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2 episodes with mouse models
7 episodes with mouse models
2 episodes with mouse models
2 episodes with mouse models
2 episodes with mouse models
2 episodes with mouse models
n the upcoming episode of The Science of Aging Podcast, we dive deep into the critical questions surrounding mouse models in aging research with our special guest, Dr. Dan Ehninger from the German Center for Neurodegenerative Diseases (DZNE) in Bonn. Dr. Ehninger, a visionary in the field of biogerontology, brings to the table his controversial and thought-provoking perspectives on the limitations and potential pitfalls of relying on mouse models for understanding human aging. We'll dissect the intricacies of rapamycin and caloric restriction studies, the debate over the mouse model's relevance to human aging, and innovative approaches to designing more effective mouse studies. This episode is a journey into the foundational challenges of aging science, highlighting the need for robust, translational research strategies. Join us for a riveting discussion that promises to enlighten, challenge, and inspire our understanding of the path forward in aging research.
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.08.03.551808v1?rss=1 Authors: Ribeiro, F. C., Cozachenco, D., Argyrousi, E. K., Staniszewski, A., Wiebe, S., Calixtro, J. D., Soares-Neto, R., Al-Chami, A., El Sayegh, F., Bermudez, S., Arsenault, E., Cossenza, M., Lacaille, J.-C., Nader, K., Sun, H., De Felice, F. G., Lourenco, M. V., Arancio, O., Aguilar-Valles, A., Sonenberg, N., Ferreira, S. T. Abstract: Impaired synaptic plasticity and progressive memory deficits are major hallmarks of Alzheimer's disease (AD). Hippocampal mRNA translation, required for memory consolidation, is defective in AD. Here, we show that genetic reduction of the translational repressors, Fragile X messenger ribonucleoprotein (FMRP) or eukaryotic initiation factor 4E (eIF4E)-binding protein 2 (4E-BP2), ameliorated the inhibition of hippocampal protein synthesis and memory impairment induced by AD-linked amyloid-b; oligomers (AbOs) in mice. Furthermore, systemic treatment with (2R,6R)-hydroxynorketamine (HNK), an active metabolite of the antidepressant ketamine, prevented deficits in hippocampal mRNA translation, long-term potentiation (LTP) and memory induced by AbOs in mice. HNK activated hippocampal signaling by extracellular signal-regulated kinase 1/2 (ERK1/2), mechanistic target of rapamycin (mTOR), and p70S6 kinase 1 (S6K1)/ribosomal protein S6 (S6), which promote protein synthesis and synaptic plasticity. S6 phosphorylation instigated by HNK was mediated by mTOR in hippocampal slices, while rescue of hippocampal LTP and memory in HNK-treated AbO-infused mice depended on ERK1/2 and, partially, on mTORC1. Remarkably, treatment with HNK corrected LTP and memory deficits in aged APP/PS1 mice. RNAseq analysis showed that HNK reversed aberrant signaling pathways that are upregulated in APP/PS1 mice, including inflammatory and hormonal responses and programmed cell death. Taken together, our findings demonstrate that upregulation of mRNA translation corrects deficits in hippocampal synaptic plasticity and memory in AD models. The results raise the prospect that HNK could serve as a therapeutic to reverse memory decline 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/2023.07.24.547147v1?rss=1 Authors: Cheng, G. W.-Y., Ma, I. W.-T., Huang, J., Yeung, S. H.-S., Ho, P., Chen, Z., Mak, H. K. F., Herrup, K., Chan, K. W. Y., Tse, K.-H. Abstract: Myelin degradation is a normal feature of brain aging that accelerates in Alzheimer's disease (AD). To date, however, the underlying biological basis of this correlation remains elusive. The amyloid cascade hypothesis predicts that demyelination is caused by increased levels of the {beta}-amyloid (A{beta}) peptide. Here we report on work supporting the alternative hypothesis that early demyelination is upstream of amyloid. We challenged two different mouse models of AD (R1.40 and APP/PS1) using cuprizone-induced demyelination and tracked the responses with both neuroimaging and neuropathology. In oppose to amyloid cascade hypothesis, R1.40 mice, carrying only a single human mutant APP (Swedish; APPSWE) transgene, showed a more abnormal changes of magnetization transfer ratio and diffusivity than in APP/PS1 mice, which carry both APPSWE and a second PSEN1 transgene (delta exon 9; PSEN1dE9). Although cuprizone targets oligodendrocytes (OL), magnetic resonance spectroscopy and targeted RNA-seq data in R1.40 mice suggested a possible metabolic alternation in axons. In support of alternative hypotheses, cuprizone induced significant intraneuronal amyloid deposition in young APP/PS1, but not in R1.40 mice, and it suggested the presence of PSEN deficiencies, may accelerate A{beta} deposition upon demyelination. In APP/PS1, mature OL is highly vulnerable to cuprizone with significant DNA double strand breaks (53BP1+) formation. Despite these major changes in myelin, OLs, and A{beta} immunoreactivity, no cognitive impairment or hippocampal pathology was detected in APP/PS1 mice after cuprizone treatment. Together, our data supports the hypothesis that myelin loss can be the cause, but not the consequence, of AD pathology. 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/2023.07.06.548027v1?rss=1 Authors: Torok, J., Maia, P., Anand, C., Raj, A. Abstract: Neurodegenerative diseases such as Alzheimer's disease (AD) exhibit pathological changes in the brain that proceed in a stereotyped and regionally specific fashion. More specifically in AD, misfolded tau aggregates first accumulate in limbic and temporal areas before spreading to other parts of the brain, while leaving some areas relatively unaffected. One explanation for this apparent selective vulnerability is that there are specific cell types that are particularly susceptible or resistant to tau tangle formation. For instance, prior work has found that tau colocalizes with only a few select subpopulations of excitatory neurons in layer II of the entorhinal cortex as opposed to affecting all excitatory neurons equally. However, while detailed work has been performed in a few focal regions of interest, the cellular underpinnings of regional vulnerability to tau has not been studied at a whole-brain level, primarily because whole-brain maps of a comprehensive collection of cell types have been inaccessible. Here, we used an established cell-type mapping pipeline, Matrix Inversion and Subset Selection (MISS), to determine the distributions of pan-hippocampal and neocortical neuronal and non-neuronal cells in the mouse brain using recently available single-cell RNA sequencing (scRNAseq) data from the Allen Institute for Brain Science (AIBS). We then performed a meta-analysis of five studies that quantified regional tau in PS19 mice comprising a total of twelve experimental conditions to identify general principles of cell-type-based selective vulnerability using these cell-type distributions. We found significant variance between cell-type classes in terms of their vulnerability to tau, with hippocampal glutamatergic neurons as a whole being strongly positive associated with patterns of end-timepoint tau deposition while cortical glutamatergic neurons and inhibitory neurons exhibited negative associations. Interestingly, the single-strongest correlate across experiments was oligodendrocytes, whose distributions were anti-correlated with tau pathology, indicating resilience. We also constructed minimal linear models of collections of associated cell types for each experiment and show that not only can cell-type vulnerability explain patterns of tau deposition in all twelve experiments, but that models using cell-type distributions outperform those using the expression patterns of AD risk genes. In short, we have demonstrated that regional cell-type composition is a compelling explanation for the selective vulnerability observed in tauopathic disease at a whole-brain level, which has important implications for better understanding AD pathophysiology and identifying mechanisms that are potential treatment targets. 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/2023.05.02.539086v1?rss=1 Authors: Weigel, T. K., Guo, C. L., Guler, A. D., Ferris, H. A. Abstract: Circadian symptoms have long been observed in Alzheimer's disease (AD) and often appear before cognitive symptoms, but the mechanisms underlying circadian alterations in AD are poorly understood. We studied circadian re-entrainment in AD model mice using a "jet lag" paradigm, observing their behavior on a running wheel after a six hour advance in the light:dark cycle. Female 3xTg mice, which carry mutations producing progressive amyloid beta and tau pathology, re-entrained following jet lag more rapidly than age-matched wild type controls at both 8 and 13 months of age. This re-entrainment phenotype has not been previously reported in a murine AD model. Because microglia are activated in AD and in AD models, and inflammation can affect circadian rhythms, we hypothesized that microglia contribute to this re-entrainment phenotype. To test this, we used the colony stimulating factor 1 receptor (CSF1R) inhibitor PLX3397, which rapidly depletes microglia from the brain. Microglia depletion did not alter re-entrainment in either wild type or 3xTg mice, demonstrating that microglia activation is not acutely responsible for the re-entrainment phenotype. To test whether mutant tau pathology is necessary for this behavioral phenotype, we repeated the jet lag behavioral test with the 5xFAD mouse model, which develops amyloid plaques, but not neurofibrillary tangles. As with 3xTg mice, 7-month-old female 5xFAD mice re-entrained more rapidly than controls, demonstrating that mutant tau is not necessary for the re-entrainment phenotype. Because AD pathology affects the retina, we tested whether differences in light sensing may contribute to altered entrainment behavior. 3xTg mice demonstrated heightened negative masking, an SCN-independent circadian behavior measuring responses to different levels of light, and re-entrained dramatically faster than WT mice in a jet lag experiment performed in dim light. 3xTg mice show a heightened sensitivity to light as a circadian cue that may contribute to accelerated photic re-entrainment. Together, these experiments demonstrate novel circadian behavioral phenotypes with heightened responses to photic cues in AD model mice which are not dependent on tauopathy or microglia. 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/2023.04.28.538728v1?rss=1 Authors: Heuer, S. E., Keezer, K. J., Hewes, A. A., Onos, K. D., Graham, K. C., Howell, G. R., Bloss, E. B. 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/2023.04.24.538135v1?rss=1 Authors: Holzel, M.-B., Winkelman, B. H. J., Howlett, M. H. C., Kamermans, W., De Zeeuw, C. I., Kamermans, M. 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/2023.04.18.537149v1?rss=1 Authors: Saghafi, S., Rumbell, T. H., Gurev, V., Kozloski, J. C., Tamagnini, F., Wedgwood, K. C., Diekman, C. O. Abstract: Alzheimer's disease (AD) is believed to occur when abnormal amounts of the proteins amyloid beta and tau aggregate in the brain, resulting in a progressive loss of neuronal function. Hippocampal neurons in transgenic mice with amyloidopathy or tauopathy exhibit altered intrinsic excitability properties. We introduce a novel parameter inference technique, deep hybrid modeling (DeepHM), that combines deep learning with biophysical modeling to map experimental data recorded from hippocampal CA1 neurons in transgenic AD mice and age-matched wildtype littermate controls to the parameter space of a conductance-based CA1 model. Although mechanistic modeling and machine learning methods are by themselves powerful tools for approximating biological systems and making accurate predictions from data, when used in isolation these approaches suffer from distinct shortcomings: model and parameter uncertainty limit mechanistic modeling, whereas machine learning methods disregard the underlying biophysical mechanisms. DeepHM addresses these shortcomings by using conditional generative adversarial networks (cGANs) to provide an inverse mapping of data to mechanistic models that identifies the distributions of mechanistic modeling parameters coherent to the data. Here, we demonstrate that DeepHM accurately infers parameter distributions of the conductance-based model and outperforms a Markov chain Monte Carlo method on several test cases using synthetic data. We then use DeepHM to estimate parameter distributions corresponding to the experimental data and infer which ion channels are altered in the Alzheimer's mouse models compared to their wildtype controls at 12 and 24 months. We find that the conductances most disrupted by tauopathy, amyloidopathy, and aging are delayed rectifier potassium, transient sodium, and hyperpolarization-activated potassium, respectively. 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/2023.04.19.537468v1?rss=1 Authors: Blondiaux, A., Jia, S., Annamneedi, A., Caliskan, G., Schulze, J., Montenegro-Venegas, C., Wykes, R. C., Fejtova, A., Walker, M., Stork, O., Gundelfinger, E. D., Dityatev, A., Seidenbecher, C. I. Abstract: Epilepsies are multifaceted neurological disorders characterized by abnormal brain activity, e.g. caused by imbalanced synaptic excitation and inhibition. The neural extracellular matrix (ECM) is dynamically modulated by physiological and pathophysiological activity and critically involved in controlling the brain's excitability. We used different epilepsy models, i.e. mice lacking the presynaptic scaffolding protein Bassoon at excitatory, inhibitory or all synapse types as genetic models for rapidly generalizing early-onset epilepsy, and intra-hippocampal kainate injection, a model for acquired temporal lobe epilepsy, to study the relationship between epileptic seizures and ECM composition. Electroencephalogram recordings revealed Bassoon deletion at excitatory or inhibitory synapses having diverse effects on epilepsy-related phenotypes. While constitutive Bsn mutants and GABAergic neuron-specific knockouts(BsnDlx5/6cKO) displayed severe epilepsy with more and stronger seizures than kainate-injected animals, mutants lacking Bassoon solely in excitatory forebrain neurons (BsnEmx1cKO) showed only mild impairments. By semiquantitative immunoblotting and immunohistochemistry we show model-specific patterns of neural ECM remodeling, and we also demonstrate significant upregulation of the ECM receptor CD44 in null and BsnDlx5/6cKO mutants. ECM-associated WFA-binding chondroitin sulfates were strongly augmented in seizure models. Strikingly, Brevican, Neurocan, Aggrecan and link protein Hapln1 levels reliably predicted seizure properties across models, suggesting a link between ECM state and epileptic 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/2023.04.17.536878v1?rss=1 Authors: Bedolla, A. M., McKinsey, G., Ware, K., Santander, N., Arnold, T., Luo, Y. Abstract: The recent proliferation of new Cre and CreER recombinase lines provides researchers with a diverse toolkit to study microglial gene function. To determine how best to apply these lines in studies of microglial gene function, a thorough and detailed comparison of their properties is needed. Here, we examined four different microglial CreER lines (Cx3cr1CreER(Litt), Cx3cr1CreER(Jung), P2ry12CreER, Tmem119CreER), focusing on (1) recombination specificity; (2) leakiness - degree of non-tamoxifen recombination in microglia and other cells; (3) efficiency of tamoxifen-induced recombination; (4) extra-neural recombination -the degree of recombination in cells outside the CNS, particularly myelo/monocyte lineages (5) off-target effects in the context of neonatal brain development. We identify important caveats and strengths for these lines which will provide broad significance for researchers interested in performing conditional gene deletion in microglia. We also provide data emphasizing the potential of these lines for injury models that result in the recruitment of splenic immune cells. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Sebastian Brunemeier, Building Puerto Rico, Puerto Rico Money, ImmuneAGE Locations, Switzerland Benefits, Distributed Biotech, ChatGPT, vitaDAO, DAOs, Non-profit, Accredited Investors, Mental Energy, Ageism, Hopelessness, Downhill After 18, Psychometrics, Healthspan Capital, Mouse Bottleneck, Business Opportunity, Mouse Models, Synthetic Models, Age-related Diseases, Human vs Mice, Cloning, Reverse Yamanaka Factors, Progeria Cells, IP, Investing, Contracting Out, Matthew "Oki" O'Connor, Cyclarity, Cholesterol, Brain Aging, Bone Marrow Transplant, ImmuneAge Special Sauce, Competitors, Biobank, Missing Team Members, Books, Longevity Biotech Fellowship, The post Immune System Rejuvenation, Startups, & Investing – Sebastian Brunemeier -Learning with Lowell 175 first appeared on Learning with Lowell.
