On 2024-09-12 09:32:02, user Fabienne Jabot-Hanin wrote:
Could you please share your supplementary table 2 with the 385 index variants which had the same direction of effect on serum creatinine and cystatin C and had significant effects on both biomarkers ?
On 2024-09-12 07:42:51, user maud de dieuleveult wrote:
Published here https://www.tandfonline.com/doi/full/10.1080/15592294.2021.1917152
On 2024-09-12 07:11:20, user Keshava Datta wrote:
Great study - Extremely important to improve genome annotation as we know it... In one of the first drafts of the human proteome (Nature, 2014), ~16 million spectra that did not match to known proteome were subjected to proteogenomic analysis and ~200 regions with protein coding potential were found. It would have been great if the authors mentioned this and maybe compared these results? As we all know, evidence from multiple groups increases confidence in a finding!!
(Full disclosure - I was a co-author on the 2014 paper)..
On 2024-09-11 02:22:16, user Shinya Fushinobu wrote:
This paper has been published in the Journal of Applied Glycoscience.<br /> https://doi.org/10.5458/jag.jag.JAG-2024_0005
On 2024-09-10 18:32:52, user Thomas Sorger wrote:
Please note that the date of the second reference (2003) is incorrect. The correct date is 1983:<br /> 2. Armstrong E. Relative brain size and metabolism in mammals. Science 220: 1302–1304 (1983).<br /> Tom Sorger
On 2024-09-09 13:34:38, user Tien Vu wrote:
The preprint has been published at Nature Plants ( https://www.nature.com/articles/s41477-024-01786-w ), and its link will be added to this page soon.
On 2024-09-08 19:36:57, user Cara J. Gottardi wrote:
Can the authors please confirm use of recombinant human WNT2 from Novus Biologicals (H00007472-P01) for their rescue experiments? The supplier says this protein is not designed to be active, and should not be used for activity-based assays (e.g., the protein is GST-tagged, not ideal for WNT proteins; also wheat germ systems do not allow for glycosylation of secreted proteins). Happy to be wrong if this protein prep really works!
On 2024-09-07 13:32:35, user D_114 wrote:
The work references Wilkes (2021) as mentioning 80% of glomalin is located within the hyphal network. However, on cross referencing this statement, the article by Wilkes (2021) makes no such claim. Therefore, the statement in this article is misrepresenting research and misleading readers.
On 2024-09-06 20:41:01, user Noam Kaplan wrote:
Hi-C data publicly available at GSE276553
On 2024-09-06 20:37:49, user Noam Kaplan wrote:
Hi-C data publicly available at GSE276554
On 2024-09-06 12:37:55, user Ashim Kumar Dubey wrote:
This article has now been published - https://pubs.acs.org/doi/full/10.1021/acsinfecdis.4c00249
On 2024-09-05 16:30:46, user Paolo Ubezio wrote:
This is a preprint of the following chapter: Ubezio, P., Challenging Age-Structured and First Order Transition Cell Cycle Models of Cell Proliferation, published in Problems in Mathematical Biophysics. SEMA SIMAI Springer Series, vol 38, edited by d'Onofrio, A., Fasano, A., Papa, F., Sinisgalli, C., 2024, Springer, reproduced with permission of Springer Nature Switzerland AG. The final revised and authenticated version is available online at: http://dx.doi.org/10.1007/978-3-031-60773-8_13 .
On 2024-09-05 09:48:00, user Moretti Sébastien wrote:
Thanks for your tool!<br /> Don't you have issues with the KEGG license for academics? https://www.kegg.jp/kegg/legal.html
On 2024-09-05 01:22:44, user GR wrote:
Hi Authors
Very interesting paper, I just noticed some small potential mistakes when reading. In Fig 3E, it looks like the beta-tubulin image has been put in place of gamma-tubulin, and in Figure 5A, the GO treatment image appears to be the same as the Figure 4D AA image. Hopefully this comment is helpful!
On 2024-09-04 21:15:50, user Alex Grossman wrote:
Hello, as a heads up you call Xenorhabdus Gram-positive in your abstract. It appears to be correctly listed as Gram-negative elsewhere in the text.
On 2024-09-04 19:28:31, user Haihui wrote:
Great work, Vikash! Could you please also share your supplemental data? There're no links for those S figures. Thank you very much!
On 2024-09-03 13:55:06, user Vikash P. Chauhan wrote:
We deposited the plasmids from this manuscript (vPE and xPE) at Addgene. Give them a try and send us your feedback: https://www.addgene.org/browse/article/28248655/
On 2024-09-04 15:39:56, user Dae-Yeon Suh wrote:
This preprint has now been published in<br /> microPublication Biology. https://doi.org/10.17912/micropub.biology.001165
On 2024-09-04 14:55:57, user Lukas wrote:
This article is now published at https://doi.org/10.1038/s41592-024-02347-x
On 2024-09-03 22:48:26, user Pooja Asthana wrote:
Summary<br /> The study investigates the human protein DJ-1, which is known for its role in detoxifying the metabolic bioproduct methylglyoxal (MG). There has been an ongoing debate over whether DJ-1 acts directly on MG (direct substrate) or requires a protein intermediate acting as a protein/nucleic acid deglycase (glycated protein substrate). The authors used fixed-target micro-crystallography and mix-and-inject serial crystallography to structurally analyze covalent intermediates in the reaction catalyzed by DJ-1. One of the significant achievements of the study is the successful use of these advanced crystallography methods to determine the structure of key reaction intermediates: hemithioacetal and L-lactoylcysteine, providing new insights into DJ-1's glyoxalase mechanism. However, a major weakness is that the authors' claim refuting the alternative deglycase mechanism are not fully supported by the presented data. Despite this limitation, the study advances our understanding of DJ-1’s enzymatic function by leveraging MISC at synchrotron using the new flow cell injector.
Major points<br /> Major point 1<br /> The claim made in the discussion that: “These results provide direct structural evidence supporting a growing number of enzymology studies also indicating that DJ-1 is not a deglycase…” is not supported by evidence presented in the manuscript. Although this work elegantly demonstrates that MG covalently modifies the catalytic cysteine of DJ-1 (Cys106), the crystallography experiments presented are unable to test whether the alternative mechanism (with a glycated substrate) occurs. More careful treatment of this logic in the discussion would strengthen the manuscript, and would help the manuscript to be more focused on the compelling X-ray crystallography results. We recognize it is difficult to “prove a negative” however these experiments affirm the primary activity without directly testing the alternative one.
Major point 2<br /> The authors report compelling evidence that the DJ-1 catalytic cysteine (Cys106) is covalently modified by MG. However, the concentration of MG used was 50 mM, and non-catalytic cysteines might be covalently modified at this concentration. Indeed, it’s possible that one of the DJ-1 surface cysteines is covalently modified (Cys53), based on the large positive difference peak in the FO-FO difference density (Figure 5b, Figure S8) (although it is suggested that this is evidence of allosteric communication). Covalent modification of a surface cysteine leading to lattice disruption is consistent with the observation that MG is known to dissolve DJ-1 crystals. The manuscript could be strengthened by consideration of these points, as well as analysis of difference maps around Cys53 for the fixed target structure (e.g. add panel to Figure S1 showing FO(methylglyoxal)-FO(free) maps around Cys53). Discussion of the differences in modification rates for the catalytic and surface cysteines, and the impact of large versus small crystals, would be helpful.
Major point 3<br /> Is it plausible that a second, synchronized turnover is captured by the mix-and-inject experiment? This claim might be developed by modeling the concentration profile of the intermediates along the 30 second time course (e.g. similar to Figure 4 in PMID 29848358). To this point, were the occupancies of the covalent adducts refined at each time point? Did the authors consider whether a mixture of species might be present? The evidence supporting the second turnover comes from the featureless difference map calculated between the 3 sec and 20 sec time points (FO(20s)-FO(3s) in Figure S6). Is there an alternative explanation for the decreased occupancy at this time point other than synchronized turnover? E.g. a problem with sample mixing resulting in lower substrate concentration at this time point.
A related concern is whether the data as presented can discriminate between the two covalent intermediates (HTA or LC). Perhaps Figure S7 would be strengthened by adding the FO-FC difference maps for each of the intermediates modeled with the other species (e.g. the HTA dataset modeled with LC and vice versa). Can the authors comment on the lack of correlated negative (or positive) density in the FO-FO difference map matrix (Figure S5) in panels comparing sp2 and sp3 carbons (e.g. FO(15s)-FO(3s)). In this example, there is a large positive peak in the difference map for the sp2 to sp3 change, but no correlated negative peak.
Minor points<br /> Minor point 1<br /> Was the covalent adduct observed in the MG-soaked DJ-1 crystals presented in Figure S1c modeled? Is the difference density consistent with the HTA or LC intermediates? Or a mixture of both?<br /> Minor point 2<br /> Is it possible that movement of the active site histidine (His126) away from covalent intermediate (Figure 4a) is consistent with histidine protonation? Or is the geometry such that protonation is unlikely?<br /> Minor point 3<br /> We find it helpful if the figure (or figure legend) includes PDB codes for their quick look up.<br /> Minor point 4<br /> The size of the scale bar in Figure S1a might be increased.
Review by:<br /> Pooja Asthana, Galen J. Correy & James S. Fraser (UCSF)
On 2024-09-03 18:05:44, user Greg Ira wrote:
On 2024-09-03 15:56:40, user Jonas Arruda wrote:
The paper has been puplished in the Proceedings of the Forty-first International Conference on Machine Learning: https://openreview.net/forum?id=uCdcXRuHnC
On 2024-09-02 16:57:35, user Jean-Felix Dallery wrote:
This preprint is now published in Microbial Genomics.<br /> https://doi.org/10.1099/mgen.0.001283
On 2024-09-02 14:42:35, user Peer wrote:
Looks like a very interesting story. Although, since the authors did not include any methodology it's hard to evaluate the quality and reproducibility of this work.
On 2024-09-02 13:32:22, user Adriano R. Lameira wrote:
What an amazing behaviour, thank you for bringing it to light!<br /> For your interest and to help keep the paper as accurate as possible, here are two former references on movement isochrony in apes:<br /> https://www.nature.com/articles/s41598-019-55360-y <br /> https://www.cell.com/current-biology/fulltext/S0960-9822(22)01601-3 <br /> Hopefully these two papers, together with the current contribution, will help bring some phylogenetic insight into discussions of dance evolution.<br /> Looking forward to the publication of this study, congratulations on this important work.
On 2024-09-02 08:32:21, user Nikolas Haass wrote:
On 2024-09-01 06:48:28, user Giorgio Cattoretti wrote:
Dear Colleagues,<br /> I read with interest the manuscript you posted about the Cyclic-multiplex TSA (CmTSA) method.<br /> In the Result subchapter titled “Gentle antibody stripping is necessary for sequential immunostaining with scores of iterations” at line 171 and following you mention several potential Ab stripping reagents, which are not further detailed in the M&M section. Furthermore, you mention beta-ME (line 173) and a low Ph buffer (line 175) as two separate stripping solutions. In the text, there is only one proprietary buffer, IRISKit® HyperView Advanced Ab Stripping Kit , for which a webpage in chinese can be found ( http://m.luminiris.cn/pd.jsp?pid=14):gTX3SSR1ouS7_HrdDaiJq0-yQz4 "http://m.luminiris.cn/pd.jsp?pid=14)") and no information on the composition can be obtained, neither you provide in the manuscript.<br /> To my knowledge, there is no mention in the scientific peer-reviewed literature of beta-ME ALONE as a stripping buffer. Besides the inventor of the 2-ME containing buffer, Laemmli (Nature. 1970;227:680–685), the earliest mention of beta-ME for stripping is Pirici (doi: 10.1369/jhc.2009.953240), after which we did quite some experiments (doi: 10.1369/0022155414536732; doi: 10.1097/pai.0000000000000203; doi: 10.1369/0022155417719419, this latter viewed 23,855 times and quoted in 101 papers). None of these references are among the one you quote.<br /> For reproducibility and to avoid re-inventing the wheel for one’s own advantage, you may wish to quote the relevant previous art and provide evidence of any modification or improvement. If the solution is proprietary, full disclosure is require or mention that the content of the proprietary solution is unknown.<br /> I do appreciate the effort put in the manuscript, which clearly appears an immature draft. Looking forward for improvements.
On 2024-08-31 00:56:13, user Alonso Favela wrote:
Published version here: https://link.springer.com/article/10.1007/s11104-024-06720-9
On 2024-08-30 21:57:17, user CruzVeralab wrote:
I like this paper, missing some TnaC references: https://pubmed.ncbi.nlm.nih.gov/16061180/ ; https://pubmed.ncbi.nlm.nih.gov/34504068/ ; Also, I am wondering how the results could explain previous data with uL22 (K90D) mutant proteins: https://pubmed.ncbi.nlm.nih.gov/35311583/
On 2024-08-30 17:42:18, user David Černý wrote:
The in-text citations are not properly linked to the corresponding bibliography entries. It would be great to post a v2 that fixes this problem.
On 2024-08-30 13:09:37, user Catherine Hogan wrote:
This preprint was published at Current Biology in 2021. https://www.sciencedirect.com/science/article/pii/S096098222100467X
On 2024-08-30 12:21:52, user Justin Lemkul wrote:
An interesting study and nice demonstration of the AMOEBA force field. I would advise the authors to edit the statement "there are no precedents to our knowledge to MD simulations on any HIV-1 forming G-quadruplex" as there have been several studies on LTR GQs in the literature. I suggest citing the following and incorporating them into the discussion:
https://doi.org/10.1016/j.bpj.2024.03.042 <br /> https://pubs.acs.org/doi/10.1021/acs.jctc.2c00291
On 2024-08-30 12:04:47, user Ljubisa Miskovic wrote:
This work is now published in Nature Catalysis https://www.nature.com/articles/s41929-024-01220-6
On 2024-08-30 06:46:42, user Daniel J. Murphy wrote:
Nice work. We also found increased expression of ITPR1, PKCa and CaMKKb following acute overexpression of MYC in MEFs. See doi:10.1038/onc.2017.394
On 2024-08-27 12:31:01, user Kate wrote:
If the authors have not read our paper I suggest they do so. https://doi.org/10.1038/s41586-022-05546-8
On 2024-08-27 08:49:43, user Gokulan wrote:
This article is peer-reviewed and published. The DOI for the same is: https://doi.org/10.1007/s00122-024-04628-7 .
On 2024-08-26 16:09:08, user Matthew Bowler wrote:
now published in Structure as https://doi.org/10.1016/j.str.2024.07.007
On 2024-08-26 07:17:25, user Cornett, Evan M. wrote:
now published DOI: 10.1016/j.jbc.2023.104651
On 2024-08-26 02:18:28, user Jesse Bloom wrote:
I have posted a reply to this pre-print at the following link: https://docs.google.com/document/d/1RaIb0hA1dp38lizkcF5rZTuLM-LTEL0Uqc0K1uZ5bsI/pub
On 2024-08-26 01:58:52, user Pravesh Gupta wrote:
This article has been published in Neuro-Oncology and can be accessed https://doi.org/10.1093/neuonc/noae139 .
On 2024-08-23 06:58:52, user viroid wrote:
Fantastic work! Integrating your domain meta-clusters (or maybe just the orphaned ones) into the Pfam would be super helpful! A pipeline of FoldMason and HMMer3 shouldn't be too tough?
On 2024-08-22 15:51:55, user Jack M wrote:
I have two comments:
A recent paper claims that "certain cancers can use ketone bodies as an alternative energy source to sustain tumor fitness, such as pancreatic tumors". The results in this paper, even without a glutamine inhibitor, would disagree with that statement. Maybe you can mention the conflicting approaches to ketogenic diet in the discussion?
Have you looked into the work of Mukherjee et al ? They report a very similar effect with ketogenic diet and DON in late stage experimental glioblastoma. Perhaps this intervention could be a more universal therapy?
Thank you for this very promising work exploring diet-drug combinations!
On 2024-08-22 07:48:09, user przemyslawlatoch wrote:
It’s out! Our first B. subtilis paper, published at @NatureComms
Translation in Bacillus subtilis is spatially and temporally coordinated during sporulation. #subtiwiki #bacillus<br /> https://rdcu.be/dRBF4 <br /> https://www.nature.com/articles/s41467-024-51654-6 <br /> https://doi.org/10.1038/s41467-024-51654-6 <br /> Performed at @IBBPAS
Funded by @FNP_org_pl<br /> @EMBO_YIP
On 2024-08-21 17:47:09, user Eric Kernfeld wrote:
This is now published in Cell Systems -- we will link it soon!<br /> https://doi.org/10.1016/j.cels.2024.07.006
On 2024-08-21 16:52:34, user DUPA- Preprint Review wrote:
The study titled “Temporal dynamics of BMP/Nodal ratio drive tissue-specific gastrulation morphogenesis” investigates how Nodal signaling dynamics and its interactions with BMP signaling affect convergence and extension (C&E) in zebrafish. Emig et.al . employs a combination of methods, including a novel tool for manipulating Nodal activation timing with optogenetics, gene expression profiles, and tissue-specific transplants in embryos.
This work shows a critical role for the temporal ratio of BMP to Nodal signaling in establishing tissue-specific C&E. High Nodal signaling at only before 4-hours post fertilization promotes mesoderm-driven extension, while a high BMP/Nodal ratio during this time window promotes extension driven by the neural ectoderm. The study efficiently utilizes explants to dissect these signaling pathways, and then supports the findings by demonstrating similar effects in intact embryos. However, the work would be strengthened by a better characterization of the BMP/Nodal ratio and downstream targets in their experimental manipulations.
The study elucidates how different methods and timings of Nodal signaling activation induce distinct modes of tissue-specific C&E in zebrafish. The interplay between Nodal and BMP signaling, particularly the timing and ratio of these signals, is crucial in determining whether mesoderm or NE-driven morphogenesis occurs. These findings enhance our understanding of early developmental processes. The paper presents compelling evidence on the distinct C&E programs within the mesoderm and ectoderm regulated by BMP/Nodal signaling ratios during a key developmental window.
Overall, this study provides valuable insights into the interplay between Nodal and BMP signaling in shaping early embryonic development.
Strengths:
Clear and Robust Experimental Design: The use of transgenic embryos, mRNA injection, and gene expression analysis provides a strong foundation for the research. The morphological observations coupled with gene expression analysis strengthens the conclusions. The uninjected controls and different concentrations of mRNA were critical in showing the threshold of Nodal signaling. Live imaging provides valuable, real-time data on the cell-autonomous effects of BMP on the ectoderm.
Time-Sensitive and Tissue-Specific Manipulation: The use of validated optogenetic tools allowed precise control of Nodal signaling onset. The optogenetic BMP tool allowed for precise control over the timing and location of BMP activity. This revealed a critical window for its influence and highlights the concept of BMP/Nodal ratio as a key factor. Furthermore, the tissue-specific activation of BMP in either mesoderm or ectoderm reinforced the link between BMP signaling and distinct tissue behaviors.
