Podcasts about Transcriptome

Doing something complex and meaningful in a new way requires thinking and acting a bit differently. This is the case with how Dr. Joey Azofeifa, from Arpeggio Bio, is using systems biology to discover new drug candidates. Join us in this Season 2 kickoff episode where we dive headlong into transcriptomics, systems biology, machine learning, and learn how they're being used to innovate drug discovery. We learn about 3'-end mRNA barcoding and in-cell reverse transcription methods that allow the pooling of up to 1,536 samples so that only a single library preparation is required while still allowing the deconvolution of RNAseq results. This reduces their RNAseq costs by up to 400-fold, which enables them to generate enormous transcriptomic data sets. We also learn about how they're using generative adversarial AI networks to use this transcriptomics data to design potential drug candidates. We even hear how one of their drug candidates, which targets iron homeostasis pathways, has progress to successful testing in mice. To access the transcript for download, please visit - https://www.thermofisher.com/us/en/home/brands/invitrogen/molecular-biology-technologies/speaking-of-mol-bio-podcast.html Subscribe to get future episodes as they drop and if you like what you're hearing we hope you'll share a review or recommend the series to a colleague.  Download Transcripts: Speaking of Mol Bio Podcast | Thermo Fisher Scientific - US Visit the Invitrogen School of Molecular Biology to access helpful molecular biology resources and educational content, and please share this resource with anyone you know working in molecular biology.

In this episode of Speaking of Mol Bio, we speak with Dr. Mandovi Chatterjee about single cell analysis. Dr. Chatterjee is the Director of Single Cell Core at Harvard University Medical School. She has spent her career at the exploring and mastering a wide variety of single cell methods . In conversation with Dr. Chatterjee, our hosts dive into the more technical aspects of this ever-evolving field. We also learn an interesting analogy to better understand the difference between bulk and single cell RNA sequencing.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.28.550894v1?rss=1 Authors: Weng, Y., Zhou, S., Morillo, K., Kaletsky, R., Lin, S., Murphy, C. Abstract: Cognitive decline is a significant public health concern in our aging society. In this study, we used the model organism C. elegans to investigate the impact of the IIS/FOXO pathway on age-related cognitive decline. The daf-2 Insulin/IGF-1 receptor mutant exhibits a significant extension of learning and memory span with age compared to wild-type worms, an effect that is dependent on the DAF-16 transcription factor. To determine the mechanisms by which aging daf-2 mutants can maintain learning and memory with age while wild-type worms lose neuronal function, we carried out neuron-specific transcriptomic analysis in aged animals. We observed downregulation of neuronal genes and upregulation of transcriptional regulation genes in aging wild-type neurons. By contrast, IIS/FOXO pathway mutants exhibit distinct neuronal transcriptomic alterations in response to cognitive aging, including upregulation of stress response genes and downregulation of specific insulin signaling genes. We tested the roles of significantly transcriptionally-changed genes in regulating cognitive functions, identifying several novel regulators of learning and memory. These findings suggest a potential mechanism for regulating cognitive function with age and offer insights into novel therapeutic targets for age-related cognitive decline. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

There are very few remaining locations on Earth that are untouched by humans, and those that do remain are in very extreme environments that are difficult to access.  However, accessing and studying life in these extreme environments can provide unique insights to the biology of life. Understanding how simple organisms adapt and survive in seemingly unlivable conditions is a unique field of study with the potential to inform and affect the human condition.  We're joined in this episode by Dr. Brandi Kiel Reese and Lydia Hayes-Guastella from the Dauphin Island Sea Lab at the University of South Alabama. They are both geomicrobiologists that study microbial life in extreme environments like the Mariana Trench and Antarctica.  They do an excellent job of painting a picture of how extreme conditions are in these environments and how they manage to collect and preserve samples from such harsh conditions. We learn about the various methods they use to analyze the microbial samples they collect, including the use of digital PCR (dPCR) to detect and quantify transcripts that would otherwise not be detectable given how few cells they're able to collect.   Brandi and Lydia also share their unpredictable career path journeys, while sharing some insights and learnings from their respective experiences. We learn what they each love about their work and what qualities is takes to be successful at what they do. Once again, we're reminded of what a small world it is, especially when you're in a specialty field such as geomicrobiology of extreme environments.   Visit the Absolute Gene-ius page to learn more about the guest, the hosts, and the Applied Biosystems QuantStudio Absolute Q Digital PCR System. 

