eLife Assessment

This valuable manuscript describes ATP5I, a subunit of F1Fo-ATP synthase, as a key target of medicinal biguanides, however, it provides incomplete evidence of a direct interaction between ATP5I and metformin. The knockout of ATP5I in pancreatic cancer cells mimics biguanide treatment, inducing a metabolic switch from OXPHOS to glycolysis due to a compromised expression of the Complex I protein NDUFB8. This results in a markedly decreased NAD/NADH ratio and decreased cell proliferation. These findings point out ATP5I as a promising mitochondrial target for cancer therapies and contribute to our understanding of metformin's mechanism of action since many of its molecular mechanisms remain poorly understood.

eLife Assessment

This valuable study utilizes a newly developed approach to culture T gondii bradyzoites in myotubes, and then takes advantage of the antiparasitic compound collection known as the Pathogen Box, to find compounds that target both tachyzoite and bradyzoite forms of the parasite. A set of compounds yielding patterns consistent with targeting the mitochondrial bc1 complex was explored further, with solid evidence for changes in ATP production in bradyzoites to support the conclusions about the importance of this complex. The paper will be interesting for parasitologists studying drug discovery of apicomplexan parasites.

eLife Assessment

The study provides valuable insights into the mechanisms underlying neurovascular coupling; the authors present solid evidence demonstrating that layer II/III pyramidal neurons can induce vasoconstriction under conditions of intense optogenetic stimulation. They identify three distinct signalling pathways responsible for this effect, involving direct action on smooth muscle cells, as well as indirect modulation via interneurons or astrocytes. This work will be of interest to the broader neuroscience community and has potential implications for understanding pathological microcirculation in the brain, particularly in conditions characterized by strong excitatory neuronal activation. There are however questions that should be clarified, especially the conflict between three identified parallel pathways and the observed complete inhibition of the constriction by blockage of the NPY Y1 receptors.

eLife Assessment

This valuable study combines experiments and theory to investigate the putative role of spontaneous correlated activity in establishing aligned topographic maps of neural activity in higher-order sensory areas, and will be of interest to researchers studying multisensory integration and brain development. However, the evidence presented is incomplete, as there are notable disconnects between the experimental data and the modeling setup, and there are methodological details that are either unclear or missing, limiting the strength of the claims.

eLife Assessment

Briola and co-authors determined the structure of the human CTF18 clamp loader bound to PCNA to high resolution, analyzed the structure, and tested a new mechanism involving a human-specific Ctf18 beta-hairpin docking onto Rfc5, which represents a valuable contribution. The data are solid and complement data recently published by others.

eLife Assessment

This manuscript describes an important study of the giant virus Jyvaskylavirus. The characterisation presented is solid, although, in the current form, it is not clear to what extent these findings change our perception of how giant viruses, especially those isolated from a cold environment, function. The work will be of interest to virologists working on giant viruses as well as those working with other members of the PRD1/Adenoviridae lineage.

eLife Assessment

This important study describes a novel flow-responsive gene and its role in regulating the inflammation-associated transcription factor IRF5. While the in vivo experiments are solid, the in vitro data is inadequate since embryonic fibroblasts are used throughout despite the work aiming to investigate mechanisms of endothelial cell activation in atherosclerosis.

eLife Assessment

This important study demonstrates that screening by artificial intelligence can identify relevant novel compounds for interacting with KATP channels. The experimental work is compelling. The broader significance of this work relates to the possibility that KATP channel mutations linked to congenital hyperinsulinism may be effectively rescued to the cell surface with a drug, which could normalize insulin secretion or enhance the effectiveness of existing KATP channel activators such as diazoxide.

eLife Assessment

In this important manuscript, the authors investigate the phospho-regulation of the C. elegans kinesin-2 motor protein OSM-3, revealing that the kinase, NEKL-3, phosphorylates a serine/threonine patch at the hinge region of the motor to mediate autoinhibition until it reaches the ciliary middle segment. The findings are supported by robust genetic data, in vivo imaging, and motility assays with wild-type and mutant motors, although the methods section lacks detailed protocols for NEKL-3 assays and in silico analyses. Overall, the study provides a solid contribution to understanding the regulation of OSM-3 kinesin activity.

eLife Assessment

This important study provides a framework for applying single-cell transcriptome data and network analysis from genetically diverse mouse cells to identify novel driver genes underlying the role of genetic loci associated with bone mineral density. The evidence supporting the identification of the driver genes and the conclusion of the paper is convincing. Overall, this approach may be broadly applicable and of interest to researchers investigating the genetics of complex diseases.

