Evaluated articles

Evaluation Summary:

This is a well-written, well-illustrated and well-conducted study of the immune cell landscape of multiple sclerosis (MS) tissue, with a particular focus on the periventricular region (septum) and choroid plexus, using single cell mass cytometry (CyTOF). Overall the work is an impressive analysis of an understudied cell-type in MS, and represents an important resource. It will be important to follow up to establish how representative the findings are given the heterogeneity of the disease and the limited population studied here.

(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 describes the regulation of ERK1/2, two protein kinases that play important roles in cell signaling, by protein cysteine palmitoylation. The intriguing observations reported here could be of broad interest to colleagues in the field of cell signaling and protein post-translational modifications. Mechanistic understanding is, however, still limited and the work would benefit from additional experimental evidence.

(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:

This paper presents results showing the temporal relationships between deletion of a resistance gene, introduction of antibiotic, and cell growth that are intriguing and novel. It will be of interest to researchers studying heterogeneity in antibiotic tolerance and the origins of drug resistance.

(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 investigates an important topic related to the initiation signals of actions sequences detected in the dorsal striatum. The authors conduct an ambitious set of experiments to study how neural activity in the dorsal striatum relates to the ability to wait for a reward. The study nicely bridges research on striatum's roles in reward-seeking actions and in time processing. Interesting activity patterns are detected that suggest a relationship to the premature versus the timely release of actions. These observations are potentially interesting, in particular, the possible difference between adult and adolescent rats. The functional significance of these activity patterns remain to be 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. Reviewer #1 agreed to share their name with the authors.)

Evaluation Summary:

The present work by Miyao and Miyauchi et al. provides new insights into the heterogeneity of mTEC. With single-cell approaches and the Fucci2a mouse model, they have found a proliferating mTEC sub-population that may be a precursor of mature mTECs expressing the Aire gene. The findings are potentially important for the field.

(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 manuscript shows that CD47, which provides inhibitory signals to myeloid cells via SIRP1alpha, is released in exosomal form by cells expressing it, and these exosomes can stick stably to other cells, resulting in CD47-mediated protection of these cells from phagocytosis by myeloid cells. The data are striking, and would be of interest to researchers working in both mechanistic and tranlational aspects of transplant-related immunoregulation.

(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 manuscript by Elferich et al. describes challenging experiments to visualize components of the hair-cell mechanotransduction complex, especially PCDH15, in unfixed, fast-frozen stereocilia. The manuscript presents exquisite images of PCDH15 in its native state, confirming the predictions of earlier studies. While much of what is presented here was predicted from less-direct measurements, it is useful to confirm these with direct imaging of single molecules.

(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 will be of interest to biologists who study RNA structure-function relationships in a broad range of systems, splicing researchers, and RNA structure bioinformaticians. An integrative analysis of RNA structure probing, model-based RNA folding energetics, cryo-EM data, and protein binding sequence motifs serves as the basis for a comprehensive, accurate, and robust framework for predictive models of splicing dynamics in a well-studied system. The modeling is leveraged by in silico mutagenesis that reveals novel insights into the mechanisms and tradeoffs that underlie the impact of disease-associated mutations on alternative splicing.

(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 report describes a new technique to detect the surface proteome of normal and myc-transformed cells in relation to extracellular vesicles from the same cells. The data obtained from this comparison may be useful in evaluating cell surface and extracellular vesicle marker proteins that may be of diagnostic value. The article could possibly be more interesting if the actual proteomic results of control vs Myc and cells vs extracellular vesicles were more extensively exploited.

(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 work is of interest to scientists studying pathogenesis-associated neutrophil dysfunction. Roy et al. investigated impaired wound healing associated with infected diabetic wounds, a major clinical problem. The data reveal substantial alterations in the functional competence of diabetic or glucose-exposed neutrophils to react to chemotactic signals and provide potential therapeutic strategies to improve neutrophil fitness and improve wound healing. Conclusions are supported by the data but the study, in its current stage, needs further analysis.

(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 manuscript by Lee et al. provides mechanistic insight into the regulatory role of micro RNAs in modulating nuclear receptor expression and function. This is likely to have a high impact on the field as nuclear receptor regulation of metabolic disease is well established, however, the molecular mechanisms governing this process still remains unknown largely. Lee et al.'s manuscript provides a molecular target (miR-20b) that holds therapeutic potential in improving hepatic steatosis.

