Evaluated articles

Evaluation Summary:

In this manuscript, the authors identify enhancer-associated (e)RNAs that are specifically associated with esophageal adenocarcinoma. Based on combining the data with analyses of patient gene expression data and epigenetic data from cell lines, they conclude that eRNAs are markers of enhancers relevant to the transition from Barrett's esophagus to cancer. This work provides new insights into the epigenetic alterations that occur in cancer progression, and it will be of interest to the cancer and epigenetics fields.

(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 describes results obtained from multi-cellular imaging of CA1 cells using large-field-of-view miniscopes in rats performing a shock avoidance task. By exploiting behavioral (barriers) and pharmacological (scopolamine) manipulations the authors explore cell remapping dynamics during aversive learning. This work will be of interest to the neuroscience community by setting new methodological standards and providing data for across-species comparisons.

(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 current paper is of interest to cell biologists studying ciliogenesis and specifically vertebrate photoreceptors, which are specialized cilia. The study shows that mutations in the small GTP binding protein ARL3 known to cause dominant inherited retinal dystrophies in humans result in ARL3 hyperactivity, disrupting the normal ciliary gradient of ARL3 activity and leading to altered retinal development. The authors demonstrate restored normal nuclear distribution by overexpression of ARL3 effectors, suggesting that the active mutants disrupt nuclear migration, at least in part, by sequestering ARL3 effectors. Overall, the experiments are properly controlled, executed, and analyzed and involve a series of extensive biochemical analyses complemented with in vivo phenotypic assessment. The development of a method to analyze snapshots of the interaction between ARL3 and its interactors is also a strength of the paper, however, significant concerns remain regarding links between nuclear migration failure and ciliogenesis in the outer segment, and alternative possibilities that could explain the phenotype of the ARL3 Y90C mutant with respect to its sequestration of the GEF ARL13B. Addressing these major concerns would improve the manuscript and could have considerable impact on 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. Reviewer #1 agreed to share their name with the authors.)

Evaluation Summary:

The authors show the utility of an AAV-based approach in non-human primates to develop an improved model of Huntington's disease. They have presented a very thorough, carefully executed, body of work that will be of benefit to a range of researchers studying HD or developing therapies for HD. While this extends the work from an earlier paper (that presented the tools used to induce phenotypes) the results presented are new, relevant, and important to the community.

(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 this work, the authors test a multivalent vaccine design they term Mos-tri-RBD, consisting of three linked spike receptor binding domains, one based on Omicron sub-lineage BA.1 and the others with different SARS-CoV-2 variant mutations. Immunization with this construct either as a prime or booster vaccine resulted in better neutralization of the Omicron and Beta variants relative to the same design, but with the ancestral receptor binding domain, and supports the notion that vaccination with variant sequences may broaden the neutralization capacity of vaccines against divergent variants.

(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 investigates the question of whether distinct brain areas differentially encode time during the learning of a simple motor timing task. The key novel result is that early in training the dynamics of the medial prefrontal cortex (mPFC) provides the best code for time, but later in training, the basal ganglia and in particular, the striatum provides a better code. In addition, the study shows that inactivation of mPFC produces a delayed learning effect, while inactivation of the striatum after learning led to impaired performance. The observation that temporal coding and the necessity of brain area for task performance transfers from medial prefrontal cortex to the striatum during learning is an intriguing observation for our understanding of the neural mechanisms underlying temporal processing in sensorimotor control.

(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:

Prior work has linked posterior urethral valves (PUV), a common cause of end stage renal disease in children, with chromosomal abnormalities and rare copy number variants, but the genetic causes of PUV remain incompletely defined. In this study, the authors have used diverse ancestry whole-genome sequencing association studies to identify two novel genes and an enrichment of rare duplications and inversions affecting candidate cis-regulatory elements as possible causes of this rare condition, illustrating the potential for this approach to other rare conditions.

(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 reports a new method for high-throughput analysis of C. elegans feeding behaviour that overcomes shortcomings of existing methods. It is a useful technique that will be interesting for scientists studying feeding dynamics in worms.

(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 manuscript describes cellular and developmental defects at late embryonic stages during Wolbachia-induced cytoplasmic incompatibility (CI), which occurs when male insects harboring the endosymbiont bacteria Wolbachia fertilize eggs of uninfected females, triggering embryonic lethality, usually at the first nuclear division. This work presents evidence that the mechanism of late embryonic defects is independent from the ones responsible for early embryonic defects. The experiments are technically superb, and the strength of evidence provided is compelling, including beautiful single-embryo PCR analyses and convincing light microscopy. While the overall significance might be limited, the knowledge will be useful to those in the fields of cytoplasmic incompatibilities and insect embryo 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. Reviewer #1 and Reviewer #2 agreed to share their names with the authors.)”

