eLife assessment

This fundamental study uncovers the detailed structural mechanisms by which covalent and non-covalent synthetic ligands can simultaneously occupy the binding pocket of the nuclear receptor transcription factor PPARγ. Supported by a compelling set of structural, biochemical, and biophysical data, the findings challenge the reliability of two widely used covalent inhibitors and have broader implications for nuclear receptor research. This study will interest structural biologists and biochemists investigating the binding mechanisms of ligands targeting the nuclear receptor superfamily.

eLife assessment

The authors' innovative use of single-cell sequencing combined with physiological phenotyping of 5 different Parkinsons models in Drosophila provides compelling support for the important conclusion that these different models have a shared convergent effect on olfactory projection neuron (OPN) dysfunction. The effect on OPN occurs early in disease progression, and likely underlies anosmia observed as an early symptom of PD. Additional experiments and analysis are required to support the authors' suggestions that: (a) the defect in these models is specific to cholinergic OPNs; (b) that OPN degeneration is (causally) connected to dopaminergic neuron (DAN) degeneration; and also (c) that observed motor defects are reasonable measure of DAN dysfunction.

eLife assessment

This study uses state-of-the-art methods to label endogenous dopamine receptors in a subset of Drosophila mushroom body neuronal types. The authors report that DopR1 and Dop2R receptors, which have opposing effects in intracellular cAMP, are present in axons termini of Kenyon cells, as well as those of two classes of dopaminergic neurons that innervate the mushroom body indicative of autocrine modulation by dopaminergic neurons. Additional experiments showing opposing effects of starvation on DopR1 and DopR2 levels in mushroom body neurons are consistent with a role for dopamine receptor levels increasing the efficiency of learned food-odour associations in starved flies. Supported by solid data, this is a valuable contribution to the field.

eLife assessment

This important work, leveraging state-of-the-art whole-night sleep EEG-fMRI methods, advances our understanding of the brain states underlying sleep and wakefulness. Despite a small sample size, the authors present convincing evidence for substates within N2 and REM sleep stages, with reliable transition structure, supporting the perspective that there are more than the five canonical sleep/wake states.

eLife assessment

This study presents a valuable finding that PRMT inhibitors may exert synergistic effects with PARP inhibitors to eliminate ovarian and triple-negative cancer cells in vitro and in vivo using preclinical mouse models. The evidence supporting the claims of the authors is solid, although the inclusion of novelty justification would have strengthened the study. The work will be of interest to scientists working on breast cancer and ovarian cancer.

eLife assessment

This fundamental study identifies protein kinases in the parasitic protozoan, Toxoplasma gondii that are required for parasite invasion of host cells and differentiation to drug-resistant chronic stages. The use of advanced proteomic and functional approaches provides compelling evidence for the proposed signalling pathway, although additional analyses are needed to fully validate some findings. The work will be of broad interest to cell biologists and parasitologists with an interest in cell signalling and environmental sensing.

eLife assessment

This study presents the valuable finding that TFIIIC interacts with MYCN to regulate RNA polymerase II dynamics by dissecting its impact on 3D chromatin architecture. Authors provide convincing evidence that MYCN and TFIIIC show long-range chromatin contacts, and that the expression of each protein limits the function of the other. The notion emerges that TFIIIC helps MYCN to maintain output at promoters while decreasing less productive associations at larger more extensively connected chromatin hubs. The paper is of interest to molecular biologists working on MYCN-dependent regulation of gene expression.

eLife assessment

This important study presents new knowledge of the spermatogonial stem cell (SSC) niche in trans women after gender-affirming hormone therapy (GAHT). The evidence supporting the claims is convincing. The work will be of interest to researchers and clinicians working in the field of reproductive medicine and andrology.

eLife assessment

This is a valuable manuscript that successfully integrates several datasets to determine genome interactions with several nuclear bodies. The integrative datasets are a major strength of the manuscript. The evidence supporting the central claims is varied in its strength ranging from solid to incomplete. Orthogonal evidence validating the novel methodologies with alternative approaches would better support the central claims. We encourage the authors to consider a revised manuscript which addresses these points.

eLife assessment

This study provides useful insights into the conformational dynamics of the nucleic acid recognition lobe of GeoCas9, a thermophilic Cas9 from Geobacillus stearothermophilus. The influence of local dynamics and allosteric regulation on guide RNA binding affinity and DNA cleavage specificity is investigated via cutting-edge NMR approaches and mutagenesis. While backed by rigorous biophysical analyses, evidence supporting the proposed mechanistic model is found to be incomplete due to the limited impact of the studied mutations on GeoCas9 cleavage activity. This work will be of interest to biochemists and biophysicists interested in interdomain communication and allosteric mechanisms in Cas9 enzymes.

eLife assessment

This study offers a useful advance by introducing a cord blood DNA methylation score for maternal smoking effects, with the inclusion of cohorts from diverse backgrounds. However, the overall strength of evidence is deemed incomplete, due to concerns regarding low exposure levels and low statistical power, which hampers the generalisability of their findings. The study provides an interesting basis for future studies, but would benefit from the addition of more cohorts to validate the findings and a focus on more diverse health outcomes.

