eLife Assessment

The authors present a critique of current usage of principal component analysis in geometric morphometrics, making a compelling case with benchmark data that standard techniques perform poorly. The work is an important contribution to the field and will hopefully lead to a reassessment of the methodology most scientists in morphometrics currently use. This work challenges a very commonly used analytical approach and is bound to raise some controversy in the community, but the authors' critique is based on a well-founded and well-thought out analysis.

eLife Assessment

The authors examined the evolution of hepatitis C virus (HCV) in a cohort of 14 subjects with recent HCV infections. By using computational methods, they showed that viral fitness declines as the virus mutates to escape the immune response and can rebound later in infection as HCV accumulates additional mutations. The study contributes to an important aspect of viral evolution. The combination of approaches is highly compelling; however, some aspects of the manuscript are incomplete and would greatly benefit from additional revision, mainly to increase their clarity.

eLife Assessment

This manuscript offers an exploration of the immune cells in the oyster Crassostrea gigas, by correlating distinct hemocyte morphotypes with specific single-cell transcriptional profiles. The evidence supporting the conclusion is convincing, deriving from the comprehensive dataset that not only captures unicellular diversity but also associates these cells with distinct immune roles, making it an important resource for the broader research community. There are some concerns on the data presentation that leave some questions.

eLife Assessment

This important study provides evidence for the role of neutrophil extracellular traps in chronic kidney damage (CKD) induced by chemotherapy and suggests a therapeutic approach to mitigate the kidney pathology caused by the NETs. The study utilizes a sound murine in vivo model of CKD with low-dose administration cisplatin and a genetic model for impairment of NET formation by deletion of the enzyme Pad4. In its current form, the study was seen as incomplete as there is not yet formal demonstration of NET production by neutrophils in the model of CKD used. Additionally, the accuracy and clarity of data presentation could be improved.

eLife Assessment

This important study substantially advances our understanding of noncoding somatic mutations by identifying a novel class of mutations that affect 3'UTR polyadenylation signals enriched in tumor suppressor genes in cancer. The evidence supporting the conclusions is convincing, with rigorous statistical analyses. The work will be of broad interest to cancer researchers.

eLife Assessment

This paper presents valuable findings on how autophagosomes are positioned along microtubules for their efficient fusion with lysosomes, providing significant insights into the mechanism. The evidence supporting the conclusions is solid, with high-quality fluorescence microscopy combined with Drosophila genetics. This work will be of broad interest to cell biologists interested in autophagy and related cell biology fields.

eLife Assessment

This study provides valuable evidence indicating that SynGap1 regulates the synaptic drive and membrane excitability of parvalbumin- and somatostatin-positive interneurons in the auditory cortex. Since haplo-insufficiency of SynGap1 has been linked to intellectual disabilities without a well-defined underlying cause, the central question of this study is timely. While in their revision the authors successfully addressed questions related to changes in thalamocortical presynaptic excitability, the support for the authors' conclusions is incomplete as concerns around the interpretability of the spontaneous/mini EPSCs, interpretation of results related to excitability, restriction of anatomical analysis of excitatory synapses to the somatic region, and technical problems regarding phase plots remain unresolved.

eLife assessment

In this valuable study, the authors analyze droplet size distributions of multiple protein condensates and their fit to a scaling ansatz, highlighting that they exhibit features of first- and second-order phase transitions. The experimental evidence is solid, and it prompts further research into the nature of the link between percolation and phase separation.

eLife Assessment

This important work advances our understanding of how memories interact to facilitate or interfere with one another, also informing our understanding of how humans build knowledge. The study provides compelling evidence that semantic relatedness proactively benefits memory using clean experimental design, rigorous statistics, large N samples, and well-characterized stimuli. The study also demonstrates the boundaries of these proactive benefits, showing that when studied items have weaker semantic relationships, proactive interference may be observed. This research will be of interest to memory researchers as well as cognitive psychologists, neuroscientists, and educators more broadly.

eLife Assessment

This study presents a valuable finding about the role of Perk (Protein kinase RNA-like endoplasmic reticulum kinase) and Atf4 (Activating Transcription Factor-4) in the integrated neurodegenerative and regenerative responses following the optic nerve injury. The authors present solid evidence, combining newly generated transcriptomic data with publicly available datasets to strengthen their findings. Despite some limitations in data quality and interpretation, the study is likely to be of interest to researchers studying optic neuropathies and axonal regeneration.

eLife Assessment

The authors are interested in the developmental origin of the neurons of the cerebellar nuclei. In this study, they identify a population of neurons with a specific complement of markers that originate in a distinct location from where cerebellar nuclear precursor cells have been thought to originate that show distinct developmental properties. The discovery of a new germinal zone giving rise to a new population of neurons is an exciting finding, and it enriches our understanding of cerebellar development. The important claims, better explained in the current version, are well supported by solid evidence with the authors using a wide range of technical approaches, including transgenic mice that allow them to disentangle the influence of distinct developmental organizers

eLife Assessment

This study reports a valuable finding for the treatment of colorectal cancer (CRC), as the authors demonstrated that the enzyme CPT1A plays an significant role in the response to radiotherapy in CRC patients. However, the reviewers found that the results presented are still incomplete.

eLife Assessment

This is a valuable study of the physiological mechanisms promoting network activity during fever in the mouse neocortex. Most of the supporting evidence is solid, however, there is incomplete support for the conclusion that the E/I balance is unchanged with temperature.

eLife Assessment

This important study describes a computational tool termed FliSimBA (Fluorescence Lifetime Simulation for Biological Applications), which uses simulations to rigorously assess experimental limitations in fluorescence lifetime imaging microscopy (FLIM), including diverse noise factors, hardware effects, and sensor expression levels. The evidence from simulation and experimental measurements supporting the usefulness of FlimSimBA is solid. The authors may improve the application of the tool to a wide range of biological samples by providing the simulation package, currently in MATLB, in other common languages such as Python, and having better descriptions of the fitting algorithm and model assumptions. The work will interest scientists who wish to perform quantitative FLIM imaging for cells and tissues.

eLife Assessment

In this manuscript, Wang et al describe the identification, and provide initial mechanistic characterization, of a potent probiotic strain with activity against Salmonella enterica infection. The evidence provided is compelling, with multiple and varied methodologies used to support the claims made by the authors. The findings reported are valuable to the probiotic and enteric infection subfields.