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.21.550124v1?rss=1 Authors: Fang, R., Halpern, A. R., Rahman, M. M., Huang, Z., Lei, Z., Hell, S. J., Dulac, C., Zhuang, X. Abstract: Multiplexed error-robust fluorescence in-situ hybridization (MERFISH) allows genome-scale imaging of RNAs in individual cells in intact tissues. To date, MERFISH has been applied to image thin tissue samples of ~10-micron thickness. Here, we present a method to enable three-dimensional (3D) single-cell transcriptome imaging of thick tissue specimens by integrating MERFISH with confocal microscopy for optical sectioning and deep learning for increasing imaging speed and quality. We demonstrated 3D MERFISH on mouse brain tissue sections of up to 200-micron thickness with high detection efficiency and accuracy. We anticipate that 3D thick-tissue MERFISH imaging will broaden the scope of questions that can be addressed by spatial genomics. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.12.548684v1?rss=1 Authors: Pranty, A. I., Wruck, W., Adjaye, J. Abstract: Bilirubin induced neurological damage (BIND), which is also known as Kernicterus, occurs as a consequence of defects in the bilirubin conjugation machinery, thus resulting in unconjugated bilirubin (UCB) to cross the blood brain barrier (BBB) and accumulation. Severe hyperbilirubinemia can be caused by a mutation within the UGT1A1 encoding gene. This mutation has a direct contribution towards bilirubin conjugation leading to Kernicterus as a symptom of Crigler Najjar Syndromes (CNS1, CNS2) and Gilbert syndrome, which results in permanent neurological sequelae. In this comparative study, we used human induced pluripotent stem cells (hiPSCs) derived 3D-brain organoids to model BIND in vitro and unveil the molecular basis of the detrimental effects of UCB in the developing human brain. hiPSC derived from healthy and CNS patients were differentiated into day 20 brain organoids, these were then stimulated with 200nM UCB. Analyses at 24 and 72 hrs post-treatment point at UCB induced neuro-inflammation in both cell lines. Transcriptome and associated KEGG and Gene Ontology analyses unveiled activation of distinct inflammatory pathways such as cytokine cytokine receptor interaction, MAPK signaling, calcium signaling, NFkB activation. Furthermore, both mRNA expression and secretome analysis confirmed an upregulation of proinflammatory cytokines such as IL6 and IL8 upon UCB stimulation. In summary, this novel study has provided insights into how a human iPSC derived 3D-brain organoid model can serve as a prospective platform for studying the etiology of BIND Kernicterus. 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/2023.07.07.547791v1?rss=1 Authors: Pass, T., Ricke, K. M., Hofmann, P., Chowdhury, R., Nie, Y., Chinnery, P. F., Endepols, H., Neumaier, B., Carvalho, A., Rigoux, L., Steculorum, S., Prudent, J., Riemer, T., Aswendt, M., Brachvogel, B., Wiesner, R. J. Abstract: Degeneration of dopamine neurons in the substantia nigra and their striatal axon terminals causes cardinal motor symptoms of Parkinson's disease (PD). In idiopathic cases, high levels of mitochondrial DNA (mtDNA) mutations associated with mitochondrial dysfunction are a central feature of these vulnerable neurons. Here we present a mouse model expressing the K320E-variant of the mitochondrial helicase Twinkle in dopamine neurons, leading to accelerated mtDNA ageing. K320E-TwinkleDaN mice showed normal motor function at 20 months of age, although already ~70% of nigral dopamine neurons had perished. The remaining neuron population still preserved ~75% of axon terminals in the dorsal striatum, which enabled normal dopamine release. Transcriptome analysis and viral tracing confirmed compensatory axonal sprouting of surviving nigral dopamine neurons. We conclude that a small population of substantia nigra neurons can adapt to mtDNA mutations and maintain motor control in mice, holding chances for new treatment strategies in PD patients. 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/2023.07.01.547315v1?rss=1 Authors: Deckers, C., Karbalaei, R., Miles, N. A., Harder, E. V., Witt, E., Harris, E. P., Reissner, K., Wimmer, M., Bangasser, D. A. Abstract: Astrocyte morphology affects function, including the regulation of glutamatergic signaling. This morphology changes dynamically in response to the environment. However, how early life manipulations alter adult cortical astrocyte morphology is underexplored. Our lab uses brief postnatal resource scarcity, the limited bedding and nesting (LBN) manipulation, in rats. We previously found that LBN promotes later resilience to adult addiction-related behaviors, reducing impulsivity, risky decision-making, and morphine self-administration. These behaviors rely on glutamatergic transmission in the medial orbitofrontal (mOFC) and medial prefrontal (mPFC) cortex. Here we tested whether LBN changed astrocyte morphology in the mOFC and mPFC of adult rats using a novel viral approach that, unlike traditional markers, fully labels astrocytes. Prior exposure to LBN causes an increase in the surface area and volume of astrocytes in the mOFC and mPFC of adult males and females relative to control-raised rats. We next used bulk RNA sequencing of OFC tissue to assess transcriptional changes that could increase astrocyte size in LBN rats. LBN caused mainly sex-specific changes in differentially expressed genes. However, Park7, which encodes for the protein DJ-1 that alters astrocyte morphology, was increased by LBN across sex. Pathway analysis revealed that OFC glutamatergic signaling is altered by LBN in males and females, but the gene changes in that pathway differed across sex. This may represent a convergent sex difference where glutamatergic signaling, which affects astrocyte morphology, is altered by LBN via sex-specific mechanisms. Collectively, these studies highlight that astrocytes may be an important cell type that mediates the effect of early resource scarcity on adult brain function. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.06.23.546309v1?rss=1 Authors: Xuan, W., Cheng, F., Han, X., Tipparaju, S., Ashraf, M. Abstract: Background: Extensive studies have been conducted in skeletal muscle and myocardium affected by Duchenne Muscular Dystrophy (DMD) disease but there is a significant gap of research in the role of vascular smooth muscle cells (VSMCs) in DMD. Here, we investigated the role of dystrophin deficiency in the maintenance of VSMCs contractile phenotype. Methods: 12-14 months old mdx mice and DMD induced pluripotent stem cells (iPSC) derived VSMCs were used as disease models. Morphological and immunohistochemistry analyses were performed to determine histological changes and the expression of contractile markers. Transmission Electron Microscopy (TEM) was used to assess ultrastructural changes in the VSMCs. Mito-tracker staining and TUNEL staining were performed to determine mitochondria fission-fusion and apoptosis respectively. mRNA Sequencing for normal iPSC derived VSMCs (WT-VSMCs) and DMD iPSC derived VSMCs (DMD-VSMCs) with or without oxidative stress was performed. KEGG signaling pathway enrichment, Go function enrichment and Gene set enrichment analysis (GESA) were conducted to explore the potential mechanism responsible for these changes. In addition, transcription factor enrichment analysis was performed to unravel mechanistic pathways of regulatory networks. Results: Spontaneous abnormal VSMCs proliferation, loss of vascular structure and degenerative changes occurred in VSMCs in aorta from 12-14 months old mdx mice. The DMD-VSMCs showed maturation defect, loss of mitochondrial hemostasis, and increased vulnerability to oxidative stress compared with WT-VSMCs. Transcriptome analysis revealed dysregulation of smooth muscle proliferation, differentiation, and vascular development in DMD-VSMCs. Transcriptional factor, target, and motif discovery analysis of the dysregulated gene set suggested potential contributions of transcriptional factors GADD45A, SOX9, TIA1, RBBP9 and FOXM to the phenotypes of DMD-VSMCs. Under oxidative stress, initiation of apoptotic process was significantly enhanced in DMD-VSMCs while their response to hypoxia and oxidative stress was downregulated. Conclusions: Dystrophin deficiency induced VSMCs phenotype switching and disrupted mitochondrial metabolism. The findings in this study underscore the importance of vascular dysfunction in DMD disease and therapeutic interventions to restore VSMC phenotype may ameliorate the propensity of disease progression. It is suggested that the transcriptome analysis may allow the discovery of potential signaling pathways involved in the dysregulation of transcription factors. 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/2023.05.05.539444v1?rss=1 Authors: Dominov, J. A., Madigan, L. A., Whitt, J. P., Rademacher, K. L., Webster, K. M., Zhang, H., Banno, H. A., Tang, S., Zhang, Y., Wightman, N., Shychuck, E. M., Page, J., Weiss, A., Kelly, K., Kucukural, A. A., Brodsky, M. H., Jaworski, A., Fallon, J. R., Lipscombe, D., Brown, R. H. Abstract: Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder affecting brain and spinal cord motor neurons. Mutations in the copper/zinc superoxide dismutase gene (SOD1) are associated with ~20% of inherited and 1-2% of sporadic ALS cases. Much has been learned from mice expressing transgenic copies of mutant SOD1, which typically involve high-level transgene expression, thereby differing from ALS patients expressing one mutant gene copy. To generate a model that more closely represents patient gene expression, we created a knock-in point mutation (G85R, a human ALS-causing mutation) in the endogenous mouse Sod1 gene, leading to mutant SOD1G85R protein expression. Heterozygous Sod1G85R mutant mice resemble wild type, whereas homozygous mutants have reduced body weight and lifespan, a mild neurodegenerative phenotype, and express very low mutant SOD1 protein levels with no detectable SOD1 activity. Homozygous mutants exhibit partial neuromuscular junction denervation at 3-4 months of age. Spinal cord motor neuron transcriptome analyses of homozygous Sod1G85R mice revealed up-regulation of cholesterol synthesis pathway genes compared to wild type. Transcriptome and phenotypic features of these mice are similar to Sod1 knock-out mice, suggesting the Sod1G85R phenotype is largely driven by loss of SOD1 function. By contrast, cholesterol synthesis genes are down-regulated in severely affected human TgSOD1G93A transgenic mice at 4 months. Our analyses implicate dysregulation of cholesterol or related lipid pathway genes in ALS pathogenesis. The Sod1G85R knock-in mouse is a useful ALS model to examine the importance of SOD1 activity in control of cholesterol homeostasis and motor neuron survival. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.05.01.538959v1?rss=1 Authors: Dorsey, S. G., Mocci, E., Lane, M. V., Krueger, B. K. Abstract: There is an increased incidence of autism among the children of women who take the anti-epileptic, mood stabilizing drug, valproic acid (VPA) during pregnancy, moreover, exposure to VPA in utero causes autistic-like symptoms in rodents and non-human primates. Analysis of RNAseq data ob-tained from fetal mouse brains 3 hr after VPA administration revealed that VPA significantly [p(FDR) less than or equal to 0.025] increased or decreased the expression of approximately 7,300 genes. No significant sex dif-ferences in VPA-induced gene expression were observed. Expression of genes associated with neurodevelopmental disorders such as autism as well as neurogenesis, axon growth and synapto-genesis, GABAergic, glutaminergic and dopaminergic synaptic transmission, perineuronal nets, and circadian rhythms was dysregulated by VPA. Moreover, expression of 400 autism risk genes was significantly altered by VPA. In addition, expression of 247 genes that have been reported to play fundamental roles in the development of the nervous system, but are not linked to autism by GWAS, was significantly increased or decreased by VPA. The goal of this study was to identify mouse genes that are: (a) significantly up- or down-regulated by VPA in the fetal brain and (b) known to be associated with autism and/or to play a role in embryonic neurodevelopmental processes, perturbation of which has the potential to alter brain connectivity in the postnatal and adult brain. The set of genes meeting these criteria provides potential targets for future hypothesis-driven approaches to elucidating the proximal underlying causes of defective brain connectivity in neuro-developmental disorders such as autism. 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/2023.04.24.538195v1?rss=1 Authors: Akhter, M. Z., Yazbeck, P., Tauseef, M., Anwar, M., Hossen, F., Datta, S., Vellingiri, V., Joshi, J. C., Srivastava, N., Lenzini, S., Zhou, G., Lee, J., Jain, M. K., Shin, J.-W., Mehta, D. Abstract: Vascular endothelium forms a restrictive barrier to defend the underlying tissue against uncontrolled influx of circulating protein and immune cells. Mechanisms that mediate the transition from restrictive to leaky endothelium, a hallmark of tissue injury exemplified by acute lung injury (ALI), remain elusive. Using endothelial cell (EC)-Fak-/- mice, we show that FAK sensing and transmission of mechanical tension to the EC nucleus governs cell fate. In FAK-deleted EC, increased EC tension induced by Rho kinase caused tyrosine phosphorylation of nuclear envelope protein, emerin at Y74/Y95, and its localization in a nuclear cap. Activated emerin stimulated DNMT3a activity and methylation of the KLF2 promoter, impairing the restrictive EC transcriptome, including S1PR1. Inhibiting emerin phosphorylation or DNMT3a activity enabled KLF2 transcription of S1PR1, rescuing the restrictive EC phenotype in EC-Fak-/- lungs. Thus, FAK sensing of tension transmission to the nucleus is crucial for maintaining a restrictive EC fate and lung homeostasis. 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/2023.04.19.537530v1?rss=1 Authors: Khan, M. M., Zukowska, J., Jung, J., Galea, G., Tuechler, N., Halavatyi, A., Tischer, C., Haberkant, P., Stein, F., Jung, F., Landry, J., Khan, A. M., Oorschot, V., Becher, I., Neumann, B., Muley, T., Winter, H., Duerr, J., Mall, M., Savitski, M., Pepperkok, R. Abstract: Excessive deposition of fibrillar collagen in the interstitial extracellular matrix (ECM) of human lung tissue causes fibrosis, which can ultimately lead to organ failure. Despite our understanding of the molecular mechanisms underlying the disease, a cure for pulmonary fibrosis has not yet been found. In this study, we screened an FDA-approved drug library containing 712 drugs and found that Dextromethorphan (DXM), a cough expectorant, significantly reduces the amount of excess fibrillar collagen deposited in the ECM in in-vitro cultured primary human lung fibroblasts (NHLF) and ex-vivo cultured human precision-cut lung slice (hPCLS) models of lung fibrosis. Reduced extracellular fibrillar collagen levels in the ECM upon DXM treatment are due to a reversible trafficking inhibition of collagen type I (COL1) in the endoplasmic reticulum (ER) in TANGO1 and HSP47 positive structures. Mass spectrometric analysis shows that DXM causes hyper-hydroxylation of proline and lysine residues on Collagen (COL1, COL3, COL4, COL5, COL7, COL12) and Latent-transforming growth factor beta-binding protein (LTBP1 and LTBP2) peptides coinciding with their secretion block. In addition, thermal proteome profiling of cells treated with DXM shows increased thermal stability of prolyl- hydroxylases such as P3H2, P3H3, P3H4, P4HA1 and P4HA2, suggesting a change in activity. Transcriptome analysis of pro-fibrotic stimulated NHLFs and hPCLS upon DXM treatment showed activation of an anti-fibrotic program via regulation of pathways such as those involved in the MMP-ADAMTS axis, WNT, and fibroblast-to-myofibroblast differentiation. Taken together, the data obtained from both in-vitro and ex-vivo models of fibrogenesis show that Dextromethorphan has potent anti-fibrotic activity by efficient inhibition of COL1 membrane trafficking in the ER. 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/2023.04.13.536811v1?rss=1 Authors: Junaid, M., Choe, H. K., Kondoh, K., Lee, E. J., Lim, S. B. Abstract: The neural stem cells (NSCs) in the hypothalamus are relatively more narrowly defined than in other neurogenic regions of the postnatal brain. By leveraging single-cell RNA sequencing (scRNA-seq) data, we generated an integrated reference dataset comprising 296,282 cells from postnatal hypothalamic regions and the adjacent region, bed nucleus of the stria terminalis (BNST), and identified 30 hypothalamic neuronal and non-neuronal cell populations. The analyses of their gene expression pattern, and specific differentiation trajectories reveal the presence of NSCs and intermediate progenitor cells (IPCs) that show a continuum of activation and differentiation processes in the hypothalamus after birth. Through comparative analyses of the integrated dataset with our lab-generated Connect-seq data obtained from the whole hypothalamus, we further assessed the technical validity of the dataset presented in this study. Our large-scale unified scRNA-seq dataset with harmonized cell-level metadata can serve as a valuable resource for investigating cell type-specific gene expression and cellular differentiation trajectories in the postnatal mouse hypothalamus. 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/2023.04.06.535955v1?rss=1 Authors: ji, h., Yue, L., Sun, H., Chen, R., Zhou, R., Xiao, A., Yang, Y., Wang, R., You, C., Liu, Y. Abstract: Intracranial aneurysm (IA) is pouch-like pathological dilations of cerebral arteries, which often affects middle-aged people and culminates in life-threatening hemorrhagic stroke. A deeper knowledge of the cellular and gene expression perturbations in human IA tissue deepens our understanding of disease mechanisms and facilitates developing pharmacological targets for unruptured IA. In this study, 21,332 qualified cells were obtained from cell-sparse ruptured and unruptured human IA tissues and a detailed cellular profile was determined, including conventional endothelial cells, smooth muscle cells (SMC), fibroblasts and the newly identified pericytes. Notably, striking proportion of immune cells were identified in IA tissue, with the number of monocyte/macrophages and neutrophils being remarkably higher in ruptured IA. By leveraging external datasets and machine learning algorithms, a subset of macrophages characterized by high expression of CCL3 and CXCL3, and transcriptional activation of NF-{kappa}B and HIVEP2 was identified as the cell most associated with IA rupture. Further, the interactome of CCL3/CXCL3 macrophages disclosed their role in regulating vascular cell survival and orchestrating inflammation. In summary, this study illustrated the profile and interactions of vascular and immune cells in human IA tissue and the opportunities for targeting local chronic inflammation. 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/2023.04.06.535855v1?rss=1 Authors: Henry, M., Fneich, S., Mathou, A., Xia, L., Foury, A., Benoit, S., Jouin, M., Junien, C., Capuron, L., Jouneau, L., Moisan, M.-P., Delpierre, C., Gabory, A., Darnaudery, M. Abstract: Adversity in childhood exerts enduring effects on brain and increases the vulnerability to psychiatric diseases. It also leads to a higher risk for eating disorders and obesity. We hypothesised that neonatal stress in mice affects motivation to obtain palatable food in adulthood and changes gene expression in reward system. Male and female pups from C57Bl/6J and C3H/HeN mice strains were subjected to a daily maternal separation (MS) protocol from PND2 to PND14. In adulthood, their motivation for palatable food reward was assessed in operant cages. Compared to control mice, male and female C3H/Hen mice exposed to MS significantly did more lever presses to obtain palatable food especially when the effort required to obtain the reward is high. Transcriptional analysis reveals 375 genes differentially expressed in the nucleus accumbens of male MS C3H/HeN mice compared to the control group, some of these being associated with the regulation of the reward system (e.g. Gnas, Pnoc). Interestingly, C57Bl/6J mice exposed to MS did not show any alteration in their motivation to obtain a palatable reward nor significant changes in gene expression in the nucleus accumbens. In conclusion, neonatal stress produces lasting changes in motivation for palatable food in C3H/HeN offspring but has no impact in C57Bl/6J offspring. These behavioural alterations are accompanied by drastic changes in gene expression specifically within the nucleus accumbens, a key structure in the regulation of motivational processes. 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/2023.03.27.534456v1?rss=1 Authors: Li, J., Jin, C., Gustafsson, S., Rao, A., Wabitsch, M., Park, C. Y., Quertermous, T., Bielczyk-Maczynska, E., Knowles, J. W. Abstract: Adipogenesis is a process in which fat-specific progenitor cells (preadipocytes) differentiate into adipocytes that carry out the key metabolic functions of the adipose tissue, including glucose uptake, energy storage, and adipokine secretion. Several cell lines are routinely used to study the molecular regulation of adipogenesis, in particular the immortalized mouse 3T3-L1 line and the primary human Simpson-Golabi-Behmel syndrome (SGBS) line. However, the cell-to-cell variability of transcriptional changes prior to and during adipogenesis in these models is not well understood. Here, we present a single-cell RNA-Sequencing (scRNA-Seq) dataset collected before and during adipogenic differentiation of 3T3-L1 and SGBS cells. To minimize the effects of experimental variation, we mixed 3T3-L1 and SGBS cells and used computational analysis to demultiplex transcriptomes of mouse and human cells. In both models, adipogenesis results in the appearance of three cell clusters, corresponding to preadipocytes, early and mature adipocytes. These data provide a groundwork for comparative studies on human and mouse adipogenesis, as well as on cell-to-cell variability in gene expression during this process. 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/2023.03.27.534387v1?rss=1 Authors: Sasaki, M., Hara, T., Wang, J. X., Zhou, Y., Kennedy, K. V., Umeweni, N. N., Alston, M. A., Spergel, Z. C., Nakagawa, R., McMillan, E. A., Whelan, K. A., Karakasheva, T. A., Hamilton, K. E., Ruffner, M. A., Muir, A. B. Abstract: Background & Aims: Epithelial disruption in eosinophilic esophagitis (EoE) encompasses both impaired differentiation and diminished barrier integrity. We have shown that lysyl oxidase (LOX), a collagen cross-linking enzyme, is upregulated in the esophageal epithelium in EoE. However, the functional roles of LOX in the esophageal epithelium remains unknown. Methods: We investigated roles for LOX in the human esophageal epithelium using 3-dimensional organoid and air-liquid interface cultures stimulated with interleukin (IL)-13 to recapitulate the EoE inflammatory milieu, followed by single-cell RNA sequencing, quantitative reverse transcription-polymerase chain reaction, western blot, histology, and functional analyses of barrier integrity. Results: Single-cell RNA sequencing analysis on patient-derived organoids revealed that LOX was induced by IL-13 in differentiated cells. LOX-overexpressing organoids demonstrated suppressed basal and upregulated differentiation markers. Additionally, LOX overexpression enhanced junctional protein genes and transepithelial electrical resistance. LOX overexpression restored the impaired differentiation and barrier function, including in the setting of IL-13 stimulation. Transcriptome analyses on LOX-overexpressing organoids identified enriched bone morphogenetic protein (BMP) signaling pathway compared to wild type organoids. Particularly, LOX overexpression increased BMP2 and decreased BMP antagonist follistatin. Finally, we found that BMP2 treatment restored the balance of basal and differentiated cells. Conclusions: Our data support a model whereby LOX exhibits non-canonical roles as a signaling molecule important for epithelial homeostasis in the setting of inflammation via activation of BMP pathway in esophagus. The LOX/BMP axis may be integral in esophageal epithelial differentiation and a promising target for future 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/2023.03.21.533694v1?rss=1 Authors: Dolivo, D. M., Rodrigues, A. E., Galiano, R. D., Mustoe, T. A., Hong, S. J. Abstract: Study of fibroblast biology, including the process of fibroblast activation, is critical to our understanding of wound healing, tissue fibrosis, and cancer. However, the rapid adoption of next-generation sequencing technologies, particularly single-cell RNA-seq and spatial transcriptomics, has revealed that fibroblast heterogeneity of both healthy and pathological tissues is more complicated than we currently understand. Therefore, a better understanding of molecular players that are not only indicative of but also that contribute to fibroblast activation is critical to piecing together the complete picture and to informing therapeutic strategies to combat associated pathologies. Here we focus on a long-noncoding RNA, LINC01013, recently implicated in pathological activation of cardiac fibroblasts and valvular interstitial cell. We analyze several sets of publicly available human transcriptomic data with the aim of determining whether LINC01013 correlates with fibroblast activation state, and whether compounds that affect fibroblast activation also modulate expression of LINC01013. We find that, in numerous independent datasets of healthy and diseased human fibroblasts, LINC01013 expression is associated with fibroblast activation. We also describe that, even in datasets comprised of small sample sizes, statistically significant correlations exist between expression of LINC01013 and expression of fibroblast activation markers ACTA2 and CCN2. This finding, while preliminary, suggests that changes in LINC01013 expression may be an indicator of changes in fibroblast activation state, and that LINC01013 might functionally contribute to fibroblast activation, lending potential rationale for greater exploration of this lncRNA in the context of tissue fibrosis or tumor stroma. 