Evaluation Summary:

The paper was viewed as generally sound. There main concern was that the findings were viewed as incremental without a demonstration of a link between the heritability of pRF properties and visual perception. The speculation in the Discussion about shared perceptual experience is intriguing, but psychophysical (or other) evidence would be needed to really make that point clearly. In addition, there was some discussion about the non-independence of vertices and correlation values. In the end, we all agreed that non-independent vertices may inflate correlation coefficient values, but that this is unlikely to substantially affect conclusions drawn from comparisons of monozygotic and dizygotic twins.

(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 new work utilizes several elegant genetic mouse models to evaluate the importance of the mitochondrial fusion protein OPA1 in thermogenic brown adipocytes. This well-written and rigorous study sheds insight into the importance of OPA1 in brown adipocytes and also uncovers an unexpected compensatory mechanism that ensures thermoregulation in mice.

(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 association between metrics of malaria transmission based on prevalence of existing infections and the incidence of new infections has epidemiologically important consequences for malaria control and elimination efforts. The association between P. falciparum entomological inoculation rate and parasite prevalence has been previously characterized, and this report evaluates the added-value of spatio-temporal models to such analyses.

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Evaluation Summary:

This paper will be of interest to a broad audience of developmental biologists and molecular biologists in the field of transcriptional control and epigenetics. It evaluates the pioneer factor activity associated with GAGA-Factor during the process of zygotic genome activation. The experiments are rigorously performed and the data analysis supports the conclusions.

This manuscript is in revision at eLife.

(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, we agree that this new method is potentially impactful although the full versatility of the approach is currently unclear for several reasons. We appreciated the application of the approach to distinct systems and also the relatively low cost of this technique. The diagrams presented (particularly in Figure 3) nicely convey the steps in the protocol with expected sample outcomes to further facilitate the ability of other researchers to employ hamPCR. Overall, we are very positive about this work, but given that the impact of this paper rests on whether or not the technique is widely adopted, some revisions will lower the barrier to entry for future researchers to adopt this approach.

(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.)

Summary: This work uses electro-encephalographic (EEG) recordings combined with an interesting experimental approach to measure temporal expansion/compression. Specifically, the question addressed here is whether adaptation to visual motion affects perceived duration, and if so, how spatially confined these effects are with respect to the processing of the stimulus in early visual areas. The authors find consistent evidence that a visual reference is judged as shorter/longer depending on a previous adaptation. They report several EEG analyses suggesting the early visual activity is correlated with such temporal distortions. This manuscript is of potential interest to cognitive neuroscientists specifically interested in temporal aspects of visual processing and time perception. Although the paradigm is well suited to assess the authors' question, the behavioral data as well as the electrophysiological analyses show important shortcomings currently hindering the interpretation of the results, and necessitating substantial revisions to the current work. Additionally, further methodological details are required to strengthen the manuscript.

Evaluation Summary:

Increasingly, neuroscience experiments require immersive virtual environments that approximate natural sensory motor loops while permitting high-bandwidth measurements of brain activity. BonVision is an open-source graphics programming library that allows experimenters to quickly implement immersive 3D visual environments across display hardware and geometry with automated calibration and integration with hundreds of different neural recording technologies, behavioral apparatuses, etc. BonVision standardizes sharing complex, closed-loop visual tasks between labs with vastly different equipment, provides a concrete and easy way to do so, and should be of interest to a wide array of visual systems neuroscientists.

Evaluation Summary:

Using mice fed with high fat diet (HFD), Boroumand et al. observed a link between bone marrow (BM) adipocyte whitening and the expansion of BM Ly6Chi monocytes and derived cells in the adipose tissue. By adopting an in vitro approach, they also show that BM conditioned medium is able to metabolically rewire Ly6Chi monocytes notably concerning mitochondrial fission/fusion gene expression. They conclude that early changes in the BM adipocytes induced by HFD drive the activation of monocytes and influence the outcome of the disease.

This study is of interest to those investigating BM adaptations to lipid signals as well as macrophage biologists interested in macrophage recruitment and differentiation in the context of obesity and beyond in inflammation.

(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 links a critical physiological function of the skin, wound healing to the ability of skin cells to migrate and the modification of migration by the mechanosensitive ion channel Piezo1. The topic of the manuscript is timely, relevant and would be of interest to a broad audience. The experimental design followed by the authors is straightforward and elegant, and the majority of the conclusions are well supported by the results.

(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 of interest to readers in the field of Microbiology and the control of microbial infectious diseases. The authors address the challenge of antibiotic resistant bacteria with an innovative anti-virulence approach using monoclonal antibodies against a Staphylococcus aureus lipid flippase involved in tolerance to cationic peptides. The work indicates that this approach could re-sensitize antibiotic resistant S. aureus and diminish the severity of infections.

(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 greatly expands our understanding of an aggressive subtype of lung cancer. The author use in vivo cancer models and extensive analysis of the cancer cells states to uncover aspects of differentiation, drug responses and pathway activation. Findings of the study will help in the development of lineage-specific targeted therapies against cancers.

(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 describes the transmission of Trypanosoma brucei by the Tsetse vector. As part of these studies, the authors discovered that (i) a single parasite is sufficient for transmission and (ii) two stages of the Trypanosoma brucei life cycle (slender and stumpy forms) can be transmitted by the Tsetse vector - although the stumpy form developed more rapidly into proliferative parasites in the Tsetse midgut. The results are unexpected because it was previously thought that only stumpy forms were important for transmission.

(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 use imaging analysis of Arabidopsis developing ovule primordia until the onset of meiosis to clarify the importance of organ morphogenesis in cell fate. They first document the growth of ovule cells in three dimensions, then use computational modelling to predict factors underlying ovule growth, shape and spore mother cell (SMC) differentiation. They test this model through analysis of a mutant of Katanin, encoding a microtubule-severing protein. Overall, this work is elegant, adds new information and confirms previous hypotheses for the field. A well appreciated feature of this paper is OvuleViz, an R-based software tool that they developed, which will provide a consistent way for others to analyze mutants with similar phenotypic abnormalities.

(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. The reviewers remained anonymous to the authors.)

Evaluation Summary:

This manuscript will be of broad interest to readers in the field of neuroscience. The authors use a serial section transmission electron microscopy data set to trace out the entire neuroendocrine system of a maggot from its sensory input to neuroendocrine cells. It highlights the complexity of brain circuits, describing how parallel processing systems can lead to a multitude of different input combinations for different neuroendocrine cell types and subcircuits. They provide interpretations about functionality of one of described neural circuits. While the analyses are generally rigorous, the functional interpretations need more supporting 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. Reviewer #1 and Reviewer #3 agreed to share their names with the authors.)

Evaluation Summary:

This paper demonstrates the involvement of Kinase Suppressor of Ras 1, a protein that acts as a scaffold in the mitogen activated protein kinase (MAPK) signaling cascade, in translational control of epithelial-to-mesenchymal transition. The analysis is thorough and includes both loss-of-function and gain-of-function studies. This study advances our understanding of cancer development.

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Evaluation Summary:

This manuscript will be of interest to cancer biologists studying cell fate transitions, particularly adenocarcinoma-to-small cell transitions that occur in prostate and lung cancer, which is a timely topic. While there is not a single linear mechanism identified that fully explains Kras-induced neuroendocrine cell fate suppression in all contexts, multiple new findings will likely be built upon by the field. Overall, the data are properly controlled and the key claims are supported.

(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 reviewers agreed to share their names with the authors.)

Evaluation Summary:

This manuscript describes an interesting regulatory mechanism that activates SARM1, an enzyme that degrade NAD+ and promote axon degeneration. Previous structural and biochemical studies mostly focus on how SARM1 is auto-inhibited at basal conditions and this manuscript provides evidences supporting that phase transition could promote its activity, thus providing new understanding about its regulatory mechanism. The finding also enables in vitro assays to be carried out more easily and thus could facilitate the development of small molecule modulators of SARM1 for therapeutics purposes.

(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.)

Summary: In this paper, the authors proposed a new approach by mounting a PDMS microwells of specific sizes on agar surface to confine swarming and planktonic SM3 cells. They found swarming bacteria exhibit a "single-swirl" motion pattern and concentrated planktonic bacteria exhibit "multi-swirls" motion pattern in the diameter range of 31-90 μm. The phase diagram shows that in smaller wells concentrated planktonic SM3 forms a single vortex and in larger wells swarming SM3 also breaks into mesoscale vortices.

In addition, they conducted systematic experiments to explore parameters defining the divergence of motion patterns in confinement including cell density, cell length, cell speed and surfactant. They concluded that the single swirl pattern depends on cohesive cell-cell interaction mediated by biochemical factors removable through matrix dilution.

This paper gives a new method to discern swarmers from planktonic bacteria and carefully studies the factors that influence the formation of bacterial vortices under restriction.

Evaluation Summary:

This work studied mice that had already taken oxycodone that then were switched to methadone treatment prior to becoming pregnant, to model prenatal methadone exposure (PME). The experimental design featured a study of a wide array of measures in the next generation progeny: including physical development, sensorimotor behavior, vocalizations, brain imaging, electrophysiology, and histology. All three reviewers agreed this work provides a novel, thorough, and highly clinically-relevant model of PME that has high value to the field of neuroscience of addictions and developmental neuropharmacology.

(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.)

Summary: Experimentally, this is a very solid and nicely replicated experimental design that provides a strong ability to interrogate the questions at hand. Both reviewers had a concern that the use of PCs was underpowering the analysis to test the key questions that were the goal of the experiment. The manuscript could also be improved by working to interleave the different omics datasets to develop a deeper insight.

