On 2015 Oct 30, KEVIN BLACK commented:

We have begun an online draft of a 2015 update of this article, and would be grateful for any constructive feedback. The platform allows readers to leave comments, using the little balloon icon at the upper right corner of each section of the article. For further explanation, see the comments below the 2014 highlights article.

On 2016 Aug 02, Sudheendra Rao commented:

Hi, there has been a lot of discussion on this paper on nature comments sections but I am surprised to see that authors have not responded to any of them. I really hope that the authors take some time out and respond either here or at Nature Comments section.

On 2017 Aug 05, Seán Turner commented:

Family name 'Egibaceraceae' (sic) in the title should be 'Egibacteraceae'.

On 2016 Jan 29, Daniel Corcos commented:

Welch et al. draw unwarranted conclusions from the incidence curves they show. In their paper, there is no information about the incidence of prostate cancer before initiation of widespread screening. However, as PSA screening is more likely to detect metastatic cancer, since high levels of PSA are associated with metastasis (1), it is very likely that screening leads to early detection of metastatic cancer, with the expected consequence of a peak of detected incidence at initiation of screening, followed by a return to basal level. In contrast mammography screening detects only primary cancers, with no bias for metastatic cancer. The incidence of metastatic cancer should be related to the incidence of primary cancer, which has risen during the same period (2). If breast cancers were metastatic at the time of detection as they claim, there would be no benefit from early surgery (3).

I conclude that there is no difference in cancer dynamics that could be inferred from these incidence curves, and that early detection of breast cancer is still the best option in order to shorten time to surgery. However, a 30% increase of primary breast cancer after implementation of x-rays screening is worrying and suggests that x-ray screening may be carcinogenic, at least in women with hereditary DNA repair defect (4). A retrospective study comparing the percentage of DNA repair defects in metastatic breast cancer before and after initiation of widespread mammography would be useful.

1) http://www.ncbi.nlm.nih.gov/pubmed/26659430 2) http://seer.cancer.gov/ 3) http://www.ncbi.nlm.nih.gov/pubmed/15126770 4) http://www.ncbi.nlm.nih.gov/pubmed/22788243

On 2016 May 17, Lydia Maniatis commented:

(My two PubPeer comments)

Here's the funny thing about vision science these days.

We are told about a prolific area of research - 'visual averaging': “New research tools and imaging techniques coupled with solid psychophysical work have added substantially to the large base of work done in the 20th century.”

Then we learn (caps mine) that: “Some lively debates regarding the scope of the putative sampler/averager and EVEN ITS EXISTENCE have sharpened the questions being asked and reminded researchers to consider scaling issues, experimenter and observer bias, and the multidimensional nature of stimuli and ensembles.”

It is the nature of a dogma and the school that collects around it to act on the basis of assumptions that are never challenged. Research projects are designed so that they cannot challenge the dogma, but only answer questions in its terms. (That something like this is going on here is evidenced by the author's concession that claims of possible non-existence of “averagers” remain viable despite decades of research activity.) It's the nature of science to test its fundamental assumptions before proceeding to elaborate on them. If a claim is falsifiable, in a healthy research environment it will be quickly falsified. (If it cannot be tested even in principle, then it's outside the game of science and cannot constitute a legitimate field of empirical investigation). In the type of environment we have now, it will remain in good standing for the foreseeable future. (This is the case, for example, with the bizarre notion of “spatial frequency filters.”)

On some of the absurdities coming out of “averaging” proponents, see comments here: https://pubpeer.com/publications/90941136CC181AFE4896477BF5BB44 and here:

https://pubpeer.com/publications/26067519

The faith-based tendency to accumulate evidence (supposedly) in favour of the dogma is related to this field's (invalid) adoption of inductive procedures rather than hypothesis-testing. If we just keep measuring things and fitting algorithms to the data, the truth will naturally emerge:

"The psychophysical function and the environmental information on which it is based should be allowed to emerge without predilection, lest the true mental algorithm be obscured by expectation (Anderson, 1968; Levin, 1975).... It is well known that psychological measurement is not impervious to the effects of context, scaling, measurement error, and other issues that can hinder the revelation of the true psychophysical relationship." Expectations, aka hypotheses, should stay well away lest they interfere with revelation.

Despite decades of patient effort and mountains of "evidence," we're still waiting for the true psychophysical function to be revealed. What if it doesn't exist? What if it can never be spotted amongst the confounds, known and unknown?

As we wait, we might ask what it means that "perceptual averages" have never been perceived? In what sense is an unperceived percept perceptible? (If averages were perceptible, there would be no question of their existence; we would be trying to explain perceptual facts rather than waiting for these facts to be revealed.)

On 2015 Dec 15, Martine Crasnier-Mednansky commented:

This article is remarkable for demonstrating an interaction between unphosphorylated Enzyme IIA^Glc and the EAL domain of CsrD. Such interaction is physiologically connected to the role of cAMP in E. coli because there is an established correlation between the phosphorylation state of Enzyme IIA^Glc and the level of cAMP, phosphorylation of Enzyme IIA^Glc typically causing an increase in the cAMP level (and concomitantly eliminating the effect of Enzyme IIA^Glc on CsrD).

The authors discussed the present regulatory interaction with no mention to the role of cAMP. However, considering (1) the inhibitory function of (CsrD-controlled) CsrA on glycogen biosynthesis, (2) the ability of stationary-phase E. coli to accumulate glycogen as a carbon reserve, and (3) the increase in cAMP occurring upon entry into the stationary phase (because of Enzyme IIA^Glc phosphorylation) (MAKMAN RS, 1965), it seems CsrD and CRP-cAMP both work 'in concert' for the timeliness of physiological processes during entry into stationary phase, particularly when cells are growing on glucose.

On 2016 Oct 24, Gwinyai Masukume commented:

It is unclear if indeed there has been a rapid rise in the sex ratio at birth because the data used to derive the estimates was more than 50% incomplete. In Nigeria civil registration of births is about 30% World Health Organisation - Global Health Observatory, UNICEF.

On 2015 Oct 28, Riccardo Percudani commented:

The authors suggest that the increased HGPRT activity in bottlenose dolphins after diving could maintain ATP concentrations through "ATP synthesis from IMP" (abstract). Could they provide information about the biochemical pathway involved? No pathways for ATP synthesis from IMP are reported in KEGG, and the authors do not cite a specific reference.

On 2015 Nov 20, Lydia Maniatis commented:

This paper has all the hallmarks of the “Bayesian program” - a predictable prediction confirmed, draped over a sketchy, ad hoc (I will dare to say unintelligible) mathematical model structured around a normal distribution, which model is then said to have “influenced” the results (as opposed to simply being (roughly and post hoc) correlated with them) – spiced, here, by the improper discarding of inconvenient datasets.

To begin with the last point, in Experiment 1, two out of fifteen subjects' datasets were “excluded from analysis.” The brief rationale “because they performed below 55% correct” might mislead readers into assuming it means that, for the purposes of the experiment, subjects were performing at chance level. However, although the task did involve a forced choice between presence or absence of a contour, the question at issue was whether certain features of contours make them more or less detectable. This question could have been answered using this data set – out of the 55% correct, did more of the detected contours contain the features that the authors predicted would lead to more reliable detection? Given the weak and noisy effects, it's possible that these data would have undermined the story; their removal is, at any rate, highly improper.

Based on the data that were used we are told, as part of the “basic analysis,” that “subjects were significantly better at detecting leaf shapes than animal shapes.” So what? There was no prediction, no experimental question, regarding the difference in the detectability of leaf vs animal shapes. And while this is the first result reported, the authors make no attempt to explain it.

Let me take a stab at it. Looking at their sample forms, I notice that the leaf shapes are fronto-parallel and symmetrical (or very nearly so), while the animal forms are not – some are side views, some three-quarters views, but none except a fish shape are bilaterally symmetrical. The symmetry of the fish is around the horizontal (and thus tends not to be salient for human viewers). This very clear and obvious shape factor is very pertinent to the authors' discussion about local vs global shape properties; but it is not at any point discussed. Despite these suggestive results, the authors do not test or refer to symmetry in their artificial shape condition. (Symmetry is a confound in their Experiment 2, because their least “complex” shape is also the one that is bilaterally symmetrical.)

Fortunately, this oversight doesn't prevent the authors from detecting the well-known fact that detection of shapes (i.e. perceptual organization of the visual field) depends on global properties, and that more “complex” (i.e. more discontinuous) shapes are less salient than less complex ones. (Because the shapes are presented in a highly unnatural setting (a field of noise) it is not clear what these particular results imply for more typical conditions. The authors are aware of this, and describe their results as showing that “subjects' detection of closed contours in noise is impaired, slightly but reliably...”)

Despite the prominence of the term, it is not clear that the authors have tested the role of “closed contours,” because they have not included an “open-contour” condition. And, in fact, they don't actually claim to have specifically tested the role of complexity in closed contours: “Our results show that when observers seek a closed contour amid noise, they are influenced by the complexity of the bounded shape.” Given their experimental parameters, there is no difference between this statement and the statement: “Our results show that when observers seek a closed contour amid noise, they are influenced by the complexity of the CONTOUR.” The role of contour complexity was the subject of another recent paper by these authors (http://jov.arvojournals.org/article.aspx?articleid=2291654). As far as the analysis goes, the data offered in the present paper would not seem to allow a differentiation between closed and open contours. The paper is thus effectively a repeat of the previous one.

The conclusions are trivial in the sense that they corroborate one of the most well-corroborated claims in visual perception: “Our results corroborate the Gestalt view that a complete understanding of contours is not, in and of itself, sufficient to understand whole shapes [I would note that a line (a long skinny object) also has a shape].” So what does the study offer? “The quantification of the complexity of whole shapes...” Given the unnatural task difficulty, noisy data, small effect sizes, unexplained results, it's not likely that the present effort has any value in this direction. The authors don't dare say that it does - concluding (very) modestly that: “...we hope that more attention to the problem of representing whole shapes, and specifically to skeletal representations, will spur the development of a more comprehensive account.” These hopes are not supported by this study.

Finally, although the authors pay lip service to “global shape” their models are fundamentally local “and-sum” approaches; their “features” are not truly global features, such as symmetry or compactness.

References that should have been included:

On shape skeletons:

1. Arnheim, Rudolf. Art and visual perception: A psychology of the creative eye. Univ of California Press, 1954.

2. 2.Firestone, Chaz, and Brian J. Scholl. "“Please Tap the Shape, Anywhere You Like” Shape Skeletons in Human Vision Revealed by an Exceedingly Simple Measure." Psychological science (2014): 0956797613507584.

On quantification of global shape features:

Articles by Pizlo and colleagues presenting computational models of shape.

On 2015 Dec 01, Lydia Maniatis commented:

Very brief summary: The central claim about the discovery of a perceptual difference in the effect on a target of a narrow gradient versus a wide gradient when both are invisible has not been corroborated because:

a. the wide gradient is visible;

b. the effect of the narrow gradient is the very same as that which would occur in the absence of this gradient. The attempt to spin it differently is based on past experiments in different conditions using narrow but visible, not invisible, surrounds.

On 2015 Nov 30, Lydia Maniatis commented:

his article claims to introduce a new illusion whose novelty and theoretical interest hinge on the presence of invisible luminance gradients - one shallow, one steep. The problem, as any reader can confirm for themselves, is that the shallow gradient is quite visible.

The discussion section contains an admission of the inaccuracy of the invisibility claim and an attempt to downplay the relevance of this failure to control for visibility: “A problem...is how to interpret the contrast effect obtained with the display pair C-D, in which the luminance gradients were barely visible...We ...conclude that the validity of a high-level interpretation of our results based on illumination cues does not hinge critically on whether the luminance gradients in our study were actually invisible or “almost” invisible.”

Contrast the above statements with others such as that “The experimental results clearly indicate that luminance gradients do not need to be visible in order to influence the lightness of embedded surfaces....the effect produced by pair C-D is not surprising. This effect is just an invisible gradient version of the effect demonstrated earlier by Agostini and Galmonte (1997, 2002);” “the luminance range of gradual transitions has been reduced to make them “invisible” and “unnoticeable;” “we manipulated the width of invisible luminance gradients.” The difference between invisible and barely visible is that the latter is visible, and the former invisible.

Given that the main empirical claim (from the summary) is that “the width of an invisible luminance gradient determines the lightness of a target that it surrounds...wide invisible gradients generate contrast effects, while narrow invisible gradients generate assimilation effects,” the visibility of the shallow gradient means that visibility/invisibility was, in fact, an uncontrolled confound in these experiments, and that the central claim has not been corroborated.

The meaningfulness of the “assimilation” description of the invisible narrow gradient is also called into question when the authors acknowledge that b/c the gradient was so narrow, “one might argue that the outer background could have had a larger effect on the disk appearance than the local surround.” They attempt to deflect this possibility by citing previous experiments in which a visible, narrow local surround produced assimilation. In this comparison between experiments, just as in the comparisons within this experiment, the visibility/invisibility factor constitutes a confound that undermines any conclusions as to a distinction between wide and narrow gradients.

But wasn't subjects' ability to perceive the shallow gradient an empirical question? The procedure used actually did not allow this key question to be settled, something which would not have been particularly difficult. Observers were simply asked to describe the displays. When they did not spontaneously report on the differences between the targets, they were directed by the experimenter to do so. Because they did not spontaneously report on the smoky or cloudy effect of the shallow gradients, the authors concluded (or at least state) that “none of the observers noticed the gradual luminance gradient.” But in this case, why do the authors themselves later describe the gradients as “barely visible”? They were obviously aware that a failure to spontaneously report on some aspect of the stimuli did not necessarily indicate a failure to perceive, and they took measures to fill in some relevant gaps. Since the shallow gradients are, in fact, visible, treating the failure to report as failure to perceive is transparently poor practice.

The discussion is conceptually confused, ad hoc and fully-hedged, but it does not seem worthwhile for the present purposes to analyze the various flawed attempts at interpretation of a confounded and biased dataset.

Finally, it should be noted that the authors refer to other “notable approaches” to lightness “including Gilchrist's Anchoring theory...critiqued by Rudd (2010, 2013, 2014)...” It would have been relevant here to mention that a paradigmatic claim of “anchoring theory” has been straightforwardly and definitively falsified (Maniatis, Lydia M. "A simple test of the “anchoring account” of simultaneous contrast." Journal of Vision 15.5 (2015): 13-13).

On 2015 Oct 28, Ziguo Zhang commented:

Human anaphase-promoting complex (APC/C) is a multimeric (14 different proteins, 19 subunits, functioning together with one of its co-activators, Cdh1 or Cdc20) RING E3 ubiquitin ligase that controls chromosome segregation and mitotic exit.

On 2017 Sep 06, Tao Liu commented:

The webserver has moved to http://ccb1.bmi.ac.cn:81/srnatarbase/

On 2015 Oct 31, Christopher Southan commented:

Useful paper - this post picks up the PubChem structure mappings http://cdsouthan.blogspot.se/2015/10/a-kinase-gift-horse.html

On 2015 Nov 14, Arnaud Chiolero MD PhD commented:

What is missing is the expected absolute reduction in breast cancer mortality from mammography screening. It would help women make an informed decision.

On 2017 Jan 02, Martin Mayer commented:

The new online format of JAMA Internal Medicine no longer shows the comments that were submitted and posted for this article (one from Peter Doshi and Tom Jefferson, and one from me). The comments to which I refer are not the same as the above-noted comments that were published as Letters to the Editor (though Doshi and Jefferson did also publish a Letter to the Editor). The comments to which I refer are available here for interested readers.

On 2017 May 16, Fang-Cheng Yeh commented:

Erratum at Fig.7a's legend:

"Low" FDR leads to more specific results but may miss true findings, while "high" FDR is more sensitive but may include false positive findings.

