eLife Assessment

This study presents a valuable methodological advancement in quantifying thoughts over time. A novel multi-dimensional experience-sampling approach is presented, identifying 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.

eLife Assessment

This study presents an important finding on the involvement of a Caspase 3-dependent pathway in the elimination of synapses for retinogeniculate circuit refinement and eye-specific territory segregation. This work fits well with the concept of "synaptosis" which has been proposed in the past but lacked in vivo support. Despite its elegant design and many strengths, the evidence supporting the claims of the authors is incomplete, particularly regarding whether Caspase-3 expression can really be isolated to synapses vs locally dying cells, whether microglia direct or instruct synapse elimination, and whether astrocytes are also involved. The work will be of interest to investigators studying cell death pathways, neurodevelopment, and neurodegenerative disease.

eLife Assessment

This valuable paper provides an unbiased landscape for the cerebellar cortical outputs to the brainstem nuclei. By conducting anatomical and physiological analyses of the axonal terminals of Purkinje cells, the data provide convincing evidence that Purkinje cells innervate brainstem nuclei directly. The results show that in addition to previously known inputs to vestibular and parabrachial nuclei, Purkinje cells synapse onto the pontine central grey nucleus but have little effect on the locus coeruleus and mesencephalic trigeminal neurons.

eLife Assessment

This important study reports that the neurohormone, bursicon, and its receptor, play a role in the seasonal polyphenism of the bug Cacopsylla chinensis. Low temperature activates the bursicon signaling pathway during the transition from the summer to the winter form, affecting cuticle pigment and thickness as well as chitin content. The solid experiments reveal how bursicon signaling, which is modulated by the microRNA miR-6012, regulates features of polyphenism related to the exoskeleton, although it is less clear what the upstream regulatory events are.

eLife Assessment

This study presents valuable findings on what networks of genes were impacted by introgression from Denisovans, to identify the biological functions involved in high-altitude adaptation in Tibet. This study applies solid and previously validated methodology to identify genes with signatures of both introgression and positive selection. This paper would be of interest to population geneticists, anthropologists, and scientists studying the genetic basis underlying high-altitude adaptation.

1. Humans have a very general ability to solve problems and achieve goals across diverse domains.
2. AI systems could become much more intelligent than humans.
3. If we create highly intelligent AI systems, their decisions will shape the future.
4. Highly intelligent AI systems won’t be beneficial by default.

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 competing models. The evidence supporting the authors' claims is solid, with well-executed comparisons. This work will be of particular interest to researchers in bioinformatics and structural biology, especially those focused on protein function and stability.

eLife assessment

This fundamental work provides creative and thoughtful analysis of rodent foraging behavior and its dependence on body reference frame-based vs world reference frame-based cues. Compelling evidence demonstrates that a robust map, capable of supporting taking novel shortcuts, is learned primarily if not exclusively based on self-motion cues, which has rarely if ever been reported outside of the human literature. The work, which will be of interest to a broad audience of neuroscientists, provides a rich discussion about the role of the hippocampus in supporting the behavior that should guide future neurophysiological investigations.

eLife Assessment

This fundamental work provides creative and thoughtful analysis of rodent foraging behavior and its dependence on body reference frame-based vs world reference frame-based cues. Compelling evidence demonstrates that a robust map, capable of supporting taking novel shortcuts, can be learned primarily if not exclusively based on self-motion cues, which has rarely if ever been reported outside of the human literature. The work, which will be of interest to a broad audience of neuroscientists, provides a rich discussion about the role of the hippocampus in supporting the behavior that should guide future neurophysiological investigations.

eLife Assessment

This valuable study addresses potential roles of the master regulator of X chromosome inactivation, the Xist long non-coding RNA, in autosomal gene regulation. Using data from mouse cells, the authors propose that Xist can coat specific autosomal promoters, which in turn leads to the attenuation of their transcriptional activity, complementing recently published results from humans. While the evidence from individual genes is suggestive, shortcomings in the data and statistical analyses leave the evidence currently incomplete. The work would be of interest to anyone studying gene regulation and noncoding RNAA

eLife Assessment

This study provides important insights into the mechanistic basis of neurological manifestations of RNA polymerase III-related disease by creating a mutant mouse to dissect transcriptional changes. The data provide compelling evidence for disease progression initiated by a global reduction in tRNA levels leading to integrated stress and innate immune responses and neuronal loss. The work will be of interest to those engaged in the study of chromosome biology, developmental biology and neurodegeneration.

eLife Assessment

This study aims to analyse the effect of polymorphism on meiotic recombination in subspecies of Saccharomyces. The detection of reciprocal and non-reciprocal events is based on sequencing the haploid products of meiosis, and frequencies are compared between strains having introgressed genomic segments and strains lacking such segments. Unfortunately, the method used are inadequate for quantifying the non-reciprocal events.

eLife Assessment

This study presents a valuable finding in understanding the role of plectin in the development and progression of hepatocellular carcinoma (HCC). The evidence supporting the conclusions is convincing because multiple orthogonal ways were used to demonstrate the requirement of this target in liver cancer models. However, the study is incomplete as the downstream molecular activities of plectin that mediate the cancer phenotypes were not fully evaluated.

eLife Assessment

This study presents a valuable examination of the prevalence of interactions between amino acids from different periods of Earth's history and coenzymes. While the premise of this work is well founded and the analysis is solid, with more data, the interpretation could change. This manuscript would be of interest to evolutionary biologists and biophysicists.

eLife Assessment

This revised study provides valuable information on the single nucleus RNA sequencing transcriptome, pathways, and cell types in pig skeletal muscle in response to conjugated linoleic acid (CLA) supplementation. Based on the comprehensive data analyses, the data are considered compelling and provide new insight into the mechanisms underlying intramuscular fat deposition and muscle fiber remodeling. The revised study clarifies major aspects of its methodology and analysis, addresses previous reviewer concerns, and contributes significantly to the understanding of nutritional strategies for fat infiltration in pig muscle.