eLife Assessment

Huson & Regehr characterize the spiking responses of UBCs to various patterns of synaptic stimulation and dissect the contributions of relevant glutamate receptors to their transformations. This study presents valuable findings describing how trains of mossy fiber stimulation control cerebellar unipolar brush cell discharges. The evidence that UBCs transform signals in diverse ways depending on their complement of AMPA, mGluR1, and mGluR2 receptors is solid.

eLife Assessment

This study provides important morphological observations related to the potential roles of Hebbian plasticity in establishing brain connectivity, by examining synapses formed by functionally distinct groups of retinal ganglion cell (RGC) axons in albino mouse dorsolateral geniculate nucleus (dLGN). Here, inappropriately projecting contralateral RGCs undergo developmental rewiring alongside ipsilateral RGCs, such that Hebbian theory would predict them to have separate synaptic targets. The authors provide compelling support for some presence of Hebbian rewiring, using combined confocal imaging and serial electron microscopy (EM) reconstructions to show that contralateral RGCs form completely segregated synaptic inputs onto islands of dLGN thalamocortical neurons, as well as somewhat segregated synaptic input onto local inhibitory interneurons. These findings will be of interest to researchers studying synaptic connectivity and plasticity during development.

eLife Assessment

This valuable study compares ChIP-seq and ChEC-seq2 techniques to investigate RNA polymerase II (RNAPII) binding patterns in yeast, revealing that ChEC-seq2 captures distinct regulatory events associated with active transcription missed by ChIP-seq. The authors use ChEC-seq2 data to build a stochastic model of RNAPII kinetics, providing convincing new insights into transcription regulation and the role of the nuclear pore complex. The paper highlights the importance of careful methodological comparisons in understanding RNAPII dynamics.

eLife Assessment

This work presents an important method for depleting ribosomal RNA from bacterial single-cell RNA sequencing libraries, enabling the study of cellular heterogeneity within microbial biofilms. The approach convincingly identifies a small subpopulation of cells at the biofilm's base with upregulated PdeI expression, offering invaluable insights into the biology of bacterial biofilms and the formation of persister cells. Further integrated analysis of gene interactions within these datasets could deepen our understanding of biofilm dynamics and resilience.

eLife Assessment

This study presents convincing evidence of the role of an intestine-released neuropeptide, FLP-2, in the oxidative stress response of C. elegans, as well as for the neural circuit pathway that regulates its release in response to sensing reactive oxygen species (i.e., H2O2). These valuable results advance the understanding of gut-brain signaling and the neural circuit basis of behavioral responses to stress.

eLife Assessment

This important manuscript describes a creative approach using dual-component gRNAs to create a new class of molecular proximity sensors for genome editing. The authors demonstrate that this tool can be coupled with several different gene editing effectors, showing convincingly that the tool functions as intended. This study not only introduces a first-of-its kind approach, but through careful measurements also enables future further development of the technology.

eLife Assessment

This study is part of an ongoing effort to clarify the effects of cochlear neural degeneration on auditory processing in listeners with normal audiograms. Here the authors provide important new data demonstrating associations between cochlear neural degeneration, non-invasive assays of auditory processing, and speech perception. Based on a cross-species comparison, these findings pose compelling evidence that cochlear synaptopathy is associated with a significant part of hearing difficulties in complex environments for some listeners with normal hearing thresholds, such as older individuals.

eLife Assessment

Although others have proposed that OHC electromotility subserves cochlear amplification by acting as a "fluid pump", and evidence for this has been found using electrical stimulation of excised cochleae, this important study substantially advances our understanding of cochlear homeostasis. This is the first report to test the pumping effect in vivo and consider its implications for cochlear homeostasis and drug delivery. The manuscript provides convincing evidence for OHC-based fluid flow within the cochlea.

eLife Assessment

This study presents valuable findings related to seasonal brain size plasticity in the Eurasian common shrew (Sorex araneus), which is an excellent model system for these studies. The evidence supporting the authors' claims is convincing. However, the authors should be careful when applying the term adaptive to the gene expression changes they observe; it would be challenging to demonstrate the differential fitness effects of these gene expression changes. The work will be of interest to biologists working on neuroscience, plasticity, and evolution.

eLife Assessment

This study used a novel continuous dot motion decision-making task to measure participants' perception and uncertainty/confidence in a social context. The social element is that participants can see another player's responses as well as their own. The study is a useful contribution to social decision-making primarily by introducing a new task and offering solid evidence on how participants are impacted by others' decisions during continuous perceptual choices. The manuscript could be improved through streamlining, more consistent use of terms such as "dyadic" and clarification about the differences between primary uncertainty and metacognitive confidence.

eLife Assessment

This valuable study uses consensus-independent component analysis to highlight transcriptional components (TC) in high-grade serous ovarian cancers (HGSOC). The study presents a convincing preliminary finding by identifying a TC linked to synaptic signaling that is associated with shorter overall survival in HGSOC patients, highlighting the potential role of neuronal interactions in the tumor microenvironment. This finding is corroborated by comparing spatially resolved transcriptomics in a small-scale study; a weakness is in being descriptive, non-mechanistic, and requiring experimental validation.

eLife Assessment

This study presents a valuable finding on the molecular mechanisms that govern GABAergic inhibitory synapse function. The authors propose that Endophilin A1 serves as a novel regulator of GABAergic synapses by acting as a component of the inhibitory postsynaptic density. Although the study employs a variety of approaches to address this question, the current analysis is incomplete and requires further experiments to substantiate the claims fully. The findings are likely to interest a broad audience of scientists focusing on inhibitory synaptic transmission, the excitation-inhibition balance, and its disruption in disorders such as epilepsy.

eLife Assessment

Computational simulation of neuron function depends on a collection of morphological properties and ion channel biophysics. This manuscript introduces DendroTweaks, a useful web application and Python library that, compared to existing modeling tools, eases interactive graphical exploration, development, and validation of single-neuron models. The authors provide a convincing demonstration that their software aids with building intuition and rapid prototyping of biophysical models of neurons, which improves the accessibility of dendritic simulation.