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/2023.03.04.531072v1?rss=1 Authors: Garza, R., Atacho, D., Adami, A., Gerdes, P., Vinod, M., Hsieh, P., Karlsson, O., Horvath, V., Johansson, P. A., Pandiloski, N., Matas, J., Quaegebeur, A., Kouli, A., Sharma, Y., Jonsson, M. E., Monni, E., Englund, E., Eichler, E. E., Gale Hammell, M., Barker, R. A., Kokaia, Z., Douse, C. H., Jakobsson, J. Abstract: The genetic mechanisms underlying the expansion in size and complexity of the human brain remains poorly understood. L1 retrotransposons are a source of divergent genetic information in hominoid genomes, but their importance in physiological functions and their contribution to human brain evolution is largely unknown. Using multi-omic profiling we here demonstrate that L1-promoters are dynamically active in the developing and adult human brain. L1s generate hundreds of developmentally regulated and cell-type specific transcripts, many which are co-opted as chimeric transcripts or regulatory RNAs. One L1-derived lncRNA, LINC01876, is a human-specific transcript expressed exclusively during brain development. CRISPRi-silencing of LINC01876 results in reduced size of cerebral organoids and premature differentiation of neural progenitors, implicating L1s in human-specific developmental processes. In summary, our results demonstrate that L1-derived transcripts provide a previously undescribed layer of primate- and human-specific transcriptome complexity that contributes to the functional diversification of the human 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/2023.02.28.530282v1?rss=1 Authors: Kuang, D., Hanchate, N. K., Lee, C.-Y., Heck, A., Ye, X., Erdenebileg, M., Buck, L. B. Abstract: The sense of smell has potent effects on appetite, but the underlying neural mechanisms are largely a mystery. The hypothalamic arcuate nucleus contains two subsets of neurons linked to appetite: AgRP (agouti-related peptide) neurons, which enhance appetite, and POMC (pro-opiomelanocortin) neurons, which suppress appetite. Here, we find that AgRP and POMC neurons receive indirect inputs from partially overlapping areas of the olfactory cortex, thus identifying their sources of odor signals. We also find neurons directly upstream of AgRP or POMC neurons in numerous other areas, identifying potential relays between the olfactory cortex and AgRP or POMC neurons. Transcriptome profiling of individual AgRP neurons reveals differential expression of receptors for multiple neuromodulators. Notably, known ligands of the receptors define subsets of neurons directly upstream of AgRP neurons in specific brain areas. Together, these findings indicate that higher olfactory areas can differentially influence AgRP and POMC appetite neurons, that subsets of AgRP neurons can be regulated by different neuromodulators, and that subsets of neurons upstream of AgRP neurons in specific brain areas use different neuromodulators, together or in distinct combinations to modulate AgRP neurons and thus appetite. 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/2023.02.17.528908v1?rss=1 Authors: Zou, Q., Yuan, R., Zhang, Y., Wang, Y., Zheng, T., Shi, R., Zhang, M., Li, Y., Fei, K., Feng, R., Pan, B., Zhang, X., Gong, Z., Zhu, L., Tang, G., Li, M., Li, X., Jiang, Y. Abstract: Different anatomic locations of the body skin dermis come from different origins, and its positional hereditary information can be maintained in adults, while highly resolvable cellular specialization is less well characterized in different anatomical regions. Pig is regarded as excellent model for human research in view of its similar physiology to human. In this study, we performed single-cell RNA sequencing of six different anatomical skin regions from the Chenghua pig with superior skin thickness traits. We obtained 215,274 cells, representing seven cell types, among which we primarily characterized the heterogeneity of smooth muscle cells, endothelial cells and fibroblasts. We identified several phenotypes of smooth muscle cell and endothelial cell and presented genes expression of pathways such as the immune response in different skin regions. By comparing differentially expressed fibroblast genes among different skin regions, we considered TNN, COL11A1, and INHBA as candidate genes for facilitating ECM accumulation. These findings of heterogeneity in the main three cell types from different anatomic skin sites will contribute to a better understanding of hereditary information and places the potential focus on skin generation, transmission and transplantation, paving the foundation for human skin priming. 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/2023.02.15.528700v1?rss=1 Authors: Stoner, A., Fu, L., Nicholson, L., Zheng, C., Toyonaga, T., Spurrier, J., Laird, W., Cai, Z., Strittmatter, S. M. Abstract: BackgroundCellular prion protein (PrPC) is a high-affinity cell-surface receptor for Amyloid-{beta} oligomers (A{beta}o). In certain overexpression models of Alzheimers Disease (AD), pharmacology and genetics demonstrate its essential role for synaptic plasticity impairment, memory deficits and synapse loss. However, PrPCs role in AD-related phenotypes with endogenous expression levels, its role in tau accumulation and its effect on imaging biomarkers are unknown. The necessity of PrPC for transcriptomic alterations driven by A{beta} across cell types is unexplored. MethodsThe role of PrPC was examined as a function of age in homozygous AppNL-G-F/hMapt double knock-in mice (DKI). Phenotypes of AppNL-G-F/hMapt mice with a deletion of Prnp expression (DKI; Prnp-/-) were compared with DKI mice with intact Prnp, mice with a targeted deletion of Prnp (Prnp-/-), and mice with intact Prnp (WT). Phenotypes examined included behavioral deficits, synapse loss by PET imaging, synapse loss by immunohistology, tau pathology, gliosis, inflammatory markers, and snRNA-seq transcriptomic profiling. ResultsBy 9 months age, DKI mice showed learning and memory impairment, but DKI; Prnp-/- and Prnp-/- groups were indistinguishable from WT. Synapse loss in DKI brain, measured by [18F]SynVesT-1 SV2A PET or anti-SV2A immunohistology, was prevented by Prnp deletion. Accumulation of Tau phosphorylated at aa 217 and 202/205, C1q tagging of synapses, and dystrophic neurites were all increased in DKI mice but each decreased to WT levels with Prnp deletion. In contrast, astrogliosis, microgliosis and A{beta} levels were unchanged between DKI and DKI; Prnp-/- groups. Single-nuclei transcriptomics revealed differential expression in neurons and glia of DKI mice relative to WT. For DKI; Prnp-/- mice, the majority of neuronal genes differentially expressed in DKI mice were no longer significantly altered relative to WT, but most glial DKI-dependent gene expression changes persisted. The DKI-dependent neuronal genes corrected by Prnp deletion associated bioinformatically with synaptic function. Additional genes were uniquely altered only in the Prnp-/-or the DKI; Prnp-/- groups. ConclusionsA functional Prnp gene is required in AppNL-G-F/hMapt double knock-in mice for synapse loss, phospho-tau accumulation and neuronal gene expression. These data support the efficacy of targeting the A{beta}o-PrPC interaction to prevent A{beta}o-neurotoxicity and pathologic tau accumulation 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/2023.02.13.528249v1?rss=1 Authors: Jing, J., Chen, S., Wu, X., Yang, J., Liu, X., Wang, J., Wang, J., Li, Y., Zhang, P., Tang, Z. Abstract: Intracerebral hemorrhage (ICH) is an acute cerebrovascular disease with high disability and mortality rates. Recombinant tissue plasminogen activator (rtPA) is commonly applied for hematoma evacuation in minimally invasive surgery (MIS) after ICH. However, rtPA may contact directly with brain tissue during MIS procedure, which makes it necessary to discuss the safety of rtPA. We found that, in the in vivo ICH model induced by VII-type collagenase, rtPA treatment improved the neurological function of ICH mice, alleviated the pathological damage and decreased the apoptosis and autophagy level of the peri-hematoma tissue. In the in-vitro model of ICH induced by hemin, the administration of rtPA down-regulated neuronal apoptosis, autophagy, and endoplasmic reticulum stress of neurons. Transcriptome sequencing analysis showed that rtPA treatment upregulated the PI3K/AKT/mTOR pathway in neurons, and PI3K inhibitor (LY294002) can reverse the protective effects of rtPA in inhibiting excessive apoptosis, autophagy and ER-stress. Epidermal growth factor receptor inhibitor (AG-1487) reversed the effect of rtPA on PI3K/AKT/mTOR pathway, which might indicate that the EGF domain played an important role in the activation of PI3K/AKT/mTOR pathway. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.28.522136v1?rss=1 Authors: Costa, D. S., Kenny-Ganzert, I. W., Chi, Q., Park, K., Kelley, L. C., Garde, A., Matus, D. Q., Park, J., Yogev, S., Goldstein, B., Gibney, T. V., Pani, A. M., Sherwood, D. R. Abstract: Cell invasion through basement membrane (BM) barriers is important in development, immune function, and cancer progression. As invasion through BM is often stochastic, capturing gene expression profiles of cells actively transmigrating BM in vivo remains elusive. Using the stereotyped timing of C. elegans anchor cell (AC) invasion, we generated an AC transcriptome during BM breaching. Through a focused RNAi screen of transcriptionally enriched genes, we identified new invasion regulators, including TCTP (Translationally Controlled Tumor Protein). We also discovered gene enrichment of ribosomal proteins. AC-specific RNAi, endogenous ribosome labeling, and ribosome biogenesis analysis revealed a burst of ribosome production occurs shortly after AC specification, which drives the translation of proteins mediating BM removal. Ribosomes also strongly localize to the ACs endoplasmic reticulum (ER) and the endomembrane system expands prior to invasion. We show that AC invasion is sensitive to ER stress, indicating a heightened requirement for translation of ER trafficked proteins. These studies reveal key roles for ribosome biogenesis and endomembrane expansion in cell invasion through BM and establish the AC transcriptome as a resource to identify mechanisms underlying BM transmigration. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.20.521295v1?rss=1 Authors: Donovan, L. J., Bridges, C. M., Nippert, A. R., Wang, M., Wu, S., Forman, T. E., Haight, E. S., Huck, N. A., Jordan, C. E., Gardner, A. S., Nair, R. V., Tawfik, V. L. Abstract: Microglia contribute to the initiation of pain, however, a translationally viable approach addressing how or when to modulate these cells remains elusive. We used a targeted, inducible genetic microglial depletion strategy at both the acute and acute-to-chronic transition phases in the clinically-relevant tibial fracture/casting model to determine the contribution of microglia to the initiation and maintenance of pain. We observed complete resolution of pain after transient microglial depletion at the acute-to-chronic phase, which coincided with the timeframe of full repopulation of microglia. These repopulated microglia were morphologically distinct from control microglia, suggesting they may exhibit a unique transcriptome. RNA sequencing of repopulated spinal cord microglia identified genes of interest using weighted gene co-expression network analysis (WGCNA). We intersected these genes with a newly-generated single nuclei microglial dataset from human dorsal horn spinal cord to identify human-relevant genes that may promote homeostatic features of microglia and ultimately promote pain resolution after injury. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.11.30.518286v1?rss=1 Authors: Uoselis, L., Lindblom, R., Skulsuppaisarn, M., Khuu, G., Nguyen, T. N., Rudler, D. L., Filipovska, A., Schittenhelm, R. B., Lazarou, M. Abstract: Breakdown of mitochondrial proteostasis activates quality control pathways including the mitochondrial unfolded protein response (UPRmt) and PINK1/Parkin mitophagy. However, beyond the upregulation of chaperones and proteases, we have a limited understanding of how the UPRmt remodels and restores damaged mito-proteomes. Here, we have developed a functional proteomics framework, termed MitoPQ (Mitochondrial Proteostasis Quantification), to dissect the UPRmts role in maintaining proteostasis during stress. We discover essential roles for the UPRmt in both protecting and repairing proteostasis, with oxidative phosphorylation metabolism being a central target of the UPRmt. Transcriptome analyses together with MitoPQ reveal that UPRmt transcription factors drive independent signaling arms that act in concert to maintain proteostasis. Unidirectional interplay between the UPRmt and PINK1/Parkin mitophagy was found to promote oxidative phosphorylation recovery when the UPRmt failed. Collectively, this study defines the network of proteostasis mediated by the UPRmt and highlights the value of functional proteomics in decoding stressed proteomes. 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/2022.11.16.516732v1?rss=1 Authors: Lu, S., Lu, H., Zheng, T., Yuan, H., Du, H., Gao, Y., Liu, Y., Pan, X., Zhang, W., Fu, S., Sun, Z., Jin, J., He, Q.-Y., Chen, Y., Zhang, G. Abstract: In recent years, the development of high-throughput omics technology has greatly promoted the development of biomedicine. However, the poor reproducibility of omics techniques limits its application. It is necessary to use standard reference materials of complex RNAs or proteins to test and calibrate the accuracy and reproducibility of omics workflows. However, the transcriptome and proteome of most cell lines shift during culturing, which limits their applicability to serve as standard samples. In this study, we demonstrated that the human hepatocellular cell line MHCC97H has a very stable transcriptome (R2=0.966-0.995) and proteome (R2=0.934-0.976 for DDA, R2=0.942-0.986 for DIA) after 9 subculturing generations, which allows this stable standard sample to be stably produced on an industrial scale for several decades. Moreover, this stability was maintained across labs and platforms. In sum, our results justified a omics standard reference material and reference datasets for transcriptomic and proteomics research. This helps to further standardize the workflow and data quality of omics techniques and thus promotes the application of omics technology in precision 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/2022.11.04.515095v1?rss=1 Authors: Sun, T., Grassam-Rowe, A., Pu, Z., Ren, H., An, Y., Guo, X., Hu, W., Liu, Y., Li, Y., Liu, Z., Kou, K., Ou, X., Chen, T., Fan, X., Liu, Y., Tu, S., He, Y., Ren, Y., Chen, A., Shang, Z., Xia, Z., Miquerol, L., Smart, N., Zhang, H., Tan, X., Shou, W., Lei, M. Abstract: Cardiac conduction system (CCS) morphogenesis is essential for correct heart function yet is incompletely understood. Here we established the transcriptional landscape of cell types populating the developing heart by integrating single-cell RNA sequencing and spatial enhanced resolution omics-sequencing (Stereo-seq). Stereo-seq provided a spatiotemporal transcriptomic cell fate map of the murine heart with a panoramic field of view and in situ cellular resolution of the CCS. This led to the identification of a previously unrecognized cardiomyocyte population expressing dopamine beta-hydroxylase (Dbh+-CMs), which is closely associated with the CCS in transcriptomic analyses. To confirm this finding, genetic fate mapping by using DbhCre/Rosa26-tdTomato reporter mouse line was performed with Stereo-seq, RNAscope, and immunohistology. We revealed that Dbh+-derived CMs first emerged in the sinus venosus at E12.5, then populated the atrial and ventricular CCS components at E14.5, with increasing abundance towards perinatal stages. Further tracing by using DbhCFP reporter and DbhCreERT/Rosa26-tdTomato inducible reporter, we confirmed that Dbh+-CMs are mostly abundant in the AVN and ventricular CCS and this persists in the adult heart. By using DbhCre/Rosa26-tdTomato/Cx40-eGFP compound reporter line, we validated a clear co-localization of tdTomato and eGFP signals in both left and right ventricular Purkinje fibre networks. Finally, electrophysiological optogenetic study using cell-type specific Channelrhodopsin2 (ChR2) expression further elucidated that Dbh+-derived CMs form a functional part of the ventricular CCS and display similar photostimulation-induced electrophysiological characteristics to Cx40CreERT/ChR2- tdTomato CCS components. Thus, by utilizing advanced transcriptomic, mouse genetic, and optogenetic functional analyses, our study provides new insights into mammalian CCS development and heterogeneity by revealing novel Dbh+-CMs. 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/2022.10.05.510979v1?rss=1 Authors: Hussain, T., Sanchez, K., Crayton, J., Saha, D., Jeter, C., Lu, Y., Abba, M., Seo, R., Noebels, J. L., Fonken, L., Aldaz, C. M. Abstract: WWOX gene loss-of-function (LoF) has been associated with neuropathologies resulting in developmental, epileptic, and ataxic phenotypes of varying severity based on the level of WWOX dysfunction. WWOX gene biallelic germline variant p.Pro47Thr (P47T) has been causally associated with a new form of autosomal recessive cerebellar ataxia with epilepsy and intellectual disability (SCAR12). This mutation affects the WW1 protein binding domain of WWOX, impairing its ability to interact with canonical proline-proline-X-tyrosine motifs in partner proteins. We generated a mutant knock-in mouse model of Wwox P47T that phenocopies SCAR12. WwoxP47T/P47T mice displayed epilepsy, profound social behavior and cognition deficits, and poor motor coordination, and unlike KO models that survive only for 1 month, live beyond 1 year of age. These deficits progressed with age, and mice became practically immobile, suggesting severe cerebellar dysfunction. WwoxP47T/P47T mice exhibited signs of progressive neuroinflammation with elevated astro-microgliosis that increased with age. The cerebellar cortex displayed significantly reduced molecular and granular layer thickness and a strikingly reduced number of Purkinje cells with degenerated dendrites. Transcriptome profiling from various brain regions from these Wwox LoF mice highlighted widespread changes in neuronal and glial pathways, enrichment of bioprocesses related to neuroinflammation and severe cerebellar dysfunction, activation of pathways compatible with compensatory neurogenesis along with major suppression of gene networks associated with excitability, neuronal cell differentiation and brain development. Our results show significant pathobiological effects and potential mechanisms through which WWOX LoF leads to epilepsy, cerebellar neurodegeneration, neuroinflammation, and ataxia. Additionally, the mouse model described here will be a useful tool for the study of WWOX in common neurodegenerative conditions in which it has been identified as a novel risk factor. 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/2022.10.03.510711v1?rss=1 Authors: DeCasien, A. R., Chiou, K. L., Testard, C., Mercer, A., Negron-Del Valle, J. E., Surratt, S. E. B., Gonzalez, O., Stock, M. K., Ruiz-Lambides, A. V., Martinez, M. I., Cayo Biobank Research Unit,, Anton, S., Walker, C. S., Sallet, J., Wilson, M. A., Brent, L. J. N., Montague, M. J. N., Sherwood, C. C., Platt, M. L., Higham, J. P., Snyder-Mackler, N. Abstract: Humans exhibit sex differences in the prevalence of many neurodevelopmental and neurodegenerative conditions. To better understand the translatability of a critical nonhuman primate model, the rhesus macaque, we generated one of the largest multi-brain region bulk transcriptional datasets for this species and characterized sex-biased gene expression patterns. We demonstrate that these patterns are similar to those in humans and are associated with overlapping regulatory mechanisms, biological processes, and genes implicated in sex-biased human disorders, including autism. We also show that sex-biased genes exhibit greater genetic variance for expression and more tissue-specific expression patterns, which may facilitate the rapid evolution of sex-biased genes. Our findings provide insights into the biological mechanisms underlying sex-biased disease and validate the rhesus macaque model for the study of these conditions. 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/2022.09.24.508386v1?rss=1 Authors: Kompotis, K., Mang, G., Hubbard, J. T., Jimenez, S., Emmenegger, Y., Polysopoulos, C., Hor, C. N., Wigger, L., Hebert, S. S., Mongrain, V., Franken, P. Abstract: MicroRNAs (miRNAs) are key post-transcriptional regulators of gene expression that have been implicated in a plethora of neuronal processes. Nevertheless, their role in regulating brain activity in the context of sleep has so far received little attention. To test their involvement, we deleted mature miRNAs in post-mitotic neurons at two developmental ages, i.e., in early adulthood using conditional Dicer knockout (cKO) mice and in adult mice using an inducible conditional Dicer cKO (icKO) line. In both models, electroencephalographic (EEG) activity was affected and the response to sleep deprivation (SD), altered; while rapid-eye-movement sleep (REMS) rebound was compromised in both, EEG delta (1-4 Hz) power during non-REM sleep (NREMS) was reduced in cKO mice and increased in icKO mice. We subsequently investigated the effects of SD on the miRNA transcriptome and found that the expression of 48 forebrain miRNAs was affected, in particular, the activity-dependent miRNA miR-709. In vivo inhibition of miR-709 in the brain increased EEG power during NREMS in the slow-delta (0.75-1.75 Hz) range, particularly after periods of prolonged wakefulness. Transcriptome analysis of primary cortical neurons in vitro revealed that miR-709 regulates endosomal trafficking and glutamatergic receptor activity. A subset of the genes involved in glutamatergic transmission was affected also in the cortices of sleep-deprived, miR-709-inhibited mice. Our data implicate miRNAs in the regulation of EEG activity and indicate that miR-709 links neuronal excitability during wakefulness to brain synchrony during sleep, likely through the regulation of endosomal trafficking and glutamatergic signaling. 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/2022.09.14.508048v1?rss=1 Authors: Allen, W. E., Blosser, T. R., Sullivan, Z. A., Dulac, C., Zhuang, X. Abstract: The cellular diversity and complex organization of the brain have hindered systematic characterization of age-related changes in its cellular and molecular architecture, limiting our ability to understand the mechanisms underlying its functional decline during aging. Here we generated a high-resolution cell atlas of brain aging within the frontal cortex and striatum using spatially resolved single-cell transcriptomics and quantified the changes in gene expression and spatial organization of major cell types in these brain regions over the lifespan of mice. We observed substantially more pronounced changes in the composition, gene expression and spatial organization of non-neuronal cells over neurons. Our data revealed molecular and spatial signatures of glial and immune cell activation during aging, particularly enriched in subcortical white matter, and identified both similarities and notable differences in cell activation patterns induced by aging and systemic inflammatory challenge. These results provide critical insights into age-related decline and inflammation in the brain. 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/2022.09.10.507291v1?rss=1 Authors: Boestrand, S. M. K., Seeker, L. A., Kazakou, N.-L., Bestard-Cuche, N., Jaekel, S., Kenkhuis, B., Henderson, N. C., de Bot, S. T., van Roon-Mom, W., Priller, J., Williams, A. Abstract: Huntington's disease (HD) is a severely debilitating, autosomal dominant neurodegenerative disease with a fatal outcome. There is accumulating evidence of a prominent role of glia in the pathology of HD, and we investigated this by conducting single nuclear RNA sequencing (snRNAseq) of human post mortem brain in four differentially affected regions; caudate nucleus, frontal cortex, hippocampus and cerebellum. Across 127,205 nuclei from people with HD, and age/sex matched controls, we found heterogeneity of glia which is altered in HD. We describe prominent changes in the abundance of certain subtypes of astrocytes, microglia, oligodendrocyte precursor cells and oligodendrocytes between HD and control samples, and these differences are widespread across brain regions. Furthermore, we highlight two possible mechanisms that characterise the glial contribution to disease pathology. Firstly, we show that upregulation of molecular chaperones represents a cross-glial signature in HD, which likely reflects an adaptive response to the accumulation of mutant Huntingtin (mHTT). Secondly, we show an oligodendrocyte-specific upregulation of the calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A (PDE1A) in HD brain compared to controls, which may cause dysfunction of key cellular functions due to the downregulation of the important second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Our results support the hypothesis that glia have an important role in the pathology of HD, and show that all types of glia are affected in the disease. As glia are more tractable to treat than neurons, our findings may be of therapeutic relevance. 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/2022.09.02.506419v1?rss=1 Authors: Dong, P., Bendl, J., Misir, R., Shao, Z., Edelstien, J., Davis, D. A., Haroutunian, V., Scott, W. K., Acker, S., Lawless, N., Hoffman, G. E., Fullard, J. F., Roussos, P. Abstract: Brain region- and cell-specific transcriptomic and epigenomic molecular features are associated with heritability for neuropsychiatric traits, but a systematic view, considering cortical and subcortical regions, is lacking. Here, we provide an atlas of chromatin accessibility and gene expression in neuronal and non-neuronal nuclei across 25 distinct human cortical and subcortical brain regions from 6 neurotypical controls. We identified extensive gene expression and chromatin accessibility differences across brain regions, including variation in alternative promoter-isoform usage and enhancer-promoter interactions. Genes with distinct promoter-isoform usage across brain regions are strongly enriched for neuropsychiatric disease risk variants. Using an integrative approach, we characterized the function of the brain region-specific chromatin co-accessibility and gene-coexpression modules that are robustly associated with genetic risk for neuropsychiatric disorders. In addition, we identified a novel set of genes that is enriched for disease risk variants but is independent of cell-type specific gene expression and known susceptibility pathways. Our results provide a valuable resource for studying molecular regulation across multiple regions of the human brain and suggest a unique contribution of epigenetic modifications from subcortical areas to neuropsychiatric disorders. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