On 2016 Feb 07, Fang-Cheng Yeh commented:

The tool and source code for connectometry are available at http://dsi-studio.labsolver.org

On 2016 Apr 14, RODERIC GUIGO commented:

The literature cite by Eduard is relevant to the topic of the relationship between histone modifications and splicing. These works, as well as others, show that there is a weak (and sometimes controversial) effect of histone modifications and exon inclusion. This weak effect could reflect a general weak effect on most exons, or a stronger effect on a smaller set of exons. The main contribution of Curado et al. (2015) is the identification of a small set of exons in which histone modifications seem to be more strongly associated with inclusion levels, and that this association seems to be mediated by proximity (linear or on tri-dimensional space) to promoter regions. The findings in Gonzalez-Vallines et al. (2015) suggest the possibility that our promoter-like exons have enhancer-like characteristicis.

On 2016 Mar 23, Eduardo Eyraa commented:

The authors failed to cite prior relevant literature related to the associations between chromatin signals and alternative splicing: Zhou Y, 2012, Shindo Y, 2013, Ye Z, 2014, Agirre E, 2015, González-Vallinas J, 2015, among others. Some of these articles already proposed specific predictive models of splicing regulation based on chromatin signals that can explain a considerable number of events. For instance, Agirre E, 2015 already showed that nearly 70% of differentially spliced events between two cell lines can be explained by a model based on the differential enrichment of chromatin signals. The proposed model included the binding activity of CTCF, which, incidentally, is also used in the model by Curado et al. On the other hand, Curado et al. describe their promoter-like exons in the following way: "...while no promoters themselves, they are, on average, closer to TSS and enriched by ChIA-PET tags associated with RNA Polymerase II". In one of the prior publications mentioned above, González-Vallinas J, 2015, the authors describe a model in which potential intragenic transcriptional enhancers, upon activation or deactivation, would change the local properties of the chromatin, thereby affecting the RNA processing of the host gene, and in particular, its alternative splicing. These potential intragenic enhancers are also shown to have enhancer-like properties, including the presence of ChIA-PET links with nearby promoters. Additionally, they produce eRNAs, they can occur on exons as well as on introns, and associate with differential splicing of nearby exons. It is unfortunate that the authors did not mention these prior results in their article, given the relevance they have for what they are discussing. If you are considering citing this publication, please consider whether you should also cite Agirre E, 2015 or González-Vallinas J, 2015.

On 2016 Jun 25, Donald Forsdyke commented:

HISTORY OF LECTIN PATHWAY RESEARCH

The history of this field has recently been reviewed (1,2).

1 Forsdyke DR (2016) Microbes & Infection 18, 450-459. Almroth Wright, opsonins, innate immunity and the lectin pathway of complement activation: a historical perspective. Forsdyke DR, 2016

2 Sims RB, Schwaeble W, Fujita T (2016) Complement research in the 18th-21st centuries: progress comes with new technology. Immunobiology 221:1037-1045 Sim RB, 2016

On 2015 Nov 16, Donald Forsdyke commented:

COMPLEMENT ACTIVATION BY PLANT AND ANIMAL LECTINS - THE LECTIN PATHWAY

The “proof-of-principle” that “lectins can be made more selective through molecular engineering” was demonstrated with the plant mannose-binding lectin Concanavalin-A in the 1970s (1). The functions then studied were mitogenicity, complement activation, and serum-binding activity. The dimeric form was found to retain mitogenicity without complement activation. The tetrameric form retained both activities (2).

The discovery that plant lectins activate the mammalian complement system (1) was initially attributed to a single antibody-independent “alternative” pathway of complement activation (3). However, subsequently the observation was extended to animal mannose-binding lectins and a second “alternative” pathways was characterized (4). This was named the “lectin pathway” and the other retained the “alternative pathway” name. Thus, there are three complement activation pathways – the classical, the lectin and the alternative.

In this light there are caveats regarding the proposed topical application of lectins to prevent HIV infection.

(i) There is suggestive evidence that lectins can cross mucous membranes, thus accessing body fluids and exerting toxic, perhaps complement-mediated, effects (5). While the elegant studies of Swanson et al. (6) show how mitogenic effects might be avoided, the possibility of toxic effects has not been excluded.

(ii) Reaction of soluble lectins with targets can be extensively buffered by competing lectin-binding activities, both associated with cell surfaces and in body fluids. When HIV buds from infected cells its envelope includes normal cell surface components that bind lectin. Furthermore, when plant lectins activate lymphocytes cultured in serum-containing medium, doubling the serum concentration doubles the lectin requirement (7). Thus, very high lectin concentrations may be needed for in vivo microbicidal effects. Is in vitro BanLec mitogenicity dependent on the BanLec/serum ratio? If so, is molecular engineering able to decrease competitive binding by serum and natural secretions?

(iii) While avoidance of initial HIV infection is important, use of lectins has not been thought promising in this respect. Hopefully the lectin work is not diverting resources from studies of the “shock-and-kill” approach that promises complete HIV eradication (8)?

(1) Milthorp P, Forsdyke DR (1970) Inhibition of lymphocyte activation at high ratios of concanavalin A to serum depends on complement. Nature 227:1351-1352. Milthorp P, 1970

(2) Forsdyke DR (1977) Role of receptor aggregation in complement-dependent inhibition of lymphocytes by high concentrations of concanavalin-A. Nature 267:358-360. Forsdyke DR, 1977

(3) Eidinger D, Gery I, Elleman C (1977) The inhibition of murine lymphocyte mitotic responses by human and mouse sera. 1. Evidence for a role of antibody-independent activation of the alternative complement pathway. Cellular Immunology 30:82-91. Eidinger D, 1977

(4) Degn SE, et al. (2014) Complement activation by ligand-driven juxtaposition of discrete pattern recognition complexes. Proc. Natl. Acad. Sci. USA 111:13445-13450. Degn SE, 2014

(5) Forsdyke DR (1978) Role of complement in the toxicity of dietary legumes. Medical Hypothesis 4:97-100. Forsdyke DR, 1978

(6) Swanson MD, et al. (2015) Engineering a therapeutic lectin by uncoupling mitogenicity from antiviral activity. Cell 163:746-758. Swanson MD, 2015

(7) Forsdyke DR (1967) Quantitative nucleic acid changes during PHA-induced lymphocyte transformation in vitro: dependence of the response on the PHA/serum ratio. Biochemical Journal 105:679-684. Forsdyke DR, 1967

(8) Forsdyke DR (1991) Programmed activation of T-lymphocytes. A theoretical basis for short term treatment of AIDS with azidothymidine. Medical Hypothesis 34:24-27. Forsdyke DR, 1991

On 2017 Jun 28, Randi Pechacek commented:

P Ji, the first author of this paper, wrote a beautiful blog on microBEnet giving some background information.

On 2016 Dec 15, Victoria MacBean commented:

Plain English summary:

Opioids are a class of drug which act by attaching to opioid receptors, found in the brain and spinal cord, reducing the perception of pain. For this reason, opioids are often prescribed for pain relief. When people misuse opioids, they are often unaware of the dangerous side effects that come with them. For example, they are respiratory depressants, meaning they can reduce the breathing rate, which can be fatal. Many of the current methods of measuring respiratory depression under-estimate the true effect these drugs have on the body (especially the breathing rate), which is why this study was undertaken. Respiratory depression is a major cause of overdose and if you cannot detect when it is happening effectively, you have less chance of helping someone suffering from it.

The participants in this study were monitored over a course of 150 minutes, after they had been given their usual opioid dose. This was done using EMGpara (a tool which assesses how hard the breathing muscles are working), pulse oximetry (measuring the blood’s oxygen levels), and measurement of carbon dioxide levels in exhaled breath. The participants were asked to rate how much they felt the drug’s effect at three minutes prior to the drug being given, and then at regular intervals afterwards. Staff ratings of intoxication and level of consciousness were also given. Pulse oximetry and observer ratings are the more commonly used methods of observing patients’ breathing currently.

However, this study found that there was an increase in the level of carbon dioxide per breath in eight of the ten participants and a low blood oxygen level in only four out of the ten patients. The difference in results shows that the traditional approach of measuring the blood’s oxygen level is not as sensitive a method to detect respiratory depression after taking an opioid. There were varying degrees of respiratory depression found in all patients. However, the pulse oximetry only picked up four of these. The study also found that just talking to a patient helped to mask episodes where they were breathing unusually slowly. This means that it is very easy to miss a potentially dangerous symptom.

The findings of this study therefore suggest that we should change the way we test for respiratory depression in clinical settings, to help identify, treat and prevent it in patients taking opioids.

This summary was produced by Lily Groom, Year 13 student from Graveney School, London as part of the investigators' departmental outreach programme.

On 2015 Dec 16, Lawrence Kane commented:

I took a great interest in this paper, given the ongoing focus of my lab on the mechanisms of Tim-3 signaling and its implications for T cell and mast cell activation. I was encouraged to see that the authors also observed association of Tim-3 with one or more tyrosine kinases in T cells, consistent with our past data Lee J, 2011. However, by contrast with our previous study in Molecular and Cellular Biology Lee J, 2011, they reach a very different set of conclusions regarding the functional effects of ectopic Tim-3 expression. While we consistently observe(d) enhancement of T cell activation after ectopic expression of Tim-3, via either transient transfection or tet induction of a stable cell line, the authors of this study observe inhibition of T cell activation.

What prompted me to write this comment, however, was the fact that the authors were not completely accurate in their representation of our previous data and why it might conflict with theirs. The authors suggest that we used primarily murine Tim-3, expressed in human T cells; however, we have performed many experiments with murine Tim-3 in murine T cells (e.g. Fig. 2D in Lee J, 2011), as well as some experiments with human Tim-3 in human T cells (Fig. 1C in ref. Lee J, 2011). In addition, we had initially generated T cell lines with stable ectopic expression of Tim-3, but these cells invariably lost expression of Tim-3 over time, despite the maintenance of drug selection (unpublished data). This is why we derived the tet-inducible cells used in the latter part of the study (ref. Lee J, 2011).

Thus, in my opinion, it remains to be seen why conflicting conclusions have been reached by different groups regarding the intrinsic effects of Tim-3 on T cell activation and TCR signaling. This is important, given the rapid push to translate findings with immune checkpoint receptors like Tim-3 Mahoney KM, 2015.

On 2016 Feb 05, Daniel Schwartz commented:

As the abstract mentions, the IPI24 can be calculated online or used in a mobile app:

https://qxmd.com/calculate/diffuse-large-b-cell-lymphoma-prognosis-ipi24

On 2016 Dec 15, Victoria MacBean commented:

Plain English summary:

Patients with Sickle Cell Disease (SCD) are often assumed to have asthma because they have 'airflow obstruction', which is when airways become narrowed and air is not able to move out of the lungs as quickly or easily as in healthy lungs.

Inflammation in the airways is one of the main features of asthma. Nitric Oxide (NO) is a substance that is produced by the airways when they are inflamed, so therefore can be used to measure the severity of asthma in a patient and find out how inflamed their airways are. As well as being produced in the airways, NO is also produced in blood vessels, and helps to widen blood vessels.

People with SCD are anaemic, meaning they have less haemoglobin (a protein in the body that carries oxygen) so their cells cannot carry as much oxygen. In order to compensate for this, the heart beats faster and with more power to make sure enough oxygen is picked up from the lungs and delivered to the body.

This study looked at measurements of NO from the airways (representative of asthma) and the alveoli (representative of blood vessel widening), and compared it to lung function tests (to look at airway narrowing) and measures of pulmonary blood flow (how fast blood was circulating around the lungs).

The results showed that the airway NO was not raised, but that there was still airway narrowing occurring. There was a relationship between how fast blood was circulating through the lungs and NO from the alveoli. This might suggest that previous findings of high NO and airway narrowing resulted in a false assumption that SCD patients' airway narrowing was down to asthma. This study suggests that the changes in heart and blood vessel function in SCD may have an effect on the airways.

This study was relevant in terms of contributing to medical research because it shows the airway narrowing in SCD patients may not always be down to asthma, so it therefore allows us to target other root causes of the problem.

This summary was produced by Ashleigh Francis, Year 13 student from Harris City Academy Crystal Palace, London, as part of the investigators' educational outreach programme.

On 2016 Jan 14, Brandon George commented:

When preparing the data and analysis code for public release, we noticed minor errors in the values reported in the paper. The errors and corrected values are detailed below, which do not substantially alter the conclusions. We apologize for the discrepancies and note that the data from the study and code for the appropriate analyses is available at ICPSR (https://www.openicpsr.org/repoEntity/show/53793?versionId=53793V1).

-In Table 2, the Mean(SD) for peak power in the HIIT group should be 957.7(209.7), and the p-value for the baseline difference between intervention groups should be 0.3875. This was due to a programming error.

-In Table 3, the p-value for the test of an overall change over time in QUICKI (complete case analysis) should be 0.3670, not 0.0254. This was due to a transcription error. Although the nominal significance of QUICKI changed, the overall pre-post change of insulin sensitivity (Si) was still significant and as Si is considered a more sensitivity measure of glucose tolerance and is the basis of our conclusion that MIT or HIIT intervention may improve glucose tolerance.

-In Table 3, the ITT analysis was done using a slightly different definition of subject compliance than was used in the complete case analysis, where subjects’ proportion of completed workouts was used as a covariate. The change in the p-values of the ITT analyses using the same covariate is small and there was no change in nominal significance. The exact values can be calculated using the available code and data at ICPSR.

On 2015 Nov 24, Lydia Maniatis commented:

Pullout quote: "As long as authors are (mostly) rewarded for publishing many articles and editors are (mostly) rewarded for publishing them rapidly, new ways of gaming the traditional publication models will be invented more quickly than new control measures can be put in place."

Everyone knows it, but what can/should be done about it?

On 2015 Nov 17, ANDRES TIRADO-SANCHEZ commented:

Peer-review fraud as a “new” type of misconduct. No politics, no committees, no reports, no referees, no interviews – just highly motivated people picked by a few men of good judgement. Sir James Black. When I read the perspective published by Haug,1 I found an alarming issue with regard to the review process of scientific articles, but a déjà vu. For more than three decades, 2 it has been said that peer-review is not an objective method for evaluating scientific work, as it lends itself to many abuses by authors, reviewers and also the editors (mainly guess-editors). The acceptance or rejection of an article is mainly based on the reviewers’ comments, and the final verdict according the editor´s criteria; this is as irresponsible as peer-reviewing the work of colleagues or their own. On the other hand, peer-review is a useful tool for irrelevant articles, but it is unlikely to detect plagiarism or misconduct, which represents a major weakness; furthermore, it also generates favorable or unfavorable criticism of an article by reviewers´ conflicts of interest. This is not a problem for a country or region, a specific journal or editors, but the entire scientific community; it´s not about the money earned or fast track publications, it´s all about ethics. The process of submitting, receiving, reviewing, editing, and acceptance of an article should be amended to impose increasingly stringent filters, in order to prevent this kind of misconduct. References. Haug CJ. Peer-review fraud – Hacking the Scientific Publication Process. N Engl J Med 2015 Oct 21. Buchele JP. The new malpractice. Peer review. Kans Med 1986; 87(9): 233-6.

On 2015 Nov 02, George McNamara commented:

Could the authors please add scale bars to their light microscope image data?

With respect to figure 3, "dendrites of the NK cells penetrating into the target cells", the word penetrating implies piercing the target cell plasma membrane. SEM cannot show this. Even multicolor fluorescence microscopy would not show this. I suggest Transmission electron microscopy and am surprised the reviewer did not ask for this and the authors did not volunteer it.

Morphology and mechanism by which real Natural Killer cells kill is by immune synapse formation and directed secretion of perforin and granzymes -- not "piercing" target cells with sword like filopodia. As the authors point out in their discussion, the induced cell type may not be either a dendritic cell or a natural killer cell, so these "AMLiK" (my suggested acronym) do not need to follow normal cell's playbooks.

On 2015 Nov 03, Mihir Shah commented:

This paper delves into a hitherto non-highlighted concept on VLC and LED technologies. It is also interesting because the authors span 3 countries, Pakistan, India and the United Kingdom. A commendable paper by Shoaib Muhammad and team.

