Evaluation Summary:

The authors comprehensively dissected the ontogeny and characteristics of thymic macrophages. These findings are helpful for better understanding of the function of macrophages in thymic tissue environment.

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Evaluation Summary:

This manuscript addresses outstanding questions about the molecular mechanisms by which the two types of arginine-methylating enzymes affect the processing and fate of transcripts in mammalian cells. This work makes important inroads into these questions, uncovering an inverse effect of the two types of enzymes on intron retention during post-transcriptional splicing, linking the effects to specific target proteins. With better support of some key claims , the paper will provide a lot of new information about the functional consequences of asymmetric and symmetric demethylation.

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Evaluation Summary:

The present work aims to increase our understanding of marine epizootics caused by the dinoflagelate parasite Hematodinium sp. in crabs. The work includes a large data set of field collected specimens from a wide geographical area. The authors have evaluated presence or absence of this parasite as well as co-infections by several other groups of pathogens and model the main factors that shape crab community structure. The topic of study is very important in the context of current marine pandemics and, therefore, adequate examination of this data set may lead to significant advances in the field. Refinement of the approaches to produce quantitative data is needed in order to reach to more solid conclusions.

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Evaluation Summary: 

This study examines whether binding antibodies that cross-react with the spikes of diverse coronaviruses are elicited by SARS-CoV-2 infection. The manuscript is well written, and the figures are laid out in an easy to interpret manner. This study will be of interest to those who are interested in developing pan coronavirus vaccines.

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Evaluation Summary: 

All three reviewers are in agreement that the study is of potential interest in the field of ER/PR signaling and endometrial cancer and that it contains significant amount of genomic data. However, functional data linking PAX2 to the PR/ER pathway are lacking, and the study is limited to a single model cell line and thus has a relatively narrow scope. There is also a concern that ChIP-seq data appear to be from a single, unreplicated experiment. 

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Evaluation Summary: 

By revealing different conformational landscapes of EGFR when responding to different types of ligands, this study significantly advances our understanding the structural basis for how EGFR generates distinct downstream signaling in response to different types of ligands. This study represents an important advance in the field and paves the way for the comprehensive understanding of structural mechanisms underlying biased agonism in EGFR and other RTKs. 

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Evaluation Summary: 

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

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Evaluation Summary:

This paper will be of interest to evolutionary biologists and geneticists, particularly those interested in the evolution of sex determination and sexual conflicts. It provides an unprecedented dataset that enables the authors to show convincingly the presence of three different Y-chromosomes segregating within a species, differential presence of the Ys among ecomorphs, and identifies candidate sex determination genes on the different Ys. Examination of the impact of genetic sex on a male fitness proxy in ecological context provides a compelling case study to explain the stable maintenance of multiple genetic sex determination systems in a species.

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Evaluation Summary:

The authors have used the UK bio-bank with sophisticated statistical modeling to predict the risk of type 2 diabetes mellitus development. Prognosis and early detection of diabetes are key factors in clinical practice and the current data suggest a new machine-learning based algorithm that further advances our ability to prevent diabetes.

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Evaluation Summary:

The cyst-forming stages of Toxoplasma gondii that perpetuate chonic infections in more than a quarter of the world's human population exist in a metabolically quiescent state. This study provides evidence that metabolic quiescence in bradyzoite cysts is associated with a profound dampening of calcium signalling, including uptake and release from internal stores, which is reversed following bradyzoite egress and exposure to exogenous calcium and carbon sources.

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Evaluation Summary:

Regulation of morphogen diffusion that controls tissue patterning is an important issue in developmental biology. The study deals with the mechanisms that establishes the Wnt gradient combining a mathematical model and experiments considering multiple extracellular components such as receptor and diffusible antagonist. The study revealed that the ligand/receptor feedback enables robust and quick formation of the morphogen gradient and that the diffusible antagonist also plays a role in this process. With some strengthening of experimental data and better explanation of the modeling, this study will be a useful contribution to the field.

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Evaluation Summary:

This paper will be of high interest to a broad audience of neuroscientists, as it provides a major advancement of our understanding of cortical circuits. The quality and quantitative nature of the neuroanatomical reconstructions at synaptic resolution are remarkable. Complementing the reconstructions with computational modeling and activity measurements, the study proposes a likely circuit function for a specific inhibitory cell type during behavior.

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Evaluation Summary:

This study investigates the morphological features of dopaminergic (DA) axons in the Nucleus Accumbens using serial electron microscopy (EM) reconstructions of genetically labelled DA axons. The authors report that DA axons (1) show extremely sparse classical synapses, (2) have varicosities with highly diverse vesicle content, and (3) undergo strong remodelling upon exposing mice to cocaine. The volume EM data set on DA axons presented is valuable. The present findings are suggestive of a mode of dopamine signaling that does not involve classical synapses and are potentially important for understanding the biology of DA neurons, whose dysfunctions have consequences on neurological disorders from Parkinson's disease to schizophrenia.

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Evaluation Summary:

This is a very interesting manuscript describing the changes of neurite position in a complex neuropil during development. The experimental system is well chosen because AIB's function within the circuit requires its neurite to be in two different neuropil "neighborhoods". The manuscript includes some technically difficult experiments of imaging neurite outgrowth in C. elegans embryos. The surprising finding here is that neurite position is not solely dependent on its growth cone navigation. In the case of the AIB neuron, the growth cone is anchored after it reaches its destination point and then a segment of the neurite shifts direction towards its final position through a zippering action. They also show that this shift in position is driven by adhesion molecules SYG-1 and SYG-2.

