Evaluation Summary:

This manuscript by Deng et al., is a valuable evaluation of zbtb14 and its role in normal myelopoiesis. The authors provided convincing data supporting the role played by zbtb14 in monocyte and macrophage development and its regulation involving the modulation of PU.1 expression. The finding that a mutation in ZBTB14 exists in AML patients also implies how important this gene product is in normal human myelopoiesis.

(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:

Drs Zhao and Sharpe have highlighted the role of a relatively understudied cell type, the telocyte, in periodontitis, using a mouse model. Periodontitis is a widely occurring inflammatory disease of the gums, that will eventually progress to bone resorption and teeth that are embedded less favorably and will eventually fall out. This disease is linked to many other illnesses, such as rheumatoid arthritis, cardiac disease and even Alzheimer's disease, so more in depth knowledge is needed on cell types that play a role in the progression of the disease.

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

Evaluation Summary:

Sefton et al. analyze how fibroblast-derived HGF integrates muscle and nerve development during morphogenesis of the mammalian diaphragm. The new findings are based on in-depth analyses of the development of the diaphragm muscle, and the role of Met and HGF in the process. The work is relevant for the understanding of muscle development, and congenital disease (hernia).

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Evaluation Summary:

This Methods paper seeks procedures evaluating the balance between muscle cell quiescence and activation. These could well permit investigations of long-standing questions in key areas of muscle function. The latter include the regulation of adult stem cell pool size and functional heterogeneities in this, as well as regulators of muscle quiescence.

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Evaluation Summary:

The Cretaceous dinosaur Spinosaurus has recently drawn significant attention as it was hypothesized to be the first aquatic dinosaur, using tail-powered swimming in surface waters and at depth. In a reappraisal of the "aquatic hypothesis", new lines of evidence – including the CT-based skeletal restoration of Spinosaurus and biomechanical tests – support the alternative "semi-aquatic hypothesis". This article will be of interest to vertebrate paleontologists and functional morphologists, as well as wider academic and non-academic audiences.

(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:

There is currently a lack of available fine-grained infant-dedicated cortical parcellation maps. The present study fills an important gap in the research of infant brain development by generating an age-dependent functional brain parcellation from birth to 24 months, leveraging on the 1064 high-resolution longitudinal resting-state fMRI scans from 197 infants. These age-specific parcellation maps have the potential to facilitate scientific discoveries, comparisons, and validations in brain functional development. Moreover, the proposed method of establishing functional correspondences across individuals using functional gradient densities can also be applied to study brain changes across lifespan.

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Evaluation Summary:

This paper will be of interest to neurophysiologists and system neuroscientists interested in memory and more specifically in hippocampo-cortical interactions. Using a combination of imaging and electrophysiological techniques, the study characterizes neocortical activity patterns around awake hippocampal ripples. Unlike sleep ripples, cortical activity seems to be dominated by inhibition around ripples but differences between intrinsic activity and synaptic transmission highlight complex interactions in the underlying neuronal circuits and dynamics.

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Evaluation Summary:

This manuscript presents an interesting and informative study on two regulatory elements found near atrial fibrillation-associated regions and their effect on Tbx5 expression and arrhythmia susceptibility in a mouse model. The multilevel approaches and analyses are rigorous, and the conclusions are justified by the data. Tbx5 expression may be of relevance for human atrial fibrillation and disease risk in patients, and the work is of potential interest to scientists in the fields of gene dosage, gene regulation, genetic susceptibility, genetic variants and cardiovascular biology.

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Evaluation Summary:

This important work provides compelling evidence for the biological plausibility of the Successor Representation (SR) algorithm. The SR is a leading computational hypothesis to explore whether neural representations are consistent with the hypothesis that the neural networks in specific brain area perform predictive computations. Establishing a biologically plausible learning rule for SR representations to form is of high importance in the field of neuroscience. This is also important for comparing the predictive ability of neural circuits with other predictive frameworks designed in machine learning.

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Evaluation Summary:

In this manuscript, of interest to those studying insect reproductive biology and specifically mosquitoes, the authors show that females of the yellow fever mosquito retain eggs when fresh water is not readily available. The authors then use RNA expression analyses to identify genes potentially involved in the trait. This leads the authors to focus on two genes that seem to be recent duplicates. The authors generate genetic knockouts and use these to show that these two alleles affect the trait in question. The study includes interesting and technically impressive experiments, but the framing in the context of previous work could be improved.

(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 from Singh and colleagues investigates neural connections between the central amygdala and the zona incerta, two subcortical brain regions previously implicated in pain, and further describes the role of the zona incerta to preclinical pain-related behavior in mice. This study employed anatomical tracing, electrophysiology, optogenetics, chemogenetics, and behavioral assays in various pain modalities to link the zona incerta to pain modulation by providing new evidence for a direct inhibitory connection from the central amygdala to the zona incerta that could explain neuropathic pain hypersensitivity. While rigorous, well written, and well executed, the study in its current form lacked evidence to directly support the PKCδ neurons in the central amygdala projecting to the zona incerta as being explicitly involved in this process.

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Evaluation Summary:

This paper introduces a light microscopy pipeline for imaging and fast reconstruction of the synaptic connections of individual neuronal types in the fruit fly and for correlated investigation of circuit structure, function and behavior in the same animal. Because of its speed and accessibility, this approach enables mapping of selected neuronal circuits of multiple animals across different conditions and behavioral states, thus filling an important gap in brain research.

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Evaluation Summary:

This valuable paper proposes an innovative iterative masking approach that enables models such as the MSA Transformer to generate new protein sequence designs, which are validated using a wide-ranging set of computational experiments. A key strength of the MSA Transformer is the ability to learn and generalize across protein families, enabling impressive performance across a range of downstream tasks. However, to date, these models have not been used to generate new protein sequence designs. The approach proposed in this paper is quite novel, and a number of metrics are used to examine the resulting performance of the MSA Transformer at generating new protein sequences from specific families.

(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:

Almeida and Macklin provide one of the first studies to closely examine early oligodendrocyte behaviors at high resolution. These studies use live imaging in zebrafish to provide valuable new insights about the earliest onset of myelination in the central nervous system and add to a body of work showing how oligodendrocytes initiate and maintain myelin sheaths.