Evaluation Summary:

This manuscript has generated novel and useful tools to mark cytoplasmic lipid droplets and monitor their dynamics in various tissues in live animals. It will be of interest to researchers studying lipid metabolism and related human 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. Reviewer #1 agreed to share their name with the authors.)

Evaluation Summary:

This study sheds new light on the function of an immune system protein termed interleukin (IL)-33 in response to parasite infection. The study provides information on alternative functions of this immune protein and details the path taken to achieve a beneficial immune response. This study is of interest to immunologists who deal with the host response to infection, particularly to parasites. Immunotherapies that enhance or inhibit IL-33 are in development. Understanding the role of this immune factor in a broad range of infections is important when considering future treatments that target this pathway.

(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 interesting paper describing the structure of the yeast THO:Sub2 complex and how it interacts with the SR like protein Gbp2. The paper extends what we have learned from two recently published Tho:Sub2 complex structures by the Conti and Plaschka groups in two ways. Firstly, it shows how Gbp2 interacts with the THO complex. Secondly, it reveals a substantially different orientation between THO:Sub2 protomers compared with the earlier structure, so provides more information on the flexibility and range of movements that the two protomers might make with respect to each other. The structural inferences are supported by some biochemical experiments but mechanistically the work has limitations, similar to other recent cryo-EM structures of this complex. However, this is an important structure of wide interest to people working on gene expression in eukaryotes and it undoubtedly advances the field.

(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 opted to remain anonymous to the authors.)

Evaluation Summary:

This manuscript will be of interest to a broad audience of immunologists especially those studying host-pathogen interactions, mucosal immunology, innate immunity and interferons. The study reveals a novel role for neutrophils in the regulation of pathological inflammation during viral infection of the genital mucosa. The main conclusions are well supported by a combination of precise technical approaches including neutrophil-specific gene targeting and antibody-mediated inhibition of selected pathways.

(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 describes the identification of an animal model that reproduces several features presented in Ogden syndrome patients and reveals the roles of two N-terminal acetyltransferases in mouse development. It will be of interest to the readers in the field of protein acetylation and modification, and also to the scientific community involved in rare diseases and syndrome studies.

(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 reviewers agreed that this is a very interesting paper that demonstrates the involvement of a specific protein degradation pathway in a form of synaptic plasticity in the cerebellum. The strength of the work results from its innovative character. The authors show that SUSD4 is expressed throughout the brain and is abundant in cerebellar dendrites and spines. Mice with deletion of SUSD4 have motor coordination and learning deficits, along with impaired LTD induction. This study provides novel insight in the uncharacterized role of SUSD4 and provides a detailed and well-performed analysis of the Susd4 loss of function phenotype in the cerebellar circuit. The exact mechanism by which SUSD4 affects GluA2 levels remains unclear. However, their findings provide leads for further functional follow-up studies of SUSD4.

(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:

All three reviewers were very enthusiastic about this manuscript describing FED3, a new and improved open-source option for a home cage pellet dispensing device. They all agreed that this open-source tool would be of wide-interest to neuroscience laboratories, that the manuscript was well-written and clear, and that the cross-lab validation was informative. They also appreciated that this Tools & Resource manuscript all necessary open-source hardware, firmware, visualization code, and Arduino and Python libraries for user customization of experiments and analysis. Minor concerns were identified with the extent to which the manuscript describes and compares to existing systems and with clarity on some details of the 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. Reviewer #3 agreed to share their name with the authors.)

Evaluation Summary:

In this study, the authors use a systems immunology approach to document innate and adaptive immune responses during clincal SARS-CoV-2 infection. This general impact of this work is a better understanding of COVID19 pathobiology and more specifically, the identification of serum antibodies as a novel classification framework to understand COVID-19 disease course and associated changes.

(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 uses complementary approaches to advance our mechanistic understanding of STIM1 activation, with elegant single molecule methods providing new details on STIM1 structure and dynamics. Full length STIM1 in a cellular environment was probed by crosslinking, but the same has not yet been possible with single-molecule Förster resonance energy transfer (smFRET).

(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:

The method presented in this article is of interest for all fields that interface with chromatin dynamics. It could provide a powerful tool to dissect the mechanisms of chromatin assembly and disassembly genome-wide, and determine how cell cycle and chromatin structure influence these dynamics. However, in the current form, the article falls short of its potential. Further validation of the data, and clarification of its implications is requested.

(This preprint has been reviewed by eLife. We include the public review from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Summary: This manuscript is interesting to circuit-neurobiologists, behavioural biologists and psychologists. The reviewers agree that this manuscript addresses an important unanswered question: what is the covariation-structure in the vast space of behavioural variables that individuals can explore, and what defines their individuality in this space? The reviewers also praise the great efforts made in the experimental approach and analyses methods, which potentially will set new benchmarks in the field. However, the work can be improved, by accounting for the trial-to-trial variability in behavioural data and clearly distinguishing these from persistent idiosyncrasies observed in individuals.

Evaluation Summary:

Judd and colleagues use a combination of mouse genetics and viral marking to expand the extra-cerebellar map of projections. These data will impact our understanding of how the cerebellum contributes to behavior and in general how brain function is packaged at the anatomical level. These data will not only impact cerebellar scientists but also those workers interested in how inter-regional brain connectivity is organized and how fine input-output circuit relationships are structured.

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Evaluation Summary:

The main finding that GPCR activity is necessary for latrophilins' role in synapse formation is both surprising and important. This work will inspire new research on compartmentalized GPCR signaling at the synapse.

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Summary: This study provides new information about how amyloid beta (Ab) oligomers (Abo) may contribute to hyperexcitability which is important because Abo and hyperexcitability have been suggested to occur early in the development of Alzheimer's disease (AD). The authors added Abo intracellularly (iAbo) using dialysis from a patch pipette. Their data suggest iAbo led to increased synaptic excitation mediated presynaptically by retrograde signalling of nitric oxide (NO). Furthermore, they present data suggesting that there is spread of this increase in excitation to neighboring neurons.

Major Comments:

1) The nature of the described effects of intracellular iAbo are quite unexpected, occurring within a minute of obtaining intracellular recording configuration, which contrasts with at least on previous study. While some controls for intracellular application of oligomers are provided, with reverse iAbo failing to reproduce the effect (Fig 2S1) and the effect being blocked by the antibody A11 (Fig 2S2), further controls are necessary to explain this rapid effect, which seems faster than that for the diffusion of the fluorescent tag into the cell (Fig 1S1). Note that Pusch and Neher (Pflug Arch 1988) determined diffusion time for different substances. That paper or others should be cited, and then some estimation of equilibrium time based on diffusibility of ab oligomers should be provided. Equations 17 and 18 in that paper provide some estimates based on molecular weight or diffusion coefficient. One point in Pusch and Neher is there is extreme variability between access times across cells and that it depends on access resistance, of course. Finally, the Pusch and Neher calculations were for small spherical cells - diffusion into spatially extended cells with long dendrites where the synapses are will take even longer. This is especially critical, as one of the major papers of precedent for this work is that of Ripoli, et al. 2014 (cited in the manuscript) in which the authors of that work examined effects of patch applied Ab42 over the course of 20 minutes, with internal controls showing differences between initial responses, right after break in, and 20 minutes later when the oligomer and/or monomers will have had a chance to equilibrate with the intracellular contents. It is not clear how such a rapid effect as indicated in the figures could be achieved by such a large molecule as Ab. The data suggest a time to effect of seconds to minutes, and the peak effect occurs before the fluorescence peaks, which seems hard to explain.

2) The data need reorganization in terms of their results using h-iAbo or iAbo. There needs to be a clear demonstration of why both were used if the results are generalized with both (or not) and if they can actually use both interchangeably.

3) The authors need to clearly indicate whether the experiments were done in culture or in slices. The authors need to provide a rationale on why specific experiments were done in culture and others in slices.

4) There are aspects of the observed phenomenon that have not been taken adequately into account. For example, the authors have not investigated the effects of application of oligomeric beta-amyloid to either the extracellular space or the presynaptic neurons, two other compartments of the synapse.

5) Aspects of the data raise questions: 1) Western blots appear to have multiple bands 2) evidence that the fluorescent probe accurately measures NO. 3) The bursts of activity are not quantified. What was defined as a burst? What was the burst frequency and did it change over the recording period? 4)The external solution for cultures contain 5.4 mM K+ which is quite high, and can induce hyperexcitability. Similarly, the use of 100uM AMPA and GABA seem very high. Justifying these high concentrations is important. They should lead to hyperexcitability and toxicity (AMPA) over time. Another point of concern is that the concentration of K+ for the slice work is 3 mM, much different than cultures. There are also differences in Mg2+ and Ca2+, making data hard to compare in the two preparations. 5) sample sizes are unclear 6) Intracellular Ab produces increases in both EPSCs and IPSCs. However, in Fig 3, the IPSC measures using a charge transfer quantification, did not show a significant change in response to iAbo, in contrast to EPSCs. 7) With regard to the inhibition, In the schematic on Fig. 10, I find this incomplete and slightly inaccurate since it shows one terminal releasing both glutamate and GABA with NO increasing both. While this is obviously an oversimplification, it's slightly inaccurate since NO was not directly shown to increase sIPSCs. Were NOS blockers able to disrupt the increase in sIPSCs? Moreover, there are many papers that have shown that PKC can also phosphorylate GABA receptors and increase their conductance. What could be the reason that this was not involved here? This needs to be discussed.