eLife assessment

This paper investigates how the EWS::FLI1 fusion protein organizes chromatin topology and regulates gene expression in an aggressive pediatric bone cancer known as Ewing sarcoma. The authors used the most recent genomics methodologies to provide solid-based evidence for the role of a short alpha helix in the DNA binding domain of FLI1 in modulating binding to GGAA microsatellites and promoting enhancer activity. The study provides valuable insight into the underlying oncogenic mechanisms in Ewing sarcoma, despite the inherent limitations of the some of the techniques used.

eLife assessment

This useful study uses fluorescence lifetime imaging (FLIM) and tmFRET to resolve resting vs. active conformational heterogeneity and free energy differences driven by cGMP and cAMP in a tetrameric arrangement of isolated CNBDs from a prokaryotic CNG channel. The data are compelling and the experimental approach features rigorous new methods and analyses. Limitations include (1) only the cytosolic fragments of the channel were studied; (2) the results are not adequately discussed in the context of the extensive prior literature about conformational dynamics and energetics of CNBD-containing ion channels; (3) ambiguity in the stoichiometry of labeled:unlabeled subunits; and (4) the lack of a discussion of alternative interpretations of the data. The study will be of interest to scientists working on the structural mechanisms of membrane proteins.

eLife assessment

The study presents a framework viewing gene-by-environment (GxE) effect estimation as a bias-variance tradeoff problem. The authors convincingly show that greater statistical power can be achieved in detecting GxE if an underlying model of polygenic GxE is assumed. This polygenic amplification model is a truly novel view with fundamental promise for the detection of GxE in genomic datasets. That said, at present the polygenic architecture investigation presented in the manuscript is somewhat limited to specific models and may not adequately build over the bias-variance tradeoff part of the manuscript. If the authors can show in their simulations that they can in principle detect more complex scenarios of amplification, then the strength of the paper would be enhanced.

eLife assessment

This valuable study explores T cell receptor activation during autoreactive T cell development and how the strength of T cell receptor engagement in naïve cells can predispose T cells to develop into effector/memory T cells. Solid evidence confirms published data that naïve T cells with higher CD5 expression were poised for activation and more pathogenic in the mouse model of autoimmune diabetes. However, the evidence regarding the regulation of differentiation of these cells during development is still incomplete.

eLife assessment

The present study provides valuable information into the regulatory mechanisms through which conjugated linoleic acids influence intramuscular fat deposition and muscle fiber transformation in pigs. The data are analyzed comprehensively using solid and validated single nuclei methodology. Overall, the provided data are convincing and support the conclusion of the study.

eLife assessment

This valuable article represents a significant body of work that addresses some novel aspects of the biology of lung cancer influence of CHIP and its impacts on responses to therapy. While a high clonal hematopoiesis 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.

eLife assessment

This important study using Drosophila genetics explores the role of TRPγ in Dh44 neuroendocrine cells for lipid and protein metabolism. Evidence for lipid storage and metabolism measured by triacylglycerol levels, lipid droplet size, and starvation resistance are generally solid to support the conclusion. However, the claim on the TRPγ functions in Dh44R2 is still unclear, as the analysis of the role and expression of Dh44R2 in the gut is incomplete.

eLife assessment

This study investigates the molecular mechanisms underlying chronic pain-related memory impairment by focusing on S1P/S1PR1 signaling in the dentate gyrus (DG) of the hippocampus. Through behavioral tests (Y-maze and Morris water maze) and RNA-seq analysis, the researchers discovered that S1P/S1PR1 signaling is crucial for determining susceptibility to memory impairment, with decreased S1PR1 expression linked to structural plasticity changes and memory deficits. This work has valuable significance and a convincing level of evidence, thus offering new insights into the mechanisms underlying chronic pain-related memory impairment.

eLife assessment

This important work uses an innovative approach to understand similarities between haemodynamic and electrophysiological activity of the human brain. The study provides incomplete evidence to indicate that while similar functional brain networks are used in both modalities, there is a tendency for these multi-modal networks to spatially converge at synchronous rather than asynchronous time points. This work will be of interest to neurophysiological and brain imaging researchers.

eLife assessment

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

eLife assessment

The work by Han and collaborators describes valuable findings on the role of Akkermansia muciniphila during ETEC infection. If confirmed, these findings will add to a growing list of beneficial properties of this organism. However, as it stands, the strength of the evidence used to justify the conclusions in the manuscript is incomplete.

eLife assessment

This valuable work explores death coding data to understand the impact of COVID-19 on cancer mortality. The work provides solid evidence that deaths with cancer as a contributing cause were not above what would be expected during pandemic waves, suggesting that cancer did not strongly increase the risk of dying of COVID-19. These results are an interesting exploration into the coding of causes of death that can be used to make sense of how deaths are coded during a pandemic in the presence of other underlying diseases, such as cancer.

eLife assessment

This work will be of interest to the motor control community as well as neuroAI researchers interested in how bodies constrain neural circuit function. The authors present "MotorNet", a useful software package to train artificial neural networks to control a biomechanical model of an effector. The manuscript provides solid evidence that MotorNet is easy to use and can reproduce past results in the field, both at the neural and behavioural levels. Validation is limited to planar arm-like plants or point-masses, so future work exploring three-dimensional movements and other types of plants would strengthen the impact of the tool.

