Evaluation Summary:

The authors here present how specific fatty acids modulate the bactericidal effect of the antibiotic vancomycin. The authors find that palmitoleic acid significantly increases the bactericidal activity of vancomycin and investigate the mechanism responsible. The key finding will be of interest to a broad audience of researchers focused on microbiology, host-pathogen interactions, and antimicrobial development, as well as to clinicians that treat antibiotic-recalcitrant infections.

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

Evaluation Summary:

Prostate cancer cellular heterogeneity is a major problem for disease progression and treatment resistance. This body of work addresses the cellular identity and populations that make up prostate cancer using single-cell sequencing technology and state-of-the-art mouse models. The cellular identities, associated signaling networks, and immune complexes accompanying the heterogeneity of the prostate are identified in this work and a resource is provided for scientists in the field.

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Evaluation Summary:

This study reports on the diagnostic utility of TRIO-based whole-exome sequencing (WES) in a cohort of 123 unrelated patients with suspected monogenic inborn errors of immunity. The authors further explored the diagnostic rate in this cohort by focusing their analyses on the identification of de novo variants (DNVs). This manuscript will be of interest to medical geneticists, immunologists, and physicians working with patients with primary immunodeficiencies.

(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:

Monteiro de Assis et al. demonstrate a role for T3 in modulating circadian metabolic rhythms both systemically and within the liver. The findings extend the molecular framework in which organismal metabolism is coordinated in a circadian fashion.

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Evaluation Summary:

This manuscript investigates the consequences of Disrupted-in-schizophrenia-1 (Disc1) gene knock out in the medial prefrontal cortex (mPFC) of mice. This work marks a potentially significant contribution to elucidate cortical circuits alterations in this genetic model of schizophrenia. The main message is that communication between cortical pyramidal neurons and fast spiking interneurons is altered with consequence on cortical network activities. The data generally support the conclusions made but analyses of electrophysiological data should improve.

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Evaluation Summary:

This study is of relevance to the field of DNA repair. It uses a cleverly designed new recombination assay in yeast to address the impact of DNA break position on global genome mobility. A centromere-proximal DNA double-strand break (DSB) induces an H2A(X) phosphorylation-dependent global mobility that accelerates but is not essential for DSB repair, while a centromere-distal DSB triggers global mobility that is essential for repair and which depends on H2A(X) phosphorylation, Rad9 and Rad51. Together, these data support a model where global genome mobility promotes homologous recombination repair, particularly for centromere-distal DSBs, and help settle some recent controversy in the field.

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Evaluation Summary:

This paper is potentially of broad interest to researchers in the chromosome biology field. With specific loading sequences identified, the condensin DC complex studied here provides an elegant system to investigate the in vivo activities of SMC complexes. Combining Hi-C, ChIP-seq and RNA-seq, the authors have a comprehensive suite of assays to probe their questions. However, not all of their major conclusions are currently supported by the data.

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Evaluation Summary:

Mechanisms for controlling gene dosage and uniparental gene expression vary widely across the eukaryotic tree, with many such mechanisms still unknown. Montgomery et al. describe an epigenetic mechanism used to modulate paternal chromosome gene dosage during the transient diploid state of the primarily haploid plant, Marchantia polymorpha. This fascinating case of genome-wide genomic imprinting will be of broad interest to evolutionary biologists, epigeneticists, and those focused on understanding the context and mechanisms of gene dosage control.

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Evaluation Summary:

This paper presents an artificial neuronal network which, from action and visual inputs, develops representations of space comparable to those found in the navigational system of the brain. They show that the representations developed by this network can be used in novel environments and in a reinforcement learning task. This demonstration of representations in absolute coordinates from agent-centered information is a significant contribution to neuroscientists as well as machine learning.

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Evaluation Summary:

This report identified NK-extracellular-vesicle (NK-EV)-associated microRNAs and characterized them by small RNA next-generation sequencing. They found that NK-EVs promote Th1 polarization and activation of monocyte and monocyte-derived dendritic cells. The findings are potentially important for understanding NK cell function.

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Evaluation Summary:

The authors set out to investigate the roles of SMAD4 and TGFbeta in regulating memory CD8 T cell differentiation during viral infection. To achieve their goal, the authors utilized a variety of available tools including, gene expression, mice that lack certain regulatory genes, and different tissue tissue culture approaches. Although the in vitro experiments yielded interesting results that will interest students of T cell immunology/biology, there is an absence of results from in vivo studies that would validate the in vitro observations.

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Evaluation Summary:

This is an outstanding manuscript evaluating a mutation commonly seen in AML and MDS in a spliceosome protein called SF3B1. The authors link this spliceosome mutation to altered transcripts and ultimately to cell cycle proteins and differentiation. This paper will be of high interest for oncologists in that it demonstrates that AML and MDS cells with this mutation can be targeted in a precision medicine approach.

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Evaluation Summary:

This study provides important new information regarding the functions and behavior of lung tissue-resident alveolar macrophages in the context of acute lung injury. New data regarding the impact of hypoxia via HIF-1 on biology of these critical cells are provided and importantly suggesting an impact on the outcome of lung injury.

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Evaluation Summary:

This study asks how diverse signals are integrated at the cellular level to generate adaptive behaviors. The authors show that prolonged food deprivation (i.e. fasting) of C. elegans broadly alters gene expression in food sensing neurons, thereby altering foraging behavior and chemosensory neuron responses to food. The fasting-induced genes include many chemoreceptors, one of which mediates responses to specific volatile components of food. Finally, they show that food controls the expression of a fasting-induced chemoreceptor via multiple external (i.e. sensory) and internal (potentially metabolic) cues. The paper is of importance to scientists with an interest in adaptive behaviour as well as the cellular and molecular mechanisms underlying integration of stimuli.

(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 is of interest to readers interested in how brain gene expression patterns differ between humans and other animals. The authors develop an innovative approach to map correspondences between the gene expression profiles of human and mouse brains, finding that the profiles of sensorimotor areas are more similar than those of transmodal association cortex. This thus contributes to our understanding of the genetic mechanisms that may drive differences in brain organization across species. The study is methodologically sound and the key claims are supported by the data.

