Evaluated articles

Evaluation Summary:

This manuscript develops a novel approach using the zebrafish to identify suitable drugs against the spread of cancer. With some stronger support of the methodology and conclusions, it will be of interest to cancer biologists, developmental biologists, and pharmacologists.

(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 paper addresses the intriguing hypothesis that different molecular chaperones may recognize and bind distinct tau species, and thus may use different mechanisms to prevent tau aggregation. The findings are very interesting and advance our understanding of how chaperones can counteract the deleterious effect of tau amyloidogenesis.

(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:

How species diversity responds to external perturbations (such as resource influxes and dilutions) is an important ecological question. Using soil microbial communities in devices where perturbations can be introduced in various forms and mathematical modelling, this study nicely illustrates how diversity is influenced by perturbations.

(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:

The plasticity of RNA folds and their ability to response to changes in selective pressure is a key aspect of understanding the evolution of life on this planet. The Class I ligase is a remarkably fast RNA ligase ribozyme that has been harnessed by a number of laboratories to power RNA polymerization. Thought by many to be the immutable catalytic core required for polymerization, Portillo et al. demonstrate evolutionary trajectories that result in a new and catalytically enhanced ligase core. An accumulation of mutations results in a the formation of a new pseudoknot structure immediately outside the active site of the ligase core. This new structure appears to more optimally position the P7-P6-P3 coaxially stacked stems of the ligase core with respect to the primer template substrate. Tracking the emergence of this new fold, which is correlated with an enhancement in RNA polymerization activity, is novel and interesting.

(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 names with the authors.)

Evaluation Summary:

CR6261 and CR9114 are two antibodies that bind to the conserved stem of influenza hemagglutinin (HA) through their VH regions and differ by 14-18 mutations from their inferred germline sequences. The authors constructed large combinatorial libraries containing all combinations of 11 and 16 binding-surface mutations for CR6261 and CR9114. These were used in yeast surface display titrations to infer individual and epistatic contributions to binding diverse HAs and to infer possible evolutionary trajectories going from germline to the mature antibodies. The study provides a wealth of knowledge on amino acid contributions to binding affinity. The study informs our understanding of biochemical epistasis, and could potentially serve as a starting point for a more detailed understanding of antibody affinity maturation more generally.

(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 names with the authors.)

Evaluation Summary:

This paper studies the evolution of herbicide resistance in Amaranthus tuberculatus, a widespread agricultural weed. By illuminating how adaptive mutations arose and spread in this remarkable example of rapid human-induced adaptation, the study will be of interest to a broad audience, ranging from plant biologists interested in herbicide resistance to evolutionary biologists and population geneticists studying the fundamental factors and processes that govern rapid adaptation. The paper applies innovative population genetic methodology to support its primary finding that resistance mutations have evolved multiple times in parallel.

(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 #2 agreed to share their names with the authors.)

Evaluation Summary:

This paper argues that simple nutritional interventions (L-leucine / insulin / sucrose) can trigger appendage regeneration in species various that do not regenerate appendages in normal conditions. Although the data on Drosophila are not fully convincing and further evidence is needed for this species, in the jellyfish Aurelia and in mice, the results are stunning and provide novel model systems for inducing appendage regeneration in animals and for studying the mechanisms underlying regeneration. These results strengthen an old idea that animals may have an intrinsic capacity to regenerate, which could be revealed by simple (e.g. nutritional) interventions. This paper will be of interest to readers in the field of signaling in regeneration and also in regenerative medicine.

(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:

The work, when completed, will provide important mechanistic detail on how Piezo channels, the most important and versatile mechanoreceptor molecules, functionally interact in the plane of the plasma membrane. It will be of interest to the field of mechanobiology and sensory mechanotransduction.

(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:

Ribosomes are among the most complex molecular machines a cell makes. The work by Chandrasekaran et al. contributes to our understanding of the molecular details of mitochondrial ribosome assembly, and how disruptions to this pathway may cause human disease. Using cryo-EM, the authors identified a subpopulation of immature human mitochondrial large ribosomal subunits that interact with assembly factors NSUN4, MTERF4 and GTPBP7. Based on this structure, they introduce mutations in C. elegans orthologs of these assembly factors that are expected to disrupt binding to the large subunit, and they show that these mutants cause sterility and disrupt mitochondrial proteostasis in the mutant animals. The work does not yet establish a direct link between the putative structural defects of the mutants and the observed developmental defects in C. elegans. Additional studies are needed to test the interesting possibility that this structure represents an on-pathway intermediate of mitoribosome biogenesis and/or ribosome recycling.

(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 #2 agreed to share their names with the authors.)

Evaluation Summary:

Jiang et al. present a study on a novel role of the ion channel TRPM7 in the regulated release of neurotransmitters and hormones. Their analysis focused on TRPM7-deficient chromaffin cells and neurons, which they studied using electrophysiological and imaging techniques. The data indicate that TRPM7 is activated during the compensatory endocytotis process that follows secretory vesicle fusion. This TRPM7 activation increases Ca2+ influx into the cytosol during endocytosis, which boosts endocytosis and reduces the tendency of synapses to progressively fatigue in phases of prolonged stimulation. Multiple aspects of the present findings are novel, interesting, and important - they provide important new insights into the mechanisms by which transmitter and hormone release is fine-tuned. The mechanism of how secretory vesicles, and in particular synaptic vesicles, recycle is important to understand, as impairment in vesicle cycling in turn impairs synaptic transmission, and therefore brain function. However, there are several issues that remain to be addressed before the present data fully justify the conclusions put forward by the authors.

