eLife Assessment

This valuable study proposes that protein secreted by colon cancer cells induces cells with Paneth-like properties that favor colon cancer metastasis. The evidence supporting the conclusions is strong but would benefit from more direct experiments to test the functional role of Paneth-like cells and to monitor metastasis from colon tumors. The work will be of interest to researchers studying colon cancer metastasis.

eLife Assessment

The ingenious design in this study achieved the observation of 3D cell spheroids from an additional lateral view and gained more comprehensive information than the traditional one angle of imaging. This extended the methods to investigate cell behaviors in the growth or migration of tumor organoids in a time-lapse manner and these extensions should be important to the field. The authors provide compelling evidence that the methods work as described.

eLife Assessment

This useful work reveals differential activity to food and shock outcomes in central amygdala GABAergic neurons. Evidence supports claims of unconditioned stimulus activity that changes with learning. Compelling evidence that the circular shift method rigorously identifies functional neuron types is also presented. However, the evidence regarding claims related to valence or salience signaling in these neurons is incomplete. This work will be of interest to neuroscientists studying sensory processing and learning in the amygdala.

eLife Assessment

This is a valuable report of a spatially-extended model to study the complex interactions between immune cells, fibroblasts, and cancer cells, providing insights into how fibroblast activation can influence tumor progression. The model opens up new possibilities for studying fibroblast-driven effects in diverse settings, which is crucial for understanding potential tumor microenvironment manipulations that could enhance immunotherapy efficacy. While the results presented are convincing and follow logically from the model's assumptions, some of these assumptions, as acknowledged by the authors, may oversimplify certain aspects in light of complex experimental findings, system geometry, and general principles of active matter research. Nonetheless, the authors provide justification for their work as a meaningful step towards more comprehensive modeling approaches.

eLife Assessment

In this manuscript, the authors describe the creation of a transgenic mouse expressing a reporter for Integrated Stress Response (ISR) activation in a CRE-dependent manner. Reliable tools for detecting ISR activation in situ are lacking, so this manuscript describes a potentially valuable tool that builds on and overcomes some of the limitations of a similar viral vector described by the authors in a previous publication. Solid evidence suggests that distinct populations of cells (ChAT) in the nervous system are marked by some level of ISR activation, and that the mouse could be most helpful as a screen for cell types in which the ISR is particularly active, although it would be difficult to draw conclusions from the reporter alone. Additional validations of the reporter activity in situ will further strengthen the manuscript.

eLife Assessment

This is an important study that reports the mechanism by which Ankle2 (LEM4 in humans) interacts with and recruits PP2A and the ER protein Vap33 to promote BAF dephosphorylation and mediate nuclear membrane reformation, using Drosophila as their model. Using Ankle2 mutants, they find that the ER protein Vap33 is key for the normal interphase localisation of Ankle2/LEM4 and also impacts on the function of Ankle2/LEM4 during mitosis. The conclusions on the subcellular localization of Ankle2 are drawn from overexpression of constructs. Overall, the authors use a variety of complementary techniques and provide convincing evidence to support the claims and advance our knowledge in the field of mitosis and nuclear envelope biology.

eLife Assessment

This study proposes a new model that could solve some long-standing puzzles about inversion polymorphisms in Drosophila melanogaster by invoking sexually antagonism and negative frequency-dependent selection. While the idea developed here is a valuable contribution to the field, the experiment only addresses one element of the hypothesis, so that the empirical evidence in support of the model remains incomplete.

eLife Assessment

This valuable work provides novel insights into the substrate binding mechanism of a tripartite ATP-independent periplasmic (TRAP) transporter, which may be helpful for the development of specific inhibitors. The structural analysis is convincing, but additional work will be required to establish the transport mechanism as well as well as binding sites for all ligands. This study will be of interest to the membrane transport and bacterial biochemistry communities.

eLife assessment

The article has important scientific merit in the field of cardiovascular research and other fields where the design and rigor of scientific experiments is key for translation of preclinical research to clinical studies. This study holds convincing evidence that sheds light on the lack of progress in this area over the past decade, despite a substantial body of existing research. Although there is a need to re-evaluate the statistical test used, the descriptive paper outcomes serves as a strong call to action for the wider scientific community.

eLife Assessment

This valuable work presents an interesting strategy to interfere with the HBV infectious cycle as it identifies two previously unexplored HBc-Ag binding pockets. The experimental data is compelling and opens the door to generating and testing novel anti-HBV therapies.

eLife Assessment

In this manuscript, the authors describe a new AlphaFold2 pipeline called PabFold that can represent a useful tool for identifying linear antibody epitopes (B-cell epitopes) for different antigens. This information can be used in the selection of different reagents in competitive ELISA assays which can save time and reduce costs. Because several questions about the work remain, the study is currently incomplete.

eLife Assessment

The objective of this important study is to assess the study design and rigor, enhance the quality of clinical research studies, and emphasize crucial design elements in basic science research. It specifically tackles the ongoing problem of experimental design deficiencies that obstruct the effective translation of research findings into clinical applications. This paper is particularly convincing as it highlights the lack of progress in addressing these issues over the past decade, despite a substantial body of existing research. It serves as a strong call to action for the broader scientific community to improve research practices.

eLife Assessment

This is a valuable study that generates an inventory of accessible genomic regions bound by a transcription factor ZFHX3 within the suprachiasmatic nucleus in the hypothalamus and details the impact of its depletion on daily rhythms in behaviour and gene expression patterns. Analysis using circadian phase-estimation algorithms makes the argument that gene regulatory networks are at play and changes in gene expression of a few clock genes cannot account for the observed animal behaviour. While the transcriptome analysis is solid, the data do not currently support the mechanism of activity of the TF in rhythmic gene expression.

eLife Assessment

This study answers an essential question about how migratory primordial germ cells mobilize based on their anterior or posterior location. Convincing data support the model that interactions of migrating mouse PGCs with their niches influences their proliferation, cytoskeletal regulation, epigenetic state and pluripotent state. Rigorous methodology and analysis of single-cell RNA sequencing of migratory primordial germ cells and surrounding somatic cells result in datasets which will be valuable to developmental biologists.

