Evaluated articles

Evaluation Summary:

Roux and colleagues measured spiking activity and local field potentials predominantly from the hippocampus and also a few surrounding structures in the medial temporal lobe from patients with pharmacologically intractable epilepsy while the patients performed a cued-recall task. They report differences in local spike-field coherence measurements between hits and misses in the gamma frequency band and differences in both local and distal spike-field coherence measurements between hits and misses in the theta frequency band. The authors further report differences in the timing of spikes between pairs of neurons, with hits correlated with putative downstream neurons firing about 30 ms after putative upstream neurons and misses correlated with delays of about 60 ms. Overall, these are interesting observations that provide intriguing data to further think about how neurons in the medial temporal lobe correlate with recognition memory.

(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:

In this important paper, Chen and colleagues identify a species of fungus, Ophiocordyceps sp. BRM1, that is able to grow on Aglaia sp. plants despite their production of rocaglate inhibitors of the eIF4A translation initiation factor. Through a series of solid experiments, the authors identify an amino acid substitution encoded in the fungal eIF4A gene that preserves eIF4A activity in the presence of these compounds. The authors conclude the substitution evolved to bypass this defense mechanism, similar to the way in which the plant itself bypasses it. The work will be of interest to fungal biologists and colleagues studying plant-microbe interactions.

(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 article may be of interest to researchers working on predator-prey interactions in the fields of biomechanics and neurosensory biology. It presents a mathematical model that outputs possible escape trajectories given parameters relevant to the predator-prey system of interest. The premise of the modeling is attractive, as it includes the time required for prey to turn, but the methods as presently reported raise questions about the validity of some of the 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 agreed to share their name with the authors.)

Evaluation Summary:

Embryonic behavior is a widespread phenomenon that remains poorly understood in any system. Ardiel et al. describe new quantitative methods for imaging late embryo behavior in C. elegans, which will be of great interest as a technical innovation. They identify a novel rhythmic behavior (which they call slow wave twitch) in very late embryogenesis that includes repeated periods of quiescence, and show that this behavior depends on a known pro-sleep neuron and neuropeptide. Although the biological function of the rhythmic sleep behavior is unclear, it has the potential to serve as a model for understanding the mechanisms and purposes of sleep in other model organisms.

(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 valuable paper addresses an important question about the neuroanatomical markers of individual and sex differences in sleep spindle frequency. The authors report associations between an anatomical marker - the length of the white matter fibre bundles underlying the thalamocortical loop and sleep spindle frequency, and highlight that the length of the white matter projections from the thalamus to the frontal cortex mediates sex differences in the sleep spindle frequency. This work advances the field of sleep and brain research by showing for the first time the association between the anatomy of a specific brain network and specific functional characteristics.

(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 study the requirement for Lis1, a dynein binding protein, in T cells, and present solid evidence that the requirement differs between different T cell lineages, suggesting cell division mechanisms differ across these cell lineages. This work is valuable for cell biologists and immunologists interested in mechanisms that contribute to cell proliferation and differentiation.

(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 researchers working in chronobiology and metabolism. The authors have found evidence that starvation decreases the abundance of the fungal circadian clock protein white collar complex (WCC), even though WC-1 is required for responses to starvation. This observation is interesting, but the authors should consider that WCC has several other functions (as a light receptor, in transcriptional regulation) that are not necessarily clock connected. As such the most interesting result from this paper is that the standard model for the molecular mechanism of the fungal circadian clock does not explain the persistence of normal rhythms under extreme starvation conditions, where the levels of clock proteins are drastically altered.

(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 manuscript, Li et al directly compare different editing strategies for human pluripotent stem cells. They demonstrate that prime editing is more efficient and precise, compared with double-strand break-based methods. They also confirm the suitability of prime editing for the introduction of different mutations related to Parkinson's disease as a model.

(This preprint has been reviewed by eLife. We include the joint public review 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 article is of potential interest to researchers working on primate social behaviour, as it presents a novel mechanism for how an association with non-relatives can be favoured under kin selection. In a wild mandrill population, mothers are observed to preferentially lead offspring to associate with paternal half-sibs, a potential mechanism for encouraging nepotistic interactions between their offspring and other members of their group. The authors' explanation for their results was considered to be only partially supported by the data and a more measured and nuanced presentation would be appropriate.

(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:
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This manuscript employs in vitro studies and elegant mouse models to detail how specific pyruvate kinase isoforms impact pancreatic beta-cell ATP/ADP levels, ATP-sensitive K+ channel (KATP channel) activity, calcium handling, and insulin secretion. This is an important study that challenges the current paradigms of KATP-channel regulation, the major signaling mechanism through which pancreatic beta cells couple blood glucose levels to insulin release. Future studies will be necessary to determine whether similar mechanisms are used in human pancreatic beta cells.

