Evaluated articles

Evaluation Summary:

This paper will be of interest to scientists across translational medicine and cancer treatment. It describes a standardized method to identify drugs that could be potentially repositioned for tumor treatment. In addition, using this new method and experimental manipulations the authors identify homoharringtonine as a new potential therapy for liver cancer and the underlying liver disease. However, while bioinformatic analysis was really comprehensive, the results and conclusions obtained are based on public datasets and therefore limited by the data available. In addition, the experimental approach to test the potential new treatments are currently based on in vitro assays and would be strengthened by in vivo validations.

(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 will be of general interest to basic researchers and clinician-scientists working on the eye and vision, developmental and inflammatory eye disorders, and cell-cell signalling in vascular tissue. Experiments are well designed, the resulting data are of very high quality, and their significance is not over-interpreted. The approach and findings with regard to myopia are quite novel, revealing exciting new possibilities for understanding the visual regulation of eye growth, with some overlap into understanding regulatory mechanisms in inflammation.

(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 aim to understand how certain transposable elements escape chromatin-based silencing. Focusing on variably methylated copies of IAP (VM-IAPs) in the mouse, the authors show that elements that can escape silencing share sequence variations that alter KRAB zinc finger protein (KZFP) binding and KAP1 recruitment, proximity to expressed genes and high CpG content. Analysis of human elements in human KZFP-free mouse cells recapitulates some of these observations. The authors propose that ZF-CxxxC proteins play a role in establishing permissive chromatin at transposable elements that harbor high CpG content and weak KZFP binding. The data are mostly correlative and open the path for further mechanistic analyses. The paper is of interest to readers in the field of epigenetics, genome biology and transposable elements.

(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 manuscript presents a careful study of nervous system regeneration in the larval sea star using new transgenic tools for marking and following cells involved in regeneration. The authors find that these animals can regenerate their nervous system by the re-specification of existing cells, which are induced to express the embryonic neurogenesis program. The experimental approach is robust and creative and the data interpretation sound. For its contribution to our understanding of how cells are induced to contribute to specific cell lineages during regeneration, this work will be of interest to the broad community of researchers inregenerative and developmental 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. The reviewers remained anonymous to the authors.)

Evaluation Summary:

The relationship between homologous chromosomes sampled in a population can be described by an "ancestral recombination graph" or as a "forest" of correlated coalescent trees describing the relationship at each locus on the chromosome. It has long been clear that this graph contains enormous amounts of information about the history of the population, and should be used in analysis. Hitherto this has been computationally infeasible, but recently developed methods are starting to make it possible, and this paper is one of the first attempts to do so. The paper should be of interest to anyone working with population genetic inference, although there are concerns about possible bias in the estimates from the 1001 Arabidopsis Genomes that need to be resolved.

(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 names with the authors.)

Evaluation Summary:

This manuscript aims to address an important issue in the study of concussion: both the brain damage caused by concussion, as well as the behavioral symptoms that result vary widely across individuals. The study uses novel and interesting methods to relate multi-variate diffusion MRI data with multi-variate symptom-related data. The methods of analysis are sophisticated and well-executed and the results are quite interesting. The methods developed here could have broad impact in their application to the many other neurological diseases that have heterogeneous outcomes.

(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:

Sample preparation for single-particle electron cryo-microscopy (cryo-EM) remains a bottleneck of this technique. The sample ice thickness cannot be accurately controlled, molecules may display strongly preferred orientations that make more elaborate data collection schemes necessary, and the sample may degrade at the air-water interface before it is finally frozen. In their pioneering work, the authors describe a prototype of a new microfluidic device that addresses some of these problems, including a refreshingly objective and critical discussion about the pros and cons of this novel approach. While some development will be required for this method to become mainstream, it has the potential to become a powerful alternative to the conventional workflow of single-particle cryo-EM, enabling full automation and making sample preparation highly reproducible.

(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:

Meiotic drivers are selfish elements that distort segregation to be over-represented in offspring of heterozygotes. Multiple meiotic drive elements are known in the yeast Schizosaccharomyces pombe, which can seem puzzling as this fungus has long been thought to undergo moslty same-clone mating because of its mating-type switching system. This manuscript reports theoretical and experimental analyses suggesting that the outcrossing rate can be high enough in this species to explain the spread of multiple meiotic drive elements. The findings support the emerging view that homothallic fungi can undergo quite high rates of outcrossing, which is also in agreement with evolutionary considerations on the evolution of mating types. This study can thus be of high relevance for scientists studying meiotic drivers and/or mating systems and their evolution.

(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 will be of broad interest to those studying adaptive immunity to SARS-CoV-2, particularly with a focus on T cell immunology. The study confirms that mRNA vaccine-elicited T cell responses maintain recognition of peptides derived from VOC, and provides phenotypic characterisation of spike-specific T cells from both convalescent and infection-naive subjects.