6) How this work relates to other studies is necessary. For example, how this study is related to others about Ab exposure is lacking. Also, regarding hyperexcitability, many possible causes exist. These should be summarized in the introduction and the authors should comment how their results fit with these studies. Regarding PKC and NO, PKC and NO have several known actions throughout the brain and body. How do the effects the authors have identified relate to all these other effects? For example, if PKC is activated by another mechanism, would it occlude effects of Ab? What are the changes in PKC and NO in AD? Regarding the ability of the data to address AD, a major issue is whether the results are relevant to AD or represent interesting pharmacological data about what Ab can potentially do in some of its forms in normal tissue.

Reviewer #2 opted to reveal their name to the authors in the decision letter after review.

Evaluation Summary:

Radaszkiewicz and collaborators describe RNF43 as a novel negative regulator of WNT5A-induced signaling in human cells. They demonstrate that RNF43 can interact with proteins in this pathway, namely ROR1, ROR2, VANGL1 and VANGL2. Specifically, they find that, through these interactions, RNF43 can suppress invasive properties of melanoma cells, as well as the development of resistance to BRAF V600E inhibitor. The experiments are well done and well explained; however, they were performed only in an in vitro setting and with a very limited number of cell lines.

(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 will be of broad interest to ion channel researchers interested in understanding the fundamental mechanisms of voltage-sensing. The researchers use a novel approach to determine the mechanism of voltage-sensing in a channel that lacks a canonical voltage-sensing domain.

(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 will be of interest to neuroscientists who study relationships between visual stimuli and their cortical representation, particularly, but not exclusively, those who use functional imaging techniques. The experiments are carefully designed, the dataset is substantial, and a model is presented that describes the data with very few parameters.

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Evaluation Summary:

Patients with myotonia congenita (or Becker disease) experience episodes of transient muscle weakness but the reasons underlying this phenomenon are unknown. This study provides the most definitive experimental evidence to date for the mechanistic basis of transient weakness in myotonia congenita and also suggests ranolazine may be beneficial for prophylactic management.

(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. Reviewers #1, #2, and #3 agreed to share their names with the authors.)

Evaluation Summary:

This study is a great example of an elaborate combination of experimental and mathematical analyses to examine an intriguing, pleiotropic immunological signaling pathway. While a good number of individual aspects of this signaling pathway have been studied and reported before, the present work pieces together many pieces and succeeds to present a conclusive and comprehensive model of this particular cytokine system. The main conclusions are well supported by the presented data and the manuscript will be of interest and relevance for the study of many other cytokine signaling pathways, being of broad relevance for immunologists and cell biologists.

(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 authors of this manuscript previously showed that ER stress, and in particular the ER stress sensor Ire1, regulates transdifferentiation in C. elegans, leading to the ectopic differentiation of germline cells. In this follow-up manuscript, the authors present several lines of evidence supporting the idea that Ire1 modules these effects through degrading a novel mRNA substrate flp6. The authors identify the neurons and neuromodulators that affect accumulation of abnormal germline cells. The reviewers agreed that the discovery that flp6 is a regulated Ire-1-dependent decay target in C. elegans, and the demonstration of a non-cell-autonomous effect of Ire1 activity, are novel and likely to be of interest to a broad readership. However, more evidence is required to support some of the main 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. The reviewers remained anonymous to the authors.)

Evaluation Summary:

This is an elegantly conducted study showing integrated stress response (ISR) contributes to protection of oligodendrocytes in the remyelination process in the setting of an inflammatory environment. The authors use both genetic (GADD43KO) and pharmacological approaches (Sephin1) to study ISR in demyelination animal models. The data are convincing and have important clinical implications for multiple sclerosis and other diseases. The reviewers agree that revisions are needed for the sake of presentation, clarity, rationale, and interpretation of datasets.

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Summary: This timely study provides important and novel findings with regard to the role of PSD-95 protein in fear extinction formation and helps to advance our understanding of how dendritic changes in the hippocampus regulates fear maintenance. The findings should appeal to those interested in hippocampal function, fear and fear-related conditions, and extinction-based therapies. The major strengths of the paper lie in the use of a wide range of complementary technical approaches, and the significance of addressing specific molecular mediators of fear attenuation. Reasonable alternative explanations were identified for some of the key findings and the conclusions may not perfectly reflect the observations and experimental designs.

Reviewer #1 opted to reveal their name to the authors in the decision letter after review.

Evaluation Summary:

In this study, the authors examined the function of the RNA-binding protein FPA through analyzing its protein interactome and its global impact on gene expression using a combined approach of Nanopore DRS, Helicos DRS, and short-read Illumina RNA-Seq. The combined datasets and new computational approaches developed by the authors permitted them to identify the predominant role of FPA in promoting poly(A) site choice. The authors further revealed that FPA mediates widespread premature cleavage and polyadenylation of transcripts of NLR genes, important plant immune regulators. Overall, this study suggests that control of transcription termination processes mediated by FPA provides an additional layer of the regulatory dynamics of NLRs in plant immune 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. Reviewer #1 and Reviewer #3 agreed to share their names with the authors.)

Evaluation Summary:

This manuscript presents some intriguing data to support the notion that B. subtilis cells have tuned a variety of parameters related to SMC loading and translocation to ensure that individual complexes do not collide. This is likely an important but poorly understood aspect of condensins/SMCs, and as such represents a valuable contribution to the field and should be of interest to a broad set of 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. The reviewers remained anonymous to the authors.)

Evaluation Summary:

This manuscript provides quantitative information of the integration of GABA-A and GABA-B receptor inhibitory responses in cortical pyramidal neurons induced by a presynaptic GABAergic neuron type called neurogliaform cell (NGFC). Experimental and modeling data suggest that NGFCs converge onto postsynaptic neurons with sublinear summation of ionotropic GABA-A potentials and linear summation of metabotropic GABA-B potentials probably due to a preferential spatial distribution of GABA-B receptor-GIRK clusters on the dendritic spines of postsynaptic neurons. The data represent an attempt to gain insights into the logic of GABA volume transmission within cortical microcircuits.

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Evaluation Summary:

Dominguez-Andrés et al. collect a large amount of immune-related trait association data from a cohort made up of 534 individuals of Western European ancestry. The goal was to track the evolutionary trajectories of cytokine production capacity over time in a number of patients with different exposure to infectious organisms, infectious disease, autoimmune and inflammatory diseases, using the 500 Functional Genomics cohort of the Human Functional Genomics Project. From this analysis it was hypothesized that the Neolithic transition was characterized by strong changes in the adaptive response to pathogens in human biology. Overall, the manuscript is interesting but could be improved by significant enhancements to statistical methodology.

(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:

Willoughby et al. examine the role of Rab25 in early embryogenesis in zebrafish. They implicate Rab25 activity in abscission and show various defects including delayed epiboly and altered cell behaviors associated with defective acting dynamics. Overall, this is an interesting and well-written paper. However, there are a number of important controls that are missing and some connections such as the implication of membrane recycling that require stronger experimental validation.

(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 takes a deep dive into the skeletal effects of burrowing and eusocial Damaraland mole rats. By exploring the genetic and skeletal consequences of breeding restricted to a single queen with multiple and closely-timed pregnancies and lactation, this study offers a compelling story that will bolster textbooks on skeletal biology, mammalian evolution, and ethology. The results show the molecular mechanisms driving adaptive plasticity within the unusually expanded lumbar spine and thin limb bones of queens are an adaptive consequence of breeding status.

(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 aims to provide a comprehensive analysis of factors governing polyadenylation site selection in yeast. Overall, the authors reveal that multiple but distinct inputs including polyadenylation machinery integrity, transcription elongation rate, nucleotide availability and chromatin landscape all contribute to controlling cleavage and polyadenylation.

(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 characterizes percepts evoked by micro-stimulating the somatosensory cortex of a human participant. The study provides some new insight into the organization of the human somatosensory cortex and represents an important step in providing more effective somatosensory feedback for brain-machine interface users.

(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 study presents extensive genetic analysis of a relatively large cohort of men with idiopathic infertility, with considerable accompanying andrological phenotypic data. Through careful step-by-step investigations, an inversion variant is identified as a risk factor for subsequent deletion variants that can lead to substantially increased risk of impaired spermatogenesis, on an age-structured basis, relative to non-carriers. This work will be of particular interest to the reproductive genetics field, but also has wide ranging implications for colleagues interested in common disease genetics, meiosis, structural variation, dosage sensitivity, and sex chromosome evolution. As part of the most comprehensive investigation of AZFc micro-deletions and structural variation to date, the authors have identified a novel structural variant of the Y-chromosome that predisposes to spermatogenic failure and provided clear guidelines for genetic counseling.

(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 study addresses a topic that is timely and of general interest. The findings represent a potentially very interesting contribution to the important question of how the brain comes to predict the future, in particular lifelike sequences of events. However, some of the main conclusions would require further statistical support.

(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 is an interesting manuscript and experiments generally make their point on Alr effects. However, additional data would strengthen the paper with respect to the relative roles of cytoplasmic vs mitochondrial isoforms as would mitochondrial function studies.

(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:

All the reviewers were in agreement that this is an exceptionally rigorous paper that sets an important precedent for how mobile genetic elements can influence host biology.

(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 paper will be of interest in the fields of circadian biology and metabolic physiology. It provides a molecular mechanism for protection against development of fatty liver in response to high sugar consumption. Quality data support the key claims of the paper in each of the main research areas (circadian biology and metabolism) but additional efforts are needed to integrate the two parts. The current study does not thoroughly connect the in vitro and in vivo findings and misses the opportunity to fully characterize the role of KLF10 in circadian regulation in response to excessive sugar consumption.

(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 paper will be of interest to scientists in the field of regenerative medicine. The authors compare effects of persistent lentiviral expression of various mitogens in cardiomyocytes in vitro. Technically experiments are of a very high standard, but the data are somewhat difficult to translate to the in vivo situation. The statistical analyses would have to be robust and sufficient for the conclusions to be supported by the 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 #3 agreed to share their name with the authors.)

