eLife Assessment

This manuscript represents a fundamental contribution demonstrating that fentanyl-induced respiratory depression can be reversed with a peripherally-restricted mu opioid receptor antagonist. The paper reports compelling and rigorous physiological, pharmacokinetic, and behavioral evidence supporting this major claim, and furthers mechanistic understanding of how peripheral opioid receptors contribute to respiratory depression. These findings reshape our understanding of opioid-related effects on respiration and have significant therapeutic implications given that medications currently used to reverse opioid overdose (such as naloxone) produce severe aversive and withdrawal effects via actions within the central nervous system.

eLife Assessment

Aging reduces tissue regeneration capacity, posing challenges for an aging population. In this fundamental study, Reeves et al. show that by combining Wnt-mediated osteoprogenitor expansion (using a special bandage) with intermittent fasting, bone healing can be restored in aged animals. By employing rigorous histological, transcriptomic, and imaging analyses in a clinically relevant model, the authors provide compelling evidence supporting the conclusions. The therapeutic approach presented in this study shows promise for rejuvenating tissue repair, not only in bones but potentially across other tissues.

eLife Assessment

The findings of this study are valuable, as they address a critical methodological gap in decision-making research by demonstrating how heuristic strategies can confound interpretations of uncertainty-driven behaviour and provide a clearer framework for distinguishing between uncertainty-seeking and heuristic-driven exploration. While the evidence is solid, with strong methodological rigour in task design and computational modelling, some claims, such as the stability of uncertainty parameters and correlations with psychopathology measures, require refinement. Overall, the data broadly support the study's claims, but interpretational ambiguities limit the impact of certain findings.

eLife Assessment

This valuable study investigates the mechanisms that contribute to nerve-injury-induced allodynia by studying the role of the estrogen receptor GPR30 in a population of CCK+ neurons in the dorsal horn of the spinal cord that receive direct inputs from primary somatosensory cortex and modulate nociceptive sensitivity. The authors provide convincing evidence, using a variety of complementary approaches, ranging from the cellular to physiology level; however, conclusions that descending corticospinal projections modulate nociceptive behaviors through GPR30 are incompletely supported. With some additional analyses, the findings will be better positioned within the context of spinal circuitry literature.

eLife Assessment

This valuable study by Xu and colleagues investigates brainstem circuits mediating evoked respiratory reflexes that they define as cough-like in a freely behaving mouse model. They have applied multiple circuit mapping and manipulation approaches to suggest that the caudal spinal trigeminal nucleus (SP5C) nucleus can play a novel role in generating a reflex cough-like behavior in mice. The authors give incomplete evidence that the reflex behavior produced in their mouse model is definitively cough, limiting functional interpretation of the putative circuit identified and requiring more thorough experimental interrogation of the behavior studied.

eLife Assessment

The authors present a biologically plausible framework for action selection and learning in the striatum that is a fundamental advance in our understanding of possible neural implementations of reinforcement learning in the basal ganglia. They provide compelling evidence that their model can reconcile realistic neural plasticity rules with the distinct functional roles of the direct and indirect spiny projection neurons of the striatum, recapitulating experimental findings regarding the activity profiles of these distinct neural populations and explaining a key aspect of striatal function.

eLife Assessment

This study presents a valuable study of early brain development using advanced MRI methods. In particular, the study investigates the relationship between the maturation of diffusion MRI tissue properties and suggests that they may precede and guide the emergence of brain folding patterns. The data is solid, however, the evidence supporting the precedence of tissue changes over brain folding appears incomplete.

eLife Assessment

This study presents valuable quantitative insights into the prevalence of functionally clustered synaptic inputs on neuronal dendrites. The simple analytical calculations and computer simulations provide solid support for the main arguments. The findings can lead to a more detailed understanding of how dendrites contribute to the computation of neuronal networks.

eLife Assessment

The study presents important findings that reveal SEPHS2 and VPS37C as new potential drug targets for dasatinib and hydroxychloroquine respectively in addition to confirming known targets of these drugs. The evidence provided is compelling as observed in the methods, data and analyses. This article will be of great interest to chemical biologists, biochemists, and scientists in drug discovery and diagnostics.

eLife Assessment

This important work presents two studies on predictive processing in subjects with and without tinnitus, matched for age, sex and hearing loss. These studies together provide compelling evidence for an enhanced predictability of upcoming sounds in regular sequences in EEG data recorded from tinnitus subjects. This work will be of interest to researchers, especially neuroscientists, in the tinnitus field and beyond.

eLife Assessment

This study investigates the role of queuosine (Q) tRNA modification in aminoglycoside tolerance in Vibrio cholerae and presents convincing evidence to conclude that Q is essential for the efficient translation of TAT codons, although this depends on the context. The absence of Q reduces aminoglycoside tolerance potentially by reprogramming the translation of an oxidative stress response gene, rxsA. Overall, the findings point to an important mechanism whereby changes in Q modification levels control the decoding of mRNAs enriched in TAT codons under antibiotic stress.

eLife Assessment

The study highlights adhesion G-protein-coupled receptor A3 (ADGRA3) as a potential target for activating adaptive thermogenesis in both white and brown adipose tissue. This finding offers valuable insights for researchers in the field of adipose tissue biology and metabolism. The authors have presented additional evidence to address the reviewers' comments, including experiments conducted on primary stromal vascular fractions from adipose tissues. However, the revised manuscript fails to address several reviewer concerns, such as the measurement of whole-body energy expenditure through indirect calorimetry and the assessment of food intake. Furthermore, the nanoparticle-mediated knockdown of Adgra3 did not adequately address the tissue selectivity of ADGRA in mice. As a result, the primary claims of the study are only partially supported by the available data, leading to the conclusion that the research is deemed incomplete.