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Evaluation Summary:

The data and analyses presented in this paper are important for understanding the sources and spread of SARS-CoV-2 across Kenya during the first two waves and are a timely contribution to our understanding of the pandemic in East Africa as a whole. The manuscript provides a clear picture of the viral lineages spreading in coastal Kenya, but sampling biases in the Kenyan and global datasets used make it difficult to evaluate conclusions concerning imports and exports of SARS-CoV-2 into and out of Kenya.

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Evaluation Summary:

This paper assesses whether transcriptional signatures in antigen-stimulated peripheral blood mononuclear cells can predict protection from clinical malaria after vaccination with RTS,S AS01 in African children. It adds to the large body of literature looking for immune correlates of protection following RTS,S vaccination and will be of interest to the malaria vaccine community and to those studying in systems vaccinology. An association of malaria risk with monocytes before vaccination may have been uncovered, which will require thorough testing in future functional and mechanistic studies.

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Evaluation Summary: 

This paper is of interest to biochemists and those focused on development of novel antibiotics. The authors present two small molecules that specifically target the essential ribonucleotide reductase of the causative agent of gonorrhea, with biochemical, biophysical, and biological data supporting the efficacy of these molecules both in vitro and in mouse models. Overall, this is a comprehensive study providing some interesting insights to guide the development of new therapies for malaria. 

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Evaluation Summary:

This manuscript is of broad interest in light of the COVID-19 pandemic. Characterization of how glycosylation affects interactions between the viral Spike protein and ACE2 receptor can inform efforts to inhibit the SARS-CoV-2. The molecular modeling and functional analysis need to be improved.

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Evaluation Summary:

This paper will be of interest to scientists who think about mechanisms of conformational signaling within transmembrane receptor proteins. It describes a model of signaling by allosteric coupling between individual domains rather than by a concerted conformational change and provides substantial experimental evidence for the model from characterization of over 30 mutational substitutions in the bacterial two-component sensor protein PhoQ. The allosteric coupling model provides a way to understand many diverse observations about signaling by two-component receptors and has the potential to be relevant to conformational signaling by many other transmembrane receptors.

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Evaluation Summary:

The metabolic, genetic, genomic, and electrochemical experiments described for lactic acid bacteria expand on the recent discovery of extracellular electron transfer in Gram Positive bacteria. The ability to shift and/or accelerate metabolism of lactic acid bacteria capable of extracellular electron transfer may have interesting biotechnological applications, but to what extent this impacts their native physiology is not yet clear.

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Evaluation Summary:

The authors describe the innovative use of a heavy-isotope labeling strategy combined with mass spectrometry analysis to investigate the role of peptidoglycan biosynthesis by an L,D-transpeptidase and penicillin binding proteins in Escherichia coli. They use isotopic labeling of the peptidoglycan following by a chase experiment with label to study how new peptidoglycan is assembled into pre-existing peptidoglycan. The data suggests that new material is inserted one strand at the time on the lateral wall while it appears to be inserted as multiple strands at the division septum. The data are novel and provide important insights, together with notable methodological advances. The study will be of interest to microbiologists studying bacterial cell wall turnover and for drug discovery efforts.

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Evaluation Summary:

This study by Guzman-Vilca et al. developed a machine learning (ML) tool to estimate the sodium/salt intake in a pooled database of a WHO surveys entailing more than 45,000 people in low- and middle-income countries. Their ML model based on age, sex, weight, height, systolic and diastolic blood pressure values provided a reasonably accurate estimate of the salt/sodium intake in the population in such countries. While waiting for further validation using the gold standard of 24-hour urinary sodium excretion, as reference, this tool can be important for estimating sodium consumption in low-mid income countries, which cannot afford measurements of sodium in the urine.

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Evaluation Summary:

Magnesium is an essential metal that is involved in vital biological processes. Using a model system, the authors discovered the presence of a conformational equilibrium between different unligated states that may explain the mechanism of magnesium transport. The combination of several different approach support the hypothesis that molecular motion is involved in the transport mechanism of Mg2+ ions.

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Evaluation Summary:

This manuscript presents a well-done integrative analysis of data from many genome-wide technologies for the study of replicative senescence, contrasting the data to non-senescence and acute senescence controls. The time-course study design and the combinatorial analyses have revealed many interesting features of senescence that were previously unknown. Data mining by scientists in the future promises to unlock other aspects of senescence biology and hence this study serves as a great resource to the community. This paper and resource will be invaluable not only for researchers specifically studying the molecular biology of cell senescence but should also be more broadly relevant for researchers studying aging, inflamm-aging, cancer, regeneration, and other fields where senescence plays a role.

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Evaluation Summary:

This paper will be interesting for understanding how the innate and learned components are synchronized and temporally coordinated in courtship behavior. This study gives the first insight into the midbrain dopaminergic region and its' role in courtship behavior.

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Evaluation Summary:

The paper describes improvement in muscle phenotype of a congenital myopathy mouse model by a combined treatment with pharmacological inhibitors of Class IIa histone deacetylases and DNA methylases. The paper demonstrates in principle that there are treatment avenues to pursue but their application could be limited as phenotypic rescue appears to be restricted to particular muscle fiber types.

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Evaluation Summary:

Mickolajczyk et al. report the development of a new optical tweezers-based unbinding-force assay to characterize the interaction between the MIDAS domain of the mechanoenzyme Mdn1 and the ubiquitin-like (UBL) domain-containing ribosomal proteins Rsa1 and Ytm1. The authors show that the bond between MIDAS and Rsa1/Ytm1 can be best explained by a catch-slip bond behavior. The observations suggest that catch bonding between MIDAS and UBL domains plays a key role in the Mdn1-mediated ribosomal biogenesis. The reported results will be of interesting for the ribosomal and single-molecule biophysics communities and the developed DNA-tether-based optical tweezers assay will be useful for characterizing other molecular bonds.

