Podcasts about sox2

In this episode of the Epigenetics Podcast, we talked with Tanja Vogel from the University Clinics Freiburg about her work on epigenetic modifications in stem cells during central nervous system development. During our discussion, Dr. Vogel shared that she and her team have investigated H3K79 methylation and its functional significance, which remains a topic of debate in the scientific community. They've also investigated the role of DOT1L in neural development and its implications for neuronal networks, as disrupting DOT1L can lead to conditions such as epilepsy and schizophrenia. They explored the function of the SOX2 enhancer in the presence or absence of DOT1L enzymatic inhibition. The conversation then shifts to FoxG1, a vital player in forebrain development. The team uncovered its role in chromatin accessibility and its connection to microRNA processing. Their study, utilizing ChIP-Seq, reveals FoxG1's interactions with enhancer regions and other transcription factors, like NeuroD1.   ### References Britanova, O., de Juan Romero, C., Cheung, A., Kwan, K. Y., Schwark, M., Gyorgy, A., Vogel, T., Akopov, S., Mitkovski, M., Agoston, D., Sestan, N., Molnár, Z., & Tarabykin, V. (2008). Satb2 is a postmitotic determinant for upper-layer neuron specification in the neocortex. Neuron, 57(3), 378–392. https://doi.org/10.1016/j.neuron.2007.12.028 Büttner, N., Johnsen, S. A., Kügler, S., & Vogel, T. (2010). Af9/Mllt3 interferes with Tbr1 expression through epigenetic modification of histone H3K79 during development of the cerebral cortex. Proceedings of the National Academy of Sciences of the United States of America, 107(15), 7042–7047. https://doi.org/10.1073/pnas.0912041107 Franz, H., Villarreal, A., Heidrich, S., Videm, P., Kilpert, F., Mestres, I., Calegari, F., Backofen, R., Manke, T., & Vogel, T. (2019). DOT1L promotes progenitor proliferation and primes neuronal layer identity in the developing cerebral cortex. Nucleic acids research, 47(1), 168–183. https://doi.org/10.1093/nar/gky953 Ferrari, F., Arrigoni, L., Franz, H., Izzo, A., Butenko, L., Trompouki, E., Vogel, T., & Manke, T. (2020). DOT1L-mediated murine neuronal differentiation associates with H3K79me2 accumulation and preserves SOX2-enhancer accessibility. Nature communications, 11(1), 5200. https://doi.org/10.1038/s41467-020-19001-7 Akol, I., Izzo, A., Gather, F., Strack, S., Heidrich, S., Ó hAilín, D., Villarreal, A., Hacker, C., Rauleac, T., Bella, C., Fischer, A., Manke, T., & Vogel, T. (2023). Multimodal epigenetic changes and altered NEUROD1 chromatin binding in the mouse hippocampus underlie FOXG1 syndrome. Proceedings of the National Academy of Sciences of the United States of America, 120(2), e2122467120. https://doi.org/10.1073/pnas.2122467120   Related Episodes Molecular Mechanisms of Chromatin Modifying Enzymes (Karim-Jean Armache)   Contact Epigenetics Podcast on Twitter Epigenetics Podcast on Instagram Epigenetics Podcast on Mastodon Epigenetics Podcast on Bluesky Active Motif on Twitter Active Motif on LinkedIn Email: podcast@activemotif.com

Ronald DePinho, M.D., explains how telomerase, typically linked to telomere maintenance, serves as a transcriptional co-activator in the brain. Epigenetic repression of TERT, the gene for telomerase, occurs with aging, contributing to aging hallmarks like cellular senescence and inflammation. DePinho's team developed a compound that reactivates TERT, which, when administered to mice, reverses age-related changes. It restores cognitive function, reduces amyloid plaque, and alleviates inflammation. This suggests that maintaining TERT levels can counteract age-related cognitive decline and neurodegeneration, offering potential for treating neurodegenerative diseases like Alzheimer's. DePinho's work expands our understanding of telomerase's multifaceted role in aging and neurodegeneration, holding promise for interventions against these age-related processes. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 39071]

Ronald DePinho, M.D., explains how telomerase, typically linked to telomere maintenance, serves as a transcriptional co-activator in the brain. Epigenetic repression of TERT, the gene for telomerase, occurs with aging, contributing to aging hallmarks like cellular senescence and inflammation. DePinho's team developed a compound that reactivates TERT, which, when administered to mice, reverses age-related changes. It restores cognitive function, reduces amyloid plaque, and alleviates inflammation. This suggests that maintaining TERT levels can counteract age-related cognitive decline and neurodegeneration, offering potential for treating neurodegenerative diseases like Alzheimer's. DePinho's work expands our understanding of telomerase's multifaceted role in aging and neurodegeneration, holding promise for interventions against these age-related processes. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 39071]

Ronald DePinho, M.D., explains how telomerase, typically linked to telomere maintenance, serves as a transcriptional co-activator in the brain. Epigenetic repression of TERT, the gene for telomerase, occurs with aging, contributing to aging hallmarks like cellular senescence and inflammation. DePinho's team developed a compound that reactivates TERT, which, when administered to mice, reverses age-related changes. It restores cognitive function, reduces amyloid plaque, and alleviates inflammation. This suggests that maintaining TERT levels can counteract age-related cognitive decline and neurodegeneration, offering potential for treating neurodegenerative diseases like Alzheimer's. DePinho's work expands our understanding of telomerase's multifaceted role in aging and neurodegeneration, holding promise for interventions against these age-related processes. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 39071]

Ronald DePinho, M.D., explains how telomerase, typically linked to telomere maintenance, serves as a transcriptional co-activator in the brain. Epigenetic repression of TERT, the gene for telomerase, occurs with aging, contributing to aging hallmarks like cellular senescence and inflammation. DePinho's team developed a compound that reactivates TERT, which, when administered to mice, reverses age-related changes. It restores cognitive function, reduces amyloid plaque, and alleviates inflammation. This suggests that maintaining TERT levels can counteract age-related cognitive decline and neurodegeneration, offering potential for treating neurodegenerative diseases like Alzheimer's. DePinho's work expands our understanding of telomerase's multifaceted role in aging and neurodegeneration, holding promise for interventions against these age-related processes. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 39071]

Ronald DePinho, M.D., explains how telomerase, typically linked to telomere maintenance, serves as a transcriptional co-activator in the brain. Epigenetic repression of TERT, the gene for telomerase, occurs with aging, contributing to aging hallmarks like cellular senescence and inflammation. DePinho's team developed a compound that reactivates TERT, which, when administered to mice, reverses age-related changes. It restores cognitive function, reduces amyloid plaque, and alleviates inflammation. This suggests that maintaining TERT levels can counteract age-related cognitive decline and neurodegeneration, offering potential for treating neurodegenerative diseases like Alzheimer's. DePinho's work expands our understanding of telomerase's multifaceted role in aging and neurodegeneration, holding promise for interventions against these age-related processes. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 39071]

Ronald DePinho, M.D., explains how telomerase, typically linked to telomere maintenance, serves as a transcriptional co-activator in the brain. Epigenetic repression of TERT, the gene for telomerase, occurs with aging, contributing to aging hallmarks like cellular senescence and inflammation. DePinho's team developed a compound that reactivates TERT, which, when administered to mice, reverses age-related changes. It restores cognitive function, reduces amyloid plaque, and alleviates inflammation. This suggests that maintaining TERT levels can counteract age-related cognitive decline and neurodegeneration, offering potential for treating neurodegenerative diseases like Alzheimer's. DePinho's work expands our understanding of telomerase's multifaceted role in aging and neurodegeneration, holding promise for interventions against these age-related processes. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 39071]

Ronald DePinho, M.D., explains how telomerase, typically linked to telomere maintenance, serves as a transcriptional co-activator in the brain. Epigenetic repression of TERT, the gene for telomerase, occurs with aging, contributing to aging hallmarks like cellular senescence and inflammation. DePinho's team developed a compound that reactivates TERT, which, when administered to mice, reverses age-related changes. It restores cognitive function, reduces amyloid plaque, and alleviates inflammation. This suggests that maintaining TERT levels can counteract age-related cognitive decline and neurodegeneration, offering potential for treating neurodegenerative diseases like Alzheimer's. DePinho's work expands our understanding of telomerase's multifaceted role in aging and neurodegeneration, holding promise for interventions against these age-related processes. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 39071]