(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:

Engineering NLR proteins to improve disease resistance in crop plants is a major goal of the field. This study applies knowledge from structural and evolutionary studies of the rice NLR protein Pik-1 and cognate effector protein AVR-Pik to engineering of new disease resistance genes. The authors nicely demonstrate that it is indeed possible to engineer resistance proteins with broad recognition specificity for the rice blast fungus. The work is of interest to colleagues in synthetic biology, protein engineering and plant-pathogen interactions.

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Evaluation Summary:

The manuscript by Li and coworkers characterizes sorted human non-hematopoietic bone marrow cells by scRNA-seq and predicts their lineage relationships and possible interactions with mature and immature hematopoietic cells. Transcriptionally-different stromal cell subsets are identified, and their lineage relationships, cell-cell interactions and possible specialized functions are inferred or predicted from in-silico studies, paving the way for future functional and validation studies. This resource significantly adds to the current understanding human non-hematopoietic bone marrow stromal cells and their hematopoietic regulatory functions.

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Evaluation Summary:

A meta-analysis of over 14,000 fMRI studies revealed a principle rostral-caudal gradient in the lateral prefrontal cortex. This gradient reflected an internal/external axis, which helps to organize the LPFC's involvement in widespread processes from affect, to memory, to control, and action. This is an important contribution to the literature, particularly as a meta-analytic approach has not been applied to this axis of organization and can complement the limitations of single studies. The evidence for the conclusions could be strengthened by ruling out bias in the analysis and drawing a clearer relationship to functional 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:

This paper makes a comprehensive survey of the relationship between mtDNAcn and the personality dimensions, as well as how and whether they mediate the relationships between personality dimensions and mortability as well as other behavioural measures that may lead to mortality. More work needs to be performed to truly understand the relationship between personality dimensions and mortality, as well as the physiological traits (like mtDNAcn) that may be mediating it.

(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:

Liu et al. describes an unsupervised method that clusters colorectal cancer samples based on perturbations to gene interactions. They show that this method strongly suggests 6 distinct clusters of samples and identifies phenotypes associated with the clusters, including survival, drug response, immune phenotype, response to immune checkpoint inhibitors and perturbed pathways. This is an interesting and significant manuscript, which has been well conducted.

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Evaluation Summary:

Fan and colleagues disclose the development of covalent TEAD inhibitors and they report on the therapeutic potential of this class of agents in the treatment of TEAD-YAP-driven cancers (e.g., malignant pleural mesothelioma, MPM). Optimized derivatives of a previously reported covalent TEAD inhibitor are described and characterized, using diverse profiling approaches that range from biochemical and cell-based assays to X-ray co-crystallographic analysis and in vivo efficacy in a relevant mouse xenograft model. The manuscript represents an impressive and deep characterization of this small molecule class. The authors' claims and conclusions are very well supported and justified by the data, although differentiation from a very closely related compound termed K-975 is not entirely clear as currently presented.

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Evaluation Summary:

This study provides a thorough functional analysis of three mutations in the BRCA2 gene that do not seem to necessarily cause breast cancer. The authors use functional assays in cancer cells and with recombinant proteins to determine that two BRCA2 variants, S1221P and T1980I, are indeed pathogenic, while the T13461 variant is fully functional and benign. The strength of the study is the rigorous assessment of these mutations in a variety of established assays for BRCA2. The work is likely to have a broad impact in the breast cancer field.

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

Evaluation Summary:

The paper by Smith and colleagues provides a framework for understanding a seemingly paradoxical observation in human genetics: two phenotypes may be closely correlated to each other, and the patterns of genetic variation that influence both phenotypes may be widely shared at the genome-wide level, but there are often specific genetic variants that show discordant patterns. Though the observations in this paper are derived from analysis of metabolic phenotypes, this may have broader relevance to interpreting the results from disease-related genetic association studies, and shed light on the processes that connect different disease phenotypes.

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Evaluation Summary:

This study will be interesting to a broad audience of neuroscientists, as it reveals for the first time that mutations in klc4, which are known to cause a form of early onset hereditary spastic paraplegia in human, affect specific aspects of neuronal development and nervous system functions. High resolution movies of developing sensory neurons in vivo and behavioral assays support the key findings that klc4 plays an essential role in the control of neuronal morphogenesis and behavior. The data presented in the manuscript are overall of a descriptive nature but provide a foundation for future mechanistic studies aimed at addressing the specific functions of KLC4.

(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:

Whether airway basal cells exhibit extensive cell state heterogeneity and whether this is relevant for their function has been unclear. This study provides important evidence that such heterogeneity exists and may dictate airway basal cell function in a spatially restricted manner.

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Evaluation Summary:

The authors made paired recordings from synaptically-connected excitatory and inhibitory neurons in slices of human neocortex and used posthoc molecular methods to identify major classes of the recorded interneurons. The principal finding is that, as found previously in rodent cortex, short-term plasticity of the synaptic connections from excitatory to inhibitory neurons depends on the molecular identity of the inhibitory neurons. This is important, as it suggests that many rodent studies carried out over the past decades are physiologically relevant to humans.

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Evaluation Summary:

The authors explore how the actin network in the fat body impacts nutrient uptake in multiple ways. Overall, this is an interesting study that sheds light on adipocyte cytoskeletal dynamics and it's impact on nutrient trafficking and fat body storage. The work can be further strengthened by additional validation of tools and data.

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

Evaluation Summary:

PTPN22 is a protein tyrosine phosphatase which negatively regulates antigen receptor signaling. It has been proposed that several genetic variants of PTPN22 might be loss of function (LOF) variants, leading to hyper-responsive T cell proliferative and effector responses. The authors investigate how the PTPN22 R620W variant, associated with multiple autoimmune diseases, might contribute to breech of peripheral T cell tolerance. This work greatly advances and clarifies ongoing confusion of whether PTPN22 SNP(620W) is a LOF mutant.

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Evaluation Summary:

This manuscript offers a valuable transcriptomic data set of known types of adult zebrafish photoreceptors (rod and cones). The study further identifies a large set of differentially expressed transcription factors, many of which still have an unidentified function in photoreceptors. Using CRISPR F0 screening, the study shows that the two tbx2 zebrafish paralogues are involved in photoreceptors specification beyond what is currently known. The study uses a solid methodology and the results will be valuable for researchers interested in photoreceptor biology. At present, however, the manuscript has a misleading title and focus: the analysis of adult photoreceptors can hardly offer a scenario of the transcription factors involved in the specification of photoreceptors.

