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Send us a textDr. Ashwin Gopinath, Ph.D. ( https://ashwingopinath.com/ ) is Co-Founder and CTO of Biostate AI ( https://biostate.ai/ ), a startup building generative AI that predicts the evolution of human disease and drug response based on RNA sequencing data. Its patented wet lab technologies, including BIRT (Barcode-Integrated Reverse Transcription), allow affordable and scalable collection of massive amounts of transcriptomic and genomic data. With sites in Houston, TX, Palo Alto, CA, Bangalore, India, and Shanghai, China, Biostate AI is an international company with collaborations with top hospitals, academic researchers, and biotech/biopharma companies. Dr. Gopinath was an Assistant Professor at MIT, working at the intersection of CMOS nanofabrication, molecular self-assembly, biology, and machine learning.Dr. Gopinath earned his Ph.D. in Electrical Engineering from Boston University, and subsequently worked as a research scientist at Caltech and Google [X].Dr. Gopinath has co-authored over 21 papers in journals including Nature, Science, and the Proceedings of the National Academy of Sciences (PNAS).Dr. Gopinath was awarded the 2017 Robert Dirk Prize in Molecular programming for his contributions to merging DND nanotechnology with conventional semiconductor processing.#AshwinGopinath #BiostateAI #GenerativeAI #RNASequencing #OpticalPhysics #DNANanotechnology #DNAOrigami #MolecularDiagnostics #RNAseq #GenAI #Leukemia #MultipleSclerosis #Reactome #TranscriptomicAgePrediction #ProgressPotentialAndPossibilities #IraPastor #Podcast #Podcaster #ViralPodcast #STEM #Innovation #Technology #Science #ResearchSupport the show

Dr. Wenqing Li joins Peng Zhang to discuss a recent study integrating genetics and transcriptomics for risk stratification of gastric cancer. The conversation explores the global epidemiology of gastric cancer, its high prevalence and mortality rates, particularly in East Asia and China, and the complex interplay of genetic and environmental risk factors, notably Helicobacter pylori infection.Read the full article:https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(25)00211-7/fulltext?dgcid=buzzsprout_icw_podcast_July_25_ebiomContinue this conversation on social!Follow us today at...https://thelancet.bsky.social/https://instagram.com/thelancetgrouphttps://facebook.com/thelancetmedicaljournalhttps://linkedIn.com/company/the-lancethttps://youtube.com/thelancettv

JCO PO authors Dr. Philippe Bedard (Staff Medical Oncologist at Princess Margaret Cancer Centre and Professor of Medicine at University of Toronto) and Dr. Alberto Hernando Calvo (Medical Oncologist at Vall d´Hebron University Hospital) share insights into their JCO PO article, “Combined Transcriptome and Circulating Tumor DNA Longitudinal Biomarker Analysis Associates With Clinical Outcomes in Advanced Solid Tumors Treated With Pembrolizumab,” one of the top downloaded articles of 2024. Host Dr. Rafeh Naqash and Drs. Bedard and Hernando Calvo discuss how combined transcriptome and ctDNA longitudinal analysis associates with pembrolizumab outcomes. TRANSCRIPT Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, podcast editor for JCO Precision Oncology and Assistant Professor at the OU Health Stephenson Cancer Center at the University of Oklahoma.  Today we are excited to be joined by Dr. Philippe Bedard, Staff Medical Oncologist at the Princess Margaret Cancer Center and Professor of Medicine at the University of Toronto, as well as by Dr. Alberto Hernando-Calvo, Medical Oncologist at the Vall d'Hebron University Hospital, both authors of the JCO Precision Oncology article titled, “Combined Transcriptome and Circulating Tumor DNA Longitudinal Biomarker Analysis Associates With Clinical Outcomes in Advanced Solid Tumors Treated With Pembrolizumab.”  Thank you for joining us today. Phil and Alberto. Dr. Alberto Hernando-Calvo: Thank you. Dr. Philippe Bedard: Great to be with you. Thanks for having us.  Dr. Rafeh Naqash: One of the reasons we do this podcast, as some of the listeners who listen to this podcast regularly may know, is to bring in novel approaches and try to understand how the field is moving towards a space where we are understanding biomarkers better. So your manuscript that was published in JCO Precision Oncology fulfills many of those criteria. And interestingly enough, I was at a conference at the Society for Immunotherapy of Cancer last month earlier in November and a lot of excitement at SITC was revolving around novel transcriptomic biomarkers, proteomic biomarkers or imaging based biomarkers. So could you tell us a little bit about why you started looking at biomarkers? This is an extremely competitive field. Why did you think that looking at the transcriptome is somewhat different from or more interesting from tumor mutational burden PDL-1 than other biomarkers that we currently use? And that question is for you Alberto to start off.  