KSQD 3-30-2022: Ironically, some allergic asthma sufferers have less severe COVID-19 symptoms! More COVID news. mRNA vaccines are easier to revise for new variants. Extracellular vesicles and a new signaling pathway based on RNA found in round worms. How to protect against side effects of long-term proton pump inhibitor use. Fighting diabetes and cancer with microRNA, which regulates protein production. Acoustic shaping of cells in solution. Adverse childhood experiences affect how one deals with stress and is treatable with acupuncture

This podcast is a summary of article "Monocytes and Macrophages in Kidney Transplantation and Insights from Single Cell RNA-Seq Studies" by Andrew Malone.

Join us for a dive into the power of essential oils in our daily lives. The interest in essential oils is rapidly on the rise according to Google Trends. The trend line is fascinating. Why? What makes essential oils so sought after? They work! Organixx carries a line of organic and pure essential oils. Today we will share the top 3 uses of the top single essential oils in our line.   Lavender Lavender oil is believed to have antiseptic and anti-inflammatory properties. We've all heard by now that lavender promotes deeper sleep, but did you know…   There's promising research for breast health too. 2014 Iranian research published in the journal Nutrition and Cancer found that lavender oil kills breast cancer cells but leaves healthy cells unharmed. It's important to note that this study was on cells in a petri dish, not on humans. The researchers concluded that: “L. angustifolia has cytotoxic and apoptotic effects in HeLa and MCF-7 cell lines, and apoptosis is proposed as the possible mechanism of action.”1 Stops the itch and burn of insect bites. Even fire ants! Put a drop of lavender oil on a bee sting, mosquito, or other bug bite to stop pain, itching, and reduce swelling. Reapply as necessary. Lavender oil works really well for this, especially if applied immediately. Use it as a flavor booster. Add a drop of high-quality lavender oil suitable for consumption to brownie batter, chocolate icing, cookie dough, dessert recipes, raw chocolate, or even salad dressings. It's absolutely delicious.   Is Lavender Oil Safe? Using diluted lavender oil topically or in aromatherapy is generally considered safe for most adults but may not be recommended for children. Applying pure lavender oil to your skin (especially open wounds) may also cause irritation, so we recommend infusing it with a carrier oil, such as olive oil or coconut oil. Dissolving it in water also works.   Be careful not to rub lavender oil in your eyes and mucous membranes. If this happens, wash it out immediately. Lavender oil may also cause allergic reactions in people with unusually sensitive skin, so do a spot test before using it. Simply apply a drop of lavender oil to your arm and see if any reaction occurs.   The U.S. National Institutes of Health (NIH) also warns against using lavender oil when taking medications like barbiturates, benzodiazepines and chloral hydrate, as it may increase their sedative effects and cause extreme drowsiness and sleepiness.     Tea Tree (Melaleuca) This versatile oil possesses antibacterial, anti-inflammatory, antiviral, and antifungal properties.   Due to its potent anti-inflammatory benefits, tea tree oil helps to relieve inflammatory skin conditions, especially eczema and psoriasis. Dilute as necessary and apply to affected area two to three times daily. Tea tree oil has long been used as a natural bug repellent by native Australian aboriginal people. Chinese research in 2016 found tea tree to be effective against the cereal weevil, Sitophilus zeamais.3 The cereal weevil is considered to be an extremely destructive pest to stored cereals all over the world. Tea tree also helps to relieve the pain, itching, and inflammation of insect bites. If it's an extra-hot day and your deodorant has failed, apply again, but this time with a drop or two of tea tree oil to help kill bacteria. Tea tree oil's potent antibacterial properties are well proven with dozens of research studies.   Is Tea Tree Oil Safe? The answer is yes, as long as it is applied topically in appropriate doses and NOT swallowed. This oil may irritate your skin, especially if used for the first time. We recommend starting with low concentrations until you figure out your tolerance. Determine if you have an allergy to tea tree oil before using it by doing a skin test — apply a small amount to your inner arm to see if any reaction such as a rash or hives occurs.   The National Center for Complementary and Alternative Medicine (NCCAM) recommends avoiding oxidized oil, which has been exposed to air, because it may help trigger allergies more than fresh tea tree oil.  Avoid using undiluted tea tree oil as well and use tea tree oil-infused products instead to reduce your risk of skin irritation.   Lemon The health benefits of lemon oil can be attributed to its stimulating, calming, astringent, detoxifying, antiseptic, disinfectant and antifungal properties. *Important to note: Lemon essential oil can make your skin more sensitive to sunlight. Lemon oil has a balancing effect on the oil glands of the scalp. Massage a drop or two of lemon oil into your scalp before you go to bed at night. Wash it out in the morning. Done over a period of weeks, you will notice much less oily hair. It will make your pillow smell nice and fresh too! Diffuse lemon oil to help kill airborne bacteria. Research carried out by Dr. Jean Valnet (co-author of the book The Practice of Aromatherapy: A Classic Compendium of Plant Medicines and Their Healing Properties) shows that diffused lemon oil can rapidly kill off the bacteria that causes meningococcal infections, typhoid fever, staph infections, pneumonia, diphtheria, and tuberculosis. Several essential oils are haemostatic, i.e. they help to stop bleeding by speeding up the coagulation of the blood. The most useful of these is oil of Lemon, though Geranium and Rose have similar, though less powerful, effects.   Is Lemon Oil Safe? It is advisable not to use lemon oil without diluting it first, as it can irritate skin. It must be used with a carrier oil for direct application to the skin. Effective carrier oils include coconut oil, olive oil and jojoba oil.   There are findings showing that lemon oil may promote photosensitivity, which increases your sensitivity to the sun and may lead to sunburn and uneven darkening of the skin. We also recommend you avoid applying lemon oil and other citrus oils to your skin when outdoors, as blistering may occur.   People with sensitivities should use essential oils with caution. Reactions can vary from person to person. Some may experience skin reactions, while some may have respiratory problems. Consult your physician first before use. Pregnant women and children should also see a doctor before applying lemon oil.   Peppermint According to a review conducted by the USDA Human Nutrition Research Center on Aging at Tufts University, peppermint has significant antimicrobial and antiviral activities. It also works as a strong antioxidant, displays anti-tumor actions in lab studies, shows anti-allergenic potential and pain-killing effects, helps to relax the gastrointestinal tract and may be chemopreventive.4   Note: Chemoprevention is the use of a medication, vitamin or supplement to stop cancer from happening. This is most often used for people who have a high risk of developing cancer. The high menthol content of peppermint makes it great for cooling off during hot flashes. At the first sign of a hot flash developing, place a drop at the back of the neck, at the base of the skull, or on the collarbones. Breathe it in. This has an instant cooling and calming effect. Peppermint oil not only relaxes skeletal muscles, it also helps to relax the muscles of the respiratory system. Inhaling the scent of peppermint helps to relieve congestion due to allergies and counteract the effects of pollen. Especially powerful when combined with lavender and lemon to ease seasonal allergies! Peppermint oil is superb for helping to relieve indigestion and heartburn. Put just one drop of peppermint oil into a glass of water and drink. It works much more quickly than peppermint tea due to the concentrated nature of peppermint oil. If it's too strong for you, just dilute it and rub it across the tummy.   Is Peppermint Oil Safe? Peppermint oil is safe in low amounts in most adults, but it can trigger side effects in people with sensitivities. It is important for the following individuals to either avoid using this essential oil or to use it carefully only with the help of a healthcare professional. Pregnant and nursing women — Peppermint oil or other similar products may have emmenagogue and abortifacient effects, so it would be wise not to use peppermint oil without your physician's approval. Infants and children 7 years old and younger — Peppermint oil must not be used undiluted because there isn't enough information regarding its safety for them. Diabetics — Using peppermint oil may raise your risk of low blood sugar levels or hypoglycemia. Gastroesophageal reflux disease (GERD) and hiatal hernia patients — Peppermint can relax the sphincter between the stomach and esophagus, and cause acid to move up to the esophagus. People with gallbladder problems — Peppermint oil may cause gallbladder inflammation; those diagnosed with gallstones should consult a physician before using peppermint oil. People taking antacids — These drugs can cause peppermint oil capsules to break down easily, increasing the risk of heartburn.   Eucalyptus The healing benefits of Eucalyptus Oil can be attributed to its anti-inflammatory, antispasmodic, decongestant, deodorant, and antiseptic qualities, among other valuable properties.   Eucalyptus oil is known to be a vasodilator, meaning it dilates, or opens, blood vessels. In 1994, Austrian researchers discovered that eucalyptol, a phytochemical in eucalyptus oil (also known as 1,8-cineol) improved global blood flow to the brain, after only 20 minutes of inhalation.9 A newer study released in 2016 by Korean researchers found that eucalyptol is also able to pass through the blood-brain barrier. This research also found eucalyptol's high antioxidant and anti-inflammatory properties to be helpful in the management of chronic conditions such as respiratory disease, cardiovascular disease, and degenerative nerve and brain diseases. Some studies have shown that several different species of eucalyptus may help to reduce blood sugar levels in mice. Also because eucalyptus is such an excellent vasodilator, the entire body benefits from this increase in blood circulation. To help combat poor blood circulation, dilute eucalyptus oil and massage it into the legs, hands, and feet as needed. Eucalyptus oil's anti-inflammatory, antiseptic, and anti-phlegm properties work very quickly to open congested airways. Make a steam inhalation by boiling two cups of water, pour it into a large bowl, then let it cool for five minutes. Add a drop or two of eucalyptus oil. Then create a tent from a small towel draped over your head. Place your face over the bowl and carefully breathe in the vapor until you get some relief. This should only take a couple of minutes. This is great for bronchitis, head colds, chest colds, and asthma.   Is Eucalyptus Oil Safe? Essential oils like eucalyptus oil are generally safe to use, but with specific precautions. Before using it, consult a holistic doctor to see if your condition would allow you to do so, and undergo an allergen patch test to check for possible allergic reactions and lower your risk for developing side effects. In general, adults should not take eucalyptus oil orally except under a doctor's supervision, and this oil mustn't be given to children, especially those under 2 years old.   While eucalyptus oil is generally safe when applied to adult skin, refrain from applying the oil, salve or chest rub on the face or nose of baby because of its potential side effects. Lastly, pregnant and breastfeeding women should also avoid using the oil as evidence is lacking regarding its safety for these groups of women.     Frankincense – The KING of essential oils! Frankincense essential oil is distilled from the resin of the Boswellia tree that grows in many regions within northern Africa and the Middle East. Oman, Somalia, and Ethiopia are the most prominent suppliers today.   Research shows that the natural plant chemical constituents in frankincense oil stimulate the immune system.2   But it supports so much more… Frankincense is a powerful health support for respiratory problems such as asthma, chronic obstructive pulmonary disease, pneumonia, and bronchitis. It even helps when suffering from laryngitis. Diffuse it into the room where you intend to spend some time. For best results, use an ultrasonic cool mist diffuser. Never heat essential oils because heating them diminishes their therapeutic effects. Whether your skin is dry and mature or oily and blotched with blemishes, frankincense oil has wonderful balancing qualities. It helps to reduce lines and wrinkles by tightening and toning skin, accelerates the healing of blemishes, skin ulcers and wounds, and stimulates cell regeneration. For anti-aging benefits, put several drops into your favorite night time moisturizer. For acne and blemishes, apply it neat directly on the problem area, unless you have very sensitive skin, then dilute. Use frankincense oil to help calm and center the mind, to promote spiritual awareness, and to cultivate a sense of inner peace while meditating. Frankincense contains compounds known as sesquiterpenes which work directly on the limbic system of the brain, the center of memory and emotions. Frankincense is calming, grounding, and centering to the nervous system. Diffuse it into your room, or just inhale directly from the bottle at the start of your meditation.   Is Frankincense Oil Safe? Yes, frankincense oil is generally safe. Just make sure to undergo an allergen patch test before applying frankincense oil topically to see if you have any sensitivity to this oil.   For some groups of people, frankincense oil isn't recommended, since it may trigger adverse reactions. If you're pregnant or nursing, avoid using frankincense oil because it may trigger contractions, prompt menstruation and lead to a miscarriage. As for children, there is very limited information regarding the potential use of this oil for this age group, so if you're a parent or guardian, do not let them use this oil.   How to Dilute Essential Oils Although essential oils can be used neat (undiluted) in many cases, it is best (and more economical) to dilute essential oils before applying them to the body. Add a drop or two of your chosen oil to one-half to one teaspoonful of an organic carrier oil such as coconut, almond, hemp, or jojoba.   If using with children or pets, use even less essential oil because their smaller bodies cannot tolerate an adult dose. It's best to consult a qualified aromatherapist before using essential oils with pets or children.    A Final Word About Quality Always choose high quality, organic essential oil that has been properly distilled so that its phytochemical content is not compromised. Look for bottles labeled 100% pure oil and beware of cheap oils that may be diluted with potentially toxic chemical ingredients.   In addition to the powerful essential oils we touched on today, Organixx carries 6 more beautiful single oils just as powerful and effective to help you maintain optimal health; Orange, Grapefruit, Oregano, Geranium Rose, Rosemary, and Clove. Resources: Organixx Essential Oils - 100% Pure, Organic, Non-GMO 1 Comparative studies of cytotoxic and apoptotic properties of different extracts and the essential oil of Lavandula angustifolia on malignant and normal cells. 2 Immunomodulatory activity of biopolymeric fraction BOS 2000 from Boswellia serrata. 3 Insecticidal Activity of Melaleuca alternifolia Essential Oil and RNA-Seq Analysis of Sitophilus zeamais Transcriptome in Response to Oil Fumigation. 4 A review of the bioactivity and potential health benefits of peppermint tea (Mentha piperita L.). National Association for Holistic Aromatherapy – Safety Information 12 Top Essential Oils & 60+ Uses Non-Toxic DIY Essential Oil Mosquito Repellent Tummy Troubles? The Best Essential Oils for Digestive Problems What Are Essential Oils? 21 Facts About Essential Oils You May Not Know

