eLife assessment

The aim of this important study is to functionally characterize neuronal circuits underlying the escape behavior in Drosophila larvae. Upon detection of a noxious stimulus, larvae follow a series of stereotyped movements that include bending of their body, rolling and crawling away. This paper combines quantitative behavioral analyses, cell-type specific manipulations, optogenetics, calcium imaging, immunostaining, and connectomic analysis to provide convincing evidence of an inhibitory descending pathway that controls the switch from rolling to fast crawling behaviors of the larval escape response.

eLife assessment

This fundamental work describes the complex interplay between light exposure, hypothalamic activity, and cognitive function. The evidence supporting the conclusion is compelling with potential therapeutic applications of light modulation. The work will be of broad interest to basic and clinical neuroscientists.

eLife assessment

This useful study aimed to quantify associations between regular use of proton-pump inhibitors (PPI) with the occurrence of respiratory infections, such as influenza, pneumonia, COVID-19, and others over a period of several years. PPI use was associated with increased risks of influenza, pneumonia, but not of COVID-19, although severity and mortality of COVID-19 infections were higher in PPI users. There are inevitable weaknesses of the study design used, such as the fact that PPI use was only measured at one time-point whereas infections were assessed over a long time period, but these are appropriately highlighted in the discussion. Weaknesses are highlighted in the discussion and the study presents convincing evidence for the conclusions overall.

eLife assessment

This important paper shows that the anti-gremlin-1 (GREM1) antibody is not effective at treating liver inflammation or fibrosis. Critically, the evidence also challenges existing data on the detection of GREM1 by ELISA in serum or plasma by demonstrating that high-affinity binding of GREM1 to heparin would lead to localisation of GREM1 in the ECM or at the plasma membrane of cells. The conclusions are supported by a convincing, well-controlled set of experiments.

eLife assessment

This study presents a valuable methodological advancement in quantifying thoughts over time. A novel multi-dimensional experience-sampling approach is used to identify data-driven patterns that the authors use to interrogate fMRI data collected during naturalistic movie-watching. The experimentation is inventive and the analyses carried out are convincing, although the conceptualization of thoughts remains too vague to allow for a clear interpretation of results.

eLife assessment

This important study provides new insights into the mechanisms that underlie perceptual and attentional impairments of conscious access. The paper presents convincing evidence of a dissociation between the early stages of low-level perception, which are impermeable to perceptual or attentional impairments, and subsequent stages of visual integration which are susceptible to perceptual impairment but resilient to attentional manipulations. This study will be of interest to scientists working on visual perception and consciousness.

eLife assessment

This fundamental state-of-the-art modeling study explores neural mechanisms underlying walking control in cats, demonstrating the probability of three different states of operation of the spinal cord circuits generating locomotion at different speeds. The biophysical modeling sufficiently reproduces and provides explanations for experimental data on how the locomotor cycle and phase durations depend on treadmill walking speed. It also points to new principles of functional architecture and operating regimes underlying how spinal circuits interact with supraspinal signals and limb sensory feedback signals to produce different locomotor behaviors at different speeds, which are major unresolved problems in the field. The modeling evidence is compelling, especially in advancing our understanding of locomotion control mechanisms, and will interest neuroscientists studying the neural control of movement.

eLife assessment

This study is an important advancement towards the understanding of animal nervous system organization and evolution by providing a compelling description of the entire connectome of the 3-day larva of the marine annelid Platynereis dumerilii. It provides a wealth of data on cell type diversity and the modules that interconnect them. Its strength in the massive amount of high-quality data is also partly a weakness as it can make it difficult to read and scientifically digest. This work lays the foundations for studies on cell type diversity, segmental vs. intersegmental connectivity, and mushroom bodies, but will certainly also be of use to scientists interested in other nervous systems parts, their functions, and evolution.

eLife assessment

This valuable study reports on electrophysiological recording of the spiking activity of single neurons in the entopeduncular nucleus (EPN) in freely-moving mice performing an auditory discrimination task. The data show that the activity of single EPN neurons is modulated by reward and movement kinematics, with the latter further affected by task contexts (e.g. movement toward or away from a reward location). The results provide solid evidence for the conclusions. Reviewer enthusiasm was reduced by the lack of investigations separating confounding factors and ambiguity as to whether the data contain the population of EPN neurons characterized in previous studies that obtained different results. The work will be of interest to those that study how the basal ganglia contribute to behavior, or the mechanisms of learning and/or movement more broadly.

eLife assessment

There is a growing interest in understanding the individuality of animal behaviours. In this article, the authors build and use an impressive array of high throughput phenotyping paradigms to examine the 'stability' (consistency) of behavioural characteristics in a range of contexts and over time. They find that certain behaviours are individualistic and persist robustly across external stimuli while others are less robust to these changing parameters. The data are solid and, with more appropriate statistical methods adopted, the findings have valuable implications for the study of individual variability.

eLife assessment

Yonk and colleagues provide a valuable and timely study showcasing the role of thalamostriatal inputs on learning and action selection. In particular, they provide solid evidence that posterior medial thalamic nucleus (POm) neurons are activated during reward expectation and arousal. A clearer conceptual assessment of the overall function of this circuit, together with sharper analyses of calcium responses and thalamic specificity, in terms of viral spread and striatal target, may further increase the impact of the study.

eLife assessment

The valuable findings in this study reveal an intricate pattern of memory expression following retrieval extinction at different intervals from retrieval-extinction to test. The novel advance is in the demonstration that, relative to a standard extinction procedure, the retrieval-extinction procedure more effectively suppresses responses to a conditioned threat stimulus when testing occurs just minutes after extinction. The manuscript provides incomplete evidence in support of the attenuation of fear recovery and solid evidence for the engagement of the dorsolateral prefrontal cortex in this "short-term" suppression of responding.

eLife assessment

This important study reveals a neural signature of a common behavioural phenomenon: serial dependence, whereby estimates of a visual feature (here motion direction) are attracted towards the recent history of encoded and reported stimuli. The study provides solid evidence that this phenomenon arises primarily during working memory maintenance. The pervasiveness of serial dependencies across modalities and species makes these findings important for researchers interested in perceptual decision-making across subfields.

