pH is very important concept inside mitochondria and lysosomes. Lysosomal enzymes generally operate most efficiently at low pH (~5). pH also alters how efficiently mitochondria can produce ATP. The active transport of H+ ions out from the mitochondrial matrix "power" the synthesis of ATP, so that if the pH gradient between the mitochondrial inner membrane and the matrix is low, there is less energy to drive ATP synthesis.

Hi Derek, thank you for the blog - I am working on making a submission to PNAS, and this was very useful. However, I think you may have switched the numbers of the tracks: Track I is "Communicated by" and Track III is "Contributed by", not the other way around.

Here is some information that can help. This is standard practice in any IT shop: 1. Use a revision control system. This saves EVERY change you ever make to a document. Subversion is the best free open source tool out there for this. http://subversion.tigris.org/ Don't be scared off by the fact that it is for developers. It works for pretty much anything. 2. Have a back-up and recovery procedure, both manual and automated. Once you check-in all your changes to Subversion, schedule a backup for the ENTIRE REPOSITORY to an external device. And know how to recover it. *** You can save documents all over the place, but at the end of the day a revision control system like Subversion will save your ass every time ***

Along the same lines, an Early View: The Effectiveness of the Peer Review Process: Inter-Referee Agreement and Predictive Validity of Manuscript Refereeing at Angewandte Chemie 10.1002/anie.200800513

PNAS is one of my very favorites, just precisely because there is some crazy stuff which gets in there. Anyone see the article on cattle and deer aligning themselves with magnetic north in the last issue? I'm not saying that it is wrong, mind you, but it IS pretty crazy. And I certainly agree with qetzal that the normal review process doesn't do such a great job of screening out the junk. Working in early research at a large company has required frequent duplication of published results, and all I can say is just because you see it in a top flight journal: 'tain't necessarily so!

There ought to be a fast way to get hard numbers regarding the Track I, II and III submissions. Sadly my first attempt to do it seems to have produced ambiguous results. Using the online PNAS search engine, I limited my search to 2007 and then searched for the phrase For Track I, I searched for "Contributed by" which got 811 hits. "This article is a PNAS Direct Submission" got 1941 hits and for Track III, I searched for "Communicated by" which got 746 hits for a total of 3498. I am in no way implying that these numbers are valid especially since searching for "www.pnas.org" (which ought to be in every publication) only got 2596 hits and by my back of the hand calculations, PNAS publishes 85 papers a week or about 4500 papers per year. I am certain, however, that better minds than my own could come up with a more authoritative set of search strings and get the actual numbers.

OilCityBioTech Thanks for your reply When you do the simulations at .3 M salt, try it with KCl (to simulate the intracellular environment) and also NaCl (to simulate the extracellular environment. If you want to get fancy (and closer to reality) you can throw in some calcium and bicarbonate ions as well. If you can, adjust the pH of the solution, so it corresponds to extracellular levels and intracellular levels. Note that different organelles inside the cell are held to have different pHs. Do you have an opinion as to whether pH is a meaningful concept inside something as small as a mitochondrion or a lysosome?

You can tell which papers are which. Track I papers say "Contributed by ..." directly below the author affiliations on the first page. Track III papers say "Communicated by ..." instead. Track II papers say "This article is a PNAS Direct Submission" in the footnotes. Of course, you have to have the full paper to know that. I don't think you can tell just by looking at PubMed or Medline. I think PNAS is a worthwhile journal. Even if NAS members can get things published with much less rigorous review, they are still NAS members. In theory, they have a track record of top quality research in their field. Besides, the normal peer review process doesn't always do such a stellar job screening out the crap.

#*-Retread. Yes, MD can include ions as well as water. Usually I just include ions to neutralize protein charges, but you can also simulate in whatever concentration of salt solution (usually NaCl) that you choose. Maybe I should try simulating at .3M salt solutions just to see what happens....

You have to figure that the "Proceedings of" a given body will reflect the prejudices of that body and its members. Otherwise it would be just another journal. As long as the reader can identify which track a paper traveled, fine. Let a hundred flowers bloom.

FrankW, I agree with you about the existence of irreproducible, aha, who would have know it, type of papers in Nature and Science. They love big stories that bring press. This is the flaw with these journals, IMO. PNAS, however, allows papers that would not pass the review process to get published. While some results or interpretations will prove to be flawed, regardless of where published, only PNAS has such a flawed review system that allows members to put out crap that wouldn't make it elsewhere. This does, for me, compromise the whole journal.

"In-cell" or "whole cell" NMR provides the ready means to look at protein structure in E.coli and other cell types as well. Here's a nice PNAS reference for you ;) http://www.pnas.org/content/103/32/11817.full I used to look at 15N-labeled proteins in E.coli and typically saw subtle, not profound, spectral differences for in-cell vs. in-solution data. Inducible promoters are routinely leveraged in transient mammalian cell expression and would seem to open the door to selective isotopic labeling of interesting eukaryotic proteins in relevant host cell types.

I would figure that if enough bad papers get through, PNAS's review policies would be modified to change that. If no one reads the journal or cares about it, the NAS is weakened a little, and one would think they would try to avoid that. Knowing which papers are which is also helpful - supposedly stringent review policies don't help if they can be circumvented or ignored (ACIEE?). If the type of review a paper receives can be readily assessed by readers, they can also easily decide whether the paper is worth reading or following. The lack of ability to know the subsequent reproducibility of results (unless the paper is retracted or corrected) affects all journals, and makes it hard to determine if Type I or III review yields less reproducible papers than Type II review, or the review processes of other journals.