eLife Assessment

The present study described GEARBOCS, an adeno-associated virus tool for in vivo gene editing in astrocytes, which is both timely and of importance for glial biologists, who often are troubled by efficient gene targeting in astrocytes. Overall, the finding is valuable, and the strength of the evidence is solid. Presumably, there will be great potential associated with GEARBOCS applications in the future.

eLife Assessment

This is an important study that describes the development of optical biosensors for various Rab GTPases and explores the contributions of Rab10 and Rab4 to structural and functional plasticity at hippocampal synapses during glutamate uncaging. Most of the evidence supporting the conclusions of the paper is solid, while the evidence supporting the finding that Rab10 activation during structural LTP is sustained is incomplete due to the characterization of the relevant sensor.

eLife Assessment

This study provides a valuable set of analyses and theoretical derivations to understand the mechanisms used by recurrent neural networks (RNNs) to perform context-dependent accumulation of evidence. The novelty of some of the findings needs clarification, and additional details need to be provided for some of the analyses. However, the results regarding the dimensionality and neural dynamical signatures of RNNs are solid and provide new avenues to study the mechanisms underlying context-dependent computations.

eLife Assessment

This valuable study introduces a novel method for controlling generalization and interference in neural networks undergoing continual learning. The authors provide solid evidence that their parsimonious method performs better than online gradient descent in several continual learning situations while providing biologically plausible links to three-factor learning rules. However, empirical validation is limited to linear networks, which raises questions about the generality of the results in non-linear networks. While the work is interesting to theoretical and experimental neuroscientists, improving the article presentation by clearly defining terminology before using it and providing more details on the setup of the simulation experiments would be vital to make the article more accessible.

eLife Assessment

This study presents an important contribution to the understanding of neural speech tracking, demonstrating how minimal background noise can enhance the neural tracking of the amplitude-onset envelope. The evidence supporting the claims of the author is solid, through a well-designed series of EEG experiments. This work will be of interest to auditory scientists, particularly those investigating biological markers of speech processing.

eLife Assessment

This important study identifies neurotrophin signaling as a molecular mechanism underlying previous findings of structural plasticity in central dopaminergic neurons of the adult fly brain. The authors present solid evidence for neurotrophin signaling in shaping the structure and synapses of certain dopaminergic circuits. The work suggests an intriguing potential link between neurotrophin signaling and experience-induced structural plasticity but further research will be necessary to establish this connection definitively.

eLife Assessment

This is an important and convincing dataset shedding new light on a role for Malat1 in osteoblast physiology. The work is of value to areas other than the bone field because it supports a role and mechanism for beta-catenin that is novel and unusual. The findings are significant in that they support the presence of another anabolic pathway in bone that can be productively targeted for therapeutic goals. Revisions further improved the paper and addressed the reviewers' concerns.

eLife Assessment

This study provides valuable new insight into the role of Fgf signalling in SUFU mutation-linked cerebellar tumors and indicates novel therapeutic interventions via inhibition of Fgf signalling. The potential impact of this work is therefore very high and it is supported by solid evidence. However, due to current limitations in the full identification of the cell types secreting FGF5, and issues with robustness of evaluation of genetically engineered animals, the validation of some interpretations awaits future experiments.

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

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.

Bistable perception example: binocular rivalry (highly relevant).

Bistable apparent motion perception example: the spinning wheel illusion.

Bistable perception example: the Necker cube (most cited).

When sensory information about a perceived stimulus is ambiguous, the visual system forms multiple distinct interpretations of said stimulus. Multistable perception occurs when perception of the stimulus alternates between interpretations over time.

Multistable perception may arise from interactions between lower-order and higher order brain processes. Lower order brain processes are involved in basic mental functions such as attention and perception, whereas higher order brain processes are involved in complex mental functions such as reasoning and abstract thinking.

The review discusses how brain processes underlying different levels of visual processing (low-level sensory, intermediate extrastriate, and high level frontoparietal) interact with one another to produce visual multistable phenomena such as binocular rivalry.