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Evaluation Summary:

The authors show that how high-dimensional neural signals can be reduced to low-dimensional models with variables that can be directly linked to behavior. The reduced model can account for long timescales of persistent activity that arise from transisions between metastable model states. The authors further show that the rate of these transitions is modulated by water temperature according to the classic Arrhenius law.

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Evaluation Summary:

The capacity to flexibly modify our actions in order to seek goals relies upon specific brain regions and neurochemicals. Cerpa et al identify norepinephrine (but not dopamine) within the ventrolateral orbitofrontal cortex (OFC) as key to updating identity-specific action-outcome associations when environmental conditions change. These conclusions are relatively well supported by the data and will be of interest to behavioural neuroscientists studying the function of OFC or noradrenaline signalling, as well as researchers studying associative learning.

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Evaluation Summary:

This is an important paper that uses state of the art technology to address the underlying neurobiology of neuropathic pain, a topic of considerable translational relevance. The study describes changes in gene expression at a single cell resolution in somatosensory neurons following peripheral nerve injury. Bioinformatics analyses were employed to segregate neurons in sub-classes and to derive predictions on potential functions of regulated genes. While the work has considerable strengths, such as the single cell approach, there are also some weaknesses, including the fact that new gene candidates did not undergo functional analysis.

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Evaluation Summary:

This paper is of potential interest to a broad audience across myeloma study and single cell technology, as it implies a major adjustment to our current understanding of pathogenesis and treatment of myeloma. Overall the data quality is good, although reasonable alternative explanations of the data can be identified.

(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 is of interest to people studying how differentially spliced genes regulate biological processes, and in particular, those interested in the intersection of cell death and immunity. This work offers new insight into how an alternatively spliced protein with a well-known function in cell death regulates the basal expression of genes involved in immunity and sensitizes cells to apoptotic cell death. Overall, the major conclusions are supported by the data but more investigation is needed to support the mechanism by which BAX splicing is inducing the phenotypes observed.

(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:

Mutations in MINAR2 causes deafness in human and mice. Loss of function of Minar2 in mice causes a reduction of stereocilia and subsequent hair cell degeneration but the underlying mechanism is unclear. This zebrafish study demonstrated that the Minar2 protein interacts with cholesterol and is localized to the stereocilia of hair cells. The loss of Minar2 reduces cholesterol enrichment in the stereocilia with concomitant accumulation in lysosomes. Thus, this study provides the mechanistic insight of Minar2 and the first glimpse at the importance of cholesterol homeostasis in hair cell function.

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Evaluation Summary:

Iago De Castro et al, constitute an exciting study conveying to readers that neutrophil-to-lymphocyte ratio dynamics predict pancreatic cancer pathologic response to neoadjuvant therapy. Specifically, the authors aim to determine the effect of gemcitabine/paclitaxel and anti-Ly6G treatment on stromal T cells and CAF populations. They conclude that neutrophil-to-lymphocyte ratios are associated with survival following this treatment and use animal models to show metastatic effects allied to it. The authors attempt to convey that microenvironmental neutrophils could play a causal role in pancreatic cancer chemoresistance. It was agreed that while the discoveries are very interesting, the public could benefit from the authors improving: the relevance to the human condition, providing a stronger link to fibroblastic cell functional transitions, broadening the discussion regarding previous/related published studies, and strengthening the anti-Ly6G specificity proof within the provided data.

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Evaluation Summary:

This work presents a new model that leverages imaging and non-imaging data for the prediction of the survival of patients with early-stage NSCLC. The new model sought to demonstrate the roles of imaging and non-imaging features in determining high-risk nodes within the graph neural network, and the results have the potential of broad interest to clinicians within the field of cancer and have a high value towards clinical application.

(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 reviewer remained anonymous to the authors.)

Evaluation Summary:

This manuscript presents the first molecular dynamics (MD) simulations of full-length membrane-bound Thyroid Stimulating Hormone Receptor (TSHR). The authors find that its linker region (LR) is disordered, contrasting previous models. While this is largely a solid study that would interest researchers working in computational modeling, thyroid hormone metabolism, and signaling, the rationale for the arbitrarily chosen starting model and unclear mechanistic relevance need to be clarified further.

(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 is of broad interest to clinicians focused on improving sepsis outcomes. The method developed by the authors can identify 10 common pathogens with species-specificity in 4 hours, thus significantly reducing the turnaround time compared to conventional diagnostic methods. Using their method to identify sepsis-causing pathogens early to guide antibiotic treatment, the authors demonstrate high clinical sensitivity and specificity, and some clinical benefit in a real-world scenario.

(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:

Chen et al. demonstrate a pro-survival role of the NRF2/DKK1 axis in mesenchymal stem cells. Furthermore, the authors provide evidence that targeting this pathway can enhance survival in response to liver failure in vivo. These data highlight a novel signaling pathway to enhance efficacy of MSCs in promoting regeneration.

(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:

Carboxysomes enable the efficient fixation of carbon dioxide in specific bacteria. Phase separation has been invoked as a mechanism that drives the formation of carboxysomes. The current work focuses on the biophysical principles of how one of two essential specific protein components enable spatial regulation over carboxysomes. This important work highlights the connection between oligomerization via specific molecular interactions and phase separation. The work is of interest to the areas of biochemistry and carbon dioxide fixation as well as phase separation.

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Evaluation Summary:

Drosophila ovarian follicle cells have been utilized as a model system to study organogenesis and epithelial tumorigenesis. The analysis of single-cell transcriptomes of follicle cells now shows that transcriptionally distinct cell populations emerge shortly after induction of loss of polarity. Strengths of the work include the use of advanced single cell omics and imaging analyses to identify cell types and factors playing a role the disruption of polarity and the implications of this work for epithelial cancers. The authors' claims are generally well supported by the data and analyses. Weaknesses include the lack of high magnification images and need to clarify motivation for the study and highlight the biology rather than technical advances in the results section. Overall, this work is viewed as an important contribution to cell biologists who work on the epithelial morphogenesis or tumorigenesis.

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Evaluation Summary:

This manuscript addresses G protein-coupled receptor signaling and proposes an additional site on Beta-arrestin2 (arrestin 3) as being responsible, in significant part, for the downregulation and likely onward signalling from endosomes of a range of GPCRs. The cell biology appears to be thoroughly carried out and data presented in a statistically appropriate manner. With some textual changes and minor experimental clarification of the route taken and molecules involved, this work will be of broad interest.

