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Review coordinated by Life Science Editors
Reviewed by: Dr. Helen Pickersgill, Life Science Editors
Potential Conflicts of Interest: None
Impact Point: Transcription factors may mediate the release of specific genes in extracellular vesicles that could be taken up by other cells and directly influence their behaviour.
Background: Extracellular vesicles (EVs) are nanoscale, membrane-bound vesicles containing proteins, nucleic acids and lipids that are released by most cell types. Originally thought of as a cell waste disposal mechanism, they have since been rebranded as a means of intercellular communication, both short and long range, (like a cellular postal service), and can, for example, modify gene expression and function in recipient cells via the transfer of specific RNAs (DOI: 10.1038/s41580-020-0251-y). One interesting function for EVs was the recent discovery that antigen presenting cells (APCs) could donate telomeres via EVs to recipient T cells and rescue them from senescence (DOI: 10.1038/s41556-022-00991-z).
Given EVs contain a wide variety of cargos derived from the secreting cells, which have been extensively profiled (e.g., DOI: 10.1016/j.cell.2020.07.009) they are particularly interesting as sources of biomarkers for diagnosing diseases such as cancer (e.g., DOI: 10.1038/s12276-019-0219-1). We might also be able to use them as stable delivery mechanisms for controlling cell behaviour or targeting therapeutics/diagnostics.
We know quite a bit about how RNAs and proteins are selected for secretion by EVs (mediated by the autophagy protein LC3: e.g., DOIs: 10.1080/15548627.2020.1756557; 10.1038/s41556-019-0450-y). But little is known about DNA. DNA presents a particular challenge as it is packed up into the nucleus. This is also particularly important to understand in the context of horizontal gene transfer, i.e., passing functional genes between cells.
Main question: How does a cell ‘select’ specific DNA cargo from the nucleus and enable it to be released by EVs?
The advance: They discover that a transcription factor (FOXM1) plays a central role in mediating DNA release in EVs.
Results: • FOXM1 and LC3 (autophagy protein) colocalize and interact in cultured cells (coIP endogenous and exogenous, EMSA, immunostaining and identify an FOXM1-binding domain mutant). • FOXM1, LC3 and DNA colocalise in the cytoplasm in cultured cells, which increases upon starvation-induced autophagy (immunofluorescence). • FOXM1 and LC3 are found in EVs released from cultured cells (Western blot). • 15,544 DNA identified in EVs released from cultured cells (evDNA sequencing), of which 25 overlapped with DNA loci binding FOXM1 (ChIP). • FOXM1-bound nuclear DNA is transported to the cytoplasm upon induction of autophagy and is released in EVs in cultured cells (knock-in tagged chromatin with CRISPR-cas9, IF and PCR). This is dependent on FOXM1 (knock-out in cultured cells).
Significance: Transcription factors display strong DNA binding specificity and so are ideal candidates for directing specific genes into EVs for potential transfer to recipient cells.
Remaining questions/points: Care needs to be taken with regard to purification of EVs. Are the FOXM1-DNAs in the EVs functional in recipient cells? Is the DNA being actively ‘selected’ for an intercellular signalling purpose or is this just random degradation? Is it all FOXM1 bound DNA that has the potential to be trafficked to EVs or just a subset? Do other transcription factors have the same function or is it specific to this protein/family? Does this mechanism occur in other contexts (e.g., in vivo, under disease conditions).
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Review coordinated by Life Science Editors.
Reviewed by: Dr. Angela Andersen, Life Science Editors
Potential Conflicts of Interest: Dr. Mill has worked with Life Science Editors on other manuscripts.
Background: Retinitis pigmentosa (RP) is a group of rare eye diseases that cause vision loss. Symptoms usually start in childhood, and most people eventually lose most of their sight. There is no cure for RP. Mutations in retinitis pigmentosa GTPase regulator (RPGR) cause RP and compromise the renewal of light-sensitive “disc” membranes (specialized cilia) at the outer segment of photoreceptors, resulting in the loss of these cells over time. Evidence suggests that disc formation is similar to the release of ectosomes (small extracellular vesicles) and that both rely on the actin cytoskeleton. Knockdown of RPGR in retinal pigmented epithelium cells showed stronger actin filaments and reduced cilia suggesting that it may regulate nascent photoreceptor disc formation by regulating actin-mediated membrane extension in the retina (Gakovic et al., Human Molecular Genetics, 2011). In addition, RPGR patient iPSC-retinal models displayed phenotypes consistent with abnormal actin regulation (Megaw et al., Nature Communications, 2017; Karam et al., J Personalized Medicine, 2022).
Question: What function of RPGR is compromised in photoreceptors to cause RP?