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Evaluation Summary:

Berryer et al. report on an automated and quantitative platform to study the number of synaptic inputs formed in networks of human excitatory neurons and astrocytes in vitro. The authors tested the utility of the platform by screening a large collection of small molecules and identified several modulators of synapse density, which were validated in follow-up experiments. The automated platform substantially extends what is currently available, particularly with respect to the automation of the initial analysis steps. The positive hits identified here, the inhibitors of bromodomain and extraterminal (BET) family of gene expression regulators, are important, and will likely contribute to the understanding of the mechanisms of human synapse assembly.

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Evaluation Summary:

This paper will be of interest to neurobiologists and developmental biologists. Identifying novel mechanisms that prevent excessive neuronal migration is an important contribution to the field of neural development. The key conclusions of the paper are well supported by the data.

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Evaluation Summary:

The authors found elevated Hsp 27 levels in brains from Alzheimer disease patients. Hsp27 co-localized with p-Tau, efficiently prevented pTau fibrillation in vitro, and mitigated neuropathology of pTau aggregation in a Drosophila tauopathy model. A series of biochemical assays is presented to supporrt the claim that Hsp27 prevents abnormal Tau aggregation and p-Tau pathology. Overall, the study is well designed and presented, and the data convincingly support this major conclusion, which is relevant to colleagues studying neurodegeneration.

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Evaluation Summary:

Pond et al. established a 2D patient-derived organoid screening platform to study tissue patterning and kinase pathway dynamics. They aim to understand how the spacing of different colonic cell types and their communication are regulated. They found that apoptosis induces Erk signaling waves that prime cell movement and are essential to maintain tissue patterning in the organoid monolayers. The work presented here is of importance to the field and provides insights into how Erk waves driven by apoptosis can help maintain gut homeostasis.

(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 article introduces "DetecDiv", a high throughput, deep learning method to perform automated cell-division tracking in yeast. The performance of the method, estimated to be 100 times faster than manual annotation, overcomes current time processing limitations that are inherent to large single cell datasets. In particular, DetecDiv allows to automatically get quantitative measurements of replicative life span in yeast. The method is of broad interest for quantitative biology as it can be used to study yeast cells dynamics across their lifespan.

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Evaluation Summary:

This study, which will be of interest to basic scientists and clinicians in the fields of dental and craniofacial malformations, explores the validity and usefulness of mouse teeth as a model for studying the role of enhancers in human dental development and disease, based on a multi-layered integrated analysis of genetic data with different available data from mice and humans. The results from the study can provide a useful tool for the manipulation of expression of reporter or other genes in a tooth- or enamel-specific manner.

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Evaluation Summary:

The web-based software developed in this study will be of interest to researchers who develop CRISPR-based diagnostic methods. The use of CRISPR-Cas to rapidly identify specific mutations in both cancer and infection is an evolving field with good potential to play a role in future research and diagnostics. This software will facilitate the implementation of such technologies and is therefore useful.

(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 manuscript builds on previous work to design yeast display libraries representing full viral proteomes with overlapping 15-mer peptides binding to specific HLA-DR alleles, and therefore potentially immunogenic for CD4 T cell responses. The authors use SARS-CoV-2 and dengue viruses as proof of concept and identify a number of potentially immunogenic peptides not predicted by current algorithms. The methods are interesting and promising and will be of interest to a wide range of researchers in immunological and infectious disease studies.

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Evaluation Summary:

This paper will be of interest to scientists interested in intergenerational transmission of phenotypes through genetic pathways. The authors propose an innovative and sound method to leverage the adoption of a design for disentangling prenatal and postnatal genetic effects. Additional analyses are needed to address the limitations of the model applied to the specific dataset that was used to illustrate the method.

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Evaluation Summary:

The authors analyze the mechanisms of entropically driven cooperativity in the human thymidylate synthase (hTS), an enzyme essential for DNA replication and a promising target for anticancer drugs. The authors conclude that the cooperative binding of dUMP ligands to its two identical sites arises from a disproportionate reduction in the enzyme's conformational entropy upon binding the first ligand. The results provide rare insights into the mechanisms of ligand binding for an essential human protein and should be of great interest to readers interested in enzyme structure/dynamics/function relationships, cooperativity and allostery, and possible drug targeting of thymidylate synthase.

(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 uses a species-hybrid model in which functional human white and thermogenic adipose tissues develop in mice. Interestingly, human adipose tissue is fully able to recruit mouse vascular networks and sympathetic innervation during human adipocyte development. These findings provide novel and valuable information about the development of human thermogenic adipose tissue.

(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:

Here, the authors performed a CRISPR/Cas9 loss of function screen in polarized human epithelial cells to identify novel regulators of epithelial polarization and polarized membrane trafficking. This study provides a powerful resource for future investigations to unravel the complexity and diversity of mechanisms underlying epithelial polarization and polarized cargo transport. Furthermore, this dataset may represent an essential contribution to investigating novel congenital diseases associated with these processes, e.g., microvillus inclusion disease and necrotizing enterocolitis. A few experiments are suggested to bolster the authors' conclusions regarding the roles of key hits.

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Evaluation Summary:

This manuscript bridges neurophysiology and biomechanics and is of broad interest in improving our understanding of insect flight control. Here, Putney et al. record the activity of the flight muscles of tethered hawkmoths and demonstrate that the direction of the visual stimulus to which the insect responds can be classified using precisely timed information on muscle activity from a subset of the flight muscles. This is an important step in identifying the mapping from visual input to motor output, albeit that the mapping identified here is qualitative (i.e. classification of visual stimulus direction) rather than quantitative (i.e. prediction of output torque or apparent angular velocity of self-motion).

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Evaluation Summary:

This is a very extensive evaluation of the impact of rapid availability of whole-gemome sequencing results from SARS-CoV2 to inform infection control policies in hospital settings. It, most likely, is the largest analysis of its kind, clearly demonstrating the possibilities and challenges with this innovative technique.