" Just my opinion, but I don't bother to read PNAS, nor trust any paper that offers really interesting results, because the quality and reproducibility is so poor. I always have to ask, if it is so good, why isn't it elsewhere (Science, Nature, etc). " You have got to be joking. Many Science, Nature etc.. papers are among the absolute worst for reproducibility, quality, etc... That is why in every issue of Science there is usually a 'technical comment' typically describing that a recent Science paper was unreproducable. Witness the recent fiasco over T Rex protein sequencing. I work in Pharma and I know of at least half a dozen Nature/Science/Cell papers that our labs have tried to replicate in the last year alone- which have turned out to be unreproducible, artifacts or only relevant for transfected HEK293 cells. I'm not saying that other journals are immune from this as we all know that JBC, J Med Chem, PNAS, etc.. all tend to publish some poor studies on occasion. I like to think of it like this: 25% of the papers in these journals are high quality, 50% are mediocre but probably true, and 25% are complete garbage.

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Just my opinion, but I don't bother to read PNAS, nor trust any paper that offers really interesting results, because the quality and reproducibility is so poor. I always have to ask, if it is so good, why isn't it elsewhere (Science, Nature, etc). The answer is usually clear when you read who the NAS member is that communicated the paper (not rejectable) and trace the connection to the author list. That person is usually an author, academic relative or in the same department. Editing and review is not up to the standards of other journals, IMHO.

"Me thinks you are being way too harsh. PNAS includes many papers not written by Academy members and these papers are throughly reviewed before publishing." I think you just said papers published by National Academy members are junk. Yikes!

Another point to keep in mind is the very high ionic strength of intracellular water (about .3 MOLAR). Back in Graduate School in the 60's we used to say that the DeBye Huckel theory applied to slightly contaminated distilled water. I checked with an old friend (now a chemistry department chair on the East Coast) last year and he says it's still pretty much true. Don't think you can use activity coefficients to fix things. They are basically fudge factors which can't be independently calculated. Activity coefficients were actually used as a dodge in Med School back in the 60s to explain why the concentration of sodium is an order of magnitude lower inside the cell than outside it, when why the concentration of potassium inside the cell is an order of magnitude higher than that found extracellularly. Knowing some chemistry on entry it drove me nuts, but I wanted to be a doc and garbaged it back on exams and made it through. I'm just getting back into P-Chem and will audit a course on it this fall. Do molecular dynamics simulations include ions as well as water? Finally, I've got to stand up for PNAS and my late friend and classmate Nick Cozzarelli who edited it for 10 years until his untimely death 2 years ago. I'll accept that some chemistry in there is poor (particularly that of Solomon Snyder). However, the papers in it are of very high quality for the most part.

"PNAS is largely filled with junk science that could not be published elsewhere Me thinks you are being way too harsh. PNAS includes many papers not written by Academy members and these papers are throughly reviewed before publishing." PNAS is just a journal with a large standard deviation in quality. There are some really good paper and some really bad papers. Often this directly correlates with the PNAS member editing, communicating, or contributing the paper.

PNAS is largely filled with junk science that could not be published elsewhere Me thinks you are being way too harsh. PNAS includes many papers not written by Academy members and these papers are throughly reviewed before publishing.

For those chemists who may not be aware, PNAS is largely filled with junk science that could not be published elsewhere. National Academy members get to publish in it free from the hassles of peer review. It is a joke.

To their evident surprise, this even agreed with their molecular modeling of the process LOL ;-)

I agree that openly posting in-progress work has many problems. But one important principle of the scientific method is reproducibility of results. So even if academic and government researchers won't share their raw data before publication, they should make it available afterward. This allows others to do their own analyses of the data to confirm that the data imply what the original researchers say they do. The availability of cheap storage and the web makes this much easier than it used to be. Yet many researchers still drag their feet when it comes to making data available, even when journals and funding agencies have explicit policies requiring this. I don't know if this is worse in climate science than in other fields, but Steve McIntyre (co-debunker of the statistical errors behind the "hockey stick") has had great difficulties getting researchers to share their data, and getting journals and agencies to enforce their policies. E.g., see here: http://www.climateaudit.org/index.php?p=66 Post-publication data sharing is the type of openness that would really help advance science. It does not guard against outright faking of data, but it allows errors of analysis and interpretation to be caught much sooner than with the traditional peer review process.

It's not always wrong to say that "cells are dilute bags of water"; it's just that the behaviors of molecules in cells changes non-linearly with the length-scale (i.e. it's not just Stoke's law). So it really depends on what you're talking about, whether it's accurate to say "a cell is a gel" or not.

Cells are gells. The most ignored fact in molecular biology. Why? because it will get your grant money taken away. See Gilbert Ling. The fact that cells are gells is the basis for a large portion of fringe biology that will not accept the reductionist mindset of most biologists. Today most biological models are built upon dilute solution chemistry from a centruy ago. It will take another 100 years to incorporate solid/gel state physics and electronics into our understanding of biological systems. Did I say electronics?..Yikes.