pfisherman

They may be charging a lot, but that does not make it a nice neighborhood. But I guess they figured they could fleece people who did not know their way around the city.

Downtown SF has always been a soulless wasteland for the homeless and people who do not actually live in the city. Life in SF has always been about the neighborhoods. So basically anything West of Van Ness, South of 16th, and North of Broadway (with the exception of Nob Hill) modulo the character of the neighborhood.

The trick with muni busses is to always sit by the second set of doors. Crazy people ride in the front. Thugs and teenagers in the back. Normal people in the middle. The muni rail is truly an abomination. But the daily game of sardines is part of the charm … I guess

Pretty well done - especially the experimental validation. The main conclusions are accurate, but there is some BS around the periphery. A few notes below.

- The secret sauce here was the large, high quality experimental dataset they generated.

- Chemprop is meh.

- Is a tanimoto similarity < 0.3 really dissimilar? Depends on the chemical fingerprint parameters they are using in RDkit. For ECFP4 the expected similarity of two random molecules is about 0.1. A value of 0.3 about the cutoff you would use for a similarity based virtual screening with ECFP4 fingerprints.

- The cheminformatic filtering steps that they did on their hits was well done.

- The experimental validation of the target was well done. A good illustration of all the preclinical work it takes to validate a molecule and mechanism on the way to an IND.

- They got very lucky. Most of the time your compound hits are not all that potent and require extensive med chem optimization. That was not the case here.

Perspective from someone who was born and raised in the bay area…

> Around Market and 9th to 11th, a mostly residential and expensive main and small streets …

What?! This is just flat out wrong. The area around 9th and Market is basically civic center BART station; which was a low rent neighborhood where most of the residential buildings were SROs. Twitter got tax breaks to put their office there because it was and still is a dump. Even after you cross Van Ness into Hayes Valley you are still not in a fancy / exclusive neighborhood. Like the projects used to be right there.

> Safest it has ever been

Yes. There was a time when you could get shot in the Fillmore, Chinatown, the Mission and most definitely in the TL. Now the only place where you might run into that kind of trouble is bayview / hunters point / sunnydale - and I don’t know why you would ever go out there.

Transit is awesome. Best public transit in western US mainly because of density - the city is only 7 miles across. Have you tried public transportation anywhere west of the Mississippi before? I’m terms of schedule / timeliness, who looks at the actual muni schedules? Just use NextBus and go out the to stop like 3 mins before your bus arrives like a normal person.

Anyway, I could go on…

I agree that for all the fact base / revenue that SF gets the quality public schools are a travesty. But they have always been trash - with the exception of Lowell.

I mean… you’re not wrong. That is the strict ontological definition.

But like 99% of the time someone mentions cytokines in an actual conversation they are taking about inflammatory / immune signaling.[1]

Immune cells are far and away the largest class of circulating motile cells, no?

1. https://testdirectory.questdiagnostics.com/test/test-detail/...

This is pretty cool. Understanding the downstream components of the pathway will be critical for developing a more targeted therapeutic approach. IFN-gamma is a cytokine - a signaling molecule that turns on your inflammatory / immune response. That is a pretty heavy hammer.

Mixing personal and work business of the same machine is just bad data hygiene.

Is it that hard to whip out a mobile phone / tablet when you need to conduct some personal business or procrastinate?

This goes hand in hand with the more general principle of maintaining strict compartmentalization between work and personal life. My personal time, devices, online accounts, etc are mine.

Hey sramsey. Glad to see the Translator is still going. I imagine that recent LLM mania has been a pretty big deal for the agent teams? Anyway, nice to see you around and say “Hi” to Noel and Christine for me ;)

Saw something where this was being exploited for purposes of misinformation adding fake headlines to news links.

Reduce the friction for people to try it out. It looks like it could be interesting, but the account creation - in particular asking for my email - to do anything is enough friction that I would rather just close the window and never revisit.

One of the weird things about oncogenes that I have observed is that there is a balance. Perturb them too far one way and you get cancer. Perturb them too far the other and you get a developmental disorder. This is not at all rigorously documented or studied. Just an anecdotal observation.

Absolutely! The truth is that nobody really knows what medications actually cost. They are often sold in bundles similar to cable tv channels.

For those who are running into coverage / affordability problems for drugs in the US… contact the manufacturer. They often have payment assistance programs or discounts to reduce out of pocket costs. They may be able to help you get costs covered by your insurer.

You should not ever be paying the full “list price” out of pocket. Pharma companies want market share and they would rather sell to you at a discount than lose you as a customer.

I own stocks that pay me dividends - a share of the company profits. The company manufactures tangible goods, sells them to people, and then distributes some of the profits from these sales to shareholders. The shares I own are a claim on some portion of those profits.

There are plenty of companies that pay dividends. The logic behind stock buybacks is that it achieves a similar end for investors with favorable tax treatment.

In either case I am receiving some portion of the cash flows generated by a business. These cash flows are being generated independently of any stock market activity.

So tell me what claim on an underlying asset / cash flow does a cryptocurrency entitle me to?

Invitae is doing the lord’s work when it comes to commercializing high quality genetic diagnostic tests and offering them directly to consumers at reasonable prices. We used them for prenatal screening. They offered the circulating DNA test - which is only covered for geriatric pregnancies - for a reasonable price. I wish the payers would cover these so they could be compensated more for what they do, but the US healthcare system is bonkers.