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Evaluation Summary:

The authors use high spatial resolution MEG in humans to link two important components (time - transient bursts, space - waves) of neural sensorimotor dynamics by investigating how transient beta bursts propagate in the brain. The authors find two directions of propagating waves during beta bursts. The work links two fundamental aspects of neural dynamics which may yield new insights into the origins of sensorimotor behavior, with wide appeal to neuroscientists and clinicians. The reviewers considered the methodological work largely sound, although concerns were raised by the reviewers to what extent the travelling waves correspond to underlying neural activity or reflect the generative nature of field potentials.

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Evaluation Summary:

This paper will be of interest to researchers studying meniscus homeostasis and knee osteoarthritis. It uncovers distinct subtypes of cell populations in inner and outer part of human meniscus using single-cell RNA sequencing. In particular, this work further identifies how alterations in meniscal cell populations may contribute to inflammation and osteoarthritis and thus serves as a resource paper for the field.

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Evaluation Summary:

This manuscript reports the development of a proteo-genomic screening methodology to identify protein-protein interactions between secreted proteins and their cell surface receptors. The authors use a CRISPRa-based approach to overexpress membrane proteins in cells and then use magnetic cell sorting to identify receptors that bind candidate ligands. This approach leads to the identification of several novel interaction pairs that are validated biochemically, including receptor tyrosine phosphatase ligands and other interactions with implications for immune system function. The work is of interest to a wide variety of fields including biochemistry and signaling.

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

Evaluation Summary:

The authors provide a summary of single and double mutants in five self-cleaving ribozymes using next-generation sequencing. They dissect their data in terms of epistasis effects, which provides a new angle to understanding ribozyme function. In principle, this allows conclusions to be drawn on bases involved in pairs and in catalysis that have the potential to be of use to the field, although there is also a series of technical weaknesses that should be addressed.

(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:

Identification of transcriptional phenotypes driven by TBI across meningeal immune cell subsets and the effect of aging on these responses is an important and not well-defined area in the field. Multiple complementary and high-end approaches are taken to demonstrate the long-lasting effects that TBI drives in the brain and support the main findings of the manuscript. This manuscript will be of interest to readers in the field(s) of neuroimmunology, aging, and traumatic brain injury.

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Evaluation Summary:

Menjivar et al. identify a previously unrecognized role of myeloid cell Arginase1 (Arg1) activity in shaping the anti-tumor immune response in pancreatic ductal adenocarcinoma (PDAC). The proposed therapeutic combination is a new approach for pancreatic cancer, with an enhanced response to immune therapy upon arginase inhibition.

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Evaluation Summary:

The authors investigate what type and degree of information (either absolute, relative, or a weighted combination of both) is used by bumblebees when retrieving the value of an item. There is recent evidence in humans and birds that suggests that these organisms use a combination of absolute memories and remembering of subjective ranking in these tasks. The authors conclude that bumblebees indeed use remembered ranking, but that they seem not to be able to retain (or at least utilise) absolute property information for very long. The absence of relevant work in invertebrates would make this study a potentially valuable addition to the scientific literature.

(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:

Li et al. use biochemical binding analysis to explore the role of Rabphilin 3A in dense-core vesicle exocytosis in neuroendocrine PC12 cells and in an in vitro SNARE assembly assay. They propose that the Rph3A binding to SNAP25 pre-structures the protein to efficiently assemble with Syntaxin and VAMP2, and thus, promoting the vesicle docking and priming process. This work will be of interest to scientists studying the molecular basis of synaptic vesicle release.

(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:

Iron acquisition is an essential problem for microbial growth and survival. Host defense mechanisms generally reduce iron availability and microbes often find themselves in iron poor environments. This study provides new insights into how the fungal pathogen Candida albicans obtains iron during infection.

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

Evaluation Summary:

This manuscript will be of interest to readers in the field of microbiology, particularly those interested in bacterial interactions, secretion systems, and stress responses. It identifies the molecules and mechanisms that explain a competitive interaction between two soil-dwelling bacterial species. The data support most of the conclusions of the manuscript, but some controls are lacking and some of the interpretations are not fully justified by the experiments shown.

(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 the CryoEM structure of OmcZ cytochrome nanowires of Geobacter sulfurreducens, the third cytochrome nanowire of Geobacter to be structurally resolved. OmcZ differs structurally from these previously determined nanowire structures, showing a different heme chain configuration. Based on these and other differences the authors speculate about the evolutionary origin of these nanowires and the mechanism of long-range electron transport. This manuscript is an important contribution to the field of electron transfer and will be of interest to everyone working in electron transfer and filament formation and interested in their evolution.

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Evaluation Summary:

This article seeks to address a key question in protein biophysics: are the amino acid positions (and mutations) that influence allostery conserved across homologs of a protein family? Or is allostery implemented by a distinct set of residues that varies amongst homologs? To address this question, the authors follow an innovative approach that combines deep mutational scanning with machine learning. Significant revisions are required to clarify whether the conclusions of the study are well-supported by the data. The work is potentially highly relevant to protein engineers and biophysicists.

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Evaluation Summary:

This paper is of interest to organismal biologists and evolutionary scientists who study cognitive and behavioral sex differences including those with interests in the evolution of complex spatial behaviors. Using intensive field monitoring and experimentally induced navigational challenges, the authors examine two different hypotheses for sex differences in spatial ability in three species of poison frog. A rich and complex story emerges, including from the provision of evidence that is consistent with (but not necessarily yet definitively or exclusively in support of) the hypothesis that androgens may inadvertently affect spatial ability.

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Evaluation Summary:

This manuscript examines the importance of PKA-dependent mTORC1 activation for the weight-loss effects of liraglutide. The work has the potential to provide important insights, but at present is deemed preliminary as it lacks details on the mouse model and control data and needs a more in-depth analysis of the metabolic phenotype.

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Evaluation Summary:

This paper is of broad interest to biologists and climate modelers that study the impact of environmental stress (especially multiple stressors) on marine life. The authors show that exposure to low pH (ocean acidification) decreases the ability of two mussel species to survive freezing stress. The authors measure multiple biochemical parameters to try and identify the mechanisms underlying the change in freeze tolerance, but future work will be needed to resolve the underlying mechanism in detail.