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Evaluation Summary:

Low voltage-activated T-type calcium channels (CaV3.1-3.3) are important for several physiological processes. It is challenging to distinguish their specific physiological / pathophysiological roles as they share similar biophysical properties, expression profiles and there is a lack of subtype selective pharmacology. This study reports a spider toxin, Pn3a, which exhibits 100-fold selectivity for inhibiting CaV3.3 over CaV3.1 and CaV3.2 isoforms, and which therefore makes for an excellent reagent for the physiological study of CaV3.3.

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Evaluation Summary:

Zebrafish strains are typically considerably polymorphic. White and colleagues tested the hypothesis that genes in linkage with a mutant allele might show allele-specific expression differences and thus potentially confound the interpretation of mutant effects. Using a variety of mutant and wild-type alleles with sophisticated analysis of RNA-seq data in zebrafish embryos they demonstrate over-representation of gene expression changes from genes that are in linkage with the mutant allele on the same chromosome. The data are extensive, carefully analyzed and of sufficient depth and quality to support their main claim of frequent occurrence of allele-specific gene expression in outcross experiments. These allele-specific expression differences may impact on the interpretation of differential gene expression caused by a specific mutation. The findings of this study will be of interest to genetics working not only with zebrafish, but potentially also other polymorphic species.

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Evaluation Summary: 

This in vitro study proposes to explain why branched actin filament networks, similar to the ones encountered in migrating cells, become denser when they grow against a mechanical load. This question is of broad interest, and has long been waiting for a molecular-scale explanation. Building on their previously published tools and results, the authors perform a series of elegant and clever experiments, and convincingly identify key molecular mechanisms. Importantly, the results also confirm the Brownian ratchet model for actin assembly. This study captures several important features of branched filament networks, and should become a reference on the topic. 

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Evaluation Summary:

This study presents new evidence that support a model of aCPSF1-dependent transcription termination in Archaea. Archaeal transcription termination is shown to rely on both poly-U tract terminator signals and the endoribonuclease aCPSF1 of the β-CASP family. This mechanism resembles the eukaryal RNAP II termination process. These new insights fill a gap in our understanding of the mechanism of transcription termination in Archaea and they are of general importance for the RNA biology community.

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Evaluation Summary:

Budjan et al. describe an organoid protocol to obtain somite-like structures from human iPSCs. Using defined culture media, the authors describe the formation after 5 days in vitro of organoids that express a variety of PSM differentiation markers, such as the segmentation clock gene Hes7 and Pax3. Optimization of their culture conditions and transcription analyses of what they name their "somitoid" system revealed that their culture system recapitulates the time course of expression markers typically observed along PSM and somite early differentiation. Furthermore, somitoid reacted to Shh activation by activating sclerotomal markers Pax1 and 9.

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Evaluation Summary: 

This work reveals the pathway by which an important human parasite synthesizes a nuclear hormone receptor ligand critical for progression through its life cycle and demonstrates the potential therapeutic implications of perturbing this pathway. The experiments are insightfully and expertly conceived, designed and executed, and the data support the conclusions. This manuscript will be of general interest to parasitologists, nematode biologists, and those studying transcriptional regulatory networks governed by ligand-gated nuclear receptors. 

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Evaluation Summary: 

This manuscript reports advances in the image analysis software package MorphGraphX (MGX). designed to capture the developmental dynamics of growing tissues at cellular resolution. This version, MGX2.0, includes new tools for precise quantitation of cellular behaviors, such as cell division and expansion, within the context of positional information in the growing organs. To illustrate multiple functionalities of MGX2.0, various tissues are analyzed. This presentation style highlights the power and broad applicability of MGX2.0, but leads to a somewhat disjointed narrative, and how it can provide insight into specific biological questions is less clear. 

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Evaluation Summary: 

This work uses large-scale genome sequencing and analysis, mass spectrometry and bioassays to investigate the genomic diversity of Pseudomonas strains and their potential role in plant protection. The authors identified a novel group of cyclic lipopeptides that could inhibit Streptomyces scabies, the causal agent of potato scab, and showed how genomic diversity in closely related bacterial strains can contribute to plant pathogen suppression in the field. 

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Evaluation Summary:

This study investigates the tolerance to change in the sequence of telomere repeats, by analyzing a strain expressing mutant TLC1, the RNA component of the telomerase. The authors conclude that Rif2 protects telomere ends in the absence of RAP1 by inhibiting MRX and promoting Rad51-dependent homologous recombination to maintain telomere homeostasis. The study clarifies the role of Rif2 in telomere homeostais and describes how cells can extend telomeres and control senescence in the absence of Rap1 binding to telomeres. The possibility of coping with telomere sequence modification through flexibility and redundancy of capping proteins is of general interest in terms of telomere evolution.

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Evaluation Summary:

This work attempts to extract information about protein thermodynamics from X-ray crystallography data, which is a challenging problem. This work presents a comprehensive examination of the structural transitions associated with small molecule binding to proteins. The heterogenous pattern of order parameter changes in response to ligand binding implies that the approach is identifying new information. This work offers insights into ligand binding affinity and specificity mechanisms, suggesting that distal (allosteric) perturbations represent a possible avenue to modulate protein function.

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Evaluation Summary:

This manuscript will be of interest to readers in the field of magnetic resonance imaging and responsive imaging probes. In this work, a new imaging probe is designed and applied in proof-of-principle animal models, with future promise for relevance in models that have higher relevance to human disease.

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Evaluation Summary:

Truncated splice variants of the androgen receptor (AR) lacking a ligand-binding domain are thought to contribute to therapeutic resistance to antiandrogens in advanced prostate cancer. In this manuscript, the authors show that AR-V7, the most well-studied such truncated variant, displays a different mechanism of nuclear targeting and interaction with chromatin compared to the full-length AR. This work provides new insights into how AR-V7 may contribute to the pathology of Castrate-Resistant Prostate Cancer and will be of interest to researchers trying to improve prostate cancer therapies.

