On 2019-02-16 22:44:42, user Seth Bordenstein wrote:

A few comments and thanks for posting and sharing your article. Hope this helps.

A. Note that primers which joined the two types of cifs (in your paper cid and cin) hit a repeated sequence and possible insertion site as a template and not the flanking regions that include the CI genes. So it is possible that you may have sequenced the repeated intergenic regions, and not the actual flanking regions for the junction. The forward primer is repeated in prophage WO regions (e.g., head, tail genes). The reverse primer is in the intergenic region adjacent to the transposase and could very well be part of a repetitive insertion site for the transposase sequence. If you push your primers out to the adjacent CI genes, you might reliably see if this is artifactual joining or not. We’ve been through something similar in the lab. All that being said, it would be very interesting if wYak swapped its Type I cifs for some other Type cifs in the same location, as the singular contig in Figure 5 implies. This could be confirmed with PCR and Sanger sequencing.

B. Figure 5 wMel shows a 5Kb gap between 632 and 633, but we only detect a 1Kb gap in the genome; that’s how we illustrate in our schematics too. Double check that. Seems off? Note there are definitely no other cif genes in that Type I family.

C. wYak cifB has a truncation at the N terminal end that may or may not ablate its function. Important to note that wRi cifB has a similar N terminal truncation and yet may cause strong CI. Nothing to really stress here, just pointing it out for context

D. Line 32 - Important to cite that WO prophage loci cause and rescue CI (Shropshire 2018). Only one group has shown rescue of CI in flies.

E. Line 34 - Now established that wMel can cause strong CI under the right conditions. Important to clarify.

F. We typically italicize genus names throughout, unless there are some journal specific rules.

G. Lines 347-350. Note that only the A protein, not the B protein, was found in spermatheca of mated females. Also note that Beckmann et al did not show rescue in D. melanogaster as implied by the citation and wording. Rescue in flies was only shown by Shropshire et al. 2018.

H. A likely explanation for transfer of CI loci is that phage WO rampantly transfers between A and B Wolbachia. This literature should be cited as a highly probable explanation for the transfers.

Great system and lots of fun ahead.

On 2020-04-26 14:01:28, user Marko Hyvonen wrote:

Hello, <br /> Interesting manuscript. A quick comment on Figure 1. Looks like the patient data for panels C and D are identical. Could you check and perhaps amend?<br /> Marko

On 2021-06-30 19:11:57, user Roberto Efraín Díaz wrote:

In your article, you refer to 3FY1 as a murine AMCase. It is a human AMCase expressed in Chinese Hamster Ovary (CHO) cells. Have you considered using Rosetta to build a homology model of murine AMCase using 3FY1 as a template?

On 2019-10-02 14:19:18, user Tom & Tom wrote:

This paper was submitted to a journal and was rejected with the following main concerns (paraphrased here by the manuscript authors):

1) The paper lacks details on the custom microphone used, and the testing protocol, making reproduciblity of our experiments impossible.<br /> 2) The paper should have included a more extensive assessment of the drones in real-world data collection scenarios to demonstrate their effectiveness<br /> 3) More detail on the drones' construction is needed so that others can reproduce them<br /> 4) More detail is required on the exact modifications made to reduce noise and quantification of the impact this had on signal to noise ratio.<br /> 5) More detail is needed for the real-world tests, including flight duration, adherence to regulation, calls per unit time, and comparison to static or 'on-foot' surveys of the same location.

On 2019-12-29 04:47:44, user Peter Rogan wrote:

Alternative splicing may also be the result of common polymorphisms: https://www.biorxiv.org/con...

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On 2020-10-31 20:24:40, user Janet Lee wrote:

This is the first study to link cytokine mediated inflammation and cell death pathways in COVID-19 infection. STAT1/IRF dysregulation appears to be a common signature observed across studies this study by the Kanneganti lab opens up therapeutic possibilities for patients exhibiting cytokine storm phenotype in severe COVID-19 disease.

On 2022-09-14 22:22:30, user Ohainle Lab wrote:

How do we explain that although IP6 binds both hexamers and pentamers and seems to play a more important role stabilizing pentamer form IP6 induces hexamers in vitro?

On 2017-05-15 04:40:03, user Michael R. Crusoe wrote:

Looks great! FYI: the correct citation for CWL is https://dx.doi.org/10.6084/...

On 2020-11-30 05:00:07, user Sergio Munoz wrote:

It would be a good idea to compare this to other more recent and presumably accurate trimming software such as ZORRO and Divvier. Cheers,

On 2015-06-19 00:48:10, user Niranjan Nagarajan wrote:

Thank you for the feedback and comments. A new release of OPERA-LG with more error-reporting and a few bug fixes is out. This should hopefully handle BWA input better. The code for PacBio scaffolding should be out soon as well. Finally, we will expand on the staged-strategy in a revised version of the manuscript to make it clearer.

On 2020-09-12 12:42:24, user Jeffrey J. Gray wrote:

This paper has been peer-reviewed and published now: https://www.nature.com/arti...

On 2021-01-07 12:26:55, user Marco Paoli wrote:

Nice paper..and I find quite interesting that OSNs innervate glomerular cortex in T1-3 but the whole glomerulus in T4 glomeruli (as in honeybees)

On 2024-12-12 18:59:34, user Adrien Jolly wrote:

Dear authors,

Thank you very much for this great study. Many smart ideas, much food for thought.<br /> I have a specific concern regarding figure 6. If I understand correctly, you make the assumption that the frequency of Ki67 positive cells directly correlates with proliferation speed. I find this assumption problematic, Ki67 protein accumulates in S-G2M and is degraded in G0/G1 (see for instance PMID: 30067968). One can find that, at steady growth, a shortening of SG2M will actually reduce the proportion of Ki67+ cells, (a shortening of G1 will however increase it), depending on these parameters, the growth rate of the population could be significantly larger for big clones with no change to the proportion of Ki67+ cells. With the Fucci markers combined with ki67 you might be able to resolve this question, but I can imagine it would be very difficult to also identify different clones in this case.

Cheers,

Adrien

On 2015-03-18 14:45:21, user Andrew Brown wrote:

This is a new version of the paper, to match a new version of the software hosted here: http://www.sanger.ac.uk/res...

The changes are:

1) The software can now take input from the stdin, allowing it to be incorporated into a pipeline.<br /> 2) The spline function for estimating pi0 now matches that used by the qvalue package, meaning both implementations will now give the same results. In my experience, the new FDR estimates tend to be slightly less conservative than previous.<br /> 3) There is a new --sep flag, specifying the delimiter to be used in the output.

Andrew Brown

On 2019-12-12 15:43:24, user Caitlin Aamodt wrote:

Very cool paper! I think there is a typo on page 8. "not enriched among the transcripts with high ribosome occupancy at the."

On 2019-03-27 23:43:44, user Arie Horowitz wrote:

Dear authors,<br /> May I provide some feedback?<br /> 1. The experimental data is sparse relative to the sophistication of the model.<br /> 2. Ex-vivo and in vivo (in zebrafish) testing of the predictions of the model would obviously <br /> increase the physiological significance of the study.<br /> 3. VE-cadherin may translocate from cell junctions without the formation of a physical gap. <br /> Visualization of f-actin would be a more robust evidence of gaps.<br /> 4. The videos are not accessible on this website.

Best regards

On 2017-03-01 05:32:47, user Rob Lanfear wrote:

My lab just read this preprint, and I thought I'd pass on our thoughts in the hopes that they are helpful.

First, we thought the approach seems eminently sensible, very useful, and that the analyses were informative.

A few things we thought might be worth considering:

1. Similar to some comments on Twitter, we wondered about the choice of variant callers to include as comparisons, and why many commonly-used callers were excluded.

2. We found the table really hard to interpret. Perhaps this is just because it's difficult data to represent, but we did wonder about the extent to which the sets of variant calls overlapped / differed, as well as the FP and FN rates. It also took us quite a bit of head scratching to get to the point where we realised that the dbSNP138 column percentages were so important to the interpretation.

3. We found the definitions of False Positives and False Negatives confusing (we appreciate that there are limitations to the short format though). This is mostly because it seems from the dbSNP138, Omni 2.5, and other results (final para of the ppr), that many/most of the False Positives are probably not False Positives at all. For this reason, we thought it might be clearer to redefine FP and FN simply in terms of differences to the GIAB NA12878 data.

4. Related to 3, but also more generally, we really wanted to see some simple simulations, so that one really could determine FP and FN rates. For my money, a simple and effective approach here is to do something like the NextGenMap paper (https://academic.oup.com/bi... "https://academic.oup.com/bioinformatics/article-lookup/doi/10.1093/bioinformatics/btt468)") which simulated 4 read sets from Human, Arabidopsis, and Drosophila, then another 11 read sets from Arabidopsis with increasing polymorphism (0-10%). Results could be summarised quickly in a single figure, comparing real FP and FN rates under simulation.

A final comment, not really relevant to the current paper: we wondered about extending the method to include technical replicates (i.e. independent extractions and libraries from the same sample). E.g. to include 3 technical replicates at 20x each, which should allow one to account quite effectively for errors from library construction and base-calling.

On 2021-01-24 22:49:04, user John Lisle wrote:

Unhappy news.<br /> A pragmatic regulatory approach that enables fast-cycle development within a broad structural family is essential.

On 2025-08-31 16:10:50, user Der Schilling wrote:

The article has been published in ISME Communications:<br /> ISME Communications volume 1, Article number: 30 (2021) <br /> https://www.nature.com/articles/s43705-021-00032-0

On 2020-10-13 07:28:47, user Tony Hillier wrote:

Is the cause of H.pylori a factor in choice of best treatment please? ie whether bacteria or anti-inflammatory drugs caused?

Friend in Kenya has it and considering kefir treatment.

Thanks

Tony UK

On 2018-02-05 07:34:28, user Samuel Terkper Ahuno wrote:

A great multi-omics study...

On 2020-07-02 08:56:10, user °christoph wrote:

Fantastic work. Clearly a study that advances the understanding of FtsZ-dependent divisome formation and therefore deserves rapid peer-review and publication. However, here - and elsewhere - it has become fashionable among authors to refer to previous work on their subject as "...remains poorly understood." This expression tends to devalue previous efforts, which is especially unfair in this case. A phrasing like "...not completely understood" or, maybe, "...not well understood" could express a more modest recognition of their own work as yet another of the customary incremental steps towards an understanding.

On 2020-09-01 19:02:36, user Giovanni Lentini wrote:

I'd like to congratulate the Authors who demonstrated that our hypotheses were sound (cfr. Lentini et al. COVID-19, Chloroquine Repurposing, and Cardiac Safety Concern: Chirality Might Help. Molecules 2020, 25 (8). https://doi.org/10.3390/mol... "https://doi.org/10.3390/molecules25081834.)")

On 2023-10-05 06:23:48, user John McBride wrote:

Thanks for the comment. This is a very good question. I will refer to the energy-minimized structures as "relaxed" and otherwise "unrelaxed". In this work I only analyzed the relaxed structures.

There were so many different things to check that I never got round to checking the effect of energy minimization originally, but I did make sure to save all of the unrelaxed structures. So I re-ran some of the analyses (originally done on the relaxed structures) with the unrelaxed structures.

(1: Structure correlations) When comparing AF-PDB correlations for pairs of structures where sequences differ by 1-3 mutations, relaxed and unrelaxed structures give almost identical results. For the case of no mutations, the correlations are actually higher for unrelaxed structures (r=0.38) compared to relaxed structures (r=0.33). This would reduce the residual correlations in Figure 1H by about 0.05. For reference, in Figure 1H the residual AF-PDB correlations range from about 0.15 to 0.35.

(2: Blue fluorescence correlation) I checked the strongest AF-phenotype correlation, from Figure 2C. For unrelaxed I get r = -0.92, for relaxed I get r = -0.93.

It seems that the energy minimization does help, but it is certainly a minor part of the overall prediction.