eLife assessment

This important study reveals the role of skin-resident mast cells in amphibians in mediating antimicrobial responses. The data are compelling and highlight species-specific biology that can cross-inform human mast cell biology in a species that does not rely on IgE as a primary mechanism for antimicrobial skin responses.

eLife assessment

This work provides a valuable characterization of neural activity in the anterior insular cortex during fear. Using behavior, single unit recording, and optogenetic control of neural activity, the paper provides convincing data on the role of anterior insular circuits in bidirectionally controlling fear. The study is a great starting point on the path to testing hypotheses about bidirectional control of behavior via neural activity in anatomically defined output populations.

eLife assessment

This important study reports that FBXO24 is essential for the normal formation and function of the sperm flagellum, motility, and male fertility in mice. The evidence supporting the direct role of this protein in preventing RNP granule formation in the sperm flagellum is compelling. This work will be of interest to biomedical researchers who work on testicular biology and male fertility.

eLife assessment

This valuable study demonstrates that there is significant variation in the susceptibility of isoniazid-resistant Mycobacterium tuberculosis clinical isolates to killing by rifampicin, in some cases at the same tolerance levels as bona fide resistant strains. The evidence provided is solid, with no clear genetic marker for increased tolerance, suggesting that there may be multiple routes to achieving this phenotype. The work will be of interest to infectious disease researchers.

eLife assessment

This study presents valuable findings on the role of the sirtuins SIRT1 and SIRT3 during Salmonella Typhimurium infection. Although the work increases our understanding of the mechanisms used by this pathogen to interact with its host and may have implications for other intracellular pathogens, the reviewers found that the evidence to support the claims is incomplete. In particular, the discrepancy between results obtained using cultured cell lines and the animal model of infection, as well as potential indirect effects through the microbiome stand out.

eLife assessment

This valuable study combines prospective cohort, metabolomics, and machine learning to identify a panel of 9 circulating metabolites that improved the ability in risk prediction of progression from prediabetes to diabetes. The findings are solid and the methods, data, and analyses support the claims. However, the interpretation would benefit from a more rigorous description. With revision of these weaknesses, this paper would provide insights into the integration of these metabolites into clinical and public health practice.

eLife assessment

This study provides important findings regarding the stability over time of the response properties of neurons in the auditory cortex, including their nonlinear sensitivity to sound context. The data obtained from chronic recordings combined with nonlinear stimulus-response estimation provide convincing evidence that auditory cortical representations are stable over a period of days to weeks. While this study should be of widespread interest to sensory neuroscientists, the paper would be strengthened by a more thorough assessment and discussion of the effects of context and of the stability of the responses, as well as by the inclusion of more information about the location and types of neurons that were sampled.

eLife assessment

This study shows that a peptide called galanin can decrease or increase seizure activity in experimental models of seizures depending on the way seizures are induced (genetic vs. pharmacological). The authors use zebrafish and several methods to address the effects of galanin. The study will be useful to researchers who use zebrafish as experimental animals and who are interested in how the peptides in the brain (neuropeptides) regulate seizures. However, the strength of evidence was considered incomplete at the present time due to several limitations of the results.

eLife assessment

This descriptive study reports the genetic requirements for growth and fitness of multiple clinical strains of a relatively understudied species of mycobacteria, Mycobacterium intracellulare. The findings are valuable however, the study is incomplete as the primary claims related to hypoxia adaptation need additional experimental support and data presentation requires more clarity. The work will be of interest to microbiologists.

eLife assessment

This important study shows the effect of gut dysbiosis on the colonization of mycobacteria in the lung. The data with comprehensive analysis of gene expression profiles in the lung with dysbiotic mice is compelling and goes beyond the current state of the art. However, the mechanistic insight and the experiments with Mtb infection are incomplete. With those parts strengthened, this paper would be of interest to researchers working on Mtb infection.

eLife assessment

The manuscript by Carbo et al. reports a novel role for the MltG homolog AgmT in gliding motility in M. xanthus. The authors provide convincing data to demonstrate that AgmT is a cell wall lytic enzyme (likely a lytic transglycosylase), its lytic activity is required for gliding motility, and that its activity is required for proper binding of a component of the motility apparatus to the cell wall. The findings are valuable as they contribute to our understanding of the molecular mechanisms underlying the interaction between gliding motility and the bacterial cell wall.

eLife assessment

This important study demonstrates a potential mechanism by which adjuvants influence T-cell responses. The observation that adjuvant impacts the exogenous peptide repertoire presented by MHC II molecules is fascinating and the strength of the evidence is solid, with studies comparing different adjuvants and an H pylori vaccine in murine models and in vitro systems, analysis of MHCII: peptide complexes in antigen-presenting cells and assessment of differential peptide binding affinities. This work will be of broad interest to vaccinologists as well as immunologists.

