Antibiotic Breakthrough Ends 25-Year Discovery Drought - <AUTHOR> http://www.bloomberg.com/news/2015-01-07/antibiotic-breakthrough-ends-25-year-discovery-drought.html <comment><USER2> I think the real meat of this article is here:

"...strikes multiple targets, including cell walls...Since the lipid structures it attacks don't evolve as quickly as frequently mutating proteins, it may take the bacteria longer than usual to develop a survival tactic."

Proteins change often and quickly, but basic cell structures may take longer or never adapt.

But I'm not a pathobiologist, I just play one on the Internet

<comment><USER3> So do the β-Lactam antibiotics (e.g. penicillin), but that doesn't stop a host of unrelated resistance mechanisms: enzymes that directly attack it, mutations to the protein(s) that are necessary for entry into the bacteria, and probably the pumps that actively remove various antibiotics.

Given that this was discovered from existing bacteria, there's a significant chance nature has already done the first and last of those. The middle mechanism is likely possible for any bacteria, if you have enough to start with (there's nothing I could find with Google in a minute to describe teixobactin's transport mechanism).

In general there was a rule of thumb when I was doing microbiology of this exact nature (an antibiotic created by some strains of _E. Coli_ ), if you exposed a million bacteria cells to a generic antibiotic, 1 would would survive due to a mutation (a useful number in microbiology, likely dead meat in the body). Streptomycin was more effective, 1 in a billion.

ADDED: it's implied by the _Nature_ abstract that the researchers have tried this general approach, that they were not able to find spontaneous resistance mutations in a couple of the standard nasties. But extending on the above thesis, ecologically, there's a respectable chance some bacteria out there have developed defenses. It's a jungle out there, and e.g. in your gut, that's why fungi and bacteria developed antibiotics in the first place. They aren't expending resources just to allow us to kill the inconvenient ones.

<comment><USER4> From the Nature article, the claim that resistance to teixobactin is hard is based on an attempt by the authors to induce resistance by culturing _S. aureus_ or _M. tuberculosis_ in the presence of sub-lethal concentrations of teixobactin for 27 days and seeing if resistant clones evolved. They did not observe any. That doesn't mean it's impossible, though. Plasmids for example are a source of resistance that doesn't require mutations.

Edit: deleted incorrect information about b-lactamase.

<comment><USER3> [ Deleted β-Lactam stuff. ]

 _Nature_ asked me for $$$ to read the article, so ... from your description, that's leaving out the hard, fast test of just culturing several billion of those, adding a lethal concentration and seeing if there are any survivors. Which is how I gather one found spontaneous transport mutations, at least circa 1977. The state of the art has likely improved, and these guys used novel microbiological methods to find the bacteria that produce teixobactin in the first place.

ADDED: thanks to betatim's link to the full text, I've skimmed it and read the discussion, and teixobactin sound quite promising. They haven't found any protein to which it binds, and they think it binds to an "Achilles's heel" in the outer cell wall. The method described to generate resistance was their most extreme attempt, so I assume they tried the fast way, and I can see why it didn't work.

Ecologically, they believe there's little gene (e.g. plasmid) transfer between these soil bacteria and human pathogens, and the "30 year" bit came from experience with vancomycin, to which it has a lot of similarity. And they've done lots of tests for human toxicity and effectiveness in mammals. It's still early in the process, but a degree of fuss is warranted, especially due to their discovery method.

<comment><USER4> Here are the pertinent bits regarding resistance, in summary it implies that _spontaneous_ resistance will be difficult, But... "life has a way":

>We were unable to obtain mutants of S. aureus or M. tuberculosis resistant to teixobactin even when plating on media with a low dose (4 X MIC [minimal inhibitory concentration]) of the compound. Serial passage of S.aureus in the presence of sub-MIC levels of teixobactin over a period of 27 days failed to produce resistant mutants as well (Fig. 2d, Supplementary Discussion)

From the Supplementary information:

>Cells were added to teixobactin present at 0.25xMIC, 0.5xMIC,1xMIC,2xMIC and 224xMIC. At 24 hour intervals, the cultures were checked for growth. Cultures from the second highest concentrations that allowed growth (OD600≥2) were diluted 1:100 into fresh media containing 0.25xMIC, 0.5xMIC,1xMIC,2xMIC and 4xMIC of teixobactin. This serial passaging was repeated daily for 30 days. Any cultures that grew at higher than the MIC levels were passaged on drug free MHA plates and the MIC was then determined by broth microdilution. No resistant mutants were obtained. This experiment was repeated, and produced the same negative result. In order to maximize the chance of obtaining a resistant mutant, we performed an additional experiment with very small incremental increases in the drug concentration. Cells were added to a series of tubes with small differences in the concentration of teixobactin (0.06xMIC, 0.25xMIC, 0.5xMIC, 0.75xMIC,1xMIC, 1.25xMIC, 1.5xMIC, and 2xMIC). At 24 hour intervals, cultures from the highest concentration that allowed growth to a minimum OD600 of 0.2 were diluted 1:100 into fresh medium containing 0.06xMIC, 0.25xMIC, 0.5xMIC, 0.75xMIC,351xMIC, 1.25xMIC, 1.5xMIC, and 2xMIC. This passaging was repeated for 27 days. Cultures that grew at levels higher than the MIC were passaged on drug free MHA plates, and the MIC was determined. For teixobactin, there were no mutants with an MIC greater than the parent S. aureus ATCC 29213.

<comment><USER5> What they're describing here is an _intensive_ selection process for resistance. It's debatably much more intensive than nature would ever perform: they're growing bacteria in the presence of various dilutions of the antibiotic, taking a sample of the culture, diluting it 100-fold, and repeating the selection many (~30) times. Then they look for any bugs that develop resistance. None were found. Even if you had a truly pathological patient (i.e. someone who was doing his level best to mis-use an antibiotic), it wouldn't come close to this level of selective pressure for antibiotic resistance.

Moreover, there's a strong biochemical argument against resistance: the region that the antibiotic targets is highly conserved, which means that it's probably functionally necessary. The bug is therefore unlikely to evolve away from the threat. This is important, because it's that most likely avenue for antibiotic resistance, energetically speaking: it doesn't cost anything for an organism to mutate a weakly conserved gene, so they do it once, and pass it on to every subsequent generation with no penalty.

The antibiotic is just a peptide, so _in theory_ you could see some sort of specialized peptidase evolve from an existing gene...but the problem is that the bug would have to then carry around that gene and _express it constantly_ (or even less likely: evolve a sensing system that allows for selective expression). It's a highly unlikely thing, and virtually impossible to maintain over multiple generations without constant selective pressure. Bacteria do not like to hold on to genes that they don't need.

Nothing is impossible over evolutionary time, of course, but the researchers don't seem to be overstating their case here.

<comment><USER6> Removed anthropomorphising:

It's a highly unlikely thing, and virtually impossible to maintain over multiple generations without constant selective pressure. Bacteria are quickly out-competed by genetic variants with fewer expressing genes that they don't need.

BTW: do you have any links/data re the relative 'cost' of expressing unneeded genes?

<comment><USER7> "Bacteria are quickly out-competed by genetic variants with fewer expressing genes that they don't need." This has not been true for MRSA, where transmission of resistant organisms in the community was sustained despite there not being particularly intense selective pressure in the community. Last I checked (I don't work in community transmission as much) we don't have a firm handle on why that's true, but I'd caution against simply assuming that resistant organisms will be out competed absent selective pressure.

Beyond that, even if they _are_ out competed, that's not sufficient. They need to be out competed to extinction.

<comment><USER5> MRSA is due to the _mecA_ gene, which is integrated into the _S. Aureus_ genome. It's not plasmid-mediated resistance, which means that it's less likely to disappear from bacterial populations, even in the absence of selective pressure:

[http://www.eurekaselect.com/68849/article](http://www.eurekaselect.com/68849/article)

<comment><USER7> True - but the post I was responding to wasn't talking about plasmid-mediated resistance, but rather a broad assertion that a competitive disadvantage will take care of things. That's a strong assumption for which we have a counter example.

</comment></comment></comment></comment></comment></comment></comment></comment></comment></comment><comment><USER8> Full text for free: [http://rdcu.be/bVbR](http://rdcu.be/bVbR)

This is a link to nature's new "share it for everyone to read if you have paid access to the article" version of 'open-access'.