Bear in mind that this analysis is nowhere near as extensive as what went into the paper, so I might have missed something. The paper has now been accepted, so I don't think it is possible to add this in a new version.

Thanks again for asking this important question. I'm personally glad to know the answer (even if it is a bit preliminary).

On 2023-10-24 01:24:43, user Anshule Takyar wrote:

Hello! This is a good piece of work, and the value to the field is very evident. It is great to see novel sequencing methods like Oxford Nanopore sequencing being validated more and more, and by employing a Nanopore-only approach, you have probably helped to assuage some of the anxieties of others in the field regarding this technique. I had a few questions and recommendations regarding this technique. Have you sequenced T. cruzi, or the Tulahuen strain specifically, with short-read sequencing? Are there any hurdles involved with that? Also, do you think that by assembling this genome using the help of short-read sequencing, you would have gotten a better result? Additionally, I think that it would be helpful to show in a figure which coding regions are not impacted by transposable elements, as that would increase the significance of your work. Other than that, I really liked this work, and congratulations!

On 2019-11-21 00:43:46, user Charles Warden wrote:

While I haven't directly worked with Nanopore data myself, there was a clear effect on species assignments in this paper (when using full barcodes versus mini-barcodes), as you can see in the comment:

https://www.biorxiv.org/con...

For Illumina, I am not sure how you are defining "full" versus "mini" barcodes, but I have definitely encountered enough issues with "index hopping" that I am at least a little concerned about discussions with increased multiplexing (even though cross-contamination can occur at various steps).

In terms of what I can currently cite, I have some notes on Biostars about possible QC metrics for de-multplexing:

https://www.biostars.org/p/...

While the PhiX is kind of a special case (which I believe you typically only see with single-barcode samples, even though I would guess there are probably other events that are more difficult to define). However, since PhiX spike-ins don't have a barcode, that is one example of a de-multiplexing issue includeed in that discussion:

https://www.biostars.org/p/...

Otherwise, I noticed drops in I2 (i5) index quality scores (with 100x100 reads), which might be a red flag for some runs (and a possible disadvantage to having a second barcode to assign samples).

While I think the most important point for Illumina de-multiplexing is that these problems are often batch effects (hard to see unless you consider a large number of batches), there was a more limited example with a small fragment size (to show that you can get at least some wrong sample assignments, even with Illumina dual-barcodes):

https://github.com/cwarden4...

On 2016-03-14 03:25:46, user kcowing wrote:

Sequencing DNA in Space http://spaceref.com/nasa-ha... "NASA is not often known for making the best use of existing COTS (commercial off the shelf technology) aboard the ISS. Then again, sometimes they are. This is an example of when the agency really grabs cutting edge biotech and sends it into space."

On 2018-04-14 14:10:02, user Arun wrote:

Worldwide Patterns of Ancestry, Divergence, and Admixture in Domesticated Cattle<br /> http://journals.plos.org/pl...

Bos taurus taurus was domesticated in the Middle East while Bos taurus indicus was domesticated in India.

It is likely is that a hypothetical Punjab_N population from even before agriculture would have been related to the Iran_N people, somewhere along a cline between Iran_N in Iran (whose aDNA has been found) and peoples in India's interior.

If Iran_N(eolithic) ingressed into India with a demic diffusion of agriculture, they didn't bring their cattle along.

On 2018-06-12 12:28:42, user Christophe Lamaze wrote:

A great study with the first cryo-EM on these intriguing tunneling nanotubes. A big step forward as this study convincingly shows that TNTs are structurally different from filopodia and that it can exchange, as nicely visualized here, cargos between distant cells. Beautiful work!

On 2015-12-17 17:47:09, user Christophe Leterrier wrote:

Our manuscript is now published (OA) in Cell Reports:<br /> http://www.cell.com/cell-re...<br /> with the following DOI: http://dx.doi.org/10.1016/j...<br /> Thanks for you interest in our work!

On 2017-02-09 02:24:56, user Jeremy Horst wrote:

Accepted @MalariaJournal!

On 2020-12-31 17:10:44, user fei_he wrote:

the denominator of Eq. (6) should be A_{22} (f), sorry for the typo :-)

On 2022-02-08 20:31:53, user smd555 smd555 wrote:

Dear authors! My question is - what is the current understanding of the genetic origin of the Baltic bronze (namely, samples from Kivutkalns)? Can they be unambiguously derived from previous known genetic components, or is some component missing? Thank you.

On 2017-03-08 18:29:21, user Jørgen K. Kanters wrote:

Very interesting and important paper. Only one comment: In extended data table 1 You use the ISOGG haplogroup nemes like I2a1a2a1a. These names have the drawback that they often changes dynamically when new haplogroups are found, and will likely be outdated at some time. Why are You not using the terminal SNP (or at least in paranthesis) instead

On 2020-02-01 23:01:05, user AronF wrote:

We really ought to be given the 'E value' of the BLAST hits to the HIV sequences in order to determine the actual "unlikely[hood]" of the 2019-nCov matching the HIV-1 inserts. That is the very reason the E-value exists. The fact of 100% coverage means little if there is an abundance of hits with 95% coverage for example - in this case the E value would be high.

On 2022-06-30 05:39:56, user NATTASIT PRAPHAWI wrote:

Hi, you have done a great work! <br /> 1) I noticed that you might need a correction on Fig.7 <br /> "Fig.7 Chromatin condensation promotes ~~osteogenesis~~ adipogenesis of hMSCs cultured on soft hydrogel"<br /> 2) It would be great if hMSCs cultured on stiff hydrogel were included as a control in every experiment.<br /> Best,

On 2020-07-15 20:02:08, user Nick Miller wrote:

Nice work!

One minor technical question. Might the "lag" seen in DvvGr43-mediated effects (lines 444 - 454) simply be due to a lag in receptor knockdown by RNAi? Even if RNAi gets rid of the DvvGr43a mRNA quickly, it could still take a while for protein turnover to clear out pre-existing receptor molecules.

On 2024-09-03 18:05:44, user Greg Ira wrote:

https://www.nature.com/articles/s41467-024-52147-2

On 2019-09-19 16:14:12, user H. Etchevers wrote:

I had previously pointed out that Kaspersky antivirus had flagged the website as engaging in phishing. After I asked them to look into it, they have now removed the flag as a false positive. ("It has been confirmed as a false positive. The link will be excluded from our anti-phishing databases.")

On 2025-01-31 13:21:04, user Koyam Morales Weil wrote:

Updated work can be found here:<br /> https://doi.org/10.1523/JNEUROSCI.1717-23.2024

On 2025-07-08 17:07:35, user Danny Yupa wrote:

The methodological approach you propose through the Genetic Diversity Index (GDI) represents a significant advancement in incorporating the genetic dimension into spatial biodiversity analyses. It is particularly valuable due to its scalability and the use of already available public data. However, its implementation presents methodological and structural limitations that must be urgently addressed to ensure robust and applicable results. The exclusive reliance on GenBank introduces clear geographic and taxonomic biases, as regions such as Eastern and Northern Europe are underrepresented, as well as ecologically dominant families like Asteraceae and Rosaceae. This unequal coverage can distort the patterns of genetic diversity presented, affecting the representativeness of the index. Moreover, reducing genetic diversity to a single metric ? significantly limits the analysis, excluding key aspects such as heterozygosity, genetic differentiation, and population structure, which are fundamental to assessing genetic health and connectivity. Another important issue is that the GDI assigns equal weight to all species, without distinguishing those that are rare, functionally important, or endangered. This may lead to a biased prioritization that favors regions with more available data rather than those with greater conservation urgency. Additionally, the study does not present a clear proposal for how to integrate the GDI into public policies, restoration plans, or protected area systems, nor does it consider current threats such as land-use change or habitat loss. Therefore, we recommend complementing GenBank with other genetic databases such as EMBL, BOLD, or GBIF; incorporating additional metrics that better reflect actual genetic diversity; establishing ecological weighting criteria among species; and linking the index’s results with real-world conservation scenarios and decision-making. With these adjustments, the GDI could become not only a methodologically robust tool, but also a practical, equitable, and useful instrument for the global conservation of genetic biodiversity.

On 2018-12-17 17:07:52, user Mariana Schuster wrote:

Thank you for posting this preprint. I am glad to see some experimental evidence around the conservation of effectors in “non-pathogenic” smut fungi. In particular I like the idea of encouraging people to study these species more in detail.

Here some thoughts and questions:

Given that “smuts” has many definitions. I would precise your definition in the introduction. I believe you are using here the term smut as synonym of: belonging to Ustilaginales?

If I understood it correctly, your hypothesis that Pseudozymas might be pathogenic is based on the fact that P. prolifica is conspecific with U. maydis. Another piece of data supporting this hypothesis, at least for some former Pseudozyma species, and that you might like to mention would be our comparison of the secretome of two Pseudozyma species to those of plant pathogenic smut fungi (https://www.sciencedirect.c... "https://www.sciencedirect.com/science/article/pii/S1087184516301530)") These data also suggest that not all former Pseudozyma species might still be pathogenic, something one could also discuss in the context of this manuscript.

Where do the 211 core PSEPs come from? I could not extract this number from Sharma et al, 2015.

Given that comparative genomics results highly depend on the quality of the genomes used, I would suggest to provide quality data on the genomes you are using or comment on this in the manuscript especially since you are working with some draft genomes (according to the cited publications). I would expect even more conservation when using high quality genomes.

Line 40. You mean “penetrating the host for colonization”?

On 2019-06-24 21:29:29, user ThePatrickWatsonLab wrote:

Hello! Very nice paper-- we are also interested in post-translational modification of SR proteins. I am wondering if you could provide more clarity regarding your phos-tag gels. They way they are currently labeled, they are difficult to interpret. Is it possible to include size markers?

On 2017-07-11 12:29:42, user Omnes Res wrote:

I posted a detailed criticism of this preprint here:<br /> https://medium.com/@OmnesRe...

Jordan Anaya, creator of PrePubMed and OncoLnc

On 2019-05-15 08:45:58, user M Parker wrote:

Combining structural information with machine learning seems to be a powerful approach for predicting drug resistance, however this work seems to have essentially just replicated work that was published last year (https://doi.org/10.1164/rcc... "https://doi.org/10.1164/rccm.201712-2572LE)"), and replicated many of the same figures, with no real gain in performance or insight.

On 2017-09-17 21:09:51, user shengchao li wrote:

This is a mini-review of this article by Metz, DG and Brainard, MS. Praises are omitted. Only concerns that may potentially improve the article are presented. I do not have major concerns. Follwing are some minor concerns.

1. Reference 12 should have only 2 authors (Mandelblat-Cerf and Fee) but 6 authors were listed.
2. There are both learners and non-learners of songbirds. The first paragraph of Introduction sounds like there are only learners. Also the song structure described there may be specific to certain songbirds.
3. Fig 2C caption said the matrix was M by N. Should that be N by M?
4. Fig 5B. The curves should not start from zero. This point will be apparent if a non-deafened control curve is added to the plot. It would start from zero, deteriorate at week two and keep flat afterwards. This would be misleading. The correct way is to use a separate set of songs for each of the birds before deafening, compute their CE's with their reference sets, and use these CE's at time 0.
5. It is not clear from the text or caption of Fig 6 whether the data was from Bengalese finch or from Zebra finch. I guess they are from Zebra finch. But it was not indicated.
6. Figure 6D caption does not match Figure 6D.

Thanks.

On 2018-04-06 15:19:34, user Haut Mar wrote:

Hi Guys,

I was wondering what could be the chance of success of a gene therapy supplemented by immunosuppressive drug as we do for organ transplant in order to inactivate the T Cell ?

On 2018-02-09 10:33:44, user Chris Foulon wrote:

We organized a Preprint Journal Club with the Frontlab (at the Brain and Spine Institute in Paris) to discuss and propose a review of this paper. Don't hesitate to contact us to further discuss.

