Evaluated articles

Evaluation Summary:

This study will be interesting to a broad audience of neuroscientists, as it reveals for the first time that mutations in klc4, which are known to cause a form of early onset hereditary spastic paraplegia in human, affect specific aspects of neuronal development and nervous system functions. High resolution movies of developing sensory neurons in vivo and behavioral assays support the key findings that klc4 plays an essential role in the control of neuronal morphogenesis and behavior. The data presented in the manuscript are overall of a descriptive nature but provide a foundation for future mechanistic studies aimed at addressing the specific functions of KLC4.

(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:

Whether airway basal cells exhibit extensive cell state heterogeneity and whether this is relevant for their function has been unclear. This study provides important evidence that such heterogeneity exists and may dictate airway basal cell function in a spatially restricted manner.

(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:

The authors made paired recordings from synaptically-connected excitatory and inhibitory neurons in slices of human neocortex and used posthoc molecular methods to identify major classes of the recorded interneurons. The principal finding is that, as found previously in rodent cortex, short-term plasticity of the synaptic connections from excitatory to inhibitory neurons depends on the molecular identity of the inhibitory neurons. This is important, as it suggests that many rodent studies carried out over the past decades are physiologically relevant to humans.

(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 explore how the actin network in the fat body impacts nutrient uptake in multiple ways. Overall, this is an interesting study that sheds light on adipocyte cytoskeletal dynamics and it's impact on nutrient trafficking and fat body storage. The work can be further strengthened by additional validation of tools and data.

(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:

PTPN22 is a protein tyrosine phosphatase which negatively regulates antigen receptor signaling. It has been proposed that several genetic variants of PTPN22 might be loss of function (LOF) variants, leading to hyper-responsive T cell proliferative and effector responses. The authors investigate how the PTPN22 R620W variant, associated with multiple autoimmune diseases, might contribute to breech of peripheral T cell tolerance. This work greatly advances and clarifies ongoing confusion of whether PTPN22 SNP(620W) is a LOF mutant.

(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:

This manuscript offers a valuable transcriptomic data set of known types of adult zebrafish photoreceptors (rod and cones). The study further identifies a large set of differentially expressed transcription factors, many of which still have an unidentified function in photoreceptors. Using CRISPR F0 screening, the study shows that the two tbx2 zebrafish paralogues are involved in photoreceptors specification beyond what is currently known. The study uses a solid methodology and the results will be valuable for researchers interested in photoreceptor biology. At present, however, the manuscript has a misleading title and focus: the analysis of adult photoreceptors can hardly offer a scenario of the transcription factors involved in the specification of photoreceptors.

(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:

The authors show that how high-dimensional neural signals can be reduced to low-dimensional models with variables that can be directly linked to behavior. The reduced model can account for long timescales of persistent activity that arise from transisions between metastable model states. The authors further show that the rate of these transitions is modulated by water temperature according to the classic Arrhenius law.

(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 capacity to flexibly modify our actions in order to seek goals relies upon specific brain regions and neurochemicals. Cerpa et al identify norepinephrine (but not dopamine) within the ventrolateral orbitofrontal cortex (OFC) as key to updating identity-specific action-outcome associations when environmental conditions change. These conclusions are relatively well supported by the data and will be of interest to behavioural neuroscientists studying the function of OFC or noradrenaline signalling, as well as researchers studying associative 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 agreed to share their name with the authors.)

Evaluation Summary:

This is an important paper that uses state of the art technology to address the underlying neurobiology of neuropathic pain, a topic of considerable translational relevance. The study describes changes in gene expression at a single cell resolution in somatosensory neurons following peripheral nerve injury. Bioinformatics analyses were employed to segregate neurons in sub-classes and to derive predictions on potential functions of regulated genes. While the work has considerable strengths, such as the single cell approach, there are also some weaknesses, including the fact that new gene candidates did not undergo functional 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:

This paper is of potential interest to a broad audience across myeloma study and single cell technology, as it implies a major adjustment to our current understanding of pathogenesis and treatment of myeloma. Overall the data quality is good, although reasonable alternative explanations of the data can be identified.

(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 people studying how differentially spliced genes regulate biological processes, and in particular, those interested in the intersection of cell death and immunity. This work offers new insight into how an alternatively spliced protein with a well-known function in cell death regulates the basal expression of genes involved in immunity and sensitizes cells to apoptotic cell death. Overall, the major conclusions are supported by the data but more investigation is needed to support the mechanism by which BAX splicing is inducing the phenotypes observed.