Points of consideration:
Measuring the BMP/Nodal Ratio: The BMP/Nodal ratio was measured over time using transcriptional profiling in the original explant models. The manipulations that the authors perform in the rest of the paper are meant to alter the BMP/Nodal dynamics throughout this time course. However, it is unclear to the reviewers if the BMP/Nodal ratio was measured in these manipulations. It would be nice to detail the dynamics of this ratio with data rather than the schematics in each figure. The authors could do this with transcriptional profiling or staining for SMAD activity as shown in Figure 2. In addition, staining for SMAD activity would perhaps be more indicative of actual signaling ratios rather than the transcriptional products, which might have multiple inputs.
On 2024-08-21 16:31:36, user DUPA- Preprint Review wrote:
The manuscript by Siyi Gu and colleagues presents an unbiased approach using well-established APEX2 proximity labeling proteomics and targeted pharmacological experiments that demonstrate different CCR5 chemokine receptor ligands-based induction of distinct receptor signaling responses and trafficking behaviors, including intracellular receptor sequestration, which offers a potential therapeutic strategy for inhibiting CCR5 functions a repertoire of CCR5 functional diversity. The study reveals the molecular basis for receptor sequestration, including information that can be exploited to develop actionable patterns for developing chemokine-based CCR5 targeting molecules that promote retention of the receptor inside the cell. This is particularly noteworthy because CCR5 plays a crucial role in the immune system and is important in numerous physiological and pathological processes such as inflammation, cancer, and HIV transmission. The work has great scope and importance as an alternative therapeutics strategy to address inflammation, cancer, and HIV transmission, and the experiments are well-designed and sound. The manuscript is well-written, clear, and has a reasonable and logical flow.<br /> We have some minor comments and a few methodological suggestions that would improve the quality of the manuscript.
On 2024-08-20 20:59:30, user Jasenka Zubcevic wrote:
This work was funded by NIH R01HL152162 to Zubcevic and de Lartigue.
On 2024-08-20 16:37:28, user Norbert Gerdes wrote:
this preprint has been published in Frontiers in Cardiovascular Medicine @ https://doi.org/10.3389/fcvm.2023.1221620
On 2024-08-20 16:32:27, user Lewis Flintham wrote:
Published article:<br /> https://doi.org/10.1093/jeb/voae080
On 2024-08-20 14:58:43, user Sam Seaver wrote:
OK, I am enjoying the Witcher reference!
On 2024-08-19 21:20:18, user Nasser Mahna wrote:
This article has been published at the following address: <br /> https://www.nature.com/articles/s41598-023-29059-0
On 2024-08-19 17:24:51, user Victoria Holden wrote:
Final published version available at: https://www.frontiersin.org/journals/agronomy/articles/10.3389/fagro.2024.1420311/full
On 2024-08-19 17:11:58, user Ricardo Aguiar wrote:
published in https://www.science.org/doi/10.1126/sciadv.adk2091
On 2024-08-19 13:52:54, user Jonathan Rondeau-Leclaire wrote:
Dear authors, <br /> This study is promising, as you seem to have gathered quality data with a very interesting design that has great potential to generate insights into the impact of microbes on plant productivitiy. I must however venture in a technical comment, as I believe the statistical approach you have chosen is weak and prevents you from truly leveraging all the precious information you have generated with the sequencing experiments.
Using correlation to find associations between microbial abundance and environmental (or sample) characteristics using data derived from sequencing experiment is generally advised against, as the data is compositional, which means the values are set in a simplex, not a euclidean space. This means that the observed relative abundance values are not independent of each other, as there is an inherent correlation between all taxa: if any microbe increases its true abundance, the relative abundance of everyone else will decrease even if they did not change in true abundance.
To find bacterial genera associated with plant traits (or any other characteristic), you should use statistical methods developed specifically for handling microbial relative abundance data. You can look up ANCOM-BC, corncob, DESeq, Aldex, and many others that have been developed to work specifically with sequencing data. Some of these even estimate the changes in absolute abundances. There are other reasons to use these methods too, that have to do with special characteristics of sequencing data (which can hardly be ignored), such as sparseness, overdispersion, to name a few. I recommend the following reads:<br /> https://academic.oup.com/gigascience/article/doi/10.1093/gigascience/giz107/5572529 <br /> https://dx.plos.org/10.1371/journal.pcbi.1010467 <br /> https://www.nature.com/articles/s41522-020-00160-w
Moreover, I do not see any mention of multiple testing correction. As you test multiple genera, it is absolutely essential to correct your p-values for multiple testing, otherwise it is almost certain that some of the genera you identified as significantly correlated were only by pure chance, not for biological reasons. Most differential abundance tests mentioned above do this by default, as it is expected for credible results whenever conducting multiple statistical tests. More on this if you are not familiar with this correction: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099145/
I hope this helps, and good luck with your publication!
On 2024-08-19 04:14:33, user Gray Shaw wrote:
Very interesting observations. Any experiments done as yet to see if a blocking anti-VISTA antibody reduces the luminescence signal generated by the cis interaction of VISTA-SmBiT and PSGL-1-LgBiT at pH6?
On 2024-08-18 20:27:14, user Lubayna Elahi wrote:
Published article link<br /> https://www.nature.com/articles/s44324-024-00021-6
On 2024-08-18 14:42:36, user David Ron wrote:
That mutations abolishing kinase activity (e.g., GCN2 Lys619Ala) also render RAF inhibitors unable to activate the ISR in cells is a powerful argument that GCN2's kinase activity links application of RAF inhibitors to ISR activation.<br /> That the same mutations also abolish GCN2's responsiveness to RAF inhibitors in vitro is less helpful - a dead donkey does not respond to the buggy whip, whether applies its back or to its head. <br /> In this vein, interpreting the inability of RAF inhibitors to activate GCN2 when the gatekeeper residue Met802 is mutated (Figure 9) is key to the conclusion that these agents exert their effect on GCN2 by engaging its kinase active site ATP binding pocket.<br /> I may have missed it, but is there evidence that the Met802 mutations retain reasonable kinase activity? The Met802Phe is not so helpful in this regard as it may lack 'headroom' for further activation.<br /> It might be helpful to measure ISR activation in GCN2∆ cells, reconstituted with GCN2 Met802 mutants in response to histidinol. Preservation of a response to histidinol in face of loss of responsiveness to RAF inhibitors would lend strong support to the authors conclusion.
On 2024-08-17 19:01:58, user Jonathan Dreyfuss wrote:
This is now published at Communications Biology https://www.nature.com/articles/s42003-024-06646-z
On 2024-08-16 10:12:09, user Unclaimed wrote:
Article published at Cell Communication and Signaling doi 10.1186/s12964-023-01378-9
On 2024-08-16 07:48:32, user Dolores Pérez-Sala wrote:
The final version of this article has been published in Redox Biology: https://www.sciencedirect.com/science/article/pii/S221323172400260X
On 2024-08-16 01:52:23, user Xiaofei Zeng wrote:
This preprint has now been published in Nature Plants: https://doi.org/10.1038/s41477-024-01755-3
On 2024-08-15 16:18:34, user Jo Wolfe wrote:
This is now published in Palaeontologia Electronica: https://doi.org/10.26879/1332
On 2024-08-14 02:05:04, user Vasily Zlatogursky wrote:
nautilus-like sounds a bit strange, because it is the shape of logarithmic spiral, which can be found in many natural objects from galaxies to trajectories of birds flight, not only nautilus. See https://en.wikipedia.org/wiki/Logarithmic_spiral
On 2024-08-13 09:24:11, user Burak Veli Kabasakal wrote:
You may want to check our recent structural proteomics work on FtsH-HflKC: https://www.sciencedirect.com/science/article/pii/S0141813024027284
On 2024-08-13 08:10:59, user William Dee wrote:
This article has now been revised and the published version can be found at: https://doi.org/10.1016/j.isci.2024.110511
On 2024-08-12 15:52:52, user Swathi Sukumar wrote:
Are the IF images in Figure 7, Z-stacks? Max projection of Z-stacks and more technical replicates are required. Additionally, how were the puncta counted?
On 2024-08-12 09:58:10, user John Hawks wrote:
The second part of the summary of revisions follows below:
Recognition of pits
Referee 3 and 4 and several additional commentators have emphasized that the recognition of pit features is necessary to the hypothesis of burial, and questioned whether the data presented in the manuscript were sufficient to demonstrate that pits were present. We have revised the manuscript in several ways to clarify how all the different kinds of evidence from the subsystem test the hypothesis that pits were present. This includes the presentation of a minimal definition of burial to include a pit dug by hominins, criteria for recognizing that a pit was present, and an evaluation of the evidence in each case to make clear how the evidence relates to the presence of a pit and subsequent infill. As referee 3 notes, it can be challenging to recognize a pit when sediment is relatively homogeneous. This point was emphasized in the review by Pomeroy and coworkers (2020b), who reflected on the difficulty seeing evidence for shallow pits constructed by hominins, and we have cited this in the main text. As a result, the evidence for pits has been a recurrent topic of debate for most Pleistocene burial sites. However in addition to the sedimentological and contextual evidence in the cases we describe, the current version also reflects upon other possible mechanisms for the accumulation of bones or bodies. The data show that the sedimentary fill associated with the H. naledi remains in the cases we examine could not have passively accumulated slowly and is not indicative of mass movement by slumping or other high-energy flow. To further put these results into context, we added a section to the Discussion that briefly reviews prior work on distinguishing pits in Pleistocene burial contexts, including the substantial number of sites with accepted burial evidence for which no evidence of a pit is present.
Extent of articulation and anatomical association
We have added significantly greater detail to the descriptions of articulated remains and orientation of remains in order to describe more specifically the configuration of the skeletal material. We also provide 14 figures in main text (13 of them new) to illustrate the configuration of skeletal remains in our data. For the Puzzle Box area, this now includes substantial evidence on the individuation of skeletal fragments, which enables us to illustrate the spatial configuration of remains associated with the DH7 partial skeleton, as well as the spatial position of fragments refitted as part of the DH1, DH2, DH3, and DH4 crania. For Dinaledi Feature 1 and the Hill Antechamber Feature we now provide figures that key skeletal parts as identified, including material that is unexcavated where possible, and a skeletal part representation figure for elements excavated from Dinaledi Feature 1.
Archaeothanatology
Reviewer 2 suggests that a greater focus on the archaeothanatology literature would be helpful to the analysis, with specific reference to the sequence of joint disarticulation, the collapse of sediment and remains into voids created by decomposition, and associated fragmentation of the remains. In the revised manuscript we have provided additional analysis of the Hill Antechamber Feature with this approach in mind. This includes greater detail and illustration of our current hypothesis for individuation of elements. We now discuss a hypothesis of body disposition, describe the persistent joints and articulation of elements, and examine likely decomposition scenarios associated with these remains. Additionally, we expand our description and illustration of the orientation of remains and degree of anatomical association and articulation within Dinaledi Feature 1. For this feature and for the Hill Antechamber Feature we have revised the text to describe how fracturing and crushing patterns are consistent with downward pressure from overlying sediment and material. In these features, postdepositional fracturing occurred subsequent to the decomposition of soft tissue and partial loss of organic integrity of the bone. We also indicate that the loss by postdepositional processes of most long bone epiphyses, vertebral bodies, and other portions of the skeleton less rich in cortical bone, poses a challenge for testing the anatomical associations of the remaining elements. This is a primary reason why we have taken a conservative approach to identification of elements and possible associations.
A further aspect of the site revealed by our analysis is the selective reworking of sediments within the Puzzle Box area subsequent to the primary deposition of some bodies. The skeletal evidence from this area includes body parts with elements in anatomical association or articulation, juxtaposed closely with bone fragments at varied pitch and orientation. This complexity of events evidenced within this area is a challenge for approaches that have been developed primarily based on comparative data from single-burial situations. In these discussions we deepen our use of references as suggested by the referee.
Burial positions
Reviewer 2 further suggests that illustrations of hypothesized burial positions would be valuable. We recognize that a hypothesized burial position may be an appealing illustration, and that some recent studies have created such illustrations in the context of their scientific articles. However such illustrations generally include a great deal of speculation and artist imagination, and tend to have an emotive character. We have added more discussion to the manuscript of possible primary disposition in the case of the Hill Antechamber Feature as discussed above. We have not created new illustrations of hypothesized burial positions for this revision.
Carnivore involvement
Referee 1 suggests that the manuscript should provide further consideration of whether carnivore activity may have introduced bones or bodies into the cave system. The reorganized Introduction now includes a review of previous work, and an expanded discussion within the Supplementary Information (“Hypotheses tested in previous work”). This includes a review of literature on the topic of carnivore accumulation and the evidence from the Dinaledi and Lesedi Chamber that rejects this hypothesis.
Water transport and mud
The eLife referees broadly accepted previous work showing that water inundation or mass flow of water-saturated sediment did not occur within the history of Unit 2 and 3 sediments, including those associated with H. naledi remains. However several outside commentators did refer specifically to water flow or mud flow as a mechanism for slumping of deposits and possible sedimentary covering of the remains. To address these comments we have added a section to the Supplementary Information (“Description of the sedimentary deposits of the Dinaledi Subsystem”) that reviews previous work on the sedimentary units and formation processes documented in this area. We also include a subsection specifically discussing the term “mud” as used in the description of the sedimentology within the system, as this term has clearly been confusing for nonspecialists who have read and commented on the work. We appreciate the referees’ attention to the previous work and its terminology.
Redescription of areas of the cave system
Reviewer 1 suggests that a detailed reanalysis of all portions of the cave system in and around the Dinaledi Subsystem is warranted to reject the hypothesis that bodies entered the space passively and were scattered from the floor by natural (i.e. noncultural) processes. The referee suggests that National Geographic could help us with these efforts. To address this comment we have made several changes to the manuscript. As noted above, we have added material in Supplementary Information to review the geochronology of the Dinaledi Subsystem and nearby Dragon’s Back Chamber, together with a discussion of the connections between these spaces.
Most directly in response to this comment we provide additional documentation of the possibility of movement of bodies or body parts by gravity within the subsystem itself. This includes detailed floor maps based on photogrammetry and LIDAR measurement, where these are physically possible, presented in Figures 2 and 3. In some parts of the subsystem the necessary equipment cannot be used due to the extremely confined spaces, and for these areas our maps are based on traditional survey methods. In addition to plan maps we have included a figure showing the elevation of the subsystem floor in a cross-section that includes key excavation areas, showing their relative elevation. All figures that illustrate excavation areas are now keyed to their location with reference to a subsystem plan. These data have been provided in previous publications but the visualization in the revised manuscript should make the relationship of areas clear for readers. The Introduction now includes text that discusses the configuration of the Hill Antechamber, Dinaledi Chamber, and nearby areas, and also discusses the instances in which gravity-driven movement may be possible, at the same time reviewing that gravity-driven movement from the entry point of the subsystem to most of the localities with hominin skeletal remains is not possible.
Within the Results, we have added a section on the relationship of features to their surroundings in order to assist readers in understanding the context of these bone-bearing areas and the evidence this context brings to the hypothesis in question. We have also included within this new section a discussion of the discrete nature of these features, a question that has been raised by outside commentators.
Passive sedimentation upon a cave floor or within a natural depression
Reviewer 3 suggests that the situation in the Dinaledi Subsystem may be similar to a European cave where a cave bear skeleton might remain articulated on a cave floor (or we can add, within a hollow for hibernation), later to be covered in sediment. The reviewer suggests that articulation is therefore no evidence of burial, and suggests that further documentation of disarticulation processes is essential to demonstrating the processes that buried the remains. We concur that articulation by itself is not sufficient evidence of cultural burial. To address this comment we have included a section in the Results that tests the hypothesis that bodies were exposed upon the cave floor or within a natural depression. To a considerable degree, additional data about disarticulation processes subsequent to deposition are provided in our reanalysis of the Puzzle Box area, including evidence for selective reworking of material after burial.
Postdepositional movement and floor drains
Reviewer 3 notes that previous work has suggested that subsurface floor drains may have caused some postdepositional movement of skeletal remains. The hypothesis of postdepositional slumping or downslope movement has also been discussed by some external commentators (including Martinón-Torres et al. 2024). We have addressed this question in several places within the revised manuscript. As we now review, previous discussion of floor drains attempted to explain the subvertical orientation of many skeletal elements excavated from the Puzzle Box area. The arrangement of these bones reflects reworking as described in our previous work, and without considering the possibility of reworking by hominins, one mechanism that conceivably might cause reworking was downward movement of sediments into subsurface drains. Further exploration and mapping, combined with additional excavation into the sediments beneath the Puzzle Box area provided more information relevant to this hypothesis. In particular this evidence shows that subsurface drains cannot explain the arrangement of skeletal material observed within the Puzzle Box area. As now discussed in the text, the reworking is selective and initiated from above rather than below. This is best explained by hominin activity subsequent to burial.
In a new section of the Results we discuss slumping as a hypothesis for the deposition of the remains. This includes discussion of downslope movement within the Hill Antechamber and the idea that floor drains may have been a mechanism for sediment reworking in and around the Puzzle Box area and Dinaledi Feature 1. As described in this section the evidence does not support these hypotheses.
Hypothesis testing and parsimony
Referees 1 and 3 and the editorial guidance all suggested that a more appropriate presentation would adopt a null hypothesis and test it. The specific suggestion that the null hypothesis should be a natural sedimentary process of deposition was provided not only by these reviewers but also by some outside commentators. To address this comment, we have edited the manuscript in two ways. The first is the addition of a section to the Discussion that specifically discusses hypothesis testing and parsimony as related to Pleistocene evidence of cultural burial. This includes a brief synopsis of recent disciplinary conversations and citation of work by other groups of authors, none of whom adopted this “null hypothesis” approach in their published work.
As we now describe in the manuscript, previous work on the Dinaledi evidence never assumed any role for H. naledi in the burial of remains. Reading the reviewer reports caused us to realize that this previous work had followed exactly the “null hypothesis” approach that some suggested we follow. By following this null hypothesis approach, we neglected a valuable avenue of investigation. In retrospect, we see how this approach impeded us from understanding the pattern of evidence within the Puzzle Box area. Thus in the revised manuscript we have mentioned this history within the Discussion and also presented more of the background to our previous work in the Introduction. Hopefully by including this discussion of these issues, the manuscript will broaden conversation about the relation of parsimony to these issues.
Language and presentation style
Reviewer 4 criticizes our presentation, suggesting that the text “gives the impression that a hypothesis was formulated before data were collected.” Other outside commentators have mentioned this notion also, including Martinón-Torres et al. (2024) who suggest that the study began from a preferred hypothesis and gathered data to support it. The accurate communication of results and hypotheses in a scientific article is a broader issue than this one study. Preferences about presentation style vary across fields of study as well as across languages. We do not regret using plain language where possible. In any study that combines data and methods from different scientific disciplines, the use of plain language is particularly important to avoid misunderstandings where terms may mean different things in different fields.