eLife Assessment

This important study represents a data processing pipeline to discover causal interactions from time-lapse imaging data, and convincingly illustrates it on a challenging application for the analysis of tumor-on-chip ecosystem data. The authors describe the raw data they used (imaging data), go through a step-by-step description on how to extract the features they are interested in from the raw data, and how to perform the causal discovery process. This paper tackles the problem of learning causal interactions from temporal data, which is applicable to many biological applications.

eLife Assessment

Despite the well-established facilitatory effects of multisensory integration on behavioural measures, standard neuroimaging approaches have yet to reliably and precisely identify the corresponding neural correlates. In this valuable paper, Buhmann et al. leverage EEG decoding methods, moving beyond traditional univariate analyses, to capture these correlates. They present solid evidence that this approach can effectively estimate multisensory integration in humans across a broad range of contexts.

eLife Assessment

This valuable research contributes to our understanding of marine plankton diversity and gene expression by employing robust methodologies for sample collection and analysis. However, it lacks a comprehensive comparison with existing single-cell transcriptomics techniques in microbial ecology, and some terminology requires clarification for consistency with field standards. The downstream data analysis therefore provides only incomplete support for the claims made by the authors.

eLife Assessment

This important study explores the relationship between the sequence of prokaryotic promoter elements and their activity using mutagenesis to generate thousands of mutant sequences. The evidence supporting these findings is convincing. This work will appeal to those interested in bacterial genetics, genome evolution, and gene regulation.

eLife Assessment

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

eLife Assessment

This valuable study combined multiple approaches to gain insight into why rising estradiol levels, by influencing hypothalamic neurons, ultimately lead to ovulation. The experimental data were solid, but evidence for the conclusion that the findings explain how estradiol acts in the intact female were incomplete because they lacked experimental conditions that better approximate physiological conditions. Nevertheless the work will be of interest to reproductive biologists working on ovarian biology and female fertility.

eLife Assessment

Abssy et al. carried out a study to test the effects of repetitive peripheral magnetic stimulation (rPMS) on pain perception in an experimental pain model and concluded that the analgesic properties of rPMS could be largely attributed to its auditory component rather than peripheral nerve stimulation per se. While the study presents valuable data on the modulation of pain perception in response to the stimulation paradigms that were tested, several issues in the experimental design and interpretation of results render the evidence incomplete to support their main claims, which should therefore be revised. In that case, these results could be of interest to pain clinicians and researchers.

eLife Assessment

The study provides valuable insight into the biological significance of SARS-CoV-2 by using a series of computational analyses of viral proteins. While the evidence is solid, the reviewers noted a lack of clarity about the objectives of the analyses. While impactful for the field, the manuscript would benefit from improved presentation.

eLife Assessment

The authors modified a common method to induce epilepsy in mice to provide an improved approach to screening new drugs for epilepsy. This is an important goal because of the need to develop drugs for patients who are refractory to current medications. The authors' method evokes seizures to circumvent a low rate of spontaneous seizures and the approach was validated using two common anti-seizure medications. The strength of evidence was solid in that some validation was provided, but incomplete because the method for quantification, definition of seizures, and some other aspects of the paper were not clear or absent.

eLife Assessment

This study presents valuable findings, based on solid methods, to link metabolic dysfunction in Wilson's disease to immune cell dysregulation and poor cholecystitis outcomes. The integration of clinical data and single-cell analyses highlights NK cell exhaustion as a key factor, offering insights with potential therapeutic implications. The work will be of interest to colleagues in inflammatory and metabolic diseases.

eLife Assessment

This potentially valuable work characterizes the changes in the microbial composition of the nasal and fecal microbiomes in COVID-19 patients based on disease severity. This study enhances the understanding of COVID-19 severity predictors by identifying changes in bacterial species abundance in nasopharyngeal and fecal samples as a biomarker for predicting disease severity. The methods and statistics used appear to be solid and in line with the standards of the field.

eLife Assessment

This important work shows how a simple geophysical setting of gas flow over a narrow channel of water can create a physical environment that leads to the isothermal replication of nucleic acids. The work presents compelling evidence for an isothermal polymerase chain reaction in careful experiments involving evaporation and convective flows, complimented with fluid dynamics simulations. This work will be of interest to scientists working on the origin of life and more broadly, on nucleic acids and diagnostic applications.

eLife Assessment

This important study provides data that challenges the standard model that binding of Type 2 Nuclear Receptors to chromatin is limited by the available pool of their common heterodimerization partner Retinoid X Receptor. The evidence supporting the conclusions is compelling, utilizing state-of-the-art single-molecule microscopy. This work will be of broad interest to cell biologists who wish to determine limiting factors in gene regulatory networks.

eLife Assessment

This valuable study addresses the potential roles of the master regulator of X chromosome inactivation, the Xist long non-coding RNA, in the regulation of autosomal genes. 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. The evidence from individual genes is interesting, and the model aligns with recently published results from humans. However, despite some improvements during revision, the data and statistical analyses in the current study are not yet strong enough to allow for conclusive inferences, leaving the evidence for mouse cells behaving like human cells incomplete. The topic of the work is of broad interest, in particular to colleagues studying gene regulation and noncoding RNAs.

eLife Assessment

This valuable study reports a chemogenetic screen for resistance and sensitivity to three cell cycle inhibitors used in the clinic: camptothecin, colchicine, and palbociclib. The screen provides a wealth of information that will be of interest to cell cycle and cancer biologists. Convincing evidence is provided that resistance to palbociclib can result from loss of PRC2.1 activity, which raises cyclin D levels. The effect of PRC2.1 on cyclin D is not universal across tested cell lines with the causal differences not yet understood.