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

Evaluation Summary:

This study, which will be of interest to behavioral ecologists, uses highly quantitative video tracking approaches to understand the predictors of predators' success in attacking schooling fish and will be of interest to behavioral, evolutionary, and movement ecologists. While some of the results seem unsurprising (e.g., that predators tend to successfully capture prey that are closer to them), the manuscript as a whole highlights the importance of tracking the perspective of the predator as well as of the prey, and shows that animals that are central to a group may sometimes be the most vulnerable. Although the experiments and data analyses are commendable, the manuscript would benefit from more careful discussion of its overall implications for the evolution of collective behavior, including potential limits of the experimental design.

(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:

He and collaborators analyse eight samples from six patients with acral melanoma through single-cell RNA sequencing. They describe the tumour microenvironment in these tumours, including descriptions of interactions among distinct cell types and potential biomarkers. The study is thoroughly done. In its final form, this study will help to inform our knowledge of the immune infiltration on the poorly studied acral melanoma subtype, the most common type of the disease in several countries in Africa, Asia and Latin America.

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Evaluation Summary:

This paper presents a modeling framework that can be used to track the complex behavioral and immunological landscape of the COVID-19 pandemic over multiple surges and variants in South Africa, which has been validated previously for other regions and time periods. This work may be useful for infectious disease modelers, epidemiologists, and public health officials as they navigate the next phase of the pandemic or seek to understand the history of the epidemic in South Africa.

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Evaluation Summary:

Patients with Gaucher disease can have significant and crippling neurological manifestations. The study uses novel mouse models of neurodegeneration associated with glucocerebrosidase 1 (GBA1) deficiency. It provides a detailed analysis of the alterations caused by targeted deletion of GBA1, including cellular, genetic and metabolic alterations in neurons, microglia, and infiltrating immune cells. The work defines novel mechanisms driving neuroinflammation in neuronopathic Gaucher disease.

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Evaluation Summary:

This manuscript by O'Herron et al. describes an all-optical method combining optogenetic stimulation and 2-photon microscopy imaging to simultaneously manipulate and monitor brain microvasculature contractility in three dimensions. The method employs a spatial light modulator to create three-dimensional activation patterns in the brains of cranial window-model transgenic mice expressing the excitatory opsin, ReaChR, in mural cells (smooth muscle cells and pericytes). This provides a powerful new in vivo technique to control blood flow into the brain and to understand its actions on brain function.

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Evaluation Summary:

This study explores the kinetics of heavy metal staining of tissue using time-lapse imaging with X-ray micro computed tomography (CT). It will be of interest to the wide community of scientists preparing biological samples for electron microscopy (EM), in particular large-volume EM. While at present the relation between CT imaging and EM contrast remains to be quantified, this study has the potential to become a reference for the field in establishing a quantitative tool for assessing and developing staining protocols.

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

Evaluation Summary:

In this study, Ogran and colleagues provide evidence suggesting that T-Cell Leukemia/Lymphoma 1 (TCL1) protein may promote alternative transcription site selection and promoter usage in chronic lymphoid leukemia. It is further proposed that these TCL1-dependent alterations lead to the production of N-terminally truncated versions of proteins including chromatin regulators while bolstering expression of transcription factors including MYC. Collectively, it was found that these results are of broad interest inasmuch as they suggest previously unappreciated rewiring of epigenetic, transcriptional, and translational programs in leukemic cells. To this end, this article should be of significant interest across a variety of fields of biomedical research ranging from regulation of gene expression to cancer research. The paper would be strengthened by mechanistic data linking TCL1 to alterations in transcription site selection and/or alternative promoter usage and by stronger validation of the expression of N-truncated proteins and their functional consequences.

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Evaluation Summary:

This paper will be of interest to marine biologists, and has particular relevance to those studying symbiotic corals. The use of compelling experimental optical measurements performed in situ allows testing of previous predictions on protein-based pigments that are found in many coral species. Specifically, the study analyzes the role of two classes of pigments, the Red Fluorescent Proteins (RFPs) and the Chromo proteins. It provides direct measurement data that suggest that RFPs can indeed provide additional light to the symbionts by converting the prevalent blue-green light at depth in orange-red light that penetrates more in the tissues of the polyps, thus increasing the number of photons available for photosynthesis. The authors also provide evidence based on light measurement for a possible photoprotective role of Chromoproteins, although the study does not yet provide any direct evidence for an ecological benefit of such light conversion/light protective functions.

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Evaluation Summary:

Osterman and Modragon report the first crystal structure of topoisomerase V in complex with DNA. Topoisomerase V is an unusual protein in that homologs have only been found in the archaeal Methanopyrus genus. The paper is likely of interest to those studying topoisomerase biology and biochemistry, and the wider audience interested in DNA replication and repair transactions.

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Evaluation Summary:

This study examined the nature of projections from the prefrontal cortex (PFC) to the nucleus accumbens (NAc) and to the ventral tegmental area (VTA). The authors show that PFC projections to NAc and VTA are largely non-overlapping, originate in different layers of PFC, and express different molecular markers. This study provides high-quality data to the long-standing question.

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Evaluation Summary:

This paper is of potential interest to readers in the fields of working memory and neural coding. It presents a model of a neural circuit that learns to optimally represent its inputs subject to an information capacity limit and claims that this model can account for a range of empirical phenomena in the visual working memory literature. However, the fit to empirical data is qualitative and in some cases unconvincing, certain aspects of the neural model seem difficult to square with established neurophysiology, and there is insufficient conceptual or quantitative comparison with other models in the WM literature that seek to explain the same data.

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Evaluation Summary:

The methods presented in this work are of potential broad interest across different domains of human neuroscience. Reliable methods for pushing the limits of spatial resolution for mesoscopic scale imaging of the living human cortex are of wide interest and utility. The image quality and high-spatial resolution of the data are exceptionally high. The paper in its current form demonstrates the application of the developed methods to a few exemplary cortical regions and sequences.

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Evaluation Summary:

This paper will be of interest to basic and clinical neurophysiologists who are focused on understanding neural mechanisms that influence recovery following spinal cord injury (SCI). The work compares the afferent regulation of motor output to soleus muscle in controls and individuals with SCI. The results indicate differences between groups such that there is less facilitation in the SCI group during muscle contraction.

