Podcasts about mouse model

Make sure to support this podcast by heading over to Paleovalley.com/NwJ and the 15% off discount will automatically be applied to your first order. _____I'm excited to sit down with Dr. Richard Horowitz. We talk about tick-borne illnesses, how to get started with Lyme treatment, and much more. Make sure to listen to the full interview to learn more.Dr. Richard Horowitz is a board-certified internist and the medical director of the Hudson Valley Healing Arts Center, an integrative medical center specializing in the treatment of Lyme and other tick-borne diseases. He has treated over 13,000 Lyme and tick-borne disease patients in the last 40 years. He is one of the founding members and past president-elect of the International Lyme and Associated Diseases Society. He has also been awarded the Humanitarian of the Year award by the Turn the Corner Foundation. His contributions have significantly advanced the medical community's understanding of tick-borne diseases.We discuss the following:All about Dr. Richard HorowitzTick-borne illnessesCoinfectionsMultiple Systemic Infectious Disease Syndrome (MSIDS)How to get started with LymeIGeneX testingMold and Lyme9-week protocol with dapsoneHow to treat a tick biteAlpha-gal and lone star tickThoughts on fungusThoughts on chronic lyme remission Mind-body connectionWhere to find Dr. Richard Horowitz_____RESOURCESWebsiteFacebookHealing from Lyme Disease SummitCombining Double-Dose and High-Dose Pulsed Dapsone Combination Therapy for Chronic Lyme Disease/Post-Treatment Lyme Disease Syndrome and Co-Infections, Including BartonellaComparison of the Efficacy of Longer versus Shorter Pulsed High Dose Dapsone Combination Therapy in the Treatment of Chronic Lyme Disease/Post Treatment Lyme Disease Syndrome with Bartonellosis and Associated CoinfectionsEfficacy of Short-Term High Dose Pulsed Dapsone Combination Therapy in the Treatment of Chronic Lyme Disease/Post-Treatment Lyme Disease Syndrome (PTLDS) and Associated Co-InfectionsEfficacy of Double-Dose Dapsone Combination Therapy in the Treatment of Chronic Lyme Disease/Post-Treatment Lyme Disease Syndrome (PTLDS) and Associated Co-infectionsEffect of dapsone alone and in combination with intracellular antibiotics against the biofilm form of B. burgdorferiPrecision Medicine: Retrospective Chart Review and Data Analysis of 200 Patients on Dapsone Combination Therapy for Chronic Lyme Disease/Post-Treatment Lyme Disease Syndrome (Part 1)Precision Medicine: The Role of the MSIDS Model in Defining, Diagnosing, and Treating Chronic Lyme Disease/Post Treatment Lyme Disease Syndrome and Other Chronic Illness (Part 2)Are Mycobacterium Drugs Effective for Treatment Resistant Lyme Disease, Tick-Borne Co-Infections, and Autoimmune Disease?Superior Efficacy of Combination Antibiotic Therapy Versus Monotherapy in a Mouse Model of Lyme Disease____SIGN UP FOR MY

BUFFALO, NY- February 15, 2024 – 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 16, Issue 3, entitled, “GV1001 reduces neurodegeneration and prolongs lifespan in 3xTg-AD mouse model through anti-aging effects.” GV1001, which mimics the activity of human telomerase reverse transcriptase, protects neural cells from amyloid beta (Aβ) toxicity and other stressors through extra-telomeric function, as noted in our prior in vitro studies. As per a recent phase II clinical trial, it improves cognitive function in patients with moderate to severe dementia. However, the underlying protective mechanisms remain unclear. In this new study, researchers Hyun-Hee Park, Hyuk Sung Kwon, Kyu-Yong Lee, Ye Eun Kim, Jeong-Woo Son, Na-Young Choi, Myung-Hoon Han, Dong Woo Park, Sangjae Kim, and Seong-Ho Koh from Hanyang University Guri Hospital, Hanyang University Graduate School of Biomedical Science and Engineering and Teloid Inc. aimed to investigate the effects of GV1001 on neurodegeneration, senescence, and survival in triple transgenic Alzheimer's disease (AD) (3xTg-AD) mice. “ [...] we hypothesised that GV1001 might have anti-aging effects and improve neurodegeneration and senescence in vivo as a possible mechanism for its beneficial effects on AD.” GV1001 (1 mg/kg) was subcutaneously injected into old 3xTg-AD mice thrice a week until the endpoint for sacrifice, and survival was analysed. Magnetic resonance imaging (MRI) and Prussian blue staining (PBS) were performed to evaluate entry of GV1001 entrance into the brain. Diverse molecular studies were performed to investigate the effect of GV1001 on neurodegeneration and cellular senescence in AD model mice, with a particular focus on BACE, amyloid beta1-42 (Aβ1-42), phosphorylated tau, volume of dentate gyrus, β-galactosidase positive cells, telomere length, telomerase activity, and ageing-associated proteins. GV1001 crossed the blood-brain barrier, as confirmed by assessing the status of ferrocenecarboxylic acid-conjugated GV1001 using magnetic resonance imaging and PBS. GV1001 increased the survival of 3xTg-AD mice. It decreased BACE and Aβ1-42 levels, neurodegeneration (i.e., reduced CA1, CA3 and dentate gyrus volume, decreased levels of senescence-associated β-galactosidase positive cells, and increased telomere length and telomerase activity), and levels of ageing-associated proteins. “We suggest that GV1001 exerts anti-ageing effects in 3xTg-AD mice by reducing neurodegeneration and senescence, which contributes to improved survival.” DOI - https://doi.org/10.18632/aging.205489 Corresponding authors - Sangjae Kim - chiron@gemvax.com, and Seong-Ho Koh - ksh213@hanyang.ac.kr Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts 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: 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

BUFFALO, NY- November 15, 2023 – A new #researchpaper 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 21, entitled, “Longitudinal characterization of behavioral, morphological and transcriptomic changes in a tauopathy mouse model.” Neurodegenerative disorders, such as Alzheimer's disease (AD), have the gradual onset of neurobiological changes preceding clinical diagnosis by decades. In their new study, researchers Qing Cao, Manasa Kumar, Allea Frazier, Jamal B. Williams, Shengkai Zhao, and Zhen Yan from the State University of New York at Buffalo's Jacobs School of Medicine and Biomedical Sciences aimed to elucidate how brain dysfunction proceeds in neurodegenerative disorders. “[...] we performed longitudinal characterization of behavioral, morphological, and transcriptomic changes in a tauopathy mouse model, P301S transgenic mice.” P301S mice exhibited cognitive deficits as early as 3 months old, and deficits in social preference and social cognition at 5–6 months. They had a significant decrease of arborization in basal dendrites of hippocampal pyramidal neurons from 3 months and apical dendrites of PFC pyramidal neurons at 9 months. Transcriptomic analysis of genome-wide changes revealed the enrichment of synaptic gene upregulation at 3 months of age, while most of these synaptic genes were downregulated in PFC and hippocampus of P301S mice at 9 months. These time-dependent changes in gene expression may lead to progressive alterations of neuronal structure and function, resulting in the manifestation of behavioral symptoms in tauopathies. “In conclusion, our longitudinal characterization of behavioral, morphological and transcriptomic changes in a tauopathy mouse model is to elucidate potential mechanisms that drive the progression of AD and related neurodegenerative disorders. Manipulation of key molecular players coupled with electrophysiological measurements of neuronal functions in future studies will help identify early intervention strategies for these diseases.” DOI - https://doi.org/10.18632/aging.205057 Corresponding author - Zhen Yan - zhenyan@buffalo.edu Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.205057 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, Alzheimer's disease, tau, cognitive behaviors, transcriptomic, neuronal morphology 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

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

Slack your lines and start hacking those sacks because this episode we're covering the cerebellum, and turns out, we ADHDers need all the balancing practice we can get.    Kristin is dropping a digestible meat nugget of brain anatomy before leading us through the latest research that shows how a smaller cerebellum affects mental coordination in addition to physical movement (which explains oh so much).    We also share activities for strengthening the cerebellum, encourage you to take up juggling, and read a bird to absolute filth before giving the imitation performance of a lifetime. Resources: Parts of the Brain: Anatomy, Functions, and Conditions (verywellmind.com) The Cerebellum and Neurodevelopmental Disorders | SpringerLink Notes on the Role of the Cerebellum in ADHD (researchgate.net) ADHD 2.0  Brain Development | Neuroplasticity Stimulation | Zing Performance Distraction Podcast The cerebellum and cognition - ScienceDirect Decreased Glial GABA and Tonic Inhibition in Cerebellum of Mouse Model for Attention-Deficit/Hyperactivity Disorder (ADHD) - PMC (nih.gov) Dysmetria - an overview | ScienceDirect Topics shoebill stork sound - Google Search

Enzyme Replacement Therapy (ERT) has changed the course of several lysosomal storage disorders but regular, intravenous administration is not without its issues. In this latest Shortcast, Dr Paulina Dabrowska-Schlepp describes her group's work to develop subcutaneous ERT for Fabry Disease. Comparison of efficacy between subcutaneous and intravenous application of moss-aGal in the mouse model of Fabry disease Paulina Dabrowska-Schlepp, et al https://doi.org/10.1002/jmd2.12393