PREPRINT REVIEW<br /> Participated to the Review:<br /> Chris Foulon, Daniel Margulies, Antoni Valero-Cabre, Benedicte Batrancourt, Pedro Alves, Richard Levy, Alexandre Routier, Marcela Ovando Tellez, Johan Ferrand-Verdejo, Angélina Bourbon, Emmanuelle Volle, Lara Migliaccio, Chloe Stengel, Michel Thiebaut de Schotten<br /> In their paper, entitled 'An empirical, 21st-century evaluation of phrenology', Jones et al. revisit the phrenological ideas of Gall and Spurzheim using modern neuroimaging techniques.<br /> Principles established by Gall at the beginning of the XIXth century were essential for establishing localizationism as a framework for brain mapping. Such approaches remain central to the methods we employ today in any study that compares voxels across individuals. In addition, the notion of a statistical association between localized brain shape and function is still very much alive in voxel-based morphometry, cortical thickness and Jacobian determinant analyses. However, one of Gall and Spurzheim's assumption, that the shape of the brain induces relatively sharp changes on the surface of the skull, and therefore that the surface of the skull can be used to infer the form of the brain, has been broadly dismissed as wrong. Empirical evidence for discarding the phrenological hypothesis is nevertheless lacking, and constitutes the focus of the current study.<br /> First, we want to salute this scientific effort. Notably, the concept of phrenology and the motivation to carry on this research is very well explained. The authors employed one of the most powerful dataset (uk biobank n=6000) to assess whether or not there was some truth behind the Gall and Spurzheim's assumption. In brief, the study found no significant relationships to support the phrenological hypothesis. <br /> However, as it currently stands, we felt the analyses fell short of adequately supporting the negative conclusions of the study. The analyses make substantial efforts to test the principles put forward by Gall and Spurzheim, but we believe the study could provide further insight by instead testing their hypotheses. In other words, our field is largely founded on the hypothesis that variation in localized brain structure relates to differences in behavior. This can be directly linked to the phrenological hypothesis of Gall and Spurzheim. However, if phrenology is empirically demonstrated to be wrong, and our current framework is right, where does the relationship between morphology and human behavior breakdown? Are the behavioral categories of Gall and Spurzheim to blame? Or is the assumption that skull morphology reflects local variation in cortical morphology faulty? We believe that tracing the assumptions of phrenology more closely with respect to current neuroscientific approaches could provide both a judicious assessment of a long-maligned field, but also further insight into where our own current assumptions succeed and fail. <br /> More specifically, we would offer the following suggestions for consideration by the authors:<br /> First, testing lifestyle but not real neuropsychological tests do not really assess the hypothesis of the link between the functional specialisation of a brain area, its size and its subsequent deformation on the skull. Additionally, the multiple regression discretely assume a proportional relationship between the measures whereas we have reasons to believe that Gall and Spurzheim had a more bimodal vision of the phrenology (bump or no bump that is the question).<br /> Second, the methodology could be further clarified to provide a clear argument.<br /> T1w images were aligned linearly in the MNI152 linear then surfaces were created to compare the curvature of the vertices between participants. Such approach will capture changes in curves, but not plateaus. This means that the measure the authors have chosen will be sensible to the scale and is underpowered to detect big cranial bumps. A surface ratio measure applied to the skull surface might be more accurate. Alternatively, would a Jacobian approach be more appropriate?<br /> Comparing vertices one by one increase drastically the number of comparisons (= no significance), how about directly testing Gall's parcellation?.<br /> Gyrification index is not a measure of the local volume of the brain and is not assessing the relationship between the size of brain areas and deformation of the skull. <br /> Finally, a univariate regression, rather than a multivariate regression, would be more appropriate and respect better the standard phrenological practice. <br /> Result section should be expanded. Particularly, non-significant statistics do not demonstrate the inexistence of an effect. What does meaningful really mean here?

A few suggestions <br /> Letter fluency can not have dof = 18<br /> How were the 3D meshes transformed into a sphere? <br /> Can people expand on the potential future research related to the correlation between fluency and the number of sexual partners? <br /> Is there some covariance in the skull morphology?<br /> It would be interesting to use a stepwise analysis of the surfaces that are modelled to see when their relationship breaks down.<br /> Can the authors run the same analysis as Smith et al. 2015?

On 2018-03-25 03:59:14, user Alan VanArsdale wrote:

This suggests the invocation of so much convergence in hominins in general can reflect weak fundamentals.

On 2020-02-10 08:04:05, user Aaron wrote:

Wait - so n=1 ?

On 2024-08-14 18:37:38, user Christian Gaser wrote:

now published in GigaScience:<br /> https://doi.org/10.1093/gigascience/giae049

On 2022-10-31 15:54:07, user Daniel Lüdke wrote:

Figure 5: It would have been interesting to see the water-soaking phenotypes as these would have been expected to appear at around 24. Can a water-soaking phenotype be “reversed” once plants are shifted from LD to LL 24h after Pst infection. Same for the stomatal aperture.

On 2018-03-18 12:55:06, user Grimm wrote:

A few things:

If you want to get feedback, you may want to include the main text figures in a better resolution. The large chronogram looks fun, but one can't read the names. You could provide a version of your chronogram (ultrametric tree) that can be opened with a treeviewer such as FigTree or Dendroscope.

And although I find the general idea worth exploring, I worry a bit about your data base: the divergence in atpB and rbcL differs profoundly from that in the matK, and the same holds for 18S (highly conserved) and 25S (about same level as matK, but focussing on different aspects of angiosperm phylogeny). Also, towards the leaves of your angiosperm tree, the plastid and nuclear signals are not fully congruent. Forcing incongruent data into one tree increases the branch lenghts (missing data can have the same effect), which may (or may not) be critical to your BAMM analysis. <br /> For one tiny bit of your tree, the Fagales subtree, I can assure you that 18S vs. your plastid genes is comparing apples with pears, we just had a post on Genealogical World of Phylogenetic Networks (GWoN) about it: <br /> http://phylonetworks.blogsp...

For the Santalales there maybe similar issues, but I only re-analysed the Loranthaceae neighbourhood; details/links can be found in this GWoN post:<br /> http://phylonetworks.blogsp...

I couldn't find any information about the gappyness of your matrix or nuclear-plastid congruence. According Supplement Table S1, at the genus level there are no gene gaps, but what about within-gene missing portions?

You also use a lot of old sequences of mediocre quality, the L... and U... accessions have not a few pseudomutations/editing artefacts. I realised this when I recruited the Soltis et al. (2011) matrix for a total evidence experiment (see footnote 7 in this post: https://researchinpeace.blo... "https://researchinpeace.blogspot.fr/2017/12/age-of-angiosperms-may-palaeobotany.html)"). I ended up spending some time cleaning out the old accessions (L.../U....) and replacing them by cleaner, newer data from genebanks, not rarely from Soltis et al. themselves. In particular the 18S and 25S partitions are not in good shape in Soltis et al.'s (2011) matrix. It is poorly curated. They just add new genes with every paper, but never bothered to update the older partitions. And rbcL, 18S, 25S, atpB and matK are among the very first ones. My feeling is that this is a neclectable problem with respect to the breadth of your data set. I uploaded my curated matrix (reduced taxon set that fitted our needs, nevertheless includes all your gene regions) to figshare: https://doi.org/10.6084/m9..... Mainly, you don't want to include re-transcripts of originally sequenced 18S and 25S rRNA fragments (by the way, in plants its "25S" [or "28S"], "26S" is a widespread error that sipped into phylogenetic literature in the late 90s).

As I see it, you would need to infer single-partition trees, so one can assess the contribution of each gene to the combined tree and its branch-lengths. At least run a nuclear vs. plastid analysis, just to make sure you have no incongruence-induced artefacts.

And I hope, once your paper is published (I have little doubt it will be), you will provide your matrix as open data (why? See again this GWoN post: http://phylonetworks.blogsp... "http://phylonetworks.blogspot.fr/2018/02/we-want-to-publish-our-phylogenetic.html)")

Probably a nice and interesting paper, but lacks a bit awareness about the primary signal isssues in the used data (not uncommon in dating studies)

Cheers, Guido

On 2018-03-19 13:19:41, user Richard Grant wrote:

This is a great title you've come up with. Kinda deserves to be a hashtag. #30clues

On 2020-01-05 16:50:53, user JJ wrote:

Where is the github repository for this?

On 2025-10-28 07:51:10, user Karthik Raman wrote:

https://www.sciencedirect.com/science/article/abs/pii/S2213343725046561

On 2021-05-04 14:53:07, user Brian Haugen wrote:

The SPIRES database and method is described in the article below, if you’d like to cite it.

Metrics associated with NIH funding: a high-level view<br /> https://www.ncbi.nlm.nih.go...

Boyack KW, Jordan P. Metrics associated with NIH funding: a high-level view. J Am Med Inform Assoc. 2011 Jul-Aug;18(4):423-31. doi: 10.1136/amiajnl-2011-000213. Epub 2011 Apr 27. PMID: 21527408; PMCID: PMC3128410.

On 2023-08-30 21:54:30, user Irina Catrina wrote:

This is now published (August 8th, 2023) in RNA Biology https://doi.org/10.1080/154....

On 2018-12-10 22:32:28, user jwilliams wrote:

The paper, by Tian, et al., seeks to address the issue of chemoresistance in hepatocellular carcinoma (HCC) treatment as it is a common solid-organ cancer that frequently develops chemotherapy resistance. Due to a lack of early symptoms in HCC, the disease is often caught too late for surgery, and therefore relies heavily on chemotherapy for treatment. The authors focus on RNA-binding protein Lin28B which promotes liver cancer through downregulation of anti-onco-miRNA expression. Their main objective is to assess the role that Lin28B plays in chemotherapy resistance, and explore how curcumin can be used in combination with chemotherapy agent paclitaxel to sensitize Lin28B overexpressing Hep3B cancer cells, and a Hep3B paclitaxel resistant cell line, to paclitaxel treatment. Their work does a great job of showing the direct impact of Lin28B on paclitaxel resistance, and how the usage of curcumin in combination with paclitaxel can be used to more effectively treat paclitaxel resistant Lin28B overexpressing HCC cells. This work adds valuable knowledge towards creating more effective cancer treatments, and especially treatment of cancer that has become resistant to chemotherapeutics.<br /> There are, however, a few concerns that I would like to share that may add to this paper. A minor critique addresses unclear interpretation of the results. Other critiques seek to understand how Lin28B, as an RNA binding protein, is mechanistically causing chemoresistance, and why they only look at paclitaxel, and its resistance, in HCC.<br /> The minor critique is aimed at addressing a confusing interpretation of Figure 5C. The figure interpretation in the results state that expression of apoptosis-related proteins was significantly reduced in tumors that underwent the combo treatment. This statement only addresses half of the result because they are looking at both apoptosis effector molecules like cleaved caspase 3, which increases, as well as anti-apoptotic protein BCL-2, which decreases. I would consider cleaved caspase 3 an apoptosis related protein, and since it increases, it directly conflicts their statement in the results. They should include more detail to specify that apoptosis effectors increase, and anti-apoptotic apoptosis proteins like BCL-2 are the proteins that are decreasing.<br /> A more broad critique is concerned with why the authors did not investigate the mechanism behind how Lin28B, as an RNA binding protein, is functionally involved in chemoresistance. In the discussion, they state that due to Lin28B overexpression inhibiting apoptosis in HCC cells, they suggest that Lin28B may be regulating apoptosis protein activity, but they never explored this experimentally or showed data. I believe that further experimentation to show the mechanism behind Lin28B mediated resistance to paclitaxel should be conducted, and could add impact value to the paper. Due to Lin28B’s involvement in blocking let-7 microRNA biogenesis, which derepresses let-7 target genes, the authors could start by exploring which pathways affected by let-7 targets would likely lead to chemoresistance. These could include pathways that lead to apoptosis resistance, increased production of proteins that would degrade or protect from drugs, or prevent the direct effects of paclitaxel. If they could show, for instance, that perhaps Lin28B is inhibiting microRNAs involved in regulating anti-apoptotic proteins like BCL-2, this could elucidate the direct mechanism of Lin28B on effecting chemoresistance. Investigating this mechanism would be a great addition to the understanding of how Lin28B, as well as other RNA-binding proteins, might be involved in chemoresistance. As this is a major focus of the paper, I feel that it would greatly enhance their narrative.<br /> A final point is about whether or not Lin28B mediated chemoresistance is specific to only paclitaxel. I believe that including an experiment using their Lin28B overexpressing Hep3B HCC cells to screen several other chemotherapy drugs would help to expand the impact of this work beyond a single drug. Additionally, the curcumin and drug sensitization experiment could be ran on any of the other drugs that are affected by Lin28B-mediated resistance to see if the treatment improvement seen with curcumin and drug combination also applies to other drugs affected by resistance.