Evaluation Summary:

This is an elegant study demonstrating the emergence of mesoderm-derived beta-like cells following beta-cell ablation in an endothelial cell deficient context. These findings will be of interest to scientists in the areas of regeneration and reprogramming, as they reveal a previously unknown degree of germ layer plasticity in the embryo. In the long term the study has potential impact in the diabetes field, as it reveals a novel path for redirecting somatic cells into insulin-producing cells in an in vivo context.

(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 manuscript is of broad interest to readers in the field of somatosensation. The identification that a common type of skin cell responds to mechanical force using a specific molecular receptor called Piezo1 is an important contribution to our understanding of mechanotransduction. A combination of conditional gene knockout with physiological and behavioral assays provides intriguing evidence that communication between skin and nerves is important for normal touch sensation, a conclusion that if further supported by additional data could become a fundamental discovery.

(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:

The manuscript by Rosello et al. represents a major advance in implementation of cutting-edge genome editing methodologies in the zebrafish. The study seeks to describe optimized tools for precise base editing in zebrafish and to demonstrate their effective application. Overall, this study demonstrates that cytosine base editing is an efficient and powerful method for introducing precise in vivo edits into the zebrafish genome, and will be of interest to scientists who use zebrafish and other genetic systems to model human development and 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 and Reviewer #2 agreed to share their names with the authors.)

Evaluation Summary:

In their manuscript titled "Archaeal chromatin 'slinkies' are inherently dynamic complexes with deflected DNA wrapping pathways", Bowerman et al. use an elegant combination of cryo-EM, analytical ultracentrifugation and molecular dynamics simulations to investigate the structure and dynamics of archaeal histone — DNA complexes, termed archaeasomes to distinguish them from eukaryotic nucleosomes. This study builds upon the crystal structure of an archaeasome and the functional analysis of its disruption recently published by the same group (Mattiroli et al, 2017) by analyzing the dynamics of this complex and discussing how these dynamics could relate to archaeal genome biology. How chromatin evolved is a fundamental question in biology, marking a striking departure from the bacterial nucleoid. This current manuscript describes a rigorous biophysical study that not only provides substantial new insights into archaeal genome biology but also raises intriguing questions for future study. This manuscript will therefore no doubt be of interest not only to the archaeal research community but also to the field of chromatin biology.

(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 try to answer an important clinical question about the previously observed connection between embolic stroke of undetermined source (ESUS) and atrial fibrillation (AF). Using cutting-edge personalized computational modeling of left atrium from both ESUS and AFib patients, the researchers try to understand why the fibrotic substrate found in both ESUS and AFib patients causes arrhythmia in the latter group but not the former. Their study concludes that the intrinsic capacity to sustain arrhythmias of fibrosis found in ESUS and AFib atrium are identical. The key claims of the manuscript are well supported by the data, and the modeling methodology is largely 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 #2 and Reviewer #3 agreed to share their names with the authors.)

Evaluation Summary:

The present study uses innovative approaches to further our knowledge of skin immunobiology. The corresponding results explain the expression of langerin on two fractions of dermal DC (CD103+ and CD103-) observed several years ago. The demonstration that epidermal LC do not contribute to LN populations in the steady state is completely unexpected and raises important questions about the in vivo function of the LC-like subset unveiled in the present study.

(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.)

Summary: The manuscript by Rae et al. reports a new protocol for labeling genetically-tagged proteins of interest with heavy atom particles for visualization by electron microscopy. The optimized protocol builds on the use of the enzyme APEX2, fused to the target protein of interest. The contrast enhancement may be useful in diverse 3D EM techniques. Also, reviewers were enthusiastic about the prospects for quantitative studies, even for low-levels of endogenous expression. Semi-quantitative studies may be enabled because the new method appears to improve the proportionality of the signal such that the number of APEX2 tags in a sample correlates with the number of heavy atom particles. The apparent simplicity of the protocol raises the potential for it to become a standard in the field of EM labeling.

Reviewer #1, Reviewer #2 and Reviewer #3 opted to reveal their name to the authors in the decision letter after review.

Summary: Hofmann et al. investigate the link between two phenomena, emotional arousal and cortical alpha activity. Although alpha activity is tightly linked to the first reports of electric activity in the brain nearly 100 years ago, a comprehensive characterization of this phenomenon is elusive. One of the reasons is that EEG, the major method to investigate electric activity in the human brain, is susceptible to motion artifacts and, thus, mostly used in laboratory settings. Here, the authors combine EEG with virtual reality (VR) to give experimental participants a roller-coaster ride with high immersion. The ride, literally, leads to large ups and downs in emotional arousal, which is quantified by the subjects during a later rerun. Three different decoding methods were evaluated (Source Power Comodulation, Common Spatial Patterns, and Long Short-Term Memory Recurrent Neural Networks), each of which demonstrated above-chance levels of performance, substantiating a link between lower levels of parietal/occipital alpha and subjective arousal in a quasi-naturalistic setting.

The reviewers both expressed some enthusiasm for the MS:

The study is timely and makes an important contribution to our understanding of the relation of emotions and sensory processing

Of potentially great interest to a broad audience

The embedding in historic literature is excellent. I like it a lot.

This work is notable because the roller-coaster simulation is a well-controlled, yet dynamic manipulation of arousal, and in its comparison of multiple decoding approaches (that can model the dynamics of affective responses). Indeed, this is an interesting proof of concept that shows it is possible to decode affective experience from brain activity measured during immersive virtual reality.

Reviewer #1 opted to reveal their name to the authors in the decision letter after review.

Summary: The reviewers appreciate that the manuscript presents a simple but compelling model that explains the dynamics of replication origin birth and death, which enhances our understanding of the selection pressures that have shaped the distribution of replication origins. However, both reviewers had a series of concerns.

Summary: This manuscript provides a comparative analysis of the cell variety present in the dorsal lateral geniculate nucleus (dLGN) of mice, non-human primates, and humans using single-cell/single-nucleus RNA-sequencing (Smart-seq). The study identifies excitatory and inhibitory dLGN cell types in the three species and shows that the different subclasses of inhibitory neurons are relatively similar across species. In contrast, excitatory neurons appear to bear cross-species differences particularly between mouse and primates. The study provides an extensive description of the dLGN neurons, an important visual relay nucleus that has been so far poorly studied. As such, these data are very welcomed and will likely attract the interest of researchers working in visual function and beyond. The strong and creative bioinformatics analysis has uncovered interesting and subtle cross species links between different types of neurons.

Reviewer #1, Reviewer #2 and Reviewer #3 opted to reveal their name to the authors in the decision letter after review.

Summary: Both reviewers found this study's findings to be interesting and novel, and they appreciated the integration of intrinsic timescale analysis, coding of behavioral signals, and exploration of mechanisms in a biophysical circuit model. However, they both raised serious concerns about methodological and interpretational aspects of the analyses which would need to be satisfactorily addressed in subsequent review. In consultation, both reviewers were in agreement with all points raised in the other's review. I view the two reviewers' requests and suggestions as appropriate and complementary, and all of them needed response.

I highlight here two of the major concerns raised by the reviewers (but all raised by the reviewers merit addressing). First is the need for intrinsic timescale analysis to not be confounded by slowly varying changes in firing rate coding task variables (Point 1.2 of Reviewer 2). This is important for interpretation on intrinsic timescale and its correlation with task variable coding as a major result. Second is the interpretation and implementation of Hidden Markov Models to non-simultaneously recorded neurons (Points 6 of Reviewer 1 and 3 of Reviewer 2). Here again the HMM states may be driven by task variable coding which is not corrected for, which could confound interpretation of results as in terms of meta-stable states and its link to the circuit model. Furthermore, HMM analysis of the circuit model does not match its methodology for experimental data, but could be through non-simultaneous model spike trains, which the manuscript does not justify. I will add my own suggestion that perhaps both of these methodological data analysis concerns could potentially be addressed through comparison to the null model of a non-homogeneous Poisson process with firing rate given by the variable-coding PSTH. I do not consider it necessary to study a network model that performs the task, as suggested for consideration by Reviewer 1.

Summary: In this study, Michaluk et al. examined the membrane dynamics of the main glial glutamate transporter GLT1 in hippocampal astrocytes, which was previously shown to shape synaptic transmission through regulating extracellular levels of glutamate. Using GLT1 tagged on its surface with a pH-sensitive fluorescent marker, GLT1-SEP, the authors performed (1) fluorescence recovery after photobleaching (FRAP) experiments to assess the basal and activity-dependent dynamics of surface GLT1-SEP and (2) super-resolution dSTORM imaging to determine the relationship between GLT1 and PSD-95, an excitatory synapse marker. A large proportion of surface GLT1-SEP underwent turnover with a surface lifetime of 22 s, whereas a smaller fraction (~25%) remained largely immobile, which was decreased upon increased activity. Notably, the cytoplasmic domain of GLT1-SEP was shown to attenuate the basal turnover of surface GLT1 and to facilitate its proximal localization to synapses; moreover, GLT1 cytoplasmic domain was required for activity-dependent increase in the mobile fraction.

While previous studies using single molecule tracking have demonstrated a role for the lateral diffusion of GLT1 in controlling the recruitment of GLT1 near active synapses, the present study uses powerful optical approaches and analysis tools to access both the surface lateral mobility and the exchange between surface and intracellular pools of GLT1. Furthermore, characterization of the nanoscale organization of GLT1 relative to synapses and its dependence on the C-terminal domain of GLT1 is presented. Altogether, the results are interesting and valuable, and underscore the importance of the GLT1 C-terminus in the membrane turnover and in the activity-dependent lateral diffusion of the surface GLT1. Nevertheless, some of the conclusions are not strongly supported by the data shown.

