Evaluated articles

Evaluation Summary:

This manuscript identifies the DNA sensor AIM2 as a target of auto-antibodies in the human autoimmune disease systemic lupus erythematosus. Importantly, the authors provide evidence that AIM2 protects extracellular DNA from destruction and propose that this property may enhance the autoimmune response to the DNA and associated proteins. The work may therefore provide an important underlying mechanism for a prevalent and important human autoimmune 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 paper is a milestone towards understanding the formation and representation of visual object structure in the brain. It shows that in the pivotal area V4, border ownership selectivity emerges in the deep layers earlier than in the granular layers which receive the input from V1/V2, indicating that border ownership is not inherited from the input, but computed by deep-layer neurons using visual context information possibly provided through horizontal connections, cortico-cortical feedback or thalamic input. They further report that the preferred side of border ownership across layers is similar, i.e. it is organized in a columnar fashion. The study is elegantly done, with the outstanding questions clearly laid out and the results presented in a clear and informative fashion.

(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 manuscript addresses the role of the Arp2/3 complex in endocytic retrieval of ciliary precursors from the plasma membrane for use in assembly of Chlamydomonas cilia, a topic of broad interest to cell biologists. The manuscript can serve as basis for future research addressing whether Arp2/3 affects cilium biogenesis solely via endocytic retrieval or through additional mechanisms, and whether these findings apply to species other than Chlamydomonas.

(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:

Proteins that form pores in biological membranes are found in diverse contexts, including pathogenic toxins that help infect or lyse target cells and organelles. The study by Nadeem et al. reports on the properties of an α-pore-forming toxin, MakA, produced by the human pathogen, V. cholerae. The study is a remarkable example of a pH-induced structural mechanism of membrane remodeling. The insights reported here will be of interest to a wide range of scientists studying host-pathogen interactions, membrane remodeling, and macromolecular structure.

(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:

The major finding of this manuscript is that cytokinin produced by a bacterial plant pathogen affects bacterial growth and physiology. Production of cytokinin is linked to the well-known type three effector XopQ, which has primarily been studied for its function inside plant cells. The authors provide evidence that XopQ is required for the pathogen Xanthomonas oryzae to produce cytokinin in culture, and that cytokinin production controls whether or not the bacterium engages in planktonic growth or biofilm formation (i.e., biofilms form in the absence of cytokinin). These data indicate that bacterially produced cytokinins affect bacterial physiology, indicating that these hormones control signaling beyond photosynthetic organisms. The findings are of interest both to those studying plant-pathogen interactions and to microbiologists in general.

(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 is a comprehensive study combining solution NMR with molecular dynamics simulations to uncover the effects of three key mutations in the Cas9 HNH domain that increase CRISP-Cas9 complex specificity and reduce off-target activity. Through the analysis of these three different mutations, the authors concluded that by tuning the conformational dynamics of the HNH module in the CRISP-Cas9 complex, it is possible to control the function and specificity of the system. Combined these findings could have important implications for the design of new variants for this important gene editing complex.

(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 will be of broad interest to readers in the field of proteomics and drug discovery. It describes a potentially robust method for the identification of biological targets of small molecules, a substantial hurdle in drug discovery. The experiments described are rigorous and this manuscript provides a useful template for the broad implementation of this method. One conclusion that needs further support is the one of the complementarity of CPP and TPP (as in "these two approaches share much in common, they remain distinct and likely serve to complement one another").

(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:

There has been a lively debate recently concerning the multiplicity of reported observations of phase-separated compartments inside of cells. Specifically, some claims of phase separation have been challenged, and an alternative model put forward in which clustering of observed particles is due to a clustering of binding sites with no phase separation. The current study does an admirable job of proposing and analyzing ways of distinguishing these two scenarios.

(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:

There has been a longstanding interest in developing normative models of how humans handle latent information in stochastic and volatile environments. This study examines recurrent neural network models trained on sequence-prediction tasks analogous to those used in human cognitive studies. The results demonstrate that such models lead to highly accurate predictions for challenging sequences in which the statistics are non-stationary and change at random times. This is a novel and remarkable result that opens up new avenues for cognitive modelling.

(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:

By using modern high-throughput sequencing this paper demonstrates the antibody mediated immune responses that are elicited by vaccination are improved by pre-existing memory CD4 T cell responses. Moreover, the experimental data are an important contribution and may also be useful as a data resource for future research. All reviewers agree that the findings are of great interest. However, there are still some clarifications needed in statistical analytical and validations so they convincingly support 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 #2 and Reviewer #3 agreed to share their names with the authors.)