On 2019-09-08 06:18:22, user Jing Lu wrote:

I compared the results generated by Kraken and CCMetagen and got a more accurate one by using CCMetagen. Thanks for providing a good tools for metagenomic. I found the abundance description in CCMetagen result is not a integer. Can you have some explain on this? Many thanks.

On 2019-04-19 20:47:05, user Stephanie Gogarten wrote:

It will be interesting to see how much this can speed up current WGS analysis pipelines that rely on VCF!

The reference to "Stilp et al." is incorrect, it should be listed as "Zheng et al.".

On 2020-02-24 22:03:07, user Fraser Lab wrote:

The authors propose a method that would automate atomic model building for near-atomic resolution cryo-EM maps of proteins for which no prior structural information is available. The proposed method is discussed in the context of segmenting cryo-EM maps of a multi-subunit protein complex in order to accurately identify individual subunits. The advantage of this method is that it allows for accurate model building of a multi-subunit complex when there are no structural models for individual subunits by leveraging evolutionary couplings (as a scoring criterion and as a validation metric). Overall, due to the lack of benchmarking against other methods and the limited test cases examined here, we are not yet sure whether this manuscript demonstrates that the method is robust or that it presents any advances over existing methods that do not rely on evolutionary couplings.

The authors state that their proposed method will improve segmentation of cryo-EM maps, but there is little discussion of how their method addresses this task. The majority of the paper focuses on model building, not segmentation. On page 4, the authors outline several tasks involved in “tracing a chain in the EM density map of a multi-component complex… i) the map needs to be segmented into sub-maps of the individual components; ii) probable locations of amino acid residues need to be identified in the map; iii) these locations need to be assigned to the primary sequences of the components; iv) full atom models of the protein need to be constructed.” Of these tasks, only the first one is relevant to the proposed method. The other tasks, including “automatic map segmentation, automatic map sharpening, automatic interpretation of multiple chain types, and automatic application of reconstruction symmetry” have already been implemented by software packages, some of which this manuscript cites (Cit. 10 - Terwilliger et al 2018; Not cited - Terwilliger et al, 2019 doi: 10.1002/pro.3740 also see: “Automated Segmentation of Molecular Subunits in Electron Cryomicroscopy Density Maps” by Baker et al, 2006). It may very well be that this method is a major advance over these previous studies, but it is currently impossible to tell from the manuscript.

The major flaw in what is presented is that the proposed method is not rigorously tested on multiple test datasets (e.g those that are publicly available on EMPIAR or EMDB). Rather, the method is used to build a model into a map of the TssF protein, a subunit of the Type 6 Secretion System baseplate. However, the authors modify their method to skip steps 1 and 2 (including the map segmentation, supposedly a major strength of the method) due to the low resolution of the map. The motivation for using a Minimum Spanning Tree in the method is not well described, especially in the absence of significantly improved results relative to existing methods. This brings into question over what resolution range this method is appropriate. It is also concerning that the authors report building an atomistic model of TssF and TssG components, but do not include the model in their manuscript or a statement about PDB deposition.

The authors acknowledge the necessity of sequence information from numerous protein homologs in order to accurately create a contact prediction map, one of the required inputs in their method. It would be informative for the manuscript to include benchmarking that demonstrates how many sequences or contact couplings are necessary for accurate segmentation. This can be achieved by plotting the local correlation per amino acid residue against a varying number of input sequences. This section could also be strengthened by a discussion in the manuscript of how sequence co-evolution information relies on sequence conservation and how this information may not be useful if homologs are highly divergent.

Finally, we encourage the authors to make the code for their method publicly available so it may be more widely useful and transparently understood.

Minor Points<br /> There is no comparison of the author’s proposed method and the automation tools provided within Coot, yet the authors declare that Coot’s tools are “largely manual, time-consuming, and prone to subjectivity.” There is also no comparison to Rosetta or Phenix. For example, running: phenix.map_to_model emd_2513.map 4ci0.fasta.txt resolution=3.4 find_symmetry=True does a pretty good job tracing the majority of the chains (in about 3 hours on a laptop), but does not perform as well as what is potentially described here. Comparison would be helpful for demonstrating the proposed method’s added capabilities, if any, or establishing the method as a less or more computationally intensive alternative to Coot, Rosetta or Phenix.

The Results section contains a great deal of detail that would be better laid out in the Methods section, not only for organizational purposes but also to make explicit what steps are intended to be routine. As written, the manuscript suggests a nontrivial number of judgement calls will be involved in applying the method, detracting from its usability by a wider audience.

Figures<br /> Fig 3 - Predicted contact maps vs final contact maps<br /> This figure does not clearly compare predicted and final residue contacts.

Fig 4 - Alignment and comparison with reference model<br /> It would be easier for readers to interpret comparisons if presented with individual chains. The reference model could be overlaid with the final model for easy visual comparison (similar to the visualization of multi-conformers).

Fig 6 - Method applied to wedge complex of bacT6SS baseplate<br /> 6A - Can the authors compare their model to a deposited model (in addition to other benchmarks listed above)?

We review non-anonymously, James Fraser, Iris Young, and Roberto Efrain Diaz (UCSF) and have posted this review on BioRxiv as a comment.

On 2020-10-22 10:17:58, user Dr Shankar Dayal wrote:

excellent work highlighting role of shRNA molecules for silencing the target genes under cell culture system.

On 2022-10-21 03:51:47, user Jared Roach wrote:

The distribution of random fragment lengths is a beta distribution. (Roach JC. Random subcloning. Genome Res. 1995 Dec;5(5):464-73. doi: 10.1101/gr.5.5.464. PMID: 8808467.) Maximum fragment length is not a robust statistic - it has high variance.

On 2016-08-16 15:31:58, user Steven Wilson wrote:

The finished manuscript is now published here:<br /> http://www.nature.com/artic...<br /> Thanks BioRxiv!!

On 2020-11-06 11:18:38, user Nabil Hajji wrote:

Since we placed our paper in the BioRxiv we have received huge number of emails from editors of distinct journals. We are please with that, however, our paper is novel and great research story with substantial data and international collaboration. Therefore, our manuscript should be published in well respected and major journal.

On 2024-12-17 10:07:24, user Preprint Journal Club at MPIPZ wrote:

We recently reviewed this preprint in the PhD preprint journal club in the Department of Plant Microbe Interactions at the MPI for Plant Breeding Research. You can find the PREreview here: https://prereview.org/reviews/14505813

On 2025-05-07 06:59:07, user Oznur wrote:

Great contribution. Please also check out our work "One-Hot News: One-Hot News: Drug Synergy Models Take a Shortcut https://www.biorxiv.org/content/10.1101/2025.04.18.649584v1 which arrives at the same conclusion on the utility of features.

On 2023-11-22 06:55:03, user Florian Pfaff wrote:

The article is now published in Virus Evolution:<br /> https://doi.org/10.1093/ve/vead062

On 2020-06-04 20:44:40, user Esmeralda R. wrote:

Great paper!<br /> I hope it gets published soon after peer review. <br /> Many scientists are seeing the involvement and relation of the SARS-CoV2 to ACE2. <br /> Real Gramas<br /> Grama Esmeralda

On 2021-01-29 15:06:35, user Martin R. Smith wrote:

A potentially minor point, but I wonder whether the Robinson–Foulds distance is the best measure of discordance in this situation? It's possible that misplacement of just one taxa could result in a high number of edges not being recovered, and this sort of error might occur more or less frequently under different methods. I've reviewed the performance of distance measures new and old across a range of scenarios in Smith (2020, Bioinformatics): https://doi.org/10.1093/bio...

On 2020-02-27 12:18:15, user Michael wrote:

This very useful report (not paper) on building new fluorescent probes would be much stronger if it explained up front how these reagents are superior to or uniquely complement, add functionality, to existing ones. There are mentions of these aspects later and towards the end of the paper, but the abstract reads more like a paper introduction than a statement of the strengths of the new fluorescent proteins.

Also, please note the endings added to two sentences pulled from the paper. Was this investigated for each of the new probes?

Ideally, the fluorescent marker combines favorable spectroscopic properties (brightness, photostability) with specific labeling of the structure or compartment of interest **while minimally perturbing the intrinsic physiology.**

Regardless of the application, it is crucial to use markers that show specific, crisp labeling and minimal spurious, non-specific localization **while minimally perturbing the intrinsic physiology.**

This report/paper would be much stronger if it explained up front how these reagents are superior to or uniquely complement, add functionality, to existing ones. Quantification of stability and brightness compared to other probes would be a great addition. Characterization of the probes with tables of data would make this a stronger paper.

On 2020-04-01 03:31:51, user Tom Terwilliger wrote:

Hi Iris Young, Alexis Rohou and James Fraser,<br /> Thanks for the helpful review of the previous version! We revised the paper and uploaded this version with changes addressing your comments.

Here are some responses to some of your specific comments (already sent them to you but posting here so that anyone can see them).

1. The smoothed squared map procedure is used to get a mask as you note in your comments, but it is not used in the map-phasing procedure beyond that.

2. One of your questions was about further validation. We have recently made a couple new tutorials on density modification. One takes a high-resolution apoferritin dataset and docks a homologous structure into it, fixes loops, and refines. You can run this tutorial with a script that is included. You could also edit this script if you want to use a non-density-modified map (an auto-sharpened one) and carry out the same procedure otherwise. When I do this I find that the density -modified map agrees better with both its own model and with the model from non-density-modified map than the original map does. Further the density-modified map and its model agree best. Here "agrees" means (1) set b values of a model to zero. (2) run map_model_cc on map and model and get CC_mask. This is the best example I have where density modification makes a clear difference in the final model. CC_mask values for this little experiment:<br /> analysis: <br /> denmod_map/denmod model 0.8698 denmod_map/std model 0.8461 std_map/denmod model 0.8114 <br /> std_map/std model 0.8244

3. You can download an excel worksheet that should have the data and figures to answer some of your questions from the bioRxiv web site.

4. If you go to the nice "full text" version of the paper on the bioRxiv site and go to Fig. S6 and click the magnifying glass then you get the plots that you request in the review of things like EMRinger scores. What you will see is that they vary, but are not improved on average by density modification. All the details are in the excel spreadsheet too.

5. "What was the FSC improvement for the 1.8 Å map shown in Fig1C,D?"

This is now clarified:

D. Density-modified map. The estimated improvement in resolution where FSCref is ½ is 0.05 Å.

1. "For the density-modified map, values of estimated Fourier shell correlation to a true map, FSC_ref, are estimated from resolution-dependent error estimates.”. This sentence makes it sound as though FSC_ref is computed not from the FSC between half maps by using eqn 1, but by some other means. Is this so? If so, please expand since FSC_ref seems everywhere else in the main text to be from eqn 1. Perhaps the authors are referring to eqn 9 here, but it is not clear why this is necessary. Why not use FSC between density-modified half maps and eqn 1?."

This is now clarified:

For the density-modified map, values of estimated Fourier shell correlation to a true map, FSCref, are estimated from resolution-dependent error estimates (Eq. 9, Methods). These error estimates are used so that any correlations among the two original half maps and the two map-phasing half maps can be taken into account (see Methods).

1. Typos and clarifications fixed...in particular:

A local weight for each set of half-maps (original half-maps, F1a, F1b and map-phasing half-maps, F2a, F2b) is then obtained as the inverse of the corresponding local variance map. These local weights are then scaled to yield an average local weight of unity and then are applied to the individual half-maps before they are averaged.