Advance: The authors generated novel Rpgr mutant mice harboring human disease-causing mutations that recapitulate human disease phenotypes: aborted membrane shedding as ectosome-like vesicles, photoreceptor death and visual loss. RPGR is located at the site of disc formation – to test if it plays a role in disc genesis, they engineered a novel reporter mouse to track outer segment turnover. Rhodopsin was tagged with the self-labelling peptide SNAP- Rhodopsin is the major protein component of outer segment discs, and so incubating RhodSNAP retinal slice cultures with SNAP fluorophores results in outer segment labelling. Perturbation of RPGR resulted in a slowed rate of disc formation, leading to shortened outer segments and increased vesicle shedding. To me, the breakthrough is in the last figure: the actin depolymerizing drug Cytochalasin D in PBS was injected intravitreally, and fixed retinas were analyzed 6 hours later by electron microscopy. Cytochalasin D treatment significantly reduced the number of shed vesicles from the base of the outer segment in Rpgr-mutant mice (they now look like wild-type).
Significance: Nails down the disease-relevant function of RPGR and a molecular mechanism of RP in photoreceptor cells, in vivo, in mice. Pharmacological rescue not only demonstrates the importance of the mechanism to disease but also sheds light on a potential therapeutic avenue for RP.
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news.ycombinator.com news.ycombinator.com
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I really highly recommend Robert Hazen's _Story of Earth_ [1] if you're into this sort of stuff. Highly knowledgeable and entertaining geologist argues that the geosphere and the biosphere should really be viewed as one co-evolving system, over deep time. There are thousands of species of minerals that can only exist because of the action of life, and those minerals in turn enable new forms of life, which enable new species of mineral, and so on in a complex and ever evolving system within which we exist for only a fraction of an instant.[1] https://www.amazon.com/Story-Earth-Billion-Stardust-Living/d...
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Manolis Kellis: Origin of Life, Humans, Ideas, Suffering, and Happiness | Lex Fridman Podcast #123
My summary:
Biology: * Life = energy + self preservation * Neanderthals could be the reason why wolves/dogs are living closely with humans. Maybe in the past generations, dogs had no choice but to live with humans as they were scared of our power? * People evolved from the deep ocean (we're made in 70% of water). We're like transporting the sea with us now * Dolphins as mammals came back into the water * RNA invented proteins. Later RNA and proteins created DNA * Life is like any kind of self-reinforcement such as self-reinforcement of RNA molecules which lead to the evolution process * Europa (moon of Jupiter) already evolves some non-DNA life there. Life could exist in its under-ice ocean, perhaps in an environment similar to Earth's deep-ocean hydrothermal vents. It will be fascinating to get to know it
Life: * Don't focus on goals but have a path to prevent the "rat race" sort of feeling * Almost every Hollywood movie has a happy ending. It prepares us, humans, really poorly for the bad times in life We need to read/watch more stories with a bad ending * Life is about accomplishing things, not about being happy all the time * As a parent, don't ask your kid if he's happy but what he's struggling to achieve * Most likely, we live on the best planet during the best time as the most beautiful mammals * If you understand yourself, you won't seek self-assurance in what other people think of you * It's hard to get to know your true self if you live all the time in the same location/environment and have the same friends who would like to have a stable image of you
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Finally, we demonstrated that LFA-1, the protein exclusively expresses in multiple leukocytes, is more likely the entry molecule that mediated SARS-CoV-2 infection in T cells, compared to a list of other known receptors. Collectively, this work confirmed a SARS-CoV-2 infection of T cells, in a spike-ACE2-independent manner, which shed novel insights into the underlying mechanisms of SARS-CoV-2-induced lymphopenia in COVID-19 patients.
Another receptor involved in covid19
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bio.libretexts.org bio.libretexts.org
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The several panels show what happens in each cycle. Each cycle consists of a denaturation step at a temperature higher than the melting temperature of the duplex DNA (e.g. 95 oC ), then an annealing step at a temperature below the melting temperature for the primer-template (e.g. 55 oC), followed by extension of the primer by DNA polymerase using dNTPs provided in the reaction. This is done at the temperature optimum for the DNA polymerase (e.g. 70 oC for a thermostable polymerase). Thermocylers are commercially available for carrying out many cycles quickly and reliably
- Denature
- Annealing primer
- Synthesize new DNA with polymerase
-
- High speed
- Extreme sensitivity
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www.shmoop.com www.shmoop.com
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Many of the molecules in a cell are polymers of various smaller molecules.
Polymers are combinations of smaller molecules. This is impressive.
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nucleotide has 3 basic components
This is helpful information. Phosphate is critical.