Reviewer #2 opted to reveal their name to the authors in the decision letter after review.

Summary:

In this manuscript the authors perform a retrospective analysis in attempt to delineate the role of goal-directed versus habitual mechanisms underlying choice between drug and non-drug rewards. Specifically, the authors utilized data generated in their laboratory to assess cocaine-versus-saccharin choice following limited and extended training paradigms. A sequential choice model was used to assess the prediction that increased latencies during choice reflect goal-directed control; whereas no change in latencies reflects habitual control. Based on this model, the authors report that rats engage in goal-directed control after limited training, and adopt more habitual responding after extended training. The authors conclude that the sequential choice model is specific to habitual choice.

While the Reviewers appreciate the approach and conceptual framework described in this manuscript, they are all in agreement that additional data and analyses are needed to better support the claims surrounding goal-directed versus habitual control of reward-seeking behavior. For example, an independent evaluation of whether the target behavior is in fact goal-directed or habitual seems necessary to support such claims. Reviewers’ comments and suggestions for improvement are included below.

Reviewer #1 and Reviewer #2 opted to reveal their name to the authors in the decision letter after review.

Summary:

The reviewers agreed that the paper provides strong in vivo data for a tumor-suppressive role for Mga in lung carcinogenesis. The authors convincingly show that MGA is important in oncogenesis. We note here that MGA is highly understudied (~200 publications) in and of itself despite its involvement with the MYC network for oncogenesis (~41,000 publications at the current time). Given a protein of 3000 amino acids, the number of potential protein partners and PTMs that might modify its tumor suppressor functions are staggering. However, the reviewers also noted that a previous paper has addressed the same topic and the novelty of the data presented here needs to be better explained and additional experiments are needed to strengthen and expand the new aspects.

Reviewer #1 opted to reveal their name to the authors in the decision letter after review.

Summary: This is an interesting study reporting an increase in the rotation speed of the E. coli flagellar motor upon the sensing of a non-metabolizable glucose analog (2Dg) by the cell. The authors conclude that this increase is due to an increase in the number of torque-generating stator complexes that drive the motor. Knockout of the trg gene abolished this effect, suggesting that sensing of 2Dg by the Trg chemosensor is responsible. Involvement of membrane potential, the PTS pathway, and the chemotaxis response regulator CheY is ruled out. The manuscript is well-written, and the data are convincing. But the mechanism remains unclear.

Reviewer #3 opted to reveal their name to the authors in the decision letter after review.

Summary: The study addresses a fundamentally important question regarding the connectivity of LVb and LVa in the medial and lateral entorhinal cortex. The authors suggest that LVb to LVa connection exists in the LEC but not in the MEC. This finding would have important implications on studies investigating circuits functions between the hippocampus and the EC. All three reviewers found the central question important and the data novel. However, there are several technical issues that limit the robustness of the authors claim.

1) While the transgenic animal used in these experiments is elegant and novel, it only labels a subpopulation of the neurons. There is a possibility of selective labelling of neurons with distinct connectivity patterns. The authors would need to show that their approach is not leading to false negative results due to the selective visualization of those neurons that project more modestly to the LVa.

2) The specificity of the injection to the LEC/MEC should be better documented and potential spread to the perirhinal or postrhinal cortex carefully excluded.

3) The findings are presented as LVb to LVa connection did not exist at all in the MEC, however the data shows that the connection is there but it is significantly less dense than in the LEC. Given the graded finding, if the authors aim to show their central claim regarding the lack of mediation of hippocampo-cortical outputs by this connection in the MEC, this would require the addition of functional studies.

Summary: This study investigates the role of the innate immune response in controlling bloodstream trypanosome infection in the zebrafish infection model recently developed by the authors. The study found that an innate immune response, characterized by controlled inflammatory response was sufficient to control infection in some individuals, while failure to control infection was associated with a strong inflammatory response characterized by expansion of foamy macrophages. The findings highlight the importance of a balanced immune response in controlling bloodstream trypanosome infections that are likely relevant to mammalian infections.

Reviewer #1 and Reviewer #2 opted to reveal their name to the authors in the decision letter after review.

Summary: This manuscript describes a longitudinal study of the adolescent structural connectome. Park et al. report on an analysis of existing semi-longitudinal NSPN 2400 data to learn how the projections of high-dimensional structural connectivity patterns onto a three dimensional subspace change with age during adolescence. They employ a non-linear manifold learning algorithm (diffusion embedding), thereby linking the maturation of global structural connectivity patterns to an emerging approach in understanding brain organization through spatial gradient representations. The authors find strong effects of expansion of structural connectomes in transmodal brain regions during adolescence. They also report findings centered on the caudate and thalamus, and supplement the structural connectivity analyses with transcriptome association analyses revealing genes enriched in specific brain regions. Finally, intelligence measures are predicted from baseline structural measures.

This is an interesting and comprehensive set of analyses on an important topic. Overall, the figures are lovely. The sensitivity analyses are particularly commendable. The paper is well written, the data are fantastic, and the analyses are interesting. Some suggestions and points for clarification (both theoretical and methodological) are below.

Reviewer #3 opted to reveal their name to the authors in the decision letter after review.

Summary: The reviewers have found the topic of your study of high interest, with very intriguing findings on the different origins of calcium transients in CSFcNs.

However, after a careful examination of your work , the reviewers have raised the following major concerns:

1) To conclude on calcium spikes, the imaging data without electrophysiological calibration leaves too much unknown. A careful electrophysiological examination should reveal how calcium transients of different amplitude correlate with the electrical activity of the cell, calcium spikes and spontaneous PKD2L1 channel openings as described extensively in these cells, is absolutely mandatory to conclude.

2) The manuscript shows a lack of consideration of the importance of the sensory functions and of the role of channel PKDL1 that are both well-established in CSFcNs in mice and other models. More work is necessary to relate to these critical aspects.

3) The number of animals for juvenile and adult mice used by the authors should be clearly stated (the manuscript only refers to the total number) but also largely increased for the authors to reach robust conclusions.

4) Overall, more rigor should be implemented throughout the entire manuscript, with a deep writing improvement and a careful inspection of figure panels (choice and fair / complete representation of the data) and more information on conditions used for experiments (promoter used, concentrations for pharmacological agents, selection of ROIs, ventral versus dorsal CSF-cNs, definition and proportion of silent cells, enrichment in the T and L type calcium channels, etc ... ).

Reviewer #2 and Reviewer #4 opted to reveal their name to the authors in the decision letter after review.

Summary: This manuscript describes a new experimental environment for training macaque monkeys to perform behavioral tasks. Using this facility, the authors trained freely moving macaques to perform a visual "same-different" task using operant conditioning, and under voluntary head restraint. The authors demonstrate that they could obtain reliable eye-tracking data and high-performance accuracy from macaques in this facility. They also noted that subordinate macaques can learn to perform basic aspects of the task by observing their dominant conspecifics perform the task in this facility. The authors conclude that this naturalistic environment can facilitate the study of brain activity during natural and controlled behavioral tasks.

The manuscript is broadly organized along three distinct lines of inquiry. First, the authors describe a customized living space for a small group of macaque monkeys. Second, the authors train two of these monkeys to perform a cognitive task in a purpose-built room of the living enclosure. Third, the authors describe their experience training a third monkey to complete the cognitive task.

Summary: We appreciate this study and find that the conclusions that reclassify Clostridiodes are largely justified by the data/analysis. The major concern is that the work represents the application of standard approaches to refine species classification, as opposed to either proposing a novel approach to classify species or defining a split that might be more surprising and/or clinically significant (e.g. Kumar et al. Nature Genetics, 2019). Consequently, despite being a useful contribution to the literature we believe it is more suitable for a specialized audience.

Reviewer #1 opted to reveal their name to the authors in the decision letter after review.

Summary: Overall the reviewers felt that the manuscript had a fair amount of promise but raised some issues about the specific tasks used and some details of the analysis. One reviewer in particular felt that the manuscript should be reworked around the functional connectivity results, which would strengthen the manuscript. I tend to agree with this assessment, particularly as concerns the lateralization framing which is not very well explored by these tasks.

Summary: The work describes a simple theoretical model for enhancer action that explains several major controversies in the field of long-range gene regulation and the role of topologically associating domains and insulating boundaries in modulating enhancer-promoter interactions. Further, the model makes predictions that can be experimentally tested. This is valuable for the field of gene regulation.

Reviewer #2 and Reviewer #3 opted to reveal their name to the authors in the decision letter after review.

Summary: This paper investigates the modulation of spatial signals in higher order visual areas in mice navigating virtual reality environments. Previous work demonstrated that the spatial position of an animal modulates neural activity in the primary visual cortex (V1). Here, the authors demonstrate that this spatial modulation however, is not a general feature of the visual circuit. Similar spatial modulation occurs in higher visual areas but not in lower visual areas, such as the lateral geniculate nucleus. Moreover, this work finds that spatial modulation was stronger when animals had more experience on the track and when the animals were actively performing a task, rather than when the animal was passively viewing the same virtual track. Since the first reports that visual neurons show modulation by spatial position during spatial navigation tasks, similar to that observed in hippocampal place cells, the source of this modulation has been an open question. This work adds new insight regarding this question, suggesting that it is likely either generated within the visual cortex itself or propagated in a top-down manner from higher brain areas, rather than in a bottom-up manner from the thalamus.