eLife Assessment

This important study addresses two questions: (i) how danger signaling is altered for people with childhood adversities, and (ii) how this differs across different operationalizations of adversity. The latter is of particularly broad interest to multiple fields, given that childhood adversity is operationalized very differently across the literature. The study provides compelling evidence using a large sample size and rigorous statistical methods. These data will be of interest to scientists and clinicians interested in early life adversity, statistical approaches for quantifying stress exposure, or aversive learning.

eLife Assessment

This study explores the mechanistic link between glycosylation at the N162 site of the Fc gamma receptor FcγRIIIa and the modulation of NK cell-mediated antibody-dependent cytotoxicity. Using innovative isotope labeling strategies and advanced NMR spectroscopy techniques, the authors provide compelling evidence of how glycan composition influences receptor stability and immune function. These findings offer fundamental insights that may contribute to the development of more effective therapeutic antibodies. The manuscript will be of significant interest to immunologists and researchers focused on therapeutic antibody design.

eLife Assessment

This valuable study focuses on gene regulatory mechanisms essential for hindbrain development. Through molecular genetics and biochemistry, the authors propose a new mechanism for the control of Hox genes, which encode highly conserved transcription factors essential for hindbrain development. The strength of evidence is solid, as most claims are supported by the data. This work will be of interest to developmental biologists.

eLife Assessment

This work reports an important new method for activity-dependent neuronal labeling in Drosophila using in situ hybridization, with the potential to establish a new standard in the field. The authors demonstrate the method's applicability by generating compelling evidence of the function of male-specific neurons in both aggression and courtship behaviors. These results and the new method will be of great interest to the neuroscience community.

eLife Assessment

The manuscript by Kolbeck and co-workers is an important contribution to understanding the physical mechanism that controls a key step in the retroviral infectious cycle. The authors employ a wide range of experimental techniques, complemented with Montecarlo simulations, that result in convincing evidence of compaction of HIV DNA by the viral integrase. This manuscript would benefit from in-depth discussion and analysis of the biophysical implications of the results.

eLife Assessment

This valuable paper reports image analysis pipelines for the automated segmentation of micronuclei and the detection and sorting of micronuclei-containing cells, which could be powerful tools for researchers studying micronuclei. While the development of the pipelines is solid, a proof-of-principle experiment is not entirely conclusive and leaves open the possibility that additional refinements are required, which would be facilitated by a more detailed explanation of the methods used.

eLife Assessment

This manuscript provides valuable mechanistic insight into NSCLC progression, both in terms of tumour metastasis and the development of chemoresistance. The authors draw upon a range of techniques and assays and although the evidence shown is solid, suggestions by the two reviewers will strengthen the message. The work presented will be of interest to cancer biologists and more broadly to those interested in NSCLC translational studies.

eLife Assessment

This manuscript reports on the crystal structures of two glycosaminoglycan (GAG) lyases from the PL35 family, along with in vitro enzyme activity assays and comprehensive structure-guided mutagenesis. While the study provides structural insights into the broad substrate specificity of these enzymes, the incomplete structural models, lack of key data such as Mn²⁺ binding confirmation, and reliance on basic docking methods diminish the overall impact. Although the work is useful for specialists in carbohydrate-active enzymes, additional data, and more rigorous analysis are required to present a complete study.

eLife Assessment

In this potentially important study, the authors conducted extensive atomistic and coarse-grained simulations as well as a lattice Monte Carlo analysis to probe the driving force and functional impact of supercomplex formation in the inner mitochondrial membrane. The study highlighted the importance of membrane mechanics to the supercomplex formation and revealed differences in structural and dynamical features of the protein components upon complex formation. In its current form, the analysis is considered incomplete, especially concerning the contributions of membrane mechanics and allosteric coupling of key regions.

eLife Assessment

This manuscript presents a valuable finding on the impact of FRMD8 loss on tumor progression and the resistance to tamoxifen therapy. The author conducted systematic experiments to explore the role of FRMD8 in breast cancer and its potential regulatory mechanisms, confirming that FRMD8 affects tamoxifen resistance and convincingly validating this hypothesis through a series of experiments.

eLife Assessment

In this valuable manuscript, the authors propose that the lysosomal protein LAPTM4B plays a role in suppressing the TGF-β/SMAD signaling pathway and suggest that enhancing LAPTM4B function could be a potential therapeutic strategy for alleviating bleomycin-induced lung fibrosis. The findings will be of interest to the lung disease field, and the data presented to support the authors' conclusions is solid. However, it remains unclear whether the suppressive effect of LAPTM4b on idiopathic pulmonary fibrosis is mediated by Nedd4l.

eLife Assessment

This valuable study describes how a single effector of the Type Six Secretion System (T6SS) has two distinct enzymatic functions that together may contribute to bacterial survival and dynamics in a community and provide potential for developing new antimicrobial compounds. The authors have deployed a range of methods in biochemistry, microbiology, and microscopy, generating solid data that support the main assertions. While the manuscript could benefit from additional clarifying experiments and a more detailed discussion of the methods, it will appeal to those studying T6SS, particularly those interested in effectors and bacterial enzymes.

eLife Assessment

This work provides a potentially valuable framework for understanding the primary causes of disease. However, the evidence supporting the utility of the approach is incomplete given the reliance on strong assumptions about the underlying causal mechanisms.

eLife Assessment

In this work, the authors propose that astrocytic aquaporin 4 (AQP4) is the main pathway for tonic water efflux, without which astrocytes undergo cell swelling. These findings are important, because they shed light on key molecular mechanisms implicated with the regulation of brain water homeostasis. The authors use a broad set of experimental tools (e.g., acute brain slices, in vivo recording, and diffusion-weighted MRI) but the evidence remains incomplete without ruling out non-specific effects of TGN-020, and without evidence that changes in sulforhodamine B fluorescence can be used as reliable readouts of cell volume dynamics.