A new antibiotic kills pathogens without detectable resistance, Nature, January, 2015. DOI: 10.1038/nature14098

</comment><comment><USER9> They author's state "it should be used, if it gets successfully developed, as broadly as possible" \- because they believe it is robust against bacteria developing resistance.

Knowing nothing about this area... isn't this a bad idea because board use would increase the risk of resistance appearing and would mean those bacteria resistant to this would be extremely resistant to most other treatments aw well (given this drug has multiple modes of attack)?

<comment><USER10> Apparently they have a very plausible reason to think it will be robust: It attacks cell walls, which are structural, rather than receptors (I think I'm using the term correctly) that are proteins and prone to mutations.

It's basically the same reason we don't fear bacteria to develop resistance to boiling or alcohol disinfectant.

<comment><USER11> I tempted to write "What could go wrong?" or "Life finds a way.".

A fast Google search gives this paper: " Relatively Alcohol-Resistant Mycobacteria Are Emerging Pathogens in Patients Receiving Acupuncture Treatment" [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC140401/](http://www.ncbi.nlm.nih.gov/pmc/articles/PMC140401/)

There are some archeas (and a few bacterias) that support boiling temperature, but IIRC they don't like meatware because it's too cold for them. [http://en.wikipedia.org/wiki/Hyperthermophile](http://en.wikipedia.org/wiki/Hyperthermophile)

<comment><USER12> > I tempted to write "What could go wrong?" or "Life finds a way.".

My thoughts exactly. Try using it in large scale animal farms for a couple decades and I'm betting something will become resistant.

<comment><USER13> I thought some bacteria had developed double walls with an insulating fluid, so that they could expunge bad chemicals.

</comment></comment></comment></comment></comment><comment><USER14> The nytimes article mentions:

"The research was paid for by the National Institutes of Health and the German government (some co-authors work at the University of Bonn). Northeastern University holds a patent on the method of producing drugs and licensed the patent to a private company, NovoBiotic Pharmaceuticals, in Cambridge, Mass., which owns the rights to any compounds produced. Dr. Lewis is a paid consultant to the company."

If the research was paid for by the National Institutes of Health, why is the patent privately owned? This does not seem fair to taxpayers.

<comment><USER15> This is not only allowed, it's encouraged by legislation called the Bayh-Dole Act. The general thought is that there would be no incentive for anyone to do clinical trials on the drug, which can get quite expensive, if they don't have some protection for exclusive use. Many, if not most drugs proceed starting from academic research funded by governmental support.

<comment><USER14> Thanks for the informative response! Do you know how expensive clinical trials would be for this kind of drug?

<comment><USER15> $100M-500M gets thrown around [1] but it's hard to find good data. This might seem not too high, but many drugs fail, and often fail at the most costly step (phase III). So you have to be sure to factor that failure rate in.

[1] [http://www.manhattan-institute.org/html/fda_05.htm](http://www.manhattan- institute.org/html/fda_05.htm)

</comment></comment></comment></comment><comment><USER16> The _Nature_ publication seems to be open access:

[http://www.nature.com/nature/journal/vaop/ncurrent/full/natu...](http://www.nature.com/nature/journal/vaop/ncurrent/full/nature14098.html)

 _The Scientist_ has quite a nice write up:

[http://www.the- scientist.com/?articles.view/articleNo/41850/...](http://www.the- scientist.com/?articles.view/articleNo/41850/title/New-Antibiotic-from-Soil- Bacteria/)

Details on the cell culture device (open access):

[http://aem.asm.org/content/76/8/2445.full.pdf+html](http://aem.asm.org/content/76/8/2445.full.pdf+html)

<comment><USER4> That device is a smart and clever approach! It will undoubtedly get used for many other applications.

</comment></comment><comment><USER17> While there are new strains this would be a new class WHICH means AWESOME if it works out. Since this is so early I am not hoping for much.

My son had cancer and he had a staph infection that was septic (AKA in his blood through out his body). Non-resistant = 95% cure rate resistant strain and if you have a compromised immune system less then 50% cure rate. Good news for cancer patients and glad to see it coming down the track.

<comment><USER18> I had a friend die from a lung infection from a compromised immune system because of leukemia.

Very glad to hear your son made it, and I echo your sentiment.

</comment></comment><comment><USER19> This is a bit of an odd article. The FDA has approved a number of different antibiotics over the past year. Most are not new mechanisms of action, but they are new products that have different profiles against different resistant bacteria.

The other issue is that this is _very_ early in development. I really hope it gets through trials, but there are graveyards full of promising antibiotics that failed.

<comment><USER17> This in fact would be a different class. So it is a HUGE deal.

<comment><USER19> There are a _number_ of different antibiotic class currently in development (in clinical trials already). This certainly isn't the "end of a drought".

<comment><USER17> There has been exactly 2 new classes since 1962. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3085877/](http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3085877/)

Now if this actually works then yes great, and I hope it does.

<comment><USER19> I think the reliance on new classes is a bit excessive. There are numerous new beta-lactams that have come out that are still in the same class, but have overcome (some of) the resistance issues.

A new class would be great, but even different drugs from the same class would be great as well.

</comment></comment></comment></comment></comment><comment><USER20> Their experimental approach was interesting and hopefully will lead to more discoveries. I feel like this drug is already being overhyped however. It doesn't work for gram negative bacteria, which are responsible for most of the serious and scary multi drug resistant infections.

Also, assuming it doesn't have weird toxicity in people, or unfavourable pharmacokinetics, the author's suggestion that we should give it to everyone is a bit cute, given that it will almost certainly cost north of $200 per day if it gets to market...

Peptide antibiotics can have some issues. A recent new peptide antibiotic called Daptomycin [1] can't be used for pneumonia for example, because it is inhibited by pulmonary surfactant.

[1] [http://en.m.wikipedia.org/wiki/Daptomycin](http://en.m.wikipedia.org/wiki/Daptomycin)

<comment><USER21> Is $200/day a lot for a highly effective antibiotic?

Genuine question--my experience is that a serious hospital stay racks up charges starting in the high five figures (and the sky's the limit), and if there's an antibiotic that's merely a couple thousand a day, it'd certainly be very cost effective.

<comment><USER22> > my experience is that a serious hospital stay racks up charges starting in > the high five figures (and the sky's the limit)

This is USA specific. Day in hospital in Poland costs around 100-400 USD (and that's for people without insurance, so for >95% of population it's free). It's probably worse quality, but still..

I don't understand how you get so outrageus prices for healthcare in USA.

</comment></comment></comment><comment><USER23> When they made roundup they expected plants would never be able to be resistant to it[1].

And in fact plants did not become resistant in the way they expected. Trouble is plants found a completely different way to resist roundup that no one expected.

Their claim that bacteria would not become resistant to this antibiotic is rubbish. They do have the ability to determine that.

If they actually want to know then deliberately try to (carefully) create resistant bacteria by continuously giving them low levels of antibiotic and slowly increasing it.

[1] [http://www.npr.org/blogs/thesalt/2012/03/11/148290731/why- mo...](http://www.npr.org/blogs/thesalt/2012/03/11/148290731/why-monsanto- thought-weeds-would-never-defeat-roundup)

<comment><USER24> > If they actually want to know then deliberately try to (carefully) create > resistant bacteria by continuously giving them low levels of antibiotic and > slowly increasing it.

That's precisely what they did while investigating teixobactin, and they didn't see any resistance develop:

[https://news.ycombinator.com/item?id=8853232](https://news.ycombinator.com/item?id=8853232)

<comment><USER23> That's quite impressive!

Was there a control? i.e. same procedure, but with a different antibiotic?

<comment><USER25> Yes. They used ofloxacin as a control. Figure 2d in the paper.

Kim Lewis, the senior author on this publication, is one of the world's foremost experts on antibiotic resistance. This isn't amateur hour.

</comment></comment></comment></comment><comment><USER26> All of the comments are by armchair biologists about how the scientists are wrong and all bacteria strains will become resistant to it in 2 days.

But anyways, if it is an issue, why can't we just require antibiotics be taken intravenously? The vast majority of bacteria exposed to antibiotics are in your digestive system and that is where resistance develops. Or at least that's how I understand it.

<comment><USER27> IV antibiotics generally mean hospital, which generally means severe life- threatening infection. Outpatient IV antibiotics are done but it's complicated and carry further risk of infection through having a line in situ for long periods of time.

