Evaluation Summary:

Bräcklein et al. provide compelling data suggesting that humans cannot learn to independently control multiple motor units innervating a single lower-limb muscle. These results suggest that common drive to motor units, along with the classical size-recruitment order, will impose strong constraints on the use of high-resolution muscle recordings for controlling brain-computer interfaces. Additional analysis related to task construction and motor unit identification/sorting is required to justify this claim.

(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 describes, characterizes, and validates a novel transgenic tool that will be useful for the study of stress neurobiology and the function of the stress-related neuropeptide corticotropin releasing factor. This tool will be especially relevant to the study of stress and related fields, such as addiction, in which rats are a critical model system. There is comprehensive histochemical and functional validation of the novel rat that broadly supports its proposed utility for visualizing and providing access to central amygdala CRF1 receptor-expressing neurons.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 and Reviewer #3 agreed to share their name with the authors.)

Evaluation Summary:

This manuscript provides a deep characterization of transcriptional regulation and conservation across key stages of complex multicellular development during mushroom formation. The authors present evidence for extensive allele-specific expression that includes many developmentally regulated genes that appear to have evolved recently. These findings help underscore how the tuning of gene expression and gains of new genes, the function of which will need to be unraveled in future, are likely the basis for the evolution of complex morphologies in fungi. This work should be of broad interest to evolutionary biologists, and especially to those studying the evolution of gene regulation.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #4 agreed to share their names with the authors.)

Evaluation Summary:

This paper represents a significant contribution to the study of gene expression and brain evolution in primates, which will be of interest to the evolutionary biology, anthropology, and comparative neuroscience communities. By performing RNA-seq on 18 taxa across the breadth of the extant primate phylogeny, the authors can examine how gene expression levels have changed over the past 70 million years of evolution and attempt to infer genes that contribute to the large amount of variation in brain size across primates. While the data set itself is valuable and exciting, methodological detail is lacking and several opportunities to leverage phylogenetically informed methods to study gene expression and brain size evolution are missed.

(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 investigates the relationships of endothelial cells that comprise the coronary vessels of the heart in mouse and humans. Starting from the knowledge that two sources of progenitor cells contribute to the coronary vessels, the work shows that adult coronary endothelial cells do not retain expression memory of their source, nor do they respond differently to cardiac injury. Finally, human datasets were generated and compared to mouse to show overall strong similarity between the species in coronary endothelial cell subtypes, suggesting that mouse is a relevant model for translation to human treatments and therapies.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their names with the authors.)

Evaluation Summary:

This manuscript is of broad interest to scientists in the field of reproduction and has clinical relevance. It builds on innovative studies interrogating the impact of cell senescence on stromal cell differentiation and embryo implantation. It presents the development of a novel co-culture system taking advantage of organoid technology to study cell-specific interactions and outcomes.

(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:

The three reviewers were overly positive about the stated goal of your T-REX method to characterize rare populations by cytometry. The potential applications in the context of analyzing antigen-specific T cells (as identified as tetramer-positive cells) were not missed on the reviewers and the use of the 2 timepoints-cohort of samples from rhinovirus-infected patients was judged clever. However, all three reviewers requested some edits and additional tests to really distinguish T-REX from other methods in terms of performance, and to better understand its analysis power. Reviewer #1 enjoined you to clarify the improvements of your method compared to previous methods. Reviewer #2 requested more stringent tests of your methods against functional datasets. Reviewer #3 inquired about corrections for batch effects, the result consistency for repeated down-sampling as well as the scalability of the method (especially when UMAP is being used).

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 and Reviewer #3 agreed to share their names with the authors.)

Evaluation Summary:

This work is of interest to clinicians, epidemiologists and policy makers as it raises concerns about under-utilization of convalescent plasma (CCP) therapy during the Covid-19 pandemic, which in turn led to an increased number of preventable patient deaths. The authors demonstrate an inverse correlation between CCP use and mortality per admission in the US. They estimate that reduced use of CCP may have resulted in 29,000 to 36,000 excess deaths over the past year in the US.

(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 addresses an important debate in the field of motor control: Can motor commands generated under uncertain conditions be better explained as an average of different candidate motor programs, or by a single motor plan that minimizes the expected costs? The paper provides evidence for the latter hypothesis. Previous studies have provided clear evidence against the motor averaging hypothesis, however the present study provides the most elegant and conclusive examination of these two ideas to date. While some of the interpretation, especially of Experiment 2, requires more nuanced consideration, overall we thought the evidence presented supported the key conclusion.

(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 is a well-presented study on the development of the central nervous system in the octopus O. vulgaris which is of broad interest to scientists in the field of evolutionary developmental biology. The authors provide an excellent in situ gene expression study of neural genes whose expression is conserved in the developing CNS across the animal kingdom. To identify the origin of neural progenitors in the early embryo, the study furthermore includes cell lineage tracing and the analysis of mitotic activity.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

Corbett and colleagues developed a novel experimental framework to account for value biases in fast-paced decisions. For this purpose, they developed detailed computational models of how value biases can alter the decision-making process and used EEG data to constrain the estimation of model parameters and their comparison. In contrast to existing accounts which describe value biases using a single bias mechanism, they found that a more complex and dynamic pattern of mechanisms best explains the EEG and behavioral 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 #1 agreed to share their name with the authors.)

Evaluation Summary:

Pupil diameter is used as an index of the brain's arousal system, and has traditionally thought to be a non-invasive index of specific neuromodulatory activity. It is therefore been heavily used as a measure in neuroscience. More recent data suggests a more complex picture whereby a pupil dilation might track cocktail of different neuromodulators. This paper provides firm data supporting this view, and introduces the new view that the make-up of this cocktail changes significantly over time. Pupil dynamics are linked with different neuromodulatory centers over different intervals of time. This is clearly important data across a broad range of human and animal systems neuroscience.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Evaluation Summary:

This manuscript will be of interest to a broad audience of researchers interested in microbe-insect interactions and how they may affect adaptation to pesticides. It presents data supporting that infection with a mutualistic virus enhances fitness in a moth, and that selection pressure represented by transgenic crops may be driving the spread of this mutualistic infection in Chinese moth populations. Specificially, infection with a densovirus appears to improve the ability of the cotton bollworm to survive on transgenic cotton expressing insecticidal proteins from Bacillus thuringiensis (Bt). The widely-grown Bt-transgenic crops control insect pests with great reductions in chemical insecticides, and anything that could reduce their efficacy is of relevance to the agricultural biotechnology community and to growers. This work suggests that virus infection of the insect pest can have unexpected interactions with the ongoing selection for Bt resistance that threatens the sustainability of Bt-transgenic crops. The impact of the work would be clearer if there was a better distinction between pest resistance (the evolution of increased tolerance due to genetic changes in the pest population) and other mechanisms of increased pest tolerance (e.g., virus infection).