1. The reason not to use Eq. 1, which is the standard estimate of map quality:

FSCref =[2 FSC /(1+ FSC)]½

at the end of density modification is that the two half-maps at this point may have some correlation (the value of A in Eq. 5b may not be zero).

If the value of A were zero, then you could use Eq. 1. In practice... it might not make that much difference, but I have not done a systematic investigation.

-Tom T

On 2020-05-31 19:52:18, user geomcnamara@earthlink.net wrote:

I hope the authors move fig S6 to the main text.<br /> Reference 29 "Protein-PAINT" should be cited in introduction and "independent validation" should be switched to credit their peer reviewed publication first.<br /> This paper is reminiscent of Fluorescent Speckle Microscopy (FSM, pre-super-resolution microscopy era).<br /> Note: mNeonGreen obsoleted by AausFP1 (6/2019) https://www.biorxiv.org/con... <br /> which is ~2x brighter than mNG and ~5x brighter than EGFP. Nice interactive chart on FP performance at https://www.fpbase.org/chart (I suggest starting with Y-axis Brightness, X-axis emission wavelength). One amino acid change (T203Y) would result in a bright yellow, likely similarly narrow spectra and likely very nice AausFP1green->AausFP1(T203Y)yellow spectral overlap for FRET.<br /> Triple FP ... record brightness published is V6 (Venus6, Nguyen ... Vogel 2015 PLoS One, pubmed 23152925) - Steve Vogel may have made "V8" (earlier multimers may be found in our thousand proteins of light review and data table, inside the PubSpectra zipo downloadable at https://works.bepress.com/g... ).. Some readers may also find of some use my suggestions on 'binary Tattletales' https://works.bepress.com/g... (pre-AausFP1).

On 2019-01-16 04:09:28, user jeff ellis wrote:

"In addition, VIGS mediated knock down of CHUP1 reduces stromule

induction (8% chloroplasts with stromule(s), n = 68 images quantified) compared to

control silencing (2% chloroplasts with stromule(s), n = 68 images quantified),

suggesting that CHUP1 is required for pathogen induced stromule development (Fig.

3C)".<br /> Are these numbers back to front?

On 2015-07-19 04:54:03, user Davidski wrote:

Hello authors,

Thanks for the paper. Are those ancient genomes going to be available in Eigenstrat or PLINK formats at any stage? That would be nice.

By the way, your PCA in which you projected the ancient genomes onto PCs computed with modern samples suffers from projection bias or space shrinkage.

So the ancient genomes are being pulled into the middle of the plot, and that's why they cluster so close to each other.

To avoid this problem, try running a PCA with all of the ancient genomes included and based on transversion SNPs only.

If that's not possible, perhaps due to a lack of markers, you can try projecting the ancient samples onto PCs computed with a much larger dataset from across West Eurasia. Adding several thousand samples from all over Europe and West Asia will help to improve the results significantly.

Cheers

D. Wesolowski

On 2017-07-13 20:13:35, user Aaron Liston wrote:

I think this same pattern was noted by Acquisti et al 2009<br /> "Ecological Nitrogen Limitation Shapes the DNA Composition of Plant Genomes" https://doi.org/10.1093/mol...

On 2021-10-07 05:29:08, user Titus Ponrathnam wrote:

An additional question. Have you used this system with G-trace and LacZ? The 2017 paper which uses tetOff had used lacZ especially in their age related analysis, so it would be nice to attempt a few laZ stainings as a way to answer Laurent's question in older adults.

On 2018-05-27 03:39:51, user Wenxi Xu wrote:

Very interesting work! I like the IL12p40-DC migration research of your group, and i am happy to see more subsequent results. I have one small question on the ?TM-IL-12R?1, the new IL-12R?1 isoform. Correct me if I am wrong, in your previous paper published on JEM, it was shown that ?TM-IL-12R?1 enhances DC migration, but in this paper, the conclusion is ?TM-IL-12R?1 inhibits bacteria transition to medLNs and spleen. In the early stage of MTB infection, the DC migration should positively associates to bacteria transition, then how do you explain the 'conflict' between these two phenotypes?<br /> thanks!

On 2020-08-13 06:05:21, user Sarah M wrote:

Response to Etebari et al. 2020 ‘Genetic structure of the coconut rhinoceros beetle (Oryctes rhinoceros) population and the incidence of its biocontrol agents (Oryctes rhinoceros nudivirus) in the South Pacific Islands’ bioRxiv preprint doi: https://doi.org/10.1101/202...

Sean D.G. Marshall, Sarah Mansfield, Trevor A. Jackson <br /> AgResearch, Lincoln Science Centre, Private Bag 4749, Christchurch 8140, New Zealand

Kayvan Etebari and co-authors present genetic data that they contend supports their claims that the recent invasion of coconut rhinoceros beetle (CRB) into new areas of the Pacific was not caused by CRB-G (Marshall et al. 2017). Instead, they argue this invasion process is driven by several genetically distinct groups of CRB. A central plank to their argument is genetic analysis of the invasive CRB population found on Guadalcanal, Solomon Islands. They also present data from several countries on infection rates in CRB populations of the Oryctes rhinoceros nudivirus (OrNV) and hypothesise that OrNV has entered the invaded countries along with the invasive CRB population.

We have serious concerns regarding the methodology used to analyse the data presented by Etebari et al., and their interpretation of the results. Previous attempts to raise these concerns with the lead author and to invite discussion of the findings with the CRB Action Group have been unsuccessful. As it stands, the preprint omits significant methodological information and fails to place their findings in the wider context of CRB invasion into the Pacific. Our concerns can be grouped under three key areas: 1) conflation of two different levels of population structure within CRB, i.e. biotype and haplotype; 2) recent research to address new CRB invasions is not taken into account, particularly in Vanuatu and the Solomon Islands; and 3) failure to prevent cross-contamination leading to artificially high ‘rates of OrNV infection’, which are not substantiated by other published techniques used to detect OrNV infection in CRB.

Below we elaborate on these three points. We invite the authors to contact us directly regarding the concerns raised.

1) conflation of two different levels of population structure within CRB: biotype and haplotype<br /> Marshall et al. 2017 presented genetic data that characterised different populations from the native and invasive range of CRB. In doing so, they identified a genetic marker that distinguished the newly invasive populations from older populations that arose from the initial Pacific invasion by CRB. They also presented bioassay data demonstrating that the new invasive CRB populations were not susceptible to infection by ingestion of the original strain of OrNV that was used to control the initial Pacific invasion of CRB (Huger 2005). Ingestion is the natural route of infection for OrNV so inability to infect new invasive populations is a serious concern for control of CRB. They concluded that there were four clades within the CRB populations they had sampled, with some further subdivision within each of these clades (Fig. 2, Marshall et al. 2017). Three of these clades, while genetically distinct, were all characterised by their susceptibility to the original strain of OrNV used to control the initial CRB invasion in the Pacific. These three clades included native CRB populations and populations from regions affected by the initial CRB invasion and collectively were named CRB-S. The fourth clade included CRB populations from the newly invaded regions (Guam, Papua New Guinea, Hawaii, Solomon Islands) as well as parts of the native range (Philippines, Indonesia). This fourth clade was named CRB-G. Thus, Marshall and co-authors identified two distinct levels of population structure within CRB. The first level (CRB-G and CRB-S) is associated with susceptibility to the original strain of OrNV introduced to the Pacific. The second, more complex, level reflects geographic groupings in the native and invasive range of CRB.

Reil et al. 2018 built on this initial analysis of CRB genetics by investigating the genetic substructure of CRB in more depth, particularly in Palau, where there may have been multiple CRB invasions. They concurred that the new Pacific invasion was correlated with the presence of CRB-G. A key outcome of their paper was the use of the term ‘biotype’, i.e. conspecifics that appear similar but exhibit variation in one or more functional traits, to characterise the CRB-S/CRB-G dichotomy. This is a useful distinction to avoid confusion between this level of population structure, and the more finely divided population structure and haplotypes associated with different geographic regions.

Etebari et al. conflate these two levels of population structure by inserting the PNG haplotype group into the CRB-S/CRB-G dichotomy. A PNG haplotype was identified by Marshall et al. 2017 and placed in Clade II, among the three clades associated with CRB-S. These specimens came from several locations in PNG known to have been affected by the earlier Pacific CRB invasions in the 1940s (Table 2, Marshall et al. 2017). The CRB-G specimens from PNG were collected solely from Port Moresby, which is presumed to be the original invasion site for CRB-G within PNG. In the Solomon Islands, CRB-G was first identified in 2015, and all field collected samples included in the analysis presented by Marshall et al. 2017 were CRB-G. We do not dispute that Etebari et al. have found CRB individuals with the PNG haplotype on Guadalcanal, but we do not support their claim that this is evidence for a separate wave of invasion into the region (see next section for further discussion).

2) recent research to address new CRB invasions, particularly in Vanuatu and the Solomon Islands <br /> Etebari et al. report the presence of OrNV in CRB-S beetles collected from Efate, Vanuatu at some point between January and October 2019, but neither collection date nor specific locality are provided. These details are important because the presence of CRB-S was only confirmed in Vanuatu during June 2019. Our CRB-S samples collected from Mangaliliu, Efate, between June and September 2019 are negative for OrNV. In mid-September 2019, as part of the local eradication efforts against CRB, live OrNV was imported into Vanuatu. Bioassays were conducted to assess virus activity against the invasive CRB-S population and planned releases of OrNV were made on Efate in 2019 (Biosecurity Vanuatu, pers. comm.). Prior to the release of this preprint, we were unaware that these research activities in Vanuatu were likely to affect the conclusions drawn by Etebari and co-authors.

Etebari et al. also report the presence of CRB-S and the presence of OrNV on Guadalcanal, Solomon Islands in 2019. The sampling period is stated as between January and October 2019, but again neither collection date nor specific locality are provided. The authors state that ‘the OrNV now infecting O. rhinoceros in Solomon Islands arrived with an incursion of infected O. rhinoceros that originated in Southeast Asia’. We do not dispute the presence of CRB-S in the wider Honiara region of Guadalcanal in 2019, nor do we dispute the presence of virus in the same location and at the same time, because we have independent samples that confirm their presence in Honiara in 2019. There is, however, a simpler explanation for these findings. As part of the response to the CRB-G invasion into Honiara, screening of imported live OrNV isolates for virulence against CRB-G began in Honiara during 2016 (Marshall 2016). At the same time, CRB-S beetles were brought to Honiara from the Shortland Islands (Western Province, Solomon Islands) as part of the same project. There have been subsequent imports of live OrNV to Honiara for research purposes at intervals since 2016. It is likely that the presence of CRB-S and OrNV in Honiara is due to accidental release into the local environment. This does not support the invasion hypothesis suggested by Etebari and co-authors.

Furthermore, we note that our CRB samples from Russell Island (n = 3, Sept. 2019; n = 13, Feb. 2020; AgResearch 2020) were negative for OrNV, in contradiction to the results presented by Etebari et al. We concur with Etebari et al. that CRB populations in the New Georgia island group are negative for OrNV.

We agree with Etebari et al. that the effect of interbreeding between CRB-S and CRB-G on OrNV susceptibility requires further investigation, particularly in Honiara, where the two biotypes now occur together outside of their native range. Care needs to be taken, however, in the assessment of OrNV infection rates (see next section).

3) failure to prevent cross-contamination leading to artificially high ‘rates of OrNV infection’<br /> Etebari et al. present evidence of OrNV infection rates (%) based solely on PCR analysis of gut tissue samples. These tissue samples came from adult beetles captured in pheromone traps. From the information presented in the methods, it is unclear if sufficient precautions were taken to prevent accidental cross-contamination between beetles during the trapping process because the trap locations, length of time between trap set up and beetle collection, and beetle handling after collection are not described adequately. If an OrNV infected beetle is present in a trap among uninfected beetles, virus particles are easily transferred between individuals. This problem was documented by Ramle et al. 2005, who recommended careful handling of trapped beetles as a first step to minimise contamination risk. A tweet from the lead author of this preprint, dated 9 April 2019, includes a photo that shows strong potential for cross-contamination between beetles.