eLife Assessment

This useful study provides incomplete evidence regarding the pathophysiological role of low estrogen levels post-menopause in hypertension, focusing on L-AABA as a key mediator. The results describe a novel hypothesis for the pathophysiology of hypertension in this population and are of interest to experts in hypertension and vascular biology.

eLife Assessment

Kan et al. report the discovery of a Bacillus amyloliquifaciens strain that kills Nerisseria gonorrhoeae via oxydifficidin which targets ribosomal proteins. Resistance occurred via mutation in the DedA flippase to influence oxydifficidin uptake. The overall mechanism of action is well described making this an important study with implications for combating clinical antibiotic resistance. The evidence presented is convincing due to rigour employed in the methodological approach. The authors should consider performing a more comprehensive genetic analyses of DedA and RpIL in this clinically relevant strain. This work will be of broad interest to microbiologists and synthetic biologists.

eLife Assessment

Protein and lipid homeostasis is essential for maintaining cellular functions but their crosstalk remains largely unknown. This important manuscript deals with this interesting topic and applies the powerful unbiased tools of somatic cell genetics to discover evidence suggesting a link between sphingolipids/cholesterol ester metabolism and lysosomal protein aggregation. The authors provide compelling orthogonal evidence to support their conclusions.

eLife Assessment

This study provides a valuable look at genome-wide RNaseA-resistant RNA-DNA interactions in human embryonic stem cells. The research indicated that RNase treatment maintained long-range RNA-chromatin connections characterized by significant sequence conservation while abolishing permissive interactions. Interestingly, coding and non-coding RNA transcripts exhibited differing sensitivity to RNase treatment. Although the study findings reveal an intriguing RNase-inaccessible regulatory RNA-chromatin interactome, conclusions about the identity and regulatory significance of RNase-resistant RNA-chromatin interactions are incomplete and would benefit from more rigorous approaches that include additional computational and experimental controls.

eLife Assessment

The current study presents useful findings about the inhibition of a membrane pyrophosphatase by non-hydrolyzable phosphonate substrate analogs. The study proposes a model in which the two monomers in a functional dimer interact with the phosphonate molecules in an asymmetric fashion. While asymmetry has been previously demonstrated through other studies, the DEER spectroscopy data presented in the current study provide incomplete evidence of the proposed asymmetry near the binding site.

eLife Assessment

This important study used whole genome data to investigate Beefalo ancestry for the first time. It provides insight into the genetics of Beefalo cattle, definitively challenging the long-held claim of 37.5% buffalo ancestry reported by the American Beefalo Association. This results are convincing, with a comprehensive range of well-established population genomics methods being used to estimate ancestry in these animals. This work will be of significant interest to evolutionary biologists, population geneticists, animal breeders, and those involved in the conservation genetics of bovine species.

eLife Assessment

This study presents a valuable finding that MK2 inhibitor CMPD1 can inhibit the growth, migration, and invasion of breast cancer cells both in vitro and in vivo by inducing microtubule depolymerization, preferentially at the microtubule plus-end, leading to cell division arrest. The evidence supporting the conclusion of this paper is solid, although additional experiments and controls are needed to further strengthen the claim. This work will be of interest to breast cancer researchers.

eLife Assessment

This important study highlights the key role of NK cells and PD-L1+ neutrophils in worsening sepsis responses in the context of of MASH (metabolic dysfunction-associated steatohepatitis). While the data are solid, the overall evidence for the role of neutrophils in mediating this effect, which is based on a choline-deficient high-fat diet model of various knockouts or selective ablation of immune cell types, remains incomplete. The study will be of interest to researchers in immunopathological disease mechanisms.

eLife Assessment

This study reports that activation of TFEB promotes lysosomal exocytosis and clearance of cholesterol from lysosomes, the strength of evidence for which is solid and considered valuable in the context of Niemann-Pick Disease Type C. However, beyond this aspect of the study, the reviewers found the strength of the evidence to be incomplete. The manuscript also needs careful editing to improve readability.

eLife Assessment

This study presents useful findings to inform and improve the in vitro differentiation of hematopoietic progenitor cells from human induced pluripotent stem cells. Relying on a well-characterised technical approach, the data analysis is overall solid and reasonably supports the main conclusions.

eLife Assessment

This valuable study describes the molecular mechanism of daptomycin insertion into bacterial membranes. The authors provide solid in vitro evidence for the early events of daptomycin interaction with phospholipid headgroups and stronger, specific interaction with phosphatidylglycerol. This work will be of interest to bacterial membrane biologists and biochemists working in the antimicrobial resistance field.

eLife Assessment

This important study provides empirical evidence of the effects of genetic diversity and species diversity on ecosystem functions across multi-trophic levels in an aquatic ecosystem. The support for these findings is solid, but a more nuanced interpretation of the results could strengthen the conclusions. The work will be of interest to ecologists working on multi-trophic relationships and biodiversity.

eLife Assessment

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

eLife Assessment

This valuable study reports a potential connection between the seminal microbiome and sperm quality/male fertility. The data are generally convincing. This study will be of interest to clinicians and biomedical researchers who work on microbiome and male fertility.

eLife Assessment

The study explored the influence of magnesium on phenotypic antibiotic resistance in two strains of Vibrios: V. alginolyticus ATCC33787 and V. parahaemolyticus VP01. This research is fundamental for revealing the phenotypic antibiotic resistance mechanism utilized by the specified model bacteria in elevated levels of magnesium. The study produced convincing evidence indicating that in high concentrations of magnesium, the efficacy of selected antibiotics was diminished due to decreased biosynthesis of unsaturated fatty acids and PE, along with an increase in the biosynthesis of PG.