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.30.534981v1?rss=1 Authors: Zielinski, M., Reyes, F. S. P., Gremer, L., Schemmert, S., Frieg, B., Willuweit, A., Donner, L., Elvers, M., Nilsson, L. N. G., Syvänen, S., Sehlin, D., Ingelsson, M., Willbold, D., Schröder, G. F. Abstract: The development of novel drugs for Alzheimer's disease has proven difficult, with a high failure rate in clinical trials. Typically, transgenic mice displaying amyloid-{beta} peptide brain pathology are used to develop therapeutic options and to test their efficacy in preclinical studies. However, the properties of A{beta} in such mice have not been systematically compared to A{beta} from the patient brains. Here, we determined the structures of nine ex vivo A{beta} fibrils from six different mouse models by cryo-EM. We found novel A{beta} fibril structures in the APP/PS1, ARTE10, and tg-SwDI models, whereas the human familial type II fibril fold was found in the ARTE10, tg-APPSwe, and APP23 models. The tg-APPArcSwe mice showed an A{beta} fibril whose structure resembles the human sporadic type I fibril. These structural elucidations are key to the selection of adequate mouse models for the development of novel plaque-targeting therapeutics and PET imaging tracers. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
How do research communities contend with controversial science? J. Benjamin Hurlbut, Ph.D., Arizona State University, Alysson Muotri, Ph.D., UC San Diego, Matthew Porteus, M.D., Ph.D., Stanford University, and Jacob (Yaqub) Hanna, M.D., Ph.D., Weizmann Institute of Science, explore controversial case studies and the limitations of scientific deliberation/dissent/ambivalence. Series: "Stem Cell Channel" [Health and Medicine] [Humanities] [Science] [Show ID: 38729]
How do research communities contend with controversial science? J. Benjamin Hurlbut, Ph.D., Arizona State University, Alysson Muotri, Ph.D., UC San Diego, Matthew Porteus, M.D., Ph.D., Stanford University, and Jacob (Yaqub) Hanna, M.D., Ph.D., Weizmann Institute of Science, explore controversial case studies and the limitations of scientific deliberation/dissent/ambivalence. Series: "Stem Cell Channel" [Health and Medicine] [Humanities] [Science] [Show ID: 38729]
How do research communities contend with controversial science? J. Benjamin Hurlbut, Ph.D., Arizona State University, Alysson Muotri, Ph.D., UC San Diego, Matthew Porteus, M.D., Ph.D., Stanford University, and Jacob (Yaqub) Hanna, M.D., Ph.D., Weizmann Institute of Science, explore controversial case studies and the limitations of scientific deliberation/dissent/ambivalence. Series: "Stem Cell Channel" [Health and Medicine] [Humanities] [Science] [Show ID: 38729]
How do research communities contend with controversial science? J. Benjamin Hurlbut, Ph.D., Arizona State University, Alysson Muotri, Ph.D., UC San Diego, Matthew Porteus, M.D., Ph.D., Stanford University, and Jacob (Yaqub) Hanna, M.D., Ph.D., Weizmann Institute of Science, explore controversial case studies and the limitations of scientific deliberation/dissent/ambivalence. Series: "Stem Cell Channel" [Health and Medicine] [Humanities] [Science] [Show ID: 38729]
How do research communities contend with controversial science? J. Benjamin Hurlbut, Ph.D., Arizona State University, Alysson Muotri, Ph.D., UC San Diego, Matthew Porteus, M.D., Ph.D., Stanford University, and Jacob (Yaqub) Hanna, M.D., Ph.D., Weizmann Institute of Science, explore controversial case studies and the limitations of scientific deliberation/dissent/ambivalence. Series: "Stem Cell Channel" [Health and Medicine] [Humanities] [Science] [Show ID: 38729]
How do research communities contend with controversial science? J. Benjamin Hurlbut, Ph.D., Arizona State University, Alysson Muotri, Ph.D., UC San Diego, Matthew Porteus, M.D., Ph.D., Stanford University, and Jacob (Yaqub) Hanna, M.D., Ph.D., Weizmann Institute of Science, explore controversial case studies and the limitations of scientific deliberation/dissent/ambivalence. Series: "Stem Cell Channel" [Health and Medicine] [Humanities] [Science] [Show ID: 38729]
How do research communities contend with controversial science? J. Benjamin Hurlbut, Ph.D., Arizona State University, Alysson Muotri, Ph.D., UC San Diego, Matthew Porteus, M.D., Ph.D., Stanford University, and Jacob (Yaqub) Hanna, M.D., Ph.D., Weizmann Institute of Science, explore controversial case studies and the limitations of scientific deliberation/dissent/ambivalence. Series: "Stem Cell Channel" [Health and Medicine] [Humanities] [Science] [Show ID: 38729]
How do research communities contend with controversial science? J. Benjamin Hurlbut, Ph.D., Arizona State University, Alysson Muotri, Ph.D., UC San Diego, Matthew Porteus, M.D., Ph.D., Stanford University, and Jacob (Yaqub) Hanna, M.D., Ph.D., Weizmann Institute of Science, explore controversial case studies and the limitations of scientific deliberation/dissent/ambivalence. Series: "Stem Cell Channel" [Health and Medicine] [Humanities] [Science] [Show ID: 38729]
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.07.531542v1?rss=1 Authors: Naia, L., Shimozawa, M., Bereczki, E., Li, X., Liu, J., Jiang, R., Leal, N. S., Pinho, C. M., Berger, E., Falk, V. L., Dentoni, G., Ankarcrona, M., Nilsson, P. Abstract: Increased amyloid beta-peptide level is one of the drivers of Alzheimer disease (AD). Amyloid precursor protein (App) knock-in mice recapitulate the human abeta pathology, allowing the elucidation of the downstream effects of abeta and their temporal appearance upon disease progression. Here we have investigated the sequential onset of AD-like pathologies in the AppNL-F and AppNL-G-F knock-in mouse models by time-course transcriptome analysis of the hippocampus, a region severely affected in AD. Energy metabolism emerged as one of the most significantly altered pathways at an early stage of the development of the pathologies. Functional experiments in mitochondria isolated from AppNL-G-F brain subsequently identified upregulation of oxidative phosphorylation driven by the activity of mitochondrial complexes I, IV and V, combined with higher susceptibility to Ca2+-overload. This was followed by a strong neuroinflammatory response and impaired autophagy. Accumulation of autophagosomes and reduced number of mitochondria content in presynaptic terminals could account for the altered synapse morphology including increased number of synaptic vesicles and lowered thickness of post synaptic density in AppNL-G-F mice. This shows that abeta-induced pathways in the App knock-in mice recapitulate some key pathologies observed in AD brain, and our data herein contributes to the understanding of their timewise appearance and potential role in new therapeutic approaches. 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/2023.02.15.528754v1?rss=1 Authors: Larrigan, S., Joshi, S., Mattar, P. Abstract: Chromatin remodellers are among the most important risk genes associated with neurodevelopmental disorders (NDDs), however, their functions during brain development are not fully understood. Here, we focused on Sifrim-Hitz-Weiss Syndrome (SIHIWES) - a brain overgrowth/intellectual disability disorder caused by mutations in the CHD4 chromodomain helicase gene. We utilized mouse genetics to excise the Chd4 ATPase/helicase domain - either in the germline, or conditionally in the developing telencephalon. Conditional heterozygotes exhibited little change in cortical size and cellular composition, and had only subtle behavioral phenotypes. Telencephalon-specific conditional knockouts had marked reductions in cortical growth, reduced numbers of upper-layer neurons, and exhibited alterations in anxiety and repetitive behaviors. Despite the fact that germline heterozygotes exhibited comparable growth defects, they were unaffected in these behaviors, but instead exhibited female-specific alterations in learning and memory. These data reveal unexpected phenotypic divergence arising from differences in the spatiotemporal deployment of loss-of-function manipulations, underscoring the importance of context in chromatin remodeller function during neurodevelopment. 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/2023.02.01.526671v1?rss=1 Authors: Luo, H., Todi, S. V., Paulson, H. L., Costa, M. d. C. Abstract: Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is the most common dominantly inherited ataxia. SCA3 is caused by a CAG repeat expansion in the ATXN3 gene that encodes an expanded tract of polyglutamine (polyQ) in the disease protein ataxin-3 (ATXN3). As a deubiquitinating enzyme, ATXN3 regulates numerous cellular processes including proteasome- and autophagy-mediated protein degradation. In SCA3 disease brain, polyQ-expanded ATXN3 accumulates with other cellular constituents, including ubiquitin (Ub)-modified proteins, in select areas like the cerebellum and the brainstem, but whether pathogenic ATXN3 affects the abundance of ubiquitinated species is unknown. Here, in mouse and cellular models of SCA3, we investigated whether elimination of murine Atxn3 or expression of wild-type or polyQ-expanded human ATXN3 alters soluble levels of overall ubiquitination, as well as K48-linked (K48-Ub) and K63-linked (K63-Ub) chains. Levels of ubiquitination were assessed in the cerebellum and brainstem of 7- and 47-week-old Atxn3 knockout and SCA3 transgenic mice, and also in relevant mouse and human cell lines. In older mice, we observed that wild-type ATXN3 impacts the cerebellar levels of K48 -Ub proteins. In contrast, pathogenic ATXN3 leads to decreased brainstem abundance of K48-Ub species in younger mice and changes in both cerebellar and brainstem K63-Ub levels in an age-dependent manner: younger SCA3 mice have higher levels of K63-Ub while older mice have lower levels of K63-Ub compared to controls. Human SCA3 neuronal progenitor cells also show a relative increase in K63-Ub proteins upon autophagy inhibition. We conclude that wild-type and mutant ATXN3 differentially impact K48-Ub- and K63-Ub-modified proteins in the brain in a region- and age-dependent manner. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.24.523981v1?rss=1 Authors: O'Brien, J., Niehaus, P., Remark, J., Salimian, M., Kevas, Y., Rubin, S., Kristian, T., Chandrasekeran, K., Lu, C. P.-J., Russell, J., Ho, C.-Y. Abstract: Diabetic neuropathy (DN) is a debilitating disorder characterized by mechanical allodynia and sensory loss. It has traditionally been considered a small-fiber neuropathy, defined by the loss of free nerve endings in the epidermis. Free nerve endings, however, are nociceptors which may not be the only sensor for mechanical pain. To investigate the role of mechanoreceptors, specifically Meissner corpuscles, in the development of diabetic mechanical allodynia, our study focused on the keratinocyte-secreted brain-derived neurotrophic factor (BDNF) and its transcriptional regulator sirtuin 1 (SIRT1). Wild-type DN mice demonstrated decreased SIRT1 deacetylase activity, leading to a decrease in BDNF expression and Meissner corpuscle densities in foot skin. Epidermal SIRT1 knockout (KO) mice developed exacerbated DN phenotypes including severe mechanical allodynia, markedly reduced Meissner corpuscles, and subcutaneous A-beta axon degeneration. Among the major skin-derived neurotrophic factors, only BDNF was down-regulated in epidermal SIRT1 KO mice. With similar KO phenotypes, epidermal BDNF appeared to belong to the same pathway as SIRT1 in modulating diabetic mechanical allodynia. Furthermore, mice overexpressing epidermal SIRT1 showed BDNF up-regulation and improved DN phenotypes, supporting an important role of epidermal SIRT1 and BDNF in skin sensory apparatus regeneration and functional recovery in the setting of diabetes. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.23.525258v1?rss=1 Authors: Borchelt, D. R., Ellison, S. Abstract: Amyotrohpic lateral sclerosis (ALS) is a progressive neurodegenerative disease that causes generalized muscle weakness and atrophy. Neuropathologically, ALS is defined by severe loss of upper and lower motor neurons with a robust neuroinflammatory response. In the present study, we have examined the potential utility of two drugs that have indications as immune modulators, levamisole HCl and thymosin 1. These drugs were tested in two models models that reproduce aspects of ALS. We conducted a 14 week dosing study of these two drugs in the SOD1G93A and Prp-TDP43A315T models of ALS. The drugs were given once daily for two weeks and then every other day for 6 weeks for a total of 8 weeks of treatment. Outcome measurements included efficacy assessment on the neuromuscular phenotypes, and pathological analyses of ubiquitin load and neuro-inflammatory markers in spinal motor neurons. Neither of these drug treatments produced significant extensions in survival; however, there were changes in ubiquitin load in SOD1G93A mice that suggest the drugs could be beneficial as additions to other therapies. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.05.522897v1?rss=1 Authors: DEL POZO, A., KNOX, K. M., LEHMANN, L., DAVIDSON, S., JAYADEV, S., BARKER-HALISKI, M. Abstract: Objective: People with early-onset Alzheimer disease (AD) with amyloid precursor protein (APP) duplications or presenilin (PSEN) variants are at elevated seizure risk within 5 years of diagnosis. Further, seizures in AD may increase neuropsychiatric comorbidity burden. We thus hypothesized that disruptions in serotonin pathway-related protein expression was impacted by 60 Hz corneal kindled seizures in an AD-genotype-related manner. Methods: Male and female 2-3-month-old APP/PS1, PSEN2-N141I, and respective transgenic (Tg) control mice underwent corneal or sham kindling for 2 weeks until reaching kindling criterion defined as five consecutive Racine stage 5 seizures. Chronic seizure-induced changes in serotonin pathway protein expression in hippocampus were then quantified by western blot. Results: Young female APP/PS1 mice kindled significantly faster than Tg- controls, whereas PSEN2-N141I mice kindled no differently versus their Tg controls. APP/PS1 mice subjected to corneal kindling were at extremely elevated mortality risk relative to kindled Tg- controls, as well as sham-kindled APP/PS1 and Tg- control mice, whereas PSEN2-N141I mice were not adversely affected by kindling. Kindled APP/PS1 mice demonstrated a marked downregulation of hippocampal tryptophan hydroxylase 2 and monoamine oxidase A protein expression versus kindled Tg- and sham-kindled APP/PS1 groups. Serotonin pathway protein expression in PSEN2-N141I mice was unchanged from Tg. Importantly, all changes in serotonin pathway protein expression in kindled APP/PS1 mice occurred in the absence of amyloid {beta} (A{beta}) deposition. Significance: The co-occurrence of seizures in the APP/PS1 mouse is sufficient to evoke unexpected mortality well ahead of pathological A{beta} deposition synonymous with a symptomatic AD model. The presence of another AD-associated variant (PSEN2-N141) does not lead to seizure-induced mortality, suggesting that AD-associated risk genes differentially influence vulnerability to chronic seizure-associated mortality. Further, disruptions in serotonin pathway synthesis coincide with heightened mortality risk exclusively in adult APP/PS1 mice, suggesting a possible non-canonical sudden unexpected death in epilepsy (SUDEP)-related phenotype. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.23.513403v1?rss=1 Authors: Ciancone-Chama, A. G., Bozzi, Y., Balasco, L. Abstract: Sensory difficulties represent a crucial issue in the life of autistic individuals. The diagnostic and statistical manual of mental disorders describes both hyper- and hypo-responsiveness to sensory stimulation as a criterion for the diagnosis autism spectrum disorders (ASD). Among the sensory domain affected in ASD, altered responses to tactile stimulation represent the most commonly reported sensory deficits. Although tactile abnormalities have been reported in monogenic cohorts of patients and genetic mouse models of ASD, the underlying mechanisms are still unknown. Traditionally, autism research has focused on the central nervous system as the target to infer the neurobiological bases of such tactile abnormalities. Nonetheless, the peripheral nervous system represents the initial site of processing of sensory information and a potential site of dysfunction in the sensory cascade. Here we investigated the gene expression deregulation in the trigeminal ganglion (which directly receives tactile information from whiskers) in two genetic models of syndromic autism (Shank3b and Cntnap2 mutant mice) at both adult and juvenile ages. We found several neuronal and non-neuronal markers involved in inhibitory, excitatory, neuroinflammatory and sensory neurotransmission to be differentially regulated within the trigeminal ganglia of both adult and juvenile Shank3b and Cntnap2 mutant mice. These results may help in entangling the multifaced complexity of sensory abnormalities in autism and open avenues for the development of peripherally targeted treatments for tactile sensory deficits exhibited in ASD. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.14.512256v1?rss=1 Authors: Maas, D. A., Manot-Saillet, B., Bun, P., Habermacher, C., Poilbout, C., Rusconi, F., Angulo, M. C. Abstract: Intracellular Ca2+ signals of oligodendroglia, the myelin-forming cells of the central nervous system, regulate vital cellular processes including myelination. However, studies on oligodendroglia Ca2+ signal dynamics are still scarce, especially during myelin repair, and there are no software solutions to properly analyze the unique Ca2+ signal characteristics in these cells. Here, we provide a comprehensive experimental and analytical workflow to acquire and analyze Ca2+ imaging data of oligodendroglia at the population and single-cell levels in preclinical mouse models of myelin repair. We report diverse ex vivo and in vivo experimental protocols to obtain reproducible Ca2+ imaging data from oligodendroglia in demyelinated lesions. Importantly, we provide an analytical pipeline containing two free, open source and cross-platform software programs, Occam and post-prOccam, that enable the fully automated analysis of one- and two-photon Ca2+ imaging datasets from oligodendroglia obtained by either ex vivo or in vivo Ca2+ imaging techniques. This versatile and accessible experimental and analytical framework, which revealed significant but uncorrelated spontaneous Ca2+ activity in oligodendroglia inside demyelinated lesions, should facilitate the elucidation of Ca2+-mediated mechanisms underlying remyelination and therefore help to accelerate the development of therapeutic strategies for the many myelin-related disorders, such as multiple sclerosis. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.11.511739v1?rss=1 Authors: Vallabh, S. M., Zou, D., Pitstick, R., O'Moore, J., Peters, J., Silvius, D., Kriz, J., Jackson, W. S., Carlson, G. A., Minikel, E. V., Cabin, D. E. Abstract: Phenotypic screening has yielded small molecule inhibitors of prion replication that are effective in vivo against certain prion strains but not others. Here we sought to test the small molecule anle138b in multiple mouse models of prion disease. In mice inoculated with the RML strain of prions, anle138b doubled survival and durably suppressed astrogliosis measured by live animal bioluminescence imaging. In knock-in mouse models of the D178N and E200K mutations that cause genetic prion disease, however, we were unable to identify a clear, quantifiable disease endpoint against which to measure therapeutic efficacy. Among untreated animals, the mutations did not impact overall survival, and bioluminescence remained low out to greater than 20 months of age. Vacuolization and PrP deposition were observed in some brain regions in a subset of mutant animals, but appeared unable to carry the weight of a primary endpoint in a therapeutic study. We conclude that not all animal models of prion disease are suited to well-powered therapeutic efficacy studies, and care should be taken in choosing the models that will support drug development programs. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.27.509669v1?rss=1 Authors: Harrington, E. P., Catenacci, R. B., Smith, M. D., Heo, D., Miller, C. E., Meyers, K. R., Glatzer, J., Bergles, D. E., Calabresi, P. A. Abstract: Oligodendrocytes and their progenitors upregulate MHC pathways in response to inflammation, but the frequency of this phenotypic change is unknown and the features of these immune oligodendroglia are poorly defined. We generated MHC class I and II transgenic reporter mice to define their dynamics in response to inflammatory demyelination, providing a means to monitor MHC activation in diverse cell types in living mice and define their roles in aging, injury and disease. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.25.508690v1?rss=1 Authors: Purro, S. A., Farmer, M., Noble, E., Sarell, C. J., Powell, M., Yip, D. C.-M., Giggins, L., Zakka, L., Thomas, D. X., Farrow, M. A., Nicoll, A. J., Walsh, D. M., Collinge, J. Abstract: The aggregation of amyloid-{beta} (A{beta}) monomers increases their neurotoxicity, and these oligomeric species are thought to be central to the pathogenesis of Alzheimer's disease. Unsurprisingly for such a complex disease, current Alzheimer's disease mouse models fail to fully mimic the clinical disease in humans. Moreover, results obtained in a given mouse model are not always reproducible in a different model. Cellular prion protein (PrPC) is now an established receptor for A{beta} oligomers. However, different groups studying the A{beta}-PrPC interaction in vivo using a variety of mouse models have obtained contradictory results. Here we performed a longitudinal study in two commonly used AD mouse models using a range of biochemical, histological and behavioural techniques and found similar contradictory results and a possible explanation for the discrepancy. We propose that these two mouse models produce A{beta} oligomers with different conformations. Therefore, binding to PrPC and the subsequent activation of toxic signalling cascade will occur only when the A{beta} oligomer species with appropriate conformation are present. Hence, it is crucial to select the appropriate model producing the appropriate species of A{beta} oligomers to study specific aspects of {beta}-amyloidosis and its downstream pathways. Further conformational characterisation of A{beta} oligomers and their binding to PrPC is required to better understand A{beta} neurotoxicity. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer
In this special episode of The Highlights, we interview Chino Eke, an undergraduate senior in the Neuroscience department. We discuss his senior thesis research, which was done with his advisor Professor Elizabeth Gould, a professor and researcher in the Princeton Neuroscience department focused on brain plasticity. Chino's paper investigates two types of social impairments in Autism mouse models, and what this may tell us about the future of autism research.This episode of The Highlights was produced under the 146th Managing Board of The Daily Princetonian. Chino Eke is a recent graduate in the Neuroscience department of Princeton University.To view the transcript for this episode, click “More Info” and then “Full Transcript” in the episode player. Correction: A previous version of this episode used the phrase "autistic mice."RESOURCESChino's Senior Thesis: Mechanisms of Social Memory Dysfunction in Mouse Models of Autism Spectrum DisorderCREDITSWritten and hosted by Senna Aldoubosh and Sophia Villacorta. Edited by Sophia Villacorta and Senna AldouboshProduced by Senna AldouboshFor more information from the Daily Princetonian, visit www.dailyprincetonian.com. Subscribe to Insights on Apple Podcasts, Spotify, or wherever you got your podcasts!
In this exciting episode, Judy goes over papers published in May 2022 on the latest research involving cognitive, behavioural and clinical changes in AD. Subjects include sensory processing, mouse models, sleep, and many more! Sensory Processing (1:45)Mouse Models (5:44)Clinical Treatments (8:34)Sleep (12:59)Other (17:29) -------------------------------------------------------------- To find the numbered bibliography with all the papers covered in this episode, click here, or use the link below: https://drive.google.com/file/d/1yY6gR2c2e_Big8_Atx_VVb2RqCw6PFZ5/view?usp=sharing To access the folder with ALL our bibliographies, follow this link (it will be updated as we publish episodes and process bibliographies), or use the link below: https://drive.google.com/drive/folders/1bzSzkY9ZHzzY8Xhzt0HZfZhRG1Gq_Si-?usp=sharing You can also find all of our bibliographies on our website: www.amindr.com. -------------------------------------------------------------- Follow-up on social media for more updates! Twitter: @AMiNDR_podcast Instagram: @AMiNDR.podcast Facebook: AMiNDR Youtube: AMiNDR Podcast LinkedIn: AMiNDR Podcast Email: amindrpodcast@gmail.com -------------------------------------------------------------- Please help us spread the word about AMiNDR to your friends, colleagues, and networks! And if you could leave us a rating and/or review on your streaming app of choice (Apple Podcasts, Spotify, or wherever you listen to the podcast), that would be greatly appreciated! It helps us a lot and we thank you in advance for leaving a review! Don't forget to subscribe to hear about new episodes as they come out too. Thank you to our sponsor, the Canadian Consortium of Neurodegeneration in Aging, or CCNA, for their financial support of this podcast. This helps us to stay on the air and bring you high quality episodes. You can find out more about the CCNA on their website: https://ccna-ccnv.ca/. Our team of volunteers works tirelessly each month to bring you every episode of AMiNDR. This episode was scripted and hosted by Judy Cheng, edited by Chihiro Abe and reviewed by Anusha Kamesh. The bibliography was created by Anjana Rajendran and the wordcloud by Lara Onbasi (www.wordart.com). Big thanks to the sorting team for taking on the enormous task of sorting all of the Alzheimer's Disease papers into episodes each month. For May 2022, the sorters were Sarah Louadi, Christy Yu, Ben Cornish, Eden Dubchak, Kira Tosefsky, Elyn Rowe, and Ellen Koch. Also, props to our management team, which includes Sarah Louadi, Ellen Koch, Naila Kuhlmann, Elyn Rowe, Anusha Kamesh, and Lara Onbasi for keeping everything running smoothly. Our music is from "Journey of a Neurotransmitter" by musician and fellow neuroscientist Anusha Kamesh; you can find the original piece and her other music on soundcloud under Anusha Kamesh or on her YouTube channel, AKMusic. https://www.youtube.com/channel/UCMH7chrAdtCUZuGia16FR4w -------------------------------------------------------------- If you are interested in joining the team, send us your CV by email. We are specifically looking for help with sorting abstracts by topic, abstract summaries and hosting, audio editing, creating bibliographies, and outreach/marketing. However, if you are interested in helping in other ways, don't hesitate to apply anyways. -------------------------------------------------------------- *About AMiNDR: * Learn more about this project and the team behind it by listening to our first episode: "Welcome to AMiNDR!"
Serial inventor and entrepreneur Alex Blyth had long held interests in health and science, but losing his mom to pancreatic cancer was the inflection point that launched LIfT Biosciences in 2016. Now, the preclinical company is on a mission to develop the world's first 'off-the-shelf' cell therapy to destroy all solid tumors, irrespective of strain or mutation, beginning with pancreatic cancer. On this episode of the Business of Biotech, Blyth shares the company's scientific approach and progress, and we explore the shortcomings of legacy clinical protocols including the inherent problems and limitations of mouse models.