eLife assessment

In this important study, the authors provide evidence that Treacle, a disease-relevant intrinsically disordered protein, undergoes biomolecular condensation to support the structure and function of the fibrillar center of the nucleolus. The findings, arising from complementary approaches, provide solid evidence for the role of Treacle condensation in supporting rDNA transcription, rRNA processing, and genome integrity. These findings may be of interest to the communities studying biomolecular condensates, nucleolar organization, and ribosome biogenesis.

eLife assessment

This valuable study reports the development of a novel organoid system for studying the emergence of autorhythmic gut peristaltic contractions through the interaction between interstitial cells of Cajal and smooth muscle cells. While the utility of the organoids for studying hindgut development is well illustrated by showing, for example, a previously unappreciated potential role for smooth muscle cells in regulating the firing rate of interstitial cells of Cajal, some of the functional analyses are incomplete. There are some concerns about the specificity and penetrance of perturbations and the reproducibility of the phenotypes. With these concerns properly addressed, this paper will be of interest to those studying the development and physiology of the gut.

eLife assessment

This important study reports the discovery of a novel nucleotide ubiquitylation activity by the DTX3L E3 ligase. Solid evidence is presented for ubiquitin attachment to single-stranded oligonucleotides. This very interesting biochemical finding can be used as a starting point for studies to establish relevance in a physiological setting.

eLife assessment

This study reports an important discovery highlighting the essential role of the putative ion channel, TMC7, in acrosome formation during sperm development and thus male fertility. The evidence for the requirement of TMC7 in acrosome biogenesis and sperm function is convincing, although its function as an ion channel remains to be further determined. Overall, this work will be of great interest to developmental biologists and ion channel physiologists alike.

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.

eLife assessment

This important study identifies a novel link between the early keratinocyte response to wounds and the subsequent regenerative capacity of local sensory neurons. The evidence supporting the claims of the authors is convincing, although inclusion of conditional genetics or cell-autonomy tests would have strengthened the mechanistic aspects. The work will be of interest to cell and developmental biologists interested in tissue regeneration and cell interactions in a broader context.

eLife assessment

This study presents a useful comparison of the dynamic properties of two RNA-binding domains. The data collection and analysis are solid, making excellent use of a suite of NMR experiments and ITC data. Nonetheless, reported evidence was found to only partially support the proposed connection between the backbone dynamics of the tandem domains and their RNA binding activity. This work will be of interest to biophysicists working on RNA-binding proteins.

eLife assessment

In this useful study, the authors investigate the regulatory mechanisms related to toxin production and pathogenicity in Aspergillus flavus. Their observations indicate that the SntB protein regulates morphogenesis, aflatoxin biosynthesis, and the oxidative stress response. The data supporting the conclusions are compelling and contribute significantly the advancing the understanding of SntB function.

eLife assessment

This important study reports, with convincing evidence, that a long non-coding RNA disrupts the activity of the tumor suppressor p53 to contribute to the growth and therapeutic response of glioblastoma. The work will be relevant to scientists working on non-coding RNAs and brain tumors.

eLife assessment

This study explores simple machine learning frameworks to distinguish between interacting and non-interacting protein pairs, offering solid computational results despite some concerns about dataset generation. The authors demonstrate a modest improvement in AlphaFold-multimers' ability to differentiate these pairs. Using a simple yet sound approach, this work is a valuable contribution to the challenging problem of reconstructing protein-protein interaction networks.

eLife assessment

This valuable study presents the development of a single turnover stopped-flow fluorescence experiment to study the kinetics of substrate unfolding and translocation by the bacterial ClpB disaggregase. Using non-physiological nucleotides to bypass the physiological regulation mechanism of ClpB, the authors convincingly show that the ClpB disaggregase is a processive motor with a slow unfolding step preceding rapid translocation. The results of this analysis are of value for future mechanistic studies on energy-dependent unfolding, degradation, and disaggregation molecular machines.

eLife assessment

This work aimed at deconstructing how sebaceous gland differentiation is controlled in adult skin. Using monoclonal antibodies designed to inhibit specific Notch ligands or receptors, the authors present solid evidence that the Jag2/Notch1 signaling axis is a crucial regulator of sebocyte progenitor proliferation and sebocyte differentiation. The valuable findings presented here contribute to the growing evidence that Notch signaling not only plays a role during the development of the skin and its appendages but also regulates cell fate in adult homeostatic tissues. From a translational perspective, it is intriguing that the effect of Jag2 or Notch1 inhibition, which leads to the accumulation of proliferative stem/progenitor cells in the sebaceous gland and prevents sebocyte differentiation, is reversible.

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 solid; however, the cryo-EM data is not properly explained, the structural and mechanistic details could be explained in greater detail, and the conclusions need to be supported by evaluating the effect of these molecules on viral infectivity.

eLife assessment

This study provides valuable insights into how the EBH domain of EB1 interacts with SxIP peptides derived from MACF. A convincing description of the thermodynamic and kinetic modes of peptide binding is provided via a combination of solution NMR techniques and ITC. Although consistent with the data, the proposed "dock-and lock" model was not found to be directly supported by evidence. This work will be of interest to structural biologists and biophysicists interested in microtubule cytoskeleton.

eLife assessment

This study provides insights into the mechanism of axonal directional changes, utilizing the pacemaker neurons of the circadian clock, the sLNVs, as a model system. The data were collected and analysed using solid methodology, resulting in valuable data on the interplay of signalling pathways and the growth of the axon. The study holds potential interest for neurobiologists focusing on axonal growth and development.

eLife assessment

The current study sheds important light on the role of sphingolipid metabolism on the maturation of Parkinson's disease-associated Synphilin-1 inclusion bodies (SY1 IBs) on the mitochondrial surface in a yeast model using Synthetic Genetic Array (SGA) and state-of-the-art imaging techniques. The authors provide compelling evidence that downregulating the sphingolipid biosynthesis pathway leads to mitochondrial dysfunction, defective maturation, and enhanced toxicity of SY1 IBs, and this effect is conserved from yeast to mammals. Altogether, this study implicates the role of sphingolipid metabolism in the detoxification process of misfolded proteins by facilitating large IB formation on the mitochondrial outer membrane.