eLife Assessment

This useful manuscript provides a newly curated database (termed AACDB) of antibody-antigens structural information, alongside annotations that are either taken and from the PDB, or added de-novo. Sequences, structures, and annotations can be easily downloaded from the AACDB website, speeding up the development of structure-based algorithms and analysis pipelines to characterize antibody-antigen interactions. The methodology presented for this data curation is solid, although some key annotations are missing which would greatly improve the database.

eLife Assessment

Mackie and colleagues present a valuable comparison of lateralized gustation in two well-studied nematodes. The evidence they present that ASEL/R lateralization exists and is achieved by different means in P. pacificus compared to C. elegans is solid, but would be strengthened by the inclusion of calcium imaging data for C. elegans and additional verification of P. pacificus AFD neuron identity. This work will be of interest to evolutionary biologists, ecologists, and sensory neurobiologists interested in how small nervous systems make sense of the environment, and how evolution can take multiple paths to asymmetry within a neuron class.

eLife Assessment

This valuable paper describes the regulatory pathway of rRNA synthesis by Meioc-Piwil1 in germ cell differentiation in zebrafish. Using the molecular genetic and cytological approaches, the authors provide convincing evidence that Meioc antagonizes Piwil1, which downregulates the 45S pre-rRNA synthesis by heterochromatin formation for spermatocyte differentiation. The key results are solid and of use to researchers in the field of germ cell/meiosis as well as RNA biosynthesis and chromatin.

­eLife Assessment

The authors examine the role of Numb, a Notch inhibitor, in intestinal stem cell self-renewal in Drosophila during homeostasis and regeneration. This is an important study providing evidence of a Numb-mediated, back-up mechanism for intestinal stem cell maintenance. The strength of evidence is convincing as the authors present a carefully constructed series of experiments, robust genetics, large sample sizes, and appropriate statistical analyses.

eLife Assessment

This is a useful study that seeks to address the role of the TET family of DNA demethylation enzymes in pancreatic beta cell senescence in the context of type 2 diabetes (T2DM). Although the concepts are novel and of interest, the study presents incomplete evidence to fully support its main conclusions.

eLife Assessment

Building on earlier evidence that Topoisomerase 2 depletion can extend yeast lifespan, the authors present convincing data demonstrating that reduced Top2 levels confer significant longevity benefits in C. elegans and mice. They show that these benefits encompass not only extended survival but also improved healthspan and mitigation of aging phenotypes, supported by robust transcriptomic, epigenetic, and histological analyses. While the exact mechanistic underpinnings-such as the potential connection to classical aging pathways and the selective down-regulation of genes with active promoters-remain to be fully elucidated, the breadth of these important findings strongly indicates a conserved role for Top2 in aging regulation.

eLife Assessment

This study offers a valuable treatment of how the population of excitatory and inhibitory neurons integrates principles of energy efficiency in their coding strategies. The convincing analysis provides a comprehensive characterisation of the model, highlighting the structured connectivity between excitatory and inhibitory neurons. The role of the many free parameters are discussed and studied in depth.

eLife Assessment

This is a useful study depicting the ultrastructural features of layer 1 of the human temporal cortex, the authors assess various synaptic parameters, astrocytic coverage, and mitochondrial morphology. High-quality data were collected using a solid methodology, however, the analysis of the functional vesicle pools is incomplete, technical issues remaining related to the identification of astrocytic processes and the measurement of vesicle diameters, and reliance solely on electron microscopy limits the scope of the work to structural observation. The work will be of interest to neuroscientists and computational researchers investigating cortical and network function.

eLife Assessment

This valuable study uses high-field fMRI to test the hypothesized involvement of subcortical structures, particularly the striatum, in updating working memory. The study overcomes limitations of prior work by applying high-field imaging with a more precise definition of regions of interest in the brain. Thus, the empirical observations are of use to specialists interested in working memory gating or the reference back task specifically. The evidence is generally solid, but strong conclusions on dopaminergic contributions must await additional work using molecular imaging or related techniques.

eLife Assessment

This important study successfully applies an innovative chemogenetic tool to investigate cerebellar function to advance our understanding of the contributions of Purkinje cell populations to postural control in larval zebrafish. The evidence supporting the conclusions is convincing and supported by rigorous statistical analysis. The study highlights the power of combining genetically targeted perturbations with quantitative high-throughput behavioral analysis and original microscopy tools.

eLife Assessment

This important study provides convincing evidence that developing neurons in the neocortex regulate glial cell development. The data demonstrates that the transcription factor FOXG1 negatively regulates gliogenesis by controlling the expression of a member of the FGF ligand family and by suppressing the receptor for this ligand in developing neurons. This study leads to a new understanding of the cascade of events regulating the timing of glial development in the neocortex.

eLife Assessment

The work by Han and collaborators describes valuable findings on the role of Akkermansia muciniphila during ETEC infection. If confirmed, these findings will add to a growing list of beneficial properties of this organism. The strength of the evidence used to justify the conclusions in the manuscript is solid, as the analyses broadly support the claims with only minor weaknesses.

eLife Assessment

This study tested the specific hypothesis that age-related changes to hearing involve a partial loss of synapse connections between sensory cells in the ear and the nerve fibers that carry information about sounds to the brain, and that this interferes with the ability to discriminate rapid temporal fluctuations in sounds. Physiological, behavioral, and histological analyses provide a powerful combination to test this hypothesis in gerbils. Contrary to previous suggestions, it was found that chemically-induced isolated synaptopathy (at similar levels as observed in aged gerbils) did not result in worse performance on a behavioral task measuring sensitivity to fine-structure. Further, altered neural coding of rapid fluctuations produced no perceptual deficits in either these gerbils or in aged gerbils. These findings are important for understanding age-related changes to hearing; however, the evidence provided is incomplete due to problems in interpretation and the discussion of possible confounds and/or limitations of these data that currently limits mechanistic insight.

eLife Assessment

This valuable study shows that a very slow (infraslow) oscillation occurs in voltage recordings from the dentate gyrus of the adult mouse. The authors suggest that it is related to sleep stage and serotonin acting at one type of serotonin receptor in the dentate gyrus. The ideas are potentially significant because they suggest that this oscillation affects memory through serotonin receptors in the dentate gyrus. Solid evidence is provided to broadly support the main claims, although analytical weaknesses remain that could be improved by clarification of methods, analyses, and data shown in the figures.