eLife Assessment

The authors utilized single-cell RNA-seq profiling of non-small cell lung cancer (NSCLC) patient tumor samples to generate useful insights into the determinants of immune checkpoint inhibitor (ICI) responsiveness in NSCLC patients. While some of the findings add weight to the current literature, the analysis is incomplete due to the small cohort size and heterogeneous population which has limited their ability to draw statistically supported conclusion after adjusting for multiple hypothesis testing, as well as the lack of functional characterization of the findings. This study would benefit from external cohorts to both validate the findings and justify the statistical analysis undertaken.

eLife Assessment

This comprehensive and compelling study presents a robust, cost-effective method for expanding pluripotent stem cells. The authors have identified a media condition that maintains iPSCs in suspension cultures by inhibiting the PKCβ and Wnt signaling pathways. The manuscript is important for the pluripotent stem cell field as it seeks robust and economical approaches to expand iPSCs at scale for high throughput screens and preclinical studies. While the authors have tested their media and protocol on a few lines, given the variability of iPSCs, further testing across more cell lines and in different laboratory settings will be crucial to evaluate its reproducibility.

eLife Assessment

This valuable study reports machine learning models derived from large-scale data to predict the risk of post-stroke epilepsy. The evidence supporting the conclusions is convincing, although there are some validation issues (lack of cross-validation, possible bias in external validation results). The study may be of interest in the field of clinical neurology

eLife Assessment

This important study provides interesting insights into the mechanisms of action of adjuvants. It shows that adjuvants, MPLA and CpG especially, modulate the peptide repertoires presented on the surface of antigen presenting cells, and surprisingly, adjuvant favored the presentation of low-stability peptides rather than high-stability peptides by antigen presenting cells. As a result, the low stability peptide presented in adjuvant groups elicits T cell response effectively. Evidence in support of these conclusions is solid, and this paper would be of interest to vaccinologists and immunologists.

eLife Assessment

This important work explores the modulation of pain by intense stress. The authors employed a series of cutting-edge techniques and provided convincing evidence suggesting that the dorsal lateral septum-> lateral hypothalamus-> rostral ventromedial medulla circuit is responsible for mediating stress-induced analgesia. This work will be of interest to neuroscientists interested in the neural circuits of behavior, and scientists interested in stress or pain.

eLife Assessment

This study uses C. elegans, a poikilothermic ("cold-blooded") animal, to investigate the interesting question of how cells and organisms adapt to prolonged exposure to cold temperature. The study employed ribosome profiling and RNAseq analyses and provides a useful inventory of genes changed in cold adapted nematodes. However, the overall conclusions that 1) translation is ongoing at a low rate and 2) IRE mediated transcriptional changes play a significant role in cold adaptation are incompletely supported by the evidence provided. The authors are encouraged to conduct additional bioinformatic analyses and rewrite the manuscript to more accurately reflect the evidence provided.

eLife Assessment

This important study develops a high throughput version of expansion microscopy that can be performed in 96-well plates. The engineered technology is convincing and compatible with standard microplates and automated microscopes and thus will be of broad interest. The application to hiPCS-derived cardiomyocytes treated with doxorubicin provides a solid proof-of-concept demonstrating the potential for high-throughput analysis.

eLife Assessment

This useful study examines relationships between tumor mutational burden and the response to immunotherapy, using new data sets along with publicly available data sets. The authors conclude that tumor mutational burden cut-offs are unreliable proxies for predicting the response to therapy, underpinned by solid evidence, but with several caveats and assumptions that leave the central question subject to further inquiry. In summary, this is an interesting study that adds to a growing body of work investigating the particular conditions governing the effectiveness of immunotherapy.

eLife assessment

This work presents a valuable new approach for self-supervised segmentation for fluorescence microscopy data, which could eliminate time-consuming data labeling and speed up quantitative analysis. The experimental evidence supplied is currently incomplete as the comparison with other methods is only done on a single dataset, lacks common metrics, and could not be easily reproduced for other sample data listed in the manuscript.

eLife Assessment

This valuable study combines agent-based modelling and in vivo experiments in medaka embryos to provide new insights into the role of the thymic niche in T cell development. The modelling yields some interesting findings regarding the importance of thymic epithelial cells, for some of which the evidence is incomplete. This study would be of interest to oncologists, immunologists, and mathematical modelers.

eLife Assessment

In this valuable study, the authors attempt to reconstruct the evolutionary history of a large and widespread group of freshwater fishes (Nemacheilidae) across Eurasia since the early Eocene, based on molecular phylogenetic analysis with very comprehensive samplings including 471 specimens belonging to 250 living species. The authors infer that range expansions of the family were facilitated by tectonic connections, favourable climatic conditions, and orogenic processes, adding to our understanding of the effects of climatic change on biodiversity during the Cenozoic. The molecular evidence is overall solid, but the calibration points from the fossil records used in the analysis have not been clearly demonstrated or cited; the different dates for the calibration points might impact the discussion on the evolutionary history relating to past climatic changes.

eLife Assessment

This study focuses on the regulation of GLP-1 in enteroendocrine L cells and how this may be stimulated by the mechanogated ion channel Piezo1 and the CaMKKbeta-CaMKIV-mTORC1 signaling pathway. The work is innovative and is considered valuable, as the hypothesis that is being tested may have significant mechanistic and translational implications. Data to support the proposed mechanism were considered incomplete, yet data to support the overall physiological characterization were considered solid.

eLife Assessment

This study investigates the role of Hox genes in determining the position of the forelimb bud using experimental loss- and gain-of-function approaches in chicken embryos, concluding that Hox4 and Hox5 provide permissive signals for forelimb formation throughout the neck region, while the final forelimb position is determined by the instructive signals of Hox6/7 in the lateral plate mesoderm. These results could potentially be fundamental to our understanding of Hox patterning. However, the evidence supporting these conclusions is incomplete; while the gain-of-function experiments are well supported, the loss-of-function experiments using dominant-negative constructs lack sufficient controls, and could be the result of an experimental artifact.