The essential question raised by these comments is whether it is appropriate to present the results of a study in terms of the hypothesis that is best supported. As noted above, we read carefully many recent studies of Pleistocene burial evidence. We note that in each of these studies that concluded that burial is the best hypothesis, the authors framed their results in the same way as our previous manuscript: an introduction that briefly reviews background evidence for treatment of the dead, a presentation of results focused on how each analysis supports the hypothesis of burial for the case, and then in some (but not all) cases discussion of why some alternative hypotheses could be rejected. We do not infer from this that these other studies started from a presupposition and collected data only to confirm it. Rather, this is a simple matter of presentation style.
The alternative to this approach is to present an exhaustive list of possible hypotheses and to describe how the data relate to each of them, at the end selecting the best. This is the approach that we have followed in the revised manuscript, as described above under the direction of the reviewer and editorial guidance. This approach has the advantage of bringing together evidence in different combinations to show how each data point rejects some hypotheses while supporting others. It has the disadvantage of length and repetition.
Possible artifact
We have chosen to keep the description of the possible artifact associated with the Hill Antechamber Feature in the Supplementary Information. We do this while acknowledging that this is against the opinion of reviewer 4, who felt the description should be removed unless the object in question is fully excavated and physically analyzed. The previous version of the manuscript did not rely upon the stone as positive evidence of grave goods or symbolic content, and it noted that the data do not test whether the possible artifact was placed or was intentionally modified. However this did not satisfy reviewer 4, and some outside commentators likewise asserted that the object must be a “geofact” and that it should be removed.
We have three arguments against this line of thinking. First, we do not omit data from our reporting. Whether Homo naledi shaped the rock or not, used it as a tool or not, whether the rock was placed with the body or not, it is unquestionably there. Omitting this one object from the report would be simply dishonest. Second, the data on this rock are at 16 micron resolution. While physical inspection of its surface may eventually reveal trace evidence and will enable better characterization of the raw material, no mode of surface scanning will produce better evidence about the object’s shape. Third, the position of this possible artifact within the feature provides significant information about the deposition of the skeletal material and associated sediments. The pitch, orientation, and position of the stone is not consistent with slow deposition but are consistent with the hypothesis that the surrounding sediment was rapidly emplaced at the same time as the articulated elements less than 2 cm away.
In the current version, we have redoubled our efforts to provide information about the position and shape of this stone while not presupposing the intentionality of its shape or placement. We add here that the attitude expressed by referee 4 and other commentators, if followed at other sites, would certainly lead to the loss or underreporting of evidence, which we are trying to avoid.
Consistency versus variability of behavior
As described in the revised manuscript, different features within the Dinaledi Subsystem exhibit some shared characteristics. At the same time, they vary in positioning, representation of individuals and extent of commingling. Other localities within the subsystem and broader cave system present different evidence. Some commentators have questioned whether the patterning is consistent with a single common explanation, or whether multiple explanations are necessary. To address this line of questioning, we have added several elements to the manuscript. We created a new section on secondary cultural burial, discussing whether any of the situations may reflect this practice. In the Discussion, we briefly review the ways in which the different features support the involvement of H. naledi without interpreting anything about the intentionality or meaning of the behavior. We further added a section to the Discussion to consider whether variation among the features reflects variation in mortuary practices by H. naledi. One aspect of this section briefly cites variation in the location and treatment of skeletal remains at other sites with evidence of burial.
Grave goods
Some commentators have argued that grave goods are a necessary criterion for recognizing evidence of ancient burial. We added a section to the Discussion to review evidence of grave goods at other Pleistocene sites where burial is accepted.
On 2024-08-12 09:57:17, user John Hawks wrote:
The authors have prepared a summary of revisions to this manuscript, which is available in the Supplementary Information section of the preprint. I have included the text of that summary across the following two comments in two parts (the whole is larger than the maximum comment length).
Summary of revisions to Evidence for deliberate burial of the dead by Homo naledi
We extend our sincere thanks to the editor, referees for eLife, and other commentators who have written evaluations of this manuscript, either in whole or in part. Sources of these comments were highly varied, including within the bioRxiv preprint server, social media (including many comments received on X/Twitter and some YouTube presentations and interviews), comments made by colleagues to journalists, and also some reviews of the work published in other academic journals. Some of these are formal and referenced with citations. Others were informal but nonetheless expressed perspectives that helped enable us to revise the manuscript with the inclusion of broader perspectives than the formal review process. It is beyond the scope of this summary to list every one of these, which have often been brought to the attention of different coauthors, but we begin by acknowledging the very wide array of peer and public commentary that have contributed to this work. The reaction speaks to a broad interest in open discussion and review of preprints.
As we compiled this summary of changes to the manuscript, we recognized that many colleagues made comments about the process of preprint dissemination and evaluation rather than the data or analyses in the manuscript. Addressing such comments is outside the scope of this revised manuscript, but we do feel that a broader discussion of these comments would be valuable in another venue. Many commentators have expressed confusion about the eLife system of evaluation of preprints, which differs from the editorial acceptance or rejection practiced in most academic journals. As authors in many different nations, in varied fields, and in varied career stages, we ourselves are still working to understand how the academic publication landscape is changing, and how best to prepare work for new models of evaluation and dissemination.
The manuscript and coauthor list reflect an interdisciplinary collaboration. Analyses presented in the manuscript come from a wide range of scientific disciplines. These range from skeletal inventory, morphology, and description, spatial taphonomy, analysis of bone fracture patterns and bone surface modifications, sedimentology, geochemistry, and traditional survey and mapping. The manuscript additionally draws upon a large number of previous studies of the Rising Star cave system and the Dinaledi Subsystem, which have shaped our current work. No analysis within any one area of research stands alone within this body of work: all are interpreted in conjunction with the outcomes of other analyses and data from other areas of research. Any single analysis in isolation might be consistent with many different hypotheses for the formation of sediments and disposition of the skeletal remains. But testing a hypothesis requires considering all data in combination and not leaving out data that do not fit the hypothesis. We highlight this general principle at the outset because a number of the comments from referees and outside specialists have presented alternative hypotheses that may arguably be consistent with one kind of analysis that we have presented, while seeming to overlook other analyses, data, or previous work that exclude these alternatives. In our revision, we have expanded all sections describing results to consider not only the results of each analysis, but how the combination of data from different kinds of analysis relate to hypotheses for the deposition and subsequent history of the Homo naledi remains. We address some specific examples and how we have responded to these in our summary of changes below.
General organization
The referee and editor comments are mostly general and not line-by-line questions, and we have compiled them and treated them as a group in this summary of changes, except where specifically noted.
The editorial comments on the previous version included the suggestion that the manuscript should be reorganized to test “natural” (i.e. noncultural) hypotheses for the situations that we examine. The editorial comment suggested this as a “null hypothesis” testing approach. Some outside comments also viewed noncultural deposition as a null hypothesis to be rejected. We do not concur that noncultural processes should be construed as a null hypothesis, as we discuss further below. However, because of the clear editorial opinion we elected to revise the manuscript to make more explicit how the data and analyses test noncultural depositional hypotheses first, followed by testing of cultural hypotheses. This reorganization means that the revised manuscript now examines each hypothesis separately in turn.
Taking this approach resulted in a substantial reorganization of the “Results” section of the manuscript. The “Results” section now begins with summaries of analyses and data conducted on material from each excavation area. After the presentation of data and analyses from each area, we then present a separate section for each of several hypotheses for the disposition and sedimentary context of the remains. These hypotheses include deposition of bodies upon a talus (as hypothesized in some previous work), slow sedimentary burial on a cave floor or within a natural depression, rapid burial by gravity-driven slumping, and burial of naturally mummified remains. We then include sections to test the hypothesis of primary cultural burial and secondary cultural burial. This approach adds substantial length to the Results. While some elements may be repeated across sections, we do consider the new version to be easier to take piece by piece for a reader trying to understand how each hypothesis relates to the evidence.
The Results section includes analyses on several different excavation areas within the Dinaledi Subsystem. Each of these presents somewhat different patterns of data. We conceived of this manuscript combining these distinct areas because each of them provides information about the formation history of the Homo naledi-associated sediments and the deposition of the Homo naledi remains. Together they speak more strongly than separately. In the previous version of the manuscript, two areas of excavation were considered in detail (Dinaledi Feature 1 and the Hill Antechamber Feature), with a third area (the Puzzle Box area) included only in the Discussion and with reference to prior work. We now describe the new work undertaken after the 2013-2014 excavations in more detail. This includes an overview of areas in the Hill Antechamber and Dinaledi Chamber that have not yielded substantial H. naledi remains and that thereby help contextualize the spatial concentration of H. naledi skeletal material. The most substantial change in the data presented is a much expanded reanalysis of the Puzzle Box area. This reanalysis provides greater clarity on how previously published descriptions relate to the new evidence. The reanalysis also provides the data to integrate the detailed information on bone identification fragmentation, and spatial taphonomy from this area with the new excavation results from the other areas.
In addition to Results, the reorganization also affected the manuscript’s Introduction section. Where the previous version led directly from a brief review of Pleistocene burial into the description of the results, this revised manuscript now includes a review of previous studies of the Rising Star cave system. This review directly addresses referee comments that express some hesitation to accept previous results concerning the structure and formation of sediments, the accessibility of the Dinaledi Subsystem, the geochronological setting of the H. naledi remains, and the relation of the Dinaledi Subsystem to nearby cave areas. Some parts of this overview are further expanded in the Supplementary Information to enable readers to dive more deeply into the previous literature on the site formation and geological configuration of the Rising Star cave system without needing to digest the entirety of the cited sources.
The Discussion section of the revised manuscript is differentiated from Results and focuses on several areas where the evidence presented in this study may benefit from greater context. One new section addresses hypothesis testing and parsimony for Pleistocene burial evidence, which we address at greater length in this summary below. The majority of the Discussion concerns the criteria for recognizing evidence for burial as applied in other studies. In this research we employ a minimal definition but other researchers have applied varied criteria. We consider whether these other criteria have relevance in light of our observations and whether they are essential to the recognition of burial evidence more broadly.
Vocabulary
We introduce the term “cultural burial” in this revised manuscript to refer to the burial of dead bodies as a mortuary practice. “Burial” as an unmodified term may refer to the passive covering of remains by sedimentary processes. Use of the term “intentional burial” would raise the question of interpreting intent, which we do not presume based on the evidence presented in this research. The relevant question in this case is whether the process of burial reflects repeated behavior by a group. As we received input from various colleagues it became clear that burial itself is a highly loaded term. In particular there is a common assumption within the literature and among professionals that burial must by definition be symbolic. We do not take any position on that question in this manuscript, and it is our hope that the term “cultural burial” may focus the conversation around the extent that the behavioral evidence is repeated and patterned.
Sedimentology and geochemistry of Dinaledi Feature 1
Reviewer 4 provided detailed comments on the sedimentological and geochemical context that we report in the manuscript. One outside review (Foecke et al. 2024) included some of the points raised by reviewer 4, and additionally addressed the reporting of geochemical and sedimentological data in previous work that we cite.
To address these comments we have revised the sedimentary context and micromorphology of sediments associated with Dinaledi Feature 1. In the new text we demonstrate the lack of microstratigraphy (supported by grain size analysis) in the unlithified mud clast breccia (UMCB), while such a microstratigraphy is observed in the laminated orange-red mudstones (LORM) that contribute clasts to the UMCB. Thus, we emphasize the presence and importance of a laterally continuous layer of LORM nature occurring at a level that appears to be the maximum depth of fossil occurrence. This layer is severely broken under extensive accumulation of fossils such as Feature 1 and only evidenced by abundant LORM clasts within and around the fossils.
We have completely reworked the geochemical context associated with Feature 1 following the comments of reviewer 4. We described the variations and trends observed in the major oxides separate from trace and rare-earth elements. We used Harker variations plots to assess relationships between these element groups with CaO and Zn, followed by principal component analysis of all elements analyzed. The new geochemical analysis clearly shows that Feature 1 is associated with localized trace element signatures that exist in the sediments only in association with the fossil bones, which suggests lack of postdepositional mobilization of the fossils and sediments. We additionally have included a fuller description of XRF methods.
To clarify the relation of all results to the features described in this study, we removed the geochemical and sedimentological samples from other sites within the Dinaledi Subsystem. These localities within the fissure network represent only surface collection of sediment, as no excavation results are available from those sites to allow for comparison in the context of assessing evidence of burial. These were initially included for comparison, but have now been removed to avoid confusion.
Micromorphology of sediments
Some referees (1, 3, and 4) and other commentators (including Martinón-Torres et al. 2024) have suggested that the previous manuscript was deficient due to an insufficient inclusion of micromorphological analysis of sediments. Because these commentators have emphasized this kind of evidence as particularly important, we review here what we have included and how our revision has addressed this comment. Previous work in the Dinaledi Chamber (Dirks et al., 2015; 2017) included thin section illustrations and analysis of sediment facies, including sediments in direct association with H. naledi remains within the Puzzle Box area. The previous work by Wiersma and coworkers (2020) used micromorphological analysis as one of several approaches to test the formation history of Unit 3 sediments in the Dinaledi Subsystem, leading to the interpretation of autobrecciation of earlier Unit 1 sediment. In the previous version of this manuscript we provided citations to this earlier work. The previous manuscript also provided new thin section illustrations of Unit 3 sediment near Dinaledi Feature 1 to place the disrupted layer of orange sediment (now designated the laminated orange silty mudstone unit) into context.
In the new revised manuscript we have added to this information in three ways. First, as noted above in response to reviewer 4, we have revised and added to our discussion of micromorphology within and adjacent to the Dinaledi Feature 1. Second, we have included more discussion in the Supplementary Information of previous descriptions of sediment facies and associated thin section analysis, with illustrations from prior work (CC-BY licensed) brought into this paper as supplementary figures, so that readers can examine these without following the citations. Third, we have included Figure 10 in the manuscript which includes six panels with microtomographic sections from the Hill Antechamber Feature. This figure illustrates the consistency of sub-unit 3b sediment in direct contact with H. naledi skeletal material, including anatomically associated skeletal elements, with previous analyses that demonstrate the angular outlines and chaotic orientations of LORM clasts. It also shows density contrasts of sediment in immediate contact with some skeletal elements, the loose texture of this sediment with air-filled voids, and apparent invertebrate burrowing activity. To our knowledge this is the first application of microtomography to sediment structure in association with a Pleistocene burial feature.
To forestall possible comments that the revised manuscript does not sufficiently employ micromorphological observations, or that any one particular approach to micromorphology is the standard, we present here some context from related studies of evidence from other research groups working at varied sites in Africa, Europe, and Asia. Hodgkins et al. (2021) noted: “Only a handful of micromorphological studies have been conducted on human burials and even fewer have been conducted on suspected burials from Paleolithic or hunter-gatherer contexts.” In that study, one supplementary figure with four photomicrographs of thin sections of sediments was presented. Interpretation of the evidence for a burial pit by Hodgkins et al. (2021) noted the more open microstructure of sediment but otherwise did not rely upon the thin section data in characterizing the sediments associated with grave fill. Martinón-Torres et al. (2021) included one Extended Data figure illustrating thin sections of sediments and bone, with two panels showing sediments (the remainder showing bone histology). The micromorphological analysis presented in the supplementary information of that paper was restricted to description of two microfacies associated with the proposed “pit” in that study. That study did carry out microCT scanning of the partially-prepared skeletal remains but did not report any sediment analysis from the microtomographic results. Maloney et al. (2022) reported no micromorphological or thin section analysis. Pomeroy et al. (2020a) included one illustration of a thin section; this study may be regarded as a preliminary account rather than a full description of the work undertaken. Goldberg et al. (2017) analyzed the geoarchaeology of the Roc de Marsal deposits in which possible burial-associated sediments had been fully excavated in the 1960s, providing new morphological assessments of sediment facies; the supplementary information to this work included five scans (not microscans) of sediment thin sections and no microphotographs. Fewlass et al. (2023) presented no thin section or micromorphological illustrations or methods. In summary of this research, we note that in one case micromorphological study provided observations that contributed to the evidence for a pit, in other cases micromorphological data did not test this hypothesis, and many researchers do not apply micromorphological techniques in their particular contexts.
Sediment micromorphology is a growing area of research and may have much to provide to the understanding of ancient burial evidence as its standards continue to develop (Pomeroy et al. 2020b). In particular microtomographic analysis of sediments, as we have initiated in this study, may open new horizons that are not possible with more destructive thin-section preparation. In this manuscript, the thin section data reveals valuable evidence about the disruption of sediment structure by features within the Dinaledi Chamber, and microtomographic analysis further documents that the Hill Antechamber Feature reflects similar processes, in addition to possible post-burial diagenesis and invertebrate activity. Following up in detail on these processes will require further analysis outside the scope of this manuscript.
Access into the Dinaledi Subsystem
Reviewer 1 emphasizes the difficulty of access into the Dinaledi Subsystem as a reason why the burial hypothesis is not parsimonious. Similar comments have been made by several outside commentators who question whether past accessibility into the Dinaledi Subsystem may at one time have been substantially different from the situation documented in previous work. Several pieces of evidence are relevant to these questions and we have included some discussion of them in the Introduction, and additionally include a section in the Supplementary Information (“Entrances to the cave system”) to provide additional context for these questions. Homo naledi remains are found not only within the Dinaledi Subsystem but also in other parts of the cave system including the Lesedi Chamber, which is similarly difficult for non-expert cavers to access. The body plan, mass, and specific morphology of H. naledi suggest that this species would be vastly more suited to moving and climbing within narrow underground passages than living people. On this basis it is not unparsimonious to suggest that the evidence resulted from H. naledi activity within these spaces. We note that the accessibility of the subsystem is not strictly relevant to the hypothesis of cultural burial, although the location of the remains does inform the overall context which may reflect a selection of a location perceived as special in some way.
Stuffing bodies down the entry to the subsystem
Reviewer 3 suggests that one explanation for the emplacement of articulated remains at the top of the sloping floor of the Hill Antechamber is that bodies were “stuffed” into the chute that comprises the entry point of the subsystem and passively buried by additional accumulation of remains. This was one hypothesis presented in earlier work (Dirks et al. 2015) and considered there as a minimal explanation because it did not entail the entry of H. naledi individuals into the subsystem. The further exploration (Elliott et al. 2021) and ongoing survey work, as well as this manuscript, all have resulted in data that rejects this hypothesis. The revised manuscript includes a section in the results “Deposition upon a talus with passive burial” that examines this hypothesis in light of the data.
On 2024-08-10 18:17:39, user Els Van Damme wrote:
Thank you for commenting on our article. We have now posted a revised version of our preprint.