Join us for a dive into the power of essential oils in our daily lives. The interest in essential oils is rapidly on the rise according to Google Trends. The trend line is fascinating. Why? What makes essential oils so sought after? They work! Organixx carries a line of organic and pure essential oils. Today we will share the top 3 uses of the top single essential oils in our line.   Lavender Lavender oil is believed to have antiseptic and anti-inflammatory properties. We've all heard by now that lavender promotes deeper sleep, but did you know…   There's promising research for breast health too. 2014 Iranian research published in the journal Nutrition and Cancer found that lavender oil kills breast cancer cells but leaves healthy cells unharmed. It's important to note that this study was on cells in a petri dish, not on humans. The researchers concluded that: “L. angustifolia has cytotoxic and apoptotic effects in HeLa and MCF-7 cell lines, and apoptosis is proposed as the possible mechanism of action.”1 Stops the itch and burn of insect bites. Even fire ants! Put a drop of lavender oil on a bee sting, mosquito, or other bug bite to stop pain, itching, and reduce swelling. Reapply as necessary. Lavender oil works really well for this, especially if applied immediately. Use it as a flavor booster. Add a drop of high-quality lavender oil suitable for consumption to brownie batter, chocolate icing, cookie dough, dessert recipes, raw chocolate, or even salad dressings. It's absolutely delicious.   Is Lavender Oil Safe? Using diluted lavender oil topically or in aromatherapy is generally considered safe for most adults but may not be recommended for children. Applying pure lavender oil to your skin (especially open wounds) may also cause irritation, so we recommend infusing it with a carrier oil, such as olive oil or coconut oil. Dissolving it in water also works.   Be careful not to rub lavender oil in your eyes and mucous membranes. If this happens, wash it out immediately. Lavender oil may also cause allergic reactions in people with unusually sensitive skin, so do a spot test before using it. Simply apply a drop of lavender oil to your arm and see if any reaction occurs.   The U.S. National Institutes of Health (NIH) also warns against using lavender oil when taking medications like barbiturates, benzodiazepines and chloral hydrate, as it may increase their sedative effects and cause extreme drowsiness and sleepiness.   Tea Tree (Melaleuca) This versatile oil possesses antibacterial, anti-inflammatory, antiviral, and antifungal properties.   Due to its potent anti-inflammatory benefits, tea tree oil helps to relieve inflammatory skin conditions, especially eczema and psoriasis. Dilute as necessary and apply to affected area two to three times daily. Tea tree oil has long been used as a natural bug repellent by native Australian aboriginal people. Chinese research in 2016 found tea tree to be effective against the cereal weevil, Sitophilus zeamais.3 The cereal weevil is considered to be an extremely destructive pest to stored cereals all over the world. Tea tree also helps to relieve the pain, itching, and inflammation of insect bites. If it's an extra-hot day and your deodorant has failed, apply again, but this time with a drop or two of tea tree oil to help kill bacteria. Tea tree oil's potent antibacterial properties are well proven with dozens of research studies.   Is Tea Tree Oil Safe? The answer is yes, as long as it is applied topically in appropriate doses and NOT swallowed. This oil may irritate your skin, especially if used for the first time. We recommend starting with low concentrations until you figure out your tolerance. Determine if you have an allergy to tea tree oil before using it by doing a skin test — apply a small amount to your inner arm to see if any reaction such as a rash or hives occurs.   The National Center for Complementary and Alternative Medicine (NCCAM) recommends avoiding oxidized oil, which has been exposed to air, because it may help trigger allergies more than fresh tea tree oil.  Avoid using undiluted tea tree oil as well and use tea tree oil-infused products instead to reduce your risk of skin irritation.   Lemon The health benefits of lemon oil can be attributed to its stimulating, calming, astringent, detoxifying, antiseptic, disinfectant and antifungal properties. *Important to note: Lemon essential oil can make your skin more sensitive to sunlight. Lemon oil has a balancing effect on the oil glands of the scalp. Massage a drop or two of lemon oil into your scalp before you go to bed at night. Wash it out in the morning. Done over a period of weeks, you will notice much less oily hair. It will make your pillow smell nice and fresh too! Diffuse lemon oil to help kill airborne bacteria. Research carried out by Dr. Jean Valnet (co-author of the book The Practice of Aromatherapy: A Classic Compendium of Plant Medicines and Their Healing Properties) shows that diffused lemon oil can rapidly kill off the bacteria that causes meningococcal infections, typhoid fever, staph infections, pneumonia, diphtheria, and tuberculosis. Several essential oils are haemostatic, i.e. they help to stop bleeding by speeding up the coagulation of the blood. The most useful of these is oil of Lemon, though Geranium and Rose have similar, though less powerful, effects.   Is Lemon Oil Safe? It is advisable not to use lemon oil without diluting it first, as it can irritate skin. It must be used with a carrier oil for direct application to the skin. Effective carrier oils include coconut oil, olive oil and jojoba oil.   There are findings showing that lemon oil may promote photosensitivity, which increases your sensitivity to the sun and may lead to sunburn and uneven darkening of the skin. We also recommend you avoid applying lemon oil and other citrus oils to your skin when outdoors, as blistering may occur.   People with sensitivities should use essential oils with caution. Reactions can vary from person to person. Some may experience skin reactions, while some may have respiratory problems. Consult your physician first before use. Pregnant women and children should also see a doctor before applying lemon oil.   Peppermint According to a review conducted by the USDA Human Nutrition Research Center on Aging at Tufts University, peppermint has significant antimicrobial and antiviral activities. It also works as a strong antioxidant, displays anti-tumor actions in lab studies, shows anti-allergenic potential and pain-killing effects, helps to relax the gastrointestinal tract and may be chemopreventive.4   Note: Chemoprevention is the use of a medication, vitamin or supplement to stop cancer from happening. This is most often used for people who have a high risk of developing cancer. The high menthol content of peppermint makes it great for cooling off during hot flashes. At the first sign of a hot flash developing, place a drop at the back of the neck, at the base of the skull, or on the collarbones. Breathe it in. This has an instant cooling and calming effect. Peppermint oil not only relaxes skeletal muscles, it also helps to relax the muscles of the respiratory system. Inhaling the scent of peppermint helps to relieve congestion due to allergies and counteract the effects of pollen. Especially powerful when combined with lavender and lemon to ease seasonal allergies! Peppermint oil is superb for helping to relieve indigestion and heartburn. Put just one drop of peppermint oil into a glass of water and drink. It works much more quickly than peppermint tea due to the concentrated nature of peppermint oil. If it's too strong for you, just dilute it and rub it across the tummy.   Is Peppermint Oil Safe? Peppermint oil is safe in low amounts in most adults, but it can trigger side effects in people with sensitivities. It is important for the following individuals to either avoid using this essential oil or to use it carefully only with the help of a healthcare professional. Pregnant and nursing women — Peppermint oil or other similar products may have emmenagogue and abortifacient effects, so it would be wise not to use peppermint oil without your physician's approval. Infants and children 7 years old and younger — Peppermint oil must not be used undiluted because there isn't enough information regarding its safety for them. Diabetics — Using peppermint oil may raise your risk of low blood sugar levels or hypoglycemia. Gastroesophageal reflux disease (GERD) and hiatal hernia patients — Peppermint can relax the sphincter between the stomach and esophagus, and cause acid to move up to the esophagus. People with gallbladder problems — Peppermint oil may cause gallbladder inflammation; those diagnosed with gallstones should consult a physician before using peppermint oil. People taking antacids — These drugs can cause peppermint oil capsules to break down easily, increasing the risk of heartburn.   Eucalyptus The healing benefits of Eucalyptus Oil can be attributed to its anti-inflammatory, antispasmodic, decongestant, deodorant, and antiseptic qualities, among other valuable properties.   Eucalyptus oil is known to be a vasodilator, meaning it dilates, or opens, blood vessels. In 1994, Austrian researchers discovered that eucalyptol, a phytochemical in eucalyptus oil (also known as 1,8-cineol) improved global blood flow to the brain, after only 20 minutes of inhalation.9 A newer study released in 2016 by Korean researchers found that eucalyptol is also able to pass through the blood-brain barrier. This research also found eucalyptol's high antioxidant and anti-inflammatory properties to be helpful in the management of chronic conditions such as respiratory disease, cardiovascular disease, and degenerative nerve and brain diseases. Some studies have shown that several different species of eucalyptus may help to reduce blood sugar levels in mice. Also because eucalyptus is such an excellent vasodilator, the entire body benefits from this increase in blood circulation. To help combat poor blood circulation, dilute eucalyptus oil and massage it into the legs, hands, and feet as needed. Eucalyptus oil's anti-inflammatory, antiseptic, and anti-phlegm properties work very quickly to open congested airways. Make a steam inhalation by boiling two cups of water, pour it into a large bowl, then let it cool for five minutes. Add a drop or two of eucalyptus oil. Then create a tent from a small towel draped over your head. Place your face over the bowl and carefully breathe in the vapor until you get some relief. This should only take a couple of minutes. This is great for bronchitis, head colds, chest colds, and asthma.   Is Eucalyptus Oil Safe? Essential oils like eucalyptus oil are generally safe to use, but with specific precautions. Before using it, consult a holistic doctor to see if your condition would allow you to do so, and undergo an allergen patch test to check for possible allergic reactions and lower your risk for developing side effects. In general, adults should not take eucalyptus oil orally except under a doctor's supervision, and this oil mustn't be given to children, especially those under 2 years old.   While eucalyptus oil is generally safe when applied to adult skin, refrain from applying the oil, salve or chest rub on the face or nose of baby because of its potential side effects. Lastly, pregnant and breastfeeding women should also avoid using the oil as evidence is lacking regarding its safety for these groups of women.   Frankincense – The KING of essential oils! Frankincense essential oil is distilled from the resin of the Boswellia tree that grows in many regions within northern Africa and the Middle East. Oman, Somalia, and Ethiopia are the most prominent suppliers today.   Research shows that the natural plant chemical constituents in frankincense oil stimulate the immune system.2   But it supports so much more… Frankincense is a powerful health support for respiratory problems such as asthma, chronic obstructive pulmonary disease, pneumonia, and bronchitis. It even helps when suffering from laryngitis. Diffuse it into the room where you intend to spend some time. For best results, use an ultrasonic cool mist diffuser. Never heat essential oils because heating them diminishes their therapeutic effects. Whether your skin is dry and mature or oily and blotched with blemishes, frankincense oil has wonderful balancing qualities. It helps to reduce lines and wrinkles by tightening and toning skin, accelerates the healing of blemishes, skin ulcers and wounds, and stimulates cell regeneration. For anti-aging benefits, put several drops into your favorite night time moisturizer. For acne and blemishes, apply it neat directly on the problem area, unless you have very sensitive skin, then dilute. Use frankincense oil to help calm and center the mind, to promote spiritual awareness, and to cultivate a sense of inner peace while meditating. Frankincense contains compounds known as sesquiterpenes which work directly on the limbic system of the brain, the center of memory and emotions. Frankincense is calming, grounding, and centering to the nervous system. Diffuse it into your room, or just inhale directly from the bottle at the start of your meditation.   Is Frankincense Oil Safe? Yes, frankincense oil is generally safe. Just make sure to undergo an allergen patch test before applying frankincense oil topically to see if you have any sensitivity to this oil.   For some groups of people, frankincense oil isn't recommended, since it may trigger adverse reactions. If you're pregnant or nursing, avoid using frankincense oil because it may trigger contractions, prompt menstruation and lead to a miscarriage. As for children, there is very limited information regarding the potential use of this oil for this age group, so if you're a parent or guardian, do not let them use this oil.   How to Dilute Essential Oils Although essential oils can be used neat (undiluted) in many cases, it is best (and more economical) to dilute essential oils before applying them to the body. Add a drop or two of your chosen oil to one-half to one teaspoonful of an organic carrier oil such as coconut, almond, hemp, or jojoba.   If using with children or pets, use even less essential oil because their smaller bodies cannot tolerate an adult dose. It's best to consult a qualified aromatherapist before using essential oils with pets or children.    A Final Word About Quality Always choose high quality, organic essential oil that has been properly distilled so that its phytochemical content is not compromised. Look for bottles labeled 100% pure oil and beware of cheap oils that may be diluted with potentially toxic chemical ingredients.   In addition to the powerful essential oils we touched on today, Organixx carries 6 more beautiful single oils just as powerful and effective to help you maintain optimal health; Orange, Grapefruit, Oregano, Geranium Rose, Rosemary, and Clove. Resources: Organixx Essential Oils - 100% Pure, Organic, Non-GMO 1 Comparative studies of cytotoxic and apoptotic properties of different extracts and the essential oil of Lavandula angustifolia on malignant and normal cells. 2 Immunomodulatory activity of biopolymeric fraction BOS 2000 from Boswellia serrata. 3 Insecticidal Activity of Melaleuca alternifolia Essential Oil and RNA-Seq Analysis of Sitophilus zeamais Transcriptome in Response to Oil Fumigation. 4 A review of the bioactivity and potential health benefits of peppermint tea (Mentha piperita L.). National Association for Holistic Aromatherapy – Safety Information 12 Top Essential Oils & 60+ Uses Non-Toxic DIY Essential Oil Mosquito Repellent Tummy Troubles? The Best Essential Oils for Digestive Problems What Are Essential Oils? 21 Facts About Essential Oils You May Not Know

We talk with Mathieu Lupien, PhD, a senior scientist at the Princess Margaret Cancer Centre and associate professor at the University of Toronto in Canada. Hear how studying chromatin state and transcription in individual cells has opened up a new area of research in gene regulation and cancer progression.

Wow - May 2021 is a productive month for AD genetics research! Tune in and Joseph will take you through 19 papers on studies to do with new variants, novel genetic insights, or studies on familial AD genetics.   Sections in this episode:  Methods for Gene and Pathway Discovery (1:46)  GWAS, Transcriptome, Exome Sequencing (5:47)  Miscellaneous (12:55)  Familial AD (17:11)  -------------------------------------------------------------- You can find the numbered bibliography for this episode by clicking here, or the link below:https://drive.google.com/file/d/1pKecrNPbkMwJyc_z7Yeo3P0frVYzs7If/view?usp=sharingTo access the folder with all the bibliographies for 2021 so far, follow this link (it will be updated as we publish episodes and process bibliographies), or click the following link below:https://drive.google.com/drive/folders/1N1zx_itPkCDNYE1yFGZzQxDDR-NiRx3p?usp=sharingYou can also join our mailing list to receive a newsletter by filling this form. Or tweet at us: @AMiNDR_podcast  --------------------------------------------------------------Follow-up on social media for more updates!Facebook:  AMiNDR  Twitter: @AMiNDR_podcastInstagram: @AMiNDR.podcastYoutube: AMiNDR PodcastLinkedIn: AMiNDR PodcastIf you have any questions or concerns, do not hesitate to contact us at: amindrpodcast@gmail.com  -------------------------------------------------------------- Please help us by spreading the word about AMiNDR to your friends, colleagues, and networks! Another way you can help us reach more researchers is by leaving us a review on Apple Podcasts or wherever you listen to podcasts. We would like to thank our amazing team for all of the work that goes into every episode of AMiNDR. Today's episode was scripted by Joseph Liang, reviewed by Ellen Koch, and edited by Joseph Liang. The bibliography was made by Jacques Ferreira and wordcloud was generated by Sarah Louadi using wordart.com.Big thanks to the sorting team for sorting all the papers published in May into themes for our episodes: Jacques Ferreira, Elyn Rowe, Ellen Koch, Christy Yu, Nicole Corso, and Naila Kuhlmann. Also, props to our management team, which includes Sarah Louadi, Ellen Koch, Naila Kuhlmann, Elyn Rowe, Anusha Kamesh, and Jacques Ferreira, 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, creating bibliographies, and promotions. 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!" 