eLife assessment

This study provides valuable insights into how IL-1 cytokines may protect cells against SARS-COV-2 infection. By inducing a non-canonical RhoA/ROCK signaling pathway, IL-1beta appears to inhibit the ability of SARS-COV-2 infected cells to fuse with uninfected cells and produce syncytia. The evidence underlying the identification of the key signaling components required for this inhibitory phenotype in vitro is solid and could be further improved by addressing key weaknesses. However, data supporting this specific mechanism of inhibition in IL-1-mediated control of SARS-COV-2 infection in vivo remains incomplete.

eLife assessment

In this valuable study, the authors propose a model wherein the bacterial redox state plays a crucial role in the differentiation of Chlamydia trachomatis into elementary and reticulate bodies. They provide evidence to argue that a highly oxidising environment favours the formation of elementary bodies while a reducing condition slows down development. Whilst aspects related to the role of AhpC in regulating redox, and implications on differentiation, are solid, more precise measurements of the redox potential are required to convincingly demonstrate the role of redox in developmental progression.

eLife assessment

This important study examines the role of TNF in modulating energy metabolism during parasite infection. The authors perform an elegant set of studies, however the evidence supporting the major claims of the manuscript is incomplete. This work integrates an interesting set of observations that will be of interest to the Plasmodium and pathogenesis communities with an expanded set of experiments.

eLife assessment

The work provides a valuable assessment of how antibiotics impact the human gut microbiota in diverse observational cohorts. Although the data presented are solid, some of the assumptions underlying their models may have affected the interpretation of their findings. The study is relevant for researchers and clinicians interested in antimicrobial resistance.

eLife assessment

This valuable study reports data showing the link between a disruption in testicular mineral (phosphate) homeostasis, FGF23 expression, and Sertoli cell dysfunction. The data supporting the conclusion remains incomplete. This work will be of interest to biomedical researchers working on testis biology and male infertility.

This was just pre-knowledge for the real argument in Alcibiades and Socrates? Because this did not confound expectations, simply established a kind of perceived imbalance in love?

Highlighting that Elio is effeminate and not manly, subverting gender expectations

eLife assessment

This valuable study shows how an intersecting network of regulators acting on genes with differences in their RNA metabolism explains why the loss of some regulators of RNAi in C. elegans can selectively impair the silencing of some target genes. The evidence presented is convincing, as the authors use a combination of computational modeling and RNAi assays to support their conclusions.

eLife assessment

This provocative manuscript from presents valuable comparisons of the morphologies of Archaean bacterial microfossils to those of microbes transformed under environmental conditions that mimic those present on Earth during the same Eon, although the evidence in support of the conclusions is currently incomplete. The reasons include that taphonomy is not presently considered, and a greater diversity of experimental environmental conditions is not evaluated – which is significant because we ultimately do not know much about Earth's early environments. The authors may want to reframe their conclusions to reflect this work as a first step towards an interpretation of some microfossils as 'proto-cells,' and less so as providing strong support for this hypothesis.

eLife assessment

This important study aims to understand how the regulation of oligodendrocyte progenitor cell (OPC) remyelination and function contributes to the treatment of multiple sclerosis. The authors provide convincing evidence for the platelets mediating OPC differentiation and remyelination. This work will be of interest to several disciplines.

eLife assessment

The authors have improved a method to differentiate human iPSC-derived microglial cells with immune responses and phagocytic abilities; and through transplantation into the adult mouse retina, the authors further demonstrated their integration and occupation of native microglial cell space, and functional response to retinal injuries. The study is important and the data are convincing for potential microglial replacement therapy to treat retinal and CNS diseases.

eLife assessment

This useful study investigates the evolution of the Mycobacterium tuberculosis Complex (MTBC) pangenome using state-of-the-art bioinformatic tools to analyse 324 complete and 11 new genomes representing all known lineages and sublineages, yielding data indicating that MTBC has a closed pangenome with relatively few accessory genes. The strength of the evidence is solid for gene presence-absence analysis and inadequate for the deletion bias claim. Their conclusions regarding pangenome evolution being driven by deletions in sublineage-specific regions of difference are difficult to interpret due to the description of methods not being complete and data interpretation not being adequate.

eLife assessment

This valuable study explores a new strategy of lysin-derived antimicrobial peptide-primed screening to find peptidoglycan hydrolases from bacterial proteomes. Using this strategy, the authors identified five peptidoglycan hydrolases from Acinetobacter baumannii, which they tested on various Gram-positive and Gram-negative pathogens for antimicrobial activity. The data presented are solid and will be of interest to microbiologists.

eLife assessment

This manuscript outlines an interaction between senescence-related 15d-PGJ2 and the proliferation and differentiation of myoblasts, with potential implications for muscle health. This manuscript is useful in understanding the role of lipid metabolite 15d-PGJ2 in myoblast proliferation and differentiation. However, in its current form, the manuscript is incomplete as there are several concerns in the statistical analysis, lack of clarity on the mechanistic details, and concerns about the use of an immortalized C2C12 myoblasts cell line to draw major conclusions related to senescence-associated secreted phenotype.

eLife assessment

The study answers the important question of whether the conformational dynamics of proteins are slaved by the motion of solvent water or are intrinsic to the polypeptide. The results from neutron scattering experiments, involving isotopic labelling, carried out on a set of four structurally different proteins are convincing, showing that protein motions are not coupled to the solvent. A strength of this work is the study of a set of proteins using spectroscopy covering a range of resolutions. A minor weakness is the limited description of computational methods and analysis of data. The work is of broad interest to researchers in the fields of protein biophysics and biochemistry.