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Evaluation Summary:

This paper describes the use of three well-established mathematical models of cervical cancer to estimate the impact of COVID-19 related-delays in screening access on cervical cancer incidence and delays in diagnosis. Consistent with previous work and the known biology of cervical cancers, the findings that short delays have relatively small effects on population-level cervical cancer risk are reassuring overall, but the impact of screening interval and screening test performance suggest that existing disparities related to screening access may be exacerbated. These results should be useful for policy makers in planning responses to future pandemics or other sources of sudden restriction of screening availability.

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Evaluation Summary:

This paper proposes a computational model that combines biologically detailed elements with more simplified components to provide a comprehensive model of synaptic plasticity. It includes the stochastic character of many of the biophysical processes and introduces a new way to readout the plasticity cascade. It is evaluated against impressively many published experimental studies of hippocampal plasticity. The paper should be of interest not only to computational neuroscience but also to the synaptic neuroscience community but will benefit from a clearer description of assumptions and weaknesses, and a clearer separation of the essential elements in this model from the less critical elements.

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Evaluation Summary:

This manuscript, of interest to those studying the evolution of immunity, investigates the evolutionary history of a recently described herbivore-associated molecular pattern (HAMP) receptor, INR, which perceives the caterpillar-derived peptide HAMP, In11. The authors compare INR homologs to identify evolutionarily conserved residues and use chimeric fusion proteins to investigate specificity. The findings presented are valuable and supported by convincing experiments and analysis.

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Evaluation Summary:

This paper will be very interesting to the large class of neuroscientists who study functional roles of glycoprotein hormone receptors in the central nervous system. It provides detailed tissue-selective gene and receptor distributions of the three anterior pituitary hormones, and thus likely facilitates further relevant studies by other scientists.

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Evaluation Summary:

This manuscript compares COVID-19 mortality during the pre-Omicron and Omicron emergence periods in several countries and finds evidence suggesting the Omicron variant was associated with lower mortality than previous dominant variants. This paper will be of interest to infectious disease scientists both for its content and its methods, as it validates that population-level variant frequency can be a good proxy for individual-level variant data to derive insights on variant biology with population data.

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Evaluation Summary:

The findings of the paper are of interest to scientists studying the learning of abstract representations. It provides insights into how feedforward networks evolve during a process of learning to map stimuli onto abstract classes via gradient descent. The results are appealing and the analyses thorough. As well, the paper makes some experimental predictions. It could benefit from a deeper discussion on how the findings may generalize to biologically more realistic networks and tasks.

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Evaluation Summary:

The early differentiation of germ cells, those that will form egg and sperm, is a critical and nearly universal step in animal development. This paper reveals new layers of molecular and cellular regulation that control this process in the fly, and as such be of broad interest to cell and developmental biologists, especially those interested in critical cell fate decisions. The paper contains a wealth of experimental data demonstrating that processes generally thought to be restricted to somatic cells alter the differentiation of germ cells, but provides only limited functional interpretation of the observed phenotypes.

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Evaluation Summary:

This manuscript is of broad interest to neuroscientists studying mechanisms regulating synapse formation and maintenance. Following up on the previous work by the authors on trans-synaptic signaling complexes involving neurexins and cerebellins, this study shows that the basic framework of the complexes operates broadly across different synapses in the brain albeit with subtle differences. The experiments are carefully executed, while some key conclusions could be better supported by additional data.

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Evaluation Summary:

The manuscript will be of broad interest to readers in the fields of biochemistry, structural, molecular, and evolutionary biology. It outlines a systematic approach in characterizing nuclear receptor ligands based on the conformational ensemble of the receptor, further exploring the idea that perturbation of the ensemble orchestrates function. The results from the combined use of experiments and simulation are promising, suggesting that the change in the ensemble is responsible for function.

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Evaluation Summary:

This paper investigates scenarios in which the environment changes during the course of a decision, and shows that optimal behavior can be highly complex. It will be of broad interest to researchers in psychology, behavioural economics, and neuroscience interested in decision-making in real-world tasks. It also awaits detailed empirical testing.

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Evaluation Summary:

A murine genetic platform reducing fibroblast expression shows normal background indicators of cardiac structure and contractile function. Yet it shows a reduced functional compromise, on ischemic or hypertrophic challenge. This suggests its value for studies of the effect of fibrosis following normal or pathological change.

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Evaluation Summary:

This paper develops evolutionary simulations to identify the type of molecular networks that can give rise to size control. We now know a lot about the functional consequences and underlying molecular biology of different cell size control strategies, but comparatively less about which factors select for particular mechanisms. The authors address this point in an evolutionary framework. They show that the evolution of a specific cell size control mechanism is dependent on the cell cycle structure. The paper will interest researchers in development, evolution, and physics of biological systems.

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COVID-19 vaccine tracker and landscape. (2022, April 22). https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines

Evaluation Summary:

This paper addresses the mechanism of entrapment of DNA in the cohesin SMC complex. Through a series of biochemical studies, the paper convincingly demonstrates that DNA enters cohesin rings through the hinge and SMC3/SCC1 interfaces. How such entrapment is regulated is important for different biological activities including sister chromatid cohesion and the formation of DNA loops. The paper will be of interest to researchers in SMC biology, DNA recombination and 3D genome organization.

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Evaluation Summary:

Adult zebra finch song is highly stereotyped, and it is driven by correspondingly stereotyped neural sequences in premotor cortical nucleus HVC. By imaging HVC activity in juvenile birds isolated from social contact with tutors, the authors discover that stereotyped HVC sequences can exist even without exposure to tutor song. Interestingly, after tutoring, existing sequences in the HVC of isolate birds transitioned from being uncoupled to vocal output to highly coupled to newly copied tutor syllables. Together, these data provide a fascinating glimpse into mechanistic foundations of how nature and nurture work together to a learned motor sequence.

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Evaluation Summary:

The complete metamorphosis of the higher insects is one of the most fascinating and complex processes in nature: The discrepancy in form and function between larvae, pupa, and adult insects is breathtaking, begging the question of how these forms and functions can so seamlessly follow each other. For the highest-order brain centre of the insects, the mushroom body, the authors provide a masterpiece analysis of this process at the cellular level. Given the breadth and depth of the data that the authors present, the current study will serve as a reference for the field of developmental neuroscience for many years to come; this study is eagerly awaited in the field. Perhaps ever more importantly, the insights into the relationship between evolutionary development and individual development at the cellular level might have a profound and lasting conceptual impact on life and natural sciences.