In this episode of the Epigenetics Podcast, we caught up with Enrico Glaab from the University of Luxemburg to talk about his work on the development of integrative machine learning tools for neurodegenerative diseases. The work of Dr. Enrico Glaab focuses on neurodegenerative disorders like Parkinson's and Alzheimer's disease. In his group his team works on the development of software tools to analyze molecular, clinical and neuroimaging data for those diseases that can be used and applied easily by scientists and deliver publication ready figures. More recently, Enrico Glaab's group got interested in the influence of Epigenetics in Parkinson's and Alzheimer's disease. In this Episode we discuss how Enrico Glaab made the switch from wet-lab to becoming a bioinformatician and how he uses integrative machine learning tools to find approaches to not only cure but also be able to detect neurodegenerative diseases like Alzheimer's or Parkinson's early on.   References Enrico Glaab, Reinhard Schneider (2015) RepExplore: addressing technical replicate variance in proteomics and metabolomics data analysis (Bioinformatics) DOI: 10.1093/bioinformatics/btv127 Enrico Glaab, Reinhard Schneider (2015) Comparative pathway and network analysis of brain transcriptome changes during adult aging and in Parkinson's disease (Neurobiology of Disease) DOI: 10.1016/j.nbd.2014.11.002 Sandra Köglsberger, Maria Lorena Cordero-Maldonado, … Enrico Glaab (2017) Gender-Specific Expression of Ubiquitin-Specific Peptidase 9 Modulates Tau Expression and Phosphorylation: Possible Implications for Tauopathies (Molecular Neurobiology) DOI: 10.1007/s12035-016-0299-z Enrico Glaab, Paul Antony, … Manuel Buttini (2019) Transcriptome profiling data reveals ubiquitin-specific peptidase 9 knockdown effects (Data in Brief) DOI: 10.1016/j.dib.2019.104130   Related Episodes Epigenetic Influence on Memory Formation and Inheritance (Isabelle Mansuy) CpG Islands, DNA Methylation, and Disease (Sir Adrian Bird) Epigenetics & Glioblastoma: New Approaches to Treat Brain Cancer (Lucy Stead) Cancer and Epigenetics (David Jones)   Contact Active Motif on Twitter Epigenetics Podcast on Twitter Active Motif on LinkedIn Active Motif on Facebook Email: podcast@activemotif.com

