eLife assessment

This important study sheds light on several apparent discrepancies observed across animal studies examining neuroimaging biomarkers of functional recovery following focal ischemia. Using 2-photon imaging of calcium activity in awake mice, the authors show compelling evidence that deficits in neuronal activity and functional connectivity after photothrombosis occur within a very small distance from the infarct (<750 microns) whereas these measures were relatively unaltered more distally, even those typically implicated with functional remapping of the forelimb representation in anaesthetized animals. These findings reveal a complex spatiotemporal relationship between perilesional neuronal network function and behavioral recovery that is more nuanced than previously reported, and motivates the need for better criteria for what is considered remapping.

eLife assessment

This is a valuable study that describes the effects of T. pallidum on neural development by applying single-cell RNA sequencing to an iPSC-derived brain organoid model. The evidence supporting the claims of the authors is solid, although further evidence to understand the differences in infection rates would strengthen the conclusions of the study. In particular, the conclusions would be strengthened by validating infection efficiency as this can impact the interpretation of single-cell sequencing results, and how these metrics affect organoid size as well as comparison with additional infectious agents. Furthermore, additional validations of downstream effectors are not adequate and could be improved.

eLife assessment

This valuable work describes a highly complex automated algorithm for analyzing vascular imaging data from two-photon microscopy. This tool has the potential to fill gaps in knowledge of hemodynamic activity across a regional network. The underlying methods and results are still incomplete; the biological application provided has several problems that make many of the scientific claims in the paper questionable and the generalizability of the pipeline needs to be further addressed. We believe these concerns could be addressed.

eLife assessment

This important study investigates various variants of the SARS-COV-2 spike protein using established computational methods, complemented by experimental validation efforts. The evidence, bolstered by an evolutionary approach and protein dynamics, is solid. Placing this research in the broader context of the field could further enrich the manuscript. It will interest biophysicists focused on allostery and protein evolution.

eLife assessment

This important study presents a framework for combining metagenomic and metabolomic data with genome-scale metabolic models to identify trophic interactions in a root microbiome. Its new approach to integrating these sources of data and model-specific trophic exchanges is compelling, but the benchmarking of the model generation process is incomplete and would benefit from a sensitivity and specificity analysis. With a stronger characterization of their method, this paper could be broadly applicable to other microbiomes and used to understand the composition and functioning of a given community, generate hypotheses, and design interventions.

eLife assessment

This important study addresses the long-term effect of warming and precipitation on microbial growth, as a proxy for understanding the impact of global warming. The evidence that warming and altered precipitation exhibit antagonistic effects on bacterial growth is compelling and advances our understanding of microbial dynamics affected by environmental factors. This study will interest microbial ecologists, microbiologists, and scientists generally concerned with climate change.

eLife assessment

This study presents a useful deep learning-based inter-protein contact prediction method named PLMGraph-Inter which combines protein language models and geometric graphs. The evidence supporting the claims of the authors is solid. The authors show that their approach may be used in cases where AlphaFold-Multimer performs poorly. This work will be of interest to researchers working on protein complex structure prediction, particularly when accurate experimental structures are available for one or both of the monomers in isolation.

eLife assessment

This important paper provides solid evidence for an alternative conceptualization of the functional role of the place and grid cell network in the medial temporal lobe for memory as opposed to spatial processing or navigation. The theory accounts for many experimental results and generates predictions for future studies. The theory's simplicity and potential explanatory power will be of interest to researchers in this field. The impact of the work at present is limited by insufficient evidence for the advantage of this model over prior models, especially as the theory does not appear to fit with some well-established existing data.

eLife assessment

This is a useful study describing an implementation of awake mouse fMRI with implanted head coils at high fields. The evidence presented is solid but could with some work become stronger. In particular, the authors need to better contextualize their work with the existing literature on awake fMRI, include further details regarding their experimental methods, and further discuss some of their unexpected (but potentially novel and interesting) brain activations.

eLife assessment

In this study, the authors develop a strategy for fluorophore-tagging endogenous proteins in human induced pluripotent stem cells (iPSCs) using a split mNeonGreen approach, and they conclude that the system will be appropriate for performing live imaging studies of highly dynamic cellular processes such as cytokinesis in iPSCs. Experimentally, the methods are solid, and the data presented support the authors' conclusions. Overall, these methodologies should be useful to a wide audience of cell biologists who want to study protein localization and dynamics at endogenous levels in iPSCs.

eLife assessment

This useful study introduces a simple mechanical model of C. elegans locomotion that captures aspects of the worm's behavioral repertoire beyond forward crawling. While the kinetic model (ElegansBot) provides a compromise and starting point to help understand the mechanical components of C. elegans behavior, the claim that this work improves on extant mechanical models is incomplete, including modeling a 3-dimensional turning behavior with a 2-dimensional model without sufficient justification. In addition, the results of the application of the model to previously unstudied behaviors are primarily qualitative and do not produce new predictions.

eLife assessment

This useful study, which systematically addresses off-target effects of a commonly used chemotherapy drug on bone and bone marrow cells and which therefore is of potential interest to a broad readership, presents evidence that reducing systemic inflammation induced by doxorubicin limits bone loss to some extent. The demonstration of the effect of systemic inflammation on bone loss is convincing. Building on prior work, this study sets the scene for additional genetic and pharmacologic experiments as well as future analyses of the bone phenotypes, which should speak to the mechanisms involved in doxorubicin-induced bone loss – which are not addressed in the current study – and which may substantiate the clinical relevance of targeting inflammation in order to limit the negative impact of chemotherapies on bone quality.

eLife assessment

This fundamental work advances our understanding of the role of Cbfβ in maintaining articular cartilage homeostasis and the underlying mechanisms. The evidence supporting the conclusion is mostly convincing, although including additional experiments and discussions would have strengthened the study. This paper is of potential interest to skeletal biologists and orthopaedic surgeons who study the pathogenesis and the therapeutics of osteoarthritis.