Huberman Lab Podcast Notes Key Takeaways “Our body is shaping the decisions that our brain is making and we're not aware of it, at all.” – Dr. Andrew HubermanWhat you do, eat, think, and feel influences your microbiomeSome microbiota make enzymes locally to digest food, others make neurochemicals that impact brain function and moodOur experience with and desire for certain foods involves how the food tastes, texture, and subconscious processing of taste in our gut which signal certain neuromodulatorsThe gut communicates to the brain to change what we think we want or to change our actual behaviors around foodFood and eating is not just about the food and nutrients we need or don't need, there are subconscious signals and waves of nerve cells always coming from our body and changing the way our brain works“Our brain is very carefully paying attention to whether the levels of dopamine that are being triggered are within a normal range or whether we gorged ourselves.” – Dr. Andrew HubermanCreating the correct environment for microbiota to thrive enhances mood and behaviorParents: the more diversity you can create early, the better chance you're giving your child at healthy brain-gut signaling and immunity In general, to create a healthy gut microbiome: eat the right foods, consume pro- and pre-biotics sparingly unless going through periods of high stress, travel, or significant change to dietThough fasting has a lot of benefits – we don't know whether it promotes or degrades the microbiome over time but it seems to cause disruption when prolongedNon-diet related ways to enhance microbiome: get deep sleep, maintain proper social interactions, limit prolonged stress and stressorsTo really improve microbiome diversity through diet, consume 4-6 ounces of fermented foods per day – start with 1 and work your way up to avoid gastric distressRead the full notes @ podcastnotes.orgIn this episode, I discuss the profound effect the gut has on the nervous system. I cover the structure and function of the gut-brain axis and the role of the gut microbiome in the brain and overall health. I describe how the gut controls hunger or satiety by affecting neurons in our brain. I also contrast the many pathways by which the gut influences the brain: direct vs. indirect pathways, chemical vs. mechanical, and fast vs. slow signaling. Additionally, I discuss what defines a healthy microbiome and how your lifestyle impacts the gut microbiome, including the effects of stress, fasting, antibiotics, pets, environment, prebiotics and probiotics. I address how different foods shape the gut microbiome, in particular, the emerging data that fermented foods can increase the diversity of healthy gut microbiota. Throughout the episode, I explain peer-reviewed and textbook findings that reveal the critical role of the gut microbiome in supporting mental and physical health and I outline simple tools that anyone can use in order to enhance their gut microbiome health. Thank you to our sponsors AG1 (Athletic Greens): https://athleticgreens.com/huberman LMNT: https://drinklmnt.com/huberman InsideTracker: https://insidetracker.com/huberman Our Patreon page https://www.patreon.com/andrewhuberman Supplements from Thorne https://www.thorne.com/u/huberman Social & Website YouTube Instagram Twitter Facebook Website Newsletter Article Links "The Emerging Biology of Gut-Brain Sensory Transduction" "Mechanisms Underlying Microbial-Mediated Changes in Social Behavior in Mouse Models of Autism Spectrum Disorder" "Association of Loneliness and Wisdom With Gut Microbial Diversity and Composition: An Exploratory Study" "Emotional well-being and gut microbiome profiles by enterotype" "Brain fogginess, gas and bloating: a link between SIBO, probiotics and metabolic acidosis" "Gut-microbiota-targeted diets modulate human immune status" "The preference for sugar over sweetener depends on a gut sensor cell" Book Links "The 4-Hour Chef: The Simple Path to Cooking Like a Pro, Learning Anything and Living the Good Life" Timestamps (00:00:00) Gut Microbiome (00:03:02) AG1 (Athletic Greens), LMNT, InsideTracker (00:06:55) Your Gut-Brain Axis (00:09:44) Gut-Brain Anatomy (00:15:32) Microbiota vs. Gut Microbiome (00:20:01) Roles of Gut Microbiome (00:23:03) Neuropod Cells: (Subconscious) Tasting with Your Stomach (00:34:13) Ghrelin: Slow Modulation of Your Brain in Hunger (00:38:02) Glucagon Like Peptide 1; GLP-1 (00:42:22) Tools: ‘Free Will' & Food Cravings (00:44:46) Mechanical Cues from Gut to Brain (00:49:05) Dopamines, Vomiting (00:52:06) Indirect Signals from Gut Microbiota (00:59:30) Gut Microbiome “Critical Periods” (01:03:08) How Gut Health Controls Overall Health (01:12:25) What is a Healthy Gut Microbiome? (01:15:00) Tools: Enhance Your Gut Microbiome (01:23:49) Foods to Enhance Microbiota Diversity; Fermented Foods (01:37:07) High-Fiber Diets & Inflammation (01:40:58) Artificial & Non-Caloric Sweeteners (01:44:27) Structure & Function of Gut-Brain Axis (01:49:47) Zero-Cost Support, YouTube, Spotify, Apple Reviews, Sponsors, Patreon, Thorne, Instagram, Twitter, Neural Network Newsletter Title Card Photo Credit: Mike Blabac Disclaimer
Deciding on the best mouse model to research myocardial ischemic injury? Stop and listen. Associate Editor Jason Carter (Montana State University) interviewed authors Zamaneh Kassiri (University of Alberta), Crystal Ripplinger (University of California Davis), John Calvert (Emory University), Kristine DeLeon-Pennell (University of South Carolina), Dominic Del Re (Rutgers New Jersey Medical School), Richard Gumina (The Ohio State University), Steven Jones (University of Louisville), and Ganesh Halade (University of South Florida). Representing the distinguished group of experts who collaborated on “Guidelines for in vivo mouse models of myocardial infarction” by Lindsey et al., these authors discussed their consensus article that documents strategies for inducing and evaluating reperfused and non-reperfused myocardial infarction mouse models. The authors emphasized that one model is not superior to another model, but rather each model addresses a different set of scientific questions. The authors also discussed comprehensive experimental design, inclusion of both male and female mice, sample sizes for sufficient statistical power analyses, and statistical tests mapped to the number of variables studied. In addition, the authors touched on providing benchmarks for left ventricular remodeling and function resulting from MI, reporting anesthetics and analgesics used in studies, and measurements and reporting of infarct size using standardized methods. This is a unique opportunity to hear how the authors navigated differing points of view to create an insightful roadmap for the field. The comprehensive checklist in Table 4 is particularly useful for new investigators. Early career researchers – add this to your playlist! Merry L. Lindsey, Keith R. Brunt, Jonathan A. Kirk, Petra Kleinbongard, John W. Calvert, Lisandra E. de Castro Brás, Kristine Y. DeLeon-Pennell, Dominic P. Del Re, Nikolaos G. Frangogiannis, Stefan Frantz, Richard J. Gumina, Ganesh V. Halade, Steven P. Jones, Rebecca H. Ritchie, Francis G. Spinale, Edward B. Thorp, Crystal M. Ripplinger, Zamaneh Kassiri Guidelines for in vivo mouse models of myocardial infarction Am J Physiol Heart Circ Physiol, published November 17, 2021. DOI: doi.org/10.1152/ajpheart.00459.2021
In this episode, I discuss the profound effect the gut has on the nervous system. I cover the structure and function of the gut-brain axis and the role of the gut microbiome in the brain and overall health. I describe how the gut controls hunger or satiety by affecting neurons in our brain. I also contrast the many pathways by which the gut influences the brain: direct vs. indirect pathways, chemical vs. mechanical, and fast vs. slow signaling. Additionally, I discuss what defines a healthy microbiome and how your lifestyle impacts the gut microbiome, including the effects of stress, fasting, antibiotics, pets, environment, prebiotics and probiotics. I address how different foods shape the gut microbiome, in particular, the emerging data that fermented foods can increase the diversity of healthy gut microbiota. Throughout the episode, I explain peer-reviewed and textbook findings that reveal the critical role of the gut microbiome in supporting mental and physical health and I outline simple tools that anyone can use in order to enhance their gut microbiome health. Thank you to our sponsors AG1 (Athletic Greens): https://athleticgreens.com/huberman LMNT: https://drinklmnt.com/huberman InsideTracker: https://insidetracker.com/huberman Our Patreon page https://www.patreon.com/andrewhuberman Supplements from Thorne https://www.thorne.com/u/huberman Social & Website YouTube Instagram Twitter Facebook Website Newsletter Article Links "The Emerging Biology of Gut-Brain Sensory Transduction" "Mechanisms Underlying Microbial-Mediated Changes in Social Behavior in Mouse Models of Autism Spectrum Disorder" "Association of Loneliness and Wisdom With Gut Microbial Diversity and Composition: An Exploratory Study" "Emotional well-being and gut microbiome profiles by enterotype" "Brain fogginess, gas and bloating: a link between SIBO, probiotics and metabolic acidosis" "Gut-microbiota-targeted diets modulate human immune status" "The preference for sugar over sweetener depends on a gut sensor cell" Book Links "The 4-Hour Chef: The Simple Path to Cooking Like a Pro, Learning Anything and Living the Good Life" Timestamps (00:00:00) Gut Microbiome (00:03:02) AG1 (Athletic Greens), LMNT, InsideTracker (00:06:55) Your Gut-Brain Axis (00:09:44) Gut-Brain Anatomy (00:15:32) Microbiota vs. Gut Microbiome (00:20:01) Roles of Gut Microbiome (00:23:03) Neuropod Cells: (Subconscious) Tasting with Your Stomach (00:34:13) Ghrelin: Slow Modulation of Your Brain in Hunger (00:38:02) Glucagon Like Peptide 1; GLP-1 (00:42:22) Tools: ‘Free Will' & Food Cravings (00:44:46) Mechanical Cues from Gut to Brain (00:49:05) Dopamines, Vomiting (00:52:06) Indirect Signals from Gut Microbiota (00:59:30) Gut Microbiome “Critical Periods” (01:03:08) How Gut Health Controls Overall Health (01:12:25) What is a Healthy Gut Microbiome? (01:15:00) Tools: Enhance Your Gut Microbiome (01:23:49) Foods to Enhance Microbiota Diversity; Fermented Foods (01:37:07) High-Fiber Diets & Inflammation (01:40:58) Artificial & Non-Caloric Sweeteners (01:44:27) Structure & Function of Gut-Brain Axis (01:49:47) Zero-Cost Support, YouTube, Spotify, Apple Reviews, Sponsors, Patreon, Thorne, Instagram, Twitter, Neural Network Newsletter Title Card Photo Credit: Mike Blabac Disclaimer
This month on Episode 28 of Discover CircRes, host Cynthia St. Hilaire highlights four original research articles featured in the August 20th and September 3rd issues of Circulation Research. This episode also features an in-depth conversation with Dr Scott Cameron from the Cleveland Clinic and Dr Milka Koupenova from the University of Massachusetts Medical Center about their study, SARS-CoV-2 Initiates Programmed Cell Death in Platelets. Article highlights: Gupta, et al. Electronic Cigarettes and Oxidized Lipids Bartosova, et al. Glucose Derivative Induced Vasculopathy in CKD Atmanli, et al. DMD Correction Attenuates Cardiac Abnormalities Ma, et al. Length Dependent Activation in Porcine Myocardium Cindy St. Hilaire: Hi, and welcome to Discover CircRes, the podcast for the American Heart Association's journal, Circulation Research. I'm your host, Dr Cindy St. Hilaire from the Vascular Medicine Institute at the University of Pittsburgh, and today I will be highlighting articles presented in our August 20th and September 3rd issues of Circulation Research. I also will speak with Dr Scott Cameron from the Cleveland Clinic and Dr Milka Koupenova from the University of Massachusetts Medical Center about their study, SARS-CoV-2 Initiates Programmed Cell Death in Platelets. Cindy St. Hilaire: The first article I want to share is titled Electronic and Tobacco Cigarettes Alter Polyunsaturated Fatty Acids and Oxidative Biomarkers. The first author is Rajat Gupta and the corresponding author is Jesus Araujo from UCLA. E-cigarettes have surged in popularity in the last decade and while many people switching from traditional cigarettes to smokeless ones view the latter as a safe alternative to smoking tobacco, emerging data shows that E-cigarettes cause adverse effects such as oxidative stress, inflammation and endothelial dysfunction in users. The aerosols produced during vaping contain similar levels of reactive oxygen species, also called ROS, as the vapors of tobacco smoke. However, data on the extent to which E-cigarettes, E-cigarette ROS, influences cardiovascular health is lacking. Cindy St. Hilaire: To address this, this group recruited 32 chronic users of E-cigarettes, 29 chronic tobacco smokers, and 45 individuals that used neither and they measured their plasma levels of oxidative biomarkers. The team found both similarities and differences between the E-cigarettes and the tobacco users. For example, both smoking groups had increased plasma antioxidant capacity and decreased levels of oxidized linoleic acid compared with the levels seen in non-users, while arachidonic acid levels were raised in tobacco smokers and reduced in E-cigarette users. Overall, however, the biomarker levels were deemed to be intermediate for E-cigarette users between the non-users and the tobacco users. This study suggests that while E-cigarettes carry a lower health risk than tobacco, they are by no means safe. Cindy St. Hilaire: The second article I want to share is titled Glucose Derivative Induced Vasculopathy in Children on Chronic Peritoneal Dialysis. The first author is Maria Bartosova and the corresponding author is Claus Schmitt and they're from the University of Heidelberg. Diabetes, high blood pressure and obesity are risk factors for both cardiovascular disease and chronic kidney disease. Worse still, loss of kidney function and even dialysis itself are thought to exacerbate cardiovascular issues. In the case of dialysis, it's thought that high levels of glucose degradation products, or GDPs, in the dialysis fluids can promote the addition of sugar moieties to vascular proteins and lipids causing vascular damage. To investigate this theory, Bartosova and colleagues studied vascular tissue from children with chronic kidney disease receiving dialysis fluids with either high levels or low levels of glucose degradation products and compared these to tissues from children not on dialysis at all. Cindy St. Hilaire: Proteome and transcriptome analysis of the vessel tissues revealed that compared with patients or no to low GDP fluids, patients receiving high GDP fluids had higher levels of damaging glycation, increased transcription of genes involved in cell death, and decreased transcription of genes involved in cell survival and cytoskeletal reorganization. In line with these findings, vessels from high GDP patients displayed considerable evidence of damage, such as markers of apoptosis, skeletal disintegration and thickened intimas. The results confirmed GDPs can cause vasculopathy and suggest low GDP fluids should be used for dialysis patients. Cindy St. Hilaire: The next article I want to share is titled Cardiac Myoediting Attenuates Cardiac Abnormalities in Human and Mouse Models of Duchenne Muscular Dystrophy. The first author is Ayhan Atmanli and the corresponding author is Eric Olson from UT Southwestern. Duchenne Muscular Dystrophy, or DMD, affects one in 5,000 baby boys and is caused by mutations in gene for dystrophin, an architectural protein essential for muscle cell integrity. Patients display profound muscle degeneration and weakness, with respiratory and heart muscle dysfunction being a major cause for death. With the recent improvements in respiratory medicine that extend the lives of patients, this group now focused on heart dysfunction and specifically, whether gene editing could mitigate it. The team created induced pluripotent stem cells, or iPSCs, from Duchenne Muscular Dystrophy patient and his healthy brother and showed that gene editing from the DMD cells enabled their