IV antibiotics do have an effect on gut bacteria as well, it's not as simple as just not giving oral; additionally (and, perhaps the crux of the issue) is that gut bacteria exposure to antibiotics is not how resistance develops; and certainly aren't the main problem. It is the more common infective agents that cause the problems - Gram positive organisms (Strep Viridians, Staph Aureus etc) that usually enter from cuts or abscesses and, in the immunocompromised, cause significant disability.

<comment><USER26> >IV antibiotics do have an effect on gut bacteria as well, it's not as simple as just not giving oral;

How so? And more importantly how much antibiotics make it to the gut, vs if you take it orally? I would guess it would be a lot less.

>It is the more common infective agents that cause the problems

I know that, but as I understand it the resistance first evolves in gut bacteria, then spreads through horizontal gene transfer. Wikipedia cites this as the main cause of antibiotic resistance: [https://en.wikipedia.org/wiki/Horizontal_gene_transfer](https://en.wikipedia.org/wiki/Horizontal_gene_transfer)

<comment><USER27> > How so? And more importantly how much antibiotics make it to the gut, vs if > you take it orally? I would guess it would be a lot less.

I have no idea what figure or percentage it would be, but for most common antibiotics which end up distributed in total body water, there will be a component that leaks into the gut through capillary action; if it is metabolised in the liver then a proportion of it will end up in bile (if fat soluble) and then enter the gut that way; either itself or a metabolite of it - it would be impossible for me to quantify and likely depends on many many factors such as molecular weight, structure and a host of other features.

Patients on IV antibiotics develop diarrhoea from IV antibiotics at a similar rate (from what I have experienced) to those on orals. hence it undoubtedly kills bacteria in a similar fashion.

And we use IV antibiotics to kill bad infections of the gut. So whatever the mechanism, if I have elucidated it or simply done some hand-waving, it clearly affects it significantly.

The only instance of antibiotic use that touches on what I feel you are pushing for is the use of oral vancomycin (It is almost always IV) for severe bacterial infections of the gut - we use it oral because it is not absorbed systemically (as opposed to other specifically oral antibiotics) so doesn't cause systemic effects.

> then spreads through horizontal gene transfer.

Sure. But if you look at how they tested this particular antibiotic for the ability to develop resistance, they exposed TB and Staph to sub-theraputic doses for 27 days, or (for Staph) or 810generations (assuming a rough rate of division somewhere around 40 min to 1 hr in ideal conditions). An epic number of cell divisions if you work it out (and I can't).

The commonly accepted knowledge, as far as I understand it and as far as I have been taught it, whether or not bowel bacteria have a significant role to play or not, is that exposure of antibiotics to sub-lethal doses for long periods of time promote the survival of strains that have a competitive advantage against the agent in use, which over time allows the strain to survive in otherwise-lethal doses, and that gene becomes incorporated into a plasmid and then ends up spreading to every other organism capable of horizontal gene transfer.

Anyway, I am at home and not going to see the next MD, PhD in Infectious Diseases until tomorrow but when I do I will ask him and reply here. So, check back in 24 hours if you're interested

<comment><USER27> On the off-chance that you read this I apologise for not delivering, I wasn't able to speak to ID but will on Monday so if this thread is locked by then then shoot me an email

<comment><USER26> It's fine you don't have to. The responses to my question were phenomenal.

</comment></comment></comment></comment></comment></comment><comment><USER28> > "It should be used, if it gets successfully developed, as broadly as > possible, because it is exceptionally well-protected from resistance > development," said Kim Lewis, one of the study's authors and a professor at > Northeastern University in Boston. Lewis estimated that it may take more > than 30 years for bacteria to become resistant to teixobactin. He is also a > co-founder of NovoBiotic Pharmaceuticals LLC, which is developing the drug.

I'd much rather get two or three more that all use different mechanisms, and use them as a cocktail.

Let the bugs try to develop 3 different kinds of resistance at once.

<comment><USER7> Multiple antibiotics often carry fairly serious medical risks. "Cured of your infection" is somewhat less heartening when we boxed your kidneys doing it.

</comment></comment><comment><USER29> Can anyone clarify the core causes of antibiotic resistance over the last several decades?

I've _heard_ the following causes, but I cannot substantiate them:

[1] Improper patient usage. Primarily, not taking the prescribed dosage long enough to eradicate all of the target bacterium, leaving (enough) survivors to meaningfully propagate their resistance. Typical to the "Hey I think my sinus infection is gone already! Adios remaining pills."

[2] Improper targeting. A functional antibiotic used on the wrong type of bacterium, or even usage against viruses.

Are there any others? Are my [1] and [2] debunked?

<comment><USER7> 1\. This is a major problem - patients start feeling better and discontinue therapy, which promotes resistance, save partially consumed prescriptions for "if this happens again", etc.

2\. This is also a thing - broad spectrum antibiotics, difficulty in diagnosing, patients wanting _something_ even if their infections are viral, etc. all lead to mistargeting of antibiotics for a number of reasons. Antimicrobial stewardship has become a major part of hospital infection control.

3\. The widespread use of antibiotics in livestock. The agricultural use of antibiotics is _staggering_

<comment><USER30> "patients wanting something even if their infections are viral"

What the market needs is a placebo anti-biotic. One thats totally wasted by resistance so it won't hurt anything, and is reasonably cheap. Give it some nasty digestive system "effects" as a special gift to patients dumb enough to demand a pill against medical advice. Something that is, in fact, an antibiotic, so when they go home and look it up on wikipedia they don't freak out when they find out what a sucrose pill is. Maybe a homeopathic dose of it, so counter-reactions are rare and minimal.

<comment><USER31> "First, do no harm" is somewhat incompatible with dumb, demanding patients, unfortunately.

<comment><USER7> Medical ethics are also very patient focused - it's hard to deal with situations that are good for _this patient_ but bad for _hypothetical future patients_.

</comment></comment></comment></comment></comment><comment><USER32> The mention of the "25 year discovery drought" made me think about this documentary I saw once about bacteriophages ("viruses that infect and replicate within bacteria") [1].

I don't remember the specific documentary but here is a wikipedia link [2] "Although extensively used and developed mainly in former Soviet Union countries circa 1920, the treatment is not approved in countries other than Russia and Georgia."

1: [http://en.wikipedia.org/wiki/Bacteriophage](http://en.wikipedia.org/wiki/Bacteriophage)

2: [http://en.wikipedia.org/wiki/Phage_therapy](http://en.wikipedia.org/wiki/Phage_therapy)

</comment><comment><USER33> I think we'll be seeing more research like this in the future, where we develop drugs by mimicking nature instead of starting from scratch in the lab. Nature has had a few millions of years more to build and test things.

<comment><USER34> Nature (at least in terms of natural antibiotic sources like fungi and bacteria) also has a relatively quick turnaround in terms of adaptation.

Ultimately, developing antibiotics is a cat-and-mouse game, and eventually nanotech will render it archaic, but in the mean time the more we can do to be responsive and quick to adjust, the better, and that means new antibiotics.

I do worry about this "30 year projection" and what that's based on. Is that a historical norm?

<comment><USER33> I think nanotech will bring about it's own problems.

What we should be doing is addressing the cause of antibiotic resistance in the first place, namely the overprescription of antibiotics, and their improper use in industrial farming.

<comment><USER34> The over-prescription of antibiotics isn't the cause of antibiotic resistance, it's the cause of accelerated antibiotic resistance.

Which for all practical purposes might be the same thing, if we're talking 80 years versus 30 years for propagation of resistance.

Nanotech will be a very, very arduous and slow process. "Its own problems" is putting it lightly. People will die due to nanotech approaches to anti- pathogenics, no question about it. We're talking about programmable biology, something will go wrong.

The biggest problem is what happens when we've eliminated human pathogens? What happens when we've extended the average life expectancy by 10 years - after all, many cancers are caused by pathogens. What happens to the ecosystem when herpesviridae is effectively gone? What are the side effects, the unintended consequences?

</comment></comment></comment></comment><comment><USER35> A very interesting submission about the big medical news story of the day. The news suggests that we can all enjoy significant gains in finding effective treatments for dangerous infections. The era of antibiotics is probably not over yet, by a long way.