eLife Assessment

This important study addresses the question of how large-scale events such as the COVID-19 pandemic can change peoples' beliefs and their updates. Using a well-validated task, the authors find that belief updating becomes less optimistically biased during COVID-19, compared to prior to it. While they have solid evidence for specific changes of positive learning rates in their RL model and should be commended for more extensive modeling of the task than many previous studies, comprehensive model confusion and recovery analyses could further strengthen their claims by clarifying the specificity of their findings. As with many manipulations outside the experimenters' control, it remains unclear which psychological factor impacted by the pandemic drives the group differences, and sample sizes are by necessity on the smaller side as data cannot readily be acquired.

eLife Assessment

The study presents important findings on inositol-requiring enzyme (IRE1α) inhibition on diet-induced obesity (overnutrition) and insulin resistance where IRE1α inhibition enhances thermogenesis and reduces the metabolically active and M1-like macrophages in adipose tissue. The evidence supporting the conclusions is convincing but can be enhanced with information/data on the validity, specificity, selectivity, and toxicity of the IRE1α inhibitor and supported with more detail on the mechanisms by which adipose tissue macrophages influence adipocyte metabolism. The work will be of interest to cell biologists and biochemists working in metabolism, insulin resistance, and inflammation.

eLife Assessment

This study provides important insights into the question of how interacting brain areas produce behaviour during the execution of a skilled multi-directional reaching task. Using a combination of single neuron and neural population analysis, as well as optogenetic stimulation and computational models, the authors provide solid evidence of an asymmetrical influence between mouse premotor and motor cortex during the execution of a well-practiced behaviour. This asymmetry can only be captured by some but not all population analysis methods, which is a key lesson to the field in and of itself. Analyzing how activity that is shared and private to these areas relates to different aspects of movements, and linking the model predictions to the actual data, would further strengthen this work.

eLife Assessment

This study presents an important finding that ant nest structure and digging behavior depend on ant age demographics for a ground-dwelling ant species (Camponotus fellah). By asking whether ants employ age-polyethism in excavation, the authors address a long-standing question about how individuals in collectives determine the overall state of the task they must perform, and their results may prove to be a key consideration for interpreting results from other studies in the field of social insect behavior. While the experimental evidence that the age of the ants and the group composition affect the digging of tunnels is solid, some of the analyses and modeling are seem superfluous, as they do not further support the results or contribute to a deeper understanding of the system.

eLife Assessment

This important paper takes a novel approach to the problem of automatically reconstructing long-range axonal projections from stacks of images. The key innovation is to separate the identification of sections of an axon from the statistical rules used to constrain global structure. The authors provide convincing evidence that their method is a significant improvement over existing measures in circumstances where the labelling of axons and dendrites is relatively dense, but the robustness to image noise remains to be tested.

eLife Assessment

This study presents a valuable finding that altruistic tendency during moral decision-making is context-dependent (present in the gain domain but absent in the loss domain) and its absence in the loss domain can be restored by the neuropeptide oxytocin. However, the evidence supporting this claim is somewhat incomplete and would benefit from better overall framing and clarity on its approaches. Overall, this study will be of interest to social scientists and neuroscientists who work on moral decision-making and oxytocin.

eLife Assessment

This valuable contribution combines high-resolution histology with magnetic resonance imaging in a novel way to study the organisation of the human amygdala. The main findings convincingly show the axes of microstructural organisation within the amygdala and how they map onto the functional organisation. Overall, the approach taken in this paper showcases the utility of combining multiple modalities at different spatial scales to help understand brain organisation.

eLife Assessment

The focus of this study is the development of a compelling method for analyzing network communication in the brain through an exhaustive computational analysis of virtual lesions. Using human neuroimaging data, the authors identified brain regions that exert the greatest influence over others. These important results revealed the characteristic connectivity profile of such brain regions and provided a network analysis method that will find applicability beyond the datasets used.

eLife Assessment

This valuable study combined whole-head magnetoencephalography (MEG) and subthalamic (STN) local field potential (LFP) recordings in patients with Parkinson's disease undergoing deep brain stimulation surgery. The paper provides solid evidence that cortical and STN beta oscillations are sensitive to movement context and may play a role in the coordination of movement redirection.

eLife Assessment

The central claim in this valuable manuscript is that microglia in the PVH sculpt the density of AgRP inputs to the PVH in a spatially restricted manner. The anatomical results are solid but the analysis of how microglia activity affects body weight when lactating dams are fed a high-fat diet is incomplete.

eLife Assessment

This study provides useful information on the potential role of ERbB4 expression in parvalbumin-positive cells on olfactory behaviour and circuit dynamics in the olfactory bulb. The question is timely and novel, and findings could shed light on the critical role that ErbB4 may play in modulating olfactory bulb cell function and olfactory perception. Although the authors use a comprehensive set of experiments for their analysis, the evidence is incomplete as many of the experiments are underpowered and the model for selective knockout of ErbB4 in olfactory parvalbumin cells is not validated.

eLife Assessment

This is a valuable work that convincingly reveals that place cells in the hippocampus that exhibit repeated firing fields incorporate information about non-positional variables in each firing field. They reveal that individual firing fields of a single place cell can exhibit tuning to different head orientations, suggesting hippocampal neurons are flexible in terms of how they incorporate non-positional inputs.

eLife Assessment

This paper reports the synthesis of covalent inhibitors bearing a unique fragment as a protected covalent warhead for irreversible binding to histidine in carbonic anhydrase (CA) enzymes. These findings are important due to the broad utility of the approach for covalent drug discovery applications and could have long-term impacts on related covalent targeting approaches. The data convincingly support the main conclusions of the paper.

eLife Assessment

This important study by Liu and colleagues uses lineage tracing of hematopoietic stem and progenitor cells in situ to infer the clonal dynamics of adult hematopoiesis. The authors apply a new mathematical analysis framework enabling a wider range of clonal estimation and the revised study 1) provides evidence of polyclonal adult hematopoiesis, 2) provides insights on clonal dynamics during fetal liver hematopoiesis, and 3) reveals unexpectedly high polyclonality in a mouse model of bone marrow failure (Fanconi anemia), arguing against the prevalent views of clonal attrition in this context. The evidence in this extensively revised and improved study is compelling, with methods, data and analyses more rigorous than the current state-of-the-art, which will be of broad interest not only to stem cell and developmental biologists working on hematopoiesis, but also to researchers working on other systems.