(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 potential interest to a broad audience on evolutionary and population genomics, particularly scientists studying genome dynamics, including transposable elements (TE) and their evolution. It takes advantage of genomics datasets from a large population of wheat pathogens collected across the globe at different times (decades) to detect ongoing processes of genome expansion and potential selection mediated by TE insertions. The work provides empirical evidence that drastic demographic processes shape TE dynamics in nature and that these contribute to intraspecific variation in genome sizes, recapitulating the well-stablished association between TE content and genome size observed across the diversity of life forms.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1, Reviewer #2 and Reviewer #3 agreed to share their names with the authors.)

Summary:

The manuscript describes a very detailed mutagenesis analysis of the dimerization / oligomerization behavior of the protein Survival Motor Neuron. Mutations in this protein cause Spinal Muscular Atrophy. Analysis of disease causing mutations show a correlation with their impact on oligomerization. A structural model that includes different domains of the protein involved in oligomerization is built from these analyses.

This analysis is an excellent source for researchers working in the field of SMN proteins. A mechanistic interpretation of how changes in the oligomerization lead to the disease or impact the formation of membraneless organelles, is however missing. Thus, the manuscript provides an enormous amount of important mutational analysis data but does not lead to a significant advancement in our understanding of the disease mechanism.

(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 provides evidence that individuals with cerebellar degeneration show reduced effects of temporal expectation on perceptual discriminability with interval timing cues, but intact effects with rhythmic cues. The authors compare individuals with cerebellar degeneration to controls, and find a selective impairment of the individuals with cerebellar degeneration to use interval-based temporal predictions to facilitate visual discrimination, whereas rhythm-based performance benefits are spared. This study is of interest to psychologists and neuroscientists investigating prediction, perception, attention, and motor control, as it demonstrates a key role for the cerebellum in mediating the effects of interval-based temporal expectation on perception.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

This paper will be of interest to biologists who study mechanisms of cell-to-cell variability in gene expression and those who wish to have a tool to alter variability in mammalian cells. Key regulators of gene expression variability in mammalian cells are identified and noise modulation in a synthetic system is shown. The data quality is high. A model for the origin of the observed noise is proposed, but will require some additional experimental evidence.

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

Evaluation Summary:

In this report the authors demonstrate convincingly that rhythmic activity in neurons that are part of the feeding CPG in Aplysia is generated via an unusual mechanism, organelle-derived intracellular calcium fluxes. The neurons that are studied (B63 neurons) play an important role in triggering cycles of motor activity and previous work from this group has demonstrated that activity in these neurons can be modified by operant conditioning. The paper was very well received by the reviewers who were impressed by the novelty of the mechanism uncovered as a driver of a fictive motor program and thus likely behavior.

(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:

Acyl-homoserine lactone (AHL) based quorum sensing systems are an important form of intercellular communication in bacteria. These systems, minimally comprised of a synthase and a receptor, often involve different types of AHLs. This paper demonstrates that amino acids in the active site of the synthase and the binding site of the receptor have co-evolved to provide specificity for different signaling molecules, even though the synthase and receptor do not directly interact. This type of information could potentially be used to rationally engineer synthases and receptors with different specificities, as well as predict the specificities of uncharacterized synthases and receptors.

(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 paper is of potential interest to an audience of DNA repair and cancer biologists because it seeks to refine the mechanism by which cells respond to DNA damage. By combining a number of genetic experiments based on cell survival of different mutant combinations and mutation analysis, their results support the view that Shu is critical for 3meC damage tolerance in yeast. Notably, expression of human ALKBH2, responsible for the repair of 3meC rescues the MMS-sensitivity of Shu mutants but not that of homologous recombination mutants. The study supports the existence of a new pathway for the removal of an important DNA lesion that seems essential in yeast, but likely contributes in other organisms, and helps clarify the distinctive role of homologous recombination in DSB repair and post-replicative repair. A few additional experiments are suggested to strengthen the mechanistic conclusions and better support the central model.

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

Evaluation Summary:

Dravet syndrome, a severe seizure disorder resulting from a sodium channel mutation, is widely thought to result from impaired synaptic inhibition. Here the authors present multi-level evidence that excess synaptic excitation in the dentate gyrus is a locus of pathology. These results provide new insight into pathological mechanisms in Dravet syndrome that will be of interest to a broad range of neuroscientists studying epilepsy, as well as the role of the hippocampus and synaptic alterations in neurological 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. The reviewers remained anonymous to the authors.)

Evaluation Summary:

This manuscript reports a significant contribution towards an improved mechanistic understanding of light gated anion channels. The studies, which use the recently established method of in meso in situ serial data collection (IMISX), provide a basis for optimizing the anion channelrhodopsin GtACR1 from the alga Guillardia theta as a neuron-inhibiting optogenetics tool. The work will be of interest to anyone using optogenetics for functional studies. The reviewers had a few comments regarding technical aspects of the work.

(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 endeavors to explain the mechanism of action of the gram-negative bacterial outer membrane TonB-dependent transporter BtuB, which acquires vitamin B12 from the external environment. The authors use electron paramagnetic resonance spectroscopy to monitor the proximity of different parts of this protein to one another during the binding of B12 directly in the E. coli outer membrane. This manuscript will be of interest to those who study the biophysics of membrane transporters and stresses the importance of studying membrane proteins in their native environment.

(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:

Mosquito saliva can enhance transmission of arboviruses. Here, authors demonstrated that the anti-immune non-coding RNA from Dengue virus, known as the subgenomic flavivirus RNA (sfRNA), is secreted into mosquito saliva within the extracellular vesicles and can facilitate infection of the acceptor human cells when delivered together with infectious virus in mosquito saliva. The study potentially expands our understanding of flavivirus 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. The reviewers remained anonymous to the authors.)

Evaluation Summary:

This manuscript combines cell biology, biochemistry, and quantitative biophysics to understand a new host cell factor, the human I-BAR domain protein IRSp53, promotes HIV type 1 (HIV-1) assembly and release. Since this new factor is a protein involved in the generation and sensing of negative membrane curvature, this manuscript will be of interest not only for retrovirologists and virologists in general but also for membrane biologists and biophysicists.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1, Reviewer #2 and Reviewer #3 agreed to share their names with the authors.)

Evaluation Summary:

The authors have highlighted an important aspect of epithelial maintenance in an environment that experiences significant biomechanical stress due to cardiac function. Using novel genetic models, detailed imaging and a thorough transcriptomic assessment, this story has the potential to enlighten both cell biologists and cardiovascular biologists on the underpinnings of myocardial integrity.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #3 agreed to share their name with the authors.)