It is also unclear if the PCR protocol used by Etebari et al. included an appropriate dilution step to further reduce the risk of false positives because no details of the protocol are presented. Marshall et al. 2017 recommended a 1 in 5000 dilution to improve the accuracy of OrNV detection using PCR. Furthermore, care needs to be taken to avoid accidental contamination between samples during processing. A second tweet from the preprint’s lead author, dated 18 July 2019, includes a photo that shows strong potential for cross-contamination between samples in the laboratory.

Finally, it is common practice in insect pathology to use more than one indicator of infection, to reduce the risk of either false positives or false negatives (Lacey 2012; Vega and Kaya 2012). When assessing OrNV infection in CRB, this should include some combination of visual assessment of the gut at dissection, PCR analysis of gut tissue, preparation of histology samples to assess internal changes to the gut lining, and bioassays to determine viral virulence under controlled conditions. All of the OrNV infection rates presented by Etebari et al. are based on a single indicator, i.e. PCR analysis, with a high risk of cross-contamination, such that we consider the OrNV infection rates were overestimated significantly.

In conclusion, we cannot support the assertion of Etebari et al. that OrNV is widespread among new, invasive populations of CRB in the Pacific. Apart from Vanuatu, which was invaded recently by CRB-S without OrNV, the new wave of Pacific invasion is dominated by CRB-G populations without OrNV (Marshall et al. 2017; Reil et al. 2018).

References<br /> AgResearch (2020) Annex 1.1-Distribution map of CRB biotypes and virus. MFAT Progress Report WPG-0101699-DOC-4049125 (June 1, 2020).<br /> Huger AM. (2005) The Oryctes virus: Its detection, identification, and implementation in biological control of the coconut palm rhinoceros beetle, Oryctes rhinoceros (Coleoptera: Scarabaeidae). Journal of Invertebrate Pathology 89, 78-84. <br /> Lacey LA (2012) Manual of Techniques in Invertebrate Pathology (Second Edition), San Diego: Academic Press.<br /> Marshall SDG (2016) FAO Mission Report for Plant Production and Plant Protection TCP/S01/3501 – OTCP140014219: Use and production of Oryctes nudivirus to assist with control of the coconut rhinoceros beetle, Oryctes rhinoceros, in Solomon Islands (August 15, 2016).<br /> Marshall SDG, Moore A, Vaqalo M, Noble A & Jackson TA (2017) A new haplotype of the coconut rhinoceros beetle, Oryctes rhinoceros, has escaped biological control by Oryctes rhinoceros nudivirus and is invading Pacific Islands. Journal of Invertebrate Pathology 149, 127-134. <br /> Ramle M, Wahid MB, Norman K, Glare TR & Jackson TA (2005) The incidence and use of Oryctes virus for control of rhinoceros beetle in oil palm plantations in Malaysia. Journal of Invertebrate Pathology 89, 85-90. <br /> Reil JB, Doorenweerd C, San Jose M, Sim SB, Geib SM & Rubinoff D (2018) Transpacific coalescent pathways of coconut rhinoceros beetle biotypes: Resistance to biological control catalyses resurgence of an old pest. Molecular Ecology 27(22), 4459-4474. <br /> Vega FE & Kaya HK (2012) Insect Pathology (Elsevier Science).

On 2022-09-22 18:25:45, user john wallingford wrote:

The paper also has me thinking about patterns of cytoplasmic mechanics. Microheology shows that cytoplasmic stiffness differs in different regions of migrating cells. How do such patterns relate to the propagation of forces at the cortex/membrane?

On 2019-08-16 00:53:33, user Torsten Seemann wrote:

Can you please put the software URL in the abstract?

On 2017-06-05 21:35:17, user Paul Katz wrote:

You might be interested in an old paper that looks at female preference in hybrid crickets.<br /> Hoy RR, Hahn J, and Paul RC. Hybrid cricket auditory behavior: evidence for genetic coupling in animal communication. Science 195: 82-84, 1977.

On 2024-12-14 15:21:00, user Stephanie Wankowicz wrote:

This publication aims to develop a platform of methods to identify small molecule ligand and RNA substrate interactions. Using a library of coumarin derivatives, they discovered a small molecule, C30, with high affinity binding to RNA single G bulges over other bulges (A, U, and C). The authors used Gaussian accelerated Molecular Dynamics (GaMD) simulations to study interactions, NMR to confirm the binding site location, and lasso regression to identify molecular descriptors for structure-activity relationships. The other narrative in this paper argues that this methodology could be used to develop better RNA-small molecule ligands for therapeutic purposes. <br /> Major Revisions:<br /> To strengthen the novel aspects of the authors' methodology, it would be beneficial to add context on why this method is more advantageous than previous workflow paths. <br /> Additionally, to drive this home in the conclusion, it would be beneficial to summarize the novel nature of this workflow and how it was used to discover these new ligands.<br /> We suggest clarifying and justifying the type of RNA substrate used in each assay (ssRNA, dsRNA, etc.). For example, we suggest clarifying if the modeled version of “SL5RNA” used in the Fig 2 in vitro assay is the same as the additional FP simulations. <br /> For Fig. 3, in these FP simulations, please clarify if this “DNA version” of the RNA5 and RNA1 substrains is dsDNA or ssDNA. If it is a helical dsDNA version of the substrate, a justification as to why this was used to probe a minor groove binding mechanism for a seemingly bulged ssRNA substrate would be beneficial.<br /> We would suggest integrating some of the supplementary figures, like Supplementary Figure 6, into the main text. This could enhance the reader's understanding of the electrostatic interactions in RNA-ligand binding and the significance of Ring A's positive charge in identifying binding pockets. <br /> Additionally, we suggest exploring alternative feature selection methods such as SHAP or Markov trees. These could potentially capture more nuanced, nonlinear interactions that might be missed by a linear selection method like LASSO.<br /> Minor Revisions:<br /> In the introduction, we suggest that the authors clarify the importance of preventing deep hydrophobic binding pockets in a pharmaceutical context, including a more streamlined discussion of coumarin derivatives and their therapeutic potential for SARS-CoV-2.<br /> We suggest in Fig. 2D that the graphs’ y-axes should be scaled the same and these curves should be labeled “GA-rich” and “G” for clarity. <br /> For Fig. 3A, we suggest the legend be enhanced and a scale bar added for clarity. <br /> For Fig 3D, it is difficult to identify the yellow, grey, and orange dashed lines. Please make this more obvious to highlight.

On 2021-09-19 08:44:21, user Aliaksei Chareshneu wrote:

In case of questions, comments or any other correspondence, please use the following email address: 479052@mail.muni.cz. Unfortunately, the corresponding author of this pre-print, professor Jaroslav Koca, recently passed away.

On 2024-07-12 14:18:11, user Prof. T. K. Wood wrote:

1. DarT/DarG is better characterized as a type V TA system; this category is based on the fact that antitoxin DarG is an enzyme but does not alter the toxin (type VII). The first member of this group is GhoT/GhoS (please cite doi: 10.1038/NChemBio.1062).

2. Toxin/antitoxin systems were first shown to inhibit phage in 1996 (please cite doi: 10.1128/jb.178.7.2044-2050.1996).

On 2024-09-15 07:54:12, user PanosMoschou wrote:

We will soon test the approach using various super-resolution approaches down to 20 nm. Will keep you updated.

On 2022-12-07 19:19:10, user Tricia T Nguyen wrote:

This paper is now online at eLife here, https://elifesciences.org/a...

On 2016-06-21 20:29:57, user Mark Chaisson wrote:

It is great to see researchers developing improvements in long read alignment. You may want to benchmark with bwa mem and blasr though instead of bowtie2.

On 2017-04-04 21:01:21, user Martin Brennan wrote:

Check out our GitHub page where we host this project: https://github.com/Biologic...

And see a demo video here: https://www.youtube.com/wat...

On 2020-04-08 04:46:46, user Andrei Drabovich wrote:

Hi. Most of your theoretical peptides have 1-2 miscleavages. How these peptides are useful at all for SRM or PRM methods?

On 2023-09-07 17:31:29, user AL wrote:

Thank you for presenting the importance of information leakage and being intentional with how to split the data.

There are a few typos that I wanted to bring to your attention: <br /> - top of pg 4, awkward phrase with 2 already's<br /> - first sentence of pg 6, compile instead of complie<br /> - pg 7, splitting was spelled as spitting<br /> - bottom of pg 7, "to evaluation"

On 2018-01-25 20:11:24, user Heather Bruce wrote:

This comment was posted a few versions back and isn't showing up here, but I think the discussion is important, so I'm reposting it.

SPXR said:<br /> Two shortcomings are: (1) lack of explicit comparison of the "large" and "small" plates of Oncopeltus with respect to the pleurae of other insects, and (2) assumption that the abdominal appendages of insects and other Pancrustacea are uniramous. With respect to 1, the pleurae of insects comprise the two pleural arcs (coxosternite: trochantin, precoxa; anapleurite: episternum, epimeron), as defined by Snodgrass (1935, Fundamentals of Insect Morphology). It is frustrating to read a paper making claims about the "body wall" of insects without ever using the term "pleuron", which appears to betray lack of comparative morphological knowledge. That said, shortcoming 2 above is less grievous, but still disheartening: The authors claim that the abdominal styli of Archaeognatha and Zygentoma are epipods, apparently forgetting that the abdominal appendages of Pancrustacea are biramous, with an endopod ("telopod") and exopod, with a number of protopodal epipods.

Please pardon the tone of this message. The work is very encouraging for the resolution of leg and pleural homologies overall!

My response:<br /> Thank you for your comments, I’m very happy for the opportunity to discuss this!

Regarding (1), we made a decision to remove as much jargon as possible so that the paper would be accessible to a wide audience. As you are probably aware, insect and crustacean morphology nomenclature can be quite daunting, and we didn’t want to lose the reader at Figure 1! In the original version of the manuscript, I went with the terms in Snodgrass 1927, where he makes a nice case for the insect subcoxa theory. So, I homologized the crustacean coxa with the insect trochantin, and the crustacean precoxa with the insect epimeron/episternum. Terminology aside, another reason not to use the insect nomenclature is that there may not be terms that correspond precisely to the ancestral crustacean structures. For example, the epimeron/episternum might only represent the lateral/pleural portion of the precoxa leg segment that was incorporated into the insect body wall, but the precoxa might also include a portion of the notum, above and adjacent to the wing. Another issue was that I did not come across a term that distinguishes the body wall part of the trochantin from the plate-like outgrowth of the trochantin, which extends over the insect coxa. It was important to distinguish these two regions, because only the plate-like outgrowth of the trochantin is deleted following the loss of wing/epipod genes (Clark-Hachtel 2013, Ohde 2013, Medved 2015, Wang, 2017), and therefore it was to this region only that I homologized the crustacean coxal epipod. Our solution to these problems was to use pictures and plain language to show our homology schema. However, I’m happy to wade into the jargon weeds with you here :)

As you probably know, “biramous” refers to a leg with an exopod, while “uniramous” legs lack an exopod, but may have epipods and endites (Boxshall 2004, Boxshall 2009). Regarding your point (2), we do not claim that the abdominal appendages of Archaeognatha or Pancrustacea are uniramous (Parhyale abdominal appendages are quite biramous, as are the thoracic and/or abdominal appendages of many crustaceans). From our manuscript, “the thoracic stylus of jumping bristletails (Fig. 4, st) is the epipod of the crustacean basis”. From a morphological standpoint, Tiegs 1940 says that Archaeognathan thoracic styli are unsegmented, and do not have intrinsic musculature, which are hallmarks of epipods (Boxshall 2004, Boxshall 2009). In contrast, the abdominal styli, while they may or may not be segmented (Matsuda 1976 vs Staniczek 2014), apparently have intrinsic musculature (Matsuda 1976, Matsuda 1957, Tiegs 1940), which suggests that they are exopods (Boxshall 2004, Boxshall 2009). However, since thoracic and abdominal styli both emerge from the insect coxa/crustacean basis (our manuscript, and following discussion), it is somewhat curious if they are not homologous structures. I certainly welcome any good sources you may have on this subject!

