"Phase 1 clinical trials of a 15-PGDH inhibitor for muscle weakness have shown that it is safe and active in healthy volunteers. Our hope is that a similar trial will be launched soon to test its effect in cartilage regeneration" - Helen Blau, Baxter Laboratory for Stem Cell Biology & the Donald E. and Delia B. Baxter Foundation Professorship
ERa activation promotes PGE2 resulting in decreased 15-PGDH.
So this is one of those standard poor estrogen signaling downstream things and simply improving the estrogen signaling and you get improved cartilage. Anyone can do this today along with getting all of the other positive effects. Those with EDS who have say variants on their TNXA/B have poor production ability to start and so we do everything we can to improve their cartilage production as they can only make so much which include doing stuff like this.
It depends on the person and their genetics. The further you get from the ERa the more complicated this gets and simply stating "Do X" wouldn't apply to everyone even if there are some incredibly common things to do. I might know all the upstream genes, their interactions, and symptoms by heart so it is pretty easy to identify, but general advice would go something like: eat well, get sleep and exercise.
I've read that specific type of exercise (repeating cycles of low impact move, cycling, rowing, elliptical machine) are the most effective at triggering cartilage growth. Is that accurate?
I recently had to select a 401(k) plan for our small startup. For a startup, the _employee_ fees was significantly better on Guideline (0.15 - 0.3%) than Fidelity (0.5% + $100 bookkeeping fee). The _employer_ fees were slightly more expensive with Guideline ($1,778 on Enterprise plan for Guideline vs $1,200 for Fidelity) but offered more features.
Important for founders in the US to know: you can put up to $70k annually into your 401k using profit sharing, which only some 401k plans offer. Your startup does not need to be making a profit to do 401k profit sharing. Employees may also be able to negotiate this!
It was a surprise learning how applicable your statement is when I was selling technology products into consumer packaged goods (CPG) companies. Consumer preference is very hard to change once it is established, and leading CPG companies spend an enormous amount establishing that preference.
I was surprised how bad Sharpie markers were, when I first came across them here in Europe a few years ago. I had started hearing the word, where we used to say "permanent marker".
But the smell! Yuerk. I don't know what it is, but I find it awful. The smell is the only problem, but as far as I'm concerned it's enough that I'll never buy another.
The similar-quality European or Japanese permanent markers don't smell anywhere near as bad, but have surely lost market share here due to Sharpie's effective marketing.
Small organizations exist largely because volunteers will them to exist by donating their time. From our elementary school, it's clear the people who have time to volunteer are the stay-at-home parents. The dominance of two-income households eroded the small organizations, which created a market (distributing the costs over many more people) for large organizations to fill the void with a worse but market-serving product.
I would concur. It's my observation from 20 years of watching and participating - the volunteers are the retired, the wealthy, the underemployed, and the stay at home parent. "Normal" working people are not volunteering and handling the complexity of doing these things, they are at their work. I can only imagine that prior generations had the working parent participate through the free time freed up by the stay at home parent.
It suggests to me that there is a long running flaw. I believe Bowling Alone pegs the inflection point in the late 50s or early 60s, ('57?) and the substantative issues came about with the generation hitting the workforce in something like 1960. So the kids born in the 1935-1945 era had something in their culture materially different than prior eras that kept on spreading.
I'll add that there are some feedback loops making it worse. When these organizations aren't available kids are more dependent on their parents for something to do, which makes the already strained parents even less likely to take on volunteer work.
And then kids who grew up without mentors are less likely to try to be that for someone else.
Basically the orgs don't have enough volunteers to do important things, and the people don't volunteer because the org isn't important to them.
Yes, the network effect and cumulative impact is profound.
If I were to make a lightly educated guess - those who were teens in the 40s and 50s saw the world of their parents and their sacrifices, along with the totalitarianism of the USSR and Nazi Germany, and decided to pursue individualism over community. So as they got to an age to participate they opted out, as well as increasing the total social individualism. And here we are.
I don't know exactly what the way out here looks like, but I believe it absolutely means involvement with local organizations. Kiwanis, elks, rotary, religious, etc.
Whatever fills the void for people. ie: instead of bowling leagues, people watch TV or play video games. It's arguably a worse product because it doesn't fulfill the socialization or exercise needs of people, but it does fill the same block of time.
I guess it’s worse in the sense of providing health benefits, but it’s better in the sense that more people would freely choose it if given the choice.
It’s the same as junk food, people will freely choose it over healthier options.