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Evaluation Summary:

Schubert and coworkers report the development of a novel CRISPR-based screening method that allows probing interactions between (a large set of) specific mutations and the abundance of specific proteins, and, more generally, investigate the spectrum of effects that (point) mutations can have on protein abundance. This complements existing strategies for measuring effects of genetic perturbations on transcript levels, which is important as for some proteins mRNA and protein levels do not correlate well. The ability to measure proteins directly therefore promises to close an important gap in our understanding of the links between genotype and phenotype, and the strategy is broadly applicable beyond the current study.

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Evaluation Summary:

The study shows that individuals with unsuppressed HIV infection had poorer T cell polyfunctionality and lower cross-reactive responses to SARS-CoV-2 variants compared to those who were HIV negative or aviremic. The conclusions of this paper are well supported by the data and will be of interest to clinicians, immunologists, and public health practitioners, particularly in Southern Africa.

(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 tests the potential of using a combination of mosquito-based approaches, transgenesis and paratransgenesis, for malaria control relative to the use of the individual technologies. The results show that a combination of approaches can be more powerful at preventing the transmission of malaria parasites, opening the possibility of using similar combination approaches to reduce the malaria burden. The findings will be interesting for a broad audience of mosquito biologists and malaria researchers, but as they are limited to a specific transgenic-paratransgenic combination, more work will be needed to determine the true potential of this strategy for disease control.

(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 unexpected observation of selenium exchange into an iron-sulfur cluster cofactor of a component of nitrogenase. The work sets the stage for future mechanistic study of this phenomenon. It also provides a roadmap for the study of sulfide exchange in other classes of iron-sulfur cluster enzymes.

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

Evaluation Summary:

The manuscript by Luo et al. showed that the cytokine receptor DR3 is selectively expressed on thymic NKT17 cells and DR3 ligation leads to the activation of NKT17 cells in the thymus. Overall, The presented experiment are properly executed, controlled and presented. The finding that DR3 acts as a costimulatory molecule for thymic NKT17 cells is interesting. The mechanism and the functional relevance of this finding remain wanting.

(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:

By using single-cell RNA sequencing, elegant computational approaches, protein validation, and in vitro functional assays, this study characterizes the cellular composition and gene expression profiles of the human placenta in mid-gestation. The findings and dataset provided by the authors represent an important resource for readers interested in human development and placenta biology. However, conclusions require additional experimental support.

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

Evaluation Summary:

This study uses social media data (namely twitter) to analyse factors of covid-vaccine acceptance. It first trains a classifier to detect whether a tweets pro-vaccine, neutral, or against. Using then a large corpus of accounts, it investigates multiple factors explaining this position in a light counterfactual analysis. The central finding is that the most socioeconomically disadvantaged groups are more likely to hold polarized opinions on COVID-19 vaccines; other findings inclduing that personal pandemic experience has an important impact on acceptance, or that interest in politics modulates acceptance. This study a good example of what machine learning can do with social media data; however it is also a good example of the high data-demands and limitations of a machine learning approach. The correlations found are plausible but the causal implications are not evidenced strongly enough to guide public policy.

(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 work will be of interest to cell biologists studying the mechanism of asymmetric cell division and its diversity across species. Building on their earlier work, the authors show that that there is considerable variability in the mechanics of the spindle among six nematode species studied here. While the authors' main conclusion is plausible - that spindle oscillations require high force and low viscosity - stronger support by the data would be needed.

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

Evaluation Summary:

This study is an extension of previous work by the same authors, which established a two step high-throughput screening approach to monitor germination and growth of fungal spores of the human pathogen Cryptococcus neoformans and identified an FDA-approved drug with antifungal activity (DOI: 10.1128/AAC.00994-19). The current work extends this approach to three libraries of drug-like molecules comprising 75,000 candidate compounds and employs automated image analysis methods to identify classes of inhibition phenotypes. The key result of this work is the identification of 191 inhibitors, of which 76 could be grouped in to 8 classes based on chemical structure - inhibitors that share structural similarities tend to share phenotypic impact.

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

Evaluation Summary:

This paper demonstrates an inactive protease in Pseudomonas aeruginosa, CtpA, is regulated by am outer membrane lipoprotein LbcA. Using crystallization and EM strategies, they also provide a complex structure; however, the precise mechanism of regulation is speculative due to the flexible arrangement of protein domains.

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Evaluation Summary:

This study demonstrates that a cysteine residue (C152) in the vWA domain of the type-iV pili tip-associated protein, PilY1 impacts surface sensing, biofilm formation and cyclic-di-GMP signaling in Pseduomonas aeruginosa. Well-executed experiments provide insight into the events that initiate cell adhesion and colonisation, the understanding of which has important implications for human health. The work will be of interest to microbiologists in general.

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

Evaluation Summary:

This study is timely and important for all scientists and policymakers with an interest in producing, using or interpreting estimates of the effective reproductive number, R, as an indicator of epidemic growth when case counts are low (e.g. at the very beginning or end of an epidemic). However, the utility and accuracy of these methods is not evaluated in the context of less-than-ideal surveillance, including time-varying case observation and long delays, which is currently the case in most countries and they fail to evaluate the performance of the metrics in real time.

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Evaluation Summary:

This manuscript is of broad interest to readers interested in heterogeneity in immune cell populations with single-cell RNA sequencing, and for students of human T cell biology. It uses and reanalyses published single-cell RNA sequencing data dataset for this purpose. However, it does not adequately address major technical concerns, and therefore the interpretations are not robustly supported.

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

Evaluation Summary:

This manuscript shows that it is possible to detect high-abundance peptide antigens in nerve cells at the electron microscope (EM) level in sections of formaldehyde-fixed monkey brain after the sections have been stored for several years in an antifreeze solution in the freezer. The topic of utilizing formalin fixed tissue for research, especially with the numerous "brain banks" worldwide, is an important topic especially if one wishes to conduct studies in post mortem human tissue. The authors used antibodies to detect the presence of vasopressin gene-related products (i.e., neurophysin II and copeptin) in the hypothalamus and pituitary of the monkey brain. This paper is of interest to anatomists who work on AVP neurons in non-human primate. Due to issues with tissue quality, methodology and interpretation, the experimental approach described in this paper may not be as useful for studying fixed and archived brain sections as the authors conclude.

