Evaluated articles

Evaluation Summary:

Wahle and colleagues investigate the pervasiveness of the non-canonical arrangement of axons emerging from dendrites rather than the soma of neocortical pyramidal cells of different mammalian species. Using a variety of anatomical techniques, the authors demonstrate that axons can originate directly from pyramidal cell dendrites in species as diverse as rodents, ferret, cats, pigs and primates. Cross-species comparisons indicate that non-primate brains have a higher proportion of axon-carrying-dendrites (AcD) than did brains of macaques or humans. This paper is of potential interest to a broad range of neuroscientists in reporting the distribution of this non-canonical structure and indicating that primate brains may potentially feature axons emanating from dendrites less commonly.

(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 will appeal to all with an interest in comparative physiology and the molecular biology of age-associated changes in muscle function. The authors draw parallels between aging skeletal muscle in humans and C. elegans, with evidence in support of age-dependent oxidation of the C. elegans ryanodine receptor ortholog, UNC-68, causing loss of the calstabin ortholog, FKB-2. This in turn results in UNC-68 "leakiness", reduced body wall Ca2+ transients and muscle weakness-changes in ryanodine receptor complex structure and function, changes that are similar to those that occur in aging human skeletal muscle despite the dramatic differences in the lifespan of the two organisms. The experimental approaches are generally sound, although the intriguing dataset that is open to multiple interpretations.

(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 infectious disease epidemiologists and modellers working on situational assessment, and public health researchers focused on COVID19 response. Through an informative case study on the Singaporean COVID19 epidemic, the paper provides estimates of case ascertainment under different levels of border restrictions and public health measures, as well as estimates of the effectiveness of contact tracing in reducing transmission. The combination of data from multiple sources with mathematical modeling provides a powerful tool to assess effectiveness of interventions. Some of the key claims of the manuscript - while plausible - are not directly supported by the analyses, and the methods and modelling assumptions require more detailed exposition.

(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 is an interesting manuscript presenting an ex vivo explant model that allows combining live cell imaging with single-cell transcriptomic analyses. Using mouse models with specific fluorescent reporters that can be used to characterize cellular behaviour in the transplanted tissue and mark individual cells, the authors show that this approach can be used to identify transcriptional differences between cells that differ in cellular movement features during epithelial repair after injury. This is a first step to further expanding the description of cellular heterogeneity, including cellular behavioural as well as transcriptomic features. This manuscript is of broad interest to cell biologists as it describes a new method that links cellular behaviour in intact tissues to single cell sequencing. The method, which relies on the use of a transgenic strain, was demonstrated for cell migration in mouse airway regeneration. It begins to bridge the gap between cellular and molecular phenotyping of single cells but the authors should be clearer the limitations of the technique.

(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 will be of interest to scientists working on genome organisation and transcriptional control of myelination during mammalian brain development. The authors combine diverse and complimentary experimental approaches to generate insights into how DNA looping contributes to transcriptional regulation in functionally specialised cell types. The experiments have been rigorously performed and the main conclusions are justified.

(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:

The article introduces a geometrical interpretation for the dynamics and function of certain spiking networks, based on earlier work of Machens and Deneve. Given that spiking networks are notoriously hard to understand, the approach could prove useful for many computational neuroscientists. Here, that visualization tool serves to assess how fragile the network is to perturbation of its parameters, such as neuronal death, or spurious noise in excitation and inhibition.

(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:

The manuscript reports on a new technical advance in fluorescence microscopy with which changes in the oligomerization of an integral membrane protein can be measured in live cells. The method is used to define the initial steps during activation of the IRE1 signaling arm of the unfolded protein response, leading to the discovery that IRE1 exists as a stable dimer in the absence of stress - which is in contrast to inferences from prior work. In response to stress, the protein assembles into a higher-order oligomer (likely a tetramer), an event that is mediated by the IRE lumenal domain and serves as a prelude to autophosphorylation. While the work will be widely noticed and excitedly discussed in the community, a reconciliation between the different results obtained in this study and in prior work, some of which was reported previously by the same lab, is currently lacking.

(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:

Yanai et al. used flow cytometry and methlyation profiling to characterize populations of immune cells in the peripheral blood of male rats, finding age-dependent differences in cell composition and DNA methylation profiles, with marked changes occurring at specific time points (e.g., at 15 months and 24 months of age). This raises the possibility that interventions to modify blood aging may be most effective if done prior to these inflection points. This manuscript will be of broad interest to scientists in the geroscience realm and in particular to those using the aging rat as a model for the aging human hematopoietic system.