Summary: Borghesani and colleagues aimed to understand how dysfunction in the anterior temporal lobe (ATL) alters dynamic activity during semantic categorization. They contrast MEG responses between 18 patients with semantic variant Primary Progressive Aphasia (PPA) and 18 age-matched healthy controls. Both groups show similar profiles of behavioural performance on the task, and broad similarities in MEG responses. Critically, however, svPPA patients show enhanced gamma synchronization in the occipital lobe compared to controls. The authors interpret this as reflecting increased engagement of / reliance on early perceptual mechanisms for completing the task, as opposed to semantic identification of the picture.

Overall, the reviewers found the manuscript interesting. As svPPA is a rare (but scientifically informative) disorder, the sample size is impressive, and given that relatively few MEG studies exist in PPA at all, this is an interesting dataset. However, the general opinion is that the results could be more fully characterized, which would allow for more expansive interpretations and inferences.

This manuscript is in revision at eLife.

Reviewer #2 and Reviewer #3 opted to reveal their name to the authors in the decision letter after review.

Summary: This work examines whether coincident firing of neurons in the visual cortex is preserved over a long timescale (one month) which is important because it provides insight into the stability and plasticity of neural circuits and visual representations. The authors find that subsets of identified neurons maintain coordinated firing despite some degree of flux in the firing activity across the population.

All reviewers agreed that the question is important but found the analysis lacked depth and there were some technical issues in the experiments that should be addressed with a fuller discussion and potentially additional analysis to eliminate confounds/artefacts. In general, and in light of earlier work (some of which is not cited) the conclusions need to be more circumspect. Specifically:

• There were concerns about movement/loss of cells/calcium indicator artefacts over this long imaging period that should be accounted for more rigorously.
• The analysis applies a somewhat arbitrary criterion for stability (50% of cells remain responsive in an assembly). This threshold should be systematically explored and justified more carefully.
• The wider literature on this topic should be more thoroughly cited, limitations of the study should be transparently laid out, claims about the overall stability found in this population response and its relevance to memories and behaviour should be moderated in line with the comments below.

Reviewer #1 and Reviewer #2 opted to reveal their name to the authors in the decision letter after review.

Summary: This study provides support for a proposed allosteric regulatory mechanism in a human iron-sulfur cluster biosynthesis protein that is linked to the human genetic disorder, Friedrich's Ataxia. In an approach guided by inspection of a structure of the human enzyme, the authors successfully converted a bacterial homolog lacking allosteric regulation into a system that behaves similarly to the human one. The work provides validation of the roles of accessory proteins in activating iron-sulfur cluster biosynthesis machinery. It also could open novel routes for therapeutic intervention in genetic disorders of this process in humans.

The major concerns about the study center on the significance of the form of the human enzyme structure used as the basis for designing the mutagenesis/activity experiments in the bacterial enzyme. To bolster the underlying framework for the experiment design, the description of the existing human enzyme structures and how exactly they were used to select sites for mutagenesis in the bacterial counterparts should be improved to include more detail and balanced perspective. Experiments are suggested to show that activity enhancement upon addition of accessory proteins is specific to those factors, along with a more comprehensive discussion of the errors and reproducibility in activity measurements. Finally, the significance of the work would be elevated if the authors could use a similar approach to install activating mutations in the human enzyme - particularly if these could overcome the requirement for frataxin.

Summary: Specifically, all of the reviewers agreed that the emerging Hydra system holds great promise for neuroscience discoveries. Moreover, some of the findings presented here have the potential to be of use to other scientists who work in this system. However, we felt that the findings here were too preliminary and underdeveloped. In particular reviewers felt that 1) multiple locations across the Hydra's body should be stimulated coupled with mapping the behavioral and neuronal correlates of such stimulation, 2) the pan-neuronal nature of the bulk calcium measurements made it challenging to fully appreciate which neuronal circuits might be driving the sensorimotor responses, 3) uniform proxies for measuring/plotting the behavior would be useful, 4) the ablation studies lacked cellular resolution, similar to the calcium imaging experiments.

Summary: In this manuscript, the authors investigated the importance of visual and vestibular sensory cues and the underlying motion dynamics to the accuracy of spatial navigation by human subjects. A virtual environment coupled with a 6-degrees of motion platform, as described in prior studies, allowed precise control over sensory cues and motion dynamics. To investigate whether control dynamics influence performance, the transfer function between joystick deflection and self-motion velocity was modified at each trial, resulting in subjects relying more on velocity or acceleration to find their way. To explain the main result that navigation error depends on control dynamics, the authors propose a probabilistic model in which an internal estimate of dynamics is biased by a strong prior. Overall, the three reviewers agree that additional data are not necessary. However, the analyses need to be clarified and the conclusion better justified.

Reviewer #1, Reviewer #2 and Reviewer #3 opted to reveal their name to the authors in the decision letter after review.

Summary: The article by Gould et al breaks new ground by demonstrating a role for lysosomal-mediated degradation in the mechanosensitive repression of Sclerostin levels in bone. Though the post-translational repression of Sclerostin has long been apparent, no one has yet unraveled the mechanisms. Therefore, this discovery is important to the skeletal biology community - both because of the findings themselves, and because the conditions/models used by this team to make these discoveries will be useful for other investigators, including their ability to manipulate and observe the rapid lysosome-dependent control of Sclerostin levels in vitro and in vivo in response to PTH or mechanical stimulation. In addition to the importance within this field, the work has broad impact on multiple levels including a) the clinical relevance for understanding and potentially treating osteoporosis and the skeletal phenotypes in individuals with lysosomal disease, and b) the mechanoregulation of lysosomal function and its relationships to crinophagy, which has implications not only for the regulation of Sclerostin, but also for other factors in and beyond the skeleton (RANKL, insulin).

Essential revisions:

The study is elegantly designed, clearly communicated, and rigorously conducted. However, the reviewers require additional data to support the overall conclusion on the significance of lysosome-mediated degradation of sclerostin in skeletal biology. First, it is important to elaborate on what gives the authors confidence that the inhibitors were effective and act as expected throughout the study - but especially Bafilomycin A1 and Apocynin in vivo. If BafA1 and Apocynin treatment in vivo work as expected, they should prevent the rapid load-dependent repression of Sclerostin levels (shown in Figure 1D). Second, the author's demonstration of mechanical load-dependent changes in sclerostin localization in osteocytes lysosomes in vivo by immunohistochemistry would be important to support the in vivo relevance of this pathway in the acute regulation of sclerostin levels. While the western blotting of mechanically loaded mouse ulnas showing previously-undocumented acute reductions in lysate sclerostin levels is interesting, it is unclear if these changes are caused by mechanical loading-induced lysosomal function.

Reviewer #1 and Reviewer #2 opted to reveal their name to the authors in the decision letter after review.

Summary: In this work, Feilong and colleagues use the Human Connectome Project fMRI data to investigate the degree to which the strength of functional connectivity is predictive of general intelligence, and the degree to which that predictive power is improved using the hyperalignment procedures their lab has developed. More specifically, the authors predict general intelligence using either coarse-grained functional connectivity (based on 360 ROIs) or fine-grained functional connectivity (vertex-wise) after hyperalignment. The results show a two-fold increase in variance explained in general intelligence between coarse-grained and fine-grained connectivity. This is a very clearly-written paper that presents an important result, which has the potential of great impact on the field of behavioral prediction. However, the reviewers and editors do have some significant concerns with the predictive modeling presented in this work.

Reviewer #2 and Reviewer #3 opted to reveal their name to the authors in the decision letter after review.

Summary: Collectively, we liked a lot about your paper and we would accordingly like to encourage its continued evolution. However, we felt that the approximately equal balance at present between the roadkill genomics assembly pipeline and the phylogenetic and genetic diversity results was not justified, and we requested a shift accordingly as described below. Second, we require several analytical updates to the manuscript to ensure robustness of the main genetic diversity results.

Summary: In this paper you describe experiments showing that PIE-1 is sumoylated at K68, and that K68 sumoylation plays a role in PIE-1 interaction with HDA-1 and its sumoylation, which leads to its activation. The reviewers found the sumoylation dependence of PIE-1 function in piRNA silencing to be of interest, but raised major issues that need to be addressed. In particular, more mechanistic insights into how sumoylation of PIE-1 at K68 enhances HDA-1 sumoylation and regulation are required.

This is a co-submission with the manuscript https://www.biorxiv.org/content/10.1101/2020.08.17.254466v2

Summary: In this paper, your studies showed that sumoylation of HDA-1, a type 1 HDAC, at two C-terminal Lys residues plays a role in establishing transcriptional silencing of piRNA-regulated genes in C. elegans through enhanced NuRD complex interaction and histone H3 deacetylation. The reviewers all found the link between HDA-1 sumoylation and silencing to be interesting, but raised a number of issues that need to be addressed.

This is a co-submission with the manuscript https://www.biorxiv.org/content/10.1101/2020.08.17.254466v2

Summary: All three reviewers were not convinced that this screening platform has been properly validated vis-à-vis the neurobiology of the adrenal gland, nor that it has a physiologic relevance for the understanding of living processes and organs.

Summary: This manuscript addresses a timely subject: the role of cognitive control (or mental effort) in value-based decision making. While there are plenty of models explaining value-based choice, and there is a growing number of computational accounts concerning effort-allocation, little theoretical work has been done to relate the two literatures. This manuscript contributes a novel and interesting step in this direction, by introducing a computational account of meta-control in value-based decision making. According to this account, meta-control can be described as a cost-benefit analysis that weighs the benefits of allocating mental effort against associated costs. The benefits of mental effort pertain to the integration of value-relevant information to form posterior beliefs about option values. Given a small set of parameters, as well as pre-choice value ratings and pre-choice uncertainty ratings as inputs to the model, it can predict relevant decision variables as outputs, such as choice accuracy, choice confidence, choice induced preference changes, response time and subjective effort ratings. The study fits the model to data from a behavioral experiment involving value-based decisions between food items. The resulting behavioral fits reproduce a number of predictions derived from the model. Finally, the article describes how the model relates to established accumulator models of decision-making.