Dr. Alberto Hernando-Calvo: So I think gene expression profiles may have a predictive performance as compared to already existing biomarkers and this was one of the points that we describe in our manuscript. The gene expression signature that we developed back in 2019 at Vall d'Hebron Institute of Oncology was initially developed based on over 45 different tumor types and tested in over 1000 patients treated with antiPD-1 and anti PDL-1. And back then and in this manuscript, we proved that for instance the gene expression signature VIGex that we developed has a potential complementary role to other predictive biomarkers. In this case, we observe this predictive power with ctDNA dynamics and we then see a correlation with other existing biomarkers such as tumor mutational burden. So I don't think we need to use one or the other, but rather they may have additive predictive power. So we need to better individualize predictive biomarkers based on tumor types and select the best combination possible to improve the performance.  Dr. Rafeh Naqash: I completely agree that one size does not fit all, especially in the landscape of immunotherapy. From your perspective, when you developed the original signature, how did you choose what genes to look at? I looked at the manuscript, on the methodology side, some of the signatures are pro-inflammatory STING interferon gamma based, so how did you try to identify that these are the 7 to 10 or whatever number of signatures on the transcriptome side? And then why did you try to combine it with ctDNA based changes?  Dr. Alberto Hernando-Calvo: Back in our initial manuscript, published in Med from Cell Press, we developed the VIGex gene expression signature, as I mentioned, with taking into consideration over 1000 tumor samples from FFPE that we can consider real world samples because they are from real patients coming from the clinic notes as part of real investigational protocol doing or performing biopsies on patients. We did observe after doing a VIGex research and doing different tests, we eventually collected these 12 different genes. Because there is a combination of both genes involved in the interferon gamma pathway, we have genes associated with Tregs as well as T cell memory cells. So it's not only looking at genes that are associated with T cell activation or CD8+ T cell infiltration, but also looking at genes that may be overactivated, overexpressed, an immunosuppressive tumor microenvironment. So it was both selecting genes, the minimum number of genes to do it more scalable and having the minimum dataset of genes and including in the signature genes that are already at targets for immune sequent inhibitors or are being tested in immunotherapy combinations.  Dr. Rafeh Naqash: Thank you. And Phil, for the sake of our listeners, could you elaborate upon this aspect of using ctDNA? So this was tumor-informed ctDNA from what I understood in the manuscript. You guys basically try to use it to understand changes in the ctDNA with treatment and then try to combine it with the transcriptome signature. How did the idea come up initially and how did you plan on combining this with an RNA-based signature? Because I have seen manuscripts and other data where people are either using one or the other, but not necessarily both together. So how did you guys come up with that idea? Dr. Philippe Bedard: Well, we thought that this was a great opportunity to look at the combination of the transcriptome as well as the ctDNA dynamics because we had run an investigator-initiated phase 2 clinical trial called INSPIRE at our institution at Princess Margaret from 2016 to 2018, where patients across five different tumor groups received single agent pembrolizumab. And we really did a deep dive on these patients where there were tumor biopsies before and while on treatment. We did exome sequencing, we did RNA sequencing to capture the transcriptome. And in a prior analysis, we had partnered with Natera to look at their Signatera assay, which is a bespoke ctDNA assay, to look at ctDNA dynamics using this test and the association with response outcomes as well as survival outcomes. So we thought that this was a really unique data set to try and address the question of whether or not there was complementarity in terms of looking at the transcriptome and transcriptome signatures of IO benefit together with the ctDNA dynamics. Dr. Rafeh Naqash: From a patient treatment standpoint, it sounded like you mostly tried to include individuals who were treated with pembrolizumab. Did this not include individuals who were treated with chemoimmunotherapy or chemotherapy with pembrolizumab? Just pembrolizumab alone? And if that's the case, some of the tumor types there included, from what I remember, ovarian cancer and some other unusual cancers that don't necessarily have approvals for single agent pembrolizumab, but perhaps in the TMB-high setting. So can you elaborate on the patient selection there for the study?  