plus the allicin supplement for six weeks. Results showed that the second group (carnitine diet) had TMAO levels 4–22 times greater than those observed in the control group. However, these increases were attenuated in the carnitine + allicin group, said the researchers. “Our study suggests that antimicrobial phytochemicals such as allicin effectively neutralize the metabolic ability of TMAO production of gut microbiota induced by daily intake of L-carnitine,” wrote the researchers. “It may offer an opportunity for us to take advantage of plants' delicately designed defense system against microorganisms, to protect ourselves by modulating gut microbiota to a healthier status. “Our research also suggested that allicin and dietary fresh garlic containing allicin might be used as functional foods for the prevention of atherosclerosis,” they concluded. Drug used to prevent miscarriage increases risk of cancer in offspring University of Texas Health Science Center, November 9, 2021 Exposure in utero to a drug used to prevent miscarriage can lead to an increased risk of developing cancer, according to researchers at The University of Texas Health Science Center at Houston (UTHealth Houston). The study was published today in the American Journal of Obstetrics and Gynecology. The drug, 17α-hydroxyprogesterone caproate (17-OHPC), is a synthetic progestogen that was frequently used by women in the 1950s and 1960s, and is still prescribed to women today to help prevent preterm birth. Progesterone helps the womb grow during pregnancy and prevents a woman from having early contractions that may lead to miscarriage. “Children who were born to women who received the drug during pregnancy have double the rate of cancer across their lifetime compared to children born to women who did not take this drug,” said Caitlin C. Murphy, PhD, MPH, lead author on the study and associate professor in the Department of Health Promotion and Behavioral Sciences at UTHealth School of Public Health in Houston. “We have seen cancers like colorectal cancer, pancreatic cancer, thyroid cancer, and many others increasing in people born in and after the 1960s, and no one really knows why.” Researchers reviewed data from the Kaiser Foundation Health Plan on women who received prenatal care between June 1959 and June 1967, and the California Cancer Registry, which traced cancer in offspring through 2019. Out of more than 18,751 live births, researchers discovered 1,008 cancer diagnoses were made in offspring ages 0 to 58 years. Additionally, a total of 234 offspring were exposed to 17-OHPC during pregnancy. Offspring exposed in the womb had cancer detected in adulthood more than twice as often as offspring not exposed to the drug – 65% of cancers occurred in adults younger than 50. “Our findings suggest taking this drug during pregnancy can disrupt early development, which may increase risk of cancer decades later,” Murphy said “With this drug, we are seeing the effects of a synthetic hormone. Things that happened to us in the womb, or exposures in utero, are important risk factors for developing cancer many decades after we're born.” A new randomized trial shows there is no benefit of taking 17-OHPC, and that it does not reduce the risk of preterm birth, according to Murphy. The U.S. Food and Drug Administration proposed in October 2020 that this particular drug be withdrawn from the market.

sent $$$ this week to Stop Line 3 Bail Funds.stopline3bailfunds.org“Line 3 is a proposed pipeline expansion to bring nearly a million barrels of tar sands per day from Alberta, Canada to Superior, Wisconsin. It was proposed in 2014 by Enbridge, a Canadian pipeline company responsible for the largest inland oil spill in the US. Enbridge seeks to build a new pipeline corridor through untouched wetlands and the treaty territory of Anishinaabe peoples, through the Mississippi River headwaters to the shore of Lake Superior.All pipelines spill. Line 3 isn’t about safe transportation of a necessary product, it’s about expansion of a dying tar sands industry. Line 3 would contribute more to climate change than Minnesota’s entire economy. Minnesota’s own Department of Commerce found our local market does not need Line 3 oil. We need to decommission the old Line 3 and justly transition to a renewable, sustainable economy. Line 3 would violate the treaty rights of Anishinaabe peoples and nations in its path – wild rice is a centerpiece of Anishinaabe culture, it grows in numerous watersheds Line 3 seeks to cross. It’s well-past time to end the legacy of theft from and destruction of indigenous peoples and territories.We can keep organizing, educating, and advocating to stop Line 3 and build the future we want. Legal and grassroots efforts have kept Enbridge’s Line 3 destruction at bay – it was supposed to be complete in 2017. We are holding events in our homes, community centers, churches, schools, and online. We are talking to our politicians, speaking up at hearings, marching in protests, taking nonviolent direct action together, and reporting Enbridge’s activity along the proposed route. We are teaching and learning from each other. We are growing food and investing in renewable energy. Wherever you are and whatever your skill set, there is a place for you in the movement to stop Line 3.Currently, we need bail funds for people who have been arrested because of their opposition to Enbridge’s Line 3 pipeline expansion project. Your contributions will make it possible for those on the ground to continue fighting. ”DOWNLOAD RECORDINGsubscribe to the podcast here: http://feeds.feedburner.com/5432fun(intro by omar)beNt “Bless You” Mattress Springs 7"Les Halles “Second Horizon” ZephyrYours Are the Only Ears “Fire in My Eyes” Knock HardMope Grooves “Vanished” VanishedSugar Skull Explosion “You Won’t Win” The Wolves of Space AwakenBlack Marble “Golden Heart” It’s ImmaterialNot For You “Water Birth” DrownKatie Von Schleicher “Midsummer” Shitty HitsOlgaa “Rogue” FortunaJib Kidder “Hole To My Skull” In Between EPBeach Bunny “Adulting” Prom QueenJeanines “You Were Mine” JeaninesEmily Jane Powers “Restless” RestlessDeathlist “Sandstone” A CanyonEvelyn Ida Morris “Forecast” Evelyn Ida MorrisBlithe Field “Farewell To Darker Days” Days Drift ByHealers “street sweeping” Street SweepingBe you me “really actually honestly” advance to boardwalkD.U.D.S “Irregular Patterns” Demos etc.C57BL/6 “Chessboard” Lawn MowerJoe Waine “Belladonna of Sadness” GaleffiWilder Maker “Multiplied” Zion

CoQ10 supplementation associated with improved trauma patient outcomes Urmia University of Medical Sciences (Iran) July 23 2021.    Findings from a trial reported on July 12, 2021 in the Journal of Nutritional Science revealed benefits for hospitalized traumapatients who were given supplements that contained coenzyme Q10.  The trial enrolled 40 men and women with traumatic injury and low plasma levels of CoQ10. Participants received a placebo or 400 milligrams CoQ10 daily for seven days. Blood samples collected at the beginning and end of the trial were analyzed for interleukin 6 (IL-6), which may be elevated during inflammation, and the oxidative stress markers malondialdehyde (MDA) and thiobarbituric acid reactive substances (TBARS). Body composition was also assessed at these time points, as well secondary outcomes that included Sequential Organ Failure Assessment (SOFA) and the Glasgow Coma Scale (GCS).  While interleukin-6 levels at the beginning of the study were similar between the CoQ10 and placebo groups at an average of 175.05 pg/mL and 177.82 pg/mL, they were reduced by 76.99 pg/mL in the CoQ10 group and 17.35 pg/mL in the placebo group. MDA values averaged 232.37 picograms per milliliter (pg/mL) and 239.96 pg/mL and were lowered by 88.84 pg/ml among participants who received CoQ10 and by 26.23 pg/mL among those who received a placebo. In comparison with the placebo group, fat free mass, skeletal muscle mass and body cell mass increased among those who received CoQ10. GCS and SOFA scores, and duration of hospital stay, ICU stay and ventilator use also improved among treated patients.  “To date, no randomized clinical trial study has been conducted to evaluate the effect of CoQ10 supplementation in traumatic mechanical ventilated patients and we hypothesized that CoQ10 administration in these patients could have beneficial effects on biochemical and clinical factors,” the authors wrote. “We have shown that CoQ10 could improve some of the clinical and anthropometric parameters in patients with a traumatic injury.”     Nigella sativa (black seed) prevents covid-induced vascular damage, scientists conclude   Oriental Institute of Science and Technology (India), July 27, 2021 New research published in the journal Vascular Pharmacology shows that Nigella sativa, also known as black seed or black cumin, binds to ACE2 in the lungs, effectively stopping the Wuhan coronavirus (Covid-19) from inducing inflammation and vascular damage. Researchers out of India investigated the effects of nigellidine, an indazole alkaloid of black seed, using molecular docking for binding to different angiotensin-binding proteins, as well as the Chinese Virus spike glycoprotein. They found that nigellidine “strongly binds” to the Chinese Virus spike protein at what is known as the hinge region or active site opening, which may in turn hamper its binding to the nCoV2-ACE2 surface. “Nigellidine effectively binds in the Angiotensin-II binding site / entry pocket,” the study explains. “Nigellidine showed strong binding to mono / multi-meric ACE1.” This process of ACE blocking could, the study goes on to suggest, restore angiotensin levels and restrict vasoturbulence in Chinese Virus patients, while the receptor blocking could help to stop resulting inflammation and vascular impairment. “Nigellidine may slow down the vaso-fluctuations due to Angiotensin deregulations in Covid patients,” the paper further explains. “Angiotensin II-ACE2 binding (ACE-value -294.81) is more favorable than nigellidine-ACE2. Conversely, nigellidine-ACE1 binding-energy / Ki is lower than nigellidine-ACE2 values indicating a balanced-state between constriction-dilatation.” Nigellidine also binds to the viral spike proteins, which when taken by Chinese Virus patients, and especially those who fall in the elderly category, could greatly reduce their risk of suffering complications or death. Nigellidine impairs SARS-CoV-2 infection, “cytokine storm” through numerous mechanisms In a related study that was published last year in the journal Europe PMC, researchers learned that nigellidine inhibits the Chinese Virus infection in several other ways. It was discovered early on in the “pandemic” that many of those who tested “positive” for the virus were suffering associated “cytokine storms,” in which their immune systems were over-responding and causing more damage, or even death. Nigellidine was then studied and discovered to possess certain properties that inhibit cytokine storms, as well as impede the SARS CoV-2 virus from causing infection. It is also hepato- and reno-protective, meaning it protects against liver damage. Beyond this, nigellidine was determined to possess unique immunomodulatory and anti-inflammatory characteristics, as well as antioxidant potential strong enough to inhibit important proteins associated with the Chinese Virus. In their quest to uncover possible “drug” candidates to protect patients against hyper-inflammation and other associated problems, the researchers learned that nigellidine – and more than likely other black seed constituents – helps tremendously with preventing negative side effects. Along with nigellicine, nigellidine is found in the seed coat of Nigella sativa. Both of these constituents in their sulfated forms are extremely bioavailable, and along with thymoquinone and dithymoquinone, two other black seed components, they show strong antioxidant, antibacterial, anti-hypertensive, anti-inflammatory and immunomodulatory effects. Black seed extracts have been shown in other experiments to decrease oxidative stress, effectively lowering the risk of inflammation-related diseases. We now know that this includes the Wuhan coronavirus (Covid-19). Black seed is also recognized as a metabolic protector, helping to improve lipid and blood sugar levels. “Most importantly, in SARS CoV-2 infection ACE-2 mediated impairment of aldosterone system may be repaired by,” the study further explains, providing relevant information to the current “pandemic.” “Vasorelaxant and anti-hypertensive function of [black seed] helps in the modulation of renin angiotensin system (RAS) or the diuretic activity, which is one of the major targets of COVID. It might have great protective role during post infective secondary disorder of the peripheral vasculature namely cardiac and renal systems. In most of the instances patients die due to this organ dysfunction/failure in COVID-19 infection.” By quelling inflammation, black seed could save lives from covid Laboratory studies have found that intake of Nigella sativa significantly improves the parameters for hyperglycemia and diabetes control, as well as glycated hemoglobin and insulin resistance. Based on this, experts believe that nigellidine specifically could play an important role in fighting the Chinese Virus by “docking” to the proteins and inflammatory molecules that can cause a cytokine storm – mainly TNF-? receptors such as TNFR1, TNFR2 and IL1R. “In the experimental rat model the source of this drug Nigella sativa; black cumin seed extracts were tested for its role on antioxidant, hepatic and renal status,” the paper states. “This work will help in the urgent therapeutic intervention against COVID-19 global pandemic.” “In the current study, we have decisively shown by molecular modeling that nigellidine can bind in the active sites of several important proteins of SARS CoV 2, several host receptors specific for SARS CoV-2 induced inflammatory markers IL1, IL6, TNF-?. Moreover, the extract from black cumin seed has been shown in experimental rat to be highly antioxidative, hepato- and reno-protective. Further studies are necessary to verify the potential effects of nigellidine in in vivo laboratory experimental animal model.”   Vitamin D supplementation improves recovery time of children with pneumonia at pediatric hospital Cairo University (Egypt), July 20, 2021 According to news reporting originating from Cairo, Egypt, by NewsRx correspondents, research stated, “Despite the well-recognized effect of vitamin D in metabolism and homeostasis, there is now growing interest in its probable association with pneumonia. This study aims to supply vitamin D3 (Cholecalciferol) (100,000 IU) to pneumonic children to minimize the duration of illness and improve their outcome.” Our news editors obtained a quote from the research from Cairo University, “A double-blinded, randomized, placebo-controlled trial was conducted in a Pediatric Cairo University affiliated hospital. An intervention arm (93 children) and a control arm (98 children), who had pneumonia with an insufficient or deficient level of vitamin D and whose parental permission was obtained, were enrolled in the trial. All children were treated with antibiotics according to WHO guidelines. Children were given a single injection of 1 mL of 100,000 IU of vitamin D3 or placebo. Clinical data were recorded every eight hours for all children. Outcomes were assessed 7 days after vitamin D injection. The primary outcome variable was the change in serum level of 25(OH)D, while the secondary outcomes were the medical state of the assigned cases (improvement or death) and duration between enrollment and hospital discharge for improved cases. In the supplementation group, the percentage of patients who suffered either deficient (38.7%) or insufficient levels (61.3%) of 25 (OH)D at day one had significantly decreased in the seventh day to (11.8%) and (52.7%), respectively. Kaplan--Meier plots highlighted that the median time to recover of the placebo group was significantly longer than that of the supplementation group (Log Rank P value < .001). VDD was detected in pediatric critical care children.” According to the news editors, the research concluded: “In pneumonic children with high VDD, it is illustrated that Vitamin D supplementation is accompanied by lowered mortality risk and pSOFA scores, reduced time to recover, and improved PaO2/FiO(2).”   Physical activity could combat fatigue, cognitive decline in cancer survivors University of Illinois, July 26, 2021 A new study indicates that cancer patients and survivors have a ready weapon against fatigue and "chemo brain": a brisk walk. Researchers at the University of Illinois, along with collaborators at Digital Artefacts in Iowa City, Iowa, and Northeastern University in Boston, looked at the association between physical activity, fatigue and performance on cognitive tasks in nearly 300 breast cancer survivors. "The data suggest that being more physically active could reduce two of the more commonly reported symptoms in breast cancer survivors: fatigue and cognitive impairment," said study leader Edward McAuley, a professor of kinesiology and community health at Illinois. "Most people think, 'If I exercise, I'll become tired.' In our study, exercise actually was associated with reduced fatigue, which in turn was associated with better cognitive function." Cognitive impairment, such as memory problems or shortened attention spans, is a common complaint among cancer patients and survivors, and is thought to be similar to decline due to aging. Past Illinois research has explored the effect of physical fitness on age-related cognitive decline, so the researchers wondered whether cancer survivors would respond similarly to exercise. "Other studies of cancer survivors have relied on small samples of cancer survivors, and used self-reporting measures of physical activity and cognitive function, which can be very biased," said postdoctoral researcher Diane Ehlers, the first author of the study, which is published in the journal Breast Cancer Research and Treatment. "What makes our study novel is that we had objective measures for both physical activity and cognitive performance, and a nationwide sample of breast cancer survivors." The researchers worked with Digital Artefacts -- developer of the commercial neuroscience app BrainBaseline - to create an iPad app tailored to this study. The app included questionnaires and activities designed to measure attention, memory and multitasking skills. The researchers also sent each participant an accelerometer to track daily physical activity. "We found that higher levels of daily moderate-to-vigorous physical activity were associated with better performance on the cognitive tasks measuring attention, memory and multitasking," Ehlers said. "What was notable was that physical activity's effect on cognitive performance was mediated by fatigue. This provides evidence that physical activity interventions targeting fatigue in cancer patients and survivors might provide promising models for improving cognitive function as well." Next, the researchers plan to conduct further studies to establish causation and further explore the pathways of how physical exercise improves cognitive performance. They are working with Digital Artefacts to conduct an iPhone-based study and focusing on diverse populations of breast cancer survivors. "The message for cancer patients and survivors is, get active!" Ehlers said. "Even if it's 10-minute bouts of brisk walking. It's not a magical cure-all, but we've seen many benefits of physical activity for cancer patients and survivors."   Cannabidiol promotes oral ulcer healing by inactivating CMPK2-mediated NLRP3 inflammasome Sichuan University (China), July 26, 2021 Xingying Qi, West China Hospital of Stomatology, Sichuan University, Chengdu, China, presented the oral session "Cannabidiol Promotes Oral Ulcer Healing by Inactivating CMPK2-Mediated NLRP3 Inflammasome" at the virtual 99th General Session & Exhibition of the International Association for Dental Research (IADR), held in conjunction with the 50th Annual Meeting of the American Association for Dental Research (AADR) and the 45th Annual Meeting of the Canadian Association for Dental Research (CADR), on July 21-24, 2021. The oral ulcer is a common oral inflammatory lesion with severe pain but little effective treatment is currently available. Cannabidiol (CBD) is recently emerging as a therapeutic agent for inflammatory diseases. However, the underlying mechanisms are not fully elucidated. Qi and colleagues sought to investigate whether and how CBD could play a therapeutic role in the oral ulcer. Oral ulcer models were performed in the tongue of C57BL/6 mice by acid etching or mechanical trauma, followed by CBD local administration. Samples were harvested for macroscopic and histological evaluation. CBD oral spray on acid- or trauma-induced oral ulcers on mice tongues inhibited inflammation, relieved pain and accelerated lesions closure in a dose-dependent manner. The results show that CBD accelerates oral ulcer healing by inhibiting CMPK2-mediated NLRP3 inflammasome activation and pyroptosis, which is mediated mostly by PPARγ in nucleus and partially by CB1 in plasma membrane. This data may shed light on the development of new therapeutic strategies for oral ulcers.   Algal solution: Could Spirulina modify the microbiome to protect against age-related damage? Louvain Drug Research Institute (Belgium), July 25 2021 Spirulina might help protect against age-related liver inflammation by modifying pathways in the microbiome, say researchers. Consumption of spirulina could help protect against hepatic inflammation in the elderly, according to the new animal research published in Nutrients. Belgian researchers carried out tests on mice, which suggest that the algae Spirulina has an impact on the gut microbiota, which in turn activates the immune system in the gut and improves inflammation in the liver that is associated with ageing. Led by senior author Professor Nathalie Delzenne from the Louvain Drug Research Institute in Belgium, the team said oral feeding of Spirulina was found to modulates several immunological functions involving, among others, the TLR4 pathway in old mice. “The fact that its oral consumption can influence both gut immunity and systemic sites, such as the liver, suggests that its immune action is not confined to the gut immune system,” wrote the team – who said the findings open the way to new therapeutic tools “in the management of immune alterations in aging, based on gut microbe-host interactions.” Furthermore, they suggested that improvement of the homeostasis in the gut ecosystem ‘could be essential' during the aging process, “and, in this perspective, dietary manipulation of the gut microbiota of the elderly with Spirulina, may represent a tool for preserving a healthy gastrointestinal microbial community in addition to its beneficial effects on immune function.” Study details Delzenne and colleagues noted that while the possible cardiovascular and immune support benefits of Spirulina have been fairly widely reported, the new study brings a fresh approach by testing whether the effects could be related to a modulation of gut micrbiota. In the trial, young mice aged three months were fed a standard diet, while older mice aged 24 months were fed a standard diet either with or without 5% Spirulina for six weeks. Upton supplementation with Spirulina, the team reported several changes to gut microbiota composition, including an increase in Roseburia and Lactobacillus populations. “Interestingly, parameters related to the innate immunity are upregulated in the small intestine of Spirulina-treated mice,” said the team. “Furthermore, the supplementation with Spirulina reduces several hepatic inflammatory and oxidative stress markers that are upregulated in old mice versus young mice.” Expression of several genetic and biochemical markers of inflammation and immunity were altered by supplementation with Spirulina, said the team. In particular, the transcription factor Foxp3 – involved in the differentiation of T cells into regulatory T cells (Tregs) – and MCP1 were increased due to Spirulina supplementation in old mice. Old mice that consumed Spirulina also showed activation of several immune parameters including Foxp3 in the ileum – suggesting an improvement of the gut immune function upon Spirulina treatment in this segment, said the Belgian researchers. Furthermore, Spirulina supplementation upregulated both TLR2 and TLR4 expression in the ileum of aged mice. “In accordance with these results, a solution of Spirulina (5%) exhibited a TLR4 agonist activity similar to the one reached in old-SP mice, suggesting a direct effect of the Spirulina, itself, on the TLR4 pathway,” they added. Microbiome mechanisms While the positive effect of Spirulina on the microbiome and liver inflammation is clear, the team noted that the mechanism by which the algae could change the composition of the intestinal microbiota remains unanswered. One possible mechanism could be the presence of antimicrobial substances produced by Spirulina, they said. “On the other hand, antimicrobial peptides (AMPs) could be mediators of the nutritional modulation of the gut microbiota.” “In the present study, RegIIIγ and Pla2g2 were increased by the supplementation with Spirulina, suggesting that the host contributes to the reduction and modification of the microbial community by modulating the production of specific AMPs,” they added.