Some of the problem with these types of genetic tests - especially for stuff like PGx - is that physicians have not integrated them into their practice / workflows, so even when they get actionable info from one of these tests they don’t really know what to do with it.

The sci-fi use case is that an prognostic / diagnostic / active learning agent pulling information from EHRs would use this as a prior.

More low tech is that you and your physician are more vigilant when it comes to monitoring or testing for certain types of cancer if you have a high impact onco-variant.

Keep in mind that prognosis for cancer improves dramatically when you can detect it early.

Free preprint version on medRxiv: https://www.medrxiv.org/content/10.1101/2022.08.09.22278592v...

I mean this is a great perspective on the failings of the panopticon. Thanks for writing it.

If you think about it, a lot of children’s stories and religions rely on this concept of the panopticon to inspirei moral behavior. Santa knows if you’ve been good or bad. God is always watching, and will reward or punish in the afterlife. Your soul will be reborn according to karma. Et cetera.

So is the use of constant, omniscient surveillance actually new to incentivize moral behavior new? Or have the methods / technology just gotten better?

This is the truth. Mid market has always been sketchy. Nobody lives or hangs out in downtown SF. Downtown is for the “bridge and tunnel” crowd. Like why would you ever put it here and not in one of the neighborhoods (ex Sunset, Richmond, Glen Park, Soma).

That being said the 5th street area losing Nordstrom is a big blow. Things there have certainly gotten worse recently as it has started more and more resemble Market street on the other side of Seventh.

Well, when one compares to other cell therapies such as CAR-Ts…

https://www.nature.com/articles/s41571-023-00754-1

I was adding in a little bit of context to explain why people should care about iPSCs - even if they are not used as therapies. Mainly because the last paragraph in GP comment focused on the dearth of direct clinical applications.

My point is that iPSCs are still quite useful in pharmaceutical research and development - a therapy adjacent area.

Improved cell models are still a pretty big deal. Part of the reason for high costs and failure rates in pharma R&D is that experimental models we use to generate data are imperfect. Better models = better data = better decisions.

iPSCs are useful when you want to run experiments in hard to obtain cell types. For example, brain cells. It’s hard to justify drilling into a person’s head to take a sample. Much easier to use some iPSCs derived from skin or fat cells.

Obviously iPSCs are cell models and not the actual cells you want, but they are usually better than immortalized cell lines or cadavers.

I wonder if that is long enough to significantly impact LD structure.

SNPs are causal in that they can be thought of as perturbations of genes that occur prior to the genesis of the phenotype.

I think what you might be trying to say is (1) the presence of a SNP may not be sufficient for the occurrence of a phenotype, or (2) another SNP in high LD may be the true causal SNP.

Is is that crazy to think that a wild swing in steroid hormone levels can lead to depression - similar to what we observe when men come off of steroid cycles? If so, is something like post cycle therapy for women recovering from pregnancy really that crazy of an idea?

I don’t know enough to speak intelligently about the underlying biology, but an interesting theory I heard from someone more knowledgeable than me is that the sudden drop in progesterone - which tamps down neuroinflammation - sends the microglia (immune cells of the brain) into overdrive which results in rapid destruction of neural tissue which is experienced by the patient as profound feelings of unhappiness / depression. This is not unlike the runaway inflammatory response that kills people with COVID — which is why dexamethosone (an immunosuppressant) reduces mortality.

No people really did not like Bernie that much. He was making a lot of promises that he did not have the political capital or chops to deliver on; and a lot of people saw through it.

Not to mention that his cohort of rabid online supporters were as insufferable as those supporting the orange man; thus giving his campaign a similar kool aid drinking cult vibe.

As far as the talk about other candidates forming a coalition against him … that whole line of argument is pretty laughable. This is politics. Success in politics is achieved by building coalitions among constituencies and their representatives to advance policy.

If Bernie were such an effective politician then why was he unable to get someone else to stay in the primary to split the establishment vote?

One thing that I think people need to understand is the distinction between science and the practice of medicine.

The practice of medicine is not science. The practice of medicine can be informed by science - to a degree that is almost entirely up to the practitioner. ; but it remains more art than science. The distinction is similar to that between an aviation maintenance and aerospace engineering.

Sometimes doctors are just out of their depth.

I don’t think sprinkling all the produce with a pharmacologically active molecule is a good idea. Side effects can and will be a big problem.

Jordans are not Veblen goods. They are entry level sneakers. Enough to set you apart from the sketchers wearing squares, but they are not margielas or visvims.

Relevant (and entertaining) “In the Pipeline” article.

https://www.science.org/content/blog-post/there-s-toxicity-a...

My experience building AI powered tools for scientists has been the opposite.

Other commenters have pointed out the difficulties users with limited domaine expertise having in parsing the output and distinguishing what is useful, novel, interesting from what is trivial or incorrect.

This slows down the iterative process of learning how to use the tool as well as refining queries because they don’t have a big enough database of ground truth knowledge to calibrate against.

That being said these can work well as educational tools to rapidly get non-experts to a point where they can participate in conversations with experts. In that regard one might say that the bulk of the value is in the non-expert users because they are far more prevalent than experts.

The biggest advantage I saw for the expert researchers was that they knew (1) which big questions to ask, and (2) how to break down those big questions into smaller, more precise questions.

Sorry but this ignores a lot of history. The plot of the first feature film - Birth of a Nation - is literally the Klu Klux Klan saving the day by driving away the black people run amok during reconstruction. How is that lighthearted and apolitical?