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Evaluation Summary:

This study builds on previous observations of arginine depletion in the pancreatic tumor microenvironment, with the goal of developing and using a cell culture medium (TIFM) that better recapitulates nutrient levels in the TME. With this system, the authors identify arginine biosynthesis as an adaptation of pancreatic cancer cells to arginine starvation. This work reinforces a timely message that builds upon the push for optimizing and reformulating cell culture media, so as to improve fidelity, and better recapitulation of physiological/pathophysiological cellular behavior. The latter is in turn critical for translational and therapeutic applications. The work will be of interest to tumor biologists.

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Evaluation Summary:

The research presented in this manuscript is focused on testing the role of peroxiredoxin (Prdx5) and heterogeneous nuclear ribonucleoprotein K (hnRNPK) in bone biology and osteoporosis. Using cell-base and animal models, as well as various experimental methodologies the authors demonstrated that Prdx5 is upregulated during osteogenesis but suppressed during osteoclastogenesis. This novel function Prdx5 was found to be associated with binding and regulation of hnRNPK which controls the expression of genes involved in osteoclastogenesis, such as osteocalcin (Ocn).

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Evaluation Summary:

This paper provides insight into a potentially new genetically defined subset of prostate tumors driven by concurrent loss of two tumor suppressor genes. This study both validates previous findings and provides new data that is compelling overall. With some additional statistical and biochemical evidence to support the conclusions, the work would be of interest to cancer biologists studying molecular mechanisms of prostate cancer.

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Evaluation Summary:

The authors identify a novel developmental role for the beta-adrenergic system in the regulation of mammalian cardiac regenerative capacity. Using genetic and pharmacological loss-of-function approaches, the authors identify a link between Yap and β-adrenergic receptor blockade. The conditional genetic loss-of-function studies are a particular strength of the manuscript and provide strong support for the Gas/Yap-dependent nature of the cardiomyocyte proliferative response to beta adrenergic blockade. Given the widespread use of beta blockers in the clinical management of heart failure, the findings are potentially very important. However, further evidence is required to substantiate the induction of bona fide cardiomyocyte proliferation and cardiac regeneration and clarify the associated mechanisms.

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Evaluation Summary:

This work is a bioinformatic analysis of HML-2-like proviruses found in the genomes of Rhesus Macaques, which convincingly argues that an HML-2 provirus underwent an ancient recombination event with a HERV-K (HML-8) related virus. The authors also provide data to suggest that the recombinant retrovirus may have acquired a distinct mechanism for the regulation of expression of spliced and unspliced transcripts. This paper should be of broad interest to virologists as it uses molecular 'fossil-like' evidence contained in the genomes of modern pirates to document the generation of what could be considered a previously undescribed retrovirus species, through recombination.

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Evaluation Summary:

This paper is an extensive analysis of the underlying basis of desiccation resistance in 50 Drosophila species from diverse habitats. The work suggests that the longer methyl-branched alkanes (mbCHC) of the cuticular hydrocarbons are critical for this resistance. The study, which informs on the evolution of desiccation resistance in flies, is well done, although the main hypothesis is currently only partially supported by coating experiments, which presently lack controls and would be greatly strengthened by "replacement" experiments to add mbCHCs to flies without CHCs. The work is of relevance to evolutionary biologists in general.

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Evaluation Summary:

This is an important paper that addresses a key mechanism that underlies the canonical computation of direction selectivity in the retina. By using fluorescence imaging of glutamate release from excitatory interneurons combined with a computational model of dendritic integration, the authors make a convincing case that the kinetics of glutamate release contributes to the direction-selectivity of individual neural processes in retinal neurons. This work will appeal to visual neuroscientists as well as cellular physiologists interested in dendritic computations.

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Evaluation Summary:

In this manuscript, of interest to the fields of animal immunity and epigenetics, the authors investigate the crosstalk between PML Nuclear Bodies and HIRA, a member of the H3.3 histone chaperone complex, during inflammatory stress. This study raises interesting perspectives on how availability of HIRA could be regulated by PML Nuclear Bodies for histone deposition onto interferon-stimulated genes, which in turn, could be relevant for immune-response mediated gene regulation.

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Evaluation Summary:

Synaptic plasticity can take place on the presynaptic and/or postsynaptic sites, and these two sites of plasticity are known to involve distinct mechanisms. Using a combined approach of physiology, Drosophila genetics, and behaviour, this study provides evidence that postsynaptic mechanisms underlie plasticity for olfactory learning. This complements the field knowledge that olfactory associative learning largely relies on the presynaptic mechanism in mushroom body neurons. The paper also emphasizes the similarities in learning and memory mechanisms between vertebrates and invertebrates.

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Evaluation Summary:

The paper provides fundamental information through the identification of an E3 ligase and kinase/phosphatase regulatory machinery that regulates the inner nuclear membrane protein SUN2 using a GFP-based assay. The data reveal a model involving extraction of ubiquitylation of SUN2 from the membrane by p97, which is an important contribution to the field. Although the biochemical evidence is solid on the GFP-tagged SUN2 protein, one question is the extent to which this pathway works on endogenous SUN2 and the extent to which this is a quality control mechanism for turnover of unassembled SUN2 or whether it acts on the fully assembled complex.

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Evaluation Summary:

This is a very fundamental study that challenges the paradigm that histones H3 and H4 are imported to the nucleus primarily as heterodimers. Instead this study provides compelling evidence that H3 and H4 are imported by importin 5 as monomers and dimerize on chaperones in the nucleus. The work is of relevance to colleagues studying nuclear import and epigenetic regulation.

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Evaluation Summary:

The authors show that MiR-27a affects osteoclast-mediated bone resorption but not osteoblast-mediated bone formation during skeletal remodeling. Through gene profiling and bioinformatics study authors also identify the specific target of miR-27a in the osteoclast gene. MiR-27a exerts its effects on osteoclast differentiation through modulation of P62. This paper is of interest to scientists within the field of bone biology. The manuscript data analysis and conclusion are clear and directly supporting the previous known findings.

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Evaluation Summary:

This study used 2017-2018 Afrobarometer surveys of more than 45,000 individuals to examine the association between the ownership of mobile phones and proximity to a health clinic in 33 African countries. Findings show that about 40% of people own smartphones and those who live closer to health clinics are more likely to own a mobile phone. This manuscript will be of interest to all people who are involved in the design and implementation of mHealth interventions in Africa.

