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Nope that’s just good ole fashioned grunt work. Mostly I was trying to figure out if the fact that alphagenome predicted so many genes being strongly affected by one variant was biologically plausible, or if it can be written off as the model hallucinating. If the variants overlap TF binding...

It says “each point represents the surface area measured from a single image” so the only way I can interpret that is: they had a number of images for each participant, chose only one per participant for 1C, and averaged across cells from one image. I’m hoping the legend is wrong because...

Images usually contain more than one cell—I think what they’re saying there is that they had 3 replicate images per sample, making sure that at least 10 cells were visible across all 3. Though the wording is very confusing so maybe something else weird is happening here. [Edit: Either way you...

Just now noticing some weird discrepancies in the number and source of data points being plotted in Figure 1: Legend says: So the right panel for 1B seems to have an issue of pseudoreplication, where each image must have been counted as one point to get that many dots. Just from a quick count...

These are people who failed to get improvement from several drugs that would affect SLPC, but had clinical improvement with dara. I don't think the simple idea of "lupus == SLPC therefore dara treats SLPC-mediated disease" holds here

Sure. For example, having stricter diagnostic criteria to make sure the people you’re studying actually have ME/CFS can end up selecting for people who are temporarily at the worst point of their illness. We know plenty of people can float in between severities. Also inadvertently selecting...

As Jonathan already said you can never safely assume that a clinical trial is randomly sampling out of a natural distribution. Things like selection criteria can and do introduce a lot of bias that even the investigators are unaware of, the intramural study is proof of that too. That’s the whole...

Someone has to cover the dark horses, I guess. Otto Antibody already has many fans.

I don't disagree, interferons are probably secondary to the thing actually giving clinical benefit in this case. What I find interesting is just the possibility that a CD38 mAb could regulate type I interferon production directly by blocking CD38 activity on IFN-I producing cells (and doing so...

Our familiarity with marmalade mostly comes from paddington bear

Potentially. It's interesting here, this supplemental plot tells us that dara does also bind to CD38 on myeloid cells that typically produce type I interferon in lupus: The question is whether the reduced type I interferon response here is a secondary effect of fewer antibodies from plasma...

I looked at one more deletion in another TF-bound regulatory region right next to the most significant SNP a little earlier in the thread. There’s a loss of an AP1 binding site—AP1 has been found to [edit: be relevant in a lot of immune responses including interferon/IL-1B, though it does a lot...

The website is just a quick way of cross referencing a given sequence with known binding motifs for TFs. A binding motif is like a footprint that the transcription factor physically binds to on the DNA (it's the last column in the links). Give the website a nucleotide sequence, it will give you...

Update: very difficult to tell. All the significant hits are in intronic regions of the lncRNA--if they're getting spliced out, they wouldn't be attached to the part of the lncRNA that has complementary specficity to ARFGEF2 (though small regions may have other complementarity...it's not...

Thanks, that's helpful. It's interesting how much the sign flip flops across tissues, even though the quantile score is similarly high. The only thing that makes me less worried is that the signs from unrelated samples in the same tissue/cell-type seem to be in the same direction (at least from...

Good question, I assume randomly because it was the next closest in the credible set outside of the island around the strongest hit. The TF binding data explains the switch in signs for some genes, but might not be relevant to ME/CFS

Oh duh, it's amazing the things you miss when you're just scrolling quickly on your phone. chr20:48914387:T>TA Most significant hit In lncRNA ENSG00000294533, described as anti-sense to ARFGEF2. Meaning that it's a complementary sequence to part of the actual sequence in the gene--when the...

@forestglip if you share the variant locations from your examples above I can check the overlap with TF binding sites when I have a chance to verify if that’s what causes the sign change

Nice work! When I looked at that locus a while ago I remember that the region of SNPs with the highest significance overlapped an area with a lot of different transcription factor binding motifs. It seems to be an important regulatory region, so theoretically these findings are biologically...

If you can use a raw sequence of DNA as input it should be possible to just manually change all the base pairs to match the SNPs from DecodeME in a certain region and then run that string as your input. Might be too labor intensive, though