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Evaluation Summary:

In this manuscript, the authors study the discrepancy between the frequency of mutations in Gq alpha subunit (GNAQ and its paralogue GNA11) in uveal vs cutaneous melanoma. They hypothesize that the restriction of GNAQ and GNA11 mutations to non-epithelial melanomas is due to epidermal factors, which convert the impact of GNAQ Q209L mutation from being oncogenic to being inhibitory to melanocyte survival and proliferation, and reduce the maintenance, rather than the establishment of interfollicular epithelial melanocytes. This work provides new insights into the poorly understood difference in mutation frequency in different melanoma types.

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Evaluation Summary:

This manuscript aims to characterize cardiac tissues from patients who developed Covid-19. The authors studied pathological and normal tissues using microtomography scans performed at different resolution scales. Starting on the reconstructed volumes, special automatic analytical procedures were developed to extract some quantitative structural parameters about the samples themselves. This characterization method was used previously in the study of murine heart models. The main outcome of the research is that there are some well defined characteristics found in tissues of COVID patients that are not revealed in other pathological and normal samples.

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Evaluation Summary: 

This manuscript uses a combination of high-quality in vivo electrophysiology and modelling to demonstrate that Behavioural Time Scale Plasticity (BTSP) is bidirectional, and the amplitude and direction of this plasticity are dictated by the current weight of the inputs and not by the correlated activity of pairs of neurons. These findings challenge our current views on synaptic plasticity, which are primarily based on Hebb's concept. In addition, the network model used in this study demonstrates that this type of plasticity can rapidly reshape population activity to respond to environmental clues. This study will be of interest to the broad neuroscience audience and foster new ideas on biological and artificial learning. 

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Evaluation Summary: 

There are mixed results from studies of COVID-19 outcomes in patients treated with statins and there are multiple confounders. The authors use two Mendelian randomization methods to explore the association between HMGCoA reductase inhibitors (statins) and other lipid lowering drugs and outcomes and find that increased expression of HMGCoA reductase and HMGCoA reductase mediated LDL cholesterol increase hospitalization risk. This makes it possible but does not prove that statins could improve outcomes which will be of broad interest.

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Evaluation Summary:

This paper is of interest to a broad audience of cell biologists, pharmacologists and researchers who work in metabolic diseases. The work provides substantial new insights into the mechanism of action for a plant derived pentacyclic triterpene called celastrol elastrol, in effectively reducing the high fat diet induced tissue hypertrophy in mouse liver and adipose. A series of compelling experiments depict the site of covalent inhibition of the ER stress sensor GRP78 as essential for the beneficial effects in-vivo, supporting the main conclusions.

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Evaluation Summary:

The authors performed transcriptomic analyses from compartment-specific, micro-dissected hippocampal region tissue from transgenic mice. One feature that distinguishes this work from previous studies is the use of conditional knock-in tags (GFP or HA) and tissue specific expression of the Cre recombinase to target a population of pyramidal neurons in the CA1 region. The strengths of the paper are the rich data sets and innovative integration of methods that will provide a valuable technical resource for the field.

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Evaluation Summary:

This study examined the effects of social isolation in adolescent and adult male mice, a topic timely and relevant. The work sheds light on oxytocin as a key regulator that modulates the dopaminergic midbrain imparting long-lasting effects on social interaction. A critical open question is whether these results would apply to female subjects. The findings will merit from more thorough interpretations and controls of social behavior data and synaptic plasticity. This paper will be of interest to those interested in social neuroscience and plasticity in general.

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Evaluation Summary:

De la Concepcion and colleagues investigated the mode of co-evolution of plant immune receptor pair that functions as a unit to detect pathogen invasion and turn on immunity. The study shows that an allelic mismatch of a receptor paired from rice can cause autoimmunity in the absence of pathogen effectors, and this can be traced to polymorphisms that arose fairly recently. Overall the study provides insights into the co-evolution of paired receptors and supports that the paired receptors have co-evolved to prevent premature inactivation and enable strong activation in response to matching effectors.

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Evaluation Summary:

This manuscript reports a robust and well-characterized expansion method that achieves 10X expansion with a single expansion step using a simple, easy-to-use protocol. The new protocol leads to an enabling methodology for super-resolution imaging of various sub-cellular structures and organelles and is likely to have a high impact.

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Evaluation Summary:

This study is of broad interest to researchers in the field of entomology and physiology. These findings may shed light on at least one mechanism underlying selective advantages conferred to insect species on evolutionary timescales. Though the chemical signal, its source and recipient tissues underlying thermogenesis are elucidated, hypotheses regarding their downstream effects remain to be substantiated.

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Evaluation Summary: 

This paper addresses the very extremely interesting question of how spontaneous activity in the cochlea prior to hearing onset impacts the development of auditory circuits in the brainstem. The study has many strengths, including the use of complementary in vitro and in vivo recording techniques to characterize both peripheral and central defects resulting from conditional deletion of the gene for the chloride channel TMEM16A. The reviewers identified some concerns over the interpretation of the data and felt that the results could be discussed more in the context of other work, which might require some additional experiments. 

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Evaluation Summary:

This paper is of broad interest to readers who are interested in understanding cell migration and the cytoskeleton. It characterizes new behaviors of actin-based stress fibers in vivo during collective cell migration, and provides important observations that contribute to our fundamental understanding of these structures. The use of high-resolution live imaging in combination with Drosophila genetics and pharmacological inhibitors provides compelling data that supports the major claims of the paper.