Rapid and cheap DNA sequencing technology can tell us a lot about which genes a patient is carrying around, but it can't tell us when and where the instructions in those genes get carried out inside cells. Resolve Biosciences—headed by this week's guest, Jason Gammack—aims to solve that problem by scaling up a form of intracellular imaging it calls molecular cartography.Gammack says the technology offers a high-resolution way to see the geography of gene transcription in single cells, that is, where specific messenger RNA molecules congregate once they’ve left the nucleus. The technology can trace up to 100 gene transcripts simultaneously. Right now it only works for mRNA, but the company says it plans to add the ability to track DNA, proteins, and “metabolic data layers.” The big idea is to make it easier to see how gene expression translates into normal tissue development and, by extension, the pathology of genetic or infectious diseases."We can go in and identify specific RNA molecules that code for a known protein," Gammack tells Harry. "We can label those molecules and with high power microscopy and molecular biology and very important software, we can then identify and literally visualize individual RNA transcripts in the context of the cell and tissue."Resolve was in stealth mode from 2016 to December 2020, when it announced a Series A financing round of $25 million. Its technology is being tested by six teams of scientist-collaborators as part of an early access program launched in 2019. Resolve reportedly plans to launch its service commercially in the first half of 2021.Gammack joined the company from Inscripta, where he was chief commercial officer helping to sell the CRISPR-based Onyx gene-editing platform. Before that, he was at Qiagen, a German provider of assays for molecular diagnostics such as a Covid-19 antigen test, where he was vice president of life sciences. Please rate and review MoneyBall Medicine on Apple Podcasts! Here's how to do that from an iPhone, iPad, or iPod touch:• Launch the “Podcasts” app on your device. If you can’t find this app, swipe all the way to the left on your home screen until you’re on the Search page. Tap the search field at the top and type in “Podcasts.” Apple’s Podcasts app should show up in the search results.• Tap the Podcasts app icon, and after it opens, tap the Search field at the top, or the little magnifying glass icon in the lower right corner.• Type MoneyBall Medicine into the search field and press the Search button.• In the search results, click on the MoneyBall Medicine logo.• On the next page, scroll down until you see the Ratings & Reviews section. Below that, you’ll see five purple stars.• Tap the stars to rate the show.• Scroll down a little farther. You’ll see a purple link saying “Write a Review.”• On the next screen, you’ll see the stars again. You can tap them to leave a rating if you haven’t already.• In the Title field, type a summary for your review.• In the Review field, type your review.• When you’re finished, click Send.• That’s it, you’re done. Thanks!TRANSCRIPTHarry Glorikian: I’m Harry Glorikian, and this is MoneyBall Medicine, the interview podcast where we meet researchers, entrepreneurs, and physicians who are using the power of data to improve patient health and make healthcare delivery more efficient. You can think of each episode as a new chapter in the never-ending audio version of my 2017 book, “MoneyBall Medicine: Thriving in the New Data-Driven Healthcare Market.” If you like the show, please do us a favor and leave a rating and review at Apple Podcasts.Harry Glorikian: We’ve come a long way in the last 25 years in our ability to sequence the DNA of individual patients. We can even see which genes are being expressed as RNA, the instructions for making proteins. But after that there’s a big blind spot in our understanding, because it’s still hard to see exactly which RNA molecules inside our cells actually get translated into proteins, and just as important, when and where they get translated. The problem is that almost everything that’s interesting about human biology and human disease happens inside that blind spot.Resolve Biosciences in Germany is one of the new biopharmaceutical startups tackling that challenge. My guest this week is Jason Gammack, the CEO of Resolve, and he says the company has come up with a way to label multiple RNA molecules with probes that glow in different fluorescent colors. Resolve built software that can decode the color patterns to see where RNA transcripts gather in the cell and how they’re involved in cell development. That kind of location information that could eventually produce a better picture of how normal cells grow, and also how that growth becomes cancerous and maybe even what kinds of drugs could stop tumors before they kill their hosts. Gammack joined the company last year, around the same time the company announced a 25 million dollar funding round to help bring its so called “Molecular Cartography” technology to market.Here’s our conversation.Harry Glorikian: Jason, welcome to the show Jason Gammack: Harry, it's great to be here. Thank you. Harry Glorikian: It's been great talking to you and getting to know you. I feel like we should be doing this over a beer and we should be talking for hours. And my I'm sure, my 19 year old would be like, do you want to go to Germany? Let's go to Germany.Cause he loves coming there and having beers when, when when we've done it in the past Molecular cartography. I feel like, you know, Galileo is about to like, you know, step into this conversation with us, but for those people who don't, who aren't molecular biologists, it it'd be great. If you could sort of paint the bigger picture for us and, and help us understand what is, what is this concept of, I think spatial transcriptomics. I almost like stuttered on my words. And why is it important?Jason Gammack: Yeah. And so it's a great question Harry. And so again, thanks for the invite to join the the podcast. So context matters. Let's start with that statement, reading a book without understanding the context makes it difficult book to read.And if you think about our genome, the DNA that makes us similar and unique, it's a book. And right now we don't have full context of what that book is and Resolve Biosciences is a company, that's focused on creating tools to help give context to the genome. And so let me explain that a bit. So the central dogma of biology is DNA.Which is in your cells is made into RNA and that RNA is then translated into proteins and those proteins are in essence. What makes you, you, it's your muscle? It's your hair? It's your skin. It's your organ systems. It's a lot. And we understand the book pretty well from the letters, a C, G and T. And we've been in an exponential phase of learning as it pertains to the genome and companies such as aluminum.It's a San Diego based biotech company has created a technology that allows us to sequence the entire human genome. So every letter in your genome, We can do that now in a couple of days and for a couple of hundred dollars and we need to keep that in context, you know, the first genome took…Harry Glorikian: I remember yeah. Jason Gammack: 15 years and $7 billion to do it. As a matter of fact, you know, this is the anniversary of that event happening, right? Harry Glorikian: Yep. Jason Gammack: So we've really learned a lot about the core code of the genome. But the disease, chronic disease still exists in our population. And so we have to ask the question, what else do we need to understand? And we at Resolve believe that the next question is really to understand where different genetic events are occurring within a cell.The interesting thing. And the big question in biology is largely we all have the same DNA in our bodies. You know, humans are remarkably, remarkably homologous and the variation in humans is very, very low, but yet we have individuals who are six and a half feet tall. We have individuals that are four feet tall.We have individuals that way, you know, 250 pounds and we have individuals that weigh 90 pounds. And so why. And even more perplexing is we have diseases such as cancer, where two women, can you present with a very similar breast tumor one, or they both can be treated with a very similar treatment, identical drops, and one can go into complete remission and eventually be here and the other cannot and potentially die. Harry Glorikian: Right.Jason Gammack: And so the question is why does that happen? And that has to come down to a number of different variables that we can't yet measure. And so our belief at Resolve Biosciences is we are going to develop tools to help understand those differences. And that's really urgent.Harry Glorikian: So let's, I mean, I'm trying to paint a picture for people that are listening to this. Right? So I think of this as, cause I feel like I've been to at least part of this movie before, when I started in immunohistochemistry, where we could actually visualize, you know, rather than grinding up a bunch of cells and looking at the moles and, you know, in breast cancer, we were able to actually stain the cells with antibodies that would specifically show us, you know, different parts of a cell that were lighting up. And that was, you know, sort of a flat file way to look at it with a certain level of resolution. And you're, I think, zooming in to the molecular level now and taking it to a different resolution. Jason Gammack: Absolutely. So that's a, that's a great point. And let me build on that one just a bit. So immune histochemistry opened the books to understand different types of disease status, where you can start profiling cell types and understand where they are in the cell cycle, which can be indicators for physicians or the biologists to prescribe a particular therapeutic. Right. We take that even to another degree.I'll use an analogy. It's perhaps overused, but think about Google Maps. So Maps allows you to start at the continent or global level, and then focus in to this country. You focus it into a state, focus into a city, focus into a stream and even focusing. So our technology and the molecular cartography platform is similar in that we can take single cells or we can take tissues license and through our molecular biology approach, we can label individual RNA transference. So going back to that: DNA makes RNA makes protein. We can go in and identify specific RNA molecules, that code for a known protein. We can label those molecules and with high power microscopy and molecular biology and very importantly software, we can then identify and literally visualize individual RNA transcripts in the context of the cell and tissue.So now going back to that Google Maps analogy, we now have that woman who has the unfortunate breast tumor. We can put sections of that breast tumor on the slide. We can use our molecular cartography technology to be able to look at the gene expression patterns within that tumor. And those patterns can give insights to researchers and eventually to clinicians in how to affect and treat that disease state very, very possible.Harry Glorikian: So I, I, we're talking about essentially creating a three-dimensional map of the cells and which ones are lighting up, which ones are not lighting up, how they affect each other, basically intercommunication between these cells, Jason Gammack: And intra-communication inside the cell as well. Harry Glorikian: So, so. Where, where are you? How far are you in this? I guess is the first question. Jason Gammack: Yeah. Good question. So this journey didn't just start. And so this journey started in 2016. When we at a previous company thought about this challenge of spatial loud. Again, you know, we have sequence genomes, but yet cancer persists in the population. And we were asking questions.What's the next answer that needs to be brought to science. And so in 2016, we brought together a truly gifted group of scientists to come up with solutions, to be able to look at the spatial relationship of gene expression within cells and tissue. And since the 2016 inception of the project, we've now been able to take bench science and automate bench science to the point where we can now run hundreds of samples, looking at thousands of genes in a fully automated process. So you're building on this existing technique of single Mol, single molecule RNA for essence. Right. And so, and this is, I don't. No, it's nothing new, right?This is a technique that's been out there. I guess the question is, is what are the fundamental advances that resolve is bringing to the table or your version of. This, that that is uniquely powerful. Yeah. So so as you said, our technology is what's generally referred to as a single molecule FISH technology, fluorescent insight to hybridization, which means we label RNA with a four or four, and then we can image that RNA using high power optics.And so there are numerous approaches to look at labeling RNA and there are numerous challenges in doing that. We have come up with a novel. And of course, because we're a biotech company, a patented process,Harry Glorikian: Ha ha. Jason Gammack: We have a process that allows us to through combinatorial. Labeling of the RNA allows us to identify very diverse RNA. Because the challenge is, is that when you want to label something, you have to attach a protein to, and then the genome or the transcriptome, there's a lot of repetitive sequences that are similar and you need to be able to discern the difference between GNA and GB.And they could be very, very homologous or very, very similar. Our technology allows us to use small, but very different probes to tile across that, that target, that RNA of interest. And then by selectively colorizing and D colorizing, those proteins, we create an essence, a color pattern. And that color modernize image, and then we'll use software to deconvolute or decode those images.So we can then see individual transcripts within the cell. Harry Glorikian: It's funny. I feel like my, you know, history has a way of building on itself. I mean, I remember when we were doing DNA in situ hybridization and trying to convince people that this was going to be something and then. You know, molecular barcodes when I was at Applied Biosystems. So this is the culmination in a, in a sense, an advancement, obviously because of software and imaging and those sorts of things of this next stage of where this technology is taking us. Jason Gammack: Indeed, indeed. I think that's a great analogy. Right? Great example. And you see this kind of. You know, you see this, this trajectory of single cell biology and, you know, transcript elements is a great example of that.You know, we started with RNA, RNA, blondes doing what's called a Northern Burlington, you know, in grad school, we're doing Northern blots where we need to use it. The RNA within the Northern block, I still have all my fingers, even with all the isotope I used in grad school. And so you've gone from very crude techniques to a much more refined technique and Illumina through their next generation sequencing brought on an amazing technology called RNAseq or RNAC.Of course RNAC, kind of back to your earlier analogy is you grind everything up and then you read all of the transcripts. The problem is, is you don't know what transcript came from. Like you know, you just got this huge mess of transcripts and you've got to kind of say, well, this is a transcript that's associated with this gene and that genes associated with this kind of cell type.And then a couple of years ago, a company called 10X genomics came up to take single cells. So instead of had that, say that fruit smoothie with everything ground up, they took the piece of the fruit and just kind of laid them out of the line and what they oxalated the cells into a droplet. And then did the sequencing reaction in that droplet.You still have a kind of a mixed population there. And then through software, they would separate out the different stuff. We now take that to the next, next level where we just look at the fruit salad instead of that food smoothie or the windup fruits. We can now look at the fruit salad and we can say, Oh yeah, cantaloupe was touching an Apple, which is touching, you know, orange and orange are next to each other.The fruit salad falls apart really quickly. Going back to the analogy of breast cancer. When we have these interactions, these patients don't survive. So maybe we need to look differently at the drug that's targeting that interaction. So that's how we want to think about these problems. Now we can move them forward.Harry Glorikian: Well, like you said, I mean, context matters. Location matters, right? As, as a guy who's got IP and location-based services, location is a big deal, right? People don't realize everything revolves around location. At some point. And having context to, it really adds another dimensionality of information that all of a sudden your eyes open up to what could be going on or why something matters for sure.Jason Gammack: And this is, I mean, and again, I keep going back to the oncology use case, but you know, oncology is a blight that is all over the world and affects all human beings at some point. And the concept, you know, a tumor is not a homogeneous massive cells. You know, tumors are heterogeneous. The cells that are in the interior of the tumor are different than the cells on the exterior of the tumor, the blood vessels that innovate the tumor look different than blood vessels that are adjacent to the tumor.And we call this the tumor microenvironment. What is going on inside that too? And, you know, coming up with a drug that can just permeate the tumor and kill it from the inside outage, whether it's hypoxia and you started of, of oxygen. So it can no longer grow or maybe encapsulating the tumor. So they can't grow and dies outside in.We just don't have a lot of visibility right now to the genetics that's happening within that micro environment. And this is an area where molecular cartography just shines a spotlight onto that tumor microenvironment. Harry Glorikian: Well, I'm also thinking, as you get to know these different cell types in the call, it the color pattern that they're giving, you can almost create a fingerprint.Jason Gammack: Absolutely. Yep. And this is the thing about the molecular cartography platform. I mean when you think about kind of science and you look at the different areas of science on one side of the spectrum, you have the basic science research. This is the hypothesis formation. You just don't know what's going on and you have to do experiments and you're continuing to refine and develop a hypothesis on the opposite side of that.Spectrum is clinical testing. When you're looking for a yes, no, almost a binary type of answer. Right? And the stops between, there are areas such as translational research where you take your hypothesis and you refine it to a use case that's specific to a disease. Right. And then from your translational research, you move to clinical research where you're really applying the hypothesis of large populations.Harry Glorikian: Yeah. But, but let's, let's let's and maybe agree to disagree or just agree. But I remember that taking. Dog years, like in, in the old days. Right. And I feel like because of innovation, because of being able to do the analytics on technology, you know, on the, on the data that time is almost collapsing in on itself.Jason Gammack: It is. Harry Glorikian: You know there are advancements that seem to be, I'm having trouble keeping up with the literature. Jason Gammack: For sure. There's no question about it. There's no question about it. The rate of sensitivity innovation, you know, it's like Moore's law backwards, right? And mean just kind of continue to, just to, you know, keep, keep accelerating, accelerating, accelerating, and you know, tools.Again, going back to the next generation sequencing has provided so much data that we're still behind when the data backlog and understanding what exactly these data are going to say, but, you know, the iterative cycles are becoming faster cycles. As new tools come online. You can really test them and tweak and adjust your hypothesis at a scale that you haven't been able to do before.But at the end of the day, you still have to get a patient population and you have to get a patient population that all exhibits the same thing the time. Right. So there still is massive inefficiency within, within the discovery special drug discovery process. Technologies like molecular cartography can help again, collapse some of those inefficiencies as well.Harry Glorikian: Yeah. I mean, but if you think about like you know, at JP Morgan, they announced a Illumina announced, like we're going to take sequencing down to $60 is our goal, like at 60 bucks, it's a rounding her, like, why wouldn't you. Why wouldn't everybody like if you had, yeah. Jason Gammack: So Elaine Mardis, who is a true thought leader in the world of genomics, she previously was at Wash U. Really at the tip of the spear in cancer genetics. She said a statement once like, I still remember it, it makes me smile, you know, it might be the thousand dollar genome, but it's the a hundred thousand dollar analysis of that genome. Right. And so, so like we can… Harry Glorikian: I'm just looking at so many things right now from an analytics perspective that are even making that easier.Jason Gammack: Sure, no question. I mean, again, the machine learning is helping us sift through reams of data, understand what's not important and what is important. And with all of the data that's being generated, you have huge training sets, right? Massive training sets algorithms. And you've seen success in a lot of, a lot of areas. You know, look at companies like Flatiron and look at companies like Foundation Medicine, right. You know, I think that, that, you know, Foundation Medicine is a brilliant example of a big data analytics company, masquerading as an asset company, right? Harry Glorikian: Yeah. I mean, and it's the same thing I was talking to Joel Dudley over at Tempus and, you know, they're planning on being, not just having the most information across different methodologies, right. Transcriptome, methylation, et cetera, from every single sample. But yeah. They're also creating the piping to be the AWS so that why would you go any place else, but their platform. So they're not just giving you an answer. They're giving you a whole infrastructure, which is that doesn't sound like a typical biological company. It sounds like a tech company to a certain degree. Jason Gammack: Well, I mean, you know, the lines blur very, very quickly. You know, I look at, at what we are doing at Resolve Bio-sciences and I have as many computational scientists, informaticians bioinformaticians as I do wet lab biologists, because you use the overused analogy, you know, data's the new goal, right? Maybe they’re able to dig in and understand what's going on, but we need to also help our customers understand these complex data sets that we generate. Harry Glorikian: Yeah, go and try and explain that to all of our brethren. Jason, come on. I mean I mean, I was, I was on a call, you know, last night where, you know, everybody's deep into the biology. I'm like, I think you guys are missing this other thing. That's moving like a freight train, right. That that's changing. And the interesting part is, is when I'm interviewing people, is the data is highlighting some things where even the world expert goes, yeah, I would have never thought about that. I would've never looked at it that way had it not been highlighted to me by this system.Jason Gammack: Indeed. Indeed, indeed. You know, you're, you're describing you know, I love. When my customers see the data for the first time that comes off the molecular cartography platform. I really like to be with them. Unfortunately, coronavirus today, being with teams by prefer to be at home.Because most, everybody has a very, very similar response where you watch them and they have a hypothesis in their head and they're looking for the data that will be the hypothesis, right. Go to the image. You can see them scan the image, looking for something, and then almost uniformly. I hear this "huh." Just that little breath as they breathe in.And they're just like, Oh my gosh, there's an answer. And then we showed them some bioinformatic tools to start looking at the day, then in a different way. And then you see that kind of sit back and go, I get it. I get it. Harry Glorikian: Well, that's what I mean. It's funny because I was trying to write this book and I think I'm going to have to leave it to the, to the next one you know, before this third one or after this third one comes out is I think the whole paradigm because of the analytics we can do is being shifted in the reverse. In other words, it's almost like the machine should present something that then you can figure out where you should develop your hypothesis as opposed to develop the hypothesis, because there's just too much data to analyze. Right. Jason Gammack: I'm just smiling because I have, so I think about developing software and I've been developing software in life science for much of my career.You know, there's a couple of pillars that are important in my view, in software development and the features you bring into software. One of those pillars is transparency. You know, black boxes don't go far. And science scientists by definition are technologists. They want to understand the knobs and the dials that are under the hood, less than themselves, the advanced ones want to be.They just want to understand, you know, where are the limits? What are you calling? What are you not competent? But the other element, and this is an element where I think the industry has largely missed and you're hitting on Mike here is the concept of guiding. The concept of guiding the customer to insights and outcomes.And even if you're wrong and your guidance, you're stimulating that scientist to think because of that, that scientists may not have thought about that hypothesis or that answer. And so by proposing the next step by proposing how that hypothesis could be tweaked, you're stimulating thought that may not have previously existed.And I find this to be a very, very powerful tool. And this is where, you know, tools like artificial intelligence and machine learning are critically important because you need those non-biased systems to come in and start looking at the data and making calls. And then you use your bias system, the gray matter to judge those calls and challenge your thoughts. Harry Glorikian: Well , yeah, but that's not the way that we're taught. Right. We're supposed to go in with the answer, go in with the miraculous hypothesis of this is absolutely going to change. And I just find, you know, predicting the weather. I mean, there's just too many factors for any one human being to go like, you know, that's the trigger.Jason Gammack: Absolutely. Harry Glorikian: So let's get back to the, to the technology, like your technology. Like I think I remember reading, it's like a 0.27 micron resolution, which I think is if I read correctly 10 times higher than some of the competitors. How do you, how do you you can't tell me the secret sauce, but how do you get to that sort of resolution? It's gotta be a combination of hardware and software to a certain point. Jason Gammack: I mean, our, our resolution limit is the diffraction limit of light and the diffraction limit of light being again, we image individual RNA transfers. You know, these are very, very small, couple of hundred base pair, a couple hundred nucleotide pieces of genetic material.And so our resolution allows us to discriminate two dots, two different transcripts that are sitting close to each other at that 0.27 micron range, which again is the, the limit of light to be able to separate those two photons from themselves. And so we are pushing the absolute edge of optics, the ability to detect these events.There are other techniques that we're exploring that would allow us to even go beyond that like super resolution microscopy. But with that there's trade offs, of course, as you zoom in, you lose larger fields of view and you got to kind of manage that. And the analogy I use is squishy squishy on the one that pops up on the other and vice versa.Harry Glorikian: Yeah. You almost wish you could layer them on top of each other and create the zoom we were talking about with the Google map. Jason Gammack: Yeah, I mean, so, in essence,, that's what we do. So we, we take a slice or cells that are on a slide you know, and we image through that individual cell later. And we stopped at a very, very fine fence license.So, you know, when you fix the tissues of the slide, you're looking at micron thick tissue stacks on top of that. So yeah, you can, then you can actually see when we image the top of the face explore and kind of like, as you think about a basketball, right, as you slice through the basketball and we see the dock, when it's really small, we see the doc, if it gets larger than it meets its maximum, that goes back down to it's intimidating.Harry Glorikian: I always have a vision. When I, when I talk to people about these technologies that sort of create the maps is you know, wearing a VR lens and being able to like, look at it spatially, which would be I've. I've tried to encourage a couple of other people and some of the companies, you need to have some of your cause you might see something through that then you might not see through a normal methodology Jason Gammack: There's no question about it. And the other thing that we need to keep in mind and, you know, as a 50 year old scientist, it's difficult to always think about who my customers are, which are non 50 year old scientist or the postdocs and grad students that are going to become the next leaders in science.You know, everybody talks about digitization, you know, that's kind of granted that things are moving to digital. But we can't ignore macro trends such as augmented reality and virtual. Right. That's even, even me being a dinosaur, I've got an Oculus, of course I have a nine year old and 11 year old as well.I, at one point in my career, I worked for a company called Sigma Ulrich. Cigna is now owned by Merck. But Sigma Ulrich was a leading company in fine organics for industry, you know, high throughput, you know, synthesis of, of pharmaceutical compounds. And 20 years ago, you would walk into the chem informatics suite and you'd see people with these huge honk and goggles on, as they're looking at structure function, relationships, they've got molecules.How do you dock molecules on the proteins. Biology surprisingly hasn't kept up, you know, how many biological tools are using augmented reality, virtual reality, right? Harry Glorikian: No, I know. I mean, I've been, I've been attending and going to different talks from the tech world, right? The entertainment world. Right. And looking at the boundaries they're pushing, and then imagining that in our world, the opportunities are mindblowing.Jason Gammack: They are. Harry Glorikian: It's just our world doesn't think about it that way. Jason Gammack: But when we think about again, the molecular cartography platform, so, you know, why did we call them molecular cartographer? Right? The cartographers were the explorers of the new world. Yeah, they were the folks that went out and map the world so everybody could follow behind and find the riches, the land, the bounty, and so on.So when we think about how we want to build a map, if we really think about building a map for a single person, we're losing that race and tools like augmented reality and virtual reality have future in our technology. And Harry, and I see a day and not far away where not only will we be able to look at these beautiful images that we create in this three dimensional space where you can sit, put your goggles on and look around at your Sunstone, your restructuring yourselves, and see the transcripts.But more importantly, my collaborator in Zurich can join me on that journey. And we can collaborate, you know, virtually, but yet looking at a actual scientific experiment underway, you then take that to the next level and get into therapeutic approaches or clinical approaches where a pathologist and a general practitioner can explore the tumor biology of the patient.It is a complete paradigm destroying proposition.Harry Glorikian: Well, I'm also, I'm just thinking about man, if you put that into the education system in a different way to have people look at this, right. As well as super-imposed tools from, you know, the artificial intelligence world to sort of highlight different things that the machine might be able to, that that now you're talking about really seeing where you could drive diagnosis treatment, therapy, you know making new drugs or for that matter. I mean, you know, we have these big projects. I talk about thetranscriptome and the genome, but we should have one around this cartography area, although I I'm sort of struggling to figure out whether how consistent the map would be. Jason Gammack: Well, I mean, so the point is we build maps of every tissue type and every disease state.And this is where, again, the ability to harm it's software to help us interpret those maps is going to be critically important. So one element where we use software in our, in our workflow and machine learning is in identifying cell types. And so, you know, most neurons look the same or have a similar phenotype to those neurons.Yeah, right now there's inefficiency in a lot of biology because in essence, we use channels to identify a cell type and that channel was then occupied, identifying the cell type. What if we could free that channel out to identify more, say disease, specific genes. And so to do that, we need to still be alive, identify the cell type.So we need to train algorithms to be able to look at tens of thousands, millions of slices of brain. To be able to identify the neurons, the different cells within the brain, so that when we put it into a wind storm, we don't have to use a channel to identify a neuron. We use all of our channels to identify disease, state genes, and then we use machine learning and envision learning to be able to overlay, okay, that's a neuron because it looks like this and we've got 57,000 data sets that support.Harry Glorikian: It feels like facial recognition in a crowd. Jason Gammack: Yeah. You know, it's it, it is. And then we take it to another level when we now start phenotyping disease States. So, you know, we've just finished an early access program with the molecular cartography platform. And we looked at, you know, a number of different disease States.One of them being Alzheimer's disease, that's a disease my grandmother passed away from. And I'll tell you, I think most people listening to the podcast. I've had someone in their life who impacted by Alzheimer's disease devastating disease that steals the person in front of you. And, you know, we have been able to make mouse models that have, you know, 10 cow tangles and amyloid plaques, and we can demonstrate Alzheimer's disease, but yet, you know, as well as I nearly every company that's been in the phase three clinical trial for Alzheimer's drug has failed. Harry Glorikian: Yes. Jason Gammack: You have to ask why is that happen? Right? What are we missing? Even within those trials, people are looking at different approaches to address that. And so we partnered with a major pharma company to use our technology, to look at amyloid plaques in a way they haven't been able to do before to look at an amyloid plaque. And then as a, as a temporal spatial approach, being able to identify a plaque and look at the cascading impacts of different genes that are expressed in proximity to the plaque itself.To say, you know, right now we have been focused on the plaque. Well, let's take that spirit further and let's focus on the micro environment around the plant and understand what is causing the plaque to grow. What are elements, what are genes that are in play that we could potentially target from the therapeutic area that we see high levels of expression.What happens if we turn that expression down? Can we get that plaque to stop growing. More importantly, it couldn't get that plaque to actually shrink in size. And so a lot of these really interesting questions that previously were difficult to ask and answer our cartography platform is now allowing some unique insights.And so it's a great study. We're writing a manuscript right now, and I look forward to being back on the podcast talking about, so.Harry Glorikian: That'll be great. I mean, I, you know, I, I have talked to some of those companies and I think one of the biggest problems is. You know, the guy that looks at images is used to looking at images, the person that works in the assets, it's hard to get them to come into a room. And I, and I've seen them in a room. They still don't do the interactive discussion. Right. They don't, they're not using the machine learning platforms that I've seen to really bring together the understanding, which would then go to being able to segment the population. Because I think half the failures are we might not be subsegment thinking the population in the right ways. Jason Gammack: I think that's spot on. I mean, the ability to phenotype the population appropriately because of phenotype is still usually determined by a person, you know, and that's a physician well-trained, but yet there's nuance and especially in diseases.Like Alzheimer's that are highly nuanced diseases in different States. And so I agree, and I made the comment earlier about, you still have to get the patient population to study and you have to make sure you can properly identify that population. Harry Glorikian: So let let's jump back here and switch to a different gear that the story of resolve the story of Qiagen, your personal story They're somehow all. Intertwined. I feel like we know a lot of the same people that caused this intertwining to happen, but, but you know, how, how did you between the startup and you becoming CEO because you were an instructor and I think that was a pretty good gig. So how did this, how did this come come about? Jason Gammack: Yeah, no. So it's a great question. So, you know, again, I was at Inscripta, it's a fantastic company and just amazingly talented people working on some really cool technology that is going to drive sustainability in a way. And so for me to leave that, obviously we have a pretty compelling opportunity here. And this story started back in 2016 at Qiagen, when we were looking at trying to come up with some really unique science to solve this spatial challenge. We brought together a team of brilliant scientists to in essence, their only job was to figure out how do we create tools that really at this phase spatial context that started in 2016, we worked together as a team to develop that technology.I stepped away for two years to go to Boulder, Colorado, and stand up and sprint. Back in 2020, a pair of shots, the former CEO of Cajun and Michael, the founder said we got a union, got opportunity to Jason to build something really special. And, you know, it was one of those things area where I remember, well, of course we were all locked in our basements during the 2020 time.And I remember having a conversation with parents walking upstairs to to talk to my wife, Adeline. I said, I think we're moving back to Germany, I think.Harry Glorikian: And she said?Jason Gammack: And she said, hell yeah, let's make that happen. And so it's you know, Germany is a very special place for, for my family. You know, we lived here for five years. The first time my children moved to Germany. We made the choice to live in Germany, like a German. We have amazing friends here and our children went to school, a great school here, public schools, and speak German like native Germans. Yeah, we really discovered the heart of a, an amazing country and just gracious people and great scientists. You know, we're starting something unique here. There aren't, there's a lot of startups in Germany. The German startup culture is a very different culture than in the United States.And as I say about a lot of things, If we could meet halfway and be the perfect world, you know, to give you an example of when we're raising money for Resolve, we'd speak to American investors and it would be don't. You need more money. And we'd speak to European investors and they'd say, why do you need so much?So if you could meet halfway, sometimes the overexuberance of just throwing money at problems versus the conservative. Well, you know, let's do this incrementally and so on. You know, when we started Resolve, we had a choice to make doing, bring the business to the United States or do we grow the business in Germany.And we had a lot of discussion around that. And you know, for me, it was a very obvious answer. The answer is we take advantage of both worlds. So in resolved bio-sciences our corporate headquarters is in Germany and our product development center of excellence is in Germany because it's thinking about what our core technology is.It's molecular biology cooked to automation and engineering with optics and software. So I think we can all agree that the best physicists and optical engineers in the world reside within 500 kilometers of where we are right now, here in Dusseldorf, Germany, just amazing talent and companies that have created huge industries, such as CISE and Leica and so on are all based in Germany. Right? And that goes to, you know, the German engineering, German physics optics itself. Great molecular biologists. We've got amazing academic centers across Europe and bull, so on and so forth that develop amazing molecular biologists. And when it comes to our computational abilities, that's a global skillset.I've got a great development in Eastern Europe. I've got great developers in Western Europe and great developers in the United States. We're opening our office in the United States and San Jose, California, and the Bay area. And one area where the us has excelled past Europe is the softer side of science.So the marketing, the commercialization, the brand development. So we're going to put our feet on both continents and really use those pillars of excellence. North America will be our commercial headquarters of our business, where our marketing and brand creation, outbound marketing content creation efforts are going to reside.And Europe will be our center of excellence for product innovation and product development. And so we're going to really be able to harness both, you know, amazing capabilities that each region brings to us. Harry Glorikian: Yeah. I, you know, whenever I'm talking to different companies and they're talking about where they're going to be geographically, I mean that, that people, people don't give that enough thought as much as they, I think they should, because there are cultural differences and that. Can really hurt you if you don't understand these little nuances. I mean, I can tell you the difference between being in Canada and being here big difference. Right. And people say, well, no, but it's right there. No, it's actually not right there. It might as well be in a different place. Jason Gammack: Yeah. You can work straight. Also the difference between being in Southern California in Northern Colorado. But it's very, very different. I've lived in San Diego and in the Bay area multiple times. And the difference between the regions are, this is significant. Yeah, no, I grew up, grew up in Northern California. And when I would say to someone, I was from California and they'd be like, Oh, you're from Southern California.I remember being like, no, absolutely not. Don't don't tell me that. Cause you know, you didn't Northern California had more of a. Well, when I was growing up a relaxed, you know, yet, you know, we want it to be ahead at least from an intellectual perspective, but. And now the Northern California has gotten a little arrogant thanks to tech, but you know, it is what it is.It's driven a just unbelievable amount of growth that tech has and unbelievable amounts of innovation has come from that region, which is why, you know, when we looked at. Where we wanted to open our us office. We were eventually the two narratives. We looked at Boston, Cambridge, and we looked at the mayor.I mean, those were the two areas that we honed in on and we made the decision to be in the San Jose, San Francisco area. You know, we know the market well, talent is amazing there. You know, Stanford, Berkeley, the universities there just contributed just an amazing amount of, of gifted computer scientists and developers and so on.You know, both cities would have been great. But California is where we will have our us operations. Well, when do you expect that to open? We hope to have that opening in April. That's our, that's our plan. Harry Glorikian: When do you guys launch, when is this gonna…Jason Gammack: Yeah. So, so, you know, within the life science tool space, there's a very say kind of common dissemination path for, for technology.So technology like ours, which is very complex and capital intensive. It starts with the company, refining that technology and then gain granted access to that technology too early access customers, usually key opinion leaders or thought leaders in particular fields. So we have just completed our early access program, or we had 15 institutions involved in that program.The focus of that program is really to understand the. Application space and how our customers are thinking about using the technology. The technology that point has exited product development. So we're not really still developing the product, finding and nudging and guiding the product in areas like software, or you never stopped developing software software where it's just a constant development.You know, we put a flag in the sand and say, this is where, what the software is going to start. And we do a lot of user acceptance testing and understand how the customers are going to use the software and then start dropping those features that we want to incorporate. Once you finished early access, usually what you then move to a dissemination approach, which is what we're in right now.And so for us, dissemination is twofold. Our product is largely data. I mean, that is our product. You know, a random molecular cartography generates four terabytes of data, which is a significant amount of data. And so we are launching a data as a service approach where we will run molecular cartography and our service lab had spoken in our North American facility expanding our European facility.And at the end of this year, our plan was to open a facility in Asia. So we can begin pushing our data to market because especially when it comes to things like software, we will never develop faster than the community will develop. And quite honestly, the community is going to bring ideas to us that we've never even thought of before, how to look at the data.So we are going to scale our services to provide more access to the technology. Early access is tough because you have to say no to customers. You have to say, yeah, we're oversubscribed. We can't take you in. We're not going to open up the phone with the brain. The second phone number dissemination strategy is we have a number of large advanced institutions that want the workflow deployed at their facilities.So major pharma that sees this as an amazing insight and a biomarker discovery and understanding, you know, how do they move the ball forward, even faster? Talk about collapsing those cycles. So we will be in the latter half of this year, deploying the technology at very advanced, very qualified customer sites.And then the last phase of dissemination is what I call the democratization phase, which is when we then kind of push the button and start pushing the platform onto benchtops. So it scientists at university scientists and non-profit research institutions and so on. And that will happen in, in the later months.Harry Glorikian: But you almost wished like… I've become a believer. And I know that this is, you know, sometimes it's a pipe dream, but you'd want this, all these images, like Google maps to at some point coalesce into one repository. Like I understand that everybody wants their own confidential information, but. We didn't build the human genome on confidential information. We, we sort of put it together and said, here's the genome, right? Otherwise, nothing we have right now would have, you know, been realized and everything is built on that, on what was done in those early years. I feel like what you're doing almost. If you're going to build a map, you need everybody mapping. And adding to the map so that everybody can then benefit from it in their own unique way. Jason Gammack: No question about it, you know, you and I are in violent agreement on that point. And so hence our urgency to get our data into the scientist's hands so that they can understand the value and the number of insights that come from the data.So there are a number of international consortium efforts on your way right now that are commonly referred to as cell Atlas efforts where they're is different cells. And so on. We want to put the cell Atlas three-dimensional context and you know, those are a couple of stories. And so, so we have a strategy to engage those organizations to be able to kind of say, okay, you're now not in the single cell sequencing.You're done single cell RNA seq now we need to take it to the next level, take that RNA seek data, which is the counting of the transcripts in a tune D kind of planar effect. Let's now blow that into a 3d effect. Let's correlate our visualization of the transcripts with the digital readouts of RNAC and this collaboration that I spoke of with this major pharma company in Alzheimer's.We did it in their Alzheimer's mouse mall. Where we correlated all of the single cell on a sick day that they'd been accumulated over the last five years and map that to three-dimensional spatial, single molecule fish data. And it was a beautiful study because we showed a correlation and R squared of 0.9, nine, seven to the RNA seek data to our visualization of the transcripts.And then we added the three-dimensional context, very importantly, at some cellular resolution where you can actually see structures within the cells. And so it was just this. Yeah, it was one of those kinds of moments where you get goosebumps and you're like, Holy smokes. This is real. I mean, we knew it was good, but this really showed how good it was.Harry Glorikian: Well, I'll look forward to that to that paper when you said it's, it's on its way for publication?Jason Gammack: We're reviewing the manuscript now. So it's an iterative process and it's a major pharma. So, you know, they're embargo mania.Harry Glorikian: Well, when it's out, you can, you can send me a copy, but Jason, it's been great to talk to you. I feel like we could talk. Knowing the last time we talked, we could probably talk for hours about these things. But I I'm sure that you'll, we'll have you back on the show when we get to the next iteration. You know, what we should do is we should, we should get Per to come on the show with us and, and, and do a three-way conversation because his perspectives are always insightful and unique.Jason Gammack: Indeed. He is a I've known Per for 20 years and the opportunity to join with pair and start this company. It was an amazing opportunity. Truly a thought leader and a visionary in the field. And we just had so much runway in front of us. We've got such an amazing team and the team is growing amazingly fast and it is truly an honor and a privilege to be working with them and bring this technology to market because we believe that this technology will absolutely have a positive impact on the human condition. There's no question about that. Harry Glorikian: Well, you know, I just, like I said, I'm reflecting on, you know, the, what immunohistochemistry opened up to us. And I still don't think it gets the credit that it deserves. Right. But I think now with the computational capabilities and the insights that that could provide, and then you can overlay other information onto that it's changing the con the context where the persistent identifier is the location, but then everything that's happening around it is what really puts it into context of what's happening in that cellular dynamic. So great talking to you and I look forward to keeping in touch. Jason Gammack: Absolutely. Thank you, Harry. Really appreciate it.Harry Glorikian:That’s it for this week’s show. We’ve made more than 50 episodes of MoneyBall Medicine, and you can find all of them at glorikian.com under the tab “Podcast.” You can follow me on Twitter at hglorikian. If you like the show, please do us a favor and leave a rating and review at Apple Podcasts. Thanks, and we’ll be back soon with our next interview.