Evaluation Summary:

This manuscript, contains fundamental findings that substantially advance understanding of an important research question, mostly uses appropriate and validated methodology in line with the current state-of-the-art, with good support for the claims, and the message of the manuscript will have a profound and lasting influence on neuroscience. In essence, the manuscript reports that dopamine converts spike-timing-dependent synaptic depression into potentiation that requires cAMP/PKA second messenger cascade and protein synthesis. The mechanism enables a separate synaptic input to induce heterosynaptic potentiation in previously primed synapses, which is shown in a network model to have desirable computational properties. The significance of the findings is threefold: First, it is the longest-lasting synaptic eligibility trace identified so far; second, the mechanism enables memory linking between temporally separate events; and third, it indicates a novel function of postsynaptic reactivation events. In addition, the finding may inspire new reinforcement learning algorithms in machine 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. The reviewers remained anonymous to the authors.)

Evaluation Summary:

This work will be of interest to the field of researchers that generate human stem cell-derived kidney organoids to model genetic kidney diseases. It describes a novel and crucial role of the protein CEP83 in mesoderm patterning, which further determines whether kidney tissues can form correctly. Using cutting-edge technologies the authors provide strong data, which support the key claims of this manuscript. This work is of high impact due to the relevance of CEP83 mutations in human kidney disease.

(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 manuscript describes de novo dominant toxic mutations in CRMP1 in 3 probands with a shared neurodevelopmental phenotype. The authors show that the mutations lead to reduced protein production from recombinant expression and that the mutations correlate with shorter neurites in cultured cells. This is the first report of mutations in CRMP1 in humans, encoding a cytoskeletal regulator protein. The results could have implications for physicians, geneticists, neurodevelopmental scientists, and cell biologists.

(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 study is of interest to researchers in the field of cell biology, especially mechanosensing. The work identifies a new context to evaluate the activity of MSL proteins in mechanosensing by identifying two novel suppressors of MSL10 as components of the ER-PM contact sites (EPCS). The work has significance for both the plant and the animal science community providing the basics for various avenues of further research in the area of mechanobiology.

(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 tackles the important question of what proteins regulate asymmetrical cell division in Mycobacteria. This will be of interest to all individuals interested in bacterial physiology. The data are sound, but some of the conclusions need to be tempered or bolstered, in relation to the models proposed.

(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 is an important body of work that addresses the role of the integrated stress response (ISR) and the role of the GCN2 protein kinase in prostate cancer. The studies comprehensively elucidate how GCN2 and amino acid transporters and uptake promote prostate cancer proliferation, as well as the therapeutic potential of inhibiting this pathway. This work, therefore, provides insights for both identification of new mechanisms and experimental therapeutics in prostate cancer.

(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:

Fluid flows in networks are ubiquitous, and in many living systems the networks are not static but instead can rearrange over time. Using vascular networks formed by the slime mold Physarum polycephalum, Marcbach et al. demonstrate that there is a time delay between the change in the flow and the change in the network geometry. They present a mechanical model of vein-radius adaptation leveraging the negative normal stress response of the actin cytoskeletal network lining the vein walls. More generally, the authors make use of the unique advantage of this simple model vascular system to connect the local shear rate to the network reorganisation and how it depends on its architecture. There are features to their work that are new to the literature and that can be impactful in advancing 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:

This manuscript examines the role of transposable element (TE) expression and the transcription factor FOXO on aging of Drosophila melanogaster. Increased TE expression in aged organisms compared to their younger counterparts has been observed in several animals, including Drosophila. Here, the authors show that artificially inducing transcription of a specific TE can reduce fly lifespan and exacerbate some aging phenotypes-paraquat resistance and rhythmicity. The authors also argue that the detrimental effects of increased TE expression can be rescued by FOXO expression, although this is less convincing.

(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 establishes a visually mediated gap-jumping behavioral task in freely moving mice, and shows that mice can perform the task using only monocular cues with little performance deficit, perhaps at the cost of additional active sensing movements before executing the jumping maneuver. Further, using acute optogenetic inhibition, the authors establish that the primary visual cortex is used to perform this task. Using vision to judge distance - such as the width of a gap to be crossed - is crucial for survival across taxa, and this new paradigm could be informative to those interested in using mice to study such vision-based estimation under naturalistic conditions.

(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:

Yang et al. provide a scientifically sound and compelling manuscript characterizing mid-to-late gestation trophoblast and decidual organoids as ex vivo models to study vertically transmitted microbial infections, using human cytomegalovirus as a model pathogen. They demonstrate organoids have tissue-specific immunological responses and susceptibilities to viral infection.

(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 researchers in the fields of motor control, visual perception, learning and brain plasticity, sight loss and rehabilitation. The paper shows the contributions of sensory-motor experience to the development of visuo-motor recalibration abilities using careful experimental methods and analyses, comparing a rare population of late-operated cataract patients with control groups.

(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.)