On 2016 Apr 05, Marko Premzl commented:

The third party data gene data set of eutherian lysozyme genes HG931734-HG931849 was deposited in European Nucleotide Archive under research project "Comparative genomic analysis of eutherian genes" (https://www.ebi.ac.uk/ena/data/view/HG931734-HG931849). The 116 complete coding sequences were curated using tests of reliability of eutherian public genomic sequences included in eutherian comparative genomic analysis protocol including gene annotations, phylogenetic analysis and protein molecular evolution analysis (RRID:SCR_014401).

Project leader: Marko Premzl PhD, ANU Alumni, 4 Kninski trg Sq., Zagreb, Croatia

E-mail address: Marko.Premzl@alumni.anu.edu.au

Internet: https://www.ncbi.nlm.nih.gov/myncbi/mpremzl/cv/130205/

On 2016 Dec 18, Laura Williams commented:

Our online journal club discussed this paper on November 10, 2015. https://www.youtube.com/watch?v=sMfHZ1zdXvk

On 2014 Dec 10, Kath Wright commented:

Other search filters are available from the InterTASC Information Specialists' Sub-Group Search Filter Resource at https://sites.google.com/a/york.ac.uk/issg-search-filters-resource/home

On 2015 Oct 21, GEANNCARLO LUGO commented:

Should you not have access to this publication, please feel free to contact me at lugo@ipbs.fr

On 2015 Oct 21, Jan Egger commented:

A video demonstrating the interactive RFA Volumetry can be found here: https://www.youtube.com/watch?v=GcEwwY2rG-c

For further information please visit: http://www.clinicimppact.eu/

On 2015 Dec 03, Benedict Nwomeh commented:

In pediatric surgery, as in all aspects of medicine, teamwork is critical to achieving the best results for kids and their families. I'm excited to be a part of #IGSJC and I invite everyone - surgeons, non-surgeons, non-physicians - to join the tweetchat on Dec 14 & 15 at 5-9pm EST.

On 2015 Dec 03, Benedict Nwomeh commented:

None

On 2015 Dec 03, Christian Jones commented:

Dr. Gusani (@nirajgusani on Twitter) is certain to be an outstanding moderator, and I'm really excited about this IGSJC session. We're only starting to realize how teamwork matters in surgery, and it's great to see such concepts being formally studied. Kudos to Dr. Greenberg and her entire team.

On 2015 Dec 03, Niraj Gusani commented:

I am delighted to moderate the International General Surgery Journal Club (#IGSJC) Twitter discussion of this manuscript. We hope to have a robust discussion about the effect of surgeon leadership styles and their effects. We are honored to be joined during the chats by several of the authors, including Drs. Sarah Parker, Caprice Greenberg, and Steven Yule. Join us by following the hashtag #IGSJC during the discussion - Dec 14th & 15th, 5-9pmET for live discussion with the paper open for comments/discussion throughout both days.

On 2015 Dec 03, IGSJC - The International General Surgery Journal Club commented:

In addition, a lay article about this paper is available at http://www.reuters.com/article/2015/10/29/us-health-surgeons-leadership-skills-idUSKCN0SN26L20151029#Al3U1ELlyhGcZiq0.97

On 2015 Dec 03, IGSJC - The International General Surgery Journal Club commented:

We're proud to announce that this article will be discussed online in a session of the International General Surgery Journal Club. The conversation will happen on Twitter with the hashtag #IGSJC on December 14 & 15, 2015, from 5-9pm EST each evening. For more information about IGSJC and how to use Twitter to participate in the conversation, visit https://igsjc.wordpress.com/guide-for-new-twitter-users/. Join us!

On 2017 Nov 14, Egon Willighagen commented:

There is a new paper on recent updates for WikiPathways: http://dx.doi.org/10.1093/nar/gkx1064

On 2016 May 22, Egon Willighagen commented:

Read about the integration of Reactome pathways into WikiPathways is this new paper: http://dx.doi.org/10.1371/journal.pcbi.1004941

On 2016 Mar 24, Egon Willighagen commented:

FYI, there is an R package to interact with the WikiPathways API: http://chem-bla-ics.blogspot.nl/2015/12/using-wikipathways-api-in-r.html and https://github.com/wikipathways/rwikipathways

I appreciate feedback!

On 2017 Feb 07, Michelle Fiander commented:

Systematic Reviews (SRs) are a common publication format, but manuscripts frequently do not follow national or international guidance in the conduct or reporting of these reviews. This is not entirely surprising considering the time it takes to become fully (or moderately?!) conversant SR methodologies. With that said, journal editors and authors should engage methodologists to assess SR manuscripts in light of conduct standards (e.g. Cochrane, AHRQ or other) and reporting standards (PRISMA) to ensure systematic reviews fulfill their role of providing reliable, synthesized evidence to inform practice, policy and further research in health care.

This manuscript addresses an interesting and important topic--the impact of state regulations on nurse practitioners' contribution to health care in the US. Unfortunately, it is not clear what systematic review methodology was followed for the conduct or reporting of the review. Conduct standards include Cochrane Handbook; Finding What Works in Health Care (National Academy of Science, etc), among others. Reporting standards include PRISMA, and Cochrane MECIR. Below are 4 areas where this manuscript does not seem to adhere to standards.

1. Risk of Bias: Tool not described or referenced; data of RoB assessment for each study is not provided; seven (7) studies were excluded from the review based on risk of bias--which is not common practice.

Examples of RoB Tools: Cochrane RoB tool-- https://sites.google.com/site/riskofbiastool/ ROBINS (RoB for non-randomized studies)-- https://sites.google.com/site/riskofbiastool/

About RoB: http://methods.cochrane.org/bias/assessing-risk-bias-included-studies. Reporting RoB: http://prisma-statement.org

1. Search Methods: incomplete; not reproducible. A search strategy is described, but is not presented; thus there is no way for readers or methodologists to verify how the evidence base was identified, or if the searches identified the included studies. PRISMA and Cochrane MECIR Standards suggest including at least 1 search strategy "as run", e.g. showing number of results per line as well as total results of the combined concepts within the strategy.

2. No evidence of an a priori protocol.

3. Inclusion criteria are folded into a paragraph on search methods. While inclusion criteria can impact a search strategy--e.g. study design (an inclusion criteria) will determine the type of methodological filter or hedge employed--they are distinct from methods used to identify the evidence base.

On 2016 Feb 01, Lu Wang commented:

Thanks for Cattoretti’s comment, including the literatures presented. Certainly, we agree with the information that specificity of any antibodies used in research should be standardized to ensure the accuracy of research (Bradbury A and Plückthun A). We also agree with the opinion that commercial antibody producers should test their antibodies more rigorously before selling them to scientists who often lack the resources and expertise to evaluate acquired antibodies (Holmseth S, et al). For example, no matter how to explain the result of a preadsorption test, it needs the enough free antigen to perform the test (Holmseth S, et al), hence PRDM1 antibody is also the case. As to the detection system of PRDM1 antibody in our study, please notice that both the final dilution and the secondary antibody were clearly stated in the paper. Meanwhile, cytoplasmic staining of PRDM1 is a question really puzzling us, because this expression pattern was different from all the previous reports. As you said that while cytoplasmic localization of PRDM1 needs to be proven and founded by some methods (for instance, preadsorption test, etc), however, our research design is scientific and rigorous. Firstly, we have established strict controls during beginning of IHC assay, including blank control. When the detecting system excluded PRDM1 antibody, no any signals were found in both cytoplasmic and nuclear of normal follicular epithelial cells. Secondly, we got same results in immunofluorescence detection. There is no exogenous or endogenous biotin participated in the response as everyone knows. Thirdly, we detected PRDM1 mRNA in whole cell mRNA, it exists in cytoplasms, too. So, we trust that there must be some unclear mechanisms to make this nuclear transcription factor expressed in cytoplasms. According the reasons mentioned above, we trust our results and decided to submit our research paper at last. Thanks again and best regards.

On 2015 Dec 04, Giorgio Cattoretti commented:

The claim that the cytoplasmic PRDM1 staining (a nuclear transcription factor) is indeed specific relies on the sole evidence of staining with an antibody known to produce non-specific cytoplasmic staining, whose concentration in the final dilution is not stated, counterstained with an unknown secondary antibody in a tissue known to be rich in endogenous biotin. As the sole first evidence of cytoplasmic localization of PRDM1, this is unproven, unfounded and false until proven otherwise with tools nowadays accepted for showing antibody specific staining in situ (see Bradbury A, Plückthun A (2015). Reproducibility: Standardize antibodies used in research. Nature 518:27-29. and Holmseth Set al (2012). Specificity controls for immunocytochemistry: the antigen preadsorption test can lead to inaccurate assessment of antibody specificity. J Histochem Cytochem 60:174-187.). Respectable Journals are increasingly called to enforce strict quality controls for these type of often flawed results. Best regards Cattoretti (see PMID:11232338, 12204275 and 15772984)

On 2015 Oct 27, Bastian Fromm commented:

the affiliations look little odd...

On 2016 Apr 09, Lydia Maniatis commented:

"This result suggests that the effect of pattern masking is not the integration of mask and target (Breitmeyer, 1984), but instead the complete suppression of the target at threshold."

As always, it depends on the structure of the mask/stimulus, something these authors don't seem to appreciate.

On 2015 Nov 18, Yuri Lazebnik commented:

Editorial or Advertorial?

An apparently objective article that is sponsored by a manufacturer to promote its products is known in the advertisement business as an advertorial, a portmanteau of ‘advertisement’ and ‘editorial’. We are concerned that this editorial has too many similarities with an advertorial, giving an impression that this genre of advertisement has found home in a venerated scientific journal.

Indeed, the editorial, which introduces the Nature Insight on precision medicine, is sponsored by AstraZeneca, a company whose financial interest depends on implementing the concept of precision medicine. As the company explains: “[AZ] is proud to support a new Insight by Nature on precision medicine. Currently, 80% of our pipeline takes a precision medicine, or personalized healthcare approach.” https://www.astrazeneca.com/our-company/media-centre/articles/astrazeneca-is-proud-to-support-a-new-insight-by-nature-on-precision-medicine-14102015.html. In other words, promoting precision medicine would promote AstraZeneca’s future products. As would also be expected from an advertorial, the editorial overlooks the voices of skeptics (1,2). Likewise, the papers commissioned by the Editor for the Insight are overwhelmingly optimistic. Although each acknowledges the enormous changes in health care that would be required for implementing precision medicine, none considers that these changes may be infeasible, unaffordable, and distract us from finding inexpensive practical alternatives. The appearance of bias is not helped by finding that three of the four articles declare competing financial interests.

Although the Nature editorial has acknowledged AstraZeneca sponsorship, this disclaimer fails to dispel the impression that the editorial promotes the products of its sponsor and can lead one to suggest that one of the most revered of scientific journals has abandoned its role as an unbiased moderator. Even a hint of advertorial practices would hardly be beneficial to anyone at a time when the influence of industry on the integrity of research and clinical practices is increasingly becoming a public concern.

Michael J. Joyner, MD, Caywood Professor of Anesthesiology,Distinguished Mayo Investigator, Mayo Clinic

Nigel Paneth, MD, MPH, University Distinguished Professor, Departments of Epidemiology & Biostatistics and Pediatrics & Human Development, College of Human Medicine, Michigan State University

Yuri Lazebnik, PhD, Lerna Consulting, LLC

The authors thank Professors Ana Soto, Carlos Sonnenschein, Sandro Galea, Richard Cooper, and Arturo Casadevall for their helpful comments

REFERENCES

1. Bayer, R. & Galea, S. Public Health in the Precision-Medicine Era. The New England Journal of Medicine 373, 499-501 (2015), doi:10.1056/NEJMp1506241.

2. Joyner, M. J. & Paneth, N. Seven Questions for Personalized Medicine. JAMA 314, 999-1000, (2015) doi:10.1001/jama.2015.7725 .

On 2017 Mar 02, Prajak Barde commented:

A study by Kaul U successfully concluded that paclitaxel-eluting stents failed to demonstrate non-inferiority against everolimus-eluting Stents that in diabetic patients undergoing PCI.

The trial was powered to detect non-inferiority on the basis of Spirit IV trait assuming that 1 year rate of target vessel failure of 8.4% with each stent, with non-inferiority margin of 4 %. However, documented failure rate in Spirit IV was 4.2 % in CAD patients and 6.4% in diabetic patients. Author did not explain the reason for these differences which potentially may lead to under powering of trial.

Author choose the margin (4%) based on Absolute risk difference that can result in under powering of the trial due to lower than expected event rates. Author might have foreseen the differences in the event rate however this was not justified why the sample size adjustment was made.

In the current the relative risk was inflated substantially increasing the risk of accepting the hypothesis of non-inferiority, which was not demonstrated due to clear differentiation of the effect.

On 2015 Nov 12, Sameer Al-Abdi commented:

Result of this outstanding trial can be summarized metaphorically as “The operation (Budesonide) was successful, but the patient died”

On 2017 Nov 18, Christopher Southan commented:

This publication is now updated in our 2018 version https://www.ncbi.nlm.nih.gov/pubmed/29149325

On 2015 Dec 22, Christopher Southan commented:

The new Concise Guide to PHARMACOLOGY (Dec 2015) has been compiled from this database content http://www.ncbi.nlm.nih.gov/pubmed/26650438

On 2015 Oct 15, Christopher Southan commented:

While this supercedes the 2014 equivalent (http://www.ncbi.nlm.nih.gov/pubmed/24234439) the information in both papers is complementary

On 2017 Jan 14, Boris Barbour commented:

I have tried to clear up my confusion about the simulation conditions and more specifically the boundary conditions, which must often represent the physical context of the sphere. The Perspective seems to offer several versions, none of which is entirely satisfactory.

1) The images in Fig. 3 might be taken to suggest that the spheres are surrounded by nothing. In consequence, my calculation in the previous comment assumed a vacuum. However, one should of course read the equations and not put one's faith in Nature illustrations. I apologise to the authors and readers for initially jumping to this probably wrong conclusion.

2) Box 1 states that there is "no flux of the electric field" at the spine boundary. I think this would imply no net charge within and no net charge outside the spine, which would appear to be inconsistent with the case where the spine contains ions. (There are other logical possibilities: a grounded boundary or some exotic distributions with very specific inside-outside symmetries. But these are implausible in the present context). I therefore believe this statement refers to some special case or is an error. Or maybe it represents that well known and remarkably accurate approximation of strict electroneutrality?

3) Box 2 equation 5 gives a different boundary condition, this time with a non-zero electric field

E = Q/(4 * pi * er * e0)

However, I believe this contains an error. If the denominator also included a factor of R² , the equation would be dimensionally correct and also compatible with an infinite aqueous medium. The physical model would then be water everywhere, with a thin, "electrically invisible" barrier enclosing the ions. There would be no ions outside the spine. (It should be understood that we are dealing with "idealised" water that contains no ions, not even from the spontaneous dissociation of water molecules that occurs in reality.)

The corrected option 3) and therefore the infinite aqueous milieu seems the most plausible to me. In this case the arguments in the previous comment about the large potentials required in the "vacuum" case are still relevant, except that the values would be attenuated 80-fold by the relative permittivity of water. Voltages would range from about 20mV for 1000 ions to about 20V for 1000000. Figs. 3b and 3c would still require clearly unphysiological voltages.

In Fig. 4, the authors argue that the model spine has a "logarithmic capacitance" (i.e. V is proportional to log(Q)). However, they define V as the voltage difference between the centre and the rim of the spine. I see two problems with this definition.

1) A minor issue is that, in the model, most ions added to the spine distribute to radii other than zero (the centre), attaining a different potential in the process. An alternative might be the potential averaged over all charges.

2) A more significant issue is that the reference voltage is taken at the rim of the spine, which is well within the potential field of the spine, thereby excluding some if not most of that potential. All practical measurements and most neuronal current loops involve much larger distances outside the spine, and for these a reference at infinity is a reasonable approximation. This alternative of an external reference would require inclusion of the large voltages mentioned above. These are proportional to the charge and are likely to dominate the small intra-spine nonlinearities highlighted by the authors.