eLife assessment

This fundamental work substantially advances our understanding of animals' foraging behaviour by monitoring the movement and body posture of barn owls in high resolution and assessing their foraging success. With a large dataset, the evidence supporting the main conclusions is compelling. This work provides new corroboration for motion-induced sound camouflage and has broad implications for understanding predator-prey interactions.

eLife assessment

This work contributes to the study of H3-K27M mutated pediatric gliomas. It convincingly demonstrates that the concomitant targeting of histone deacetylases (HDACs) and the transcription factor MYC results in a notable reduction in cell viability and tumor growth. This reduction is linked to the suppression of critical oncogenic pathways, particularly mTOR signaling, emphasizing the role of these pathways in the disease's pathogenesis. The current version of the manuscript is important because it unveils a vulnerability from dual targeting HDACs and MYC in the context of pediatric gliomas. This work will be of interest to cancer epigenetics and therapeutics research, with a focus on the neuro-oncology field.

eLife assessment

The authors report solid evidence for a valuable set of findings in rats performing a new virtual place-preference task. Temporary pharmacological inhibition targeting the dorsal or intermediate hippocampus disrupted navigation to a goal location in the task, and functional inhibition of the intermediate hippocampus was more detrimental than functional inhibition of the dorsal hippocampus. The work provides novel insights into functional differentiation along the dorsal-ventral axis of the hippocampus.

eLife assessment

This paper provides an important method that uses a computational model to predict photoreceptor currents in mammalian photoreceptors. By inverting the model, visual stimuli can be constructed to produce desired photoreceptor current responses. The authors provide compelling evidence that this approach can disentangle the effects of photoreceptor nonlinearities including light adaptation from downstream nonlinear processing, thus facilitating future studies of the higher visual system.

eLife assessment

This important work examines the role of blood flow and Ghrelin in influencing the migration speed of adult-born olfactory neurons. The authors present solid evidence that newborn rostral migratory stream (RMS) neurons are closely situated alongside blood vessels, preferentially along arterioles, and that migratory speed is correlated with blood flow. They also provide evidence (in vitro and some in vivo) that Ghrelin from blood is involved in augmenting RMS neuron migration speed. While the data from the imaging experiments are convincing, the evidence for the causal roles of Ghrelin is limited and requires additional experimental clarifications to reach a strong conclusion.

eLife assessment

This important study identifies the anti-inflammatory function of PEGylated PDZ peptides that are derived from the ZO-1 protein. Results from cellular and in vivo experiments tracking key inflammatory markers are compelling. Although the mechanism of action needs further investigation, this study provides a proof of concept for developing novel strategies against acute inflammatory conditions such as sepsis.

eLife assessment

This paper presents useful findings on the dysmyelination phenotype of nervous system-specific Spns1 (a lysosomal lipid transporter) knockout mice. While the analysis of the phenotype is solid, the evidence for the underlying mechanisms, especially the molecular function for SPNS1, is incomplete. With more careful interpretation and/or additional experimental data, this work could have implications for understanding lipid transport and lysosomal storage diseases.

eLife assessment

This short manuscript uses mutation counts in phylogenies of millions of SARS-CoV-2 genomes to show that mutation rates systematically differ between regions that are paired or unpaired in the predicted RNA secondary structure of the viral genome. Such an effect of pairing state is not unexpected, but its systematic demonstration using millions of viral genomes is valuable and convincing.

eLife assessment

Floeder and colleagues report that dopamine ramps are determined by the duration of the intertrial interval of the task and the presence of dynamic cues that indicate reward proximity. The manuscript provides valuable new information on a topic of active discussion in the dopamine and reinforcement learning field and the strength of the evidence supporting the claims is solid.

eLife assessment

This report details the creation and wide-scale utilization of "Repix", a new technique for chronic neurophysiological recordings using and re-using Neuropixels probes in freely behaving mice and rats. The authors include data and feedback from a variety of labs and researchers who have used this technique, setting an example for open science and reproducibility, and providing convincing evidence that this approach can be employed for chronic Neuropixels recordings. However, evidence is currently incomplete for claims about the advantages of this design over previous approaches and for cell yield and stability claims. This important work will have an impact on a broad range of neuroscientists seeking a straightforward methodology for chronic Neuropixels recordings and will facilitate ethologically relevant experimental designs.

Editors Assessment:

Oxford nanopore direct RNA sequencing (DRS) is a relatively new sequencing technology enabling measurements of RNA modifications. In vitro transcription (IVT)-based negative controls (i.e. modification-free transcripts) are a practical and targeted control for this direct sequencing, providing a baseline measurement for canonical nucleotides within a matched and biologically-derived sequence context. This work presents exactly this type of a long-read, multicellular, poly-A RNA-based, IVT-derived, unmodified transcriptome dataset. Review flagging more statistical analyses needed be performed for the data quality, and this was provided. The resulting data providing a resource to the direct RNA analysis community, helping reduce the need for expensive IVT library preparation and sequencing for human samples. And also serving as a framework for RNA modification analysis in other organisms.

This evaluation refers to version 1 and 2 of the preprint

eLife assessment

This valuable manuscript describes a novel role of Vangl2, a core planar cell polarity protein, in linking the NF-kB pathway to selective autophagic protein degradation in myeloid cells. The mechanistic studies suggest that Vangl2 targets p65 for NDP52-mediated autophagic degradation, limiting inflammatory NF-kB response, with functional significance of the proposed mechanism in sepsis. The presented evidence is convincing. Additional studies dissecting autophagic Vangl2 functions in various myeloid subsets in the context of inflammation could be informative, and additional Vangl2 targets in the inflammatory pathway, including IKK2, could also be explored. Overall, this exciting study will likely advance our understanding of NF-kB control, particularly in the context of inflammatory diseases.

eLife assessment

This valuable study presents findings on the role of the ubiquitin-conjugating enzyme UBE2D/eff in maintaining proteostasis during aging. The evidence supporting the conclusions is solid, although one reviewer had concerns about the readout for protein aggregation and the loss-of-function studies. In the future, mechanistic insights explaining the impact of UBE2D/eff deficiency on the accumulation of poly-ubiquitinated proteins and in shortening lifespan would be interesting. The present study is of broad interest to cell biologists working in aging and age-related diseases.