(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 reports the results of a transposon inactivation screen to identify essential genes in Mycobacterium abscessus. The authors investigate one hit, the gene encoding the class B penicillin-binding protein, PBP-lipo. They confirm that the PBP-lipo gene is essential despite the presence of a homologous gene and that PBP-lipo is present in other mycobacteria, but not essential in these. They further characterize the consequences of PBP-lipo gene depletion in M. abscessus and demonstrate that the gene product is required for maintaining cell morphology, whilst also participating in a network with other cell wall enzymes. The manuscript will be of interest for researchers working on fundamental aspects of cell wall synthesis in mycobacteria. It may also be relevant for researchers who aim to specifically target M. abscessus using new drugs or drug combinations.

(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 how putative C. elegans H3K9me methyltransferases affect aging by investigating their effects on long-lived daf-2 mutants. They surprisingly find that modifiers of H3K9me1/2, but not H3K9me3, can synergistically extend the lifespan of daf-2 (in some cases, to three times as long as wild-type). They demonstrate that this synergistic effect on lifespan requires the DAF-16 transcription factor and some of its downstream regulatory targets, and compellingly, they show that the effects on lifespan are phenocopied by a small molecular inhibitor known to target a conserved H3K9me1/2 HMT.

(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 study employs cutting-edge, multiview light-sheet microscopy and advanced image analysis to investigate how the mechanical interplay of two adjacent tissue layers shapes a developing organ. The finding that genetically-patterned calcium pulses induce local muscle contractions that constrict and fold the adjacent endoderm offers a novel mechanism by which genetically encoded patterning information shapes organs across tissue layers.

(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 provides well documented and solid biochemical data to show how phosphorylation of AGO2 modulate its binding to target mRNAs, releasing the complex to allow its recycling in the cell via electrostatic repulsion. This result could explain how a small amount of Ago proteins could target a very large number of mRNA molecules . The data support the key claims of the manuscript, and the approaches used are rigorous. This very well-written and elegant study will be of great interest to those working in the miRNA field as it addresses important open questions concerning the dynamic regulation of mIRNA-mediated gene repression.

(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:

Smith et al. examine jaw development across three different species of birds, chick, quail and duck, all of which have jaws of different shapes and sizes. This study provides interesting new data and insights into jaw development and 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. The reviewers remained anonymous to the authors.)

Evaluation Summary:

The manuscript by Li et al. identifies the polyether ionophore nanchangmycin as a novel anti-fibrotic compound through a comprehensive chemical library screen. Given the lack of clinically available treatments for liver fibrosis, the anti-activation properties of nanchangmycin could represent a novel therapeutic avenue for the treatment of this 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 #2 agreed to share their name with the authors.)

Evaluation Summary:

The manuscript by Kanda GN, Natsume T et al. describes a robotic artificial intelligence system with a batch Bayesian optimization algorithm that allows to optimise and reliably repeat cell culture protocols. The authors utilise induced pluripotent stem cell-derived retinal pigment epithelial cells as a model culture system of broad interest in regenerative medicine. They demonstrate that the robotic system with Bayesian algorithm accelerates the optimisation of cell culture protocols and increases the quality and quantity of cell products, compared with manual operations - these results will likely inform and strongly impact modern cell culture strategies in regenerative medicine.

(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:

In this paper, the authors demonstrate that the macrophage efferocytic response in SARS-CoV-2 infection is compromised for two reasons. Internalization of apoptotic SARS-CoV-2 infected cells leads to: 1) A proinflammatory as opposed to an anti-inflammatory response; and 2) reduction in macrophage capacity to perform further efferocytosis

(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 rigorous, carefully designed and executed functional magnetic-resonance imaging study provides compelling evidence against a rigid, fixed model for how working-memory representations are maintained in the human brain. By analyzing patterns and strength of brain activity, the authors show that networks for maintaining contents in mind vary depending on the task demands and foreknowledge of anticipated responses. This manuscript will be of interest to scientists studying working memory, both in humans and in non-human primates.

(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 will be of interest to cognitive and developmental neuroscientists who are interested in brain oscillations and their changes with development. This study decomposes the EEG alpha power, demonstrating the confound of aperiodic activity in true oscillatory power and elucidating opposing relation of periodic and aperiodic components with age. The main approach of this paper is well motivated, and the main conclusions are supported by the analysis, which is applied to multiple large datasets, though there are some minor issues with some of the follow up analyses. Overall, this manuscript makes a timely and important case for the consideration of aperiodic signals in future research.

(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 is a very significant new model for papillomavirus infection but all the reviewers have major reservations about the data as they stand, and the quality of some of the data. The manuscript is not publishable without better/more data and a re-write. The work has potential but there is quite a bit of essential experimental work required to make this manuscript sound.

(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:

Persistence of the viral reservoir is hampering HIV cure and thus understanding how these cells persist is important. This study describes a possible way that HIV-infected cells in the reservoir may escape antibody killing. The reservoir cells tend to have less availability of a receptor that binds HIV antibodies that would ordinarily help in killing. These cells are not only less susceptible to antibody killing but also seem to be susceptible to proliferation, which helps maintain the reservoir.

(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.)