This week's podcast features author Nicholas Mills and Guest Editor Allan Jaffe as they discuss the article "High-Sensitivity Cardiac Troponin on Presentation to Rule Out Myocardial Infarction: A Stepped-Wedge Cluster Randomized Controlled Trial." (https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.052380) Dr. Carolyn Lam: Welcome to Circulation On The Run, your weekly podcast summary, and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke-National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, Associate Editor/Director of the Pauley Heart Center and VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature, we're going to examine cardiac troponin, high-sensitive cardiac troponin, and its association with myocardial infarction. But first, before we get to that, how about we grab a cup of coffee and start in and review some of the other articles in the issue? Would you like to go first? Dr. Carolyn Lam: I would love that. The first paper brings up the problem of stroke, remaining a devastating complication of transcatheter aortic valve replacement or TAVR. Now, this stroke risk has persisted despite refinements and the technique and increased operator experience, while cerebral embolic protection devices have been developed to mitigate this risk data regarding their impact on stroke and other outcomes after TAVR are limited. Dr. Carolyn Lam: Dr. David Cohen from Cardiovascular Research Foundation in New York and colleagues performed an observational study using data from the STS-ACC TVT registry, including more than 123,000 patients from almost 600 sites who underwent elective or urgent transfemoral TAVR between January 2018 and December 2019. Dr. Greg Hundley: Wow, Carolyn, this sounds like a really good use of the registry. What were the results? Dr. Carolyn Lam: Indeed, in this nationally representative observational study, the authors did not find an association between embolic protection device use for TAVR and in-hospital stroke in their primary instrumental variable analysis. And that's a technique designed to support causal inference from observational data with site-level preference for embolic protection device use within the same quarter of the procedure as the instrument. Dr. Carolyn Lam: However, they found a modestly lower risk of in-hospital stroke in their secondary propensity weighted analysis. These findings provide a strong basis for large-scale randomized control trials to really test whether embolic protection devices provide meaningful clinical benefit for patients undergoing TAVR. And this is discussed in a nice accompanying editorial by Dr. Tam and with Wijeysundera from University of Toronto. Dr. Greg Hundley: Very nice Carolyn. Well, my first paper comes to us from Professor Hua Zhang from Shanghai Children's Medical Center. Cyanotic congenital heart disease is a complex pathophysiological condition involving systemic chronic hypoxia and some cyanotic congenital heart disease patients are chronically hypoxic throughout their lives which heightens their risk of heart failure as they age. Dr. Greg Hundley: Hypoxia activates cellular metabolic adaptation to balance energy demands by accumulating hypoxia-inducible factor 1-Alpha. And Carolyn, this study aims to determine the effect of chronic hypoxia on cardiac metabolism and function in cyanotic congenital heart disease patients and its association with age. The authors investigated the role of hypoxia-inducible factor 1-Alpha in this process, and the potential therapeutic targets for this were explored. Dr. Carolyn Lam: What did they find Greg? Dr. Greg Hundley: In cyanotic congenital heart disease patients maladaptation of cardiac metabolism occurred during puberty, along with impaired cardiac function. In cardiomyocytes, specific HIF1-Alpha knockout mice, chronic hypoxia failed to initiate the switch of myocardial substrates from fatty acids to glucose, thereby inhibiting ATP production and impairing cardiac function. Increased insulin resistance during puberty suppressed myocardial HIF1-Alpha and was responsible for cardiac metabolic maladaptation in animals exposed to chronic hypoxia. Dr. Greg Hundley: Pioglitazone significantly reduced myocardial insulin resistance, restored glucose metabolism, and improved cardiac function in pubertal chronic hypoxia animals. And so, Carolyn, perhaps future studies could test whether pioglitazone administration during puberty might improve cardiac function in cyanotic congenital heart disease patients. And this article is nicely accompanied by an editorial from Professor Ghofrani. Dr. Carolyn Lam: That's really interesting. For the next paper we're going from cyanotic congenital heart disease to plain old hypertension asking the question, What is the association of blood pressure classification using the 2017 ACC/AHA blood pressure guideline with risk of heart failure and atrial fibrillation? Well, this question was addressed by Dr. Kaneko and colleagues from University of Tokyo who performed analysis using a nationwide health claims database collected in the JMDC claims database between 2005 and 2018. Now note, this was more than 2 million patients followed for a mean of more than a thousand days in whom more than 28,000 incident heart failure, and more than 7,700 incident atrial fibrillation events occurred. Dr. Greg Hundley: Carolyn, this is a really large cohort a lot of events. What did they find here? Dr. Carolyn Lam: Among adults not taking anti-hypertensive medications and with no prevalent history of cardiovascular disease, stage one and stage two hypertension, according to the 2017 ACC/AHA blood pressure guidelines was associated with a higher incidence of heart failure and atrial fibrillation. The population attributable fractions for heart failure associated with stage 1 and stage 2 hypertension were 23.2% and 51.2% respectively. The population attributable fractions for atrial fibrillation associated with stage 1 and 2 hypertension were 17.4% and 34.3% respectively. The categorization based on 2017, ATC/AHA blood pressure guidelines may improve risk stratification for identifying adults at high risk for heart failure and atrial fibrillation. Dr. Greg Hundley: Wow Carolyn. Really useful data and something I love about our journal, a transition from a large cohort study on hypertension, and now we're going to delve into the world of preclinical science and talk about myocardial hypertrophy. Carolyn, exercise can induce physiological myocardial hypertrophy and former athletes can live five to six years longer than non-athletic control suggesting a benefit after regression of physiological myocardial hypertrophy. Dr. Greg Hundley: Accordingly, these authors led by Professor Yulin Liao from Nanfang Hospital and Southern Medical University hypothesized that anti-hypertrophic memory exists after physiologic myocardial hypertrophy has regressed increasing myocardial resistance to subsequent pathological hypertrophic stress. In this study, C57BL, six mice were submitted to 21 days of swimming training to develop physiological myocardial hypertrophy. Then after termination of the swimming events and exercise, the physiological myocardial hypertrophy regressed within a week. And these physiological myocardial hypertrophy regression mice termed the exercise preconditioning group or HP, and then sedentary mice as a control group underwent transverse aortic constriction, or a sham operation and were observed for four weeks. Dr. Greg Hundley: Finally, in these two groups, cardiac remodeling and function were evaluated using echocardiography invasive left ventricular hemodynamic measurements and histological analysis. Dr. Carolyn Lam: Wow. Exercise induced and I hypertrophic memory in the heart. That is so cool. Greg, could you summarize what they found? Dr. Greg Hundley: Yeah. And how about that exercise stimulus? The mice were swimming. Carolyn, these authors found that exercise-induced physiological myocardial hypertrophy can produce cardioprotective effect. And this cardioprotective effect continues to exist after the physiological myocardial hypertrophy subsides. And it's termed a phenomenon exercise hypertrophy preconditioning. Dr. Greg Hundley: Now, mechanistically, the investigators found that exercise hypertrophy preconditioning up regulates the expression of the long noncoding RNA Mhrt779 by increasing the three methylation of histone 3 at the A4 promoter of Mhrt779. Dr. Greg Hundley: Carolyn, also cardiac overexpression are knocked down of Mhrt779 respectively enhanced or weakened the anti hypertrophy effect of exercise hypertrophy preconditioning. The clinical implications of this research are that these results will likely stimulate further research into the mechanisms of exercise hypertrophy preconditioning, and Mhrt779 may be a potential therapeutic target for myocardial heart hypertrophy and heart failure in clinical practice. Dr. Carolyn Lam: Wow. Thanks so much, Greg. That was an incredible summary. Dr. Carolyn Lam: Let me tell you what else is in today's issue. There's an exchange of letters amongst doctors Mehmood Donkor, and Westermann regarding the article “Left Ventricular Unloading is Associated with Lower Mortality in Cardiogenic Shock Patients Treated with Venal Arterial Extracorporeal Membrane Oxygenation.” There's an ECG Challenge by Dr. Bhasin regarding “A Young Woman with Palpitations. Is It a Poison or Is It a Reality?” Dr. Carolyn Lam: In Cardiology News by Tracy Hampton, she describes new research, revealing mechanisms behind exercise-induced heart damage, new details behind muscle injury repair, and new insights on plasma membrane rupture during cell death. Very interesting. A new section there. There's a Perspective piece by Dr. Passman on “'Pill in the Pocket?' Anticoagulation for Atrial Fibrillation. Is That Fiction, Fact, or Foolish?” Dr. Greg Hundley: Great, Carolyn. Well also in the mailbag, there's a Frontiers and medicine piece from Professor Rohatgi entitled “HDL in the 21st Century: A Multifunctional Roadmap for Future HDL Research.” And then finally, Carolyn, a Research Letter from Professor Felker, entitled Probabilistic Re-adjudication of Heart Failure Hospitalization: Events in the Paragon-HF Study.” Well, Carolyn, what a great group of articles summarized. How about now we proceed to that feature discussion? Dr. Carolyn Lam: Let's go Greg. Dr. Greg Hundley: Well, listeners. We are now to our featured discussion today and we have with us one of our associate editors who has submitted a paper, Dr. Nick Mills from Edinburgh, Scotland. And then we have a guest editor. Sometimes he's been a feature author, but now he's serving as a guest editor, Dr. Alan Jaffe from Rochester, Minnesota. Welcome gentlemen. Dr. Greg Hundley: Well, Nick, could you start us off first and describe for us the hypothesis that you wanted to test, and then maybe also provide a little bit of context or background around the study that you and your team have just performed. Dr. Nicholas Mills: Thanks, Greg. I've been working for about a decade trying to understand how we can get the value from high-sensitivity cardiac troponin in our clinical practice. We've tried a number of different approaches to implement them for the benefit of patient care that I'm particularly proud of this trial. What we'd recognized that I think with the rollout of these assays across Europe and more recently in America is that they're excellent tests, but they do generate some diagnostic uncertainty in clinical practice. Dr. Nicholas Mills: But as we've got used to using them, we've learned that actually their major strength is that the confidence that they bring in ruling out myocardial infarction rather than ruling it in. And they allow us to make really early decisions often with a single test at the point of arrival, where we can say with absolute confidence that a patient does not have acute coronary syndrome and it's unlikely to have a problem in the next 30 days or one year based on just how low that high sense of high-sensitivity cardiac troponin result is. And I've been a strong advocate for using these tests in that way for some time. But the limitation has been that much of the work in this field has been observational. And so the patients were actually managed accordingly because of uncertain pathways. And there's always been some uncertainty as just how effective they are when in clinical practice, whether using these approaches are safe. And so we designed the Historic Trial to address that definitively in our hospitals in Scotland. Dr. Greg Hundley: Very nice Nick. So what was the study population and what was the design for this Dr. Nicholas Mills: Thanks Greg. So we use an interesting study design set wage cluster, randomized controlled trial, where rather than randomizing individual patients and randomized hospitals in Scotland, in order to do a trial like this, you need very detailed infrastructure because we wanted to enroll every consecutive patient, attending our emergency departments with symptoms, suspicions of acute cardiac syndrome. We embed it so into our care path, which allows our clinicians to enroll patients for us. We were keen to enroll all consecutive patients because we wants to be confident that our findings were truly generalizable at any included patients with complex comorbidities presenting that of ours who were sick unwell, which is often not the case; they've been observational studies. We randomized hospitals and follow up patients with acute coronary syndrome up for a year in order to determine whether the implementation of already changed clinical care and that was safe and did not lead to recurrent and in the future. Dr. Greg Hundley: Very nice. So Nick, in this randomization of hospitals, how many total patients did you encounter and then what were your study results? Dr. Nicholas Mills: So we enrolled 31,492 consecutive patients. I've crossed all seven hospitals implementing our early relapse pathway, reduced length of stay overall in the hospital. By just over three hours, we increased the proportion of patients who are directly discharged home from the emergency department by more than 50%. So that overall 71% of patients attending hospital with possible acute coronary syndrome were able to be discharged from the emergency department rather than being admitted unnecessarily for further investigations. But the critical result was, was that major change in the care pathway safe. We had a non-inferiority design. We had a very small number of safety outcomes at 30 days, and it was difficult to prove non-inferiority, but the event rate favored the implementation there. Dr. Nicholas Mills: They will have pathway with the 0.4% of patients we attend within 30 days of heart attack or dying from heart disease for our implementing it and 0.3% in and crucially, we followed everyone up for a year and were able to demonstrate that the safety outcome was not increased in those that we are able to that pathway one year with absolute confidence. And furthermore, there was no difference in re attendance or an all-cause mortality. We the two different arms of the trial. So we concluded that the early relapse pathway was effective and safe, and that using this approach we'd have major benefits from patients who can avoid unnecessary for healthcare providers in terms of reducing actual cost limitations. Dr. Greg Hundley: Fantastic. Well listeners, we're now going to turn to our guest editor, Dr. Alan Jaffe, and Alan, could you help us put into perspective these new data regarding high sensitivity, proponent, and also comment what attracted you to this article so much so that you feel it's needs to be published and circulated worldwide in the literature? Dr. Allan Jaffe: One of the important areas in the field of biomarkers is the movement just finally occurring. And Nick has been the forefront of this, of starting to do randomized trials. Observational data is just that it's observational. The patients are not created based on the information that is by the biomarkers. Patients can be missed if you're missing a sample, you exclude those patients. In addition, most observational trials, try and get informed consent. And by getting informed consent often miss the sickest patients. So what's desperately needed by the field. And which is just now starting with two or three ongoing randomized trials is just that a randomized trial where the investigators are forced to use the data, to manage the patient. And by using the step wedge design that Nick and his group has used in other trials as well, they guarantee that they don't miss patients either. Dr. Allan Jaffe: So that it's comprehensive and takes all into account. This is terribly important to then validate things like in this instance, the rule-out pathway. And I think these data do substantially confirm the fact that a single sample rule-out strategy using the cutoff value that Nick had previously established as optimizing the percentage of the population that can be included works well. It is unfortunate that the way in which they design their trial mist and design their non-inferiority outcome for safety was such that they ended up not finding significance to that. But I agree with Dr. Mills in the sense that the outcome adverse effects were so low, that despite that I think there's very important and reasonable data that this strategy is also safe. Dr. Greg Hundley: Very good. Well, Nick, thinking forward, what do you feel is the next study that needs to really be performed in this area? Dr. Nicholas Mills: I completely agree with everything Alan said. I think there's lots of really interesting approaches to find a group diagnosis, risk stratification of this really common condition. We need trials that demonstrate these approaches actually influence care and outcomes. For me, the challenge remains how to really harness these great tests to route the ruler of my cognitive function. I run about ads of patients with elevated cardiac troponin added due to an underlying condition that is an acute coronary syndrome. And we're starting to think about ways in which we can individualize our decision-making a little bit moving to walk away from binary thresholds, because values are influenced by age, by sex, by comorbidities like renal disease and preexisting heart failure about heart disease. Dr. Nicholas Mills: And by incorporating some of these patient factors into the interpretation of cardiac troponin. I think we can give clinicians better guidance on who to treat early with antiplatelet therapies and who needs invasive investigation than just simply saying that the troponin concentration is all positive or negative. And it's our challenge, I think, is how to harness that information, make it workable in clinical practice, and then demonstrate that by doing so we actually target effective therapies better, and that it makes a difference for patient care. So this is where we're working on at the moment. And I hope that in due course, we'll be able to do randomized trials in this space and that will move things forward again. Dr. Greg Hundley: Alan, do you have anything you'd like to add to that? Dr. Allan Jaffe: Yes. I think we're in a new era. We are finally starting to see there are now two or three randomized trials. It is time that the biomarker diagnostic studies graduate to a higher level of evidence, meaning randomized controlled trials. Nick is leading the way in that regard and I suspect and hope that subsequent trials, although observational trials may help inform which ones we should do, but that subsequent trials will continue to be randomized and generate the more robust data that randomized trials are capable of generating. Dr. Greg Hundley: Well, thank you both. And Nick, thank you for bringing us this research and also Alan, for evaluating it and providing this commentary today. It's quite exciting to have really this new information produced from a randomized trial, which evaluated the utility of a low high sensitivity treponema value in patients presenting to hospitals with chest pain syndromes. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association for more visit ahajournals.org.  