eLife assessment

This important study combines in vivo and in vitro models to characterise the role of CYRI-B, an interactor of the small GTPase Rac1, in controlling pancreatic cancer progression towards a higher proliferative and metastatic stage. The evidence supporting the claims of the authors is convincing in characterizing a novel Rac1 binding protein, CYRI-B, as a regulator of metastatic potential in vivo, with distinct functions at different stages of tumour progression. CYRI-B reduces the typical hyperactivation of Rac1 in the early stages of tumour progression; subsequently, CYRI-B mediates internalization of lysophosphatidic acid receptor 1 (LPAR1) uptake through macropinocytosis, thus regulating chemotactic migration of cancer cells towards lysophosphatidic acid (LPA). Although the inclusion of human pancreatic cancer cell lines would have strengthened the study, the work will be of broad interest to cell biologists and the signalling research communities.

eLife assessment

This study presents an interesting set of findings that connects N-cadherin and glypican-4 to Slit signaling during the regulation of contact inhibition of locomotion of Schwann cells in culture. Solid evidence is provided showing that N-cadherin not only regulates cell recognition but also proper trafficking of Slit to the cell surface. An ex-vivo model demonstrates the importance of Slit signaling during cell migration but the molecular details of how N-cadherin traffics Slit to the surface and role of glypican are unclear. The data would have been strengthened with a similar interrogation of N-cadherin in this system. The work will be of interest to cell biologists studying the mechanisms behind peripheral nervous system regeneration.

eLife assessment

This work presents a potentially important behavioral finding: that perceptual learning may not only improve but also distort the appearance of visual stimuli. The strength of the presented evidence in support of the main claim is however incomplete, and requires further analyses to confirm that perceptual learning does increase overestimation bias, and clarify why a very large baseline overestimation bias is present in the data.

eLife assessment

This important study provides a new, apparently high-performance algorithm for B cell clonal family inference. The new algorithm is highly innovative and based on a rigorous probabilistic analysis of the relevant biological processes and their imprint on the resulting sequences, however, the strength of evidence regarding the algorithm's performance is incomplete, due to (1) a lack of clarity regarding how different data sets were used for different steps during algorithm development and validation, resulting in concerns of circularity, (2) a lack of detail regarding the settings for competitor programs during benchmarking, and (3) method development, data simulation for method validation, and empirical analyses all based on the B cell repertoire of a single subject. With clarity around these issues and application to a more diverse set of real samples, this paper could be fundamental to immunologists and important to any researcher or clinician utilizing B cell receptor repertoires in their field (e.g., cancer immunology).

eLife assessment

The authors present a critique of current usage of principal component analysis in geometric morphometrics, making a convincing 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. The authors also present a new Python package that uses machine learning to provide better-supported results than principal component analysis. While the package is in the title of the manuscript, it is not its main focus.

eLife assessment

Through a theoretical approach, this study makes important contributions to our understanding of the evolutionary causes of the ageing process. Using a simple individual-based model and computational simulations, the authors provide convincing evidence that ageing can be a trait under natural selection, opening the door for further discussion in the context of lifespan extension research.

eLife assessment

The study presents valuable findings on compensatory mechanisms in response to glycosuria. The evidence supporting the claims is solid, although a causal relationship is somewhat uncertain and the addition of a more clinically relevant model would have strengthened the findings. The work will be of interest to diabetes investigators.

eLife assessment

This study explores the interplay between fungal colonization and controlled programmed cell death in Arabidopsis thaliana root cells. The authors reveal how this process is affected by corpse clearance in the root cap, highlighting some of the key elements in this process including a root cap-specific transcription factor. With this, the authors have discovered an important relationship between transcriptional regulation of developmentally controlled cell death and the beneficial colonization of plants by fungi. The work thus establishes a solid basis for further studies of plant-microbiome associations along the root axis.

eLife assessment

This important work addressed the identifcation of antimalarial drug resistance mutations that do not readily transmit to new human hosts, focusing on azithromycin resistance. The technically challenging analyses of azithromycin-resistant parasites as they traverse the mosquito host and human liver are conducted using state-of-the-art tools, including humanized mice. While the claim regarding the lack of transmission by atovaquone-resistant P. berghei is convincing, the evidence for the lack of transmission by atovaquone-resistant P. falciparum is insufficient. This work will appeal to biologists and biomedical scientists in parasitology and drug discovery, offering insights into combating antimalarial drug resistance and understanding the fitness costs associated with drug-resistant parasites.

eLife assessment

This study provides important biophysical insights into the molecular mechanism underlying the association of alpha-synuclein chains, which is essential for understanding the pathogenesis of Parkinson's disease. The data analysis is solid, and the methodology can help investigate other molecular processes involving intrinsically disordered proteins. The benchmarking of the cgMD simulations should be improved to give the reader greater confidence in the conclusions presented.

eLife assessment

The authors present evidence that small extracellular vesicles can be secreted from cells inside larger vesicles that they call amphiectosomes, which then tear to release their small vesicle contents. There are questions and concerns relating to the quality of the data and the in vivo significance of the observations. The findings are potentially important but the data are incomplete and the claims are only partially supported.

eLife assessment

This work addresses an important biological question: what is the cellular basis of wound healing? Using the Drosophila pupal notum as a model, the paper provides an elegant, thorough, descriptive characterisation of syncytia-driven wound closure using state-of-the-art confocal live imaging of the pupal notum. The authors meticulously characterize the cell-cell fusion events during wound healing, but without any mechanisms to inhibit cell fusion, it is incomplete, since it remains unclear whether cell fusion is required or not for speeding wound healing and/ or increasing the level of actin resources at the leading edge.

eLife assessment

This important study describes the new observation that nuclear volume responds to confinement in a manner that requires transit through mitosis. The authors present solid evidence demonstrating that nuclear volume decreases upon nuclear envelope reformation under confinement in a manner that reestablishes a homeostatic state of nuclear envelope tension. Additional experimental support could provide a more complete case for the proposed underlying mechanisms governing this response. The work will be of broad interest to cell biologists and those interested in cell and organismal scaling.

eLife assessment

Tatekoshi et al. endeavored to utilize human-induced pluripotent stem cell-derived cardiomyocytes to create an in vitro model of Heart Failure with preserved Ejection Fraction (HFpEF) to investigate the impacts of inflammation, sera from HIV patients, and the application of cardioprotective and antiviral medications on cardiomyocyte relaxation as a proxy for diastolic function. Their investigations revealed that inflammatory cytokines lead to an increased decay in calcium transients, a process that could be alleviated through the use of SGLT2 inhibitors and mitochondrial antioxidants. These results indicate that inflammation might contribute to diastolic dysfunction and suggest that SGLT2 inhibitors and mitochondrial antioxidants could offer cardioprotective benefits by reducing inflammation in cardiomyocytes. These valuable, yet incomplete results, can be complemented by employing biomechanical and molecular analyses, alongside validation of the therapeutic duration and dosages.