On 2024-06-20 16:05:39, user Kishore Babu wrote:
SEC- MALLS experiment (Supplementary Fig1a) appears strange: (a) While Nictaba is eluting much later than BSA monomer (Mr = 66,000) the authors claim Nictaba to be a tetramer in solution (Mr = 76,000; subunit mol.wt. = 19,000 Da), so that they can claim a difference in their protein from that of PP2 gene family of proteins all of which have been shown in at least dozen other studies to exist as dimers only. (b) Only two molecular weight markers have been used as the standards for calibrating the column. (c) Nictaba a PP2 gene family protein is expected to be impeded on the gel media of their column as in a number of studies in the past on PP2 gene family of proteins they have been shown to get retarded on on gel media ranging from Sephadex, Acrylamide, Superdex etc.(Read, SM and Northcote, DH (1983) Planta 158, 119-127; Anantharam, V. et al. (1986) J. Biol.Chem. 261,14621-27 and Bobbili, KB et al. (2023) Structure 31,1-16).
The location, geometry of the binding site, the stereochemistry of the bound chitotriose and its interaction in Nictaba are identical to that reported for Cus17- the founding member of the PP2 gene family fold (Ref. Structure (2023) vol 31 pp1-16). Moreover ,the key residues tethering chitotriose to Nictaba are Thr14, Trp15, Tyr21, Val39, Ala40 and Trp151 are identical and correspond with Thr18, Trp19, Tyr25, Val46, Ser47, Trp48 and Trp141. Given this remarkably striking level of identities of the binding residues and the groups in the sugar one fails to see any novelty in Nictaba-sugar interactions as compared to the fold founding member of the family, namely Cus17. In this context, the authors should discuss their results in comparison with the structure of Cus17.
Even the backbone Cα atoms of the subunit of Nictaba overlap within 1.06A of the Cα atoms of Cus17 indicating that Nictaba fold is not new and is a faithful copy of Cus17. This should be stated in the Results and Discussion sections of the manuscript as appropriate.
The InterPro site that curates protein folds has created a separate folder for PP2 gene family of proteins since the appearance of Cus17 structure recognising it as a novel fold. It is therefore not surprising that Nictaba fold is curated and subsequent to the fold of Cus17.
Authors do not report on study on the stoichiometry of binding by any method including ITC but they claim Nictaba has a single binding site per subunit for the sugar perhaps based on crystal structure which is not a conclusive evidence for their assumption as there are numerous examples of differences for the number of binding sites seen in crystal structure or modeling vis-a-vis what are found in solution. Extensive ITC studies on several PP2 type lectins have given a wealth of information on the binding constants and thermodynamic factors associated with the binding of chitooligosaccharides to them as well as on the binding stoichiometry (see Nareddy, PK et al. (2017) Int. J. Biol. Macromol. 95, 910-919; Bobbili, KB et al. (2018) Int. J. Biol. Macromol. 108, 1227-1236; Bobbili, KB et al. (2019) Int. J. Biol. Macromol. 137, 774-782).
Nearly 40% of the 60 references cited in this manuscript are citations to the publications of the corresponding author! On the other hand many important, relevant publications of other scientists (mentioned above) are not cited.
On 2024-06-07 04:15:26, user Swamy wrote:
This study reports the crystal structure of Nictaba, the Nicotiana tabacum lectin which is specific for chitooligosaccharides and also binds N-linked glycans. The tertiary structure of this protein is essentially the same as that of Cus17, the 17 kDa phloem exudate lectin from Cucumis sativus (Bobbili et al. (2023) Structure 31, 1-16). Hence the term “archetypal” used in the title is misleading and hence it should be removed.
Nictaba is homologous to PP2 family proteins from Cucurbitaceae and other species. Some background information about PP2 proteins is relevant here. Two major proteins, phloem proteins 1 and 2 (short form PP1 and PP2) in the sieve elements of plants were studied since early 1970s by several groups (Sabnis and Hart (1973) Planta, 142, 97-101; Allen (1979) Biochem. J. 183, 133-137; Read & Northcote (1983) Planta 158, 119-127; Read & Northcote (1983) Eur. J. Biochem. 134, 561-567). That PP2 is a lectin was well established in these studies and its activity was clearly shown to be inhibited by oligomers of GlcNAc and by N-linked glycopeptides by Allen (Biochem. J. (1979) 183, 133-137). The PP2 proteins have been found in a wide variety of plant species, both monocots and dicots. In 1986 Anantharam et al. (J. Biol. Chem. 261, 14621-14627) clearly established that the chitobiosyl core of N-linked glycopeptides is crucial for binding of the phloem exudate lectin from Luffa acutangula (ridge gourd) as treatment of the N-linked glycans with endo-β-N-acetylglucosaminidase H completely abrogated their binding. While some of these early workers did not consistently use the designation PP2 protein while describing these lectins, over the last 30 years the term ‘PP2 proteins’ is commonly used by scientists working on these proteins. In fact, Gary Thompson’s group, who have extensively investigated the PP2 family genes referred to these proteins as a Superfamily (Dinant et al. (2003) Plant Physiol. 131, 115-131) and also referred to the Nicotiana tabacum lectin as a PP2-like agglutinin. Now Els Van Damme’s group, which has been working on plant lectins for over 3 decades refers to other PP2 family lectins that were investigated from much earlier as Nictaba-related lectins. This is a gross violation of scientific propriety and Nictaba should be referred to as a member of the PP2 Superfamily of proteins.
Since the high-resolution crystal structure of Cus17 is already known, and the structure of Nictaba is highly similar to it, the same should be mentioned in the Abstract, Introduction and Discussion sections in an appropriate manner. In particular, in Discussion section (para 2) the sentence “A similar crystal structure was reported recently for the phloem lectin from Cucumis sativus (Cus17), a member of the Nictaba-related lectin family” should be modified to indicate that “the first crystal structure of the PP2 fold to which Nictaba belongs”. In fact, the narrative of referring to all PP2 family lectins as Nictaba-related lectins at various places in the manuscript should be changed and Nictaba should be referred to as PP2 family protein.
In the light of the fact that the structural fold of Nictaba is quite similar to that of Cus17, it would be appropriate to give a detailed comparison of the Nictaba structure with Cus17 structure. <br /> Since the glycan array investigations on Nictaba have been reported earlier by the same group (Lannoo et al. (2006) FEBS Lett. 580, 6329-6337; Schouppe et al. (2010) Glycoconj. J. 27, 613–623) the discussion on this aspect should be condensed. Importantly, the glycan array data is at best semi-quantitative and the authors should have used a method like ITC (Isothermal Titration Calorimetry) which gives reliable and quantitative information on not only the association (binding) constants, but also important additional information on the carbohydrate binding by the lectin, viz., stoichiometry, enthalpy and entropy associated with the binding.
Although extensive studies on the binding of chitooligosaccharides to phloem exudate lectins have been reported, especially employing ITC, the authors cited just one paper published in 2011 (Narahari et al. (2011) J. Phys. Chem. B. 115, 4110–4117). Since then several ITC studies on chitooligosaccharide binding to PP2 family lectins have been reported (reviewed by Swamy et al. (2022) Phytochemistry, Article No. 113251.) This information should be suitably cited. Also, the study of Bobbili et al. (2023) on Cus17 also reports extensive ITC studies on the binding of various chitooligosaccharides and the N-linked glycan, Man3GlcNAc2 to the lectin. It is important to cite this work while discussing the carbohydrate binding characteristics of Nictaba.
On 2024-08-10 09:02:59, user ani1977 wrote:
Trying to download the data but facing "unzip: inflate error"? Below is the details of file and wget-log
wget --ftp-user=MSV000095162 --ftp-password=hgu89\!hgb -r " ftp://MSV000095162@massive.ucsd.edu/raw/Raw2/8 --2024-08-09 15:24:16-- ftp://MSV000095162@massive.ucsd.edu/raw/Raw2/80-2.zip => ‘ http://massive.ucsd.edu/raw/Raw2/.listing’ Resolving http://massive.ucsd.edu ... 132.249.211.16
Connecting to http://massive.ucsd.edu |132.249.211.16|:21... connected.
Logging in as MSV000095162 ... Logged in!
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2024-08-09 15:24:18 (3.41 MB/s) - ‘[http://massive.ucsd.edu/raw/Raw2/.listing’](http://massive.ucsd.edu/raw/Raw2/.listing’:GdLBFgBQICCkUtR2vybJkVCxpvA "http://massive.ucsd.edu/raw/Raw2/.listing’")saved [326]
Removed ‘[http://massive.ucsd.edu/raw/Raw2/.listing’](http://massive.ucsd.edu/raw/Raw2/.listing’:GdLBFgBQICCkUtR2vybJkVCxpvA "http://massive.ucsd.edu/raw/Raw2/.listing’").<br />
--2024-08-09 15:24:18--[ftp://MSV000095162@massive.ucsd.edu/raw/Raw2/80-2.zip](ftp://MSV000095162@massive.ucsd.edu/raw/Raw2/80-2.zip:Y9SeoGJEmkqa4Bl1VBmCaBwr2E4 "ftp://MSV000095162@massive.ucsd.edu/raw/Raw2/80-2.zip")=> ‘[http://massive.ucsd.edu/raw/Raw2/80-2.zip’](http://massive.ucsd.edu/raw/Raw2/80-2.zip’:O5ImlsutePNNEZ3_IaMs7NMHh6I "http://massive.ucsd.edu/raw/Raw2/80-2.zip’")==> CWD not required.<br />
==> PASV ... done. ==> RETR[http://80-2.zip](http://80-2.zip:qseKzsDg34VmYze3eF17fnrtQFY "http://80-2.zip")... done.<br />
Length: 173832044544 (162G)[http://massive.ucsd.edu/raw/Raw2/80-2.zip](http://massive.ucsd.edu/raw/Raw2/80-2.zip:eXxGRDBvC8fBOclrVFpPmsM5rs0 "http://massive.ucsd.edu/raw/Raw2/80-2.zip")63%[====================================================================================>
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Logging in as MSV000095162 ... Logged in!<br />
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2024-08-10 04:49:45 (698 KB/s) - Data connection: Connection timed out; Data transfer aborted.<br /> Retrying.
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--2024-08-10 04:49:52--[ftp://MSV000095162@massive.ucsd.edu/raw/Raw2/80-2.zip](ftp://MSV000095162@massive.ucsd.edu/raw/Raw2/80-2.zip:Y9SeoGJEmkqa4Bl1VBmCaBwr2E4 "ftp://MSV000095162@massive.ucsd.edu/raw/Raw2/80-2.zip")(try: 5) => ‘[http://massive.ucsd.edu/raw/Raw2/80-2.zip’](http://massive.ucsd.edu/raw/Raw2/80-2.zip’:O5ImlsutePNNEZ3_IaMs7NMHh6I "http://massive.ucsd.edu/raw/Raw2/80-2.zip’")Connecting to[http://massive.ucsd.edu](http://massive.ucsd.edu:fnwcjh3df7hMG7pe2bJ2IK5qRBc "http://massive.ucsd.edu")|132.249.211.16|:21... connected.<br />
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2024-08-10 09:33:02 (3.26 MB/s) - ‘[http://massive.ucsd.edu/raw/Raw2/80-2.zip’](http://massive.ucsd.edu/raw/Raw2/80-2.zip’:O5ImlsutePNNEZ3_IaMs7NMHh6I "http://massive.ucsd.edu/raw/Raw2/80-2.zip’")saved [173832044544]
FINISHED --2024-08-10 09:33:02--<br /> Total wall clock time: 18h 8m 45s<br /> Downloaded: 1 files, 54G in 18h 8m 25s (869 KB/s)<br /> ✓
10/08/2024 09:45.41 /mnt/z/d80 cd[http://massive.ucsd.edu/raw/Raw2/](http://massive.ucsd.edu/raw/Raw2/:PrfWHyVCVLrSn8uZCBTcW9kil6E "http://massive.ucsd.edu/raw/Raw2/")✓
10/08/2024 09:45.56 /mnt/z/d80/[http://massive.ucsd.edu/raw/Raw2](http://massive.ucsd.edu/raw/Raw2:wwDJqyDJge16is8KfZcnO2bFthc "http://massive.ucsd.edu/raw/Raw2") unzip[http://80-2.zip](http://80-2.zip:qseKzsDg34VmYze3eF17fnrtQFY "http://80-2.zip")Archive:[http://80-2.zip](http://80-2.zip:qseKzsDg34VmYze3eF17fnrtQFY "http://80-2.zip")creating: BORA_10_16_HEK_80C_C10_RC11_1_22017.d/<br />
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On 2024-08-10 01:44:41, user ML Gaynor wrote:
This preprint was published July 14th, 2024: https://doi.org/10.1002/aps3.11606
On 2024-08-09 16:40:34, user mavillanueva wrote:
This work has been submitted for peer review.
On 2024-08-08 22:01:21, user Emile Gluck-Thaler wrote:
This preprint has now been published: https://doi.org/10.1093/nar/gkae327
On 2024-08-08 13:15:41, user F. Laclé wrote:
Also, if you can publish your model code in a repository would be great for reproducibility (the model itself is not necessary I reckon). As you know, there are much more system configuration elements to consider, which makes reproducibility efforts complicated. Publishing your model code would allow others to attempt and improve the reproducibility challenges.
On 2024-08-08 13:11:45, user F. Laclé wrote:
Hi. In Figure 6b, shouldn't the number of filters of the skip connection be equal to 4 times the number of filters in the last Xception module? You have it specified as 16, shouldn't it be 32?
On 2024-08-08 08:28:33, user Ashleigh Shannon wrote:
AUTHORS COMMENT / UPDATE <br /> 21 June 2024
Part of this work, describing the inhibition of both the NiRAN and RdRp domains by the guanosine analogue 5’-triphosphate AT-9010 has now been published in Nature Communications ( http://doi.org/10.1038/s41467-022-28113-1)11:bWV2b7IKjzmu98TO74CkaGwQqk8 "http://doi.org/10.1038/s41467-022-28113-1)1") . This includes the structural characterization of the mechanism of inhibition at both active-sites, which importantly revealed that the SARS-CoV-2 NiRAN domain contains a guanine-specific pocket. This has now been confirmed in other studies 2,3, and represents a promising avenue for future drug development studies.
Following several contradictory reports on the ability of the NiRAN to NMPylate different cofactor proteins (4–6), we have now carried out additional analysis on the protein-priming activity and NMPylation specificity. This has revealed that our nsp8 product is labeled at the primary amine of a non-native glycine residue, present at the N-terminus of the expression construct (following cleavage with TEV protease), and negating the biological relevance of these findings. Surprisingly, removal of this single residue, exposing the true N-terminal alanine, eliminates all labeling and protein-primed activity, stressing the importance for using proteins with native N- and C- termini. Of note, the current publication does not reflect these new findings, but instead has been left as the initially submitted manuscript.
Later studies have now revealed nsp9 to be the primary target for both NMPylation5,7, and RNAylation8 – a conclusion that we fully agree with.
With the exception of our finding that nsp8 can be used to prime-synthesis, albeit by a non-native residue, there was no other evidence for protein-priming until recently. In October, 2023, Schmidt et al., published the finding that nsp9 is covalently linked to the 5' end of positive- and negative-sense RNA produced during SARS-CoV-2 infection9. This linkage was found to be regulated by its interaction with the host protein, staphylococcal nuclease domain-containing protein 1 (SND1), which was found to specifically recognize the 5’ end of negative-sense RNA and be important for viral RNA synthesis. Although it is highly frustrating to have spent several years focused on the wrong protein, this finding supports the notion that protein-priming is occurring in CoVs, and opens up a plethora of options for further mechanistic and structural studies.
Of note, Schmidt et al. also showed that nsp9-linkage on the (-)sense strand mapped roughly between the genome and poly(A) tail. Intriguingly, we also found a similar specificity for this region. Here we show that the SARS-CoV mRTC (nsp12-nsp7-nsp8) can initiate synthesis through a de novo, NiRAN independent pathway, through the synthesis of a pppGpU primer. This dinucleotide is complementary to the last two nucleotides of the SARS-CoV-2 genome, located precisely at the genome-poly(A) junction. De novo initiation was found to directly compete with the (artificial) nsp8-poly(U) protein-primed synthesis. This shows that the poly(A) tail and 3’ genomic RNA sequence elements guide the positioning of the mRTC to the true 3’-end of the genome.
The specific details behind initiation of RNA synthesis, including the role of SND1 and potential coordination between protein-priming and/or de novo induction remains to be studied. Synthesis initiation, and the precise role of the NiRAN therefore appears to be a complicated story, which remains to be fully elucidated.
Ashleigh Shannon and Bruno Canard
On 2024-08-07 20:02:40, user jan wrote:
This was published in a peer-reviewed journal quite some time ago, but as of today the link is still missing: Smits, A.H., Ziebell, F., Joberty, G. et al. Biological plasticity rescues target activity in CRISPR knock outs. Nat Methods 16, 1087–1093 (2019). https://doi.org/10.1038/s41592-019-0614-5
On 2024-08-07 19:00:20, user Zheng Fu wrote:
Cells 2024, 13(15), 1258; https://doi.org/10.3390/cells13151258
On 2024-08-06 23:47:01, user Jorge Ramirez wrote:
Please add a link to the published version of the paper. The link of the journal publication is: https://www.frontiersin.org/journals/plant-science/articles/10.3389/fpls.2024.1375958/full . https://doi.org/10.3389/fpls.2024.1375958 . Thanks!
On 2024-08-05 20:26:55, user Zach Hensel wrote:
Summary: Zhan et al argue that nearly identical (>99.9% in the S gene or across a whole genome) sequences sampled within a single species indicate transmission within a single species subsequent to a period of host adaptation, assuming the necessity of adaptive mutations in any new host. They repeatedly claim that similar identical genomes were never sampled in different species in SARS outbreak between 2002 and 2004. This is incorrect. In fact, the data cited in this paper includes at least four examples of 100% sequence identity in samples from different species. Thus, the statement "In the SARS-CoV outbreaks, >99.9% genome or S identity was only observed among isolates collected within a narrow window of time from within the same species" was incorrect.
Example 1: Figure 5 and the manuscript discuss samples SZ3 and SZ16 collected from palm civets in 2004 in Dongmen market in Shenzhen. However, sample SZ13, reported from the same study (Guan et al, Science 2003, accession AY304487) is not mentioned. It was collected from a raccoon dog and it is 100% identical to SZ16 over 8581 bases in a partial genome sequence inclusive of S.
Furthermore, Guan et al also reported neutralization of SZ16 infection by sera from masked palm civets (3 of 6 samples), raccoon dog (1 of 1), Chinese ferret badger (1 of 2), and human (12/55; 8/20 for humans in wild animal trade). This indicates widespread infection of diverse species by SARS with >99.9% identical genomes without requiring further host adaptation. It's possible this error is inherited from Song et al (PNAS 2005), which twice states that SZ13 is a sample from a civet.