eLife Assessment

This important study provides insights into the role of maternal behavior in the learning and ontogeny of vocalization, finding evidence that the maternal behavior of sac-winged bats (Saccopteryx bilineata) can influence the learned territorial songs of their pups. The behavioral analyses are solid, although a more comprehensive and quantitative description of the babblings and the female displays would have strengthened the study. The work will interest biologists and neuroscientists studying vocal learning and its evolution.

eLife Assessment

These are valuable findings for those interested in how neural signals reflect auditory speech streams, and in understanding the roles of prediction, attention, and eye movements in this tracking. However, the evidence as it stands is incomplete. Further details are needed on how the observed quantities relate to the relevant theoretical claims and mathematical models. Moreover, additional motivation is required for several analytical choices.

eLife Assessment

This study provides convincing evidence that the Kinesin protein family member KIF7 regulates the development of the cerebral cortex and its connectivity and the specificity of Sonic Hedgehog signaling by controlling the details of Gli repressor vs activator functions. This study provides important new insights into general aspects of cortical development.

eLife Assessment

This is an important study demonstrating that cholecystokinin is a key modulator of auditory thalamocortical plasticity during development and in young adults but not aged mice, though the cortical application of this neuropeptide in older animals appears to go some way to restoring this age-dependent loss in plasticity. A strength of this work is the use of multiple experimental approaches, which together provide convincing support for the proposed involvement of cholecystokinin. Nevertheless, the specificity of the electrical and optical stimulation experiments requires further validation and some key details are missing in the presentation and discussion of these findings. This work is likely to be influential in opening up a new avenue of investigation into the roles of neuropeptides in sensory plasticity.

eLife Assessment

This important study highlights the key role of the gut-liver axis mediated by LPS in causing hepatic steatosis. The authors provide solid evidence, in vivo, in vitro, and in silico, for the role of acyloxyacyl hydrolase in mediating this effect using KO mice subjected to MASD-inducing diets. The findings are significant for the liver research community and others interested in the gut-liver axis.

eLife Assessment

This important study provides solid in-vivo evidence that CCR4 regulates the early inflammatory response during atherosclerotic plaque formation. The authors propose that altered T-cell response plays a role in this process, shedding light on mechanisms that may be of interest to medical biologists, biochemists, cell biologists, and immunologists. Further in vivo validation, mechanistic studies, and discussion of results in vitro suggested would be helpful to cement the significance and implications of these findings.

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 are discussed within a general framework that encompasses their research questions, hypotheses, and analysis of results. Although the choice of conditions and their influence on the results might accept different interpretations, the manuscript is strong and contributes beneficial insights to the field.

eLife Assessment

This valuable study provides convincing evidence that white matter diffusion imaging of the right superior longitudinal fasciculus might help to develop a predictive biomarker of chronic back pain chronicity. The results are based on a discovery-replication approach with different cohorts, but the sample size is limited. The findings will interest researchers interested in the brain mechanisms of chronic pain and in developing brain-based biomarkers of chronic pain.

eLife Assessment

By combining psychophysics and computational modelling based on the Theory of Visual Attention, this study examines the mechanisms underlying self-prioritization by revealing the influence of self-associations on early attentional selection. While the findings are important, the experimental evidence is incomplete. The relationship between consciousness (awareness) and attention, the potential contamination by arousal, the inconsistent and unexpected results, and the distinguishing between social and perceptual tasks need to be addressed or improved. The work will be of interest to researchers in psychology, cognitive science, and neuroscience.

eLife Assessment

This study describes a useful technique to improve imaging depth using confocal microscopy for imaging large, cleared samples. It is as yet unclear if their proposed technique presents a significant advance to the field since their comparisons to existing techniques remain incomplete. However, the work will be of broad interest to many researchers in different fields.

eLife Assessment

This valuable study investigates how biologically plausible learning mechanisms can support assembly formation that encodes statistics of the environment, by enabling neural sampling that is based on within-assembly connectivity strength. It convincingly shows that assembly formation can emerge from predictive plasticity in excitatory synapses, while two types of plasticity in inhibitory synapses are required: inhibitory homeostatic (predictive) plasticity and inhibitory competitive (anti-predictive) plasticity.

eLife Assessment

This timely and important study used functional near-infrared spectroscopy hyperscanning to examine the neural correlates of how group identification influences collective behavior. The work provides incomplete evidence to indicate that the synchronization of brain activity between different people underlies collective performance and that changes in brain activity patterns within individuals may, in turn, underlie this between-person synchrony. This study will be of interest to researchers investigating the neuroscience of social behaviour.

eLife Assessment

This important study challenges conventional life-history theory by demonstrating that reproductive-survival trade-offs are minimal in birds, except when reproductive effort is experimentally exaggerated. The evidence is solid, drawing from a meta-analysis of over 30 bird species, and effectively separates the effects of individual quality from reproductive costs. The findings will be of broad interest to evolutionary biologists and ecologists studying life-history trade-offs and reproductive strategies.

eLife Assessment

The manuscript provides useful findings to explore the heterogeneity of hematopoietic stem cells and age-related myeloid-biased hematopoiesis. The results presented in this study are incomplete and additional data are necessary to bolster the conclusions. Certain aspects of the methods, experimental design, and data analyses remain inadequate and only partially support the central claims.

eLife Assessment

This valuable study investigates both online responses to, and offline replay of, visual motion sequences. Sophisticated EEG analyses provide solid evidence for both feature-specific and non-specific sequence representations, though the explanation of the statistical methods used is currently incomplete.

eLife Assessment

This important study advances our understanding of the role of dopamine in modulating pair bonding in mandarin voles by examining dopamine signaling within the nucleus accumbens across various social stimuli using state-of-the-art causal perturbations. The evidence supporting the findings is compelling, particularly cutting-edge approaches for measuring dopamine release as well as the activity of dopamine receptor populations during social bonding. However, statistical analyses were found to lack rigor and clarity, and the lack of complementary experiments in females was noted as a weakness. Additionally, the manuscript would be strengthened by placing findings within a broader framework, such as by highlighting similarities and/or differences between mandarin and prairie voles.