eLife assessment

This useful study reports data supporting the importance of sterol homeostasis in sperm development and consequently male reproduction. While most of the data are supportive of the conclusion, some remain incomplete and need more experimental verification. This work would be of interest to basic researchers and clinicians working on sterol homeostasis and male fertility.

eLife assessment

The study is solid and reports interesting findings on the sensitivity of different cell types to EDCs in vitro. The data are valuable but the manuscript requires more experimental details. Bioinformatic analyses need to be improved and the interpretation of results and conclusions adjusted to the results.

eLife assessment

This study provides important findings on the evolution and function of the X-linked miR-506 miRNA cluster. The evidence supporting the conclusions is convincing, including the generation and characterization of an impressive number of the miRNA deletion mutants. This work will be of interest to RNA biologists, evolution biologists and reproductive biologists.

eLife assessment

This important study dissects the role of octopamine in the interplay between internal energy homeostasis, food intake and food-related memories. The solid experimental evidence will shed additional light on previously published work and should be of interest to the growing community of biologists interested in how internal state shapes behavior, including decision making processes, learning and memory.

eLife assessment

This study reports important evidence that infants' internal factors guide children's attention, and that caregivers respond to infants' attentional shifts during caregiver-infant interactions. The authors analyzed EEG data and multiple types of behaviors using solid methodologies that can guide future studies of neural responses during social interaction in infants.

eLife assessment

In this valuable study, the authors present findings that suggest that people do not faithfully replicate the physics of the real world but rather have a stochastic world model, specifically a stochastic representation of gravity. This contrasts with prior accounts that suggested a potentially noisy Newtonian model where the noise arises from perceptual uncertainty or (inferred) external perturbations. The experimental evidence is generally solid, with all experiments and model simulations being consistent with the proposed account. In the revision, the authors also added a number of control experiments that address some of the most pressing concerns of the original submission.

eLife assessment

Following synaptic vesicle fusion events at release sites, vesicle remnants will need to be cleared in order to allow new rounds of vesicle docking and fusion. This fundamental study of Mahapatra and Takahashi examines the role of release site clearance in synaptic transmission during repetitive activity in two types of central synapses, the giant calyx of Held and hippocampal CA1 synapses. The study uses pharmacological approaches to interfere with release site clearance by blocking membrane retrieval (endocytosis). They compare the effects on short-term plasticity with those obtained by pharmacologically inhibiting scaffold protein activity. The data presented make a compelling case for fast endocytosis as necessary for rapid site clearance and vesicle recruitment to active zones. The data reveal an unexpected, fast role for local site clearance in counteracting synaptic depression.

eLife assessment

This study tests the effects of using neurofeedback, in the form of reward delivery when large sharp wave-ripples (SWRs) are detected, on neurophysiological and behavioral measures. The results are important, and the authors provide convincing evidence that the rate of SWRs increased prior to reward delivery and decreased in the period after reward delivery, with no significant effect on memory performance. The ability to manipulate SWR rate in a naturalistic way is an exciting new tool for studies that seek to understand the function of SWRs.

eLife assessment

This important study contributes to the understanding of how parafoveal words are neurally processed during naturalistic sentence reading. Solid evidence is provided that the MEG response to a word can be modulated by the semantic congruency of a parafoveal target word. The study addresses a classic question in reading using a new Rapid Invisible Frequency Tagging (RIFT) technique, which can separately monitor the neural processing of multiple words during sentence reading.

eLife assessment

The study by Zhu et al. provides important insights into cell-specific genome-wide histone modifications in the frontal cortex of individuals with schizophrenia, as well as shedding light on the role of age and antipsychotic treatment in these associations. The evidence supporting the conclusions is solid.

eLife assessment

This manuscript presents important results indicating a plastic enhancement in the vasomotion response of pial cortical arterioles to external stimulation in awake mice using a wide range of external visual stimulation paradigms. The evidence for this interesting effect, with broad potential applications, is solid. These results are relevant for scientists and clinicians interested in the regulation of blood flow in the brain.

eLife assessment

This study concerns how macaque visual cortical area MT represents stimuli composed of more than one speed of motion. The study is valuable because little is known about how the visual pathway segments and preserves information about multiple stimuli, and the study involves perceptual reports from both humans and one monkey regarding whether there are one or two speeds in the stimulus. The study presents compelling evidence that (on average) MT neurons represent the average of the two speeds, with a bias that accentuates the faster of the two speeds. Ultimately, this study raises intriguing questions about how exactly the response patterns in visual cortical area MT might preserve information about each speed, since such information could potentially be lost in an average response as described here, depending on assumptions about how MT activity is evaluated by other visual areas.

eLife assessment

This work provides a valuable analysis of the effect of two commonly used hyperparameters, noise amplitude and firing rate regularization, on the representations of relevant and irrelevant stimuli in trained recurrent neural networks (RNNs). The results suggest an interesting interpretation of prefrontal cortex (PFC) dynamics, based on comparisons to previously published data from the same lab, in terms of decreasing metabolic cost during learning. The evidence indicating that the mechanisms identified in the RNNs are the same ones operating in PFC was considered incomplete, but could potentially be bolstered by additional analyses and appropriate revisions.

eLife assessment

This important study investigates the transcriptional changes in neurons that underlie loss of learning and memory with age in C. elegans, and how cognition is maintained in insulin/IGF-1-like signaling mutants. The presented evidence is convincing, utilizing a cutting-edge method to isolate neurons from worms for genomics that is clearly conveyed with a rigorous experimental approach. Overall, this study supports that older daf-2 worms maintain cognitive function via mechanisms that are unique from younger wild type worms, which will be of interest to neuroscientists and researchers studying ageing.

eLife assessment

The authors present valuable empirical and modelling evidence that statistical learning in speech perception may contain processes like segmentation and anticipation. While the evidence for statistical learning effects is solid, the link between the pattern of effects (both empirical and simulated) and the theoretical concepts of segmentation and anticipation would need to be much stronger to exclude other accounts of the data. This work will be of broad interest to researchers working on, or with, statistical learning, and to any researcher interested in the challenges of whether data and modeling can effectively adjudicate between competing theoretical constructs.