(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.)

eLife assessment

This study is valuable and contains results that are supported by convincing evidence. In the future, the observations could be further strengthened by independent validation, and by looking at larger numbers of patients, as well as by determining whether patient heterogeneity is either contributing to or obscuring certain patterns. The work will be of interest to a broad audience in the oncology and immunology fields as it is on a cancer type that does not respond well to immune checkpoint therapeutics.

eLife assessment

In this potentially important study, the authors attempt to explain why hormone replacement therapy with estrogen is not effective in preventing atherosclerosis in post-menopausal women by showing that iron accumulation prevents the hormone replacement therapy benefit through negative regulation of estrogen receptor expression via Mdm2-mediated proteolysis. The strength of evidence is currently incomplete as control groups are missing and there is a lack of clear-cut evidence that this effect is related to the estradiol therapy in addition to the accumulation of iron in the post-menopausal state. The general public as well as specialists might find this work to be of interest.

Evaluation Summary:

Iago De Castro et al, constitute an exciting study conveying to readers that neutrophil-to-lymphocyte ratio dynamics predict pancreatic cancer pathologic response to neoadjuvant therapy. Specifically, the authors aim to determine the effect of gemcitabine/paclitaxel and anti-Ly6G treatment on stromal T cells and CAF populations. They conclude that neutrophil-to-lymphocyte ratios are associated with survival following this treatment and use animal models to show metastatic effects allied to it. The authors attempt to convey that microenvironmental neutrophils could play a causal role in pancreatic cancer chemoresistance. It was agreed that while the discoveries are very interesting, the public could benefit from the authors improving: the relevance to the human condition, providing a stronger link to fibroblastic cell functional transitions, broadening the discussion regarding previous/related published studies, and strengthening the anti-Ly6G specificity proof within the provided data.

(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 work presents a new model that leverages imaging and non-imaging data for the prediction of the survival of patients with early-stage NSCLC. The new model sought to demonstrate the roles of imaging and non-imaging features in determining high-risk nodes within the graph neural network, and the results have the potential of broad interest to clinicians within the field of cancer and have a high value towards clinical application.

(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 reviewer remained anonymous to the authors.)

Evaluation Summary:

This manuscript presents the first molecular dynamics (MD) simulations of full-length membrane-bound Thyroid Stimulating Hormone Receptor (TSHR). The authors find that its linker region (LR) is disordered, contrasting previous models. While this is largely a solid study that would interest researchers working in computational modeling, thyroid hormone metabolism, and signaling, the rationale for the arbitrarily chosen starting model and unclear mechanistic relevance need to be clarified further.

(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 broad interest to clinicians focused on improving sepsis outcomes. The method developed by the authors can identify 10 common pathogens with species-specificity in 4 hours, thus significantly reducing the turnaround time compared to conventional diagnostic methods. Using their method to identify sepsis-causing pathogens early to guide antibiotic treatment, the authors demonstrate high clinical sensitivity and specificity, and some clinical benefit in a real-world scenario.

(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:

Mutations in MINAR2 causes deafness in human and mice. Loss of function of Minar2 in mice causes a reduction of stereocilia and subsequent hair cell degeneration but the underlying mechanism is unclear. This zebrafish study demonstrated that the Minar2 protein interacts with cholesterol and is localized to the stereocilia of hair cells. The loss of Minar2 reduces cholesterol enrichment in the stereocilia with concomitant accumulation in lysosomes. Thus, this study provides the mechanistic insight of Minar2 and the first glimpse at the importance of cholesterol homeostasis in hair cell 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.)

eLife assessment

This important study reports that a high-fat diet induces biliary epithelial cell proliferation and suggests this may account for the so-called ductular reaction in advanced fatty liver disease. Convincing data support the finding that the transcription factor E2F1 is required for biliary epithelial cell proliferation in mice fed with a high-fat diet, and organoid models indicate that lipid abundance promotes glycolysis in an E2F-dependent manner. These findings are potentially of broad interest to the field of liver biology and disease.

eLife assessment

This is an important manuscript that will be of interest to a broad range of researchers studying immunology, obesity and metabolism, as well as the links between maternal health and pathophysiological responses in the offspring. The comprehensive studies using RNA-seq, scRNA-seq, ATAC-seq and scATAC-seq in human umbilical cord monocytes represent an important resource for understanding the transcriptomic and epigenetic shifts in the monocytes of newborns. The experiments involving stimulation of monocytes with pathogens offer convincing evidence for the dysfunction of monocytes in the newborn.