Ronald DePinho, M.D., explains how telomerase, typically linked to telomere maintenance, serves as a transcriptional co-activator in the brain. Epigenetic repression of TERT, the gene for telomerase, occurs with aging, contributing to aging hallmarks like cellular senescence and inflammation. DePinho's team developed a compound that reactivates TERT, which, when administered to mice, reverses age-related changes. It restores cognitive function, reduces amyloid plaque, and alleviates inflammation. This suggests that maintaining TERT levels can counteract age-related cognitive decline and neurodegeneration, offering potential for treating neurodegenerative diseases like Alzheimer's. DePinho's work expands our understanding of telomerase's multifaceted role in aging and neurodegeneration, holding promise for interventions against these age-related processes. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 39071]

Ronald DePinho, M.D., explains how telomerase, typically linked to telomere maintenance, serves as a transcriptional co-activator in the brain. Epigenetic repression of TERT, the gene for telomerase, occurs with aging, contributing to aging hallmarks like cellular senescence and inflammation. DePinho's team developed a compound that reactivates TERT, which, when administered to mice, reverses age-related changes. It restores cognitive function, reduces amyloid plaque, and alleviates inflammation. This suggests that maintaining TERT levels can counteract age-related cognitive decline and neurodegeneration, offering potential for treating neurodegenerative diseases like Alzheimer's. DePinho's work expands our understanding of telomerase's multifaceted role in aging and neurodegeneration, holding promise for interventions against these age-related processes. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 39071]

Ronald DePinho, M.D., explains how telomerase, typically linked to telomere maintenance, serves as a transcriptional co-activator in the brain. Epigenetic repression of TERT, the gene for telomerase, occurs with aging, contributing to aging hallmarks like cellular senescence and inflammation. DePinho's team developed a compound that reactivates TERT, which, when administered to mice, reverses age-related changes. It restores cognitive function, reduces amyloid plaque, and alleviates inflammation. This suggests that maintaining TERT levels can counteract age-related cognitive decline and neurodegeneration, offering potential for treating neurodegenerative diseases like Alzheimer's. DePinho's work expands our understanding of telomerase's multifaceted role in aging and neurodegeneration, holding promise for interventions against these age-related processes. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 39071]