eLife assessment

This important paper presents a thoroughly detailed methodology for mesoscale-imaging of extensive areas of the cortex, either from a top or lateral perspective, in behaving mice. The examples of scientific results to be derived with this method offer promising and stimulating insights. Overall, the method and results presented are convincing and will be of interest to neuroscientists focused on cortical processing in rodents and beyond.

eLife assessment

The authors report valuable findings that temporary pharmacological inhibition targeting the dorsal or intermediate hippocampus in rats disrupted navigation to a goal location in a new virtual place-preference task and that functional inhibition of the intermediate hippocampus is more detrimental than functional inhibition of the dorsal hippocampus. The work has the potential to provide novel insights into function differentiation along the dorsal-ventral axis of the hippocampus. However, the evidence for the paper's claim that the dorsal hippocampus is responsible for accurate spatial navigation and the intermediate hippocampus for place-value associations is currently incomplete.

eLife assessment

This paper reports a valuable set of new results. The main result is that the projection from adult-born granule cells in the dentate gyrus to the hippocampal subfield CA2 is necessary for the retrieval of a social memory formed during development, and solid evidence is provided to support this conclusion.

eLife assessment

In their study, Diana et al. introduce a novel method for spike inference from calcium imaging data using a Monte Carlo-based approach, emphasizing the quantification of uncertainties in spike time estimates through a Bayesian framework. This method employs particle Gibbs sampling for estimating model parameter probabilities, offering accuracy comparable to existing methods with the added benefit of directly assessing uncertainties. Although the paper provides a solid methodological explanation, it lacks a thorough comparison with other inference methods. Nevertheless, it presents a valuable advancement for neuroscientists interested in new approaches for parameter estimation from calcium imaging data.

eLife assessment

This study explores the role of one the most abundant circRNAs, circHIPK3, in bladder cancer cells, providing convincing data that circHIPK3 depletion affects thousands of genes and that those downregulated (including STAT3) share an 11-mer motif with circHIPK3, corresponding to a binding site for IGF2BP2. The experiments demonstrate that circHIPK3 can compete with the downregulated mRNAs targets for IGF2BP2 binding and that IGF2BP2 depletion antagonizes the effect of circHIPK3 depletion by upregulating the genes containing the 11-mer motif. These valuable findings contribute to the growing recognition of the complexity of cancer signaling regulation and highlight the intricate interplay between circRNAs and protein-coding genes in tumorigenesis.

eLife assessment

This important study represents a follow-up of previous papers by Huff et al. (2023) in which the authors further investigate a specific medullary region named the Postinspiratory Complex (PiCo) involved in the control of swallow behaviour and its coordination with breathing. In the present work, they tested the impact of chronic intermittent hypoxia on the swallow motor pattern evoked by optogenetic stimulation of the same medullary area in transgenic mice. These solid results indicate that in chronic intermittent hypoxia-exposed mice PiCo stimulation triggers atypical swallow motor patterns. The experimental procedures are rigorous and technically remarkable. The work will be of interest in the field of respiratory physiology and pathophysiology since a disruption of swallowing and possibly discoordination with breathing may be involved in diseases characterized by the presence of hypoxic conditions such as obstructive sleep apnea.

eLife assessment

This valuable study examines the activity and function of dorsomedial striatal neurons in estimating time. The authors examine striatal activity as a function of time and the impact of optogenetic striatal manipulation on the animal's ability to estimate a time interval. However, the task's design and methodology present several confounding factors that mean the evidence in support of the authors' claims is incomplete. With these limitations addressed, the work would be of interest to neuroscientists examining how striatum contributes to behavior.

eLife assessment

This valuable study describes early postnatal compartmental differences in the functional maturation of striatal projection neurons. It explores how the postnatal activity of these neurons may determine the GABAergic innervation of dopaminergic neurons in the adult substantia nigra pars compacta. While the functional characterization of striatal neuron development is solid, analysis of how early postnatal activity of striatal projection neurons shapes their functional innervation of dopaminergic neurons is incomplete.

eLife assessment

This study presents a valuable finding on the structural role of glycosylation at position N343 of the SARS-CoV-2 spike protein's receptor-binding domain in maintaining its stability, with implications across different variants of concern. The evidence supporting the claims of the authors is solid, although a more complete discussion of published data would have strengthened the study by providing a foundation for the new findings. The work will be of interest to evolutionary virologists.

eLife assessment

This study is a useful showcase of a workflow to perform large-scale characterization of drug mechanisms of action using proteomics. The work is backed by solid evidence, however, more statistical analyses and a user-friendly interface to enhance data mining by the readers are recommended. The strengths of this study include the large number of compounds tested within a common workflow and well-described experimental protocols. This will be of broad interest to medicinal chemists, toxicologists, and biochemists.

eLife assessment

This is a very strong, well-written, and interesting paper analyzing in an original way how tension pattern dynamics can reveal the contribution of active versus passive intercalation during tissue elongation. The authors apply a new concept of isogonal tension decomposition to extract a global map of tissue mechanics that will be extremely valuable in the field of biomechanics. The model is convincing to explain the authors' data but could be strengthened further by analyzing data from mutant backgrounds that could serve as a test.

eLife assessment

The study by Long et al. presents valuable findings on the role of the SUL1 gene in yeast longevity, proposing that lifespan extension can occur through signaling pathways independent of its sulfate transport function, offering new insights into aging mechanisms with potential implications beyond yeast biology. However, the evidence supporting the uncoupling of SUL1's transport and signaling functions is inadequate, relying on limited lifespan analysis without measurements for nutrients and nutrient signaling status. This research is of particular interest to the aging research community, although additional experiments are needed to fully substantiate the claims.

eLife assessment

This paper makes a valuable contribution by implicating S-acylation of Cys-130 in recruitment of the inflammasome receptor NLRP3 to the Golgi. Enzymes are identified as candidates for mediating S-acylation and de-acylation of NLRP3, and evidence is presented that S-acylation plays a role in response to the stress induced by nigericin treatment. Although it seems likely that Cys-130 does indeed contribute to membrane association of NLRP3, the mechanistic analyses are incomplete and the interpretations about the effects of nigericin are not fully conclusive.