eLife assessment

This study provides valuable insights by demonstrating that BYL719 is a promising therapeutic agent for the treatment of heterotopic ossification (HO), with inhibition of PI3Ka via BYL719 appearing to be a critical factor. However, the results of the study are incomplete because BYL719 affects multiple intracellular signaling pathways beyond PI3Ka, and it thus remains uncertain whether BYL719 attenuates HO exclusively through suppression of the PI3Ka pathway or through modulation of alternative signaling pathways. A detailed elucidation of the molecular mechanisms of action of BYL719 is essential for a thorough understanding of its effects.

eLife assessment

This study presents the cryo-EM structures of two human biotin-dependent mitochondria carboxylases involved in various biological pathways, including the metabolism of certain amino acids, cholesterol, and odd chain fatty acids. The cryo-EM structures offer a valuable addition to the structural description of biotin-dependent carboxylases and provide solid evidence to support the major conclusions of this study. This paper would be of interest to biochemists and structural biologists working on biotin-dependent carboxylases.

eLife assessment

This study presents an important contribution to cardiac arrhythmia research by demonstrating long noncoding RNA Dachshund homolog 1 (lncDACH1) tunes sodium channel functional expression and affects cardiac action potential conduction and rhythms. The evidence supporting the major claims are convincing. The work will be of broad interest to cell biologists and cardiac electrophysiologists.

eLife assessment

This important study provides a new perspective on how human immunity shapes the antigenic evolution of pathogens. By combining theory and simulation the authors make a solid case for the importance of eco-evolutionary interactions in population-level virus-host dynamics, which arise due to coupling between the dynamics of immune memories and viral variants. Although the work does not propose improved data-driven viral forecasting methods, it makes a conceptual contribution that advances the field's understanding of this problem's intrinsic difficulty.

eLife assessment

This study reports on the in vivo dynamics of insulin-producing cells (IPCs) in Drosophila. IPC activity is shown to be modulated by the nutritional state and age of the animal, with convincing evidence for an incretin-like effect. These important findings establish IPCs in Drosophila as a system to study circuits governing behaviors related to the internal state in competition with the feeding state, and will be of interest to both neuroscientists and cell biologists.

eLife assessment

This study reports valuable insights into the interactome of the RNA-binding protein SERBP1 and possible links through PARylation to a diverse set of processes including splicing, cell division, and ribosome biogenesis. The diversity of processes SERBP1 may regulate means this work would be of very broad interest to the cell biology community. However, whereas the proteomics data are solid, the functional connection to downstream processes and the link to Alzheimer's disease are still incomplete, as they rely on a very limited set of experiments and patient samples.

eLife assessment

This important paper addresses the role of fluid flows in nutrient uptake by microorganisms propelled by the action of cilia or flagella. Using a range of mathematical models for the flows created by such appendages, the authors provide convincing evidence that the two strategies of swimming and sessile motion can be competitive. These results will have significant implications for our understanding of the evolution of multicellularity in its various forms.

Editors Assessment:

This paper presents a new tool to make using PhysiCell easier, which is an open-source, physics-based multicellular simulation framework with a very wide user base. PhysiCell Studio is a graphical tool that makes it easier to build, run, and visualize PhysiCell models. Over time, it has evolved from being a GUI to include many additional functionalities, and can be used as desktop and cloud versions. This paper outlines the many features and functions, the design and development process behind it, and deployment instructions. Peer review improved the organisation of the various repositories and adding both a requirements.txt and environment.yml files. Looking to the future the developers are planning to add new features based on community feedback and contributions, and this paper presents the many code repositories if readers wish to contribute to the development process.

This evaluation refers to version 1 of the preprint

Editors Assessment:

Many studies have explored the genetic determinants of COVID-19 severity, these GWAS studies using microarrays or expensive whole-genome sequencing (WGS). Low-coverage WGS data can be imputed using reference panels to enhance resolution and statistical power while maintaining much lower costs, but imputation accuracy is difficult to balance. This work demonstrates how to address these challenges utilising the GLIMPSE1 algorithm, a less resource-intensive tool that produces more accurate imputed data than its predecessors. Generating a dataset containing 79 imputed low-coverage WGS samples from patients with severe COVID-19 symptoms during the initial wave of the SARS-CoV-2 pandemic in Spain. The validation of this imputation and filtering process shows that GLIMPSE1 can be confidently used to impute variants with minor allele frequency up to approximately 2%. After peer review the authors clarified and provided more validation and statistics and figures to help convince this approach was valid. This work showcasing the viability of using low-coverage WGS imputation to generate data for the study of disease-related genetic markers, alongside a validation methodology to ensure the accuracy of the data produced. Helping inspire confidence and encouraging others to deploy similar approaches to other infectious diseases, genetic disorders, or population-based genetic studies. Particularly in large-scale genomic projects and resource-limited settings where sequencing at higher coverage could prove to be prohibitively expensive.

This evaluation refers to version 1 of the preprint

eLife assessment

In this study, Tutak and colleagues set out to identify factors that mediate Repeat Associated Non-AUG (RAN) translation of CGG repeats in the FMR1 mRNA which are implicated in toxic protein accumulation that underpins ensuing neurological pathologies. This is a useful article that suggests that RPS26 may be implicated in mediating the RAN translation of FMR1 mRNA. However, the evidence supporting the proposed mechanism is incomplete, since the provided data only partially support the authors' conclusion.

eLife assessment

This fundamental work has completed our understanding of the singular binding profile of the Rhino HP1 protein to chromatin, a key step in converting certain genomic regions into piRNA source loci. The evidence supporting the conclusions is compelling. Phylogenetic analyses, structure prediction, rigorous biochemical assays and in vivo genetics emphasize the importance of the Rhino chromodomain in the recognition of both a histone mark and a DNA-binding protein, and highlight the importance of a single chromodomain residue in the protein-protein interaction.

eLife assessment

Schafer et al. investigate the extremely interesting and important claim that the human hippocampus represents the interactions with multiple social interaction partners on two relatively abstract social dimensions – and that this ability correlates with the social network size of the participant. This research potentially demonstrates the intricate role of the hippocampus in navigating our social world. While some results are tantalizing, the empirical evidence for the main claims is currently incomplete and requires clarifications and substantial revisions.

eLife assessment

This useful study reports the behavioural and physiological effects of the longitudinal activation of neurons associated with negative experiences. The main claims of the paper are supported by solid experimental evidence, although the specificity of the long-term manipulation could have benefitted from additional validation. This study will be of interest to neuroscientists working on memory.

