dm319

Wasn't there something about Elon trying to sell Twitter stock privately? I think in the financial times. They have probably lost a lot of advertisers, and Elon might be in financial trouble.

> I don't buy into all the freedom of speech rhetoric he has been spewing.

I think what you meant was you didn't buy into it, and this is proving your point of view.

He's gone from freedom of speech absolutionist to defining the limits of freedom of speech by whether you discuss social interactions on other websites.

It isn't as simple as a one-dimensional scale between freedom of speech absolutism and not, and the fact that so many people seem to believe this makes me think that people don't have a basic grasp of ethics, nor an ethical framework to make decisions on.

Even worse, does it apply any ethical principles to the decision making around the limits of freedom of speech? I.e. when you're weighing up whether, say, incitement of violence, or Nazi support are beyond the line of what is acceptable, do you also place 'promoting alternative social media technology' as somewhere near these limits of freedom of speech?

Ok, what do you think of that rule?

I'm curious - I've seen his tweet. Can I ask you:

1. Are you just an advocate for following a website's terms?

2. Or do you think there is credibility in these terms?

Honestly, I care less about 'fixing' something so it is profitable, and more about what ethical compass people are using to make their decisions. A couple months ago it was the free speech absolutionists versus those who felt some form of regulation is needed. Now we seem to be asking "if there are limits to free speech, should discussing other media platforms be part of that?".

This makes me think that we, as a world, are failing at building an ethical framework for people to work by. Why is it that so many of us struggle to evaluate what is ethical and what isn't? It isn't taught at school, except in the context of religion. We all need to understand the principals of autonomy, beneficience, nonmaleficence & justice for starters.

I'm gonna disagree on everything here...

> 1. If you don't encounter any trouble daily driving GNU/Linux, that is actually a sign of inexperience. That or you're doing nothing interesting.

I do loads of interesting stuff on linux, I use it for research, numerical computing, biology etc. None of these things cause linux to skip a beat.

> 2. If principles mattered more than convenience, most Linux users would be on FreeBSD or OpenBSD instead of GNU/Linux. Either follow your arguments to their conclusions, or understand that Windows/macOS users are doing the same thing as you—making practical tradeoffs.

The world is not black and white! There are degrees to which people behave, and there is a spectrum of behaviour that abides by certain principals and doesn't. I had someone say to me recently that they didn't believe there are 'ethical people', instead people make use of the opportunities presented to them. This isn't true and is more a sign of how they've justified their own life choices.

> 3. Unless you are doing tons of system administration on your daily driver, most of your time is spent in applications, and the choice of operating system doesn't matter too much.

I, like many people, tend to use more than one application, so I find the OS does matter. On Windows 10, when I hit the start bar, and start typing the name of an application I want to launch, I really do care when the bar sits there loading up, scraping internet data to show me its suggested apps and adverts.

Yes, I remember, even up until very recently, having to google help on Windows. You'd get webpages full of adverts with a heading '12 ways to fix Win10 freezing during upgrade bug!'. And the first two would be something like 'switch it off and on again', 'try again', 'reconnect to your wifi'.

I always felt I could dive deeper with linux problems _if I wanted to_, and that weirdly gives me some confidence that I can fix it.

I think it makes more sense to give figures for consumption rather than distance/energy, as we're usually more interested in how much fuel it will cost us to travel a certain distance. Bit like going into a sweet shop and having all the sweet's price as "100 per dollar" or "35 per dollar" etc..

It also helps to compare costs, as 20mpg is far less efficient to 30pmg than 30mpg is to 40mpg, but the numbers suggest the difference is similar.

Fascinating read, wasn't aware of this history of python. I thought the line about the fear of not having a copyright statement for ABC was interesting - and applies to many aspects of life in general where setting things free is the right thing to do but also scary.

The combination of wind farms, solar and large energy storage has huge potential for the UK.

A reduction in 'pitting people against each other', could paradoxically allow for civil disagreement because of decreased polarisation. I.e. if I go on a platform and I expect strong/aggressive disagreement as my engagement, I am more likely to counter argue. If I'm on a platform where views are more moderate, I am more likely to carefully consider a different viewpoint.

I agree there are risks of bubbles though.