A new editorial paper was published in Oncotarget's Volume 14 on May 26, 2023, entitled, “Combined targeting of HEDGEHOG signaling and BRD4 as a novel therapeutic option against melanoma.” The Hedgehog-GLI (HH/GLI) pathway is aberrantly activated in several types of cancer. Canonical HH/ GLI pathway is triggered by binding of HH ligands to the twelve-pass transmembrane receptor Patched 1 (PTCH1), which retrieves its inhibition on the seven-pass transmembrane G protein-coupled receptor Smoothened (SMO), leading to the activation of the GLI transcription factors. Small molecules inhibitors targeting the essential pathway transducer SMO (e.g., vismodegib, sonidegib) have demonstrated therapeutic efficacy in HH-dependent tumors, such as basal cell carcinoma (BCC) and medulloblastoma (MB). However, the therapeutic efficacy of these SMO antagonists is limited by the development of acquired resistance and recurrence after drug withdrawal, and by additional oncogenic signals responsible for noncanonical activation of GLI transcription factors [1]. In this new editorial, researchers Silvia Pietrobono and Barbara Stecca from the University of Verona and the Institute for Cancer Research and Prevention (CRL-ISPRO) state that they subscribe to the idea that targeting non-canonical HH/GLI signaling will improve the response rate and durability of therapeutic effects exerted by SMO inhibition. Therefore, they propose that the identification of novel targetable regulators that function downstream of SMO, especially those acting at the transcriptional level, is of critical importance to effectively inhibit the HH pathway and prevent tumor relapse. “Collectively, the findings presented by Pietrobono et al. pave the path for the development of a novel therapeutic strategy in tumors having both canonical and non-canonical HH/GLI signaling activation, such as melanoma.” DOI - https://doi.org/10.18632/oncotarget.28441 Correspondence to - Silvia Pietrobono - silvia.pietrobono@univr.it, and Barbara Stecca - b.stecca@ispro.toscana.it Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28441 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, melanoma, hedgehog signaling, BRD4, SOX2, GLI1 About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.02.547408v1?rss=1 Authors: Nguyen, V., Gao, C., Hochman, M., Kravitz, J., Chen, E., Friedman, H., Wenceslau, C., Chen, D., Wang, Y., Nelson, J. S., Jegga, A. G., Tan, W. Abstract: Background: Port Wine Birthmark (PWB) is a congenital vascular malformation resulting from developmentally defective endothelial cells (ECs). Developing clinically relevant disease models is an unmet need for PWB studies. Objective: This study aims to generate PWB-derived induced pluripotent stem cells (iPSCs) and those-iPSC-derived ECs that preserve disease-related phenotypes. Method: PWB iPSCs were generated by reprogramming lesional dermal fibroblasts and were differentiated into ECs. Bulk RNA-seq and ATAC-seq were performed to identify enriched pathways. The functional phenotypes of iPSC-derived ECs were characterized using capillary-like structure (CLS) formation in vitro and Geltrex plug-in assay in vivo. Result: Human PWB and normal iPSC lines were generated through reprogramming of dermal fibroblasts by introducing the Yamanaka factors (Oct3/4, Sox2, Klf4, c-Myc) into them; The iPSCs were differentiated into ECs. These iPSCs and their-derived ECs were validated by expression of series of stem cell and EC biomarkers, respectively. PWB EC showed impaired CLS in vitro with larger perimeters and thicker branches comparing with control iPSC-derived ECs. In plug-in assay, perfused human vasculature formed by PWB iPSC-derived ECs showed bigger perimeters and greater densities than those formed by control iPSC-derived ECs in SCID mice. The transcriptome analysis showed that the impaired pathways of stem cell differentiation, Hippo, Wnt, and focal adhersion persisted through PWB iPSCs to ECs during differentiation. Interactive networks showed that the Hippo and Wnt pathway-related differentially expressed genes (DEGs) significantly function in vasculature development, tube morphology, endothelium development, and EC differentiation. Members of zinc-finger (ZNF) gene family were among the top changed DEGs in both PWB iPSCs and ECs. The ZNF DEGs confer significant functions in transcriptional regulation, chromatin remodeling, protein ubiquitination, and retinol acid pathway. In addition, NF-kappa B, TNF, MAPK, and cholesterol metabolism pathways were upregulated in PWB ECs as readouts of impaired differentiation. Conclusion: PWB iPSC-derived ECs can be served as novel and clinically relevant disease models by retaining pathological phenotypes. Our data suggests the impaired Hippo and Wnt pathways underlie the development of differentiation-defective ECs in PWB lesions. 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/2023.04.25.538222v1?rss=1 Authors: Platania, A., Erb, C., Barbieri, M., Molcrette, B., Grandgirard, E., de Kort, M. A., Meaburn, K., Taylor, T., Shchuka, V. M., Kocanova, S., Monteiro Oliveira, G., Mitchell, J. A., Soutoglou, E., Lenstra, T. L., Molina, N., Papantonis, A., Bystricky, K., Sexton, T. Abstract: The spatiotemporal configuration of genes with distal regulatory elements, and the impact of chromatin mobility on transcription, remain unclear. Loop extrusion is an attractive model for bringing genetic elements together, but how this functionally interacts with transcription is also largely unknown. We combine live tracking of genomic loci and nascent transcripts with molecular dynamics simulations to assess the 4D arrangement of the Sox2 gene and its enhancer, in response to a battery of perturbations. We find that alterations in chromatin mobility, not promoter-enhancer distance, is more informative about transcriptional status. Active elements display more constrained mobility, consistent with confinement within specialized nuclear sites, and alterations in enhancer mobility distinguish poised from transcribing alleles. Strikingly, we find that whereas loop extrusion and transcription factor-mediated clustering contribute to promoter-enhancer proximity, they have antagonistic effects on chromatin dynamics. This provides an experimental framework for the underappreciated role of chromatin dynamics in genome regulation. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.22.533592v1?rss=1 Authors: Yu, X., Yuan, H., Yang, Y., Zheng, W., Zheng, X., Lu, S.-H., Jiang, W., Yu, X. Abstract: Self-renewing, damage-repair and differentiation of mammalian stratified squamous epithelia are subject to tissue homeostasis, but the regulation mechanisms remain elusive. Here, we investigate the esophageal squamous epithelial tissue homeostasis in vitro and in vivo. We establish a rat esophageal organoid (rEO) in vitro system and show that the landscapes of rEO formation, development and maturation trajectories can mimic those of rat esophageal epithelia in vivo. Single-cell RNA sequencing (scRNA-seq), snap-shot immunostaining and functional analyses of stratified "matured" rEOs define that the epithelial pluripotent stem-cell determinants, p63 and Sox2, play crucial but distinctive roles for regulating mammalian esophageal tissue homeostasis. We identify two cell populations, p63+Sox2+ and p63-Sox2+, of which the p63+Sox2+ population presented at the basal layer is the cells of origin required for esophageal epithelial stemness maintenance and proliferation whereas the p63-Sox2+ population presented at the suprabasal layers is the cells of origin having a dual role for esophageal epithelial differentiation (differentiation-prone fate) and rapid tissue damage-repair responses (proliferation-prone fate). Given the fact that p63 and Sox2 are developmental lineage oncogenes and commonly overexpressed in ESCC tissues, p63-Sox2+ population could not be detected in organoids formed by esophageal squamous cell carcinoma (ESCC) cell lines. Taken together, these findings reveal that the tissue homeostasis is maintained distinctively by p63 and/or Sox2 dependent cell lineage populations required for the tissue renewing, damage-repair and protection of carcinogenesis in mammalian esophagi. 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/2023.02.28.530533v1?rss=1 Authors: Avila Lopez, J., Abboud, C., Ibrahim, M., Rocha Ahumada, J., Avino, M., Plourde, M., Fernandes, K., Bentzinger, C. F., Laurent, B. Abstract: In vivo reprogramming using the transient expression of Oct3/4, Sox2, Klf4 and c-Myc (OSKM) transcription factors can be used to induce tissue regeneration. A cyclic regime for short-term OSKM expression has been shown to promote regeneration of several organs however its impact on the brain remains largely unknown. We investigated the effects of a cyclic short-term OSKM expression on the choroid plexus (CP), a highly vascularized tissue found within the brain ventricles which is responsible for producing the cerebrospinal fluid (CSF). Transient reprogramming was done on 8-week-old mice carrying the polycistronic OSKM cassette under tetracycline operator (tetO) and confirmed the successful transient reprogramming. We then performed the analysis of the CP at cellular and molecular levels. The CP tissue exhibited minor morphological changes in height and area of epithelial cells. We did not observe any significant differences in the integrity of the brain-CSF barrier but noticed an increase of NKCC1 expression, a protein involved in CSF production. A whole transcriptome analysis (RNA-seq) was also carried on the tissue and showed no difference in gene expression after the transient reprogramming, at the exception of blood-related genes. Our results indicate that surprisingly the CP mainly remains insensible to in vivo transient reprogramming as only morphological and protein changes were observed in the tissue, suggesting that translational changes might be at stake during the reprogramming process but are not present at the transcriptomic level. Our results also highlight that more tailored strategies need to be developed for exploring the potential of CP reprogramming in regenerative medicine. 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/2023.02.25.530001v1?rss=1 Authors: Kim, J., Kim, S., Lee, S.-Y., Jo, B.-K., Oh, J.-Y., Kwon, E.-J., Kim, K.-T., Adpaikar, A., Kim, E.-J., Jung, H.-S., Kim, H.-R., Roe, J.-S., Hong, C. P., Kim, J. K., Koo, B. K., Cha, H.-J. Abstract: Tissue regeneration after injury involves the dedifferentiation of somatic cells, a natural adaptive reprogramming process that leads to the emergence of injury-responsive cells with fetal-like characteristics in the intestinal epithelium. However, there is no direct evidence that adaptive reprogramming involves a shared molecular mechanism with direct cellular reprogramming. Here, we induced dedifferentiation of intestinal epithelial cells through forced partial reprogramming in vivo using Yamanaka factors (Oct4, Sox2, Klf4, and c-Myc: OSKM). The OSKM-induced dedifferentiation showed similar molecular features of intestinal regeneration, including a rapid transition from homeostatic cell types to injury-responsive-like cell types. These injury-responsive-like cells, sharing a gene signature of revival stem cells and atrophy-induced villus epithelial cells, actively assisted tissue regeneration following ionizing radiation-induced acute tissue damage. In contrast to normal intestinal regeneration, which involves epi-mesenchymal crosstalk through induction of Ptgs2 (encoding Cox2) upon injury, the OSKM expression promotes the autonomous production of prostaglandin E2 via epithelial Ptgs1 (encoding Cox1) expression. These results indicate that prostaglandin synthesis is a common mechanism for intestine epithelial regeneration, but involves a different enzyme (Ptgs1 for Cox1) when partial reprogramming is directly applied to the intestinal epithelium. 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/2023.02.24.529879v1?rss=1 Authors: Duarte Guterman, P., Richard, J., Lieblich, S., Eid, R., Lamers, Y., Galea, L. Abstract: Pregnancy is marked by robust changes involving all organ systems, including brain changes to volume, structure, connectivity, and neuroplasticity. Although some brain changes are restricted to pregnancy and the postpartum, others are long-lasting. Few studies have examined possible mechanisms of these change or and the effects of multiple pregnancies. Here, we characterized various cellular and molecular signatures of parity (nulliparous, primiparous, biparous) in the hippocampus, an important area for cognitive and emotional regulation. We investigated density of neural stems cells(Sox2), microglia (Iba-1), and levels of a synaptic protein (PSD-95), cell signalling pathways, neuroinflammation, and the tryptophan-kynurenine (TRP-KYN) pathway, 1 week after weaning (7 months) and in middle-age (13 months). Parity increased PSD-95 levels in both age groups and prevented the age-related decrease in neural stem cell density observed in nulliparous rats. Biparity increased cell signalling phosphoproteins (pp706sk, S6RP) and number of microglia in the dentate gyrus, regardless of age. Parity resulted in transient changes to the TRP-KYN system. Thus, previous parity has lasting effects on synaptic plasticity and alters the trajectory of hippocampal aging. 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/2023.02.09.527879v1?rss=1 Authors: Jensen, G. S., Beaulieu, A. N., Curtis, C. D., Passarelli, J., Blaszkiewicz, M., Thomas, S., Morin, T., Willows, J. W., Greco, C. W., Brennan, C. J., Aniapam, C., Caron, L., Alves, M. J., Lynes, M. D., Carlone, D. L., Breault, D. T., Townsend, K. L. Abstract: Telomerase reverse transcriptase (TERT) is expressed by quiescent adult stem cells (ASC) in numerous adult murine and human tissues, but has never been explored in the adult brain. Here, we demonstrate that TERT+ cells in the adult mouse brain represent a novel population of multipotent ASCs that are localized to numerous classical neuro/gliogenic niches (including the ventricular-subventricular zone, hypothalamus, and olfactory bulb), as well as more recently described regions of adult brain plasticity such as the meninges and choroid plexus. Using a direct-reporter mouse line, we found that TERT+ cells expressed known neural stem cell markers such as Nestin and Sox2, but not markers of committed stem/progenitor cells, nor markers of mature neuronal or glial cells. TERT+ ASCs rarely expressed the proliferation marker Ki67, and in vitro TERT+ cells lost TERT expression when activated by growth factors, together indicating a quiescent phenotype similar to what has been observed in other tissues. When cultured, TERT+ cells behaved like neural stem cells by forming neurospheres, which could proliferate and become more metabolically active once stimulated by growth factors. TERT+ cells were observed in numerous brain niches, particularly near the ventricles and cerebrospinal fluid barriers, but notably, TERT+ cells were never observed in the hippocampus. Lineage tracing of TERT+ cells in adult transgenic mice (mTERTrtTA::oTET-Cre::RosamTmG) revealed large-scale expansion of TERT+ progeny and differentiation to diverse cell types in multiple brain regions. For example, lineage-traced cells expressed markers of mature neurons, oligodendrocytes, astrocytes, ependymal cells, and choroid epithelial cells, thus demonstrating the striking multipotency of this stem cell population in basal tissue turnover of the adult brain. Together, these data demonstrate that TERT+ cells represent a novel population of multipotent stem cells that contribute to basal plasticity and regeneration in the adult mouse brain. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.01.526619v1?rss=1 Authors: Anton Fernandez, A., Cuadros, R., Peinado-Cahuchola, R., Hernandez, F., Avila, J. Abstract: Here we report a novel strategy to rejuvenate dentate gyrus cells in old mice. This approach involves the use of simple compounds such as folate and a peptide that binds to folate receptor alpha. The injection of folate or folate-mimicking peptide into the brain brought about a significant enhancement of cognition. Likewise, the dentate gyrus cells of these mice showed increased plasticity and DNA methylation levels. On the basis of our findings, we propose that folate, and folate-mimicking peptides acting on folate receptor alpha enhance neural plasticity in a similar fashion to the OSKM (Oct4, Sox2, Klf4, and Myc) Yamanaka factors. However, in marked contrast with the long-term cyclic treatment used for cell reprogramming with the latter, our method involves only a single injection of very simple small compounds. Our observations may facilitate future studies aimed at improving the clinical translation of cell reprogramming methods into the field of neurodegenerative disorders. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Videos: Brought to you by… Pfizer! FORMER PFIZER VP, DR. MIKE YEADON – EVERYTHING WE HAVE BEEN TOLD ABOUT COVID-19 WAS A LIE Fauci didn't want autopsies done on Covid victims. I wonder why? Dr. Peter McCullough SLAMS Pfizer board member over censorship and propaganda | Redacted News Study explores effects of dietary choline deficiency on neurologic and system-wide health Arizona State University, January 16, 2023 Choline, an essential nutrient produced in small amounts in the liver and found in foods including eggs, broccoli, beans, meat and poultry, is a vital ingredient for human health. A new study explores how a deficiency of dietary choline adversely affects the body and may be a missing piece in the puzzle of Alzheimer's disease. It's estimated that more than 90% of Americans are not meeting the recommended daily intake of choline. The current research, conducted in mice, suggests that dietary choline deficiency can have profound negative effects on the heart, liver and other organs. Lack of adequate choline is also linked with profound changes in the brain associated with Alzheimer's disease. These include pathologies implicated in the development of two classic hallmarks of the illness: amyloid plaques, which aggregate in the intercellular spaces between neurons; and tau tangles, which condense within the bodies of neurons. The new research, led by scientists at Arizona State University and published in Aging Cell, describes pathologies in normal mice deprived of dietary choline and in choline-deficient transgenic mice, the latter of which already exhibit symptoms associated with the disease. In both cases, dietary choline deficiency results in liver damage, enlargement of the heart and neurologic alterations in the AD mice, typically accompanying Alzheimer's disease and including increased levels of plaque-forming amyloid-beta protein and disease-linked alterations in tau protein. Further, the study illustrates that choline deficiency in mice causes significant weight gain, alterations in glucose metabolism (which are tied to conditions such as diabetes), and deficits in motor skills. In the case of humans, “it's a twofold problem,” according to Ramon Velazquez, senior author of the study and assistant professor with the ASU-Banner Neurodegenerative Disease Research Center. “First, people don't reach the adequate daily intake of choline established by the Institute of Medicine in 1998. And secondly, there is vast literature showing that the recommended daily intake amounts are not optimal for brain-related functions.” The research highlights a constellation of physical and neurological changes linked to choline deficiency. Sufficient choline in the diet reduces levels of the amino acid homocysteine, which has been recognized as a neurotoxin contributing to neurodegeneration, and is important for mediating functions such as learning and memory through the production of acetylcholine. The growing awareness of choline's importance should encourage all adults to ensure proper choline intake. This is particularly true for those on plant-based diets, which may be low in naturally occurring choline, given that many foods high in choline are eggs, meats, and poultry. Plant-based, choline-rich foods, including soybeans, Brussels sprouts and certain nuts can help boost choline in these cases. Moreover, inexpensive, over-the-counter choline supplements are encouraged to promote overall health and guard the brain from the effects of neurodegeneration. The new study examines mice at 3-12 months, or early to late adulthood (roughly equivalent to 20-60 years of age for humans). In the case of both normal and transgenic mice displaying symptoms of Alzheimer's, those exposed to a choline-deficient diet exhibited weight gain and adverse effects to their metabolism. Damage to the liver was observed through tissue analysis, as was enlargement of the heart. Elevated soluble, oligomeric and insoluble amyloid-beta protein were detected, as well as modifications to tau protein characteristic of those leading to neurofibrillary tangles in the brain. Further, choline-deficient mice performed poorly in a test of motor skills, when compared with mice receiving adequate choline in their diet. These adverse effects were heightened in the transgenic mice. Translating these findings to humans, this implies that people who are predisposed to Alzheimer's disease or in the throes of the illness should ensure they are getting enough choline.”Our work provides further support that dietary choline should be consumed on a daily basis given the need throughout the body,” Velazquez says. (NEXT) Melanoma: Vitamin D supplements linked to reduced skin cancer risk University of Eastern Finland & Kuopio University, January 15, 2023 A new study finds that the regular use of vitamin D is associated with lower rates of melanoma skin cancer. The cross-sectional study was a collaboration between the University of Eastern Finland and Kuopio University Hospital. The research involved 498 Finnish adults determined by dermatologists to be at high risk of skin cancer, such as melanoma, as well as squamous cell carcinoma and basal cell carcinoma. According to researchers, people who took vitamin D regularly were less likely to have had melanoma in the past or currently and were deemed by dermatologists to be less likely to develop melanoma in the future. Study participants ranged in age from 21 to 79 years old, including 253 males and 245 females. Participants were divided into three groups based on their intake of vitamin D supplements: non-use, occasional use, or regular use. The researchers were also interested in finding out whether regular use of vitamin D supplements corresponded to higher blood levels of vitamin D, known as serum calcidiol or 25-hydroxy-vitamin D3. This is the “storage form” of vitamin D in the body. Some research has linked low serum calcidiol with increased cancer risk, while other research has suggested otherwise. Nonetheless, it is a measure often used to determine a person's vitamin D levels. After testing serum calcidiol levels in 260 participants, researchers found that regular vitamin D supplementation corresponded with the highest levels of serum calcidiol and non-supplementation with the lowest levels. “Human skin itself expresses [the enzyme] CYP27A1 that produces calcidiol from vitamin D, and CYP27B1 that produces biologically very active calcitriol from calcidiol,” Dr. Harvima explained, noting that enzyme expression determines the level of vitamin D and its metabolites in the body. (NEXT) New research furthers case for exercise promoting youthfulness University of Arkansas, January 17, 2023 A recent paper published in the Journal of Physiology deepened the case for the youthfulness-promoting effects of exercise on aging organisms, building on previous work done with lab mice nearing the end of their natural lifespan that had access to a weighted exercise wheel. For this paper, the researchers compared aging mice that had access to a weighted exercise wheel with mice that had undergone epigenetic reprogramming via the expression of Yamanaka factors. The Yamanaka factors are four protein transcription factors (identified as Oct3/4, Sox2, Klf4 and c-Myc, often abbreviated to OKSM) that can revert highly specified cells (such as a skin cell) back to a stem cell, which is a younger and more adaptable state. The Nobel Prize in Physiology or Medicine was awarded to Dr. Shinya Yamanaka for this discovery in 2012. In the correct dosages, inducing the Yamanaka factors throughout the body in rodents can ameliorate the hallmarks of aging by mimicking the adaptability that is common to more youthful cells. Of the four factors, Myc is induced by exercising skeletal muscle. Myc may serve as a naturally induced reprogramming stimulus in muscle, making it a useful point of comparison between cells that have been reprogrammed via over expression of the Yamanaka factors and cells that have been reprogrammed through exercise—”reprogramming” in the latter case reflecting how an environmental stimulus can alter the accessibility and expression of genes. Ultimately, the team determined that exercise promotes a molecular profile consistent with epigenetic partial programming. That is to say, exercise can mimic aspects of the molecular profile of muscles that have been exposed to Yamanaka factors (thus displaying molecular characteristics of more youthful cells). This beneficial effect of exercise may in part be attributed to the specific actions of Myc in muscle. Murach sees their research as further validation of exercise as a polypill. “Exercise is the most powerful drug we have,” he says, and should be considered a health-enhancing—and potentially life-extending—treatment along with medications and a healthy diet. (NEXT) Exploiting the synergy of nutraceuticals for cancer prevention and treatment Research suggests that free radicals (ROS) generated upon mixing two nutraceuticals—resveratrol and copper—can help ameliorate various diseases by inactivating cell-free chromatin particles Tata Memorial Centre (India), January 16, 2023 Chromatin comprises a complex mixture of DNA and proteins that forms the structural basis of chromosomes in the cellular nuclei. When cells die, they release cell-free chromatin particles or “cfChPs” into the circulatory system. In 1996, evidence for tumour-derived DNA circulating in the blood of cancer patients was first reported. This evidence caught the interest Dr. Indraneel Mittra, who is now Professor Emeritus and the Dr. Ernest Borges Chair in Translational Research at Tata Memorial Centre in Mumbai, India. His tryst with research on genetic material in cancer metastases began, and after 15 years of research he has presented various papers, developing a body of evidence that indicates the critical role of cfChPs in orchestrating development of not only cancer, but various other diseases. Emerging evidence indicates that cfChPs play an essential role in ageing, sepsis, cancer development, and chemotherapy-related toxicity. With respect to the latter, Prof. Mittra explains, “Chemo-toxicity is not primarily caused by chemotherapeutic drugs, but rather by cfChPs that are released from the first cells that die after chemotherapy. The released cfChPs set in motion a cascading effect, increasingly damaging the DNA of healthy host cells, and triggering inflammatory processes in a vicious cycle that perpetuates and prolongs the toxicity of chemotherapy.” Recently, a team from Tata Memorial Centre have demonstrated the therapeutic benefits of a pro-oxidant mixture of resveratrol and copper, R-Cu, in patients undergoing chemotherapy for advanced gastric cancer. Combining R with Cu (R-Cu) leads to the generation of free oxygen radicals which can inactivate the offending cfChPs. In this context, the research team launched a single-arm phase II clinical trial to study the synergistic effects of R-Cu administration on cfChPs inactivation in patients with advanced gastric cancer. The primary objective was to determine whether R-Cu, via cfChPs' inactivation, was successful in reducing the grade ≥ 3 toxicity seen with docetaxel-based chemotherapies. To this end, the researchers monitored the likely changes in the toxicities of chemotherapeutic treatments using a grading system that provides a framework for the assessment of unwanted physiological effects. The results were promising—although R-Cu did not reduce haematological toxicities, it significantly reduced the incidence of non-haematological toxicities comprising hand-foot syndrome, diarrhoea, and vomiting. Moreover, R-Cu reduced docetaxel exposure compared to the control arm without affecting efficacy in terms of overall survival. (NEXT) Deep meditation may alter gut microbes for better health Shanghai Jiao Tong University School of Medicine (China), January 16, 2023 Regular deep meditation, practiced for several years, may help to regulate the gut microbiome and potentially lower the risks of physical and mental ill health, finds a small comparative study published in the open access journal General Psychiatry. The gut microbes found in a group of Tibetan Buddhist monks differed substantially from those of their secular neighbors, and have been linked to a lower risk of anxiety, depression, and cardiovascular disease. Research shows that the gut microbiome can affect mood and behavior through the gut–brain axis. This includes the body's immune response, hormonal signaling, stress response and the vagus nerve—the main component of the parasympathetic nervous system, which oversees an array of crucial bodily functions. The significance of the group and specimen design is that these deep-thinking Tibetan monks can serve as representatives of some deeper meditations. Although the number of samples is small, they are rare because of their geographical location. The researchers analyzed the stool and blood samples of 37 Tibetan Buddhist monks from three temples and 19 secular residents in the neighboring areas. None of the participants had used agents that can alter the volume and diversity of gut microbes: antibiotics; probiotics; prebiotics; or antifungal drugs in the preceding 3 months. Sample analysis revealed significant differences in the diversity and volume of microbes between the monks and their neighbors.”Collectively, several bacteria enriched in the meditation group [have been] associated with the alleviation of mental illness, suggesting that meditation can influence certain bacteria that may have a role in mental health,” write the researchers. These include Prevotella, Bacteroidetes, Megamonas and Faecalibacterium species, the previously published research suggests. Finally, blood sample analysis showed that levels of agents associated with a heightened risk of cardiovascular disease, including total cholesterol and apolipoprotein B, were significantly lower in the monks than in their secular neighbors by their functional analysis with the gut microbes. (NEXT) Curcumin/Boswellia shows promise in chronic kidney disease Baylor University, January 14, 2023. The Journal of Complementary and Integrative Medicine reports the finding of researchers at Baylor University of a reduction in a marker of inflammation among chronic kidney disease patients given a combination of Curcuma longa (curcumin) and Boswellia serrata. The study included sixteen individuals receiving standard care for chronic kidney disease who were not undergoing dialysis. Participants were randomized to receive capsules containing curcumin from turmeric extract plus Boswellia serrata, or a placebo for eight weeks. Blood samples collected before and after treatment were analyzed for plasma interleukin-6 (IL-6), tumor necrosis factor alpha (markers of inflammation), and the endogenous antioxidant enzyme glutathione peroxidase, as well as serum C-reactive protein (CRP, another marker of inflammation.) Blood test results from the beginning of the study revealed increased inflammation and reduced glutathione peroxide levels. At the study's conclusion, participants who received curcumin and Boswellia serrata experienced a reduction in interleukin-6 in comparison with pretreatment values, indicating decreased inflammation, while IL-6 values rose among those who received a placebo. In their discussion of the findings, the authors remark that curcumin and Boswellia serrata have been separately shown to lower interleukin-6 via inhibition of the nuclear factor kappa beta and mitogen activated protein kinase (MAPK) signaling pathways.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.08.519564v1?rss=1 Authors: Royan, M. R., Kayo, D., Weltzien, F.-A., Fontaine, R. Abstract: The two pituitary gonadotropins, Fsh and Lh, regulate the reproductive function in vertebrates. While many studies have investigated the regulation of gonadotropin production and release by the sex steroid feedback, its role on the regulation of gonadotrope cell number remains unclear. Using medaka as a model and an optimized protocol to restore physiological sex steroids levels following gonadectomy, we show that gonadal sex steroids not only decrease fshb transcript levels, but also Fsh cell number in both sexes. We then investigated the origin of the Fsh cell hyperplasia induced by gonadectomy. In both sexes, BrdU incubation shows that this is achieved via Fsh cell mitosis. In situ hybridization reveals that new Fsh cells also originate from transdifferentiating Tsh cells in females, but not in males. Both phenomena are inhibited by sex steroid supplementation via feeding. In males (but not females), gonadectomy (without recovery with sex steroid supplementation) also reduces sox2 transcript levels and Sox2-immunopositive population volume, suggesting that sox2-progenitors may be recruited to produce new Fsh cells. Opposite to Fsh cells, gonadectomy decreases lhb levels in both sexes, and levels are not restored by sex steroid supplementation. In addition, the regulation of Lh cell number also seems to be sex dependent. Removal of gonadal sex steroids stimulates Lh cell mitosis in male (like Fsh cells), but not in females. To conclude, our study provides the first evidence on sexually dimorphic mechanisms used in the fish pituitary to remodel gonadotrope populations in response to sex steroids. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Alysson Muotri discusses modeling Pitt-Hopkins syndrome (PTHS) using stem cells and brain organoids. He shares how rescuing TCF4 expression with CRISPR-mediated epigenetic induction of AAV vector delivery provides a gateway for targeted therapeutics for PTHS and related conditions. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 38516]