The (relatively simple) model is impressive in its apparent ability to reproduce qualitative patterns across diverse data including choices, RTs, choice confidence ratings, subjective effort, and choice-induced changes in relative preferences successfully. The model also appears well-motivated, well-reasoned, and well-formulated. While all reviewers agreed that the manuscript is of potential interest, they also all felt that a stronger case needs to be made for the explanatory power of the model, and that the model should be embedded more thoroughly in the existing literature on this topic.

Summary: This is a nice study that is clearly written and makes use of several datasets. It attempts to explain perinatal risk factors and the associated risk of developing pediatric asthma in the mid-childhood and early teenage years. Identified among maternal characteristics that were associated with risks of subsequent asthma development included atopy, BMI, race/ethnicity and demographics, birth characteristics, and mode of delivery. The paper then goes on to demonstrate the differences in immune response during the different time frames of pregnancy. Most notably, a gene signature associated with increased myelopoiesis in utero is associated with increased risk of pediatric asthma. Furthermore they show that cord blood serum PGLYRP -1 is associated with reduced risk of pediatric asthma and increased FEV1/FVC. Interestingly sIL6ra which is derived from neutrophils but not associated with neutrophil granules did not show any association with pulmonary outcomes. This suggests that it is the neutrophil granules rather than the neutrophils per se that are the problem association.

Summary: This paper tests the biological embedding model by asking whether and how early maternal loss affects cortisol levels and diurnal cortisol slopes among wild chimpanzees at the Tai Forest, Côte d'Ivoire. The results suggest that maternal loss alters the HPA stress axis in wild chimpanzees, but these effects are not visible later in life. Authors suggest that the lack of a later life association between maternal loss and cortisol levels may be due to selective early mortality of individuals with high cortisol levels but did not provide any survival or behavioural data to show that orphans and non-orphans differ in any fitness-related traits other than cortisol. Furthermore, the association between cortisol and the HPA axis is in the opposite direction to that observed in humans and there seems to be no significant increase in cortisol in orphans compared to non-orphans. Overall, the study is the result of extensive fieldwork, the number of samples collected is impressive and the subject is very interesting.

The analyses will benefit greatly if the authors use effect sizes and confidence intervals for inferences instead of p-values. This may solve the significance threshold issues. Moreover, the reliance on p-values seem to limit the value of the data. For example, authors suggest that results from model 1 should be treated with caution because the full model is not significantly different from the null model, but by relying on it as the key finding of the study without exploring effect sizes, it does not seem that they did exercise sufficient caution.

Summary: This is an interesting study researching how educational achievement (EA) can be predicted using genomic data when the sample is stratified to those without and those with diagnoses of common psychiatric disorders. The study is well powered using an impressive and representative sample and offers insights into the etiology of associations between psychiatric traits and educational achievement. The authors find evidence that the influence of common variants on EA is attenuated in individuals with a diagnosis of autism spectrum disorder (ASD) or ADHD.

Summary: The study addresses a timely and important question of the role of prior choices on perceptual decisions in individuals diagnosed with autism; 17 high functioning (but not mild cases) children and teenagers (8-17 years) with ASD. The experiments are well motivated and thoughtfully designed. Using a model to dissociate the contribution of prior stimuli and choices, the authors found a strong effect of prior choices not stimuli, which is stronger in ASD than controls. Similar results from another data set are also reported.

Overall, this is a strong study with a sophisticated protocol, elaborate data analysis, ASD participants who were tested on a large battery, in-depth analysis of the literature with interesting insights, interesting results and a well written manuscript.

The first two experiments provided compelling evidence that prior choices affect perceptual decision making in ASD, but the outcome of the response invariant condition suggests that the authors' interpretation goes beyond the data. This has serious implications for the interpretations of the findings. Also, the bias interpretation should be informed by measures of performance.

Summary: Nonlinear microscopy is in the unique position that high-resolution images of cells and other tissue components can be obtained in live tissue. However, scattering and absorption limit the penetration depth. The impact of nonlinear microscopy in biomedicine and biology would be much improved if higher imaging depths can be achieved. In this manuscript, the authors show they can accomplish imaging in complex specimens using 3- and 4-photon excitation, deeper in the specimen than comparable optics can accomplish with 2-photon excitation laser scanning microscopy. Using a customised commercial system, the authors have incorporated a high-powered laser source with an OPA and dispersion compensation to generate either 1330nm or 1650nm laser lines with high peak pulse energies at low pulse repetition rates. They then compare the relative capabilities of each laser line in terms of number of fluorescence emission channels measured (skin tumour xenografts), fluorescence bleaching analysis and functional toxicity thresholds and fluorescence signal attenuation (excised murine bone).

This is a very interesting study with some potentially important findings from a technical perspective. However, there is a disconnect at present between the quality of the work and the quality of the presentation. There are many areas of quantitative imaging and intravital imaging that are well known to those in the direct field, and that are a complete mystery to the vast majority of those that are not. It would therefore be highly beneficial to restructure the manuscript in such a way that the findings can reach the many researchers that could benefit from this powerful approach rather than the few who already use it.

Summary: The description of how faster melanization is associated with LC3-mediated phagocytosis evasion, virulence and outcomes in humans is interesting and does provide some new information. In general, the study has been executed well, with clear articulation of the results and appending conclusions. However, the work falls short of investigating any substantive mechanistic basis for the observations and how they relate to the broader metabolism in Cryptococcus. .

Summary: Both reviewers found that the analysis of data was too shallow and that the HCO model was insufficiently justified in the context of spinal cord CPGs. The reviewers argue that a more robust analysis including a discussion of the dynamic properties of the model (in the context of dynamic switching) was needed to support conclusions.

Summary: In the present study, the authors searched for early signs (during the neonatal period) of amyotrophic lateral sclerosis (ALS) disease focusing on a specific class of spinal interneurons; i.e.: glycinergic interneurons. In SOD1 mice, they aimed at testing whether these inhibitory neurons exhibit measurable changes at young age that could then contribute to the MN pathology known to develop later. The originality of this study is that, for the first time, it examines specifically inhibitory neurons. The authors investigated the morphological and electrophysiological properties of lumbar glycinergic interneurons in the spinal ventral horn in one model of SOD1 mice compared to WT P6-P10 mice. In addition, the authors more specifically considered Renshaw cells in this process and found that these cells were less excitable in SOD1 mice.. Based on these experimental data they created a statistical model to make predictions on RC cells (and non-Renshaw cells found to be more excitable in SOD1 mice) to further demonstrate that early changes in their excitability could account for the disease.

Despite the fact that this paper addresses the potential role of an unprecedentedly investigated class of neurons (inhibitory ones) in ALS disease, reviewers pointed to several concerns. First, there is a major problem with the identification of the Renshaw cells. Indeed arguments using the localization within the ventral horn of the spinal cord, the calbindin expression, the size and the number are questionable as it is done here. In addition, because the characteristics of this type of cell has been later used for the predictive statistical model, it importantly attenuates the validity of the model and credibility of the conclusions reached. Finally, because of the problems addressed above and because this paper is mainly descriptive without bringing real new hypotheses this paper might not participate in moving the field of ALS significantly forward. Thus, the three reviewers and I agree that the paper would be better suited for a specialised audience assuming detailed comments about the methodology are addressed.

Summary: The reviewers all appreciated the potential of the work and felt that the general approach followed was strong. The reviewers, however, raised several important concerns. Discussion among the reviewers emphasized the importance of these. Chief among these was a concern about the extent to which the paper breaks new ground in a way that will appeal to a broad audience. Specifically, several of the results reported are expected based on prior work on the retinal pathways involved, and the results that do not fit with existing knowledge were not pursued in sufficient detail. These, and several other concerns, are detailed in the individual reviews below.

Summary: Zhang et al. describe an interesting method to label newly synthesized lipids with fluorescent fatty acids and track their movement in cells. All reviewers agreed that this could potentially be a useful tool. However, they all raised concerns regarding the rigor of the characterization of this methodology.

Summary: All three reviewers were enthusiastic about the identification and characterization of a hybrid secretion system involved in lipoprotein acylation and trafficking. We were impressed by the strength and extent of the data and the clever use of genetic, biochemical and bioinformatic approaches. At the same time, there was agreement that the conclusion that acylation is involved in CexE secretion is not fully supported. There was also consensus that overlap between this study and the 2020 PLOS Pathogen paper from Belmont-Monroy, necessitates more direct acknowledgement.

Summary: Kim and colleagues present a secondary analysis of an already published imaging dataset in 40 participants going through a two-week compassion training paradigm. They show participants standardized statements that are emotional or neutral and further have participants either engage in "self-criticism" or "self-reassurance" while considering the statements. The authors report on differences in brain regions (what they refer to as "neural pain") depending on criticism or reassurance condition. Concerns with the conceptual framework, approach, and interpretation substantially dampened our enthusiasm.