eLife assessment

This method paper proposes a valuable Oscillation Component Analysis (OCA) approach, in analogy to Independent Component Analysis (ICA), in which source separation is achieved through biophysically inspired generative modeling of neural oscillations. The empirical evidence justifying the approach's advantage is solid. This work will be of interest to researchers in the fields of cognitive neuroscience, neural oscillation, and MEG/EEG.

eLife assessment

This study provides important new insight into how non-synaptic interactions affect the activity of adjacent gustatory neurons housed within the same sensillum. The conclusions are supported by convincing electrophysiological, behavioral, and genetic data. This work will be of interest to neuroscientists studying chemosensory processing or regulation of neuronal excitability.

eLife assessment

This important study enhances our understanding of how habitat fragmentation and climate change jointly influence bird community thermophilization in a fragmented island system. The evidence supporting some conclusions is incomplete, as while the overall trends are convincing, some methodological aspects, particularly the isolation metrics and interpretation of colonization/extinction rates, require further clarification. This work will be of broad interest to ecologists and conservation biologists, providing crucial insights into how ecosystems and communities react to climate change.

eLife assessment

This potentially important study employs advanced imaging techniques to directly visualize molecular dynamics and of the immune receptor kinase FLS2 in specific microenvironments. The evidence supporting the ligand-induced association with remorin and the requirement of a previously reported phosphosite as presented is solid, although support by independent methods would be welcome. The work will be of interest to plant biologists working on cell surface receptors.

eLife assessment

This important study explores how cells maintain subcellular structures in the face of constant protein turnover, focusing on neurons, whose synapses must be kept stable over long periods of time for memory storage. Using proteins from knock-in mice expressing tagged variants of the synaptic scaffold protein PSD95, nanobodies, and multiple imaging methods, there is compelling evidence that PSD95 proteins form complexes at synapses in which single protein copies are sequentially replaced over time. This happens at different rates in different synapse types and is slowest in areas where PSD95 lifetime is the longest and long-term memories are stored. While of general relevance to cell biology, these findings are of particular interest to neuroscientists because they support the notion put forward by Francis Crick that stable synapses, and hence stable long-term memories, can be maintained in the face of short protein lifetimes by sequential replacement of individual subunits in synaptic protein complexes.

eLife assessment

This important study explored a molecular comparison of smooth muscle and neighboring fibroblast cells found in lung blood vessels afflicted by a disease called pulmonary arterial hypertension. In doing so, the authors described distinct disease-associated states of each of these cell types with further insights into the cellular communication and crosstalk between them. The strength of evidence was convincing through the use of complementary and sophisticated tools, accompanied by rare isolation of human diseased lung blood vessel cells that were source-matched to the same donor for direct comparison.

eLife assessment

This important study shows that age-related gut microbiota modulates uric acid metabolism through the NLRP3 inflammasome pathway and thereby regulates susceptibility to age-related gout. Whereas some of the data are compelling, several experimental approaches and methods are currently incomplete, which could be remedied with more rigorous approaches. If strengthened, this paper would be of broad interest to researchers working on gout and microbiota.

eLife assessment

This fundamental study by Yogesh and Keller provides a set of results describing the response properties of cholinergic input and its functional impacts in the mouse visual cortex. They found that cholinergic inputs are elevated by locomotion in a binary manner regardless of locomotor speeds, and activation of cholinergic input differently modulated the activity of Later 2/3 and Layer 5 visual cortex neurons induced by bottom-up (visual stimuli) and top-down (visuomotor mismatch) inputs. The experiments are cutting-edge and well-executed, and the results are convincing.

eLife assessment

In this compelling study, the authors examine the interactions between stellate cells and PV+ interneurons in the medial entorhinal cortex, shedding light on the circuit mechanisms that underlie grid cell activity. Huang et al., focus on the spatial distribution of synaptic inputs and report 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 important findings offer significant insights into the functional dynamics of the entorhinal cortex.

eLife assessment

In this fundamental study, authors present compelling evidence for the diversity in cellular and synaptic properties of one class of spinal interneurons and tie it to their differentiated role in locomotor pattern generation. The findings reported here will be of broad interest to neuroscientists in general and to motor systems scientists in particular.

eLife assessment

The authors provide a valuable analysis of what neural circuit mechanisms enable varying the speed of retrieval of sequences, which is needed in situations such as reproducing motor patterns. Their use of heterogeneous plasticity rules to allow external currents to control speed of sequence recall is a novel alternative to other mechanisms proposed in the literature. They perform a convincing characterization of relevant properties of recall via simulations and theory, though a better mapping to biologically plausible mechanisms is left for future work.

eLife assessment

This important study extends our understanding of how the medial prefrontal cortex regulates flexible action during adversity. The data provide compelling evidence of a role for prefrontal PV neuron activity in active avoidance. This builds on the general idea that these neurons play a role in flexible behavior and demonstrates this in the context of freezing/avoidance conflict. The overall findings contribute to our understanding of mechanisms that support aversively motivated instrumental learning and may provide insight into both stress vulnerability and resilience processes. This work will be of interest to those interested in learning, aversive motivation, interneuron and/or prefrontal cortex function, or conditions relates to these processes and mechanisms.