eLife Assessment

This valuable study investigates the role of Complement 3a Receptor 1 (C3aR) in the pathogenesis of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) using mouse models with specific target deletions in various cell types. While the general relevance of C3aR in inflammatory contexts has been established before, the authors provide solid evidence here that C3aR does not contribute significantly to MASLD pathogenesis in their models. The work will be of interest to colleagues studying diseases of the liver and the intersection with inflammation.

eLife Assessment

This is an important study suggesting that neuron-specific loss of function of the RNA splicing factor Ptbp1 in striatal neurons induces dopaminergic markers and alleviates motor defects in a 6-hydroxydopamine (6-OHDA) mouse model of Parkinson's Disease. The evidence supporting the rescue of motor deficits following Ptbp1 manipulation is solid, and, while additional characterization of dopaminergic neuronal identity may be required in future studies, these results have clear implications for Parkinson's disease therapeutics. The study also addresses recent controversial literature on cell reprogramming in Parkinson's Disease and will be of interest to researchers with a focus on the application of gene therapy to rescue neurodegeneration.

eLife Assessment

This important study reports findings on the GnRH pulse generator's role in androgen-exposed mouse models, providing further insights into PCOS pathophysiology and advancing the field of reproductive endocrinology. The experimental data were collected using cutting-edge methodologies and are solid. The findings, while interesting, are primarily applicable to mouse models, and their translation to human physiology requires cautious interpretation and further validation. This work will be of interest to endocrinologists and reproductive biologists.

eLife Assessment

This paper presents a new method called MINT that is effective at BCI-style decoding tasks. The authors show convincing evidence to support their claims regarding how MINT is a new method that produces excellent decoding performance relative to the state-of-the-art. This work is important and will be of broad interest to neuroscientists and neuroengineers.

eLife Assessment

This is an important study that investigates how neural networks can learn to stochastically replay presented sequences of activity according to learned transition probabilities. The authors use error-based excitatory plasticity to minimize the difference between internally predicted activity and stimulus-driven activity, and inhibitory plasticity to maintain E-I balance. The approach is solid but the choice of learning rules and parameters is not always always justified, with some unclear aspects to the formal derivation.

eLife Assessment

This fundamental study combines Global Positioning System tracking and the analysis of social interactions among feral pigs, to provide insights into the likelihood of disease transmission based on contact rates both within and between sounders. The method used for data collection is compelling, but the varying sample sizes across populations could be a potential source of bias. With the potential biases from varying sample sizes strengthened this paper would be of interest to the fields of Veterinary Medicine, Public Health, and Epidemiology.

eLife Assessment

This valuable study uses extensive comparative analysis to examine the relationship between plasma glucose levels, albumin glycation levels, and diet and life history, within the framework of the "pace of life syndrome" hypothesis. The evidence that glucose and glycation levels are broadly correlated is convincing. However, concerns about the consistency of the data quality across species and some aspects of data analysis make the key conclusion about higher glycation resistance in species with higher glucose levels currently incomplete. Still, as the first extensive comparative analysis of glycation rates, life history, and glucose levels in birds, the study has potential to be of interest to evolutionary ecologists and the aging research community more broadly.

eLife Assessment

This study aims to investigate the RNA binding activities of a conserved heterochromatin protein (Swi6) and proposes an entirely new model for how heterochromatin formation is initiated in fission yeast. While the concept is interesting, the data provided are inadequate, both for support of the claims regarding the new RNA binding activities and for support of the new model. The paper requires extensive editing as well as the inclusion of numerous experiments with appropriately controlled conditions.

eLife Assessment

This manuscript provides a valuable in-depth biochemical analysis of p53 isoforms, highlighting their aggregation propensity, interaction with chaperones, and potential dominant-negative effects on p53 family members. The study presents solid evidence of isoform-specific properties, which may contribute to protein misfolding and impaired cellular function in cancer. While highly informative, the findings would benefit from further discussion of physiological relevance, given the high isoform expression levels used, and addressing prior evidence of isoform-specific transcriptional activity. Overall, this work significantly advances our understanding of p53 isoform biochemistry and its implications for cancer research.

eLife Assessment

This study examines age-related, sex-specific gene expression and alternative splicing in humans using the GTEx dataset. Solid evidence is provided to demonstrate that alternative splicing was affected by both sex and age across many tissues in this dataset. Although the authors performed comprehensive computational analyses with useful 'transcriptomic' changes with sex/age, they did not validate their findings with independent longitudinal datasets. This limits the wide impact of this study but can be used as a starting point to examine sex- and age differences in the transcriptome due to alternative splicing.

eLife Assessment

This useful study informs the transcriptional mechanisms that promote stem cell differentiation and prevent degeneration in the adult eye. Through inducible mouse mutagenesis, the authors uncover a dual role for a transcription factor (Sox9) in stem cell differentiation and prevention of retinal degeneration. The data at hand provide solid support to the main conclusions with several minor weaknesses identified as well. The study will be of general interest to the fields of neuronal development and neurodegeneration.

eLife Assessment

This study presents numerical results on a framework for understanding the dynamics of subthreshold waves in a network of electrical synapses modeled on the connectome data of the C elegans nematode. The strength of the evidence presented in favor of interference effects being a major component in subthreshold wave dynamics is inadequate and the approach is flawed. Substantial methodological issues are present, including altering the original network structure of the connectome without a clear justification and providing little motivation for the choice of numerical parameters values that were used.

eLife Assessment

This important study uses calcium imaging to show an increase in the selectivity of the sensory-evoked response in the apical dendritic tuft of layer 5 barrel cortex neurons as mice learn a whisker-dependent discrimination task. The evidence supporting the conclusions is compelling, and this work will be of great interest to neuroscientists working on reward-based learning and sensory processing.

