stanley

https://www.science.org/content/blog-post/reviewers-behaving-badly

I’ve never been on the receiving end of the sorts of manuscript peer reviews detailed in this article, but I know for sure that they’re out there. Examples shown include things like “This manuscript was not worth my time so I did not read it and recommend rejection”, “What the authors have done is an insult to science” and “This young lady is lucky to have been mentored by the leading men in the field”. Completely unacceptable.

The point of reviewing an article for publication is to offer constructive criticism, not ad hominem zingers. I mean, even if a manuscript is an insult to science, you can tell the authors what you think is wrong with it and why you don’t think it should be published. I realize that takes longer than insulting them, but there you have it. There really are worthless manuscripts out there, God knows, but just saying “This is worthless” doesn’t do anything to help solve the problem. Tell the authors, tell the editors what the problems are. And if the paper isn’t down in that category but (in your view) has significant problems, well, tell the authors what those problems are without mocking them.

As the article mentions, cultural factors can blur the line between plainspoken criticism and insults, but the examples above (and many others quoted) definitely cross the line in anybody’s culture. I have (for example) told authors that their paper is (in my view) not ready for publication until they cite some extremely relevant literature, but I didn’t go on to add my suspicions that they were avoiding doing so to try to make their own work look more novel, or perhaps that they were just too slapdash to have realized that there was any such precedent at all. At most, I might say something like this in the “Notes to the Editors” section that the authors don’t see. Another common problem is poor English on the part of the authors, but that doesn’t call for insults, either: just note that the paper needs polishing up, perhaps giving a few examples of what you mean. All of us who have had to get by in second (or third!) languages are familiar with the problem of sounding unintelligent in them, but just as we don’t want others to make that assumption about us, we shouldn’t turn around and do the same.

I’ve also given “Do not publish” reviews that are more “Do not publish here” when I think that a paper is not a good fit for the journal that it’s been sent to. Given today’s landscape, I think that the old-fashioned category of “Not fit to be published at all” is long dead - there are so many journals out there, many of them hungry for manuscripts and/or author fees, that anything at all can be published somewhere. But most of the time I end up recommended publication after some fixes (and I try not to be one of those reviewers who suggest something that means nine more months of experimental work).

It’s the anonymity that breeds the nastiness, for sure. I have said unkind things about published work here on the blog, of course, but by gosh I say it under my own name with my email address attached. You shouldn’t use reviewer anonymization, in my view, just to say things to authors that you wouldn’t tell them to their faces. As the article says, a key test is for authors in turn to ask themselves, when they get unfavorable comments, whether these things will help them revise their paper or strengthen their results, or whether all they do is shake their confidence (or piss them off, I will add myself). There may be some of each, naturally. But you shouldn’t be afraid to call out unprofessional comments with the editors themselves.

A lot of people who make it a point to talk about how they tell it like it is and how they aren’t afraid to hurt anyone’s feelings are actually trying to give themselves licenses to behave like assholes, because that’s the part that they really enjoy. We have our share of those in the research world, perhaps an outright statistical surplus. But that doesn’t mean we have to give them what they want.

https://www.science.org/content/blog-post/reviewers-behaving-badly

https://www.science.org/content/blog-post/more-legislation-watch

Biocentury has a story on a legislative move that I haven’t seen anyone else covering. The House of Representatives recently passed its version of the National Defense Authorization Act (NDAA), and an amendment was added to it incorporated the terms of the Securing American Funding and Expertise From Adversarial Research Exploitation (SAFE) Act. That one would bar any federal funding for researchers who work with institutions that are deemed “hostile foreign entities”.

What might those be, you ask? Well, most Chinese universities would probably end up on that list, because it covers those that have participated in any sort of talent-recruitment efforts in the past ten years, or if they have worked in any areas that could be considered “dual use”, i.e. with potential for military/security applications. Those are roomy categories, and they have a lot of eye-of-the-beholder in them as well. So this could bring on some significant disruption in all kinds of international collaborations that US groups might be involved in.

This legislation might remind some readers of the “Biosecure Act” that did not make it through in the previous legislative session, and according to the Biocentury piece that one, in a somewhat revised version, could make it back into the final version of the NDAA as well. That’s because the Senate will have its own version of the bill, then a joint committee will work it over to come up with a version that will pass both chambers. That’s not going to happen until the end of the year, so a lot could go on between now and then. God knows, a lot seems to go on every flippin’ day in US politics recently, so I would not wish to predict what will or will not make it into a bill like this in December.