This error is perplexing since the primary source for this data is clear on what animals were sampled and sequence identity. What's less well known is that Dongmen market continued to be sampled after May (Yaqing et al, Disease Surveillance 2004). Civets, raccoon dogs, and badgers were still available for sampling and still positive by PCR for SARS in October, November, and December 2003. It wasn't until spillover from civets to humans was definitively shown for the Guangzhou outbreak (Wang et al, Emerg Infect Dis 2005) that Guangdong province acted to close wildlife markets and end the civet trade. Dr. Garry notes similar findings at Xinyuan market in Guangzhou in January 2024.
Example 2 and 3: Zhan et al write, "The human and civet isolates of the 2003/2004 outbreak, which were collected most closely in time and at the site of cross-species transmission, shared only up to 99.79% S identity.” This is incorrect. Wang et al (Emergency Infect Dis 2005) write, "The 286-bp S gene sequences from isolates from the waitress and the physician were identical to 4 of 5 S gene sequences from palm civets from the restaurant.”
Example 4: The 99.79% identical sequence described by Wang et al (Emergency Infect Dis 2005) is instead from a different patient without a known link to the civet or other animal trade — a patient identified about one month before the first patient in the restaurant cluster. However, “An isogenic strain with the same SNV pattern, B012G, was detected in a palm civet from the Xinyuan animal market” (Kan et al J Virol 2005).
Conclusion: Repeated claims of no examples of 99.9% identical viruses in different species during SARS outbreaks were provably incorrect when this manuscript was preprinted. Furthermore, the manuscript appeals to near-identity of sequences obtained within Huanan market. Subsequently, it has been shown that both lineage A and lineage B were found in environmental sampling of Huanan market. I hope that authors will revisit their conclusions given the reality of the facts they based their arguments on.
On 2024-08-05 16:25:30, user Ra Hel wrote:
Hi, thank you for the thorough article. I would like to comment on : "We then employed GB classifiers in subsequent studies and utilized them to exclude studies that cannot discriminate the disease phenotype based on microbial profile."<br /> It would be really useful to have information on what percentage of studies for each disease passed this criterion - did you need to screen 10 studies per disease to have one that would be able to discriminate the phenotype based on microbial profile or rather vice versa that there were very few odd studies that didn't pass this selection.
On 2024-08-05 11:33:13, user Josh A wrote:
Nice paper, but ignores previous work on CHD1L/ALC1 and EMT and DNA-damage response.
On 2024-08-05 08:51:01, user Bayazit Yunusbayev wrote:
Hi, this sentence is not clear to me: "the probability that a given edge carries at least one mutation is inversely proportional to its<br /> time-length (assuming mutations occur as a Poisson process along the edges)." I might be missing here something, but isn't it so that older edges are expected to encounter more mutations?
On 2024-08-04 17:58:17, user Alex wrote:
The preprint has now been published in PNAS: Alexander M. Sandercock, Jared W. Westbrook, Qian Zhang, Jason A. Holliday. A genome-guided strategy for climate resilience in American chestnut restoration populations. Proceedings of the National Academy of Sciences, 2024; 121 (30) DOI: 10.1073/pnas.2403505121
On 2024-08-03 21:35:22, user Coleen Murphy wrote:
https://www.biorxiv.org/content/10.1101/2024.06.07.597568v2.full <br /> addresses all of the choice assay issues in Gainey et al..
On 2024-06-08 13:34:05, user Coleen Murphy wrote:
On 2024-06-07 16:53:51, user Reviewer 6 wrote:
I am a C. elegans researcher with some familiarity with the topics discussed. I do not personally know, nor have I interacted with any of the authors involved. I have read in detail both the preprint and the response in the comments. Below I provide some comments in the hope that they will hone arguments from both sides. For brevity, I refer to the authors of this preprint as “the authors” and Dr. Coleen Murphy as “CM”.
Summary:<br /> In my view, there are two issues here (1): the technical reproducibility of the choice assay; and (2) the physiological importance of CM’s results in a natural setting given the points raised by the authors. While CM makes some valid arguments on (1) – the authors should really have shown at least a few assays that attempted to follow the protocol exactly as stated by CM – the deviations here are in my view minor enough to raise significant questions about the choice assay and its interpretation. I believe the authors are justified in stating that (2) if the variables discussed here indeed significantly obscure detection of the phenotype, then the ecological significance of the inherited learned avoidance in a natural setting is in question. This is especially important given that, contrary to CM’s response, the authors do in fact see learned avoidance of PA14 as well as daf-7 expression at P0 and F1 in some experiments (indicating that the learning was induced) but not beyond in the F2 progeny of these same worms which displayed learned avoidance. Below is a detailed discussion of these points.
Specific comments:<br /> - CM states that the lack of naïve PA14 preference seen by the authors is a “serious cause for concern”. In CM’s 2024 paper (Fig 1, https://journals.plos.org/p... , worms are tested for bacterial food choice between OP50 (the lab food) versus bacterial species C. elegans may be exposed to in the wild. However, it seems that worms naively avoid OP50 (i.e. ‘prefer’ test bacteria) in essentially every comparison made by CM. This is contrary to reports by other labs (PMID: 38228683, PMID: 38228683) and in my view potentially a more serious concern with the assay. Contrary to CM’s assertion, while CM’s group and others see *mild* PA14 preference in naïve worms, other groups also do not observe such a preference in naïve worms or report more variable results (e.g., PMID: 21172617, PMID: 28877481, PMID: 31371455). Overall, the authors did replicate P0 and F1 learned avoidance in some runs and had a “learning index” consistent with prior reports in these experiments, so I do not see how the lack of purported naïve PA14 preference (which is quite minor and variable to begin with) is a significant concern here. <br /> - Looking at the authors’ raw data (table S2) for individual experiments, it seems the authors used <200 worms as advised by CM for most of their plates. The “up to 770 on a spot” was from a single plate, so I do not think this would change the conclusions of the authors. The authors compared worm density with choice index and found that there is no correlation within the ranges tested here.<br /> - “no azide or other paralytic used” (CM) – the authors claim to have tested this and state that addition of azide did not affect their results. They also claim that worms make a choice within 15 minutes and do not leave the respective lawn in the first hour of the assay. But none of this data is shown (it should be). <br /> - It seems that CM’s group counts worms in proximity to lawns “if they are within a few millimeters of the bacterial spot.” (STAR protocol). This may introduce systemic bias given the OP50 and PA14 lawns are clearly visibly distinct. Again, this raises questions to me regarding the reliability of this assay for interpreting minute effects and making broad generalizations.<br /> - Aspirating worms for counting would be unlikely to affect results.<br /> - The fact that conditions tested by the authors are varied between experiments is in my view a strength of this study given they did not observe F2 effects in any of their tests (you would normally change parameters rather than keep repeating the same protocol if you were unable to reproduce something, no?). However, testing variables/conditions such as temperature, light/dark etc. are informative only in a context where the authors have first fully followed through on the exact CM protocol with no deviations. So, I do think it is crucial to show a few attempts where the protocol is followed exactly as stated by CM.<br /> - The use of Triton X after bleaching may be a concern as CM points out. Though seemingly low (0.01%), this may hypothetically make bleached (i.e. already somewhat stressed) embryos or newly hatched L1s more vulnerable to pathogenic bacteria or alter their physiology. I do not see a point in including Triton X during or after bleaching, it is not standard nor required and is certainly a confounding variable. However, given the CMC of Triton X is 0.02% and the authors use below this concentration and only during plating, I would be surprised if this led to a dramatic change in the phenotype observed.<br /> - I do not find CM’s critique on daf-7 expression to be substantive. CM asserts that the authors do not see elevated daf-7p::gfp expression. Except they do! Which is especially evident with the single copy (SC) construct Fig 2 under SC at both 20 and 25oC. The magnitude of P0 daf-7 increase with the SC construct (~2 fold) is similar to what other groups observe at this generation (albeit with the multicopy strain, so it is hard to compare). I think the use of a single copy reporter is a strength of this paper, but in the future assays of daf-7 expression should really be done using endogenous CRISPR/Cas9 reporters. That an F2 response is not observed in runs where there is a high upregulation in the F1 generation is consistent with the authors’ interpretation.<br /> - The authors should show representative images of what is being quantified as CM states, as without this we do not know which neurons are being assayed. I do not think averaging both ASI neurons in a worm is a concern – even if there is an increase in one ASI, it would still be reflected in the average (as long as the correct neuron is being quantified). It may even reduce variability or bimodality to average the two, given the brightness of reporters on a confocal image can depend on the depth of the imaging plane as the authors state. <br /> - CM states that chunking is an unusual way to maintain the fluorescent strain. But this is a genomically INTEGRATED multi copy array (ksIs2), no? The point of the authors is that the fluorescence expression and associated Rol marker are unstable in their expression, which is not unusual for such integrated repetitive multicopy arrays. This is not an extrachromosomal array wherein fluorescent worms need to be picked to maintain the array, so CM’s statement that it is “standard accepted practice” to do so is simply wrong. In fact I find it quite concerning if CM’s group picks fluorescent worms to maintain this strain as it biases the worms for an epigenetic state in which the integrant is poised for expression, which may indicate other epigenetic issues in the strain’s background (i.e., lack of silencing of repetitive sequences). The instability of this strain I assume is why the authors obtained a single copy daf-7 reporter, which in any case would supersede any results obtained from a multicopy array. CM says nothing about the single copy integrant results, and I believe that given the authors observe P0 and F1 upregulation with the single copy integrant, I think the case is solid that there is no response observed in F2 worms from F1s showing daf-7 upregulation. An endogenous CRISPR/Cas9 reporter (e.g., transcriptional/SL2::GFP if a translational fusion is not possible) would really push home this point. <br /> - CM states that the authors replicates show poor “consistency”. However, we can only see this because the authors, unlike CM, show each experiment independently! We have no idea whether every experiment CM performed actually displayed learned avoidance behaviour, given the source data for CM’s choice assays is apparently not public. CM’s reports only show all learning experiments in aggregate, and I believe if the authors aggregated all their runs herein to a single plot, they would indeed see a seemingly ‘consistent’ avoidance effect. CM could easily address this by releasing raw/source data for choice/learning assays.<br /> - CM claims that in their hands behaviour from a set of training plates is ‘always’ consistent, but data are not shown. Both sides need to avoid making important claims without showing data.<br /> - CM states that the authors use of the same population to assay and then maintain for the next generation may confound the results. Again, the authors need to do the assay exactly as stated by CM, but if a few extra minutes of suspension in buffer really so obscures the phenotype beyond any detection, then how ecologically relevant can it possibly be? To my knowledge, there is no major phenotype that is completely ablated by a few minutes additional incubation in buffer. By this standard nothing involving washing off worms in a buffer would be interpretable.<br /> - It is interesting that sid-1 and 2 mutants do not show a learned F1 avoidance, but daf-7 expression is still elevated. It may be sufficient to have one SID protein for elevated daf-7 expression in progeny but require both for the behavior. Given both sid-1 and 2 are RNA transport channels, without double mutants and reliable daf-7 readout from an endogenous reporter, it is difficult for either group to infer any epistatic relationships between these genes. <br /> - I read the protocol file with notes from CM. I did not find any changes that are severe enough to cause concern and it seems that these are more clarifications/updates than changes to the fundamental principles of the assay. I also did not find the authors’ statements on this disingenuous, as there were clearly differences between the original STAR protocol and the updates provided. It is important for both parties here to refrain from personal attacks and address the substance of the arguments made.<br /> - I did find that some details in the STAR protocol were excessive, e.g., the height of plate stacks. I appreciate the detail but again, this raises the question that if such artificial variables really influence the phenotype so severely that it is no longer at all detectable, how physiologically relevant or robust can the phenotype be? <br /> - The statistical error in the STAR protocol pointed out by the authors: it seems either CM is misinterpreting a two-way ANOVA or that this was an oversight. I did not find this point too important overall as correcting such a statistical error would not change the conclusion of CM’s papers given the magnitude of effects previously described. <br /> - CM states that expression of P11 is essential for TEI. In CM’s 2020 paper (Kaletsky et al) it is stated that: “moreover, training on a P11 mutant that disrupts the perfect match to maco-1 but conserves P11 secondary structure induced no avoidance (Fig. 4e)”. As written, it seems essential not just for TEI (F2 effect) but also the P0 learning itself (unless CM can clarify that it is only required for the F2+ effect and that in Fig 4e only F2+ are being tested). So as I understand it, if lack of P11 expression is the issue, then there should be no P0 or F1 avoidance at all in any of these runs. Given the authors do not see an F2 effect in worms with robust P0 and F1 responses, it seems that this point is moot. I also do not think the authors can be blamed for any putative lack of P11 expression as it seems that for this portion (PA14 growth) they adhered to the protocol quite closely and explored various PA14 lines including those obtained from CM’s and other labs.
In summary, I think CM’s response is insufficient to alleviate many of the key concerns raised by the authors herein. I do not believe the lack of naïve PA14 attraction is a major concern, as there are literature examples where (a quite minor) naïve PA14 attraction is not observed. Furthermore, this is also confounded by CM’s recent (2024) paper wherein their worms prefer essentially every bacterium among a panel over OP50 in a naïve test, again contrary to prior reports from other labs. This makes me question the robustness as well as any broad conclusions that can be drawn from this assay.
The authors do also observe P0/F1 learned avoidance and elevated daf-7 expression contrary to CM’s rebuttal. I agree that the effects shown are not consistent between experiments here, but we cannot say whether this is simply because we are seeing here individual runs of inherently inconsistent assays whereas looking at an aggregate of data in CM’s papers (since the source data for the choice assays are not public). The major concern is that in those populations with P0/F1 responses (meaning the learning has been successfully induced), there is no further inheritance of avoidance beyond F1, and similarly for daf-7 wherein populations expressing high daf-7 at P0 and F1 do not transmit this to progeny. I believe this precludes “basic concerns about [the authors’] bacterial and C. elegans growth conditions, assay conditions, and assay techniques”. Overall, while it is important for the authors to show a few runs where the protocol is followed exactly as described by CM, I believe the deviations here are minor enough that even if they were able to replicate the transgenerational effect successfully, the sensitivity of the effect to such minutia would greatly diminish its physiological relevance to the worms - and its importance as an adaptive paradigm of transgenerational epigenetic inheritance - in a natural setting.
I also do not find it constructive for any party involved to address anything other than the scientific substance of arguments or engage in personal attacks. Given the attention and broad reach these studies have garnered, as well as the important implications, it is essential – and the normal course of the scientific endeavor – for such claims to be rigorously tested.
I also very much appreciate that the authors have shared these observations, and find it very commendable that CM has responded in a timely and comprehensive manner (as well as been responsive to the authors in refining their protocol).
On 2024-08-03 16:25:52, user James Hurley wrote:
The community should be aware that the structure that is reported to be predicted here was already solved by cryo-EM and preprinted on Jun. 1, 2023 https://www.biorxiv.org/content/10.1101/2023.06.01.543278v3 and the cryo-EM coordinates of the same complex were released on Jun. 23, 2023 https://rcsb.org/structure/8SOI .
On 2024-08-03 15:08:52, user Mario Stanke wrote:
That should be Supplementary Table S1, rather than Table 1. Thanks for pointing the wrong reference out. The training species are also shown as a tree in Supplementary Figure S1.
On 2024-07-31 13:32:54, user kbseah wrote:
This looks very promising, congratulations! One point was unclear to me: which genome datasets were used to train the current mammalian model? The text refers to Table 1, but that just shows benchmarking results.
On 2024-08-02 17:16:23, user Lonki wrote:
The authors have errored by assuming that pregabalin and gabapentin are GABA-receptor ligands. Despite their names, they are not.
As stated in Wikipedia; “Pregabalin inhibits certain calcium channels, namely, it blocks α2δ subunit-containing voltage-dependent calcium channels (VDCCs).[13][26].
Also from Wikipedia “Despite the fact that gabapentin is a structural GABA analogue, and in spite of its name, it does not bind to the GABA receptors, does not convert into GABATooltip γ-aminobutyric acid or another GABA receptor agonist in vivo, and does not modulate GABA transport or metabolism within the range of clinical dosing.[82]<br /> “Gabapentin is a ligand of the α2δ calcium channel subunit.[82][83] α2δ is an auxiliary protein connected to the main α1 subunit (the channel-forming protein) of high voltage activated voltage-dependent calcium channels (L-type, N-type, P/Q type, and R-type).[13] Gabapentin is not a direct channel blocker”
Please read up on these drugs and re-interpret your observations.
On 2024-08-02 16:28:00, user Ana Vasque wrote:
Dear authors,
First I'd like to congratulate you on your work. I have read your article on the unique reproductive structure of Euphorbia species with great interest. However, I have specific inquiries regarding the filiform structures that were analyzed to determine the floral identity of the cyathium, and I would appreciate further clarification
In your study, did you observe results that suggested the upregulation of the B and E genes in these filiform structures, which would indicate a implying reduction in flowering? What is the correlation between these findings and previous research, such as that of Prenner and Rudall (2007), which discusses the presence of these structures associated with individual male flowers in certain species and their absence in others? Additionally, Prenner and Rudall (2007) reference Warming (1870), who observed and interpreted these structures as trichomes, noting their formation subsequent to the initiation of staminate flowers
Could you provide deeper insights into your interpretation of the formation and functionality of these threadlike structures in your analyses?
I am grateful for your attention to my inquiries. I look forward to your explanations and further discussion on the outcomes of your study.
Sincerely,
On 2024-08-01 16:35:16, user John McCusker wrote:
I just saw ( https://www.science.org/content/article/bad-agar-killing-lab-yeast-around-world-where-it-coming ). Many years ago, I had a similar problem with S. cerevisiae and C. albicans (but not E. coli) growth on agar. (Multiple vendors/suppliers, none of whom found anything wrong.) I eventually found that exposure of agar plates to light while drying (or incubating) caused the problem. Dried/incubated plates in dark and no problem.
On 2024-08-01 12:05:39, user Kenichiro Abe wrote:
Given the result of transcriptional inhibitor treatment with DRB or THZ1 in Fig.S9 and the report of Abe et al.,2010, NSN-SN transition seems like to be occurred independently of RPB1 degradation <br /> If you have any comments about this point, I would be happy to hear that
On 2024-08-01 07:43:29, user Ben wrote:
Hi. In the graphical abstract, the mus musculus heart cartoon shows a sagittal section. I would believe you wanted to show a heart with a scar.
On 2024-07-31 11:50:30, user Leyli Borner wrote:
This article has been published in Neobiota journal: https://doi.org/10.3897/neo...
On 2024-07-29 19:25:57, user disqus_FNcjH0JLKv wrote:
This paper has been published in Plos Comp Biol, please add link: https://doi.org/10.1371/journal.pcbi.1011586
On 2024-07-27 13:29:27, user Prof. T. K. Wood wrote:
Schumacher, M.A., et al., 2009. Molecular Mechanisms of HipA-Mediated Multidrug Tolerance and 531 Its Neutralization by HipB. Science, 323 (5912), 396-401, was found to be false in that HipA is a kinase but has nothing to do with EF-Tu. You should actually read the literature about the TA system you cite.