Dr. Philippe Bedard: Yeah, that's a great question. So at the time that the study was designed in 2015, this was really the early days of immune checkpoint inhibitor therapy, so we didn't have the approvals that we have now in specific tumor types for immunotherapy and chemotherapy combinations. So when the study was designed as an investigator initiated clinical trial, the idea was really to capture patients across different tumor types - so head and neck squamous cell carcinoma, malignant melanoma, ovarian cancer, triple negative breast cancer, and a kind of mixed histology solid tumor cohort, where we knew that there were some patients who were going to be immunotherapy responsive, where there was already approvals or evidence of single agent activity, and others where the responses were more anecdotal, to try and understand in a phase 2 clinical trial with kind of a deep dive, which patients benefited from treatment and which didn't. Dr. Rafeh Naqash: Interesting approach. Going to the results, Alberto, could you help us understand some of the important findings from these data? Because there's different sections of how you tried to look at the response rates, the survival, looking at the immune deconvolution, if you could explain that. Dr. Alberto Hernando-Calvo: So the first thing that we tried was to further confirm the external validation of this immune gene expression signature, VIGex in the INSPIRE asset. So what we observed at VIGex-Hot, the category defined by VIGex-Hot tumor microenvironment, was associated with better progression free survival. After including that in a multivariable analysis adjusted by other biomarkers such as TMB, PDL-1 or tumor type, this was also confirmed for overall survival. So then the next step was to really try to hypothesize if the addition of ctDNA dynamics, taking into consideration the ctDNA quantification at baseline as compared to cycle three, if those dynamics could further improve the predictive performance of VIGex categories taken in the baseline samples. What we did observe was that, for instance, VIGex-Hot tumors in baseline tumor samples that were having a ctDNA decrease, as I mentioned before on cycle three assessment as compared to baseline, were having both better progression free survival and better prognosis overall. Another important finding was the evaluation of response rate across tumor types considering both biomarkers. I would say the most important finding is that when we were considering a cold tumor microenvironment in baseline samples before pembrolizumab initiation plus an increase in ctDNA values, what we observed is that those patients were having a 0% response rate. So this may help as a future strategy either for intensification of immunotherapy regimens in a more individualized way or for an early stop to immunotherapy and try to avoid financial toxicities as well as toxicities for our patients. Dr. Rafeh Naqash: From the data that you showed, it seems that there was a strong correlation, as you sort of mentioned, between individuals that had ctDNA clearance and baseline immune pro-inflammatory signatures. So do you really need the transcriptome signature or could the ctDNA just serve as an easy quick surrogate? Because from a cost standpoint, doing whole transcriptome sequencing or more RNA sequencing or tissue standpoint, where tissue is often limited, can become a big issue. So do you think that validation of this may perhaps more revolve around using ctDNA as an easier metric or surrogate? Or am I overestimating the utility of ctDNA? Dr. Philippe Bedard: I think it's a really good question. In our data set which was relatively small, there were 10 patients who had ctDNA clearance, meaning ctDNA that was positive at baseline was not detected. And so 9 out of those 10 patients, as you alluded to, were VIGex-Hot. So the question is a good one, could you do the same with just ctDNA clearance alone, particularly in identifying these patients who really do well, who have long term disease control on immunotherapy? I think it's a tough question to answer because the field is also changing in terms of sensitivity of detection of ctDNA tests. So we know now that there are newer generations of tests which can detect even at logs down in terms of allele variants in the circulation. So I think we need more data to address the question. I think it is important as to what is the best test, what is the endpoint that we should be using from a drug development point of view in terms of really trying to push and understand which treatment regimens are the most effective and have early readouts in terms of activity. Because we all recognize in the clinic that radiographic response doesn't tell the whole story, especially early radiographic assessments using RECIST or other criteria that we apply in clinical trials. Dr. Rafeh Naqash: From a clinical trial standpoint, we often talk about validation of these studies. You may have heard of other tests where, for example, the NCI iMatch, which is incorporating transcriptome sequencing based approach to stratify patients as an integral biomarker for treatment stratification. Is that something that you guys are thinking of using, this approach where individuals who are signature highly inflamed perhaps get lesser therapies or there's a de-intensification of some sort similar to what people are trying to do with ctDNA-based approaches? Dr. Philippe Bedard: I think that's a great question. I think it makes a lot of sense. And certainly, with the new wave antibody drug conjugates in terms of identifying patients who have expression of targets for antibody drug conjugates, that's very attractive as an approach because we