eLife Assessment

This useful study holds importance within the focused scope of endometriosis treatment, providing initial evidence of a potential new therapeutic target. The strength of the evidence is solid, as the methods, data, and analyses support the authors' conclusions regarding the specific aims. The study provides promising preliminary evidence of KMO implication in endometriosis, but it falls short of establishing a strong rationale for proposing KNS898 as a treatment for endometriosis given the limitations in evidence and mechanistic insights.

eLife Assessment

This study highlights an important discovery: a bacterial pathogen's effector influences plant responses that in turn affect how the leafhopper insect vector for the bacteria is attracted to the plants in a sex-dependent manner. The research is backed by convincing physiological and transcriptome analyses. This study unveils a complex interdependence between the pathogen effector, male leafhoppers, and a plant transcription factor in modulating female attraction to the plant, shedding light on previously unexplored aspects of plant-bacteria-insect interactions.

eLife Assessment

The toxin mycolactone is produced by Mycobacterium ulcerans which is responsible for the Buruli ulcer lesions. The authors performed a valuable study showing the effects of mycolactone on blood vessel integrity. This convincing data provides new therapeutic targets to accelerate the healing of Buruli ulcer lesions.

eLife Assessment

The investigators studied the membrane-targeting sequence (MTS) of bactofilin A (BacA) in Caulobacter crescentus to explore its role in membrane binding and polymerization. They used various techniques, including microscopy, liposome binding assays, and simulations, to show that membrane targeting may be crucial for BacA polymerization. While their findings on membrane association are valuable, the absence of direct polymerization assays and lack of proper controls in some experiments make the study incomplete.

eLife Assessment

This study presents an important finding regarding a significant, understudied question: How does adaptation affect spatial frequency processing in the human visual cortex? Using both psychophysics and neuroimaging the authors conclude that adaptation induces changes in perceived spatial frequency and population receptive field size (pRF) size, depending on the adaptation state. Specifically, adapting to a low spatial frequency increases perceived spatial frequency and results in smaller pRFs, whereas adapting to a high spatial frequency decreases perceived spatial frequency and leads to broader pRFs. These results offer an explanation for previous seemingly conflicting findings regarding the effects of adaptation on size illusions and the evidence is solid; however, including a clear, direct comparison between pRF sizes in the high-adapted and low-adapted conditions would further strengthen the argument.

eLife Assessment

This valuable study investigates how the neural representation of individual finger movements changes during the early period of sequence learning. By combining a new method for extracting features from human magnetoencephalography data and decoding analyses, the authors provide incomplete evidence of an early, swift change in the brain regions correlated with sequence learning, including a set of previously unreported frontal cortical regions. The addition of more control analyses to rule out that head movement artefacts influence the findings, and to further explain the proposal of offline contextualization during short rest periods as the basis for improvement performance would strengthen the manuscript.

eLife Assessment

This study presents valuable insights into the organization of second-order circuits for gustatory neurons, particularly how they integrate opposing taste inputs and the metabolic states that regulate feeding behavior. An elegant, compelling combination of multiple techniques discovered the target neurons for gustatory integration. However, the functional and behavioral evidence for the function of these neurons is incomplete.

eLife Assessment

This study presents an important finding on durotaxis in various amoeboid cells that is independent of focal adhesions. The evidence supporting the authors' claims is compelling. The work will be of interest to cell biologists and biophysicists working on rigidity sensing, the cytoskeleton, and cell migration.

eLife Assessment

This work describes a new software platform for machine-learning-based segmentation of and particle-picking in cryo-electron tomograms. The program and its corresponding online database of trained models will allow experimentalists to conveniently test different models and share their results with others. The paper provides convincing evidence that the software will be valuable to the community.

eLife Assessment

The authors report that a secreted ubiquitin ligase of Shigella, called IpaH1.4, mediates the degradation of a host defense factor, RNF213. The data are solid and represent an important contribution to our understanding of cell-autonomous immunity and bacterial pathogenesis, as they provide new mechanistic insight into how the cytosolic bacterial pathogen Shigella flexneri evades IFN-induced host immunity.

eLife assessment

This fundamental work describes an understudied bird migration pattern using data from an Arctic raptor. With an extensive dataset and comprehensive analyses, the observed pattern is convincing. This study will be of interest to researchers exploring the ecological drivers of bird migration.

eLife Assessment

Treatment of Pseudomonas aeruginosa (PA) infections is challenging because of intrinsic and acquired antibiotic resistance to most antibiotic drug classes. Therefore, by using donor B cells in subjects with cystic fibrosis who undergo intermittent or chronic airway PA infections, the authors aimed to isolate B-cell receptors against PA virulence factors and examined their biological activities. The data are solid and the protective antibodies identified in this study could be useful for protection against PA.

eLife Assessment

This study presents an important finding on durotaxis in various amoeboid cells that is independent of focal adhesions. The evidence supporting the authors' claims is compelling. The work will be of interest to cell biologists and biophysicists working on rigidity sensing, the cytoskeleton, and cell migration.

eLife Assessment

This study presents an important finding on durotaxis in various amoeboid cells that is independent of focal adhesions. The evidence supporting the authors' claims is compelling. The work will be of interest to cell biologists and biophysicists working on rigidity sensing, the cytoskeleton, and cell migration.

eLife Assessment

This manuscript reports important findings on the impact of maternal obesity on offspring metabolism. It presents solid evidence that maternal obesity induces genomic methylation alterations in oocytes, which can be partly transmitted to F2 in females, and that melatonin is involved in regulating the hyper-methylation of high fat diet oocytes by increasing the expression of DNMTs via the cAMP/PKA/CREB pathway. This study would be of interest to biologists in the fields of epigenetics and metabolism.

eLife Assessment

This valuable study advances our understanding of how Nipah virus fusion protein F (NiV-F) organizes into nanoclusters on cell and viral membranes using biochemical and super-resolution microscopy methods. The conclusions are supported by solid evidence and the revision has addressed most of the reviewers' concerns. The relationship between clustering and fusion is of high interest and an interesting hypothesis to continue investigating in future studies.

eLife Assessment

This important work presents a novel approach to infer causal relations in non-stationary time series data. To do so, the authors introduce a novel machine-learning model of Temporal Autoencoders for Causal Inference to identify and measure the direction and strength of time-varying causal interactions. The authors provide solid evidence for their claims through thorough numerical validation and comprehensive exploration of the method on both synthetic and real-world datasets. This is a timely contribution that may have theoretical and practical implications for diverse real-life applications.