eLife Assessment

The authors propose a new methodology to survey insects, using new sensors and analytical capabilities that could be valuable for addressing urgent conservation challenges. While the results of the optical sensors appear to be comparable to those obtained with classical survey methodologies, current analyses are considered incomplete.

eLife Assessment

This paper explores the important question of how two major inhibitory interneuron classes in the neocortex differentially affect cortical dynamics. Using a linearized fixed point approach, they provide convincing evidence that the existence of multiple interneuron classes can explain the counterintuitive finding that inhibitory modulation can increase the gain of the excitatory cell population while also increasing the stability of the circuit's state to minor perturbations. Support for the main conclusions is solid, but could be strengthened by additional analyses.

eLife Assessment

This useful manuscript presents findings on Tom1p's interaction with Spt6p and its role in chromatin dynamics, supported by structural analysis through CryoEM. The evidence for the conclusions is currently incomplete, lacking key experiments including continuation in vivo interaction and orthogonal binding assays (e.g., SPR, MST, ITC) to fully support the proposed mechanism. While the results are promising, further validation is needed to strengthen the evidence and improve the manuscript's overall cohesion.

eLife Assessment

By combining the 'pinging' technique with fMRI-based multivariate decoding, this important study examined the nature of the representation of the attentional template during preparation. While the findings are very interesting and the experimental evidence is solid, the methodological (e.g., the manipulation of attention, the potential cross-contamination between attention and working memory, and the representational distance analysis) and interpretation confounds (e.g., more thorough clarification of "pinging" and dual-format attentional templates) need to be addressed. The work will be of interest to researchers in psychology, cognitive science, and neuroscience.

eLife Assessment

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

eLife Assessment

This important study confirms the molecular function of putative components of the N-glycan-dependent endoplasmic reticulum protein quality control (ERQC) system in the pathogen Cryptococcus neoformans. The study demonstrates an involvement in fitness, virulence, and the secretion and composition of extracellular vesicles, albeit in ways that are not yet fully understood. The evidence provided is largely convincing, with rigorous well-controlled assays and the use of complemented strains.

eLife Assessment

This study provides valuable evidence for the mechanism underlying KCNC1-related developmental and epileptic encephalopathy. The authors have generated and characterized a new knock-in mouse with a pathogenic mutation found in patients to determine the synaptic and circuit mechanisms contributing to KCNC1-associated epilepsy. They provide convincing evidence for reduced excitability of parvalbumin-positive fast-spiking interneurons, but not in neighboring excitatory neurons, and suggest that this may contribute to seizures and premature death in the mice.

eLife Assessment

This important study by Bi and colleagues employed a clever genetics screen to uncover the role of the GidB rRNA methylase in translation fidelity, under certain conditions, in Mycobacterium smegmatis. The findings are solid, supporting the conclusions, but the structural analyses lack the necessary rigor and depth to provide a clear mechanism. The work will be of interest to microbiologists.

eLife Assessment

The study follows up on previous work suggesting that lower glucose concentrations are protective from sepsis but put the patient at risk for hypoglycemia. In this paper, the authors identify that a slightly higher dose of glucose is still protective but no longer puts the patients at risk for hypoglycemia. The study is important, supported by convincing data, and will be of interest to a broad audience.

eLife Assessment

In this important study, significant advancements are made in how cell division in Chlamydia trachomatis, lacking FtsZ, is mediated. With the careful use of fluorescence microscopy and genetic tools, the evidence identifying the DNA translocase, FtsK, as an early and essential component of the divisome, is convincing. As this role is distinct from what has been found in most other bacteria, this study will be of broad interest to microbiologists and molecular biologists.

eLife Assessment

This valuable study uses steered molecular dynamics simulations to interrogate force transmission in the mechanosensitive NOMPC channel, which plays roles including soft-touch perception, auditory function, and locomotion. The finding that the ankyrin spring transmits force through torsional rather than compression forces may help understand the entire TRP channel family. The evidence is, however, considered to be still incomplete. It could be strengthened by testing how the channel responds to different twisting and compressional force magnitudes over longer simulation times to see a full gating motion, or to prove that the partial or initial motion observed relates to physiological gating. Experimental validation of reduced mechano-sensitivity through mutagenesis of proposed ankyrin/TRP domain coupling interactions would be best to enhance the manuscript.

eLife Assessment

Maloney et al. offer an important contribution to understanding the potential ecological mechanisms behind individual behavioral variation. By providing compelling theoretical data and convincing experimental data, the study bridges the gap between individual, apparently stochastic behavior with its evolutionary purpose and consequences. The work further provides a testable and generalizable model framework to explore behavioral drift in other behaviors.

eLife Assessment

The results by Zhu et al provide valuable insights into the representation of border ownership in area V1. They used neuropixel recording to demonstrate the clustering of border ownership, and compared cross-correlation functions between neurons in different layers to demonstrate that they depend on the type of stimulus. The strength of the evidence is solid but can be improved by performing additional analyses and accounting for the differences in classical and non-classical receptive field stimulation conditions.

eLife Assessment

This study provides valuable insights into the differential impact of intrinsic and synaptic conductances on circuit robustness, emphasizing intrinsic plasticity as a crucial but often overlooked factor in neural dynamics. Although the findings are solid and underscore the significance of intrinsic factors, they are limited by the simplified model and the potential confounding effects of drastic intrinsic perturbations on single-neuron activity. Further refinements would help validate the generality of these conclusions across diverse networks and functions.

eLife Assessment

This important study highlights a critical challenge to a great many studies of the neural correlates of consciousness that were based on post hoc sorting of reported awareness experience. The evidence supporting this criticism is convincing, based on simulations and decoding analysis of EEG data. The results will be of interest not only to psychologists and neuroscientists but also to philosophers who work on addressing mind-body relationships.