ニューロンの細胞種はどう定義されるのか？萩原が in vivo Caイメージングとspatial transcriptomicsを組み合わせた研究２報を紹介しながら議論。トランスクリプトーム回の前編。 Show Notes: ・Dense Functional and Molecular Readout of a Circuit Hub in Sensory Cortex...今回メインで話題にした論文その１。CRACK: Comprehensive Readout of Activity and Cell Type Markers. (Jerry Chenラボ) ・Behavioral state coding by molecularly defined paraventricular hypothalamic cell type ensembles...今回メインで話題にした論文その２。CaRMA: Calcium and RNA multiplexed activity (Scott Sternsonラボ) ・Allen Institute for Brain Science...ポール・アレンの寄付によるシアトルにある研究所。脳のアトラス・マップ等のデータベース作り、Aiシリーズのマウスライン作りを中心に大規模リソースの提供を行っている。 ・Genetic Dissection of Neural Circuits...神経回路理解への遺伝学的アプローチのレビュー。Luo, Callaway, Svobodaらの2008年時点での見解。細胞種とは何か、という議論も。 ・Genetic Dissection of Neural Circuits: A Decade of Progress...同著者らによる2018年時点での10年間の振り返りと未来への展望。 ・t-type...遺伝子発現(transcriptome)により定義される神経細胞の細胞種 (by Allen) ・me-type...形態および電気生理的性質(morpho-electric)により定義される神経細胞の細胞種 (by Allen) ・生理研のKawaguchi, Kubota, Kondoらによる細胞種分類の先駆け的な仕事。1, 2, 3 ・Integrated Morphoelectric and Transcriptomic Classification of Cortical GABAergic Cells...Allen InstituteのPatch-seq論文。大量の抑制性ニューロンについてmet-typeの分類を試みた。 ・Phenotypic variation of transcriptomic cell types in mouse motor cortex...上とペアになるToliasらのPatch-seq論文。M1の興奮性/抑制性ニューロンについて。 ・Spatial Transcriptomes...様々な種類のmRNAの空間局在を見る手法 ・HCR v3...Hybridization chain reactionの略。FISHシグナル増幅手法の一種。v3はコンポーネント数が増えておりSN比が高い ・Janelia...HHMIによる研究所。各ラボのサイズを小さく保ち、プラットフォーム・プロジェクト・コアファシリティに重点を置く実験的・革新的な研究所。ハエの遺伝学およびGCaMPのアップデート等のリソース提供による分野への貢献も大きい。 ・RNAscope...FISHシグナル増幅手法の一種。Z型のプローブを用いるのが特徴。 ・GRINレンズ...視床など脳深部からCaイメージングをする際、脳へのダメージを最小限にするために脳表から刺入する内視鏡のこと。 ・Sensory coding mechanisms revealed by optical tagging of physiologically defined neuronal types...GCaMP-2A-PAmCherry (photoactivatable mCherry) 発現->Caイメージング->局所的な光照射によるsingle-cell解像度でのPAmCherryのphotoactivation-> FACS -> RNAseqにより、ex vivoカルシウムイメージングの結果を受けて特定の細胞種を標識し、その遺伝子発現プロファイルを調べる手法を作成。(Tim Holyラボ) ・RecV recombinase system for in vivo targeted optogenomic modifications of single cells or cell populations...光で会合するタンパク質VVDとsplit-Creを結合し、光照射によって活性を持つリコンビナーゼを作った論文。in vivo, 2photon刺激でも動いていそう。(Ali CetinらAllen, Stanford) ・Allenによるenhancerを利用したsubclassへのgenetic accessとAAVの作成。Creラインが要らなくなる日も近いか。 ・HongKui Zeng's #WWNDev​ Forum on March 11th 2021...HongKui Zengによる最新のAllen Insituteのshowcase。1時間のトークに現状の全てがいっぱいに詰め込まれていてThe answer感漂う仕上がり。 Editorial Notes: ・FISHプローブ剥がすのって比較的容易にできるんですね（宮脇） ・XXX-seqという手法が大量に出てくるのですが、どうもXXXスィークと流暢に言えずXXXセックと呼んでしまうのをやめたい。'下ネタ言おうとして踏みとどまったおじさん'みたいに見えてないか心配です(嘘) 尚、宮脇さんは'sick'と言いがちですが、病気なのか、あるいは"ヤバい"というポジティブなニュアンスを今風に付加しているのかは謎 (萩原)

CPLF 2020 – Fil orange. A23 – Prédiction du risque de maladies respiratoires

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.21.392449v1?rss=1 Authors: Baik, S.-H., Selvaraji, S., Fann, D. Y., Jo, D.-G., Herr, D. R., Lai, M. K. P., Chen, C. L.-H., Drummond, G. R., Lim, K.-L., Sobey, C. G., Arumugam, T. Abstract: Vascular dementia (VaD) is a progressive cognitive impairment of vascular etiology. VaD is characterized by cerebral hypoperfusion, increased blood-brain barrier permeability and white matter lesions. An increased burden of VaD is expected due to rapidly aging populations. The hippocampus is particularly susceptible to hypoperfusion, and the resulting memory impairment may play a crucial role in VaD. Here we have investigated the hippocampal gene expression profile of young and old mice subjected to chronic cerebral hypoperfusion by bilateral common carotid artery stenosis (BCAS). Our data in sham-operated young and aged mice show the normal age-associated decline in cerebral blood flow and differential gene expression. BCAS and ageing caused broadly similar effects, however, BCAS-induced changes in hippocampal gene expression differed between young and aged mice. Specifically, transcriptomic analysis indicated that in comparison to young sham mice, many pathways altered by BCAS in young mice resembled those present in sham aged mice. Immunoblot analyses confirmed these findings. Finally, relative to young sham mice the cell type-specific profile of genes in both young BCAS and old sham animals further revealed common cell-specific genes. Our data provide a genetic-based molecular framework for chronic hypoperfusion-induced hippocampal damage and reveal common cellular signaling pathways likely to be important in the pathophysiology of VaD. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.19.390617v1?rss=1 Authors: Cao, C., Kwok, D., Li, Q., He, J., Guo, X., Zhang, Q., Long, Q. Abstract: The success of transcriptome-wide association studies (TWAS) has led to substantial research towards improving its core component of genetically regulated expression (GReX). GReX links expression information with phenotype by serving as both the outcome of genotype-based expression models and the predictor for downstream association testing. In this work, we demonstrate that current linear models of GReX inadvertently combine two separable steps of machine learning - feature selection and aggregation - which can be independently replaced to improve overall power. We show that the monolithic approach of GReX limits the adaptability of TWAS methodology and practice, especially given low expression heritability. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.13.375055v1?rss=1 Authors: Gedman, G. L., Haase, B., Durieux, G., Biegler, M., Fedrigo, O., Jarvis, E. D. Abstract: Over the last two decades, beginning with the Avian Brain Nomenclature Forum in 2000, major revisions have been made to our understanding of the organization and nomenclature of the avian brain. However, there are still unresolved questions on avian pallial organization, particularly whether the cells above the ventricle represent different populations to those below it. Concerns included limited number of genes profiled, biased selection of genes, and potential independent origins of cell types in different parts of the brain. Here we test two competing hypotheses, using RNA sequencing to profile the transcriptomes of the major avian pallial subdivisions dorsal and ventral to the ventricle boundary, and a new zebra finch genome assembly containing about 22,000 annotated, complete genes. We found that the transcriptomes of neural populations below and above the ventricle were remarkably similar. What had been previously named hyperpallium densocellulare above the ventricle had nearly the same molecular profile as the mesopallium below it; the hyperpallium apicale above was highly similar to the nidopallium below; the primary sensory intercalated hyperpallium apicale above was most similar to the sensory population below, although more divergent than the other populations were to each other. These shared population expression profiles define unique functional specializations in anatomical structure development, synaptic transmission, signaling, and neurogenesis. These findings support the continuum hypothesis of avian brain subdivisions above and below the ventricle space, with the pallium as a whole consisting of four major cell populations instead of seven and has some profound implications for our understanding of vertebrate brain evolution. Copy rights belong to original authors. Visit the link for more info

Editor's Choice Paper: Genomic heterogeneity in peritoneal implants: A differential analysis of gene expression using nanostring Human Cancer Reference panel identifies a malignant signature Editorial Paper: Not All Peritoneal Implants Are Created EqualHosted by: Dr. David Cohn, Deputy Editor Featuring: Dr. Cohn, Dr. Fauceglia, Dr. Shih