In the end, however, spines exist neither in a vacuum nor even in distilled water. As discussed in my earlier comments, most if not all of the electrical behaviour in insulators (dielectrics) described by the authors is likely a poor guide for what happens in conductors. The phenomena could thus be radically altered by the inclusion of a conducting external solution, ions of opposite charges at realistic (near equal) concentrations and a membrane.

On 2017 Jan 07, Boris Barbour commented:

[This comment has been edited as a result of uncertainty about the exact conditions for the simulations. Follow up in next comment.]

A simple calculation shows how unrealistic assumptions of significant deviations from electroneutrality are.

Imagine the sphere is in a vacuum, such that there is no external solution and the membrane capacitance is therefore absent. Then from Gauss' Law and symmetry it can be shown that the potential at the rim of the sphere with respect to infinity (i.e. a distant reference) will be:

V = Q/(4 * pi * e_0 * r),

where V is the potential, Q the charge, r the radius of the sphere and e_0 the vacuum permittivity. (This is equivalent to the classical isolated spherical conductor.)

Taking e_0 = 8.85E-12F/m, r = 0.5E-6m and an electronic charge of 1.6E-19C, we can calculate that just a single ion produces a potential of about 2.8mV. The 1000 ions in the simulation of Fig. 3a will therefore create a voltage of 2.8V (in my slightly smaller sphere), while the 1E6 charges of Fig. 3c would generate a whopping 2.8kV. Thus, the largest physiological potential could not generate a deviation from electroneutrality greater than the equivalent of a few tens of ions in the spine.

In practice a few thousand ions of the same sign can be accumulated (calculated in my first comment), but this is only possible because the charge-compensating mechanisms of the membrane capacitance and polarisation of the medium are present, which largely preserve electroneutrality.

On 2016 Dec 26, Boris Barbour commented:

Despite this article appearing in a journal dedicated to reviews, I appreciate it is tagged as a "Perspective", which presumably indicates that it contains some speculation. However, I still think it is worth pointing out to readers that electrostatic screening has in effect been omitted from the modelling, which could have an extremely strong influence on the phenomena illustrated, particularly as this is not made clear in the article.

This problem will only be addressed by analytical or numerical approaches that include at least two oppositely charged species at approximately physiological concentrations. I insist on this point because the cited preprint (like this Perspective) models the charge alone, which means only a single charged species is considered. Additional manuscripts treating this non-biological situation do not help address the biologically relevant questions. The standard approach to simulating the two-species system would be to include distinct electrodiffusion equations for the concentrations of cations and anions, whose difference yields the net charge distribution.

In the spirit of not jumping to conclusions or trusting to intuition in a complex situation, I would equally encourage readers (and the authors) to exercise due care before extrapolating from simulations with low concentrations of a single charged species to the situation with high concentrations of oppositely charged species.

EDIT: The effective omission of the membrane capacitance should also be rectified in any realistic modelling. This is because most if not all of the net charge in the spine will accumulate below the membrane, where it is quasi-neutralised by a symmetrical accumulation of opposite net charge the other side of the membrane. Without this mechanism, the actual capacitance of the spine/membrane will presumably be lower than observed in situ. In other words, biologically relevant voltages could not drive many charges into a spine without a membrane capacitance. The present modelling ignores the membrane capacitance because there is no extracellular saline in which an oppositely charged accumulation of ions can occur.

On 2016 Dec 26, Rafael Yuste commented:

We appreciate the concerns of Dr. Barbour and thank him for his frankness. But we alert the reader that this publication is not a proper experimental study but an opinion piece with a very limited set of data, which were added strictly to illustrate the point, and did not represent a comprehensive analysis of electrodiffusion in spines. Our review should be viewed precisely as what it is, a "Perspective", highlighting new and potentially controversial topics. The role of electrodiffusion in nanophysiology has been traditionally ignored by cable theory because of the difficulty to analytically solve the corresponding joint equations. Moreover, the interaction between electric fields and diffusion and geometry are not easy to dissect because they are highly nonlinear and sometimes counter intuitive and consequently difficult to discuss without adequate computational simulations. We, and others, are exploring this potentially important phenomenon with simulations and theoretical studies, some of which have already been published (https://arxiv.org/pdf/1612.07941.pdf), and which will hopefully address all the concerns of Dr. Barbour. We encourage the reader not to jump to quick dismissive conclusions but to be patient and wait for further work.

On 2016 Dec 26, Boris Barbour commented:

In this "perspective", the authors build up the importance of using full electrodiffusion simulations without an electroneutrality constraint to describe current flow and ion distributions within dendritic spines, rather than treating the cytoplasm as an Ohmic conductor. Although an electrodiffusion model is in principle more accurate and may in some cases be necessary, the authors do little to make their case here, because their illustrative model in Fig. 3 is quite divorced from physiological conditions.

They illustrate the equilibrium spatial distribution of ions within a small and isolated sphere of water, a situation loosely representing the head of a dendritic spine. When electrical interactions between the ions are considered at high concentrations, a highly nonuniform spatial distribution emerges. However, there are both trivial and fundamental problems with this apparently dramatic illustration.

It is worth fixing some numbers. Empirical measurements of membrane capacitance typically yield values of ~1microF/cm^2. So the capacitance of a typical spine head with diameter 0.5 microns will be about 10fF. Charging this capacitance to the most extreme membrane potentials observed in neurones (of the order of 100mV) will therefore require about 1fC, a charge that represents about 5000 ions. The volume of such a spine head would be about 70aL (attoLitres) and, assuming a 150mM saline of monovalents, would contain about 600000 each of cations and anions. The authors use a rather oversized spine head compared to this, but the numerical differences will be unimportant to what follows.

The authors simulate 1000, 100000 and 1000000 charges, but already the second number exceeds the largest net concentration of charges that will occur physiologically.

The concentrations they report are numerically incorrect at least in Fig. 3b (where the mean concentration should be 40 microM) and in Fig. 3c (where the mean concentration should be 400 microM).

A true representation of these gradients would include the existing 150mM saline. Thus, for Fig. 3a, the ~100nM gradient would be superimposed upon 150mM, about one part in a million, which may not be that significant.

Another important problem arises from the fact that the authors only include charges of one sign in their model, while physiological saline contains both cations and anions, in roughly if not exactly equivalent concentrations (we calculated above that the net charge represents of the order of 1% of ions present, and even this number is only made possible by the membrane capacitance). This unrealistic situation is likely to have a very strong influence on the behaviour illustrated, because the existence of ions of the opposite sign would allow electrostatic screening, which the authors have in effect banished from their model by only including a single ionic species.

The ionic gradients illustrated by the authors arise from collective mutual Coulombic repulsion (note that the submembrane ionic concentration shown is unrelated to the concentrations of charges normally occurring on either side of the membrane capacitance, because the external saline is absent in this model). Such Coulombic forces are usually annihilated over all but the shortest distances and times by electrostatic screening. The habitual approximation considers electrostatic shielding to cause an exponential attenuation of Coulombic interactions with a length constant of the Debye length. In 150mM monovalent saline the Debye length is about 0.6nm (using an approximate formula given on wikipedia), so, even over a fraction of a micron, Coulombic interactions should be attenuated to a cosmic degree and the forces generating the interesting concentration gradients of Fig. 3 are unlikely to operate.

In conclusion, although I'm not in a position to describe exactly the distribution of net charges in the spine head under physiological conditions in the absence of strict electroneutrality, neither are the authors. However, ignoring electrostatic screening seems to be an extremely unrealistic approximation.

On 2015 Nov 19, Cecile Janssens commented:

It is important to distinguish the method from how it was investigated. We applied the method to an unselected sample of meta-analyses rather than limiting to high-quality meta-analyses, because we wanted to show when the method works and when it doesn’t. Our results show that the method does not work that well when the topic of the meta-analysis is heterogeneous, and when there is a need to include grey literature or articles from non-English languages, which is no surprise. The poor performance of the method for these meta-analyses should not be interpreted as a shortcoming of the method, but as guidance for when and when not to use the method.

We did not suggest that the method should be used standalone. We mention in the first paragraph of page 8 that “additional strategies like these can be used to complement our search method–either to find more eligible studies or to increase confidence in the results of the search method when no other studies are found.”

Regarding the specific meta-analyses: The method does not improve the efficiency of meta-analyses that were already efficient. We screened more than 100% of the articles in the studies of Kumar, Stevens and Shan because they screened 573, 400 and 243 articles, compared to 1013, 536 and 289 using our method. More than half of the studies in the meta-analysis of Kumar were case studies, which often have no or a limited number of citations, and several of the other studies were published in non-English language. The topics of both other studies were quite heterogeneous. Shan investigated quality of life, covering quality of life instruments and assessments of functional status, and Stevens summarized six studies on a post-operative drug interaction, which investigated six entirely different surgeries. As said, the method does not work well when topics are heterogeneous.

Finally, this is the first paper on this method, describing two pilot studies. More work is certainly needed. Given the high efficiency of the method and the impressive accuracy, we are most interested in a direct comparison of the method with keyword searching in Pubmed as a first search. The method may well be a more efficient start of literature searching than keyword searching.

On 2015 Nov 10, Wichor Bramer commented:

This article investagates the effectiveness of citation based searching for systematic reviews, because the gold standard keyword-based searching is inefficient. The authors propose a new method of co-citation and bibliographic coupling. Their conclusion is that Citation searching is a reasonably accurate method. But what is reasonably accurate? One should not look at the median or mean or overall recall, but at the minimum recall. A researcher is not performing 20 reviews for which the median recall is accurate enough, researchers decide on which method they want to use for their single review. They want to minimize the chances of missing relevant articles in their N=1 case.

What was the question that the authors tried to answer? Can it be used as a standalone method for indetifying included references in systematic reviews? The answer has te be 'No!'. The most complete method in study 1 (screening all co-citations) retrieves and appropriate median of 94% of all included references, but the minimum of 75% is unacceptable. And that method is only occasionally more efficient than the traditional method. The method that is more efficient than traditional (all co-cited > 1) retrieves sometimes only 50% of all included references. In study 2 the best method (indirect and direct citations) retrieves a minimum of 10% of all included references. In seven out of 42 studies 50% or less of all included references were retrieved, and sometimes not even by reducing the number of hits needed to screen, such as Kumar, where screening 177% of the traditional method resulted in a recall of only 31% of the originally included studies. In their discussion the authors give reasons why their method does not work for the 5 lowest scoring articles, concluding that if these are not taken into account 89% of all references is found. But that still does not explain Stevens [68] in which 138% of hits have to be screened to find 50% of all includes, and Shan [65], where 142% is needed to find 58%.

An interesting question would be whether the described method can add additional references that were not found with the traditional keyword-based approach or traditional citation screening? This cannot be concluded from these results, as the investigators only tried to find the articles that were already included (and thus had been found by the traditional methods).

The conclusion of the authors that: "Researchers … [have] … the advantage of being able to screen only half of the number of articles compared to keyword-base literature search …[which]… is an efficient strategy for finding key articles related to one or more “known” articles" might be correct, but it cannot replace traditional keyword based searching, but only complement it, but that was not investigated.

On 2016 Jun 10, Ali Poormohammadi commented:

If it is possible please mention the experimental conditions in each step.

On 2016 Jun 09, Ali Poormohammadi commented:

None

On 2016 May 10, Morten Oksvold commented:

Please pay attention to the following report from ORI (Office of Research Integrity) before reading this article:

https://ori.hhs.gov/content/case-summary-pastorino-john-g

On 2017 Jun 28, Randi Pechacek commented:

Alex Alexiev briefly described this paper for the public on microBEnet.

On 2016 Mar 01, Ram Dessau commented:

Residual symptoms after Lyme neuroborreliosis. The prevalence is unknown? Comment by Ram B. Dessau

Department clinical microbiology Slagelse Hospital, Region Zealand Ingemannsvej 46, DK4200, Slagelse, Denmark ramd@regionsjaelland.dk

Dersch et al. have performed a systematic review and meta-analysis on the prevalence and spectrum of residual symptoms in patients after treatment for Lyme neuroborreliosis (LNB)[1]. 5579 bibliographic records were screened and 38 studies were included. An overview of treatment studies reporting residual symptoms is given. The follow up time is about one year concerning most of the studies. The conclusion is that 28% of LNB patients may experience symptoms after treatment. This conclusion may be misinterpreted as associated to LNB or caused by LNB. The 38 treatment studies were not designed to elucidate the association of LNB with residual symptoms, as control groups without LNB were not included.

Many of the cited symptoms like sensory disturbances, cognitive disturbances, pain and headache are non-specific and even common in the population at large. Thus, it would be of paramount importance to compare the prevalence of events to a control group using the same methods. Only a higher frequency of residual symptoms in the LNB group may indicate association with LNB. Due to the design of the included studies the residual symptoms could as well be due to other causes such as adverse effects of treatment [2].

Reporting the gross proportion of events may be misleading for other reasons. The load of residual symptoms will depend on not only the number of events for each symptom, but also the number of recorded items and the length of time, where symptoms may occur. The more questions you ask and the higher the gross rate of symptoms will become and eventually the rate of symptoms may approach 100%. Especially if there is also a long time span for the observations.

Along this line of reasoning Dersch et al. also misinterpreted the studies including a control group[1]. The results of these studies do not “remain inconclusive”, but show comparable results, even if there are differences. These differences are not very large and a substantial proportion of the controls also have a similar level of problems. For example the mean physical component FS36 score in LNB was 44(9) compared to 51(6) in controls[3]. A significant difference in mean score was found, but the size of the standard deviation show that the distribution of scores in the two groups have a large overlap. Given that the 95% interval is about 2 SD then FS36 score in LNB is 26-62 and in controls 39-63. Even if LNB patients have “significantly” lower FS36 score than controls, this is not a large difference. Thus a weak or absent association alone could explain that some studies do not report statistical differences and some do due to random variation. Thus, residual symptoms associated with LNB are probably quite rare, if at all.

Grouping together any symptoms without considering a variable relevance to LNB is problematic. For example, it was found in Swedish children that residual symptoms were persistent nerve defects such as facial palsy, but not nonspecific subjective symptoms [4]. Thus, it would be important to distinguish different types of symptoms and their severity. The study by Dersch et al. adds to a large volume of uncontrolled case reports and case series overstating the possible risk of symptoms associated with Lyme borreliosis[5]. This may contribute to unnecessary anxiety about Lyme borreliosis.

It is acknowledged that Dersch et al [1] do state important reservations about especially the "possible" case definitions, as patients with other conditions could contribute to the high load of reported symptomps.

Conclusion The prevalence of residual symptoms associated with LNB after treatment may not be concluded from the study by Dersch et al [1] because control groups are missing. A meaningfull interpretation is not possible. The authors should have focused on the available controlled studies instead.

Conflict of interests: None to declare.

References

1.Dersch R, Sommer H, Rauer S, Meerpohl JJ. Prevalence and spectrum of residual symptoms in Lyme neuroborreliosis after pharmacological treatment: a systematic review. J Neurol 2015 Oct 12.

2.Dersch R, Freitag MH, Schmidt S, Sommer H, Rauer S, Meerpohl JJ. Efficacy and safety of pharmacological treatments for acute Lyme neuroborreliosis - a systematic review. Eur J Neurol 2015 Sep;22:1249-59.

3.Eikeland R, Mygland A, Herlofson K, Ljostad U. European neuroborreliosis: quality of life 30 months after treatment. Acta Neurol Scand 2011 Nov;124:349-54.

4.Skogman BH, Glimaker K, Nordwall M, Vrethem M, Odkvist L, Forsberg P. Long-term clinical outcome after Lyme neuroborreliosis in childhood. Pediatrics 2012 Aug;130:262-9.

5.Baker CJ, et al. Final report of the Lyme disease review panel of the infectious diseases society of America (http://www.idsociety.org).2010.