eLife Assessment

This important study introduces a new cortical circuit model for predictive processing. Simulations effectively illustrate that, with appropriate synaptic plasticity, a canonical layer 2/3 cortical circuit - comprising two classes of interneurons providing subtractive and divisive inhibition - can generate uncertainty-modulated prediction errors by pyramidal neurons. The model is compelling; although it relies on many assumptions and has not yet been compared directly to data, the model does align with empirical observations and yields a range of testable predictions. The study is expected to be of great interest to those involved in cortical and predictive processing research.

eLife Assessment

This valuable study reports the induction of supernumerary inner hair cells in the mouse cochlea upon reducing the expression level of a tight-junction protein (claudin-9) at developmental stages. Although these ectopic hair cells are functional and persists through adulthood, the evidence supporting some of the claims is incomplete, particularly regarding the underlying mechanisms of cell differentiation and the potential of the approach for hair-cell regeneration. The work will be of interest to scientists working in the development and regeneration of hair cells in the inner ear.

eLife Assessment

What makes one member of the species behave differently from another? This is a core problem in behavioral neuroscience. This valuable study seeks an answer for the specific case of the fruit fly expressing preferences for one odor over another. By a combination of behavioral measurements, neurophysiology, and network modeling, the authors find solid evidence for at least one locus of individuality in the peripheral olfactory system.

eLife Assessment

The study evaluates the feasibility, safety, and tolerability of neoadjuvant radiotherapy followed by a CDK4/6 inhibitor (dalpiciclib) and hormonal therapy in treatment-naive patients with unilateral early-stage HR+/HER2- breast cancer. The findings are convincing, with a strong scientific rationale supported by integrated correlative studies. The trial is considered to be important as the outcomes could inform the design of larger, future studies. The strength of the conclusions should be tempered as the study included only a small cohort of patients (n=12) and was not adequately powered to definitively assess the efficacy or safety of this combinatorial treatment approach.

eLife Assessment

This valuable study uses zebrafish as a model to reveal a role for the cell cycle protein kinase CDK2 as a negative regulator of type I interferon signaling. The evidence supporting the authors' claims is convincing, including both in vivo and in vitro investigative approaches that corroborate a role for CDK2 in regulating TBK1 degradation. In this latest version, the authors included data addressing concerns raised by the reviewers at the first peer review round that strengthens the conclusions. This work will interest cell biologists, immunologists, and virologists.

eLife Assessment

In this important work, Lodhiya et al. provide evidence that excessive ATP underlies the killing of the model organism Mycobacterium smegmatis by two mechanistically-distinct antibiotics. The data are generally solid as the authors deploy multiple, orthogonal readouts and methods for manipulating reactive oxygen species and ATP. The work will be of interest to those studying antibiotic mechanisms of action.

eLife Assessment

This fundamental work extends our understanding of the role of TGFβ2 as a modulator of mechanosensing in the eye and identifies the TRPV4 ion channel as a common regulator of Trabecular Meshwork (TM) contractility and pathological OHT. The data and evidence are convincing, with some minor limitations. This work will clearly be of interest to researchers investigating the role of mechanosensors in the TM and may underpin future research into treatments that aim to lower intra ocular pressure. This work will additionally be of interest to the growing field of researchers investigating the regulation of force sensing via ion channels and their roles in health and disease, in particular the ion channel TRPV4.

eLife Assessment

The findings are important and intriguing, with theoretical or practical implications beyond a single subfield. The computational methods employed are clever and sophisticated and the strength of evidence is convincing. However, all three reviewers also highlight a lack of focus and clarity, as well as missing information about model comparison, fit statistics and group comparison of parameters from different models.

eLife Assessment

This valuable study tests a methodology for the discovery of new honey bee-repellent odorants via machine learning. The conclusions of the study are supported by solid evidence, with predicted compounds validated in the lab and the field. This work will be of interest to researchers in ecology, pest control and olfactory neuroscience.

eLife Assessment

This is a fundamental body of work reporting anatomical, molecular, and functional mapping of the central complex in Drosophila. The tools generated and the findings, which include characterization of neuromodulators used by different cells, will undoubtedly serve as a foundation for future studies of this brain region. Overall, the data are compelling and likely to have a major impact.

eLife Assessment

This important study investigates how hummingbird hawkmoths integrate stimuli from across their visual field to guide flight behavior. Cue conflict experiments provide solid evidence for an integration hierarchy within the visual field: hawkmoths prioritize the avoidance of dorsal visual stimuli, potentially to avoid crashing into foliage, while they use ventrolateral optic flow to guide flight control. With a more systematic quantification of specific parameter combinations, this paper would be of broad interest to enthusiasts of visual neuroscience and ethology.

eLife Assessment

This important Research Advance presents convincing evidence on the neuroprotective effects of reserpine in a well-established model of retinitis pigmentosa (P23H-1). This study builds on previous work establishing reserpine as a neuroprotectant in models of Leber congenital amaurosis. Here authors show reserpine's disease gene-independent influence on photoreceptor survival and emphasizes the importance of considering biological sex in understanding inherited retinal degeneration and the impact of drug treatments on mutant retinas. The work will be of interest to vision researchers as well as a broad audience in translational research.

eLife Assessment

This valuable study addresses the growing threat of multi-drug-resistant (MDR) pathogens by focusing on the enhanced efficacy of colistin when combined with artesunate and EDTA against colistin-resistant Salmonella strains. The evidence is solid, supported by comprehensive microbiological assays, molecular analyses, and in vivo experiments demonstrating the effectiveness of this synergic combination.

eLife Assessment

This study provides important insights into how IL-1 cytokines protect cells against SARS-CoV-2 infection. By inducing a non-canonical RhoA/ROCK signaling pathway, IL-1beta inhibits the ability of SARS-CoV-2 infected cells to fuse with uninfected cells and produce syncytia. Convincing evidence underlies the identification of the key signaling components required for this inhibitory phenotype, and suggests that this process may also function to inhibit SARS-CoV-2 infection in vivo.

eLife Assessment

This fundamental study demonstrates the role of TRPV4 channels in mechano-transduction during carcinoma progression, showing how high cell confluence in DCIS cells activates pathways regulating calcium homeostasis, cell volume reduction, and invasiveness. The authors addressed all prior concerns, with the shRNA knockdown providing compelling evidence for TRPV4's role in metastasis.

