Evaluated articles

Evaluation Summary:

This paper provides a new approach, Mixed Neural Likelihood Estimator (MNLE) to build likelihood emulators for simulation-based models where the likelihood is unavailable. The authors show that the MNLE approach is equally accurate but orders of magnitude more efficient than a recent proposal, likelihood approximation networks (LAN), on two variants of the drift-diffusion model (a widely used model in cognitive neuroscience). The comparison between LAN and MNLE approaches could be improved to strengthen the merits of the proposed approach over existing alternatives.

(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:

Previous studies found that a component of the microbiota, Lactobacillus plantarum, can provide support to its host Drosophila melanogaster during development. They further explore this interaction using defined diets where they find that under conditions that have low levels of some essential amino acids, the bacteria can still promote survival even though the bacteria is not synthesizing the amino acid. Through a screen of bacterial transposon insertion mutants, these authors identify bacterial transfer and ribosomal RNAs as necessary for this effect. And studies in the fly demonstrate that the host kinase GCN2, a protein known to associate with host tRNAs, in enterocytes is the mediator of this response. This manuscript links the intestinal microbiota to host protective responses.

(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:

Overall, these authors show that BDNF at the axon terminal can be retrogradely transported to promote new protein synthesis in the neuronal cell body and regulate dendritic morphology, which requires activated TrkB, Akt and mTOR in the soma and nuclear phospho-CREB. Although target-derived neurotrophin effects are well-established in the peripheral nervous system, this mechanism of signaling is less well-understood in the CNS. The manuscript presents a comprehensive analysis of the retrograde transport of BDNF/TrkB from the axon terminal to regulate dendritic morphology.

(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 name with the authors.)

Evaluation Summary:

This work is relevant to all who are interested in genome editing. The versatile Cas9 nuclease has enabled creative genome editing applications, yet the targetable sequence space is limited by the PAM specificity of the Cas9 RNP. This manuscript expands the Cas9 toolbox by defining the PAM specificity and genome editing activity of a large group of smaller-sized type II-C Cas9s. The results also contribute to our understanding of the diversity of Cas enzymes and show that there is a significant potential in mining for non-trivial genome editing tools amongst highly similar Cas orthologs.

(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 is an important paper describing the work to develop defined surface coatings for cardiac cell differentiation. The described experiments are convincingly supporting the critical role of fibronectin (FN) in the formation of precardiac mesoderm. The exploration of FN as necessary for pre-cardiac mesoderm formation was explored using various other ECM conditions, endogenous FN knock-out, blocking antibodies against integrin subunits, and inhibition of ILK via small molecule cdp22. In the case of the FN knock-out, experiments included rescue conditions that established a causal link between FN and the formation of precardiac mesoderm. Particularly insightful was the tracking of FN deposition over time with or without exogenously provided FN (i.e., the LN-111 case). This work is of interest to developmental biologists, stem cell biologists, and engineers as they work to optimize defined matrices for differentiation and manufacturing protocols of all cell types including cardiomyocytes.

(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 analyzes data from 150 previously published phylogenies of plants and animals from the Neotropics. A range of diversification models is fit in order to characterize patterns of diversification through time and across space. The authors reveal five biogeographic provinces within which long-term diversification has occurred, but they find that contrasting patterns of diversification for lineages are better explained by their phylogenetic relationship than by biogeographic province, such that the observed modern diversity of seed plants and tetrapods is a consequence of the groups' contrasting diversification dynamics. This paper is of potential interest to a broad audience of biologists who are working on the evolution of large-scale biodiversity, diversity hotspots, lineage diversification, and biogeography.

(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:

Kim et al. investigate interactions between Seipin transmembrane domains and triacylglycerol using molecular dynamics simulations. They identify the leading steps in droplet formation and provide a physical basis for understanding the initial phases of this process, highlighting the importance of transmembrane helices in the function of seipin protein. This paper will be of interest to cell biologists and biophysicists aiming to unveil and understand how lipid droplets are formed inside cells. The topic is important given that lipid droplets are key organelles used for energy storage, and that the failure in their formation can result in various metabolic diseases.

(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 provides a novel insight into regulation of osteogenesis by ERK-mTOR pathway. The authors proposed that the effect of Erk pathway would be mediated mTOR2-SGK1. The mitochondrial metabolisms appears to be involved in this regulation. This study is well performed, and the manuscript is clearly written.