On 2024-07-26 15:46:59, user Prof. T. K. Wood wrote:
Line 70: Dy et al. is the 3rd report of phage inhibition by TAs; please cite the seminal ref doi: 10.1128/jb.178.7.2044-2050.1996 that predates it by 18 years.
Line 69: the TA refs related to persistence in this manuscript have been retracted so the link with persistence is not justified by this ref.
On 2024-07-26 14:37:06, user Julien Racle wrote:
This is a preprint of the following book chapter: Julien Racle and David Gfeller, How to Predict Binding Specificity and Ligands for New MHC-II Alleles with MixMHC2pred, published in HLA Typing, edited by Sebastian Boegel, 2024, Humana Press reproduced with permission of Springer Science+Business Media, LLC, part of Springer Nature. The final authenticated version is available online at: http://dx.doi.org/10.1007/978-1-0716-3874-3_14 .
On 2024-07-25 20:29:22, user disqus_FNcjH0JLKv wrote:
The paper has been published in Protein Science, please add link: https://onlinelibrary.wiley.com/doi/full/10.1002/pro.5116
On 2024-07-25 20:28:20, user disqus_FNcjH0JLKv wrote:
The paper has been published in Scientific Reports: https://www.nature.com/articles/s41598-024-60991-x
On 2024-07-25 18:45:57, user Zhongmou Chao wrote:
It has been published in here: https://www.nature.com/articles/s41467-024-49415-6
On 2024-07-25 15:52:06, user Lynda Delph wrote:
This is terrific work. The authors might want to cite Lynda F. Delph, Keely E. Brown, Luis Diego Ríos, and John K. Kelly. Sex-specific natural selection on SNPs in Silene latifolia. Evolution Letters 6:308-318.<br /> In that paper they say "Finally, alleles favored by paternity selection tended to reduce female survival (Fig. 3D). The negative correlation here (ρ = −0.10) must be driven by a highly polygenic response."
On 2024-07-25 11:46:14, user Duchenne François wrote:
a revised version is published here:<br /> https://doi.org/10.1111/icad.12769
On 2024-07-23 22:12:13, user Anthony Baptista wrote:
Hello,
Your paper is very clear and interesting; congratulations on your work. I would like to suggest adding a relevant reference to your paper:
Baptista, A., Gonzalez, A., & Baudot, A. (2022). Universal multilayer network exploration by random walk with restart. Communications Physics, 5, 170. https://doi.org/10.1038/s42005-022-00937-9
Best regards
On 2024-07-23 21:06:26, user Christian Schröter wrote:
This work has now been published in Nature Communications, pmid: 38871742, https://doi.org/10.1038/s41467-024-49380-0
On 2024-07-23 17:58:20, user Ioannis Zervantonakis wrote:
Paper accepted and published in APL Bioengineering: https://pubs.aip.org/aip/apb/article/8/3/036105/3304419/CAR-T-cell-infiltration-and-cytotoxic-killing
On 2024-07-23 17:47:50, user Eric S wrote:
Accepted at JGP:<br /> https://doi.org/10.1085/jgp.202313523
On 2024-07-23 16:05:44, user Zach Hensel wrote:
I also have one brief comment regarding the discussion of "no expected interference to biological function" for a recombination breakpoint at position 21,314. The authors suggest that mutation to an isoleucine residue at position nsp16 I219 will "occur without having a significant impact on fitness linked to a disruptive function at a protein level."
The residue I219 is well resolved in crystal structures (e.g. PDB 6WVN) and makes hydrophobic contacts with other hydrophobic sidechains, suggesting that this is unlikely to be the case. This is testable by mutational fitness analysis -- https://jbloomlab.github.io/SARS2-mut-fitness/nsp16.html -- out of possible non-synonymous mutations that are sufficiently sampled during the pandemic, I219 tolerates substitution to leucine or valine, methionine is slightly disfavored, and mutation to any of arginine, lysine, or threonine is very rare. This suggests a significant fitness impact of substitutions at this position.
On 2024-07-23 16:03:09, user ryhisner wrote:
This preprint claims that the BA.2.86 lineage, which first appeared in the sequencing record in late July 2023, evolved gradually, while cryptically circulating over the course of about 17 months, beginning in early 2022. I do not find any of the evidence presented here convincing.
Three clusters of sequences, named C1, C2, and C3, are cited as evidence of cryptic BA.2.86 circulation prior to its emergence on the world stage. Each cluster has a far simpler, more parsimonious explanation than the hypothesis presented by the authors.
I have documented and analyzed cluster C1 as they have been uploaded, beginning in October 2023, and it appears to be a classic case of a chronic infection in an immunocompromised individual who may have transmitted to one other person. Three of the four C1 sequences have matching metadata—same location, age, and sex—while the fourth has the same location and age but a different sex. Furthermore, there are two additional, closely related sequences collected in 2024 (EPI_ISL_18969735 and EPI_ISL_19259365) whose metadata also match the other three.
It seems very unlikely the C1 sequences have any relation to BA.2.86. I count approximately 17 spike substitutions and one large deletion (∆138-144) that are in two or more of these four sequences but not in BA.2.86, including P9L, H69D, K77E, T95I, ∆136-144, R158K, Q183E, G213E, D215G, R346T, L452R, F486L, V615A, V642G, H681Y, L841R, D936Y, and D1146N. None of the four C1 sequences have the most distinctive spike mutations of BA.2.86, such as ins16MPLF, the triple-nucleotide F157S-R158G, A264D, I332V, K356T, L452W, or ∆V483. All C1 sequences have ORF1a:L3201F, which is found in BA.2 but not BA.2.86, and none of the C1 sequences possess any of the seven synonymous mutations found in the BA.2.86 branch (C8293T, T13339C, T15756A, A18492G, C21622T, C25207T, C26681T).
Of the more than 30 spike mutations (relative to baseline BA.2) in BA.2.86, I only see four that are shared between BA.2.86 and the C1 sequences: R403K, A484K, R493Q (reversion), and P621S. All of these are extremely convergent in highly mutated, chronic-infection sequences. I maintain a list of such sequences, and the R493Q reversion is the single most common private mutation, occurring 304 times independently, while R403K appears 103 times, and P621S 60 times. A484K, despite being a two-nucleotide mutation, has independently evolved at least 15 times among the sequences I've recorded. (G446S—very common both in chronic-infection sequences and circulating lineages—is in 2/6 sequences from this cluster).
Furthermore, the most recently uploaded sequence from this cluster—collected on May 22, 2024, but not listed in the C1 cluster in this paper—contains 16 new spike mutations (at least two of which I suspect can be attributed to sotrovimab treatment). Four of the 16 new spike mutations are also in BA.2.86 (I332V, K356T, L486P, and S939F), a textbook example of how, through convergent intrahost evolution, chronic-infection sequences can come to acquire mutations found in other chronic infections and in unrelated circulating lineages.
I do not see any resemblance between BA.2.86 and the C1 cluster in the non-spike part of the genome, apart from M:A104V, which is commonly found in chronic-infection sequences (32 independent acquisitions by my count), and is also found in the Pango-designated GS.4/5 lineage (XBB.2.3.11.4/5). It seems to me that this is a case of a chronically infected, immunocompromised individual who developed a few mutations also found in BA.2.86—mutations which are convergent in such chronic infections—and who may have transmitted to one other person (assuming there was not a mistake in the sex assignment of EPI_ISL_18415854, in which case these sequences almost certainly all came from the same patient).
The phylogenetic relationship between these sequences, as determined by USHER (Ultrafast Sample placement on Existing tRee, created at University of California Santa Cruz and maintained by Angie Hinrichs), can be seen at the following link: <br /> https://nextstrain.org/fetch/raw.githubusercontent.com/ryhisner/posited_BA.2.86_intermediates/main/BA.2.86_C1_posited_intermediates_Mexico_6_seq.json?c=gt-S_841&gmax=25384&gmin=21563&label=id:node_3061533
The C2 cluster (12 sequences of XBB.1.5.90, 11 from Japan, one from Finland) does not seem to resemble BA.2.86 at all. It is part of a large branch of XBB.1.5.90 (>400 sequences) with S:P621S, also found in BA.2.86, and the only other private mutation I see that it shares with BA.2.86 (but not other hundreds of other XBB.1.5.90 sequences) is C26681T, which is a highly homoplasic synonymous mutation in the coding region of M. Perhaps I am overlooking something, but the C2 cluster looks like a relatively humdrum branch of XBB.1.5.90 to me.
The Usher tree for these 12 sequences from C2 can be viewed here: https://nextstrain.org/fetch/raw.githubusercontent.com/ryhisner/posited_BA.2.86_intermediates/main/BA.2.86_C2_posited_intermediates_JPN_FIN_12_seq.json?c=userOrOld&label=id:node_4041697
The C3 cluster consisting of 10 sequences from Sarawak, Malaysia, were all uploaded on the same day (2024-1-25), bear the same collection date (2022-3-11), and have spikes identical to JN.1—including S:L455S—from S:356 to S:681, while the rest of spike is identical to baseline BA.2. The remainder of the genome in these sequences is extremely odd. Two sequences contain the XBB mutation ORF1b:S959P. Seven have the universal BA.2.86 mutation ORF1a:N2526S, while three lack it. One has the BA.2.86.1 mutation ORF1a:K1973R. Seven of the ten have ORF1a:L3201F, which is absent from all BA.2.86. No dropout is indicated in any of the sequences.
The same Malaysian lab uploaded 321 other sequences (EPI_ISL_18821317-18821647), all from Sarawak, Malaysia, on the same day they uploaded the 10 C3 sequences. The collection dates of these sequences range from 2022-2-27 to 2024-1-9 and include 153 JN.1* sequences and 12 XBB* sequences. As Zach Hensel has noted, six of the ten C3 sequences have G19677T (ORF1b:2070H), which is the defining mutation of BA.2.40, a variant that made up about 60% of all sequences in Sarawak, Malaysia, in mid-March 2022. (Source: https://cov-spectrum.org/explore/Malaysia/AllSamples/from%3D2022-01-15%26to%3D2022-04-28/variants?nextcladeQcSnpClustersScoreTo=55&variantQuery=Nextcladepangolineage%3ABA.2.40*&)
Sixty-three sequences in this upload are categorized by Nextclade as being BA.2.40 and have 0-3 mutations relative to baseline BA.2.40. Most suspicious of all, 29 of the 153 JN.1* sequences in this same upload also have G19677T. From July 1, 2023 to the present, just 77 sequences categorized by CovSpectrum as BA.2.86* (from 13 different Pango-designated lineages) have had G19677T, with 30 of those coming from Malaysia. (Source: https://cov-spectrum.org/explore/World/AllSamples/from%3D2023-07-01%26to%3D2024-07-14/variants?variantQuery=Nextcladepangolineage%3ABA.2.86*+%26+G19677T&)
It seems clear that the 10 C2 sequences were BA.2 sequences contaminated by JN.1 sequences from the same upload.
The authors list 129 sequences they claim shorten the branch leading to BA.2.86, of which I was able to find 128 on GISAID. Ten of these sequences are from the C3 Malaysian cluster described above, along with one additional sequence from the same upload. Apart from these C3 sequences, there are only six sequences with collection dates preceding the first BA.2.86 sequences. All others were collected more than seven weeks after the first BA.2.86 sequences. Six sequences were collected between 7-14 weeks after the first BA.2.86, while the remaining 105 sequences were collected more than 15 weeks afterward.
It would be surprising if one could not find hundreds of such "hybrid" sequences due purely to contamination. Such sequences have frequently appeared in the sequencing record throughout the pandemic. A few sequences may result from coinfection, but the quality of these sequences, described below, along with the fact that a large proportion of them come from a small number of labs with records of quality-control issues, support the hypothesis that these sequences result from contamination or other lab errors.
All of the sequences in this list are low quality. They feature a mixture of extensive dropout (particularly in spike), frameshifts, large numbers of mixed nucleotides, clearly artifactual reversions, and mutations from multiple lineages (primarily BA.2.86 and XBB) with no distinct breakpoints. Many of these sequences come from labs known to have frequent quality-control issues. For example, there are 52 sequences from the United States, but none are from the CDC, whose sequences are virtually always first-rate. Instead, they come from smaller local and state labs, whose sequencing quality is often inconsistent.
The 28 sequences from Texas, for example, come from city hospitals. The average Nextclade qc score of these sequences is 2901 (median 2882). Anything over 100 is designated "bad" by Nextclade. The average number of ambiguous nucleotides per sequences is 17 (median 17), and they average 690 nucleotides of dropout. (EPI_ISL_16599325, EPI_ISL_16599747, EPI_ISL_18546432, EPI_ISL_18690036, EPI_ISL_18690080, EPI_ISL_18690421, EPI_ISL_18690466, EPI_ISL_18690496, EPI_ISL_18743044, EPI_ISL_18743073, EPI_ISL_18743094, EPI_ISL_18743097, EPI_ISL_18743159, EPI_ISL_18743350, EPI_ISL_18743431, EPI_ISL_18743464, EPI_ISL_18743470, EPI_ISL_18743477, EPI_ISL_18743592, EPI_ISL_18816401, EPI_ISL_18816517, EPI_ISL_18816528, EPI_ISL_18816612, EPI_ISL_18816709, EPI_ISL_18816890, EPI_ISL_18816980, EPI_ISL_18874714, EPI_ISL_18908998)
Similarly, the 17 sequences on this list from Italy are all from the same lab, have an average Nextclade qc score of 2356 (median 2253) and average 1349 nucleotides of dropout. Some sequences on the list are somewhat less bad than these, but none are high-quality. <br /> (EPI_ISL_18496352, EPI_ISL_18674020, EPI_ISL_18677248, EPI_ISL_18721993, EPI_ISL_18722001, EPI_ISL_18722007, EPI_ISL_18722009, EPI_ISL_18755145, EPI_ISL_18792827, EPI_ISL_18792828, EPI_ISL_18792829, EPI_ISL_18792831, EPI_ISL_18820147, EPI_ISL_18820149, EPI_ISL_18820150, EPI_ISL_18820154, EPI_ISL_18820157)
Finally, I also examined the list of 100 sequences from Supplementary Data 1, Table 5, containing genomes posited by the authors to be recombinants related to ancestors of BA.2.86. These sequences seem to me to fall into five different categories.
First, there are numerous sequences here that are also listed in one of the C1-C3 clusters—three sequences from C1 (EPI_ISL_18415832, EPI_ISL_18415854, EPI_ISL_18798234), three from C2 (EPI_ISL_18040349, EPI_ISL_18060516, EPI_ISL_18106303, EPI_ISL_18116248), and four from C3 (EPI_ISL_18821484, EPI_ISL_18821485, EPI_ISL_18821487).
Second, nine of the sequences appear to be fairly unremarkable XDD sequences, which is a designated JN.1/EG.5.1.1 recombinant (EPI_ISL_18617332, EPI_ISL_18706019, EPI_ISL_18706171, EPI_ISL_18553650, EPI_ISL_18653986, EPI_ISL_18531477, EPI_ISL_18569411, EPI_ISL_18695627).
The third category consists of what seem to me to be relatively normal sequences from a variety of Omicron lineages but with little resemblance to BA.2.86. Some of them have extensive dropout and come from labs known for high rates of artifacts and contamination. (EPI_ISL_18076898, EPI_ISL_17990180, EPI_ISL_18062641, EPI_ISL_18000549, EPI_ISL_18042058, EPI_ISL_18104305, EPI_ISL_18070023, EPI_ISL_18044667, EPI_ISL_18111437, EPI_ISL_15153261, EPI_ISL_17255807, EPI_ISL_15153261, EPI_ISL_16282414, EPI_ISL_16457740)
The fourth category is BA.2.86 or JN.1 sequences that either don't strike me as very unusual or else have extensive dropout and artifactual reversions. A few of these are from unreliable labs. (EPI_ISL_18097345, EPI_ISL_18556860, EPI_ISL_18567791, EPI_ISL_18682823, EPI_ISL_18705393, EPI_ISL_18635682, EPI_ISL_18503709, EPI_ISL_18400531, EPI_ISL_18717823, EPI_ISL_18446586, EPI_ISL_18584588, EPI_ISL_18631046, EPI_ISL_18700743, EPI_ISL_18675075, EPI_ISL_18659819, EPI_ISL_18713456, EPI_ISL_18636806, EPI_ISL_18704459, EPI_ISL_18686183)
The fifth and largest category is highly divergent sequences almost certainly deriving from chronic infections, but which appear to me to bear almost no resemblance to BA.2.86 apart from the possession of a few mutations that are widely convergent in such sequences. I've documented most of these, and almost all contain a large number of mutations and deletions not found in BA.2.86 and lack the vast majority of BA.2.86 mutations.
I hope I haven't misinterpreted any of the authors' hypotheses or data.
-Ryan Hisner
On 2024-07-20 14:19:32, user Zach Hensel wrote:
The cluster described in Malaysia (C3) jumped out as having identical collection dates that are earlier than those typically associated with GISAID accessions this high (and consistent with those for Malaysia sequence circa November 2023) and also differ at multiple, overlapping positions despite being sampled on the same day.
Briefly, further investigation (using cov-spectrum and UShER phyloplace) identified four sequences from Mayasia with March 2022 collection dates containing both M:D3H and M:T30A:
EPI_ISL_18821484 (in C3)<br /> EPI_ISL_18821485 (in C3)<br /> EPI_ISL_18821546<br /> EPI_ISL_18821638
These all share G19677T, which is a mutation characterizing BA.2.40 in Malaysia which was common in March 2022 (760 out of 855 sequences worldwide with G19677T were found in Malaysia that month; 52% of sequences from from Sarawak, Malaysia collected in March 2022 have this mutation).
Further, the three sequences that are placed by phyloplace are found together with other sequences from Malaysia. This identifies another sequence with M:D3H and M:T30A sampled in Malaysia, EPI_ISL_18821317. Other mutations in these sequences are shared with various other lineages prevalent in Malaysia in March 2022.
One sequence with M:D3H and M:T30A, EPI_ISL_18821638, could not be placed by phyloplace, but NextClade calls it as BA.1.1 because it contains the BA.1-defining EPE insert in S.
The manuscript notes, regarding the period of Omicron emergence, "South Africa and Botswana, where genomic surveillance was more robust than in many other parts of Africa." BA.2.86 emergence in Southern Africa is well supported: <br /> https://www.nature.com/articles/s41467-023-43703-3
It is implausible that an intermediate between BA.2 and BA.2.86 would recombine with multiple lineages circulating in Malaysia and only be detected in Malaysia without leaving a trace in southern Africa given that this surveillance continued. Rather, I suspect that these observations are likely artifacts arising from processing samples collected in March 2022 together with samples collected in late 2023.