Fructose Malabsorption and IBS, High IGF-1 and Prostate Cancer, Air Purifiers, Lymphocytic Colitis and Heart Palpitations/Extreme Anxiety/Brain Fog, Heavy Lifting on Joints Make your health an act of rebellion. Join The Healthy Rebellion Please Subscribe and Review: Apple Podcasts | RSS Submit your questions for the podcast here Show Notes: News topic du jour: Reframing Nutritional Microbiota Studies To Reflect an Inherent Metabolic Flexibility of the Human Gut: a Narrative Review Focusing on High-Fat Diets "While human metabolism can adapt to diets higher in either fats or carbohydrates, the natural diet of a mouse is low in fat and high in carbohydrates. It is therefore unsurprising that mice develop issues when eating a species-inappropriate diet. The strain of mice commonly used for such studies, C57BL/6, has also been genetically selected for its ability to gain weight in response to a HF diet. While humans are capable of weight loss or gain on a variety of dietary patterns (32–34), C57BL/6 mice have greater weight gain and metabolic disruptions on low-carbohydrate diets (35). Consequently, “…rodent models of obesity may be most valuable in the understanding of how metabolic mechanisms can work in ways different from the effect in humans” (35). Broadly translating findings from inbred mice fed a highly refined HF diet to humans is therefore fraught with potential for misunderstanding." 1. Fructose Malabsorption and IBS [23:57] Jack says: Hi Robb, I've been experiencing IBS over the past few years, awful cramping and diarrhea. I finally decided to have a food sensitivity test done, and have a fructan & fructose malabsorption. The GI specialist didn't really give me any direction or recommendations, only a diagnosis. I would like to try and do a paleo/primal diet, but low in fructose/fructans. This leaves me with a pretty limited choice on fruits and veggies that sit well with me. I love the way veggies taste and the way they make me feel. Do you have any suggestions for me? I found a supplement called FRUCTAID (Glucose Isomerase Enzyme) that helps. Do you recommend I just take that with every meal high in fructose/fructans? Should I be taking a greens powder and a multivitamin to make sure and get all the good stuff and just eat what I can and skip the FRUCTAID? Worried that I will get palate fatigue and become deficient in some nutrients by eating this way. I could be overthinking this, but its all pretty new to me. Thanks, Jack 2. High IGF-1 and Prostate Cancer [27:35] Eric says: Hi All, In the fall of 2021, I went through an early stage prostate cancer treatment that included radiation, brachytherapy, and androgen deprivation. Fun stuff. I'm getting my androgens back, slowly but surely, making "morning wood" a thing again. Hooray for me! I'm taking my chances with a high protein, low glycemic approach to eating to help prevent the cancer from coming back. I'm likely in and out of ketosis on a daily basis depending on when I ate my last meal. I keep under 25 carbs, and eat 205 grams of protein a day. I'm 5'10, 232lbs, and right around 22-23% body fat. I'm also 40 years old. I weight train 4-5 times per week, and roll jiujitsu 3x per week. Since I've heard of the relationship between IGF-1 and prostate cancer, my question pertains to it. At 40, my IGF-1 levels are around 337ng/dl. That's about 100ng/dl over what my high point "should" be at this age (I'm great for a teenager but without that level of morning wood). This stays true regardless of whether I'm insulin sensitive or not. I tested before my androgen deprivation therapy and my fasting insulin was 5uIU/ml. At the height of the deprivation my fasting insulin was 15 and the igf-1 was 357. Now my fasting insulin it has begun to drop back to within the 8-10 range, going down, and the IGF-1 levels remain about the same. We don't think I have a benign pituitary tumor, which would be nice to not have brain surgery; but we are testing for that despite my mri coming back negative. My question, then, is twofold: is this something to worry about, or would you take these levels to be "normal" given my athletic endeavors, pretty large frame, and protein intake? If you think it's something to worry about, do you have any strategies I might suggest to my doctor for eeking out some answers? Carbohydrate Restriction, Prostate Cancer Growth, and the Insulin-Like Growth Factor Axis Nutritional Predictors of Insulin-like Growth Factor I and Their Relationships to Cancer in Men "Men with relatively high intakes of total protein (top quintile) and minerals (top quintile of the five minerals combined) had a 25% higher mean plasma level of IGF-I compared with those in the low quintiles simultaneously. The major sources of animal protein, including milk, fish, and poultry, but not red meat, as well as total vegetable protein, were associated with an increase in IGF-I levels. Energy intake was positively related to plasma IGF-I level but only in men with body mass index