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Evaluation Summary:

The paper addresses a subject of potential great interest regarding the evolution of gene regulation and of enhancer landscapes. Available chromatin looping and gene expression data in mouse and human are analyzed to compare diverse properties of genome-wide promoter-centered maps, including associations with gene expression. It is shown that there is conservation of regulatory landscape across the two species, and that the extent of conservation in the TSS-distal landscape is associated with gene expression similarities. These overall results are in agreement with a large body of work in the field.

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Evaluation Summary:

This manuscript extends the evidence that ribosomal DNA has substantial interindividual variation, and presents evidence that variants are associated with differences in DNA methylation. The authors show that some rDNA types respond to environmental signals during in utero development, whereas others are changed during the aging process - thus broadening the known communication between development/nutrition/aging and the cellular protein synthesis machinery. These findings have relevance for the influence of such epialleles on gene expression and disease risk.

(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 new approach to the important and challenging problem of predicting T cell receptor:peptide-MHC interactions, one that relies on molecular model building (with previously published tools) followed by feature extraction and machine learning. The strengths of the study are more conceptual than practical: the overall framework and analytical approach; a balanced, critical assessment of the method's performance (which does not shy away from negative results); some observations on TCR:pMHC docking geometry. On the practical side, the classifier does not appear to generalize well to unseen epitopes (neither do the published tools it's compared to), so at the end of the day it's not clear that it will be preferable to simpler sequence-based approaches.

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

Evaluation Summary:

In this study, the authors used a chick and a mouse model and human tissues to analyze the role of the conserved protein TALPID3/KIAA0586, previously linked to ciliogenesis, in gut development. Using a multi-species approach, the authors conclude that TALPID3 has an evolutionary conserved role in regulating gut patterning along the radial axis, apparently orchestrated by neural crest cells in a non-cell-autonomous manner and mediated by perturbation of Sonic Hedgehog signaling and the composition of extracellular matrix.

(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 interesting for people performing all optical electrophysiology. It describes a new combination of previously available genetic tools to allow simultaneous optogenetic manipulation and optical electrophysiology. The manuscript does not provide a major conceptual advance but provides good evidence that this assay can be employed for large-scale screening in hIPSC-derived 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.The reviewers remained anonymous to the authors.)

Evaluation Summary:

In their manuscript, Eira et al. investigate the role of transthyretin in promoting axon elongation by modulating microtubule dynamics. The data point to a possible role of transthyretin in regulating microtubule dynamics by modulating tubulin acetylation levels during axon outgrowth. With additional support to strengthen this conclusion, the paper will be of interest to those in the neurodevelopment, neurodegeneration, and microtubule cytoskeleton 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.The reviewers remained anonymous to the authors.)

Evaluation Summary:

This behavioural study in healthy participants examines how people trade-off a brief phasic pain stimulus with a monetary reward, reporting a quadratic effect of pain on decision making. It supports and adds to previous findings of a context-dependency deriving from the distribution of rewards, which is a deviation from conventional rational choice theory (which proposes that a particular level of pain should carry the same price, regardless of small context changes). Broadly, the reviewers found the work well executed and the data compelling, but there were some suggestions for alternative explanations that are not ruled out given the current data.

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Public Evaluation Summary:

Determining when cells acquire their individual identity is critical for understanding the patterning and growth of embryos. The authors use state-of-the-art methods to map the lineages of cells that emerge during the earliest stages of development in chick embryos and that contribute to the central and peripheral nervous system. The authors have characterised the gene signature of ectoderm sub-clusters and used algorithms to infer lineage trajectories using the dataset. However, the analysis of placode and neural crest emergence is not clear-cut or well supported by in vivo experiments in the embryo. The work overall will be of broad interest to developmental and stem cell biologists, as well as neurobiologists interested in the understanding of the neural and neural crest gene regulatory networks.

(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 paper, the authors use a mathematical model of plant and water dynamics in drylands to show that drylands adaptive capacity to respond to changes, via spatial self-organization in space, has also beneficial effects in preserving its biodiversity and ecosystem functions. The current study extends previous work by considering a trait diversity gradient that ranges from stress-tolerant to fast-growing plant species.

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Evaluation Summary:

In this manuscript, the authors explore mechanisms involved in predation of other bacteria by Myxococcus xanthus. They identify two gene clusters, which encode proteins with homology to proteins of the Tad pilus system and some of which are important for predation. The work represents a good starting point for understanding how Myxococcus cells may engage in contact-dependent killing of other bacteria.

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Evaluation Summary:

This manuscript will be of interest to geneticists seeking to establish rules that govern gene regulation. To explain why a sequence enhances, rather than silences, gene transcription the authors draw our attention away from the binding of a single transcription factor, to focus instead on the number and diversity of transcription factor molecules that bind to it. Using a relatively simple metric called sequence information content they appear to be able to improve the prediction of enhancer over silencer sequences. A concern is whether the silencers are true silencers, or whether they only act as such in this specific experimental paradigm.

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Evaluation Summary:

This is potentially an interesting paper in which extensive MD simulations are used to probe the effect of phosphorylation of a tyrosine residue on the conformational ensemble of Ras GTPase. The insights form the basis for a screen of small molecule(s) that disrupt interaction with its target Raf kinase, and predictions are tested experimentally. Overall, the integrated approach is of interest to a wide range of biochemist and protein scientists and could potentially be used to modulate the activities of other proteins.

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Evaluation Summary:

This work describes the function of N6-methyladenosine (m6A) modification in developing retina. Enriched scRNA-seq and MeRIP-seq data will be an excellent resource for neurodevelopmental 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. The reviewers remained anonymous to the authors.)

Evaluation Summary:

This manuscript provides a comprehensive analysis of expression patterns and genomic features of long non-coding RNAs (lncRNAs) in the human developing gonad, using available single-cell RNA-seq datasets from both somatic and germ cells. Using multiple genetic strategies in an in vitro system of female germ cell differentiation, the study further shows a positive regulatory function of the LNC1845 lncRNA on its protein-coding neighbor LHX8, known to have a role in ovarian follicle development. This study has potential interest for reproductive biologists and for the non-coding RNA community.