Evaluation Summary:

The authors found a mechanosensitive channel gene in T. cruzi, and aimed to characterize its functions. The authors provide conclusive evidence that TcMscS is a mechanosensitive channel. They also show that TcMscS has additional roles outside of mechanosensation, likely playing a role in the infectivity of T. cruzi.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

This study lays the groundwork for a new level of precision in understanding mouse navigation behaviour by studying complex decisions that approximate those made in the wild, but can nevertheless be analysed with mathematically precise tools. Several exciting observations are made about navigation strategy. The manuscript will therefore be of broad interest across behavioural neuroscience. However, in its current form, some questions remain about some of the major claims.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Evaluation Summary:

This paper will be of interest to scientists interested in mechanistic studies of ion-coupled transporters. The authors demonstrate that dopamine, catecholamine and serotonin transporters - albeit structurally very similar - differ in the number of transport substrates and they define the underlying functional basis of this difference using a range of sophisticated techniques. This is an extremely nice and interesting study. providing new tools and new insights into an important class of transporter. Since many drugs that block one of the transporters also modify the two others, the paper may help to define pharmaceutical approaches that specifically block only one of them and that might allow for a better treatment of psychiatric diseases. The data analysis is rigorous and the conclusions are justified by the data, but the paper should be made more "user friendly" so that a wider audience could appreciate it better.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)

Evaluation Summary:

This study could help shed light on mechanistic connections between latent infection by EBV with an age-dependent autoimmune condition, such as rheumatoid arthritis. The authors use two models: a murine model of rheumatoid arthritis (CIA), and a murine analog of human EBV: 𝜸HV68. The use of these two models allows the investigation of how latent viral infection exacerbates the autoimmune condition via the action of a special class of B cells: Age-associated B cells.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

This study advances our understanding of the Moody G-protein coupled receptor (GPCR) pathway in blood-brain barrier development, and describes a new role for protein kinase A (PKA) and two downstream signaling molecules in this process. It is not entirely surprising that PKA is involved, as it is downstream of many/most GPCRs, but the reciprocal localization and signaling relationship that the authors describe within subperineurial glia for Moody/PKA is very interesting. Generally, the data look very good, and the electron microscopy work is particularly nice. With some improved statistical analyses, this manuscript will make an interesting contribution to the field of neurodevelopment.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1, Reviewer #2 and Reviewer #3 agreed to share their names with the authors.)

Evaluation Summary:

This is a comprehensive study of genomic and phenotypic diversity in the orphan crop quinoa. Based on whole genome resequencing of 310 accessions and field phenotyping of the same set of accessions for two years, the study identified the genetic basis of agronomically important traits. Based on this promising work, there will likely be scope for quick improvement of this orphan crop through breeding.

(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 objective of this study is to develop a novel immunofluorescence technique allowing for the multiplexed analysis of protein targets. This 4i method is an important technical advance will be of great interest for the scientific community.

(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 manuscript will be of interest to neuroscientists as well as a broad audience of cell biologists, as it provides new insight into the myriad of cellular functions regulated by the well-studied cAMP-dependent protein kinase, PKA. Rigorous biochemical data supports a model for PKA inactivation wherein dephosphorylation of the PKA regulatory subunit within a multiprotein complex leads to rapid capture of the PKA catalytic subunit limiting signaling duration. Overall, the biochemical data and modeling support the conclusions although a few details can be addressed further and the in vivo data remains preliminary. The work nevertheless presents exciting findings that provide a tantalizing mechanism to selectively modulate PKA activity at precise subcellular locations.

(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 paper presents a sequence of models, simulating with increasing accuracy the production of phloem and xylem in a cross-section of a generalized circularly symmetric plant organ. The results may serve as a stepping stone for the construction of predictive models.

(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 identifies a cardioprotective factor, GJA1-20k (a truncated form of Cx43), which appears to confer protection against ischemia/reperfusion (I/R) injury via promotion of mitochondrial fission. This finding is particularly interesting given that hyperfission is generally thought of as an index of toxicity in I/R or hypoxic injury. I/R lesion size in a GJA1 heterozygous mutant mouse is strikingly exacerbated compared to control animals, providing strong in vivo evidence supporting a role for this factor in protection from I/R. However, while the findings are interesting and novel, key results require additional experimental support, including to address the lack of key control data, and a significant revision will be necessary to address these issues.

(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 manuscript reports a study that sought evidence of patterned inter-areal activity in the spinal cord of anesthetized rats. This could be a very significant finding, with potentially important scientific and therapeutic implications. However, the Methods lacks some necessary details, and the Results raise substantial issues that need to be resolved. Until these gaps and uncertainties are resolved, it is not possible to evaluate the results and their implications with confidence. Substantial revisions are essential.

(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 is of broad interest to psychologists, neuroscientists, and engineers who seek to understand how color information is represented in visual cortex. The experiments provide sharply focussed tests of how chromatic information is compared across different spatial locations by individual neurons in visual cortex. The experiments are sound and the results speak to fundamental principles of encoding.

(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:

Rhythmic activities play an important role in cognition and disease, and there is an increasing interest in real-time phase tracking for closed-loop applications. In this manuscript, a novel approach based on state-space modeling to estimate the phase of EEG and LFP signals in real-time is presented. Open code for distribution is readily available. The proposed model is novel, timely and makes a clear contribution to the methods base in 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. Reviewer #1 agreed to share their name with the authors.)

Evaluation Summary:

This paper is of interest to scientists within the field of thymus development and function. Analysis of the data is overall rigorous and conclusions are justified. The work presented builds upon previous studies that have shown that alterations of Wnt/beta-catenin signaling in thymic epithelial cells impact the normal development and or maintenance of thymic epithelial microenvironment critical for the proper development and selection of functional self-tolerant T cell repertoire. The surprise that a thymus epithelial cell specific loss of function of beta-catenin only showed a rather minor phenotype is interesting, but it would be good to also address whether TEC recovery after a challenge, or in aging, is also affected in a minor manner or perhaps more dramatically than the steady-state situation. The author's claims are well supported by the data presented and will be of great interest to scientists and clinicians interested in understanding the signaling pathways important in thymic maintenance, as well as the development of strategies to counteract thymic involution in the aging population and cancer patients.

(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 addresses a long-standing question, namely how does the poly(A) tail influence translational efficiency? It will therefore be of broad interest to readers from many areas of molecular biology including those interested in translation, mRNA stability, development and gene expression in general. The authors convincingly set out three criteria that must be met for coupling of poly(A) tail length with translation.

(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 excellent paper by Ma and colleagues assesses the role of assortative mixing in regards to racial and ethnic disparities to estimate herd immunity thresholds (HIT) for SARS-CoV-2. The paper is conceptual in nature and builds on similar models which have been particularly useful to understand the dynamics of sexually transmitted diseases. The model is explained well and the paper is clearly written. The conclusions are justified by the analysis. One limitation is that the model is trained against a single cross-sectional seroprevalence estimate (one in NYC & one in Long Island) which allows for multiple models (ranging from homogeneous mixing to proportionate mixing) to recapitulate the data and in turn does not allow general estimates of HIT for these regions. It is also unclear if a more realistic epidemic simulation that included repeated waves of infection &/or vaccine roll out would change the conclusions regarding HIT according to race and ethnicity.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1, Reviewer #2 and Reviewer #3 agreed to share their names with the authors.)