On 2015 Oct 17, David Keller commented:

Wine should be diluted to reduce epithelial carcinogenic effects in the upper aerodigestive tract

Epidemiologic evidence suggests that people with diabetes are at significantly higher risk for many forms of cancer [1]. It has also been observed that cancer patients with pre-existing diabetes experience higher mortality than cancer patients without diabetes [2]. The randomized controlled trial by Gepner and colleagues confirmed prior observations that moderate ethanol consumption is associated with improved cardiometabolic risk in diabetics and in other groups [3].

A large observational study reported data on cancer and other harms among drinkers whose usual alcoholic beverage was wine, beer or spirits [4]. A dose-response relationship was identified between the concentration of ethanol in the beverage of choice, and the incidence of cancers among those who consumed it [5]. The risk of cancer for drinkers of beer (which contains about 5% ethanol), wine (12% ethanol) and distilled spirits (40% ethanol) were each divided by the cancer risk for teetotalers to yield respective cancer harm ratios (HRs) of 1.2, 1.38 and 1.69; note the dose-response relationship between the ethanol concentration in a beverage, and cancer rates for those who drink that beverage. The cancer HR for beer drinkers was not statistically significantly elevated above that for teetotalers, but its trend is consistent with the proposed dose-response relationship.

Given the elevated risk of cancer in diabetics, and a risk of cancer in drinkers of alcoholic beverages which increases monotonically with the concentration of ethanol in the beverage, it seems prudent for diabetics who consume ethanol to dilute their beverage of choice to a concentration of 5% or less. Wine can be diluted to 4% ethanol by combining one part wine with two parts water or juice.

References:

1: Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, Pollak M, Regensteiner JG, Yee D. Diabetes and cancer: a consensus report. Diabetes Care. 2010 Jul;33(7):1674-85. doi: 10.2337/dc10-0666. PubMed PMID: 20587728; PubMed Central PMCID: PMC2890380.

2: Ranc K, Jørgensen ME, Friis S, Carstensen B. Mortality after cancer among patients with diabetes mellitus: effect of diabetes duration and treatment. Diabetologia. 2014 May;57(5):927-34. doi: 10.1007/s00125-014-3186-z. Epub 2014 Mar 15. PubMed PMID: 24633676.

3: Gepner Y, Golan R, Harman-Boehm I, Henkin Y, Schwarzfuchs D, Shelef I, et al. Effects of Initiating Moderate Alcohol Intake on Cardiometabolic Risk in Adults With Type 2 Diabetes: A 2-Year Randomized, Controlled Trial. Ann Intern Med. [Epub ahead of print 13 October 2015] doi:10.7326/M14-1650

4: Smyth A, Teo KK, and the PURE Investigators. Alcohol consumption and cardiovascular disease, cancer, injury, admission to hospital, and mortality: a prospective cohort study. Lancet. 2015 Sep 17. doi:10.1016/S0140-6736(15)00235-4. PubMed PMID: 26386538.

5: Keller DL. Dose-response relationship observed between concentration of ingested alcohol and cancer rate. Comment on PMID 26386538. In: PubMed Commons [Internet]. National Library of Medicine; 2015 Sept 26 [cited 2015 Oct 12]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26386538#cm26386538_11980

The above comment is also posted on the following Annals of Internal Medicine web page:

http://annals.org/article.aspx?articleid=2456121

On 2015 Oct 15, Andrea Messori commented:

Producing evidence in support of disinvestment: the experience of the Tuscany region in Italy

HTA Unit, ESTAV, 50100 Firenze (Italy)

In June 2013, the regional institution (ESTAV) responsible for drug acquisition in Tuscany (Italy) started a project aimed at identifying a series of pharmacological treatments suitable for disinvestment (i.e. suitable to be replaced by an equi-effective and less costly alternative). One criterion for this initiative was to write a full scientific report focused on comparative effectiveness for each therapeutic issue.<br> Table 1 shows the bibliografic details of the main 10 analyses of disinvestment conducted within this project.

Table 1. Information shown in this table: (a) therapeutic issue; (b) more costly treatment; (c) less costly tretament; (d) references

[1] -----------------------------------------------------------------------

(a) First line treatment of previously untreated patients with genotype-1 HCV infection ; (b) Sofosbuvir + ledipasvir (12 weeks) ; (c) Ritonavir-boosted dual therapy (12 weeks) ; (d) Trippoli S, Fadda V, Maratea D, Messori A. Bayesian network meta-analysis to evaluate interferon-free treatments in naive patients with genotype 1 hepatitis C virus infection. Eur J Gastroenterol Hepatol. 2015 Aug;27(8):983-4.

[2] -----------------------------------------------------------------------

(a) First line treatment of previously untreated patients with multiple sclerosis ; (b) Beta-Interferon ; (c) Azathoprine ; (d) Messori A, Fadda V, Maratea D, Trippoli S. Indirect meta-analytical comparison of azathioprine and of beta interferon effectiveness in all forms of multiple sclerosis pooled together. J Neurol Sci. 2014 Dec 15;347(1-2):408-10.

[3] -----------------------------------------------------------------------

(a) Prevention of Venous Thromboembolism in Major Orthopedic Surgery ; (b) Enoxaparin ; (c) Dalteparin ; (d) Messori A, Trippoli S, Maratea D, Fadda V, Marinai C. Prevention of venous thromboembolism in major orthopedic surgery: Bayesian network meta-analysis of 21 randomized trials evaluating unfractionated heparins, low-molecular weight heparins, and new oral anticoagulants. Int Cardiovasc Res J.2015;9(4):238-242

[4]------------------------------------------------------------------------

(a) Targeted Treatments for Pulmonary Arterial Hypertension: ; (b) Various agents of recent approval ; (c) Sildenafil ; (d) Badiani B, Messori A. Targeted Treatments for Pulmonary Arterial Hypertension: Interpreting Outcomes by Network Meta-analysis. Heart Lung Circ. 2015 Jul 6. pii:S1443-9506(15)01248-2. doi: 10.1016/j.hlc.2015.05.020. [Epub ahead of print]

[5]------------------------------------------------------------------------

(a) Thromboprophylaxis in orthopedic surgery ; (b) Rivaroxaban ; (c) Apixaban ; (d) Messori A, Fadda V, Maratea D, Trippoli S, Marinai C. Testing the therapeutic equivalence of novel oral anticoagulants for thromboprophylaxis in orthopaedic surgery and for prevention of stroke in atrial fibrillation. Int J Clin Pharmacol Ther. 2015 Mar;53(3):211-9. doi: 10.5414/CP202183.

[6]------------------------------------------------------------------------

(a) Treatment of Moderate-to-Severe Psoriasis by Subcutaneous Route ; (b) Ustekinumab 45mg ; (c) Adalimumab ; (d) Messori A, Fadda V, Maratea D, Trippoli S, Gatto R, De Rosa M, Marinai C. Biological drugs for the treatment of moderate-to-severe psoriasis by subcutaneous route: determining statistical equivalence according to evidence-based methods. Clin Drug Investig. 2014 Aug;34(8):593-8.

[7]------------------------------------------------------------------------

(a) Anti-reabsorptive treatment in women with osteoporosis ; (b) Risedronate or ibandronate or denosumab ; (c) Alendronate ; (d) Messori A, Fadda V, Maratea D, Trippoli S, Marinai C. Anti-reabsorptive agents in women with osteoporosis: determining statistical equivalence according to evidence-based methods. J Endocrinol Invest. 2014 Aug;37(8):769-73.

[8]------------------------------------------------------------------------

(a) Intravenous proton pump inhibitors for stress ulcer prophylaxis in critically ill patients ; (b) Omeprazole ; (c) Pantoprazole ; (d) Messori A, Fadda V, Maratea D, Gatto R, Trippoli S, De Rosa M, Marinai C. Intravenous proton pump inhibitors for stress ulcer prophylaxis in critically ill patients: determining statistical equivalence according to evidence-based methods. Int J Clin Pharmacol Ther. 2014 Oct;52(10):825-9.

[9]------------------------------------------------------------------------

(a) Stroke prevention in atrial fibrillation: ; (b) Novel oral anticoagulants ; (c) Devices for closure of appendage (Watchman) ; (d) Messori A, Trippoli S. Left atrial appendage occlusion devices vs pharmacological agents for stroke prevention in atrial fibrillation: testing non-inferiority. Journal of the American College of Cardiology 2015 (in press) http://www.osservatorioinnovazione.net/papers/jacc2015.pdf

[10]-----------------------------------------------------------------------

(a) Biological drugs for inducing remission in patients with Crohn’s disease ; (b) Certolizumab ; (c) Adalimumab ; (d) Messori A, Maratea D, Fadda V, Trippoli S, Marinai C. Biological drugs for inducing remission in patients with Crohn's disease: determining statistical equivalence according to evidence-based methods. Arch Med Sci 2014 in press http://www.osservatorioinnovazione.net/papers/arch-med-sci-2014.pdf

On 2015 Nov 17, Suomeng Dong commented:

Erratum: The repeat content (%) of Magnaporthe oryzae is 10% instead of 52% (Table1). We are sorry for any confusion we brought by this mistake. Authors: Suomeng Dong, Sylvain Raffaele, and Sophien Kamoun.

On 2015 Nov 30, Chandan Kumar commented:

Actually, author is listed at the bottom of the article as Robert P. Kruger

On 2017 Dec 15, Franz Schelling commented:

Is it allowed to remind this fact: An improved lesion detection cannot make do for a clear lesion identification: T2 hyperintense ovoid areas can hardly be regarded as a hallmark of a particular pathology. It is quite sobering besides if brain loss and (a growth in) T2 lesion volume and counts must be viewed to as the clinical MS trials' typical imaging endpoints.

On 2016 Jan 30, Johannes M Dijkstra commented:

Dear Rachel Wolfson,

Thank you for your extensive answer, and my compliments for your work and attitude.

Johannes Dijkstra

On 2016 Jan 28, Rachel Wolfson commented:

My name is Rachel Wolfson and I am one of the co-first authors on this paper. I am submitting these comments on behalf of all the authors.

1) Yes, we have noticed the shift in the Sestrin2 band. The modification on Sestrin2 is phosphorylation. This phosphorylation seems to be induced by binding to GATOR2, as overexpression of GATOR2 is sufficient to drive the phosphorylation of Sestrin2. We have created mutants of Sestrin2 that are either phospho-mimetic or that do not get phosphorylated. In either case, these mutants bind leucine to similar degrees as wild-type Sestrin2, still bind to GATOR2, and have leucine-regulated interactions with GATOR2. Thus, the phosphorylation of Sestrin2 does not seem to be important for any of the conclusions made in our papers. Furthermore, the leucine binding data and crystal structure were obtained from Sestrin2 purified from bacterial cells, which is not phosphorylated. Future work will be needed to understand the function of Sestrin2 phosphorylation.

2) We agree that understanding how leucine can have such a profound effect on the Sestrin2-GATOR2 interaction is a fascinating question, and this was indeed a major motivation for us to solve the crystal structure of leucine-bound Sestrin2. Below are some points to consider:

A) Due to the highly specific and closed nature of the pocket (observed in Fig. 2A of Saxton et. al), leucine is able to make numerous direct contacts with Sestrin2, including 2 salt bridges and 6 hydrogen bonds, in addition to the hydrophobic van der waals contacts, which all together could contribute several kcal/mol of free energy. This is a non-trivial amount in the context of protein-protein interactions (which are also noncovalent). For an intuitive comparison, consider that the mutation of just two acidic residues (DD406-407AA in Fig. 5 of Saxton et. al) likely corresponding the elimination of 2 salt bridges at the Sestrin2-GATOR2 interface, is sufficient to completely abolish the Sestrin2-GATOR2 interaction.

B) In addition, our model actually suggests that the leucine signal is amplified: not by external factors, but rather by its ability to facilitate a conformational change in Sestrin2 that allows for the formation of additional stabilizing contacts. For example, the closing of the lid and formation of the latch contacts, observed in Fig. 3 of Saxton et. al.

With these considerations it becomes easy to imagine how leucine binding could contribute enough free energy to overcome the Sestrin2-GATOR2 interaction. Importantly, the ability of small molecule mediators to have profound effects on protein-protein interactions is not specific to Sestrin, but is actually a common theme found throughout biological signaling systems and forms the basis for many drug discovery efforts.

3) Thank you for catching the mix up in the blots. Both control blots look nearly identical and while our mistake does not affect any of our conclusions we have asked Science to have the correct panel inserted. Here is an image of the published and corrected figure: http://i.imgur.com/aHT8PV0.png

Rachel Wolfson, Lynne Chantranupong, Robert Saxton, and David Sabatini

On 2016 Jan 28, Rachel Wolfson commented:

None

On 2016 Jan 26, Johannes M Dijkstra commented:

The Sabatini group published two related articles, Wolfson et al. and Saxton et al. Saxton RA, 2016, in the January 1^st edition of Science. They convincingly showed that the interaction between Sestrin2 and GATOR2, which affects mTORC1 activity, is leucine-dependent, and that the Sestrin2 molecule has a specific pocket for binding leucine. I think that overall their study is an important and solid contribution to science. However, I have a few issues/questions in regard to their discussion/presentation of the data.

1. The authors did not discuss that their Western blot analyses suggest that Sestrin2 is represented by multiple differently modified forms, the largest of which is increased by leucine starvation and has the highest affinity for GATOR2 (or FLAG-WDR24). I couldn’t find any mentioning in the two articles by the Sabatini group of the fact that Sestrin2 is represented by multiple, probably differently covalently modified, forms. However, Wolfson Fig. 1A cell lysate anti-Sestrin2 shows that absence of leucine in the cell medium enhances the presence of a larger band, and playing with the contrast of the Fig. 1A IP-FLAG anti-Sestrin2 picture suggests that it is this larger band which efficiently binds to FLAG-WDR24 or its associated proteins (the GATOR2 complex). Once one is aware of this, once can find this phenomenon in many figures of the two papers, of which I will only give a few examples. In Wolfson Fig. 3B cell lysate anti-Sestrin2 picture, the larger Sestrin2 band disappears with larger concentrations of leucine, and this larger band seems to represent the form that is most efficiently precipitated with anti-FLAG-WDR. In Wolfson Fig. 4B cell lysate anti-HA-Sestrin2 picture the relative amount of the larger Sestrin2 band increases when the binding site for leucine was mutated, and similar effects might be present in Saxton Figs. 2D, 3D and 4C; admittedly, in those Saxton figures the cell lysates were not directly analyzed prohibiting a distinction between differences in presence and efficiencies of co-precipitation. Actually, this leucine-dependent (probably covalent) modification of Sestrin2 into a form which is more efficiently bound by the GATOR2 complex, fits beautifully with the major conclusion of the authors that Sestrin2 is a leucine-dependent regulator of GATOR2 activity. However, strangely, the authors did not discuss this phenomenon at all, leave alone that they investigated the nature of the modification(s). The only model that they postulated was an effect of leucine on Sestrin2 conformation (and not on covalent modification).

2. I wonder how non-covalent binding of a single leucine can provide enough energy to directly break the specific interaction between two (much larger) proteins. By showing that leucine can interfere with the interaction between Sestrin2 and GATOR2 when added to cell lysates for 2h at 4°C, Wolfson et al. claim to provide evidence that enzymatic activity is not necessary for explanation of the leucine effect. Within the in vitro experimental setting they are probably right in this, and the in vivo effect on apparent Sestrin2 size (see item 1) is not observed. However, I am not a biochemist, but wonder how non-covalent binding of a single amino acid can provide enough energy for disrupting a specific bond between two proteins. Shouldn’t the leucine signal somehow be amplified? I guess that in vivo it may be amplified by stimulation of some covalent change (see item 1), and that in vitro it may be amplified by the binding of Sestrin2 to additional cellular factors or by the immunoprecipitation procedure. I know that the authors do not particularly exclude the possibility of such amplification, and that their Saxton Fig. 5D model may be a simplified depiction of the core principle. Nevertheless, especially since I don’t know enough about these matters and would like to learn, I would appreciate if the authors and others could discuss this matter. Hence, this item 2 is more a question than a criticism.