eLife Assessment

This manuscript offers valuable information on the combinatory effect of small molecules, CHIR99021 and A-485 (2C), during the reprogramming of mature cardiomyocytes into regenerative cardiac cells on stimulating cardiac cell regeneration. Although the study used several hESC lines and an in vivo model of myocardial injury to demonstrate the regenerative potential of cardiac cells, the manuscript is still incomplete as several concerns remain unanswered, including the lack of validation of the conclusions from scRNA-seq. It is still unclear how a small fraction of dedifferentiating cardiac cells can offer such broad effects on regeneration both in vitro and in vivo. If validated, this study might unlock potential therapeutic strategies for cardiac regeneration.

eLife Assessment

This valuable article represents a significant body of work that addresses some novel aspects of the biology of lung cancer, the overall influence of CHIP and its impacts on responses to therapy. While a high clonal hematopoiesis (CHIP) burden was previously linked with an inflammatory phenotype in other disease settings, the authors demonstrate with solid evidence that this is also true for lung cancer. CHIP is complex and more data will be required to substantiate more evidence with regard perhaps to specific mutations in certain situations and how this might influence therapy choices.

eLife Assessment

This work is of fundamental significance and has an exceptional level of evidence for a new population that protects against obesity-induced hypothalamic inflammation. This topic will attract attention from a broad base of readers, from hypothalamic neuroscientists to immunologists with an interest in metabolism.

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 important work substantially advances our understanding of RNA structure analysis by introducing an innovative method that extends DMS probing to include guanosine residues, thereby enhancing our ability to detect complex tertiary interactions. The evidence supporting the conclusions is compelling, with detailed analyses demonstrating the method's capacity to differentiate structural contexts and improve RNA structure predictions. This work will be of broad interest to RNA structural biology, biochemistry, and biophysics researchers.

eLife Assessment

This study by Graca et al. explores ethanol metabolism pathways in mycobacteria. The enzyme, MftG, a flavoprotein dehydrogenase, is shown to act as an electron shuttle between an uncommon redox cofactor and the electron transport chain thereby regenerating mycofactocin. Whilst this study was conducted in Mycobacterium smegmatis, the findings are important and have general implications for elucidating broader mycobacterial metabolism. Overall, the data presented are convincing supported by well-designed experiments.

eLife Assessment

This important, clearly written, and timely manuscript links the timing of ART with the kinetics of total and intact proviral HIV DNA. The conclusions are interesting and somewhat novel, and the importance of the work is high because the focus is on African women and clade C virus, both of which are understudied in the HIV reservoir field. The strength of the evidence is convincing. Overall, this work will be of very high interest to scientists and clinicians in the HIV cure/persistence fields.

eLife Assessment

This study reports an important finding on the mechanism underlying the enhancement of anti-viral immune responses by febrile temperatures, especially the role of the conserved heat-shock factor, HSF-1. The data provide compelling support for the authors' model wherein increased temperature in the shrimp Litopenaeus vannamei activates HSF1, which in turn enhances anti-viral response via up-regulation of the nSWD protein and antibacterial peptides. The work, which will be of interest to virologists, immunologists, and cell biologists, would benefit from more discussion of the function and roles of HSF-1 at 25°C vs. 32°C.

eLife Assessment

In this important study, the authors set out to investigate the biogenesis of extracellular vesicles in mycobacteria and provide several observations to link VirR with vesiculogenesis, PG metabolism, lipid metabolism, and cell wall permeability. Whilst some of the evidence provided is convincing, there are still some shortcomings in the revised manuscript where the data to support the proposed mechanism remain incomplete. The work will be of interest to bacteriologists.

eLife Assessment

This fundamental work advances our understanding of the mechanisms underlying lactation-induced infertility. Compelling evidence supports the notion that prolactin inhibits kisspeptin activity and LH pulsatile release and that loss of this signal results in an early reestablishment of fertility during lactation. This work will be of interest to endocrinologists and reproductive biologists.

eLife Assessment

In this useful study, Wang and colleagues investigate the potential probiotic effects of Bacillus velezensis in a murine model. They provide convincing evidence that B. velezensis limits the growth of Salmonella typhimurium in lab culture and in mice, together with beneficial effects on the microbiota. The overall presentation of the manuscript has improved and the work will be of interest to infectious disease researchers.

eLife Assessment

This study reports the fundamental discovery of a novel structure in the developing gut that acts as a midline barrier between left and right asymmetries. Some of the evidence supporting the dynamics, composition, and function of this novel basement membrane in the chick is solid, some is even convincing, but investigation of its origin and impact on asymmetric organogenesis remains challenging and is not yet conclusive. This careful work is of broad relevance to patterning mechanisms, the importance of the extracellular matrix, and laterality disorders.

eLife Assessment

This potentially useful study introduces an orthogonal approach for detecting RNA modification, without chemical modification of RNA, which often results in RNA degradation and therefore loss of RNA molecules. While the authors have improved the work compared to a previous version, uncertainty regarding false positive and false negative rates leave the evidence for the broad applicability of the method incomplete. If properly validated, the approach might be of particular interest for sites where modifications are rare.

eLife Assessment

This interesting study focuses on a previously reported positive correlation between translational efficiency and protein noise. This is unexpected as typically noise is inversely related to expression and increasing translation efficiency would increase the protein expression and thus be expected to reduce noise in gene expression. Using mathematical modeling and analysis of experimental data the authors argue that this phenomenon arises due to ribosomal demand. However, the work appears incomplete, with the reviewers having raised questions regarding the validity of the assumptions used in the mathematical model as well as the clarity of the presentation.

eLife Assessment

This work presents a valuable finding on how the interplay between transcription factors SOX2 and OCT4 establishes the pluripotency network in early mouse embryos. Despite the high quality of the data, the evidence supporting the claims of the authors is currently incomplete and would benefit from more omics analysis such as H3K4me1 and H3K27ac CUT&Tag. The work will be of interest to biologists working on embryonic development.