eLife assessment

This fundamental work proposes a novel mechanism for memory consolidation where short-term memory provides a gating signal for memories to be consolidated into long-term storage. The work combines extensive analytical and numerical work applied to three different scenarios and provides a convincing analysis of the benefits of the proposed model, although some of the analyses are limited to the type of memory consolidation the authors consider (and don't consider), which limits the impact. The work will be of interest to neuroscientists and many other researchers interested in the mechanistic underpinnings of memory.

eLife assessment

This valuable manuscript delineates the role of YAP/TAZ-dependent transcriptional suppression in a mechanodransductive feedback loop. The evidence presented in the manuscript is generally solid. However, compared to an earlier version, some concerns remain. In particular, the in vivo validation should be strengthened, and the in vitro and in vivo models used in this work should be carefully compared in order to improve the main message of the manuscript.

eLife assessment

This work explores the role of one the most abundant circRNAs, circHIPK3, in bladder cancer cells, showing with 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. These important 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 work is an important contribution to the development of a biologically plausible theory of statistical modeling of spiking activity. The authors convincingly implemented the statistical inference of input likelihood in a simple neural circuit, demonstrating the relationship between synaptic homeostasis, neural representations, and computational accuracy. This work will be of interest to neuroscientists, both theoretical and experimental, who are exploring how statistical computation is implemented in neural networks. There are questions about the performance of the methods in the case where other biologically significant parameters, such as firing rate and thresholds, are optimized together with the synaptic weights.

eLife assessment

This study provides valuable new insights into how multisensory information is processed in the lateral cortex of the inferior colliculus, a poorly understood part of the auditory midbrain. By developing new imaging techniques that provide the first optical access to the lateral cortex in a living animal, the authors provide convincing in vivo evidence that this region contains separate subregions that can be distinguished by their sensory inputs and neurochemical profiles, as suggested by previous anatomical and in vitro studies. This work provides a foundation for future research exploring how this part of the auditory midbrain contributes to multisensory-based behavior.

eLife assessment

The study presents a valuable tool for searching molecular dynamics simulation data, making such datasets accessible for open science. The authors provide convincing evidence that it is possible to identify noteworthy molecular dynamics simulation datasets and that their analysis can produce information of value to the community.

eLife assessment

The authors make the intriguing proposal that the NuRD complex in C. elegans, which has been linked to regulation of the cell death protein EGL-1 before, becomes asymmetrically distributed after cell division and that this asymmetry relies on V-ATPase activity. Whereas some disagreement remained between the reviewers' and the authors' interpretation, the final version incorporated alternative possibilities in the text, and with careful interpretation, the current manuscript's model is supported by solid data, and represents a valuable contribution to the field.

eLife assessment

The authors propose that the asymmetric segregation of the NuRD complex in C. elegans is regulated in a V-ATPase-dependent manner, that this plays a crucial role in determining the differential expression of the apoptosis activator egl-1, and that it is therefore critical for the life/death fate decision in this species. If proven, the proposed model of the V-ATPase-NuRD-EGL-1-Apoptosis cascade would shed light onto the mechanisms underlying the regulation of apoptosis fate during asymmetric cell division, and stimulate further investigation into the intricate interplay between V-ATPase, NuRD, and epigenetic modifications. However, the strength of evidence for this is currently incomplete.

eLife assessment

The manuscript describes a careful, quantitative analysis of Myosin 10 molecules in U2OS cells, a widely used model for studying filopodia, and how many are present in the cytosol versus filopodia. This important study provides key parameters that are required for building a biophysical model of filopodia which is required to gain a complete understanding of these major actin-based structures. The evidence for the conclusions is compelling, but there are also certain areas of the manuscript that require clarification.

eLife assessment

Chang et al. have investigated the catalytic mechanism of I-PpoI nuclease, a one-metal-ion dependent nuclease, by time-resolved X-ray crystallography using soaking of crystals with metal ions under different pH conditions. This convincing study revealed that I-PpoI catalyzes the reaction process through a single divalent cation. The study uncovers important details of the roles of the metal ion and the active site histidine in catalysis.

eLife assessment

This interesting and important study follows up on the authors' observations that lower glucose parental nutrition leads to lower rates of sepsis from Staphylococcus epidermis in a preterm pig model. Sepsis in early life, particularly in premature infants, has significant morbidity and mortality and the authors present convincing evidence that glycemic state affects hepatic metabolism-dependent immune function and improved clearance of coagulase-negative staphylococcal infection. The authors provide a robust multi-omic dataset for the use of the scientific community. However, there are also several concerns that will limit the impact of the work, including that the model does not reflect early onset sepsis that is observed in premature infants, and the question of whether low glucose parental nutrition (PN) is protective versus high glucose PN is harmful as the levels of glucose in the high PN were incredibly high.

eLife assessment

This study provides an important advance in the molecular understanding of the lipopolysaccharide export mechanism and machinery in bacteria. By using advanced spectroscopy approaches, the experiments provide solid biophysical support for the dynamic behavior of the multisubunit Lpt transport system. This work has implications for understanding bacterial cell envelope biogenesis and may contribute to the development of drugs that target Gram-negative pathogens.

eLife assessment

The study presents a valuable finding in advancing our understanding of the cellular and molecular mechanisms that regulate the switching of the migration mode from parallel to radial in cerebellar granule cell development. The evidence supporting the claims of the authors is solid and supports the main conclusion; the highlight was the imaging system's visualization of the cell-recognition event associated with neuronal migration, which established a new standard for the field. This study would be of interest to cell biologists and neurodevelopmental biologists working on cell-cell interaction and neuronal migration.

eLife assessment

Wittkamp et al. investigated the spatiotemporal dynamics of expectation of pain using an original fMRI-EEG approach. The methods are solid and the evidence for a substantially different neural representation between the anticipatory and the actual pain period is convincing. These important findings would benefit from a general framework to encompass their research questions, hypotheses, and interpretation of results. Furthermore, a more in-depth discussion about the choice of conditions would be desirable, specifically whether the definitions of nocebo and placebo in the study are comparable with traditional paradigms, and whether the control condition can be considered as a situation with no expectation or no prediction.