3. The pictures portraying anti-FLAG-metap2 in Fig. 1B IP:FLAG and cell lysate seem to be identical. From checking the rest of the papers and because of the nature of the duplication, I deem it an unintentional honest mistake.

In summary, the Sabatini group made very important and believable contributions to elucidation of the mTORC1 pathway system in regard to Sestrin2 structure and its leucine sensitivity. However, they failed to note a very important observation, and their explanation model needs discussion. I would very much appreciate if the Sabatini group, but also other experts on the energy of protein interactions, could discuss the above items 1 and 2.

On 2015 Oct 20, Gaetano Santulli commented:

"G-protein-coupled receptor kinase 2 and hypertension: molecular insights and pathophysiological mechanisms".

Santulli G, Trimarco B, Iaccarino G. High Blood Press Cardiovasc Prev. 2013 Mar;20(1):5-12. doi: 10.1007/s40292-013-0001-8.

PMID: 23532739 http://www.ncbi.nlm.nih.gov/pubmed/23532739

Full text: http://www.researchgate.net/publication/235747571_G-Protein-Coupled_Receptor_Kinase_2_and_Hypertension

On 2016 Jan 25, Robert Eibl commented:

The publication could have included a reference on the first specific measurements of beta(1) integrins on living cells: IEE Proc Nanobiotechnol. 2004 Jun;151(3):128-32. Molecular resolution of cell adhesion forces. Eibl RH1, Benoit M. PMID: 16475855

On 2015 Oct 11, Donald Forsdyke commented:

GC% – A COLLECTIVE VARIATION THAT FOSTERS SPECIATION

Among members of a species there is generally a mean genomic GC% value with a bell-curve distribution about this mean. The small group to the left of the mean are biased towards low GC%. The small group to the right of the mean are biased towards high GC%. These fringe groups can be said to have collectively varied away from the mean.

In keeping with the proposal that the reproductive isolation needed for speciation would be fostered by a collective variation (1), it has been shown how differences in GC% would impair recombination between a group on the fringe of the bell-curve and the main species group at the centre of the bell-curve (2). Other conditions being propitious (e.g. further rein is given to natural selection), a fringe group could then become a separate species with its own bell-curve GC% distribution.

Thus, if through reproductive isolation the low GC% group departed the main species, the population mean value would move slightly to the right (higher GC%). While Mugal and her colleagues (3) provide a valuable review of the literature on genomic base composition, the implications for speciation are not mentioned. For more please see my speciation text (4) and my bioinformatics textbook (5). There are also recent PubMed comments (6, 7).

(1) Romanes GJ (1886) Physiological selection: An additional suggestion on the origin of species. Journal of the Linnaean Society, Zoology 19, 337-411.

(2) Forsdyke DR (1996) Different biological species "broadcast" their DNAs at different (G+C)% "wavelengths". J. Theoret. Biol. 178, 405-417. Forsdyke DR, 1996% "wavelengths".")

(3) Mugal CF, Weber DD, Ellegren H (2015) GC-biased gene conversion links the recombination landscape and demography to genomic base composition. BioEssays 35: (in press) doi:10.1002/bies.201500058 Mugal CF, 2015

(4) Forsdyke DR (2001) The Origin of Species Revisited. McGill-Queen’s University Press, Montreal.

(5) Forsdyke DR (2011) Evolutionary Bioinformatics. 2nd edition. Springer, New York.

(6) Clément Y, Fustier M-A, Nabholz B, Glémin S. (2014) The bimodal distribution of genic GC content is ancestral to monocot species. Genome Biology and Evolution 7, 336-348. Clément Y, 2014

(7) Turner LM, Harr B (2014) Genome-wide mapping in a house mouse hybrid zone reveals hybrid sterility loci and Dobzhansky-Muller interactions. Elife Dec 9;3 doi: 10.7554/eLife.02504 Turner LM, 2014

On 2017 Oct 03, Morten Oksvold commented:

I am puzzled how the authors can be sure they are stuyding exosomes, referring to the TEM data in figure 6 and 7. The presented micrographs could be everything from artefacts in the grid to dust or other rubbish.

On 2015 Oct 25, Brendan Everett commented:

We appreciate and agree with Dr. Gortler’s comments about the long-term benefits and safety of statin therapy in preventing important clinical cardiovascular events. We expressed concern in our Perspective that PCSK9 inhibitors might be broadly substituted for statins, when statins have a substantial body of evidence supporting their role in cardiovascular event reduction, as well as an excellent safety profile. This is of particular concern among patients with statin intolerance, which remains a difficult condition to define. For example, approximately 70% of patients who were considered unable to take statins prior to enrolling in a blinded alirocumab study who were randomized to the statin arm were able to tolerate atorvastatin 20 mg for 24 weeks. Nonetheless, many patients cannot tolerate the intensity of statin therapy that would be indicated based on their own specific clinical situation, even after switching statins or trying alternate-day dosing, as suggested by Dr. Gortler. While many non-statin treatments for hyperlipidemia have demonstrated safety, very few of these medications have shown evidence for cardiovascular event reduction when added to ongoing statin therapy, even when those statins are not at goal intensity. For patients and physicians caught in this clinical bind, PCSK9 inhibitors may represent a reasonable adjunctive therapy, particularly if the ongoing studies show evidence of cardiovascular event reduction with a tolerable safety profile. - Brendan M. Everett, Robert J. Smith, and William R. Hiatt

On 2015 Oct 11, David Gortler commented:

Unlike PCSK9 inhibitors alirocumab and evolocumab, long term findings from statins show that statins are unquestionably beneficial and safe for lowering LDL-cholesterol in hypercholesterolemic and hyperlipidemic patients. Prescribers are far too hasty to label their statin patients as intolerant, often grossly misdiagnosing and/or not differentiating between myopathy, myalgia and rhabdomyolysis due to a lack of established critera. True statin intolerance is very rare -- and there are clear pharmacologic options in those cases. Most obvious: if a patient experiences statin intolerance with one particular statin, he may be eligible for dosing of any one of the six other FDA approved statins available on the market.

Statin intolerance may be attributed directly to drug levels in the body and good data in multiple clinical pharmacy publications have shown that QOD dosing of the Type 2 statins cuts down true and legitimate cases to about half. For those that are still statin intolerant, there are non-statin drug treatment options for hyperlipidemia, all of which have more long-term safety data as compared to PCSK9 inhibitors alirocumab and evolocumab.

There is a “niche” need for PCSK9 inhibitors alirocumab and evolocumab for patients who fail all statin and all other pharmacology treatments, or who are unable to meet their goals with all available pharmacological treatment options. This residual population represents a very small percentage of hyperlipidemic patients eligible for the PCSK9 class.

On 2016 Aug 23, Ben Goldacre commented:

This trial has the wrong trial registry ID associated with it on PubMed: both in the XML on PubMed, and in the originating journal article. The ID given is NCT0161323. We believe the correct ID, which we have found by hand searching, is NCT01613235.

This comment is being posted as part of the OpenTrials.net project^[1] , an open database threading together all publicly accessible documents and data on each trial, globally. In the course of creating the database, and matching documents and data sources about trials from different locations, we have identified various anomalies in datasets such as PubMed, and in published papers. Alongside documenting the prevalence of problems, we are also attempting to correct these errors and anomalies wherever possible, by feeding back to the originators. We have corrected this data in the OpenTrials.net database; we hope that this trial’s text and metadata can also be corrected at source, in PubMed and in the accompanying paper.

Many thanks,

Jessica Fleminger, Ben Goldacre*

[1] Goldacre, B., Gray, J., 2016. OpenTrials: towards a collaborative open database of all available information on all clinical trials. Trials 17. doi:10.1186/s13063-016-1290-8 PMID: 27056367

* Dr Ben Goldacre BA MA MSc MBBS MRCPsych<br> Senior Clinical Research Fellow<br> ben.goldacre@phc.ox.ac.uk<br> www.ebmDataLab.net<br> Centre for Evidence Based Medicine<br> Department of Primary Care Health Sciences<br> University of Oxford<br> Radcliffe Observatory Quarter<br> Woodstock Road<br> Oxford OX2 6GG

On 2017 Jul 07, Wei Wang commented:

Several issues has been raised about this paper on PubPeer below I highlight a few of the comments:

Comment #1: "This review focuses on highlighting two research papers coauthored by Maria Barna. Peers have raised questions about both papers and the questions remain unanswered: 1) https://pubpeer.com/publications/A77C7AE5A8AEF8F5E36C4FC7139B03 2) https://pubpeer.com/publications/25409156

The review omits many of the seminal papers, including:

1) The the ribosome filter hypothesis that introduced the idea of specialized ribosomes in the post-genomic era: Mauro, V.P., and Edelman, G.M. (2002). The ribosome filter hypothesis. PNAS 99, 12031–36

2) Earlier demonstrations of translation initiation dependent on the interaction between IRESs and ribosomal proteins: Landry, D.M., Hertz, M.I., and Thompson, S.R. (2009). RPS25 is essential for translation initiation by the Dicistroviridae and hepatitis C viral IRESs. Genes Dev. 23, 2753–64".

Comment #3: "This review offers two line of evidence for heterogeneous ribosomes:

1) Levels of mRNAs encoding ribosomal proteins. -- Inferring protein levels from mRNA levels is generally precarious, especially for ribosomal proteins that correlate very poorly (or even negatively) to their transcript levels. For example see Figure 2c in Zhang et al., 2014: doi:10.1038/nature13438. Why are these data not mentioned ? -- There is wealth of transcript data, and the data included in this review are among the least convincing.

2) Protein separated on 1-D gels and stained with coomassie blue -- How do the authors know that the spots correspond to ribosomal proteins, as apposed to translation factors ? -- How do the authors know that the spots do not correspond mostly to immature ribosomes ? -- How do the authors know that the spots staining is quantitative ? -- I did not find these papers convincing decades ago when they were first published, and they did not convince the community. Are they more convincing now? What am I missing?

Many of the references are incorrect. Examples include asserting a change in the ribosomal composition, while the referenced article actually reported change in the total cytoplasmic levels of ribosomal proteins or change in their rate of protein synthesis."

On 2017 Jul 04, Randi Pechacek commented:

Jennifer Glass, first author of this paper, wrote a blog on microBEnet that chronicles her journey from first falling in love with marine science as a college freshman, to the first original research paper out of her own lab.

On 2015 Sep 30, Bill Cayley commented:

A good example (even if low-quality evidence) of when "Less" is "More" in fracture care. Other similar evidence is at: https://lessismoreebm.wordpress.com/?s=fractur

On 2015 Oct 19, David Keller commented:

Actual patient wait times were not measured directly, and the estimation method was flawed

In their editorial comments about a study on patient waiting times in medical clinics, Ross and Katz state "on average, Americans spend 80 minutes at a clinic to receive care, during which approximately only 20 minutes are spent face-to-face with the physician" [1]. They implicitly attribute the remaining 60 minutes of clinic time to excessive waiting and call for "effective interventions to shorten the time patients spend waiting."

However, the "other activities" patients engaged in during their 60 minutes in the clinic when they were not face-to-face with the physician included "completing paperwork, paying bills, interacting with non-physician staff and/or waiting", as noted in the study's Discussion section [2]. One important way in which patients interact with non-physician staff is having their blood drawn for tests ordered by the physician. An electrocardiogram, if indicated, would be obtained during this time, usually without the doctor's face anywhere in sight. Other tests, such as spirometry, audiometry, visual testing, even the measurement of height, weight and vital signs are performed by non-physician staff, while the ordering physician might be examining another patient altogether.

The bottom line is that the data sources used in this study only ascertained 2 time intervals in the doctor's office: the total time patients spent in the doctor's office, from arrival to departure, and the duration of facetime with the doctor. Subtracting the facetime from the total time spent in the office does not provide accurate information about the amount of time the patients spent waiting. They may have been undergoing diagnostic or therapeutic interventions during this interval rather than just waiting.

References:

1: Ross JS, Katz MH. No Time to Wait. JAMA Intern Med. 2015 Oct 5:1. doi: 10.1001/jamainternmed.2015.5393. [Epub ahead of print] PubMed PMID: 26437319.

2: Ray KN, Chari AV, Engberg J, Bertolet M, Mehrotra A. Disparities in Time Spent Seeking Medical Care in the United States.JAMA Intern Med. Published online October 05, 2015. doi:10.1001/jamainternmed.2015.4468.

On 2015 Oct 11, David Keller commented:

Time is Money - the cost of reducing outpatient waits for medical care

The editorial "No Time to Wait" argues that when a patient is made to wait a long time to receive care from a physician "the implicit message is clear: the patient’s time is less important than the clinician’s", adding that "if a patient must wait a long time every time he or she sees the doctor, there is a problem in the system" and concludes that doctors "need additional work" to "shorten the time spent waiting." I reply below:

First, physicians who intentionally keep patients waiting to send a message about the importance of their time should have their licenses revoked before they can do any real harm. All zero of them.

However, in the clinic, the doctor's time is clearly a scarce and valuable commodity which must be allocated efficiently among many patients. This task is complicated by the fact that each patient requires an unpredictable amount of physician time to diagnose and treat. In addition, it is common for a doctor to allow a number of patients with urgent problems to be added onto an already full schedule, and for patients who do have appointments to simply not show up, without notice. It is rare for these no-shows and added-on appointments to occur with the timing required to cancel out each other's effects.

The underlying reason doctors run late is overbooking, which is the practice of scheduling more patients to be treated than there is time on the schedule for their treatment. The opposite of overbooked time is downtime, when there are no patients for an available physician to treat during office hours, when there are high fixed overhead expenses. Overbooking reduces physician downtime caused by no-shows, but it increases the number of patients waiting to be treated, reducing physician downtime at the cost of increased patient waiting times.

In order to heed the call to reduce patient waiting times, overbooking could be reduced or eliminated. However, less overbooking would also increase physician downtime, because fewer patients would be waiting and ready to fill in for no-shows, which often occur in clusters. Overbooking increases waiting times for patients, but it reduces costly physician downtime. Are patients willing to pay extra for the convenience of reduced wait times?

Low physician payments and marginally profitable practices increase the need for overbooking to ensure that patients are waiting for the physician, and not the other way around. Actions taken to reduce patient waiting times may have the unintended effect of increasing physician downtime, and thereby jacking up the cost of medical care. Lastly, requiring "additional work" of already overworked physicians to reduce patient waiting time could cause unintended side-effects far more deleterious than spending an hour or twelve in a waitinig room.

On 2016 Aug 26, Brandon Horn commented:

The phagocytic function of neutrophils is decreased significantly with the addition of glucose (PMID:4748178). Dextrose (the "placebo") is simply D-glucose. This would compromise patients' immunological function: a highly relevant effect given the outcome measure of this study. Therefore, dextrose is an inappropriate "placebo" and essentially invalidates the conclusions of the study. See PMC:3137704 for a discussion of the improper use of sham control groups.

On 2015 Oct 07, Bill Cayley commented:

Suggestive evidence that when it comes to beta-blockers and non-cardiac surgery, "Less" is better": https://lessismoreebm.wordpress.com/?s=beta

On 2015 Dec 12, Yuwei Fan commented:

Figure 3 doesn't make any sense. How could they compare materials with curves? Release should always be expressed by either accumulative release amount or release rate.

On 2015 Nov 04, Jeffrey Beall commented:

I am commenting here to express a concern about this article, "Clinical significance of microRNA-130b in osteosarcoma and in cell growth and invasion." My concern is that the article contains unattributed text that matches or nearly matches the text of the article "miR-218 expression in osteosarcoma tissues and its effect on cell growth in osteosarcoma cells": Wang HT, 2014. Both articles appear in the same journal. The earlier article was published in late 2014. The later article was published at the end of July, 2015 and does not cite the earlier article, despite the abundance of similarities.