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Evaluation Summary:

This study will be of high interest to readers in the field of the molecular mechanisms of synaptic operation. The functional demonstration of two different topological states of Munc13 involved in, Ca2+-independent and Ca2+-dependent, synaptic vesicle priming is a remarkable contribution to further understand key mechanisms of neurotransmitter release and its modulation. A multidisciplinary, solid and careful study supported by simulations of molecular dynamics, in vitro assays of membrane fusion and synaptic electrophysiology of mouse hippocampal neurons.

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Evaluation Summary:

Aggregates of the protein Tau are a key pathological features of Alzheimer's Disease and several other neurodegenerative disorders (Tauopathies). Hori et al. examined the effects of an acute elevation of Tau levels in synapses, employing high-end paired pre-post-synaptic patch-clamp recordings at the Calyx of Held model synapse. The authors generated a technically very rigorous dataset indicating that increased levels of soluble Tau impair pre-synaptic endocytosis and, consequently, neurotransmission by sequestering Dynamin-1 on microtubules, and propose that this process is part of a synaptic manifestation of Tauopathies. The findings are of major relevance for basic neuronal cell biology and translational neuroscience alike. However, several aspects of the proposed molecular mechanism underlying the synaptic effects of elevated Tau levels remain less clear.

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Evaluation Summary: 

This paper examines model neuron solution sets - combinations of ionic membrane conductance parameters that allow the model to produce functional output properties - and how the extent and shape of these solutions sets depends on ion channel pleiotropy, i.e., that ion channels can influence multiple outputs simultaneously. The work provides an organizing framework for previous experimental and modeling studies related to degeneracy of solutions, ion channel correlations, and homeostatic regulation, and should therefore be of interest to researchers in this area. 

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Evaluation Summary: 

This paper is of potential interest to a broad audience of neuroscientists. By concluding that fear conditioning does not occur in a semi-naturalistic experimental setup, the study implies a major adjustment in our current understanding of Pavlovian fear conditioning and associative learning. However, additional controls and data analyses are required to validate the authors' conclusions. 

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Evaluation Summary:

In this paper the authors study the Rolle of small chain fatty acids receptors FFA2 and FFA3 in the dorsal root ganglia with the goal to define molecularly a gut to brain axis. They identified MOMBA as a compound that binds to FFA2. This paper presents a powerful screening strategy to identify receptor agonists. The main concerns are the specificity of the model, and the functional purpose of this gut to brain axis.

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Evaluation Summary:

This work develops a multistage/component mathematical model to analyze advanced colorectal adenomas and the impact that aspirin therapy has on adenoma formation rates. This study will be interesting to the cancer evolution community and in particular those interested in colorectal cancer incidence. While the model is mainly focused on aspirin chemoprevention, the model could be adapted to test other putative preventative agents, and thus could have a broad impact.

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Evaluation Summary:

This paper presents groundbreaking data on the effects of antimicrobial peptides on bacterial cells, obtained by time resolved small angle X-ray and neutron scattering experiments coupled to stopped-flow mixing. Application of this approach to cells is highly innovative and provides ms time resolution, and information on multiple length scales (from conformational changes in the cell, to structural changes in the membranes). This is an important extension of the effort of the scientific community to study model membranes. The main result is that the peptides reach the cytosol in a few seconds, accumulating to high concentrations. The data analysis should be improved, and many conclusions are speculative, in particular on the mechanism of entry of the peptides.

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Evaluation Summary: 

This manuscript features high quality experimental data with a detailed and clear analysis, combined with a neural network model to address the concept of differentiation in cerebellar functioning. This is an intensively debated topic currently and this work has an important, clear message to add to that debate. The data is very exciting, and the analyses and computational modeling very revealing and insightful. This stands on its own as a major contribution. The authors also raise an extremely interesting mechanistic interpretation of these data, which is tantalising but requires further support. 

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Evaluation Summary: 

This paper uses a powerful combination of imaging techniques to provide a thorough view of the structure of the gap junction network connecting rod and cone photoreceptors in the mouse retina. The main conclusion - that rod-cone coupling is much more prevalent than rod-rod or cone-cone coupling - is well supported by the data although some results require qualification. The main concern in review centers around the importance of this result beyond the retina community. 

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Evaluation Summary: 

This manuscript will be of interest to community ecologists working on the impact of predators on prey populations, as well as disease ecologists interested in understanding the potential role of predators on vector traits. The authors uncovered trends in the research that support beneficial impacts of predators on mosquito traits, from the standpoint of vector control. 

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Evaluation Summary: 

The authors of this study investigate the consequences of acute or chronic disruption of parts of the TCA cycle, and how different interventions can drive different transcriptional responses. Specifically, the authors use both pharmacological and genetic methods to disrupt succinate dehydrogenase or fumarate hydratase, and characterize the effect of each on metabolism. They also find that disruption of these enzymes elicits a transcriptional response through ATF4. This work provides insight into how metabolism is affected by TCA cycle loss, and how how this affects metabolic stress signaling. 

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Evaluation Summary

This paper will be of interest to readers in the fields of exercise physiology, muscle biology and energy metabolism. The authors provide a proteomic resource where changes in the skeletal muscle proteome and acetyl-proteome have been assessed following the increasingly popular exercise intervention of high intensity interval training (HIIT). The adaptive responses reported provide new insight into the metabolic, contractile and transcriptional changes in muscle, and may represent an excellent resource for stimulating future focussed molecular studies in the field.

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Evaluation Summary: 

Baker et al. investigates the molecular evolution in primates of one protein family, the CEACAMs, that are a recurrent target of bacterial surface adhesions at epithelial surfaces. They show that multiple members of this gene family have experienced repeated episodes of positive selection in primates, especially in the N-terminal domains that are associated with protein binding and go on to evaluate the functional consequences of these evolutionary changes. 