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Evaluation Summary:

This manuscript will interest a large community of molecular biologists studying translation and mRNA decay. The study provides a large-scale comparison of the roles of protein factors in No-Go Decay (NGD) and Codon-Optimality-Mediated Decay (COMD) in the yeast S. cerevisiae. A major strength of the manuscript is the direct comparison between one mRNA with a single strong translational stall and another similar mRNA with many slow translation sites (caused by changes in the genetic code). The analysis of both the factors that cause decay of these mRNAs as well as the ribosome states on the different mRNAs has the potential to reveal the molecular basis for the different mechanisms of mRNA quality control.

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

Evaluation Summary:

The authors advance our understanding of the molecular underpinnings of allostery in GPCRs by showing the effects of allosteric modulators of mGluR2 on receptor conformation at distinct sites in the presence and absence of orthosteric modulators. This is important as drugs and drug candidates acting outside the site where the orthosteric or endogenous ligands bind are harder to identify. This work provides insights into allosteric changes at the level of individual receptors and provides a new path for drug discovery and is this of interest to colleagues studying GPCRs in health and disease.

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

Evaluation Summary:

The work describes the energetic constraints and preferred operating conditions of these "strategies" in particular on how nature has solved the problem of low energy "headroom'" required to prevent deleterious back reactions while maintaining efficient energy storage. The differences between the species are quite interesting and show that nature has evolved multiple solutions to fundamental limitations. Given the importance of understanding and improving the efficiency of photosynthesis, and the new insights revealed, the work will be of interest to a broad audience.

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Evaluation Summary:

Menicucci et al. investigate the implication of sleep in the maintenance of ocular dominance plasticity in adult humans. This is an interesting study as it shows that sleep can maintain the changes in ocular dominance obtained after applying an eye-path on the dominant eye for two hours. This contrasts with the rapid decline of these changes during quiet wake in darkness. The authors further report correlations between sleep oscillations and the magnitude of the plasticity effect. These results highlight a possible implication of sleep in a new form of plasticity

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Evaluation Summary:

In this study, the role of different cortical areas on three distinct tasks all relying on the same virtual maze set-up was examined using optogenetic interventions and calcium imaging. The paper is potentially of interest to people interested in understanding the neural substrates of learning and how these can be impacted by previous knowledge and experience of stimuli. It could also be of use to behavioral neuroscientists when considering possible order effects of experiments.

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Evaluation Summary:

This paper addresses a very notable gap that exists between evolutionary computing and experimental evolution. While artificial and computational approaches have long been used as an analogy for biological systems (with studies that have produced findings relevant for evolutionary theory), few studies have directly used methods and results from evolutionary computing to directly inform the shape and structure of experimental evolution studies. This study's approach is creative, and its approaches and results may be of use to both computational and experimental audiences. Lastly, this study can spawn future ones that draw even more connections between evolutionary computation/artificial life and evolutionary theory.

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Evaluation Summary: 

This manuscript probes the mechanism of postsynaptic retinoic acid (RA) signaling on presynaptic function. BDNF has important roles in synaptic plasticity, but how retrograde BDNF signaling is controlled following synaptic inactivity is unclear. The authors use genetic tools to localize the action of different components of the pathway to pre- or post-synaptic compartments and use biochemical approaches to define a molecular link between retinoic acid and local translation of distinct BDNF transcripts. The findings presented here fill a gap in our knowledge regarding how presynaptic function is adaptively modulated by BDNF by highlighting the role of RA in this process. The experiments have been well-executed and the data provide compelling support for the model proposed by the authors.

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Evaluation Summary:

The authors report on the coordination mechanisms between oscillations recorded in the CA1 subfield of the hippocampus, prefrontal cortex, and olfactory bulb and cell ensemble activity in CA1 and prefrontal cortex that are associated with odor-cued decision making. The findings support the hypothesis that the beta rhythm plays a role in coordinating CA1-prefrontal cortex ensembles associated with an animal's accurate decisions. Sensory-guided decision-making is of broad significance to many readers who are studying executive functions and cognitive behaviors, and the observations reported in this manuscript provide insights into mechanisms that may support these functions and behaviors.

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Evaluation Summary:

Houy and co-workers investigated the function of Munc13-1 and ubMunc13-2 in chromaffin cells and the interaction with phorbol esters (PMA). They combined calcium uncaging, capacitance measurements, amperometry, and activity-dependent movements of the EGFP-labeled Munc13 proteins. This study reveals that phorbolesters have a stimulatory effect via ubMunc13-2 but an inhibitory effect via Munc13-1. These opposing effects of the two Munc13 paralogs are surprising considering the closely related domain architectures.

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Evaluation Summary:

In this manuscript, the authors specifically look at the interaction between epidural stimulation of the spinal cord and the descending input evoked voluntarily in 2 intact monkeys. The results show that spinal stimulation could facilitate or suppress voluntarily evoked EMG and wrist torque, depending on voluntarily evoked activity as well as the stimulation parameters. This shows that spinal stimulation could enhance the descending inputs in cases of partial lesions. The conclusions of this paper are well supported by data, although they could be made stronger with additional analysis and clarification.

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Evaluation Summary:

This manuscript will be of general interest to Drosophila researchers, whose work has long relied on the tools generated by the Gene Disruption Project (GDP). This manuscript provides a notable update on the work of the GDP. In it, the authors demonstrate the efficacy of new, streamlined transformation vectors, which they use to generate several hundred novel gene-specific Gal4 driver lines using CRISPR technology. The new vectors promise to allow the GDP to complete its goal of creating null mutations for every gene in the fly genome. The elegant functionality of the new vectors will also likely be of interest to workers outside of Drosophila.

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Evaluation Summary: 

This paper, which is of interest to membrane biologists and colleagues in signal transduction, examines the interesting question of whether LRRK2 recruitment to membranes may regulate its activity. Membrane association involves binding to membrane-tethered Rab GTPases via LRRK2's armadillo domain, and the authors propose an elegant feedforward mechanism to describe how recruitment could lead to Rab phosphorylation, but not all features of the feed-forward model are directly supported by data. 