As noted in another comment, the underlying _Nature_ article is up on the World Wide Web, [after edit:] and now shared to all of us by a subscriber who posted a subscriber's-sharing link in this thread.[1] I searched for some other news stories about this preliminary research finding to link to others based on independent reporting as well as the authors' press release and the _Nature_ article. I found a story in _Financial Times_ [2] reporting, "Teixobactin quickly kills Gram-positive bacteria, which are prominent in discussions of antibiotic resistance, including _Clostridium difficile,_ _Mycobacterium tuberculosis_ and _Staphylococcus aureus._

"Neil Woodford, head of the antimicrobial resistance unit at Public Health England, commented:

"'The rise in antibiotic resistance is a threat to modern healthcare as we know it, so this discovery could potentially help to bridge the ever increasing gap between infections and the medicines we have available to treat them.'

"But Prof Woodford added: 'Although it is a step forward, this new discovery would not be suitable for treating infections caused by _E. coli,_ _Klebsiella_ or other Gram-negative bacteria.'"

The _Washington Post_ reports,[3] "But all good things must eventually come to an end.

"'They didn't find resistance in a couple of simple tests, so it won't happen in a minute, but there is no compound on this planet that bacteria will not develop resistance to,' Said Richard Novick, an NYU Langone Medical Center professor who wasn't involved in the study. 'But it would certainly happen more slowly with this one.'

"And unfortunately, the drug's genius mechanism is also its biggest flaw. It can only target so-called gram-positive bacteria, like staph, strep, and TB, because they're unprotected once their cell wall starts to break down. Gram- negative bacteria like _E. coli_ and the organisms that cause many sexually transmitted infections have an outer membrane that Teixobactin can't penetrate. That's probably a safety mechanism built-in by the gram-negative bacteria that created Teixobactin in the first place."

That expert also comments that he would strictly limit application of this antibiotic at first to hospital settings, and that would be my policy recommendation too, to reduce the chance of producing selection pressure for resistant strains of bacteria. But this does look like it could be a big advance in clinical treatment of gram-positive bacterial infections resistant to other antibiotics.

The reporting in _The Scientist_ ,[4] already linked by an earlier participant, includes a comment on the laboratory technique used to find the microorganism that produces this new antibiotic: "'This is a very clever technique,' added Robert Austin, a physicist at Princeton University who studies the evolution of microbes and was not involved in the current study. 'The bacteriology community needs to get away from culturing bacteria on agar plates, because this will not lead to new antibiotics.'" That's a familiar principle in science: look in a new place, and make new discoveries.

The reporting in _The Guardian_ [5] picks up on that idea in the words of another expert: "'What most excites me is the tantalising prospect that this discovery is just the tip of the iceberg,' said Mark Woolhouse, professor of infectious disease epidemiology at the University of Edinburgh. 'It may be that we will find more, perhaps many more, antibiotics using these latest techniques.'"

It's very likely that there are more antibiotics yet to be discovered, because all microorganisms live in a world full of other microorganisms, and haphazard adaptation to that environment must have produced selection pressure for many microorganisms to produce natural chemicals ("antibiotics") that kill off other kinds of microorganisms. Putting those chemicals into human bodies applies human knowledge to take advantage of the variety of life that has arisen from evolution.

[1] [http://rdcu.be/bVbR](http://rdcu.be/bVbR)

"A new antibiotic kills pathogens without detectable resistance" [http://www.nature.com/nature/journal/vaop/ncurrent/full/natu...](http://www.nature.com/nature/journal/vaop/ncurrent/full/nature14098.html)

DOI: 10.1038/nature14098

[2] [http://www.ft.com/intl/cms/s/0/701a3c36-95be-11e4-a390-00144...](http://www.ft.com/intl/cms/s/0/701a3c36-95be-11e4-a390-00144feabdc0.html#axzz3OAXfp1y4)

[3] [http://www.washingtonpost.com/news/speaking-of- science/wp/20...](http://www.washingtonpost.com/news/speaking-of- science/wp/2015/01/07/new-class-of-antibiotic-found-in-dirt-could-prove- resistant-to-resistance/)

[4] [http://www.the- scientist.com/?articles.view/articleNo/41850/...](http://www.the- scientist.com/?articles.view/articleNo/41850/title/New-Antibiotic-from-Soil- Bacteria/)

[5] [http://www.theguardian.com/science/2015/jan/07/antibiotic- dr...](http://www.theguardian.com/science/2015/jan/07/antibiotic-drug- resistance-teixobactin)

</comment><comment><USER36> I'm skeptical that this is a good thing given how the profit motive motivates people to "externalize" side effects; Environmental damage from antibacterial soaps, disrupting natural biological processes, disease-resistant bacteria, are a few effects.

> Scientists have discovered an antibiotic capable of fighting infections that > kill hundreds of thousands of people each year

Given it's potential as a medicine, the media will hype it into public consciousness. Marketers & Entrepreneurs will use this social inertia to sell it in places where it is dangerous to use. The FDA has a history of revolving doors with big pharma & playing loose in pandering to corporate interests, at the expense of the public & environment.

I'm merely presenting a minority view here on Hacker News. It's good to have all your t's crossed and i's dotted.

</comment><comment><USER3> Derek Lowe has his usual great analysis of this paper and the antibiotic: [https://news.ycombinator.com/item?id=8862148](https://news.ycombinator.com/item?id=8862148)

</comment><comment><USER37> Company's press release [http://s831.us/1Dml4G5](http://s831.us/1Dml4G5)

</comment><comment><USER38> Headline should read: Zombie apocalypse averted for now.</comment>


Installing gems - <AUTHOR> http://mwunsch.tumblr.com/post/8645762505/installing-gems

<comment><USER2> Actually, I don't get what's wrong with using sudo for the use-case of installing an executable system-wide? In principle that's what every installer does, even the MacOS-installer when installing system-wide applications. The only other option would be to install system-wide apps in a directory where every user has write access - a situation I'd find far more problematic.

However, if you'd like to install the gem just for yourself set the proper environment variables and install to your home folder.

</comment><comment><USER3> I haven't really used Ruby much until recently, but what's wrong with just setting the GEM_HOME environment variable?

Wholeheartedly agree with not using sudo if not necessary, though. That seems to have become a bad habit for a lot of people.

<comment><USER4> While I agree that installing programs as an unprivileged user is appropriate, installing programs as an unprivileged user to a global executable directory is misguided.

`/usr/local/bin` is typically in root's PATH, so root will faithfully search for programs in this directory. If root (or an admin group) does not have sole write privileges to that directory, it becomes a very easy to exploit privilege escalation vulnerability.

What _is_ risky about running `sudo make install` and the like, is that the Makefile may have malicious / risky code that may get executed as root.

Summary:

If you trust / verify the code you are installing, and you want it to be globally available, install it with sudo.

If you aren't willing to install as root, but want it to be available to a group of users, install to another directory not in root's PATH.

Otherwise just install to ~/bin

</comment></comment><comment><USER5> BS.

RVM is not an overkill. It is simply the right tool for the job in case you are doing ANY ruby related development.

If you don't, then it's "sudo gem nstall". It will install it system wide using system provided ruby binaries.</comment>


How to Destroy the Business Model of Breitbart and Fake News - <AUTHOR> http://www.nytimes.com/2017/01/07/opinion/sunday/how-to-destroy-the-business-model-of-breitbart-and-fake-news.html <comment><USER2> Here is another narrative:

Attack the business models of companies who produce content we find offensive, politically incorrect, or don't align with our world view -- yet are still protected under the first amendment.

The problem is that Mr Phillips mentioned in the article must lack a sense of humor and/or information literacy if he thought he was reading hate speech. He was reading an opinion / sarcasm piece from Milo, Breitbart's in-house provocateur.

It is such a tiresome narrative that the liberal media outlets continue to trot out their own versions of fake news when they attempt to label breitbart sexist, racist, homophobic, or antisemitic.

It is sites like the nytimes who, through their reporting, have completely defanged the labels of "racist" and "hate speech" to the point that they mean nothing.

Calling women fat and unattractive for their use of birth control is not hate speech. It might be in poor taste, but it is not hate speech. Mr Phillips, the professor quoted in the article, would do well to leave his ivory tower and actually talk to someone from another walk of life. Leave the coddled campus life, head to a bowling alley, and listen to the Thursday league banter. Maybe then, in the cloud of rough and jockular language Mr Phillips and his ilk will see a small piece of the substrate of Americans who tell dirty jokes. Who make fun of their spouses. Who call each other names (often politically incorrect) and do so as members of a tribe.