This can be tested by comparing mutations in these sequences to those observed in BA.2.86* strains common in Malaysia in late 2023. The most common of these is JN.1, which contains S:L455S as well as the S deletion shown for the C3 sequences here.
On 2024-07-23 09:42:00, user Prof. T. K. Wood wrote:
Line 86 is false: reduction in ATP has been shown to increase persistence by 10,000-fold in 2013 (doi:10.1128/AAC.02135-12).
On 2024-07-23 09:33:40, user Prof. T. K. Wood wrote:
Lines 36 and 46 are false; please cite the relevant primary literature for the mechanism of persister cell formation in regard to ppGpp leading to ribosome dimerization and resuscitation based on reactivating ribosomes, all based on single-cell microscopy ( https://doi.org/10.1016/j.bbrc.2020.01.102 and https://doi.org/10.1016/j.isci.2019.100792 ) .
On 2024-07-22 12:47:53, user Simon Crouzet wrote:
This article has been now published in CSBJ. Link to the publication: https://doi.org/10.1016/j.csbj.2024.06.029
On 2024-07-21 18:44:35, user Terri Mitchell wrote:
While the idea of AI condensing 500 million years of evolution into a few minutes sounds very grandiose, a protein mutated in isolation is not fast forward evolution--it's just a mutated protein. AI has provided the blue print for an artificial protein situated outside of evolved life. The marine organisms that actually evolved molecules to transduce blue wavelengths of light into longer wavelengths of other colors and reemit them for a reason having to do with natural selection have done it already. They evolved the fluorescent molecules. ESM3's value is solely commercial, and no doubt it will be a hop, skip and jump from making the sequence available to researchers to commercializing it as contrast dye. Its origins will soon be forgotten, but its effects on the environment, and therefore life, will undoubtedly be persistent and deleterious.
Wrapping the report in intellectual arguments about evolution doesn't scientifically validate the claim that an AI-generated mutant is "evolved". Even if the AI endgame was reached--replacing all life with a human-devised approximation, and it was somehow achieved by pseudo-evolution--ESM3 would still have no evolutionary value since it was synthesized in isolation. AI mutated a protein: it didn't evolve a protein. Making scientifically invalid claims doesn't advance the case for AI. Just the opposite.
On 2024-07-21 16:01:56, user Min Zhu wrote:
The full version of this manuscript is online in Science Advances. https://www.science.org/doi/10.1126/sciadv.adl6366
On 2024-07-21 00:09:37, user Meet Zandawala wrote:
Manuscript title: TRPγ regulates lipid metabolism through Dh44 neuroendocrine cells
Summary: This manuscript from Youngseok Lee lab examines the role of TRP gamma channel in regulating metabolic physiology. Specifically, it focuses on the regulation of lipid metabolism via DH44 neuroendocrine cells. It is a follow-up on the work from the same lab where they showcased the importance of TRP gamma in DH44 cells in regulating post-ingestive food selection (Dhakal et al 2022: https://doi.org/10.7554/eLife.56726 ). Overall, this work adds to the growing body of work on DH44 neuroendocrine cells which appear to be crucial internal metabolic sensors. We have a few major comments and suggestions on the preprint which could help clarify the mechanisms by which TRP gamma regulates lipid metabolism.
Minor comment:<br /> 1. Stock numbers for fly strains have not been provided.
Signed by,<br /> Meet Zandawala <br /> Jayati Gera<br /> (Zandawala lab members)
On 2024-07-20 17:34:16, user Andrea Ravasio wrote:
This preprint has now been published here:<br /> https://doi.org/10.1038/s41467-024-49850-5
On 2024-07-19 21:58:04, user Matt Jones wrote:
This work has now been peer-reviewed and published in Molecular Plant- https://www.cell.com/molecular-plant/pdf/S1674-2052(24)00226-0.pdf?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1674205224002260%3Fshowall%3Dtrue
On 2024-07-19 19:06:04, user Maryam Foroozani wrote:
May I ask where I can find the supplementary figures?
On 2024-07-19 16:59:13, user Michael Silverstein wrote:
On 2024-07-19 03:05:31, user Adriana Ludwig wrote:
Congratulations on your excellent work! I'm wondering, if still possible, if you could consider citing our work ( https://doi.org/10.1186/s13100-019-0175-2 ) when you mention VIPER's potential activity, since all previous works indicated VIPER as a degenerate family. Cheers!
On 2024-07-18 19:44:19, user Jorge Cruz-Reyes wrote:
This paper in now in press. NAR-01088-C-2024.R2<br /> KREH2 helicase represses ND7 mRNA editing in procyclic-stage Trypanosoma brucei by opposite modulation of canonical and “moonlighting” gRNA utilization creating a proposed mRNA structure
On 2024-07-17 15:41:07, user Matilda wrote:
https://www.cell.com/iscience/fulltext/S2589-0042(24)01665-1
On 2024-07-17 11:55:37, user Ryan Sheldon wrote:
A peer reviewed version of this paper is now available here:<br /> https://www.nature.com/articles/s41467-024-50128-z
On 2024-07-17 09:55:16, user disqus_DPScP8M4wg wrote:
This study is now published at Nature Structural & Molecular Biology:<br /> Lange, S.M., McFarland, M.R., Lamoliatte, F. et al. VCP/p97-associated proteins are binders and debranching enzymes of K48–K63-branched ubiquitin chains. Nat Struct Mol Biol (2024). https://doi.org/10.1038/s41594-024-01354-y
On 2024-07-16 22:58:40, user Jim T wrote:
My congratulations to the authors on this impressive work! Your estimated 300kya date for the divergence of the ancestry of Khoe-San seems like a relatively good fit for the newer dates for the emergence of the Lupemban culture. Has this possible match been considered?
“Early Stone Age (ESA) archaeology is effectively absent from the rainforest zone, with the early Middle Stone Age (MSA) Lupemban industry representing the earliest sustained archaeological signature. Uranium-series dates of approximately 265 ka BP for the Lupemban at Twin Rivers (Zambia), although queried, suggest a precocious late Middle Pleistocene dispersal of early Homo sapiens into the equatorial rainforest belt.” - Taylor 2021
https://royalsocietypublishing.org/doi/full/10.1098/rstb.2020.0484
On 2024-07-16 19:03:57, user Zehua Zeng wrote:
* Published Article: OmicVerse: a framework for bridging and deepening insights across bulk and single-cell sequencing
* Link: https://www.nature.com/articles/s41467-024-50194-3#Ack1
On 2024-07-16 16:40:35, user Susana wrote:
This paper has now been published at Journal of Molecular Biology. It is available online at https://authors.elsevier.com/sd/article/S0022-2836(24)00320-6
On 2024-07-16 09:31:08, user Sudin Bhattacharya wrote:
Very interesting work. However, analyzing distances in high-D space is problematic. Couldn't these findings be attributed to the curse of dimensionality, where far-away points all appear equidistant?
On 2024-07-16 00:37:36, user Lana wrote:
Nice work, I didn't know ENTs could have so many phenotypes. Interesting
On 2024-07-15 17:57:37, user Sergio Verjovski-Almeida wrote:
I am glad to inform that this preprint has now been published at Molecular Biology and Evolution, Volume 41, Issue 7, July 2024, msae123, https://doi.org/10.1093/molbev/msae123 <br /> Published: 24 June 2024
On 2024-07-15 17:30:04, user priyanka.bajaj3193@gmail.com wrote:
Reviewed by Priyanka Bajaj and Christian B. Macdonald (UCSF)
Summary:
Fusion oncoproteins occurring from genomic rearrangements are commonly observed in cancers and often drive oncogenesis. Although these fusions frequently involve kinases or transcription factors, they are a diverse group at both molecular and functional levels, and a unified description of their oncogenetic properties is lacking. Robust methods for predicting oncogenicity of unknown fusions would be immediately clinically useful, making this an important gap. At a more basic level, this points to a gap in our ability to describe a key biological phenomenon. Some recent work has tackled this problem by examining the physicochemical properties of fusion oncoproteins, notably [1], but this is essentially still an open question.
In this manuscript, the authors present a language model of fusion oncoproteins, FusOn-pLM, by fine-tuning ESM-2 with two recent databases of human fusion oncoproteins. They compare random masking vs. one using their previous fine-tuned ESM-2 model SaLT&PepPr and benchmark their results on a number of tasks, demonstrating reasonably increased specificity on specific tasks and improvement with non-random masking. The model training and benchmarking are sound and convincingly demonstrate the improvement.
Despite this, the lack of clarity about what unifies fusion oncogenes is a major challenge. Language models can be powerful ways to learn these sorts of definitions in a less biased way, and in that light this is an important step towards clarifying this basic gap. However, as written, the work uses a working definition of fusion oncogene that is based on physicochemical properties that may or may not be specific to oncogenes. Examining the benchmarking tasks the authors use makes this clearer: they are almost entirely predictions of condensate and IDR properties rather than oncogenetic ones. The one truly cancer-specific benchmark, differentiating carcinoma classes, is fairly narrow and no model performs particularly well here. As a result, we are unsure how strongly this model will perform in discrimination or generalization tasks.
Another general problem for the field is the lack of negative controls. Gene fusions are relatively common mutations, but bona fide oncogenic fusions are a small fraction of all fusions, making this a class imbalance problem. Even within tumors, the majority of fusions are thought to be passengers rather than driver mutations. Any predictor should be able to discriminate between these, but the lack of good data on non-oncogenetic fusions makes this challenging. This is evident in this work, where the model’s discrimination is not strongly tested.
In summary, we believe this is technically strong work which addresses a pressing need, and which also presents some general strategies for domain-specific language model fine-tuning, but which is unfortunately hamstrung by defects in the available data and conceptualization of the field that are outside of the authors’ control. As presented, it will be of interest to AI practitioners and oncofusion researchers, but the clinical utility is unclear.
Major points:
1) As discussed, we think the concept of an “oncofusion” is somewhat diffuse, as it describes an extremely heterogeneous set of proteins. This makes the prediction task particularly difficult. While the introduction discusses the barriers to prediction of fusion oncoproteins due to their intrinsically disordered regions and large size, we believe a bit more care with the effective definition they are using is warranted. Related to this is the choice of FOdb to train their model, which is essentially a database of condensate properties of oncofusions rather than oncogenetic ones. The implications of this choice also warrant a bit more discussion.
2) We wonder if there is a class imbalance problem. The databases used to fine-tune their model have a small fraction of possible fusion proteins, and don’t contain large amounts of negative training information. We are thus unsure if FusOn-pLM’s significant improvements over ESM-2 are specific to driver fusion oncogenes.
3) The method is not contextualized with respect to prior work in computational oncofusion prediction and characterization. Such methods are few ([2],[3],[4],[5],[6] among others) but important to understand FusOn-pLM’s performance.
4) Several experimental datasets for fusion oncogenes have been published, including [7], [5], and [8]. FusON-pLM’s performance on these would be a compelling way to show its utility, as well as a more specific oncogenetic task.
Minor points:
1) Figure 2D: Although FusON-pLM is doing a slightly better job at distinguishing carcinoma prediction into two classes (BRCA vs. STAD), the performance metrics are the worst across the board. What does this mean for the prediction problem overall? Does the fact that IDR and condensate properties are much better predicted mean that the model is actually not learning an oncogenetic task? This seems worthy of more discussion.
2) Figure 4A: The authors present a FusOn-pLM embedding visualization of fusion oncoproteins, along with the corresponding head and tail protein sequences. It would be beneficial to clarify whether the protein sequences used for the head and tail counterparts are full-length sequences or only up to the exon breakpoint that forms the chimeric fusion protein. This information can be included in the Materials and Methods section.
3) Figure 4A: The authors demonstrate that FusON-pLM is able to separate out fusions from their head and tail components. To demonstrate that it is learning more specific embeddings for fusion oncoproteins, a comparison of the embeddings with untuned ESM-2 would be appropriate.
4) Figure 4B: In the main text of results section the authors write “FusOn-pLM largely clusters sequences by key properties such as the fraction of polar, charged, and disordered residues as well as the propensity to form pi-pi and pi-cation interactions and prion-like domains, via the PLAC NLLR score.” From the data shown in Figure 4B, this conclusion seems fine for polar residues and NLLR scores, but not for disordered residues and pi-pi/pi-cation interaction propensity by eye. Without quantification of the clustering, we are not sure this statement is supported.
References:<br /> 1. Tripathi S, Shirnekhi HK, Gorman SD, Chandra B, Baggett DW, Park C-G, et al. Defining the condensate landscape of fusion oncoproteins. Nat Commun. 2023;14: 6008.<br /> 2. Shugay M, Ortiz de Mendíbil I, Vizmanos JL, Novo FJ. Oncofuse: a computational framework for the prediction of the oncogenic potential of gene fusions. Bioinformatics. 2013;29: 2539–2546.<br /> 3. Abate F, Zairis S, Ficarra E, Acquaviva A, Wiggins CH, Frattini V, et al. Pegasus: a comprehensive annotation and prediction tool for detection of driver gene fusions in cancer. BMC Syst Biol. 2014;8: 97.<br /> 4. Lovino M, Montemurro M, Barrese VS, Ficarra E. Identifying the oncogenic potential of gene fusions exploiting miRNAs. J Biomed Inform. 2022;129: 104057.<br /> 5. Li J, Lu H, Ng PK-S, Pantazi A, Ip CKM, Jeong KJ, et al. A functional genomic approach to actionable gene fusions for precision oncology. Sci Adv. 2022;8: eabm2382.<br /> 6. Liu J, Tokheim C, Lee JD, Gan W, North BJ, Liu XS, et al. Genetic fusions favor tumorigenesis through degron loss in oncogenes. Nat Commun. 2021;12: 6704.<br /> 7. Frenkel M, Hujoel MLA, Morris Z, Raman S. Discovering chromatin dysregulation induced by protein-coding perturbations at scale. bioRxiv. 2023. doi:10.1101/2023.09.20.555752<br /> 8. Kobayashi Y, Oxnard GR, Cohen EF, Mahadevan NR, Alessi JV, Hung YP, et al. Genomic and biological study of fusion genes as resistance mechanisms to EGFR inhibitors. Nat Commun. 2022;13: 5614.
On 2024-07-14 15:14:50, user Dd wrote:
Great work! <br /> We always wonder if the size of EVs is interfering with the binding capacity of the beads? Thus result in a lower detection maybe? Can you also share some images from the bead based flow cytometry? Thanks!
On 2024-07-13 07:51:37, user alexander_zlobin wrote:
Hi, I commented on the same issue before, but there is still one figure in the SI that retain the confusion between HID and HIE states of the catalytic His in serine triad proteases. This is figure S49, and it should be corrected.
On the unrelated topic, are you planning to provide your datasets later? I am particularly interested in all PDB entries you found and classified into GSA/TSA. As you of coarse are familiar, PDB searches are quite tiresome, and having this data already available would help tremendously.
Sincerely yours,<br /> Alexander Zlobin<br /> MeilerLab Leipzig, Germany
On 2024-07-12 23:46:41, user Alex wrote:
I hate myself for doing this, but apparently this is the only way to point this out: why doesn’t this benchmark include singleCellHaystack? Haystack was published in Nat Commun in 2020, has >75 citations now, is easy to install and run. An updated was published last year In Scientific Rep. Still, a part of this field that has apparently decided that it is completely fine to ignore this method.
On 2024-07-12 14:18:11, user Prof. T. K. Wood wrote:
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).
Toxin/antitoxin systems were first shown to inhibit phage in 1996 (please cite doi: 10.1128/jb.178.7.2044-2050.1996).
On 2024-07-12 04:36:28, user Sam Buckberry wrote:
Our response to this preprint, titled ‘Transient Naive Treatment (TNT) iPS cells do not feature Sendai virus expression: Response to Sendai virus persistence questions the transient naive reprogramming method for iPSC generation’ is available here: https://www.biorxiv.org/content/10.1101/2024.07.10.602807v1
On 2024-07-11 13:25:32, user Pookey532 wrote:
A small correction in Table 1.<br /> CRISPR gRNA vector wrongly including PAM sequence, the consequence should say "gRNA plasmid becomes target of CRISPR cleavage" with the caveat that this would only be the case if the wrongly included PAM is followed by another PAM, which is not the case in many CRISPR plasmids such as the pX330 derived ones. This would obviously affect cleaving at the target if its PAM is not followed by a second PAM.
While some errors in the table are almost certainly errors in design (ex stop codons before a 2A sequence, mutations in ITRs, etc...) I'm curious why some of the other design "errors" are deemed errors. For example, using CMV in AAV vectors can be a perfectly acceptable choice depending on the use of the virus, especially if it isn't intended for long term expression. Likewise, use of "unstable" sequences in high copy plasmids can be a problem, however if those plasmids are maintained in bacteria that maintain plasmids at a low copy (Epi400, Stbl2, etc...), the replication origin of the plasmid becomes less relevant as the copy number becomes more dependent on the host strain. Similar to this, "Vectors containing toxic genes to E. coli host" is not necessarily a design error. Sometimes this simply the only option.
On 2024-07-10 18:49:28, user Björn Reumont wrote:
This preprint is published since Oct 2023 in BMC Biology, Open Access: Prevalent bee venom genes evolved before the aculeate stinger and eusociality, Link https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-023-01656-5
On 2024-07-10 18:05:43, user Matthias Samwald wrote:
Final article has been published in Computers in Biology and Medicine:
GPT-4 as a biomedical simulator https://doi.org/10.1016/j.compbiomed.2024.108796
On 2024-07-10 07:25:49, user Constantinos Constantinides wrote:
Published version: https://onlinelibrary.wiley...
On 2024-07-10 03:40:12, user Zach Hensel wrote:
This article does not match my experience in Okinawa and the caricature of Okinawa here is not necessary to make the point.
Some of the claims are simply wrong (e.g. the description of civil marriage registration). Others are caricatures for rhetorical effect (e.g. "14 cans of SPAM" is not what the reference says). In general, the list of supposed ills in Okinawa today has no direct connection to the longevity of today's 100-or-so-year-olds.
I hope that the author can speak with people in Okinawa and perhaps reconsider this approach.
On 2024-07-09 08:31:45, user Rouslan Efremov wrote:
This preprint has been published in Nature Communications https://doi.org/10.1038/s41...
On 2024-07-08 22:32:03, user Tara wrote:
This manuscript is now published at the Journal of Infectious Diseases<br /> https://doi.org/10.1093/inf...
On 2024-07-08 17:53:48, user David Lukac wrote:
Link to peer-reviewed publication: https://pubmed.ncbi.nlm.nih...
On 2024-07-08 16:13:36, user Agnieszka Lipinska wrote:
Just to clarify, the data provided for Fucus serratus does not correspond to 'released sperm and eggs'. We sequenced vegetative tissue as well as reproductive tissue (whole receptacles) containing sperm or eggs, but not isolated gametes. Please see https://doi.org/10.1111/nph... for reference.