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Evaluation Summary: 

In this manuscript, an in vitro Cas1-Cas2 model system is used to study the reaction used to insert foreign DNA elements into a CRISPR array during the adaptive phase of immunity. The authors propose that hydrolysis of one end of the transposon DNA may be the primary mechanism for the insertion of very small DNA elements (which are difficult to bend tightly) that are found for the proto spacer sequences, and that cellular repair pathways are responsible for ligating the CRISPR array back together in vivo. The findings additionally suggest that water-mediated disintegration has an unappreciated role in the generation of CRISPR arrays as part of the bacterial immune response. These hypotheses are intriguing and of potential interest to those in the CRISPR field. However, it is unclear how this in vitro study, which does not monitor the full the reaction (directionality is lost due to the lack of a PAM sequence in the substrate and several required cellular factors are missing), relates to transposition as it occurs in vivo. Overall, this is an interesting study that challenges the current thinking in the field, but it does not present sufficient evidence to establish the physiological significance of the observed effects, thereby limiting its potential broader impact. 

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Evaluation Summary: 

This paper is of interest to scientists within the field of motor learning. Converging evidence from several behavioural experiments support key claims of the paper. However, it is unclear to what degree the reported effects can be strongly linked to motor versus cognitive systems, and to what degree they novel demand revision of existing theoretical frameworks. 

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Evaluation Summary:

This paper addresses the mechanisms regulating cytoskeletal changes mediating neuronal branching and axon growth. The authors assess the role of the scaffolding protein giant ankyrin B in cortical neuron differentiation and present strong data implicating ankyrin B functions with the cell adhesion molecule/Sema3A receptor complex and an actin severing protein. With a better explanation of the function of ankyrin B in the Sema3A signaling pathway, this manuscript will be of interest to cell biologists and developmental neurobiologists working to uncover the biological mechanisms of early circuit development, and how these mechanisms relate to autism spectrum disorders.

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Evaluation Summary:

Feedforward inhibition (FFI) typically exerts a powerful effect shaping neural activity. In this paper, Suzuki et al use a combination of in vivo and in vitro experiments to characterize, for the first time, responses in the two main classes of FFIs in the mouse olfactory cortex, neurogliaform cells (NG) and horizontal cells (HZ). They find that these two cell types have different responses and different connectivity, which partially explains their different responses. This paper also helps resolve a previously perplexing result from a recent high-profile publication that claimed that FFI in the mouse olfactory cortex appears to play a negligible role in shaping cortical odor responses, presumably because those authors were only recording from HZ cells. 

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Evaluation Summary:

This study examines a potential mechanosensation mechanism in fly intestinal stem cells and their terminal enteroblast progeny. The manuscript’s data clearly demonstrate a role for vinc in suppressing the proliferation of midgut stem cells and the differentiation of their terminal enteroblast progeny and suggest that this role is exerted specifically through enteroblast vinc. The authors find that similar phenotypes are induced by genetic manipulations of vinc, a-cat, and myosin, and they argue that this similarity implies that vinc activity in enteroblasts is mechanosensitive. These findings are potentially relevant to biologists interested in stem cells, tissue homeostasis, fate decisions, and mechanobiology. Initial studies of vinc null flies failed to reveal any essential functions in development or viability, so the report of an adult-specific phenotype in the intestine is notable. However, the current manuscript falls short of demonstrating a key pillar of its model – that enteroblast vinc is regulated by mechanical tension. In addition, some important experiments using either whole-animal mutants or cell-specific manipulations leave room for alternate interpretations.

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Evaluation Summary:

The research conducted examines how the patterns of human eye-movements recorded during the navigation of complex mazes in immersive virtual reality relates to the computational demands of navigating the mazes. A key result is evidence of sweeps to the goal across the maze and back from the goal towards the current location prior to movement, which may help with understanding computational principles of planning. A key strength is its sophisticated computational measures for characterizing the multiple dimensions of eye movement data and the fact this work is novel with few prior studies investigating this important topic. Its findings and methodology are of interest to many areas within cognitive neuroscience, notably decision making and navigation.

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Evaluation Summary:

Initial insights were provided by yeast genetic experiments into the mechanisms of starvation-induced autophagy. Since malfunctioning of this process is involved in numerous diseases, there is a need for further understanding the role and regulation of autophagy in different physiological settings. This work convincingly shows that a newly identified phosphatase controls basal levels of autophagy via regulation of phospho-acinus levels and reveals how cadmium intoxication triggers a neuroprotective autophagic response in the popular animal model Drosophila.

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Evaluation Summary:

This work provides valuable new information to those who study enzyme mechanisms, nucleotide metabolism, and the response of cells to stress such as nutrient deprivation. The study focuses on CTP Synthase (CTPS), an important enzyme in nucleotide biosynthesis that has been shown to assemble into foci and filaments in yeast cells undergoing starvation conditions. The authors study the structure of yeast CTPS and its propensity to polymerize in low pH (mimicking starvation conditions), and how CTPS filamentation relates to the cellular assemblies.

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Evaluation Summary:

This paper uses a multi-model virtual reality system to assess which combinations of visual, wind, and olfactory information male silk moths rely on to find a female. The overall conclusion is that for the moths to search effectively, wind direction information is an important input. Vision, on the other hand, while it is used to control angular velocity, does not appear to be important for the moths to search effectively. This paper is of interest to neuroscientists and engineers interested in how multimodal sensory input controls navigational behavior. The experiments and modeling effort provide an advance in our understanding of how odor and wind information are combined in male silkmoths as they search for females.