They read breitbart and Drudge Report because those sites offer an alternative narrative to what comes from regular mass media.

Just because it is a different point of view does not make it fake or hateful or undeserving of ad dollars.

How does this end? My guess is it won't matter in the end. Thankfully.

Breitbarts traffic shows no signs of slowing. That inventory vacated by the brands too weak to ignore these internet-crybullies will be snapped up by the brands who want to reach a conservative readership.

<comment><USER3> > Hate speech is speech that attacks a person or group on the basis of > attributes such as gender, ethnic origin, religion, race, disability, or > sexual orientation

> Calling women fat and unattractive for their use of birth control is not > hate speech

Something isn't quite lining up here...

<comment><USER2> Calling someone fat and unattractive is NOT hate speech.

Besides, whatever happened to just ignoring it and getting on with one's life? It is this constant cry-bully public outcry and constant whinging that has propelled people like Milo into the daily news cycle.

<comment><USER3> Right, calling a person fat and unattractive isn't hate speech. Calling "women fat and unattractive for using birth control" is. Nice strawman though.

<comment><USER2> Strawman-schrawman....

Your threshold for hate speech much be pretty low if you think "fat and unattractive" fits the definition.

</comment></comment></comment></comment></comment><comment><USER4> So I only see right-wing fake news sites called out by Mr Phillips. Is he not worried about the damage that left-wing fake news causes?

<comment><USER5> Given the rise Trump, Brexit, AfD in Germany, M5S in Italy, and all the rest, it seems obvious the problem at the moment is mainly right-wing fake news sites.

</comment></comment><comment><AUTHOR> Crowdsourcing a "hitting them where it hurts" approach to fake news seems like an interesting and promising strategy to eliminate the income streams of websites that promote hatred. I am trying to think of the downsides, i.e. how will this come to bite us in the butt...

<comment><USER6> A version of that idea was the winning project from the Reboot Democracy hackathon last month in San Francisco. They called it AdStrike.

[https://twitter.com/rebootdem/status/808456933795475456](https://twitter.com/rebootdem/status/808456933795475456)

[http://adstrike.us/](http://adstrike.us/)

<comment><AUTHOR> Very neat. Thanks for the link.

</comment></comment></comment><comment><USER7> I think articles like this are what helped Trump get elected. People are tired of being told what to think. They're tired of SJWs. They're tired of the pitchforks and public shaming.

Nobody changes by bring attacked.

<comment><USER5> Well, doing nothing and hoping the whole thing goes away also doesn't seem to get us anywhere.

</comment></comment><comment><USER8> We need more "real news" like all the mainstream reports about how the Russians just penetrated our power grid. ;-)

</comment><comment><USER9> Complaining about "fake news" while citing "BuzzFeed News" as a source?

Mote. Beam.

<comment><USER10> BuzzFeed News has actually become a pretty reputable organization in the past couple of years. They have quality journalists working there (according to journalist friends). I was also surprised when I heard about this since I associate them with listicles, but appearently that's how they fund things...

</comment></comment><comment><USER11> Pretty ballsy coming from nytimes. If this election taught me anything, they are not much better than breitbart.</comment>


Pocket spectrometer lets you measure the molecular makeup of nearly anything - <AUTHOR> http://inhabitat.com/worlds-first-pocket-molecular-sensor-measures-the-chemical-makeup-of-everything/ <comment><USER2> having built the system and analysis method behind an absorption photospectroscopy (IR/VIS/UV) based device to measure a specific set of rigorously prepared and filtered bio-analytes, i would strongly advise against accepting this devices claims. Spectroscopy is a wonderful tool, but it's not a new one, and far more sophisticated machines have tried and failed at this consumer level device's claims. caveat emptor.

<comment><USER3> Can you be more specific? What claims are unrealistic? What do you think are good consumer applications for photo spectroscopy?

<comment><USER2> they give examples of alcohol in beer and sugar content of foods.

experimental specific:

alcohol lies in the vis spectra near what we would call yellow. beer is often yellow, but not due to its alcohol content. beer is yellow because of the malt used in it's creation. reflective vis. spec. cannot differentiate the two, and would always give a vastly false reading.

practical specific:

Glucose lies in the near ir (and has been known to for a long time), so this device could theoretically be used measure glucose levels in diabetic patients. a potentially multi billion dollar industry. So why would we worry about trivial things like sugar content in food (that could be obtained from reading the food's label), if we could instead be helping millions of people and making tons of money while doing it?

...Simply because it doesn't work well.

Sugar, in wine is often assessed transparently (absorption spectra, as reflectance is quite difficult to get clear signals due to surface shape, and air surface interface on incidence angles etc...) via polarization spectroscopy. there is visible spectroscopy, mass spectroscopy perpetrated spectroscopy... this does one, and in a narrow RF range. And in our studies and research, isolating one spectral signal from another was extremely difficult and required an enormous catalog of known solution variants to build our model. This doesn't even mention the technological issues of calibrating, and certifying light sources, varying saturation time of your ccd array, warming up a light source (LED is a weak spectroscopy source as it is designed specifically to be narrow band).

these things come out once every few years and almost always fall flat. I'm sure kickstarter is littered with these things.

One use: Could be used with things that have reagents added to expose the analyte more clearly, and then to assess the degree that analyte presents itself using the before reagent added as a baseline.

</comment></comment></comment><comment><USER4> Also worth checking out, the $10 Open Source spectrometer that attaches to your phone.

[http://store.publiclab.org/products/foldable-mini- spectromet...](http://store.publiclab.org/products/foldable-mini-spectrometer)

The challenge seems to be to understand how to interpret the results. SpectralWorkbench.org is place that folks are sharing scans and comparing.

[http://spectralworkbench.org/](http://spectralworkbench.org/)

</comment><comment><USER5> I could see something like this being very useful for preventing deaths due to contaminated party drugs. If it works.

<comment><USER6> That's not the sort of test you'll be able to do with this device. Pills tend to be opaque for one, and the contamination may very well be too small to detect anyway.

<comment><USER7> I agree that this device wouldn't work for that assay, but the opacity of the pills isn't a factor: the optical bench is too small and the illumination will be too low to do anything worthwhile.

<comment><USER6> What about: handedness of the molecules, variations in density (the surface of pills tends to be compressed)?

<comment><USER7> You're right that chirality is important and this thing isn't able to probe that. As to what I'll broadly call "sample prep", you're right again to point out how that is a critical consideration. So you're double right. Operating in NIR does give deeper penetration, which is one of the reasons to consider NIR spectroscopy in an application; I'd guess that this thing operates somewhere in the 700–900nm range, but I admittedly don't know what kind of interrogation volume that gives for a pill.

So, I'm wrong to casually dismiss opacity of the target. That stems from a bias due to a background in instrumentation (meaning, I start my thinking there). I think I'm still right though to think that instrumentation is a bigger problem than sample prep _for this device_ , which I didn't do a good job in stating earlier.

<comment><USER6> Fair enough. And I should have done a (much) better job at indicating why I thought this instrument would not be suitable.

</comment></comment></comment></comment></comment></comment><comment> saiya-jin if I understood correctly it works with surface light reflection near IR spectrum, which is fine for certain set of food, and useless for many others. Anything that has different structure inside compared to surface will give only partial results (from apples to chocolate coating to ... well you get the point).

</comment><comment><USER8> It sounds like what the Vessyl was trying to do and has failed miserably, as evidenced from repeated delays.

</comment><comment> florian-f from [the store]([https://www.consumerphysics.com/myscio/order](https://www.consumerphysics.com/myscio/order)):

$249/ $449 for the dev kit.

> Expected shipping date: March 2016

Sadly, no mention of (F)OSS anywhere on the site.