On 2024-07-08 10:19:50, user Frederica Theodoulou wrote:
This paper is now published at: doi: 10.1093/plcell/koae117
On 2024-07-07 15:56:39, user Ben Davis wrote:
Now published at https://www.nature.com/arti...
On 2024-07-05 13:00:12, user Xuan Zhang wrote:
Now published in Genome Biology: https://genomebiology.biome...
On 2024-07-05 12:57:48, user Thomas BN Jensen wrote:
Please see https://zenodo.org/records/... for the additional datafiles (metagenome assemblies, metagenome bins).
On 2024-07-04 17:58:15, user Dhiman Pal wrote:
This preprint has been published recently.<br /> Please use following link to the final published version:<br /> Lin, Y., Pal, D.S., Banerjee, P. et al. Ras suppression potentiates rear actomyosin contractility-driven cell polarization and migration. Nat Cell Biol (2024). https://doi.org/10.1038/s41...
On 2024-07-04 16:16:55, user Michael F Miles wrote:
This article is now published in Neuropsychopharmacology. There is a change in the order of the first 2 authors and the first name of Jeremy Nguyen (Angel Nguyen) in the final published version.
Mignogna KM, Tatom Z, Macleod L, Sergi Z, Nguyen A, Michenkova M, Smith ML, Miles MF. Identification of novel genetic loci and candidate genes for progressive ethanol consumption in diversity outbred mice. Neuropsychopharmacology. 2024 Jun 29. doi: 10.1038/s41386-024-01902-6. Epub ahead of print. PMID: 38951586.
On 2024-07-04 13:19:42, user Gyawali, Rajan wrote:
Hi,
Could you please link this preprint to the published journal in Briefings in Bioinformatics titled "CryoSegNet: accurate cryo-EM protein particle picking by integrating the foundational AI image segmentation model and attention-gated U-Net". The link to the published version is https://academic.oup.com/bi...
Thank you!
On 2024-07-03 16:05:42, user Jeffrey Duncan-Lowey wrote:
Congratulations on this interesting and important work establishing phage defense systems as a widespread and abundant source of gene cassettes of unknown function in functional mobile integrons.
Some work relevant to these findings -- a group has recently studied the type I CBASS system studied here (pic135AB) demonstrating that pic135B homologs, called Cap15 (interpro entries: PF18153/IPR041208), are cyclic di-nucleotide-activated beta-barrels that embed in and disrupt the bacterial membrane to cause cell death, validating the predicted role in membrane translocation (line 148). https://pubmed.ncbi.nlm.nih...
On 2024-07-03 15:10:50, user Peter Cattini wrote:
Our preprint manuscript on bioRxiv (doi: https://doi.org/10.1101/202... has now been published in final form in the Journal of Molecular Endocrinology under the title "Increased capacity to maintain glucose homeostasis in a transgenic mouse expressing human but not mouse growth hormone with developing high-fat diet-related insulin resistance, hepatic steatosis and adipose dysfunction". This paper can be found at: https://doi.org/10.1530/JME....
On 2024-07-03 13:55:44, user Jennifer Oyler-Yaniv wrote:
Hello, this paper has since been published in PNAS. Please see the accompanying link: https://www.pnas.org/doi/fu...
On 2024-07-03 07:48:24, user Niranjan Kumar wrote:
This pre-print has been published in Nucleic Acids Research (NAR). 2024 Feb 9;52(3):1450-1470. <br /> https://doi.org/10.1093/nar...
On 2024-07-02 23:49:22, user Brian wrote:
It has been reasonably well-established that if there is sufficient water, transpiration rate must not be restricted for the purpose of conserving water early season to gain benefits late-season. Even the current study shows "Early-season water use was positively correlated with above-ground biomass, challenging the assumption that early-season water conservation can be leveraged for late-season benefits". This study explores three treatments, all fully or partially irrigated. As authors' concluded that "We question the efficacy of LT traits, highlighting the physiological link between water use and carbon gain, and the potential opportunity costs of reduced early-season growth", I am unsure whether such treatments were the best choice. LT trait has been proved beneficial when soil moisture is scarce, and/or soil profile is deep enough to store sufficient water to be used late-season.
On 2024-07-02 15:48:40, user Donald R. Forsdyke wrote:
James Mallet's comments on an earlier version of this paper, noted the authors' claim that "This theory offers a level of parsimony and generality rarely seen in biology," and excused the absence of citation of his laboratory's study because it had come out "very recently, probably after you'd done most of this work."
However, the subjects of dosage compensation, Haldane's rule and speciation was covered together in the 1990s with some level of "parsimony and generality," which also included taking into account the immunological significance of collective gene functions (1-4). The growing evidence consistent with this viewpoint was more recently summarized in a textbook (5).
Perhaps, as part of their paper, the authors might more critically evaluate earlier work that so closely matches their own.
(1) Forsdyke, D. R. (1994) J. Theor. Biol. 167, 7-12 Relationship of X chromosome dosage compensation to intracellular self/not-self discrimination: a resolution of Muller's paradox?
(2) Forsdyke, D.R. (1995) J. Theoret. Biol. 172, 335-345. Fine-tuning of intracellular protein concentrations, a collective protein function involved in aneuploid lethality, sex determination and speciation?
(3) Forsdyke, D. R. (1996) J. Theoret. Biol. 178, 405-417. Different biological species "broadcast" their DNAs at different (G+C)% "wavelengths"
(4) Forsdyke, D. R. (2000) J. Theor. Biol. 204, 443-452. Haldane's rule: hybrid sterility affects the heterogametic sex first because sexual differentiation is on the path to species differentiation
(5) Forsdyke, D. R. (2016) Evolutionary Bioinformatics, 3rd edition. Springer, New York.
On 2024-07-02 11:48:52, user Hervé Acloque wrote:
The revised and peer-reviewed version of this paper is now available in the special issue of Genomics dedicated to FAANG:<br /> https://doi.org/10.1016/j.y...
On 2024-07-01 21:00:22, user Frank Koopmans wrote:
The manuscript has been published in Nature Communications and is available at https://doi.org/10.1038/s42...
On 2024-07-01 15:29:34, user Marcos Suárez wrote:
Now published in Global Ecology and Conservation doi: https://doi.org/10.1016/j.g...
On 2024-06-29 12:04:48, user moof wrote:
a little typo: "Stochastic Gradient Decent" (and not "Descent")
On 2024-06-28 16:26:14, user Yat Ho Chan wrote:
Hi everyone,
We are excited to share that our article has been peer-reviewed and published in Nature Communications! You can find the article at the link below.
On 2024-06-28 13:20:02, user Jo Wolfe wrote:
Interesting preprint! Regarding the intro, indeed the oldest direct fossil evidence is Jurassic...but we recently found that the crown group of Brachyura are probably Triassic<br /> https://academic.oup.com/sy...
Also, in our 2021 Bioessays paper, we did suggest the pleon folding in metamorphosis may be due to Abd-A repression, so it's cool that you found support for that result
On 2024-06-28 09:25:30, user Helle Jorgensen wrote:
Published after peer review<br /> Lambert, J., Oc, S., Worssam, M.D. et al. Network-based prioritization and validation of regulators of vascular smooth muscle cell proliferation in disease. Nat Cardiovasc Res 3, 714–733 (2024). https://doi.org/10.1038/s44...
On 2024-06-27 16:17:06, user Ivana Jerkovic wrote:
The scripts from this study can be found at:<br /> https://github.com/MarcoDiS...
On 2024-06-25 00:34:52, user Jiazheng Miao wrote:
This manuscript has been published in Scientific Reports. Please access the latest published version.
Miao, J., Chen, T., Misir, M. et al. Deep learning for predicting 16S rRNA gene copy number. Sci Rep 14, 14282 (2024). https://doi.org/10.1038/s41...
On 2024-06-24 14:14:02, user Flo Débarre wrote:
Following up on my previous comment about the pangolin datasets featured in Figure 2:
As mentioned previously, according to INSDC medatadata, SRR11119760 and SRR11119761 were made public again on June 16, 2021. However, because the data were pushed to the cloud on June 18 only, which is the day the preprint was submitted to bioRxiv and shared via email with officials, it had been suggested that the data release could still be linked to the preprint submission. Careful inspection of the exact times of the different events on June 18 shows that this suggestion does not hold.
The preprint PDF was indeed generated at 17:52 EST (cf. pdf metadata), which corresponds to the time of the last Github commit on the preprint's associated repository. Communication of the results to NCBI/NIH officials took place at 19:00 EST ( source ). SRR11119760 was however public on the cloud at 14:00 EST ( source ), i.e. before the preprint's final version was compiled.
On 2024-06-21 22:08:57, user MarkC wrote:
When will OMF or others consider a controlled clinical trial for these or other simple supplements?
On 2024-06-21 15:28:02, user Yan Cui wrote:
An extensively revised version of this paper has been published in Genome Medicine https://doi.org/10.1186/s13...
On 2024-06-21 10:40:11, user JamminOnTheOne wrote:
The materials and methods section regarding the production of mRNA is insufficient: "Subsequently, the mRNA and circular RNA (circRNA) were synthesized as described previously (10; 23)." The cited reference for mRNA production (Ref 10) gives two alternative types of protocols for mRNA production (post-transcriptional and co-transcriptional capping) and it is unclear which method was used. In the discussion section, it is also indicated that "GEMORNA-generated elements exhibit enhanced translation capacity with m1Ψ modification", however there is no mention in the text or in Ref 10 of the mRNAs being tested carrying this modification. It would be preferable to include the complete mRNA sequences and all of the reagents and procedures required to produce them.
On 2024-06-21 10:08:37, user Leonard Frach wrote:
Published version: https://doi.org/10.1038/s41...
On 2024-06-19 16:20:06, user John wrote:
Where are the Supplementary Tables 1-7?
On 2024-06-19 07:46:07, user Guillermo del Angel wrote:
I was trying to see the actual list of variants referenced in Table S1 but there doesn't seem to be any link to view and download these?
On 2024-06-19 00:31:10, user Rajan K C wrote:
This article has been published. Please update the article.
K. C. R, Patel NR, Shenoy A, Scallan JP, Chiang MY, et al. (2024) Zmiz1 is a novel regulator of lymphatic endothelial cell gene expression and function. PLOS ONE 19(5): e0302926. https://doi.org/10.1371/jou...
Thank you!
On 2024-06-18 15:19:14, user Todd Gaines wrote:
This preprint has now been published in Genome Biology:<br /> https://link.springer.com/a...
On 2024-06-17 06:43:17, user Sebastian Gregoricchio wrote:
Now published on Nucleic Acids Research:<br /> https://doi.org/10.1093/nar/gkad267
On 2024-06-17 06:37:44, user Sebastian Gregoricchio wrote:
Now published on Genome Research:<br /> https://www.genome.org/cgi/doi/10.1101/gr.278680.123
On 2024-06-17 03:46:27, user mittimithai wrote:
I thought this sentence was odd:
"Excluding Physics, the highest presence of EP authors<br /> 300 after adjusting for the total number of authors in each country is seen in Arab countries<br /> 301 (Saudi Arabia, Iraq, United Arab Emirates, Pakistan) and in Malaysia and Philippines."
Pakistan is not an Arab country.
On 2024-06-16 18:39:42, user Ashley Winn wrote:
Nice to see lymphangiogenesis getting some attention in regeneration. Thought this paper would be of of interest:
Simkin, Jennifer, Ajoy Aloysius, Mike Adam, Fatemeh Safaee, Renée R. Donahue, Shishir Biswas, Zohaib Lakhani et al. "Tissue-resident macrophages specifically express Lactotransferrin and Vegfc during ear pinna regeneration in spiny mice." Developmental Cell (2024).
On 2024-06-16 07:52:20, user James wrote:
The tidyverse isn't exactly good and promotes truly awful coding practice. Why continue expanding it? It's also hard to understand what this adds besides bloat to these analyses.
On 2024-06-15 11:45:28, user Jiashun wrote:
Great works！Cogratulations, Dr Cheng. While I found there may be a small mistake. "Of the sixteen F1 double heterozygotes we derived from the cross between gpgp and the TILLING mutant heterozygotes, half had yellow pods, and all of these yellow podded F1s carried the ChlGW121* null allele (Fig. 3i-j)". I checked the figures and found 10 yellow pods rather than the half of sixteen (8). Please let me know if I misunderstood.
On 2024-06-15 08:59:37, user Marc RobinsonRechavi wrote:
In the manuscript you write:
"Supplementary information including the Python code used for the simulations is available at https://10.5281/zenodo.11562472"
but this link does not work and I did not find this data in Zenodo. Can you please provide the correct link?
On 2024-06-15 06:00:47, user Yongheng Wang wrote:
Pease check the demo here: https://youtu.be/3-RSjPakGH...
On 2024-06-14 16:27:04, user Georg wrote:
It's great work. Could you please ask ftdna or yfull or yseq to define terminal SNPs of 4 unidentified I1 samples
On 2024-06-14 09:00:46, user Markus Proft wrote:
This preprint has been published in Frontiers of Microbiology: <br /> 2023 Apr 3:14:1152249. doi: 10.3389/fmicb.2023.1152249. eCollection 2023.
On 2024-06-11 22:23:41, user Clashing_titans wrote:
Awesome database!
On 2024-06-11 13:08:39, user wonderfulponderfulponds wrote:
I feel the research design and some conclusion drawn is premature due to an overlook of the following aspects:
Lacking data on Fatty acids analysis of some representative wild capelin testis, semen or centrifuged spermatozoa: The regeneration of sperm and endurance of males largely relate to absence/ presence of enough "raw materials" (i.e., high quality lipids, phospholipids and long-chain polyunsaturated fatty acids to be precise). The original hypothesis tested would be dubious, irrespective of any male sub-cohorts or phenotypes, if the above basic requirement is missing.
Lacking data on a gastrosomatic index (gut/ visceral weight divided by body weight and expressed in %) or gut content analysis: if some capelins are not feeding in between their spawning, it is highly unlikely they would replenish depleted energy reserves, and bioenergetically channel 50% of such intake energy in food to invest in gamete/ milt production. As such the original experimental design does not take into account a careful bioenergetics point of view either. Some whole-body carcass analysis of some representative capelin would have been beneficial as an alternative.
I urge the authors to consider these in future work and good luck with the revisions.
On 2024-06-10 13:18:54, user Benoit Laventie wrote:
Final paper available in Nature Microbiology: https://doi.org/10.1038/s41...
On 2024-06-09 05:52:19, user Barend de Graaf wrote:
I found a level of confusion about the ‘SPH protein family’, and the working mechanism of the SI system in Papaver specifically, in this very interesting MS …..
In the introduction, authors mention:
“In poppy, when two members of the SPH protein family (PrsS1 and PrpS1) are cognate, they confer sporophytic self-incompatibility (Foote et al., 1994; Wheeler et al., 2009; de Graaf et al., 2012)”
This is not correct, poppy does not express ‘sporophytic SI’ but ‘gametophytic SI’.
Furthermore, authors also state ‘when two members of the SPH protein family (PrsS1 and PrpS1) are cognate’.
This is not correct either, PrpS proteins are not part of the SPH protein family, instead these are classified as the poppy SI membrane ‘receptor’ proteins that are essential for SI signalling in pollen, male component of SI system in poppy.
On 2024-06-08 16:21:26, user Reviewer 6 wrote:
I have read Gainey et al, the response by Coleen Murphy in the comments as well as the preprint here. I previously made a detailed assessment of these which are found in the comments of Gainey et al., bioRxiv 2024.
In my opinion the debate to whether the effect can be triggered under highly specific lab conditions is not particularly relevant. But I think the point is that if the effect is so sensitive to such artificial conditions (or one sRNA that is only expressed under even more specific conditions), then how physiologically important can it be in nature? CM's group points to their 2024 (Sengupta et al, plos genet) paper testing various bacteria C. elegans may be exposed to the wild. However, it seems that worms naively avoid OP50 (i.e. ‘prefer’ test bacteria) in essentially every comparison made by CM. This is contrary to reports by other labs (PMID: 38228683, PMID: 38228683) and potentially a more serious concern with the assay.
Furthermore, in the 2024 Sengupta paper, it seems that both pathogenic and non-pathogenic bacteria can trigger avoidance (or not), which is odd and makes me think the effect is rather random. If this is really something so specific or adaptive that prevents worms from infection or confers fitness - I believe CM refers to the effect as the worms "reading" bacterial sRNAs in their Nature papers (is there any evidence that the recognition sequence on maco-1 mRNA co-evolves with bacterial preference in wild nematode isolates?) - then wouldn't the worms have evolved at least some preference for avoiding pathogenic vs non pathogenic bacteria from their habitat?
To me it just seems that random bacterial sRNAs that may be complementary to some worm genes that regulate behavior (I mean, you would expect to see some matches among a panel of total bacterial small RNAs from many species worms are exposed to versus total worm mRNAs...) are being silenced through an RNAi like mechanism... It's not news that RNAi can be inherited, which was described nearly two decades ago and is a well understood process.
Perhaps Hunter et al should visit CM's lab to learn the technique, but given how meaningful the assay/readout is in my view (and how already overstudied/saturated sRNA based inheritance is), perhaps it is not the best investment of time and effort.
On 2024-06-07 14:13:23, user Sonja Grath wrote:
Please link with: https://doi.org/10.1534/g3....
On 2024-06-07 13:43:51, user marodon wrote:
Great job in line with works from other teams. May I suggest that the authors include two publications related to the subject in their discussion? <br /> Midavaine É, Moraes BC, Benitez J, Rodriguez SR, Braz JM, Kochhar NP, Eckalbar WL, Domingos AI, Pintar JE, Basbaum AI, Kashem SW. 2024. Regulatory T cell-derived enkephalin imparts pregnancy-induced analgesia. doi:10.1101/2024.05.11.593442<br /> Aubert N, Purcarea M, Fornier M, Cagnet L, Naturel M, Casrouge A, Dietrich G, Dieu-Nosjean M-C, Marodon G. 2024. Enkephalin-mediated modulation of basal somatic sensitivity by regulatory T cells in mice. eLife 13. doi:10.7554/eLife.91359.1<br /> Some other omments:<br /> -p3 Treg cells restrain exacerbated activation of peripheral neurons during early during inflammatory challenge<br /> -p6 CarboxypeptidaseE (Cpe) has been shown to process proenkephalin (Hook VYH, Eiden LE, Brownstein MJ. 1982. A carboxypeptidase processing enzyme for enkephalin precursors. Nature 295:341–342. doi:10.1038/295341a0)<br /> -Ref 50 is incomplete
On 2024-06-07 12:51:36, user Duchenne François wrote:
This work has now been peer-reviewed and published here:<br /> https://doi.org/10.1098/rsp...
On 2024-06-07 03:54:29, user Mohamed Hoballa wrote:
This preprint has been reviewed and published under the DOI: https://doi.org/10.30491/ja...