eLife assessment

The authors introduce a valuable machine-learning model for predicting binding sites of diverse ligands, including DNA, RNA, peptides, proteins, ATP, HEM, and metal ions, on proteins. The method is freely accessible and user-friendly. The authors have conducted thorough benchmarking and ablation studies, providing convincing evidence of the model's overall performance, despite some imperfections of the comparisons to other methods that arise from intrinsic differences between training methods and data.

eLife assessment

This study presents a rather valuable finding that vilazodone can restore the normal platelet level through regulating 5-HT1A receptor. The evidence supporting the claims of the authors is solid, although inclusion of more cell lines and more detailed analysis of the results would have strengthened the study. The work will be of interest to scientists working in the field of thrombocytopenia.

eLife assessment

This important study unveils the significant impact of prenatal alcohol exposure on epigenetic patterns, offering new insights into its adverse health outcomes through solid evidence from both mouse models and human data. The findings, which reveal how a high-methyl diet can mitigate these epigenetic alterations, present a promising prenatal care strategy. Despite its solid data overall, the study's small sample size and unaccounted confounders suggest the need for further research to confirm these findings and explore their practical implications.

eLife assessment

The study presented in this manuscript makes important contributions to our understanding of cell fate decisions and the role of noise in gene regulatory networks. Through computational and theoretical analysis, the authors provide solid support for distinguishing distinct driving forces behind fate decisions based on noise profiles and reprogramming trajectories. While acknowledging the potential limitations of small gene regulatory networks in capturing the richness of whole-transcriptome sequencing datasets, this study offers a creative approach for formulating hypotheses about gene regulation during stem cell differentiation using single-cell sequencing data.

eLife assessment

This work presents some valuable information regarding the molecular mechanisms controlling the regeneration of pancreatic beta cells following induced cell ablation. However, the study lacks the critical lineage tracing result to support the conclusion about the origin of the regenerated beta cells. The results of the pharmacological manipulation of CaN signaling are also incomplete. In particular, these manipulation are not cell-specific, making it difficult to interpret and thus a genetic approach is recommended.

eLife assessment

This potentially useful work characterizes the changes in microbial composition of the nasal and fecal microbiomes of COVID-19 patients according to the severity of disease. However, the description of methods and statistics used for several figures is incomplete.

eLife assessment

This comprehensive study provides valuable information on the cooperation of Ikaros with Foxp3 to establish and regulate a major portion of the epigenome and transcriptome of T-regulatory cells. While the data are compelling, the evidence that these features are solely intrinsic, independent of the micro-environment, could be strengthened.

eLife assessment

The development of this mouse model is an important step to establish the role of the FSH Receptor in tissues beyond the reproductive system, and the data provided in this paper are convincing for a role for the FSH receptor in cell systems well beyond the classic reproductive tissues. Such model(s) have long been needed in this field and will provide expanded opportunities to better define FSH biology in vivo in these important target tissues. Ultimately, this model could shed light on FSH biology in women after menopause, when endogenous FSH levels rise dramatically, or in men with hypogonadism when FSH levels are high.

eLife assessment

This study on scRNA-seq of allergic contact dermatitis (ACD) is important in that it presents new data on fibroblasts in ACD and links to recent studies on other cell types and their signatures. The evidence presented is solid in that the data support claims of unique roles for subtypes of fibroblasts in ACD. Overall, this paper will be used as a resource by many in the skin inflammation field.

eLife assessment

This valuable work provides a near-complete description of the mechanosensory bristles on the Drosophila melanogaster head and the anatomy and projection patterns of the bristle mechanosensory neurons that innervate them. The data presented are solid. The study has generated numerous resources for the community that will be of interest to neuroscientists in the field of circuits and behaviour, particularly those interested in mechanosensation and behavioural sequence generation.

eLife assessment

This important study outlines how the agr quorum sensing system in Staphylococcus aureus confers long-lived protection against oxidative stress, thereby linking bacterial metabolism to virulence in this pathogen. While the findings, which are supported by solid data, seem at first glance to contradict earlier findings that show increased fitness of agr mutants under oxidative stress, the core conclusions of the study are well-substantiated. The topic of the paper holds broad relevance to microbiologists, especially those focusing on host-pathogen interactions and bacterial responses to ROS.

eLife assessment

This fundamental study substantially advances our understanding of sibling chimerism in marmosets by demonstrating that chimerism is limited to hematopoietic cells. The evidence supporting these findings is compelling, demonstrated through comprehensive analyses, including single-cell RNA-seq data from multiple individuals and tissues. The work will be of broad interest to many fields of biology.

eLife assessment

This important study uses citizen science-generated diversity records and quantitative methodologies to improve species distribution estimates. This combination of fields, technologies, and methodologies is solid and improves species distribution maps formerly based solely on limited data gathered by scientists in traditional ways/surveys. This paper will be of interest to researchers interested in citizen science and new sources of big data in biodiversity, and to biogeographers exploring the distributions of species on the planet.

eLife assessment

This study provides important findings on the modulation of cortical neuronal responses to sensory stimuli by motor-driven predictive signals. The study is methodologically sound and well-designed. The data, as analysed, provide incomplete support for the conclusion that audiomotor mismatch responses are observed in the auditory cortex and that these are strongly modulated by cross-modal signals.

eLife assessment

This important study combines fMRI and electrophysiology in sedated and awake rats to show that LFPs strongly explain spatial correlations in resting-state fMRI but only weakly explain temporal variability. They propose that other, electrophysiology-invisible mechanisms contribute to the fMRI signal. The evidence supporting the separation of spatial and temporal correlations is convincing, however, the support of electrophysiological-invisible mechanisms is incomplete, considering alternative potential factors that could account for the differences in spatial and temporal correlation that were observed. This work will be of interest to researchers who study the mechanisms behind resting-state fMRI.

eLife assessment

The paper reports rare compound heterozygous deletion variants that affect the kinase domains of non-receptor tyrosine kinases TNK and ACK1 in families with human systemic lupus erythematosus (SLE). Using a mouse experimental model and human induced pluripotent stem cell (hiPSC)-derived macrophages, the study provides solid evidence that clarifies cause-effect relationships and that suggests a potential cellular mechanism underlying the resultant nephritis. With the identification of novel SLE-related genes, this manuscript provides an important basis for understanding the molecular and cellular basis of SLE pathogenesis.