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.03.367151v1?rss=1 Authors: Kodati, B., Stankowska, D. L., Krishnamoorthy, V. R., Krishnamoorthy, R. R. Abstract: Purpose: The goal of this study was to determine if JNK2 plays a causative role in endothelin-mediated loss of RGCs in mice. Methods: JNK2-/- and wild type (C57BL/6) mice were intravitreally injected in one eye with 1 nmole of ET-1, while the contralateral eye was injected with the vehicle. At two time points (2 h and 24 h) following the intravitreal injections, retinal sections were obtained and phosphorylated c-Jun was assessed. In a separate set of experiments, JNK2-/- and wild type mice were intravitreally injected with either 1 nmole of ET-1 or its vehicle, and euthanized 7 days post-injection. Retinal flat mounts were stained with antibodies to the RGC marker, Brn3a, and surviving RGCs were quantified. Axonal degeneration was assessed by imaging PPD stained optic nerve sections. Results: Intravitreal ET-1 administration produced a significant increase in immunostaining for phospho c-Jun in wild type mice, which was appreciably lower in the JNK2 -/- mice. A significant (p

รายการ สุขใจใกล้หมอ ใกล้หมอชะลอวัยกับหมอแอมป์ "ถั่งเช่า ดีจริงหรือไม่?" ตอนที่ 2 โดย หมอแอมป์ - นพ. ตนุพล วิรุฬหการุญ -ประธานเจ้าหน้าที่ปฏิบัติการ และ ผู้อำนวยการ BDMS Welness Clinic -ผู้อำนวยการ RoyalLife โรงพยาบาลกรุงเทพ -นายกสมาคมแพทย์ฟื้นฟูสุขภาพและส่งเสริมการศึกษาโรคอ้วน กรุงเทพ (BARSO) ออกอากาศทางช่อง PPTV HD 36 เมื่อ พ.ศ.2558 Keywords for Education: -Cordyceps Sinensis -Herbal Medicine -Lifestyle Medicine

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.09.290148v1?rss=1 Authors: Pernold, K., Rullman, E., Ulfhake, B. Abstract: Using 14-20 months of cumulative 24/7 home-cage activity recorded with a non-intrusive technique and a data driven analytical approach, we here provide evidence for the existence of a circannual oscillation (1-2 SD of the mean, on average 65% higher during peak of highs than lows; P=7E-50) in spontaneous activity of male and female C57BL/6 mice held under constant barrier conditions (dark-light cycle 12/12 h (DL), temperature 21{+/-}1{degrees}C, humidity 40-60%). The periodicity of the season-like oscillation is in the range of 2-4 months (on average 97 days across cohorts of cages) and off-sets also responses to environmental stimuli but does not significantly alter the preference for activity during the dark hours of this nocturnal mouse strain (P=0.11 difference between highs and lows). The significance of this hitherto not recognized slow rhythmic alteration in spontaneous activity is further substantiated by its co-variation with the feeding behaviour of the mice. The absence of coordination within and between cohorts of cages or synchronization to the seasons of the year, suggests that the oscillation of in-cage activity and behavioural responses is generated by a free-running intrinsic oscillator devoid of synchronization with an out-of-cage environmental time-keeper. Since the variation over time has such a magnitude and correlate with the feeding behaviour it is likely that it will impact a range of long term experiments conducted on laboratory mice if left unrecognized. Copy rights belong to original authors. Visit the link for more info

รายการ สุขใจใกล้หมอ ใกล้หมอชะลอวัยกับหมอแอมป์ "ถั่งเช่า ดีจริงหรือไม่?" ตอนที่ 1 โดย หมอแอมป์ - นพ. ตนุพล วิรุฬหการุญ -ประธานเจ้าหน้าที่ปฏิบัติการ และ ผู้อำนวยการ BDMS Welness Clinic -ผู้อำนวยการ RoyalLife โรงพยาบาลกรุงเทพ -นายกสมาคมแพทย์ฟื้นฟูสุขภาพและส่งเสริมการศึกษาโรคอ้วน กรุงเทพ (BARSO) ออกอากาศทางช่อง PPTV HD 36 เมื่อ พ.ศ.2558 Keywords for Education: -Cordyceps Sinensis -Herbal Medicine -Lifestyle Medicine

sent $$$ this week to Justice for Jacob Blake.https://gf.me/u/ytqyyx“On August 23rd my son was shot multiple times in the back by a Kenosha Police Department officer, after my son broke up an altercation by an unrelated party. The shooting has now left my son critically injured as he fights for his life. The extent of my son’s injuries is unknown, but we remain prayerful as he continues to undergo multiple rounds of operations to save his life. This fund is established to cover my son’s medical expenses, mental and grief counseling for our family and to assist our family in the days to come, as we continue to seek justice for Jacob. A portion of these proceeds will also be used to benefit my son’s six children, some of whom witnessed this horrific act of violence.”DOWNLOAD RECORDINGsubscribe to the podcast here: http://feeds.feedburner.com/5432fun(intro by omar)Dollys “another thing coming” tenseawksymoron “simple pleasantries” right-handedPracticing Sincerity “Goner” I Am Coming Home SoonC57BL/6 “Automate Dominate” Cell DegenerateLEG “hand me my award” LEG (seven inch and some)wished bone “seed” spring demosSobs “Girl” Catflapsoccer mommy “3 AM at a Party” CollectionGrand Lady Dance House “Your Love” House Musicleor miller “year 3000” xtra strengthBusiness Of Dreams “Bottom Feeders” Business Of DreamsBukkake Moms “Roach Boy” Landfill IIINEUTRAL SHIRT “You Are Never Alone” IN A ROOM DEMOS AND GREATEST HITSGreat Grandpa “Faithful” Plastic CoughDolphin midwives “(((prism)))” orchid milkworm hears “my head” happy or gratefulTerror Pigeon! “Trying > Dying (featuring Yohuna)” We Will Never Run Out of LoveNaomi Punk “Cookie” YellowThe Lentils “crow physics” 11 new flavors of oblivion and why the shining ones don’t want you to know about themPouty “The Pink Moment” Saint Mary of the MoodsAshby and the Oceanns “Nobody’s Son” Dead Names