don't necessarily have IHC markers for all of the different targets of antibody drug conjugates. We don't necessarily have IHC markers to completely understand different contributions to the tumor microenvironment and whether or not tumors are inflamed. But it's also a challenging approach too because RNA-seq currently is not a routine clinical test. Sometimes there are issues, particularly in patients who have stored specimens that are formalin-fixed and paraffin-embedded in terms of the quality of the RNA for RNA sequencing. And it's not always feasible to get pre-treatment biopsies and turn them around in an approach. So I think it is an attractive approach for clinical trials, but it's a hypothesis that needs to be tested. It's not something that is ready for clinical prime time today in 2024. Dr. Rafeh Naqash: One of the other interesting observations that I came across in your manuscript was that tumor mutational burden, interestingly, did not correlate with signature high tumors. What is the explanation for that? Because generally you would expect a TMB high to perhaps also have an immune gene high signature. Could it have something to do with the tumor types because there was a heterogeneous mixture of tumor type? Or I'm not sure. What else could you possibly think of that you didn't see those correlations or just sample size limitations? Dr. Alberto Hernando-Calvo: Yes. So our findings are consistent with prior data suggesting for instance T cell inflamed gene expression profile was also not correlated with tumor mutational burden and both biomarkers in a prior publication. So to have additive predictive performance for identifying patients most likely to benefit from anti PD-1 regimen, so we somehow were expecting this observation, the fact that both biomarkers are not very correlated. Dr. Rafeh Naqash: So given the proof of concept findings from your study, Phil, what is the next interesting step that you guys are thinking of to expand this? Would you think that a nivolumab-ipilimumab treated cohort would have similar findings? Or is this a treatment specific single agent immunotherapy specific correlation that you found versus something else that you may find in a nivo-ipi cohort or a doublet immune checkpoint cohort?  Dr. Philippe Bedard: The findings are really hypothesis generating. They require additional validation. And you're quite right, there may be nuances in terms of specific tumor types, combinations with other immunotherapy or combinations with chemotherapy or other agents. So I think it would be great if there are other data sets that are collecting this type of information that have ctDNA dynamics and also have transcriptome and potentially exome or genome analysis to look at these types of questions because the field is moving quickly and we really need more data sets in order to understand some of the nuances and greater numbers to validate the signals that we see. Dr. Rafeh Naqash: And one thing, as you said, the field is definitely moving very quickly. I was meeting with a company an hour back and they have an imaging-based approach using fresh tissue to look at pharmacodynamic biomarkers. And I used to work in the NCI with a group that was very interested and they developed an immuno-oncology pharmacodynamic panel that has been used and published in a few clinical trials where they did phosphorylation status. So the final theme that comes out of most of these research based studies that are being done is that one size does not fit all. But the question that comes to my mind is how many things do you necessarily need to combine to get to a predictive biomarker that is useful, that is patient centric, and that perhaps is able to identify the right therapy for the right patient. What is your take on that, Phil?  Dr. Philippe Bedard: Yeah, that's a great question too. The challenge is it depends on the context in terms of what degree of positive predictive value do you need as well as the negative predictive value to drive clinical decisions. So I think in certain situations where you don't have other approved treatment options and with a therapy that is potentially low toxicity and low financial toxicity, then I think the bar is very high in terms of being able to really confidently identify that patients aren't going to benefit. I think the nuance and the challenge becomes when you move into earlier lines of therapy, or when you talk about combinations of agents, or trying to understand within the context of other available options, particularly with treatments that have significant side effect profiles as well as financial risks, then it becomes a much more nuanced question and you really need comparative studies to understand how it fits versus the existing treatment paradigm. So I'm not really answering your question with a specific number because I think it's hard to give you a number. Some of that we also need input from patients in terms of what kind of level of validation do you need and what kind of level of discrimination do you need in order to drive decisions that are meaningful for them. Dr. Rafeh Naqash: Definitely early days, as you pointed out. More and more work in this field will hopefully lead us in the direction that we all want to go in.  