But it’s a good bet that something like these proposals will. That’s the way the wind is obviously blowing - America First, tough on China, tough on everybody and everything, yanking universities and federally-funded researchers into line no matter what they have to say about it. In years past, legislation like the SAFE Act would have really stood out as a worrisome development, but now? If someone’s looking to disrupt and hinder US federally-funded research by cutting back work with China, well, they’re going to have to get in line. We’ve been demolishing, disorganizing, and demoralizing all of that on our own all year now.

https://www.science.org/content/blog-post/more-legislation-watch

https://www.science.org/content/blog-post/tuberculosis-defenses

Mycobacteria, I think I can say without fear of contradiction, are a real pain in the behind, scientifically speaking. Don’t get me wrong: bacteria in general are no fun to develop drugs against. Whatever fun was available in that area drained away by the early 1970s at the latest as the major classes of antibiotics were discovered and as the bacteria themselves set about busily developing resistance to them. The rate of drug discovery in the area has famously slowed down, with most of the advances being improvements on existing scaffolds. Meanwhile, the bacterial resistance problem has not slowed down appreciably at all, and the intersection of these two trends has been the subject of a lot of worry and a lot of warnings over the years.

But mycobacteria in particular are a tough problem to crack. Gram-positive bacteria are generally the easiest to kill with drug therapies because of their single-membrane structures, although please note that this “ease” is on a relative scale. Most readers will have heard of MRSA (“mer-sa” in the lingo), which is the source of some extremely unwelcome infections that are very hard to treat and in which the underlying Staphylococcus aureus organism is Gram-positive. These strains are able to resist a broad spectrum of beta-lactam-based antibiotics, although there are (for now) some other types that are still useful for treatment (linezolid, clindamycin, vancomycin and others).

Gram-negative bacteria, though, have a double-membrane structure with a thin peptidoglycan cell wall in between, and that’s a more formidable barrier to getting antibiotics inside them at all. These membranes are well stocked with efflux-pump proteins, and those are a big part of the problem. Many are the compounds that can kill off efflux-pump-crippled engineered bacteria in the lab, but unfortunately none of us are going to be infected with any of those. And the great majority of such compounds, when exposed to real Gram-negative pathogens, barely even ruffle their bacteria hair. Finding a really active compound against these is a real accomplishment.

And so is finding one against the Mycobacteria. Those guys have an arrangement all their own: a cell membrane, on top of which is a periplasmic space capped by a layer of peptidoglycan gunk, and on top of that is a layer of arabinoglycan (a unique feature). On top of that is yet another unique feature, though, a double layer of mycolic-acid-based gorp with various surface lipids and proteins imbedded in it. This is a really tough gauntlet to run for a small-molecule antibiotic, and it’s fortunately that most Mycobacteria are not pathogenic. The bad part is that the ones that are cause tuberculosis and leprosy, with the former being present in maybe a third of the entire world population (!) In many of these people the M. tuberculosis infection is just sitting around latent in the lung tissue, growing very slowly. This growth rate is seen in culture, too - even if you have the right medium for them (and many of the common ones don’t work), it can take weeks to grow visible waxy colonies of the things. As a human pathogen (and we’re the only animal that’s a reservoir for them), the bacteria are extremely resistant to being killed by macophages because of that coating.

There are antibiotics that work, although of course there are now plenty of resistant strains out there, particularly in garden spots like the Russian prison system. Resistance is showing up and increasing in countries around the world, though, and finding new antibiotics is a real world health priority. I thought this paper made an interesting contribution to that. The authors are doing wide-ranging structural studies on model peptides to see what factors are more likely to get these compounds past those thick multi-level defenses.

A first takeaway is that peptides themselves can actually get through at all - the prevailing idea has been that you need smaller and more hydrophobic molecules to have a real chance. A second lesson is that the best modification to make is cyclization, although you do need to pay particular attention to the overall ring size and the structures that you’re using to close the rings. But this seems to be the category that showed the most notable success, and the differences between the cyclized compounds and their linear counterparts is often impressive. The second-best strategy is N-methylation of the peptide, but that has a lot of variability in it, for reasons that are not really clear (or at least aren’t to me). The paper demonstrates improvement on an antibiotic candidate by adopting these features, and also shows that removing them from an existing compound (griselimycin) significantly weakens its activity.

We need plenty of these sorts of insights to deal with drug-resistant tuberculosis, because the only reason that it’s not an even bigger problem is that slow growth rate mentioned above and thus its relatively slow spread through the human population. But that tends to bring on complacency, because it’s not just ripping through the population in real time like a new respiratory virus (you remember those, right?) The last thing we need is another plague, even a slow one.

https://www.science.org/content/blog-post/tuberculosis-defenses