eLife Assessment

In an important fMRI study with an elegant experimental design and rigorous cross-decoding analyses, this work shows a convincing dissociation between two parietal regions in visually processing actions. Specifically, aIPL is found to be sensitive to the causal effects of observed actions, while SPL is sensitive to the patterns of body motion involved in those actions. The work will be of broad interest to cognitive neuroscientists, particularly vision and action researchers.

eLife Assessment

Wang et al. presented visual (dot) motion and/or the sound of a walking person and found solid evidence that EEG activity tracks the step rhythm, as well as the gait (2-step cycle) rhythm, with some demonstration that the gait rhythm is tracked superadditively (power for A+V condition is higher than the sum of the A-only and V-only condition). The valuable findings will be of wide interest to those examining biological motion perception and oscillatory processes more broadly. Some of the theoretical interpretations concerning entrainment must remain speculative when the authors cannot dissociate evoked responses from entrained oscillatory effects.

eLife Assessment

This study empirically investigates the neural noise hypothesis of developmental dyslexia using electroencephalography (EEG) during a spoken language task and 7T magnetic resonance spectroscopy (MRS). The convincing findings indicate no evidence of an imbalance between excitatory and inhibitory (E/I) brain activity in adolescents and young adults with dyslexia compared to controls, thereby challenging the neural noise hypothesis. This research is valuable for advancing our understanding of the neural mechanisms underlying dyslexia and offers broader insights into the neural processes involved in reading development.

eLife Assessment

In this valuable study, the authors studied a novel Zn2+- and NAD+-independent KDAC protein, AhCobQ, in Aeromonas hydrophila, which lacks homology with eukaryotic counterparts, thus underscoring its unique evolutionary trajectory within the bacterial domain. They attempt to demonstrate deacetylase activity, however, whilst the revised manuscript has been improved, significant aspects of the data are still incomplete and require further refinement. The work will be of interest to microbiologists studying metabolism and post-translational modifications.

eLife Assessment

This work shows that newborn Thbs4-positive astrocytes generated in the adult subventricular zone (SVZ) respond to middle carotid artery occlusion (MCAO) by secreting hyaluronan at the lesion penumbra, and that hyaluronin is a chemoattractant to SVZ astrocytes. These findings are valuable, despite being mostly descriptive, as they point to a relevant function of SVZ newborn astrocytes in the modulation of the glial scar after brain ischemia. The methods, data and analyses are convincing and broadly support the claims made by the authors with only some weaknesses.

eLife Assessment

This valuable study decoded target-associated information in prefrontal and sensory cortex during the preparatory period of a visual search task, suggesting a memory-driven attentional template. The evidence supporting this claim is convincing, based on multivariate pattern analyses of fMRI data. The results will be of interest to psychologists and cognitive neuroscientists.

eLife Assessment

MGPfactXMBD is a novel computational method for investigating cell evolutionary trajectory for scRNA-seq samples. It is important, with several potential future applications. The authors benchmarked this method using synthetic and real-world samples and showed superior performance for some of the tasks in cell trajectory analysis compared to other methods with compelling evidence.

eLife Assessment

This study uses all-optical electrophysiology methods to provide a valuable insight into the organization of cortical networks and their ability to balance the activity of groups of neurons with similar functional tuning. The all-optical approach used in this study is impressive, but the claim that the effects of optical stimulation correspond to a specific homeostatic mechanism are incompletely supported by the statistical analysis of the results. The work will be of interest to neurobiologists and to developers of optical approaches for interrogating brain function.

eLife Assessment

This important study enhances our understanding of Pseudomonas aeruginosa's transcriptional regulatory network by revealing its hierarchical structure through analysis of transcription factor binding patterns. The conclusions are supported by compelling evidence and will appeal to researchers investigating P. aeruginosa and the regulatory mechanisms underlying its pathogenicity. The paper would be strengthened by clarifying implications of binding and regulatory networks with virulence, and transcription factor divergence across species.

eLife Assessment

This important study uses machine learning-based network analysis on transcriptomic data from different tissue cell types to identify a small set of conserved (pan-tissue) genes associated with changes in cell mechanics. The new method, which provides a new type of approach for mechanobiology, is accessible, compelling, and well-validated using in silico and experimental approaches. The study provides motivation for researchers to test hypotheses concerning the identified five-gene network, and the method will be strengthened over time with expanded sets of validations, such as testing genes with hitherto unknown roles and different perturbation techniques.

eLife Assessment

This study addresses a novel and interesting question about how the rise of the Qinghai-Tibet Plateau influenced patterns of bird migration, employing a multi-faceted approach that combines species distribution data with environmental modeling. The findings are valuable for understanding avian migration within a subfield, but the strength of evidence is incomplete due to critical methodological assumptions about historical species-environment correlations, limited tracking data, and insufficient clarity in species selection criteria. Addressing these weaknesses would significantly enhance the reliability and interpretability of the results.

eLife Assessment

This study presents important findings demonstrating that FZD5 and FZD8, two of the ten Frizzled proteins, undergo Wnt-mediated endocytosis. The E3 ubiquitin ligases RNF43/ZNRF3 regulate their degradation in a Wnt-dependent manner, a mechanism that was not previously recognized. The evidence supporting the claims of the authors is solid. This research will be of interest to biologists specializing in Wnt signaling, cancer, and regenerative medicine.

eLife Assessment

This important work provides another layer of regulatory mechanism for TGF-beta signaling activity. The evidence supports the involvement of microtubules as a reservoir of Smad2/3 and additional evidence convincingly demonstrates functional involvement of Rudhira in this process. The work will be of board interest to developmental biologists in general and molecular biologists in the field of growth factor signaling.

eLife Assessment

The authors show that a middle carotid artery occlusion (MCAO) hypoxia lesion leads to hyaluronan-mediated chemoattraction to the lesion penumbra of Thbs-4-expressing astrocytes of the sub-ventricular zone (SVZ). These findings are valuable because they shed light on the function of astrocytes from the adult SVZ in pathological states like brain ischemic injury. The results are convincing, as they rely on a comprehensive analysis of experimental data.

eLife Assessment

Bowler et al. present a software/hardware system for behavioral control of navigation-based virtual reality experiments, particularly suited for pairing with 2-photon imaging but applicable to a variety of techniques. This system represents a valuable contribution to the field of behavioral and systems neuroscience, as it provides a standardized, easy to implement, and flexible system that could be adopted across multiple laboratories. The authors provide compelling evidence of the functionality of their system by reporting benchmark tests and demonstrating hippocampal activity patterns consistent with standards in the field. This work will be of interest to systems neuroscientists looking to integrate flexible head-fixed behavioral control with neural data acquisition.