Today, you'll learn about how researchers are using stem cells to cure infertility in mice, the health benefits of honey made by ants, and the potential emotional toll of using AI at work. Ovarian Failure Cure “Stem Cell Therapy Restores Fertility in Mouse Model.” by Katie Brighton. 2023. https://www.technologynetworks.com/tn/news/stem-cell-therapy-restores-fertility-in-mouse-model-376618“Fertility restoration in mice with chemotherapy induced ovarian failure using differentiated iPSCs.” by Kevin M. Elias, et al. 2023. https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(23)00280-3/fulltext“Pathogenesis and Causes of Premature ovarian Failure: An Update.” by Mahbod Ebrahimi, M.D. & Firoozeh Akbari Asbagh, M.D. 2011. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4059950/“Mechanisms of epigenetic memory.” by Agustina D'Urso & Jason H. Brickner. 2014. https://www.sciencedirect.com/science/article/abs/pii/S0168952514000584Honeypot Ants “Western science catches up with First Nations' medicinal use of ant honey.” The University of Sydney. 2023. https://www.scimex.org/newsfeed/western-science-catches-up-with-first-nations-medicinal-use-of-ant-honey“Honeypot Ant Facts.” Fact Animal. N.d. https://factanimal.com/honeypot-ant/“Honeypot Ant: Good At Sharing.” San Diego Zoo Wildlife Explorers. 2023. https://sdzwildlifeexplorers.org/animals/honeypot-antAI Insomnia“Loneliness, insomnia linked to work with AI systems.” American Psychological Association. 2023. https://www.sciencedaily.com/releases/2023/06/230612114659.htm“Loneliness, insomnia linked to work with AI systems.” American Psychological Association. 2023. https://www.apa.org/news/press/releases/2023/06/loneliness-insomnia-ai-systems Hosted on Acast. See acast.com/privacy for more information.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.08.01.551291v1?rss=1 Authors: Hamilton, L. K., Mbra, P. E. H., Mailloux, S., Galoppin, M., Aumont, A., Fernandes, K. J. L. Abstract: Evidence from genetic and epidemiological studies point to lipid metabolism defects in both the brain and periphery being at the core of Alzheimer's disease (AD) pathogenesis. Previously, we reported that central inhibition of the rate-limiting enzyme in monounsaturated fatty acid synthesis, Stearoyl-CoA Desaturase (SCD), improves brain structure and function in the 3xTg mouse model of AD. Here, we tested whether these beneficial central effects involve recovery of peripheral metabolic defects, such as fat accumulation and glucose and insulin handling. As early as 3 months of age, 3xTg-AD mice exhibited obesity-like phenotypes including increased body weight and visceral and subcutaneous white adipose tissue deposition, as well as diabetic-like peripheral gluco-regulatory abnormalities. Intracerebral infusion of an SCD inhibitor that normalizes brain fatty acid metabolism, synapse loss and learning and memory deficits in middle-aged symptomatic 3xTg-AD mice did not affect peripheral phenotypes. This suggests that the beneficial effects of central SCD inhibition on cognitive function are not mediated by recovery of peripheral metabolic abnormalities. Given the widespread side-effects of systemically administered SCD inhibitors, these data suggest that selective inhibition of SCD in the brain may represent a clinically safer and more effective strategy for AD. 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/2023.07.26.550698v1?rss=1 Authors: Navacerrada, M. E. S., Kim, E., Siow, B., Ma, D., Gonzalez, L. R., Simmons, C., Hayward, D., Gibbins, D., Singh, N., Strydom, A., Fisher, E. M. C., Tybulewicz, V. L. J., Cash, D. Abstract: Down syndrome (DS) is one of the most common birth defects and the most prevalent genetic form of intellectual disability. DS arises from trisomy of chromosome 21, but its molecular and pathological consequences are not fully understood. In this study, we compared Dp1Tyb mice, a DS model, against their wild-type (WT) littermates of both sexes to investigate the impact of DS-related genetic abnormalities on the brain phenotype. We performed in vivo whole brain magnetic resonance imaging (MRI) and hippocampal 1H magnetic resonance spectroscopy (MRS) on the animals at 3 months of age. Subsequently, ex vivo MRI scans and histological analyses were conducted post-mortem. Our findings unveiled distinct neuroanatomical and biochemical alterations in the Dp1Tyb brains. Dp1Tyb brains exhibited a smaller surface area and a rounder shape compared to WT brains. Regional volumetric analysis revealed significant changes in 26 out of 72 examined brain regions, including the medial prefrontal cortex and dorsal hippocampus. These alterations were consistently observed in both in vivo and ex vivo imaging data. Additionally, high-resolution ex vivo imaging enabled us to investigate cerebellar layers and hippocampal subregions, revealing selective areas of decrease and remodelling in these structures. An analysis of hippocampal metabolites revealed an elevation in glutamine and the glutamine/glutamate ratio in the Dp1Tyb mice compared to controls, suggesting a possible imbalance in the excitation/inhibition ratio. This was accompanied by the decreased levels of taurine. Histological analysis revealed fewer neurons in the hippocampal CA3 and DG layers, along with an increase in astrocytes and microglia. These findings recapitulate multiple neuroanatomical and biochemical features associated with DS, enriching our understanding of the potential connection between chromosome 21 trisomy and the resultant 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/2023.07.25.550555v1?rss=1 Authors: Sun, X., Badachhape, A., Chin, J., Annapragada, A., Tanifum, E. Abstract: Parkinson's disease is characterized progressive deposition of pathologic alpha-synuclein aggregates, neuroinflammation, and death of dopaminergic neurons in the substantia nigra projecting to the striatum. Noninvasive in vivo profiling of alpha-synuclein aggregate accumulation and microgliosis by molecular imaging can provide insights on the underlying mechanisms of disease progression, facilitating the development of effective treatment. However, no classical imaging methods have been successful, despite several attempts. We demonstrate a novel method to noninvasive in vivo profiling of pathologic alpha-synuclein in combination with microgliosis using molecular magnetic resonance imaging (MRI), by targeting oligomeric alpha-synuclein in cerebrospinal fluid with nano scavengers (T) bearing a T1-relaxive Gd(III) payload. In this proof-of-concept report we demonstrate, in vitro, that microglia and neuroblastoma cell lines internalize cross-linked T/oligomeric alpha-synuclein agglomerates. Delayed in vivo T1-weighted MRI scans following intravenous administration in the M83 alpha-synuclein transgenic mouse line show statistically significant T1 signal enhancement in test mice versus controls. The in vivo data was validated by ex-vivo immunohistochemical analysis which showed a strong correlation between in vivo MRI signal enhancement, Lewy pathology distribution, and microglia activity in the treated brain tissue. Furthermore, neuronal, and microglial cells in brain tissue from treated mice displayed strong cytosolic signal originating from T, confirming in vivo cell uptake of the nano scavengers. 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/2023.07.21.550014v1?rss=1 Authors: Boi, L., Johansson, Y., Tonini, R., Moratalla, R., Fisone, G., Silberberg, G. Abstract: Parkinson's disease (PD) is characterized by motor impairments caused by degeneration of dopamine neurons in the substantia nigra pars compacta. In addition to these symptoms, PD patients often suffer from non-motor co-morbidities including sleep and psychiatric disturbances, which are thought to depend on concomitant alterations of serotonergic and noradrenergic transmission. A primary locus of serotonergic neurons is the dorsal raphe nucleus (DRN), providing brain-wide serotonergic input. Here, we identified electrophysiological and morphological parameters to classify serotonergic and dopaminergic neurons in the murine DRN under control conditions and following striatal injection of the catecholamine toxin, 6-hydroxydopamine (6-OHDA). Electrical and morphological properties of both neuronal populations were altered by 6-OHDA. In serotonergic neurons, most changes were reversed when 6-OHDA was injected in combination with desipramine, a noradrenaline reuptake inhibitor, protecting the noradrenergic terminals. Our results show that the depletion of both noradrenaline and dopamine in the 6-OHDA mouse model causes changes in the DRN neural circuitry. 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/2023.07.14.549070v1?rss=1 Authors: Martinez, J. D., Wilson, L. G., Brancaleone, W., Peterson, K., Popke, D. S., Caicedo Garzon, V., Perez Tremble, R., Donnelly, M. J., Mendez Ortega, S., Torres, D., Shaver, J., Clawson, B. C., Jiang, S., Yang, Z., Aton, S. Abstract: Fragile X syndrome (FXS) is a highly-prevalent genetic cause of intellectual disability, associated with disrupted cognition and sleep abnormalities. Sleep loss itself negatively impacts cognitive function, yet the contribution of sleep loss to impaired cognition in FXS is vastly understudied. One untested possibility is that disrupted cognition in FXS is exacerbated by abnormal sleep. We hypothesized that restoration of sleep-dependent mechanisms could improve functions such as memory consolidation in FXS. We examined whether administration of ML297, a hypnotic drug acting on G-protein-activated inward-rectifying potassium channels, could restore sleep phenotypes and improve disrupted memory consolidation in Fmr1-/y mice. Using 24-h polysomnographic recordings, we found that Fmr1-/y mice exhibit reduced non-rapid eye movement (NREM) sleep and fragmented NREM sleep architecture, alterations in NREM EEG spectral power (including reductions in sleep spindles), and reduced EEG coherence between cortical areas. These alterations were reversed in the hours following ML297 administration. Hypnotic treatment following contextual fear or spatial learning also ameliorated disrupted memory consolidation in Fmr1-/y mice. Hippocampal activation patterns during memory recall was altered in Fmr1-/y mice, reflecting an altered balance of activity among principal neurons vs. parvalbumin-expressing (PV+) interneurons. This phenotype was partially reversed by post-learning ML297 administration. These studies suggest that sleep disruption could have a major impact on neurophysiological and behavioral phenotypes in FXS, and that hypnotic therapy may significantly improve disrupted cognition in this disorder. 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/2023.07.14.548970v1?rss=1 Authors: Hsu, T.-T., Wang, C.-Y., Hsueh, Y.-P. Abstract: Autism spectrum disorders (ASD) are recognized as neural disconnectivity syndromes. Here, we establish a whole-brain immunostaining and quantification platform to investigate structural and functional connectivity in a Tbr1+/- autism mouse model, which shares a defect in the anterior commissure that is evolutionarily conserved with human patients. Since the basolateral amygdala (BLA) is particularly susceptible to Tbr1 haploinsufficiency and it projects to the contralateral brain hemisphere via the anterior commissure, we express a channelrhodopsin variant oChIEF fused with Citrine at the BLA to outline axonal projections of BLA neurons and to activate the BLA under blue light theta-burst stimulation (TBS). Next, we evaluate C-FOS expression to represent neural activity. We show that Tbr1haploinsufficiency almost completely disrupts contralateral BLA axonal projections and results in ipsilateral mistargeting, thereby globally altering BLA functional connectivity. Based on correlated C-FOS expression among brain regions, we further report that Tbr1 deficiency severely disrupts whole-brain synchronization in the absence of salient stimulation. Tbr1+/- and wild-type mice exhibit opposing responses to TBS-induced amygdalar activation, with it reducing synchronization in wild-type mice but enhancing it in Tbr1+/- mice. Whole-brain modular organization and inter-module connectivity are also affected by Tbr1 deficiency and amygdalar activation. In fact, the synchronization and intra- and inter-modular connectivities of TBS-treated Tbr1+/- mice are more comparable to those of non-treated wild-type mice, suggesting a potential ameliorating effect of amygdalar stimulation on brain function. Moreover, Tbr1+/- mice exhibit attenuated connectivity between the amygdala and default mode network, a subnetwork highly relevant to social behaviors, strengthening the link between the impaired connectivity and social behavior deficits displayed by Tbr1+/-mice. Our high-resolution analytical platform reveals the inter- and intra-hemispheric connectopathies arising from an ASD condition and emphasizes the defective synchronization at a whole-brain scale caused by Tbr1 deficiency. 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 (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 15, Issue 12, entitled, “Hepatic hydrogen sulfide levels are reduced in mouse model of Hutchinson-Gilford progeria syndrome.” Hutchinson-Gilford progeria syndrome (HGPS) is a rare human disease characterized by accelerated biological aging. Current treatments are limited, and most patients die before 15 years of age. Hydrogen sulfide (H2S) is an important gaseous signaling molecule that is central to multiple cellular homeostasis mechanisms. Dysregulation of tissue H2S levels is thought to contribute to an aging phenotype in many tissues across animal models. Whether H2S is altered in HGPS is unknown. In a new study, researchers Stephen E. Wilkie, Diana E. Marcu, Roderick N. Carter, Nicholas M. Morton, Susana Gonzalo, and Colin Selman from the University of Glasgow, University of Edinburgh, Saint Louis University, and Karolinska Institute investigated hepatic H2S production capacity and transcript, protein and enzymatic activity of proteins that regulate hepatic H2S production and disposal in a mouse model of HGPS (G609G mice, mutated Lmna gene equivalent to a causative mutation in HGPS patients). “This study was designed and undertaken due to the lack of understanding in the mechanistic targets of known treatments against HGPS and considering the positive association between H2S and longevity in model organisms.” Here, the researchers employed the HGPS mouse model G609G to test the hypothesis that, in contrast to anti-aging increases in H2S production, the accelerated aging typical of progeroid mice is associated with reduced hepatic H2S production. G609G mice were maintained on either regular chow (RC) or high fat diet (HFD). HFD has been previously shown to significantly extend lifespan of G609G mice, and compared to wild type (WT) mice maintained on RC. RC-fed G609G mice had significantly reduced hepatic H2S production capacity relative to WT mice, with a compensatory elevation in mRNA transcripts associated with several H2S production enzymes, including cystathionine-γ-lyase (CSE). H2S levels and CSE protein were partially rescued in HFD fed G609G mice. The data acquired here confirmed some aspects of the relevance of H2S in HGPS but raises more questions about the specific mechanisms at play. “Regardless, the work presented here addresses an area of research that remains critically understudied and provides new evidence that the accelerated ageing phenotype observed in HGPS may be partially explained by a reduction in hepatic H2S levels.” DOI - https://doi.org/10.18632/aging.204835 Corresponding authors - Colin Selman - colin.selman@glasgow.ac.uk, and Stephen E. Wilkie - stephen.wilkie@ki.se Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204835 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, progeria, hydrogen sulfide, high-fat diet, ageing, lamin A About Aging-US: Launched in 2009, Aging 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. Please visit our website at www.Aging-US.com​​ and connect with us on social media. MEDIA@IMPACTJOURNALS.COM

