Evaluated articles

Evaluation Summary:

This study presents an in-depth analyses of carbon oxidation state and hydration state of proteomes in different taxa and environmental settings, which contributes to our understanding of how microbial communities are shaped by their surroundings. The study has merit, but there also some technical weaknesses.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Evaluation Summary:

Deposition of hyperphosphorylated misfolded tau is a hallmark of many neurodegenerative diseases, but the exact mechanisms by which misfolded tau spreads to adjacent areas of the brain are not known. In this manuscript, which will be of broad interest to cell biologists and neuroscientists, the authors suggest that tau fibrils that translocate directly through the cell membrane induce aggregation of cytosolic tau. While the results appear stunning, there are alternative explanations to the authors' hypothesis that require further investigation.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

Vignogna et al. used yeast genetics, experimental evolution and biochemistry to investigate human congenital disorders of glycosylation, often caused by mutations in PMM2. They took advantage of the observation that the budding yeast gene SEC53 is almost identical to human PMM2, and used experimental evolution to find interactors of SEC53/PMM2. Mutations in genes corresponding to other human CDG genes, including PGM1, were overrepresented. The mechanisms of how reduced pgm1 activity could compensate for defects of sec53 are not yet clear.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 and Reviewer #3 agreed to share their name with the authors.)

Evaluation Summary:

The authors of this study characterize human Fip1, an important component of the 3' end processing machinery. They use X-ray crystallography to determine the molecular basis of the interactions between Fip1 and CPSF30 (at a 2:1 stoichiometry) and between Fip1 and CstF77 (at a 2:2 stoichiometry). Together with biochemical assays, they suggest that Fip1 may be central to regulating transitions with CPSF. The work will of relevance to colleagues interested in transcription and RNA processing.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)

Evaluation Summary:

This is an in-depth and rigorous analysis of transcriptomic changes in myogenic cells lacking dystrophin. Studies are made in both a mouse model and human subjects. the paper bears on possible roles of such alterations in pathogenesis of Duchenne muscular dystrophy. They draw attention to new therapeutic interventions for this condition.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

This work is of interest to neuroscientists and medical professionals involved in the study of Alzheimer's disease and related neurodegenerative conditions. The findings provide important information about how potential network-based structural and metabolic imaging biomarkers are associated with memory performance during distinct disease stages, in line with previous hypothetical biomarker models. The study is conceptually and methodologically sound, although some aspects of the analysis and reporting of the results could be further clarified.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

Barber et al present a manuscript discussing predictive factors for chemotherapy efficacy in head and neck squamous cancer (HNSCC). The paper is well written, and its style/formatting are optimal. The baseline signature moderately predicted outcome, and the data after one cycle further improved the algorithm, though this decreases its utility as a pure predictive tool. It is interesting that a subpopulation of monocytes, a subset of white peripheral cells long suspected to correlate with outcomes in HNSCC was one of the key drivers of the algorithm. However the overall impact in the field of this work seems limited by a number of factors, including that the authors focused on immune cell subpopulations and exosomes, which narrows the scope (no cytokines or other biomarkers were included); the signatures were not prospectively validated on an independent cohort; the algorithm was developed around a first-line therapy that is no longer considered to be the standard of care for HNSCC; and, while most of the conclusions are supported by the data, some of the caveats (such as the lack of a validation cohort, key in predictive biomarker development), are not addressed.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

Individual cells may act in response to stimuli or in a self-organized fashion. The relative weight of these two modes determines in the end to which degree cells or rather organs/organisms carry function. This study reports an example of very complex self-organization of actin waves as the coexistence of slowly moving broad waves of high F-actin concentration and rapidly propagating planar F-actin pulses. The paper is interesting for everybody interested in conceptual questions like signalling versus self-organization, in cellular morpho-dynamics and theory of dynamic patterns.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

The study is overall well-planned and the amount of data presented by the authors is impressive. The work nicely incorporates animal-level physiology (echocardiography data), tests for known canonical markers of hypertrophy, and then delves into an unbiased analysis of the transcriptome and proteome of LV tissue in bulk. The techniques and analyses in the study are adequately executed and within the realm of expertise of the Lakatta laboratory. This study is a necessary and crucial first step to extensively phenotype this mouse line and generate hypotheses for further work.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Evaluation Summary:

Cancers have frequently been found to show little evidence for purifying selection in their patterns of mutations. The key observation here is that tumors with low mutation burden show compelling evidence of efficient selection, but that tumors with high mutation burden do not. This is an important finding. The broader implication is that high mutation load tumors carry a substantial deleterious mutation load and may use common strategies to tolerate them, possibly providing a therapeutic target. Overall this work makes important observational and conceptual contributions to cancer genomics.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #3 agreed to share their name with the authors.)