eLife assessment

This interesting study explores whether tumor cells can manipulate their Hydra hosts and has useful findings on the consequences for the fitness of the host Hydra.<br /> However, the evidence supporting these findings was incomplete, would benefit from the addition of several control experiments. The work will be of broad interest to many fields including development biology, evolutionary biology and tumor biology.

eLife assessment

This study introduces the MRAD database, which provides a useful tool for evaluating risk and protective factors for Alzheimer's disease through Mendelian randomization analysis. While the findings are supported by solid evidence, the study's value could be enhanced by addressing methodological concerns and ensuring rigorous validation of significant associations. The MRAD database has the potential to aid researchers and clinicians, but the current analysis appears incomplete without these refinements.

eLife assessment

This is an important and timely study that advances our understanding of the role of lateral hypothalamic orexin/hypocretin neurons in appetitive approach and consummatory behaviors. Specifically, using fiber photometry, the authors provide solid and convincing evidence that orexin neurons are primarily active during approach and not consummatory behavior, in a manner that is dependent on metabolic state. Further, using optogenetics and cell type-specific electrophysiology, they show that inputs from the ventral pallidum and lateral nucleus accumbens shell to orexin/hypocretin neurons in the lateral hypothalamus are predominantly inhibitory.

eLife assessment

This important work significantly advances the field of computational modelling of genome organisation through the development of OpenNucleome. The evidence supporting the tool's effectiveness is compelling, as the authors compare their predictions with experimental data. It is anticipated that OpenNucleome will attract significant interest from the biophysics and genomics communities.

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, however, additional evidence to convincingly demonstrate the functional involvement of Rudhira in this process is highly appreciated. The work will be of broad interest to developmental biologists in general and molecular biologists in the field of growth factor signaling.

eLife assessment

This important study provides new insight into the dynamics that underlie the development of therapy resistance in prostate cancer by revealing that divergent tumor evolutionary paths occur in response to different treatment timing and that these converge on common resistance mechanisms. The use of barcoded lineage tracing and characterization of isolated tumor clonal populations provides compelling evidence supporting the importance of clonal dynamics in a tumor ecosystem for treatment resistance. Several open questions remain, however, raising the possibility of alternative interpretations of the data set in its current form. Overall, the findings deepen our understanding of prostate cancer evolution and hold promising implications for how drug resistance can be addressed or prevented.

eLife assessment

This valuable study demonstrates that genomic insertion of a G4-containing sequence can be sufficient to induce chromosome loops and alter gene expression. The evidence supporting the conclusions is convincing. Effects were shown by Hi-C as well as qPCR for chromatin modifications and expression, and the specificity of the effects was controlled by mutating the G4-containing sequence or treating with LNA probes to abolish G4 structure formation. The work will be of interest to researchers working on chromatin organization and gene regulation.

eLife assessment

This important study addresses the idea that defective lysosomal clearance might be causal to renal dysfunction in cystinosis. They observe that restoring expression of vATPase subunits and treatment with Astaxanthin ameliorate mitochondrial function in a model of renal epithelial cells, opening opportunities for translational application to humans. The data are convincing, but the description of methodologies is incomplete.

eLife assessment

This study provides valuable findings that improve our understanding of the evolutionary conservation of the role of DDX6 in mRNA decay. The evidence supporting the authors' conclusions is convincing. This work will be of interest to molecular, cell biologists and biochemists, especially those studying RNA.

eLife assessment

This study presents a useful description of RNA in extracellular vesicles (EV-RNAs) and highlights the potential to develop biomarkers for the early detection of colorectal cancer (CRC) and precancerous adenoma (AA). The data were analysed using overall solid methodology and would benefit from further validation of predicted lncRNAs and biomarker validation at each stage of CRC/AA to evaluate the potential application to early detection of CRC and AA.

eLife assessment

In this study, Ger and colleagues present a valuable new technique that uses recurrent neural networks to distinguish between model misspecification and behavioral stochasticity when interpreting cognitive-behavioral model fits. Simulations provide solid evidence for the validity of this technique and broadly support the claims of the paper, although more work is needed to understand its applicability to real behavioral experiments. This technique addresses a long-standing problem that is likely to be of interest to researchers pushing the limits of cognitive computational modeling.

eLife assessment

This useful study aimed to examine the relationship of spatial frequency selectivity of single macaque inferotemporal (IT) neurons to category selectivity. There are some interesting findings in this report but some of these findings were difficult to evaluate because several critical details of the analysis are incomplete. The conclusion that single-unit spatial frequency selectivity can predict object coding needs further evidence to confirm.

eLife assessment

These are important findings that support a link between low-dimensional brain network organisation, patterns of ongoing thought, and trait-level personality factors, making it relevant for researchers in the field of spontaneous cognition, personality, and neuropsychiatry. While this link is not entirely new, the paper brings to bear a rich dataset and a well-conducted study, to approach this question in a novel way. The evidence in support of the findings is convincing.

eLife assessment

This is a fundamental study examining the role of prediction error in state allocation of memories. The data provided are convincing and largely support the conclusion that a gradual change between acquisition and extinction maintains the memory state of acquisition and thus results in extinction that is resistant to restoration. This paper is of interest to behavioural and neuroscience researchers studying learning, memory, and the neural mechanisms of those processes as well as to clinicians using extinction-based therapies in treating anxiety-based disorders

eLife assessment

This study presents valuable findings as it shows that sleep rhythm formation and memory capabilities depend on a balanced and rich diet in fly larvae. The evidence supporting the claims of the authors is convincing with rigorous behavioral assays and state-of-the-art genetic manipulations. The work will be of interest to researchers working on sleep and memory.

eLife assessment

This important study provides new insights into the maturation of ribbon synapses in zebrafish neuromast hair cells. Convincing evidence, based on live-cell imaging and pharmacological and genetic manipulations, is provided to show that the formation of this synaptic organelle is a dynamic process involving the fusion of presynaptic elements and microtubule transport. These findings will be of interest to neuroscientists studying synapse formation and function and should inspire further research into the molecular basis for synaptic ribbon maturation.