eLife Assessment

This study describes the application of machine learning and Markov state models to characterize the binding mechanism of alpha-Synuclein to the small molecule Fasudil. The results suggest that entropic expansion can explain such binding. However, the simulations and analyses in their present form are inadequate.

eLife Assessment

This important manuscript demonstrates that UGGT1 is involved in preventing the premature degradation of endoplasmic reticulum (ER) glycoproteins through the re-glucosylation of their N-linked glycans following release from the calnexin/calreticulin lectins. The authors include a wealth of convincing data in support of their findings, although extending these findings to other types of substrates, such as secreted proteins, could further demonstrate the global importance of this mechanism for protein trafficking through the secretory pathway. This work will be of interest to scientists interested in ER protein quality control, proteostasis, and protein trafficking.

eLife Assessment

This work is an important contribution to understanding the role of FGF signaling in the induction of primitive-like cells in a 2D system of human gastrulation. The authors provide compelling evidence showing that endogenous FGF ligands, acting through FGF receptors localized basolaterally, are determinant in the acquisition of a primitive streak cell fate. These observations will be of broad relevance to the FGF field.

eLife Assessment

The study provides valuable findings regarding the identification of a new bacteriophage that uses the Pseudomonas aeruginosa exopolysaccharide Psl as a receptor, thus suggesting a novel approach to control biofilms. While much of the data presented is solid, additional work and clarifications are still required to fully support some of the main claims. This manuscript will interest those working on biofilms, specifically in Pseudomonas, on phage physiology and discovery, and on alternatives to controlling bacterial pathogens.

eLife Assessment

Abdelmageed et al. demonstrate POLK expression in neurons and report an important observation that POLK exhibits an age-dependent change in subcellular localization, from the nucleus in young tissue to the cytoplasm in old tissue. Despite potentially exciting and novel findings, many of the authors' claims are provided with incomplete support (e.g. lack of validation of the POLK antibody, characterization of the subcellular compartment, etc).

eLife Assessment

This valuable study by Ganesh and colleagues examined how both the value and salience of sensory information can affect economic decision-making. The results provide insights into how different sources of uncertainty found in the real world, including those related to the perception of objects and those related to values associated with objects, can together influence decision-making behavior in systematic ways. The evidence is solid but overlaps with previous studies and could be improved by clarifying novelty and experimental details and considering additional models.

eLife Assessment

This important study introduces an approach to discovering antibiotic resistance determinants by leveraging diverse susceptibility profiles among related mycobacterial species, with particular relevance to high-level resistance against natural product-derived antibiotics. The research provides convincing evidence for the role of ADP-ribosylation enzymes in rifamycin resistance among mycobacteria, whilst also demonstrating that antibiotic susceptibility is not correlated with growth rate or intracellular compound concentration. Although some broader claims require additional experimental support, this work lays a significant foundation for understanding the complexity of antibiotic resistance mechanisms in mycobacteria and opens new avenues for future antimicrobial research.

eLife Assessment

This important manuscript provides insights into the competition between Splicing Factor 1 (SF1) and Quaking (QKI) for binding at the ACUAA branch point sequence in a model intron, regulating exon inclusion. The study employs rigorous transcriptomic, proteomic, and reporter assays, with both mammalian cell culture and yeast models. Nevertheless, while the data are convincing, broadening the analysis to additional exons and narrowing the manuscript's title to better align with the experimental scope would strengthen the work.

eLife Assessment

This study presents an important finding on the role of telomeres in modulating interleukin-1 signaling and tumor immunity in TNBC. The evidence supporting these findings is solid, presented through comprehensive analyses including TNBC clinical samples, tumor-derived organoids, cancer cells, and xenografts. The work will be of broad interest to cell and medical biologists focusing on TNBC.

eLife Assessment

This study presents a valuable finding on how the sensorimotor control system deals with redundancy within our body, based on a novel bimanual task. The evidence supporting the authors' claims is convincing, as demonstrated over four different experiments. The work will be of interest to researchers from the motor control community and related fields, and further investigation into the interpretation of the findings could increase the generalisation of the study to a broader audience.

eLife Assessment

The contributions of ipsilateral cortical pathways to motor control are yet not fully understood. Here, the authors present important insights into their role in locomotion following unilateral spinal cord injury. Their data provide convincing evidence in rats that stimulation of ipsilateral motor cortex improves the injured side's ability to support weight and leads to improved locomotion, a result that may inspire new treatments for spinal or cerebral injuries.

eLife Assessment

This study provides convincing evidence for functional subpopulations of β-cells responsible for Ca2+ signal initiation and maintenance using novel three-dimensional light sheet microscopy imaging and analysis of pancreatic islets. The findings are important as they help decode the mechanistic underpinnings of islet calcium oscillations and the resulting pulsatile insulin secretion. The work will be of general interest to cell biologists and of particular interest to islet biologists.

eLife Assessment

The manuscript by Hills, et al. presents data that support multiple conclusions regarding the gene expression patterns of cells, especially chemosensory neurons. The evidence is largely solid, with transcriptomic analysis combined and validated by spatially resolved expression in tissue sections, but is incomplete in other ways with some claims not fully supported. This large-scale single-cell transcriptomics dataset is an important resource, alongside a thorough exploration of the molecular features of the different cell types within the mouse vomeronasal organ, including expression of chemosensory receptors.

eLife Assessment

This valuable study uses fluorescence lifetime imaging and steady-state and time-resolved transition metal ion FRET to characterize conformational transitions in the isolated cyclic nucleotide binding domain of a bacterial CNG channel. The data are compelling and support the authors' conclusions. The results advance the understanding of allosteric mechanisms in CNBD channels and have theoretical and practical implications for other studies of protein allostery. A limitation is that only the cytosolic fragments of the channel were studied.

eLife Assessment

The paper will be of broad interest to fungal biologists and fungal immunologists seeking to understand the biosynthesis of the fungal cell wall, in particular of ß-1,6-glucan synthesis and the importance of this so far understudied constituent of the cell wall for cell wall integrity and immune response. The study is of fundamental significance and adds structural clarity to the genetic, and biochemical basis of this difficult-to-analyze carbohydrate. It opens the potential for understanding its role in immune recognition and potentially as a drug target. Overall, the data is compelling, properly controlled and analyzed.