eLife Assessment

In this important study, Li et al. identify estrogen receptor 1-expressing neurons (ESR1+) in Barrington's nucleus as key regulators coordinating both bladder contraction and the relaxation of the external urethral sphincter. Using appropriate and validated methodologies aligned with the current state of the art, the data are convincing and of generally high quality.

eLife Assessment

This work presents important findings regarding the interaction of the monkeypox virus (MPXV) attachment H3 protein with the cellular receptor heparan sulfate and the use of this information to develop antivirals potentially effective against all orthopoxviruses. Using a combination of state-of-the art computational and wet experiments the authors present convincing evidence to sustain their claims. These results will interest those working on basic orthopoxviruses biology and antiviral development.

eLife Assessment

This fundamental work provides evidence that glutamate and GABA are released from different synaptic vesicles at supramammillary axon terminals onto granule cells of the dentate gyrus. The study uses complementary electrophysiological and anatomical experimental approaches. Together, these provide convincing evidence that the co-release of glutamate and GABA from different vesicles within the same terminal could modulate granule cell firing in a frequency-dependent manner, although thorough elimination of alternative mechanisms would have strengthened the study. The work will be of interest to neuroscientists investigating co-release of neurotransmitters in various synapses in the brain and those interested in subcortical control of hippocampal function.

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, with a potential to resolve how pterosaurs were able to control and maintain tail stiffness to furnish flight control.

eLife Assessment

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

eLife Assessment

In this important study the authors develop an elegant lung metastasis mouse model that closely mimics the events in human patients. They provide convincing evidence for the effectiveness of IL-15/12-conditioned NK cells in this design, which was also critical for the authors being able to conclusively reveal the T cell-dependency of NK-cell-mediated long-term control of experimental metastasis. Of note, an investigator-initiated clinical trial demonstrated that similar NK cell infusions in cancer patients after resections were safe and showed signs of efficacy, which is of promising clinical application value.

eLife Assessment

This important study presents work on the molecular mechanism driving asymmetric cell division and fate decisions during embryonic development of echinoids. The evidence supporting the claims of the authors is convincing. The work will be of interest to developmental biologists and cell biologists working in the field of self-renewal.

eLife Assessment

This manuscript offers valuable insights by identifying two distinct liver cancer subtypes through multi-omics integration and developing a robust prognostic model, validated across various datasets, including single-cell RNA sequencing. The evidence is solid, with comprehensive validation in both internal and independent cohorts; however, the reliance on computational methods highlights the necessity for further experimental validation to fully confirm the mechanistic insights.

eLife Assessment

The paper illustrates a valuable approach to generating TCR transgenic mice specific for known epitopes. Solid evidence validates the described pipeline for identification of TCRs from single-cell datasets for the generation of TCR transgenic mice, while obviating the need for generation of T-cell lines and hybridomas.

eLife Assessment

This useful study examines how deletion of a major DNA repair gene in bacteria may facilitate the rise of mutations that confer resistance against a range of different antibiotics. Although the phenotypic evidence is intriguing, the interpretation of the phenotypic data presented and the proposed mechanism by which these mutations are generated are incomplete, relying on untested assumptions and methodology that merits optimization. For instance, the authors cannot fully rule out the possibility that the resistance mutations are the result of selection. Nevertheless, this work could be of interest to microbiologists studying antibiotic resistance, genome integrity, and evolution, but the significance remains uncertain.

eLife Assessment

The authors analyze the relationship between human mobility and genomic data of SARS-CoV-2 using mobile phone mobility data and sequence data and present a solid proof of concept. This useful work was conducted on a fine spatial scale and provides suggestions on how mobility-derived surveillance could be conducted, although these results are mixed. The primary significance of this work is the strong use of large datasets that were highly granular. The authors provide a rigorous study, but with less clear predictive power of mobility to inform transmission patterns.

eLife Assessment

In their important manuscript, Costa et al. establish an in vitro model for dorsal root ganglion (DRG) axonal asymmetry, revealing that central and peripheral axon branches have distinct patterns of microtubule populations that are linked to their differential regenerative capacities. The authors employ creative tissue culture methods to demonstrate how these branches develop uniquely in vitro, offering a potential explanation for long-observed regeneration disparities. The evidence provides a solid contribution to our understanding of the neuronal cytoskeleton and axonal regeneration, but the paper would benefit from additional methodology details and controls.

eLife Assessment

This important study reports new insights into the roles of a long noncoding RNA, lnc-FANCI-2, in the progression of cervical cancer induced by a type of human papillomavirus. Through a blend of cell biological, biochemical, and genetic analyses of RNA and protein expression, protein-protein interaction, cell signaling, and cell morphology, the authors provide convincing evidence that lnc-FANCI-2 affects cervical cancer outcome by regulating the RAG signaling pathway. These findings will be of interest to scientists in the fields of cervical cancer, long noncoding RNA, and cell signaling.

eLife Assessment

This valuable study proposes a novel rapid-entry mechanism of S. aureus that involves the rapid release of calcium from lysosomes. The strength of the paper lies in a very interesting hypothesis; what diminishes enthusiasm is the lack of appropriate methodology, thus making the study incomplete. The methods used are deficient: they are largely reliant on the use of chemical inhibitors and do not adequately support the conclusions.

eLife Assessment

In this potentially important study, the authors employed advanced computational techniques to explore a detailed atomistic description of the mechanism and energetics of substrate translocation in the MelB transporter. The overall approach is solid and reveals the coupling between sodium binding and melibiose transport through a series of conformational transitions, and the results for a mutant are also in qualitative agreement with the experiment, providing further support to the computational analyses. Nevertheless, the level of evidence is considered incomplete since there are concerns regarding the convergence and initial guess of the string calculations, leaving doubts that the computed pathway does not reflect the most energetically favorable mechanism.