Evaluation Summary:

Recent experiments have raised questions regarding concentration buffering provided by the formation of multicomponent biomolecular condensates via phase separation driven by heterotypic interactions. In this work, Chattaraja et al., demonstrate that the concept of a solubility product, used to describe the solubility limits of ionic solutions, sets an upper limit on concentration thresholds, even in systems where the driving forces for phase separation are primarily heterotypic in nature. Their work suggests that the concept of a solubility product rescues the concept of buffering via phase separation.

(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:

SARM1, an enzyme that can convert NAD+ to ADP-ribose or cyclic ADP-ribose, is implicated in axon degeneration. This manuscript describes the development of small molecule probes that can detect the activity of SARM1 in live cells. In the course of the work, a small molecule derived from an hypertension drug was discovered as an effective SARM1 inhibitor. Although the activity probes are novel, the mechanism of SARM1 inactivation by dHNN has not been established. The probe and the inhibitor described in the manuscript could lead to future therapeutic development targeting SARM1 to treat axon degeneration.

(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 is a large population based study examining the familial risks of cancer in a California population limiting the analysis to cancers occurring under the age of 30. The work has found that risk of cancer is increased if a person has a first degree relative with cancer. Increased familial risk of cancer to first (and second) degree relatives is long established, but this is a large source of data and it is nonetheless valuable to have this published. They have been able to look specifically at Latino risks as this is a common ethnic group in California.

(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:

Different ESCRT-III subunits share sequence similarity but have been characterized in distinct conformations and perform distinct roles in the polymerization process that is central to ESCRT membrane fission pathways. Here it is shown that mutations in one ESCRT-III subunit can compensate for loss of a different subunit by encoding the specialized roles of both subunits within one polypeptide. These findings will be of interest to investigators studying ESCRT pathway mechanisms and those more generally interested in the adaptability of protein sequences and functions.

(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 paper is of broad interest to neuroscientists studying Parkinson's disease, dopamine (DA) modulation and striatum. The authors use a layered in vivo calcium imaging approach with cell-type reporters and universal GCaMP expression to simultaneously evaluate striatal projection neurons in the direct and indirect pathways (dSPNs, iSPNs) during basic locomotion. The authors report relationships between dSPN and iSPN ensemble sizes and DA pharmacology and dopamine depletion states. These results advance understanding of DA modulation and Parkinson's 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 #3 agreed to share their name with the authors.)

Evaluation Summary:

This paper sought to assess the relationship between developmental lineage and connectivity. It relies on detailed EM reconstructions and the knowledge of complete neuroblast lineages, thus correlating wiring with lineage. Through genetic manipulations of Notch function, it also correlates developmental programs with wiring. The conclusion is important and provides a well described cellular and genetic system for linking the developmental program of a cell to its connection specificity. It provides a framework for considering how to study these questions in other regions of the Drosophila brain and can be extended to the study of more complex mammalian systems where a similar neuroblast-lineage strategy generates different neuron types.

(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 reviewers found your description of the new method interesting and potentially useful for the field. They raised concerns about fusion protein's functionality and reagent accessibility among other technical questions.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Evaluation Summary:

This paper will be of interest to a larger neuroscience community as this is the first functional demonstration of presynaptic NMDA receptors at mossy fiber terminals in the hippocampus. NMDA receptors are generally known for being critically involved in learning & memory as coincidence detectors in Hebbian plasticity. Some studies, however, find NMDA receptors that function in more unconventional manners. The present paper provides strong evidence for the existence of such unconventional NMDA receptors at a specific subset of hippocampal mossy-fibre boutons. The combined use of electron microscopy, electrophysiological, optogenetic, calcium imaging, and genetic manipulation approaches expertly employed by the authors yields high quality compelling evidence in full support of the study's main conclusions. Overall, the investigation is well designed with a clear hypothesis, appropriate methodological considerations, and logical flow resulting in a well written manuscript that is sure to be of broad scientific interest.

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Evaluation Summary:

This study by Wang et al. used a series of carefully designed behavioral experiments to convincingly demonstrate that the attentional blink (AB) could be modulated by higher-order rhythmic regularity. EEG results further support the link between the elicited neural entrainment and the AB modulation effect. They propose that the rhythmic context implements a second-order temporal structure to the first-order regularities posited in dynamic attention theory.

(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 reveals the existence of a novel Notch-containing signaling hub, organized by Sanpodo and Par3, that operates in Notch receptor signaling during cell fate decisions in the peripheral nervous system of Drosophila. These Notch clusters are modulated by components of the Notch signaling pathway, and are proposed to reinforce Notch signaling by concentrating ligands and receptors. These findings are highly relevant to different areas of biology including membrane biology, cytokinesis, PAR polarity, Notch signaling and cell fate decisions making.

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Evaluation Summary:

This study identifies and describes the functional properties of antennal lobe output neurons towards the response to pheromone odors in the moth brain. This paper will be of interest to neuroscientists investigating how sensory information is organized in the brain. Through a combination of technically challenging experiments, the paper identifies the brain regions that differentially process attractive vs aversive olfactory pheromone signals. While not an exhaustive data set, it provides compelling evidence for one model of how the moth brain interprets complex pheromone olfactory odors.

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Evaluation Summary:

This study, based on an elaborated animal sample collection, reconstructs a comprehensive tree of Eulipotyphla, especially concentrating on Talpidae (moles), and infers the transitions of their lifestyles. It also models myoglobin structure and calculate electrophoretic mobility, demonstrating that semiaquatic eulipotyphlans have a higher net surface charge than fossorial, semifossorial, and terrestrial relatives. This variable myoglobin property indicates convergent shifts to a semi-aquatic lifestyle in multiple independent lineages including three separate times by ‘water shrews’, the smallest endothermic divers.

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Evaluation Summary:

This is an interesting and thorough study of the developmental roles of the G-coupled protein receptor Adgr6 in spine development that contributes both to the understanding of spine morphogenesis and the etiology of common types of scoliosis that are of unknown origin. Using conditional mouse knockouts, the authors dissect the contributions of Adgr6 in each spine-associated tissue. In addition to the use of state-of-the-art genetic tools, the authors show beautiful histological and tomography data illustrating developmental processes and phenotypes with great detail. Their results also implicate cAMP signaling and CREB activity in the regulation of mechanical properties of dense spine tissues.

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Evaluation Summary:

Binding of cargo to sorting receptors in membrane trafficking is essential to cellular organization. This work is significant because it generates a detailed model of the key residues accounting for specificity and affinity of binding by the KDEL receptor. Interestingly, it is not the affinity per se that accounts for the specificity of cargo binding but rather charge-based exclusion of potentially competing signals.