(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:

This work explores a topic of high interest to cell and cancer biologists - the role of actin polymerization, and here specifically the role of fascin, in the nucleus. The authors show that fascin regulates nuclear actin, chromatin organization, response to DNA damage, and demonstrate the need for control of steady-state nuclear levels to avoid cell death. Studying nuclear actin is technically challenging, and the authors deploy some novel technologies towards this goal. There are some very elegant experiments in this paper that suggest fascin has an important role in regulating nuclear actin and other important aspects of cancer cell behaviour. The work could be enhanced by the authors considering adding some additional experiments and providing clarifications and some further details or discussion.

(This preprint has been reviewed by eLife. We include the joint public review from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. All three Reviewers agreed to share their names with the authors.)

Evaluation Summary:

This paper provides evidence on public opinion from six European countries on key attributes according to which they believe COVID-19 vaccines should be prioritized. The paper presents significant and valuable findings supported by solid 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. The reviewer remained anonymous to the authors)

Evaluation Summary:

This work will be of interest to biological and clinical specialists interested in the fields of behavioural neuroscience, biological psychiatry, neuroendocrinology, and developmental psychology for its focus on the origins of adult aggressive behavior in early life stress. The authors used an unbiased transcriptomic analysis and identified the thyroid hormone system as a potential mediator of the enduring impact of early stress and aberrant aggressive behavior in adulthood.

(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 extends previous work from the same group on the mechanism of 5' splice site recognition using co-localization single-molecule spectroscopy. There are three important conclusions: 1) the association of the U1 snRNP with the 5' splice site is largely determined by the snRNP itself and does not require other splicing factors; 2) sequence features of the 5' splice site determine whether a short-lived complex with U1 dissociates or transitions into a longer-lived, "productive" complex, potentially mediated by stabilized contacts with U1 associated proteins; and 3) the ability to form the longer-lived complex cannot be accurately predicted by base-pairing potential alone, as presumed by many predictive algorithms. Currently, a test for the role of specific protein-RNA contacts is lacking; additionally, a comparison with other nucleic acid recognition events is missing, particularly those also showing a two-step binding mechanism. This work will be of interest to colleagues in the splicing field as well as to others in fields where nucleic acid recognition by snRNPs plays a major role.

(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 is an excellent manuscript that addresses the role of the molecule (RETICULON 1A / RTN1A) in the biology of human Langerhans cells (the epidermal resident dendritic cell). The study shows that RTN1A critically regulates the retention within the epidermis versus the emigration from the epidermis of these cells. Since Langerhans cells are central in the induction of immune responses (e.g. in vaccinations, allergic hypersensitivities) as well as in the maintenance of immunological tolerance (e.g. in autoimmune diseases of the skin) this manuscript will be of wide interest to the scientific community working in the fields of immunology/vaccinology, dermatology, cell biology and beyond.

(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:

Goering and colleagues investigate subcellular RNA localization across different cell types and species. The major insight is that there may be general mechanisms and specifically conserved proteins that regulate RNA localization in diverse cell types and morphologies. This manuscript will be of interest to those studying gene expression and how its regulation occurs within the cell.

(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 article constructs a four-step assessment of the informativeness of a clinical trial that measures its feasibility, reporting, importance, and risk of bias. This is a potentially highly relevant methodology for the class of trials for which it is defined, namely 'clinically directed randomized controlled trials'. It could also be translated and validated in other areas, using data from a wider set of sources beyond the trial registry clinicaltrials.gov. However, the extended longitudinal nature of the assessment and its potential subjectivity limit this tool's utility to being a retrospective diagnostic rather than as a prospective diagnostic and/or fix for at-risk designs.

(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 three Reviewers agreed to share their names with the authors.)

Evaluation Summary:

By integrating in silico predictions and mass-spectrometry, this manuscript tackles the problem of annotating the currently nameless stretches of genomic sequence that actually code for proteins. The hundreds of protein coding fruit fly genes described here offer new inroads for studying some of the very youngest functional elements in genomes, particularly those that have recently emerged from non-coding DNA sequences. To clarify the biological significance of the present study, the authors should both highlight the genes mostly like to encode functional products and conduct a comparison to published datasets that used different methods to identify such genes in fruit flies.

(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 manuscript, the authors explore the circuit mechanism underlying mating-induced change of odor preference in Drosophila. Olfactory cues during mating induce a long-lasting increase in attraction to polyamines in female flies. The authors use a combination of neurogenetics, imaging, and behaviour to identify elements of the mushroom body and lateral horn circuitry involved in this behaviour. The importance of mushroom body plasticity in female postmating changes highlights a novel pathway for these changes and reveals the variety of mechanisms by which the brain can encode experience and adapt behavior. This paper will be of interest to scientists within the field of reproductive behaviors and neuroscience of internal states.

(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 increased use of gene and exome sequencing of individuals for diagnostic purposes has led to the identification of numerous single nucleotide variants (SNVs). However, annotating the probable clinical significance of every newly identified variant relies on multiple criteria, and in silico predictions can be used by curation experts to classify variants in databases. Since the reliability of such predictions is of paramount importance, this study compares the performance of 31 computational tools in classifying the pathogenicity of SNVs in the human adult globin genes and proposes an improved approach to achieve balanced predictions. The paper will be of interest to scientists and clinicians in the field of hemoglobinopathies.

(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.)