Daniel Sirkis

Staff scientist @UCSF. Formerly @UCBerkeley, @HHMINEWS.

[Jason Fernandes @jdf_ev]

Five years ago we sketched out the designs for our first epigenome editors. Proud to see those sketches move into the clinic.

You can read more about the technology underpinning our epi-editors in this preprint we recently presented at ASGCT: https://t.co/SuSGvwgnPb

[Daniel Sirkis @dwsir]

@tangming2005 Curious where the evidence for ~97% clustering agreement comes from. Doesn't this analysis from 10x indicate that clustering results change a fair amount between intron-included vs. intron-excluded modes?

[Daniel Sirkis @dwsir]

...so it would seem quite surprising that none of the ROSMAP control donor nuclei would have detectable HSV-1. Please let me know if I'm misunderstanding! (2 of 2)

[Daniel Sirkis @dwsir]

This story sounds awesome, but I am a bit confused by your ROSMAP findings summarized in Table 1. Do I understand correctly that no HSV-1 reads were detected in *any* of the 427 donors? My understanding is that only ~56% of these donors had a path Dx of AD, ... (1 of 2)

[Caleb Lareau @CalebLareau]

A history of viral encephalitis is one of the strongest risk factors for developing dementia. With @JacobJacobog02, Yifan Chen, @RNA_Life, and @RyanDhindsa, we refine this link by describing a neuronal cell type that can reactivate HSV-1 in humans 1/n

https://t.co/y8D2orzUur

[Daniel Sirkis @dwsir]

@BoWang87 This is not smooth ER or rough ER:

[Daniel Sirkis @dwsir]

@BoWang87 This is not a secretory vesicle:

[Daniel Sirkis @dwsir]

@EWidera @alzassociation (2/2) ...from 0-50 is also not optimal--primarily because that scale is not relevant to the delta that the control group shows over this time period. Again, it's totally fine (maybe best) to show both scales together. Important context can be lost by showing either in isolation.

[Daniel Sirkis @dwsir]

@EWidera @alzassociation (1/2) Totally agree that it makes sense to show a plot with a zoomed-in scale as an inset, and, as far as I can tell, this seems to be standard policy for NEJM articles. However, to take your example, looking *in isolation* at change in ADCS-MCI-ADL over 18 months, on a scale...

[Daniel Sirkis @dwsir]

@EWidera @alzassociation In addition, although this was not the point of your post, I think the fact that lecanemab and donanemab are having real knock-on effects on p-tau should be a cause for (measured) optimism among scientists and physicians in this space.

[Daniel Sirkis @dwsir]

@EWidera @alzassociation Yep, I completely agree that we need longer trial data. Also 100% agree that overly optimistic, extrapolative plots are not helpful. My middle-of-the-road take is that it's best not to join camps seeking to show the actual data in overly flattering *or* overly pessimistic light.

[Daniel Sirkis @dwsir]

@EWidera @alzassociation I'm trying to think of a good analogy. I'm not an MD, but this seems kind of like showing a plot of systolic BP on a scale from 100-250 and then implying that losartan barely does anything meaningful because it's hard to see its effect on such a scale.

[Daniel Sirkis @dwsir]

@EWidera @alzassociation The thing about the scale of the top plot is: even in the case of a hypothetical miracle drug that completely prevented an increase in CDR-SB over 18 months, this plot would still make it look like a nothing burger. That's how you know it's not a very informative y-axis scale.

[Mitchell (Min Woo) Kim @mitchkim_mw]

Transforming traditional views laid by “CNS immune privilege,” our research uncovers the brain’s purposeful presentation of self – that is the brain engages with the immune system through “guardian” peptides to ensure immune tolerance. @jonykipnis
https://t.co/XRr11LC82M

[Jennifer Yokoyama @YokoyamaLabUCSF]

Check out our new preprint showing our ability to use epigenetic age measured from blood to predict AD progression & cortical atrophy! ⁦@dwsir⁩ ⁦@UCSFimaging⁩ ⁦@UCSFmac⁩ ⁦@nanosanta⁩ ⁦@AgustinMIbanez⁩ ⁦⁦@Cornell⁩ https://t.co/QiB9IcvJhR

[Petter Brodin @BrodinPetter]

New paper out📢! Toxic effects of IFN-I in humans has been suggested in patients with rare monogenic autoinflammatory diseases (SAVI, CANDLE, AGS) where IFN-I are elevated. In the absence of specific inhibitors, their causal role has been difficult to prove. We now report benefit of specific anti-IFNAR1 (#Anifrolumab) in 5 patients verifying the causal role of IFN-I in these diseases: https://t.co/GIZxzB6ljA

[Daniel Sirkis @dwsir]

@OdedRechavi I stay excited by reading all the crazy new ideas people have, like using Toxoplasma secretion machinery to delivery proteins to the brain.

[Daniel Sirkis @dwsir]

Holy moly. In some individuals, p-tau181 is >300-fold higher in cervical lymph nodes than plasma. Seems like this could be a reasonable location to predict exposure of T cells to tau-derived peptides.

[Daniel Sirkis @dwsir]

@JasonSynaptic Regardless, congrats on the work--looks like a great advance!

[Daniel Sirkis @dwsir]

Having worked on mechanisms of unconventional synuclein secretion, this paper looks awesome and the data compelling. However--not having read the full text--I am left with the following dispiriting impression:
- Arc function = bad outcome
- lack of Arc function = bad outcome

[Jason Shepherd @JasonSynaptic]

At the end of 2018 I was lucky to receive a @cziscience Ben Barres award. This preprint is the culmination of that funding, which allowed us to try "out of the box" ideas to study neurodegeneration. Fearlessly led by amazing student @MitaliTyagi2! 🧵 /1 https://t.co/5EOxdXLGKb

[Daniel Sirkis @dwsir]

@JasonSynaptic Good point. I was actually thinking about this from a tau-specific perspective, in which you don't want it to spread, but you also don't want it to build up in the cytoplasm. Perhaps blocking the harmful spreading while amping up the CMA pathway would be a reasonable strategy.