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histones are positively charged molecules
Ah ha! Histones are molecules. And proteins.
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Histones are positively charged proteins that wrap up DNA through interactions between their positive charges and the negative charges of DNA.
Are histones molcules?
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bafybeiac2nvojjb56tfpqsi44jhpartgxychh5djt4g4l4m4yo263plqau.ipfs.dweb.link bafybeiac2nvojjb56tfpqsi44jhpartgxychh5djt4g4l4m4yo263plqau.ipfs.dweb.link
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FollowingSimondon’s social theory [37] and our previous work [10 ], social systems are themselves individualsthat harbour in them preindividual forces of transformation. Therefore we do not see in the currentorganization of personhood, inasmuch as it seems unassailable, a final unchangeable state of affairs.
!- references : evolutionary biology * Evolutionary biologists have developed similar ideas to explain how throughout history, groups of individual organisms that clustered together and discovered better fitness as a result of symbiotic relationships began to reproduce as a whole new entity. Hence the collective became the new individual * Robin et al. paper: https://hyp.is/go?url=https%3A%2F%2Fwww.frontiersin.org%2Farticles%2F10.3389%2Ffevo.2021.711556%2Ffull&group=world * Robin et al. video presentation: https://hyp.is/go?url=http%3A%2F%2Fdocdrop.org%2Fvideo%2F6J-J72GoqhY%2F&group=world * Stuart West video: https://hyp.is/go?url=http%3A%2F%2Fdocdrop.org%2Fvideo%2FVUfNEHl44hc%2F&group=world
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www.scientificamerican.com www.scientificamerican.com
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https://www.scientificamerican.com/article/the-complicated-legacy-of-e-o-wilson/
I can see why there's so much backlash on this piece.
It could and should easily have been written without any reference at all to E. O. Wilson and been broadly interesting and true. However given the editorial headline "The Complicated Legacy of E. O. Wilson", the recency of his death, and the photo at the top, it becomes clickbait for something wholly other.
There is only passing reference to Wilson and any of his work and no citations whatsoever about who he was or why his work was supposedly controversial. Instead the author leans in on the the idea of the biology being the problem instead of the application of biology to early anthropology which dramatically mis-read the biology and misapplied it for the past century and a half to bolster racist ideas and policies.
The author indicates that we should be better with "citational practices when using or reporting on problematic work", but wholly forgets to apply it to her own writing in this very piece.
I'm aware that the magazine editors are most likely the ones that chose the headline and the accompanying photo, but there's a failure here in both editorial and writing for this piece to have appeared in Scientific American in a way as to make it more of a hit piece on Wilson just days after his death. Worse, the backlash of the broadly unsupported criticism of Wilson totally washed out the attention that should have been placed on the meat of the actual argument in the final paragraphs.
Editorial failed massively on all fronts here.
This article seems to be a clear example of the following:
Any time one uses the word "problematic" to describe cultural issues, it can't stand alone without some significant context building and clear arguments about exactly what was problematic and precisely why. Otherwise the exercise is a lot of handwaving and puffery that does neither side of an argument or its intended audiences any good.
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Second, the application of the scientific method matters: what works for ants and other nonhuman species is not always relevant for health and/or human outcomes. For example, the associations of Black people with poor health outcomes, economic disadvantage and reduced life expectancy can be explained by structural racism, yet Blackness or Black culture is frequently cited as the driver of those health disparities. Ant culture is hierarchal and matriarchal, based on human understandings of gender. And the descriptions and importance of ant societies existing as colonies is a component of Wilson’s work that should have been critiqued. Context matters.
The author is going in two opposite directions here and neither match up. A massive swath of our medicine research is wholly based on translational genetics. (That is, our basic research on organisms like flies (drosophila), worms (C. elegans), zebrafish, mice, rats, primates, etc. is contingent on moving medicines applicable to simpler genetic models in these animals will also work for humans who share large amounts of genetic material as the result of evolutionary dynamics. Sure some of it may not be relevant for humans because of both genetic and epigenetic (environmental) factors, but generally we expect that more will than won't.
This basic fact is wholly separate from the health disparities issue. While there are some (and few of these are generally scientists in my experience) who believe that culture is the driving factor, there is enough proof to show that structural racism is the driving factor in almost all cases. I'm unaware of any translational genetic work on ant culture into human culture in any of the scientific literature and she certainly doesn't cite any to provide any sort of evidence to the contrary. As a result, she isn't providing any context at all.
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whyevolutionistrue.com whyevolutionistrue.com
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Wilson might have been accused of racism by people like my own Ph.D. advisor Dick Lewontin (I don’t know about that, though), but they never adduced evidence for that.