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

This important study combines compelling experiments with optogenetic actuation and convincing theory to understand how signalling proteins control the switch between cell protrusion and retraction, two essential processes in single cell migration. The authors examine the importance of the basal concentration and recruitment dynamics of a guanine exchange factor (GEF) on the activity of the downstream effectors RhoA and Cdc42, which control retraction and protrusion. The experimental and theoretical evidence provides a model of RhoA's involvment in both protrusion and retraction and shows that these complex processes are highly dependent on the concentration and activity dynamics of the components.

eLife Assessment

The authors provide a solid set of data supporting the safety of transcutaneous auricular vagal nerve stimulation on cardiovascular parameters in the acute setting of critically ill patients presenting with subarachnoid hemorrhage. This important study also suggests a promising effect on autonomic balance.

eLife Assessment

Ferredoxins are ubiquitous electron transfer proteins that drive essential metabolic processes across all domains of life. This fundamental contribution to the field provides the first description of how specific amino acids, though a series of hydrogen bonds, control the ability of iron-sulfur clusters in ferrodoxins to accept and donate electrons. The evidence supporting the conclusions is compelling as is the combined use of neutron crystallography with X-ray crystallography and classical spectral/redox studies.

eLife Assessment

This manuscript presents important finding regarding the regulation of a key stem cell population, namely muscle stem cells (or "satellite cells"). The evidence presented is convincing that Scx, a marker for tendon, is expressed in some myogenic cells and is essential for adult muscle regeneration.

eLife Assessment

This study presents valuable experimental and numerical results on the motility of a magnetotactic bacterium living in sedimentary environments, particularly in environments of varying magnetic field strengths. The evidence supporting the claims of the authors is compelling and the study will be of specific relevance to biophysicists interested in bacterial motility.

eLife Assessment

This paper provides fundamental insights into the control of Salmonella within human macrophages, with convincing evidence that Salmonella can replicate in the macrophage cytosol in the absence of inflammasome signaling. This paper, which improves our understanding of how the immune system fights bacterial infections, will be of broad interest to cell biologists, immunologists and microbiologists.

eLife Assessment

This manuscript applies a theoretical analysis to two published datasets on yeast and bacterial evolution to compare different ways of quantifying fitness. It makes an important advance by clarifying how discrepancies can arise by using different approaches and provides recommendations for best practices. While the evidence is solid, some improvements in the presentation of the data and a greater focus on the causes of the discrepancies between the various fitness estimates would strengthen the paper further.

eLife Assessment

This study provides valuable insights into the efficacy and safety of pyrotinib as an extended adjuvant therapy following trastuzumab-based treatment in patients with high-risk HER2-positive breast cancer. The strength of evidence is solid, supported by the multicenter phase II trial design, which included a substantial number of patients across 23 centers in China. However, the single-arm study design without a control group limits the ability to draw definitive conclusions about the comparative effectiveness of pyrotinib.

eLife Assessment

This useful modeling study alters a previous model of the intact cat spinal locomotor network to simulate a lateral hemi-section of the spinal cord. The modeling and experimental work described provide solid evidence that this model is capable of qualitatively predicting alterations to the swing and stance phase durations during locomotion at different speeds on intact or split-belt treadmills, but a revision of the figures to overlay the model predictions with the experimental data would facilitate the assessment of this qualitative agreement. This paper will interest neuroscientists studying vertebrate motor systems, including researchers investigating motor dysfunction after spinal cord injury.

eLife Assessment

This fundamental article significantly advances our understanding of FGF signalling, and in particular, highlights the complex modifications affecting this pathway. The evidence for the authors' claims is convincing, combining state-of-the-art conditional gene deletion in the mouse lens with histological and molecular approaches. This work should be of great interest to molecular and developmental biologists beyond the lens community. The manuscript itself deserves minor editorial improvements, in particular, the literature on FGFR and SHC should be expanded in the introduction and discussed in more detail in the discussion.

eLife Assessment

This useful study highlights the largely redundant role of the decapping activators Edc3 and Scd6 in orchestrating post-transcriptional programs to modulate metabolic responses to nutrients in yeast. The authors provide solid evidence for their conclusions, employing a variety of mutants in conjunction with a battery of transcriptome-wide analyses. This study could be further strengthened by direct biochemical validation of the functional interactions observed by systems biology approaches.

eLife Assessment

By exploring the conservation and functional diversity of RIPK3 and related RHIM-containing proteins across vertebrates, this important work sheds light on the evolutionary dynamics of these key immune pathways. The evidence supporting the claims is overall solid, although thorough documentation of the evolutionary analysis (e.g. in the 'Phylogenetic analysis' section), and additional work beyond human HEK293 cells, would strengthen the functional validation in support of the study's conclusions.

eLife Assessment

In this work, the authors use a Drosophila adult ventral nerve cord injury model extending and confirming previous observations; this important study reveals key aspects of adult neural plasticity. Taking advantage of several genetic reporter and fate tracing tools, the authors provide solid evidence for different forms of glial plasticity, that are increased upon injury. The data on detected plasticity under physiologic conditions and especially the extent of cell divisions and cell fate changes upon injury would benefit from validation by additional markers. The experimental part would improve if strengthened and accompanied by a more comprehensive integration of results regarding glial reactivity in the adult CNS.