eLife Assessment

This fundamental work provides new mechanistic insight in regulation of PDGF signaling through splicing controls. The evidence is compelling to demonstrate functional involvement of Srsf3, an RNA binding protein to this new and interesting 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 processing.

eLife Assessment

This valuable manuscript presents a spatiotemporal genetic analysis of malaria-infected individuals from four villages in The Gambia, covering the period between December 2014 and May 2017. Overall, laboratory and data analyses are solid, although details of the methods are lacking. This study offers evidence to advance the understanding of malaria epidemiology in sub-Saharan Africa, but would benefit from additional analysis to strengthen the findings.

eLife Assessment

This manuscript describes a novel magnetic steering technique to target human adipose derived mesenchymal stem cells (hAMSC) or induce pluripotent stem cells to the TM (iPSC-TM). The authors demonstrate the valuable findings that delivery of the stem cells compared to baseline lowered IOP, increased outflow facility, and increased TM cellularity. Although the methods, data, and analysis are solid, there is an overall weakness in the experimental controls, and questions around the transgenic mouse model. If these issues are addressed, the manuscript will be significantly improved.

eLife Assessment

In this potentially valuable study, the authors employed in vivo experiments and theoretical modeling to study the growth dynamics of nuclear condensates. They observed that condensates can exhibit distinct growth modes, as dictated by the competition between condensate surface tension and local elasticity of chromatin. While the theoretical model appears to capture the experimental observations, the level of evidence supporting the proposed growth mechanism is incomplete due to, among other limitations, the multiple fitting parameters and poorly justified Neo-Hookean elasticity.

eLife Assessment

This study presents important advances in the discovery and assessment of microcins that improve our understanding of their prevalence and roles. The bioinformatics analysis, expression, and antimicrobial assays are solid, although the diverging evaluations also indicated the need for additional support regarding the sequence analysis and validation to fully back some of the claims and conclusions. This study will appeal to researchers working on the discovery and analysis of novel peptide natural products.

eLife Assessment

Ulcerative colitis (UC) is a chronic gut inflammatory condition affecting the colon in humans. This study uses human samples as well as a mouse model of colitis induced by a chemical, DSS, to investigate the role of an immune marker, CD131, in UC pathogenesis. The study, as presented, is incomplete, as experimental details are lacking, the statistical analyses are deficient, and there is not yet direct evidence for a CD131-mediated mechanism of gut inflammation.

eLife Assessment

This important paper reports functional interactions between L1TD1, an RNA binding protein (RBP), and its ancestral LINE-1 retrotransposon which is not modulated at the translational level. The evidence for the association between L1TD1 and LINE-1 ORF1p is solid. The work implies that the a transposon-derived RNA binding protein in the human genome can interact with the ancestral transposable element from which this protein was initially derived. This work spurs interesting questions for cancer types, where LINE1 and L1TD1 are aberrantly expressed.

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 and results presented are convincing.

eLife Assessment

Rachubinski and colleagues provide an important manuscript that includes two major advances in understanding immune dysregulation in a large cohort of individuals with Down syndrome. The work comprises compelling, comprehensive, and state-of-the-art clinical, immunological, and autoantibody assessment of autoimmune/inflammatory manifestations. Additionally, the authors report promising results from a clinical trial with the JAK inhibitor tofacitinib for individuals with dermatological autoimmune disease.

eLife Assessment

This valuable study reports a novel function of ATG14 in preventing pyroptosis and inflammation in oviduct cells, thus allowing smooth transport of the early embryo to the uterus and implantation. The data supporting the main conclusion are solid. This work will be of interest to reproductive biologists and physicians practicing reproductive medicine.

eLife Assessment

This important study offers insights into the function and connectivity patterns of a relatively unknown afferent input from the endopiriform to the CA1 subfield of the ventral hippocampus, suggesting a neural mechanism that suppresses the processing of familiar stimuli in favor of detecting memory guided novelty. The strength of evidence is solid, with careful anatomical and electrophysiological circuit characterization. The work will be of broad interest to researchers studying the neural circuitry of behavior.

eLife Assessment

This important work presents two studies on predictive processes in subjects with and without tinnitus. The evidence supporting the authors' claims is compelling, as their second study serves as an independent replication of the first. Rigorous matching between study groups was performed, especially in the second study, increasing the probability that the identified differences in predictive processing can truly be attributed to the presence of tinnitus. This work will be of interest to researchers, especially neuroscientists, in the tinnitus field.

eLife Assessment

This is a potentially important study on interpretation of protein coding genetic variation in CDKN2A. The presentation of the data has improved, revealing that the experimental design is flawed and concerns that the data that are not robust enough to support the major claim of supporting clinical variant interpretation for CDKN2A. This work, while incomplete, will serve as a resource for diagnostic labs as well as cancer geneticists.

eLife Assessment

This work presents a valuable exploration of AI-assisted protein engineering, particularly in designing a VHH antibody with enhanced resistance and stability to extreme environments. However, the approach is weakened by incomplete support, with computational methods and experimental design appearing somewhat arbitrary and lacking clear justification. Further justification of the chosen methods and clearer exposition would strengthen the study's support and conclusions.

eLife Assessment

This study follows up on Arimura et al's powerful new method MagIC-Cryo-EM for imaging native complexes at high resolution. Using a clever design embedding protein spacers between the antibody and the nucleosomes purified, thereby minimizing interference from the beads, the authors concentrate linker histone variant H1.8 containing nucleosomes. From these samples, the authors obtain convincing atomic structures of the H1.8 bound chromatosome purified from interphase and metaphase cells, finding a NPM2 chaperone bound form exists as well. Caveats include the use of formaldehyde crosslinking and tagged H1.8 which might affect the structures obtained; and the NPM2 work could be better incorporated into the main findings. Overall this is an important new tool in the arsenal of single molecule biologists, permitting a deep dive into structure of native complexes. This work will be of high interest to a broad swathe of scientists studying native macromolecules present at low concentrations in cells.