And you were right. I suspect bigots. I miss slashdot's reasons for up/down voting.

I'm all over the place with pocket computing devices and remain confused. I once has an iphone. Beautifully crafted, both inside and out, but so frustratingly locked down that I was desperate to leave it behind. They have progressively opened up the platform, but it always lags behind (I remember I couldn't access the cloud storage from anything other than a mac).

My favourite devices have been more alternative. E90 running symbian, which was fairly 'open' for its time - I could install any software, proper multitasking. The N900 also, full linux system, great phone. But then the apps I find useful, are often not available for that platform.

At the moment I'm on Pixel, which has been a good balance between being well supported, while still fairly open. I can sideload apps, run a linux distro in the form of termux. As a bonus the camera is great. I have to remind myself that while it might not quite compare to iphones in terms of refinement and hardware, I do at least have more freedom on the platform, and it's easy to take that for granted until you lose it.

When I was younger I used to believe when people talked about how amazing certain items or experiences were. They were often very expensive, or very hard to get to. I used to believe that they really were such a unique and special experience and that was why people would go to the trouble and expense of having it.

Being older now, I see that the real value in the item or experience was being able to tell me about it. So many things fall into this category, if not completely, at least partially.

I don't see myself going to the effort/expense of having authentic truffles. It's just a very particular mild taste. I think I can do without it.

For older patients and those with significant co-morbidities, we often advise against intubation and ICU admission in the UK. Usually if the disease process can't be reversed on the ward with current therapy, it is often unlikely in this group of patients for it to reverse on ICU. However, it does depend on the context. There was an interesting article that talks about doctor's choices as an end-of-life patient [1] - they often choose not to opt for aggressive life-prolonging treatments because they know how it is like. I think that doctors need to improve the way we talk about death with patients, and doctors can be just as guilty as everyone else at ignoring the inevitability of death.

[1] https://www.zocalopublicsquare.org/2011/11/30/how-doctors-di...

That's weird, the E90 was the last phone I had with reliable phone features. The N900 could be buggy, but I've had iphones and pixels since then and I give answering a phone that is ringing in my pocket to be very often a miss, even now. More an issue with a touchscreen I think.

I think there is more information than that. There are 20 amino acids, so around 1x10^13 possible sequences.

This is also a clue as to why we don't have a perfectly rigid system, as a library of T cells capable of recognising every combination would weigh 600+ kg.

When I got my Nokia E90 in 2007ish, it's hard to describe the power and potential in that device. It was multitasking, 3G, GPS, camera, video, email, web, app store etc. The big downfall of these devices was that consumers weren't familiar with the types of mobile contracts, and specifically data. The iphone got it right by only selling the iphone with a data package, whereas people bought these symbian smartphone and later found they couldn't make full use of them. Not to mention back then we had to set up the internet connection ourselves.

I moved onto the N900 when my E90 slipped out my linen trousers in a taxi in Morocco.

Are those the shortcuts for it? I can't believe I didn't realise vim had this.

Yes, I didn't mean impossible, I just mean compared to accumulating new mutations elsewhere, and compared to downregulating surface proteins (which can be the issue in CAR-T).

Yes good point.

Yes you are right, I should have said that re-mutation of mutations happen far less often than accumulation of additional mutations.

Novel epitopes should be high copy number - and driver mutations will be present in 80-100% of the cancer cells. It depends how many cancer cells you get in your biopsy that you sequence I guess.

It is easier for a cancer cell to mutate or remove a cell surface protein than to mutate the same mutation targeted, but you are right - that can happen and I'm sure will be a form of treatment resistance for these types of treatment in the future.

Yes, CAR-Ts are really a B cell receptor (otherwise known as an antibody) grafted onto a T cell. Antibody directly binds things like proteins, and usually targeted to things found on cell membranes.

Also on the cell membrane is MHC-1, which shows a short (9-11 amino acid) fragment of protein produced from inside the cell. Our T cells are trained in our T cell kindergarten (the thymus) to not identify our usual self proteins, but detects anything different. They have already been demonstrated to identify single amino acid changes from normal.