eLife Assessment

This valuable work presents the latest version of CTFFIND, which is the most popular software for determination of the contrast transfer function (CTF) in cryo-electron microscopy. CTFFIND5 estimates and considers acquisition geometry and sample thickness, which leads to improved CTF determination. The paper describes compelling evidence that CTFFIND5 finds better CTF parameters than previous methods, in particular for tilted samples (e.g. for cryo-electron tomography) or where thickness is an issue (e.g. cellular samples, or electron microscopy at low voltages).

eLife Assessment

This computational study integrates detailed electrophysiology and mechanical contraction predictions, which are often modeled separately. The findings of this important work are that abnormal ECGs that are associated with higher risk of sudden cardiac death are predicted to have almost no relationship with left ventricular ejection fraction, which is conventionally used as a risk factor for arrhythmia. The conclusions are based on compelling evidence for the need of incorporating additional risk factors for assessing post-myocardial infarction patients.

eLife Assessment

This work describes a circadian regulation in the expression of HERP, a regulator of endoplasmic reticulum calcium, in primary astrocytic cultures. This work is important because it highlights the potential importance of circadian rhythms in astrocytes, even though making a direct comparison between these rhythms in vitro and in vivo remains challenging. The technical approaches used in this work (RNA-seq, siRNA, Ca2+ imaging) are a solid support for data interpretation.

eLife Assessment

This valuable study provides solid support for the participation of the BMP-binding domain of MuSK, a tyrosine kinase mostly known for its role at the neuromuscular junction, in the maintenance and activation of muscle stem cells (SCs). These mononucleated cells, located between the muscle fiber basal lamina and its plasma membrane, are normally quiescent, but following muscle damage, become activated, proliferate, and mediate muscle regeneration. These cells are known to respond to a variety of signaling pathways, but this study makes the case for BMP acting via binding to MuSK in maintaining the quiescent state.

eLife Assessment

This valuable study reveals extensive binding of eukaryotic translation initiation factor 3 (eIF3) to the 3' untranslated regions (UTRs) of efficiently translated mRNAs in human pluripotent stem cell-derived neuronal progenitor cells. The authors provide solid evidence to support their conclusions, although this study may be enhanced by addressing potential biases of techniques employed to study eIF3:mRNA binding and providing additional mechanistic detail. This work will be of significant interest to researchers exploring post-transcriptional regulation of gene expression, including cellular, molecular, and developmental biologists, as well as biochemists.

eLife Assessment

The authors use single molecule imaging and in vivo loop-capture genomic approaches to investigate estrogen mediated enhancer-target gene activation in human cancer cells. These potentially important results suggest that ER-alpha can, in a temporal delay, activate a non-target gene TFF3, which is in proximity to the main target gene TFF1, even though the estrogen responsive enhancer does not loop with the TFF3 promoter. To explain these results, the authors invoke a transcriptional condensate model. The reviewers were split on the strength and interpretation of the evidence presented, which is considered incomplete at this stage. We encourage a revision which buttresses the findings with additional control experiments and careful consideration of alternative explanations and mathematical models. Further, the depth of the discussion on existing literature could be improved. This work will be of interest to those studying transcriptional gene regulation and hormone-aggravated cancers.

eLife Assessment

In this manuscript, the authors sought to elucidate mechanistic intricacies of inflammatory responses, with emphasis on T cell dysfunction, to S. aureus-induced pneumonia in the context of aging process using Terc deficient mice. Conceptually, the study is very interesting with a set of useful findings. Although some experimental approaches are appropriate, the work as shown in the revised manuscript remains significantly underpowered and the absence of rigorous controls make this study incomplete in support of its claims.

eLife Assessment

In this useful study, the authors present convincing evidence linking the enzyme D-alanine-D-alanine ligase (Ddl), crucial for cell wall fortification, to organic acid exposure in Staphylococcus aureus. While it's established that organic acids impede bacterial growth, the researchers reveal a novel coping mechanism where S. aureus maintains elevated levels of D-alanine, the substrate for Ddl, to counteract this inhibition. This discovery illuminates a bacterial strategy for organic acid tolerance, offering new insights for microbiologists and potentially informing future antimicrobial approaches.

eLife Assessment

The authors have developed a robust machine learning approach to predict radio sensitivity in patients with NPC based on a defined gene signature. Some key aspects of this signature have been validated in vitro using relevant cell lines which strengthens the conclusions of this important and convincing study. The publication will be of interest to clinicians working on this indication as well as a more broader readership made up of scientists working on radiation biology and those with a bioinformatics/machine learning background.

eLife Assessment

This study represents a potentially useful tool for extracting quantitative data from intravital microscopy directed at in vivo cancer models. In general, this is an area of interest as accessible non-proprietary tools are needed and some evidence of the tool's utility is provided. However, the work in its current form is incomplete as it is heavily reliant on proprietary software to segment, track, and correct the data. In addition, there are significant reservations regarding the methods used to produce statistics in the software, limiting its applicability and the potential advance over other approaches.

eLife Assessment

The study identifies the adhesion G-protein-coupled receptor A3 (ADGRA3) as a potential target for activating adaptive thermogenesis in white and brown adipose tissue, providing valuable information for scientists in the field of adipose tissue biology and metabolism. Although the authors have addressed some concerns raised by reviewers, the interpretations remain somewhat limited, and the work is deemed incomplete. The evidence supporting ADGRA3's role in thermogenesis is insufficient, necessitating more rigorous experiments to validate the receptor's relevance in adipose tissue. Additionally, the lack of experiments using primary cultures, despite feedback from multiple reviewers, highlights significant shortcomings.

eLife Assessment

This manuscript reports important data providing evidence that a 42 amino acid region of Rev7 is necessary and sufficient for interaction with the Rad50-Mre11-Xrs2 complex in budding yeast. The authors conclude that Rev7 inhibits the Rad50 ATPase and the Mre11 nuclease with the exception of ssDNA exonuclease activity. The convincing data largely support the conclusions, although the effect of Rev7 on homologous recombination is less well documented and the observed effect on resection is moderate. Specifically, the result that the Rev7 C-terminal truncation lacking the 42 amino acid region still suppresses homologous recombination is unexpected and unexplained.