(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 paper is of interest to scientists within the field of lifespan developmental neuroscience. The data analysis is rigorous and the conclusions are justified by the data. The key claims of the manuscript are directly related to, and support, a more reasonable interpretation of previous known findings.

(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 use numerical simulations and analyses of neural data from non-human primates to investigate whether rotational dynamics in motor cortical population activity which are typically attributed to recurrent connections can alternatively be explained by sensory feedback alone. They find that neural networks performing the same tasks will produce rotational dynamics even without any internal recurrent units. Overall, this paper examines an important question in the motor control field. The authors should clarify in more detail how the case with no recurrent dynamics has been simulated and address/discuss the role of task structure in their conclusions. Once the authors address issues associated with precisely how they eliminated recurrence from their simulations, the results that rotational dynamics are not necessarily generated autonomously due to recurrent connections will be a valuable and important addition to the ongoing debate about the nature of these rotational dynamics.

(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 paper by Mayer-Blackwell et al. builds on the idea that TCRs to the same antigen often share sequence similarities, which they quantify using a bespoke tool TCRdist3. Using this tool they develop the idea of a metaclone, a set of TCRs sharing similarities and potentially recognising the same antigen. They further show that such clonotypes show increased sharing between HLA-related individuals, and explore the use of such clonotypes in characterising antigen-specific immune response across cohorts of individuals. The paper is novel and of interest to a broad range of immunologists interested in repertoire. However, as raised in a series of detailed comments by the reviewers, the message of the paper needs to be sharpened and clearly focused on the development of the metaclone concept (with less emphasis on SARS-Cov-2. The concept of the metaclone itself, which is the main message of the paper, needs to be clarified, and characterised.

(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 names with the authors.)

Evaluation Summary:

This work offers an in-depth exploration of within-host influenza evolution that helps untangle the process by which global trends arise from host-level dynamics. The manuscript will be of interest to virologists and evolutionary biologists alike, and the dataset provides a unique opportunity to explore evolutionary dynamics late in acute infections of both endemic and emerging viruses. Technical concerns relating to data interpretation and modeling assumptions suggest that some results might change after 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:

Nava Gonzales et al. have reconstructed in unprecedented detail the morphology of olfactory sensory neurons (OSNs) and supporting cells within the sensilla in D. melanogaster, characterising the majority of sensory hairs, and OSN types. The morphometric dataset collected will be a reference point for the field of olfaction research in Drosophila, and furthermore might inspire similar analyses of other sensory systems, building our understanding of how peripheral morphological features contribute to sensory neuron 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 #2 agreed to share their name with the authors.)

Evaluation Summary:

This paper describes the transcriptome and synaptogenic function of astrocytes in the developing visual cortex (VC), a widely used model for neural development. The central questions examined are two-fold: 1) deciphering layer specific organization of astrocytes and 2) how neuronal activity can influence layer specific astrocyte profiles that relate to synaptogenic gene families. Using bulk RNAseq and detailed histology, they demonstrate that expression of key synaptogenic genes are timepoint and layer specific during development, providing an essential resource for understanding how astrocytes change and impact the development of VC circuits. Moreover, the authors revealed that expression of synapse-regulating genes is also regulated by input from thalamic neuronal activity (using vGlut2 KO mice) and astrocyte calcium activity in vivo (using IP3R2 KO mice). They further demonstrate astrocyte molecular changes using snRNA-seq in VGlut2 cKO and Ip3r2 cKO mice. Collectively, these results show that neuronal activity drives the changes in astrocyte function and layer-specific expression of synaptogenic secreted proteins. Overall, this a rigorous and well conducted study that provides important and new information on astrocyte diversity, neuron-astrocyte interactions during development, and mechanisms underlying the expression of key astrocyte synaptogenic genes.

(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:

The authors report a user-friendly software package (PARROT) that allows non-experts to use machine learning approaches to analyze high-throughput experiments on proteins. This package will allow more scientists to apply these powerful machine learning methods, thus increasing our ability to understand the chemistry and biological function of proteins.

(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 report that intracellular transport of glutamine and asparagine is critical for osteoblast anabolism. The authors use a variety of in vivo and in vitro assays for the testing of their working hypothesis. The paper expands and deepens our knowledge of the role of cellular metabolism in osteoblast function and bone development.

(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 manuscript presents the development and validation of a new tool for the characterization of peptidoglycan (PG), the essential cell wall polymer of bacteria. PG is a single large macromolecule that protects almost all bacterial cells. The newly developed open access tool will greatly facilitate comparative quantitative analyses and the determination of compositional diversity of PG, which might ultimately contribute to the development of new antibacterials that target this essential cell wall component.

(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 names with the authors.)

Evaluation Summary:

The authors developed an approach for surveillance screening for SARS-CoV-2, which involves the isothermic amplification of a region of the SARS-CoV-2 nucleocapsid gene using RT-LAMP, followed by detection with deep sequencing. High-throughput and cost effectiveness is achieved by two sets of barcodes that allow up to about 37,000 samples to be combined into one deep sequencing run. Moreover, the authors demonstrate they can do the detection from saliva collected on paper, which should make sample collection easier. The main strength of the work lies in solving the technical aspects for the approach to work. The main weakness is that real-world high-throughput detection is not conclusively demonstrated as only 8 clinical saliva samples are examined.

(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.)