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Evaluation Summary:

This paper is of interest to scientists within the field of motor control and biomechanics studying human locomotion. The work provides evidence for the optimization of muscle function during locomotion depending on the specific biomechanical constraints. The overall methodology is sound and data are properly analyzed, although the in vivo measurements required a complex experimental setup together with sophisticated modeling which on the one hand conclusively support the key claims of the paper for the experiment within this paper, on the other hand weakens the generalizability of 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 manuscript describes the effects of maternal diet-induced obesity on lipid composition in maternal and fetal serum and the fetal heart, and in the fetal heart transcriptome. This study revealed sex-specific effects of obesity during pregnancy. The results presented provide insight into the still poorly understood processes influencing the long-term health of the fetus.

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Evaluation Summary:

The main strength of the manuscript is the data sets generated by the cell type-specific RNA-seq and TRAP-seq in cerebellar PCs that lack Tsc1. In addition, the bioinformatic analysis revealed several interesting findings, including the observation that FMRP target RNAs are reduced in the Tsc1 mutant PCs and that the translational efficiency of these RNAs is actually increased, likely through compensatory mechanisms.

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Evaluation Summary:

This manuscript describes a critical function for interferons (IFNs) in suppression of spontaneous autoinflammatory disease. The inflammatory disease is seen in mice lacking all types (I, II, III) of IFN signaling and is ameliorated by deficiency in interleukin-17 as well as by antibiotic treatment. The latter result implies a role for the microbiota in disease pathogenesis, but it remains unclear whether or how IFNs regulate the microbiota composition, whether this occurs across genetic backgrounds or housing conditions, or how exactly IFN deficiency leads to inflammatory disease. Nevertheless this work demonstrates a critical regulatory function for tonic IFN signaling in suppressing autoinflammation that serves as a foundation for future studies and will be of interest to a broad audience of immunologists.

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Evaluation Summary:

The present paper investigated the role of cortico-cerebellar loops in motor control with high density physiological recordings and by using optogenetics to perturb responses of precerebellar neurons in the pontine nuclei during reaching. The study adds to a long line of work supporting the view that the cortico-cerebellar pathway is required for fine motor control. The experiments are well performed, but a number of revisions in analysis and presentation are required.

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Evaluation Summary:

This article contributes to the fundamental understanding of how a cell grows. It provides a broadly applicable method for dry mass measurement of single cells and, using it, it describe how cell density varies accross the cell division cycle. The key finding of this article is the fact that growth in mass and volume seem to be generally uncoupled, leading to significant density changes.

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Evaluation Summary:

Non-canonical pathways for regulating protein synthesis in animals serve important roles for controlling gene expression in critical developmental pathways. Homeobox (Hox) genes encode many mRNAs regulated at the level of translation. A general feature for many of these mRNAs has been the proposal they are regulated by Internal Ribosome Entry Sites and possess sequences in the 5'-untranslated regions of the mRNA that prevent canonical cap-dependent translation, termed "translation inhibitory elements". Here, the authors focus on two Hox mRNAs and find they use entirely different means to achieve the same end of repressing cap-dependent translation. Overall, the experiments support the major conclusions drawn by the authors, and nail down mechanisms that have been left unresolved since the Hox mRNAs were first discovered to be regulated at the level of translation.

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

Evaluation Summary:

This work will be of general interest to neuroscientists, especially those studying how the brain processes itch stimuli and controls itch-related behavior. The authors show that specific cells in the central amygdala (and their communication with other parts of the brain) play an important role in itching (pruritic) behavior. Overall, the authors provides several lines of evidence to support their conclusions.

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Evaluation Summary:

The manuscript revisits an enduring and central question in population genetics known as Lewontin's paradox: that in contrast to the prediction of the field's null model, which suggests that levels of neutral genetic diversity should be proportional to the census population size, in reality, census population sizes span several orders of magnitude more than the approximately three orders of magnitude spanned by levels of genetic diversity. The manuscript provides a nice review of previous work as well as thought-provoking novel analyses. There are also several issues that make it difficult to interpret the new results.

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Evaluation Summary:

Stephani et al. address the question of how ongoing fluctuations in neuronal excitability, as well as stimulus strength, impact the perception of above-threshold tactile stimuli and the subsequent stimulus-evoked brain activity. The results are puzzling in an interesting way, and while the authors provide a nicely parsimonious explanation rooted in the underlying neurophysiology, editors and reviewers think this study has the potential to further motivate many lines of investigation. This manuscript will be of interest mainly to researchers using electrophysiological methods (EEG, MEG, ECoG etc.), as the authors have produced a very high-quality EEG data-set (including uncommon peripheral measurements).

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Evaluation Summary:

By using mice lacking the hypoxia inducible factor-1α (HIF1α) in NK cells, the study unravels a previously unknown function of this transcription factor in virus control by NK cells. Mechanistically, the authors provided evidence that HIF1α supports survival of NK cells through an efficient glucose metabolism required for optimal NK cell response to viral infection.

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Evaluation Summary:

This is an interesting and informative study reporting on the molecular features of reversible hair graying in humans and the connection with psychological stress. The study appears to have been very well conducted and the interpretations are generally supported by the data. While the results are primarily correlative at this stage, this work will set the stage for future more mechanistic studies and represents an important conceptual and methodological advance.

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Evaluation Summary:

The manuscript outlines an epidemiological framework to investigate the relative contribution of different hosts and vectors to the initial spread of a zoonotic disease. It focuses on Ross River virus in Brisbane and collates previously published estimates of abundance, biometrics and viral profiles to highlight the most epidemiologically important routes of transmission.

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Evaluation Summary:

The development of single-cell genomic methods has transformed our understanding of cell types and their attributes across organisms. Here, Tarashansky et al develop SAMap (Self-Assembling Manifold mapping), a graph-based data integration method which builds upon their previously described SAM algorithm to facilitate assignment of homologous genes and cell types across diverse species. As the authors show, this empowers comparative analyses across phyla to facilitate cellular annotation and examine the evolutionary origins of cellular diversity. Overall, the manuscript is well-written and the algorithm has the potential to be foundation for comparative cellular atlasing.

(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:

Ferroptotic cell death underlies tissue dysfunction inflicted by transient ischemia/reperfusion particularly in renal tissue. Here, the authors provide experimental evidence in animal models and human biopsies that mild and severe ischemic stress trigger distinctive cellular responses in proximal tubular cells which decide upon whether or not tissue may regenerate or fail. This is further corroborated in a genetic mouse model with mild ischemic stress-induced ablation of the key ferroptosis regulator glutathione peroxidase 4 (GPX4). These studies will be of significant interest both to those studying acute kidney injury and others interested in ischemic injury in other organ systems.

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Evaluation Summary:

This interesting and well-executed work addresses the function of one of the subunits of the signal peptidase, a complex that processes signal peptides in a wide variety of secretory and membrane proteins. This topic is of relevance to the membrane cell biology community, and the study will be of broader interest when the authors demonstrate the relevance of their findings to the natural substrates of the studied enzyme.