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Evaluation Summary: 

This manuscript by Fox, Birman, and Gardner combines human behavioral experiments with spatial attention manipulation and computational modeling (image-computable convolutional neural network models) to investigate the computational mechanisms that may underlie improvements in behavioral performance when deploying spatial attention. Through carefully controlled manipulations of computational architecture and parameters, the authors dissociate the effects of different tuning properties (e.g. tuning gain vs. tuning shifts) and conclude that increases in gain are the primary means by which attention improves behavioral performance. The analyses and results are technically sound and clearly presented, but the generality of the conclusions is limited by certain modeling/task choices made in the work. 

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Evaluation Summary: 

This paper will be of interest to microbiologists, clinicians, and public health workers with an interest in the possible impact of antibiotic use and regulations. The scope of the study is unusually high, integrating economic and geographical factors as well as genomic data among others. However, reasonable alternative explanations can be identified such that the data do not strongly favor the preferred hypothesis put forward by the authors. 

(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 finds that the levels of many immune markers are higher in vaginal samples in women taken after initiation of vaginal sex than before initiation of vaginal sex. This result may indicate that initiation of vaginal sex potentially influences vaginal immune responses, but it is possible that unmeasured confounding and selection bias might contribute to some of the difference across samples. This study will be of highest interest to those interested in how immune markers can change within individuals over time. 

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Evaluation Summary: 

The manuscript presents a high-quality quantitative analysis of plant embryo cell division in 3D. Authors combine computer modeling with detailed microscopy imaging to reveal underlying patterns and biases in cell divisions. The manuscript will likely be of interest to cell and developmental biologists. The conclusion can be straightened following additional analysis and data interpretation. 

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Evaluation Summary:

This manuscript explores the establishment and spread of antimalarial drug-resistant P. falciparum parasites using a combination of transmission modeling and model emulation. The authors add an important component to the broader understanding by jointly considering multiple factors driving drug resistance.

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Evaluation Summary:

This paper analyses the synaptic connections of two subsets of clock neurons in the Drosophila brain, the small ventral lateral neurons and the dorsal lateral neurons that control the sleep-wake behavior. The study reveals interesting features of the clock network, including the high heterogeneity of the LNd subset and the existence of non-clock cells that are predicted to act as "inter-clock neurons". The manuscript will be of interest to chronobiologists and neuroscientists working on neuronal networks, and it provides new insights into circadian clock network organization that may be of general value. The data analysis is rigorous, and the conclusions are justified by the data.

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Evaluation Summary:

This study provides a comprehensive analysis of the effects of polymorphism in an immune gene (the immunoglobulin E receptor Fcer1a) on immune responses, resistance to infection, and reproductive fitness in a wild rodent population. The authors claim to have found evidence for sex-specific effects of Fcer1a polymorphism, a result that would have broad implications for our understanding of the maintenance of genetic variation. The support for this claim is currently rather weak.

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Evaluation Summary:

This manuscript is of interest to several fields, in particular to microbiologists and structural biologists interested in pore-forming proteins and peptides. The data presented reveal insights into the mode of action of a newly identified peptide toxin secreted by Candida albicans (candidalysin). Using different techniques the authors propose and test a model for membrane perforation by candidalysin and identify an intriguing inactive mutant. While the presented data supports the main conclusions of the paper some of the initial assumptions need further assessment while the described mutants could benefit from more extensive characterization.

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Evaluation Summary:

The authors collected human samples from a rare cancer type in which evolutionary features have not been well-defined. They describe the clonal evolution through sampling at precancerous, primary tumour, and metastatic stages. Whole exome sequencing was performed and one of the mutation types was confirmed with other techniques.

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Evaluation Summary:

This work will be of interest for researchers studying the functions of microbial communities, microbial ecology and interactions. Using the Kombucha tea (KT) microbiome as a case study, Huang et al. provide a framework for simplifying complex communities into core communities that capture aspects of complex communities. Authors demonstrated that core communities can facilitate a mechanistic understanding of how microbes interact, especially when member species are individually culturable. The work presents a fresh, novel approach for the coarse-grained analysis of complex microbiomes.

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Evaluation Summary:

This manuscript analyses the inhibitory role of IL-10 producing regulatory T-cells in a mouse cytomegalovirus infection model. The authors report that IL-10 producing CD4+T-cells express genes of chronically activated Th1-cells, are clonally expanded and inhibit anti-viral T-cell responses via arginase, an enzyme that breaks down an essential amino acid for T-cell activation. The manuscript presents some novel and potentially important data; however, it requires the provision of additional experimental data and clarifications.

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Evaluation Summary:

This manuscript will be of interest to a broad audience of cancer biologists, especially those interested in esophageal cancer or treatment strategies involving ATR inhibition. It provides novel information about how FDA-approved antiretroviral compound Arbidol is a potential ATR inhibitor, which is of interest in the treatment of multiple tumor types. The key claims of the manuscript are supported by in silico, in vitro, and in vivo data.

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Evaluation Summary:

This manuscript will be of interest to stem cell and developmental biologists who aim to use newly emerging brain organoid models to understand the structure and function of the developing human brain. It presents a technological advance in imaging and describes an innovative method for labeling and tracking of cells within organoids to enable the assessment of dynamic processes within the intact organoid. The method is validated in a disease model and addresses a challenge in the field of human stem cell modeling of assessing cells within the 3D structure.

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Evaluation Summary:

This study provides computational predictions on optimal combinations of broadly neutralizing antibodies for treating HIV-1, based on the finding that population diversity alone permits the prediction of the timing of viral escape from broadly neutralizing antibodies. The idea behind the approach used is good, although the analyses and computational data/results highlight important limitations of the modeling approach. Nonetheless, the study should be of broad interest to those studying viral responses to therapeutic interventions as well as to both evolutionary and computational biologists.

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Evaluation Summary:

This paper is of potential interest to a broad audience in the fields of germ cell biology and cytoskeleton, as it implies a microtubule-based motor function in intra-manchette cargo transport in developing sperm tail. However, some conclusions of this paper require stronger experimental support.