Alysson Muotri discusses modeling Pitt-Hopkins syndrome (PTHS) using stem cells and brain organoids. He shares how rescuing TCF4 expression with CRISPR-mediated epigenetic induction of AAV vector delivery provides a gateway for targeted therapeutics for PTHS and related conditions. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 38516]

Alysson Muotri discusses modeling Pitt-Hopkins syndrome (PTHS) using stem cells and brain organoids. He shares how rescuing TCF4 expression with CRISPR-mediated epigenetic induction of AAV vector delivery provides a gateway for targeted therapeutics for PTHS and related conditions. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 38516]

Alysson Muotri discusses modeling Pitt-Hopkins syndrome (PTHS) using stem cells and brain organoids. He shares how rescuing TCF4 expression with CRISPR-mediated epigenetic induction of AAV vector delivery provides a gateway for targeted therapeutics for PTHS and related conditions. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 38516]

Alysson Muotri discusses modeling Pitt-Hopkins syndrome (PTHS) using stem cells and brain organoids. He shares how rescuing TCF4 expression with CRISPR-mediated epigenetic induction of AAV vector delivery provides a gateway for targeted therapeutics for PTHS and related conditions. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 38516]

Alysson Muotri discusses modeling Pitt-Hopkins syndrome (PTHS) using stem cells and brain organoids. He shares how rescuing TCF4 expression with CRISPR-mediated epigenetic induction of AAV vector delivery provides a gateway for targeted therapeutics for PTHS and related conditions. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 38516]

Alysson Muotri discusses modeling Pitt-Hopkins syndrome (PTHS) using stem cells and brain organoids. He shares how rescuing TCF4 expression with CRISPR-mediated epigenetic induction of AAV vector delivery provides a gateway for targeted therapeutics for PTHS and related conditions. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 38516]

Alysson Muotri discusses modeling Pitt-Hopkins syndrome (PTHS) using stem cells and brain organoids. He shares how rescuing TCF4 expression with CRISPR-mediated epigenetic induction of AAV vector delivery provides a gateway for targeted therapeutics for PTHS and related conditions. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 38516]

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.30.510371v1?rss=1 Authors: Yagi, S., Wen, Y., Galea, L. Abstract: Estrone and estradiol differentially modulate neuroplasticity and cognition but how they influence maturation pathways of new neurons is not known. The present study assessed the effects of estrone and estradiol on various aspects of neurogenesis in the dentate gyrus (DG) of ovariectomized young adult Sprague-Dawley rats using daily subcutaneous injections of 17{beta}-estradiol or estrone. Rats were injected with a DNA synthesis marker, 5-bromo-2-deoxyuridine (BrdU), and were perfused one, two, or three weeks after BrdU injection and treatment. Immunofluorescent labelling for Sox2 and Ki67 were used to examine the density of neural stem cells and proliferating cells, respectively. Double-immunofluorescent labelling of BrdU with doublecortin (DCX) or NeuN was used to examine the attrition and maturation of adult-born neurons over time. Estradiol reduced the density of neural stem cells in the dorsal DG, whereas estrone reduced the density of neural stem cells in the ventral DG. Furthermore, estradiol enhanced, whereas estrone reduced, cell proliferation after one week but not after longer exposure to hormones. Both estrogens increased the density of BrdU/DCX-ir cells after one week of exposure but showed greater attrition of new neurons between one and two weeks after exposure. Lastly, estradiol decreased the percentage of BrdU/NeuN-ir cells in the dorsal DG after three weeks of treatment. These results demonstrate that estrogens have differential effects to modulate several aspects of adult hippocampal neurogenesis in the short term, but fewer effects after long-term exposure and that estradiol and estrone modulate neurogenesis via different pathways. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