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Evaluation Summary:

The present paper addresses the relationship between the electrophysiological and the anatomical connectomes, utilising a method to describe avalances of activity. The editors feel that this work might be pushing the limits of MEG as a modality, since it implies more spatial precision that most would assume possible, which makes the manuscript particularly interesting to M/EEG researchers. While all reviewers agree that the paper has broad interest and the method is promising, some potential concerns have however been raised that compromise the validity of the results. Most importantly: the issue of volume conduction (proximity) driving the results as opposed to anatomical connectivity, which in the worst case could deemed the results trivial. Other confounds, such as the size of the parcels and their SNR, would also require major review.

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Evaluation Summary:

This study uses a genome-wide association approach combining pool-seq data with whole-genome resequencing, which provides a cost-effective means to scale genome-wide association studies to a larger number of individuals, to dissect the genetic basis of drought resistance in several German populations of European beech. European beech is an ecologically important forest tree species and drought resistance is a trait that is likely to be becoming increasingly relevant to the survival of these trees as climate change leads to more frequent and prolonged periods of drought. Knowledge of the genetic basis of such variation existing within current populations can help with management of those populations in the face of increasing threats, especially when such information is used to develop tools for predicting individuals that are likely to have the highest chances of survival, and to suggest hypotheses regarding traits and genetic material which will be important for the future of forests.

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Evaluation Summary:

This well-done study establishes a work flow for the analysis of the peptidome of wound fluids. By doing so it enables the identification of peptide patterns associated with wounds that are healing versus non-healing. The method may therefore help to define candidate biomarkers for wound healing. Overall enthusiasm was somewhat dampened by findings previously reported by the same group and also by others.

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Evaluation Summary:

The authors consider how the geometry and motility of cilia affect their performance in detecting chemicals in the surrounding fluid. Based on a theoretical model, the authors suggest that the distinctive elongated shape of a cilium may be coupled to its sensory function. The conjectures presented in this work are likely to be of interest to a wide readership, but whether this actually applies to real biological systems requires more careful validation.

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Evaluation Summary:

This study uses a new approach to map all neurons in the brain that have been infected with Toxoplasma gondii or injected with parasite proteins. The authors show that Toxoplasma injected neurons are heterogeneously distributed in murine brain tissues, that excitatory neurons are the primary targets, and that injection of parasite proteins leads to neuronal death. This work provides new insights into Toxoplasma-neuron interactions that underlie the pathology and potential changes in behaviour of infected individuals. The manuscript will be of interest to those working in neuroscience and/or parasitic infections.

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Evaluation Summary:

This paper addresses the important question of multidrug resistance evolution, which is of both theoretical and applied interest. The authors efforts to carefully distinguish population and metapopulation linkage disequilibrium and to develop a framework to rigorously analyze the relationship between the two has promise, although we have noted concerns about the modeling framework used and results interpretation. If these concerns can be sufficiently addressed, then this paper has the potential to represent a clear advance in our understanding of microbial population dynamics.

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Evaluation summary:

This manuscript will be of interest for scientists interested in cell cycle, DNA repair, transcription and genome stability opening a new chapter in studies of cell cycle dependent regulation of DSB repair. Much of the prior work has focused on cell cycle-driven post-translational regulatory modification of DSB end resection, whereas the current work finds transcriptional programs are equally, if not more, important in controlling resection in G0. This could open possibilities for gene therapy in post-mitotic tissues. The data are of high quality and the conclusions drawn are supported by the experimental evidence.

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Evaluation Summary:

This paper will be of broad interest to cell biologists and advances the current understanding of the connection between lipid metabolism and stem cell function. The data generated from multiple complementary experimental approaches are of high quality and convincingly support the claims made.

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Evaluation Summary:

The authors used EEG-based multivariate pattern analysis and acute stress induction to assess the neural representations mediating a previously demonstrated influence of stress on the balance between goal-directed and habitual responding. While the results should be of interest to a wide range of neuroscientists, the temporal alignment of clinical, behavioral, and neural measures somewhat obscures the underlying causal mechanisms.

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Evaluation Summary:

The study investigates the molecular characteristics of chemotherapy-resistant colorectal cancer cells and proposes a therapeutic alternative for chemo-resistant cancer. The authors provide evidence in vitro that chemo-resistant cells are pro-apoptotic in the presence of the death receptor ligand TRAIL due to the enhanced localization of the death receptor DR4 in the lipid rafts of their plasma membrane. Based on this finding, the authors treat blood samples from 5 colorectal cancer patients with TRAIL-conjugated liposomes and observed reduction in the number of circulating cancer cells in the blood draws.

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Evaluation Summary:

Since DBS of the habenula is a new treatment, these are the first data of its kind and potentially of high interest to the field. Although the study mostly confirms findings from animal studies rather than bringing up completely new aspects of emotion processing, it certainly closes a knowledge gap. This paper is of interest to neuroscientists studying emotions and clinicians treating psychiatric disorders. Specifically the paper shows that the habenula is involved in processing of negative emotions and that it is synchronized to the prefrontal cortex in the theta band. These are important insights into the electrophysiology of emotion processing in the human brain.

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Evaluation Summary:

This manuscript describes extensively a fully automated procedure to train mice to perform voluntary head-fixation, and a whisker-based tactile discrimantion task. In addition the authors demonstrate that with this procedure, light illumination of red-shifted opsins expressed in inhibitory neurons can be used to selectively silence targeted brain regions during the task in a non-invasive manner. Together, although volontary head-fixation training and automated behavior has been readily implemented in different contexts, this study elegantly delineates important steps to boost the acceptancy and duration of head-fixations and thereby train more complex tasks. The demonstration of transcranial optogenetics in this context also opens the possibility to perform precise brain inactivations during well-controlled sensory stimulations, in self-initiated behavior.

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Evaluation Summary:

The manuscript describes an improved methodology for performing electrophysiological experiments (involving recording of the activity of tens or hundreds of neurons in the brain simultaneously) in freely behaving mice and rats using silicon probes. By providing a versatile microdrive and head cap design for rodents, this paper may contribute to ease silicon probe chronic recording and recovery, thus reducing experimental costs and making the technique more accessible. The paper is expected to appeal to a broad range of systems neuroscientists who seek to understand how the brain commands movement and behavior.

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Evaluation Summary:

This paper will be of considerable interest to researchers studying the interactions between metabolic responses in myocardial infarction. Ultimately increased understanding of these interactive metabolic responses could lead to exploration of new avenues of treatment.

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Evaluation Summary:

This manuscript will find a broad audience in the fields of evolutionary and developmental biology, especially herpetology, systematics, and those interested in the evolutionary history of vertebrate teeth. The expansive dataset presented by the authors has allowed for rigorous computational analyses yielding new insight into the evolutionary history of teeth in frogs, which is a topic that has received little attention from the scientific community. The resulting data largely support the key claims of the manuscript.