eLife assessment

This study demonstrates mRNA-specific regulation of translation by subunits of the eukaryotic initiation factor complex 3 (eIF3) using convincing methods, data, and analyses. The investigations have generated important information that will be of interest to biologists studying translation regulation. However, the physiological significance of the gene expression changes that were observed is not clear.

eLife assessment:

In flies defective for axonal transport of mitochondria, the authors report the upregulation of one subunit, the beta subunit, of the heterotrimeric eIF2 complex via mass spectroscopy proteome analysis. Neuronal overexpression of eIF2β phenocopied aspects of neuronal dysfunction observed when axonal transport of mitochondria was compromised. Conversely, lowering eIF2β expression suppressed aspects of neuronal dysfunction. While these are intriguing observations that are potentially useful, several technical weaknesses limit the interpretation and mean the evidence supporting the current claims is incomplete.

eLife assessment

This important study combines a range of biophysical techniques to carry out a series of compelling experiments to explore whether glutamine binding protein binds glutamine via an induced fit or a conformational selection process. The evidence supporting the major conclusion of the work is convincing, although it may not be generalized to other protein-ligand or protein-protein systems. The work will be of broad interest to biochemists and biophysicists.

eLife assessment

The demonstration that the PARG dePARylation enzyme is required in S phase to remove polyADP-ribose (PAR) protein adducts that are generated in response to the presence of unligated Okazaki fragments is potentially valuable, but the evidence is incomplete, and identification of relevant PARylated PARG substrates in S-phase is needed to understand the role of PARP1-mediated PARylation and PARG-catalyzed dePARylation in S-phase progression.

eLife assessment

This paper provides a useful analysis of the variation of the burden of strokes across geographic regions, finding differences in the relationship between strokes and their comorbidities. This dataset and the correlations found within will be a resource for directing the focus of future investigations. The statistical analyses are incomplete.

eLife assessment

This study provides valuable information on how Arg-II participates in cardiac aging. Although the phenotypic data appear robust, the study is incomplete in elucidating the mechanisms, particularly in explaining how Arg II influences IL-1b and affects cardiac aging. It would be beneficial to investigate the possibility of NO involvement in this mice model. A co-culture system may be required to understand the non-cell-autonomous functions of macrophages. Lastly, the MI mouse model may not be directly linked to cardiac aging.

eLife assessment

This useful paper looks for correlations between immunophenotypic markers and several measures of HIV reservoir volume in cross-sectional cohorts of people living with HIV on ART using several bioinformatic and machine-learning tools. The level of evidence linking these variables is incomplete given possible confounding variables, lack of directionality & effect size, and mechanistic basis.

eLife assessment

This paper reports a valuable platform for cardiac tissue cultivation. The throughput, consistency of the tissue, and the potential integration of high-throughput automation are an advantage over other approaches. The tissues and the platform are validated using appropriate methodology to provide convincing evidence of the tissue cultivation capability.

eLife assessment

This fundamental study provides evidence that de novo beige adipogenesis from Pdgfra+ adipocyte progenitor cells is blocked during early aging in subcutaneous fat. The depth of the data at early ages is compelling, with rigorous cell tracing methodology employed. The study will aid in identifying new approaches to switch dormant adipocytes into an active thermogenic phenotype, and should be of interest to cell biologists at large.

eLife assessment

This study includes fundamental findings on protein evolution, namely that changes in function are largely attributable to pairwise rather than higher-order interactions, and that epistasis potentiates rather than constrains evolutionary paths. Compelling evidence supporting the conclusions is provided by applying a new model to a previously generated experimental dataset on deep mutational scanning of the DNA-binding domain (DBD) of steroid hormone receptor. The implications of this work are of considerable interest to protein biochemistry, evolutionary biology, and numerous other fields.

eLife assessment

This study presents fundamental findings on the evolution of extremely elongated mandibular symphysis and tusks in longirostrine gomphotheres from the Early and Middle Miocene of northern China. The integration of multiple methods provides compelling results in the eco-morphology, behavioral ecology, and co-evolutionary biology of these taxa. In doing so, the authors elucidate the diversification of fossil proboscideans and their likely evolutionary responses to late Cenozoic global climatic changes.

eLife assessment

This important study advances our understanding of the biological significance of the DNA sequence adjacent to telomeres. The data presented convincingly demonstrate that subtelomeric repeats are non-essential and have a minimal, if any, role in maintaining telomere integrity of budding yeast. The work will be of interest to the telomere community specifically and the genome integrity community more broadly.

eLife assessment

In this study, the authors offer a theoretical explanation for the emergence of nematic bundles in the actin cortex, carrying implications for the assembly of actomyosin stress fibers. As such, the study is a valuable contribution to the field actomyosin organization in the actin cortex. While the theoretical work is solid, experimental evidence in support of the model assumptions remains incomplete. The presentation could be improved to enhance accessibility for readers without a strong background in hydrodynamic and nematic theories.

eLife assessment

This valuable study describes mRNA shortening during cellular stress and interestingly observes that this shortening is dependent on localization in stress granules. Surprisingly, this mRNA shortening does not appear to require the shortening of polyA tails. These are in principle novel findings, but the evidence for them is currently incomplete. Additional experiments would help bolster confidence in how the authors interpret their data.

eLife assessment

This is an important study on the regulation of chlorophyll biosynthesis in rice embryos. It provides insights into the genetic and molecular interactions that underlie chlorophyll accumulation, highlighting the inhibition of OsGLK1 by OsNF-YB7 and the broader implications for understanding chloroplast development and seed maturation in angiosperms. The results presented, including mutation analysis, gene expression profiles, and protein interaction studies, provide convincing evidence for the function of OsNF-YB7 as a repressor in the chlorophyll biosynthesis pathway.

eLife assessment

The authors report useful findings on novel function of apical ICAM1 in regulating bile duct homeostasis in the liver. The strength of evidence is solid using appropriate methodolgy with only minor weakness. The findings will be of interest to researchers in hepatology and membrane traffic biology.