eLife Assessment

This interesting study presents valuable information on how human cytomegalovirus (HCMV) infection disrupts the activity of the TEAD1 transcription factor, leading to widespread chromatin alterations. However, the precise mechanisms underlying this disruption and the extent to which these chromatin changes influence HCMV replication remain unclear. The study is supported by solid evidence, which would be made stronger by including functional analyses. This work will be of interest to virology, chromosome biology and transcriptional co-regulation fields.

eLife Assessment

This study examines the impact of DNA methylation on CTCF binding in two cancer cell lines. Increased CTCF binding sites are enriched in gene bodies, and associate with nuclear speckles, indicating a potential role in increased transcription. However, the association with nuclear speckles needs to be more diligently demonstrated. Thus the strength of the evidence is considered incomplete. This work would be made more valuable to the community if these claims were buttressed by additional evidence and a deeper discussion of new findings in the light of previous relevant literature. This work will be of interest to the chromosome biology/epigenetics field.

eLife Assessment

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

eLife Assessment

This valuable study reports the first characterization of the CG14545 gene in Drosophila melanogaster, which the authors name "Sakura." Acting during germline stem cell fate and differentiation, Sakura is required for both oogenesis and female fertility. The evidence supporting the claims of the authors is solid, but the manuscript would be strengthened by a more in-depth investigation into the cause-and-effect relationships for the different defects observed.

eLife Assessment

This useful study presents findings on how some antibiotics, which inhibit protein synthesis in bacteria, affect the translation in mitochondrial ribosomes. The authors provide solid evidence that most tested antibiotics act similarly on bacterial and mitochondrial translation. Additionally, this work shows that alternative translation initiation events might exist in two specific mt-mRNAs (MT-ND1 and MT-ND5). The conclusions of this manuscript are of broad interest to the antibiotic and the mitochondrial fields.

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 compelling due to a large sample size, inter-rater reliability, and corrections for multiple comparisons. The associations in this important work might serve as a reference for future targeted-studies on brain lateralization.

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 important 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 investigates how orientation signals detected in higher brain areas may be transformed into motor responses in behaving animals. The authors characterize two types of descending neurons (DNs) that connect the brain to motor units and are involved in different aspects of turning control. They further show that orientation signals act by preferentially increasing relative stimulation onto left- or right-turn-inducing DNs. These convincing results, together with the independent work that they have inspired, represent significant progress in our understanding of mechanisms of animal navigation.

eLife Assessment

This study presents an important finding on sperm flagellum and HTCA stabilization. The evidence supporting the authors' claims is convincing. The work will be of broad interest to cell and reproductive biologists working on cilium and sperm biology.

eLife Assessment

This valuable study investigates the oscillatory activity of gonadotropin-releasing hormone (GnRH) neurones in mice using GCaMP fiber photometry. It demonstrates three distinct patterns of oscillatory activity that occur in GnRH neurons comprising low-level rapid baseline activity, abrupt short-duration oscillations that drive pulsatile gonadotropin secretion, and, in females, a gradual and prolonged oscillating increase in activity responsible for the relatively short-lived preovulatory LH surge. The evidence presented in the study is solid, offering theoretical implications for understanding the behaviour of GnRH neurones in the context of reproductive physiology, and will be of interest to researchers in neuroendocrinology and reproductive biology.

eLife Assessment

This important study presents genome-wide high-resolution chromatin-based 3D genomic interaction maps for over 50 diverse human cell types and integrates these data with pediatric obesity GWAS. The work provides convincing evidence that multiple pancreatic islet cell types are key effector cell types. The authors also perform variant-to-gene mapping to nominate genes underlying several GWAS hits. Overall, the results will be of interest to both the fields of 3D genome architecture and pediatric obesity.

eLife Assessment

This study's findings substantially advance our understanding of an important aspect of mitochondrial metabolism. The data are compelling and the study is well executed. The work is relevant to all who are interested in the biogenesis of mitochondria.

eLife Assessment

This valuable study investigates the signaling pathways regulating retina regeneration. Solid evidence shows that the sphingosine-1-phosphate (S1P) signaling pathway is inhibited following retinal injury. Small-molecule activators and inhibitors support a model in which S1P signaling must be inhibited to generate Müller glia progenitor cells-a key step in retinal regeneration. The presented results support the major conclusions. However, the methodology concerning drug treatments is unclear, and the conceptual innovation is, to some extent, incremental.

eLife Assessment

This is a useful contribution to our understanding of taste perception. The idea that specific receptors function in the pharynx to mediate responses to carboxylic acids is interesting, although the expression analysis is incomplete. Reviewers also have a number of other suggestions for improvement, including the request that authors provide more details about the methodology used. In general, the claims are supported by solid evidence and add to a growing body of literature on this topic.

eLife Assessment

This important work advances our understanding of the impact of malnutrition on hematopoiesis and subsequently infection susceptibility. Support for the overall claims is convincing in some respects and incomplete in others as highlighted by reviewers. This work will be of general interest to those in the fields of hematopoiesis, malnutrition, and dietary influence on immunity.

eLife Assessment

Through cellular, developmental, and physiological analysis, this valuable study identifies a gene that regulates the relative growth of roots and shoots under salt stress. The holistic approach taken provides solid evidence that this member of a larger tandemly duplicated gene family together with an upstream regulator contributes to salt tolerance, although the statistical or biological support for some conclusions could be more robust. The manuscript will be of interest to plant biologists studying mechanisms of abiotic stress tolerance and gene family evolution.