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.18.249995v1?rss=1 Authors: Newton, D. F., Oh, H., Shukla, R., Misquitta, K., Fee, C., Banasr, M., Sibille, E. Abstract: Major depressive disorder (MDD) is associated with altered GABAergic and glutamatergic signalling, suggesting altered excitation-inhibition balance (EIB) in cortical mood- and cognition-regulating brain regions. Information processing in cortical microcircuits involves regulation of pyramidal (PYR) cells by Somatostatin- (SST), Parvalbumin- (PV), and Vasoactive intestinal peptide- (VIP) expressing interneurons. Human and rodent studies suggest that impaired PYR-cell dendritic morphology and decreased SST-cell function may mediate altered EIB in MDD. However, knowledge of co-ordinated changes across microcircuit cell types is virtually absent. We thus investigated the co-ordinated transcriptomic effects of UCMS on microcircuit cell types in the medial prefrontal cortex. C57Bl/6 mice, exposed to unpredictable chronic mild stress (UCMS) or control housing for five weeks were assessed for anxiety- and depressive-like behaviours. Microcircuit cell types were laser-microdissected and processed for RNA-sequencing. UCMS-exposed mice displayed predicted elevated behavioural emotionality. Each microcircuit cell type showed a unique transcriptional signature after UCMS. Pre-synaptic functions, oxidative stress response, metabolism, and translational regulation were differentially dysregulated across cell types, whereas nearly all cell types showed down-regulated post-synaptic gene signatures. At the microcircuit level, we observed a shift from distributed transcriptomic co-ordination across cell types in controls towards UCMS-induced increased co-ordination between PYR-, SST- and PV-cells, and a hub-like role for PYR-cells. Lastly, we identified a microcircuit-wide co-expression network enriched in synaptic, bioenergetic, and oxidative stress response genes that correlated with UCMS-induced behaviours. Together, these findings suggest cell-specific deficits, microcircuit-wide synaptic reorganization, and a shift in cortical EIB mediated by increased co-ordinated regulation of PYR-cells by SST- and PV-cells. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.04.235481v1?rss=1 Authors: Qi, C., Chen, X., Gao, X., Xu, J., Liu, S., Ge, J. Abstract: Background: Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, psychiatric symptoms and behavioral disorders, resulting in disability and loss of self-sufficiency. Objective: To establish an AD mice model, investigate the behavioral performance, and explore the potential mechanism. Methods: Streptozotocin (STZ, 3 mg/kg) was microinjected bilaterally into the dorsal hippocampus of C57BL /6 mice to establish the AD model. Behavioral changes (anhedonia and despair, balance and motor coordination, locomotion, and learning and memory) were examined and the serum concentrations of insulin and nesfatin-1 were measured by ELISA. The activation of hippocampal microglia was assessed by immunohistochemistry and the protein expression of several molecular associated with the regulation of synaptic plasticity in the hippocampus and the prefrontal cortex (PFC) was detected via western blotting. Results: The STZ model mice showed a slower bodyweight gain and higher serum concentrations of insulin and nesfatin-1. Although there was no significant difference between groups with regard to the ability of balance and motor coordination, the model mice presented a decline of spontaneous movement and exploratory behavior, together with an impairment of learning and memory ability. Increased activated microglia was aggregated in the hippocampal dentate gyrus of model mice. Moreover, the protein expression of NMDAR2A, NMDAR2B, SynGAP, PSD95, BDNF, and p-{beta}-catenin/{beta}-catenin were remarkably decreased in the hippocampus and the PFC of model mice, and the expression of p-GSK-3{beta} (ser9)/GSK-3{beta} were reduced in the hippocampus. Conclusion: A bilateral hippocampal microinjection of STZ could successfully duplicate an AD mice model, as indicated by the impaired learning and memory and the alternated synaptic plasticity, together with the hyperactive inflammatory response in the hippocampus and the imbalanced abundance of serum insulin and nesfatin-1. Apart from these, the mechanism might be associated with the imbalanced expression of the key proteins of Wnt signaling pathway in the hippocampus and the PFC. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.21.214619v1?rss=1 Authors: Stagkourakis, S., Spigolon, G., Liu, G., Anderson, D. J. Abstract: All animals can perform certain survival behaviors without prior experience, suggesting a "hard wiring" of underlying neural circuits. Experience, however, can alter the expression of innate behaviors. Where in the brain and how such plasticity occurs remains largely unknown. Previous studies have established the phenomenon of "aggression training," in which the repeated experience of winning successive aggressive encounters across multiple days leads to increased aggressiveness. Here we show that this procedure also leads to long-term potentiation (LTP) at an excitatory synapse, derived from the Anterior Hippocampus/Posterior Medial amygdala (AHiPM), onto estrogen receptor 1-expressing (Esr1+) neurons in the ventrolateral subdivision of the ventromedial hypothalamus (VMHvl). We demonstrate further that the optogenetic induction of such LTP in vivo facilitates, while optogenetic long-term depression (LTD) diminishes, the behavioral effect of aggression training, implying a causal role for potentiation of the AHiPM to VMHvlEsr1 projection in mediating the effect of this training. Interestingly, ~25% of inbred C57BL/6 mice fail to respond to aggression training. We show that these individual differences are correlated both with lower levels of testosterone, relative to mice that respond to such training, and with a failure to exhibit LTP in vivo after aggression training. Administration of exogenous testosterone to such non-aggressive mice restores both behavioral and physiological plasticity in vivo. Together, these findings reveal that LTP at a hypothalamic circuit node mediates a form of experience-dependent plasticity in an innate social behavior, and a potential hormone-dependent basis for individual differences in such plasticity among genetically identical mice. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.14.202101v1?rss=1 Authors: Bandet, M. V., Dong, B., Winship, I. R. Abstract: To distinguish between somatic stimuli, the primary somatosensory cortex should process dissimilar stimuli with distinct patterns of neuronal activation. Two-photon calcium imaging permits simultaneous optical recording of sensory evoked activity in hundreds of cortical neurons during varied sensory stimulation. Hence, it allows a visualization of patterns of activity in individual neurons and local cortical networks in response to distinct stimulation. Here, flavoprotein autofluorescence imaging was used to map the somatosensory cortex of anaesthetized C57BL/6 mice, and in vivo two-photon Ca2+ imaging was used to define patterns of neuronal activation during mechanical stimulation of the contralateral forelimb or hindlimb at various frequencies (3, 10, 100, 200, and 300 Hz). The data revealed that neurons within the limb associated somatosensory cortex exhibit stimulus-specific patterns of activity. Subsets of neurons were found to have sensory-evoked activity that is either primarily responsive to single stimulus frequencies or broadly responsive to multiple frequencies of limb movement. High frequency stimuli were shown to elicit more activation across the population, with a greater percentage of the population responding and greater percentage of cells with high amplitude responses. Stimulus-evoked cell-cell correlations within these neuronal networks varied as a function of frequency of stimulation, such that each stimulus elicited a distinct pattern that was more consistent across multiple trials of the same stimulus compared to trials at different frequencies of stimulation. The variation in cortical response to these artificial stimuli can thus be represented by the population pattern of supra-threshold Ca2+ transients, the magnitude and temporal properties of the evoked activity, and the structure of the stimulus-evoked correlation between responsive neurons. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.01.182782v1?rss=1 Authors: Cincotta, C., Murawski, N. J., Grella, S. L., McKissick, O., Doucette, E., Ramirez, S. Abstract: Alcohol withdrawal directly impacts the brain's stress and memory systems, which may underlie individual susceptibility to persistent drug and alcohol-seeking behaviors. Numerous studies demonstrate that forced alcohol abstinence, which may lead to withdrawal, can impair fear-related memory processes in rodents such as extinction learning, however the underlying neural circuits mediating these impairments remain elusive. Here, we tested an optogenetic strategy aimed at mitigating fear extinction impairments in male c57BL/6 mice following exposure to alcohol (i.e., ethanol) and forced abstinence. In the first experiment, extensive behavioral extinction training in a fear-conditioned context was impaired in ethanol-exposed mice compared to controls. In the second experiment, neuronal ensembles processing a contextual fear memory in the dorsal hippocampus were tagged and optogenetically reactivated repeatedly in a distinct context in ethanol-exposed and control mice. Chronic activation of these cells resulted in a context-specific, extinction-like reduction in fear responses in both control and ethanol-exposed mice. These findings suggest that while ethanol can impair fear extinction learning, optogenetic manipulation of a fear engram is sufficient to induce an extinction-like reduction in fear responses. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.11.144766v1?rss=1 Authors: Cansler, S. M., Guilhaume-Correa, F., Day, D., Bedolla, A., Evanson, N. K. Abstract: Traumatic brain injury (TBI) results in a number of impairments, often including visual symptoms. In some cases, visual symptoms after head trauma are mediated by traumatic injury to the optic nerve, termed traumatic optic neuropathy (TON), which has few options for treatment. Using a murine closed head model of head trauma, we have previously reported in adult mice that there is relatively selective injury to the optic system of the brain. In the current study, we performed blunt head trauma on adolescent C57BL/6 mice, and investigated visual impairment and retinal and optic system injury, using behavioral and histologic methods. After injury, mice display evidence of decreased optomotor responses, as evidence by decreased optokinetic nystagmus responses. There does not appear to be a significant change in circadian locomotor behavior patterns, although there is an overall decrease in locomotor behavior in mice with head injury. There is evidence of axonal degeneration of optic nerve fibers, with associated retinal ganglion cell death. There is also evidence of astrogliosis and microgliosis in major central targets of optic nerve projections. Further, there is elevated expression of markers of endoplasmic reticulum (ER) stress in retinas of injured mice. The current results extend our previous findings in adult mice into adolescent mice, provide direct evidence of retinal ganglion cell injury after head trauma, and suggest that axonal degeneration is associated with elevated ER stress in this model of TON. Visual impairment, histologic markers of gliosis and neurodegeneration, and elevated ER stress marker expression persist for at least 30 days after injury. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.26.116343v1?rss=1 Authors: Sun, D., Kermani, M., Hudson, M., He, X., Unnithan, R. R., French, C. Abstract: Local field potentials (LFPs) recorded intracranially display a range of location specific oscillatory spectra which have been related to cognitive processes. Although the exact mechanisms producing LFPs are not completely understood, it is likely that voltage-gated ion channels which produce action potentials and patterned discharges play a significant role. It is also known that antipsychotic drugs (APDs) affect LFPs spectra and a direct inhibitory effect on voltage-gated potassium (K_v) channels has been reported. Additionally, K_v channels have been implicated in the pathophysiology of schizophrenia, a disorder for which APDs are primary therapies. In this study we sought to: i) better characterise the effects of two APDs on LFPs and connectivity measures and ii) examine the effects of potassium channel modulators on LFPs and potential overlap of effects with APDs. Intracranial electrodes were implanted in the hippocampus (HIP) and pre-frontal cortex (PFC) of C57BL/6 mice; power spectra, coherence and phase-amplitude cross frequency coupling were measured. Drugs tested were the APDs haloperidol and clozapine as well as voltage-gated potassium channel modulators (KVMs) 4-aminopyridine(4AP), tetraethylammonium (TEA), E-4031 and retigabine. All drugs and vehicle controls were administered intraperitoneally. Both APDs and KVMs significantly reduced gamma power with the exception of 4AP, which conversely increased slow-gamma power. Clozapine and retigabine additionally reduced coherence between HIP and PFC. Phase-amplitude coupling between theta and gamma oscillations in HIP was significantly reduced by the administration of haloperidol and retigabine. These results provide previously undescribed effects of APDs on LFP properties and demonstrate novel modulation of LFP characteristics by KVMs that intriguingly overlaps with the effects of APDs. The possibility of a common mechanism of action deserves further study. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.12.092338v1?rss=1 Authors: Conte, G., Parras, A., Alves, M., Olla, I., de Diego-Garcia, L., Beamer, E., Alalqam, R., Ocampo, A., Mendez, R., Lucas, J. J., Engel, T. Abstract: Objective: Pharmacoresistance and the lack of disease-modifying actions of current anti-seizure drugs persist as major challenges in the treatment of epilepsy. Experimental models of chemoconvulsant-induced status epilepticus remain the models of choice to discover potential anti-epileptogenic drugs but doubts remain as to the extent to which they model human pathophysiology. The aim of the present study was to compare the molecular landscape of the intraamygdala kainic acid model of status epilepticus in mice with findings in resected brain tissue from patients with drug-resistant temporal lobe epilepsy (TLE). Methods: Status epilepticus was induced via intraamygdala microinjection of kainic acid in C57BL/6 mice and gene expression analysed via microarrays in hippocampal tissue at acute and chronic time-points. Results were compared to reference datasets in the intraperitoneal pilocarpine and intrahippocampal kainic acid model and to human resected brain tissue (hippocampus and cortex) from patients with drug-resistant TLE. Results: Intraamygdala kainic acid injection in mice triggered extensive dysregulation of gene expression which was ~3-fold greater shortly after status epilepticus (2729 genes) when compared to epilepsy (412). Comparison to samples of patients with TLE revealed a particular high correlation of gene dysregulation during established epilepsy. Pathway analysis found suppression of calcium signalling to be highly conserved across different models of epilepsy and patients. CREB was predicted as one of the main up-stream transcription factors regulating gene expression during acute and chronic phases and inhibition of CREB reduced seizure severity in the intraamygdala kainic acid model. Significance: Our findings suggest the intraamygdala kainic acid model faithfully replicates key molecular features of human drug-resistant temporal lobe epilepsy and provides potential rationale target approaches for disease-modification through new insights into the unique and shared gene expression landscape in experimental epilepsy. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.05.076570v1?rss=1 Authors: Vyazovskiy, V. V., Peirson, S. N., Foster, R. G., Huang, Y.-G., Flaherty, S., Pothecary, C. Abstract: Torpor is a regulated reversible state of metabolic suppression used by many mammalian species to conserve energy. Although torpor has been studied extensively in terms of general physiology, metabolism and neuroendocrinology, the effects of hypometabolism and associated hypothermia on brain activity and states of vigilance have received little attention. Here we performed continuous monitoring of electroencephalogram (EEG), electromyogram (EMG) and peripheral body temperature in adult, male C57BL/6 mice over consecutive days of scheduled restricted feeding. All animals showed prominent bouts of hypothermia that became progressively deeper and longer as fasting progressed. EEG and EMG were markedly affected by hypothermia, although the typical electrophysiological signatures of NREM sleep, REM sleep and wakefulness allowed us to perform vigilance-state classification in all cases. Invariably, hypothermia bouts were initiated from a state indistinguishable from NREM sleep, with EEG power decreasing gradually in parallel with decreasing body temperature. Furthermore, during deep hypothermia REM sleep was largely abolished, but we observed brief and intense bursts of muscle activity, which resembled the regular motor discharges seen during early ontogeny associated with immature sleep patterns. We conclude that torpor and sleep are electrophysiologically on a continuum, and that, in order for torpor to occur, mice need to first transition through euthermic sleep. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.04.25.060939v1?rss=1 Authors: Mikhailov, N., Koroleva, K., Abdollahzadeh, A., Giniatullina, R., Gafurov, O., Malm, T., Sierra Lopez, A., Tohka, J., Noe, F. M., Giniatullin, R. Abstract: Background: A system of lymphatic vessels has been recently characterized in the meninges, with a postulated role in cleaning of the brain via cerebro-spinal fluid drainage. As meninges are an important tissue involved in the origin of migraine pain, we hypothesized that malfunctioning of a cleaning lymphatic system should affect the functional properties of meningeal nociception. To test this hypothesis, we studied migraine-related nociceptive and inflammatory mechanisms in the meninges, in a mouse model of primary lymphedema (K14-VEGFR3-Ig mice) characterized by the lack of functional meningeal lymphatic system. Methods: To study the migraine-related nociceptive and inflammatory mechanisms we recorded spiking activity from meningeal fibers of the trigeminal nerve, estimated the local mast cells infiltration, calcitonin gene-related peptide (CGRP) and cytokine levels (basal and under stimulating conditions), as well as the dura mater innervation in freshly-isolated hemiskull preparations from K14-VEGFR3-Ig (K14) or wild type C57BL/6 mice (WT). Results: We found that the level of CGRP and the production of TNF , which both are implicated in migraine, were reduced in meninges of K14 mice. There was a trend of having a larger number of dural mast cells, consistent with the increased level of the mast cell activator MCP-1 found in these animals. In addition, we found an increased spontaneous and ATP-induced nociceptive firing in the meningeal afferents of mice lacking meningeal lymphatic system. However, the patterns of trigeminal innervation in meninges remained unchanged. Conclusions: In summary, the lack of meningeal lymphatic system leads to a new balance between pro- and anti-inflammatory mechanisms implicated in peripheral nociception, affecting key cellular and humoral factors implicated in migraine. Copy rights belong to original authors. Visit the link for more info

Welcome to the September episode of 3-Minute 3Rs, brought to you by Lab Animal (www.nature.com/laban), the NC3Rs (www.nc3rs.org.uk) & the North American 3Rs Collaborative (www.na3rsc.org) Here are the papers behind the pod: 1. Assessing animal affect: an automated and self-initiated judgment bias task based on natural investigative behaviour. https://doi.org/10.1038/s41598-018-30571-x 2. Comparison of serial blood collection by facial vein and retrobulbar methods in C57BL/6 mice. https://doi.org/10.30802/AALAS-JAALAS-17-000134 3. Can grimace scales estimate the pain status in horses and mice? A statistical approach to identify a classifier. https://doi.org/10.1371/journal.pone.0200339 Transcript: [LA]...Your valence, that is, whether you're feeling positive or negative, can influence your judgment. There's evidence that animals are no different, and how an animal responds to an ambiguous cue could a way to gauge their affective state and refine their welfare. But testing for judgment biases can be time consuming for the people involved. In August, researchers at the University of Bristol published an automated judgment bias test involving a natural rat behavior in the journal Scientific Reports. They developed a set up to train rats without human intervention to associate one audio tone with a food reward and another with an unpleasant puff of air. The rats have to nose poke into a food trough to start a trial, and either leave their nose in place or withdraw it according to what they hear. How they respond to ambiguous tones should reflect their valence. The cues still need a bit more work, but rats are at least up to the challenge of learning such an automated judgment bias task that could potential be used for future welfare research. [NA3RsC] Serial blood collection in mice is often necessary for sentinel testing and for tracking experimental processes. In July, Jennifer Frohlich and her colleagues published a study in JAALAS that could help refine the process of recurring blood draws in mice. The study, Comparison of Serial Blood Collection by Facial Vein and Retrobulbar Methods, performed single and serial blood draws for both methods. The single facial vein group experienced the least clinical signs after blood collection and the least histological lesions. The single and serial retrobulbar groups both had a similar amount of harderian adenitis and ocular trauma on histology. Meanwhile, the serial facial vein group had a 33% mortality rate, the most clinical signs post-collection which included seizures, head tilt, and convulsions; and 2 mice had histologic brain lesions consistent with trauma. The researchers concluded that the facial vein method is less desirable for serial blood collection in mice compared with the retrobulbar method. [NC3Rs] Effective, accurate pain assessment is key to safeguarding the welfare of any animal. And one such approach growing in use among animal researchers are grimace scales. Using this methods, individuals observe specific expressions associated with pain in a particular species and score them collectively for their intensity. The higher the score, the greater the pain the animal is perceived to be in. Of course, it is vital to validate that any method of pain assessment is effective and reliable. In her paper published this August in PLoS One, Dr. Emanuela Dalla Costa, from the University of Milan, has done just this. In her study, Dr. Dalla Costa collected over 1000 grimace scores from individual observations of horses and mice, pre- and post-surgery. Their data was subjected to exhaustive statistical analysis to determine how the level of pain the animal was experiencing, and the variation in the different observers used, influenced the overall pain score the animals received. The analysis identified both mouse and horse grimace scales to a high level of consistency across each of the individual users, demonstrating these scales to be a reliable method of assessing pain... See acast.com/privacy for privacy and opt-out information.

Inbred mice are critical tools in biomedical research and one particular strain, known as C57BL/6 (Black 6 or B6, for short), is rapidly becoming the standard model for many applications and revolutionising modern research. Understanding the B6 mouse, its origins, characteristics and potential is required to make full and appropriate use of this model in research and drug discovery. The B6 mouse is a versatile and powerful tool in preclinical research. These mice form the basis for many research models, including those in the fields of metabolic disease, obesity, diabetes, immune disorders, immuno-oncology and neurobiology, among others. No single animal model is as versatile as the B6 mouse, and its power is enhanced by the rich diversity of genetically-engineered models (GEMs) on the B6 background. These combined properties make the B6 a vital tool for research efforts throughout the spectrum of drug discovery and development. This article was written by Dr Philip Dubé If you'd like to view the original article then follow the link below: http://www.ddw-online.com/drug-discovery/p320744-how-one-mouse-strain-is-revolutionising-drug-discovery.html You can also download the original article pdf here: http://www.ddw-online.com/media/32/126801/(5)-how-one-mouse-strain-is-revolutionising-drug-discovery.pdf For more information on Drug Discovery World, head to: http://www.ddw-online.com

Full Text- https://tinyurl.com/yavmxbxt The genetic heterogeneity of acute myeloid leukemia (AML) and the variable responses of individual patients to therapy suggest that different AML genotypes may influence the bone marrow (BM) microenvironment in different ways. We performed gene expression profiling of bone marrow mesenchymal stromal cells (BM-MSC) isolated from normal C57BL/6 mice or mice inoculated with syngeneic murine leukemia cells carrying different human AML genotypes, developed in mice with Trp53 wild-type or nullgenetic backgrounds. We identified a set of genes whose expression in BM-MSC was modulated by all four AML genotypes tested. In addition, there were sets of differentially-expressed genes in AML-exposed BM-MSC that were unique to the particular AML genotype or Trp53 status. Our findings support the hypothesis that leukemia cells alter the transcriptome of surrounding BM stromal cells, in both common and genotype-specific ways. These changes are likely to be advantageous to AML cells, affecting disease progression and response to chemotherapy, and suggest opportunities for stroma-targeting therapy, including those based on AML genotype. Facebook - bit.ly/2xznxjV Twitter - bit.ly/2xzWvsu LinkedIn - bit.ly/2xzJ6kc Pintrest - bit.ly/2xzX8SS Reddit - bit.ly/2hoxI0N www.Oncotarget.com