Basically, products on the free market optimize for what people prefer to buy, and people’s preferences are shaped by evolution to a world in which physical rest and high-calorie foods were scarce. This makes us mismatched to the modern landscape.
This is certainly true in Silicon Valley. It provides an interesting tentative answer to the question that has been posed by some AI optimists about what people are going to do with all their leisure time after the AI is able to do their jobs for them.
I majored in Engineering Physics with an EE focus. Our classes were scheduled so we took the dependent math courses a semester before the relevant EE topics (ie: learned Laplace & Fourier transformations before circuit analysis). The EE majors all took the related math & EE courses simultaneously and visibly struggled, with every class we took together having a bimodal grade distribution.
Paraphrasing from an Oakland police officer reflecting on the spike in crime 3 years ago to today: "Flock has been a game changer. The officers who use it are getting results. Criminals will steal a car, drive through a neighborhood and rob someone. Pretty quickly we can look up 'black BMWs driving around this location'. Maybe 10 come back, you figure out which is the likely one, and then can see where it shows up in the next few hours. Then you have officers on patrol in that area look out for it. The criminals get a police car tailing them & they ditch the vehicle. Instead of doing 5 or 6 robberies with a stolen car, they can do 1 or 2. That makes it much less worth it to do the crimes."
Fresno / Central Valley is not the circuitous route, which is quite close to the I-5 near Bakersfield. The true circuitous detour is between Bakersfield and LA, where the route is planned to go East through the Antelope Valley with a station at Palmdale.
It's utterly asinine, and will result in "low speed rail". Which already exists... you can take the Coastal Starlight if you aren't in a hurry. There is no market (none) for rail service between LA and Bakersfield.
AC Transit (eg: East San Francisco Bay) performed a detailed 2 year study (July 2020 - June 2022) comparing newer Hydrogen Fuel Cell & Battery -powered buses to existing Diesel, Fuel Cell, & Hybrid -powered buses, 5 of each type. The key results are the Hydrogen Fuel Cells have significantly more expensive infrastructure, fuel, and maintenance costs than Battery. However, both technologies are still less reliable than Diesel.
The maintenance costs are only marginally higher per the report at $1.33 FCEB vs $1.15 BEB , $2.37 for Hybrids and $1.28 for Diesel (with additional public health costs for respiratory illnesses), the sample size(5x5) is too small to draw any meaningful conclusion on infrastructure costs or even reliability given the limited experience in operating anything not diesel.
Economics of hydrogen in CA are also complicated given our on-off approach to hydrogen infrastructure[2] for both personal and commercial vehicles but there is some progress on commercial side at least last year [1].
Hydrogen is not everyone but there are use cases for it.
The uptime (i.e. the refueling time) is an key factor [4]. Battery operated vehicles need a lot of downtime for charging thus you will need more vehicles for the same coverage. Fast charging can help but impacts battery life and thus TCO.
All green public transit are expensive. It is not a easy choice for administrators, should they improve coverage/ service frequency etc for their residents who need transit the the most or better air quality and less noise pollution for all of them.
Remember Fuel Cells are far cleaner for the air much more than BEV also, because it needs oxygen from the air FCs purify the air to do so. Kind of like having a big vacuum on the road in addition to not emitting direct pollutants[3]
[3] Ignoring tire dust, it is problem for all vehicles of course, that is independent of propulsion systems
[4] Even for personal vehicles it can be a decision factor when considering going green, as an owner of a Mirai with no easy access to EV charging stations I have benefited from being to refuel like a gar car.
If I'm reading that right the Battery Electric busses had the lowest maintenance costs? The need to charge is a potential issue, but at the same time busses do lots of low speed stop and go where battery systems are most efficient. As long as the bus has enough capacity for an entire day and can be recharged overnight it seems like an ideal solution, minus of course the up-front cost of the bus. Lower fuel costs, no noxious pollutants, less noise, lower maintenance, there is a lot to love.
An other option BEV busses give is hybrid trolleys, that way once a popular line gets fixed you can add overhead lines to it and later upgrade it to tram more easily.
It also means charge is a matter of having overhead lines which can be added as hoc (as overhead docking stations) to end-of-line stops, letting the bus juice up for some time before it runs the route back.