eLife Assessment

Periods in which experience regulates early plasticity in sensory circuits are well established, but the mechanisms that control these critical periods are poorly understood. In this important study, the authors examine early-life critical periods that regulate the Drosophila antennal lobe and show that constant odor exposure markedly reduces the volume, synapse number, and function of a specific glomerulus. The authors offer compelling evidence that these changes are mediated by the invasion of ensheathing glia into the glomerulus where they phagocytose connections via a mechanism involving the engulfment receptor Draper.

eLife Assessment

With the goal of investigating the assembly and fragmentation of cellular aggregates, this work investigates cyanobacterial aggregates in a laboratory setting. Investigating the conditions and mechanisms behind aggregation is an important contribution as it yields basic understanding of natural processes and offers potential strategies for control. The combination of computational and experimental investigations in this manuscript provides solid support for the proposed processes for aggregation and fragmentation, with some concerns about the strength of evidence for a subset of claims.

eLife Assessment

This report details convincing evidence that experience with multilingualism in general, and with larger phonological inventories specifically, is related to differences in the structure of the transverse temporal gyri. The project is notable for using a relatively large sample, and confirming the primary finding in a second sample. The important findings strongly point to experience-dependent plasticity related to language experience as a driver of neuroanatomy of the auditory cortex.

eLife Assessment

This is an important study providing compelling evidence that the Mediator kinase module mediates an elevated inflammatory response, manifested by heightened cytokine levels, associated with Downs syndrome (DS) via transcriptional changes impacting cell signaling and metabolism that involve mobilization of nuclear receptors by altered lipid metabolites, which has significance for the treatment of DS and other chronic inflammatory conditions. Particular strengths of the study include the combined experimental approaches of transcriptomics, untargeted metabolomics and cytokine screens and the use of sibling matched cell lines (trisomy 21 vs disomy 21) from various donors. Evidence is also provided implicating the Mediator kinase module in controlling mRNA splicing and mitochondrial function that should stimulate new research to elucidate the mechanistic bases for these novel functions.

eLife Assessment

This study presents a new quantitative method, CROWN-seq, to map the cap-adjacent RNA modification N6,2'-O-dimethyladenosine (m6Am) with single nucleotide resolution. Using thoughtful controls and well-validated reagents, the authors provide compelling evidence that the method is reliable and reproducible. Additionally, the study provides important evidence that m6Am may increase transcription in modified mRNAs. However, the data only demonstrates a correlation between m6Am and transcriptional regulation rather than causality. Overall, this study is poised to advance m6Am research, being of broad interest to the RNA biology and gene regulation fields.

eLife Assessment

In this article, Cheng et al present an important finding that advances the understanding of mitochondrial stress response(s). The authors employed mass spectrometry-based methods in conjunction with standard molecular and cellular biology techniques to provide compelling evidence that phosphatidylethanolamine-binding protein 1 (PEBP1) acts as a pivotal regulator of the mitochondrial component of integrated stress response. Notwithstanding that this discovery is likely to be of significant interest to researchers across a broad spectrum of disciplines ranging from cell biology to neuroscience, it was thought that further mechanistic dissection of the role of PEBP1 in modulating integrated stress response may further strengthen this study.

eLife Assessment

This manuscript provides fundamental studies to gain insight into the mutations in the presenilin-1 (PSEN1) gene on proteolytic processing of the amyloid precursor protein (APP). The authors provide compelling evidence using mutations in PSEN to understand what drives alternative substrate turnover with convincing data and rigorous analysis. This deep mechanistic study provides a framework towards the development of small molecule inhibitors to treat AD.

eLife assessment

The identification of NCS1 as a distal appendage protein that captures preciliary vesicles has important implications for understanding the early steps of ciliary assembly. Furthermore, the work has important implications for the broader understanding of NCS1, which prior to this work was focused on roles in neurotransmission, but now must be considered in a broader context. The investigators used a variety of state-of-the-art methodologies, and the conclusions are convincingly supported by the experimental data. This work will be of interest to cell biologists studying ciliary assembly, human geneticists exploring the pathology of cilia as well as neurobiologists studying NCS1.

eLife Assessment

This fundamental work substantially advances our understanding of how the glycocalyx of cells provide a non-specific barrier for the interaction of viruses with cell-surface receptors. Using both in vitro experiments and in vivo manipulations they provide solid evidence for the properties of the glycocalyx to serve as an energy barrier as a main attribute of its mode of action. The work will be of broad interest to virologists and the cell biology community that studies host-pathogen interactions.

eLife Assessment

This manuscript reports valuable findings on the role of the Srs2 protein in turning off the DNA damage signaling response initiated by Mec1 (human ATR) kinase. The data provide solid evidence that Srs2 interaction with PCNA and ensuing SUMO modification is required for checkpoint downregulation. However, while the model that Srs2 acts at gaps after camptothecin-induced DNA damage is reasonable, direct experimental evidence for this is currently lacking. The work will be of interest to cell biologists studying genome integrity.

eLife Assessment

This study provides useful in vitro evidence to support a mechanism whereby dyslipidemia could accelerate renal functional decline through the activation of the AT1R/LOX1 complex by oxLDL and AngII. As such, it improves the knowledge regarding the complex interplay between dyslipidemia and renal disease and provides a solid basis for the discovery of novel therapeutic strategies for patients with lipid disorders. The methods, data, and analyses partly support the presented findings, although the observed variability and need for further in vivo validation require additional research in this key area.

eLife assessment

This fundamental work describes for the first time the combined gene expression and chromatin structure at the genome level in isolated chondrocytes and classical (cranial) and non-classical (notochordal) osteoblasts. In a compelling analysis of RNA-Seq and ATAC data, the authors characterize the two osteoblast populations relative to their associated chondrocyte cells and further proceed with a convincing analysis of the crucial entpd5a gene regulatory elements by investigating their respective transcriptional activity and specificity in developing zebrafish.

eLife Assessment

Graca et al. reports a fundamental missing link in the ethanol metabolism of mycobacteria and illuminates the role of a flavoprotein dehydrogenase that acts as an electron shuttle between an uncommon redox cofactor and the electron transport chain. Overall, the data presented are compelling, supported by a range of well designed and meticulous experiments. The findings will be of broad interest to researchers investigating bacterial metabolism.