eLife Assessment

The authors established a useful syndetome differentiation protocol from human induced pluripotent stem cells, guided by single-cell transcriptomic analysis. Their findings could significantly impact the field, particularly for patients needing tendon cell therapy. However, the evidence presented is currently incomplete, as the authors did not yet test the applicability of their protocol across multiple human induced pluripotent stem cell lines.

eLife Assessment

The study describes a link between beta-amyloid monomers, regulation of microglial activity and assembly of neocortex during development. It brings valuable findings that have theoretical and practical implications in the field of neuronal migration, neuronal ectopia and type II lissencephaly. Unfortunately, the evidence is incomplete and the manuscript would benefit from additional experiments to clarify the relationship between Ric8a and APP and bolster the findings.

eLife Assessment

This important study describes the function of Laminin y1-dependent basement membranes in development of the olfactory placode, including morphogenesis of the placode, boundary formation, and olfactory axonal pathfinding. The study uses elegant live imaging approaches and extensive quantitative analyses, combined with detailed mutant analyses to provide a compelling description of the role of Laminin in olfactory placode development. In addition to the contributions this study makes to understanding olfactory placode development, it will also be of broader interest to individuals studying extracellular matrix regulation of tissue morphogenesis, and neural development including neuronal pathfinding.

eLife Assessment

This important study suggests that the composition of the extracellular matrix in a mouse model of liver fibrosis changes depending on the cause of liver fibrosis. The data could be used as a foundation for future antifibrotic therapies. The strength of evidence is solid with respect to the use of animal models and proteomic analysis. The study provides a helpful inventory of proteins up or down-regulated, but functional analyses are limited and translational data are lacking.

eLife Assessment

This study provides valuable insights into the evolutionary histories and cellular infection responses of two Salmonella Dublin genotypes. While the evidence is compelling, a more phylogenetically diverse bacterial collection would enhance the findings. This research is relevant to scientists studying Salmonella and gastroenteritis-related pathogens.

eLife Assessment

Following up on their previous work, the authors investigated whether cell-to-cell transmission of HIV-1 activates the CARD8 inflammasome in macrophages. This is important given that inflammasome activation in myeloid cells triggers proinflammatory cytokine release. The data are solid and support the idea that CARD8 is activated by the viral protease and promotes inflammation. However, time-course analyses in primary T cells and macrophages and further information on the specific inflammasome involved would further increase the significance of the study.

eLife Assessment

This valuable study investigates prey capture by archer fish, showing that even though the visuomotor behavior unfolds very rapidly (within 40-70 ms), it is not hardwired; it can adapt to different simulated physics and different prey shapes. Although there was agreement that the model system, experimental design, and main hypothesis are certainly interesting, opinions were divided on whether the evidence supporting the central claims is incomplete. A more rigorous definition and assessment of "reflex speed", more detailed evidence of stimulus control, and a more detailed analysis of individual subjects could potentially increase confidence in the main conclusions.

eLife Assessment

This study provides evidence that cerebellar projections to the thalamus are required for learning and execution of motor skills in the accelerating rotarod task. This important study adds to a growing body of literature on the interactions between the cerebellum, motor cortex, and basal ganglia during motor learning. The data presentation is generally sound, especially the main observations, with some limitations in describing the statistical methods and a lack of support for two segregated cerebello-thalamic pathways, which is incomplete in supporting the overall claim.

eLife Assessment

This important study advances our understanding of the way neurons in the auditory cortex of mice respond to unpredictable sounds. Through the use of state-of-the-art recording methods, compelling evidence is provided that responses to local and global violations in sound sequences are prediction errors and not simply the consequence of stimulus-specific adaptation. Although the cell-type-specific results are intriguing, further work is needed to establish their reliability.

eLife Assessment

This important study partially fills the gap in the knowledge of olfaction at the level of the Anterior Olfactory Nucleus (AON) and Piriform Cortex with functional magnetic resonance imaging, electrophysiology, and modeling. The methods used are convincing. Some of the findings confirm ongoing hypotheses, such as the behavioral importance of AON for odor source discrimination. Other results shed light on the dynamics of the connection between the olfactory system and the rest of the brain.

eLife Assessment

This important collection of over 800 new cell type-specific driver lines will be an invaluable resource for researchers studying associative learning in Drosophila. Thoroughly characterized and well documented, this collection will permit researchers to selectively target neurons that deliver information to, or receive it from, the memory center of the fly brain called the Mushroom Body. Given the wealth of new drivers and the genetic access they provide to over 300 cell types, this compelling work will be of interest not only to researchers studying the mechanisms of associative learning but more generally to those dissecting sensorimotor circuits in the fly nervous system.

eLife Assessment

This study compiles a wide range of results on the connectivity, stimulus selectivity, and potential role of the claustrum in sensory behavior. While most of the connectivity results confirm earlier studies, this valuable work provides incomplete evidence that the claustrum responds to multimodal stimuli and that local connectivity is reduced across cells that have similar long-range connectivity. The conclusions drawn from the behavioral results are weakened by the animals' poor performance on the designed task. This study has the potential to be of interest to neuroscientists.

eLife Assessment

This valuable study investigates the relationship between neuronal dynamics in the thalamus and brain state modulation. The claims that a specific channel is a critical player in the regulation of brain-states and ethanol-resistance in mice are supported by convincing evidence. The work will be of interest to systems neuroscientists interested in brain dynamics and behavioural states.

eLife Assessment

This important study investigates how AD(H)D affects attention using neural and physiological measures in a Virtual Reality (VR) environment. Solid evidence is provided that individuals diagnosed with AD(H)D differ from control participants in both the encoding of the target sound and the encoding of acoustic interference. The VR paradigm here can potentially bridge lab experiments and real-life experiments. However, the reviewers identified a few potential technical issues that will need to be verified and discussed.

eLife Assessment

This study describes a new analysis strategy to compare active neurons during behavioral tasks across the brain. This is significant because analysing how different brain areas are active during behavior requires better methods. The evidence provided in support of the method is solid. Although useful now, the work may increase its significance following appropriate revisions.

eLife Assessment

This study presents an important application of high-content image-based morphological profiling to quantitatively and systematically characterize induced pluripotent stem cell-derived mixed neural cultures cell type compositions. Compelling evidence through rigorous experimental and computational validations support new potential applications of this cheap and simple assay.