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Evaluation Summary:

Regulation of NAD and its intermediary metabolites is of critical importance in axon degeneration and in neurodegenerative disease. In mammals, the SARM1 NADase has been shown to be a metabolic sensor activated by an increase in the NMN/NAD+ ratio and SARM1 activation then leads to catastrophic energetic collapse and axon degeneration in disease and injury. This manuscript clarifies the role of NMN in activating the axon degeneration trigger dSARM in Drosophila. The authors analyze the signaling role of NMN, a NAD precursor metabolite involved in injury-induced axon degeneration, by overexpressing NMN-D, a prokaryotic enzyme that consumes NMN, using a stabilized version allowing for prolonged NMN depletion, and find that it is strongly protective in several in vivo injury paradigms in flies. This paper will be of interest to those in the neurodegeneration/axon injury field in general as an extensive set of optimized reagents is presented, confirming the crucial role of for exploring NAD-related axon degenerative pathways, and providing tools for neuroscientists to use Drosophila as a model for neurodegenerative research.

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Evaluation Summary:

This work will be of interest to behavioral neuroscientists with a focus on social behavior. The interrogation of the transcriptional signature of pair-bonding, in both short and long-term, is unique and made possible with the use of the monogamous vole. That there is a "degrading" of the transcriptome of pair bonding following separation is evident but there is a gap in understanding how the gene expression changes relate to behavior.

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Evaluation Summary:

This study presents an in-depth analyses of carbon oxidation state and hydration state of proteomes in different taxa and environmental settings, which contributes to our understanding of how microbial communities are shaped by their surroundings. The study has merit, but there also some technical weaknesses.

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Evaluation Summary:

Deposition of hyperphosphorylated misfolded tau is a hallmark of many neurodegenerative diseases, but the exact mechanisms by which misfolded tau spreads to adjacent areas of the brain are not known. In this manuscript, which will be of broad interest to cell biologists and neuroscientists, the authors suggest that tau fibrils that translocate directly through the cell membrane induce aggregation of cytosolic tau. While the results appear stunning, there are alternative explanations to the authors' hypothesis that require further investigation.

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Evaluation Summary:

Vignogna et al. used yeast genetics, experimental evolution and biochemistry to investigate human congenital disorders of glycosylation, often caused by mutations in PMM2. They took advantage of the observation that the budding yeast gene SEC53 is almost identical to human PMM2, and used experimental evolution to find interactors of SEC53/PMM2. Mutations in genes corresponding to other human CDG genes, including PGM1, were overrepresented. The mechanisms of how reduced pgm1 activity could compensate for defects of sec53 are not yet clear.

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Evaluation Summary:

The authors of this study characterize human Fip1, an important component of the 3' end processing machinery. They use X-ray crystallography to determine the molecular basis of the interactions between Fip1 and CPSF30 (at a 2:1 stoichiometry) and between Fip1 and CstF77 (at a 2:2 stoichiometry). Together with biochemical assays, they suggest that Fip1 may be central to regulating transitions with CPSF. The work will of relevance to colleagues interested in transcription and RNA processing.

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Evaluation Summary:

This is an in-depth and rigorous analysis of transcriptomic changes in myogenic cells lacking dystrophin. Studies are made in both a mouse model and human subjects. the paper bears on possible roles of such alterations in pathogenesis of Duchenne muscular dystrophy. They draw attention to new therapeutic interventions for this condition.

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Evaluation Summary:

Individual cells may act in response to stimuli or in a self-organized fashion. The relative weight of these two modes determines in the end to which degree cells or rather organs/organisms carry function. This study reports an example of very complex self-organization of actin waves as the coexistence of slowly moving broad waves of high F-actin concentration and rapidly propagating planar F-actin pulses. The paper is interesting for everybody interested in conceptual questions like signalling versus self-organization, in cellular morpho-dynamics and theory of dynamic patterns.

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Evaluation Summary:

This work is of interest to neuroscientists and medical professionals involved in the study of Alzheimer's disease and related neurodegenerative conditions. The findings provide important information about how potential network-based structural and metabolic imaging biomarkers are associated with memory performance during distinct disease stages, in line with previous hypothetical biomarker models. The study is conceptually and methodologically sound, although some aspects of the analysis and reporting of the results could be further clarified.

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Evaluation Summary:

Barber et al present a manuscript discussing predictive factors for chemotherapy efficacy in head and neck squamous cancer (HNSCC). The paper is well written, and its style/formatting are optimal. The baseline signature moderately predicted outcome, and the data after one cycle further improved the algorithm, though this decreases its utility as a pure predictive tool. It is interesting that a subpopulation of monocytes, a subset of white peripheral cells long suspected to correlate with outcomes in HNSCC was one of the key drivers of the algorithm. However the overall impact in the field of this work seems limited by a number of factors, including that the authors focused on immune cell subpopulations and exosomes, which narrows the scope (no cytokines or other biomarkers were included); the signatures were not prospectively validated on an independent cohort; the algorithm was developed around a first-line therapy that is no longer considered to be the standard of care for HNSCC; and, while most of the conclusions are supported by the data, some of the caveats (such as the lack of a validation cohort, key in predictive biomarker development), are not addressed.

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Evaluation Summary:

The study is overall well-planned and the amount of data presented by the authors is impressive. The work nicely incorporates animal-level physiology (echocardiography data), tests for known canonical markers of hypertrophy, and then delves into an unbiased analysis of the transcriptome and proteome of LV tissue in bulk. The techniques and analyses in the study are adequately executed and within the realm of expertise of the Lakatta laboratory. This study is a necessary and crucial first step to extensively phenotype this mouse line and generate hypotheses for further work.

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Evaluation Summary:

Park et al.'s work provides insight into the infection processes of the human pathogen Coxiella burnetii with unprecedented detail. Their time course of cellular infection reveals the timing of key events and detects a previously unrecognized membrane structure. This work will shed new insight into the infection process of this pathogen allowing new targets for the treatment of infection with Coxiella.

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Evaluation Summary:

In this paper, the authors show that autobiographical memory recall is related to a specific biophysical property of the parahippocampal cingulum bundle, the so-called MR g-ratio. This paper will be of interest to neuroscientists studying associations between brain structure and cognitive processes. The data support the main conclusions of the paper. However, it is unclear how reliable the results are and whether the findings would generalize to situations beyond the specific one studied.