Jiun Youn bestudeerde de interactie tussen cognitie en emotie van knaagdieren, met name bij muizen. Dierexperimenteel onderzoek is belangrijk voor het ontwikkelen van nieuwe therapieën voor mensen met een psychiatrische aandoening. Tot nu toe werd alleen cognitie of alleen emotie onderzocht, slechts weinigen onderzochten de interactie, terwijl deze juist zo belangrijk is bij mensen. Youn ontwikkelde een test waarmee ze de invloed van emotie op het ruimtelijk geheugen bestudeerde. Hiervoor vergeleek zij twee veel gebruikte muizensoorten waarvan al bekend was dat de C57BL-muizen een beter ruimtelijk geheugen hebben dan de DBA. Youn toont echter aan dat de verschillen tussen de twee stammen sterk afhankelijk is van het type beloning. Datum: 14-05-2014

Jiun Youn bestudeerde de interactie tussen cognitie en emotie van knaagdieren, met name bij muizen. Dierexperimenteel onderzoek is belangrijk voor het ontwikkelen van nieuwe therapieën voor mensen met een psychiatrische aandoening. Tot nu toe werd alleen cognitie of alleen emotie onderzocht, slechts weinigen onderzochten de interactie, terwijl deze juist zo belangrijk is bij mensen. Youn ontwikkelde een test waarmee ze de invloed van emotie op het ruimtelijk geheugen bestudeerde. Hiervoor vergeleek zij twee veel gebruikte muizensoorten waarvan al bekend was dat de C57BL-muizen een beter ruimtelijk geheugen hebben dan de DBA. Youn toont echter aan dat de verschillen tussen de twee stammen sterk afhankelijk is van het type beloning. Datum: 14-05-2014

Mesenchymale Stammzellen (MSCs) besitzen eine Vielzahl einzigartiger Eigenschaften, hierunter ihr Differenzierungs- und immunregulatorisches Potenzial, die sie sehr interessant für die biomedizinische Forschung machen. Ziel der vorliegenden Arbeit war es zu untersuchen, welche Mechanismen der immunmodulierenden Wirkung der MSCs zugrunde liegen. Zu diesem Zweck wurden mesenchymale Stammzellen aus dem Knochenmark von 5-16 Wochen alten Balb/c-Mäusen isoliert und in der Zellkultur expandiert. Das Oberflächenmarkerprofil der Zellen wurde durch Durchflusszytometrie (FACS) charakterisiert und die Expression potenziell immunsuppressiver Faktoren durch ELISA, Reverse Transkriptase-PCR beziehungsweise Western-Blot bestimmt. Für die Untersuchung der MSC-vermittelten Immunmodulation wurde ein Proliferationsassay etabliert, in dem Lymphozyten aus C57Bl/6-Mäusen durch das Mitogen ConA stimuliert und mit den murinen MSCs kokultiviert wurden. Durch die Zugabe spezifischer Inhibitoren gegen TGFβ, die Prostaglandin E2-Synthese (Indomethacin), den HGF-Rezeptor und den Adenosinrezeptor (SCH58261) wurde die Vermittlung der immunmodulierenden Effekte durch die MSCs untersucht. In der Studie konnte eine reine Population muriner MSCs mit charakteristischen Oberflächenmarkern (CD29, CD73, CD90, CD105, CD140b, Sca-1) expandiert werden, die in vitro starke immunsuppressive Effekte im Proliferationsassay aufwies. Die Untersuchungen potenzieller Effektormoleküle zeigten, dass bei den murinen MSCs TGFβ, HGF und das Enzym IDO keine entscheidende Rolle spielten und von den bekannten Mechanismen vor allem die Produktion von PGE2 die Lymphozytenproliferation hemmte. Als wichtigstes Ergebnis kann der Nachweis, dass die murinen MSCs die Ektonukleotidasen CD39 und CD73 koexprimieren, die extrazelluläres ATP über 5’-AMP in das extrem stark immunsuppressiv wirkende Adenosin konvertieren können, angesehen werden. Zusammenfassend wurde in der vorliegenden Arbeit erstmals die Expression von CD39 auf murinen MSCs beschrieben. Die Koexpression von CD39/CD73 auf den MSCs und die daraus folgende Produktion von Adenosin stellt einen neuen Ansatz dar, um die Funktion der MSCs besser zu verstehen. Die CD39+/CD73+-MSCs sind demnach eine vielversprechende Zellpopulation für die Behandlung von Autoimmunerkrankungen und für die Entwicklung neuer lokaler oder systemischer Therapien zur Toleranzinduktion nach Transplantation.

Background: Metabolic syndrome (MetS) is associated with increased risk of cardiovascular disease (CVD). One important feature underlying the pathophysiology of many types of CVD is microvascular dysfunction. Although components of MetS are themselves CVD risk factors, the risk is increased when the syndrome is considered as one entity. We aimed to characterize microvascular function and some of its influencing factors in the course of MetS development. Methods: Development of MetS in C57BL/6 mice on a high-fat diet (HFD, 51% of energy from fat) was studied. The initial phase of MetS (I-MetS) was defined as the first 2 weeks of HFD feeding, with the fully developed phase occurring after 8 weeks of HFD. We characterized these phases by assessing changes in adiposity, blood pressure, and microvascular function. All data are presented as mean +/- standard error (SEM). Differences between cumulative dose-response curves of myograph experiments were calculated using non-linear regression analysis. In other experiments, comparisons between two groups were made with Student's t-test. Comparisons between more than two groups were made using one-way ANOVA with Tukey post-hoc test. A probability value

Multiphoton microscopy (MPM) offers a unique approach for addressing both the function and structure of an organ in near-real time in the live animal. The method however is limited by the tissue-specific penetration depth of the excitation laser. In the kidney, structures in the range of 100 µm from the surface are accessible for MPM. This limitation of MPM aggravates the investigation of the function of structures located deeper in the renal cortex, like the glomerulus and the juxtaglomerular apparatus. In view of the relevance of gene-targeted mice for investigating the function of these structures, we aimed to identify a mouse strain with a high percentage of superficially located glomeruli. The mean distance of the 30 most superficial glomeruli from the kidney surface was determined in 10 commonly used mouse strains. The mean depth of glomeruli was 118.4±3.4, 123.0±2.7, 133.7±3.0, 132.3±2.6, 141.0±4.0, 145.3±4.3, 148.9±4.2, 151.6±2.7, 167.7±3.9, and 207.8±3.2 µm in kidney sections from 4-week-old C3H/HeN, BALB/cAnN, SJL/J, C57BL/6N, DBA/2N, CD1 (CRI), 129S2/SvPas, CB6F1, FVB/N and NMRI (Han) mice, respectively (n = 5 animals from each strain). The mean distance from the kidney surface of the most superficial glomeruli was significantly lower in the strains C3H/HeN Crl, BALB/cAnN, DBA/2NCrl, and C57BL/6N when compared to a peer group consisting of all the other strains (p

Objectives: The anti-inflammatory effects of O-1602 and cannabidiol (CBD), the ligands of G protein-coupled receptor 55 (GPR55), on experimental acute pancreatitis (AP) were investigated. Methods: Acute pancreatitis was induced in C57BL mice by intraperitoneal injection of 50 mu g/kg cerulein hourly, with a total of 6 times. Drugs (O-1602, 10 mg/kg, or CBD, 0.5 mg/kg) were given by intraperitoneal injection 2 times at 30 minutes before the first injection and immediately before the fifth cerulein injection. At 3 hours after the last injection, the blood, the lungs, and the pancreas were harvested for the pancreatic enzyme activity, myeloperoxidase activity, and pro-inflammatory cytokines measurement; and the expressions of GPR55 mRNA and protein in the pancreas were detected. Results: Cannabidiol or O-1602 treatment significantly improved the pathological changes of mice with AP and decreased the enzyme activities, IL-6 and tumor necrosis factor alpha levels, and the myeloperoxidase activities in plasma and in the organ tissues. G protein-coupled receptor 55 mRNA and protein expressed in the pancreatic tissue, and the expressions were decreased in the mice with AP, and either CBD or O-1602 attenuated these changes to a certain extent. Conclusion: Cannabidiol and O-1602 showed anti-inflammatory effects in mice with AP and improved the expression of GPR55 in the pancreatic tissue as well.

Introduction. Inflammation and endothelium-derived superoxides are important pathomechanisms in atherothrombotic diseases. We could previously show that the tyrosine phosphatase SHP-1 acts as a negative regulator in endothelial superoxide production. In this study we investigated the influence of SHP-1 on platelet-endothelium interaction and arterial thrombosis in TNF alpha-induced endothelial inflammation in vivo. Methods. Arteriolar thrombosis and platelet rolling in vivo were investigated in C57BL/6 mice using intravital microscopy in the dorsal skinfold chamber microcirculation model. Results. Inhibition of SHP-1 by the specific pharmacological inhibitor sodium stibogluconate did not significantly enhance platelet-endothelium interaction in vivo under physiological conditions but led to an augmented fraction of rolling platelets in TNF alpha-induced systemic inflammation. Accordingly, ferric-chloride-induced arteriolar thrombus formation, which was already increased by SHP-1 inhibition, was further enhanced in the setting of TNF alpha-induced inflammation. Platelet aggregation in vitro as well as ex vivo was not influenced by SHP-1-inhibition. In cultured endothelial cells, sodium stibogluconate increased TNF alpha-induced surface expression of p-selectin and von Willebrand factor. Additionally, TNF alpha increased SHP-1 activity and protein expression. Conclusions. The endothelial tyrosine phosphatase SHP-1 plays an important role for vascular hemostasis in vivo, which is crucial in TNF alpha-induced endothelial inflammation where it may serve as an autoinhibitory molecule to prevent excess inflammatory response and thrombus formation.

Background: Duchenne Muscular Dystrophy is an inherited degenerative neuromuscular disease characterised by rapidly progressive muscle weakness. Currently, curative treatment is not available. Approaches for new treatments that improve muscle strength and quality of life depend on preclinical testing in animal models. The mdx mouse model is the most frequently used animal model for preclinical studies in muscular dystrophy research. Standardised pathology-relevant parameters of dystrophic muscle in mdx mice for histological analysis have been developed in international, collaborative efforts, but automation has not been accessible to most research groups. A standardised and mainly automated quantitative assessment of histopathological parameters in the mdx mouse model is desirable to allow an objective comparison between laboratories. Methods: Immunological and histochemical reactions were used to obtain a double staining for fast and slow myosin. Additionally, fluorescence staining of the myofibre membranes allows defining the minimal Feret's diameter. The staining of myonuclei with the fluorescence dye bisbenzimide H was utilised to identify nuclei located internally within myofibres. Relevant structures were extracted from the image as single objects and assigned to different object classes using web-based image analysis (MyoScan). Quantitative and morphometric data were analysed, e. g. the number of nuclei per fibre and minimal Feret's diameter in 6 month old wild-type C57BL/10 mice and mdx mice. Results: In the current version of the module "MyoScan", essential parameters for histologic analysis of muscle sections were implemented including the minimal Feret’s diameter of the myofibres and the automated calculation of the percentage of internally nucleated myofibres. Morphometric data obtained in the present study were in good agreement with previously reported data in the literature and with data obtained from manual analysis. Conclusions: A standardised and mainly automated quantitative assessment of histopathological parameters in the mdx mouse model is now available. Automated analysis of histological parameters is more rapid and less time-consuming. Moreover, results are unbiased and more reliable. Efficacy of therapeutic interventions, e.g. within the scope of a drug screening or therapeutic exon skipping, can be monitored. The automatic analysis system MyoScan used in this study is not limited exclusively to dystrophin-deficient mice but also represents a useful tool for applications in the research of other dystrophic pathologies, various other skeletal muscle diseases and degenerative neuromuscular disorders.

Sat, 11 Feb 2012 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/14205/ https://edoc.ub.uni-muenchen.de/14205/1/Kosanke_Yvonne.pdf Kosanke, Yvonne ddc:5

Treatment of acute lung injury (ALI) remains an unsolved problem in intensive care medicine. As simvastatin exerts protective effects in inflammatory diseases we explored its effects on development of ALI and due to the importance of neutrophils in ALI also on neutrophil effector functions. C57Bl/6 mice were exposed to aerosolized LPS (500 µg/ml) for 30 min. The count of alveolar, interstitial, and intravasal neutrophils were assessed 4 h later by flow cytometry. Lung permeability changes were assessed by FITC-dextran clearance and albumin content in the BAL fluid. In vitro, we analyzed the effect of simvastatin on neutrophil adhesion, degranulation, apoptosis, and formation of reactive oxygen species. To monitor effects of simvastatin on bacterial clearance we performed phagocytosis and bacterial killing studies in vitro as well as sepsis experiments in mice. Simvastatin treatment before and after onset of ALI reduces neutrophil influx into the lung as well as lung permeability indicating the protective role of simvastatin in ALI. Moreover, simvastatin reduces the formation of ROS species and adhesion of neutrophils without affecting apoptosis, bacterial phagocytosis and bacterial clearance. Simvastatin reduces recruitment and activation of neutrophils hereby protecting from LPS-induced ALI. Our results imply a potential role for statins in the management of ALI.