eLife Assessment

This study provides valuable new information on the role of the endoplasmic reticulum calcium pump, TgSERCA, in the human pathogen Toxoplasma gondii. It is proposed that the endoplasmic reticulum is the major calcium store in these protists and that calcium is directly transported to other organelles via membrane contact sites. While the experimental work is solid and supported by complementary approaches, direct evidence for intra-organellar calcium transport via membrane domains and specific calcium efflux transporters is lacking.

eLife Assessment

This important study examined neuronal activity in the dentate nucleus of the cerebellum when monkeys performed a difficult perceptual decision-making task. The authors provide convincing evidence that the cerebellum represents sensory, motor, and behavioral outcome signals that are sent to the attentional system. This paper is of great general interest in that it shows the involvement of the cerebellum in cognitive processes at the neuronal level.

eLife Assessment

This is a valuable study describing an implementation of awake mouse fMRI with implanted head coils at high fields. The evidence presented is convincing, combining technical advances with interesting neuroscience applications showing that mice anticipate stimuli given at regular (but at irregular) intervals.

eLife Assessment

This study presents valuable findings on the role of the satiety hormone cholecystokinin typically associated with feeding in the control of a pituitary hormone, FSH, which is a critical regulator of reproductive physiology. The authors provide solid pharmacological evidence that cholecystokinin is sufficient to regulate FSH and compelling genetic evidence that one of its receptors is required for gonadal development, with uncertainties remaining about the physiological regulation and necessity of the peptide. The work will be of interest to reproductive biologists, especially those with an interest in the endocrine control of fertility.

eLife Assessment

This important work investigates how two distinct processes, morphological changes and synaptic plasticity, contribute to the final shape of neuronal dendrites and the spatial structure of their synaptic inputs. The modelling is convincing and could be broadly applied to other similar questions. The work will be of interest to neuroscientists studying dendritic development and connectivity at a single-cell level.

eLife Assessment

This valuable study gives new insight into decision-making during C. elegans foraging, providing evidence that animals can make accept-reject decisions upon encountering a food patch. Using rigorous behavioral analysis and quantitative modeling, the authors provide evidence that nematodes integrate sensory information with prior experience and internal state when making this decision. While some of the evidence is compelling, some key claims are only incompletely supported and would benefit from further validation.

eLife Assessment

This study provides important insights into the role of the Mid1 gene in hippocampal development and its implications in Opitz G/BBB syndrome, with much evidence supporting its impact on synaptic plasticity, neural rhythms, and cognitive functions. The methods, data, and analyses are solid, supporting the claims, presenting several minor weaknesses, and establishing Mid1 as a potential therapeutic target for neurological deficits associated with OS. The conclusions are largely supported by the results, but additional data are needed.

eLife Assessment

This study makes a valuable advance in our understanding of defensive symbionts in insects. It uses a meta-analysis to quantify the magnitude of change in host fitness components when symbionts are present in hosts exposed to natural enemies. The evidence supporting the study conclusions is solid, with analyses confirming common assumptions that symbionts generally provide defence at low cost to hosts.

eLife Assessment

This valuable study provides new insights into the role of the conserved protein FLWR-1/Flower in synaptic transmission using C. elegans. The authors employ a range of techniques, including calcium imaging, ultrastructural analysis, and electrophysiology, providing evidence that challenges previous assumptions about FLWR-1 function. While some findings are solid, several conclusions remain incomplete and require further study to substantiate the proposed mechanisms.

eLife Assessment

This important study introduces rationally designed, genetically encoded tools for the selective and reversible ablation of excitatory and inhibitory synapses. The evidence is convincing, supported by robust experiments and clear results that validate the effectiveness of each tool. This work will be of particular interest to researchers exploring the roles of specific synapses within neural circuitry.

eLife Assessment

This paper is an important overview of the currently published literature on low-intensity focussed ultrasound stimulation (TUS) in humans, with a meta-analysis of this literature that explores which stimulation parameters might predict the directionality of the physiological stimulation effects. Whilst currently incomplete, the database proposed by the paper has the potential to become a key community resource if carefully curated and developed.

eLife Assessment

This important study includes convincing evidence to show that behavioral measures and hippocampal representations of cognitive control are not dependent upon the medial prefrontal cortex. Whilst overall the study is of importance, it is possible that the conceptual framework used to interpret and discuss the findings could be strengthened in a revised version. The results are expected to be of interest to those studying neural mechanisms of cognitive control and functions of associational brain regions.

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

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.