Summary: Specifically, the proposed model system is valuable to study ex vivo the infiltration of the growing thrombus by granulocytes using fluorescent microscopy. In addition, this system has the potential to facilitate investigations on the role of granulocytes in thrombus growth and immune-thrombosis. Granulocytes have been classified into two different types based on their DiOC6 staining pattern, namely, type A with uniform DiOC6 and type B with cluster-like DiOC6. However, it remains unclear if the staining pattern is homogeneously so clear-cut and if the type A and B granulocytes are in addition defined by their velocity. Granulocyte activation process by "priming agents" has to be validated and the rationale for using the chosen agents needs to be provided. Finally, better-defined controls for the part of the paper dedicated to the synergistic effect between granulocytes and platelets during thrombus growth are necessary. Because in the Wiskott-Aldrich syndrome (WAS) granulocyte motility as well as platelet number and function are impaired, blood from patients with WAS is not an appropriate control for this study. For example, for the control experiments, the following controls might be used in replacement of WAS blood: (1) blood from thrombocytopenic patients or platelet-depleted blood and (2) blood in which granulocyte mobility/activation is inhibited. Finally, it would be interesting to see if neutrophil extracellular traps (NETs) develop in this model system.

Summary: The authors propose a new approach to the derivation of cancer signatures and compare the relative impact of gene expression data with respect to other variables, particularly SVN and CVNs. The simplicity of the idea and of the technical approach, to the point of singling out a single gene predictive value, is a positive aspect. There are also critical aspects that will require substantial revision including the underlying influence of tissue specific genes. Overall, the paper provides a good basis for the generation of specific hypotheses that can be followed by additional validation studies at the computational and/or experimental level.

Summary: Mishra et al. present data characterizing the effect of asprosin neutralizing antibodies on the parameters of metabolic syndrome (weight, glucose, lipids, etc). This group were the initial discoverers and characterized asprosin as a hormone that increases blood sugar and stimulates appetite. In their Nature Medicine 2017 article they also present data on a neutralizing antibody. In this follow-up manuscript the group characterizes the impact of neutralizing monoclonal antibodies on metabolic parameters of three mouse models of obesity (DIO, NASH diet and Leptin receptor knockout). The translational focus of the manuscript is potential use of monoclonal antibodies against aprosin as a treatment of metabolic syndrome.

Summary: All reviewers agreed that the neural mechanisms by which value is conferred to stimuli that were never directly paired with reinforcement is an important topic. However, individual reviewers raised questions regarding the study design and data analysis. In particular, reviewers agreed it was not clear how you could distinguish BOLD responses to CS1 and CS2 given the temporal proximity of their presentation. They also wondered whether the current results would provide enough advance beyond previous work.

Summary: The manuscript is a replication of findings from Griffis et al., 2017, and it seeks to validate those findings using a different modality (diffusion-weighted imaging; DWI). While the questions asked in this manuscript are of considerable interest to the field, the findings' focus and implications are relatively narrow. Further, the study does not reveal new conclusions about brain function or organization. Authors may be cautious about interpreting the findings as representing direct structural connections between the occipital and frontal cortex -- as the reported structural and functional connectivity values may not be strong enough to support such a strong interpretation. The reviewers also agree that the methods are not presented clearly, in a manner that is straightforward to follow and critique.

Summary: The reviewers were excited by the structural data, and felt that the structure represents an important advance in our understanding of ANTAR domain proteins. Nonetheless, while the reviewers found the proposed model of ANTAR regulation to be interesting, they raised concerns about the limited evidence in support of this model. In addition to the suggestions in the individual reviews, the authors thought the model could be tested using mutagenesis together with an in vivo or in vitro reporter system, and/or by structural studies of nascent transcripts in transcription complexes with EutV.

Summary: The findings presented in this manuscript are interesting. They show that selection is happening at multiple scales - among viruses within a cell - and between their host cells within a population. The conflict between these levels of selection results in evolved populations that are less fit than the ancestors. This work demonstrates that evolution may not be a simple linear march of progress. Rather, progress over short time scales can sometimes lead to a reduction of fitness over the longer time scale due to the evolution of ecological interactions.

Summary: Your manuscript is an excellent account of the cellular and genetic mechanisms involved in the diversity of corpus callosum dysgenesis (CCD) phenotypes in humans and in a mouse model. Your work over the years has revealed that interhemispheric fissure (IHF) fusion is critical for proper formation of the callosum and its failure is the main cause of complete CCD. Here you nicely show that the extent of aberrant interhemispheric fissure (IHF) remodeling does in fact correlate with commissure dysgenesis severity, in inbred and outcrossed BTBR mouse strains, as well as in humans with partial CCD. The phenotypes in the mouse are very similar to what is found in humans, and also variable, perhaps related to stochasticity on the mechanisms involved, or to the dependency on other allelic variants.

You also identify an eight base pair deletion in Draxin and misregulated astroglial and leptomeningeal proliferation as genetic and cellular factors for variable IHF remodelling and CCD in BTBR acallosal strains. The Draxin mutations interrupt the normal remodeling (closing) of interhemispheric fissure necessary for callosal axons to cross. Your study thus places the focus on midline cellular populations and away from axonal navigation as the main source of corpus callosum dysgenesis. The findings are important to understand what mutations cause CCD in humans and how, mechanistically, it occurs.

This manuscript was co-submitted with https://www.biorxiv.org/content/10.1101/2020.08.03.233593v1

Summary: Your study used simulated elephant poaching to investigate the impact of selective individual removal on the functional resilience of animal social networks to human-induced disturbance. This topic is interesting and timely, because understanding how threatened animal populations are impacted by humans is of critical importance and requires more study -- especially for species/processes with limited real-world data, but with a potentially strong impact on ecosystem functioning. However, the reviewers unanimously agreed that the logic and assumptions underlying the study are problematic and, thus, limit the insights that can be drawn from the simulation results. They highlighted specifically that the network metrics used to infer functionality are not supported by field data on elephants, or indeed any other study systems. Please find more detailed comments from all three reviewers appended below.

Summary: This work builds on prior studies by the Foisner group that investigated the function(s) of the soluble A-type lamin binding protein, LAP2a. One of their prior observations using antibody labeling was that there appeared to be a depletion of the nucleoplasmic pool of A-type lamins in cells lacking LAP2a. In this manuscript, the authors employ CRISPR-Cas9 editing to develop new tools to investigate the attributes specific to nucleoplasmic versus lamina-integrated A-type lamins. Using this new approach (and comparing it with their prior observations), the authors hit upon a new model in which LAP2a influences the conformational state of A-type lamins, which in turn influences its detection by a commonly used antibody. This technical detail explains the new realization that nucleoplasmic lamin A persists in LAP2a-null cells, albeit in a different state. The authors provide evidence that LAP2a antagonizes stable lamin A filament assembly, that is absence leads to stabilized intranuclear lamin A assemblies, and that telomere mobility is negatively influenced by loss of LAP2a in a manner depending on the presence of lamin A/C. The authors' work further identifies two pathways by which nucleoplasmic lamins emerge, namely by 1) initial localization to the lamina followed by relocalization to the nucleoplasm, and 2) from the pool of mitotic lamins which are not associated to the lamina.

Overall there was enthusiasm for the study, with the reviewers stating their appreciation for the author's mechanistic approach to studying lamin assembly state and the use of complementary cell biology/microscopy and biochemical approaches. The rigor of the science was also lauded, including inclusion of, for example, genome editing quality control measures. Taken together the reviewers felt that the findings provided a new perspective on how LAP2a influences the state of A-type lamins. As the impact of lamins on nuclear organization is critical for nuclear functions and important for nuclear integrity, these results are fundamental for the understanding of both lamin A/C and LAP2a.

Summary: This cognitive modeling study on a timely topic investigates the combination of reinforcement learning and decision-making for modeling choice and reaction-time data in sequential reinforcement problems (e.g., bandit tasks). The central claim of the paper is that the often-used combination of reinforcement learning with the drift-diffusion model (which decides based on the difference between option values) does not provide an adequate model of instrumental learning. Instead, the authors propose an "advantage racing" model which provides better fits to choice and reaction-time data in different variants of two-alternative forced-choice tasks. Furthermore, the authors emphasize that their advantage racing model allows for fitting decision problems with more than two alternatives - something which the standard drift-diffusion model cannot do. These findings can be of interest for researchers investigating learning and decision-making.

The study asks an important question for understanding the interaction between reinforcement learning and decision-making, the methods appear sound, and the manuscript is clearly written. The superiority of the advantage racing model is key to the novelty of the study, which otherwise relies on a canonical task studied in several recent papers on the same issue. However, the reviewers feel that the framing of the study and its conclusions would require additional analyses and experiments to transform the manuscript from a modest quantitative improvement into a qualitative theoretical advance. In particular, as described in the paragraphs below, the authors should test how their advantage racing model fares in reinforcement problems with more than two alternatives. This is, from their own account throughout the paper, a situation where their model could show most clearly its superiority over standard drift-diffusion models used in the recent literature.

Summary: This study investigates how uncertainty about the values of choice alternatives affects decision-making from the perspective of drift-diffusion modeling. Both reviewers agree that this is an interesting question. The authors propose different candidate models for how uncertainty might affect the drift rate or the diffusion variance, and test these candidates on four food-preference datasets. The authors report that the best model is one in which the drift rate scales with the value of the options normalized by their respective uncertainties.

Despite the relevance of the research question, both reviewers have found the contribution of the findings to existing knowledge to be not sufficiently strong and clear. Several empirical observations reported in the study are already well known, and several of the alternative models are known to be "strawmen" for researchers in value-based decision-making and drift-diffusion modeling. In particular, the reviewers have noted that is not surprising that a lower certainty alone cannot correspond to higher diffusion noise in a drift-diffusion model, and can thus be captured by a lower drift. They agreed, and further amplified in the consultation session amongst reviewers, that the precise computational way by which this drift modulation is implemented would need to be investigated much further. Furthermore, to increase the strength of the conclusions, the authors should explore in more detail the different classes of DDMs, and the ways in which value certainty could affect other parameters of the model than the ones considered in the manuscript.