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Evaluation Summary:

This study combines behavioral data from guinea pigs and data from a classifier model to ask what auditory features are important for classifying vocalisations. This study is likely to be of interest to both computational and experimental neuroscientists, in particular auditory neurophysiologists and cognitive and comparative neuroscientists. A strength of this work is that a model trained on natural calls was able to predict some aspects of responses to temporally and spectrally altered cues. However, additional data, analysis, or modelling would be required to support some of the stronger claims.

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Evaluation Summary:

In this manuscript, effective force-distance curves between cells are inferred for various tissues. This study is potentially interesting for researchers interested in tissue dynamics, because computer models of growing cellular tissues are becoming an increasingly important tool to understand experimental data and eventually predict medical interventions.

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Evaluation Summary:

This manuscript described a role of Vitamin C in promoting plasma cell differentiation by remodeling the epigenome via TET (Ten Eleven Translation) family proteins. Overall, most of experiments are properly executed, controlled and presented. This paper will be of interest to scientists in molecular immunologists, particularly those involved in of epigenetic mechanisms of B cell differentiation to plasma cells.

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Evaluation Summary:

The manuscript shows that OTOP proton channels are proton-gated with distinct pH sensitivities, and identifies regions on the proteins that alter pH-dependent gating. The main claims are well supported by the data. These findings are likely to be of interest to researchers studying acid/base physiology, sensory physiology, or ion channel biophysics.

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Evaluation Summary:

This manuscript puts forward a new toolkit of viruses for manipulation and visualization of zebrafish neural circuits. The authors overcome several challenges in the field and present a set of resources likely to be of high value to the zebrafish community.

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Evaluation Summary:

Hososhima et al. characterize a marine virus Heliorhodopsin as the first of its class to show ion transport activity. These bacteriorhodopsin homologs have been recently described and the present careful characterization of V2HeR3 represents an important step in the understanding of these interesting membrane proteins. Though the experiments are carried out carefully and the results, in general, support the conclusions, some experiments are needed and the interpretation of results needs to be clarified.

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Evaluation Summary:

This paper is of interest to neuroscientists studying the interaction between working memory, decision making, cell types, and neural oscillations. It introduces a detailed model of different brain areas which interact giving rise to the complex pattern of oscillations that are observed during a visual attention task. Additionally, the model reproduces the phase-dependent behavioral performance observed experimentally during such a task. This provides a new level of precision in our understanding of how rhythmic attention works in the brain.

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Evaluation Summary: 

This manuscript presents a creative, unique, and well-explained theoretical analysis of the shapes adopted by chromosome-attached microtubule bundles during manipulation with glass microneedles inside dividing cells. The overall conclusion is that the bundles are laterally anchored to other structures in the mitotic apparatus within several micrometers of their chromosome-attached ends, but relatively freer at their pole-proximal ends. This interesting work should appeal broadly to cell biologists and biophysicists. 

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Evaluation Summary:

This paper is mainly for an audience of genetic epidemiologists interested in the evaluation and portability of polygenic scores. The authors show that a polygenic risk score to predict prostate cancer risk is very informative for individuals that are classified on three different ancestry categories. The authors show that the polygenic risk score can be used to predict the risk to develop prostate cancer as a function of age. This paper provides evidence that genetic information could be used to provide guidance to clinicians on when to perform screenings to detect prostate cancer in 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 #2 agreed to share their name with the authors.)

Evaluation Summary:

This manuscript contributes to a circuit-based understanding of how sweet and bitter tastes are integrated with hunger state to drive feeding initiation in Drosophila. Anatomical, behavioral, and neuronal activity data support a multi-step pathway from sensory input to motor output. This manuscript, thus, contributes to our understanding of how multiple sensory cues are integrated with an internal state to reach a behavioral decision.

(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:

Through the use of multiplexed in situ hybridization with careful embryo staging, this manuscript represents exemplary documentation of dynamic gene expression patterns in early fly development. By comparison of these patterns in various mutant combinations, a simple logical model for specification of expression is proposed. This manuscript will be of broad significance to developmental biologists interested in embryo segmentation and gene regulatory networks underpinning patterning.

(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 interested in the functions of the hippocampus, as well as those in the field of sensorimotor timing. The reported data and findings point towards the possibility that the hippocampus supports specific and generalized learning of short time intervals relevant to behavior. While the conclusions are mostly supported by the evidence, further clarification of methodology as well as additional analyses and discussion would strengthen the authors' conclusions.

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

Evaluation Summary:

The authors use a combination of proteome-specific protein complex structures and publicly available ribosome profiling data to show that cotranslational assembly is favored by large N-terminal intermolecular interfaces. The manuscript represents an important contribution to the field of protein biosynthesis pathways by suggesting an intuitive evolutionary mechanism that can promote co-translational assembly pathways in mammalians, yeast, and bacteria.

(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:

Second order conditioning is a higher form of learning where a previously conditioned stimulus (e.g. odor A by food) is used to condition the perception of another stimulus (e.g. odor B by odor A). Yamada et al. have used the fly to identify a neural circuit in the insect mushroom body underpinning second order conditioning. This work elegantly combines neural circuit mapping, electrophysiology and modeling to put forward a mechanistic model for this highly conserved form of learning.

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

Evaluation Summary:

The authors measured the heartbeat and touch perception while people touched a variety of surfaces. The results indicate that people's heart rates and heartbeats vary systematically according to the type of touch performed and how difficult it was to perceive the grooved surfaces. The paradigm and the results appear very interesting though the specific analyses of choice and their presentation require some improvement to make a more convincing case.

(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 paper is an impressive and deep look at a very important problem: understanding the genetic underpinnings of evolution acting on a quantitative trait. The authors analytically study the response to an abrupt shift in phenotypic optimum, in terms of both phenotype and genetic basis (how various alleles/loci contribute to this response). The basic assumptions are classic, but the methods and findings are new (especially finite population effects) and well supported by clear analytical approximations and extensive simulation checks. The main finding is that the relative contribution of large vs moderate effect alleles changes substantially and predictably over a long-term period after the shift, even though the phenotypic changes are already undetectable over this period.

(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 investigates on how weight loss by bariatric surgery or weight-matched dietary intervention impairs breast cancer growth as well as immunotherapy. This study can potentially provide some therapeutic intervention strategies on combining vertical sleeve gastrectomy and immunotherapy in treating breast cancer.

(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.)