(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 will be of interest to neuroscientists who wish to understand how descending cortical projections interact in auditory midbrain neurons with their ascending inputs. The results have implications for other sensory systems and potentially other subcortical structures too. The data support the main conclusions of the manuscript, but additional control experiments and clarification of some parts are needed to strengthen the conclusions drawn and ensure that the findings of this interesting study can provide the basis for future modelling 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. All reviewers agreed to share their names with the authors.)

Evaluation Summary:

This study is of interest to the broader audience of cell biologists, as it aims to dissect the hierarchy of protein recruitment and lipid conversion events that may provide a potential mechanism for the formation, maturation and fate of macropinosomes. The conclusions are based on the observation that pharmacological inhibition of the lipid kinase VPS34, which generates the signalling lipid PI3P on endosomes, prevents accumulation of Rab5 on macropinosomes, blocking their maturation and causing them to re-fuse with the plasma membrane.

(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 describes a pipeline to assess the number of a certain cell type in the larval Drosophila brain. Their work provides automated neuronal segmentation and topographical analysis methods for the whole larval nervous system organization in flies, revealing the previously unexpected sexual dimorphism. This paper may be of interest to the large class of neuroscientists and specialists, from those who use larval Drosophila as their study model to others who are generally interested in connectomics and transcriptomics, among others.

(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 the brain is organized to represent various concepts has long been a central cognitive neuroscience research topic. Zhang and colleagues investigated the spatial distribution of feature tuning for different face-parts within face-selective regions of human visual cortex using ultra-high resolution 7.0 T fMRI. The findings complement non-human primate studies of face-selective patches and will be of interest to psychologists and system neuroscientists.

(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 is of broad interest to readers interested in motile cilia and cargo transport mediated by intraflagellar transport (IFT). It examines how radial spokes are trafficked into cilia by IFT, which represents a key process in the assembly of motile cilia. The authors demonstrate that an adaptor protein (ARMC2) is needed for association of radial spokes with the IFT machinery. They also find that the interaction of ARMC2/radial spokes with individual IFT trains (or particles) occurs in a stochastic manner rather than there being a specialized subset of trains specifically designated for a particular cargo. The results support the key claims in the paper.

(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 development, fate and homology of the egg tooth and caruncle of the short-beaked echidna (Tachyglossus aculeatus) and will be of broad interest to workers in the fields of vertebrate evolutionary/developmental biology, comparative anatomy and palaeontology. This manuscript features high quality histological and tomographic data from an unprecedented developmental series of pre- and post-hatching echidna stages. The study is well-organised and clearly reported, though additional image data would strengthen the authors' conclusions.

(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 name with the authors.)

Evaluation Summary:

This manuscript addresses important questions: what is the relationship between circadian and homeostatic regulation of sleep, and how do the circuits underlying these levels of control interact? The authors have designed a very elegant method to answer these questions in Drosophila: a new sleep-deprivation protocol that allows them to test sleep rebound over the course of the day. Interesting observations are made, such as time-of-day dependence of sleep homeostasis, identification of important neural pathways modulating sleep rebound in a time-dependent manner, and molecular and physiological variations that might drive time-dependent sleep homeostasis. Experiments establishing a link between the circadian clock/neurons and molecular and physiological changes observed in sleep homeostat neurons would help to provide support for the claims made in the title and abstract.

(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:

This study addresses a major missing element in the understanding of how bacteria grow their cell wall and the role of lytic transglycosylases in this process. It had been previously assumed these enzymes cut glycan strands to make room for the insertion of new glycans. However, results presented in this manuscript demonstrate these enzymes have a very different, yet essential role in degrading uncrosslinked glycan strands in the periplasm. The authors further demonstrate that in the absence of lytic transglycosylases, cells undergo periplasmic stress due a toxic accumulation of these "free strands" in the periplasm. The work will be of interest to those in the bacterial growth and division field.

(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 data from the 1970 British Birth Cohort study, the authors demonstrated the utility of Generalized Additive Models for Location, Scale and Shape (GAMLSS) to investigate the association of three risk factors (sex, socioeconomic circumstances, and physical inactivity) with body mass index and mental wellbeing. This work provides empirical evidence for why we should consider how risk factors influence the variability and not just the mean of outcomes. From the perspective of developing personalized medicine, it is important to know whether interventions have response heterogeneity as the first step. If such heterogeneity is identified, the next step will be to identify the factors associated with the heterogeneity (or those who will be benefitted from the intervention). Therefore, this study contributes to the first step by investigating the possibility of response heterogeneity.

(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.)