(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 is an elegant imaging experiment in humans that shows that visual area hMT+, but not other candidate brain areas, signal the perceived motion path in a visual drift illusion. Using a powerful computational decoding approach, the results show a perceptual representation of the illusory position in space for moving stimuli even when the actual retinal position of the stimulus is kept stable. Such a representation and the underlying neural mechanisms are of broad importance for our understanding of the neural basis of sensory perception.

(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 manuscript, the authors map the cellular landscape in the tongue, which is an underrated immunological organ, with a main focus on tissue-resident myeloid cells under homeostatic and inflammatory conditions. They identify two major subsets of macrophages, which occupy distinct anatomical niches and develop from local precursors, while under immune compromised conditions they can also be replenished from circulating hematopoietic precursors. These findings provide an important basis for future investigations of the tongue immune function in the context of infection, inflammation, and neoplastic diseases.

(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 authors study the important problem of how to achieve accurate oscillation robustly in biological networks where noise level may be high. The authors adopted a comprehensive approach and study how different network configurations affect oscillation. This work makes an important contribution to the field, as it offers the first comprehensive survey of networks motifs capable of oscillation, with further characterization of their robustness.

(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 employs a diverse array of approaches including single cell RNA sequencing, bioinformatic analyses, and whole genome bisulfite sequencing to propose a mechanism underlying their findings that will interest scientists broadly in fields of metabolism, development, and epigenetics.

(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:

Nagle and colleagues studied the determinants of key physical properties of multicellular assemblies, using magnetic flattening of spheroids. Their key and insightful result is that intermediate filaments could also be implicated in the setting the elastic properties of these assemblies, shedding light on this central cellular component and how their modifications could be important to the understanding of some pathologies. The paper would be strengthened by additional experiments to better support the claims.

(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:

Genetic forms of deafness are a major health challenge. This study deciphers the cochlear roles of Repressor element 1-silencing transcription factor (REST), a gene involved in the DFNA27 dominant form of deafness, using the mouse as a model system. This study provides evidence for a pathophysiological mechanism of deafness and shows how genes involved in different forms of deafness may interact together. The manuscript will be interesting to readers who work in the field of hearing research, REST regulation, or Kv7.4 regulation.

(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 develops a new method to probe protein-protein interactions using proximity-assisted photoactivation, in which a receiver fluorophore (longer wavelength) can be photoactivated by the excitation of a nearby sender fluorophore (shorter wavelength). This new method is validated through in-depth characterization, comparison with FRET, and application to known systems of protein-protein interactions. While the new method bears the potential to expand the tool kit for probing protein-protein interactions, further characterizations of its photoactivation properties and comparisons with existing methods would be needed to inform researchers interested to apply this method to their own systems.

(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 name with the authors.)

Evaluation Summary:

Kinetochores are large protein complexes that mediate faithful chromosome segregation in eukaryotes. The authors develop an in vitro system to study interactions between kinetochores and microtubules in yeast cell extracts and detect a role for a kinesin motor protein in the generation of kinetochore movements. This paper should be interesting to researchers working in the field of mitosis, molecular motors, the cell cycle, the cytoskeleton, and, more broadly, for those studying macromolecular complexes with reconstitution and in vitro imaging approaches.

(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 name with the authors.)

Evaluation Summary:

This manuscript is of interest to neuroscientists willing to deepen their knowledge related to the role of the insula and to any scientist interested in oscillatory activities. The substantial dataset and the novel methodological approach provide interesting insights on the functional organization of this brain region.

(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 should be of broad interest to all virologists and many students of molecular genetics. It examines the constraints in a part of the HIV 1 genome that encodes important functional regions of two proteins, Rev and Env, in overlapping reading frames. It is convincingly shown that functional segregation occurs in a part of the overlap region that is critical for both proteins, which has important implications for HIV biology and may aid in the design of future HIV therapies.

(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:

DNA replication forks can become arrested either in a cellular program or by accident. In fission yeast, DNA replication fork arrests at the locus called the RTS1 are mediated by a DNA binding protein, Rtf1. In this paper, by combining genetics, proteomics, and genomics approaches, the authors nicely showed the role of Rtf2 as a fork barrier to mediate the splicing of rtf1 mRNA. The splicing-mediated control of protein abundance provides a new regulatory mechanism for the programmed DNA replication barrier.

(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 paper addresses how cells can robustly maintain direction during movement by ignoring noise in concentration gradients while also being able to adapt to new signals in those gradients. The authors study this tension in EGFR signaling by postulating a form of cellular memory in a theoretical framework based on dynamical systems and bifurcation theory. The authors also carry out experiments that raise interesting unresolved questions. This paper will be of interest to scientists of all stripes working on cell motility and for theorists who take a dynamical systems view of biological phenomena.

(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.)