<comment><USER4> Check out [http://store.publiclab.org/products/foldable-mini- spectromet...](http://store.publiclab.org/products/foldable-mini-spectrometer) and [http://spectralworkbench.org/](http://spectralworkbench.org/)

</comment></comment><comment><USER9> Really hoping this is legit and the crowdsourcing of samples provides more accuracy! This would have a significant change on the future of the world more quickly than most.</comment>


Ask HN: Ideas for load balancing under Apache? - <AUTHOR>

I am currently facing a challenge were I must load balance a series of domains for a client/friend, but there are some issues that I've been unable to fix just yet, allow me to explain:
* Solution must be a low-cost solution as money is a determining factor here. * Client currently only has 2 VPS servers (and can't afford to get more) * Server specs are: 2.3 GHz monocore CPU, 1 GB RAM, 20 GB SSD Storage (both of them). * Both servers are running Debian 7.5 Wheezy. * Client has already installed and running zPanel in one of the servers and has configured a series of Wordpress sites. * Client uses some WP Plugins to generate content, this hangs the server every time as CPU consumption is a lot. * I have transfered the DB Server to the second server to help leverage the load. * Client can't afford downtime in the websites. * Just managed to convince him that zPanel would not be necessary (I will write a couple of bash scripts to automate vhost creation and wordpress configuration).
My question/challenge here is: How can I help leverage CPU load in the server with little to no downtime? I have read about HAPROXY and I know for sure that this would be relatively easy with nginx, but the main setup is done with Apache and one of the sites refused to work properly under nginx (still can't figure out why, probably .htaccess or the use of some other Apache Module, I haven't investigated enough). Any ideas? Any help is much appreciated. <comment><AUTHOR> Hello again and thanks for your responses, I have been analyzing the server performance and checked logs for when CPU peaks and I know now, as I previously stated, that the issue is when that particular plugin (Traffic Commando) runs.

I have been analyzing its code and it's not optimized at all (not that I was surprised when I found out), it seems to not have any kind of limitant on how many posts it creates on the wordpress site (it creates posts to the DB) and it hogs up all resources. I have convinced my friend/client that the best way is to avoid using that plugin for now until it is optimized (by me, obviously... sigh), and it seems like we will start using some kind of caching system as well as CDNs to leverage the toll the sites take with traffic (I'm not really worried about that).

All in all, I guess it'll come up as a total rewrite of the plugin he is using and implementing a caching system along with a CDN system for static files as suggested in your comments.

Thanks a lot again for all your help!

<comment><USER2> You could run the plugin as a cron job on off-peak traffic hours.

<comment><AUTHOR> I actually did that, I disabled the wp-cron function and switched to crontab. I am currently monitoring the server to see if this helps or if the issue is somewhere else.

Thanks for the suggestion!

</comment></comment></comment><comment><USER3> You could use Cloudflare and their free level.

As for the WordPress sites, I would make sure there is at least a caching plugin installed for each of the sites.

</comment><comment><USER4> Replace your two crappy VPSes with one slightly less crappy VPS.

</comment><comment><USER5> My recommendation would be to actually measure the performance of the servers, isolate and address any possible bottle-necks in the application side of things[1] before attempting to solve the problem using load-balancing. If, for instance the problem is with your DB or with the communication with the DB, splitting the incoming traffic really won't help much and depending on the actual case, might worsen the situation.

At the very least, get the numbers for:

      1. Response time for a single static file request
      2. Response time for a non-db php request (eg: phpinfo() )
      3. Response time from the application for a non-db request
      4. Response time from the application with a db request
      5. .... with/without plugins ...you get the idea

This will tell you where you need to concentrate your performance improvement efforts on.

Also, look at solutions that are easy to implement and offer immense benefit for very low effort like server-side caching (eg:[https://github.com/BenjaminAdams/wp-redis- cache](https://github.com/BenjaminAdams/wp-redis-cache) / [http://www.jimwestergren.com/wordpress-with-redis-as-a- front...](http://www.jimwestergren.com/wordpress-with-redis-as-a-frontend- cache/) )

cheers,

[1] Your statement that _Client uses some WP Plugins to generate content, this hangs the server every time as CPU consumption is a lot._ is an alert.

</comment><comment><USER2> I'm not sure what your goal is here... manage CPU load or traffic load? Sounds like you have a couple of problems.

1\. Web services (http), how much traffic? What version of PHP? Did you shut down all unnecessary modules?

2\. Inbound traffic (content generation) These processes are creating content on the fly, or writing to the DB?

Reality is it would cost you less (time is money), to put in a couple of multi-core processors and 4Gs of RAM, and its going to be necessary if traffic continues to grow.

Also you can offload much of the static serving load to AWS S3. There is a CDN for Wordpress that's free too.</comment>


Tetris in 36 lines of JavaScript - <AUTHOR> http://jsfiddle.net/ova777/kFxja/

<comment><USER2> ...and 64 lines of html... i'm curious what all these "___ in X lines of js" would look like if all the html elements were created and appended to the body in js too.

<comment><USER3> Not to mention how obfuscated it is. Why not just minify it and call it one line of javascript?

</comment></comment><comment><AUTHOR> Original: [http://habrahabr.ru/post/202628/](http://habrahabr.ru/post/202628/)</comment>


Chimps' behavior following death disturbing to ISU anthropologist - <AUTHOR> http://www.news.iastate.edu/news/2017/01/31/chimpaggression <comment><USER2> This is a big contrast to other filmed encounters where chimps and bonobos gather ("mourn", to anthropomorphize it) or even defend a corpse:

[https://www.youtube.com/watch?v=9CkSy6mw3Og](https://www.youtube.com/watch?v=9CkSy6mw3Og)

[http://video.nationalgeographic.com/video/news/zambia- chimpa...](http://video.nationalgeographic.com/video/news/zambia-chimpanzee- death-reaction-vin)</comment>


Switching from SVN to Git: A Startup's Perspective - <AUTHOR> http://www.gazehawk.com/blog/switching-from-svn-to-git-a-startups-perspective/

<comment><USER2> Nice story, but there's no need to categorize a switch from svn to git as optimization, especially as part of the phrase "premature optimization".

That refers to exchanging clarity or simplicity for performance. If a technique is fundamentally superior then it's just the way you should do things, and few things in tech are as unilaterally superior as git over svn.

<comment><USER3> In this case optimization refers to trying to pick the best option. PG talks about it a lot: we could spend hours trying to pick the most efficient desk layout, the best apartment for getting work done during YC, or a hundred other things. As a startup, the right thing to do in most cases is to shut the hell up, pick something, and get back to work. That was SVN for us.

<comment><USER4> Shut the hell up? Sorry, that's not really recommended advice to tell your developers.

At least in the Ruby world, if you are on SVN, say goodbye to any competent devs. We can't work under those conditions.

<comment><USER5> I'm sorry, if you're competent you can make svn work.

<comment><USER6> But if you're really good you might not be willing to spend a big chunk of your day fighting with obsolete technologies. Unless the money makes up for it of course.

<comment><USER7> <http://www.kernel.org/pub/software/scm/git/docs/git-svn.html> < Doesn't require much fighting at all.

</comment></comment></comment></comment></comment></comment><comment><USER8> I just attended a DVCS talk today (<http://worldtour.fogcreek.com/>) and one simple difference between SVN and DVCSs is still fresh in my mind:

When you are pushing your changes back to trunk, how safe is that process?

In a normal SVN workflow, when you're ready to commit your changes to the central repository to which a team member has also committed changes, you'll end up running 'svn up' followed by 'svn commit.' If you have substantial code changes and you screw up the merge during 'svn up,' there's little record of your pre-update code. In the case that you accidentally select the trunk version of a changed file for the merge, your own recent code may be overwritten.

With Git/Hg/etc, you are constantly committing your changes to the VCS. And you commit before you merge your working copy with any changes pulled from the "central" repository. If you screw up the merge, the DVCS has a record of your local work-in-progress code changes.

You could argue with SVN that any sufficiently large feature transaction should be done in a branch. Then the merge back to trunk will be safe with the branch's commit history. Pragmatically speaking, however, many people - especially small teams - end up doing all of their SVN-based development simply using 'svn up' and 'svn commit.' I know I have.

The safety that comes with a detailed commit history, especially for day-to- day file merges, is one big advantage of DCVSs.

</comment><comment><USER9> _We're self-hosting SVN on AWS…on our webdev server. Having all of our revision history and development code on one machine, especially one as potentially ethereal as AWS, is terrifying._

You might want to investigate how to to set up an EBS backed persistent root filesystem on AWS as well as how to do S3 snapshot backups. EC2 instances fail. EBS volumes fail. You need to be ready for that regardless of the revision control choices you make.

<comment> a-priori Advantage of Git: if your central repository fails, you can recover from any developer's repository.