News: NASA Solar Sail Spacecraft to Chase Tiny Asteroid After Artemis I Launch | SciTechDaily (01:25) Launching with the Artemis I uncrewed test flight, NASA's shoebox-size Near-Earth Asteroid Scout will chase down what will become the smallest asteroid ever to be visited by a spacecraft. The asteroid being targeted is, 2020 GEnear-Earth asteroid (NEA) that is less than 60 feet (18 meters) in size Asteroids smaller than 330 feet (100 meters) across have never been explored up close before. The spacecraft will use its science camera to get a closer look, measuring the object's size, shape, rotation, and surface properties. It will ride as one of 10 secondary payloads aboard the powerful Space Launch System (SLS) rocket, which will launch no earlier than March 2022. After it is dispensed in space it will use stainless steel alloy booms to unfurl a solar sail that will expand from a small package to a sail about the size of a racquetball court, or 925 square feet (86 square meters).Will generate thrust by reflecting solar photons – quantum particles of light radiating from the Sun Sunlight acts as a constant force, so a tiny spacecraft equipped with a large solar sail can eventually travel many miles per second. Maneuver by tipping and tilting its sail to change the angle of sunlight The mission will act as a nimble scout for future human and robotic missions that may utilize asteroid resources – and will gain important planetary defense insights about this class of NEA. Julie Castillo-Rogez, the mission's principal science investigator, provides insight as to why looking at even small asteroids are important:“Although large asteroids are of most concern from a planetary defense perspective, objects like 2020 GE are far more common and can pose a hazard to our planet, despite their smaller size.”   Altos bursts out of stealth with $3B, a dream team C-suite and a wildly ambitious plan to reverse disease | FierceBiotech (08:11) Early details of Altos leaked out last year when MIT Technology Review reported Jeff Bezos had invested to support development of technology that could “revitalize entire animal bodies, ultimately prolonging human life.” The official reveal fleshes out the vision in more detail Hal Barron, M.D, the future CEO of Altos, provided a statement on the company:“It's clear from work by Shinya Yamanaka, and many others since his initial discoveries, that cells have the ability to rejuvenate, resetting their epigenetic clocks and erasing damage from a myriad of stressors. These insights, combined with major advances in a number of transformative technologies, inspired Altos to reimagine medical treatments where reversing disease for patients of any age is possible.” Yamanaka is a 2012 Nobel Prize winner for the discovery of the ‘Yamanaka factors' — four transcription factors (Oct3/4, Sox2, c-Myc and Klf4) that can reprogram cells to roll back cellular aging and repair tissues.  Altos is bringing in the biggest names in life sciences to staff out their C level positions at the company. The team will use $3 billion in capital committed by investors to turn breakthroughs in our understanding of cellular rejuvenation into transformational medicines.  Co-founder, Rick Klausner, M.D., stated in a press release:"Remarkable work over the last few years beginning to quantify cellular health and the mechanisms behind that, coupled with the ability to effectively and safely reprogram cells and tissues via rejuvenation pathways, opens this new vista into the medicine of the future. Altos begins with many of the leading scientists who are creating this new science. Together, we are building a company where many of the world's best scientists can collaborate internally and externally and develop their research with the speed, mission, and focus of private enterprise. Our success will depend upon a culture of intense collaboration, enthusiasm, and openness." David Baltimore, PhD, a board member provided a positive goal Altos is shooting for:“The goal of Altos will be to reverse the ravages of disease and aging that lead to disability and death, reinvigorating and extending the quality of life. Altos will provide an unparalleled environment for collaborative discovery and has already attracted a most impressive group of investigators to the daunting task of reversing ill health and taking medicine in a new direction.”   Patient-specific spinal model may predict the effect of disc implants | New Atlas (16:28) As people get older, the intervertebral discs in their spine tend to deteriorate, some of which end up being surgically replaced with implants. Who doesn't know someone that has a bad back? A new patient-specific spinal model by scientists at Florida Atlantic University, could help determine how successful such surgery will be. Process:Obtain a CT scan of a patient's spine Create a 3D computer model from the scan Produce a 3D-printed model of one section of the spine with a cervical disc implant already in place Utilize a robotic arm to flex and extend the spinal replica, simulating five different real-life spinal postures Sensors then monitored the manner in which the added implant was causing stress to be distributed throughout the spine. The setup was found to be 100 percent accurate at replicating the effects that the postures would have on the real spine, with the addition of the implanted disc. Once developed further, the technology could be used to determine what sort of implant and/or surgical technique would work best, before the surgery is performed. Additionally, simulations could provide information as to what movements are best while recovering from the surgery.   Intel Is Investing $20 Billion Towards a Massive New Semiconductor Plant | Interesting Engineering (21:10) According to a Reuters report, Intel is set to invest $20 billion into a massive new semiconductor chip manufacturing site near Columbus, Ohio. All coincides with a recent analysis informing that China is "three or four generations" away from being at the cutting edge of semiconductor production. Chipmakers worldwide are frantically trying to boost output amid the global chip shortage brought on by massive demand and supply chain disruption fueled by the pandemic. Intel's new investment will go towards building two new semiconductor manufacturing plants, bringing 3,000 new permanent jobs to the 1,000-acre site in Albany, OhioThe first step in building an eight-factory complex that could cost additional tens of billions of dollars. Intel also recently announced plans for another U.S. campus site that would begin construction before the end of the year.The new site, according to reports, could cost $100 billion and eventually employ 10,000 people.   Elon Musk's brain chip firm Neuralink lines up clinical trials in humans | The Guardian (27:10) The billionaire entrepreneur Elon Musk's brain chip startup is preparing to launch clinical trials in humans. This is stemming from a job post for Neuralink for a “Clinical Trial Director.” What is mentioned in this post?“As the clinical trial director, you'll work closely with some of the most innovative doctors and top engineers, as well as working with Neuralink's first clinical trial participants …. You will lead and help build the team responsible for enabling Neuralink's clinical research activities and developing the regulatory interactions that come with a fast-paced and ever-evolving environment.” Just last month, Elon Musk, mentioned his optimism in allowing quadriplegics to move again:“We hope to have this in our first humans, which will be people that have severe spinal cord injuries like tetraplegics, quadriplegics, next year, pending FDA approval … I think we have a chance with Neuralink to restore full-body functionality to someone who has a spinal cord injury. Neuralink's working well in monkeys, and we're actually doing just a lot of testing and just confirming that it's very safe and reliable and the Neuralink device can be removed safely.” The company is also recruiting for a “clinical trial coordinator” to help build a team of people to run the trial and liaise with regulators.  These applicants, according to the posting, have an “opportunity to change the world and work with some of the smartest and the most talented experts from different fields”.  

Thu, 31 Jul 2014 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/18578/ https://edoc.ub.uni-muenchen.de/18578/1/Ahlfeld_Julia.pdf Ahlfeld, Julia

Mon, 21 Oct 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/17556/ https://edoc.ub.uni-muenchen.de/17556/1/Huetz_Katharina.pdf Hütz, Katharina Antonia ddc:610, ddc:600, M

Reprogramming of somatic cells into neurons provides a new approach toward cell-based therapy of neurodegenerative diseases. Conversion of postnatal astroglia from the cerebral cortex of mice into functional neurons in vitro can be achieved by forced expression of a single transcription factor. Also skin fibroblasts have been successfully reprogrammed into functional neurons yet through the synergistic action of several transcription factors. A major challenge for the translation of neuronal reprogramming into therapy concerns the feasibility of this approach in adult human tissues. This work demonstrates the potential of perivascular cells isolated from the adult human brain to serve as a substrate prompted to neuronal reprogramming by forced co-expression of neurogenic transcription factors, namely the SRY-related HMG box protein Sox2 and the basic helix loop helix (bHLH) mammalian homologue of achaete-schute-1 Mash1 (also known as Ascl1). The cells used in this study display characteristics of pericytes assessed by immunocytochemistry, fluorescence-activated cell sorting (FACS) and real time RT-PCR. The presence of neural progenitor cells was excluded by real time RT-PCR analysis of mRNAs typically expressed by these cell lineages. Upon expression of Sox2 and Mash1, these cells adopt a neuronal phenotype characterized by the expression of neuronal markers such us ßIII-Tubulin, MAP2, NeuN, GABA and calretinin. Electrophysiological recordings reveal the ability of these cells to fire repetitive action potentials and to integrate into neuronal networks when co-cultured with mouse embryonic neurons. The pericytic nature of the reprogrammed cells was further demonstrated by isolation of PDGFRß-positive cells from adult human brain cultures by FACS and monitoring the Mash1/Sox2-induced neuronal conversion by time-lapse video microscopy. Genetic fate-mapping in mice expressing an inducible Cre recombinase under the tissue non-specific alkaline phosphatase promoter corroborated that pericytes from the adult cerebral cortex can be expanded and reprogrammed in vitro into neurons by co-expression of Sox2 and Mash1. These results demonstrate the feasibility of an in vitro neuronal reprogramming approach on somatic cells isolated from the adult human cerebral cortex which could have important implications in the development of in vivo direct repair strategies in neurodegenerative diseases and brain injury.