Now, going to a different aspect of this podcast, which is trying to understand the trajectories for both of you, Phil and Alberto. And as you mentioned, this project seemed to have started in 2015. So I'm guessing there's a history there between Princess Margaret and Vall d'Hebron. Could you highlight that a little bit? And then perhaps, Alberto, after that you could tell us a little bit about your career when you worked at Princess Margaret as a fellow and then now back at Vall d'Hebron. Phil, you as well. Dr. Philippe Bedard: So absolutely. We have a long history of collaborating with Vall d'Hebron in Barcelona. It's really a great cancer institution with a lot of like minded individuals. We have a formal partnership and we have a lot of informal links in terms of scientists and clinicians who we work with and who we collaborate with on early phase clinical trials, as well as through different investigator networks and other translational projects. So this was really how this collaboration came about and we were fortunate to have Alberto, who came to work with us for two years and brought this great idea of looking at this signature they had developed at Vall d'Hebron in their phase one group and applying it to a data set that we had through the INSPIRE clinical trial.  Dr. Rafeh Naqash: Sounds like a very successful academia-academic collaboration, which is very nice to see. So, Alberto, could you tell us a little bit about your career trajectory and how you ended up at Princess Margaret and then back at Vall d'Hebron and what you do currently? Dr. Alberto Hernando-Calvo: Yes. So I did my oncology residency at Vall d'Hebron in Barcelona, Spain. Then I decided to further specialize in early drug development as well as head and neck cancer oncology. So I decided to pursue a clinical research fellowship under the supervision of Phil Bedard, among others. And so we decided to further validate the signature that we had developed both in the cancer genomic lab at Vall d'Hebron Institute of Oncology and the phase one unit at Vall d'Hebron, and apply the signature that have been originally tested in patients receiving anti PD-1 or anti PDL-1 combinations in early phase clinical trials. In the phase 2 clinical trial of INSPIRE, where we also had ctDNA dynamics and allowed us to test both biomarkers and see that additive predictive power when we were using both. That was one of my research topics under the mentorship of Dr. Bedard and my fellowship at Princess Margaret. And this was one of the manuscripts describing all the findings of this collaboration between Vall d'Hebron and Princess Margaret Cancer Center. Dr. Rafeh Naqash: And then, Phil, if you could highlight some of the things that you've done over the course of your career and perhaps some advice for early career junior investigators and trainees.  Dr. Philippe Bedard: I finished my oncology, medical oncology training at the University of Toronto in 2008. And then I did a breast cancer fellowship in Brussels at Breast International Group. At the time, I was really intrigued because it was really kind of the early days of microarray and RNA signatures in terms of expressing signatures were being used as part of a clinical trial that BIG was running called the MINDACT Study. And so when I finished my fellowship, I came back to Princess Margaret, started on staff. I've been here now for 15 years. I was fortunate to work with the phase 1 group and kind of my career has sort of morphed in terms of early drug development as well as genomics. I've been involved with the American Association for Cancer Research project GENIE, where I'm the current chair. This is really an international data sharing project with panel based sequencing, which both Princess Margaret and Vall d'Hebron have contributed to. And I've been fortunate to work with a number of really talented early career investigators like Alberto, who spend time with us in our drug development program and launched transitional research projects that leverage some existing data sets at their own institutions and also bring together with different research groups at our institution to lead to publications like this one. Dr. Rafeh Naqash: Thank you so much. This was very exciting. Phil and Albert, thanks for joining us today and thank you for allowing us to discuss your interesting manuscript and hopefully we'll see more of this biomarker work from you guys in the near future, perhaps published in JCO Precision Oncology.   And thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts.     The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