eLife assessment

This valuable manuscript reveals sex differences in bi-conditional Pavlovian learning and conditional behavior. Males learn hierarchical context-cue-outcome associations more quickly, but females show more stable and robust task performance. These sex differences are related to cellular activation in the orbitofrontal cortex. Although the evidence supporting these claims is convincing, some assertions of sex differences in context-dependent discrimination behaviour may be slightly overstated yet have strong potential to guide future research to clarify the nature of these differences. The results will be of interest to many behavioural neuroscientists, particularly those who investigate sex-specific behaviours.

eLife assessment

This important study investigates neurobiological mechanisms underlying the maintenance of stable, functionally appropriate rhythmic motor patterns during changing environmental conditions - temperature in this study in the crab Cancer borealis stomatogastric central neural pattern generating circuits producing the rhythmic pyloric motor pattern, which is naturally subjected to temperature perturbations over a substantial range. The authors present compelling evidence that the neuronal hyperpolarization-activated inward current (Ih), known to contribute to rhythm control, plays a key role in the ability of these circuits to appropriately adjust the frequency of rhythmic neural activity in a smooth monotonic fashion while maintaining the relative timing of different phases of the activity pattern that determines proper motor coordination transiently and persistently to temperature perturbations. This study will interest neurobiologists studying rhythmic motor circuits and systems and their physiological adaptations.

eLife assessment

This study presents valuable findings on tumor-reactive T cells in liver metastases of uveal melanoma (UM). The authors conducted single-cell RNA sequencing to identify potential tumor-reactive T cells and used PDX models for functional analysis. The evidence supporting their claims is solid. The work will be of interest to scientists working in the field of uveal melanoma.

eLife assessment

This study presents valuable findings on core genome mutations that might have driven the emergence of the Staphylococcus aureus lineage USA300, a frequent cause of community-acquired infections. The authors present a solid novel approach that combines genome-wide association studies and RNA-expression analyses, both applied to extensive publicly available datasets. This approach generated an intriguing hypothesis that should be validated experimentally. The work will interest microbiologists working in genomic epidemiology and phenotype-genotype association studies.

eLife assessment

The authors studied the relationship between structural and functional lateralization in the planum temporale region of the brain, whilst also considering the morphological presentation of a single or duplicated Heschl's gyrus. The analyses are convincing due to a large sample size, inter-rater reliability, and corrections for multiple comparisons. The associations in this valuable work might serve as a reference for future targeted-studies on brain lateralization.

eLife assessment

This study used deep neural networks (DNN) to reconstruct voice information (viz., speaker identity), from fMRI responses in the auditory cortex and temporal voice areas, and assessed the representational content in these areas with decoding. A DNN-derived feature space approximated the neural representation of speaker identity-related information. While some of the neural decoding results are valuable, the overall evidence for general representational and computational principles is incomplete as the results rely on a very specific model architecture.

eLife assessment

This useful study measured how information about object categories varies with time in EEG responses to object images in human participants and found that real-world size, retinal size, and real-world depth are represented at different time points in the response. The evidence presented is incomplete and can be further strengthened by removing confounds related to other covarying properties such as semantic categories, and by clarifying the partial correlations that are used to support the conclusions.

eLife assessment

Some delayed rectifier currents in neurons are formed by the combination of Kv2 and silent subunits, KvS. However, we lack the tools to identify these heteromeric channels in vivo. In this valuable study by the Sack group, the authors identify a pharmacological tool that can reveal the presence of KvS subunits as components of the delayed rectifier potassium currents in selected neurons. The experimental evidence presented in the manuscript is compelling and represents an advance that should be of interest to a wide community of neuroscientists and channel physiologists.

eLife assessment

This work represents a new toolkit for implementing virtual reality experiments in head-fixed animals. It is a valuable contribution to the field and the evidence for its utility and performance is solid. Some minor improvements in the material presented - including clarifying design decisions and providing more details about design features - would improve the readability and thereby potentially increase its impact.

eLife assessment

In their manuscript, Cummings et al. use in vitro reconstitution to examine the differential activities of tubulin polyglycylases, providing valuable insights into the enzymatic regulation of microtubule glycylation and its mechanistic role in maintaining cilia function and microtubule dynamics. The convincing evidence, supported by well-designed experiments and appropriate controls, significantly advances our understanding of the tubulin code and its biochemical mechanisms.