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Evaluation Summary:

This study seeks to develop the use of a FRET-based sensor for the formation of the folded 'interacting heads motif' structure for cardiac myosin, which is thought by some to represent a super-relaxed state with lower basal ATPase activity. This study offers some evidence that there is a relationship between the super-relaxed state and the 'interacting heads motif' structure, and that a specific dilated cardiomyopathy mutant in this myosin stabilizes the 'interacting heads motif' conformation. This paper will be of interest to muscle and cardiovascular biologists as it provides important insights into the correlation of structural and functional states of motor proteins in the context of cardiac muscle. The data qualitatively support this correlation and suggest a new mode of action of disease-causing mutations that lead to impaired contractile function.

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Evaluation Summary:

This study by Krug et al. uses the turquoise killifish, an emerging model for biomedical research, to generate a valuable live-imaging platform. Initially, the authors generate a transparent killifish they named Klara. Specifically, using optimized CRISPR approaches, they simultaneously inactivate three genes that are required for the formation of primary pigment cells in fish (melanophores, iridophores, xanthophores) and next, to monitor cell-cycle arrest and cellular senescence, they generate a cdkn1a-GFP reporter line using HDR-mediated integration. The paper would benefit from a further description of the HDR approach, the genetic models, and improved figures. Together, this platform will be an extremely valuable resource with broad application, including for aging research, physiology, toxicology, and regeneration.

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Evaluation Summary:

This pre-registration study by Kerrén et al. used a proactive interference task in combination with MEG recordings on humans to test predictions of a previous computational model postulating that neural representations of competing memories are associated with varied phases of the hippocampus theta-band rhythm. Their results largely confirmed the hypothesis and suggest that reactivations of target and competitor memories indeed occur at different phases of theta oscillations, which is further related to the intrusion effect in behavior.

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Evaluation Summary:

Using an elegant combination of cutting-edge techniques, the authors show that in the neuromuscular junction of the nematode C. elegans two different classes of voltage-activated calcium channels differentially trigger exocytosis of distinct pools of synaptic vesicles, one docked to the active zone and a second one localized more distant from the active zone. These findings will be of broad interest to neuroscientists interested in the mechanisms of calcium-mediated release of neurotransmitters at chemical synapses.

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Evaluation Summary:

The authors describe a newly developed software, ProteInfer, that analyses protein sequences to predict their functions. It is based on a single convolutional neural network scan for all known domains in parallel. This software provides a convincing approach for all computational scientists as well as experimentalists working near the interface of machine learning and molecular biology.

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

Evaluation Summary:

The authors aim to tackle a fundamental question with their study: whether there is a direct age-associated increase of transcriptional noise. To investigate this question, they develop tools to analyze single-cell sequencing data from mouse and human aging datasets. Ultimately, application of their novel tool (Scallop) suggests that transcriptional noise does not change with age, changes in transcriptional noise can be attributed to other sources such as subtle shifts in cell identity. This study is in principle of broad interest, but it currently lacks a definitive demonstration of the robustness of Scallop. Systematic testing of this new package would ultimately strengthen the key conclusion of the work and give additional users more confidence when using the tool to estimate expression noise.

(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 addition to providing extensive proteomics profiling datasets. this manuscript is fundamental that sheds light on the importance of appropriate experimental design for mouse disease model which have been overlooked so far. The results look quite solid based on the proper methodology. This type of work is extremely valuable to many biomedical scientists in the field for conducting reproducible research especially in the preclinical studies and properly interpreting the results.

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

Evaluation Summary:

This paper will be of interest to scientists within the field of neuromuscular disorders and has potential clinical relevance. It reveals a novel targeted strategy to improve the pathophysiology of children with neonatal brachial plexus injury. The key claims of the manuscript are well supported by the data, and the approaches used are thoughtful and rigorous.

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

Evaluation Summary:

This is a paper that will be of particular interest to neuroscientists with a focus on food intake and neural responses to food ingestion. This paper provides new insights into how the body responds to weight loss and helps identify those that may not be successful.

(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 theoretical models to examine the joint evolution of different cheating strategies: selfish cheating (not contributing to a common good), and manipulative cheating (inducing a competitor to preferentially provide benefits to the cheat). The models seem well formulated and the results robust. That said, improvements could be made to the presentation to clarify the assumptions and wider applicability of the model. An improved article would provide a better understanding of the mechanisms behind cheating, which would be of interest to readers working on the evolution of cooperation, potentially opening up new directions for theoretical and empirical work.

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

Evaluation Summary:

This work has potential value for researchers in several areas of cognitive and systems neuroscience. Range adaptation is a widespread property in neuronal circuits, and a network mechanism that relates neuronal adaptation to behavioral outputs is a valuable addition to the literature. However, limitations in the current framing and analyses leave some uncertainty about the interpretation of the results and their broader applicability.

(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 tackles the timely and interesting research question of whether meningeal lymphatic drainage is required for the control of brain infection with Toxoplasma gondii. It contains a sophisticated experimental approach using cutting-edge methods, it has an easy-to-follow narrative, and comes up with an interesting albeit negative finding which the authors even tried to explain by an additional set of experiments. Although there are some limitations and weaknesses of the paper in its present form it will certainly contribute to the growing body of literature on how the once "immune-privileged" CNS is protected against environmental challenges.

(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 shows that mutations in the gene encoding an enhancer chromatin-modifying enzyme MLL3 cooperate with Myc overexpression to drive hepatocellular carcinoma in mouse models. The authors identify Cyclin Dependent Kinase Inhibitor 2A (Cdkn2a) as a critical direct target gene of MLL3. Overall, the manuscript makes a compelling case that MLL3 is a hepatocellular carcinoma tumor suppressor that directly binds and activates the Cdkn2a locus. This study provides important insights for cancer biologists and those interested in specific epigenetic mechanisms that regulate liver cancer development. Editorial and some experimental suggestions were made to strengthen the work.

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

Evaluation Summary:

By performing homeostatic longitudinal IgH repertoire analysis of human memory B cells and plasma cells, authors draw two major unique conclusions; first, a high degree of clonal persistence in individual memory B cell subsets with inter individual convergence in memory B and plasma cells; second, reactivation of persisting memory B cells with new rounds of affinity maturation during proliferation and differentiation into plasma cells. These conclusions provide a significant insight into how human memory B and plasma cells are generated in a homeostatic condition.

(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.)