The transcription factor SOX2 (3q26.3-q27) is an embryonic stem cell factor contributing to the induction of pluripotency in terminally differentiated somatic cells. Recently, amplification of the SOX2 gene locus has been described in squamous cell carcinoma (SCC) of different organ sites. Aim of this study was to investigate amplification and expression status of SOX2 in sinonasal carcinomas and to correlate the results with clinico-pathological data. A total of 119 primary tumor samples from the sinonasal region were assessed by fluorescence in-situ hybridization and immunohistochemistry for SOX2 gene amplification and protein expression, respectively. Of these, 59 were SSCs, 18 sinonasal undifferentiated carcinomas (SNUC), 10 carcinomas associated with an inverted papilloma (INVC), 19 adenocarcinomas (AD) and 13 adenoid cystic carcinomas (ACC). SOX2 amplifications were found in subsets of SCCs (37.5%), SNUCs (35.3%), INVCs (37.5%) and ADs (8.3%) but not in ACCs. SOX2 amplification resulted in increased protein expression. Patients with SOX2-amplified sinonasal carcinomas showed a significantly higher rate of tumor recurrences than SOX2 non-amplified tumors. This is the first study assessing SOX2 amplification and expression in a large cohort of sinonasal carcinomas. As opposed to AD and ACC, SOX2 amplifications were detected in more than 1/3 of all SCCs, SNUCs and INVCs. We therefore suggest that SNUCs are molecularly closely related to SCCs and INVCs and that these entities represent a subgroup of sinonasal carcinomas relying on SOX2 acquisition during oncogenesis. SOX2 amplification appears to identify sinonasal carcinomas that are more likely to relapse after primary therapy, suggesting that these patients might benefit from a more aggressive therapy regime.

In this work, we were able to take advantage of a deregulated wnt signaling pathway – a condition which is found in most gastrointestinal cancers, in particular in colorectal carcinomas. In order to restrict reporter gene expression to the desired cell type, we utilized the β-catenin dependent CTP4-promoter to restrict the expression of Firefly Luciferase and enhanced green fluorescent fusion protein (EGFPLuc) to cell lines with deregulated wnt signaling including SW480, LS174T, HepG2, Coga2 and Coga12. Stable cell lines containing this CTP4-driven EGFPLuc construct were established with the help of a lentiviral vector to monitor wnt activity by transgene expression. With these stably transduced cell lines, we performed a therapeutic target screen via siRNA-mediated knock-down of a number of potentially therapeutic targets within the wnt pathway – osteoprotegerin (OPG), Traf2 and Nck-interacting kinase (TNIK), SRY-related HMG-box (Sox2), protease-activated receptor 1 (PAR-1), β-catenin and transcription factor 4 (TCF4). The in vitro screening system was utilized as a prevalidation tool for therapeutically relevant targets. The degree of interference of our novel targets was determined and the search for a suitable siRNA target in colorectal cancer cells was narrowed down to β-catenin, PAR-1 and TNIK. As proof of principle the siRNA-mediated knock down of β-catenin was verified on mRNA and protein level in LS174T cells. After the initial read-out of various cell lines with different siRNAs has been established via the reduction of Luciferase expression levels, the biological effect of these targets were validated. For this purpose colony formation and cell motility/invasion assays were conducted for all relevant target cell lines. Furthermore in the in vitro experiments, the tumor-selectivtiy of the CTP4-promoter was employed in the delivery of the cytotoxic protein diphteria toxin A (DTA) in colorectal cancer target cells. Data evaluation of all in vitro assays pointed at reduced levels of proliferation, invasive behavior and aggressiveness, which yielded three candidates (PAR-1, TNIK and β-catenin) considered as viable for a treatment attempt in vivo. In the in vivo experiments, systemic delivery of siRNA against β-catenin, sticky siRNA targeting PAR-1 and plasmid DNA encoding for CTP4 controlled DTA were evaluated in a disseminated liver metastasis model of LS174T colorectal cancer. Specific knock-downs of β-catenin and PAR-1 were achieved which was confirmed via mRNA analysis. As for CTP4-DTA pDNA delivery the overall tumor load of the liver was reduced without any significant systemic toxicity, indicating specific DTA expression in tumor tissue. Also knock down of PAR1 using sticky siRNA significantly reduced tumor growth. All in all, the therapeutic effect of PAR-1 and β-catenin knock-down could be verified in various in vitro assays analyzing invasive behavior and anchorage independent growth and ultimately also in vivo. The tumor-specific expression of DTA pDNA could also be confirmed in vitro and was further investigated in an orthotopic liver dissemination model in NMRI nude mice.

Die vorliegende Arbeit hatte zum Ziel, die prinzipielle Fragestellung zu beantworten, ob Stammzellen aus humanen Haarfollikeln in ausreichender Menge expandiert werden können und inwieweit eine Differenzierung in neuroendokrine Zellen möglich ist. Es sollte eine Methode zur Isolierung und Langzeitkultivierung von Haarfollikelstammzellen etabliert und optimiert werden, um eine neue Quelle autologer adulter Stammzellen für zelltherapeutische Ansätze zu gewinnen. Durch Verwendung verschiedener Medien und Beschichtungsarten wurde ein Protokoll entwickelt, aus Dispase-verdauten Hautbiopsien Progenitorzellen zu isolieren. Die auf diese Weise expandierten Zellen wurden mit FACS-Analyse, RT-PCR und Immunhistologie charakterisiert. Im letzten Teil der Arbeit wurde durch Zugabe von spezifischen Faktoren die Fähigkeit zur Differenzierung in unterschiedliche Zelltypen untersucht. Nach Austestung verschiedener Zellkulturbedingungen wurde eine neue Population von Zellen aus der Haarfollikelregion isoliert. Diese Zellen, die als hBSCs bezeichnet wurden, waren über mehr als 30 Passagen mit stabilem Phänotyp kultivierbar (Self-Renewal). Zudem waren sie im Colony-Unit-Assay positiv und zeigten die Expression pluripotenter (Oct4) und multipotenter Stammzellmarker (Nestin, BCRP1, Sox2). Die molekulare Signatur der hBSCs zeigt einige Übereinstimmung mit Merkelzellen, neuroektodermalen Zellen der Haut, die eine Rolle als Mechanorezeptoren und neurosekretorische Zellen der Haut spielen. Unter Verwendung von etablierten Protokollen wurde die Fähigkeit der Differenzierung in Adipozyten, Osteoblasten, glatte Muskelzellen, Neuronen und endokrine Zellen untersucht. Der Nachweis der Entwicklung von glatten Muskelzellen, Neuronen und in eingeschränktem Maße auch Adipozyten belegt die Multipotenz der hBSCs. Darüber hinaus besitzen die hBSCs die Fähigkeit, stimulusabhängig Somatostatin zu exprimieren und zu sezernieren. Somit ist es erstmals gelungen, humane adulte Stammzellen/Progenitorzellen mit neuroendokrinen Eigenschaften zu isolieren. Zusammenfassend ist es in der vorliegenden Arbeit gelungen, eine Methode zu etablieren, mittels derer eine neue Population von humanen multipotenten Stammzellen aus der Haarfollikelregion in Langzeitkultur expandiert werden konnte. Die Plastizität der hBSCs und insbesondere die Differenzierung in reife endokrine Zellen muss in weiteren Studien untersucht werden.