development into normal-looking cardiomyocytes with normal contractile function and calcium handling, equivalent to that seen in healthy control cells. The unedited DMD cells, by contrast, did not develop normally. For great clinical relevance, the team edited DMD cells after cardiomyocyte differentiation showing that this reduced their propensity for arrhythmia, compared with that of unedited cells. Cindy St. Hilaire: Lastly, the team provided evidence to suggest gene editing may improve heart abnormalities in mice with the same mutation. All together the results are proof of principle and support of the development of gene editing therapy as treatment for DMD. Cindy St. Hilaire: The last article I want to share is titled The Super-Relaxed State and Length Dependent Activation in Porcine Myocardium. The first authors are Weikang Ma and Marcus Henze and the corresponding author is Thomas Irving and they're from the Illinois Institute of Technology. Myofilament length-dependent activation or LDA is the fundamental mechanism coupling the force of the heart's contraction to it's proceeding diastolic volume. In other words, LDA ensures that the more the heart fills, the stronger it contracts. Studies of rodent hearts have given insights into LDA mechanics. However, how it operates in large mammalian hearts is unknown. Using structural and biochemical analysis of pig myocardial fibers, this group found that compared with small stretches of the fibers which were equivalent to small diastolic volumes, long stretches induced greater ATP turnover and greater numbers of cross bridges between myosin and actin filaments which are critical contractile machinery proteins. Cindy St. Hilaire: Myosin motors can be found in three stages, engaged with actin, unengaged in a disordered, relaxed state but ready to engage, or super-relaxed state where they are essentially switched off. The team showed that as muscle stretch increased, the amount of super-relaxed myosin motors diminished with more myosin motors becoming engaged to enable a stronger contraction. When the fibers were treated with a myosin motor inhibitor, these stretch effects were impaired. In revealing the mechanisms of myofilament length-dependent activation, this study provides a platform for studying cardiomyopathies in which this system goes awry. Cindy St. Hilaire: So today, Dr Scott Cameron from the Cleveland Clinic and corresponding author of the paper, Dr Milka Koupenova from the University of Massachusetts Medical Center, are both with me to discuss their study, SARS-CoV-2 Initiates Programmed Cell Death in Platelets. And this article is in our September 3rd issue of Circ Research and for full disclosure, the editor of Circ Res, Dr Jane Freedman is also an author on this manuscript. And for full double disclosure, I know Dr Koupenova quite well as we were both graduate students together back in the Ravid Lab at Boston University. However, the full Editorial Board selects these articles, not just me alone and this one is timely, novel, and an amazing story. So thank you both for joining me today. Milka Koupenova: Thank you for having us. Scott Cameron: Privileged to be here. Cindy St. Hilaire: So before we jump into the story that is your paper, can you give us a little bit of background about platelets? I know for years, I guess certainly before Katya's lab, I just thought of platelets as little nucleus-free particles that clot. But we know they are so much more than that. So why are they so important? And how do they function to do more than just stop a bleed? Milka Koupenova: So this is a great question, Cindy, and I am happy that you alluded exactly to the anucleated nature of platelets. So platelets are cell fragments. They're precursors in the bone marrow, the megakaryocyte. They are the second most abundant blood component after the red blood cells. And traditionally, platelets have been known, as what you pointed out, as these little units that change their conformation once there is some form of a problem with either the vascular, which we have a cut, they come together, they form this clot, and bleeding is prevented. But as we have learned perhaps in the past 20 years that platelets have a profound immune role during various immune processes and infections for different kind of microbes. And particularly relevant to this paper is that we understand that platelets have clearly a role responding to the viruses and activating the immune system. Cindy St. Hilaire: Yeah, and that was actually my next question. You and Jane are the world-leading experts on platelets and viral responses. So what was known about that interaction, I guess before we started looking at SARS-CoV-2, what was known about that platelet virus or even type of virus interaction? Milka Koupenova: So SARS-CoV-2 is a RNA virus--respiratory virus that we actually thought similarly to influenza that it mostly stays in the lower respiratory tract where it becomes problematic. However, from our work with influenza, when we saw that in certain patients you actually can detect the virus in platelet. In the beginning of the pandemic, we hypothesized that perhaps, in some people, the virus crosses over into the circulation. And based on our previous studies with influenza, we wanted to see if that indeed is the case. Hence we initiated a study here at UMass with the department head who is also on the paper, Dr Finberg, who is a leading expert in influenza and novel virus and we collected platelets from people to see if we can detect it. And so in the beginning, we were not able to detect SARS-CoV-2 in platelets. So we collected platelets from 17 patients and by qPCR with the primers that the CDC has, for whatever reason I couldn't detect anything. And I was really frustrated because previous reports have shown that about 25%, in some people even 35% of the study population, SARS can be detected. So very interesting observations. Milka Koupenova: I could see it by immunofluorescence but I couldn't detect the RNA. And the story goes, that I attended a seminar on SARS-CoV-2 and the person was actually referencing a company that started from University of Pitt where you are. Cindy St. Hilaire: Oh, very nice. Milka Koupenova: And they do specific, it's called amplicon ARTIC v3 sequencing so they enrich for the SARS-CoV-2 RNA and screen by sequencing. And when we did that, we were able to detect it in all patients. So I freaked out and I said, "Oh my gosh, something is wrong." Milka Koupenova: And so I sent plasma, and I sent controls, and actually RNA from the virus and you can see beautifully that it's only in platelets. Four of the 17 people actually had RNA in the plasma, but what you can observe in all these people is that the virus is fragmented, meaning it's not infectious. And in a way what this tells us, it suggests that platelets are super important in the removing it from the circulation and they probably serve as a dead-end for the virus because you cannot find virus coming out of platelets and the RNA is chopped off. So what I would say, is that platelets are these amazing little units that serve as removal of the viral RNA for these particular viruses, respiratory viruses that are RNA viruses. Cindy St. Hilaire: I think that is so interesting. So essentially, they're almost like little composters that are chewing it up and preventing it from spreading in the organism. Milka Koupenova: Yes, and as a result there is a response. Cindy St. Hilaire: Scott, probably the most common thing that people know with SARS is that loss of smell, or taste, and things like that, but really that doesn't send anybody to the hospital. So really what are the symptoms of COVID-19 patients that tie in with platelets specifically? I feel like that's a lot of things that we maybe in the public, or on Twitter, and things didn't hear as much about. So really what are those big symptoms linking COVID and platelets and what are the implications of platelet death in the pathogenesis of COVID? Scott Cameron: So certainly I think several investigators are in the world of now showing that platelets are hyperactivated, Robbie Campbell and Matt Rondina put a really nice paper in Blood last year showing that platelets are hyperactive and there are other investigators who found something similar. And so the question is, what are the symptoms of hyperactive platelets in the SARS-CoV-2 patient? So what most of them would find is shortness of breath or dyspnea, and when they present to the emergency department, and certainly we saw this, the oxygen saturation which should be in the mid to high 90s on room air on an average person, was quite often low. It was in the 80s or 70s, sometimes even the 60s. Scott Cameron: And the real surprising thing was those are patients that would normally immediately be on a ventilator, but yet they could still be talking to you. And so if you have a platelet that's activated in a hyperthrombotic condition, like SARS-CoV-2, COVID-19, and then that forms a blood clot, you have a situation where the amount of oxygen the patients taking in and the amount of oxygen you're measuring in the artery is quite discrepant and we call that the alveolar arterial or oxygen gradient. So if you've got lots of platelet plugs through the microvasculature, it's going to take up some space the oxygen should be using for diffusing in. And so that would be manifested as shortness of breath and that's certainly one of the biggest tip-offs that a patient might have a blood clot, particularly in the lung. Cindy St. Hilaire: Some of these symptoms of COVID-19 are really worse in patients with comorbidities, diabetes, obesity and heart failure. Are platelets central to kind of the pathogenesis of those disease or the symptoms of those diseases? I guess the root of my question is, why do the comorbidities of diabetes, obesity, and heart failure make COVID worse? Is it something about those disease states themselves or is there a role for platelet? Scott Cameron: That's a brilliant question, no one's ever asked that before. And as Dr Koupenova said, I'm a little bit biased too because I firmly believe that in different disease states, the disease educates the platelets so you've got a different platelets phenotype. So focusing on diabetes, we know the platelet phenotype is different in diabetic patients. We know that platelet reactivity seems to be higher through the P2Y12 receptor. In terms of obesity, it is true, we know that, and this has been published also, and we know that the platelet phenotype is hyperactive in a patient with obesity and so that tells me that, that's a comorbidity that might affect platelet function and also vice versa for that case. And then in terms of why is it affecting males more prominently and more severely than females, well one of the beefs, I guess, that I had is that we treat diseases in women the same as we do in men assuming that the platelet phenotype in disease must be the same, but that's absolutely not true. And that's actually a theme that we have in our lab right now, we know that the behavior of platelets, and how platelets are educated in diseases is not all the same in women as in men and I think it's a huge disservice that we really had to have a pandemic that would make that quite clear to us. Cindy St. Hilaire: You kind of hit onto something that's really, I think it's now becoming more recognized certainly in the cardiovascular field and that is so many studies are really only on male mice, or only younger or older men, and we are missing not only a huge patient population, but probably some really interesting biology that is distinct. Milka Koupenova: So expanding on that, we know that in platelets, the toll-like receptors, and we've looked at the expression of all 10 in a study that we published in ATVB in 2015, actually, significantly if you look at Farmingham Heart Study data and the expression of these toll-like receptors they are increased in women versus men. And also, an interesting observation that never got published, once upon a time when I was doing studies with TLR7 mice is that if you inject TLR7 agonists, male mice would have a higher level of reduced platelet count than female mice at the same time points, right? And at that time it wasn't published. Definitely there are differences, but I also want to extrapolate a little bit on what was said at the beginning. We have to understand that when it comes to these comorbidities, everything affects a unit that doesn't have a nucleus, right? And diabetes and obesity have the so called profound, chronic inflammation of cytokines, such as IL6, that keep circulating. These things have effect on platelets. So we have two responses, we have the environment that affects platelets and we have the direct response of the virus that affects platelets. And that cumulative response truly can exhaust them and once they become exhausted, once they release their contents, as we show in this paper, then you're compromising their function and you will be compromising taking out the virus from one side and from the other side you're going to be compromising the environment because all of the content that comes out from a unit that already has free form proteins, it exhibits a true insult on what's being surrounded. So these clots that form in the lung or the platelets that circulate they no longer can be resolved properly. Cindy St. Hilaire: Yeah. Milka Koupenova: It's a balance. Cindy St. Hilaire: Yeah, so really it's like destroying the platelet not only are you destroying the vacuum that has to suck up those particles, you're then just dumping a whole bunch of pro-inflammatory things on all of the endothelial cell vasculature that those platelets are nearby. Cindy St. Hilaire: Actually that was one thing that I thought you spent a decent portion of the discussion on, and that is the method by which the blood is collected really impacts the outputs you observe in quote unquote platelets. Can you talk about the importance of that because I think that's one thing, certainly as a PhD who's just like, "Oh, yeah. I'm just going to collect blood from my mice and do this thing," how critical is that point in the experiment, in the blood collection? Milka Koupenova: So I am very adamant when it comes to platelets for the blood to be drawn in citrate. And I have to say that a lot of the studies that you would see in the literature are done using EDTA blood or serum. They all have their importance. I'm not going to dismiss it, but if you want to truly measure what's inside in plasma, versus what's inside in platelets, or what's inside in any cell for that matter, you got to go for citrate. You have to be very careful not to shake the blood. You have to be very careful not to cool down the blood. So the nurses probably hated me because often I would be like, "You can't do this. You can't put it on ice. You can't warm it up to above certain degrees. Everything has to be controlled and done correctly." Milka Koupenova: And so I had done in the past studies in which I would take plasma from the same patient in EDTA, in citrate and then isolate the RNA, have my tech isolate the RNA, and we send it to a fragment analyzer, and you can see how much more RNA you will get in the EDTA plasma. I'm not even talking about serum. Milka Koupenova: Serum is a very different thing, then you're definitely going to get platelet content in it, in the serum, right? So it's important to distinguish that perhaps when you're getting EDTA plasma you are looking at a content that could have been inside in platelet and I can't stress enough that when it comes to these particular studies, citrate, dextrose, phosphate is your place to go and be. Cindy St. Hilaire: So in terms of translational potential, what do your findings suggest about future therapies or targets to investigate as therapy? And is modulating platelets a potential for combating viral infections or mitigating their severity? Milka Koupenova: Well, Scott and I actually talk a lot about that. Scott Cameron: That's right. Milka Koupenova: I personally would say, control the inflammation, never let it go to platelet. Let me back up a little bit, if you have to, you