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.03.547034v1?rss=1 Authors: Lopes, F. M., Grenier, C., Jarvis, B. W., Al Mahdy, S., Lene-Mckay, A., Gurney, A. M., Newman, W. G., Waddington, S. N., Woolf, A. S., Roberts, N. A. Abstract: Rare early onset lower urinary tract disorders include defects of functional maturation of the bladder. Current treatments do not target the primary pathobiology of these diseases. Some have a monogenic basis, such as urofacial, or Ochoa, syndrome (UFS). Here, the bladder does not empty fully because of incomplete relaxation of its outflow tract, and subsequent urosepsis can cause kidney failure. UFS is associated with biallelic variants of HPSE2, encoding heparanase-2. This protein is detected in pelvic ganglia, autonomic relay stations that innervate the bladder and control voiding. Bladder outflow tracts of Hpse2 mutant mice display impaired neurogenic relaxation. We hypothesized that HPSE2 gene transfer soon after birth would ameliorate this defect and explored an adeno-associated viral (AAV) vector-based approach. AAV9/HPSE2, carrying human HPSE2 driven by CAG, was administered intravenously into neonatal mice. In the third postnatal week, transgene transduction and expression were sought, and ex vivo myography was undertaken to measure bladder function. In mice administered AAV9/HPSE2, the transduced genome was detected in pelvic ganglia, where human HPSE2 was also expressed. Moreover, heparanase-2 became detectable in pelvic ganglia of treated mutant mice. On autopsy, untreated mutant mice had distended urinary bladders, consistent with bladder outflow obstruction, but AAV9/HPSE2-administered mice did not, thus resembling wild-type mice. AAV9/HPSE2 significantly ameliorated impaired neurogenic relaxation of Hpse2 mutant bladder outflow tracts. Impaired neurogenic contractility of mutant detrusor smooth muscle was also significantly ameliorated by AAV9/HPSE2. These results constitute first steps towards curing UFS, a clinically devastating genetic disease featuring a bladder autonomic neuropathy. 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/2023.06.28.546962v1?rss=1 Authors: Straumann, N., Combes, B. F., Dean-Ben, X. L., Steernke, R., Gerez, J., Dias, I., Chen, Z., Watts, B., Rostami, I., Shi, K., Rominger, A., Baumann, C. R., Luo, J., Noain, D., Nitsch, R. M., Okamura, N., Razansky, D., Ni, R. Abstract: Background: Abnormal alpha-synuclein and iron accumulation in the brain play an important role in Parkinson's disease (PD). Herein, we aim at visualizing alpha-synuclein inclusions and iron deposition in the brains of M83 (A53T) mouse models of PD in vivo. Methods: Fluorescently labelled pyrimidoindole-derivative THK-565 was characterized by using recombinant fibrils and brains from 10-11 months old M83 mice, which subsequently underwent in vivo concurrent wide-field fluorescence and volumetric multispectral optoacoustic tomography (vMSOT) imaging. The in vivo results were verified against structural and susceptibility weighted imaging (SWI) magnetic resonance imaging (MRI) at 9.4 Tesla and scanning transmission X-ray microscopy (STXM) of perfused brains. Brain slice immunofluorescence and Prussian blue staining were further performed to validate the detection of alpha-synuclein inclusions and iron deposition in the brain, respectively. Results: THK-565 showed increased fluorescence upon binding to recombinant alpha-synuclein fibrils and alpha-synuclein inclusions in post-mortem brain slices from patients with Parkinson's disease and M83 mice. i.v. administration of THK-565 in M83 mice showed higher cerebral retention at 20 and 40 minutes post-injection by wide-field fluorescence compared to non-transgenic littermate mice, in congruence with the vMSOT findings. SWI/phase images and Prussian blue indicated the accumulation of iron deposits in the brains of M83 mice, presumably in the Fe3+ form, as evinced by the STXM results. Conclusion: We demonstrated in vivo mapping of alpha-synuclein by means of non-invasive epifluorescence and vMSOT imaging assisted with a targeted THK-565 label and SWI/STXM identification of iron deposits in M83 mouse brains ex vivo. 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/2023.06.28.546916v1?rss=1 Authors: Dominguez-Martinez, A., Molina-Menor, E., Blanco-Ramos, M., Urpi, A., Pereto, J., Porcar, M., Quintana, A. Abstract: Mitochondrial dysfunction lead to a wide group of progressive and fatal pathologies known as mitochondrial diseases (MD). One of the most common pediatric representation of MD is Leigh Syndrome, affecting 1/40.000 births. LS is characterized by neurodegeneration in specific brain areas, such as brainstem and basal ganglia, and by respiratory and motor alterations. However, the results obtained from clinical trials based on antioxidant therapies are controversial. Thus, the development novel antioxidant strategy is required to improve the efficacy of current palliative treatments. In this regard, Ndufs4KO mouse model is a suitable model to test new drugs in the field of MD and LS. Therefore, we set to assess the therapeutic potential of oral administration of Micrococcus luteus, a high-antioxidant content microorganism. Incidentally, we identified that while M. luteus administration did not possess any beneficial actions, the cryopreservant maltodextrin (MDX), included in the preparation, ameliorated the phenotype of Ndufs4KO mice. Our results show that MDX treatment at a concentration of 30 g/L increased lifespan and reduced microglial reaction compared to vehicle-treated Ndufs4KO mice. However, no improvement in locomotion nor respiratory function was observed in MDX-treated mice compared to vehicle-treated Ndufs4KO mice. Metataxonomic characterization of intestinal microbiome identified differential profiles in Ndufs4KO mice at the genus level. Furthermore, MDX treatment increased the variability of the abundance of Akkermansia sp. Thus, this work paves the way for further studies to confirm the therapeutic potential of MDX in mitochondrial disease. 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/2023.06.22.546125v1?rss=1 Authors: Yu, J. S., Zhu, H., Taheri, S., Lee, J.-Y., Diamond, D. M., Kirstein, C., Kindy, M. S. Abstract: BACKGROUND: Serum amyloid A (SAA) proteins increase dramatically in the blood following inflammation. Recently, SAAs are increased in humans following stroke and in ischemic animal models. However, the impact of SAAs on whether this signal is critical in the ischemic brain remains unknown. Therefore, we investigated the role of SAA and SAA signaling in the ischemic brain. METHODS: Wildtype and SAA deficient mice were exposed to middle cerebral artery occlusion and reperfusion, examined for the impact of infarct volumes, behavioral changes, inflammatory markers, TUNEL staining, and BBB changes. The underlying mechanisms were investigated using SAA deficient mice, transgenic mice and viral vectors. RESULTS: SAA levels were significantly increase following MCAo and mice deficient in SAAs showed reduced infarct volumes and improved behavioral outcomes. SAA deficient mice showed a reduction in TUNEL staining, inflammation and decreased glial activation. Mice lacking acute phase SAAs demonstrated a reduction in expression of the NLRP3 inflammasome and SAA/NLRP3 KO mice showed improvement. Restoration of SAA expression via SAA tg mice or adenoviral expression reestablished the detrimental effects of SAA. A reduction in BBB permeability was seen in the SAA KO mice and anti-SAA antibody treatment reduced the effects on ischemic injury. CONCLUSIONS: SAA signaling plays a critical role in regulating NLRP3-induced inflammation and glial activation in the ischemic brain. Blocking this signal will be a promising approach for treating ischemic stroke. 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/2023.06.21.545918v1?rss=1 Authors: Chumin, E. J., Burton, C., Silvola, R., Persohn, S. C., Veronese, M., Territo, P. R. Abstract: INTRODUCTION: Alzheimer's disease (AD), the leading cause of dementia worldwide, represents a human and financial impact for which few effective drugs exist to treat the disease. Advances in molecular imaging have enabled assessment of cerebral glycolytic metabolism, and network modeling of brain region have linked to alterations in metabolic activity to AD stage. METHODS: We performed 18F-FDG Positron Emission Tomography (PET) imaging in 4, 6, and 12 month old 5XFAD and littermate controls (WT) of both sexes, and analyzed region data via brain metabolic covariance analysis. RESULTS: 5XFAD model mice show age related changes glucose uptake relative to WT mice. Analysis of community structure of covariance networks was different across age and sex, with a disruption of metabolic coupling in the 5XFAD model. DISCUSSION: The current study replicates clinical AD findings and indicates that metabolic network covariance modeling provides a translational tool to assess disease progression in AD models. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Dr Manuel Schiff and Dr Clément Pontoizeau join us for the first JIMD Podcast on Maple Syrup Urine Disease, hi-lighting their recent successes treating a Bckdhb knock-out mouse model using gene therapy. Successful treatment of severe MSUD in Bckdhb−/− mice with neonatal AAV gene therapy Clément Pontoizeau, et al https://doi.org/10.1002/jimd.12604