It is likely that new models had higher costs, including maintainers becoming familiar. Long-term, electric is unquestionably cheaper to fuel and maintain, assuming they are built to the same standards and scale as outgoing diesel models
I wonder about the added wear on roads that comes with so much added weight. That is the kind of cost that is easy to put in someone else's bucket until it impacts everyone. One of the roads near here was closed for a while putting a large amount of truck traffic on another road. It is impressive how quickly ruts have formed in a relatively short period of time from what I assume is a combination of increased traffic and the increased weight.
A typical diesel or natural gas city bus has a curb weight between 20,000 and 33,000 lbs[1]. An electric bus I found lists a curb weight of 28,000 lbs[2]. It doesn't seem like extra road wear is going to be a major issue.
Lowest short term maintenence cost. Until the battery is destroyed in a couple of years.
Charging a fleet of 100 buses overnight looks like a huge infrastructure issue to me. 100 charging ports, huge grid connection, substation etc. That is if the local grid even has capacity. Anyone who has tried to open a factory will know that is not always the case.
EV batteries have been performing much better than dying after just 700 cycles. Also, power is generally cheapest overnight when there is excess grid capacity. People with variable electricity pricing and battery banks make money by charging overnight and releasing power to the grid during peak hours. Commercial vehicles typically get more like 6,000 cycles out of a battery pack.
I think the case for using hydrogen today is pretty weak, but a lot of the details for why it's a bad choice are (as you say) exacerbated by the one-off deploys of the technology. If you were testing gas busses and needed to truck gasoline in just for your busses you would expect the numbers to get worse too.
My view is that if you want a clean alternative today you'd go with electric and also the tech seems worth continuing to develop for other applications. I also think that public transit doesn't seem like it plays to the strengths (such as they are) of hydrogen.
I get the impression they've had similar results in London. They've had ~20 hydrogen busses for a while but apparently are expensive like £500k per bus plus you need to find hydrogen.
On the other hand battery seems to be cracking along: "over 1,600 zero-emission buses currently in service, and TfL aims to have a fully zero-emission bus fleet by 2030, accelerating plans with increased government funding."
Only two years? They operated hydrogen buses from 2006 to 2010 and then got some more in 2011 and 2019. There are budget line items for new buses in 2023 and 2024 that I assume got bought
I'm not going to dispute your numbers with diesel versus EV reliability, but I have to think the simplicity of an EV drivetrain will win that battle in the next version or two.
The reliability speaks to the technology immaturity. I agree with the inevitability of the EV drivetrain + charging off the existing distribution network being more reliable than competing technologies.
idk these sound like very specific problems they had. The chargers had an availability of only 23% because of a recurring issue with the power modules failing. In a later volume they also again attribute a lot of unavailability to the same chargers:
> The BEB fleet operated at 66% availability with more than half of the total days related to retrofit of the charger cabling and programming by the OEM.
I guess you could say this is due to immature technology but honestly I don't see 75% of HPC chargers being offline for maintenance at any given time. This is probably just bad luck with a vendor.
If you look at the road calls the BEB is by far the most reliable one, causing one road call out of 45. It was also the cheapest per mile by a long stretch.
It’s hard to imagine it not. And also kudos and crazy respect for all the thousands of engineers that poured their work into making combustion engines as efficient and reliable as they are. A true marvel of humanity, and something to be respected even as we leave it behind.
Relative to EVs it’s not. But relative to ICE engines from 50 years ago it’s great. EVs are obviously going to take over ICE, my only point is that we shouldn’t discount all the work and ingenuity that went into ICE engines simply because a disruptive technology came about.
Based on personal experience my guess is that the unreliability would be in the battery not the drive train.
Or more precisely put, batteries are a sort of black box they ether work or they don't work but either way you are not going to be able to open one up and find out why. that is, they are a high cost unrepairable item on the vehicle and this is a huge liability.
Batteries aren't unrepairable; you wouldn't open one up in the middle of the road to try fix it but at the bus depot with enough volume of battery electric vehicles, they'll have reason to hire repair technicians that can refurbish and repair batteries.
Obviously anything has a bunch of single points of failure, or catastrophic means of failure, but a battery isn't like "one engine". It's basically hundreds of little power modules wired in parallel, so an individual battery cell loss shouldn't bring down the whole pack.
So a battery pack should actually be heavily redundant ... assuming the pack has enough modules for a loss of vehicle to get to some charging station.
Limerick City in Ireland has electric double decker buses. They are dead quiet and it's a total treat to be a pedestrian without the buses passing by and blowing my ears off.
This is exactly correct. This is Salesforce's 3rd or 4th rebranding of Customer Data Platform, which has never taken off. This latest positioning is targeting Snowflake.
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