have to, right? But your go to method should be inflammation, if you don't get to the point that you need to control platelets then you're in a better place because it becomes very fickle. From everything that you hear me say, you push it to one side and the balance is destroyed. You deactivate platelets or inhibit platelets well, are they now not able to pick up the virus and then you're now having the virus circulating somewhere. Now, if you don't treat platelets that's also not good. So you're in the very fickle situation if you get to the point that you need to control the activation of platelets and there are trials currently that are trying to look at those things. Scott, I'm going to refer this a little bit more to you because you have done some interesting things with that particular point. Scott Cameron: No, it's a great question, Milka, and I think that as platelet biologists, nobody more than I wanted it to be true that platelets would be the ultimate target. I mean, clearly patients with SARS-CoV-2 have thrombosis, clearly platelets are activated, so should we inactivate them? That was the whole point of the RECOVERY trial and one of the benefits I'll tell you before I sort of go into that is, working in a large organization like the Cleveland Clinic and we have access to data and lots of it extremely quickly, and so because of that I of course could see how many patients were coming into our hospital with thrombotic events. And I could see what the independent predictors of thrombotic events was and it wasn't the platelet count, sometimes platelet count was low, sometimes it's high in the SARS-CoV-2 patient. And if you took those individuals that were on aspirin, comparing them to those that are not in a propensity match study, one of the things that we find is that aspirin doesn't seem to affect or improve mortality or the number of blood clots in the patient with SARS-CoV-2. Scott Cameron: We compared that to all non-steroidal anti-inflammatory medications that patients may have been taking also in a propensity match study just in case it was the mechanism action of the drug, rather than the drug itself, and we found that NSAIDs not only did not protect patients, but they were not necessarily harmful either, which was one of the things that came out at the start of the pandemic. Among, I'll add, the absence of evidence based medicine and a lot of cases where naturally people, including clinicians, were scared and so they were going off label and they were trying a lot of different medications with really not a shred of randomized controlled data. Scott Cameron: But now that we're 18 months into it, the first and biggest study that came back was the RECOVERY trial, which we were all waiting on, where patients were given aspirin and short term mortality was examined over an observational period of one month. And just like we found in a propensity match study, which is as close as you'll get to a clinical trial in a retrospective manner, the prospect of RECOVERY trial actually showed the curves were almost super imposeable, those that got aspirin versus those that didn't. So I think low dose aspirin clearly is not going to be enough for those patients, but I'll also add that over the observational period of one month they also didn't see a higher incidence of death in those patients. And I think Milka's point is really well taken that you have to remember that as well being an entity of thrombosis, platelets are immunological entities and so you've got to really consider should we be inhibiting them and if you are inhibiting them, I think the time point at which you should inhibit them is what we should examine, not just an all or nothing, inhibited or not. Milka Koupenova: It's just in our linear brains we prefer to think of it as one straight, linear pathway, but it isn't, and I think platelets are actually a great example of how many pathways are feeding into one tiny fragment and that particular blood cell is inducing this profound response during these infections. Cindy St. Hilaire: I think most people have heard that angiotensin-converting enzyme 2, also called ACE2 is the receptor of SARS-CoV-2. The virus itself uses it to bind and become internalized into the cell, but there's been some discussion or even some discrepancy of data as to whether platelets truly express ACE2 and if that is the means for the virus to enter the platelets. So can you share with us what is the current state of knowledge about that? Scott Cameron: Yeah, just as a segue of some of the things that Milka said, I think the preparation of your sample is part of the answer. If you draw in the incorrect tube, if you the tube is not completely filled, and the ratio of citrates to whole blood isn't correct you're going to have discrepant results. If you biomechanically activate the platelets by drawing through a short needle, in a small-bore needle for example, that's going to activate the platelets. If you cool them, it's going to activate them. But then also, depending on how you decide to separate them, we always washed platelets in my lab, we wash them two or sometimes three times, and I can tell you if you use flow cytometer we get one white blood cell for every 12,000 platelets. Scott Cameron: And some investigators might go one step further and they'll a CD45 depletion set, which is certainly important if you're studying RNA. But one of the issues, as you well know, a CD45 is also on the surface of platelets, so if you start with a low expressing protein and you CD45 deplete them, you are actually going to get a decrease in your platelet yields. I've seen it, I think Milka's seen it, various other investigators have, and you might find yourself at the threshold of what your antibody can detect. It's also variably expressed. If you look at even healthy individuals, some of them have almost none. So if you look at 10 individuals, you might actually find none, but then if you look at another 10, the amount of expression that we see is kind of all over the place. It's not like other receptors where one tends to express a certain amount and that's the way it is in health. ACE2 doesn't seem to be that way for whatever reason. Milka Koupenova: We were able to detect in some of the people by qPCR, but what was interesting is that from the three primers that I used there was never the same person who we were able to detect all three primers with for that receptor. That tells you that maybe they are changes of one base that is not enough for the primer to detect it, right? That becomes another possibility of not being able to detect. Milka Koupenova: And so I go to confocal microscopy where I use 100 lens and tons of hours in the microscope room, and Scott is completely right, it's really hard to see it particularly in healthy people. And it starts to pick a little bit more in people with cardiovascular disease or people with COVID that are old. So it's a bit complicated, but the important thing here is, besides the fact that we are detecting ACE2 and we're detecting proteins and I use controls, biological controls to prove that this is the case and it's not just an antibody problem, is that the virus will get picked up by platelets even if you don't have ACE2. That is the take home message from this paper is that the platelet has evolved various mechanisms by which is utilizes getting it inside. It is that important for this virus. This type of virus is not recirculating. In this case, what we observed is that the virus is attached to microparticles that are of platelet origin for that matter. Cindy St. Hilaire: So really what you're saying, what I'm hearing is the platelet is the superhero of the body. Milka Koupenova: Definitely. Absolutely. No bias, absolutely. Cindy St. Hilaire: Unbiasedly, it is a superhero. Well, Dr Cameron and Dr Koupenova, thank you so much not only for this amazing discussion, but for really an elegant, elegant paper that is really bringing to light the complex interaction between SARS-CoV-2 and platelets. So thank you so much for joining me and keep publishing amazing stories like this. Milka Koupenova: Thank you for having us. Scott Cameron: Thank you, an honor to be here. Thanks again. Cindy St. Hilaire: That's it for the highlights from August 20th and September 3rd issues of Circulation Research. Thank you for listening. Please check out the CircRes Facebook page and follow us on Twitter and Instagram with the handle @CircRes and #DiscoverCircRes. Thank you to our guests, Dr Scott Cameron and Dr Milka Koupenova. This podcast is produced by Ashara Ratnayaka, edited by Melissa Stoner, and supported by the editorial team of Circulation Research. Some of the copy text for the highlighted articles is provided by Ruth Williams. I'm your host, Dr Cynthia St. Hilaire, and this is Discover CircRes, your on-the-go source for the most exciting discoveries in basic cardiovascular research. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more information, please visit ahajournals.org.
De fleste har lært om tarmbakterier i skolen og er blevet forklaret at mikroorganismerne er til for at hjælpe os med at nedbryde visse typer af mad for på den måde at give os (og dem) adgang til flere forskellige fødevarer. I dag er Frederik Neergaard taget med Mark i studiet for at fortælle om sin egen og andres forskning i det menneskelige tarmmikrobiom og hvordan det ikke bare påvirker vores tarm, men også vores indlæring, hukommelse og mentale diagnoser!Hør med og få forklaringen på hvordan og hvorfor bakterier både kan være årsagen og kuren mod Parkinson's (og andre lignende sygdomme).Tusind tak til Frederik for at være med os i dag og dele ud af sin viden og forskning!Hvis du vil være med til at optage live med os på Discord kan du støtte os på 10er og blive en af vores kernelyttere https://bit.ly/VU10er - hvis pengene er knappe kan du også bare tjekke vores Facebookgruppe ud, vi hygger max!Du kan også tjekke vores webshop: bit.ly/vushop. Vi har T-shirts, kaffekopper og tasker! Og meget mere! Der er også en hønsetrøje!Send os water hilarious science eller stil et spørgsmål på facebook, Instagram eller vudfordret@gmail.comTak til Christian Eiming for disclaimer.Tak til Barometer-Bjarke for Gak-O-meteretHusk at være dumme
Huntington's Disease is characterised by a clear line of heritability within families, and an early onset of disease towards the middle of ones life. As such, the more knowledge researchers gain about development of the disease, the earlier interventions may be developed, and the longer their benefits felt.Dr Jessica Cao is researching the onset of Huntington's Disease in a mouse model, how the sex-dependent differences may reflect in humans, and prospects for therapies to improve the wellbeing of patients facing the disease.Read the original paper: https://doi.org/10.1016/j.nbd.2019.104607
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.06.371625v1?rss=1 Authors: Mezias, C., Raj, A. Abstract: Introduction: Current research indicates divergent spatiotemporal tauopathy progression between conditions and implicates transsynaptic connectome-based spread as a main mechanism. We examine tauopathy and connectome interactions to investigate why different spatiotemporal patterns of pathology arise. Methods: We test whether divergent spatiotemporal tau pathology patterns from 15 mouse-model datasets can be explained by a directional bias in tau transmission along fiber tracts via a mathematical model called Directed Network Transmission (DNT). Results: Amyloid-comorbid tauopathic mouse models meant to mimic AD demonstrate spatiotemporal tauopathy patterns consistent with retrograde direction spread biases. Non-amyloid-comorbid mice demonstrate no consistent spread biases. Further, canonically early tau pathology regions in AD are implicated as having earliest pathology in a simulation with random tauopathy seeding locations with retrograde biased spread. Discussion: These results implicate directional biases in tau pathology spread along fiber tracts as a strong candidate explanation for divergent spatiotemporal tau progression between conditions. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.23.352310v1?rss=1 Authors: Van Hook, M. J., Monaco, C., Smith, J. Abstract: Homeostatic plasticity plays important roles in regulating synaptic and intrinsic neuronal function to stabilize output following perturbations to circuit activity. In glaucoma, a neurodegenerative disease of the visual system commonly associated with elevated intraocular pressure (IOP), early disease is associated with altered synaptic inputs to retinal ganglion cells (RGCs), changes in RGC intrinsic excitability, and deficits in optic nerve transport and energy metabolism. These early functional changes can precede RGC degeneration and are likely to alter RGC outputs to their target structures in the brain and thereby trigger homeostatic changes in synaptic and neuronal properties in those brain regions. In this study, we sought to determine whether and how neuronal and synaptic function is altered in the dorsal lateral geniculate nucleus (dLGN), an important RGC projection target in the thalamus, and how functional changes relate to IOP. We accomplished this using patch-clamp recordings from thalamocortical (TC) relay neurons in the dLGN in two established mouse models of glaucoma - the DBA/2J (D2) genetic mouse model and an inducible glaucoma model with intracameral microbead injections to elevate IOP. We found that the intrinsic excitability of TC neurons was enhanced in D2 mice and these functional changes were mirrored in recordings of TC neurons from microbead-injected mice. Notably, many neuronal properties were correlated with IOP in older D2 mice, but not younger D2 mice or microbead-injected mice. The frequency of miniature excitatory synaptic currents (mEPSCs) was reduced in both ages of D2 mice, and vGlut2 staining of RGC synaptic terminals was reduced in an IOP-dependent manner in older D2 mice. Among D2 mice, functional changes observed in younger mice without elevated IOP were distinct from those observed in older mice with elevated IOP and RGC degeneration, suggesting that glaucoma-associated changes to neurons in the dLGN might represent a combination of stabilizing/homeostatic plasticity at earlier stages and pathological dysfunction at later stages. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.21.348334v1?rss=1 Authors: Kandasamy, L. C., Tsukamoto, M., Banov, V., Tsetsegee, S., Nagasawa, Y., Kato, M., Matsumoto, N., Takeda, J., Itohara, S., Ogawa, S., Young, L. J., Zhang, Q. Abstract: Post-translational modification of a protein with glycosylphosphatidylinositol (GPI) is a conserved mechanism exists in all eukaryotes. Thus far, more than 150 human GPI anchored proteins have been discovered and about 30 enzymes have been reported to be involved in the biosynthesis and maturation of mammalian GPI. Phosphatidylinositol glycan biosynthesis class A protein (PIGA) catalyzes the very first step of GPI anchor biosynthesis. Patients carrying a mutation of the PIGA gene usually suffer from intractable epilepsy and intellectual developmental disorder. We generated three mouse models with PIGA deficits specifically in telencephalon excitatory neurons (Ex-M-cko), inhibitory neurons (In-M-cko), or thalamic neurons (Th-H-cko), respectively. Both Ex-M-cko and In-M-cko mice showed impaired long-term fear memory and were more susceptible to kainic acid (KA)-induced seizures. In addition, In-M-cko demonstrated a severe limb-clasping phenotype. Hippocampal synapse changes were observed in Ex-M-cko mice. Our Piga conditional knockout mouse models provide powerful tools to understand the cell-type specific mechanisms underlying inherited GPI deficiency and to test different therapeutic modalities. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.19.344564v1?rss=1 Authors: Oliveira, M. M., Lourenco, M. V., Longo, F., Kasica, N. P., Yang, W., Ureta, G., Ferreira, D. D. P., Mendonca, P. H. J., Bernales, S., Ma, T., De Felice, F. G., Klann, E., Ferreira, S. T. Abstract: Neuronal protein synthesis is essential for long-term memory consolidation. Conversely, dysregulation of protein synthesis has been implicated in a number o neurodegenerative disorders, including Alzheimer's disease (AD). Several types of cellular stress trigger the activation of protein kinases that converge on the phosphorylation of eukaryotic translation initiation facor 2 (eIF2-P). This leads to attenuation of cap-dependent mRNA translation, a component of the integrated stress response (ISR). We show that AD brains exhibit increased eIF2-P and reduced eIF2B, key components of the eIF2 translation initiation complex. We further demonstrate that attenuating the ISR wit the small molecule compound ISRIB (ISR inhibitor) rescues hippocampal protein synthesis and corrects impaired synaptic plasticity and memory in mouse models of AD. Our findings suggest that attenuating eIF2-P-mediated translational inhibition may comprise an effective approach to alleviate cognitive decline in AD. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.15.340588v1?rss=1 Authors: Zerbi, V., Pagani, M., Markicevic, M., Matteoli, M., Pozzi, D., Fagiolini, M., Bozzi, Y., Galbusera, A., Scattoni, M. L., Provenzano, G., Banerjee, A., Helmchen, F., Basson, A., Ellegood, J., Lerch, J., Rudin, M., Gozzi, A., Wenderoth, N. Abstract: Autism Spectrum Disorder (ASD) is characterized by substantial, yet highly heterogeneous abnormalities in functional brain connectivity. However, the origin and significance of this phenomenon remain unclear. To unravel ASD connectopathy and relate it to underlying etiological heterogeneity, we carried out a bi-center cross-etiological investigation of fMRI-based connectivity in the mouse, in which specific ASD-relevant mutations can be isolated and modelled minimizing environmental contributions. By performing brain-wide connectivity mapping across 16 mouse mutants, we show that different ASD-associated etiologies cause a broad spectrum of connectional abnormalities in which diverse, often diverging, connectivity signatures are recognizable. Despite this heterogeneity, the identified connectivity alterations could be classified into four subtypes characterized by discrete signatures of network dysfunction. Our findings show that etiological variability is a key determinant of connectivity heterogeneity in ASD, hence reconciling conflicting findings in clinical populations. The identification of etiologically-relevant connectivity subtypes could improve diagnostic label accuracy in the non-syndromic ASD population and paves the way for personalized treatment approaches. Copy rights belong to original authors. Visit the link for more info
The emergence of SARS-CoV-2 virus and the disease it causes, COVID-19, have fuelled significant shifts in preclinical research across the globe. Amid the worldwide health emergency created by high infection rates, rapid transmission spread and relatively high mortality rates, researchers are under pressure to understand the disease’s pathogenesis, develop and test investigational therapeutics and explore viable vaccine approaches. By Dr Megan MacBride If you'd like to view the original article then follow the link below: https://www.ddw-online.com/therapeutics/p323646-the-covid-19-race-how-mouse-models-will-help-researchers-cross-the-finish-line.html You can also download the original article pdf here: https://www.ddw-online.com/media/32/138653/7-the-covid-19-race-how-mouse-models.pdf For more information on Drug Discovery World, head to: https://www.ddw-online.com
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.12.336586v1?rss=1 Authors: Rahn, R. M., Weichselbaum, C. T., Gutmann, D. H., Dougherty, J. D., Maloney, S. E. Abstract: Motor deficits such as abnormal gait are an underappreciated yet characteristic phenotype of many neurodevelopmental disorders (NDDs), including Williams Syndrome (WS) and Neurofibromatosis Type 1 (NF1). Compared to cognitive phenotypes, gait phenotypes are readily and comparably assessed in both humans and model organisms, and are controlled by well-defined CNS circuits. Discovery of a common gait phenotype between NDDs might suggest shared cellular and molecular deficits and highlight simple outcome variables to potentially quantify longitudinal treatment efficacy in NDDs. We therefore characterized gait using the DigiGait assay in two different murine NDD models: the complete deletion (CD) mouse, which models hemizygous loss of the complete WS locus, and the Nf1+/R681X mouse, which models a NF1 patient-derived heterozygous germline NF1 mutation. Longitudinal data were collected across five developmental time points (postnatal days 21-30) and one early adulthood time point. Compared to wild type littermate controls, both models displayed markedly similar spatial, temporal, and postural gait abnormalities during development. Developing CD mice also displayed significant decreases in variability metrics. Multiple gait abnormalities observed across development in the Nf1+/R681X mice persisted into early adulthood, including increased stride length and decreased stride frequency, while developmental abnormalities in the CD model largely resolved by adulthood. These findings suggest that the subcomponents of gait affected in NDDs show overlap between disorders as well as some disorder-specific features, which may change over the course of development. Our incorporation of spatial, temporal, and postural gait measures also provides a template for gait characterization in other NDD models, and a platform to examining circuits or longitudinal therapeutics. Copy rights belong to original authors. Visit the link for more info
Dr Megan O'Hare is joined by three researchers based at the UK Dementia Research Institute in Cardiff - Dr Sarah Carpanini, Dr Tom Phillips and Dr Megan Torvell to discuss neuroinflammation in neurodegeneration this time using mouse models to examine underlying pathophysiology during brain development and beyond. Join them to hear about physiological synapse loss that occurs during normal, healthy development of the brain contrasting to pathological synapse loss that occurs in disease states such as Alzheimer's Disease. Hear more about the role of microglia and the role of the complement cascade as well as the virtues of using mouse models in general for studying an ageing disease. You can find out more about our panellists, and their work on our website www.dementiaresearcher.nihr.ac.uk. A transcript of this podcast is also available here https://www.dementiaresearcher.nihr.ac.uk/podcast-neuroinflammation-in-mouse-models/ Like what you hear? Please review, like, and share our podcast - and don't forget to subscribe to ensure you never miss an episode. Regular host Adam Smith is hosting a 12 hour Dementia Research Live Chatathon - 7th September, 12 hours, over 55 researchers to raise much needed funding for Alzheimer's Research UK. To find out more visit http://www.chatathon.uk This podcast is brought to you in association with Alzheimer's Research UK and Alzheimer's Society, who we thank for their ongoing support.
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.21.214106v1?rss=1 Authors: Siegel, A. E., Bianchi, D. W., Guedj, F. Abstract: Humans with Down syndrome (DS) exhibit hippocampal learning deficits in the Cambridge Neuropsychological Test Automated Battery (CANTAB). Here we translated the CANTAB Visual Discrimination (VD) and Extinction tasks to investigate hippocampal learning and cortical inhibitory control in the Dp(16)1/Yey, Ts65Dn and Ts1Cje mouse models of DS. No food or water restriction was used prior to testing. The number of days to reach 70% correct answers and percent of correct responses were analyzed. All Dp(16)1/Yey, Ts1Cje and WT mice reached Stage 5 of pre-training. No differences between genotypes were found in percent of correct responses. Five Ts65Dn and one WT animals reached Stage 5 and only one Ts65Dn mouse reached VD. Ts1Cje mice took longer (17.86{+/-}3.19 days) to move to VD vs. WT (11.44{+/-}1.96 days, P=0.09). There were no differences between Dp(16)1/Yey and WT mice. At VD, the average percent of correct answers was significantly lower in Dp(16)1/Yey (22.70{+/-}1.93%) and Ts1Cje (34.39{+/-}1.98%) compared to WT littermates (32.18{+/-}1.49% and 41.11{+/-}1.45%, respectively, P
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.19.162115v1?rss=1 Authors: Tosh, J. L., Rhymes, E., Mumford, P., Whittaker, H. T., Pulford, L. J., Noy, S. J., Cleverley, K., Walker, M. L., Tybulewicz, V. L. J., Wykes, R. C., Fisher, E. M. C., Wiseman, F. K. Abstract: Individuals who have Down syndrome (caused by trisomy of chromosome 21), have a greatly elevated risk of early-onset Alzheimer's disease, in which amyloid-{beta}; accumulates in the brain. Amyloid-{beta}; is a product of the chromosome 21 gene APP (amyloid precursor protein) and the extra copy or 'dose' of APP is thought to be the cause of this early-onset Alzheimer's disease. However, other chromosome 21 genes likely modulate disease when in three-copies in people with Down syndrome. Here we show that an extra copy of chromosome 21 genes, other than APP, influences APP/A{beta}; biology. We crossed Down syndrome mouse models with partial trisomies, to an APP transgenic model and found that extra copies of subgroups of chromosome 21 gene(s) modulate amyloid-{beta}; aggregation and APP transgene-associated mortality, independently of changing amyloid precursor protein abundance. Thus, genes on chromosome 21, other than APP, likely modulate Alzheimer's disease in people who have Down syndrome. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.02.130237v1?rss=1 Authors: Yang, H. S., Onos, K. D., Choi, K., Keezer, K. J., Skelly, D. A., Carter, G. W., Howell, G. R. Abstract: Microglia are now considered drivers of Alzheimer's disease (AD) pathology. However, single-cell RNA-sequencing (scRNA-seq) of microglia in mice, a key preclinical model organism, have shown mixed results regarding translatability to human studies. To address this, scRNA-seq of microglia from C57BL/6J (B6) and wild-derived strains WSB/EiJ, CAST/EiJ and PWK/PhJ carrying APP/PS1 was performed and demonstrated that genetic diversity significantly altered features and dynamics of microglia in baseline neuroimmune functions and in response to amyloidosis. There was significant variation in abundance of microglial subpopulations, including numbers of disease-associated microglia and interferon-responding microglia across the strains. Further, for each subpopulation, significant gene expression differences were observed between strains, and relative to B6 that included nineteen genes previously associated with human AD including Apoe, Trem2, Bin1, Sorl1. This resource will be critical in the development of appropriately targeted therapeutics for AD and a range of other neurological diseases. Copy rights belong to original authors. Visit the link for more info
Dr. Bility works with humanized mouse models to investigate infectious viruses like HIV. He explains his microbiology work by sharing with listeners The inspirational background for recapitulating human disease study with a new paradigm, How these humanized mouse models with human organ systems and immune systems are developed, and Their recent ability to control HIV in these mouse models that may enable vaccine development. Moses T. Bility, Ph.D., is Assistant Professor of Infectious Diseases and Microbiology at the School of Public Health and the University of Pittsburgh. In this conversation he explains how Stephen Hawking's theory of model-dependent realism inspired his approach to studying infectious viruses. In an effort to rethink the paradigm that can explain and predict human disease in a more effective way, he works with rodent models that are humanized. He explains the technique for introducing human organ systems in mice, including the liver, hypothalamus, kidney capsule, skin, and the whole immune system. This realigns how a microbiology lab can analyze infectious viruses, from HIV to Covid-19. Dr. Bility describes his current investigation, namely in HIV interaction with macrophages and iron. Macrophages are multifunctional cells that play a role in maintaining tissue integrity and initiating an immune response. He describes how they developed a humanized mouse model with a human spleen and studied the model to see what allows the HIV virus to persist and how they could affect the virus. They had an exciting outcome, namely that they were able to control HIV in their mouse model. They now will do some machine learning and other studies to see how they can design a vaccine around their findings in terms of controlling the virus. For more, see his faculty page at https://publichealth.pitt.edu/home/directory/moses-bility.
Corey and Steve talk with MSU Neuroscientist A.J. Robison about why females may be more likely to suffer from depression than males. A.J. reviews past findings that low testosterone and having a smaller hippocampus may predict depression risk. He explains how a serendipitous observation opened up his current line of research and describes tools he uses to study neural circuits. Steve asks about the politics of studying sex differences and tells of a start up using CRISPR to attack heart disease. The three end with a discussion of the psychological effects of ketamine, testosterone and deep brain stimulation.Topics 01:18 – Link between antidepressants, neurogenesis and reducing risk of depression 13:54 – Nature of Mouse models 23:19 – How you tell whether a mouse exhibits depressive symptoms 32:36 – Liz Williams' serendipitous finding and the issue of biological sex 45:47 – A.J.'s research plans for circuit specific gene editing in the mouse brain and a start up's plan to use it to tackle human cardiovascular disease 59:07 – Psychological and Neurological Effects of Ketamine. Testosterone and Deep Brain Stimulation Resources Transcript Robison Lab at MSU @RobisonLabMSU Papers Androgen-dependent excitability of mouse ventral hippocampal afferents to nucleus accumbens underlies sex-specific susceptibility to stress. Neurogenesis and The Effect of Antidepressants Integrating Interleukin-6 into depression diagnosis and treatment Sub-chronic variable stress induces sex-specific effects on glutamatergic synapses in the nucleus accumbens. Prefrontal cortical circuit for depression- and anxiety-related behaviors mediated by cholecystokinin: role of ΔFosB. Emerging role of viral vectors for circuit-specific gene interrogation and manipulation in rodent brain.
Corey and Steve talk with MSU Neuroscientist A.J. Robison about why females may be more likely to suffer from depression than males. A.J. reviews past findings that low testosterone and having a smaller hippocampus may predict depression risk. He explains how a serendipitous observation opened up his current line of research and describes tools he uses to study neural circuits. Steve asks about the politics of studying sex differences and tells of a start up using CRISPR to attack heart disease. The three end with a discussion of the psychological effects of ketamine, testosterone and deep brain stimulation.Topics 01:18 – Link between antidepressants, neurogenesis and reducing risk of depression 13:54 – Nature of Mouse models 23:19 – How you tell whether a mouse exhibits depressive symptoms 32:36 – Liz Williams' serendipitous finding and the issue of biological sex 45:47 – A.J.'s research plans for circuit specific gene editing in the mouse brain and a start up's plan to use it to tackle human cardiovascular disease 59:07 – Psychological and Neurological Effects of Ketamine. Testosterone and Deep Brain Stimulation Resources Transcript Robison Lab at MSU @RobisonLabMSU Papers Androgen-dependent excitability of mouse ventral hippocampal afferents to nucleus accumbens underlies sex-specific susceptibility to stress. Neurogenesis and The Effect of Antidepressants Integrating Interleukin-6 into depression diagnosis and treatment Sub-chronic variable stress induces sex-specific effects on glutamatergic synapses in the nucleus accumbens. Prefrontal cortical circuit for depression- and anxiety-related behaviors mediated by cholecystokinin: role of ΔFosB. Emerging role of viral vectors for circuit-specific gene interrogation and manipulation in rodent brain.