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.05.05.539444v1?rss=1 Authors: Dominov, J. A., Madigan, L. A., Whitt, J. P., Rademacher, K. L., Webster, K. M., Zhang, H., Banno, H. A., Tang, S., Zhang, Y., Wightman, N., Shychuck, E. M., Page, J., Weiss, A., Kelly, K., Kucukural, A. A., Brodsky, M. H., Jaworski, A., Fallon, J. R., Lipscombe, D., Brown, R. H. Abstract: Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder affecting brain and spinal cord motor neurons. Mutations in the copper/zinc superoxide dismutase gene (SOD1) are associated with ~20% of inherited and 1-2% of sporadic ALS cases. Much has been learned from mice expressing transgenic copies of mutant SOD1, which typically involve high-level transgene expression, thereby differing from ALS patients expressing one mutant gene copy. To generate a model that more closely represents patient gene expression, we created a knock-in point mutation (G85R, a human ALS-causing mutation) in the endogenous mouse Sod1 gene, leading to mutant SOD1G85R protein expression. Heterozygous Sod1G85R mutant mice resemble wild type, whereas homozygous mutants have reduced body weight and lifespan, a mild neurodegenerative phenotype, and express very low mutant SOD1 protein levels with no detectable SOD1 activity. Homozygous mutants exhibit partial neuromuscular junction denervation at 3-4 months of age. Spinal cord motor neuron transcriptome analyses of homozygous Sod1G85R mice revealed up-regulation of cholesterol synthesis pathway genes compared to wild type. Transcriptome and phenotypic features of these mice are similar to Sod1 knock-out mice, suggesting the Sod1G85R phenotype is largely driven by loss of SOD1 function. By contrast, cholesterol synthesis genes are down-regulated in severely affected human TgSOD1G93A transgenic mice at 4 months. Our analyses implicate dysregulation of cholesterol or related lipid pathway genes in ALS pathogenesis. The Sod1G85R knock-in mouse is a useful ALS model to examine the importance of SOD1 activity in control of cholesterol homeostasis and motor neuron survival. 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/2023.05.03.539260v1?rss=1 Authors: Irwin, A. B., Martina, V., Sint Jago, S. C., Bahabry, R., Schreiber, A. M., Lubin, F. D. Abstract: Dysregulation of long non-coding RNAs (lncRNAs) have been associated with Alzheimer's disease (AD). However, the functional role of lncRNAs in AD remains unclear. Here, we report a crucial role for the lncRNA Neat1 in astrocyte dysfunction and memory deficits associated with AD. Transcriptomics analysis show abnormally high expression levels of NEAT1 in the brains of AD patients relative to aged-matched healthy controls, with the most significantly elevated levels in glial cells. In a human transgenic APP-J20 (J20) mouse model of AD, RNA-fluorescent in situ hybridization characterization of Neat1 expression in hippocampal astrocyte versus non-astrocyte cell populations revealed a significant increase in Neat1 expression in astrocytes of male, but not female, mice. This corresponded with increased seizure susceptibility in J20 male mice. Interestingly, Neat1 deficiency in the dCA1 in J20 male mice did not alter seizure threshold. Mechanistically, Neat1 deficiency in the dorsal area CA1 of the hippocampus (dCA1) J20 male mice significantly improved hippocampus-dependent memory. Neat1 deficiency also remarkably reduced astrocyte reactivity markers suggesting that Neat1 overexpression is associated with astrocyte dysfunction induced by hAPP/A{beta} in the J20 mice. Together, these findings indicate that abnormal Neat1 overexpression may contribute to memory deficits in the J20 AD model not through altered neuronal activity, but through astrocyte dysfunction. 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/2023.05.01.538924v1?rss=1 Authors: Braz, S. O., Morgado, M. M., Pereira, M. I., Monteiro, A. C., Jarpe, M., Brites, P., Sousa, M. M., Nogueira-Rodrigues, J. 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/2023.04.28.538324v1?rss=1 Authors: Chiem, E., Zhao, K., Stark, G., Ghiani, C. A., Colwell, C. S., Paul, K. N. Abstract: Sleep and circadian rhythm disturbances are common features of Huntington's disease (HD). HD is an autosomal dominant neurodegenerative disorder that affects men and women in equal numbers. Epidemiological studies as well as preclinical work indicate that there may be sex differences in disease progression. Since sex differences in HD could provide important insights to understand cellular and molecular mechanisms, we used the bacterial artificial chromosome transgenic mouse model of HD (BACHD) to examine whether sex differences in circadian behavioral rhythms are detectable in an animal model of the disease. Electroencephalography (EEG) was used to measure sleep/wake states and EEG patterns in young adult (3 month-old) male and female wild-type and BACHD mice. Our findings show that male, but not female, BACHD mice exhibited increased variation in phases of the rhythms as compared to age and sex matched wild-types. For both REM and NREM sleep, genotypic and sex differences were detected. In particular, For NREM sleep, the BACHD males slept less and exhibited a more fragmented sleep than the other groups. Both male and female BACHD mice exhibited significant changes in delta but not in gamma power compared to wild-type mice. Finally, in response to a 6-hrs sleep deprivation, both genotypes and sexes displayed appropriate homeostatic responses. These findings suggest that females are relatively protected early in disease progression in this HD mode. 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/2023.04.28.538536v1?rss=1 Authors: Tejchman-Skrzyszewska, A., Strzelec, M., Kot, M., Chlebanowska, P., Badyra, B., Sobocinska, M., Zecca, L., Majka, M. Abstract: Parkinson's disease (PD) is a neurodegenerative disease that is an increasing threat to an aging society. The idiopathic form of PD accounts for over 90% of all cases, and the current etiology is still unknown. One of the reasons hindering research on this form of PD is the lack of an appropriate animal models. Among mouse models of the disease, those based on the administration of neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 6-hydroxydopamine (6-OHDA) to the substantia nigra pars compacta (SNpc) or striatum are predominantly used. In these models, there are metabolic disturbances causing oxidative stress in the SNpc or striatum, which ultimately leads to the death of dopaminergic neurons. However, the models used so far have serious limitations, most of all they do not fully reflect the processes occurring in the course of the disease and do not consider the involvement of inflammation in the etiology and pathogenesis of PD. In this study we show that the administration of synthetic neuromelanin, which activates astrocytes and microglia, induces the inflammation and may be involved in degeneration of dopaminergic neurons. Neuromelanin under physiological conditions acts as a neuroprotector, however, released from dying dopaminergic neurons is an important factor activating astrocytes, microglia and causing neuroinflammation. Since one of the causes of Parkinson's appear to be the death of dopaminergic neurons overloaded with neuromelanin and consequent pathological activation of microglia, the use of synthetic neuromelanin reflect the natural pathological processes occurring during the development of the disease. 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/2023.04.26.538461v1?rss=1 Authors: Akbarian, S., Min, A. K., Chen, B. K., Swartz, T. H., de Witte, L., Marro, S., Doanman, D., Durens, M., St. Vil, S., Masih, Z., Graziani, M., Javidfar, B., Missall, R., Mordelt, A. Abstract: The central nervous system (CNS) is a major human immunodeficiency virus type 1 reservoir. Microglia are the primary target cell of HIV-1 infection in the CNS. Current models have not allowed the precise molecular pathways of acute and chronic CNS microglial infection to be tested with in vivo genetic methods. Here, we describe a novel humanized mouse model utilizing human-induced pluripotent stem cell-derived microglia to xenograft into murine hosts. These mice are additionally engrafted with human peripheral blood mononuclear cells that served as a medium to establish a peripheral infection that then spread to the CNS microglia xenograft, modeling a trans blood brain barrier route of acute CNS HIV-1 infection with human target cells. The approach is compatible with iPSC genetic engineering, including inserting targeted transgenic reporter cassettes to track the xenografted human cells, enabling the testing of novel treatment and viral tracking strategies in a comparatively simple and cost-effective way vivo model for neuroHIV. 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/2023.04.24.538123v1?rss=1 Authors: Hooshmandi, M., Sharma, V., Perez, C. T., Sood, R., Simbriger, K., Wong, C., Lister, K. C., Guzman, A. U., Bartley, T. D., Rocha, C., Maussion, G., Nadler, E., Roque, P. M., Gantois, I., Popic, J., Levesque, M., Kaufman, R. J., Avoli, M., Sanz, E., Nader, K., Hagerman, R. J., Durcan, T. M., Costa-Mattioli, M., Lacaille, J.-C., Martinez-Cerdeno, V., Gibson, J. R., Huber, K., Sonenberg, N., Gkogkas, C. G., Khoutorsky, A. Abstract: Dysregulation of protein synthesis is one of the key mechanisms underlying autism spectrum disorder (ASD). However, the role of a major pathway controlling protein synthesis, the integrated stress response (ISR), in ASD remains poorly understood. Here, we demonstrate that the main arm of the ISR, eIF2 phosphorylation (p-eIF2), is suppressed in excitatory but not inhibitory neurons in a mouse model of fragile X syndrome (FXS; Fmr1-/y). We further show that the decrease in p-eIF2 is mediated via activation of the mTORC1. Genetic reduction of p-eIF2 only in excitatory neurons is sufficient to increase general protein synthesis and cause autism-like behavior. In Fmr1-/y mice, genetic restoration of p-eIF2 solely in excitatory neurons reverses elevated protein synthesis and rescues autism-related phenotypes. Thus, we reveal a previously unknown causal relationship between excitatory neuron-specific translational control via the ISR pathway, general protein synthesis and core phenotypes reminiscent of autism in a mouse model of FXS. 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/2023.04.20.537660v1?rss=1 Authors: Kotah, J. M., Kater, M. S. J., Hoeijmakers, L., Brosens, N., Lesuis, S., Tandari, R., Marchetto, L., Yusaf, E., Smit, A., Lucassen, P., Krugers, H., Verheijen, M., Korosi, A. Abstract: Epidemiological evidence indicates that early life stress (ES) exposure increases the risk for later-life diseases, such as Alzheimer's disease (AD). Accordingly, we and others have shown that ES aggravates the development of, and response to, amyloid-beta (A{beta}) pathology in animal models. Moreover, ES-exposed transgenic APP/PS1 mice display deficits in both cognitive flexibility and synaptic function. As the mechanisms behind these changes were unclear, we here investigated how exposure to ES, using the limited nesting and bedding model, affects the synaptic proteome across 2 different ages in both wildtype and APP/PS1 transgenic mice. We found that, compared to wildtype mice, the hippocampal synaptosomes of APP/PS1 mice at an early pathological stage (4 months) showed a higher abundance of mitochondrial proteins and lower levels of proteins involved in actin dynamics. Interestingly, ES exposure in wildtype mice had similar effects on the level of mitochondrial and actin-related synaptosomal proteins at this age, whereas ES exposure had no additional effect on the synaptosomal proteome of early-stage APP/PS1 mice. Accordingly, ultrastructural analysis of the synapse using electron microscopy in a follow-up cohort showed fewer mitochondria in pre- and post-synaptic compartments of APP/PS1 and ES-exposed mice, respectively. At a later pathological stage (10 months), the hippocampal synaptic proteome of APP/PS1 mice revealed an upregulation of proteins related to A{beta} processing, that was accompanied by a downregulation of proteins related to postsynaptic receptor endocytosis. ES exposure no longer affected the synaptic proteome of wildtype animals by this age, whereas it affected the expression of astrocytic proteins involved in lipid metabolism in APP/PS1 mice. We confirmed a dysregulation of astrocyte protein expression in a separate cohort of 12-month-old mice, by immunostaining for the alpha subunit of the mitochondrial trifunctional protein and fatty acid synthase in astrocytes. In conclusion, our data suggest that ES and amyloidosis share pathogenic pathways involving synaptic mitochondrial dysfunction and astrocytic lipid metabolism. These pathways might be underlying contributors to the long-term aggravation of the APP/PS1 phenotype by ES, as well as to the ES-associated risk for AD progression. These data are publicly accessible online as a web app via https://amsterdamstudygroup.shinyapps.io/ES_Synaptosome_Proteomics_Visualizer/. 