Maligne Zellen wachsen in einem komplexen zellulären und extrazellulären Umfeld, welches die Initiierung und Aufrechterhaltung des malignen Phänotyps bedeutend beeinflusst. Tumore bestehen zum einen aus den Tumorzellen, zum anderen aus dem unterstützenden Stroma, das Fibroblasten, Endothelien, Perizyten, Lymphgefäße, ein mononukleäres Infiltrat und die Extrazellulärmatrix einschließt. Dieses Tumor-Mikromilieu hat einen großen modulierenden Einfluss auf das Tumorwachstum, die Invasivität und das Metastasierungspotential. Mesenchymale Stammzellen (MSC) sind pluripotente Vorläuferzellen, die an der Aufrechterhaltung und Wiederherstellung der Gewebeintegrität beteiligt sind. Geschädigtes Gewebe führt zur Mobilisation von MSC und deren Rekrutierung an den Ort der Schädigung. Tumore werden vom Organismus als nicht-heilende Wunden angesehen, so dass MSC in das tumorassoziierte Stroma rekrutiert werden. Dort tragen die Zellen zu verschiedenen Aspekten des Tumorwachstums bei, indem sie als Progenitorzellen für die Tumorgefäße und stromale fibroblastenartige Zellen dienen. Im Rahmen dieses Ausdifferenzierungsprozesses werden gewebespezifische Gensets wie das CC-Chemokin CCL5 in den mesenchymalen Stammzellen aktiviert und zur Expression gebracht. Das Pankreasadenokarzinom ist eines der aggressivsten soliden Malignome des Menschen und ist gekennzeichnet durch eine ausgeprägte Proliferation des Stromas. Ziel der vorliegenden Arbeit war es, zum einen die Rolle mesenchymaler Stammzellen im Stroma des Pankreaskarzinoms zu evaluieren und zum anderen eine gewebespezifische stammzellbasierte und promoterkontrollierte Suizidgentherapie mit dem Stroma als Angriffspunkt zu etablieren. Mesenchymale Stammzellen wurden aus dem Knochenmark von C57BL/6 p53-/- Mäusen isoliert und sowohl mit den Reportergenen des rot fluoreszierendem Proteins (RFP) und des grün fluoreszierenden Proteins (eGFP) als auch mit dem Suizidgen der Herpes Simplex I Thymidinkinase (HSV-TK) unter Kontrolle des CCL5-Promoters transfiziert. Die HSV-TK führt zu einer Phosphorylierung und Aktivierung der Prodrug Ganciclovir, welches zytotoxisch auf Thymidinkinase-positive (TK+) Zellen und über den sogenannten „Bystandereffect“ auf umgebende Thymidinkinase-negative (TK-) Zellen wirkt. Diese Stammzellen wurden C57BL/6 Mäusen intravenös injiziert, die orthotope und syngene panc02- Pankreastumore trugen. Die i.v. Applikation von nativen MSC führte zu einer Verdopplung der Tumormasse und einer gesteigerten lokalen Aggressivität im Sinne einer Peritonealkarzinose im Vergleich zur Kontrollgruppe. Dabei zeigten sich erhöhte Ccl5-Expressionsniveaus im Tumorgewebe von Tieren, die MSC erhalten hatten. In-vitro konnte gezeigt werden, dass MSC bei adäquater Stimulation zur Ccl5 Expression angeregt werden und somit als Quelle des beobachteten Ccl5-Anstiegs in Frage kommen. Die stromale Aktivierung des CCL5-Promoters in den mesenchymalen Stammzellen konnte durch Verwendung von CCL5-Promoter/Reportergen Stammzellen direkt nachgewiesen werden. Dabei zeigten sich spezifisch im Tumorgewebe Fluoreszenzsignale, die sich in der Immunhistochemie morphologisch genauer darstellen ließen. Eine Reportergenexpression war spezifisch im stromalen Kompartiment der panc02- Tumore nachweisbar, andere untersuchte Organe mit Ausnahme der Milz zeigten keine Reportergenexpression. Der Einsatz der therapeutischen CCL5-Promoter/HSV-TK MSC in Kombination mit der intraperitonealen Gabe von Ganciclovir führte zu einer Tumormassenreduktion um 50%. Darüberhinaus konnte die Therapie die Metastasierungsrate in Milz, Leber und Peritoneum signifikant senken. Es wurden keine systemischen Nebenwirkungen beobachtet. Bei der Untersuchung von humanen Pankreaskarzinomen und korrespondierenden Pankreasnormalgeweben aus den gleichen Patienten zeigte sich bei der Mehrheit eine Hochregulation von CCL5-mRNA. Im immunhistochemischen Nachweis konnte die CCL5 Expression auf Proteinebene im Tumorstroma gezeigt werden, entsprechendes Normalgewebe zeigte bis auf vereinzelte Zellen keine CCL5 Produktion. Das Tumorstroma stellt aufgrund seiner vitalen Bedeutung für die Tumorprogression einen vielversprechenden Ansatzpunkt künftiger therapeutischer Interventionen dar. Mesenchymale Stammzellen eigenen sich hierbei im Rahmen einer Suizidgentherapie als zellbasierte Vehikel. Dank der gezielten Migration und des Einsatzes gewebespezifischer Promoter kann dabei eine hohe Selektivität der Genexpression im Tumorgewebe mit Minimierung der systemischen Nebenwirkungen erreicht werden. Der CCL5-Promoter wird im stromalen Kompartiment des murinen pankreatischen Adenokarzinoms aktiviert und eignet sich daher für die selektive und spezifische Expression von therapeutischen Genen wie der HSV-TK. Dieser Ansatz kann eine mögliche Therapieoption des ansonsten therapieresistenten humanenPankreaskarzinoms darstellen.

Background: Hearing loss is a frequent long-term complication of pneumococcal meningitis (PM). Its main pathological correlate is damage to the organ of Corti and loss of spiral ganglion neurons. The only current treatment option is cochlear implants which require surviving neurons. Here, we investigated the impact of systemically applied neurotrophin-3 (NT-3) on long-term hearing loss and the survival of neurons. Methods: Eighteen hours after infection with S. pneumoniae, C57BL/6 mice were treated with a combination of ceftriaxone with NT-3 or dexamethasone or placebo. Hearing, cochlear damage, and brain damage were assessed by audiometry and histology. Results: The main findings from immunohistochemical visualization of neurotrophins (NT-3, BDNF) and their receptors (TrkB, TrkC, and p75) in the cochlea were (i) enhanced staining for the cell survival-promoting receptor TrkB and (ii) increased NT-3 staining in NT-3 treated mice, showing that systemically applied NT-3 reaches the cochlea. The major effects of adjunctive NT-3 treatment were (i) a reduction of meningitis-induced hearing impairment and (ii) a reduction of spiral ganglion neuronal loss. The efficacy of NT-3 therapy was comparable to that of dexamethasone. Conclusion: Systemically applied NT-3 might be an interesting candidate to improve hearing outcome after pneumococcal meningitis.

Background: Clinical trials evaluating anti-CD20-mediated B-cell depletion in multiple sclerosis (MS) and neuromyelitis optica (NMO) generated encouraging results. Our recent studies in the MS model experimental autoimmune encephalomyelitis (EAE) attributed clinical benefit to extinction of activated B-cells, but cautioned that depletion of naive B-cells may be undesirable. We elucidated the regulatory role of un-activated B-cells in EAE and investigated whether anti-CD20 may collaterally diminish regulatory B-cell properties in treatment of neuroimmunological disorders. Methods: Myelin oligodendrocyte glycoprotein (MOG) peptide-immunized C57Bl/6 mice were depleted of B-cells. Functional consequences for regulatory T-cells (Treg) and cytokine production of CD11b(+) antigen presenting cells (APC) were assessed. Peripheral blood mononuclear cells from 22 patients receiving anti-CD20 and 23 untreated neuroimmunological patients were evaluated for frequencies of B-cells, T-cells and monocytes; monocytic reactivity was determined by TNF-production and expression of signalling lymphocytic activation molecule (SLAM). Results: We observed that EAE-exacerbation upon depletion of un-activated B-cells closely correlated with an enhanced production of pro-inflammatory TNF by CD11b(+) APC. Paralleling this pre-clinical finding, anti-CD20 treatment of human neuroimmunological disorders increased the relative frequency of monocytes and accentuated pro-inflammatory monocyte function; when reactivated ex vivo, a higher frequency of monocytes from B-cell depleted patients produced TNF and expressed the activation marker SLAM. Conclusions: These data suggest that in neuroimmunological disorders, pro-inflammatory APC activity is controlled by a subset of B-cells which is eliminated concomitantly upon anti-CD20 treatment. While this observation does not conflict with the general concept of B-cell depletion in human autoimmunity, it implies that its safety and effectiveness may further advance by selectively targeting pathogenic B-cell function.

The long pentraxin PTX3 has multiple roles in innate immunity. For example, PTX3 regulates C1q binding to pathogens and dead cells and regulates their uptake by phagocytes. It also inhibits P-selectin-mediated recruitment of leukocytes. Both of these mechanisms are known to be involved in autoimmunity and autoimmune tissue injury, e.g. in systemic lupus erythematosus, but a contribution of PTX3 is hypothetical. To evaluate a potential immunoregulatory role of PTX3 in autoimmunity we crossed Ptx3-deficient mice with Fas-deficient (lpr) C57BL/6 (B6) mice with mild lupus-like autoimmunity. PTX3 was found to be increasingly expressed in kidneys and lungs of B6lpr along disease progression. Lack of PTX3 impaired the phagocytic uptake of apoptotic T cells into peritoneal macrophages and selectively expanded CD4/CD8 double negative T cells while other immune cell subsets and lupus autoantibody production remained unaffected. Lack of PTX3 also aggravated autoimmune lung disease, i.e. peribronchial and perivascular CD3+ T cell and macrophage infiltrates of B6lpr mice. In contrast, histomorphological and functional parameters of lupus nephritis remained unaffected by the Ptx3 genotype. Together, PTX3 specifically suppresses autoimmune lung disease that is associated with systemic lupus erythematosus. Vice versa, loss-of-function mutations in the Ptx3 gene might represent a genetic risk factor for pulmonary (but not renal) manifestations of systemic lupus or other autoimmune diseases.

The use of antimycotic drugs in fungal infections is based on the concept that they suppress fungal growth by a direct killing effect. However, amphotericin and nystatin have been reported to also trigger interleukin-1β (IL-1β) secretion in monocytes but the molecular mechanism is unknown. Here we report that only the polyene macrolides amphotericin B, nystatin, and natamycin but none of the tested azole antimycotic drugs induce significant IL-1β secretion in-vitro in dendritic cells isolated from C57BL/6 mouse bone marrow. IL-1β release depended on Toll-like receptor-mediated induction of pro-IL-1β as well as the NLRP3 inflammasome, its adaptor ASC, and caspase-1 for enzymatic cleavage of pro-IL-1β into its mature form. All three drugs induced potassium efflux from the cells as a known mechanism for NLRP3 activation but the P2X7 receptor was not required for this process. Natamycin-induced IL-1β secretion also involved phagocytosis, as cathepsin activation as described for crystal-induced IL-1β release. Together, the polyene macrolides amphotericin B, nystatin, and natamycin trigger IL-1β secretion by causing potassium efflux from which activates the NLRP3-ASC-caspase-1. We conclude that beyond their effects on fungal growth, these antifungal drugs directly activate the host's innate immunity.

Die Bakteriophagen Integrase PhiC31 stellt ein viel versprechendes Werkzeug zur Integration genetischen Materials im nicht viral-basierten Gentransfer dar. Die PhiC31 Integrase vermittelt die Rekombination von spezifische Erkennungssequenz attB enthaltenden Plasmiden mit natürlich vorkommenden attP Erkennungssequenzen innerhalb des Zielgenoms mit unterschiedlicher Integrationsfrequenz und -spezifität. Nebeneffekte der Integration in Form von insertioneller Mutagenese, wie z.B. große Deletionen und chromosomale Veränderungen im Genom der Zielzelle konnten beobachtet werden. Ziel dieser Dissertation war, die PhiC31 vermittelte Effizienz zu verbessern und die Spezifität zu adressieren. Als Ansatz wurde die Mutagenese der DNA-Bindungsdomäne der Integrase basierend auf Punktmutanten zur verbesserten Integrationseffizienz gewählt. Integrationsassays wurden in verschiedenen humanen Zelllinien durchgeführt. Etablierung von Doppelmutanten, sowie Dosisoptimierung des Integrase kodierenden Plasmids verbesserten die Integrationseffizienz mehr als dreifach, verglichen mit der Wildtypintegrase in den Zelllinien HeLa und HCT. Weitere Assays verglichen die Exzisionsaktivität der Integrasemutanten mit dem Wildtyp. Bei fünf Mutanten wurde eine etwa zweifach erhöhte Exzision gefunden. Die Beurteilung der Spezifität der Integrasemutanten erfolgte durch Substitution der Wildtyp-attP Sequenz mit drei Pseudo attP Erkennungssequenzen des Reporterplasmids, deren erhöhte Spezifität bereits dokumentiert war. Einzelne Mutanten zeigten eine zweifach erhöhte Exzisionsaktivität. Die Rekombinationsaktivität von Integrasemutanten wurde im Kontext chromosomaler DNA mittels einer stabil GFP-exprimierenden Reporterzelllinie, in der die eGFP Expression mittels Integrase-vermittelter „Raus-Rekombination“ eines polyA Stoppsignals angeschaltet wird, untersucht. Auf chromosomaler Ebene wurde keine verbesserte Ausschneidungsaktivität erreicht. Zur Evaluierung der in vivo Effizienz zweier ausgewählter PhiC31 Integrasemutanten, die in vitro erhöhte Integrationsaktivität aufwiesen, wurden zwei Plasmide am C57BL/6 Mausmodell getestet. Reportergen war ein für den humanen Koagulationsfaktor IX kodierendes Gen. In Abhängigkeit von der Integrationseffizienz der Mutanten und des Wildtyps, wurden im Zeitraum von einhundert Tagen ähnliche Expressionslevel gefunden. Die Mutanten zeigten keine Verbesserung der Langzeitexpression von humanem Faktor IX. Die hier durchgeführten Studien zur Mutationsanalyse der Phagenintegrase PhiC31 zeigten einen wirksamen Ansatz zur Verbesserung der PhiC31 Integrase-vermittelten Integrationseffizienz in vitro.