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 valuable study combines evolution experiments with molecular and genetic techniques to study how a genetic lesion in MreB that causes rod-shape cells to become spherical, with concomitant deleterious fitness effects, can be rescued by natural selection. The results are convincing, although the statistical analyses and figure presentation could be improved, and the concrete contribution of the paper and how it relates to previous literature clarified.

eLife assessment

In this manuscript the authors present high-speed atomic force microscopy (HSAFM) to analyze real-time structural changes in actin filaments induced by cofilin binding. This important study enhances our understanding of actin dynamics which plays a crucial role in a broad spectrum of cellular activities based on solid experimental evidence. Some technical questions, however, remain, making the data interpretation incomplete.

eLife assessment

The authors provide solid data on a functional investigation of potential nucleoid-associated proteins and the modulation of chromosomal conformation in a model cyanobacterium. These valuable findings will be of interest to the chromosome and microbiology fields. Additional analysis and the tempering of conclusions has helped to improve the work, although further refinement remains possible.

eLife assessment

This useful manuscript presents an analysis of different factors that are required for release of the lipid-linked morphogen Shh from cellular membranes. The evidence is still incomplete, as experiments rely on over-expression of Shh in a single cell line and are sometimes of a correlative nature. The study, which otherwise confirms and extends previous findings, will be of interest to developmental biologists who work on Hedgehog signaling.

eLife assessment

This study presents valuable empirical work and simulations that are relevant for the evolution of genetic load linked to self-incompatibility alleles in two Arabidopsis species. The evidence supporting the findings is solid, although it remains to be seen how generalizable the conclusions are beyond the specific system investigated here, not least because the statistical significance varied between the two species. The work will be of relevance to geneticists interested in the evolution of allelic diversity in similar systems.

eLife assessment

This important modeling work demonstrates out-of-distribution generalization using a grid cell coding scheme combined with Determinantal Point Process Attention. The simulations provide convincing evidence that the model improves generalization performance across several tasks. The generality of the approach is unclear, however, and there is limited comparison to relevant prior work.

eLife assessment

This important work introduces a method to express fluorogenic DNA aptamers in E. coli, paving the way for genetically encoded fluorescent DNA. The evidence supporting the conclusions is solid, consisting of comparisons of the aptamer's activity in vitro and within bacterial cells. This advancement described in this study is likely to become a standard technique in the DNA aptamer field, and the work will be of interest and utility to researchers in synthetic biology, molecular imaging, and bacterial genetics fields.

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 solid 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

In this valuable study, Huffer et al posit that non-cold sensing members of the TRPM subfamily of ion channels (e.g., TRPM2, TRPM4, TRPM5) contain a binding pocket for icilin that overlaps with the one found in the cold-activated TRPM8 channel. By examining a body of TRP channel cryo-EM structures to identify the conserved site, this study presents convincing electrophysiological evidence supporting the identification of an icilin binding pocket within TRPM4. This study shows that icilin has modulatory effects on the TRPM4 channel and will be of direct interest to those working in the TRP-channel field, but it also has implications for studies of somatosensation, taste, as well as pharmacological targeting of the TRPM subfamily.

eLife assessment

The authors combined molecular dynamics simulations and experiments to study the role of ATP as a hydrotrope of protein aggregates. The topic is of major current interest and thus the study potentially makes a useful contribution to the community. In the current form, however, the level of evidence from the computation is considered incomplete, due to several issues such as limited convergence test, analysis, and the very high ATP concentration used in the simulation.

eLife assessment

This fundamental work provides new mechanistic insight into the regulation of PDGF signaling through splicing controls. The evidence is compelling to demonstrate the involvement of Srsf3, an RNA-binding protein, in this new mechanism. The work will be of broad interest to developmental biologists in general and molecular biologists/biochemists in the field of growth factor signaling and RNA splicing.

eLife assessment

This study presents a potentially valuable finding regarding the role of cytokine signaling in the mechanism of response and resistance to castration therapy in prostate cancer. The evidence, although solid for some aspects of the work, is incomplete and only partially supports the main claims.

eLife assessment

This study provides valuable insights into the influence of sex on bile acid metabolism and the risk of hepatocellular carcinoma (HCC). The data to support that there are inter-relationships between sex, bile acids, and HCC in mice are solid, but for the most part, they are descriptive. At this point, there is not enough evidence to determine the clinical significance of the findings, given the differences in bile acid composition between mice and men.

eLife assessment

The findings are useful for understanding the disease's pathology and immune dysregulation, but the evidence is still incomplete regarding whether these immune changes are directly caused by copper metabolism alterations or are secondary to liver dysfunction.

eLife assessment

This study investigates BMP signaling mechanisms in the developing chick cerebellum to better understand germinal layer formation, cellular amplification and neuronal differentiation. The data from human tissue is compelling and lends support to the possible links of these processes to medulloblastoma, although this study does raise exciting questions regarding the generalized role of BMP signaling during normal development and malignant growth. Overall, this is an important study with beautifully presented findings.

eLife assessment

This is an important study on changes in newborns' neural abilities to distinguish auditory signals at 37 weeks of gestation. The evidence of change in neural discrimination as a function of gestational age is convincing, but further analysis of the acoustic signals and control of the infants' language environment is necessary for the results to be used in clinical applications. The work contributes to the field of neurodevelopment.

eLife assessment

In this important study, the authors explore ER stress signaling mediated by ATF6 using a genome-wide gene depletion screen. They find that the ER chaperone Calreticulin binds and directly represses ATF6, a new and intriguing function for Calreticulin. The evidence presented is convincing, based on CHO genetics and biochemical analysis.