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Evaluation Summary:

Hernandez et al use an elegant mathematical framework to build a novel tool for extracting unusually frequent (or infrequent) patterns in multidimensional biological data when only a small number of measurements are available. This is a common problem in many biological settings, so the tool could potentially be used to answer a wide range of statistically hard questions. As a first demonstration of its use, the authors show that the new tool can be used to reveal novel properties about neural responses in zebra finches during song generation.

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Evaluation Summary:

Tworig and colleagues use the mouse retina to explore the motility of Muller glial processes during development and during retinal waves that drive intracellular calcium signals in Muller glia. This is an important topic, because astrocytes in the brain have been suggested to move relative to synapses during neuronal activity. By performing careful and rigorous experiments, the authors find Muller glia processes move during development, but are not driven to move by neuronal activity. This is an important finding that will be of interest to diverse groups of readers.

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Evaluation Summary:

The manuscript by Munoz et al describes the effect of the bisphosphonate zoledronic acid on tissue-resident macrophages. For this, the investigators used both a fluorescent bisphosphonate derivative and an unmodified zoledronic acid, in combination with macrophage populations isolated from different tissues. Based on the pattern of cytokines released by macrophages in the presence of zoledronic acid, the authors conclude that administration of bisphosphonates could, in addition to preventing bone loss, boost immune responses and lessen the consequences of respiratory infections.

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Evaluation Summary: 

The manuscript provides novel data to support the role of CNP (C Type Natriuretic peptide) in the proliferation and stimulation of growth plate chondrocytes for development of bone. The methods used are innovative and the data provided support the overall hypothesis of the study presented in the paper, which should be of broad interest to bone and cartilage biologists. 

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Evaluation Summary:

Zhang and colleagues have conduced extensive multi-omic data analyses and functional assays, aiming to identify novel risk variants and to then explore the potential mechanisms with which the identified variants mediate risk of systemic lupus erythematosus. The findings could advance the understanding of the genetic susceptibility and biology of systemic lupus erythematosus.

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Evaluation Summary:

Transient Receptor Potential (TRP) cation channels, related to voltage-gated channels, appeared before plants and animals diverged in evolution and expanded in vertebrates into seven major subfamilies and took multiple essential physiological functions encoding chemical and physical information into electrical signals. In this manuscript, Deny Cabezas-Bratesco and co-workers draw from multiple sequence alignments and available structural information to identify highly conserved features in the transmembrane domains across several major TRP subfamilies in vertebrate and invertebrate animals and even in unicellular organisms. By systematically analyzing their findings, the authors propose a structural framework hinting at common mechanisms utilized by TRP channels to integrate stimuli into electric signals, which has major implications for a wide range of biological processes where TRP channels play a role.

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Evaluation Summary:

This manuscript is of broad interest for the neuroscience and imaging community. The authors employ an array of advanced imaging techniques to bridge the understanding of neuronal function in whole organisms to the sub-cellular physiology of specific neuronal types. The microscopical observations, combined with system perturbations strongly support the claims.

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Evaluation Summary:

This paper is of potential interest to cognitive neuroscientists seeking to understand commonalities and differences in the neural basis of instructed and experiential reversal learning in the context of human pain. The authors report that learning from instructions versus experience leads to differences in the behavioral ratings of and the neural responses to noxious stimuli. The innovative experimental design and analyses in this study offer new perspectives on using neuro-computational models for understanding how explicitly informed vs experientially acquired information influences learning about cues predicting painful stimuli. 

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Evaluation Summary:

This study elucidates the molecular mechanisms whereby Gastrodia elata Blume confers neuroprotection in G2019S-induced PD models and provides a potential therapeutic treatment for PD patients. The experiments are very well designed; the images are of high-quality and convincing. The conclusions are well supported by multiple of lines of genetic and biochemical evidence. This is an important and innovative study.

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Evaluation Summary:

This manuscript will be of interest to those studying the neuroscience of movement, as it addresses a fundamental aspect of movement: motoneuron recruitment. The authors provide a comprehensive analysis of motoneuron intrinsic properties that mature in the early post-natal period in mice and may lead to differentiation into "slow" and "fast" phenotypes. The authors argue that these properties, studied in spinal cord slices, contribute to motoneuron recruitment. While the study provides insights on the maturation of electrophysiological properties in motoneuron subtypes, the claims related to ionic mechanisms involved in orderly recruitment require further justification.

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Evaluation Summary:

The manuscript by Hoehn et al use a novel approach to quantify the somatic evolution in B cells. It brings together existing datasets to investigate the evidence for detectable evolution across longitudinal samples of BCR repertoires. This work provides significant new insight into which stimuli induce effective immune responses, and has the potential to improve vaccine design. Notably, these results are of interest for characterizing B cell responses, especially to vaccinations that induce a poor immune response, such as influenza.

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Evaluation Summary:

This paper will be of interest to researchers in the fields of biomechanics, movement control, and decision making. It presents a novel mechanistic model of metabolic cost that includes a cost for rate of muscle force production explains metabolic cost better than current models. They next demonstrate how this metabolic model can improve our understanding of movement control by revealing an energetic basis for smooth movements.

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Evaluation Summary:

This study examines the degree to which idiosyncrasies in visual object representations (beyond just image-driven objective representations) exist in visual areas of the brain. The authors report that later stages of the visual processing stream (specifically involving the perirhinal cortex and parts of the entorhinal cortex) do show these idiosyncratic representations, and for all levels of similarity (even for distinguishing very highly similar stimuli). These findings are interesting to vision scientists working to understand the role of different regions within the visual processing stream and to memory scientists interested in how this visual input is transformed in medial temporal lobe regions.

