Review v1 · round 1 · manuscript v1
Activity-based profiling of primary brain cells identifies covalent allosteric modulators of HCN channels
Panel readout
5 specialists · scored 1–5
Legacy scaled score
Range 4.0–5.0, a spread of 1.0.
- ethics5.0Confidence 5 of 5
- data analysis4.0Confidence 4 of 5
- reporting reproducibility4.0Confidence 4 of 5
- scientific validity4.0Confidence 4 of 5
- contribution context4.0Confidence 4 of 5
Score is the referee's assessment of the work.Confidence is how sure that referee was of its own reading, recorded separately and never combined. The editor's verdict is its own judgment of the reports, not a threshold applied to this mean. The legacy aggregate is the historical panel mean multiplied by 20. It is not comparable to the Editor-in-Chief's publication readiness score.
Abstract
as posted by the authors
Chemical proteomics can provide global portraits of small molecule-protein interactions in native biological systems. Such ligandability maps have, however, been mostly restricted to readily accessible cell lines and primary immune cells. Here, we describe an activity-based protein profiling (ABPP) strategy for mapping the covalent ligandability of primary brain cells isolated from mice. By investigating sets of stereochemically defined electrophilic small molecules (stereoprobes), we identify liganding events for diverse brain cell proteins, including many with nervous system-enriched expression. In this category were multiple hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels, which we show are covalently liganded by tryptoline acrylamide stereoprobes at a conserved cysteine in their cyclic nucleotide-binding domain. The stereoprobes were found to block cAMP-dependent shifts in voltage dependence while sparing basal activity of HCN channels. We thus describe an advanced ABPP platform for identifying ligands targeting nervous system-enriched proteins, including chemical probes that modulate HCN channel function in cells.
The review
- SummaryThe panel's assessment in brief.
- Decision letterThe editor's verdict and what it requires.
- Desk screenWhether the submission cleared the bar for full review.
- Advocate / skeptic debateThe case for and against, in full.
- Debate synthesisThe condensed account of the debate the editor read.
- Venue suggestionsWhere this might be submitted.
- Manuscript statisticsDeterministic counts over the text the panel read.
Specialist reports
Editorial audits
Factual checklists, not opinions. They skip the debate and go straight to the editor.
The text the panel read
counted, not judged
Counted at ingest, no model involved. These describe theconverted text the referees read, not your PDF.
Size
- Words
- 21,679
- Main text
- not separable
- Sentences
- 1,228
- Display equations
- 0
the reference list could not be located
Sentences
- Median sentence
- 14 words
- Longest tenth
- 43 words
- Over 40 words
- 12%
- Passive
- ~0.2891/sentence
regex approximation
Evidence on the page
- Citations
- not countable
- Numbers
- 129.25
- p-values
- 2 exact, 0 threshold
this venue most likely sets them as superscript numerals, which convert to bare digits
per 1000 words
Hedging against amplifying
Per 1000 words. Softening ("may", "suggests") against strengthening ("clearly", "demonstrates"). No referee saw these.
Provenance
PeerReviewAgents 0.5.0 · 1cf57690
Reviewed file
v1 · 5269 KiB
sha256 63b3b5f8c165631c88fa0033…
Debate rounds
2
Run cost
$2.95
Manuscript read as
markdown
Converted by rustypaper 0.2.0. Quotations match the manuscript text.
Desk screen
triage gate
Which model wrote which report
| Stage | Model |
|---|---|
| Editorial audits (×2) | claude-haiku-4-5 |
| Advocate / skeptic | claude-sonnet-5 |
| Specialist reviewers (×5) + desk screen | claude-haiku-4-5 |
| Editor, debate synthesizer | claude-opus-5 |
| debate synthesizer (override) | claude-sonnet-5 |
| journal recommender (override) | claude-haiku-4-5 |
The widest fan-out runs on the cheapest model. Only the agents that decide the verdict run on the most capable one.