eLife assessment

This valuable study describes mice with a knock out of the IQ motif-containing H (IQCH) gene, to model a human loss-of-function mutation in IQCH associated with male sterility. While the evidence for interaction between IQCH and potential RNA binding proteins is limited, the human infertility is reproduced in the mouse, making it a compelling model. The paper could be of interest to cell biologists and male reproductive biologists working on the sperm flagellar cytoskeleton and mitochondrial structure.

eLife assessment

This study builds upon previous work which demonstrated that brain injury results in the entry of a protein called albumin into the brain which then causes diverse effects. The present study shows that prolonged stimulation of a forelimb in a rat leads to albumin entry, and is associated with effects that suggest plasticity is enhanced in the stimulated side of the brain. The strength of evidence was convincing and results are important because they suggest a previously-considered pathological process may be relevant to the normal brain and have benefits.

eLife assessment

This study provides an important cell type atlas of the gill of the mussel Gigantidas platifrons using a single nucleus RNA-seq dataset, a resource for the community of scientists studying deep sea physiology and metabolism and intracellular host-symbiont relationships. The evidence supporting the conclusions is convincing with high-quality single-nucleus RNA sequencing and transplant experiments. This work will be of broad relevance for scientists interested in host-symbiont relationships across ecosystems.

eLife assessment

This manuscript provides important information on the calcification process, especially the properties and formation of freshly formed tests (the foraminiferan shells), in the miliolid foraminiferan species Pseudolachlanella eburnea. The evidence from the high-quality SEM images is convincing although the fluorescence images only provide indirect support for the calcification process.

eLife assessment

This useful modeling study explores how the biophysical properties of interneuron subtypes in the basolateral amygdala enable them to produce nested oscillations whose interactions facilitate functions such as spike-timing-dependent plasticity. The strength of evidence is currently viewed as incomplete because of insufficient grounding in prior experimental results and insufficient consideration of alternative explanations. This work will be of interest to investigators studying circuit mechanisms of fear conditioning as well as rhythms in the basolateral amygdala. (The authors explain why they disagree with this assessment in their author response.)

eLife assessment

This fundamental study advances our understanding of the role of bacterial-derived extracellular ATP in the pathogenesis of sepsis. The evidence supporting the conclusions is compelling, although not all concerns from a previous round of reviews were adequately addressed. The work will be of broad interest to researchers on microbiology and infectious diseases.

eLife assessment

This important study advances our understanding of early Cambrian cnidarian paleoecology and suggests that the reconstructed ancestral feeding and respiration mechanisms predate jet-propelled swimming utilized by modern jellyfish. The work combines solid evidence of fluid and structural mechanics modeling, simulating for the first time the feeding and respiratory capacities in a microfossil (Quadrapyrgites), which in turn opens new possibilities using this approach for paleontological research. Assuming that the prior interpretations and assumptions concerning the modeled organism's soft part and skeletal anatomy are correct, the hypotheses that (1) the organism could alternately contract and expand the oral region and (2) such movement increased feeding efficiency seem plausible.

eLife assessment

This valuable study examines the role of the interaction between cytoplasmic N- and C-terminal domains in voltage-dependent gating of Kv10.1 channels. The authors claim to have identified a hidden open state in Kv10.1 mutant channels, thus providing a window for observing early conformational transitions associated with channel gating. The evidence supporting the major conclusions is incomplete, however, and additional work is required to determine the molecular mechanism underlying the observations in this study. With the experimental conditions clarified and the mechanistic interpretations addressed, this work could be significant in understanding the gating mechanisms of the KCNH family and will appeal to biophysicists interested in ion channels and physiologists interested in cancer biology.

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eLife assessment

This manuscript probes the ways in which a protein tag might influence the structure, dynamics and stability of a covalently-attached substrate protein. Such findings are of important significance to several fields, particularly in understanding how these influences control the abundance of proteins within a cell. The evidence provided to support the authors' conclusions are, however, incomplete and further control experiments are necessary to fully support the proposed model.

eLife assessment

This study presents a valuable finding on the precision conferred by dynamical interpretation of morphogen gradients. The evidence supporting the claims of the authors is convincing, with compelling theoretical analysis and solid yet incomplete experimental data. With the experimental part strengthened, the work could be of interest to the developmental biology and developmental systems biology communities.

eLife assessment

fMRI was used to address an important aspect of human cognition - the capacity for structured representations and symbolic processing - in a cross-species comparison with macaques; the experimental design probed implicit symbolic processing through reversal of learned stimulus pairs. The authors present solid evidence in humans that helps elucidate the role of brain networks in symbolic processing, however the evidence from macaques was necessarily incomplete (e.g., hard-to-quantify differences in learning trajectories and lived experience between species).

eLife assessment

This important work advances our understanding of the differences in locomotion-induced modulation in primate and rodent visual cortexes and underlines the significant contribution cross-species comparisons make to investigating brain function. The evidence in support of these differences across species is convincing. This work will be of broad interest to neuroscientists.

eLife assessment

This manuscript provides a valuable demonstration that distractor effects in multi-attribute decision-making correlate with the form of attribute integration (additive vs. multiplicative). The evidence supporting the conclusions is convincing, but there are questions about how to interpret the findings. The manuscript will be interesting to decision-making researchers in neuroscience, psychology, and related fields.

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.