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/2023.04.20.537697v1?rss=1 Authors: Richardson, M. E. S., Browne, C.-A., Huerta Mazariegos, C. I. Abstract: Arrhythmia is considered the most disrupted state of the biological circadian clock, and usually occurs when circadian regulatory genes are rendered non-functional, or the master clock (Suprachiasmatic Nucleus) is ablated. Since clock gene expression is aligned by the external solar day-night cycle to exhibit a 24-hour rhythm, we hypothesized that ill-timed light and dark exposure could negatively impact endogenous circadian clock function in mice. In this study, we present an environmentally driven approach to induce arrhythmia in mice that is also reversible. Using the previously characterized fragmented day-night cycle (FDN) where the 8-hour night is split into four 2-hour fragments and equally distributed across the 24-hour day, we show that mice gradually exposed to the FDN for 1 month lose their circadian rhythmicity. Furthermore, subsequent exposure to constant light or constant-dark conditions does not yield typical circadian rhythms, but instead, reveals circadian arrhythmia. Finally, we show that the arrhythmic locomotion phenotype is reversible with one week of reintroduction to a 12 hr day-12 hr night cycle. This is the first study to show how the light-dark environment induces arrhythmia of an intact circadian clock and how it can be reversed. 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/2023.04.17.537272v1?rss=1 Authors: Spicer, M. M., Yang, J., Fu, D. A., DeVore, A. N., Lauffer, M., Sayar-Atasoy, N., Atasoy, D. M., Fisher, R. A. Abstract: Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer's disease (AD). Adult hippocampal neurogenesis (AHN) is reduced in AD patients. Exercise stimulates AHN in rodents and improves memory and slows cognitive decline in AD patients. However, the molecular pathways for exercise-induced AHN and improved cognition in AD are poorly understood. Here, we show that voluntary running in APPSWE mice restores their hippocampal cognitive impairments to that of control mice. This cognitive rescue was abolished by RSG6 deletion in dentate gyrus (DG) neuronal progenitors (NPs), which also abolished running-mediated increases in AHN. AHN was reduced in sedentary APPSWE mice versus control mice, with basal AHN reduced by RGS6 deletion in DG NPs. RGS6 expression is significantly lower in the DG of AD patients. Thus, RGS6 mediates exercise-induced rescue of impaired cognition and AHN in AD mice, identifying RGS6 in DG NPs as a potential target to combat hippocampal neuron loss in AD. 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/2023.04.17.536004v1?rss=1 Authors: Root, J., Mendsaikhan, A., Nandy, S., Taylor, G., Wang, M., Troiano Araujo, L., Merino, P., Ryu, D., Holler, C., Thompson, B. M., Astarita, G., Blain, J.-F., Kukar, T. Abstract: Progranulin (PGRN) deficiency is linked to neurodegenerative diseases including frontotemporal dementia, Alzheimers disease, Parkinsons disease, and neuronal ceroid lipofuscinosis. Proper PGRN levels are critical to maintain brain health and neuronal survival, however the function of PGRN is not well understood. PGRN is composed of 7.5 tandem repeat domains, called granulins, and is proteolytically processed into individual granulins inside the lysosome. The neuroprotective effects of full-length PGRN are well-documented, but the role of granulins is still unclear. Here we report, for the first time, that expression of single granulins is sufficient to rescue the full spectrum of disease pathology in mice with complete PGRN deficiency (Grn-/-). Specifically, rAAV delivery of either human granulin-2 or granulin-4 to Grn-/- mouse brain ameliorates lysosome dysfunction, lipid dysregulation, microgliosis, and lipofuscinosis similar to full-length PGRN. These findings support the idea that individual granulins are the functional units of PGRN, likely mediate neuroprotection within the lysosome, and highlight their importance for developing therapeutics to treat FTD-GRN and other neurodegenerative diseases. 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/2023.04.17.537139v1?rss=1 Authors: Rusu, B., Kukreja, B., Wu, T., Dan, S. J., Feng, M. Y., Kalish, B. T. Abstract: Down Syndrome (DS), the most common genetic cause of intellectual disability, is associated with lifelong cognitive disability. However, the mechanisms by which triplication of human chromosome 21 genes drive neuroinflammation and cognitive dysfunction are poorly understood. Here, using the Ts65Dn mouse model of DS, we performed an integrated single-nucleus RNA- and ATAC-seq analysis of the cortex. We identify cell type-specific transcriptional and chromatin-associated changes in the Ts65Dn cortex, including regulators of neuroinflammation, transcription and translation, myelination, and mitochondrial function. We discover enrichment of a senescence-associated transcriptional signature in Ts65Dn oligodendrocyte precursor cells (OPCs) and epigenetic changes consistent with a loss of heterochromatin. We find that senescence is restricted to a subset of cortical OPCs concentrated in deep cortical layers. Treatment of Ts65Dn mice with a senescence-reducing flavonoid rescues cortical OPC proliferation, restores microglial homeostasis, and improves contextual fear memory. Together, these findings suggest that cortical OPC senescence may be an important driver of neuropathology in DS. 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/2023.04.14.536870v1?rss=1 Authors: Bonnycastle, K., Dobson, K. L., Blumrich, E.-M., Gajbhiye, A., Davenport, E. C., Pronot, M., Steinruecke, M., Trost, M., Gonzalez-Sulser, A., Cousin, M. A. Abstract: Pathogenic heterozygous missense mutations in the DNM1 gene result in a novel form of epileptic encephalopathy. DNM1 encodes for the large GTPase dynamin-1, an enzyme with an obligatory role in the endocytosis of synaptic vesicles (SVs) at mammalian nerve terminals. Pathogenic DNM1 mutations cluster within regions required for its essential GTPase activity, implicating disruption of this enzyme activity as being central to epileptic encephalopathy. We reveal that the most prevalent pathogenic mutation of DNM1, R237W, disrupts dynamin-1 enzyme activity and SV endocytosis when overexpressed in central neurons. To determine how this dominant-negative heterozygous mutant impacted cell, circuit and behaviour when expressed from its endogenous locus, we generated a mouse carrying the R237W mutation. Neurons isolated from heterozygous mice displayed dysfunctional SV endocytosis, which translated into altered excitatory neurotransmission and seizure-like phenotypes. Importantly, these phenotypes were corrected at the cell, circuit and in vivo level by the drug, BMS-204352, which accelerates SV endocytosis. This study therefore provides the first direct link between dysfunctional SV endocytosis and epilepsy, and importantly reveals that SV endocytosis is a viable therapeutic route for monogenic intractable epilepsies. 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/2023.04.10.536251v1?rss=1 Authors: Kuruppath, P., Xue, L., Pouille, F., Jones, S. T., Schoppa, N. Abstract: Fragile X syndrome (FXS) is the single most common monogenetic cause of autism spectrum disorders in humans. FXS is caused by loss of expression of the Fragile X mental retardation protein (FMRP), an mRNA-binding protein encoded on the X chromosome involved in suppressing protein translation. Sensory processing deficits have been a major focus of studies of FXS in both humans and rodent models of FXS, but olfactory deficits remain poorly understood. Here we conducted experiments in wild-type and Fmr1 KO (Fmr1-/y) mice (males) that lack expression of the gene encoding FMRP to assess olfactory circuit and behavioral abnormalities. In patch-clamp recordings conducted in slices of the olfactory bulb, output mitral cells (MCs) in Fmr1 KO mice displayed greatly enhanced excitation, as evidenced by a much higher rate of occurrence of spontaneous network-level events known as long-lasting depolarizations (LLDs). The higher probability of LLDs did not appear to reflect changes in inhibitory connections onto MCs but rather enhanced spontaneous excitation of external tufted cells (eTCs) that provide feedforward excitation onto MCs within glomeruli. In addition, in a go/no-go operant discrimination paradigm, we found that Fmr1 KO mice displayed impaired discrimination of odors in difficult tasks that involved odor mixtures but not altered discrimination of monomolecular odors. We suggest that the higher excitability of MCs in Fmr1 KO mice may impair fine odor discrimination by broadening odor tuning curves of MCs and/or altering synchronized oscillations through changes in transient inhibition. 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/2023.04.09.536152v1?rss=1 Authors: Rhymes, E. R., Simkin, R. L., Surana, S. N., Tong, Y., Villarroel-Campos, D., Yang, X.-L., Schiavo, G., Sleigh, J. N. Abstract: Charcot-Marie-Tooth disease (CMT) is a form of genetic peripheral neuropathy caused by mutations in many functionally diverse genes. The aminoacyl-tRNA synthetase (ARS) enzymes, which charge amino acids to partner tRNAs for protein synthesis, represent the largest protein family linked to CMT aetiology, suggestive of pathomechanistic commonalities. Dominant intermediate CMT type C (DI-CMTC) is caused by YARS1 mutations driving a toxic gain-of-function in the encoded tyrosyl-tRNA synthetase (TyrRS), which is mediated by exposure of consensus neomorphic surfaces through conformational changes of the mutant protein. In this study, we first showed that DI-CMTC-causing TyrRSE196K mis-interacts with the extracellular domain of the BDNF receptor TrkB, an aberrant association we have previously characterised for CMT type 2D (CMT2D)-causing mutant glycyl-tRNA synthetase. We then performed temporal neuromuscular assessments of recently generated YarsE196K mice modelling DI-CMT. Through in vivo imaging of exposed sciatic nerves, we determined that YarsE196K homozygotes display a selective, age-dependent impairment in axonal transport of neurotrophin-containing signalling endosomes, phenocopying CMT2D mice. Increasing BDNF in DI-CMTC mouse muscle, through injection of recombinant protein or muscle-specific gene therapy, resulted in complete axonal transport correction. Therefore, this work identifies a pathomechanism common to neuropathies caused by mutations in YARS1 and GARS1, and highlights the potential of boosting BDNF in muscles as a therapeutic strategy to treat ARS-related CMTs. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