On 2015 Oct 08, David A Coil commented:

This comment is cross-posted from the original article.

This is the first time I’ve commented on an article using this system, but this paper was so riddled with problems I felt that I had to start. “Respiratory” is mis-spelled in the title and the rest of the paper is in a similar vein. I understand that it is difficult to write in a foreign language, and that seeing “have your paper read by a native English speaker” is annoying. However, in this case the writing is so confusing as to be nonsensical in places. For example, I’ve read this sentence a dozen times and I still don’t know what it means “This reminder the potential network monitor of this method due to the lower detection limit of which VS culture based technology and the easy handling of the system.”

But what I really can’t understand how the spelling mistakes made it through editorial and peer review (starting with the title). Just a few examples easily found by any spell checker include “postion”, “microorgnisms”, “maliganant”, “leathal”, and “noncosomicol”. Not to mention random capitalization such as “Petri dish” and “petridish” in the same paragraph.

I won’t get into the lack of stats, the total lack of references to much of the related work in the field, and the fact that demonstrating the increase in taxa seen by metagenomics versus culturing is not exactly news.

On 2017 Mar 05, thomas samaras commented:

This results of this study are consistent with a similar study by Shapiro, et al. This study is also consistent with many longevity and mortality studies published over the last 40 years. For example, a short list is presented next.

He, et al. Japanese-Hawaiian: shorter elderly have lower mortality and live longer Chmeilewski: Based on 800,000 deceased Polish men and women, shorter people live longer Samaras: Eight difference types of studies support the greater longevity of smaller people Samaras: shorter men lived longer based on a study of deceased San Diego veterans Mueller: shorter elderly West Point graduates had a lower mortality after 60 years of age Salaris: shorter deceased men in Sardinia lived longer Miller: shorter men and women who died in Ohio lived longer Willcox: short Okinawans have highest percentage of centenarians Wilhelmsen: men who were shorter at 67 years of age were more likely to reach 90 years of age Bartke: smaller body size promotes greater longevity

On 2016 Jan 25, Dimitrios Tzalis commented:

The European Public Compound Collection (PCC) is a very unique collection of compounds that are already synthesized and available for screening within ELF Screening Campaign. The goal of the paper was to compare PCC with other compounds that are available for biological screening or that were actually screened. That is why, with a full awareness, we have analyzed it against part of the PubChem collection called MLP of NIH, commercially available Maybridge and already tested compounds represented by ChEMBL. It might be interesting to collate the PCC and the 15 millions of patent-extracted compounds, in respect to broadly understood novelty, but we wanted to avoid the contamination of our comparison with theoretical compounds. In such a way the work is much more consistent. Nevertheless, thank you for your valuable comment and we can think of extending our novelty check also in respect to theoretical compounds in the future analysis since our collection is still growing. We believe that by focusing on exploring underrepresented chemical space of spiro-compounds and saturated, fused hetero rings we are offering a very competitive and unprecedented collection.

On 2016 Jan 14, Christopher Southan commented:

Interesting paper but it would have been more rigourous to define uniqueness against PubChem, especially since the recent patent-extracted chemistry expansion (see http://www.ncbi.nlm.nih.gov/pubmed/26194581)

On 2016 Oct 11, David Keller commented:

Frequent ejaculation is associated with lower incidence of prostate cancer: how frequent is frequent enough?

Kotb and colleagues conclude in this review that "frequent" ejaculation is associated with reduced incidence of prostate cancer.[1] This finding begs the question: how frequent is "frequent"? Two of the reviewed studies provided relevant answers.

A study of 2,338 men found that men who averaged 5 or more ejaculations per week in their 20's had only 2/3 the risk of later developing prostate cancer, compared with men who ejaculated less frequently.[2]

Another study, of 29,342 men, found the lifetime relative risk of prostate cancer for men reporting 21 or more ejaculations per month (about 5 ejaculations per week) was 33% lower compared to men reporting 4 to 7 ejaculations per month (about 1 to 2 ejaculations per week).[3]

Kotb and colleagues do not present any data on whether ejaculation rates significantly higher than 5 times per week are associated with even lower risk of prostate cancer, or whether the benefit maxes out at a certain rate.

References

1: Kotb AF, Beltagy A, Ismail AM, Hashad MM. Sexual activity and the risk of prostate cancer: Review article. Arch Ital Urol Androl. 2015 Sep 30;87(3):214-5. doi:10.4081/aiua.2015.3.214. PubMed PMID: 26428643.

2: Giles GG, Severi G, English DR, et al. Sexual factors and prostate cancer. BJU Int 2003; 92:211-6.

3: Leitzmann MF, Platz EA, Stampfer MJ, Willett WC,Giovannucci E. Ejaculation frequency and subsequent risk of prostate cancer. JAMA. 2004; 291:1578- 86.

On 2015 Nov 08, Lydia Maniatis commented:

As was the case with the authors' previous article this year (Testing the role of luminance edges..), this article should be read starting with the last section of the discussion (pp. 14-15). It is here that readers are filled in on methodological problems so severe that they (almost) render any theoretical criticism of the study moot.

We learn that pilot experiments showed that there was a “high variability in responses even between experienced observers.” In some conditions the “test patch” was so “hard to detect” that “some observers looked at the stimulus for a very long time trying to detect the test patch, while others simply matched the lightness of the grating bar.” In other words, in some conditions the “test patch” was for some viewers a purely theoretical construct of the authors.

The authors then attempted to make the task “more objective” (meaning the tried to make the data appear less messy) by imposing a forced-choice paradigm, but this couldn't solve the problem of the unseen target. On further testing, the authors found that “reducing presentation time...led to more similar behavior across subjects, so [they] opted for a lightness-matching paradigm with short presentation times.” Does “similar behavior” translate into comparable and/or interpretable behavior, or are subjects using an unknown strategy to achieve a common solution to an awkward task? What are they perceiving? Are they all perceiving the same thing? The authors don't know and don't seem to care, as long as the data seem consistent.

Unfortunately, despite all these manipulations, the data remained messy: “...two of our 11 observers showed behavior very different from the others, and the magnitude of both White's illusion and the effect of noise differed widely across observers...”

The authors understand that “One possible explanation for these difficulties is that the noise may make the matching task perceptually ill-defined.” In addition to ambiguity, it appears that “the noise can appear as a layer of clouds or haze in front of a homogeneous grating...At very high noise frequencies, the noise is so fine-grained that it is not difficult to get an impression of the average lightness of the test patch, which...may appear textured...At intermediate noise frequencies...it can be difficult even to detect the test patch as a separate region, which makes the matching most difficult.” Most difficult, indeed.

Three related facts should be very clear from the above description.

1) The data are uninterpretable and thus have no theoretical significance.

2) The descriptor “noise frequency” is wholly inadequate to describe a manipulation that produces qualitatively different effects, ranging from haze/clouds to textured surfaces to invisibility. It is theoretically and practically meaningless.

It is something like adding lines to a square to produce a cube percept, and describing the manipulation simply as “adding an intermediate number of lines;” or adding various chemical substances to a solution and describing them on the basis of their color. Such theoretically blind (a term that in perception science has a literal as well as metaphorical meaning) manipulations are antithetical to scientific investigation.

3) The first of the effects in (2) – transparent layers - cannot, to my knowledge (and please correct me if I'm wrong), currently be accounted for by any of the ad hoc spatial filtering models being tested, all of which are “successful” for a narrow set of stimulus types, but cannot begin to handle most perceptual lightness effects. Thus, they are already extensively falsified. The fact that contemporary perception science seems to give standing to failed models incapable of rationalizing their failures - even in principle - should not be allowed to obscure this fact.

In sum, this study contains no usable data and has no necessary theoretical purpose.

On 2015 Oct 03, Friedrich Thinnes commented:

miR-29 and VDAC-1

According to a recent paper of Reema Roshane et al. (2014) the expression of miR-29a is reduced in patients and animal models of several neurodegenerative disorders, including Alzheimer’s disease, Huntington’s disease, and spinocerebellar ataxias. Furthermore, the authors reported on cellular and behavioral effects of in vivo, brain-specific knockdown of miR-29. Large regions of the hippocampus and cerebellum showed massive cell death, reiterating the role of miR-29 in neuronal survival.

Interestingly, the apoptotic targets of miR-29, such as Puma, Bim, Bak, or Bace1, failed to show expected levels of up-regulation in mice, following knockdown of miR-29 while another miR-29 target, voltage dependent anion channel (VDAC-1), was found to be induced several fold in the hippocampus, cerebellum, and cortex of mice following miRNA knockdown.

Partial restoration of apoptosis was achieved by down-regulation of VDAC1 in miR-29 knockdown cells.

Anyway, it may pay to keep this observation on the schedule.

References

Roshan R, Shridhar S, Sarangdhar MA, Banik A, Chawla M, Garg M, Singh VP, Pillai B. (2014) Brain-specific knockdown of miR-29 results in neuronal cell death and ataxia in mice. RNA. 20:1287-1297. doi: 10.1261/rna.044008.113. Epub 2014 Jun 23. PMID: 24958907 Free PMC Article

Thinnes FP (2015) Plasmalemmal VDAC-1 corroborated as amyloid Aß-receptor. Front. Aging Neurosci., 30 September 2015 | http://dx.doi.org/10.3389/fnagi.2015.00188 OPINION ARTICLE

On 2015 Oct 05, Klaus Okkenhaug commented:

In their discussion, Louie and colleagues suggest that mesenteric B cells may inhibit Treg and that idelalisib dysregulates Treg by inhibiting B cell differentiation. Not only is this argument internally inconsistent, but also ignores the potential direct effect of idelalisib on Treg. PI3Kδ-deficient mice develop colitis Okkenhaug K, 2002, PI3Kδ-deficient Treg fail to prevent colitis Patton DT, 2006, and there is a T cell-intrinsic role for PI3Kδ required for effective suppression of CD8⁺ T cells Ali K, 2014. It is therefore reasonable and more parsimonious to sugest that idelalisib causes enterocolitis through a direct effect on Treg. In addition, if depletion of B cells were the main mechanism behind idelalisib-induced colitis, then surely rituximab would have a similar or greater effect as this is a more effective way of depleting B cells.

On 2015 Oct 03, Seyed Moayed Alavian commented:

Today the improatnce of occult HCV infection is more obvious and I think detection of HCV RNA in PBMC is critical for this issue. Yours Alavian SM

On 2015 Nov 03, Martine Crasnier-Mednansky commented:

Figure 7 is improperly done and rife with error. One of the characteristic of the PTS is that its substrates are transported and phosphorylated concomitantly. Therefore glucose phosphorylation does not occur inside the cell as depicted in the figure. Representation of the phosphorylation state of the PTS proteins is misleading (a pale P for Enzyme IIA^Glc does not lead to a dark P for Enzyme IICB^Glc).

The figure legend wrongly indicates excess glucose increases the level of 2-oxoglutarate thereby inhibiting the phosphorylation cascade. In fact 2-oxoglutarate, which accumulates in nitrogen limitation, inhibits the PTS phosphorylation cascade Doucette CD, 2011. On the other hand, an increase in nitrogen availability (figure 7C) causes an increase in glucose uptake, which cannot possibly activate adenylate cyclase to allow for transport of alternative carbon sources (in these conditions, glucose transport also prevents utilization of alternative carbon sources due to inducer exclusion). Thus, in the presence of glucose, a decrease in 2-oxoglutarate upon sudden nitrogen availability is unlikely to 'partially activate adenylate cyclase' and 'activate carbon catabolite pathways', as stated in the figure legend.

A direct inhibition of adenylate cyclase by 2-oxoglutarate, as depicted in Figure 7B, relies on questionable studies (see PubMed Commons comment attached to You C, 2013), and is not supported by data from Yang JK, 1983 (Table VII, caption a) indicating 10 mM 2-oxoglutarate (α-ketoglutarate) did not inhibit adenylate cyclase activity.

On 2015 Oct 13, Francesco Buonocore commented:

As you can see from: Bioessays. 2015 Aug;37(8):877-87. "Evolution of vertebrate adaptive immunity: immune cells and tissues, and AID/APOBEC cytidine deaminases." from Hirano M., one of the theory is that: "Around 500 million years ago, a common ancestor of jawed and jawless vertebrates evolved a genetic program for the development of prototypic lymphoid cells as a foundation for an adaptive immune system. This acquisition preceded the convergent evolution of alternative types of clonally diverse receptors for antigens in all vertebrates"

On 2015 Oct 02, Jens Staal commented:

Cool! Personally I am very curious about the adaptive immune system development between the lampreys and the sharks - especially since homologs of my "pet protein" MALT1 underwent a double duplication event from PCASP3 in lampreys to PCASP1(MALT1), PCASP2 and PCASP3 in sharks (and the rest of the vertebrates except mammals). My "gut feeling" says that this has something to do with the evolution of the adaptive immune system found in jawed vertebrates, since MALT1 is a critical signaling protein in T- and B-cell antigen receptor signaling.

On 2018 Jan 24, Erick H Turner commented:

As the last author on this paper, I must say that Dr Berger has a point. There do seem to be systematic differences in the degree of blinding. Can anyone be blind to the fact that he or she is receiving psychotherapy? And can an investigator be blind to whether he or she is administering psychotherapy (or which kind)? Perhaps we are comparing apples and oranges.

On 2018 Jan 21, Doug Berger commented:

It is hard to understand why the authors state that both psychological interventions and pharmacotherapy for depression are both "efficacious". While medications for depression have been studied and approved by the FDA based on clinical trials that are double-blinded and have a blind-placebo control groups, no psychotherapy has ever been studied with either a single-(patient blind) nor double-blind (patient and therapist blind), and neither has there ever been a blind-placebo control. It is impossible to weed-out the effects of hope and expectation that can bias results in psychiatric conditions such as depression that have subjective endpoints and large random error. "Blind raters" are not part of a double-blind and these raters only record the reports of unblinded subjects. Non-blind outcome research is only acceptable in conditions with objectively measurable endpoints such as bone fracture rates, myocardial infarction, stroke, tumor size etc.Thus, psychotherapy has never been actually shown to be "efficacious" in a clinical trial with robust control on bias (and never can be as the subject and treaters must be ublind to the treatment given).

These and other points are discussed in more detail and are referenced in this article: https://www.ncbi.nlm.nih.gov/pubmed/26870318.2

On 2016 Dec 18, Laura Williams commented:

Our online journal club discussed this paper on January 25, 2016. https://www.youtube.com/watch?v=YGA3Pn8dz7c

On 2016 Mar 06, Boris Barbour commented:

The debate continues under Blatt's follow up editorial Blatt MR, 2016.

On 2015 Dec 24, Michael R Blatt commented:

Dear Gerhard,

Thank you for your comment. Setting aside the issues of fraud and whistleblowing, I agree that there is no place for anonymous commenting in scientific debate.

Open debate is the cornerstone of scientific progress, especially in the "massively cooperative exercise" (to quote one of the PubPeer commenters) that is scientific research. Publication is only the beginning of scientific debate. Furthermore, contrary to arguments commonly raised about the flood of supposedly 'ultimately unreliable publications', history has shown time and again that progress often arises from what, in hindsight, is ultimately unreliable.

The SCIENCE article from 2011 that I referred to is a classic example. There was nothing fraudlent about the data presented at the time. It proved unreliable only in the hyperbole of its interpretation and it stimulated research leading to important insights about a transporter that scavenges phosphate in the presence of exceptionally high levels of the structurally similar arsenate anion.

Let us hope that this next generation of internet-literate scientists take the time to think through, and rectify, the conflated reasoning that has been promoted by certain elements behind PPPR.

Best regards,

Mike

On 2017 Jun 17, Misha Koksharov commented:

"Is what we do really science or a glorified marketing exercise?"

This is indeed a very interesting and controversial question. Opinions vary from "problems are minor" to "iceberg dead ahead, sir".

Yuri Lazebnik wrote a really interesting and thoughtful paper (Lazebnik Y, 2015) trying to dissect this problem.

