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  • 0 posts edited
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  • 26 votes cast
Jul
20
comment What specific mutations can cause an apoptosis mechanism to malfunction?
Yes, it's just not a magic bullet. There's been lots of research on this-- try reading the review I linked above. Also, try looking into the concept of "immune checkpoint inhibitors" that shut down genes like CTLA4 and PD1. Those are showing some promise in certain settings.
Jul
16
comment What specific mutations can cause an apoptosis mechanism to malfunction?
That's part of it. They also downregulate their MHC complexes and secrete their own inhibitory cytokines. It's a big and complicated problem that's had a lot of research done on it. Here's a review: ncbi.nlm.nih.gov/pmc/articles/PMC1857231
Jul
16
comment What specific mutations can cause an apoptosis mechanism to malfunction?
Tumor immunosurveillance is a whole new topic worth its own question, but there are two basic reasons: (1) Mutated KRAS is not immunologically very different from wild-type KRAS-- it just doesn't change the overall surface shape of the protein that much, and (2) even when the immune system does recognize mutated cell products, the tumor cells react by upregulating anti-inflammatory pathways, such as recruiting regulatory T cells.
Jun
29
comment Deciding a reasonable threshold for copy number variation in a CNV (SNP array) TCGA dataset
Hmm, okay, I think I see. No, you don't want to compare the intensity of the tumor at any one position against the 5-95% distribution of the normal across the whole array. You want to compare the intensity of the tumor at one position against the normal at that position. This will normalize for sequence-specific binding differences.
Jun
22
comment What does it mean to “map the human genome”
Good point, I'll edit. I was thinking of the Celera DNA, which I thought was Venter's, but it turns out that they were using a pool, too. (Venter was just in the pool.)
May
13
comment Downstream analysis after in vivo pathogen RNAseq
Right. The main thing is that you want your groups in an RNA-Seq experiment to focus as cleanly as possible on the difference you want to investigate. If you're interested in antibiotic resistance, use a resistant and a non-resistant strain. If you're interested in immune evasion, use samples in the presence and absence of an immune response. You expect many differences between cultured and in vivo samples-- you've already mentioned metabolism, antibiotic resistance, and immune evasion, and I'm sure there are lots more. So it's hard to relate any given gene expression change to a phenotype.
May
12
comment Downstream analysis after in vivo pathogen RNAseq
The reason I say it's not the clearest model, especially for antibiotic design, is that you're investigating the difference between bacteria in the host and bacteria on the plate. An antibiotic in particular probably isn't going to care about that-- it should kill in both situations, right? And for a vaccine, there are so many differences between culture and in vivo that I'm not sure that you can attribute differences you see to immune evasion. Are there immune-compromised pig models? In vivo samples from those would be a much cleaner control for immune evasion.
May
12
comment Downstream analysis after in vivo pathogen RNAseq
Okay, that does make experimental design much easier.
May
11
comment Downstream analysis after in vivo pathogen RNAseq
You're going to need to be a lot more specific. To start with, when you say a pathway is up or down-regulated, what comparison are you making? Is there a treatment and you're comparing treated versus control? Are there different populations and you're comparing to each other?
May
11
comment Do gene expression levels necessarily correspond to levels of protein activation?
I think you'll find very few papers that demonstrate changes in mRNA levels by microarray, claim that an increase in the gene product's activity is responsible for the biological effect, and then stop. mRNA data is complicated, not useless. Almost anywhere that mRNA upregulation is reported, it will be followed by a measurement of the protein levels and other follow-on experiments to confirm the protein's involvement.
May
2
comment Why isn't the p16-INK4a gene involved in apoptosis expressed in heart or liver tissues?
That's a good question. The Nature paper referenced in the NYT article says it, but with no citation, and their tissue work backs it up. The GeneCard data does run counter to that, though. I'd add the caveat that the Nature paper is talking about mice, and mice handle senescence differently than humans do. For one thing, they don't turn off their telomerase.
May
2
comment Why isn't the p16-INK4a gene involved in apoptosis expressed in heart or liver tissues?
Yeah, that's an interesting question. I'd say main advantage of senescence in most tissues is that the cell gets to hang around and do its job. If it goes through apoptosis, it's going to need to be replaced. Senescence as a strategy, then, would keep overall proliferation rates lower in the tissue as a whole, which could have upsides, like limiting the potential for errors to creep in. Which one gets selected for in which tissue could definitely be influenced by the balance of those factors compared to reproduction time.