This week, please join author Vincent Aengevaeren and Associate Editor Jarett Berry as they discuss the article "Exercise Volume Versus Intensity and the Progression of Coronary Atherosclerosis in Middle-Aged and Older Athletes: Findings From the MARC-2 Study." Dr. Gregory Hundley: Welcome listeners to this March 28th issue, and I am one of your co-hosts, Dr. Gregory Hundley, Associate Editor and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Peder Myhre: And I'm Dr. Peder Myhre, Social Media Editor from Akershus University Hospital and University of Oslo in Norway. And today, Greg, we have such an interesting feature paper. It comes to us from Professor Aengevaeren and it discusses the progression of coronary atherosclerosis in middle-aged and older athletes. They're looking at exercise volume versus intensity in the MARC-2 study. So Greg, this is really something us master athletes are interested in, and I'm really excited to hear this discussion. Dr. Gregory Hundley: Very nice. Well, how about we jump into some of the other articles first, Peder? And I could go first. So Peder, my first article involves pregnancy related complications. And as you know, these pregnancy complications are associated with increased risk of developing cardiometabolic diseases and an earlier mortality. However, much of the prior research has been limited to individuals of White race. So these investigators led by Professor Cuilin Zhang from the National Institutes of Health aimed to investigate pregnancy complications in association with total and cause specific mortality in a racially diverse cohort, and then evaluate whether associations differ between Black and White individuals. And they performed their work using the Collaborative Perinatal Project, which was a prospective cohort study of 48,197 pregnant women across 12 US clinical centers from the period of time of 1959 through 1966. Dr. Peder Myhre: Oh wow, Greg. Almost 50,000 pregnant women. Very huge initiative. So what did they find? Dr. Gregory Hundley: Right, Peder. So overall, 15% of participants had preterm delivery, 5% had hypertensive disorders of pregnancy, and 1% had gestational diabetes or impaired fasting glucose. Now, the preterm delivery was higher in individuals of Black race at 20% relative to those of White race, which were 10%. Now, in relation to all-cause mortality, the following were associated with increase adjusted hazard ratios. One, spontaneous labor; two, induced labor; three, pre-labor cesarean delivery. And all of those, those adjusted hazard ratios in comparison with a full term delivery. Next, in the world of blood pressure, preeclampsia and eclampsia as well as superimposed preeclampsia and eclampsia were all associated with adjusted hazard ratios that were elevated compared to individuals with normal blood pressure. And then finally, in those individuals with gestational diabetes or impaired fasting glucose, their adjusted hazard ratio, again for all-cause mortality, was elevated relative to those with normal glycemia. Now interestingly, in comparing the two racial groups, preterm induced labor was associated with greater mortality risk among those of Black race relative to those of White race. However, or while, preterm pre-labor cesarean delivery interestingly and conversely was associated with a higher adjusted hazard ratio for those of White race as compared to individuals of Black race. So Peder, in summary, within this large diverse US cohort, pregnancy complications were associated with higher mortality almost 50 years later. And the higher incidents of some complications occurred in individuals of Black race. And differential associations with mortality risk indicate that because of these racial differences, there could really be disparities in pregnancy related health. And finally, that these disparities and their relationship with overall health really could have long life implications for earlier mortality in these patients. Dr. Peder Myhre: Well, that is really interesting, Greg. Are you ready for the next paper? Dr. Gregory Hundley: Absolutely. Dr. Peder Myhre: So this paper is about the glucagon-like peptide-1 receptor agonist and large CV outcome trials clearly show that several GLP-1 agonists reduce CV outcomes in patients with Type 2 diabetes. Whether their cardioprotective effects are related to drug dose or potency remains uncertain however, but important due to recent introduction of high dose and high potency agents for diabetes and for weight loss indications. And therefore, Greg, in this paper, the investigators from the AMPLITUDE-O trial led by corresponding author Hertzel Gerstein from McMaster University Hamilton Health Sciences analyzed the effect of the different doses of the GLP-1 agonist efpeglenatide that is four milligram, six milligram compared to placebo. And the effect was assessed on major adverse cardiovascular events. Dr. Gregory Hundley: Interesting, Peder. So what did they find? Dr. Peder Myhre: So Greg, during a median follow-up of 1.8 years, MACE occurred in 9.2 participants assigned to placebo, 7.7 in participants assigned to efpeglenatide four milligrams, and 6.2% in participants assigned to efpeglenatide six milligrams. And participants receiving high dose of this GLP-1 agonist also experienced fewer secondary outcomes, including the composite of MACE coronary revascularizations or hospitalizations for unstable angina, a kidney composite outcome comprising sustained new microalbuminuria, decline in eGFR more than 40%, or renal failure. And there was also a clear dose response relationship noted for all primary and secondary outcomes with a P4 trend that was significant. So Greg, the authors conclude that the graded relationship between efpeglenatide dose and CV outcomes suggests that titrating this drug and potentially other GLP-1 agonists to high doses may maximize their cardiovascular and kidney benefits. Dr. Gregory Hundley: Very nice, Peder. Well, my next paper comes to us and involves the world of bleeding associated with Factor Xa inhibitors. So Peder, andexanet alfa is a modified recombinant inactive Factor Xa designed to reverse Factor Xa inhibitors. ANNEXA-4 is a multicenter prospective phase 3B single group cohort study that evaluated andexanet alfa in patients with acute major bleeding. And the study is led by Dr. Truman Milling of Seton Dell Medical School Stroke Institute and colleagues, and they present the results of their final analyses. Dr. Peder Myhre: Oh, this is really interesting, Greg. So what did they find? Dr. Gregory Hundley: Right, Peder. So first, 479 patients were enrolled. And their average age was 78 years. 54% were men, 86% were White. 81% of the individuals enrolled were anticoagulated for atrial fibrillation. And they had received this drug 11 hours median time since the last dose. 51% of the individuals were on a apixaban, 37% were on rivaroxaban, and 8% were on edoxaban, and then finally 5% were on enoxaparin. Now bleeding, Peder, was predominantly intracranial in 69%, it was GI in 23%. In evaluable apixaban patients, median anti Factor Xa activity decreased from 146.9 to 10 nanograms per milliliter. That's a 93% reduction. In rivaroxaban patients, it decreased from 214 to 10.8 nanograms per milliliter. That's a 94% reduction. In edoxaban patients, it decreased from 121 to 24 nanograms per milliliter; a 71% reduction. And in enoxaparin, it decreased from 0.48 to 0.11 international units per milliliter or a 75% reduction. So Peder, excellent or good hemostasis occurred in 274 of the 342 evaluable patients. So in 80%. In the safety population, thrombotic events occurred in about 10% of patients. And in 16 patients, this occurred during treatment with prophylactic anticoagulation that began after the bleeding event. So no thrombotic episodes occurred after oral anticoagulation restart. So Peder, in conclusion, in patients with major bleeding associated with the use of Factor Xa inhibitors, treatment with enoxaparin and andexanet alfa reduced anti Factor Xa activity and was associated with good or excellent hemostatic efficacy in 80% of patients. Dr. Peder Myhre: Oh wow. That was really impressive. Dr. Gregory Hundley: Yeah, what a very practical study. Well, Peder, we have some other articles in the issue. How about I go first? So first, there's a Research Letter from Professor Eleanor entitled “A Mouse Model of Atrial Fibrillation in Sepsis.” And then from Tracy Hampton we have some Cardiology News. First from Professor Shane et al, a paper on the impact of coffee subtypes on incident cardiovascular disease, arrhythmias, and mortality, long-term outcomes from the UK Biobank study, which is published in the European Journal of Preventive Cardiology. Next from Professor Morashige, there is a paper entitled “Extra Cardiac BCAA Metabolism Lowers Blood Pressure and Protects From Heart Failure.” And that's published in Cell Metabolism. And then finally from Professor Kessler and associates, the paper is entitled “Common and Rare Variant Associations with Colonial Haematopoiesis Phenotypes.” And that particular paper is published in Nature. Dr. Peder Myhre: That's great, Greg. And we also have an exchange of letters by Dr. Ding and Dr. Kirshenbaum regarding the article “Proteasomal Degradation of TRAF2 Mediates Mitochondrial Dysfunction in Doxorubicin-Cardiomyopathy.” And finally we have On My Mind by Bertram Pitt entitled “Early Implementation of aldosterone Targeted Therapy in Patients with Hypertension.” Now Greg, let's go to the feature paper to discuss the progression of coronary atherosclerosis in middle-aged and older athletes. Dr. Gregory Hundley: Very good. Let's go. Welcome listeners to this feature discussion on March 28th. And we have with us today Dr. Vincent Aengevaeren from Radboud University Medical Center in Nijmegen in the Netherlands. And also with us one of our associated editors, Dr. Jarett Berry from University of Texas Southwestern Medical Center in Dallas, Texas. Welcome gentlemen. Well, Vince, we'll start with you. Can you describe for us some of the background information that went into the preparation of your study and what was the hypothesis that you wanted to address? Dr. Vincent Aengevaeren: So this specific study is actually a follow-up study of a previous study that we did on the relationship between exercise and coronary atherosclerosis. The original study was published also in circulation in 2017 and it really looked at the association of relationship between exercise volume, lifelong exercise volume and coronary atherosclerosis. And at that time we found that there was actually a sort of paradoxical association between lifelong exercise volume and coronary atherosclerosis that with higher lifelong exercise volumes, there was a dose upon dependent association with the prevalence of coronary atherosclerosis. And there was actually in the same issue, there was another paper in 2017 from a London group shown similar findings. And actually, yesterday on the ACC, there was another paper also showing increased coronary atherosclerosis in athletes. And this study of course there was also some critic like is this caused by confounding, these were observational perceptional studies, could there be other factors playing, but also none of the studies looked at the differentiation between exercise volume and exercise intensity. So the composition of the exercise. So that was the main question actually for this study. We want to do a follow-up study after at least five years do another CT scan, again, get everyone back the questionnaire, exercise habits, and then also specifically look at exercise volume versus exercise and density. Dr. Gregory Hundley: Very nice. So it sounds like in this study you have a cohort that you're following over time. So maybe describe for us a little bit more the specific study design and who is included. Who is your study population here? Dr. Vincent Aengevaeren: The study population is called the MARC study, Measuring Athletes Risk of Cardiac events. And the study was originally designed mainly based on the fact that healthy athletes, mainly male athletes, sometimes suddenly die of coronary atherosclerosis, which is not really recognized beforehand. So the main study idea was to look at healthy male athletes who didn't experience any symptoms and who underwent the screening, including an exercise test with EKG with normal findings and who then subsequently underwent a coronary CT scan. So blank CT scan for corona calcification score, but also contrast enhanced CT scan to look at the degree of coronary atherosclerosis to those of [inaudible 00:15:18] characteristics. So that's how the original study was designed and it included 318 male individuals over the age of 45 with a very heterogeneous exercise exposure. So they all had to do some type of sports, but there was no minimal dose. So it really depended. So we have some very high level athletes, but also some more of the regular people who exercise a lot less. So very heterogeneous exposure. And for this study, so in the follow-up study, we actually included 291 of those 318 individuals after six years, which I was pretty happy with. And for this specific analysis we excluded two individuals due to their PCI in between. So that's pretty much the cohort that we're looking at. And during this follow-up period of six years, they did the equivalent of about 40 MET hours per week, which equates to about five hours of the exercise. Dr. Gregory Hundley: Very nice. And Vince, you said you had a very diverse group. I mean, a lot of times I'll think about the extremes here. Folks that do a lot of aerobic exercise, those that I think about the power weightlifter. What kind of distribution of athlete, maybe just some practical identifiers for our listeners here. Dr. Vincent Aengevaeren: So it's a very important point. So the main type of athletes in this group who are endurance athletes, so mainly runners and cyclists. Of course also some other type athletes and some athletes do multiple type of sports, but mainly runners and cyclists and definitely large proportion of [inaudible 00:16:53] athletes. Dr. Gregory Hundley: Very nice. So Vince, describe for us your study results. Dr. Vincent Aengevaeren: During this follow-up period, and it's important to state that for this follow-up study we used the exercise characteristics during the follow-up period, we found that exercise volume during follow-up was not associated with progression of coronary atherosclerosis, but exercise intensity was. So we defined exercise intensity based on the MET score, the metabolic equipment of task score, which is derived from previous studies. And there's a compendium explaining MET scores for all the different sports and we used that to categorize the different sports. And we've found that vigorous intensity exercise, for example cycling, was associated with less progression of coronary calcification, but very vigorous intensity exercise, for example running was associated with more progression or coronary calcification. And if you then also look at plaque types, we also saw that those who did the most very vigorous exercise also had a bit more calcified plaque progression. So that was the main findings. Dr. Gregory Hundley: And Vince, describe for our listeners, many whom are cardiologists or others fellows, et cetera. Can you give me a specific example of vigorous exercise versus very vigorous exercise? Like, if I'm doing something during the week, describe for me those two categories, examples. Dr. Vincent Aengevaeren: So typically, and of course this is a very typical vigorous exercise was cycling and very vigorous exercise was running. But of course as you do cycling at a higher intensity, for example spinning on a spinning bike, it's traditionally at a higher exercise intensity. So that was counted as a very vigorous intensity exercise. And I have to say this was based on questionnaire data, so I did not have six-year or lifelong heart rate data. So it is based on questionnaire data, the categorization of exercise intensity. That's a good example. Other things of [inaudible 00:19:03] intensives, for example, soccer, hockey, I don't know how popular those sports are in America, but those are pretty popular in Netherlands as well. Dr. Gregory Hundley: When you mean very vigorous for some of our runners out there, I mean for the casual runner that might run two or three miles a day, is that very vigorous or are you talking about someone that's training periodically for marathons and running three or four marathons a year? Dr. Vincent Aengevaeren: That is really more, I guess, about volume. So if people do a lot of marathons, that can actually be at a lower intensity. Like, with intensity, we really, really mean the heart rate intensity and not the intensity of the volume. So I have to specify that. It's really exercise intensity such as for oxygen consumption or heart rate and not the volume in the hours per week. So typically the runners that we had were mostly very vigorous runners. So couple hours per week traditionally they did like trainings of one and a half hour, which is usually at a higher intensity. Dr. Gregory Hundley: Very nice. Well listeners, now we're going to turn to one of our associate editors, Dr. Jarett Berry, who really has some expertise in this area. And Jarett, you see many papers in circulation. What do you find is unique about this particular study and then how do you put its results really in the context of other studies that have focused on exercise both in duration as well as intensity? Dr. Jarett Berry: Yeah, thanks Greg. And Vince, a fantastic paper, such a privilege to be able to visit with both of you today about this important paper. I think if you take a step back here, challenges I think we all have as physicians is dealing with these uncertain questions that arise clinically where you encounter patients who are exercising at these extreme levels. And although it's not super common, we do encounter these scenarios clinically. And what we need in context like this is we need some data and understanding of what's happening clinically to be able to provide guidance. And so we're really in a context like this in a scenario where we have the common clinical problem of incomplete information. And I think it's studies like this that really help us move the needle to help us understand how to think about those patients of ours that exercise at very high levels. I do think it's important to put it into context, about 10% of the participants in this study exercised below 1,000 minutes per week. And so for those of you taking notes at home, that's the guidelines in 500 and 1,000 minutes per week would be, I mean you'd be hitting the guidelines. And two-thirds of these individuals were exercising at 2,000 minutes per week. So I think it's important to put it into context when we think about applying and understanding the question about toxicity of exercise, putting that into context that most of the patients that we encounter are not exercising at these high levels. However, as I mentioned, we do encounter this and we have to know what to do with it. The key here I think is... The other context is with a point that's been raised already in some of the questions and discussion is the heterogeneity that we see in individuals who exercise at these high levels. When you're trying to think about dose of exercise, we have to think about not just intensity but volume. And I think what the study's done here has done a really nice job of trying to parse that out because we can achieve the dose of exercise that's recommended or the dose of exercise that we want to achieve for personal reasons, but we can get there through different ways. We can get there through more hours or we can get there through a higher intensity. And then of course, obviously combinations of the two. And I think this study here does two things for us. Number one, it gives us a delta question. We've seen this before with just looking cross-sectionally and we have all the challenges that come with that with regard to recall of exercise. Here we have a prospective cohort that we're following or that events followed. And secondly, the ability to parse out both volume and intensity over time. And I think that for me, the finding that really sticks out is that in addition to all the complexities that are right here, we see that the story with regard the components of the dose may not be uniform. That intensity or exercising at very high intensity may be a different part of the equation beyond just volume. And I think that as we think about counseling our patients as they are engaging in this type of high level of exercise, I think it's one additional component of our way of interpreting this and providing counsel to these patients about how to think about volume and intensity. And maybe these data suggests the hypothesis that the volume part of the dose equation may be safer or maybe something that's more palatable for the heart perhaps over time than the intensity. I think the big elephant in the room, of course, is the fundamental question is that we're dealing with an intermediate phenotype and we know lots of observational data showing that more atheros bad. We all recognize that, but you can get to athero through different mechanisms here. And I think that these data and others suggest that exercise is one mechanism perhaps that though you can get athero, the question is what is the true clinical significance from a [inaudible 00:24:32] standpoint down the road as we try to extrapolate the intermediate phenotype into the future. And I think there's controversy, I think agreement about what the intermediate phenotype means in these high volume exercisers. And I think that question remains unknown, I think. But in the interim, as I said in the beginning, that as we think about putting all this into context, we don't have perfect information and we do have to take the information that we do have to provide the counsel that we need to provide if these patients. And I think I take away from this that when providing counsel, maybe I lean more towards volume and less towards this really high volume, sorry, this really high intensity for those individuals whose coronary calcium or their athero burden is particularly high. But a fantastic study. Another step in the road and it's really trying to understand an incredibly complex story and one that will continue to unfold. Dr. Gregory Hundley: Very nice, Jarett. And listeners, we're going to turn back to both Vince and Jarett here each in 30 seconds. Vince, what do you see as the next study that your group or others might want to be considering in this sphere of research? Dr. Vincent Aengevaeren: For me personally, the next big thing that we should do is really cardiovascular risk. So what's the clinical relevance of this finding? So coronary calcification is strongly associated with cardiovascular risk, but how that is in these athletes in which we see increased coronary calcification, that's still pretty much the question. I mean, any plaque is worse than no plaque, but how is this for the very vigorous exercisers who may show some more calcification and whether that risk is different. I mean, that's the question that all the athletes that email me after this type of publication have the question. And also the mechanisms. Like, what are the underlying mechanisms? That's also a next lead study for me. Dr. Gregory Hundley: Very nice. And Jarett? Dr. Jarett Berry: Yeah, I think the ultimate question is, I completely agree, is what is the clinical significance. I think that's going to be... That's a challenging question to answer just because of the on average these individuals are more rare. And so following these individuals over time to really tease out the clinical significance of this type of athero in these athletes, I think, is a challenge. I think for me the next step would be more studies like this where we can get more granular with regard to measured exercise intensity. I think wearable devices, things that Vince alluded to with regard to heart rate, really trying to get more quantitative to try to parse out the contribution of more objectively measured exercise intensities, I think would probably, for me, represents kind of probably the next step, is digging a little deeper into the phenotype and being a little bit more precise perhaps with studies like this to help us begin to understand the significance of these findings. Dr. Gregory Hundley: Very nice. Well, listeners, we want to thank Dr. Vincent Aengevaeren from Radboud University Medical Center in Nijmegen in the Netherlands, and our own associated editor, Dr. Jarett Berry from University of Texas Southwestern Medical Center in Dallas, Texas for bringing us this study highlighting that exercise intensity but not volume was associated with progression of coronary atherosclerosis during a six-year follow-up of this cohort of really trained athletes and intriguingly the very vigorous. So we want to distinguish that. The very vigorous intensity exercise was associated with greater coronary artery calcium calcified plaque progression, whereas simply just vigorous intensity exercise, casual riding of the bike, casual running, et cetera, was associated with less coronary artery calcium progression. Well, on behalf of Peder and 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 2023. 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, please visit ahajournals.org.