Evaluation Summary:

This manuscript addresses the role of the deubiquitylating enzyme UCH37 in facilitating proteasomal clearance of branched polyubiquitylated substrates. Using a wide-range of chemical biological, biophysical and cell biological techniques, the authors have convincingly demonstrated that UCH37 binds to branched ubiquitin trimers, with at least one K48 linkage, by binding to both distal ubiquitins attached to the proximal, or central, ubiquitin. They further demonstrate that mutations of UCH37 lead to the formation of proteasomal foci in cells and that these foci are rich in polyubiquitinated species, presumably due to the lack of debranching by UCH37. Overall, this excellent study adds to our understanding of UCH37 function, especially with regard to the newly observed phenomenon of reversible proteasome aggregation in cells. Readers will benefit from the large array of ubiquitin-centric tools that are described to study key aspects of UCH37 function and from knowledge of the specific role of UCH37.

(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 uses primary placental units and villous explants to examine the placental metabolism of vitamin D and effects of vitamin D on placental gene expression. The studies demonstrate that the placenta actively transports 25D, such that the fetal levels are dependent on placental function rather than simple diffusion from the maternal circulation. Furthermore, they demonstrate actions of vitamin D on placental gene expression. This paper should be of interest to cell biologists and obstetricians/gynaecologists studying the role of the placenta in fetal growth and 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. The reviewers remained anonymous to the authors.)

Evaluation Summary:

In this study, Hahn et al. taught crows to perform a working memory task designed to mimic traditional monkey tasks. Using a combination of behavior and electrophysiology, the authors convincingly show that the neural mechanisms that limit working memory capacity in mammals and primates also limit working memory capacity in crows. What makes this finding particularly interesting is that the architecture of the avian brain is dramatically different than the architecture of the primate brain. Thus, two dramatically different architectures give rise to the same behavioral functions and neural computations. Such cross-species comparisons are fundamental to understanding the computational constraints that are placed on cognition and the brain.

(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:

Accumulation of redox-active iron in the brain is a significant cause of neurotoxicity in neurodegenerative diseases of old age. Thus, this manuscript could be of interest to neuroscientists, iron biologists, and those studying mechanisms of aging as it provides some new mechanistic insight on the role of age-related increases in hepcidin in brain iron accumulation. The current study demonstrates increased cytosolic and mitochondrial non-heme iron only in the aging brain, increased local hepcidin expression, and decreased levels of FPN1, together supporting a hypothesis that local brain hepcidin sequesters iron in neuronal cells and is associated with aging.

(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:

Thiery et al. propose that the development of shark teeth employ a similar embryonic signaling center as the development of mammalian teeth. The implication is that the regulatory logic of tooth development is an ancient, shared feature among vertebrates. The research will be of interest to the developmental as well as evolutionary biology readers.

(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:

How was it possible for prebiotic RNA or DNA molecules to reliably self-replicate, in the absence of sophisticated enzymes capable of error correction? This paper proposes a novel mechanism for error correction in templated copying, and is therefore of interest for cell and evolutionary biologists, biophysicists and readers in the field of origin-of-life science. The kinetic error filtering proposed here does not require sophisticated machinery but reduces errors significantly while retaining a reasonable yield rate. Crucial to this mechanism is a cyclically varying environment, such as might exist in hydrothermal vents. The plausibility of the mechanism is supported by thoughtful and rigourous calculations rooted in an experimentally-grounded model.

(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 study uses intracranial EEG to explore links between broad-band gamma oscillations and mood, and their impact on decisions. While the results are potentially interesting, additional details and analyses are necessary to show that results are not driven by confounds. In addition, there is about a major concern that statistics are performed across electrodes instead of across subjects.

(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 provides a novel mouse model for the study of the central respiratory chemoreceptor circuit and, therefore, of interest for the respiratory physiology community. Nonetheless, in its present form, this work still lacks more physiological, developmental, and anatomical characterizations to place this study in a broader context and gain new insights into the physiology of respiratory chemoreflexes.

(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 names with the authors.)

Evaluation Summary:

This paper presents crystal structures of sCoaT, a heavy metal transporting P-type ATPase. These structures and complementary functional data define the overall fold of this protein and provide insight into several mechanistic features, including a conserved histidine proposed to act as a novel counter-ion during transport. The study will be of interest to biochemists and microbiologists interested in the transport of transition metals, structural biology of membrane proteins and drug 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 agreed to share their name with the authors.)

Evaluation Summary:

This study investigates evolutionary changes in ligand preference that occur in an olfactory receptor (IR75a) across the Drosophila phylogeny. The authors find that IR75a displays different odor preferences, for acetic acid or butyric acid, across Drosophila species, and link odor preference to particular protein mutations in the receptor. Reconstruction of a putative ancestral IR75a revises the timeline for IR75a evolution, and structural modeling suggests how mutations alter odor preference.

(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.)