Der Typ-2-Diabetes mellitus ist durch eine chronische Hyperglykämie charakterisiert, welche auf eine Kombination aus peripherer Insulinresistenz und Dysfunktion der insulinproduzierenden β-Zellen des endokrinen Pankreas zurückzuführen ist. Um eine bessere Prävention und Therapie dieser häufig vorkommenden Stoffwechselerkrankung zu ermöglichen, war es das Ziel der vorliegenden Dissertation, neue Aspekte der β-Zelldysfunktion in der Pathogenese des Typ-2-Diabetes mellitus aufzuklären. Im ersten Teil dieser Arbeit sollten auf zellulärer Ebene am Typ-2-Diabetesmodell der db/db-Maus neue Erkenntnisse über die sequenzielle Abfolge von Ereignissen gewonnen werden, welche sich im endokrinen Pankreas bei der Entwicklung eines Typ-2-Diabetes abspielen. Durch den direkten Vergleich diabetesresistenter db/db-Mäuse mit C57BL/6J-Hintergrund (db/db B6) und diabetessuszeptibler db/db-Mäuse mit C57BLKS/J-Hintergrund (db/db BKS) wurde erstmalig gezeigt, dass beide Mausstämme eine ähnlich ausgeprägte Insulinresistenz aufweisen und zunächst in der Lage sind, den dadurch erhöhten Insulinbedarf effektiv zu kompensieren. Der sich ab einem Alter von 9 Wochen bei db/db BKS-Mäusen manifestierende Typ-2-Diabetes ist auf einer altersbedingten, inadäquaten Expansion der β-Zellmasse begründet, welche aus einer abnehmenden β-Zellhyperproliferation und einer signifikant gestei-gerten Apoptose der β-Zellen resultiert. Da kompensatorische Defizite der β-Zellmasse möglicherweise auch die humane Typ-2-Diabetesentstehung entscheidend beeinflussen, ist bei prädisponierten Personen eine frühzeitige therapeutische Unterstützung der β-Zellmasse als erfolgversprechende Maßnahme zur Prävention eines Typ-2-Diabetes mellitus vorstellbar. Im zweiten Abschnitt der vorliegenden Arbeit sollten neue Gene identifiziert werden, die eine regulatorische Funktion in den β-Zellen einnehmen und deshalb mögliche Angriffspunkte für neue Therapieformen der β-Zelldysfunktion beim Typ-2-Diabetes darstellen. In Voruntersuchungen wurden die Proteine OPG (Osteoprotegerin) und SOCS2 („suppressor of cytokine signaling 2“) zur genaueren Analyse ausgewählt. Die Hypothese einer positiven Regulatorfunktion von OPG in den pankreatischen β-Zellen konnte zunächst durch die Feststellung einer zeitlichen Korrelation zwischen der β-zellspezifischen OPG-Expression und den kompensatorischen β-Zellveränderungen während der murinen Schwangerschaft bekräftigt werden. In vitro-Versuche an den Insulinomzelllinien Ins-1E und MIN6 sowie an isolierten C57BL/6-Pankreasinseln ergaben, dass das Sekretionsprotein OPG keinen signifikanten Einfluss auf die glukosestimulierte Insulinsekretion und Proliferation von β-Zellen ausübt. OPG wird jedoch durch Zytokine in Ins-1E-Zellen induziert und schützt diese Zellen partiell vor einer IL-1β-induzierten Apoptose. Somit kann eine Rolle von OPG als autokriner Überlebensfaktor pankreatischer β-Zellen postuliert werden. Dieser protektive Effekt geschieht vermutlich unabhängig von den klassischen OPG-Liganden RANKL und TRAIL über eine Inhibierung der IL-1β-induzierten MAP-Kinasen JNK1/2, p38 und ERK1/2. Die physiologische Funktion von SOCS2 wurde sowohl in vivo an SOCS2-Knockout-Mäusen als auch in vitro an Ins-1E-Zellen und isolierten Pankreasinseln untersucht. Dabei konnte kein signifikanter Einfluss von SOCS2 auf die GH-induzierte β-Zellproliferation und die zytokininduzierte Apoptose der β-Zellen demonstriert werden. Unter Anwendung glukosestimulierter Insulinsekretionsversuche und Glukosetoleranztests wurde des Weiteren nachgewiesen, dass SOCS2 weder in vitro noch in vivo die Funktion von β-Zellen signifikant beeinflusst. Auch ein Effekt von SOCS2 auf die Insulinsensitivität konnte an SOCS2-Knockout-Mäusen ausgeschlossen werden. Die erhaltenen Ergebnisse zeigen, dass SOCS2 - im Gegensatz zu SOCS1 und SOCS3 - keine nicht-kompensierbaren Effekte auf die Physiologie pankreatischer β-Zellen und auf den Glukosemetabolismus ausübt. Erklärt werden kann dies wahrscheinlich durch die hohe Redundanz innerhalb der SOCS-Proteinfamilie. Zusammenfassend tragen die in dieser Arbeit gewonnenen Ergebnisse zu einem besseren Verständnis der pankreatischen β-Zellphysiologie und der Pathogenese des Typ-2-Diabetes mellitus bei und ermöglichen es dadurch, die diesbezügliche Entwicklung präventiver und therapeutischer Maßnahmen voranzutreiben.

Background The proinflammatory cytokines interleukin 1 beta (IL-1 beta) and IL-18 are central players in the pathogenesis of inflammatory bowel disease (IBD). In response to a variety of microbial components and crystalline substances, both cytokines are processed via the caspase-1-activating multiprotein complex, the NLRP3 inflammasome. Here, the role of the NLRP3 inflammasome in experimental colitis induced by dextran sodium sulfate (DSS) was examined. Methods IL-1b production in response to DSS was studied in macrophages of wild-type, caspase-1(-/-), NLRP3(-/-), ASC(-/-), cathepsin B(-/-) or cathepsin L(-/-) mice. Colitis was induced in C57BL/6 and NLRP3(-/-) mice by oral DSS administration. A clinical disease activity score was evaluated daily. Histological colitis severity and expression of cytokines were determined in colonic tissue. Results Macrophages incubated with DSS in vitro secreted high levels of IL-1b in a caspase-1-dependent manner. IL-1b secretion was abrogated in macrophages lacking NLRP3, ASC or caspase-1, indicating that DSS activates caspase-1 via the NLRP3 inflammasome. Moreover, IL-1b secretion was dependent on phagocytosis, lysosomal maturation, cathepsin B and L, and reactive oxygen species (ROS). After oral administration of DSS, NLRP3(-/-) mice developed a less severe colitis than wild-type mice and produced lower levels of proinflammatory cytokines in colonic tissue. Pharmacological inhibition of caspase-1 with pralnacasan achieved a level of mucosal protection comparable with NLRP3 deficiency. Conclusions The NLRP3 inflammasome was identified as a critical mechanism of intestinal inflammation in the DSS colitis model. The NLRP3 inflammasome may serve as a potential target for the development of novel therapeutics for patients with IBD.

Thu, 29 Jan 2009 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/9764/ https://edoc.ub.uni-muenchen.de/9764/1/Naumann_Pauline.pdf Naumann, P

Background: We have previously shown that small molecule PDGF receptor tyrosine kinase inhibitors (RTKI) can drastically attenuate radiation-induced pulmonary fibrosis if the drug administration starts at the time of radiation during acute inflammation with present but limited effects against acute inflammation. To rule out interactions of the drug with acute inflammation, we investigated here in an interventive trial if a later drug administration start at a time when the acute inflammation has subsided - has also beneficial antifibrotic effects. Methods: Whole thoraces of C57BL/6 mice were irradiated with 20 Gy and treated with the RTKI imatinib starting either 3 days after radiation ( during acute inflammation) or two weeks after radiation ( after the acute inflammation has subsided as demonstrated by leucocyte count). Lungs were monitored and analyzed by clinical, histological and in vivo non-invasive computed tomography as a quantitative measure for lung density and lung fibrosis. Results: Irradiation induced severe lung fibrosis resulting in markedly reduced mouse survival vs. non-irradiated controls. Both early start of imatinib treatment during inflammation and late imatinib start markedly attenuated the development of pulmonary fibrosis as demonstrated by clinical, histological and qualitative and quantitative computed tomography results such as reduced lung density. Both administration schedules resulted in prolonged lifespans. The earlier drug treatment start resulted in slightly stronger beneficial antifibrotic effects along all measured endpoints than the later start. Conclusions: Our findings show that imatinib, even when administered after the acute inflammation has subsided, attenuates radiation-induced lung fibrosis in mice. Our data also indicate that the fibrotic fate is not only determined by the early inflammatory events but rather a complex process in which secondary events at later time points are important. Because of the clinical availability of imatinib or similar compounds, a meaningful attenuation of radiation-induced lung fibrosis in patients seems possible.

The incidence of high grade B cell lymphoma in western countries has increased over the last decades. Improvement of conventional chemotherapy regimens has significantly contributed to prolonged 5-year survival rates which currently reach around 60%. However, relapse after conventional chemotherapy is an important challenge, especially in high grade B cell lymphomas. The potential benefit of immunological approaches for the elimination of such lymphomas still remains unclear. In this study, we attempted to address whether the forced expression of foreign antigens in a tumor of B cell origin leads to immune recognition and elimination of the tumor and to assess the potential role of IFN-gamma (IFN-g) in tumor rejection. To this end, we used a transgenic mouse lymphoma model, where the human proto-oncogene c-myc (a foreign antigen for the mouse host) is under the control of regulatory elements of the immunoglobulin lambda locus, thereby recapitulating the important features of a t(8;22) translocation as found in human Burkitt’s lymphoma. From these spontaneously developing tumors, lymphoma cell lines were established that either express (line 291) or are deficient (line 9) in Stat1- a key signaling molecule in the response to interferons. We found that the expression of foreign antigens such as chicken ovalbumin (OVA) and green fluorescent protein (GFP) in Stat1-competent 291 cells led to immune responses that delayed tumor progression and improved survival of wild-type animals. Consistent with this, loss of foreign antigen inevitably led to accelerated tumor progression upon transfer into immunocompetent wild-type mice. Transfer of immunogenic 291-OVA-GFP lymphoma cells led to increased tumor progression without loss of foreign antigen upon transfer into IFN-γ-/- and Stat1-/- mice indicating that no selection of antigen loss-variants occurred in these mice. The rejection of 291-OVA-GFP cells in wild-type mice was at least in part mediated by CD8+ T cells as measured by enrichment of the OVA antigen-derived MHC class I-restricted SIINFEKL epitope-specific cells in wild-type recipients.. Interestingly, Stat1-deficient lymphoma cells (9-GFP and 9-OVA-GFP) were rejected by immunocompetent UBQ-GFP transgenic wild-type C57BL/6 mice irrespectively of the presence of a foreign antigen, indicating the existence of immunosurveillance against these Stat1-deficient lymphomas. To evaluate the key players behind lymphoma rejection, we transferred 9-GFP cells into IFN-γ-/- and Stat1-/- recipients. This led to enhanced tumor growth indicating that endogenous IFN-γ production and Stat1 signaling are critical for tumor rejection. To gain an insight into the mechanistic aspects of innate immunosurveillance against the Stat1-competent and Stat1-deficient lymphomas, NK cell functionality was evaluated. We found that NK cells could efficiently lyse both Stat1-competent and Stat1-deficient lymphoma cell lines in vitro. Treatment with IFN-γ increased the susceptibility of Stat1-deficient lymphoma cells to NK cell killing, but decreased that of Stat1-competent cells, presumably by upregulating MHC class I expression. The results of this work show that host IFN-γ and Stat1 signaling are important for tumor clearance, and that paradoxically, the absence of Stat1 within the lymphoma is required for rejection.

Dendritische Zellen (DC) übernehmen essentielle Aufgaben in der Homöostase des Immunsys-tems und in der Induktion von Toleranz oder Immunität. Eine besondere Wechselwirkung findet hierbei zwischen DC und T-Zellen statt, welche durch die Präsentation und Erkennung von Selbstpeptiden, beziehungsweise Fremdantigenen, vermittelt wird. DC spielen eine wichtige Rolle bei der Selektion eines funktionellen T-Zell-Kompartiments im Thymus. In der vorliegenden Stu-die wurde die Funktion der Antigenpräsentation von DC für die Homöostase und die Aktivierung von CD8-T-Zellen in vivo untersucht. Diese Arbeit soll zeigen, dass die Präsentation von Selbstpeptiden auf DC die homöostatische Pro-liferation (HP) von naiven CD8-T-Zellen induziert. Nach der Depletion von T-Zellen durch Be-strahlung oder Antikörpergabe kam es zu einer HP von naiven CD8-T-Zellen. Diese Proliferation war streng MHC-abhängig. Die Expression von MHC-I auf DC reichte aus, um eine komplette HP zu erlauben, welche im Teilungsmuster, der Aktivierungsmarkermodulation und den Proliferati-onsraten jener von proliferierenden Zellen in C57BL/6-Wildtypmäusen glich. Überraschenderwei-se waren CD4-T-Zellen in der Lage, die HP von transferierten naiven CD8-T-Zellen zu inhibieren. Erst durch die Depletion von endogenen CD4-T-Zellen kam es zu Teilungen, während CD25-positive regulatorische T-Zellen keinen Einfluss auf die HP von naiven CD8-T-Zellen ausübten. DC sind essentiell um Toleranz beziehungsweise Immunität nach der Erkennung von Fremdanti-genen zu generieren. Um die Bedeutung der Antigenpräsentation auf DC genauer zu charakterisie-ren, wurde die Immunantwort in einem Mausstamm, in welchem alle Zellen MHC-I tragen zu Tie-ren, in denen nur DC MHC-I exprimieren und somit naive CD8-T-Zellen aktivieren können, un-tersucht. Hierbei wurde deutlich, dass DC ausreichten um Toleranz, als auch Immunität von nai-ven CD8-T-Zellen zu induzieren. Kam es jedoch zu einer differentiellen Antigenpräsentation nach systemischer Administration des Antigens (als Peptid oder Virus in die Blutbahn), waren antigen-präsentierende nicht-DC in der Lage, die Immunantwort abzuschwächen. Dies geschah durch In-duktion von Apoptose, wodurch die Anzahl antigenspezifischer Effektor-T-Zellen verringert und somit auch die Formation des immunologischen Gedächtnisses beeinträchtigt werden konnte. Diese Ergebnisse betonen die enorme Bedeutung der Antigenpräsentation durch DC, weisen aber auch auf die besondere Rolle der Antigenpräsentation durch andere Zelltypen als DC hin, welche in der Lage sind eine Immunantwort deutlich zu modulieren.