eLife Assessment

This valuable study provides a detailed picture of the synapse distributions for a set of visual projection neurons and their downstream partners, in combination with multi-compartmental modelling fitted to electrophysiological data. The model reveals interesting consequences of synapse topography for neuronal computation. The analysis, however, seems incomplete as the authors only analyze passive models of these spiking neurons, and do not attempt to connect their analysis to the bigger picture at the behavioral level.

eLife Assessment

This valuable study on strategies used by Pseudomonas to subvert hots immunity identifies a new immune evasion strategy. The study presents solid evidence on the cleavage of VgrG2B by Caspase 11 and the generation of fragments that inhibit activity of the NLRP3 inflammasome. This work should be of interest to immunologists and microbiologists.

eLife Assessment

Wang et al's study addresses an important critical gap in our understanding of de novo epithelial polarization using MDCK cell doublets surrounded by ECM, providing convincing evidence through imaging and depletion studies on the role of conserved polarity proteins and the centrosome during this process. While the authors propose a clear hierarchical model, there is a need for further exploration of how microtubule organization contributes to this process. Specifically, live cell imaging of microtubules under mutants and their included ECM conditions, along with a more precise temporal mapping of microtubule dynamics in relation to proteins like Gp135, would strengthen the study's conclusions.

eLife Assessment

This important study shows that Toxoplasma gondii uses paracrine mechanisms, in addition to cell-intrinsic methods, to evade the host immune system, with MYR1 playing a key role in transporting effector molecules into host cells. The authors present convincing evidence that in vivo, MYR1-deficient parasites can be rescued by wild-type parasites, revealing a limitation in pooled CRISPR screens, where such paracrine effects may obscure the identification of key parasite pathways involved in immune evasion.

eLife Assessment

This important study reports a detailed quantification of the population dynamics of Salmonella enterica serovar Typhimurium in mice. Bacterial burden and founding population sizes across various organs were quantified, revealing pathways of dissemination and reseeding of the gastrointestinal tract from systemic organs. Using various techniques, including genetic distance measurements, the authors present compelling evidence to support their conclusions, thus presenting new knowledge that will be of broad interest to scientists focusing on infectious diseases.

eLife Assessment

This important study uses a large dataset from both recent isolates and genomes in databases to provide an analysis of the population structure of the pathogen Salmonella gallinarum. The results regarding regional adaptation and the evolutionary trajectory of the resistome and mobilome remain incomplete, requiring additional details to fully support their claims and assess the value of these insights for future policy interventions regarding this and other pathogens. This work will interest microbiologists and researchers working on genomics, evolution, and antimicrobial resistance.

eLife Assessment

This study provides important information on pre-existing epigenetic modification in T cell plasticity. The evidence supporting the conclusions is compelling, supported by comprehensive transcriptional and epigenetic analyses. The work will be of interest to immunologists and colleagues studying transcriptional regulation.

eLife Assessment

The authors have developed a valuable approach that employs cell-free expression to reconstitute ion channels into giant unilamellar vesicles for biophysical characterisation. The work is convincing and will be of particular interest to those studying ion channels that primarily occur in organelles and are therefore not amenable to be studied by more traditional methods.

eLife Assessment

This important study reveals insights into how calcineurin influences C. elegans pathogen susceptibility and lifespan through its role in controlling the defecation motor program. The authors provide convincing evidence to support a new mechanism through which calcineurin impacts longevity. This work will be of interest to investigators studying host-pathogen interactions and aging in a number of experimental systems.

eLife Assessment

This important study presents a high-resolution cryoEM structure of the supercomplex between photosystem I (PSI) and fucoxanthin chlorophyll a/c-binding proteins (FCPs) from the model diatom Thalassiosira pseudonana CCMP1335, revealing subunits, protein:protein interactions and pigments not previously seen in other diatoms or red/green photosynthetic lineages. Combining structural, sequence and phylogenetic analyses, the authors provide convincing evidence of conserved motifs crucial for the binding of FCPs, accompanied by interesting speculation about the mechanisms governing the assembly of PSI-FCP supercomplexes in diatoms and their implications for related PSI-LHC supercomplexes in plants. The findings set the stage for functional experiments that will further advance the fields of photosynthesis, bioenergy, ocean biogeochemistry and evolutionary relationships between photosynthetic organisms.

eLife Assessment

This valuable study provides convincing evidence that mutant hair cells with abnormal, reversed polarity of their hair bundles in mouse otolith organs retain wild-type localization, mechanoelectrical transduction and firing properties of their afferent innervation, leading to mild behavioral dysfunction. It thus demonstrates that the bimodal pattern of afferent nerve projections in this organ is not causally related to the bimodal distribution of hair-bundle orientations, as also confirmed in the zebrafish lateral line. The work will be of interest to scientists interested in the development and function of the vestibular system as well as in planar-cell polarity.

eLife Assessment

The authors describe a model for tracking time-varying functional connectivity between neurons from multi-electrode spike recordings. This is an interesting and potentially useful approach to an open problem in neural data analysis, and could be an essential tool for investigating the neural code from large-scale in-vivo recordings of spiking activity. However, the evidence is incomplete: systematic comparisons with existing methods and/or demonstration of its utility relative to conventional methods are essential to demonstrate the usefulness of the method.

eLife Assessment

This work provides an important and novel framework for interpreting the interactions between recurrent dynamics across stages of neural processing. The authors report that two different kinds of dynamics exist in recurrent networks differing in the extent to which they align with the output weights. The authors also present convincing evidence that both types of dynamics exist in the brain.

eLife Assessment

This study presents useful findings on the role of the small GTPase Rab3A in homeostatic synaptic plasticity following activity suppression. While the study demonstrates that Rab3A is required for homeostatic scaling, the evidence supporting the model put forward by the authors is incomplete. The work will be of interest to the field of synaptic transmission and synaptic plasticity.