eLife assessment

Using electrophysiological recordings in freely moving rats, this valuable study investigates the role of different gamma frequency bands in the development of spatial representations in the hippocampus. However, the evidence is incomplete as the methods and data analysis need significant improvement. Critically, alternative interpretations and analyses must be provided, especially regarding the nature of gamma oscillations in the hippocampus and their interaction with neuronal firing dynamics and theta sequence features. This study will be of interest to neuroscientists working in the field of spatial navigation and neuronal dynamics.

eLife assessment

The study by Pudlowski et al. shows that a protein complex composed of delta- and epsilon-tubulin together with TEDC1 and TEDC2, which was previously identified, functions in generating centriolar triplet microtubules, and that this is crucial for the proper formation of centriolar subdomains and the stability of centrioles throughout the cell cycle. The findings are valuable for a better understanding of centriole biogenesis and structure and are largely supported by solid evidence based on knockout cell lines, immunoprecipitation, and ultrastructure expansion microscopy. The work is of interest to cell biologists, in particular researchers with interest in centrosome biology.

eLife assessment

This useful study explores the relationship between the sequence of prokaryotic promoter elements and their activity using mutagenesis to generate thousands of mutant sequences. The evidence supporting these findings is incomplete, and would benefit from additional experiments, clarification of methods, and a more detailed discussion of related literature. This work will appeal to those interested in bacterial genetics, genome evolution, and gene regulation.

eLife assessment

This useful work provides a risk-prediction tool, in the form of a nomogram, for practitioners and elderly patients with non-metastatic colon cancer using data from the SEER registry. The unique contribution of this work is the focus on conditional survival. However, the underlying statistical approach is suboptimal and therefore incomplete, which substantially lessens the potential impact of this work. The analysis could use a more rigorous consideration of competing risks.

eLife assessment

The work is important and of potential value to areas other than the bone field because it supports a role and mechanism for beta-catenin that is novel and unusual. The findings are significant in that they support the presence of another anabolic pathway in bone that can be productively targeted for therapeutic goals. The data for the most part are convincing. The work could be strengthened by better characterizing the osteoclast KO of Malat1 related to the Lys cre model and by including biochemical markers of bone turnover from the mice.

eLife assessment

In this valuable study, Gue, Hue et al. describe how two poorly understood rhabdomyosarcoma fusion-oncogenes, VGLL2::NCOA2 and TEAD1::NCOA2, function at the genomic, transcriptional, and proteomic levels in multiple systems. They generated solid data that support that these fusion-oncogenes leverage TEAD transcriptional signatures, in a mechanism that is independent of YAP/TAZ, and that this activity potentially contributes to tumorigenesis. This work offers new mechanistic insights into oncogenic gene fusion events identified in cancer patients and reveals potential therapeutic strategies for the treatment of rhabdomyosarcomas.

eLife assessment

Approaches for quantifying synaptic activity events are currently limited, and recent advances in AI and deep learning provide an opportunity to develop powerful new ways to automate this process. In this study, the authors have generated a valuable tool, miniML, that uses open-source software that convincingly enables rapid, automated, and accurate quantification of synaptic events from a variety of systems and approaches. This software will be of significant utility to a variety of neuroscience researchers.

eLife assessment

This study provides a novel and promising NPRL2 gene therapy for enhanced immunotherapy response in a KRAS/STK11 mutant anti-PD1 resistant metastatic NSCLC humanized mouse model. Overall, the authors presented a large amount of convincing in vivo data to demonstrate that NPRL2 gene therapy induces antitumor activity through DC-mediated antigen presentation and cytotoxic immune cell activation. This work will be of interest and useful to medical biologists and oncologists in the research field of KRAS-mutant NSCLC.

eLife assessment

This work proposes that positive biodiversity-ecosystem functioning relationships found in experiments have been exaggerated because commonly used statistical analyses are flawed. As an alternative, the authors suggest a new analysis based on species competitive responses. Unfortunately, the presented methods are not reproducibly described, not yet complete, and inadequate for hypothesis testing. The reviewers agreed that the authors have either misinterpreted or chosen not to take into account much of the current research literature in the field of plant competition and biodiversity research.

eLife assessment

This valuable manuscript describes evidence of sex differences in specific corticostriatal projections during alcohol consumption, and this is noteworthy given the increasing rates/levels of drinking in females and the liability for Alcohol Use disorder. They provide solid evidence of the lateralisation of the activity of the circuit, but other evidence is incomplete, particularly with regard to its description of the drinking measure and how this relates to intoxication. The analyses of the histology data are not complete, and there are further inconsistencies that make it difficult to reconcile the photometry and behavioral data. The findings will be of partial interest to researchers investigating functional circuitry underlying alcohol-driven behaviors.

eLife assessment

Here the authors present a useful extension of their previous method to cluster neuronal activity into cell assemblies (groups of neurons with correlated activity). The authors provide solid evidence that this method can identify temporal dynamics of neuronal clusters in sample simulated data, and they show how this method can be applied to whole-brain zebrafish data.

eLife assessment

The paper characterized a specific defect in the spatial working memory of mice with a deficit in a protein called Rac1. Rac1 inhibition was limited to the presynaptic compartment of neurons, which is significant because past work has inhibited both pre- and postsynaptic compartments. The study also identified potential effectors of Rac1. The work is important for these reasons, and the strength of the evidence is exceptional.

eLife assessment

This study provides important information about the formation of ribbon synapses in mouse cochlear hair cells, which facilitate the temporally-precise transmission of acoustic information to the auditory nerve. Live-cell imaging provides compelling evidence that ribbon precursor volume is dynamically modified by fission and fusion events on microtubules, but some of the other evidence included, particularly in relation to the directed transport of these precursors to the hair cell active zone is incomplete. These findings will be of interest to neuroscientists studying synapse formation and function and should inspire further research into the molecular basis for synaptic ribbon maturation.

eLife assessment

This valuable study investigates the brain representations of Braille letters in blind participants and provides convincing evidence using EEG and fMRI that the decoding of letter identity across the reading hand takes place in the visual cortex. The evidence supporting the claims of the authors is solid, although the inclusion of a sighted control group and additional analyses would have strengthened the study. The work will be of interest to neuroscientists working on brain plasticity.

eLife assessment

This valuable study uses recently developed EEG analysis methods to investigate spatial distractor suppression in a combined visual search/working memory task. While the reported results are convincing, the combined task design leaves open alternative interpretations than those currently discussed in the manuscript, potentially limiting the generalisability of the findings to other task settings. The study will be of interest to cognitive neuroscientists and psychologists working on visual attention and memory.