Evaluation Summary:

Park et al.'s work provides insight into the infection processes of the human pathogen Coxiella burnetii with unprecedented detail. Their time course of cellular infection reveals the timing of key events and detects a previously unrecognized membrane structure. This work will shed new insight into the infection process of this pathogen allowing new targets for the treatment of infection with Coxiella.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

In this paper, the authors show that autobiographical memory recall is related to a specific biophysical property of the parahippocampal cingulum bundle, the so-called MR g-ratio. This paper will be of interest to neuroscientists studying associations between brain structure and cognitive processes. The data support the main conclusions of the paper. However, it is unclear how reliable the results are and whether the findings would generalize to situations beyond the specific one studied.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

This study seeks to develop the use of a FRET-based sensor for the formation of the folded 'interacting heads motif' structure for cardiac myosin, which is thought by some to represent a super-relaxed state with lower basal ATPase activity. This study offers some evidence that there is a relationship between the super-relaxed state and the 'interacting heads motif' structure, and that a specific dilated cardiomyopathy mutant in this myosin stabilizes the 'interacting heads motif' conformation. This paper will be of interest to muscle and cardiovascular biologists as it provides important insights into the correlation of structural and functional states of motor proteins in the context of cardiac muscle. The data qualitatively support this correlation and suggest a new mode of action of disease-causing mutations that lead to impaired contractile function.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

This study by Krug et al. uses the turquoise killifish, an emerging model for biomedical research, to generate a valuable live-imaging platform. Initially, the authors generate a transparent killifish they named Klara. Specifically, using optimized CRISPR approaches, they simultaneously inactivate three genes that are required for the formation of primary pigment cells in fish (melanophores, iridophores, xanthophores) and next, to monitor cell-cycle arrest and cellular senescence, they generate a cdkn1a-GFP reporter line using HDR-mediated integration. The paper would benefit from a further description of the HDR approach, the genetic models, and improved figures. Together, this platform will be an extremely valuable resource with broad application, including for aging research, physiology, toxicology, and regeneration.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1, Reviewer #2 and Reviewer #3 agreed to share their name with the authors.)

Evaluation Summary:

This pre-registration study by Kerrén et al. used a proactive interference task in combination with MEG recordings on humans to test predictions of a previous computational model postulating that neural representations of competing memories are associated with varied phases of the hippocampus theta-band rhythm. Their results largely confirmed the hypothesis and suggest that reactivations of target and competitor memories indeed occur at different phases of theta oscillations, which is further related to the intrusion effect in behavior.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

Using an elegant combination of cutting-edge techniques, the authors show that in the neuromuscular junction of the nematode C. elegans two different classes of voltage-activated calcium channels differentially trigger exocytosis of distinct pools of synaptic vesicles, one docked to the active zone and a second one localized more distant from the active zone. These findings will be of broad interest to neuroscientists interested in the mechanisms of calcium-mediated release of neurotransmitters at chemical synapses.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1, Reviewer #2 and Reviewer #3 agreed to share their name with the authors.)

Evaluation Summary:

The authors describe a newly developed software, ProteInfer, that analyses protein sequences to predict their functions. It is based on a single convolutional neural network scan for all known domains in parallel. This software provides a convincing approach for all computational scientists as well as experimentalists working near the interface of machine learning and molecular biology.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

The authors aim to tackle a fundamental question with their study: whether there is a direct age-associated increase of transcriptional noise. To investigate this question, they develop tools to analyze single-cell sequencing data from mouse and human aging datasets. Ultimately, application of their novel tool (Scallop) suggests that transcriptional noise does not change with age, changes in transcriptional noise can be attributed to other sources such as subtle shifts in cell identity. This study is in principle of broad interest, but it currently lacks a definitive demonstration of the robustness of Scallop. Systematic testing of this new package would ultimately strengthen the key conclusion of the work and give additional users more confidence when using the tool to estimate expression noise.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

In addition to providing extensive proteomics profiling datasets. this manuscript is fundamental that sheds light on the importance of appropriate experimental design for mouse disease model which have been overlooked so far. The results look quite solid based on the proper methodology. This type of work is extremely valuable to many biomedical scientists in the field for conducting reproducible research especially in the preclinical studies and properly interpreting the results.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)

Evaluation Summary:

This paper will be of interest to scientists within the field of neuromuscular disorders and has potential clinical relevance. It reveals a novel targeted strategy to improve the pathophysiology of children with neonatal brachial plexus injury. The key claims of the manuscript are well supported by the data, and the approaches used are thoughtful and rigorous.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)