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Evaluation Summary:

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

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Evaluation Summary: 

This manuscript reports high-resolution crystallographic structures of the L,D, transpeptidase from Mycobacterium tuberculosis. These structures were obtained with ligands (a sugar molecule and a beta-lactam). A surprising finding is that the enzyme contains a ligand-binding site located greater than 20 Å away from the catalytic site. The authors propose and provide some evidence for an allosteric role of the new ligand site (S-pocket), which would be significant because it could allow new ways of targeting the protein for inhibition. While enthusiasm is high for the discovery of a putative allosteric site, more rigorous computation is necessary, along with some biochemical investigations and mutagenesis studies to rule out the possibility of a different role for the S-site. Moreover, a better articulation of the connection/crosstalk between the two sites in the form of a mechanistic hypothesis would strengthen the paper. 

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Evaluation Summary: 

The study proposes a new evolutionary-ecological scenario for Late Paleozoic and early Mesozoic beetles, supported by the summary of all available knowledge about early beetle fossils, including analyses of their taxon and morphological diversity and phylogenetic relationships. The effects of xylophagous beetles during the Paleozoic may have played a fundamental role in global biochemical cycles. The results advance our understanding of the evolutionary success of beetles and the many ways in which large environmental changes may affect biodiversity in general. 

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Evaluation Summary:

The manuscript by Mast et al. describes an impressive collection of new nanobodies against SARS-CoV-2 spike, which probably provides the most complete coverage of the accessible epitopes of spike to date. The authors thoroughly characterize biophysical and functional properties of the nanobodies and set an example of how to best combine multiple nanobodies to target a pathogen. As the latest in a long series of SARS-CoV-2 nanobody papers, this study stands out for its completeness, although it does not provide a novel mechanism of action or biological insights.

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Evaluation Summary: 

This study aims to find the genetic mechanisms underlying sex-ratio distortion through male-killing in Drosophila melanogaster flies infected with the endosymbiont Wolbachia. The endosymbiont carries the prophage WO, which is in the center of interested in this study. The key result of this study is that a synonymous mutation in a prophage gene can explain the differences between sex-ratio distorting and not distorting symbionts. 

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Evaluation Summary:

This paper is of broad interest to biologists and oncologists who study tumour evolution. The study provides new insights into the propagation of a transmissible cancer in clams. Remarkably, based on the analysis of mitochondrial DNA, the transmissible cancer seems to have jumped species. The findings reported have implications to understand the conditions that allow this cancer to spread across huge regions, threatening certain clam species.

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Evaluation Summary:

This work provides direct evidence that PcTx1, a modulator commonly used to study acid-sensing ion channels, induces a conformational change that persists long after an effect on the channel activity has dissipated. The data support this central claim of the paper and invite future investigation of the precise mechanism. The work is of general interest to those studying ion channel biophysics and pharmacology and is a fine example of the power of combined functional and fluorescence measurements.

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Evaluation Summary: 

This paper is a milestone towards understanding the formation and representation of visual object structure in the brain. It shows that in the pivotal area V4, border ownership selectivity emerges in the deep layers earlier than in the granular layers which receive the input from V1/V2, indicating that border ownership is not inherited from the input, but computed by deep-layer neurons using visual context information possibly provided through horizontal connections, cortico-cortical feedback or thalamic input. They further report that the preferred side of border ownership across layers is similar, i.e. it is organized in a columnar fashion. The study is elegantly done, with the outstanding questions clearly laid out and the results presented in a clear and informative fashion. 

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Evaluation Summary: 

Endosome maturation in animal cells has been challenging to characterize by microscopy because the fluorescence patterns are complex and dynamic. This study uses acute ionophore treatment to generate enlarged early endosomes, whose behavior and maturation can then be readily tracked. The results offer new insights into several phenomena, including the regulation of endosomal acidification during the maturation process. 

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Evaluation Summary: 

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

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Evaluation Summary: 

This manuscript provides some clear ideas on the use of next-generation sequencing data to rapidly increase biodiversity inventories and set the basis for future research. The principal objective of this study is to demonstrate how biodiversity information for a hyperdiverse tropical group can be rapidly expanded via targeted field research and large-scale sequencing. The authors use a comprehensive sampling for a tribe of beetles with complicated morphological characters, highlight the existence of multiple undescribed taxa. The database of sequences could set a benchmark for the spatiotemporal evaluation of biodiversity, would support evidence-based conservation planning, and would provide a robust framework for systematic, biogeographic, and evolutionary studies. 

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Evaluation Summary:

This manuscript identifies the DNA sensor AIM2 as a target of auto-antibodies in the human autoimmune disease systemic lupus erythematosus. Importantly, the authors provide evidence that AIM2 protects extracellular DNA from destruction and propose that this property may enhance the autoimmune response to the DNA and associated proteins. The work may therefore provide an important underlying mechanism for a prevalent and important human autoimmune disease.

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Evaluation Summary:

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

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Evaluation Summary:

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

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Evaluation Summary:

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

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Evaluation Summary:

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

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

Evaluation Summary: 

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

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

Evaluation Summary: 

This paper will be of interest to scientists across translational medicine and cancer treatment. It describes a standardized method to identify drugs that could be potentially repositioned for tumor treatment. In addition, using this new method and experimental manipulations the authors identify homoharringtonine as a new potential therapy for liver cancer and the underlying liver disease. However, while bioinformatic analysis was really comprehensive, the results and conclusions obtained are based on public datasets and therefore limited by the data available. In addition, the experimental approach to test the potential new treatments are currently based on in vitro assays and would be strengthened by in vivo validations. 

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

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

Evaluation Summary: 

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

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

Evaluation Summary: 

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

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

Evaluation Summary: 

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

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

Evaluation Summary: 

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

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

Evaluation Summary: 

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

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

Evaluation Summary: 

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

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

Evaluation Summary: 

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

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

Evaluation Summary: 

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

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

Evaluation Summary:

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

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