eLife Assessment

In this valuable study, Roiuk et al employed a combination of ribosome profiling and reporter assays to provide convincing evidence that eIF2A is not involved in translational regulation in cultured human cells. In conjunction with several recent publications (spanning yeast to mammalian systems), these findings disaffirm the previously proposed role of eIF2A in directing protein synthesis, including its implication in translational reprogramming under stress. Whilst clearly delinating something eIF2A does not do, identifying cellular role(s) for eIF2A could further strengthen this article.

eLife Assessment

Notch1 is expressed uniformly throughout the mouse endocardium during the initial stages of heart valve formation, yet it remains unclear how Notch signaling is activated specifically in the AVC region to induce valve formation. To answer this question, the authors used a combination of in vivo and ex vivo experiments in mice to demonstrate ligand-independent activation of Notch1 by circulation induced-mechanical stress and provide evidence for stimulation of a novel mechanotransduction pathway involving post-translational modification of mTORC2 and Protein Kinase C (PKC) upstream of Notch1. These findings represent an important advance in our understanding of valve formation and the conclusions are supported by convincing data.

eLife Assessment

This manuscript reports useful data suggesting a critical role of two cyclin-dependent kinases, CDK8 and CDK19, in spermatogenesis. However, the data supporting the conclusion remains incomplete. This work may be of interest to reproductive biologists and physicians working on male fertility.

eLife Assessment

Data presented in this useful report suggest a potentially new model for chemotaxis regulation in the gram-negative bacterium P. putida. Data supporting interactions between CheA and the copper-binding protein CsoR, reveal potential mechanisms for coordinating chemotaxis and copper resistance. There was, however, concern about the large number of CheA interactors identified in the initial screen and it was felt that the study was incomplete without a substantial number of additional experiments to test the model and bolster the authors' conclusions.

eLife Assessment

This important study identifies a new class of small molecules that activate the integrated stress response (ISR) via the kinase HRI. Convincing evidence, including the image analysis pipeline, indicates that two of these compounds promote mitochondrial elongation and protect against mitochondrial fragmentation caused by chemical stress conditions or by genetic alterations. These findings open an avenue for new strategies for mitochondrial dysfunction targeting linked to ISR alterations.

eLife Assessment

This fundamental work describes for the first time the combined gene expression and chromatin structure at the genome level in isolated chondrocytes and classical (cranial) and non-classical (notochordal) osteoblasts. In a compelling analysis of RNA-Seq and ATAC data, the authors characterize the two osteoblast populations relative to their associated chondrocyte cells and further proceed with a convincing analysis of the crucial entpd5a gene regulatory elements by investigating their respective transcriptional activity and specificity in developing zebrafish.

eLife Assessment

In this potentially important study, the authors report results of QM/MM simulations and kinetic measurements for the phosphoryl-transfer step in adenylate kinase. The results point to the mechanistic proposal that the transition state ensemble is broader in the most efficient form of the enzyme (i.e., in the presence of Mg2+ in the active site) and thus a different activation entropy. With a broad set of computations and experimental analyses, the level of evidence is considered solid by some reviewers. On the other hand, there remain limitations in the computational analyses, especially regarding free energy profiles using different methodologies (shape of free energy profiles with DFTB vs. PBE QM/MM, and barriers with steered MD and umbrella sampling) and the activation entropy, leading some reviewers to the evaluation that the level of evidence is incomplete.

eLife Assessment

This valuable work suggests a new physical model of centrosome maturation: a catalytic growth model with a shared enzyme pool. The authors provide compelling evidence to show that the model is able to reproduce various experimental results such as centrosome size scaling with cell size and centrosome growth curves in C. elegans, and that the final centrosome size is more robust to differences in initial centrosome size. While direct experimental support for this theory is currently lacking, the authors propose concrete experiments that could distinguish their shared-enzyme model from previously proposed alternatives.

eLife Assessment

This manuscript describes the identification and characterization of 12 specific phosphomimetic mutations in the recombinant full-length human tau protein that trigger tau to form fibrils. This fundamental study will allow in vitro mechanistic investigations. The presented evidence is solid but a higher purity of these fibril types might be required for future studies. This manuscript will be of interest to all scientists in the amyloid formation field.

eLife Assessment

Cardiolipin is known to play an important role in modulating the assembly and function of membrane proteins in bacterial and mitochondrial membranes. In this study, authors convincingly define the molecular determinants of cardiolipin binding on de novo-designed and native membrane proteins combining the coarse-grained molecular dynamics simulation with the state-of-the-art experimental approaches such as native mass spectrometry and cryogenic electron microscopy. The major findings in this study, which are the identification of degenerate cardiolipin binding motifs and their role in membrane protein stability and activity, will provide much needed insight into the still poorly understood nature of protein-cardiolipin interactions.

eLife Assessment

The bacterial cell wall is crucial to maintain viability. It has previously been suggested that Gram-positive bacteria have a periplasmic region between the cell membrane and peptidoglycan cell wall that this is maintained by the presence of teichoic acids. In this valuable study, Nguyen et al. make clever use of electron microscopy and metabolic labelling to interrogate the role of teichoic acids in supporting the maintenance of the periplasmic region in Streptococcus pneumoniae. The findings are potentially significant but incomplete to fully support the conclusions drawn.

eLife Assessment

This study estimates the fraction of apoptotic motor neurons during the development of the zebrafish spinal cord. The results are useful, but incomplete. Importantly, the data are inadequate to support the title or the conclusions presented in the abstract. A correct title could be: "A surprisingly small percentage of early developing zebrafish motor neurons die through apoptosis in non-limb innervating regions of the spinal cord."

eLife Assessment

This study presents a valuable finding on the role of secretory leukocyte protease inhibitors (SLPI) in developing Lyme disease in mice infected with Borrelia burgdorferi. The evidence supporting the claims of the authors is solid, although there are a few concerns that need to be addressed, including patient sample sizes, and the potential contribution of the greater bacterial burden to the enhanced inflammation. This paper would be of interest to scientists in the infectious inflammatory disease field.