eLife assessment

This important study identifies the mitotic localization mechanism for Aurora B and INCENP (parts of the chromosomal passenger complex, CPC) in Trypanosoma brucei. The mechanism differs from that in the more commonly studied opisthokonts and is supported by compelling RNAi and imaging experiments, targeted mutations, immunoprecipitations with crosslinking/mass spec, and AlphaFold interaction predictions. The findings will be of interest to cell biologists working on cell division, parasitologists, and those interested in the evolution of mitotic mechanisms.

eLife assessment

This valuable paper presents a new approach for association testing, using the output of neural networks that have been trained to predict functional changes from DNA sequences. As such, the approach is an interesting addition to statistical genetics, and the evidence for the presented method being able to identify trait-associations in regions where GWASs are typically underpowered is solid. A limitation is, however, that it is unclear how the quality of these associations compares to those detected using conventional methods. Additional work assessing this method's power and characterizing false positives / false negative regions would be critical to ensure that the method is broadly adopted by the field.

eLife assessment

Using state-of-the-art single-nucleus RNA sequencing, Yao et al. investigate the transcriptomic features of neural stem cells (NSCs) in the human hippocampus to address how they vary across different age groups and stroke conditions. The authors report alterations in NSC subtype proportions and gene expression profiles after stroke. Although the study is valuable and the analysis is comprehensive, the significance is restricted by well-acknowledged technical limitations leading to incomplete evidence supporting some main conclusions.

eLife assessment

This manuscript supports the intriguing idea that some aspects of novel learning can occur during sleep and outside of awareness. The authors provide solid evidence that presenting participants with novel words and their translations during sleep, especially during slow oscillation troughs, leads to the ability to categorize the semantic meaning of those words during awake testing 36 hours later. These findings represent a valuable contribution to the literature on unconscious processing and learning during sleep, although the claim that the results reflect episodic memory formation, in particular, deviates from the typical use of this term in the literature.

eLife assessment

This important work illuminates the dynamics of BRAF in both its monomeric and dimeric forms, with or without inhibitors, combining traditional techniques and sophisticated computational analyses. The evidence presented is convincing, though a more detailed description of the analyses could enhance reproducibility and the quality of the results. This study will interest structural biologists, medicinal chemists, and pharmacologists.

eLife assessment

This important paper compares cross-species cortical folding patterns in human and non-human primates, showing that most gyral peaks shared across species are in lower-order cortical regions. The supporting evidence is solid and multi-faceted, encompassing anatomy, connectivity and gene expression. This paper will be of interest to a broad readership within the neuroscience community, especially for those interested in cross-species correspondences in brain organisation.

eLife assessment

This study by Ghafari et al. tackles a question relevant for the field of attention as it connects structural differences in subcortical regions with oscillatory modulations during attention allocation. Using a combination of Magnetoencephalography (MEG) and magnetic resonance imaging (MRI) data in human subjects, the valuable results show that inter-individual differences in the lateralisation of alpha oscillations are explained by asymmetry of subcortical brain regions. The strength of evidence is deemed convincing in line with current state-of-the-art.

eLife assessment

Parkkinen et al. describe distinct biophysical profiles of brain-derived alpha-synuclein vs. in vitro-seeded synuclein fibrils. The findings are important and relevant to the emerging potential role of SAA as a biomarker of PD. The evidence is solid, using appropriate methodology and providing some support for the main claims with some limitations.

eLife assessment

Songbirds provide a tractable model system to study mechanisms of vocal production and sequencing, and past work showed that the lesions to LMAN, the output of a basal ganglia thalamocortical loop, reduced vocal variability, consistent with a role in motor exploration. In this fundamental work, the authors rigorously examined how lesions to an understudied neighboring region, MMAN, part of a parallel basal ganglia loop, affect singing in Bengalese finches, whose songs exhibit complex sequential transitions. The authors provide compelling evidence that MMAN lesions resulted in increased sequential variability but do not affect syllable acoustic structure, showing that distinct frontal systems can have distinct functions for producing and sequencing song syllables.

eLife assessment

These ingenious and thoughtful studies present important findings concerning how people can represent and generalise abstract patterns of sensory data. The issue of generalization is a core topic in neuroscience and psychology, relevant across a wide range of areas, and the findings will be of interest to researchers across areas in perception, learning and cognitive science. The findings are convincing in this setting, but future research must establish their generality and interrogate the precise nature of the underlying mechanism.

eLife assessment

The authors provide convincing experimental evidence of extended motivational signals encoded in the mouse anterior cingulate cortex (ACC) that are implemented by the orbitofrontal cortex (OFC)-to-ACC signaling during learning. The results are valuable to the field of motivation and cognition. The experimental methods used were state-of-the-art. The manuscript would further benefit from theory-driven analyses to inform a mechanistic understanding, particularly for the single-cell calcium imaging results. These results will be of interest to those interested in cortical function, learning, and/or motivation.

eLife assessment

This study presents important methodologies for repeated brain ultrasound localization microscopy (ULM) in awake mice and a set of results indicating that wakefulness reduces vascularity and blood flow velocity. The efficiency of the technique is however incompletely demonstrated, in particular regarding the reliability of longitudinal imaging. This study is relevant for scientists investigating vascular physiology in the brain.

eLife assessment

This valuable manuscript shows that the optogenetic stimulation of direct and indirect pathway spiny projection neurons (SPNs) in the dorsomedial versus the dorsolateral striatum has different consequences for locomotor activity, real-time place preference, and action selection, in a contextually mediated manner. The evidence in support of this conclusion is solid but would be further strengthened through deeper analysis of the effect and specificity of optogenetic manipulations on SPN activity. These findings will be of interest to neuroscientists, particularly behavioral neuroscientists.

eLife assessment

The authors of this study implemented an important toolset for 3D reconstruction and segmentation of dissection photographs, which could serve as an alternative for cadaveric and ex vivo MRIs. The tools were tested on synthetic and real data with compelling performance. This toolset could further contribute to the study of neuroimaging-neuropathological correlations.

eLife assessment

This paper investigates how the EWS::FLI1 fusion protein organizes chromatin topology and regulates gene expression in an aggressive pediatric bone cancer known as Ewing sarcoma. The authors used the most recent genomics methodologies to provide a solid base of evidence for the role of a short alpha helix in the DNA binding domain of FLI1 in modulating binding to GGAA microsatellites and promoting enhancer activity. The study provides valuable insight into the underlying oncogenic mechanisms in Ewing sarcoma, but is limited to a single cell line and would benefit from consolidation of the main conclusions using additional techniques.