References Dr. Guerra's lipid lectures JCI Insight. 2020 Sep 3;5(17):e138443 Proc Natl Acad Sci U S A. 1998 Mar 31; 95(7): 4061–4065. --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

Dr Suzanne Jackowski shares the fruits of a career looking at Co-enzyme A and the results of recent work looking at a promising molecule in a propionic acidemia mouse model. Relief of CoA sequestration and restoration of mitochondrial function in a mouse model of propionic acidemia Chitra Subramanian, et al https://doi.org/10.1002/jimd.12570

Today, we look to Casby Bartley on TikTok for some mind blowing proof of god!Sources:What is dirt made of? Soil particles, minerals, and chemical elements: https://tinyurl.com/2ozb2wyuWhat Chemical Elements are Found in the Human Body?: https://tinyurl.com/2quwloqnThe Most Abundant Elements In The Earth's Crust: https://tinyurl.com/ydcued9sSilicon And Bone Health: https://tinyurl.com/hpqxx6dNatural Large-Scale Regeneration of Rib Cartilage in a Mouse Model: https://tinyurl.com/2kvvf3qoWe can regenerate! Researchers reveal our ribs regrow if damaged - and say the same could be true for our entire skeleton: https://tinyurl.com/2q4k5rocThe Discovery of the Sin Cities of Sodom & Gomorrah: https://tinyurl.com/2ft9kau5Bab edh-Dhra: https://tinyurl.com/2qqgkmmzNumeira: https://tinyurl.com/2oeonkpkA Tunguska sized airburst destroyed Tall el-Hammam a Middle Bronze Age city in the Jordan Valley near the Dead Sea: https://tinyurl.com/4bf559ymEvaluation of the Crustal Features of the Gulf of Aqaba Deduced from Geophysical Data: https://tinyurl.com/2fezfqkaFake News In Biblical Archaeology: https://tinyurl.com/2qwyw9b7Letter from John Baumgardner Regarding the claims of Ron Wyatt: https://tinyurl.com/2qsoglq9Why not Jebel al-Lawz, then?: https://tinyurl.com/2o9fd6zyMount Sinai is NOT Jebel al-Lawz in Saudi Arabia: https://tinyurl.com/2nu2xn8xA supposed cast of Noah's ark in eastern Turkey: https://tinyurl.com/2opf6oz6Cephalopods Can Pass a Cognitive Test Designed For Human Children: https://tinyurl.com/2kdn6vubAnimal Morality: What It Means and Why It Matters: https://tinyurl.com/2jmuqxmvWhat does it mean that humanity is made in the image of God (imago dei)?: https://tinyurl.com/y6c9zmoaList of the Dead Sea Scrolls: https://tinyurl.com/2jnkpughOldest Known Rock on Earth Discovered: https://tinyurl.com/2eh4zxv28 Oldest Artifacts in the World: https://tinyurl.com/2g36mmopThe Holy Scriptures According To The Masoretic Text: https://tinyurl.com/yxfj8834Debunking "The Forbidden Chapter” Conspiracy: https://tinyurl.com/2mc8pywzIsaiah 53 from Scroll 1Q Isaiah: https://tinyurl.com/ybbwmqxrOriginal Video (Part 1 at least…TikTok isn't built to be easily navigated, they just want you to sit back and let the algorithm do the work for you): https://tinyurl.com/2qza5fzqCards:The BEST arguments for the flood!:https://www.youtube.com/watch?v=1wjTsW8ewdIAll my various links can be found here:http://links.vicedrhino.com