eLife Assessment

This valuable study investigates how the proteins of the Cdv division system in Metallosphaera sedula archaea sequentially interact with curved membranes in vitro, extending our understanding of this reduced ESCRT-like machinery. While the data support key aspects of protein recruitment and membrane remodeling, missing controls and statistical analysis information, unaddressed discrepancies, and limitations in recapitulating native geometry leave the data incomplete to fully support the proposed conclusions. The work will be of interest to evolutionary and synthetic biologists as membrane biophysicists but would benefit from additional experiments and a more cautious interpretation of results.

eLife Assessment

This important study reveals a role for IκBα in the regulation of embryonic stem cell pluripotency. The solid data in mouse embryonic stem cells include separation of function mutations in IκBα to dissect its non-canonical role as a chromatin regulator and its canonical function as NF-κB inhibitor. The conclusions could be strengthened by including better markers of differentiation status and additional controls or orthogonal approaches.

eLife Assessment

This paper reports the analysis of coevolutionary patterns and dynamical information for identifying functionally relevant sites. These findings are considered important due to the broad utility of the unified framework and network analysis capable of revealing communities of key residues that go beyond the residue-pair concept. The data is solid, and the results are clearly presented.

eLife Assessment

Based on the perceived low efficacy of current therapies targeted to FGFR2 in gastric cancer (GC), the authors investigate an approach which combines SHP2 inhibition with existing FGFR2 inhibitors. The data were largely collected and analysed using solid and validated methodology. There is some useful data regarding combination therapy in a new clinical cohort, which supports previous studies that have reported the potential of targeting RTKs together with phosphatases.

eLife Assessment

In this manuscript, the authors present useful findings demonstrating that the RNA modification enzyme Mettl5 regulates sleep in Drosophila. Through transcriptome- and proteome-wide analyses, the authors identified downstream targets affected in heterozygous mutants and proposed that Mettl5 regulates the translation and degradation of clock genes to maintain normal sleep function. However, the mechanisms by which Mettl5 achieves these functions, and whether they are direct or indirect, remain incomplete and would benefit from further analysis.

eLife Assessment

This manuscript describes a method using EM polyclonal epitope mapping to help elucidate endogenous antibodies. Overall the work described is interesting and the contribution will be of use to the field that is expected to only increase in impact and value over time. The significance of the work is considered valuable and the strength of evidence to support its findings is considered solid.

eLife Assessment

This fundamental work presents two clinically relevant BMP4 mutations that contribute to vertebrate development. The convincing evidence supports that the site-specific cleavage at the BMP4 pro-domain precisely regulates its function and provides mechanistic insight into how homodimers and heterodimers behave differently. The work will be of broad interest to researchers working on growth factor signaling mechanisms and vertebrate development.

eLife Assessment

This useful study introduces the peptidisc-TPP approach as a promising solution to challenges in membrane proteomics, enabling thermal proteome profiling in a detergent-free system. While the concept is innovative and holds significant potential, the demonstration of its utility and validation remains incomplete. The method presents a strong foundation for broader applications in identifying physiologically and pharmacologically relevant membrane protein-ligand interactions.

eLife Assessment

This valuable study addresses a gap in our understanding of how the size of the attentional field is represented within the visual cortex. The evidence supporting the role of visual cortical activity is solid, based on a novel modeling analysis of fMRI data. The results will be of interest to psychologists and cognitive neuroscientists.

eLife Assessment

Understanding bacterial growth mechanisms can potentially help uncover novel drug targets that are crucial for maintaining cellular viability, particularly for bacterial pathogens. In this important study, the authors investigate the role of mycobacterial Wag31 in lipid and peptidoglycan biosynthesis. A detailed analysis of Wag31 domain architecture revealed a role in membrane tethering, more specifically, the N-terminal and C-terminal domains appear to display distinct functional roles therein. Whilst the data presented are of use, the experimental evidence is currently incomplete and does not yet fully support the conclusions made.

eLife Assessment

This valuable study combines massively parallel reporter assays and regression analysis to identify sequence features in untranslated regions contributing to the stability of in vitro transcribed mRNA delivered to cells. The strength of evidence presented is solid, although some points about half-life measurements and the relevance of identified sequence features to native transcript stability will inform future discussion surrounding the present study. Taken together, the work will be of interest to a broad swath of colleagues studying post-transcriptional gene regulation and especially to those using massively parallel reporter assays.

eLife Assessment

This important study enhances our understanding of the foraging behaviour of aerial insectivorous birds. Using solid methodology, the authors have collected extensive data on bird movements and prey availability, which in turn provide support for the main claim of the study. The work will be of broad interest to behavioural ecologists.

eLife Assessment

In this valuable study, Li et al., set out to understand the mechanisms of audiovisual temporal recalibration - the brain's ability to adjust to the latency differences that emerge due to different (distance-dependent) transduction latencies of auditory and visual signals - through psychophysical measurements and modeling. The analysis and specification of a formal model for this process provide convincing evidence to supports a role for causal inference in recalibration.

eLife Assessment

This valuable study presents the design of a new device for using high-density electrophysiological probes ('Neuropixels') in freely moving rodents. The evidence demonstrating the system's versatility and ability to record high-quality extracellular data in both mice and rats is compelling. This study will be of significant interest to neuroscientists performing chronic electrophysiological recordings.

eLife Assessment

The manuscript provides important new insights into the mechanisms of statistical learning in early human development, showing that statistical learning in neonates occurs robustly and is not limited to linguistic features but occurs across different domains. The evidence is convincing and the findings are highly relevant for researchers working in several domains, including developmental cognitive neuroscience, developmental psychology, linguistics, and speech pathology.

eLife Assessment

This study presents a valuable finding on how the interplay between transcription factors SOX2 and OCT4 establishes the pluripotency network in early mouse embryos. The evidence supporting the claims of the authors is solid, although inclusion of additional omics data would further strengthen the study. The work will be of interest to biologists working on embryonic development and gene regulation.

eLife Assessment

This analysis of the formation of the oral-aboral body axis in cnidarians, the sister group of bilaterians, is a significant and fundamental contribution to the field of Wnt signalling and planar cell polarity. The evidence supporting the conclusions is compelling and has the potential to contribute to a deeper understanding of the origin and evolution of Wnt signalling in metazoans. These findings will be of broad interest to developmental and evolutionary biologists.

eLife assessment

This important and detailed study presents the most comprehensive view of the functional organization and requirements for a mother centriole's distal appendage in primary cilia assembly published to date. Crispr-knockouts and super-resolution microscopy analysis of the distal appendage proteins provides convincing evidence to support the claims of the authors. This work will be of high value to cell biologists and biophysicists working on the structure and function of the centrosome as well as human geneticists exploring ciliary pathology.