eLife Assessment

This study provides important findings that during credit assignment, the lateral orbitofrontal cortex (lOFC) and hippocampus (HC) encode causal choice representations, while the frontopolar cortex (FPl) mediates HC -lOFC interactions when the causality needs to be maintained over longer distractions. While this research offers compelling evidence and employs sophisticated multivariate pattern analysis, there are some concerns regarding a) task design which may have oversimplified real-world credit assignment complexities, and b) the interpretation of results. This work will be of interest to cognitive and computational neuroscientists who work on value-based decision-making and fronto-hippocampal circuits.

eLife Assessment

The study from Frank and colleagues reports potentially important cryo-EM observations of mouse glutamatergic synapses isolated from adult mammalian brains. The authors used a combination of mouse genetics to generate PSD95-GFP labeling in vivo, a rapid synaptosome isolation and cryo-protectant strategy, and cryogenic correlated light-electron microscopy (cryoCLEM) to record tomograms of synapses, which together provide convincing support for their conclusions. Controversially, the authors report that forebrain glutamatergic synapses do not contain postsynaptic "densities" (PSD), a defining feature of synapse structure identified in chemically-fixed and resin-embedded brain samples. The work questions a long-standing concept in neurobiology and is primarily of interest to specialists in synaptic structure and function.

eLife Assessment

This important study provides new and nuanced insights into the evolution of morphs in a textbook example of Batesian mimicry. The evidence supporting the claims about the origin and dominance relationships among morphs is convincing, but the interpretation of signals needs improvement with complementary analysis and some nuanced interpretation. Pending a revision, this work will be of interest to a broad range of evolutionary biologists.

eLife Assessment

This important study advances our understanding of the temporal dynamics and cortical mechanisms of eye movements and the cognitive process of attention. The evidence supporting the conclusions is convincing and based on measuring the time course of the eye movement-attention interaction in a novel, carefully-controlled experimental task. This study will be of broad interest to psychologists and neuroscientists interested in the dynamics of cognitive processes.

eLife Assessment

This study reports differences in proteomic profiles of embryonic versus induced pluripotent stem cells. This important finding cautions against the interchangeable use of both types of cells in biomedical research, although the mechanisms responsible for these differences remains unknown. The proteomic evidence is convincing, even though there is limited validation with other methods.

eLife Assessment

The main idea tested in this work is that host galectin-9 inhibits Mycobacterium tuberculosis (Mtb) growth by recognizing the Mtb cell wall component arabinogalactan (AG) and, as a result, disrupting mycobacterial cell wall structure. Moreover, a similar effect is achieved by anti-AG antibodies. While the hypothesis is intriguing and the work has the potential to make a valuable contribution to Mtb therapy, the evidence presented is incomplete and does not explain several critical points including the dose-independent effect of galectin-9 on Mtb growth and how anti-AG antibodies and galectin-9 access the AG layer of intact Mtb.

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 valuable study provides a novel method to detect sleep cycles based on variations in the slope of the power spectrum from electroencephalography signals. The method, dispensing with time-consuming and potentially subjective manual identification of sleep cycles, is supported by solid evidence and analyses but some aspects could be better illustrated and the source of the discrepancies between classical and fractal cycles should be identified. This study will be of interest to researchers and clinicians working on sleep and brain dynamics.

eLife Assessment

Liu and colleagues' study provides important insights into the neural mechanisms of narrative comprehension by identifying three distinct brain states using a hidden Markov model on fMRI data. The work is compelling, as it demonstrates that the dynamics of these brain states, particularly their timely expression, are linked to better comprehension and are specific to spoken language processing. The study's robust findings, validated in a separate dataset, will be of broad interest to researchers exploring the neural basis of speech and language comprehension, as well as those studying the relationship between dynamic brain states and cognition.

eLife assessment

This study seeks to expand the understanding of insulin and glucose responses in the brain, specifically by implicating a family of protein kinases responsive to insulin. The significance of the study to the field is valuable. The evidence supporting the conclusions about brain glucose utilization is convincing, although there are several aspects that could benefit from additional validation to strengthen the claims.

eLife Assessment

This important study examines the stability and compensatory plasticity in the retinotopic mapping in patients with congenital achromatopsia. It provides convincing evidence for a stable mapping of the visual field in V1, alongside changes of the readout from V1 into V3, which shows revised receptive field location and size. With the controlling for potential confounding variables, this paper would be of interest to scientists studying the visual system, brain plasticity, and development.

eLife Assessment

This work provides important findings characterizing potential synaptic mechanisms supporting the role of midline thalamus-hippocampal projections in fear memory extinction in mice. The methods and approaches used were solid. However, the evidence itself is incomplete, as there are concerns with whether the findings fully support the conclusions drawn.

eLife Assessment

This valuable report describes the changing antiviral activity of IFIT1 across mammals and in response to distinct viruses, likely as a result of past arms races. One of the main strengths of the manuscript is the breadth of mammalian IFIT1 orthologs and viruses that were tested. Overall the evidence is solid, but the analysis of positive selection could benefit from more thorough validation with complementary selection tests and also from assessing or more extended discussion of the impact of recombination and/or physical interactions with other IFITs.

eLife Assessment

This valuable study reports on a novel role of PD-1 in early T cell differentiation, showing that PD-1 stimulation impairs Th2 differentiation more effectively than that of Th1, with implications for the treatment of allergies. However, whereas the series of well-designed experiments using OVA-specific CD4 T cells from DO.11.10 mice and the use of an allergy model generated compelling data, the study is still incomplete since it shows gaps in the rationale for the experimental protocols, contradictory data regarding IFN-gamma and IL-4 production, and the lack of in vivo experiments on Th2 differentiation to further support the main hypothesis. Nonetheless, the reported data would be of interest to immunologists working on T cell differentiation and allergy.

eLife Assessment

The presented soft tissue data of pterosaur tail vanes represent a valuable contribution to ongoing research efforts to decipher the flight abilities of pterosaurs in the fields of paleontology, comparative biomechanics, and bioinspired design. The new methods are compelling and give new detail on tail morphology that has the potential to resolve how pterosaurs were able to control and maintain tail stiffness to furnish flight control.