"Never mind manoeuvres, always go at them". Dr. Bob Bloch from the University of Maryland School of Medicine joins us to discuss his development of the human FSHD muscle xenograft mouse model that is a key tool in the pre-clinical testing pipeline for FSHD therapeutics and biomarker discovery. --- Send in a voice message: https://anchor.fm/peter-l-jones/message

Multiple Sclerosis News Today's multimedia associate, Price Wooldridge, discusses how an experimental multiple sclerosis vaccine, PAS002 by Pasithea Therapeutics, is designed to prevent autoimmune attacks against myelin. He also reads “Seeing Double, and I'm Not Even Drunk”, a column by John Connor. =================================== Are you interested in learning more about multiple sclerosis? If so, please visit: https://multiplesclerosisnewstoday.com/ ===================================== To join in on conversations regarding multiple sclerosis, please visit: https://multiplesclerosisnewstoday.com/forums/

Headlines: Sludge containing forever chemicals spread on Illinois farmland  New study shows that commonly used herbicide crosses blood-brain barrier References Mentioned: Alzheimer's drugs: Does reducing amyloid work? Dietary patterns and β-amyloid deposition in aging Australian women β-Amyloid accumulation in the human brain after one night of sleep deprivation Glucocorticoids Increase Amyloid-β and Tau Pathology in a Mouse Model of Alzheimer's Disease Potential Research Fabrication Joe Knows Turf: Pesties In the Kitchen Sink Sponsor: The Patrons Burns: North Dakota man dies after being pinned under a lawn mower  1 dead after lawn mower collides with car  Soil microbiome biomass, activity, composition and CO2 emissions in a long‐term organic and conventional farming systems  Deciphering the soil microbiome for optimized intercropping  Returns: NewsNation network lauds Rodney Smith's free lawn care - The Madison Record  Florida turf program celebrates centennial anniversary this year  NTEP rolls out new, user-friendly interface    Special Thanks to Our Co-Producers: 6r33k633k Benjamin Mossing Lonegoose Ch1v3Force1 Jesse Bousquet Jr Jbartleyw Outsidefire Barthoda Deadphishy Tifway Lawn NateKrez Harperexplores Tdougiefresh bwerthmann Mtech Miggity LCS Turf LTK Trucking & Freight Jbt200 Nreyes Tedaut RTFU Sumbeach Lush Lawns JLavoe 813King matix webcivilian bkf7884 JSmit Zach_H Kennard Squirt&Burn SchaneyTurf87 SlicknicK DynoSportDan MattMac1r

References Dr Guerra's Lecture notes Cell Chem Biol. 2020 May 21; 27(5): 538–550.e7 Circulation. 2020 Dec 15;142(24):2356-2370 --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

Money is back this week talking a tea to help calm your nerves, which was much needed after hearing that WNBA star (and lesbian heartthrob) and 2x Olympic Gold Medalist Brittney Griner has been detained in Russia for over 3 weeks. I talk my understandings of what's going on, what scares me about the timing of her detainment, and hopes for her safe return home (timestamp in the description for this discussion). Gloria Anzaldua is QueerWOC of the week this week and her words were a much needed and timely reminder of what we face as QWOC. #FreeBG #FreeBrittney #FreeBrittneyGriner Where to find us: IG & Twitter - @queerwocpod FB - https://www.facebook.com/QueerWOCpod/ Tumblr - www.QueerWOC.com Listen to us on Spotify, Soundcloud, Stitcher, Castbox, PocketCasts Contribute to QueerWOC via CashApp: $QueerWOCPod Become a Patron: https://www.patreon.com/queerwocpod Rate, Review, Request, Repost, Retweet, and Reply! Use the hashtag #QueerWOC to talk all things the podcast Send us an email or submit your Curved Chronicles: QueerWOCpod@gmail.com QueerWOC of the Week 00:05:13 Theorist, Writer and Chicana lesbian feminist Gloria E. Anzaldúa Her book Borderlands/La Frontera: The New Mestiza (1987) and her essay “La Prieta” are considered groundbreaking works in cultural, feminist, and queer theories. With Cherríe Moraga, Anzaldúa co-edited the landmark anthology This Bridge Called My Back: Writings by Radical Women of Color (1981). lit review episode here: https://soundcloud.com/thelitreviewchi/episode-53-borderlands-with-trina-reyolds-tyler Book here: Teaching Gloria E. Anzaldúa: Pedagogy and Practice for Our Classrooms and Communities Margaret Cantú-Sánchez (Editor), Candace de León-Zepeda (Editor), Norma Elia Cantú Mental Moment with Money 00:24:33 Dandelion Root Tea Use to treat skin problems and digestion issues dates back to 16th century, but it is becoming increasingly popular now as a coffee substitute New Research shows dandelion root might be a natural Wellbutrin! Gao, C., Kong, S., Guo, B., Liang, X., Duan, H., & Li, D. (2019). Antidepressive Effects of Taraxacum Officinale in a Mouse Model of Depression Are Due to Inhibition of Corticosterone Levels and Modulation of Mitogen-Activated Protein Kinase Phosphatase-1 (Mkp-1) and Brain-Derived Neurotrophic Factor (Bdnf) Expression. Medical science monitor : international medical journal of experimental and clinical research, 25, 389–394. https://doi.org/10.12659/MSM.912922 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340315/ Topic 00:38:38 #FreeBrittneyGriner Why isnt this story bigger? Brittney as a worker, but the WNBA is silent! WFT is happening in Russia?!? Listen to “The Dig” Russia Invades and “Red Nation Podcast” No War no NATO in Ukraine episodes https://nymag.com/intelligencer/2022/03/why-isnt-brittney-griner-the-biggest-sports-story.html https://www.cnn.com/2022/03/10/world/brittney-griner-arrest-russia-thursday/index.html To better understand what's happening in Russia: The Red Nation Pod https://directory.libsyn.com/episode/index/show/therednation/id/22352348 The Dig Pod: https://www.thedigradio.com/podcast-episodes/ Curved Chronicles 01:11:40 That time i curved myself - park date Community Contributors Now Credits This episode of QueerWOC the podcast was made possible thanks to the monetary contributions of Luna and Marina, who became new patrons and Tiff V. who upped their pledge This episode was also made possible by the listeners in Franklin, NC; North Adams, MA; and Humble, TX

Drs. Malin Hernebring, Julia Adelöf, Jaime Ross discuss their 2019 study published by Aging (Aging-US) in Volume 11, Issue 17, entitled, “Conclusions from a behavioral aging study on male and female F2 hybrid mice on age-related behavior, buoyancy in water-based tests, and an ethical method to assess lifespan.” DOI - https://doi.org/10.18632/aging.102242 Correspondence to - Malin Hernebring - malin.hernebring@gu.se Abstract Due to strain-specific behavioral idiosyncrasies, inbred mouse strains are suboptimal research models for behavioral aging studies. The aim of this study is to determine age-related behavioral changes of F2 hybrid C57BL/6NxBALB/c male and female mice. Lifespan was followed (nmales=48, nfemales=51) and cohorts of mature adult (7 months), middle-aged (15 months), and old mice (22 months of age; n=7-12 per group) were assessed regarding open-field activity, exploration, passive avoidance learning/memory, and depressive-like behavior. We found that both males and females demonstrated decreased exploratory behavior with age, while memory and depressive-like behavior were maintained. Females exhibited enhanced depressive-like behavior compared to males; however, a correlation between fat mass and swimming activity in the test directly accounted for 30-46% of this behavioral sex difference. In addition, we suggest a method to qualitatively estimate natural lifespan from survival analyses in which animals with signs of pain or severe disease are euthanized. This is, to our knowledge, the first behavioral study to consider both sex and aging in hybrid mice. We here define decreased exploratory behavior as a conserved hallmark of aging independent of sex, highlight the effect of buoyancy in water tests, and provide a method to assay lifespan with reduced animal suffering. Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.102242 Press release - https://www.aging-us.com/news_room/conclusions-from-a-behavioral-aging-study-on-male-and-female-f2-hybrid-mice-on-age-related-behavior-buoyancy-in-water-based-tests-and-an-ethical-method-to-assess-lifespan Keywords: F2 hybrid mice, aging, sex comparison, exploratory activity, water-based behavioral tests 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 http://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/agingus​ LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Aging-US is published by Impact Journals, LLC: http://www.ImpactJournals.com​​ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

Activating the immune system blunts social behavior in mice missing a copy of the autism-linked gene SHANK3, according to a new study. Blocking TRPV4, which encodes an ion channel involved in inflammatory responses, can reverse this effect. The post Immune gene tied to social behavior in autism mouse model appeared first on Spectrum | Autism Research News.

Activating the immune system blunts social behavior in mice missing a copy of the autism-linked gene SHANK3, according to a new study. Blocking TRPV4, which encodes an ion channel involved in inflammatory responses, can reverse this effect.

The latest DDW Sitting Down With sponsored podcast features Dominque Bröhl and Evert-Jan Uringa, Scientific Program Managers at Taconic Biosciences who discuss how mouse model generation can be accelerated without any loss of quality. The generation of genetically engineered custom mouse models can be a lengthy process that conflicts with the general time constraints of the drug discovery and development industry. Finding ways to shorten the time to create new mouse models is tempting but carries the risk of trading short timelines for poor quality. Taconic Biosciences developed the ExpressMODEL® portfolio of products to achieve the industry's fastest timelines to study cohort without compromising quality, whether embryonic stem cell (ESC), CRISPR, or random integration transgenic (RITg) methodology is used to generate a mouse model. Listen in to learn how ExpressMODEL® accelerates timelines and which benefits it brings to your drug discovery and development program.

Compared with a previous mouse strain, a new model better reflects some of the difficulties that people with a rare autism-related syndrome experience, and may help identify biomarkers of the syndrome.

University of California, Irvine biologists have developed a new genetically engineered mouse model that, unlike its predecessors, is based on the most common form of Alzheimer's disease (AD). The advance holds promise for making new strides against the neurodegenerative disease as cases continue to soar. Their study appears in the journal, Nature Communications.While over 170 Alzheimer's mouse models have been in use since the 1990s, those models mimic early-onset AD, also known as “familial AD,” which accounts for less than 5 percent of total AD cases. Until recently, scientists introduced mutations found in familial risk human genes, such as and presenilin 1, into the mouse genome to generate the mouse models. The UCI team decided to take a new approach by developing a mouse model better positioned to analyze the causes of late-onset AD. Also called “sporadic AD,” this new model encompasses the remaining 95 percent of cases.Professor Frank LaFerla is the study's co-senior author, the Dean of the UC Irvine School of Biological Sciences, and a Chancellor's Professor in the Department of Neurobiology and Behavior.  He is the Director of the NIH-funded Alzheimer's Disease Research Center and Co-Director of the NIH consortium called MODEL-AD. He joins us today to talk about his findings.Want better health and nutrition? Now you can get personalized supplement recommendations and custom vitamin packs delivered to your door! Go to PersonaNutrition.com/Roizen and take your free assessment and get 50% off your order today. - sponsor  BonusHow Your Diet Affects Your Risk for Cancer