<comment><USER10> Is your backup culture really that sketchy? Your source code is probably just one of several digital assets the loss of which would cripple your company. If you don't consider an SVN repository reliable, it might be a good time to check your database backup procedures.

Also, SVN stores a local copy of the codebase as well. If you're working off trunk and the SVN server detonates, all you lose is the history and any branches you didn't have checked out.

</comment></comment></comment><comment><USER11> Having gone through the same process, for a small company, that "one extra level" is the key. Now I can check my code in early and often without worrying about stepping on anybody else's code. That encourages me to use SCM even more.

<comment><USER12> You can do the same thing with a personal branch in SVN. There was sort of a competing line of thought that keeping it local is a bit of "cave-hiding" behavior. <http://blog.red-bean.com/sussman/?p=20>

<comment><USER13> While there may be some equivalent in SVN, it gives you nowhere near the flexibility. I can't for example, create an idea branch for one feature I'm working on, try another idea on another branch, delete the first branch, switch back to the second, create another branch off of that and stop midway to checkout master (trunk) to work on something urgent and the then continue development and merge back into master when I'm done.

The equivalent in svn would make me groan, for complexity and for the performance.

Also, the same rules apply when 'cave-hiding'. You should still be committing early and often, but in gitland, 'committing' really means syncing up with an authoritative repo. You can 'cave-hide' in svn by just not committing anything and keeping your changes in your local working copy.

<comment><USER14> Agree on 'cave-hiding' being just as possible in svn as git, but I disagree that your workflow is particularly complicated or poorly performing in svn.

Creating branches in svn is cheap, switching branches is cheap, checking out a new working copy if you want to work on two changes at once is also cheap, merging is cheap. There's no reason not to do what you're suggesting in svn.

One of the things that git does better than svn is merging branches when files have moved, but I don't think your use case addresses this directly. Git does some things better than svn, but svn does a good enough job that you have to be a little careful when making the case against it.

<comment><USER13> > Creating branches in svn is cheap, switching branches is cheap, checking out > a new working copy if you want to work on two changes at once is also cheap, > merging is cheap.

I think then the problem is our definitions of 'cheap'.

A typical switch command on a working copy of our codebase at work (20,000 + files) takes 1-2 minutes, and its a lot longer for creating a new branch. In a git version of the same repository both these operations are comparatively instantaneous. YMMV.

Also, regarding merging, I believe that in new versions of the svn client there is mergeinfo, however older repositories without this metadata will give you issues when you for example create a branch, merge changes from trunk into your branch and then subsequently attempt to merge that branch back into trunk.

This is the classic 'svn sucks at merging' problem and to me, its complexity overhead that would deter me from branching, i.e. not 'cheap'. I normally get around this by remembering the revision number of the last 'rebase' from trunk (or give it an easily greppable commit message) and then when I do the merge back into trunk I specify that I only want changes from the last rebase to HEAD.

The internal model of git makes this a non-issue, i.e. each commit has a parent commit, and for any given commit on two separate branches, git just walks the tree up to the nearest common ancestor.

<comment><USER14> Any version from 1.5, which was released in June 2008, has merge tracking. If you're using svn and don't understand how mergeinfo works, then you're not in a position to make a fair comparison on merging. A lot of the comparisons between svn and git/hg/etc. are made by people who don't seem to understand recent versions of svn well.

Yes, old versions of svn "suck at merging", but the workflows with merges between multiple branches you describe work well in modern versions of svn with merge tracking. Your "remembering the revision number of the last 'rebase'" is unnecessary in modern svn.

I grant you that switch can take a while on a large code base, as can a checkout of a new working copy. Creating a new branch is contrary to what you say instantaneous in svn due to the cheap copies, however getting that new branch in a new working copy to work on I admit might take a while. A large part of this problem is mitigated if you just have multiple working copies checked out, but not all.

The details on why branching is cheap in svn are described here:

[http://svn.apache.org/repos/asf/subversion/trunk/notes/subve...](http://svn.apache.org/repos/asf/subversion/trunk/notes/subversion- design.html#server.fs.struct.bubble-up)

Part of the problem with svn is that the model is too flexible compared to git: the merge tracking supports tracking partial merges between branches, which is arguably an unnecessary complexity - the svn developers have expressed concern about whether this feature is valuable given the complexity it adds.

For general merge scenarios if you're using mergeinfo correctly, follow the practices laid out in the svn book, you shouldn't find merging particularly difficult or expensive in svn, even if you're doing relatively complicated workflows.

I'm not saying this is easier or works better than svn than git, just that it's doable and not as bad as many people make out. The merging in svn is (too) complex, but once you figure out how it works then it works well. With your "I believe...there is mergeinfo" and loewenskind's "I've done it. Once." I get the impression that neither of you have put the time in to really figure out how it works, but are still arguing against it.

Personally I prefer the way git works. But as someone who uses it everyday, for scenarios like the ones you say are nightmares, I don't think svn is as bad as you make out. There is an argument to be made for using git, but neither you, loewenskind nor the article make it as well as you could.

</comment></comment></comment></comment></comment></comment><comment><USER15> "I figured we may as well be one of the cool kids with something: version control seemed like a good choice"

It seems like this is the main reason why you switched from SVN to Git -- hype.

<comment><USER2> Yes, if you ignore the first 3 real reasons.

<comment><USER15> The other 3 reasons have weak arguments.

</comment></comment></comment><comment><USER16> We moved from CVS to Git over the summer. It was a pretty easy transition (we only have seven employees) though it took some explaining about the local-vs- remote copies.

The founders originally wanted to upgrade from CVS to SVN. I pointed-out that not only would they have transactional commits in Git, but that they could recover from anyone's copy of the repository, since everyone has a local clone. That, plus the first check-in (which ran blazingly fast) ended the argument.

</comment><comment><USER17> It seems like this article is premature. I would like to have read about their experiences a few more months down the line when there's been a bit more real world use.</comment>


Anders Hejlsberg on Modern Compiler Construction [video] - <AUTHOR> https://channel9.msdn.com/Blogs/Seth-Juarez/Anders-Hejlsberg-on-Modern-Compiler-Construction <comment><USER2> Anders Hejlsberg wrote the first mass-market Compiler+IDE with Turbo Pascal. What was unique is that TP would automatically bring up the editor and position the cursor on the offending error. Seems trivial now, but it was a game changer for writing code on a PC. TP sold for around $49. The competitor, Pascal MT+, sold for $400.

I doubt if Anders would remember me, but I was lucky enough to be contracted by Borland to write their first test suite for TP 4.5. It was their first object oriented language. The spec was one of the most beautiful and concise pieces of technical documentation I've ever read.

<comment><USER3> Last month I recovered an old backup tape with TP.EXE. Couldn't resist but to play with it in dosbox.

[http://imgur.com/oT3u4fR](http://imgur.com/oT3u4fR)

It really was a brilliant piece of software. 600KB.

ps: the text GUI shadows.

<comment><USER2> Ah yes, text mode graphics! I spent a few thousand hours writing a text mode version of Augment, with TP. Amazing what you could do with 80x25x16 colors.

<comment><USER3> In terms of ergonomy, that amount of text was very nice. As a long emacs user, I felt straight jacketed by their keyboard shortcuts.

ps: really, these pseudo alpha transparent text shadows ...

</comment></comment></comment></comment><comment><USER4> As Anders said near the end of the video, if you want to know more, look at the source code[1]. Speaking as someone who's worked on it (so I'm biased), I feel it's pretty easy to jump in and edit (though I'd advise new people to avoid the typechecker unless you feel particularly adventurous, it's a multi- thousand line long monster file). There are piles of easy issues[2] that are looking for community members to work on them.

By the way - one of the most meaningful comments he made in this talk (to me) was when he said that your parser had to "parse more than the allowed grammar" so you can provide better error messages. Compilers are, ultimately, tools for developers - so developer experience is tantamount. This, I've found, is so very very true in any smaller projects I've worked on, and is easily one of the first things neglected by some of my more algebraically inclined peers (who are very satisfied with a perfect ABNF and a parser which strictly adheres to it).

