Inspired by urban sketchers in Vancouver
Happy Lunar New Year
Harry and I started making hand pulled noodles for the New Year!
Although we’re still mastering the pulling, the flavors and textures are quite good.
If you’re looking to get started, check out the recipe from Xi’an Famous Foods:
Phonics!
I’m taking a Swahili class and it’s awesome!
In particular, I’m loving the bits about linguistics. I’m really enjoying all the classifications of sounds and phonemes, especially “ng” (ŋ) and “ny” (ɳ).
These two sounds are challenging for me so I’m doing a lot of practice. Turns out ŋ is in English too, so this is definitely helping me distinguish “thin” from “thing”.
Pseudouridylyl, not pseudouridine
Bert Hubert recently published Reverse Engineering the source code of the BioNTech/Pfizer SARS-CoV-2 Vaccine and I (along with the rest of the internet) loved it! It provided a clear review of Pfizer’s mRNA vaccine written for a software engineering audience. Given my previous synthetic biology experience, I was excited to read about how their vaccine actually worked.
Bert linked to a document by the WHO containing the genetic sequence of the mRNA. In that sequence, the symbol “Ψ” represents 1-methyl-3′-pseudouridylyl. Bert explained that this was a clever substitution to help the mRNA escape our immune system’s detection. He also linked to a tweet about Karikó and Weissman which implied that they had discovered 1-methyl-3′-pseudouridylyl.
I was fascinated! I’d never heard of Ψ before. Digging in a little deeper I realized that the symbolic representation had confused me, and maybe other folks were confused too.
Karikó and Weissman published a lot of papers about pseudouridine, which they denoted with “Ψ.” Replacing uracil for pseudouridine in mRNA does indeed help the mRNA escape our immune system’s detection [1]. However, pseudouridine is not pseudouridylyl.
Looking at the WHO document that Bert linked, the two molecules are structurally similar but definitely not the same. I’m not any good at organic chemistry, but my guess is the extra phosphorus and oxygens are from the sugar phosphate backbone. But what’s with the extra methyl group (carbons and hydrogens) on the nitrogen? My intuition says that’s important.
| pseudouridine | 1-methyl-3′-pseudouridylyl |
|---|---|
 |
 |
| Wikipedia | WHO 11889 |
So what’s pseudouridylyl?
Why did Pfizer choose to use pseudouridylyl instead of pseudouridine? I had guessed that it must offer either a biological benefit (increasing effectiveness) or a manufacturing benefit (reducing cost). “Pseudouridylyl” (or even “uridylyl”) is not a common word either on the internet or in the literature. I found lots of references to similar chemicals, but couldn’t find literature linking any of them to immune system responses or mRNA synthesis.
And then came the a-ha moment!
In the WHO document, the author represented 1-methyl-3′-pseudouridylyl as “m1Ψ” (with “m1” indicating a modification). However, in the actual genetic sequence, the author chose to abbreviate “m1Ψ” to simply “Ψ.”
Now that I knew what I was looking for, I found an abundance of papers referencing m1Ψ. The canonical name seems to be “N(1)-methylpseudouridine.”
N(1)-methylpseudouridine looks to be an even better substitution than pseudouridine [2]. It also shares the convenient property of escaping immune system detection [3]. The N(1)-methylpseudouridine papers definitely build upon the work of Karikó and Weissman.
The diagrams show that they’re pretty close! See the methyl group?
| N1-Methylpseudouridine-UTP | 1-methylpseudouridine | 1-methyl-3′-pseudouridylyl |
|---|---|---|
 |
 |
|
| Jena Bioscience | Modomics | WHO 11889 |
I’m now fairly confident that Ψ in the Pfizer sequence is m1Ψ. They’re calling it “1-methyl-3′-pseudouridylyl,” but it’s also known as “N(1)-methylpseudouridine” or “1-methylpseudouridine.”
References
[2] Callum J C Parr, Shunsuke Wada, Kenjiro Kotake, Shigetoshi Kameda, Satoshi Matsuura, Souhei Sakashita, Soyoung Park, Hiroshi Sugiyama, Yi Kuang, Hirohide Saito, N1-Methylpseudouridine substitution enhances the performance of synthetic mRNA switches in cells, Nucleic Acids Research, Volume 48, Issue 6, 06 April 2020, Page e35, https://doi.org/10.1093/nar/gkaa070
Holiday Sweets
Here’s a set that reminds me of sugary treats
Average Time Difference Between Rows
Suppose you had sales table with timestamp and customer_id as the columns.
| id | timestamp | customer_id |
|---|---|---|
| 1 | 2011-03-17 10:31:01 | 7 |
| 2 | 2011-03-17 10:45:05 | 8 |
| 3 | 2011-03-17 10:47:05 | 7 | 4 | 2011-03-17 10:50:10 | 8 |
You want to query for what’s the average time between purchases for each customer.
You can use:
SELECT t.customer_id,
AVG(t.difference) as interval
FROM (
SELECT customer_id,
timestamp - lag(timestamp) OVER (PARTITION BY customer_id ORDER BY timestamp) AS difference
FROM sales
) t
GROUP BY t.customer_id
You’ll get:
| customer_id | interval |
|---|---|
| 7 | 00:16:04 |
| 8 | 00:05:05 |
Sources:
Twin Fish
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How to Make Fish Keycaps
Here are the steps I use to cast a fish keycap. If you’re completely new, see the Z-Butt wiki and my older blog post.
First I cast a bottom piece. Thanks to the Z-Butt community, I learned to get the petri effect, you need to wait for about 1-2 hours before adding in alcohol ink to the resin. Here I waited for 1.5 hours.
After the bottom piece is cured, I add a polymer clay fish. I use acrylic paint to add details and dab a dollop of resin to secure the fish to the base. When everything looks dry, I invert it to cast the top piece.
That’s it!
Splish Splash
I did it! I made a keycap with a fish with a water effect!
I’m gonna practice sculpting better fish but I’m loving the look.
Gone Fishing
After a lot of practice, I cast some better lakes and better fish. I’m using a pearlescent acrylic paint on the fish body to give it a silvery glow.
My next challenge is to create fish keycaps with bases with petri effects to look more like water. I’m aiming to replicate jellykey’s Zen Pond effect.
Caret Dash Caret 