(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 addresses how antiviral treatment regimens impact persistence of an HIV reservoir in individuals who are treated for a long period. The authors examine measures of viral reservoir to understand how different antiviral treatment regimens impact residual virus in HIV infection. They find that NNRTI-based treatments are associated with lower viral reservoirs and better viral suppression than PI-based regimens, suggesting they may have some advantage at reducing HIV levels long term.

(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 study by Song and colleagues explores the role of circRNAs in fibrosis of the endometrium. The paper is of interest for scientists working in the field of endometrial fibrosis and most likely can have implications for other endometrial disorders characterised by fibrotic tissues. The study unravel the molecular mechanism underlying the disease and the thorough experimental part fully support the author's claim.

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Evaluation Summary:

The paper describes an algorithm that combines epidemiological and sequence data to provide a rapid assessment of the probability of healthcare-associated infections among hospital onset SARS-CoV-2 infections, that also may be associated with outbreak events. There is an urgent need for tools that can synthesise multiple data streams to provide real time information to healthcare professionals. It is questionable to what extent the tool presented is generalisable to medical facilities outside of the specific data rich settings considered here, or if the tool is useful for prospective analyses. This study would be of interest to specialists working in hospital infection prevention, with more limited further interest.

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Evaluation Summary:

In this manuscript, Katrukha et al. use STED and Expansion Microscopy techniques to map the distribution of different microtubule populations within the dendrites of neurons, a challenging task due to the tight bundling of microtubules along neuronal processes. They are able to show that dendritic microtubules are either acetylated or tyrosinated, but rarely have both or neither of these post-translational modifications. The strength of this paper is the quality of the experiments, the thoroughness of the analyses, and most importantly the transparent and critical discussion of the limitations the authors have encountered. This manuscript is of broad interest to the cytoskeletal and neurobiology fields.

(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:

30 million years ago the ancestors of Old World primates lost the ability to produce alpha-gal due to the fixation of several loss-of-function mutations in the GGTA1 gene. The evolutionary advantage of such loss remains elusive. Here, the authors provide additional insights into the pleiotropic role of ggta1 in shaping the gut microbiota, immune function, susceptibility to sepsis, and eventual fitness advantage.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1, Reviewer #2 and Reviewer #3 agreed to share their names with the authors.)

Evaluation Summary:

Paget disease of bone (PDB) results in focal areas of disorganized bone, leading to bone deformities and fragility. There is substantial interest in finding circulating biomarkers that might be of use for possible diagnostic applications and towards this end, these authors identified novel DNA methylation patterns in peripheral blood mononuclear cells that are able to differentiate PDB cases from controls with a high level of accuracy. This prediction model has functional relevance as these candidate methylation sites and regions are associated with osteological and immunologic processes and in the longer term, has future clinical potential.

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

Evaluation Summary:

This manuscript will be of interest to neuroscientists and psychologists interested in how semantic information is encoded in the brain. It provides a framework for a model driven comparison of semantic encoding in recurrent neural networks and neural data. Limitations in the ways the neural data are analyzed and compared to the model provide only limited support for the major claim regarding the nature of the semantic code in human anterior temporal lobe.

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Evaluation Summary:

This manuscript is of potential interest to the field of cell death research in terms of understanding basic mechanisms and in the context of disease. The authors have used a broad range of methodologies and identified key phosphorylation sites on the protein kinase RIPK3 that determine whether cells undergo necroptotic or apoptotic cell death. The authors examine this phosphorylation event in the context of corpus luteum regression.

(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 is of broad interest to readers in the field of clinical neuroscience and movement disorders. The identification and characterization of dynamic networks that are differentially affected by dopaminergic medication in patients with Parkinson's disease is an important contribution to our understanding of physiologic and pathologic brain activities. The used methods provide the potential to uncover spectral, local, and temporal properties of dynamic neural systems. Overall, the data are properly analyzed, although many aspects of reporting the results could be worked out better.

(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:

Infantile parkinsonism-dystonia is a rare but devastating condition that leads to early mortality. Mutations in the dopamine transporter that decrease its transport activity or cell surface expression have been identified as potential causes of this disease. Here, Aguilar et al perform a series of experiments to examine the effect of one of the mutations, R445C, on properties of the transporter in cell culture and on motor function in newly generated transgenic flies. They also explore structure function relationships of the mutation using X-ray crystallography of LeuT, a bacterial homolog, and molecular modeling. Lastly, they show blocking lysosomal degradation rescues a motor deficit in the flies. Insights from the work could lead to new approaches to specifically modulate the transporter structure to restore surface expression and function of the mutant dopamine transporter in this disorder. This elegant and technically sophisticated analysis is of interest to readers in the fields of neurobiology, behavior, and movement disorders, as the work provides an excellent example of using a variety of different approaches to determine the relationship between transporter structure and activity and potentially underlying pathology in human disease.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Evaluation Summary:

These data provide in vivo evidence for a previously described kinetic-proofreading mechanism in phase-separated condensates. The strength is being able to compare the impacts of clustering of signaling molecules with a non-clustered control in the same cell. The limitations are that there is not necessarily new biological insight gained and the effects reported are surprisingly modest compared with expectations from reconstituted systems. This paper will be of broad interest to scientists who study membrane-associated cell signaling.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Evaluation Summary:

This paper will be of interest to neuroscientists studying decision-making and the frontal lobe. The paper combines computational modeling with brain imaging across several datasets to better understand the role of brain regions previously implicated in self-control during normative behavior (generosity, healthy eating). On balance, the data provide more support for the view that dorsolateral prefrontal cortex is involved in reading out the evidence in favor of different choice alternatives than the view that this region implements control processes that bias choices towards normative goals.

(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:

Loss or decrease of cholinergic tone occurs during brain aging or in pathologies such as Alzheimer's disease. This elegant study has used in vitro and in vivo approaches to explore the impact of decreased cholinergic signaling on hippocampal/cortical microglial state. The study demonstrates that the neurotransmitter Acetylcholine (ACh) maintain microglial cells in a homeostatic state, preventing their priming towards an activated state that leads to an exacerbated response to an inflammatory stimulus. The study thus provides important insights on the feed-forward contribution of microglial cells to neurodegenerative conditions.

(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 identified the enzyme involved in the transfer of the second GlcNAC residue on the nascent oligosaccharide in protein N-glycosylation of the thermophilic Crenarchaeon Sulfolobus acidocaldarius. Although N-glycosylation is well-known in Euryarchaeota, the enzymes involved in this process, their substrates, and the mechanisms followed to produce the mature glycan are still elusive in Crenarchaeota. This work will impact the community interested in glycoprotein biogenesis and evolution. The experiments reported in this study were well-performed and the results are solid, but text and figure editing is required to enhance the accuracy, readability and strengthen the message of the work.