At this time it may be even more important than his famous piece ('Can a biologist fix a radio?' Lazebnik Y, 2002) on still current challenges of comprehensive understanding of biological systems.

Regarding the marketing topic, the entertaining and educative paper by Dan Graur (Graur D, 2013) is too good not to mention here. He is also sometimes depicted as a 'vigilante scientist' (Bhattacharjee Y, 2014).

On 2015 Dec 15, Gerhard Nebe-von-Caron commented:

a thought provoking editorial indeed. Do we want to foster an environment were people hide in anonymity or do we want to promote openness and honesty. To turn into anonymity is only showing that one has no faith in openness and honesty as one is not prepared to take a personal risk for its value. If they are however not the foundation of ones science, is what we do really science or a glorified marketing exercise?

On 2015 Nov 01, Brandon Stell commented:

PubPeer has responded to this editorial in a post titled "Vigilant Scientists" http://blog.pubpeer.com/?p=200

On 2015 Oct 14, Jaime A. Teixeira da Silva commented:

I think we need to give time to all parties to evaluate the need, or not, for anonymity. I personally believe that anonymous opinions are important, even if sometimes there are risks involved, simply because a large segment of scientists might be feeling afraid to comment openly by name, not because they are trying to hide, or to be malicous in any way, but simply because they are afraid. The fear of whistle-blowers, vigilantes and vigilant scientists who prefer to comment anonymously needs to be respected.

A few things: 1) A disclaimer. I have never met, or communicated with Lydia, below. 2) Prof. Blatt has given his personal assurances to enact reform and improve the system at Plant Physiology. This is an extremely positive thing, and an example we would pray for in so many other plant science journals. So, to be fair, Prof. Blatt should be given some space, and time, to fulfill his promises. The only aspect I am concerned that he might not consider, is to act upon the anonymous voice. 3) Given the real risks, as Lydia has pointed out, of abuse by publishers to silence the voices of critics, I have opened up a question at ResearchGate, namely: When should scientists be banned by journals and publishers?

http://www.researchgate.net/post/When_should_scientists_be_banned_by_journals_and_publishers

On 2015 Oct 12, Lydia Maniatis commented:

Mike, T&S and Elsevier evidently have the de facto right to ban any author they want from their journals, for whatever reason they see fit, without warning, without appeal, making up the rules as they go along, picking off critics who annoy them. It doesn't matter whether you or I agree or disagree with their decision (should you choose to take a position); as you said in an earlier comment, it wouldn't make much difference. Given that these journals are conduits for scientific communication, this is an extraordinary power for the scientific (and any democratic) community – including the editorial boards of all the journals involved - to tacitly grant them. At a minimum, I would expect some verbal protest, some minor effort to push back on this worrying state of affairs.

Anonymity on PubPeer is here to stay, for all the excellent reasons its editors laid out in their blog post. It's clear that it has enabled more information to emerge, much in the public interest - and more information is better than less. From now on, scientists who publish their work should expect it to be gone over with a fine-tooth comb, and problems publicly aired, by Peers, Unregistereds, and people with names. You express faith in the majority of your colleagues – among these are the Peers commenting on PP.

In case there's a misunderstanding, I have no connection to, nor have I ever communicated with, Dr. T. da Silva. T&S's side of the story was laid out in the email they sent him, which was published in the article in Retraction Watch.

On 2015 Oct 12, Michael R Blatt commented:

Dear Lydia,

I did not unmask you; one of your PubPeer ‘Unreg’ colleagues did. However, that you should choose to hide in this way does not lend credence to your stance nor, as Moriarty notes, does it command respect.

Your desire to see the world in black and white also does not do Jaime’s cause justice. Let’s just say that it is presumptuous to suggest that I believe T&S acted properly. I did not declare my support for T&S. What I did say was that I reserve the right to withold comment until I can know the full details, or at least hear the other side of the argument. I would certainly welcome what further correspondence you (or Jaime) might have. However, you need to have the courtesy to allow me to think for myself.

On one matter we can agree, however: this conversation is probably over.

Regards,

Mike

On 2015 Oct 09, Lydia Maniatis commented:

Dear Mike,

Take your time. I think our conversation has run its course. You believe that Taylor and Francis may have acted properly, that it is sometimes OK for a publisher to ban an author. I believe the opposite, to the point that I find it difficult to believe they were within their legal rights. If and when you find the time to inform yourself to your satisfaction about this particular case, we can continue the conversation.

If I had been particularly concerned with guarding my anonymity on PubPeer, you would have needed to be far more clever to unmask me. Your attempt to make this conversation about me (to label me as "highly emotional" - another evasive tactic on your part) and your triumph in "unmasking" me as Peer 14, as though this mattered (did I make any comments there I should be ashamed of?) is one of the reasons I support anonymity. Fortunately, my participation in future PubPeer discussions, when I choose to remain anonymous, won't be subject to such unworthy, ad hominem tactics.

Regards, Lydia

On 2015 Oct 08, Michael R Blatt commented:

Dear Lydia:-

I can see that this is a highly emotionally-charged issue for you, whereas it appears less so for Jaime (though I can fully imagine why it might be otherwise). So, I do think it important to step back for a moment.

Let me relate another matter to you. This pertains to a case that goes back more than a quarter of a century and took place in a university in the mid-West of the United States. I was peripherally associated with the case, primarily because of my knowledge of the professor involved (a good friend, as it happens, and we remain so still). The professor, let’s call him Fred for now, became embroiled in an argument with his head of institute. The details of the argument are less important than the consequences. Fred was so aggrieved by the way he felt he had been treated, that he became disruptive, aggressive and threatening to other academic staff and students alike. In the end, following disciplinary proceedings, Fred was barred from the institute and took ‘early retirement.’ From my own perspective, I could understand why Fred was aggrieved – I, too, felt that the initial handling of the argument was problematic – but I could also see that his reaction was inappropriate and disproportionate, and that the institute had no choice but to bar him. In effect, Fred was within his rights, but was unwilling to accept responsibility for his actions and their consequences.

I am not suggesting that there is a parallel here, but I recall the story to point out that there are always two sides to an argument. In Fred’s case, I was close enough to the events that it was easy to see what was going on, from both sides. In Jaime’s case, I have gathered what information I can from RetractionWatch, but I note that the information is presented almost entirely from his perspective. In your insistence that I choose a side, do you really mean to deny me the right to hear both sides of the argument?

Bests,

Mike

p.s. I’ll need to attend to my own day job now, so it may be a few days before I respond to any more comments.

On 2015 Oct 08, Lydia Maniatis commented:

Are there circumstances that, in your opinion, would justify banning an individual from the literature in order to stifle and punish legally protected speech?

If not, then it's not much of a stretch to say that you oppose, not only the "idea that a scientist could be unjustly banned", but the real-life act itself, as inflicted, for example by Taylor and Francis, on TdS. Do you still feel uncomfortable making such a statement, and if so, what type of information do you feel you would need in order to make a decision, one way or the other - to be able to say, in other words, either: "I think what Taylor and Francis did was proper or justifiable;" or "I think TdS was banned unjustly as the consequence of signed critiques."

As discussed in my earlier comments, I think it's important that you take a position on this. It's hollow to say, well, I oppose injustice/censorship in theory, but I won't take a position on any particular case. You might as well be for it.

On 2015 Oct 08, Michael R Blatt commented:

Dear Lydia, My apologies for misinterpreting your question. Let me also rephrase my answer then. Of course I am dismayed at the idea that a scientist could be banned unjustly from publishing as the consequence of signed critiques. Bests, Mike

On 2015 Oct 07, Lydia Maniatis commented:

Dear Dr. Blatt: Please allow me to rephrase my question: Do you oppose, as a matter of principle, the banning of scientists from the scientific literature by corporations in retaliation for their speech? If not, then I can only surmise that you endorse the right of your own journal, and any journal, to ban troublesome critics. Is this correct? Ethically speaking, do you believe scientific publishers have the right to punish their critics in this way?

As he himself points out, the Texeira da Silva case is extremely pertinent to what we are discussing here. It shows that the system can effectively silence critics (that he stubbornly persists is to his credit, but he has been gravely disadvantaged). So as an ardent opponent of anonymous post-publication peer review, the choice you are proposing is this: a. Don't criticize the scientific establishment; b. Criticize by name, but don't expect members in good standing of said establishment to stand up for you - even when your scientific speech is censored in retaliation (what worse can happen to a scientist?). You will simply be neutralized if your criticism hits too close to the bone, and that will be OK with, for example, Dr. Michael Blatt. This isn't a case where an institution can fudge an excuse about irreconcilable differences – this is banning from the literature because a corporation wants to silence a critic! The situation could not be more clearcut, nor your reply more evasive.

In short, and with all due respect, you cannot play the innocent bystander in all this and still be a credible voice in the conversation. Anyone could be next. What if you were banned by PubPeer, for your opposition to anonymity? I suspect you would have something to say about that. I am not asking you to “speak out without knowledge,” but to inform yourself about, and take the proper action with regard to -at a minimum, express an opinion - facts that are, again, highly pertinent to the present conversation.

On 2015 Oct 12, Michael R Blatt commented:

Dear Jaime,

There are a lot of threads in your comment above. However, I suspect that your stance in ‘vigilance’ is not that different from the Anglo-Saxon definition. Certainly, you will understand the commonality of the two.

I guess where we part ways is that I do not see academia as somehow deeply tainted. Of course, as with any human endeavor, there are always a small number of individuals who will misuse the system. However, I am cautious to apply generalizations (I think Oscar Wilde had something to say about this!). The majority of the colleagues I have come to know in my career are firmly committed to improving society through knowledge and understanding, and they are open to criticism and debate. They certainly do not fall in the category of self-serving hypocrits.

With best regards,

Mike

On 2015 Oct 08, Jaime A. Teixeira da Silva commented:

Mike, once again, thank you for taking the time to respond. I guess you never imagined what a response your editorial would bring. Again, you should be praised for bringing the topics of anonymity and post-publication peer review or PPPR to the table among more respectable plant scientists. As you now know well, I have been struggling for years to convince plant scientists (and I have been in contact with several tens of thousands already) that there are very serious problems with the publishing process like traditional peer review, with what I perceive to be pseudo-ethics by some of the mainstream STM publishers, or at least double standards, and problems that range from small to serious in a wide range of plant science journals. I have even seen some comments critiquing Plant Physiology papers. This then tells me, as you have already confirmed, that there are some very fundamental problems. And one of the reasons why some of the most basic problems do not appear to be resolved is because of what I call an "editorial firewall". In other words, editors and publishers who are actively resisting correcting the literature for sometimes some very valid reasons, such as no pay, no time, or too much stress. Their excuses are sometimes valid, but the truth of the matter is that the problems remain and the issues don't get resolved. And this is ultimately their responsibility. Editors benefit from the glory of their positions, journals benefit from gambling the impact factor, which brings with it tremendous economic benefits since the IF is literally used as a form of currency in some countries. That is why individuals like me stand up against what we perceive to be hypocrisy, failure in leadership, double standards, lack of editorial ethics, common sense and professionalism, and cronyism.

I know, like you, that those who hold a position in academia have much to lose, including their position, salary, benefits, travel funding and of course research funding and grants. So, the vast majority most likely do not see any benefit in getting involved with PPPR, because it does not benefit them. This is the true sad part about the plant science community: it’s ultimately selfish. Indeed, some will argue ferociously about this claim, but think about it, for whose good exactly are you serving when you are serving as the EIC of Plant Physiology? What is the end game and final objective? Actually, I suspect that in your particular case, the objective is noble and the means to achieve it are thorough. So, it is not individuals like you whose integrity I am questioning. I am questioning the integrity of editors who have abused their power and positions, as I have documented abundantly about Elsevier’s Scientia Horticulturae and some editors in Taylor and Francis journals. Revelations about other editors in other publishers’ journals are likely going to surface as this “ban Jaime” trend expands.

But we will expand on these issues in more detail later on because they are intricately linked with your editorial.

To answer your question: yes, I am a science vigilante. When searching for the term vigilante online, it tends to result in a definition that is associated with anti-governance, anti-law, anti-establishment and, most importantly, using criminal methods. At least that is the predominant definition in the Anglo-Saxonic literature, and thus based upon which your editorial’s title has been based. Yet, in Latino cultures, the term “vigilante” means to be vigilant, or aware, or conscious. And it is within this framework that I would like to consider myself as a vigilante, as one who is aware of the issues, is concerned with them, and who is taking a pro-active stance to resolve them. Yet, I use no illegal methods or weapons, even though I have often described the state we are in in science and science publishing as a war. So, those who criticize my methods of criticism, who emphasize tone over facts and who prefer to point out politically-insensitive language over academically unsound literature are, very unfortunately, those who are in power. In editor boards, serving as the front-line of academic defense (actually farce) for publishers, and serving as PR managers for the publishers’ share-holders. I get it know. They really don’t like my voice. But they do lke to make profit from my intellect… do you understand what I’m getting at, Mike?

If in fact you did manage to see the move I pointed to, you will see a common thread between the grass-roots struggle. That is why I believe that the anonymous voice must never be removed, despite its darker side, because it serves to balance the scales of excessive and abusive power and injustice. It is this powerful elite that is hoping to expand, as Pope Francis so eloquently describes as the “globalization of indifference”. Have a good day Mike. Hope to continue this conversation at PMC.

On 2015 Oct 08, Michael R Blatt commented:

Dear Jaime:-

Okay. I’ve just checked my OED and Wikipedia. Here’s the latter’s summary:

"Vigilante justice" is often rationalized by the idea that adequate legal mechanisms for criminal punishment are either nonexistent, insufficient, or inefficient. Vigilantes typically see the government as ineffective in enforcing the law; such individuals often claim to justify their actions as a fulfillment of the wishes of the community.

Now, to answer your questions, perhaps obliquely, would you not agree that PubPeer has effectively (if inadvertently) associated itself with vigilantism? And is it not possible for such activities to include some identified individuals, even if the larger number are faceless? Finally, do you consider yourself a vigilante?

I suspect that you are coming back to the questions of anonymity, scientific commentary, and whistleblowing. Could I point you to the post on PubPeer (below)?

Unreg from 5th October: Whistleblowers need protection.

Scientists do too. For all its good intentions, PubPeer has become the Reddit of the sciences, full of bullies and harassers. Blatt’s editorial says in a nutshell “Don’t feed the trolls”.

Vigilante justice assumes guilt and is associated with murder by mob. Fortunately in science as in society at large we have agreed-upon systems to protect the rights of both the innocent and the guilty (yes, even those who err or worse should be treated with due process).

It takes little investment to pull up a figure, adjust the contrast, and slap it onto FigShare. Then the “guilty until proven innocent” army chimes in. How many times have you read words to the effect of “If you have nothing to hide than show us the blots”, and threatening statements to the effect of “hiring committees need to be informed of this”. (Yes, I realize a few criticisms are meticulously documented on PubPeer, but the majority involve little intellectual investment – I assume that this is the intention of Blatt’s widely disparaged comments about “minor issues with blots”).

Can you imagine a world where we interacted by shouting at each other “Your top button’s unbuttoned” “Your socks don’t match” – valid statements yes, but ultimately pointless. Is this really PubPeer’s vision for post-publication peer review? I don’t see where Blatt says there is no place for criticism, just an appeal for that criticism to be meaningful. Whether or not anonymity has a place in PPPR is an interesting question, but Blatt has a right to express his opinion.

A massively cooperative function like science requires a level of courtesy that goes beyond even those we afford to individual citizens. I applaud PubPeer for its efforts to initiate PPPR, but appeal for the implementation of policies that remove the witch-hunt element.

As I noted in my response to you before, anonymity embeds inequality in any debate and, from my perspective, is the cause of more problems than it solves. I noted too, in my response to Leonid Schneider, that I would be one of the first to jump onboard with PubPeer if they found a way to address the problems associated with anonymous posting.

I hope this helps.

Bests,

Mike