eLife assessment

This important work uses in vivo foveal cone-resolved imaging and simultaneous microscopic photostimulation to investigate the relationship between ocular drift - eye movements long thought to be random - and visual acuity. The surprising result is that ocular drift is systematic - causing the object to move to the center of the cone mosaic over the course of each perceptual trial. The tools used to reach this conclusion are state-of-the-art and the evidence presented is convincing. This work advances our understanding of the visuomotor system and the interplay of anatomy, oculomotor behavior, and visual acuity.

eLife assessment

This manuscript aims to unravel the contribution of cholesterol to aquaporin-0 (AQP0) tetramer array formation within lens membranes. Compelling electron crystallography data are combined with solid molecular dynamics experiments to identify a specific cholesterol binding site of significance to protein clustering within lipid rafts. The important work advances our understanding of membrane biology and will be of broad interest to membrane transport biologists, biochemists, and structural biologists.

eLife assessment

This manuscript describes a deep mutational scanning study of the kinase domain of the MET receptor tyrosine kinase. The study yields an important catalog of essentially all possible deleterious mutations in this portion of the receptor., with convincing evidence. The manuscript will be of interest to researchers working in the field of receptor tyrosine kinases.

eLife assessment

This valuable study uses single-cell transcriptomics to explore the mouse vomeronasal organ and represents an advance that enhances our understanding of neural diversity within this sensory system. Findings suggest a unique endoplasmic reticulum (ER) structure in Gnao1 neurons and allow for the synthesis of a developmental trajectory from stem cells to mature vomeronasal sensory neurons. Convincing methods, data, and analyses broadly support the claims, although experiments supporting the main ER-related claim require additional quantification of co-expression and statistics on labeling intensity or coverage. Adding these data would greatly strengthen the conclusions of the paper.

eLife assessment

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

eLife assessment

This valuable study uses dynamic metabolic models to compare perturbation responses in a bacterial system, analyzing whether they return to their steady state or amplify beyond the initial perturbation. The evidence supporting the emergent properties of perturbed metabolic systems to network topology and sensitivity to specific metabolites is compelling. However, the mathematical explanation of the perturbation response is incomplete, and a more comprehensive metabolic and biosynthesis model would be beneficial.

eLife assessment

This important work offers a thorough exploration of the molecular features of different cell types within the mouse vomeronasal organ, including the expression of chemosensory receptors, using single-cell transcriptomics. The data are thoughtfully analyzed and presented, although the evidence is incomplete and only partially supports some of the claims made by the authors.

eLife assessment

This important study demonstrates a novel method for imaging glutamate receptors in situ via cryo-ET. The use of cutting-edge methods is well-described and is convincing, but there are minor concerns as to how generally this approach can be used in imaging cell surface receptors. This paper is broadly relevant to biophysicists and neuroscientists.

eLife assessment

This study provides the first analysis of vascular stabilization on the critical and evolutionarily conserved structure around the Circle of Willis in the brain, strengthened by using parallel in vivo and in vitro experimental approaches. The evidence supporting the claims is solid and the work will be valuable for scientists studying developmental and disease-related vascular stabilization.

eLife assessment

This important study demonstrates that combining AlphaFold2 with the author's sampling method AF2-RAVE improves protein-ligand docking for three protein kinases and their inhibitors. The evidence is compelling but would benefit from a more complete description of the methodology and a clear assessment of the method's range of applicability. The work will be of interest to researchers who work on computer-aided drug design.

eLife assessment

The mechanisms that ensure accurate chromosome segregation are key for genome integrity and defects therein can cause human disease. Although the involvement of MAP kinases in modulating mitosis is known, this manuscript makes a valuable contribution by going to some lengths to reveal links between Spindle Assembly Checkpoint dynamics and stress-responsive MAP-kinase pathways. The strength of the evidence is solid but there are minor weaknesses, which need to be addressed.

eLife assessment

The study is noteworthy for its effort to achieve a deeper understanding of PTH-1 Receptor signaling. This molecular pathway which underpins the control of calcium and phosphate metabolism throughout life in land-dwelling animals, can be targeted to the therapeutic benefit of people with osteoporosis. We consider the significance of the findings in this paper to be valuable to the community of investigators working on PTH receptor and PTH ligand signaling. The strength of the evidence is solid and it could become even stronger by addressing a few shortcomings.

eLife assessment

This valuable study uses neuroanatomical techniques to investigate somatosensory projections from the elephant trunk to the brainstem. Given its unique specializations, understanding how the elephant trunk is represented within the brain is of general interest to evolutionary and comparative neuroscientists. The authors present solid evidence for the existence of a novel isomorphism in which the folds of the trunk are mapped onto the trigeminal nucleus; however, due to their unusual structure, some uncertainty remains about the identification and anatomical organization of nuclei within the elephant brainstem.

eLife assessment

The authors further corroborated their model that Netrin signaling promotes survival and dissemination of non-proliferating ovarian cancer cells. These valuable results were found to be of significant potential interest to cancer biologists in as much as they address gaps in knowledge pertinent to the mechanisms underpinning ovarian cancer spread. In general, it was thought that solid experimental evidence was provided to support the role of Netrin signaling in fueling ovarian cancer progression.

eLife assessment

This is a useful study that used DEGAS, a deep transfer learning tool, to identify distinct pancreatic beta cell subpopulations that could be associated with type 2 diabetes (T2D) and/or obesity status. The data supporting the authors' findings is solid and demonstrates that DEGAS will be a helpful tool for analyzing cell-specific transcriptomic phenotypes. This study will be of interest to researchers studying the genetics of T2D.

eLife assessment

ProtSSN is a valuable approach that generates protein embeddings by integrating sequence and structural information, demonstrating improved prediction of mutation effects on thermostability compared to sequence-only models. The work is currently incomplete as it lacks a thorough comparison against other recent top-performing methods that also incorporate structural data, such as SaProt, EVE-based models, and GEMME. Providing a comprehensive analysis benchmarking ProtSSN against these state-of-the-art structure-based approaches would significantly strengthen the evidence supporting the utility of ProtSSN's joint sequence-structure representations.