(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 a large study of the development of human sensorimotor control using unique populations who have undergone limb loss at different times in their lives.This paper will be of interest to scientists within the field of motor control and for those interested in the development and plasticity of the motor system. An important finding is that reaching performance with an artificial arm is better in people who lost their limb in adulthood and worse in those with congenital limb loss. While the mechanisms underlying this result are not yet clear, it suggests that the benefits of early developmental experience with an intact limb are superior to early experience with an artificial arm.

(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, which will be of interest to students of evolution and anybody interested in protein function, uses an original, clever, high throughput, and rapid experimental protein evolution method to assess the roles and contributions of contingency, chance, and necessity in the evolution of protein-protein interactions. The authors focus on the animal BCL-2 protein family and on the evolution of their binding properties to two proteins, NOXA and BID. Using several replicates and several starting points, they found little predictability between replicates of single starting points and among those from multiple starting points, indicating that there is no single pathway through sequence space to the selected function, and that historical contingency is the primary cause of protein evolution here. The presented results convincingly illustrate the potential of this novel technology for future work in directed protein evolution.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #3 agreed to share their names with the authors.)

Evaluation Summary:

Light and coworkers provide evidence from mining 31,910 prokaryotic genomes for the widespread occurrence of extracytosolic flavinylated FMN-binding domains in bacteria. They discovered extracytosolic flavinylation of five protein classes potentially involved in transmembrane electron transfer. The study also proposes new connections between respiration and iron assimilation and identifies two novel substrates of ApbE enzymes. This work should inspire further work in the fields of redox enzymology and bioenergetics to characterize the suggested involvement of flavinylated protein complexes in prokaryotes.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1, Reviewer #2 and Reviewer #3 agreed to share their names with the authors.)

Evaluation Summary:

This paper will be of interest not only to scientists working in the primary field of DNA replication, but also to molecular biologists employing deep mutagenesis as well as structural biologists interested in the functions of the broader class of AAA+ ATPase molecular machines. The work examines relationships between protein sequence, structure and function in the bacteriophage T4 clamp-clamp loader complex, a highly studied AAA+ ATPase that deposits ring-shaped proteins onto DNA to support DNA polymerase processivity and DNA replication. The clamp loader system is revealed to have a high tolerance to amino acid substitution, with little correlation between permitted substitutions and phylogenetic variation. A hitherto unrecognized residue in the clamp loader, which appears to be shared among certain AAA+ ATPase members, is identified as critical for the maintenance of a functional structure and for allosteric coupling. The key claims of the paper are well supported by the data presented, and the employed methodology has undergone rigorous validation. Although a few control studies are still needed, this is a novel and significant paper overall.

(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 work reveals a novel form of Drosophila long-term memory (LTM) that is of potential interest to most neuroscientists working on various animals. While classical protein-synthesis-dependent LTM forms only after repetitive spaced trials of olfactory conditioning, the authors discovered that flies also form a "blurred" or "vague" protein-synthesis-dependent LTM which distinguishes the experienced two odors from the third naive odor after single-trial training. This merged LTM lacking the event details likely occurs in most animals since long-lasting memory of occasional threatening experiences for future escape behavior is crucial for survival.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Evaluation Summary:

This paper will be of interest to developmental biologists and neuroscientists as it aims to resolve the unknown mechanism by which loss of a key enzyme in cholesterol biosynthesis results in neurodevelopmental defects. It provides a conceptual framework for understanding how altered lipid metabolism can impact brain development. Many of the key claims of the paper are well-supported, but reasonable alternative explanations remain.

(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:

There are many of membrane-embedded mini-proteins, which fulfill a large range of regulatory functions. One of them is phospholamban, a single transmembrane helix protein that regulates the sarcoplasmic reticulum Ca2+-ATPase by binding in the membrane. The work presented here combines new experiments with computer simulations with the aim of arriving at a more definitive answer to the long-standing mechanistic question of how exactly phosphorylation of phospholamban modulates its regulatory behavior. In this manuscript, an allosteric mechanism is presented, which could be of general importance for the whole family of these mini-proteins.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Evaluation Summary:

The authors study how individual synapses can compute information by tuning the properties of the individual components that drive synaptic communication between neurons. Using cutting edge physiology and morphology they show that the reliability of synaptic communication depends not only on how many units drive synaptic communication, but also the authors suggest that individual units vary in their quantitative molecular composition.

(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:

Wnt signaling plays critical roles in cell fate determination in essentially every tissue in all animals, regulates tissue homeostasis in many adult tissues, and is inappropriately activated in many human cancers. It has been the focus of research for decades, and we have an outline of signal transduction. Remarkably, some of the key questions of Wnt signaling remain controversial. Central among these are questions about the nature of the negative regulatory destruction complex, its mechanism of action and how it is turned down by Wnt signaling. Here Saskia and colleagues take a novel and very exciting approach to these questions, combining innovative quantitative live-cell imaging and computational modelling.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

This paper is of potential interest to a broad audience of neuroscientists, as it adds to our growing understanding of transcriptional mechanisms that regulate neural connectivity. Specifically, the paper provides support for the idea that transcriptional pathways previously implicated in neuronal cell fate determination can have independent roles in specifying connectivity between neurons. The study is highly technically innovative and cleverly uses a set of newly developed tools to analyze the developmental time window over which transcriptional activity is required to achieve to proper connectivity. However, the paper falls a little short in defining specific mechanisms involved downstream of the transcription factors themselves.

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

Evaluation Summary:

This work combines experiments and simulations together with previously reported biophysical and structural observations to develop a structure-based model that provides mechanistic insight into the two functions of cohesin: cohesion and loop extrusion. This intriguing and informative manuscript will be of broad interest to those working in the fields of chromatin structure, chromosome biology and molecular machines. While the data and analysis support the authors' conclusions, the presentation of the work can be improved for clarity.

(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:

Redmond et al. use single-cell and single-nucleus RNA-sequencing to reveal the molecular heterogeneity that underlies regional differences in neural stem cells in the adult mouse. Prior work had separate subventricular stem cells as type A and B. By generating bulk and single cell transcriptome sequence data, the authors identified a distinct subtype of both A and B cells that differentiate into dorsal and ventral identities. They also identify a set of genes that constitute a conserved molecular signature of these cell types.

(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 work explores the cellular and behavioural effects of a genetically induced reduction of the expression of a glutamate (excitatory) receptor (GluA4), focusing on the cerebellum , a structure involved in the acquisition of arbitrary, complex motor reflexes. The authors show that synaptic transmission at the input layer to the cerebellar cortex is reduced, despite some compensation by other mechanisms, which are characterised. Locomotion is little affected while acquisition of a "conditioned eyeblink" is abolished. The authors try to link the cellular and behavioural phenomena via modelling of the cerebellar computation, although this is not definitive. The work is of high quality, of interest to cerebellar physicists and neurocomputational modellers in particular.

(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.)