Basal hexapods aside, a more satisfying answer regarding the identity of the lateral nubs of insect embryonic abdominal appendages lies in a comparison of Sp6-9/btd and Dll expression. The crustacean basis/insect coxa expresses Sp6-9 and btd (our manuscript). It carries the exopod and endopod, which each express Dll (Fig. S1, Hejnol 2004, Williams 2002, Panganiban 1995). Thus, if insect abdominal appendages had exopods, they should express Dll. However, most insects do not express Dll in the abdomen (this is why many molecular researchers didn’t know that insects form abdominal appendages as embryos and regarded them in adults as novel structures). While Dll, and thus exopods, are not expressed in insect A2-8, there are paired, leg-like domains of btd expression on each abdominal segment of some insects (Schaeper 2010), which, according to our leg segment homology model (Fig. 4), suggests that these appendages are comprised of three leg segments: the precoxa (pink), crustacean coxa (red), and insect coxa (orange, expresses Sp6-9/btd), but not the trochanter (yellow, expresses Dll). See also the beautiful SEM images of the lateral nubs of the embryonic abdominal appendages in terrestrial carabid beetles in Kobayashi 2013 compared to the gills in aquatic carabid beetles in Komatsu 2012. Komatsu 2012 note that the gills of the aquatic beetle do not develop from the insect coxa, but from a proximal region, the subcoxa, which fuses to the body wall. This is most apparent by examining the nub/gill of the A1 pleuropod, which emerges from a position proximal to the insect coxa. Notably, the A1 pleuropodia, which is longer, expresses both Sp6-9/btd and Dll at the tip, while the A2-8 appendages, which are shorter, express only Sp6-9/btd (Schaeper 2010, Beerman 2004, Beerman 2001, Rogers 2002). This is explained by our model (Fig. 4): the longer A1 pleuropod is comprised of at least four leg segments (precoxa, crustacean coxa, insect coxa, trochanter) expressing both Sp6-9/btd and Dll, while the shorter A2-8 appendages have three leg segments (precoxa, crustacean coxa, insect coxa), expressing only Sp6-9/btd. Since the A2-8 appendages do not express Dll, they do not have exopods, and cannot be considered biramous.

We are planning to submit this manuscript to a journal soon, and due to space limits, we could not include as much of the background supporting information as we would have liked. However, I am currently writing a review that more fully discusses the morphological, molecular, and embryological evidence for the model we propose in this manuscript. I hope this was helpful :)

On 2020-01-24 13:09:06, user Yen Shu Chen wrote:

The authors did not share (no GenBank/GISAID accession number are provided) the genome sequence of the critical bat-CoV that represents a close relative to human 2019-nCoV. <br /> No way to access/reproduce/further use their result. Do scientific journals accept such practice?

On 2022-09-30 22:29:46, user MIT Microbiome Club wrote:

Small things: S6, S7,... There's a typo in multiple figures, "Addative". The sign of Figure 4D and E might be reversed. In Methods "rfc" is supposed to be "rcf". The author's point could be strengthened by mentioning the RMSE of the trio models in the text (rather than just in the Figure), as was done for the pair models. Figure 3A is a little confusing regarding the relationship between all the bar graphs-- could be useful to add an "=" before the 4th bar graph in each series so show what each model predicts the outcome to be.

On 2018-11-09 06:45:27, user Wendy Adams wrote:

"Long-term use of antibiotics is associated with serious complications, including post-treatment Lyme disease syndrome (PTLDS)."<br /> Unclear what this means - if it means that LT abx cause PTLDS, then that's not a true statement. LT antibiotics may be prescribed for PTLDS (or chronic Lyme) but PTLDS by definition is dx'ed after a standard course of doxy or amox, not a long course, of antibiotics. You may have meant "PTLDS may be treated with LT abx, which may be associated with serious complications". Also important to remember that PTLDS is only a small subset of those patients who are still symptomatic after initial treatment for Lyme disease.

On 2023-05-13 15:27:12, user Mario Inchiosa wrote:

This preprint has been accepted for publication. A link will be provided when it is published.

On 2018-01-02 18:33:55, user AdamMarblestone wrote:

-"The distributed nature of working memory" http://wyblelab.com/docs/jc...<br /> -"Memory-Augmented Neural Networks: Enhancing Biological Plausibility and Task-Learnability" https://www.politesi.polimi...

-"Closing the loop between neural network simulators and the OpenAI Gym" https://arxiv.org/pdf/1709....

On 2015-01-17 16:16:44, user Guest wrote:

This is a copy of the communication from May 2014 that the authors refer to in their paper:

Subject: Re: Mbd3 and Reprogramming<br /> From: Jacob Hanna jhannawis@gmail.com<br /> Date: May 24, 2014 at 8:36:20 PM GMT+3<br /> Cc: Jose Silva jcs64@cscr.cam.ac.uk, Paul Bertone bertone@ebi.ac.uk<br /> To: Brian Hendrich brian.hendrich@cscr.cam.ac.uk

Hi Brian,

Thanks for the comments. Throughout the study and as we had been working on this since 2010 we have extensively used three reporters to mark naive pluripotency - Oct4-GFP complete transgene, delta-PE Oct4-GFP transgene and Nanog-GFP knock-in cells (Figure 2). All systems were made from WT and Mbd3 flox/- cells and confirmed matching results. In case of random transgenes, we always validated specific activation in bona-fide iPS/ESCs and not in differentiated cells in vitro or teratomas. We have used multiple Mbd3 depleted clones and multiple wild-type clones to make sure we are covering different stoichiometries. Please also note that we have also conducted Mbd3 reconstitution with Wt and mutant vectors as indicated in the study on Mbd3 flox/- cells. Imaging analysis was done on both types of Oct4-GFP reporters because they are the brightest and allow detection at 5X resolution of entire wells. We have also conducted in single cell well assays, confirming staining for Nanog when it was not used as a reporter. I am extremely confident of the up to 100% iPSC formation one can get, as modestly speaking, i have experience with validating iPSCs. The WT cells in our reprogramming conditions never gives us higher than 20% form somatic cells. As our paper indicates, there could be NuRD independent ways to get deterministic reprogramming, as apparently is the case of C/EBPa in pre-B cells published by Thomas Graf.

At the times reviewer were debating which is the best marker, Oct4 or Nanog and so on, but to me the best argument is harvesting cells after 8 days of DOX without any passaging and sorting and seeing chromatin and transcription that is indistinguishable from ESCs/iPSCs. This is evident from our published data and not form WT cells even after longer days on DOX (11 days). As I have emailed u 2 months ago but u preferred not to discuss, we can map at high resolution reprogramming by harvesting secondary Mbd3 flox/- cells every 24 hours until day 8 ( RNA-seq, DNA methylation, ATAC-seq etc), and the cells completely reprogram to naive pluripotency (again wihtout sorting, passaging or any kind of biasing..but not from our most efficient wild type cells).

Our data are consistent with Grummt paper that NuRD activity blocks somatic cell reprogramming, and consistent with your publication that Mbd3 -/- cells are hyper-pluripotent (Reynolds 2012 CSC.) We do not believe in authentic differences in a factor promoting maintenance of naive pluripotency but blocks induction of pluripotency, unless the experiments are done in such a way to disrupt somatic cells in such a harsh manner that they can no longer be reprogrammed. e.g. Harsh and early depletion/inhibition of DNMT1 or ERK1/2 can lead to apoptosis and loss of proliferation of somatic cells or EpiSCs if done sub-optimally and in absence of adequate and rapid OKSM expression and rich naive conditions, and lead to a distorted of context dependent promotion of iPSC formation by these factors.

Finally, we have accumulated great mechanistic data on NuRD activity and manipulation leading to deterministic reprogramming, and in new systems completely not related to your cell lines, hopefully to be published soon.

Cheers,<br /> Jacob

On May 23, 2014, at 4:37 PM, Brian Hendrich brian.hendrich@cscr.cam.ac.uk wrote:

Dear Jacob,

I am writing to ask your comments on a technical aspect of your Nature study, showing 100% reprogramming efficiency of MEFs upon depletion or deletion of Mbd3 (Rais et al. (2013).

We downloaded the ChIP-seq data to see how various changes are manifested in the iPS cells, which might point to how such efficient reprogramming can be facilitated by the lack of a functional NuRD complex. When we looked at the data, we saw a pronounced over-representation of reads at the Oct4 locus in both the ChIP and input (“Whole Cell Extracts”) samples. Similar read density was not found at other pluripotency-associated gene loci (e.g. Nanog or Esrrb), nor was it seen for the other reprogramming factors Myc, Sox2 or Klf4. Rather, this readout appears to correspond to your Oct4 promoter transgene construct (it is around 18kb, please see the attached genome browser figure).

There are two aspects that we are confused about. First, the read counts are very high above background, indicating the presence of many transgene copies in the cells that were transformed. It isn't entirely clear from the main text of your paper, but how exactly were these made? Did you use the same lentiviral transduction method as was used for the reprogramming factors, and did you attempt to characterize the integration sites? With so many copies (at least 15-20) it becomes likely that one or more could be expressed under the control of a different regulatory element, activating GFP independently of endogenous Oct4 upregulation.

A second issue came up when we compared the ChIP-seq tracks from the Mbd3fl/- and WT MEFs. In the Mbd3fl/- cells, which apparently reprogram very easily, the entire Oct4 promoter locus is represented. That is expected. However in your WT cells, which were reported as being more refractory to reprogramming, a gap is evident in the read coverage spanning the Oct4 proximal enhancer (PE) element.

It therefore seems that the two cell lines were transformed with different reporter constructs: the Mbd3fl/- MEFs received a construct containing the full Oct4 promoter sequence, whereas the WT MEFs were transformed with a different version where the PE is missing. Note that this is not due to lack of sequencing depth, as the WT cells actually have more reads (33-50M reads) than the Flox/- cells (10-33M reads). If anything was present in this region it would have been detected.

The PE element is the most highly conserved region of the Oct4 promoter; the absence of this sequence in your negative/control cells would lead them to activate GFP expression much less efficiently and with slower kinetics than the Mbd3fl/- (positive) cells. Combined with the apparent high number of transgene insertions that may lead to misregulation of the Oct4-GFP reporter when the full promoter sequence is present, we are concerned that these effects could lead to an erroneous conclusion that cells lacking NuRD activity display more efficient reprogramming.

We feel that these are both serious issues which could potentially undermine the main conclusions of your paper. Could you please let us know what you make of these observations, and whether you can reassure us that the findings in Rais et al. are still sound?

Thank you very much for your assistance.

Yours Sincerely,

Brian Hendrich<br /> Paul Bertone<br /> Jose Silva

Wellcome Trust - MRC Stem Cell Institute<br /> Department of Biochemistry<br /> University of Cambridge<br /> Tennis Court Road<br /> Cambridge<br /> CB2 1QR<br /> United Kingdom

www.stemcells.cam.ac.uk

On 2017-09-18 19:48:09, user Jacob H Hanna wrote:

11/09/2017 -

Follow-up papers from Hanna group further dismissing these critiques and substantiating out initial discoveries are now available:<br /> http://www.biorxiv.org/cont...

On 2019-11-20 17:31:12, user Connor Rosen wrote:

I thank the authors for this investigation and I am excited by the potential of this analysis. However, without the full gene expression information it is difficult to fully understand the role of Langerhans cells and the impact of their absence. The authors should provide the full data (e.g. tables of differentially expressed genes in each cell type), and the accession number for the underlying RNA-seq data for re-analysis.

On 2021-10-28 08:34:48, user Patrick Deelen wrote:

Very nice manuscript, congratulations. Can you elaborate on how this method compares to: https://pubmed.ncbi.nlm.nih...