Yes, the micro-environment means the immune cells reach a dynamic equibrium. This is because when a cancer presents to healthcare, it is already a chronic process. The T cells are termed 'exhausted', but it's debatable whether this is a good term for it, because they are still active.

A lot of cancer treatment 'shakes up' the microenvironment. This can be enough to tip into a cure. When you make CAR-Ts and adoptive TILS you either pick healthy T cells not involved in the cancer or buff them up in the lab, both in numbers and health.

The hope is that a refreshed army of T cells will push that dynamic equilibrium towards a cure.

I'm a haematologist who is involved with patients who have CAR-T (I don't do it myself, but do other types of transplant and I look after the patients before and after) and my research area is in the way T cells target cancer.

This study isn't CAR-T. It is more similar to adoptive TIL therapy because it is using the T cell receptor (TCR) to target the cancer's mutations. This has a huge advantage over CAR-T.

At the moment we use CAR-T to target, mostly, B cell cancers. These cancers have CD19 and CD20 on their cell surface, as do most B cells. We can safely target these cells because it turns out your B cells aren't critical for life. Think of it like an amputation. Your B cells went rogue, you wipe them out.

The problem is this doesn't translate to other cancers, which don't have an obvious cell protein you can target specific to a group of cells you can do without.

All cancer cells have mutations, and all cells in the human body have to display a sample of its proteins on its cell surface. This way our immune system regularly identifies cancer and removes it. Cancers that get established have somehow leveraged local immunosuppression to hold off the immune system, and so the immune system and cancer become a stalemate, or worse the cancer takes off and kills the person.

If we can target the mutations of the cancer, then we can get at the heart of the cancer itself.

You might ask why the cancer just doesn't display it's antigens on the surface. If a cell does this it gets removed by NK cells (natural killers) - our body's fail safe.

What I find interesting is that I didn't think we were close to predicting what TCRs can bind to to a peptide on MHC on the cell surface. I'm going to need to look at the article to findout how they did this. I suspect they used a library of known TCR-antigen interactions.

OP is talking about CAR-T therapy which is in routine clinical practice. In the UK costs have gone from £600k to around £250K That includes the surrounding medical, nursing and follow up care. In the US costs are likely to be more than that.

The article is talking about a very bespoke process where they take a patient's cancer, sequence the whole thing, select mutations they think will be presented on MHC-1, predict the antigens visible, and 'somehow' (I need to read the article more carefully to figure out how they did this) select a TCR sequence which will bind to that. Then they use CRISPR to graft that onto the TCR gene of a T cell from the patient (3 types by the looks of it), and re-infuse the targeted cells.

So yes, that would cost several million.

This is an ongoing discussion in CAR-T. At the moment we only have 'autologous' CAR-T, which means they are manufactured from our own cells. The big advantage to 'allogeneic' CAR-T is that we don't have to take the time (several weeks) to modify T cells for adminstration, during which patients can die of the disease. 'Off the shelf' would be preferable, but there are lots of problems with trying to use someone else's T cells for the job.

The main issue is that our immune system is very good at removing non-self, so a lot of work would need to go into stopping the immune system doing this.

The article isn't talking about CAR-T though, rather TCR-modified T cells. These are very patient-specific because we have a unique MHC signature (this is why we have to find a 'match' for a transplant recipient). Previously people have taken the T cells from the tumour site, boosted them in the lab, and re-infused with some remarkable and curative results. The outcomes in this trial weren't so great but it is novel to splice in a new TCR.

I haven't seen evidence of cancers re-mutating mutations. They tend to develop new mutations (as in the clonal evolution hypothesis), and they can completely change their cell surface expression. But I suspect that they are unlikely to mutate an already mutated gene.

I guess for the treatment to be most effective you need to target some of the earlier mutations, rather than a small clone.

From my perspective, and not having read the paper, I thought the technology to predict what TCR would bind a particular peptide on a particular MHC-1 was not there yet.

Your CD4 T cells are basically the directors of your immune system. They license CD8 T cells (T killer cells), B cells and recruit NK and immune cells to sites. The type thought to be most anti-cancer are the Th1, which recruit CD8 T cells and NKs, and are optimised for intracellular pathogens. Cancer can be thought of as an intracellular pathogen because it harbors mutations.