Richard Lewontin was Jerry Coyne's Ph.D. thesis advisor.
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bioregistry.io bioregistry.io
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bmcbioinformatics.biomedcentral.com bmcbioinformatics.biomedcentral.com
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github.com github.com
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<details open> <summary>
Nanotate Annotations Samples
</summary> ```json [ { "id":"d5JrdABbEeuatj9X3vvoXw", "authority":"__world__", "url":"https://protocolexchange.researchsquare.com/article/pex-1069/v1", "created":"2020-09-27T00:50:41.265044+00:00", "updated":"2020-09-27T00:50:41.265044+00:00", "title":[ "Sample preparation and imaging procedures for fast and multiplexed superresolution microscopy with DNA-PAINT-ERS" ], "refs":[ ], "isReply":false, "isPagenote":false, "user":"acct:miguel.ruano@hypothes.is", "displayName":null, "text":"", "prefix":"for 10 minutes. Wash with PBS3. ", "exact":"Add imaging buffer with desired ratios of Buffer C (500 mM), ethylene carbonate, and IS-CF660R at 1-2 nM final concentration. The exact concentration of IS may need to be adjusted depending on the target and based on the imaging kinetics.", "suffix":"", "start":15158, "end":15396, "tags":[ "step" ], "group":"__world__", "ontologies":[ ] }, { "id":"FrhgjABcEeu5B4dnXgvb_A", "authority":"__world__", "url":"https://protocolexchange.researchsquare.com/article/pex-1069/v1", "created":"2020-09-27T00:55:08.276888+00:00", "updated":"2020-10-05T14:15:00.764415+00:00", "title":[ "Sample preparation and imaging procedures for fast and multiplexed superresolution microscopy with DNA-PAINT-ERS" ], "refs":[ ], "isReply":false, "isPagenote":false, "user":"acct:miguel.ruano@hypothes.is", "displayName":null, "text":"my other text modificate", "prefix":"ed ratios of Buffer C (500 mM), ", "exact":"ethylene carbonate", "suffix":"", "start":15219, "end":15237, "tags":[ "reagent" ], "group":"__world__", "ontologies":[ "CHEBI" ], "settings":{ "bio_annotations":[ "" ] } }, { "id":"7Z1sugBbEeu9_wtvk1iAjw", "authority":"__world__", "url":"https://protocolexchange.researchsquare.com/article/pex-1069/v1", "created":"2020-09-27T00:53:59.317703+00:00", "updated":"2020-09-30T00:39:50.822216+00:00", "title":[ "Sample preparation and imaging procedures for fast and multiplexed superresolution microscopy with DNA-PAINT-ERS" ], "refs":[ ], "isReply":false, "isPagenote":false, "user":"acct:miguel.ruano@hypothes.is", "displayName":null, "text":"", "prefix":"10 minutes. Wash with PBS3. Add ", "exact":"imaging buffer", "suffix":"", "start":15162, "end":15176, "tags":[ "reagent" ], "group":"__world__", "ontologies":[ "CHEBI" ], "settings":{ "bio_annotations":[ "http://purl.obolibrary.org/obo/CHEBI_35225" ] } } ] </summary>
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nanotate.bitsfetch.com nanotate.bitsfetch.comNanotate1
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Tool for the generation of 'nanopublications' based on hypothesis annotations
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cris.maastrichtuniversity.nl cris.maastrichtuniversity.nl
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www.macs.hw.ac.uk www.macs.hw.ac.uk
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bioschemas.org bioschemas.org
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Bioschemas Types Included into Schema.org
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CellPaint-VR, virtual-reality software that takes users into the cellscape.
I want this software.
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A poster hanging in many labs shows the Roche Biochemical Pathways diagram, a flowchart of cellular metabolism.
This is the poster to look for, alike with the one with pork's meat parts.
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www.thehindu.com www.thehindu.com
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two-thirds of common large moth species have declined over the last 40 years in some parts of world. One of main reasons for the decline is light pollution (an increase in artificial light in moth habitats).
Artificial Light pollution endangering moth species
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Frere, J. J., Serafini, R. A., Pryce, K. D., Zazhytska, M., Oishi, K., Golynker, I., Panis, M., Zimering, J., Horiuchi, S., Hoagland, D. A., Moller, R., Ruiz, A., Overdevest, J. B., Kodra, A., Canoll, P. D., Goldman, J. E., Borczuk, A. C., Chandar, V., Bram, Y., … tenOever, B. (2022). SARS-CoV-2 infection results in lasting and systemic perturbations post recovery (p. 2022.01.18.476786). https://doi.org/10.1101/2022.01.18.476786
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