On 2018-07-07 07:10:11, user Jaydeep Sidhaye wrote:

I find it surprising that this wasn't adopted so far for human mesenchymal stem cells. The feeder free human embryonic stem cells are routinely grown on coated plates.

On 2022-12-02 07:44:58, user Andrzej Dziembowski wrote:

mRNA vaccines against COVID-19 have revolutionized vaccinology and have been administered in billions of doses, demonstrating their safety and effectiveness (I was also vaccinated with the mRNA vaccine). Our data provide another reason why they are so effective.

On 2025-05-07 00:51:43, user Young Cho wrote:

Non-Invasive dsRNA Delivery via Feeding for Effective Gene Silencing in Teleost Fish: A Novel Approach in the Study of Gene Function Analysis <br /> Reviewer in Chief: Branndon Evans <br /> ? Summary <br /> ? Introduction <br /> ? Results <br /> ? Discussion <br /> ? Overall takeaways <br /> As an emerging professional in aquaculture biotechnology, I found this paper to be very fascinating. Your research is quite novel and brings interesting implications for the further development use of RNA biotech in aquaculture. <br /> Summary <br /> Summary: This paper demonstrated a novel approach of feeding fish E.coli engineered to express double-stranded RNA (dsRNA) as a vector. The authors demonstrated that non-invasive dsRNA delivery via feeding technique can knock down the dnd gene during PGCs migration and differentiation in S. schlegelii. The authors demonstrated that transformed E.coli vectors can be combined with rotifers, brine shrimp and dry feed to serve as an effective means of introducing dsRNA. <br /> Introduction <br /> A comprehensive review and introduction on the topic was given. Objective was clearly stated and achieved. <br /> Materials & Methods <br /> Methods are straightforward and easy to follow. Someone who is not necessarily an expert in aquaculture or RNAi technology would be able to understand how this experiment was conducted. Methods are put in succinct and desirable detail. The inclusion of a figure to represent the construct generated did enhance the section but would have benefited from a caption rather than representation at the end of the paper. Including supplementary material on primers specific sequence would also be good to add for improved reproducability. <br /> Results <br /> The results of this experiment were very interesting. An approximated 50% of fish displayed dysplasia in their gonads. Insinuating that a large number of these fish would be infertile. Taking off target effects into account would have been useful, but did not seem to be tested for in this experiment. I viewed your paper on biorxiv, so this may have contributed to formatting issues, but I found it difficult to interpret some figures because they were displayed at the end of the article without an explanatory paragraph. This made full interpretation difficult and required<br /> heavier interpretation by the reader. You explain your results in the discussion which allows an attentive reader to understand the results. <br /> Discussion <br /> The significance and relevance of your results are clearly explained. The value not only in scientific but also commercial realms is illuminated to draw maximum There is some conjecture that the gonads in the fish are ideal candidates for germ cell transplantation. However it is not clear that these gonads would be functional, especially considering the dysplasia and sex reversal observed in many individuals. In lines 462 through 463, describing these fish as ideal recipients for PGCs is dubious due to seemingly described gonad dysfunction and deformity. Further exploration on how gonads could be made useable would help to backup this view. <br /> Figures <br /> Some issues in viewing the figures may be due to the nature of how I viewed the document, however the imaging of gonads would have benefitted from additional explanation. Comparison between normal and altered gonads would have made the significance of these images more understandable. Tables (a) & (b) lacked a nearby description which made interpretation difficult. A way to demonstrate recorded effects over sampling time in a table or graph would have been favorable as well. Also including a figure categorizing gonad manifestation would have been useful. <br /> References <br /> They are well arranged, easy to understand and suitable for this paper. <br /> Overall Review <br /> This paper presented very novel techniques and had fascinating results. Someone with adequate technical skill could replicate this experiment. I wonder if this can be applied to the more efficient creation of transgenic organisms, vaccine delivery and other benefits. I look forward to reading about more applications of this research. <br /> Thank you for your time, <br /> Mahalo, Sincerely Branndon Evans

On 2021-02-16 19:00:29, user Andor Kiss wrote:

Welp! Going to give this one a go - very happy to see CUDA functionality builtin from the start! #GPUs #Assembler #Genome

On 2025-03-18 19:59:26, user Brett Pike wrote:

Hello, thank you for sharing this mountain of data. In my preliminary evaluation I find that the orientation of the chromosomes is not standardized, i.e. about half need to be reverse complemented. I am writing to ask that you fix this, and I suggest using the orientation from cs10. ntSynt-viz with '--normalize' flag I find to be the simplest visualizer for this task. Thank you!

On 2021-03-26 07:44:31, user Jorg Tost wrote:

Please note, that the annotation files have been updated to the latest genome versions for the rhesus macaque in the final published version in Epigenomics. The article published in Epigenomcis is freely available.

On 2015-10-09 23:52:59, user David Basanta wrote:

This paper is part of a series done for the NCI (the ICBP and PSOC initiatives), it's not peer review nor original research but an example of how evolutionary game theory could be used to study various aspects of cancer progression.

On 2023-06-08 17:05:11, user KA Garrett wrote:

The peer-reviewed and updated version of this paper in PhytoFrontiers is available here: https://apsjournals.apsnet.org/doi/abs/10.1094/PHYTOFR-01-23-0004-SC

On 2017-07-07 12:26:30, user Alex wrote:

Hello, I was wondering if it is possible for the RNA-seq data with identifier EGAS00001000828 to be released? This would be of great help, thank you for the consideration.

On 2017-05-10 16:40:46, user razibkhan wrote:

line 274-275 you flipped the gene/SNP id

On 2021-02-21 10:44:49, user Stuart Cook wrote:

Very nice manuscript. For the link to IL11, I think the references below would be much stronger as they relate to cardiac fibrosis/fibroblasts whereas the current reference (16) is specific to lung. Happy to help with IL11-related follow on experiments, if useful.

Schafer et al. 2017. “IL-11 Is a Crucial Determinant of Cardiovascular Fibrosis.” Nature 552 (7683): 110–15.

Lim, Wei-Wen, et al 2021. “Antibody-Mediated Neutralization of IL11 Signalling Reduces ERK Activation and Cardiac Fibrosis in a Mouse Model of Severe Pressure Overload.” Clinical and Experimental Pharmacology & Physiology, January. https://doi.org/10.1111/144....

Corden, Ben, et al. 2020. “Therapeutic Targeting of Interleukin-11 Signalling Reduces Pressure Overload-Induced Cardiac Fibrosis in Mice.” Journal of Cardiovascular Translational Research, June. https://doi.org/10.1007/s12....

On 2020-11-13 19:48:02, user Marcel Ramirez wrote:

manuscript published in Frontiers

On 2015-11-30 14:55:42, user Raphael Levy wrote:

PNAS rejected the letter: "After careful consideration, the Board has decided that your letter does not contribute significantly to the discussion of this paper." (https://raphazlab.wordpress... "https://raphazlab.wordpress.com/2015/11/16/pnas-your-letter-does-not-contribute-significantly-to-the-discussion-of-this-paper/)")

More info on our work and analysis of SmartFlare can be found at my blog (https://raphazlab.wordpress... "https://raphazlab.wordpress.com/tag/smartflare/)").

On 2018-06-23 10:11:09, user Collin Ewald wrote:

Since Insulin/IGF-1 signaling also regulates axon regeneration and the extracellular domain of APL-1 has been shown to mediated several processes such as development, learning, and aging through DAF-16, have you considered that APL-1EXT regulates axon regeneration through DAF-16?

On 2018-10-25 01:36:05, user Ajay Singh wrote:

In this paper authors have developed quinazoline derivative and analyze the efficacy against Aspergillus fumigatus. The number of the tested strains is sufficient to draw general conclusions. the authors have cited adequately references for the assays used in the study. The introduction is relevant. Sufficient information about the previous study findings is presented for readers to follow the present study rationale and procedures. The results appear to be valid and the methodology is appropriate. English language needs to correct and need to add one more figure related to microscopic examination of spore in control and treated with compound.

On 2017-09-10 09:53:52, user Gregory Kucherov wrote:

Excellent clarification, and very useful, thanks!

On 2023-10-27 19:33:35, user Federico wrote:

The claim that you have generated brown adipocytes is overstated. There is no clear proof morphologically or by significant changes in gene expression (UCP1) that would support brown adipocyte character. I would revisit that experiment.

Showing tissue that has formed (and analyze it histomorphological) would make the in vivo work much more convincing. In line with that, survival for up to 28 weeks seems overstated as IVIS data thresholding doesn't seem to be corrected for background noise.

On 2016-11-02 21:06:32, user Mike Weale wrote:

Apologies to all interested parties! The title of this paper is missing a crucial negative! The title should be: "True causal effect size heterogeneity is not required to explain trans-ethnic differences in GWAS signals". We will correct ASAP. Mike Weale & Daniela Zanetti

On 2016-06-24 04:02:20, user A.Folg wrote:

I'm trying to find "PF7466" position: 13904842 within the y-chromosome of the sample I1707 but only can find this position tested within chromosome 1. Positive SNPs only give us IJK for this sample and anyway is negative for all known main T subclades T1a1, T1a2 and T1a3a.

On 2017-05-29 01:27:40, user jotan wrote:

This is a useful guide which I would like to share with my students. Unfortunately, the students who need this the most, also have the poorest English skills.

It would be very helpful if the authors could apply some principles of "Plain English campaign" (https://en.wikipedia.org/wi... "https://en.wikipedia.org/wiki/Plain_English_Campaign)") to make this article more accessible to people who use English as a second language.

For example:

"Clear communication is also crucial for the broader scientific enterprise because ‘concept transfer’ is a rate-limiting step in scientific cross-pollination."

This is a nicely crafted sentence for scientists who are fluent in English but is virtually unreadable for someone struggling with English. "Rate-limiting step" and "cross-pollination" restricts the audience.

I would also recommend that the authors consider substituting rarely-used words with more common versions wherever possible.

"credible" -> believable<br /> "chronological path" -> timeline<br /> "exposition" -> explanation<br /> "cognition" -> thinking<br /> "paramount" -> most important

etc.

On 2021-04-09 22:39:45, user kdrl nakle wrote:

I don't trust your research at all. You concluded that 30% Ethanol is effective while 80% is not (or a lot less). This contradicts all the researches previously. You did not bother one iota to explain this huge elephant in your paper. By the way, your graphs lack clarity.

On 2024-01-02 19:52:05, user Adam Zeno wrote:

Incredibly interesting work in elucidating the molecular pathology of SMDCF ! I hope to see this work used in future investigations and treatments of skeletal disorders

On 2020-04-08 13:26:50, user Scott Nichols wrote:

Excellent findings! A quick questions and two comments from our lab meeting discussion:

Question -The integrin-blocking antibody was assayed for adhesion phenotypes on a fibronectin (Mammalian origin?) substrate. Does it also disrupt filopodial attachment to uncoated glass slides, on which Capsaspora is presumably attaching to its endogenously secreted substrate? Just wondering if Capsaspora integrins 'normally' adhere in the same way as animal integrins.

Comment 1. The vinculin staining is certainly punctate, but doesn't seem particularly co-localized with integrin in most places on the filopodia. It is possible that the vinculin that isn't co-localized with this integrin could be bound to attachments that use other integrins. Might be nice to show the co-localization quantitatively. Were there no co-precipitates in the IP's?

Comment 2. We were all very curious to see some low-exposure images to see what the integrin and vinculin staining looked like in the cell body. Any idea why there might be high levels in the cytosol of the cell body (or perhaps it is also membrane localized there?). Is it punctate or diffuse, localized with actin filaments?

Comment 3. "Vinculin" in Capsaspora is definitely a VIN-family member, but isn't a vinculin orthology. Vinculin, alpha-catenin, alpha-catenin-like and alpha-catulin proteins in animals are all more closely related to each other than any are to non-animal family members. It might be worth clarifying this distinction.

Anyway, really cool paper and finding. Just wanted to let you know the questions that came up.