[1] [https://github.com/Microsoft/TypeScript](https://github.com/Microsoft/TypeScript) [2] [https://github.com/Microsoft/TypeScript/labels/Effort%3A%20E...](https://github.com/Microsoft/TypeScript/labels/Effort%3A%20Easy)

<comment><USER5> I've developed a couple of cool tricks to get very error tolerant parsers (I design/build live programming languages). We can go pure shunting yard (precedence parser), which will basically parse anything since it doesn't rely on grammar rules. Even if going with grammar based parsing (they are convenient), braces can be matched on tokens in a pre-pass before parsing occurs, eliminating an entire class of difficult to deal with errors, and allowing for brace stickiness in an incremental edit context; no need to rebalance because someone typed an opening paren without brace completion!

Though I can't help but think that someone will eventually develop an NN-based PL parser that will be much more error tolerant than straight grammar-based implementations could ever be.

<comment><USER6> Do you have those tricks written up anywhere?

<comment><USER5> Not really. I haven't taken the time to do any analysis given that they are always details in the languages I'm building (which are written up). I gave a talk about this at Parsing SLE (2013?) but I guess it didn't need a PDF.

They are really simple ideas (really, pre match your braces, I'm sure I'm not the first one to do that!), I'm not sure they are publishable.

</comment></comment></comment></comment><comment><USER7> This is a fantastic overview. If you've ever wondered why JetBrains build specific editor support for each language they support (including, effectively, a compiler), this is why.

As the developer of an IDE for Clojure, I'm also very happy that one of the secret sauces is persistent data structures.

</comment><comment><USER8> As a quick aside, Anders had committed code the same day to the TypeScript compiler. He also is in a team room with like 20 devs (not in his own plush window office). He told me he loves that kind of environment. The dude is a really cool dev.

</comment><comment><USER9> This is a very good talk but I wonder if this alternate compiler design has actually made the TypeScript compiler slower in normal compilation mode. If you really do "helicopter in" to every point in the syntax tree and run IDE queries to implement type checking then that could potentially be much slower if there's any overhead at all to doing that.

I've been experimenting with programming languages and compilers myself ([https://github.com/evanw/skew](https://github.com/evanw/skew)) and my compiler appears to be ~2x faster than tsc when run with node even though it's also doing constant folding, tree shaking, inlining, and minification while tsc is just removing type annotations (my compiler appears to be ~15x faster when run natively). The slow compilation speed of tsc is my main complaint about the TypeScript ecosystem.

<comment> nv-vn The compiler doesn't just remove the type annotation, it has to go through and check that the annotations are valid and that the type safety is kept throughout the program. Type checking is often not a quick process, since it requires every single value in the program to have its type verified. If I declare that a variable is an integer and set it to the result of the function, the compiler has to make sure that that function returns an integer and not some other type, or that the type that function returns can be implicitly converted to an integer. And for that to be safe, it has to first prove that the function being called can be given that type, etc.

<comment><USER9> I know what type checking is. :) Both Skew and TypeScript are type-checked languages. Just because a compiler does type checking doesn't mean it has to be a lot slower. I was just pointing out that it would be interesting if this alternate compiler design was the reason why the TypeScript compiler is so slow relative to another compiler for a similar language (object-oriented, typed, garbage collected, etc.) that also uses the node runtime, especially since that other compiler is doing even more work than tsc.

</comment></comment></comment><comment><USER10> Are there books or more developed material on these strategies? I understand the concepts mentioned here but reading some implementation strategies would be helpful.

<comment><USER11> The C# compiler he is taking about is open source, so you could have a play around with it to see how they implemented it. [https://github.com/dotnet/roslyn](https://github.com/dotnet/roslyn)

</comment></comment><comment><USER12> Is it common to see people at Anders's age so enthusiastic about CS as he is?

<comment><USER13> He's 56. What's your point? Do you imagine that people who devote themselves to a field have some kind of expiry date built in?

<comment><USER14> Our expiry date is not har coded. It is a nondeterministic finite state machine.

</comment></comment></comment><comment><USER15> It looks like they are building syntax trees in a similar way to how React is building the DOM tree - using functional programming and caching/diffing.

</comment><comment><USER16> So it's not that the classic compiler architecture that had to change -- it's the addition of languages services that broke the existing model.

<comment><USER17> The classic compiler architecture did change, unless you want to maintain two compilers. That's the main point of the talk.

<comment><USER16> Yes, I'm just saying that the requirement was external to the original function of compilers.

<comment><USER17> Sure... they mentioned the fact that the TypeScript compiler barely generates code, if that's what you mean by the original function of compilers.

The architecture is completely dominated by the front end for usability and incrementality now. Generating JavaScript after all that is trivial.

You can imagine that during a typical program's development lifetime, 99% of the time is spent with the program in a non-working state, and 1% is when it's working. The compiler has to help with the 99% case now, not just the 1% case.

<comment><USER16> Typically langauge services are decoupled from compilers. The 1% case still dominates how compilers functions. Furthermore, typically compilers are not deamons and build systems would take care of caching etc. Do you have other examples of consolidated tooling like that? It seems like a good idea but I don't think it's the standard thing yet or that everyone thinks it's a good idea.

<comment><USER18> Yes the model of programmer workstation as envisioned by Xerox PARC and followed up by ETHZ.

Smalltalk, Interlisp-D, Mesa/Cedar at Xerox PARC, followed by Niklaus Wirth work at ETHZ with Oberon, Oberon-2, Active Oberon and Component Pascal environments.

Also the initial Ada Workstation developed as the first product from Rational Software and Eiffel development environments.

The Energize C++ environment created by Lucid after pivoting from Lisp Machines.</comment></comment></comment></comment></comment></comment>


The many ways of parallel computing with Julia [video] - <AUTHOR> https://www.youtube.com/watch?v=HCcO-715acM&feature=youtu.be <comment><USER2> Why would you use Julia over something like Erlang for parallel? Is it better math support? Seems like Erlang has a good model for this but does lack in other areas.

<comment><USER3> Erlang is particularly good at distributed concurrency. Erlang loses much of its value when deployed only on a single machine. Also, Erlang's single-minded focus on keeping the application going may be a little overkill for compute.

There are at least two reasons why Erlang for single-machine concurrency is bad:

1: Erlang is slow. It just is. They're working on making it faster, but Erlang has a inherent overhead coming from its focus on responsiveness and uptime. Let-it-crash, actor monitoring and one-GC-per-actor isn't free.

2: Erlang's concurrency model is based on the actor model, which assumes infinite message queue capacity. In case of insufficient memory, messages are simply discarded. While this is something you have to deal with anyway in multi-machine systems (think network buffers) it's an unnecessary worry in single-machine ones.

Now, Erlang is designed to call into native binaries for all of its single- thread high-performance needs, so assuming you only use Erlang to handle inter-thread communication on a grid/supercomputer and that communication isn't a super-frequent event, then I guess Erlang+C/FORTRAN/Julia makes sense. I guess it's the convenience of having a single language that speaks for a pure Julia solution, more than anything else.

</comment></comment><comment><USER4> Did the developers fix the start up time yet?

<comment><USER5> Yes and yes. Julia's startup time has been fast for over a year – accomplished by pre-compiling the base language as a shared library (.so, .dll, or .dylib). As of a few weeks ago, packages get the same treatment and thus also load quickly.</comment></comment>


Ask HN: How has a near doubling of atmospheric CO2 not affected our respiration? - <AUTHOR> CO2 is basically poison within the context of our respiration. How has there been no serious biological/performance implications from such a drastic change in atmospheric composition? Obviously as a percentage of atmospheric makeup, CO2 is extremely low, but I would assume that the relative figures are what matters here. <comment><USER2> Atmospheric CO2 concentration is ~0.04%. When you exhale, your breath contains a CO2 concentration of ~3.8%.

Acidosis occurs in humans at atmospheric CO2 concentrations of ~5%.

Looking at statistics of indoor CO2 concentrations, it seems that offices, classrooms and under ventilated spaces often have CO2 concentrations reaching 2%.

I'd posit that there is probably an order of magnitude of leeway in regard to increasing atmospheric CO2 concentration affecting human respiration.

</comment><comment><USER3> Also of note - we don't have an extensive history of human resting pulse & respiration over generational time (primarily because modern medicine isn't old enough)</comment>


The Effects of Rent Control Expansion: Evidence from San Francisco - <AUTHOR> https://pubs.aeaweb.org/doi/pdfplus/10.1257/aer.20181289 <comment><USER2> This is pretty much in line with the other rent control studies I've read. It succeeds only in its stated goal of keeping incumbent renters from getting priced out of their homes. It is long-term counterproductive in basically ever other way.</comment>