eLife Assessment

This important paper explores the impact of early life stress (ELS) on adult brain and behavior. The significance of the convincing findings are that they implicate regulation of non-neuronal cells in the development of brain and behavioral dysfunction associated with ELS. With an elegant combination of behavioral models, morphological and functional assessments using immunostaining, electrophysiology, and viral-mediated loss-of-function approaches, the authors report that astrocyte dysfunction plays a role in ELS responses. The work is of interest to a broad behavioral and cellular neuroscience audience.

eLife Assessment

This important study combines the use of Fisher Kernels with Hidden Markov models aiming to improve brain-behaviour prediction. The evidence supporting the authors' conclusions is compelling, comparing brain-behaviour prediction accuracies across a range of different traits, including out of sample assessment. This work is timely and will be of interest to neuroscientists working on functional connectivity for brain-behaviour association.

eLife Assessment

This important modeling study alters a previous model of the intact cat spinal locomotor network to simulate a lateral hemi-section of the spinal cord. The modeling and experimental work described provide convincing evidence that this model is capable of qualitatively predicting alterations to the swing and stance phase durations during locomotion at different speeds on intact or split-belt treadmills. This paper will interest neuroscientists studying vertebrate motor systems, including researchers working on motor dysfunction after spinal cord injury.

eLife Assessment

This valuable study revealed numerous distinct lineages that evolved within a local human population in Alberta, Canada, leading to persistent cases of E. coli O157:H7 infections for over a decade and highlighting the ongoing involvement of local cattle in disease transmission, as well as the possibility of intermediate hosts and environmental reservoirs. This study also showed a shift towards more virulent stx2a-only strains becoming predominant in the local lineages. The evidence supporting the role played by cattle in the transmission system of human cases of E. coli O157:H7 in Alberta is solid.

eLife Assessment

This work models reinforcement-learning experiments using a recurrent neural network. It examines if the detailed credit assignment necessary for back-propagation through time can be replaced with random feedback. In this useful study the authors show that it yields a satisfactory approximation but the evidence to support that it holds in general is incomplete. As only short temporal delays are used and the examples simulated are overly simple, the approximation would need to be tested on more complex task and with larger networks.

eLife Assessment

The current human tissue-based study provides convincing evidence correlating hippocampal expressions of RNA guanine-rich G-quadruplexes with aging and with Alzheimer's Disease presence and severity. The results are important and hold promise for deeper understanding of AD's pathogenesis and potential new therapeutic strategies.

[Editors' note: this paper was reviewed by Review Commons.]

eLife Assessment

In this valuable study the authors use electrophysiology in brain slices and computer modeling and suggest that layer 2/3 pyramidal neurons of the mouse cortex have functional HCN channels on the proximal apical dendrite which allows distinct processing of input at that location from the input to distal apical dendrites. The revisions improved the solid paper but some of the concerns were not addressed sufficiently and many of these concerns could be addressed by further revision.

eLife Assessment

The revised report provides valuable findings for the field, suggesting a relationship between CRF1 receptors, sociability deficits in morphine-treated male mice yet not females, and a potential mechanism involving oxytocin neurons in the paraventricular nucleus of the hypothalamus. Generally, the strength of evidence is solid in terms of the methods, data, and analyses. This work will be of interest to those interested in social behavior and addiction.

eLife Assessment

This fundamental study illuminates the dynamics of BRAF in its monomeric and dimeric forms, both in the absence and presence of inhibitors, through a convincing combination of traditional experiments and sophisticated computational analyses. By revealing novel insights into the selectivity and cooperative processes of BRAF inhibitors, it holds significant promise for the development of future therapeutics, particularly against mutant isoforms in cancer. Overall, these findings will be of great interest to structural biologists, medicinal chemists, and pharmacologists.

eLife Assessment

This study presents valuable evidence of sex differences in oxycodone relapse-related behavior in rats and provides insight into associated synaptic plasticity in the paraventricular thalamus to the nucleus accumbens shell (PVT-NAcSh) circuit. The report reveals that females show heightened cue-induced oxycodone seeking compared to males after 14 days – but not 1 day – of abstinence; however, an increase in synaptic strength from the PVT inputs to the NAcSh was observed in both males and females at 14 days of abstinence. Therefore, whereas the behavioral data and much of the electrophysiology data are solid, the link between them is incomplete. Further investigation of the functional role of the PVT-NAcSh pathway in the observed sex differences in oxycodone relapse and examination of input and cell-type specificity of synaptic alterations would greatly strengthen this study.

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 valuable manuscript presents a thorough analysis of the evolution of Major Histocompatibility Complex gene families across Primates. A key strength of this analysis is the use of state-of-the-art phylogenetic methods to estimate rates of gene gain and loss, but estimates of gene loss may suffer from the issue of genes entirely or partially missing from genome assemblies represented in the public databases used, given the notorious difficulty to properly assemble MHC gene genomic regions. Overall the evidence provided is still convincing, but the manuscript may benefit from discussing approaches that can address the issue of entirely or partially missing genes, in particular how the use of long reads to completely re-assemble complex loci might improve the assessment of the complex evolutionary processes at play in MHC gene families.

eLife Assessment

The authors present new expression analysis software (TEKRABber) to help analyze expression correlations between transposable elements (TEs) and KRAB zinc finger (KRAB-ZNF) genes in experimentaly validated datasets. The authors use this method to decipher the regulatory networks of KRAB-ZNFs and TEs during human brain evolution and in Alzheimer's disease. The direction of the work is important, with potentially significant interest from others looking for a tool for correlative gene expression analysis across individual genomes and species. However, identified biases and shortcomings in the current analysis pipeline could lead to an unacceptable number of false positive and negative signals and thus impact the conclusions, leaving this work in its current form incomplete.

eLife Assessment

This study provides useful insights into the ways in which germinal center B cell metabolism, particularly lipid metabolism, affects cellular responses. The authors use sophisticated mouse models to demonstrate that ether lipids are relevant for B cell homeostasis and efficient humoral responses. Although the data were collected from in vitro and in vivo experiments and analyzed using solid and validated methodology, more careful experiments and extensive revision of the manuscript will be required to strengthen the authors' conclusions.