What the referees looked up (30 searches)
| Agent | Search | Answered by | Hits |
|---|---|---|---|
| audit citation integrity | find related workactivity-based protein profiling ABPP covalent ligands Cravatt | N/A | 5 |
| find related workHCN channels cyclic nucleotide binding domain cAMP modulation | N/A | 5 | |
| search biomedical literatureDPYSL2 CRMP2 collapsin response mediator protein | N/A | 5 | |
| find related workWainger DeGennaro Santoro Siegelbaum cAMP HCN pacemaker channels Nature 2001 | N/A | 3 | |
| find related workLee MacKinnon HCN1 hyperpolarization-activated channel structure Cell 2017 | N/A | 3 | |
| find related workPelizaeus-Merzbacher disease PLP1 proteolipid protein mutations | N/A | 3 | |
| reviewer contribution context | find related workactivity-based protein profiling ABPP brain cells primary neurons | N/A | 10 |
| find related workcovalent ligands HCN channels cyclic nucleotide binding domain | N/A | 10 | |
| find related workstereoprobes cysteine-targeted electrophilic small molecules proteomics | N/A | 10 | |
| search preprintsABPP brain tissue primary cells chemical proteomics | N/A | 0 | |
| find related worktryptoline acrylamide stereoprobes protein liganding | N/A | 10 | |
| find related workcomplexoform-restricted liganding adaptor proteins DPYSL CRMP | N/A | 10 | |
| find related workCravatt activity-based protein profiling covalent ligands | N/A | 10 | |
| find related workserine hydrolase ABPP brain lysates endocannabinoid | N/A | 10 | |
| search biomedical literatureactivity-based protein profiling ABPP primary cells intact | N/A | 0 | |
| search biomedical literatureHCN channel allosteric modulation cAMP cyclic nucleotide binding | N/A | 10 | |
| search biomedical literaturecovalent inhibitors HCN channels ivabradine pore blockers | N/A | 0 | |
| search biomedical literatureABPP activity-based protein profiling cancer cells immune cells | N/A | 2 | |
| search biomedical literaturecysteine-directed ABPP iodoacetamide-desthiobiotin IA-DTB | N/A | 0 | |
| search biomedical literatureDPYSL2 CRMP2 collapsin response mediator protein | N/A | 2 | |
| search biomedical literaturePLP1 proteolipid protein myelin palmitoylation | N/A | 0 | |
| search biomedical literaturePDE7B phosphodiesterase cAMP brain neuroprotection | N/A | 0 | |
| search biomedical literatureVinogradova activity-guided map electrophile-cysteine primary T cells | N/A | 1 | |
| search biomedical literatureBackus proteome-wide covalent ligand discovery native biological systems | N/A | 0 | |
| search biomedical literatureWeerapana quantitative reactivity profiling functional cysteines proteomes | N/A | 0 | |
| search biomedical literatureTRIP8b HCN1 epilepsy gain-of-function cAMP antagonistic | N/A | 0 | |
| search biomedical literatureVinogradova 2020 activity-guided map electrophile-cysteine Cell | N/A | 0 | |
| search biomedical literatureNjomen tryptoline acrylamide stereoprobes cancer cells | N/A | 0 | |
| search biomedical literatureSpradlin reimagining druggability chemoproteomic platforms | N/A | 0 | |
| search biomedical literatureNiphakis ligand discovery activity-based protein profiling | N/A | 0 |
Run against arXiv, Semantic Scholar, PubMed and bioRxiv while the review was being written. A search returning zero hits is kept: it is the evidence behind a referee saying it found no prior art.
What each agent cost
| Agent | USD |
|---|---|
| editor | $1.0122 |
| skeptic | $0.6464 |
| advocate | $0.5629 |
| reviewer contribution context | $0.2239 |
| audit citation integrity | $0.1579 |
| desk screen | $0.1114 |
| debate synthesizer | $0.0946 |
| audit methods completeness | $0.0520 |
| reviewer scientific validity | $0.0208 |
| reviewer data analysis | $0.0192 |
| reviewer reporting reproducibility | $0.0185 |
| journal recommender | $0.0184 |
| reviewer ethics | $0.0108 |
Cite this review
Permanent: this review only
This URL is a permanent link to this specific review, and will not change.
In Silico (2026). Review of "Activity-based profiling of primary brain cells identifies covalent allosteric modulators of HCN channels". In Silico. https://pgarrett-scripps.github.io/insilico/reviews/2026/activity-based-profiling-of-primary-brain-cells-10-64898-2026-08-25-747126/v1/
@misc{insilico-activity-based-profiling-of-primary-brain-cells-10-64898-2026-08-25-747126-v1,
title = {Review of {Activity-based profiling of primary brain cells identifies covalent allosteric modulators of HCN channels}},
author = {{In Silico}},
year = {2026},
howpublished = {In Silico, an AI-refereed overlay journal},
url = {https://pgarrett-scripps.github.io/insilico/reviews/2026/activity-based-profiling-of-primary-brain-cells-10-64898-2026-08-25-747126/v1/},
note = {Machine-generated peer review of doi:10.64898/2026.08.25.747126 v1. Produced by PeerReviewAgents 0.5.0. Produced by PeerReviewAgents, doi:10.5281/zenodo.21781895.}
}Please cite the preprint itself as well. This reviews that work, it does not replace it. The review is machine-generated and advisory. If you are citing it as evidence about the paper, say so explicitly.