The human brain is a complex organ, and its aging process is influenced by a plethora of factors, both genetic and environmental. Aging-related changes in the brain can lead to cognitive decline and susceptibility to neurodegenerative diseases. Therefore, understanding the molecular mechanisms underlying these changes is crucial for developing therapeutic strategies to delay or prevent age-related cognitive decline. Over the past few years, a myriad of scientific studies have been conducted to understand the intricate relationship between our genes and the aging process. In a new study, researchers Joseph A. Zarrella and Amy Tsurumi from Harvard T.H. Chan School of Public Health, Massachusetts General Hospital, Harvard Medical School, and Shriner's Hospitals for Children-Boston explored the concept of genome brain age prediction, a groundbreaking area of study that employs advanced bioinformatics tools to analyze changes in gene expression associated with aging. On February 28, 2024, their research paper was published and chosen as the cover paper for Aging's Volume 16, Issue 5, entitled, “Genome-wide transcriptome profiling and development of age prediction models in the human brain.” “[…] we aimed to profile transcriptome changes in the aging PFC [prefrontal cortex] overall and compare females and males, and develop prediction models for age.” Full blog - https://aging-us.org/2024/03/predicting-brain-age-with-machine-learning-and-transcriptome-profiling/ Paper DOI - https://doi.org/10.18632/aging.205609 Corresponding author - Amy Tsurumi - atsurumi@mgh.harvard.edu Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.205609 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, machine learning, prediction model, biomarker, transcriptome About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at https://www.Aging-US.com​​ and connect with us: Facebook - https://www.facebook.com/AgingUS/ X - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Spotify - https://open.spotify.com/show/1X4HQQgegjReaf6Mozn6Mc Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

References Developmental Cell 2022. Volume 57, Issue 6, 28 March Pages 691-706 Cell Rep. 2014 Feb 13; 6(3): 541–552. Dr Guerra: graduate lecture notes Mozart, WA 1791.Requiem in D Minor, K 626 https://youtu.be/YaH3zI0bYkM?si=X1yv50zY6nKTZmV9 Lennon/McCartney.1964 "I Don't Want to Spoil the Party" https://youtu.be/zqVDvLDLsjI?si=K1ve_5zJLZjqclsb --- Send in a voice message: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/message Support this podcast: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/support

BUFFALO, NY- March 15, 2024 – A new #research paper was #published on the #cover of Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 16, Issue 5, entitled, “Genome-wide transcriptome profiling and development of age prediction models in the human brain.” Aging-related transcriptome changes in various regions of the healthy human brain have been explored in previous works, however, a study to develop prediction models for age based on the expression levels of specific panels of transcripts is lacking. Moreover, studies that have assessed sexually dimorphic gene activities in the aging brain have reported discrepant results, suggesting that additional studies would be advantageous. The prefrontal cortex (PFC) region was previously shown to have a particularly large number of significant transcriptome alterations during healthy aging in a study that compared different regions in the human brain. In this new study, researchers Joseph A. Zarrella and Amy Tsurumi from the Harvard T.H. Chan School of Public Health, Massachusetts General Hospital, Harvard Medical School, and Shriner's Hospitals for Children-Boston aimed to profile PFC transcriptome changes during healthy human aging overall and comparing potential differences between female and male samples, as well as developing chronological age prediction models by various methods. “We harmonized neuropathologically normal PFC transcriptome datasets obtained from the Gene Expression Omnibus (GEO) repository, ranging in age from 21 to 105 years, and found a large number of differentially regulated transcripts in the old and elderly, compared to young samples overall, and compared female and male-specific expression alterations.” The team assessed the genes that were associated with age by employing ontology, pathway, and network analyses. Furthermore, they applied various established (least absolute shrinkage and selection operator (Lasso) and Elastic Net (EN)) and recent (eXtreme Gradient Boosting (XGBoost) and Light Gradient Boosting Machine (LightGBM)) machine learning algorithms to develop accurate prediction models for chronological age and validated them. Studies to further validate these models in other large populations and molecular studies to elucidate the potential mechanisms by which the transcripts identified may be related to aging phenotypes would be advantageous. “Our results support the notions that specific gene expression changes in the PFC are highly correlated with age, that some transcripts show female and male-specific differences, and that machine learning algorithms are useful tools for developing prediction models for age based on transcriptome information.” DOI - https://doi.org/10.18632/aging.205609 Corresponding author - Amy Tsurumi - atsurumi@mgh.harvard.edu Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at https://www.Aging-US.com​​ and connect with us: Facebook - https://www.facebook.com/AgingUS/ X - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Spotify - https://open.spotify.com/show/1X4HQQgegjReaf6Mozn6Mc MEDIA@IMPACTJOURNALS.COM

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!" 

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