eLife Assessment

This study presents numerical results on a potentially useful framework for understanding the dynamics of subthreshold waves in a network of electrical synapses modeled on the connectome data of the C elegans nematode. However, the strength of the evidence presented in favor of interference effects being a major component in subthreshold wave dynamics is inadequate.

eLife Assessment

Gil Ávila et al. evaluated the aperiodic component in the medial prefrontal cortex using resting-state EEG recordings from 149 individuals with chronic pain and 115 healthy participants. The authors present compelling evidence that the aperiodic component of the EEG does not differentiate between those with chronic pain and healthy individuals. The study was well-designed and rigorously conducted, and the clear and conclusive results provide important insights that can guide future research in the field of pain neuroscience.

eLife Assessment

This important study presents results for the theory of odor coding in hyperbolic spaces by revealing spiral trajectories in the dynamics of odors during natural, ethologically relevant processes such as ripening. In the current manuscript, the strength of the evidence is solid and would be strengthened by answering several technical points raised by reviewers.

eLife Assessment

This technical study presents a novel sampling strategy for detecting synaptic coupling between neurons from dual pipette patch-clamp recordings in acute slices of mammalian brain tissue in vitro. The authors present solid evidence that this strategy, which incorporates automated patch clamp electrode positioning and cleaning for reuse with strategic neuron targeting, has the potential to substantially improve the efficiency of neuronal sampling with paired recordings. This technique and the extensions discussed will be useful for neuroscientists wanting to apply or already conducting automated multi-pipette patch clamp recording electrophysiology experiments in vitro for neuron connectivity analyses.

eLife Assessment

This important study provides proof of principle that C. elegans models can be used to accelerate the discovery of candidate treatments for human Mendelian diseases by detailed high-throughput phenotyping of strains harboring mutations in orthologs of human disease genes. The data are compelling and support an approach that enables the potential rapid repurposing of FDA-approved drugs to treat rare diseases for which there are currently no effective treatments. The authors should provide a clearer explanation of how the statistical analyses were performed, as well as a link to a GitHub repository to clarify how figures and tables in the manuscript were generated from the phenotypic data.

eLife Assessment

This valuable study explores the sequence characteristics and conservation of high-occupancy target loci, regions in the human genome such as promoters and enhancers that are bound by a multitude of transcription factors. The computational analyses presented in this study are solid. This study would be a helpful resource for researchers performing ChIP-seq based analyses of transcription factor binding.

eLife Assessment

This important study identifies biallelic variants of DNAH3 in unrelated infertile men and reports infertility in DNAH3 knockout mice. The authors demonstrate that compromised DNAH3 activity decreases the expression of IDA-associated proteins in the spermatozoa of human patients and knockout mice, providing convincing evidence that DNAH3 is a novel pathogenic gene for asthenoteratozoospermia and male infertility. The study will be of substantial interest to clinicians, reproductive counselors, embryologists, and basic researchers working on infertility and assisted reproductive technology.

eLife Assessment

This study, which proposes a new role of ATG6 in plant immune response, makes a valuable contribution to our understanding of plant immunity. The results suggest a direct interaction between ATG6 and NPR1, a salicylic acid receptor protein, and they will be of interest to scientists studying the regulation of plant immunity. The data presented are convincing, although the discrepancies between data from fluorescence microscopy and protein blots, particularly in the interpretation of ATG6-mCherry fusion proteins. Addressing these inconsistencies would enhance the study's overall impact.

eLife Assessment

This important work substantially advances our understanding of nocturnal animal navigation and the ways that animals use polarized light. The evidence supporting the conclusions is convincing, with elegant behavioural experiments in actively navigating ants. The work will be of interest to biologists working on animal navigation or sensory ecology.

eLife Assessment

In this compelling study, the authors examine the interactions between stellate cells and PV+ interneurons in the medial entorhinal cortex. Huang et al. focus on the spatial distribution of synaptic inputs and demonstrate that closely located neuron pairs receive common inputs, suggesting a structured functional organization in the entorhinal cortex. Advanced dual whole-cell patch recordings further reveal patterns of postsynaptic activation, indicating intensive interactions within clusters of these neurons, with weaker interactions between clusters. These findings offer significant insights into the functional dynamics of the entorhinal cortex and the circuit mechanisms that shape grid cell activity. This study is important not only for the field of MEC and grid cells, but also for broader fields of continuous attractor networks and neural circuits.

eLife Assessment

The research has the potential to be a valuable addition to the field, and the conclusions are solid, but there is a need for more reproducible data to address existing discrepancies and enhance its impact.

eLife Assessment

The authors tested the hypothesis that age-dependent factors in human sera affect the core circadian clock or its outputs in cultured fibroblasts, and they provide compelling evidence that genes involved in the cell cycle and transcription/translation remain rhythmic in both conditions, genes associated with oxidative phosphorylation and Alzheimer's Disease lose rhythmicity in the aged condition, while the expression of cycling genes associated with cholesterol biosynthesis increase in the cells entrained with old serum. Together, the findings suggest that yet to be identified age-dependent blood-borne factors affect circadian rhythms in the periphery. The paper provides fundamental insights and a possible explanation for previous observations showing that circadian gene expression in peripheral tissues tends to dampen or phase-shift with age.

eLife Assessment

The manuscript represents a valuable conceptual and technical contribution to our understanding of ciliogenesis and intraflagellar transport in vertebrates. Through a series of solid and technically superb live imaging experiments to directly visualize intraflagellar transport in various zebrafish ciliated tissues, the authors unveil the surprising breadth of intraflagellar transport speed among differing organs and link this to cell type-specific differences in cilia length and intraflagellar transport train size. This work will be of broad interest to researchers in numerous fields, including development, cell biology, and imaging.

eLife Assessment

This study provides an important resource by thoroughly benchmarking multiple sequencing-based tRNA quantification methods. The suggested best practice is supported by convincing evidence from in silico experiments in multiple scenarios.