eLife Assessment

This study provides a valuable description of subtypes of V1 neurons, including birthdates and connections to motor neurons. V1 neurons are one of the main groups of inhibitory neurons in the spinal cord. The methods of data collection and analysis are convincing. This work will interest developmental biologists and neuroscientists working on spinal circuits.

eLife Assessment

This important study investigates the contribution of cytosolic S100A/8 to neutrophil migration to inflamed tissues. The authors provide convincing evidence for how the loss of cytosolic S100A/8 specifically affects the ability of neutrophils to crawl and subsequently adhere under shear stress. This study will be of interest in fields where inflammation is implicated, such as autoimmunity or sepsis.

eLife Assessment

This valuable study reports the existence of specific spike-timing dependent synaptic plasticity processes at two excitatory synapses of the dentate gyrus granule cells. These synapses link the entorhinal cortex and the dentate gyrus but via different circuits. With state-of-the-art patch-clamp electrophysiological analysis, the authors provide convincing information on the molecular mechanisms underlying these 2 forms of synaptic plasticity showing a critical role for astrocytes in both alongside some features distinctive to each pathway. These results will be of interest to neuroscientists as they uncover detailed plasticity mechanisms involving the hippocampus.

eLife Assessment

This study is deemed to be an important work that carefully deconstructs multi-faceted conditioned fear behavior in mice. The well-controlled experiments provide convincing data that will be of interest to other researchers in the field.

eLife Assessment

This valuable modeling study explores how biophysical properties of different interneuron subtypes in the basolateral amygdala (BLA) enable production of oscillations that facilitate functions such as spike-timing-dependent plasticity. Simulated networks provide solid evidence that highlights the importance of interactions between interneurons for some forms of spike-timing dependent plasticity. This work will likely be of interest to investigators studying interactions among interneurons, rhythms in the amygdala, and mechanisms of plasticity thought to underlie associative learning.

eLife Assessment

This important study demonstrated that ablation of astrocytes in the lumbar spinal cord not only reduced neuropathic pain but also caused microglia activation. The findings presented add considerable value to the current understanding of the role of astrocyte elimination in neuropathic pain, offering convincing evidence that supports existing hypotheses and insights into the interactions between astrocytes and microglial cells, likely through IFN-mediated mechanisms

eLife Assessment

The study is valuable to the field, introducing a new model to test BM-periosteal stem cell function in vivo. The authors' findings suggested that periosteal stem cells are linked to hematopoietic regeneration. More comparisons with the conventional model and direct examination of periosteal stem cell factors in hematopoietic regeneration are missing. The observations are solid, however, the limitations in their experimental model made the overall impact incomplete; there is potential for improvements to be made in this area.

eLife Assessment

This important study aimed to identify how chronic heat exposure affects subsequent behavior and brain function. This work positively expands the field of thermoregulation. The data were collected using a myriad of next-generation approaches, including extensive behavior testing, thermal monitoring, electrophysiology, circuit mapping, and manipulations. As a result the strength of evidence is mostly solid, however a few weaknesses drove the some of the conclusions to be incompletely supported. These largely circle around the question of how unique these effects are to thermal stress (as opposed to other forms of stress), a lack of statistical analyses and rigor in some of the experiments and figures, and the specificity of the POA-pPVT pathway compared to other inputs to the PVT in the control of observed effects.

eLife Assessment

This valuable manuscript reports a large-scale, data-driven, biophysically detailed model of the non-barrel primary somatosensory cortex and generates numerous predictions that can further our understanding of how the multiscale organization of the cortex shapes neural activity. While the approach is solid, many of the findings are obtained using a much smaller portion of the model, which, together with the broad scope of the work, makes the narrative somewhat confusing and the strength of findings not entirely clear.

eLife Assessment

This study provides abundant valuable scRNA-Seq data that profiles fibroblasts involved in myocardium and coronary vasculature development. However, the evidence supporting the authors' claims is currently incomplete. The inclusion of additional citations, more in-depth discussions, and further analyses or experiments to validate the scRNA-Seq data would have significantly strengthened the study. Nonetheless, the scRNA-Seq expression data will be a resource that is of value to researchers in the field.

eLife Assessment

This study presents two main findings regarding HIV-1 genomic integration. The first, based on convincing evidence in primary cell models, is that HIV-1 induces R loop formation, though the viral driver of this process remains undefined. The second, based on model cell systems with limited physiological relevance to HIV-1, is that a portion of HIV-1 genomes integrates in the vicinity of where R loops form. This finding has the potential to offer fundamental insight into HIV-1 integration, but the strength of the presented evidence was viewed as incomplete and needing additional validation by more direct experimental methods in order to understand what the mechanistic relationship between the formation of R loops and HIV-1 integration is.

eLife Assessment

This useful study presents a biologically realistic, large-scale cortical model of the rat's non-barrel somatosensory cortex, investigating synaptic plasticity of excitatory connections under varying patterns of external activations and characterizing relations between network architecture and plasticity outcomes. While the model demonstrates several interesting phenomena, the results are less explanatory of causal relationships and more observational in nature; hence the evidence supporting the main conclusions remains incomplete.

eLife Assessment

This important study explores the interplay between gene dosage and gene mutations in the evolution of antibiotic resistance. The authors provide solid evidence to connect proteostasis with gene duplication during experimental evolution in a model system. If the experiments are found to be rigorous and reproducible, then this paper will be of high interest to other researchers studying antibiotic resistance, proteostasis, and bacterial evolution.

eLife Assessment

This valuable work explores the timely idea that aperiodic activity in human electrophysiology recordings shows changes in response to task events, which may be relevant for performance, and that these changes could be misinterpreted as oscillatory changes. While it is a timely and interesting topic in principle, in the present form, the analytic approach is incomplete. Further, the data offer inadequate support for the conclusions related to theta without demonstrations that the task evokes theta power. Impressions were split, but there was consensus that the Discussion should be tempered and that revisions would improve the manuscript.

eLife Assessment

This important study showing that sleep deprivation increases functional synapses while depleting silent synapses supports previous findings that excitatory signaling increases during wakefulness. This manuscript focuses in particular on AMPA/NMDA ratios. An interesting, although speculative, aspect of the manuscript is the inclusion of a model for the accumulation of sleep need that is based upon the MEF2C transcription factor but also links to the sleep-regulating SIK3-HDAC4/5 pathway. The authors have clarified some questions raised in the previous review, but the evidence for major claims was still found to be incomplete, requiring additional experimentation.