eLife assessment

This important manuscript details the characterization of ClpL from L. monocytogenes as an effective and autonomous AAA+ disaggregase that provides enhanced heat resistance to this food-borne pathogen. Supported by compelling evidence, the authors demonstrate that ClpL has DnaK-independent disaggregase activity towards a variety of aggregated model substrates, which is more potent than that observed with the endogenous canonical DnaK/ClpB bi-chaperone system. The work will be of broad interest to microbiologists and biochemists.

eLife assessment

This study aims to explore the diabetes-bone paradox using the Mendelian Randomization approach. That diabetes itself is not the direct cause, but rather the complications or associated risk factors increase the risk of fracture, constitutes a valuable insight. Mendelian randomization to explain the relationship of two complex conditions is solid and conducted properly; however, the efforts to reconcile the discrepancies between the Mendelian Randomization analysis and observational studies are incomplete.

eLife assessment

This is an important paper as it is the first to use a reconstituted translation system to study competition among mRNAs for the initiation machinery. Understanding the principles of the biochemistry of mRNA competition for initiation factors cannot be achieved without such a system. The authors provide compelling evidence that Ded1 is required for efficient initiation of highly structured mRNAs. The findings are significant and validate the in vitro reconstituted system by recapitulating the effects of in-vivo perturbations of translation initiation by Ded1 mutants.

eLife assessment

This fundamental study advances our understanding of the cell specific treatment of cone photoreceptor degeneration by Txnip. The evidence supporting the conclusions is compelling with rigorous genetic manipulation of Txnip mutations. The work will be of broad interest to vision researchers, cell biologists and biochemists.

eLife assessment

This valuable study on the molecular and cellular mechanisms of ingestion avoidance of high salt in insects is focused in scope, but the authors present convincing evidence that a specific subset of gustatory receptors in a pair of pharyngeal taste neurons are necessary and sufficient for avoiding ingestion of high salt during feeding. This work will be of interest to Drosophila neuroscientists interested in taste coding and feeding behavior.

eLife assessment

This valuable paper provides convincing evidence that loss of the tumor suppressor TMEM127 causes disorganization of plasma membrane lipid domains, alters clathrin assembly, and inhibits endocytosis of a variety of cell surface receptors, leading to increased cell surface levels of signaling proteins including RET and other transmembrane receptor tyrosine kinases. The results are significant for understanding how RET127 loss contributes to pheochromocytoma, although the evidence is indirect owing to the lack of human pheochromocytoma cell lines. The results will be of interest for researchers studying pheochromocytoma and endocytosis mechanisms.

eLife assessment

This fundamental study advances our understanding of how Notch signaling activates transcription by analyzing dynamics of the Mastermind transcriptional co-activator and its role in the activation complex. The evidence is compelling and based on state of the art methods with precise quantitative measurements.

eLife assessment

This useful study describes expression profiling by scRNA-seq of thousands of cells of recombinant yeast genotypes from a system that models natural genetic variation. The rigorous new method presented here holds promise for improving the efficiency of genotype-to-phenotype mapping in yeast, providing convincing evidence for its efficacy. This manuscript focuses on overcoming technical challenges with this approach. It currently offers somewhat limited new biological insights to place the work within the broader context of the field. Doing so would broaden the interest of the work for all geneticists and evolutionary biologists.

eLife assessment

This important study presents a new quantitative imaging pipeline that describes with high temporal precision and throughput the movements of late-stage Drosophila embryos, a critical moment when motion first appears. A new approach is used to explore the role of miRNAs in motion onset and presents solid evidence that shows a role for miR-2b-1 and its target Janus in embryonic motion. The data are well supported but do not provide mechanistic insight into the emergence of movement while the writing inflates the importance of the conclusions. The authors must change the name of Janus which is already used in Drosophila genetics.

eLife assessment

This study presents valuable findings on two distinct modes of endosomal fusion and the roles of actin dynamics in this process. The evidence supporting the authors' claims is solid, although the underlying molecular mechanisms and whether the proposed fusion modes are applicable in other cell types remain unclear. The work will be of interest to cell biologists and biophysicists working on the cytoskeleton and organelles.

eLife assessment

This important study addresses the mechanisms by which mutations in the PURA protein, a regulator of gene transcription and mRNA transport and translation, cause the neurodevelopmental PURA syndrome. Based on convincing evidence from structural biology, molecular dynamics simulation, biochemical, and cell biological analyses, the authors show that the PURA structure is very dynamic, rendering it generally sensitive to structure-altering mutations that affect its folding, DNA-unwinding activity, RNA binding, dimerization, and partitioning into processing bodies. These findings are of substantial importance to cell biology, neurogenetics, and neurology alike, because they provide first insights into how very diverse PURA mutations can cause similar and penetrant molecular, cellular, and clinical defects.

eLife assessment

This study by Sheng and colleagues provides valuable insights into the mechanism of competitive inhibitors of P2X receptors. The structural and functional evidence supporting the subtype specificity of pyridoxal-5'-phosphate derivatives is compelling and provides information for designing drugs that selectively target different subtypes of P2X receptor channels. The work will be of interest to biochemists, structural biologists, and pharmacologists.

eLife assessment

This important study used Voltage Sensitive Dye Imaging (VSDI) to measure neural activity in the primary visual cortex of monkeys trained to detect an oriented grating target that was presented either alone or against an oriented mask. The authors show convincingly that the initial effect of the mask ran counter to the behavioral effects of the mask, a pattern that reversed in the latter phase of the response. They interpret these results in terms of influences from the receptive field center, and although an alternative view that emphasizes the role of the receptive field surround also seems reasonable, this study stands as an interesting contribution to our understanding of mechanisms of visual perception.

eLife assessment

In this manuscript, the authors investigate the properties of prokaryotic NADPH oxidases (NOX) and discuss the implications for NOX regulation and function. The structure of the S. pneumoniae Nox protein is an important step forward in our understanding of procaryotic NOX enzymes and the characterization and interpretation are convincing. The results will be of interest to structural biologists as well as biochemists focusing on enzymatic functions.