Embryonic development represents a sophisticated multistep process. Hereby, specification, patterning and differentiation of cells and tissue need to be extremely well regulated in a temporo-spatial manner. This is based on repression and activation of a vast number of cell-type specific genes, but only a small number of transcription factors seem to be responsible for their regulation. The transcription factor network of Oct4, Sox2 and Nanog are thought to play an essential role in the maintenance of pluripotency and in timing the onset of differentiation. The importance of mouse Oct4 in the regulation of pluripotency is underscored by recent findings providing evidence that Oct4 is essential for reprogramming somatic cells. Nevertheless, little is known on the molecular function of this transcription factor during normogenesis. Given the extra uterine development of the embryos, the well-studied early development and the established manipulation methods like injection of RNA or DNA, Xenopus leavis offers an ideal model organism to study the role of Oct4 homologs in early development. In Xenopus laevis three Oct4 paralogs – Oct25, Oct60 and Oct91 – are known, which are similar in size and have a high sequence homology compared to mammalian Oct4. There are strong evidences that Xenopus Oct proteins and mammalian Oct4 share similar functions. To gain further insights into the function of Oct proteins I generated dominant activating- (VP16-Oct60), dominant repressing- (EnR-Oct60) and hormone inducible (GR-Oct60) transcription factor variants for all three Xenopus Oct proteins. Protein expression was verified in vitro as well as in vivo. Oct60 shows a unique expression pattern among Xenopus Oct proteins: Oct60 is maternally transcribed and its RNA is detectable in mature oocytes. Expression is downregulated in the gastrula, when the expression of other Xenopus POU proteins begins. Therefore, it is one of the earliest genes to be expressed. I decided to concentrate first efforts on Oct60. The transactivating functions of the Oct60 G.o.F. variants were tested in a luciferase assay on two different Oct4 reporter constructs in vivo. Oct60 and VP16-Oct60 acted as strong activators whereas EnR-Oct60 repressed both reporter constructs. By overexpression of Oct60 and its G.o.F. variants, several phenotypes were observed that affected distinct parts of the body. Beside impaired head differentiation, observed by overexpression of VP16-Oct60 and Oct60, a strong hyperpigmentation was observed by injection of EnR-Oct60 and Oct60. Additionally, EnR-Oct60 injected embryos showed hyperpigmented outgrowths in the trunk region. All injected embryos possessed a shortened body axis that was specifically curved depending on the injected mRNA. In situ hybridizations were performed to investigate the molecular mechanism of the observed phenotypic changes. Experiments revealed that all examined constructs promote neuroectodermal fate while repressing mesoderm formation. These results indicate that Oct60 plays an important role in the induction and specification of germ layer formation. By cloning and testing these different G.o.F. variants I accomplished to obtain important tools for further dissecting the molecular function of Oct4 homologs in Xenopus embryos.

The occurrence of SOX2-specific autoantibodies seems to be associated with an improved prognosis in patients with monoclonal gammopathy of undetermined significance (MGUS). However, it is unclear if SOX2-specific antibodies also develop in established multiple myeloma (MM). Screening 1094 peripheral blood (PB) sera from 196 MM patients and 100 PB sera from healthy donors, we detected SOX2-specific autoantibodies in 7.7% and 2.0% of patients and donors, respectively. We identified SOX2211-230 as an immunodominant antibody-epitope within the full protein sequence. SOX2 antigen was expressed in most healthy tissues and its expression did not correlate with the number of BM-resident plasma cells. Accordingly, anti-SOX2 immunity was not related to SOX2 expression levels or tumor burden in the patients' BM. The only clinical factor predicting the development of anti-SOX2 immunity was application of allogeneic stem cell transplantation (alloSCT). Anti-SOX2 antibodies occurred more frequently in patients who had received alloSCT (n = 74). Moreover, most SOX2-seropositive patients had only developed antibodies after alloSCT. This finding indicates that alloSCT is able to break tolerance towards this commonly expressed antigen. The questions whether SOX2-specific autoantibodies merely represent an epiphenomenon, are related to graft-versus-host effects or participate in the immune control of myeloma needs to be answered in prospective studies.

Background: The transcription factor SOX2, which is involved in the induction of pluripotent stem cells and contributes to colorectal carcinogenesis, is associated with a poor prognosis in colon cancer (CC). Furthermore, SOX2 is a repressor of the transcriptional activity of beta-catenin in vitro. Since the majority of CC develop via an activation of the Wnt/beta-catenin signalling pathway, indicated by nuclear expression of beta-catenin, we wanted to investigate the expression patterns of SOX2 and beta-catenin and correlate them with the occurrence of lymph node and distant metastases as indicators of malignant progression. Methods: The expression of SOX2 and beta-catenin was investigated in a case control study utilizing a matched pair collection (N = 114) of right-sided CCs with either corresponding distant metastases (N = 57) or without distant spread (N = 57) by applying immunohistochemistry. Results: Elevated protein expression of SOX2 significantly correlated with the presence of lymph node (p = 0.006) and distant metastases (p = 0.022). Nuclear beta-catenin expression correlated significantly only with distant metastases (p = 0.001). Less than 10% of cases showed a coexpression of high levels of beta-catenin and SOX2. The positivity for both markers was also associated with a very high risk for lymph-node metastases (p = 0.007) and distant spread (p = 0.028). Conclusion: We demonstrated that increased expression of either SOX2 or nuclear beta-catenin are associated with distant metastases in right-sided CC. Additionally, SOX2 is also associated with lymph-node metastases. These data underline the importance of stemness-associated markers for the identification of CC with high risk for distant spread.

The hallmark of embryonic stem (ES) cells is their ability for self-renewal (capability of unlimited cell division without the loss of pluripotency) as well as for differentiation into all cell types of the adult organism. One factor supposed to be involved in self-renewal is the rapid proliferation rate of ES cells, which is coupled to an unusual cell cycle distribution with the majority of cells in S-phase and a very short G1-phase. This is linked to the lack of a functional G1/S-phase checkpoint, which allows the cells to enter the S-phase almost directly after mitosis. Generally, cells have to closely coordinate growth and cell cycle progression during proliferation to prevent premature division. One important factor for cell growth is ribosome biogenesis. In mature cells, disruptions in ribosome biogenesis are directly linked to the cell cycle machinery by a p53-dependent activation of the G1/S-phase checkpoint, leading to an arrest of cells in G1-phase. During this work, the function of the proteins Pes1, Bop1 and WDR12, which were shown previously to be involved in ribosome biogenesis of mature cell lines, was investigated in mouse ES cells. Moreover, a putative crosstalk between ribosome biogenesis and proliferation of ES cells was assessed. A high expression of Pes1, Bop1 and WDR12 was observed in ES cells, which strongly decreased during in vitro differentiation. Localization of the proteins was predominantly nucleolar and the formation of a stable complex (PeBoW-complex), including all three proteins, was experimentally validated in mature mouse cells as well as in mouse ES cells. The function and stability of the proteins seems to be dependent on incorporation into the PeBOW-complex, as protein levels were interdependent on each other and no free, non-incorporated proteins were observed, except for WDR12. According to their nucleolar localization, depletion of Pes1 and Bop1 were shown to inhibit maturation of the 28S rRNA and thereby the large 60S ribosomal subunit. Further, impaired proliferation of ES cells was observed. Thus, the PeBoW-complex seems to be an essential factor for the rapid proliferation of ES cells and might therefore also be involved in self-renewal. However, first results suggest that the complex is not directly involved in the maintenance of pluripotency. No changes in the expression levels of pluripotency-genes like Nanog, KLF4 and Sox2 were observed. Moreover, alkaline phosphatase activity was equally detectable after depletion of Pes1 or Bop1 and no morphological changes within the ES cell colonies were observed. Impaired ribosome biogenesis is known to activate a p53-dependent checkpoint in mature cell lines, which leads to an arrest of cells in G1-phase. Treatment of mouse NIH3T3 cells with 5FU, a potent inhibitor of rRNA maturation, confirmed an activation of this checkpoint, leading to weak induction of the tumor suppressor p53, induction of the Cdk-inhibitor p21, an increase in active, hypo-phosphorylated Rb, and to accumulation of cells in the G1- and S-phase with an increase of cells in G1-phase. In contrast, ES cells showed strong induction of p53, but no induction of its target gene p21. The overall levels of Rb were strongly induced, but the ratio between inactive, hyper-phosphorylated Rb and active, hypo-phosphorylated Rb was not changed towards the active form. These results were observed upon 5FU treatment and upon depletion of Pes1 or Bop1. Hence, ribosomal stress does not lead to checkpoint activation via the p53-p21-Rb pathway in ES cells. Moreover, no robust accumulation of cells in G1-phase was observed. 5FU treated ES cells showed an accumulation of cells in S-phase instead. Whether this effect is regulated by the induced p53 needs further investigation. Overall, the results suggest that ES cells use different mechanisms as mature cells to coordinate their proliferation rate with ribosome biogenesis.