(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 a combination of biochemical approaches and yeast genetics, the authors study the function of the DNA double-strand break factor Mer2. The authors show that Mer2 interacts with a meiotic chromosome axis factor (Hop1), nucleosomes, the nucleosome-binding protein Spp1, and the double-strand break factor Mre11 to serve as a "keystone" for meiotic DNA break formation. These findings represent an important step forward in understanding the functions of this highly conserved protein in meiosis.

(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:

Sanchez et al investigate how morphogenetic movements driving epithelial tube formation are patterned to occur with the correct spatiotemporal dynamics, a fundamental question in developmental biology. By correlating dynamic patterns of transcription factor expression with rigorous, quantitative analyses of cell behaviors across the salivary gland primordium, their results suggest Hkb and Fkh transcription factor patterning induces switches in cell behaviors at fixed positions to promote continued morphogenesis of the tubular structure. This mechanism is likely to be more generally important for the development of complex tubular organs.

(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 manuscript describes a novel role of the E3 ubiquitin ligase Mindbomb1 (Mib1), a known key regulator of Notch signaling, in regulating convergent extension movements of the zebrafish gastrula, which are dependent on planar cell polarity (PCP) signaling. The authors show that the ability of Mib1 to modulate PCP is totally dependent on the receptor tyrosine kinase Ryk via endocytosis. This paper will be of interest to scientists studying cell signaling and cell movement.

(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:

Huang et al have identified SOX4 as a key regulatory factor that controls prolactin and FOXO1 transcription factor which in turn regulate decidualization, an important process in embryo development. Further, they have identified that SOX4 also regulates progesterone receptor and dysregulated SOX4-progesterone and ubiquitin ligase HERC4can lead to embryo implantation failure thus explaining the molecular basis of recurrent implantation failure in humans. Overall the study is interesting and the data are very strong. Some concerns noted were the use of immortalized stromal cells, and incomplete nature of studies with human endometrial stroll cells from endometriosis patients, and lack of sufficient discussion in some parts of the text, and whether specific progesterone isofoms are involved downstream of SOX4.

(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 investigates a process by which hair cell stereocilia, the sensory structures that respond to sound in the hearing organ and to head motion or tilt in the vestibular organ, can recover from damage-induced gaps in their actin core, possibly allowing for the rescue of transient hearing loss after exposure to noise. This manuscript will be of strong interest to the inner ear field as well as readers with broader interest in actin cytoskeleton dynamics. Although meticulous controls, a combination of molecular, histological and functional studies and an innovative mouse model generally support the major conclusions of this study, additional controls are needed to confirm the mechanistic claims made in the manuscript.

(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:

HCV is unique in its glycoprotein structure, complex receptor usage and its unusual persistence for a (+)RNA virus. This is a well done study that explains a number of observations regarding receptor usage and how HCV may evade antibody control via HVR1 due to its disordered nature, enable mutation to continually evade antibody responses. This manuscript should be of substantial interest to those in the fields of virus entry, vaccination against human viruses, and the study of how intrinsically disordered regions can play regulatory roles.

(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 developmental neuroscientists who study the early stages of cortical maturation and specialization, particularly in the context of somatosensory and pain system development. The authors suggest that, relative to the infant touch somatotopic map, the infant nociceptive map is more widespread and poorly localised, consistent with infants' poorly directed pain behaviour. However, there are differences in the the implementation of touch and pain conditions and concerns around the analyses that limit support for this interpretation.

(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 defines the role of a divergent mitochondrial-localized isoform of a FASII acyl carrier protein (mACP) in the malaria parasite, Plasmodium falciparum. In contrast to the situation in other eukaryotes, mACP is not involved in fatty acid biosynthesis, but is primarily involved in stabilizing proteins involved in mitochondrial Fe-S complex formation. Analysis of mACP function in these protists indicates that ACP acquired a role in Fe-S complex formation early in eukaryotic evolution and highlights additional components of the Plasmodium respiratory chain that are important for viability.

(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 names with the authors.)

Evaluation Summary:

In this manuscript one novel model was constructed to be predictive of cancer immunotherapy based on three parameters proposed to be associated with treatment efficacy. The parameters are easy to fetch under the clinical setting, so the model is simple for application to help predict potential patients who would benefit from immunotherapy.

(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 will be of interest to scientists studying the large-scale transcriptomic organization of the human brain, and in particular those who have used or plan to use the Allen Human Brain Atlas dataset. The study is well-motivated and novel. The most striking finding is the magnitude of variability that is introduced by different data-processing decisions. The open-source software described in this study is an important contribution to the field and will be of broad utility.

(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:

Using advanced live brain imaging techniques, the authors studied the activities of neurons in the primary motor cortex of mice during a classical conditional task, in which a tone is paired with water reward. They found that distinct types of neurons respond differently to the auditory cue or the reward, and the responses evolve differentially as learning proceeds. This work reveals an interesting role of the motor cortex beyond its well-recognized function in motor control, and suggests distinct functions of pyramidal neurons as well as various interneurons in reinforcement learning.

(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.)