Why are models needed to assess and develop treatments in rare diseases? What types of models are there? When are different models used? To help answer these questions we talk to Dr Snezana Maljevic from The Florey Institute for Neuroscience and Mental Health. Hosted by Kris Pierce and David Cunnington, parents of Will, who has SCN2A. Leave a review and subscribe via Apple Podcasts. You can also find SCN2A Insights on Spotify, and Google Podcasts or in your podcast app. Links Dr Snezana Maljevic - The Florey Brain in a Dish - talk by Dr Maljevic
We discuss how raising levels of Alpha-COP proteins, seems to ease SMA disease severity in mouse models. Also, SMA News Today forums moderator DeAnn Runge shares her perspective about being on Spinraza for 2 years, and also gives an update regarding her 9th Spinraza injection. Are you interested in understanding gene therapy? ExploreGeneTherapy.com has helpful information about gene therapy, including its history and how it is being investigated for the treatment of genetic diseases. Visit www.exploregenetherapy.com
We discuss how a new compound improves clinical outcomes in mouse models of SMA. Also, SMA News Today’s Director of Multichannel Content, Michael Morale, shares his perspectives on his upcoming maintenance dose injection of Spinraza. Are you interested in understanding gene therapy? ExploreGeneTherapy.com has helpful information about gene therapy, including its history and how it is being investigated for the treatment of genetic diseases. Visit www.exploregenetherapy.com
Hearing how one of the world’s leading researchers on genetically engineered mouse models rises to success from his or her beginnings is a valuable experience for anyone pursuing the path of biomedical research. Transnetyx CEO, Bob Bean, sits down and interviews individuals impacting the world of science to discover characteristics, disciplines, and memorable moments that have shaped them. In this episode, Bob had the privilege to interview one of cancer research’s pioneers. Tyler Jacks, Ph.D., Director of the Koch Institute for Integrative Cancer Research at MIT, shares his journey from early childhood, his amazing circle of influence, the power of mentorship, and shares invaluable wisdom from his long career to aspiring researchers.
This week’s Boiling Point brought to you by Alex, Cat and Nick. Removal of tonsils and no worries? A recent study shows the long-term health impacts. Skin cells of mice as a new model for the ageing processes in the human brain, and ‘the man with the golden arm‘ and how he saved the lives […]
Scientists discuss the problems with using mice to study autism, and explain how the field might move forward. The post Spectrum Stories: Talking about autism mouse models appeared first on Spectrum | Autism Research News.
Dr Bouwman describes his talk delivered at the 3rd EurocanPlatform Translational Research Course on the need for mouse models in cancer research, and how these are the best way to investigate the different complex facets of cancer biology. He feels that mouse models will improve the rate of new cancer drugs reaching phase III trials and the market. He also describes the models they have made for breast cancer, what the next steps are for this work, what the obstacles are and what the eventual benefit will be.
Steve Brown, MRC, Harwell, UK speaks on "Mouse models for otitis media: dissecting the molecular basis of middle ear disease". This movie has been recorded at ICGEB Trieste.
Dr Berns speaks with ecancertv at EACR 2016 about modelling tumourigenesis in mice. He describes the value of moving from genomic testing and cellular screening to in vivo observations to determine the effect of trial therapeutics on a whole organism.
Researchers are now able to turn one cell type into another within the body of a mouse. But how can they make sure these changes happen in the right spot? To track the transformation of diseased liver cells into healthy ones, study leader Milad Rezvani of the University of California, San Francisco used a special kind of transgenic, or genetically altered, mouse model. "We focused primarily on one transgenic model that labels this cell type that is the main culprit in liver cirrhosis. So when we reprogrammed this cirrhosis-causing cell type into liver cells, it would maintain this label. We really knew where this cell was coming from." Although the cell transformation materials sent into the mouse ended up in some other places, like a few muscle cells, Rezvani says the amounts were negligible. More importantly, the mice revealed new patches of healthy liver tissue. "That’s why mice are extremely important, still, to not only understand disease, but to find new therapeutic approaches."
Tierärztliche Fakultät - Digitale Hochschulschriften der LMU - Teil 07/07
Glioblastoma multiforme (GBM) is the most common malignant primary brain tumour in adults with a median survival, despite of multimodal aggressive therapy, of only 15 months. Relapse occurs inevitably because of the infiltrative nature of GBM. To date, only the MGMT promoter methylation is a reliable marker for therapy sensitivity. Survival-associated prognostic factors as well as novel therapy targets are urgently needed. Multiple genetic and metabolic pathway alterations contribute to tumour progression and therapy resistance. Recently proposed CSC markers for solid cancers include the aldehyde dehydrogenase (ALDH) superfamily. This cytoplasmic enzyme family consists of 19 different isoforms. The ALDH enzymes act upon oxidative stress and participate in proliferation, differentiation, and cell cycle arrest. The evolutionary conservation of the protein family enables comparative considerations of different species. In the presented study, isotype specific expression of ALDH is analysed in human GBM tumours and in two commonly used mouse GBM models. Expression of ALDH in the mouse models is then compared with the human GBM to find a suitable model for further research. The presented results indicate that there is, though challenging, a necessity for isotype specific analysis of ALDH expression. ALDH1A1 immunohistochemical expression in human PGBM was found primarily in the tumour adjacent region, whereas ALDH1A3 positive cells were more frequently found among tumour cells. Prognostic relevance for PGBM patients’ outcome was found for the ALDH1 immunohistochemical expression. Moreover, female PGBM patients were shown to have prolonged survival if neither ALDH1A1 nor ALDH1A3 expression is present. For male PGBM patients, ALDH1A1 and ALDH1A3 immunohistochemical expression could not be correlated to the medium overall survival. The reasons for this gender difference remain yet undetermined. Both the murine and the human GBM cells analysed in this thesis did not show ALDH1A1 immunohistochemical expression in cell culture or after implantation. The expression of ALDH1A3 is inhomogeneous in the analysed groups, raising further questions, which will be investigated in the future.The investigative approach of this thesis showed that the analysed canine GBM samples express ALDH1A3 but not ALDH1A1. This difference to human PGBM tumours in ALDH expression can help to understand more about the metabolic processes in tumour cells and the reactions to the tumour cells in the surrounding tissue. Finally, there are two particularly promising research subjects for future investigations: the gender specific prognostic power of ALDH expression in PGBM patients and the reason for the change in ALDH1A3 expression between in vitro and in vivo conditions. This knowledge can contribute to finding new targets for PGBM therapy and to prolonging patient survival.
Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 05/06
Fri, 6 Jun 2014 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/17240/ https://edoc.ub.uni-muenchen.de/17240/1/Heger_Klaus-Dieter.pdf Heger, Klaus-Dieter ddc:570, dd
Dr Laura Soucek talks to ecancer at the 2013 AACR Annual Meeting in Washington DC about the inhibition of the Myc pathway in mouse models. The work conducted by the Mouse Models of Cancer Therapy group at the VHIO, led by Dr Laura Soucek, shows that Myc can be controlled and inhibited through a mutant called Omomyc that hijacks Myc and prevents it from acting. In the study, multiple lung tumours were induced in the mouse (up to 200 tumours in each individual) and Myc inhibition episodes were achieved by activating Omomyc expression for 4-weeks, followed by 4-week rest periods. This therapy - known as metronomic therapy - was maintained for more than a year, regularly checking tumour progress in each mouse.
Dr Laura Soucek talks to ecancer at the 2013 AACR Annual Meeting in Washington DC about the inhibition of the Myc pathway in mouse models. The work conducted by the Mouse Models of Cancer Therapy group at the VHIO, led by Dr Laura Soucek, shows that Myc can be controlled and inhibited through a mutant called Omomyc that hijacks Myc and prevents it from acting. In the study, multiple lung tumours were induced in the mouse (up to 200 tumours in each individual) and Myc inhibition episodes were achieved by activating Omomyc expression for 4-weeks, followed by 4-week rest periods. This therapy - known as metronomic therapy - was maintained for more than a year, regularly checking tumour progress in each mouse.
Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 05/06
Ein großer Teil der Fragestellungen in den Neurowissenschaften beschäftigt sich mit dem Thema, wie das Säugerhirn Verhalten auslöst und steuert. Die Schreckreaktion ist ein relativ einfaches Verhalten, welches bei Säugetieren ohne großen Aufwand ausgelöst werden kann und variabel auf eine Vielfalt von experimentellen Behandlungen reagiert. Das Ziel der vorliegenden Arbeit war es, Schreckreaktions-Messungen am Max-Planck- Institut für Psychiatrie in München (MPI-P) zu etablieren. Vor dem Hintergrund aktueller Fragestellungen sollten die Experimente zu einsatzbereiten Messmethoden und Verhaltensparadigmen führen. In der vorliegenden Arbeit gelang es nicht, das Paradigma der furchtpotenzierten Schreckreaktion (FPS) zuverlässig in einem häufig am MPI-P eingesetzten Mausstamm anzuwenden. Das FPS maskierende Phänomen, daß die Präsentation eines unkonditionierten Tons bereits zu einer deutlich verstärkten Schreckreaktion in diesen Mäusen führt ("tone enhanced startle", TES) wurde dann charakterisiert und im Folgenden als ergänzendes Paradigma zur Messung und Abschätzung des Hörvermögens, der Stimulus Adaptation und der Aufmerksamkeit in Mäusen vorgeschlagen. Eine Literaturrecherche ergab, daß im Paradigma der Furchtkonditionierung ("fear conditioning", FC) und deren aktives Verlernen ("extinction of FC", ExFC) verwendete Stimulus-Parameter eine hohe Varianz zwischen verschiedenen Laboratorien aufweisen. Der im Verhalten ausgelesene Lernerfolg während einer FC wie auch einem ExFC hingen in den vorliegenden Experimenten wesentlich von der verwendeten Stimulusqualität ab (d.h. sinus-Ton oder weißes Rauschen). Im Umkehrschluß empfiehlt die vorliegende Arbeit einen überlegteren Umgang mit den eingetzten Stimulus-Parametern. Es zeigte sich, daß eine erhöhte Schreckreaktion (Übererregbarkeit) ohne weiteres in einem Tiermodell der Posttraumatischen Belastungsstörung ("posttraumatic stress disorder",PTSD) gemessen werden kann. Im Weiteren konnte gezeigt werden, daß verändertes Hippocampus-Volumen in diesen Tieren, gemessen über ultramikroskopische Aufnahmen und analog zu Hippocampusveränderungen in Patienten, unabhängig von anderen PTSD-ähnlichen Symptomen dieser Mäuse ist. In einem weiteren Abschnitt widmet sich die vorliegende Arbeit der laufenden Charakterisierung der Rolle von Dopaminrezeptoren (DR) in der Präpulsinhibition (PPI) und -Faszilitierung (PPF) der Schreckreaktion. Durch lokale injektion von DR-Antagonisten konnte gezeigt werden, daß die Blockade von DR1 wiederholbar PPI verstärkt, während die Rolle von DR2, getestet mit zwei verschiedenen Antagonisten, als ambivalent gedeutet werden muß. Basierend auf diesen Experimenten wurden optogenetische Methoden in die Schreckreaktionsmessung eingeführt. Transgenen Mäusen, die lichtsensitive Ionenkanäle in ihren neuronalen Zellmembranen bestimmter Zellpopulationen tragen, wurden Lichtblitze ins Gehirn appliziert. Auf diese Weise konnten PPI und PPF unabhängig voneinander manipuliert werden. Daraus folgend, und im Unterschied zur populären Summationshypothese der PPF, schlägt die vorliegende Arbeit einen eigenständigen, von der PPI unabhängigen PPF-Schaltkreis vor, der Pyramidenneuronen der präfrontalen Kortexschicht V beinhaltet. Die vorliegende Arbeit konnte erfolgreich verschiedene Protokolle und Verhaltensparadigmen der Schreckreaktionsmessung am MPI-P etablieren und zur sofortigen Nutzung zur Verfügung stellen. Es wurden nicht nur neue Techniken wie z.B. optogenetische Methoden in die Schreckreaktionsmessung eingeführt, die vorliegenden Experiemente leisten auch ihren Beitrag zur aktiven Forschung, in dem sie z.B. die große Bedeutung der Stimulus-Parameter für den Lernerfolg von Versuchstieren nachweisen.
Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 04/06
Tue, 8 May 2012 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/14380/ https://edoc.ub.uni-muenchen.de/14380/1/Widner_Andrae_Regina.pdf Widner-Andrä, Regina Andrea ddc:570, ddc:500, Faku
Graduate School of Systemic Neurosciences - Digitale Hochschulschriften der LMU
Thu, 12 Jan 2012 12:00:00 +0100 http://edoc.ub.uni-muenchen.de/14767/ http://edoc.ub.uni-muenchen.de/14767/1/Behrendt_Mona_Gwendolyn.pdf Behrendt, Mona Gwendolyn Graduate School of Systemic N
Dr. Ben Stanger discusses his manuscript "Inhibition of gamma-Secretase Activity Inhibits Tumor Progression in a Mouse Model of Pancreatic Ductal Adenocarcinoma." To view the print version of this abstract go to http://tinyurl.com/cs4ms9
Kwok-Kin Wong, MD, PhD, Dana-Farber Cancer Institute, Boston, Massachusetts
Tierärztliche Fakultät - Digitale Hochschulschriften der LMU - Teil 05/07
Sat, 30 Jul 2011 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/13417/ https://edoc.ub.uni-muenchen.de/13417/1/Kumar_Sudhir.pdf Kumar, Sudhir ddc:590, d
John M. Hancock, Medical Research Council, Harwell - UK, speaks on " Finding mouse models of disease". This seminar has been recorded at ICTP Trieste by ICGEB Trieste
Guest Lecturer from NIMH from 5 November 2010.
DLS from March 10, 2010
Enhanced Video PodcastAired date: 3/11/2010 3:00:00 PM Eastern Time
Enhanced Audio PodcastAired date: 3/11/2010 3:00:00 PM Eastern Time
Tierärztliche Fakultät - Digitale Hochschulschriften der LMU - Teil 04/07
Sat, 13 Feb 2010 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/13029/ https://edoc.ub.uni-muenchen.de/13029/1/Buerck_Lelia_van.pdf Bürck, Lelia van
Guest: Thomas Seyfried, PhD Host: Bruce Bloom, DDS, JD We almost always cure mice of cancer, but the same treatment often fails in humans. Is the problem the mouse model? Join host Dr. Bruce Bloom, and his guest, Dr. Thomas Seyfried, professor of biology at Boston College and associate editor of the Journal of Nutrition and Metabolism, as they review the first mouse model that manifests all the major hallmarks of human metastatic cancer.
Tierärztliche Fakultät - Digitale Hochschulschriften der LMU - Teil 02/07
Fri, 11 Feb 2005 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/3404/ https://edoc.ub.uni-muenchen.de/3404/1/Fisch_Thomas_M.pdf Fisch, Thomas Martin
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